We’ve been writing regular round ups for a little while now, but so much has happened recently that this month’s post feels like it contains a year’s worth of breakthroughs. So pour yourself something cool, get cosy, and enjoy!

First, everything new in cancer. In our round up last month, we shared the news of daraxonrasib, the new breakthrough drug that roughly doubles survival in late-stage pancreatic cancer, which has long been considered untreatable.

This past week, however, there were results from many more major cancer trials presented at the American Society of Clinical Oncology conference (ASCO 2026), and we wanted to share some highlights.1

One presentation showed 7 year results for lorlatinib, a precision drug for metastatic lung cancers: specifically, a type (ALK-positive) that’s common in non-smokers. You rarely see a survival curve like it. 55 percent of patients were still progression-free after 7 years, versus just 3 percent on the older drug crizotinib.

A new prostate cancer drug, talazoparib, halved the risk of progression when added to hormone therapy, compared to hormone therapy alone, for prostate cancers carrying specific DNA repair gene mutations. Talazoparib belongs to a class of drugs (PARP inhibitors) that have already advanced treatment of breast and ovarian cancers with BRCA mutations. This trial suggests the same strategy also works for prostate cancer.

There was also long-term data on a recent endometrial cancer drug, dostarlimab, an antibody that was approved in 2023. The headline result after 4 years on the RUBY trial was that 58 percent of patients whose tumours carried ‘mismatch repair deficient’ mutations still hadn’t progressed when the drug was added to chemotherapy, versus just 16 percent on chemotherapy alone. That’s a huge difference! The drug is a ‘checkpoint inhibitor’: T cells have built-in ‘checkpoints’ that hold them back from attacking cells unnecessarily, but tumours exploit these to avoid being attacked, so blocking the checkpoint frees the T cells to attack the tumour.

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An early cancer detection blood test, the NHS Galleri blood test, was tested in a large RCT in England with about 142,000 people. The results are a little confusing, so let’s start by clarifying what a ‘good result’ here would look like: detecting non-benign cancers that would’ve missed otherwise, or catching them earlier so treatment could start sooner.

On the first count, it was successful: roughly quadrupling the overall detection rate and cutting cancers caught only at emergency presentation by around a quarter. On the second, it detected some cancers earlier: with a 16 percent rise at stage I–II, and 14 percent reduction at stage IV. But the trial missed its primary goal: there was no significant drop in combined stage III and IV cancers (because stage III diagnoses rose more than expected and roughly cancelled out the stage IV reduction). One way to interpret this – since the largest jump in detection was at stage III and the combined late-stage count barely changed – is that the ‘early’ detection test was mostly catching cancers at around stage III, rather than much earlier. That may still be useful, of course.

And finally, an mRNA cancer vaccine that might actually work. In people with high-risk melanoma, who’ve already undergone surgery, it halved the risk of cancer recurrence or death, compared to Keytruda (the blockbuster cancer immunotherapy drug) alone, in a phase 2b trial over 5 years.

Many previous mRNA cancer vaccines have been doomed by how they pick their targets. They sequence a tumour’s mutations and design the vaccine against the resulting ‘neoantigens’ (newly formed mutant proteins in a cancer cell), but most of those neoantigens are never actually displayed on the cell surface so the immune system can’t recognize them anyway. Melanoma is different: its neoantigens are readily displayed and recognize, which is why drugs like Keytruda already work well against it and why a vaccine has a much better chance of working as well.

Now, let’s move over to non-ASCO2026 news.

The most effective weight loss drug so far. Retatrutide, a new weight-loss drug, led to the largest reductions seen so far: roughly 28 percent loss in body weight at the highest dose in a phase 3 trial. The effect roughly matches the effects of bariatric surgery, where surgeons reduce the size of the stomach and reroute the small intestine so patients feel full earlier.

Retatrutide is an engineered peptide that acts on three receptors at once: the GLP-1 receptor, where it mimics a gut hormone that curbs appetite and slows gastric emptying; GIP, which also dampens appetite and improves how the body handles fats and sugars; and glucagon, which increases energy expenditure. It can do this because the three hormones are evolutionarily related, with similarly shaped receptors, and scientists engineered it as a single peptide that fits into all three of them.

Over the past few years, weight loss drugs have broadened in their effects: from one receptor (semaglutide) to two (tirzepatide) to three (retatrutide). More targets probably means higher efficacy in general, but it’s probably not linearly additive, with each added receptor contributing somewhat less than the last.

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The first in vivo gene editing therapy. A single injection has permanently edited away a rare disease: hereditary angioedema, a rare condition where a genetic mutation causes sudden, potentially fatal swelling attacks. In a phase 3 trial, a single dose of gene editing therapy reduced attack rates by 87 percent relative to placebo, and 60 percent of patients remained attack-free entirely over 6 months.

It’s notable because it’s the first time gene editing has worked inside a living human body (in vivo) in a late-stage trial. Previous gene editing medicines like Casgevy, the first approved CRISPR drug, for sickle cell disease, worked outside the body, ex vivo, meaning they involved removing cells from the patient, editing them in the lab, and replacing them. But this new gene editing therapy packages CRISPR machinery inside a lipid nanoparticle, a tiny fat bubble, that travels through the bloodstream to the liver and edits DNA there directly.

Editing within the body will make the therapy far simpler in the real world than editing outside the body. It’s likely easier to scale up, and opens the door to treating diseases where you can’t easily remove and return cells. For now, the lipid nanoparticle delivery system mostly targets diseases of the liver, but researchers are working to extend it to other tissues like the lungs and eyes.

Permanent gene-editing to reduce cholesterol. Speaking of gene editing: a gene therapy has now been used to permanently edit a gene in liver cells to lower LDL cholesterol. These results come from a phase I trial, in which 35 adults with an inherited disease causing very high blood cholesterol (hypercholesterolemia) or premature coronary artery disease got the therapy.

The therapy, called VERVE-102, is carried by a GalNAc lipid nanoparticle, which delivers it to the liver, where cholesterol is produced. There, the therapy edits the PCSK9 gene. PCSK9 regulates cholesterol levels in the body, typically reducing how much cholesterol is removed from the blood and taken up by liver cells. The way it does this is by binding to the LDL receptor, which grabs cholesterol, and tagging it for destruction, meaning less cholesterol is absorbed from the blood. So, by editing the PCSK9 gene, LDL receptors aren’t broken down as much, more cholesterol is taken up by liver cells from the bloodstream, and blood cholesterol levels are reduced.

At the highest dose, the average reductions were huge: PCSK9 levels fell by 88 percent and LDL cholesterol fell by 62 percent. These changes lasted more than a year, with no observed toxicity at the higher doses. VERVE-102 is possibly a one-off treatment, which is great because around 40 percent of people taking cholesterol-lowering medicines stop taking them regularly.

The target of the gene edit, PCSK9, has actually become one of the most heavily pursued ones in cholesterol medicine. Several recent drugs act on it, including injectable antibodies like evolocumab, which mop up PCSK9 directly, and the oral pill enlicitide. There’s also inclisiran, an siRNA drug that reduces the liver’s production of the protein, which is off-the-shelf and needs an injection just once every six months. The patients who’d benefit most from a one-time gene edit instead of those alternatives are likely not the wider population, but rather people with inherited conditions causing high blood cholesterol, who have a strong lifelong need to reduce their cholesterol and would most value a permanent fix.

An incredible feat of pharmaceutical synthesis. One of the recent drugs that helps patients lower their cholesterol level by blocking PCSK9 is called enlicitide. In a recent phase 3 trial, it lowered LDL cholesterol by an additional 50–60 percent for people already on statins.

Enlicitide is chemically fascinating for two reasons. One is that it’s formulated as a daily pill: all the other PCSK9 drugs on the market, including antibodies like evolocumab, the siRNA inclisiran, and the gene editor VERVE-102, have to be injected. The second is that enlicitide is a synthetic peptide. That’s surprising, because peptides are normally broken down in the gut before they can work. So how can a peptide be taken orally?

Well, enlicitide has an unusual structure. It’s a synthetic peptide made from eight amino acids that fold into a ring. This ‘closed’ shape helps the molecule survive the stomach and get absorbed in the small intestine. But the ring also makes enlicitide hard to manufacture. Some of its amino acids are ‘unnatural’, meaning they don’t appear in nature, so the peptide can’t easily be made by engineered cells, unlike other peptide drugs like semaglutide. And it’s hard to make chemically, too: the original synthesis took 63 reactions, and resulted in very low yields. The main bottleneck is the step where the chain closes into a ring, called macrocyclization.

Now, in a new study, Merck scientists improved the yield massively: with a 14-fold increase (to 70 g/L, at over 99 percent purity) by merging traditional chemistry with enzymes. They split enlicitide into three segments, called Northern, Eastern, and Western. The Eastern and Western parts were easy to make with conventional chemistry, but the Northern bit, which contains the unnatural amino acids, was instead built using enzymes. The team used directed evolution – repeatedly mutating an enzyme and keeping the best-performing ones over successive rounds – to engineer seven enzymes which, together with three natural ones, assemble the fragments and close the final ring. It’s one of the most ambitious feats of pharmaceutical chemistry ever published. And it shows that, even the most complex peptide drugs, made today at low yields, could in principle be manufactured at industrial scale through clever enzyme engineering.

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A cure for some patients with hepatitis B. Hepatitis B is a virus that causes liver damage and liver cancer in middle- and old-age. It’s preventable with birth-dose hepatitis B vaccines, but there are still around 250–300 million people globally who have chronic infections, mostly being infected before the vaccines were introduced.

Hepatitis B infections are particularly difficult to ‘cure’ because the virus has a little mini-chromosome that goes inside the nuclei of liver cells. So even if you destroy all the RNA transcripts, the mini-chromosome lives on and the infection persists.

But new drugs could destroy them. In two phase 3 trials, about 1,800 adults with chronic hepatitis B infections were treated weekly for 24 weeks with antisense oligonucleotides (short strings of nucleotides, called ASOs) or placebo. These ASOs bind to the virus’ RNA transcripts and mark them for destruction by enzymes. Then, the ASOs are recycled by the body.

Interestingly, even though the ASOs target RNA, they also reduce viral DNA, because hepatitis B can only make new DNA by reverse transcription (turning its RNA back into DNA), so cutting off the RNA cuts off the supply of new DNA. It also stops the virus churning out viral proteins like HBsAg, a surface antigen produced in enormous quantities to misdirect our immune cells.

About 20 percent of the patients who received the drug, called bepirovirsen, had a ‘functional cure,’ versus none in the placebo group. Here, a functional cure meant no detectable hepatitis B viral DNA and a loss of HBsAg sustained for at least 24 weeks post-treatment.

Human cells can ‘swap’ DNA with each other. It’s long been assumed that each human cell’s genome is sealed up in the nucleus and evolves independently of its neighbours. A new study finds that isn’t always true. The researchers found that large, chromosome-sized pieces of DNA can move directly from one human cell into another, lodge in the next cell’s genome, and remain functional, getting transcribed into RNA and translated into protein.

How on earth are they doing it? The authors observed DNA passing through ‘nanotubes’, which are thin bridges that briefly form when cells touch. Scientists have known about these for a few decades, and that cells were shuttling things like mitochondria through them, but it wasn’t confirmed that genomic DNA could be transferred through them until now.

To measure it, the researchers grew two batches of human cells together, and tagged DNA packaging proteins in each batch with a different fluorescent colour, one green and one red. They then stressed the cells to break their chromosomes or scatter them during cell division (using mitosis-blocking drugs, radiation, and CRISPR) and filmed what happened. On the time-lapses, they watched DNA of one colour travel down a nanotube into a cell of the other colour.

It’s not yet clear how much this matters in the body. But the authors note it could let genomically unstable cancer cells pass on their mutations to neighbouring cells. If that’s the case, the nanotubes themselves could be a target for cancer therapies.

CRISPR’s ancestors, hiding in bacteriophages. Researchers in Jennifer Doudna’s lab at UC Berkeley, which helped pioneer CRISPR as a gene-editing tool, have found a system that predates CRISPR and described it in two new preprints. CRISPR is a defense system bacteria use to recognize and cut up invading DNA, including from viruses. A subset of its proteins are built around a core structure called a RAMP, which has stayed remarkably constant over many millions of years, even as the genes encoding it have drifted apart. So the team used AlphaFold, the protein structure prediction tool, to hunt for proteins that look like RAMPs but are encoded by unrelated sequences. They found some hidden in bacteriophages, probably as a weapon that they use against rival phages.

They named the system VIPR, and it appears to be older than CRISPR itself. Like CRISPR, it’s guided by an RNA, but it differs in a few notable ways. It doesn’t cut DNA at all; instead it clamps onto a target sequence and silences the gene by physically blocking the enzymes that read it, leaving the DNA unaltered. It also finds that target with an unusual ‘noncontiguous’ code: the guide RNA reads the DNA two bases at a time and skips every third one, wrapping around the intact double helix rather than unzipping it. And it’s tiny: Vipr proteins are only about 180 amino acids, roughly an eighth the size of Cas9, paired with an RNA under 100 nucleotides. That means the whole thing can fit very easily into an AAV vector (often used as a delivery vehicle for gene therapy), and in principle you could pack many of them into a single therapy to fix several genetic errors at once.

A preventive antiviral for Covid-19, finally. The first oral drug to prevent COVID after exposure succeeded in phase 3 trials. It’s called ensitrelvir and is taken as a 5-day course of pills. In a phase 3 trial, people who took it after a household member caught COVID were 67 percent less likely to develop symptoms themselves.

It’s taken a long time to get here. A preventive antiviral pill is scientifically more challenging to develop than an mRNA vaccine, which mostly needs the specific genetic sequence (of the virus’s spike protein) to be identified and swapped in. In contrast, an antiviral like this is a custom-designed molecule that physically blocks a viral protein. That’s exactly why the vaccines were so important: they could be developed quickly, at a time when they were needed most.

Unlike the vaccines, ensitrelvir works by blocking the virus’s protease, a cutting enzyme it uses to mature its proteins. Because the protease mutates far more slowly than the spike protein the vaccines target, the drug should stay effective across naturally circulating variants. It could still face drug resistance over time, but the escape mutations seen so far seem to come at a cost to the virus’s own fitness. It’s worth noting that it’s approved in the US for post-exposure prevention specifically, not as a general pre-exposure prophylactic, and not for treating active infection.

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The first approved PROTAC drug. The FDA approved the first-ever ‘PROTAC’ drug, vepdegestrant, to treat a common form of advanced breast cancer. While most drugs work by blocking a disease-causing protein by binding to a pocket it uses to attach to its natural target, a PROTAC instead just destroys the protein. It’s a two-sided molecule that uses one end to grab the target protein and the other end to grab an enzyme (an E3 ubiquitin ligase) that tags the protein for recycling. This physically brings the two together, so the target protein gets marked for destruction and broken down.

Here, the target is the oestrogen receptor, which drives a common form of breast cancer. The drug treats tumours in which the receptor has mutated to stay permanently switched on and grows despite hormone therapy. In its phase 3 trial, it roughly doubled the time before the cancer progressed compared to the existing drug fulvestrant.

The approach could in principle reach the many disease-causing proteins that have no good pocket to block, which have long been considered ‘undruggable.’ This is just the first approved PROTAC, and many more are likely to come through the pipeline, and change the trajectory of diseases that we consider untreatable today.

What’s behind so much progress?

Part of it is timing: many cancer papers are published to coincide with the American Society for Clinical Oncology’s annual conference. But there’s more beneath that too.

Many new breakthroughs were precision drugs, targeted towards particular genetic mutations and tumours with certain genetic markers. Although the genomic revolution began a few decades ago, some of those advances have taken a long time to make it through the pipeline.

Another part is advances in structural chemistry. Daraxonrasib (the pancreatic cancer breakthrough), enlicitide (the oral PCSK9 cholesterol drug), and retatrutide (the new weight loss drug), for example, came from better understanding of the precise structure of proteins and how they interact with each other.

Both the genomic revolution and structural chemistry have helped researchers understand drug targets better and engineer them, including producing mutant KRAS proteins to find new druggable pockets for the pancreatic cancer drugs, and adapting new platforms, like the mRNA cancer vaccines, for melanoma.

This progress seems like an odd contrast with the cuts we’re seeing to science in the US, including to the National Cancer Institute, which is spending 80 percent less this year than its typical pace. It was responsible for funding fundamental research that eventually led to some of the breakthroughs in this post, including 1980s research into KRAS, which led to new pancreatic cancer drugs, and 2010s research into cancer immunotherapy targeted towards neoantigens, which led to cancer vaccines. The National Heart, Lung, and Blood Institute is also spending around 80 percent less than usual; decades ago, it funded fundamental research on LDL-receptor biology and PCSK9 that brought about cholesterol drugs.

In other words, the breakthroughs we’re seeing today are a lagging indicator of inputs into the pipeline: they reflect choices people made in the past. We’ll only be able to see the gaps created by reduced investment in retrospect, years from now, and see that technology isn’t the only reason for progress; sometimes it’s about the funding, institutions and incentives we create.

Illustration: Bacteriophages at work.

In a corner of the prestigious Kits Point suburb in Vancouver, eleven great towers are beginning to rise from their foundations. This is Senakw (pronounced sen-AHK), a new development owned, managed and championed by the Squamish Nation, an indigenous group native to British Columbia. It will ultimately house 9,000 people, and represents seven percent of Vancouver’s entire projected housing output up to 2033.

Senakw has an unusual history. The land it is built on was home to the Squamish people until they were forced out in 1913. Almost a century later, a court case restored the land to the descendants of those who were expelled, along with almost 100 million Canadian dollars in compensation. Freed from the restrictive planning rules that hold back densification in the rest of Vancouver, the Squamish decided in 2019 to use the land to build apartment blocks that, as well as housing Squamish people, are expected to generate around C$10 billion in income, equivalent to more than two million per person.

This is a story of a dispossessed group that is making the most of a rare and remarkable set of circumstances to generate wealth through upzoning. But it is also a story with relevance all over the world. Senakw shows that when local residents stand to benefit from development, obstacles to housebuilding can be overcome, to the benefit of a much broader group of people.

The village that was lost

The Squamish are one of the Coast Salish peoples, the precolonial inhabitants of British Columbia. Today there are about 4,000 Squamish, and historically, the population inhabited a considerable territory, including the land on which the city of Vancouver was built.

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Wilson Williams, council chairperson of the Squamish Nation, explains that in the precolonial period, the False Creek inlet served as a seasonal gathering place: ‘Senakw was a place of abundance ... It was the mainstay for spring and summer for our people. It was a welcome place for our families during those warm seasons because of the abundance of food’. Salmon, oysters, and berries, key ingredients in Coast Salish cuisine, thrived there. By the 1860s, records suggest it had evolved into a permanent village, featuring traditional Squamish longhouses.

Between 1869 and 1877, eighty acres were allocated by the Canadian government as False Creek Indian Reserve No. 6, more commonly known as the Kitsilano Indian Reserve. Like all reserves, the land was owned by the federal government and held in trust for its indigenous residents, a legal arrangement that would prove crucial more than a century later.

European settlers quickly drove out the existing villagers. The city of Vancouver was incorporated in 1886 and expanded rapidly. Conflict between settlers and natives over space began to worsen. A 1911 amendment to the Indian Act enabled the forced removal of indigenous people from urban areas. Vancouver did not wait: in 1913, the residents of the Kitsilano Indian Reserve village were summoned to meet British Columbia officials under attorney general William John Bowser. They were told they either had to accept a small cash offer for the land or receive nothing. They had no federal representatives to support them, which was unlawful even at the time, and many did not even speak English. Believing they had no choice but to accept, the residents disinterred the remains of their ancestors. Most sailed north to relatives in Howe Sound, and the village was burned.

Contemporary newspaper articles imply that the motive for removal was not primarily financial. At the time, the land was not nearly as valuable as it is now: it sits on the opposite side of the False Creek inlet from the city, and the Burrard Street Bridge that links it today would not be constructed for another twenty years. Instead, newspapers focused on concerns about noise from traditional ceremonies, and alleged immorality and public disorder.

City officials originally intended to designate the land for either courthouses or a public park, but had no fixed plans. The land seizure itself was the primary goal.

After the Squamish residents were evicted, the site was neglected for decades. It ended up being occupied by squatters, who made a living fishing and pulling in logs that floated down the creek. Throughout the 1920s and 1930s, newspapers complained of worsening disorder and mess, as well as the city’s repeated failed attempts to evict the squatters. Ironically, the removal of the original residents in the interest of public order had failed even on its own terms.

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Throughout the twentieth century, the land was parceled up and passed between various public bodies, including the harbor authority, as well as private companies like sawmills and breweries. From the 1940s, it was used by the Royal Canadian Airforce as a storage depot. In 1967, it was eventually turned into Vanier Park and became a museum complex.

The long fight back

The 1911 Indian Act amendment made it easier to expropriate land from indigenous people. Unfamiliar with legal processes and sometimes lacking a working command of the English language, they found the deck stacked against them. But even in 1913, the province’s actions in the Kitsilano Indian Reserve village were not lawful: the land was federally owned, and the province could not acquire it without federal consent. The Crown immediately began efforts to reclaim the land.

The Squamish people also began organizing. Between 1913 and 1923, sixteen local families amalgamated into the Squamish Nation band. But for the first few decades, they were legally prohibited from pursuing their claim to the land.

Wilson Williams’s great-grandfather, Andy Paull, was a young man when the village burned. Selected at a community meeting to learn English and represent the nation’s interests, Paull studied in a Catholic residential school in North Vancouver and was educated as a lawyer. Williams recalls his grandfather telling him that the seizure of the village was the catalyst for the nation’s focus on strengthening their legal capabilities. But indigenous people were legally prohibited from joining the bar unless they gave up their indigenous status, which Paull was unwilling to do. ‘He became an off-the-record lawyer’, Williams explains, helping not just the Squamish Nation but other indigenous people across Canada.

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The Indian Act heavily restricted the ability of indigenous people to seek legal redress over land. Throughout his career, Paull focused instead on advocacy, using his legal skills indirectly to push for the right to launch land claims, a right that was eventually won in 1973.

The eventual breakthrough for the Squamish came from an unexpected direction: academic research. In 1971, anthropologists Dorothy Kennedy and Randy Bouchard began what at first seemed an uncontroversial project: recording historical place names to preserve indigenous peoples’ languages and history. Working with Squamish chief Louie Miranda, they had no idea they were assembling evidence for a legal case that wouldn’t be heard for decades.

Chief Miranda, who had himself been a resident of the Kitsilano reserve, was the Squamish Keeper of the Names, responsible for memorizing ancestral names and history going back generations. Without him, there would have been little to work with.

Following Catholic missionary efforts from the 1840s, almost all Squamish people had converted to Catholicism by 1913. Accordingly, their births, deaths and marriages were usually recorded by the Church. However, Kennedy recalls that ‘the church was reluctant to hand over information’. They did eventually gain access, and not only did they accurately reflect Chief Miranda’s memory, the records also enabled them to ‘bring back hundreds and hundreds of names’, something of great cultural significance in Squamish tradition.

By cross-referencing Miranda’s extraordinary memory against Catholic church records, government surveys, and early anthropological notes, Kennedy and Bouchard could reconstruct not just genealogies but precise information on who lived where. ‘We transcribed all the Catholic records for the Squamish back to 1860’, Kennedy explains. Thanks to the connection between anglicized names in the church record and traditional Squamish names, ‘We could reconstruct where the houses were, who lived there, and their descendants... All of the success was thanks to Chief Miranda’. This painstaking work would prove invaluable in the court battles that began in late 1977, led by Chief Joe Mathias. It took several decades of legal dispute, but the case that turned the tide was decided in 2001: Mathias vs Canada. The case centered on the fiduciary duty of the federal government towards Indian Bands. Several other indigenous groups also made competing claims over the same land.

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One focus was proving that the 1869 residents, when the land was originally set aside as a reserve, were Squamish. The court accepted the anthropological evidence as overwhelming proof, largely because of Kennedy, Bouchard, and Miranda’s meticulous work decades earlier.

Most of the other claims were dismissed by the court, partly due to the statute of limitations expiring. But in order to close the decades of continued legal battles, the federal government came to an out-of-court settlement with the Squamish Nation: it paid C$92.5 million (USD $66.9m) in compensation, which, under the terms of the settlement, would be held in a trust fund for band members. The settlement also included something that received much less media attention at the time, but which has since proven far more significant: 11.7 acres of the original 80 acres of land.

In a ceremony in 2002, the Squamish Nation sailed 28 canoes to the beach in Kitsilano, a symbolic homecoming for the Squamish people. The site did not seem especially valuable: a thin patch of land, approximately half of which lies directly beneath the Burrard Street Bridge in an unusual tri-point shape. With the neighborhood zoned largely for single-family housing, observers did not initially notice its development potential.

The grand bargain

Vancouver is one of the most expensive housing markets in Canada. An average detached house there now costs over C$2 million (USD $1.5 million). Data scientist Jens von Bergmann and UBC associate professor Nathan Lauster estimate that the metro area has 130,000 to 200,000 suppressed households: people doubling up with family or roommates who would live independently if they could afford to. That backlog alone represents six to ten years of recent construction. In 1981, two thirds of 25- to 29-year-olds in Vancouver lived in their own households; by 2021, only a third did. Rental vacancy rates often hover below one percent; vacancy rates in more affordable housing markets, such as Austin, Texas, hover around ten.

This pressure comes in part from Vancouver’s success. Vancouver is Canada’s third-largest metropolitan economy. With its stunning backdrop of mountains and ocean and its mild winters, it repeatedly ranks among the world’s most liveable cities. Accordingly, the metro area adds over 40,000 new residents each year, each needing somewhere to live.

Despite this massive demand for housing, and its dense urban core, most of the city looks as it did decades ago. Vancouver pioneered single-family zoning in Canada: the municipality of Point Grey became the first in the country to adopt such rules in 1922. When Point Grey amalgamated with Vancouver in 1929, the principle spread citywide, although initially in a relatively permissive fashion. In the 1960s, the city briefly experimented with allowing apartment towers in residential areas, but a political backlash voted in a council in 1972 that was more resistant to development. From that point onwards, Vancouver systematically downzoned, restricting building heights and locking most of its land into low-density use. Today, 52 percent of Vancouver’s residential land supports just 15 percent of its homes.

Vancouver never managed to comprehensively reverse the downzoning of the early 1970s, despite the huge pressure on housing affordability since. But it did find a way to permit intensive development in narrow strips, typically along transport corridors, while leaving the suburban expanses largely untouched. The city is dependent on such developments: property taxes are low, so almost half of its C$3.5 billion capital budget comes from developer payments. Through a mixture of fixed development fees and Community Amenity Contributions, which are negotiated during spot rezoning on a case-by-case basis, planners extract funding for parks, childcare centers, and affordable housing units in exchange for permission to build. They aim to capture 75–80 percent of the land value uplift. Because each negotiation process can be lengthy, the city prefers to allocate a small number of highly valuable permits, creating an incentive structure that favors concentrated towers, rather than gentle density across the city.

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The downside is that the negotiation process is slow, expensive, and unpredictable. Von Bergmann notes that planners ‘typically get it wrong – they either charge too much or too little’. Getting it right requires predicting market conditions years in advance. Charge too much and the project is rendered unviable and dies, potentially taking the developer and many jobs down with it. Charge too little and the city misses out on valuable capital spending opportunities. Frances Bula, a journalist who has covered Vancouver planning for decades, describes the practical reality: ‘Big developers just cough up when planners demand.’ Smaller builders, including homeowners wishing to add small extensions to their own houses, lack the resources to play the game.

This system is what is known as Vancouver’s grand bargain, and what leads to the largely untouched suburbs occasionally punctuated with tall, thin towers. The grand bargain generates some income for public spending, while minimizing property taxes and development across most of the city. But the price is paid through worsened housing affordability and the economic costs of suppressed construction.

The mandate to build

After the land at Kits Point was returned to the Squamish Nation, they initially made plans to develop it at low density: two residential towers and some mid-rise offices, barely distinguishable in scale from the commercial buildings that already exist nearby. However, these plans stalled after the 2008 financial crisis, and it took some time for the Nation to return to its development ambitions.

In 2018, the Nation established a development arm, Nch’ḵay Development Corporation, bringing in much-needed expertise in construction. Moving quickly, in April 2019, they formally requested the Minister to order a referendum on the designation of the site, which Squamish people were eligible to vote in. In two votes, they approved the land designation for a mixed-use development, passing with 87 percent approval, and business terms with the development partner Westbank, one of Canada’s largest developers, passing with 81 percent approval. The Nation agreed to a 50-50 partnership with Westbank, though Westbank later sold its shares to OPTrust, which manages one of Canada’s largest pension funds. Despite a low turnout of 27 percent, the votes were considered to give a decisive mandate to the development plans.

But why did designating the land for development require a referendum? The site at Kits Point was returned to the Squamish Nation as reserve land. The Indian Act requires that reserve land be ‘designated’ by the federal government before it can be leased, a process that is considered ‘tedious, expensive and time consuming… with no guarantee of the outcome’, and which makes development difficult. Senakw’s swift progression is a testament to both political will and the Squamish Nation’s effective navigation of the system.

While reserve land can be leased with federal permission, it cannot be alienated from the band, meaning freehold ownership cannot be transferred in any way. This means it cannot be parceled up and sold off. It also means that the land cannot be borrowed against, because securing a loan on land is only possible if the land’s ownership can be alienated in the case of default. Traditional development finance uses loans as residential mortgages. Apartments cannot be sold as condominiums (where each unit is privately owned, like a house, and each owner also has a share of the overall building), but must instead use leasehold, where residents purchase a right to live in a property for a set period of time rather than owning their home outright.

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These restrictions might have made the project impossible without support from the federal government, which agreed to a C$1.4 billion loan through the Canadian Mortgage and Housing Corporation, the largest in the corporation’s history. To work within leasehold constraints, the residential units were earmarked for 100 percent rental.

Yet reserve land also offered a crucial advantage: because it is reserve land, it is exempt from zoning rules which apply to the rest of Vancouver. The Squamish Nation made the decision to ‘maximize economic benefits for the Squamish community’, which, in Vancouver’s housing-starved market, meant maximizing density: 6,000 rental homes plus commercial space. It also meant opting not to impose many of the costly mandates that cities typically require. They maintained the same safety and building standards that other Vancouver developments adhere to, but stripped away height limits, inclusionary zoning, zero-emissions requirements, parking minimums, design panels, and the years of public consultation that other projects must stick to.

Although Senakw is not subject to the normal city zoning rules, it nonetheless required standard public amenities like sewerage connection and transport access, including installing roads through public land. The City of Vancouver could have blocked or severely delayed the project simply by refusing these services, and might have been tempted to, given that the development sidesteps the city’s own planning rules.

Yet the city proved amenable. Kennedy Stewart, Vancouver’s mayor from 2018 to 2022, strongly supported the development and oversaw the signing of a services agreement in 2022. The Squamish Nation agreed to fund the sewerage upgrades, as well as the installation of cycle paths and seawall repairs to reduce flood risk to the neighborhood, paying roughly what they would have for site infrastructure under the standard planning process. They were not, however, required to pay the far larger sums that Vancouver normally extracts from developers to fund other municipal priorities.

Mayor Stewart emphasized to me that Canada’s intensifying political discourse around ‘reconciliation’ was critical. Many dismissed this discourse as performative symbolism, but at Senakw it had practical consequences: ‘Promises about reconciliation forced governments’ hands when it came to enabling indigenous-led developments’. The Squamish Nation’s referendums gave the project a democratic legitimacy that Vancouver’s usual stakeholder consultations rarely achieve. A city government that had spent years resisting modest density increases facilitated a far more ambitious project when backed by a clear community mandate and a compelling moral case.

The financial rewards to the Squamish Nation are substantial. A minority of the homes are earmarked as below market rate housing that will be let out to members of the Squamish Nation. The rest will be let out at market rates. With their 50 percent stake expected to generate up to C$10 billion in rental income over the entire lifespan of the buildings, and around 4,000 members, the project could be worth around C$2.5 million per person. How it will be distributed or spent is as yet undecided.

Beyond Senakw

On just one site, Senakw will provide a year’s worth of housing normally built in the city of Vancouver. It functions as a sort of policy laboratory, showing that cities like Vancouver can build many more homes if the decision-makers allow it.

Senakw also offers two lessons for those of us in other cities who want to get more homes built. The first is about incentives. When the Squamish Nation’s members voted on development, they were voting on their own land, and for the economic development of their own community. They chose to maximize density and limit the costly requirements that cities like Vancouver typically impose on new developments because they would bear the costs of these requirements directly. Yet in terms of quality and safety, Senakw is just as good or better than other new developments built just across the river. But residents voting on their own projects make very different assessments of the value of some of these mandates and vote accordingly. Similar dynamics have appeared in other resident-led ballots such as estate regeneration programs in England, and Israel’s Pinui Binui program.

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The second lesson concerns democratic legitimacy. It is partly a myth that Senakw slipped through a loophole in normal land-use restrictions. The City of Vancouver could have obstructed Senakw by refusing infrastructure connections and services. The federal government could have obstructed it by refusing the land designation or not offering the financing agreement. That both chose not to do so reflects the power of a clear democratic mandate. Governments that spend years resisting modest density increases may nonetheless facilitate ambitious projects when backed by direct community approval and a compelling moral case.

It’s an open question how replicable Senakw’s model is in the rest of Canada. Most reserve land in Canada is not urban; the Indian Act ensured that most such sites were seized long ago. However, ongoing legal battles make the future unpredictable. Indigenous groups may apply to the federal government to convert land they own to reserve status, and at the moment the federal government is amenable to doing so.

Nations may also build on land they own outside of reserves using standard zoning processes. Not far away from Senakw sit the Jericho Lands, a 90-acre site being developed in a joint partnership of the federal government and the Musqueam, Squamish and Tsleil-Waututh Nations. This site is owned on a freehold basis. The overall development plan has been approved through the standard city planning process, although it will require further approvals of rezonings on individual parcels. It is expected to take 25–30 years to deliver around 13,000 new homes, an annual rate much slower than Senakw.

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Whatever lessons cities do or do not draw from Senakw, for the Squamish Nation, the significance extends beyond housing policy. For Wilson Williams, it represents something important: ‘We’re no longer out of sight and out of mind in our own village.’ More than a century after his ancestors were forced to sail away from the burning ruins of their homes, a new generation of Squamish people will return to live where their ancestors once fished for salmon in the abundance of False Creek.

Anya Martin is policy lead at YIMBY Alliance.

Artwork by Nina Bunjevac.

The author would like to thank for their generously given time and expertise: Squamish Nation, Abundant Housing Vancouver, Revery Architecture, Jens von Bergmann, Randy Bouchard, Frances Bula, Dorothy Kennedy, Nathan Lauster, Vanna Orecchio, Kennedy Stewart, Sam Sullivan and Lynn Zanatta.

Each autumn in early modern India, certain men drifted out of the central provinces to take up their craft. Known as ‘Thuggees’, these men were said to be inspired by a bloodthirsty goddess and would attach themselves to a caravan on the road, posing as a merchant glad of the company or a cook looking for work. Days passed, sometimes weeks. The Thuggee played his part and earned the trust of the men he travelled with, and he waited. Then one night, with the camp asleep, he rose from his blanket, strangled his companions with a scarf, knifed each one in the stomach to be sure, and vanished with the caravan’s money. The perfect crime.

The modern vexillology movement works the same way. Give or take the strangling. In 2006 a pamphlet went out to the members of the North American Vexillological Association, enthusiasts who study flags. It was called Good Flag, Bad Flag, by Ted Kaye, and it laid down five principles of good design. Keep it simple, simple enough that a child could draw it from memory. Use meaningful symbolism. Hold to two or three colors that contrast and come from a standard set. No lettering, no seals. And be distinctive, or be deliberately related to flags you share something with. Like most pamphlets from fringe outfits, it sold nothing and lay dormant.

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Then in 2015 the radio host Roman Mars built a TED talk on it, ‘Why city flags may be the worst-designed thing you’ve never noticed’. Millions watched. It remains one of the most watched TED talks ever produced. American flags were wrong, Mars said. Seals on plain fields, that isn’t what a flag is for. Others were too busy. Age was no defense. A flag could have flown for a century and still stand condemned as badly designed.

His favorite target, and Kaye’s, was Milwaukee. Milwaukee’s flag, adopted in 1954, is an utterly mad chaos of city skyline, a ship, a stalk of barley, and various texts and numbers. In the middle, big as a sun, sits a gear. Tucked inside it is a Native American in a war bonnet, lifted more or less from the Milwaukee Braves logo of the day. But if that wasn’t enough, your eye continues to roam across the flag and finds a church, the county stadium, a factory, a lamp, a few houses, a flock of gulls. And just when you thought you had been overstimulated enough, you squint and realize there is a picture of another flag on it. Milwaukee put a flag on its flag.

The flag obsessives began their campaign in Milwaukee, and the city began to trust the thugs in disguise. In 2016 the city government ran a design contest, a thousand-odd entries, and crowned a winner: ‘Sunrise Over the Lake’, by a local designer named Robert Lenz. A golden sun comes up over a blue field, the blue for the lake and the rivers, three thin lines for the city's three founders. It ticks every single one of Kaye’s boxes. But hang on, could it not also be Tulsa’s flag? No, it could be Reno’s. In fact it is so similar to Reno’s that both cities believe the other stole their design.

And the city never adopted it. The council picked the fight up in 2018, dropped it, raised it again in 2024, and kept finding reasons to wait, among them that the original contest hadn’t been inclusive enough. The 1954 design is still the official flag of Milwaukee. Meanwhile the sunrise spread across the city on its own, on t-shirts and stickers and bike frames and beer cans, with no legal standing at all. So upset were the thugs that they have insisted unilaterally that their design, while not official, is the ‘Milwaukee People’s Flag’.

That is the pattern wherever the redesigners get their way. NAVA grade flags like schoolwork, F to A+, and they now sort municipal flag changes into before 2015 and after, a vexillological BC and AD. Pull up the twenty cities they rate highest and they are the same flag. Navy, near enough every one, carrying white and a single hit of gold. A sun or a star. Often a wavy line where a lake or a river should be, now and then a triangle standing in for a mountain. Tulsa, Reno, Topeka, St George. Twenty different American towns, indistinguishable. One flag drawn twenty ways.

Which is the joke. Kaye’s fifth principle, the one the movement hurries past on the way to the part about the child, says ‘be distinctive’. Do not duplicate other flags. By the rubric these people carry into council chambers, their own redesigns fail. They have built a continent of flags so well behaved you cannot tell them apart, and they call it a job well done.

The twenty flags they rate worst are ugly. They are also, every one of them, unique. Belle Glade, Florida, painted an entire landscape into an oval. Nitro, West Virginia, kept a small red figure and a name left over from the explosives plant that built the town. Hideous, the lot of them, and not one you could mistake for anywhere else.

The movement’s base is r/vexillology, half a million of them looking in each week, a fresh municipality in the crosshairs every time. A man watches the talk one evening and by midnight has drawn a new flag for some town of three thousand in Iowa he has never set foot in. The forum encourages him. The design gets refined.

And then they move like the Thuggee. Not marching on anything, just drifting in. A flag nerd turns up at a council meeting wearing the face of a concerned citizen, and somewhere between the sanitation budget and the painting of the municipal fences, asks to speak on the matter of the flag. Nobody else has come. Nobody ever does. He runs through Kaye’s pamphlet from memory, explains in patient detail why the town’s flag is wrong, and the council, who have a budget to pass, defer to the helpful expert and wave through a consultation and a contest. What harm could it do? The town of three thousand never knew what hit it. Milwaukee, which is not a town of three thousand, is where the thing became a decade of trench warfare but in most of these places, the old flag is strangled in the night before anyone can realise.

A fair point cuts the other way, and it should be made before someone makes it for me. Plenty of the old flags were not like Milwaukee. But most did commit the flag obsessive’s greatest held sins, a ‘seal on a bedsheet’ (SOB), illegible from afar and identical to four hundred other city seals on four hundred other navy bedsheets. The flag thugs are right about them in theory: an SOB is never full of character but neither is the minimalist sunrise.

Paul Skallas, who writes as the Lindy Man, calls the instinct ‘refinement culture’. He claims that our civilization has lost its nerve for making new things and instead sands the character off old ones, then calls the sawdust left on the floor progress. Once you are told about refinement culture, it is hard to miss. The car badges that all went flat and wordless within about three years of each other. Every new film in the cinema being an already exhausted intellectual property. And of course the old fashion houses that swapped their idiosyncratic and romantic logos for the same anonymous sans font.

James Scott wrote the book on it, more or less. Seeing Like a State is about taking a tangled reality and making it clean and legible from above, then finding the clean version holds none of what made the thing worth having.

Which brings us back to the Thuggee sneaking through the camp at night, because there is something about them I left out. The strangling cult, the goddess, the scripture that blessed the killings, much of it may never have existed as imperial Britain described it. The more recent histories tell us that the thuggee was a colonial construction, to cover up good old fashioned banditry scattered across central India. Tidied up by an administration into a single category with a scary backstory so it could be cataloged and stamped out. The British did to highway robbery exactly what the refiners do to flags. They took something various and local and difficult, and made it simple enough to draw from memory. Twenty cities, one flag. Stand a man from Tulsa in front of the winning twenty and he could not find his own.

Ned Donovan is a policeman. You can follow him on Twitter.

This piece will not appear in Issue 24 of Works in Progress which arrives with subscribers next week. Subscribe in the next few weeks to receive it, and a further issue, every two months. Want- to subscribe for your business or institution? Check out our recently launched corporate subscriptions.

Multiple myeloma is among the most painful of all cancers. The disease originates in the bone marrow, where a single abnormal plasma cell, one of the blood cells that normally fights against infection, begins to proliferate uncontrollably, crowding out healthy blood-forming cells. In doing so, multiple myeloma destroys the bone from within.

Healthy bone is maintained by a perpetual exchange between osteoclasts, which dismantle old bone, and osteoblasts, which rebuild it. Myeloma disrupts this equilibrium, accelerating the action of osteoclasts and silencing that of osteoblasts – more bone is dismantled and less is rebuilt. The spine is especially exposed: its vertebrae bear the body’s weight and harbor the marrow in which myeloma thrives. As they are eroded from within, the result is a persistent ache, unrelieved by rest and often worse at night. As the disease advances, weakened vertebrae may collapse under the simple burden of standing upright, adding acute fracture pain to a chronic background ebb.

During the twentieth century, cancer treatment rested on three pillars: surgery, radiotherapy, and chemotherapy. Surgery has been used against tumors since antiquity and radiotherapy since the discovery of X-rays in the 1890s. Chemotherapy, the newest of the three, was developed in the 1940s and 1950s, its origins tracing back to observations about mustard gas during the Second World War.

These therapies were developed before anyone understood cancer at a molecular level. Blunt and often brutal tools, they work by exploiting the fact that cancer cells tend to divide faster than normal ones, and then doing something destructive enough to kill dividing cells preferentially. And while these treatments can cure some cancers discovered at an early stage, they offer little hope of a real cure for more advanced or relapsed cases.

Then, in the mid-2010s, a new class of genuinely transformative drugs arrived: immunotherapies. These treatments recruit the body’s own immune system to recognize and destroy malignant cells. The results, particularly in metastatic and relapsed disease, have been extraordinary. Multiple myeloma is one of the cancers that illustrates this most vividly, with the immunotherapy Carvytki, which was first approved by the FDA in 2022 for patients who had returning disease after four or more lines of therapy. Carvykti marks a turning point in the treatment of multiple myeloma for two reasons. First, unlike the conventional approach, in which patients endure continuous cycles of treatment, remission, and relapse for the rest of their lives, it is administered as a single, one-time infusion. Second, it is producing something that has never before been seen in this disease: durable, long-term remissions in patients which had been refractory to several other treatments, raising the possibility of a cure.

But Carvykti matters beyond multiple myeloma. In retrospect, its development story, which began in 2016, was an early signal of a transformation that is only now, a decade later, making headlines: the United States is beginning to lose its dominance in drug discovery to China. The foundational science behind Carvykti was largely American, but the therapy that changed the field came from a Chinese company that moved quickly from idea to patient. If the US does not address the regulatory and clinical-trial bottlenecks that slow the generation of early in-human data, more breakthroughs like Carvykti will be developed elsewhere, weakening the ecosystem on which American biopharma depends.

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The brutality of myeloma treatment

The treatment regimen for multiple myeloma is particularly brutal, even compared to other cancers. Under the newest standard approach, it often begins with months of induction therapy built around four drugs: daratumumab, an antibody that marks myeloma cells for immune attack; bortezomib, a proteasome inhibitor injected under the skin; lenalidomide, an immunomodulatory drug taken as a pill; and dexamethasone, a steroid powerful enough to restructure the rhythm of every week.

Patients come in and out of the clinic for injections, take pills at home and undergo repeated blood tests, living according to a calendar organized around treatment days and recovery days. They also have to contend with the side effects of the medications. Dexamethasone can produce a sleepless agitation followed by a physical and emotional crash. Bortezomib often damages peripheral nerves, causing tingling and a burning pain in the hands. Daratumumab often leads to immune suppression, leaving patients more vulnerable to infections.

For patients fit enough to withstand it, this induction regimen is followed by a stem cell transplant. This begins with high-dose chemotherapy that destroys the bone marrow entirely, followed by weeks of isolation with no functioning immune system and a recovery that continues for months after discharge. This stage is accompanied by repeated infections, extreme fatigue and mucositis, a painful inflammation of the digestive tract lining from mouth to gut. Patients are also profoundly vulnerable to even ordinarily minor pathogens that would pose no risk in a healthy person. After the transplant, the patient still has to do lenalidomide maintenance.

What is worse is that even after this brutal treatment most patients relapse, meaning their cancer returns. For these patients, what follows is further cycles of treatment. Doctors start patients on new combinations of drugs, including proteasome inhibitors and more chemotherapy. While these combinations can lead to remission, the myeloma almost always relapses again, leaving patients with progressively fewer options. Each treatment cycle means a lower possibility of survival.

Then there is quality of life. Many of the therapies for relapsed multiple myeloma are administered with intravenous injections or infusions and are given frequently, even weekly. For most patients, a one-time shot would represent a major improvement for their quality of life, even if efficacy were the same. What if the one-time shot also prolonged survival by years and appeared to cure relapsed cancers completely in a proportion of patients? This is what CAR-T therapies like Carvykti can offer.

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My other car is a T cell

CAR-T therapies make clever use of a patient’s own immune system. T cells, a type of immune cell that can attack tumours, are first extracted from a patient’s blood. Then, they are shipped to a manufacturing facility where they are genetically re-engineered to carry a new receptor on their surface. This is a chimeric antigen receptor, abbreviated as CAR, which is designed to recognize and bind to a specific protein on cancer cells.

The modified cells are then cultured until there are hundreds of millions of them, before they are frozen and shipped back. After a short course of chemotherapy to clear space in the immune system, they are infused back into the patient. From that point, the CAR-T cells are free to seek out cells carrying their target protein and destroy them. Because they are living cells rather than inert drugs, they can persist, proliferate, and continue hunting for months or years.

Multiple myeloma is perfectly suited to this approach for two reasons. First, because multiple myeloma is a blood cancer. Unlike solid tumors which form dense, poorly vascularized masses that T cells struggle to penetrate, myeloma cells circulate through the bone marrow and bloodstream. They are, in the language of immunotherapy, accessible. The same feature that makes blood cancers so difficult to surgically remove makes them unusually vulnerable to a therapy that travels through the blood to find its target.

The second reason comes from a protein called B cell maturation antigen, or BCMA. The fundamental challenge of any targeted cancer therapy is selectivity: the ability to kill tumor cells without destroying healthy ones. Most oncology targets are imperfect in this regard, expressed on tumor cells at elevated levels but present in healthy tissue too, which limits how aggressively they can be pursued. BCMA was first identified in 1992 by a French research group led by Yves Laabi. Laabi’s group were trying to find genes preferentially expressed in mature B cells, but had no idea what use to put their discovery to.

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For most of the decade following its discovery, BCMA sat in relative scientific obscurity: an interesting receptor without an obvious clinical application. But researchers gradually began to understand that BCMA was expressed at high levels on malignant plasma cells in multiple myeloma and that it was largely absent from most other tissues in the body.

In 2013, preclinical data from the lab of James Kochenfelder at the National Cancer Institute showed that BCMA-targeted CAR-T cells were effective against myeloma cells in the laboratory. But what followed illustrates the enormous and often underappreciated gap between a promising laboratory finding and a treatment that reaches patients.

The importance of being llama

Today, there are two CAR-T cell therapies for multiple myeloma in the US market: Abecma, approved in 2021, and Carvykti, approved in 2022. Both target BCMA on the surface of myeloma cells. Yet they arrived by strikingly different routes: Abecma from American research institutions and corporate laboratories in the early 2010s; Carvykti from an early-stage biotechnology company and a clinical trial first conducted in China in 2016. Only later was it licensed to a Western company and eventually brought to global approval.

Of the two, Carvykti is the clear winner. Its story speaks to the outsized role that China’s 2015 regulatory reforms have played in accelerating the country’s path from laboratory to clinic, and to producing medicines that work. Being first to market or doing the fundamental science counts for far less than being the nimblest in getting to the clinic. Carvykti also carries another important lesson for the industry: never underestimate the llama.

The technology developed in Kochenfelder lab was licensed to the biotech start-up Bluebird Bio, which developed it in partnership with the large biopharmaceutical company Bristol Myers Squibb into what would eventually become Abecma, the first CAR-T therapy approved for multiple myeloma. Over 80 percent of patients saw their cancers shrink in the National Cancer Institute’s first-in-human trial, published in 2016. This validated the premise of BCMA targeting and set the field moving.

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Meanwhile, a parallel story was unfolding on the other side of the world. In 2014, a team of Chinese scientists began investigating cell therapies for cancer, initially working in what the company describes as a room the size of a freight elevator. After focusing their research solely on BCMA-targeting CAR-T cells in 2015, Legend Biotech began conducting its first clinical trials in 2016.

Central to their approach was a significant departure from convention. Traditional CAR-T constructs relied on using existing antibody fragments, derived from humans, to seek out and bind to their target protein; in this case, BCMA. Legend took a different path, turning to an unlikely source: the llama. Human antibody fragments almost always bind to at least two targets, meaning that if doctors give a patient too much of the drug, they risk causing side effects associated with the second protein the drug binds to.

Camelid animals, including llamas and alpacas, produce a unique class of antibodies known as nanobodies, which can be engineered to do the work of their much larger human counterparts. Their compact size and remarkable stability allow CAR-T cells armed with them to target tumors more efficiently. CAR-T cells using nanobodies also seem to stay active longer and kill tumors more effectively.

The Chinese researchers enrolled their first patient in a clinical trial in 2016, the same year the American team published their initial results. But they moved fast. By 2017, just a year later, they were presenting stunning data at one of the biggest conferences in the field. The decision to learn from the llamas seemed to have massively paid off.

Xi loves you (yeah, yeah, yeah)

It can take years for enough people in a cancer trial to die to clarify that one treatment is prolonging survival over another, so researchers rely on proxies instead. In the American trial, 80 percent of patients responded to treatment, meaning their tumors shrank to some measurable degree, a result already considered impressive given how much these patients had already been treated, to no avail. The Chinese trial did better: every single patient responded. What’s more, 74 percent of patients in the Chinese trial saw their cancer completely wiped out, compared to 56 percent in the American equivalent.

Such results did not go unnoticed. Within months of the 2017 presentation, Janssen Pharmaceuticals, the pharmaceutical subsidiary of the large American company Johnson & Johnson, was in negotiations with Legend Biotech. In December 2017, the two companies announced a global licensing and codevelopment agreement: Legend got $350 million upfront plus half of any revenue generated in the US, while also contributing to half of the development costs.

After years of clinical development, later-stage trial results confirmed what earlier data had suggested: Carvykti was the superior treatment. In later stage trials, oncologists and regulators switch from looking at how many patients respond at all to looking at progression-free survival, or the length of time a patient lives without their disease worsening or claiming their life. The gold standard is overall survival, but it is also the hardest to measure, requiring trials long enough to capture the full arc of a patient’s outcome. For that reason, regulators often grant approval on the basis of progression-free survival data, with overall survival figures following later as evidence accumulates.

On both measures, Carvykti pulled clearly ahead. In the CARTITUDE-1 trial, its 12-month progression-free survival rate was 76 percent. In the KarMMa trial for Abecma, by contrast, this figure was 55 percent. But what happened afterwards is perhaps even more striking: in the Abecma progression free survival curve, the line falls continuously. By contrast, in Carvykti, the line starts to plateau. Extended follow-up at five years confirmed that 33 percent of Carvykti patients remained disease-free. The significance of this result cannot be overstated. These were patients for whom, on average, four prior lines of therapy had already failed and whose immune systems were heavily challenged.

The CARTITUDE-1 trial results led to Carvytki’s approval in 2022 for patients with myeloma who have failed four other lines of treatment. In 2024 the FDA approved Carvytki in patients who have relapsed after just one prior treatment, on the basis of results from the CARTITUDE-4 trial. Here, Carvykti shows even greater benefits over standard care. The best hypothesis as to why has to do with the fitness level of the patients’ T cells. CAR-T therapies are made from the patient’s own T cells, but those cells wear down over years of fighting cancer and enduring multiple rounds of chemotherapy. Used earlier, after just one prior treatment, the harvested T cells are in far better shape, and the therapy built from them is more effective at fighting disease.

Carvykti is currently being evaluated in clinical trials as a first-line treatment, which means that it would be given to newly diagnosed myeloma patients before any other therapy has been tried. If the trial results are positive, this would be a historic game-changer in how patients are treated, with a one-time injection becoming the standard over the arduous procedure of induction regimen, bone marrow transplant and lenalidomide maintenance.

Kochenderfer's lab at the National Cancer Institute first validated BCMA as a target and ran the first-in-human trial. Most of the intellectual groundwork was largely laid in Bethesda, Maryland, in the US. But the therapy that ultimately reached patients and that is now rewriting the prognosis for multiple myeloma did not emerge from that lineage. This was an early sign that China would become an important force in biotechnology.

Made in China

Just last week, in late May 2026, the New York Times ran an article reporting on a clear shift at ASCO, oncology’s most prestigious annual conference. The stage was increasingly dominated by novel therapeutics developed in China. Global pharmaceutical companies are racing to license Chinese-developed drugs, drawn by a combination of lower costs, faster development timelines and a streamlined regulatory environment. The end result of this is a realignment of where the world’s medicines are being discovered. Roughly half of all major drug licensing deals struck so far this year involve drugs originating from China. What is striking is that this share was nearly zero just a decade ago.

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The Carvykti case should have been an early warning. Already by 2016, the same year Legend began the clinical trial that would first reveal Carvykti’s potential, China had overtaken the United States in the number of cell-therapy clinical trials. The gap has been growing since.

China’s ongoing biotechnology transformation is the product of deliberate industrial policy. The Made in China 2025 initiative explicitly identified biotechnology and advanced medical technologies as strategic national priorities, and a series of targeted policies followed. Among them was the Thousand Talents Plan, designed to draw overseas Chinese scientists back from Western institutions. BeiGene, Innovent, and Junshi, which are now three of China’s leading oncology biotechs, were all founded or are now led by researchers who had trained in the United States before returning home.

Yet perhaps the most consequential advantage China has built lies in its clinical trial ecosystem. Chinese hospitals make extensive use of investigator-initiated trials. These are early-stage studies that allow oncologists to quickly assess whether a drug shows genuine promise. In China, such a trial can be up and running within roughly six months of a patient consultation with an academic oncologist. In the United States, the same process can take eighteen months or more, bogged down by regulatory preparation that includes a lengthy Investigational New Drug application. This is a document that can run to thousands of pages and is laden with a host of requirements which are unnecessary at such an early stage of development.

The most valuable thing early-stage trials enable is iteration. They allow tight feedback between the clinic and the lab. There are countless ways to engineer a better CAR-T cell, and many cannot be evaluated in the laboratory alone. No cell culture or animal model fully replicates the complexity of a human tumor, and AI is unlikely to close that gap anytime soon. We simply lack the training data to capture what tumors are actually like in vivo: their geometry, vascularization and biomechanical properties.

China’s ability to run these trials quickly and at scale gave it a structural advantage in that learning process, whereas the US is currently undermining itself through burdensome manufacturing requirements and regulatory bureaucracy that make early experimentation slower and more costly than it needs to be. The policy world has, belatedly, taken notice of this. A proposal in the President’s 2027 FDA budget would streamline early-stage trials. This a welcome recognition that regulatory friction on early experimentation is a competitive liability. But a budget proposal is not a policy and will remain aspirational unless Congress acts.

For now, American and European pharmaceutical companies largely retain the upper hand in the later stages of clinical development, as shown by the fact that Legend ultimately licensed Carvytki to a large American biopharmaceutical company to get it approved. But the pipeline that feeds those late-stage trials is increasingly Chinese. Such early-stage dominance turned into vertical integration of the entire chain in solar panels, batteries and electric vehicles, and LCD panels. The question is how long Western companies can sustain their advantage at the later stages, when the discoveries that make those stages possible are increasingly being made elsewhere.

Ruxandra Teslo is an editor at Works in Progress. Amol Punjabi is chief product officer at OpenEvidence.

You can also watch the rest of the episode on Apple Podcasts, Spotify, and YouTube.

Cities are often centers of agglomeration, places where people gather to collaborate with one another. But this is not the only reason they exist. Sometimes, cities are chiefly centers of consumption, where elites gather to devour resources extracted from the rest of the country. And occasionally, they are something like prisons, where troublesome social groups are concentrated so that the authorities can keep an eye on them. Many premodern cities, like Versailles, Naples, or Imperial Rome, were a little like this. But perhaps the greatest example was Tokugawa Edo.

Between 1600 and 1868, Japan was dominated by the Tokugawa family. The Tokugawas had prevailed over their rivals after a series of civil wars, establishing a sort of dictatorship known as the Shogunate. They developed a remarkable social system, crafted to preserve their power, and with it, the peace and social stability of Japan. At the apex of this system was the city of Edo (today’s Tokyo), at times the largest city in the world, and one of the strangest urban structures in history.

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The Tokugawa social system

In early modern Europe, most people were tenant farmers, who paid rent to landowners. The state sometimes taxed landowners, sometimes tenants, and sometimes both through consumption taxes. In peacetime, however, the early modern state did not do very much, so taxes generally ran at just a few percent of national income.

The picture in Japan was profoundly different. The peasantry was directly taxed by the government, at rates varying from 15 to 70 percent of the harvest, with 40 percent as a rough norm. The authorities distributed most of their tax receipts to the samurai, a hereditary, quasi-noble class making up about six percent of the population. In both cases, the agricultural surplus ended up in the hands of a leisure class, but the Japanese system was structured very differently, with the surplus reaching the leisure class only through the funnel of public taxation.

Measured by agricultural output, about 15 percent of Japan fell under the direct control of the Shogunate. These were areas that had always belonged to the Tokugawa, or that had been conquered by them during the civil wars. About a tenth of samurai were Tokugawa retainers, who received their stipends directly from the Shogunate.

In about three quarters of Japan, the tax authorities were a different group, the daimyo. The daimyo had originally been the territorial nobility, and in the pre-Tokugawa era, the breakdown of central authority had left them as the effective rulers of their domains. After 1600 the surviving daimyo submitted to the Tokugawa and were rewarded with a role somewhat akin to that of regional governors. There were about 260 daimyo, and about nine tenths of samurai were their retainers.

Urban design as a panopticon for the nobility

The city of Edo played a crucial role in this system. The daimyo were required to maintain mansions in Edo, in which their families were obliged to live permanently. Any act of disloyalty by a daimyo would thus place his family in the gravest peril. Most women of the daimyo class passed their lives as effective hostages of the state, never visiting the domains that their husbands, fathers, and sons governed. The daimyo themselves were also required to spend alternate years or half-years in Edo, bringing with them great crowds of samurai retainers. Edo thus had a dual nature: on the one hand, it was the apex of Japanese society, in which the country’s agricultural surplus was consumed; on the other, it was a kind of prison, in which Japan’s potentially dangerous elites were contained and monitored.

This gave Edo a peculiar demographic and economic character. For one thing, it was enormous. Japanese rice agriculture was extremely productive by premodern standards and generated a huge surplus for the capital’s benefit. Edo’s population seems to have been over a million by 1700, which would make it the largest city in the world at the time: London reached a population of a million only around 1800, while New York did not reach it until 1880.

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It was also extremely top-heavy socially. Unlike the knights of the European feudal system, Tokugawa-era samurai were usually required to live in cities. The Shogun’s own samurai were permanently concentrated in Edo, while each daimyo brought hundreds or thousands of his samurai with him during his years of residence in the capital. This meant that almost half of Edo’s population at any given time were samurai.

The samurai were theoretically a warrior class, but since Tokugawa Japan was at peace, there was little real soldiering to do. Most non-military work was seen as degrading, with the exception of gentlemanly occupations like civil administration and tutoring in calligraphy. Most samurai thus lived as pensioners of the state, deriving the bulk of their income from hereditary government stipends assigned to their families at the start of the Tokugawa era.

Stipends were generous for high-ranking samurai but very modest for the majority: in 1876 the Japanese state calculated that only 5.1 percent of samurai had stipends worth more than 100 yen, equivalent to a little over $4,000 today. The result was that most samurai lived in dignified but extreme poverty. It is a testament to the primacy of status among human ends that, although some samurai surreptitiously took on side jobs to supplement their tiny incomes, very few abjured their rank to take up more gainful occupations openly. Interclass marriages were forbidden, and there was theoretically no process for ennoblement, though some wealthy commoners worked around this by arranging to be adopted into impecunious samurai families.

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The High City

Edo was zoned according to social class, probably the largest-scale use of zoning before modern times. Samurai neighborhoods made up a large minority of the total surface area, concentrated in western areas that came to be known as the High City. Higher-ranking samurai had substantial homes, but most lived in extremely austere conditions: the median family lived in a tiny, two-room rowhouse with no garden and communal latrines.

The samurai shared the High City with the daimyo. Each daimyo was expected to maintain several estates in Edo, including a more compact estate near the Shogun’s castle and a more spacious garden estate further out. These were made up of single-storey buildings connected by covered walkways, set amid exquisitely landscaped gardens. Each estate was surrounded by a perimeter wall broken by just one or two richly ornamented gates. The great expense of all this was, from the Shogunate’s perspective, part of its appeal: the more resources daimyo expended on maintaining mansions and circulating between them, the less remained for fomenting trouble.

These samurai and daimyo neighborhoods made up a substantial majority of Edo’s surface area. In some ways, they foreshadowed affluent American suburbs, though they would have felt quite different at street level. Physically, the closest modern parallel might be elite neighborhoods in countries like South Africa or Brazil, where fear of crime has driven the wealthy behind high walls and electric fences.

In fact, however, Edo seems to have been an unusually safe city, a fact that often struck early Western visitors. Most people had no locks on their front doors. The English writer Isabella Bird wrote that a solitary foreign woman could travel in Japan in ‘perfect safety’ and that she had never encountered ‘a single instance of incivility’, though at home she would often have been ‘exposed to rudeness, insult, and extortion, if not to actual danger’. The walls and gates of the High City may thus tell us more about elite culture and status display than they do about any distinctive security needs.

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The Low City

Much of the rest of Edo’s surface area was taken up with religious complexes and institutional buildings belonging to the Shogunate. The commoners were crowded into the remainder, mostly in riverside areas known as the Low City. Though most commoners were very poor, some were richer than most samurai, and even richer than minor daimyo. Some of the greatest artistic legacies of Tokugawa Japan, like ukiyo-e prints and the kabuki theater, arose from the patronage of this class. However wealthy they might become, however, commoners’ status was axiomatically lower than that of the samurai.

Edo’s commoners worked mostly in providing goods and services to the city’s elite. The city as a whole produced little, consuming resources from the rest of Japan and providing little in return save the arguable gift of government. No international trade took place in Edo: the government was intensely wary of destabilizing foreign influences, and by the late-eighteenth century it allowed only two Dutch and ten Chinese ships to visit Japan each year, all through the carefully controlled port at Nagasaki. (For comparison, about fifteen thousand ships arrived in British harbors from foreign ports annually in the same period.) In this as in other respects, the Shogunate’s political needs had a decidedly fitful relationship to the country’s economic growth: although the political stability that the regime provided certainly did foster prosperity, the steps it took to ensure that stability often stifled it.

The physical form of the Low City was even more remarkable than that of the daimyo neighborhoods. Commoner Edo was divided into some 1,500-2,000 fenced and gated blocks called chō. These were then subdivided into roji, alleys lined with small houses, often also gated. The Low City was thus divided up by many thousands of internal checkpoints, all of which closed at night. Edo was not under threat of attack in the Tokugawa period and the city as a whole was not fortified. The purpose of this immense labyrinth of walls and gates was to control and monitor the movement of the population.

Wealthy merchants lived in substantial houses called machiya, featuring a series of small garden courtyards around which living spaces were ingeniously laid out. In plan, machiya recall the domus house type of the urban middle and upper classes in the Roman Empire. Many machiya must have been rather agreeable houses, and some Japanese people still live in modernized machiya today. Most commoners, however, lived in nagaya, tiny terraced houses frequently built back-to-back. A standard specification for nagaya was 2.7 meters wide and 3.6 meters deep, yielding a total floorspace of only 13.2 square meters.

An enormous number of people were crammed into commoner neighborhoods. The most crowded had 58,000 inhabitants per square kilometer, about twice the population density of Manhattan today. Remarkably enough, however, their dwellings were largely single-storey. This seems to have been required by regulation, in turn motivated by fire risk or by dislike of commoner buildings towering over the mansions of the nobility. Japanese builders were perfectly capable of erecting taller structures, so the fact that these intensely crowded neighborhoods forewent the floorspace that additional storeys could have provided is not least among the paradoxes that Tokugawa Edo presents to history.

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* * * *

In a way, the Tokugawa system was a success. Japan experienced near-total peace between 1600 and the late nineteenth century, a remarkable achievement for a premodern society and a dramatic contrast to Europe or China, where tens of millions of people died in wars. The Tokugawa succeeded in bribing, blackmailing, and intimidating Japan’s armed elites into a quarter of a millennium of passivity, enabling steady economic growth and a remarkable artistic flowering. One might thus argue that Edo’s apparent parasitism was an illusion. Edo was indeed a gilded prison, but prisons can be useful things.

Still, it would have been nice if Japan had not needed a vast prison capital in the first place. Tokugawa Edo stands as a monument to the power of rent-seekers, producing little and demanding immense resources as a condition of civil peace. It shows how the physical form of cities may be reshaped by these demands, as governments apportion space and limit movement in line with their political needs. These forces yielded a city with tight restrictions on built density and land use, an acute housing shortage, and a huge share of privileged state stipendiaries. Edo is a particularly striking example of these phenomena. But it is far from alone.

Samuel Hughes is an editor at Works in Progress. Follow him on Twitter.

Thanks to Fabian Drixler for generous help.

In the TV miniseries Lessons in Chemistry, chemist Elizabeth Zott presents her research on de novo nucleotide synthesis to a panel of suited and bespectacled colleagues. ‘Unlike the amino study group’, says Zott, ‘we are starting with the basic assumption that DNA, not protein, is the basic foundation of life’. The panel scoffs at this apparently ridiculous claim. The head of her department dismisses DNA as a ‘dead end’ and Zott’s method for making it from scratch as ‘nothing more than a party trick’. Zott’s proposal is rejected.

Zott was a fictional character, but the scientific debate was real. The fact that DNA encodes genetic information is now taught in biology classrooms worldwide, but until the late 1940s it was a fringe idea. Most scientists instead believed genes were made of protein. James Watson and Francis Crick are now household names for discovering DNA’s double helix structure, but the importance of that discovery rested on earlier work establishing that DNA, not protein, carries genetic information. The scientists who made this more fundamental discovery have often been overlooked.

The organisms that enabled this discovery were similarly unexpected: bacteria. At the time, few scientists, even microbiologists, thought that bacteria could offer anything of value to genetics. Many doubted they even had genes! Those primitive blobs swimming under microscope lenses were thought to be nothing more than tiny bags of enzymes – a totally different kind of life. So it came as a surprise when the pivotal discovery of modern genetics emerged not from a geneticist but a microbiologist.

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What parents pass on

Evolution by natural selection requires that organisms inherit characteristics from their parents. Heredity wasn’t a new idea when Darwin published On the Origin of Species in 1859. Farmers had exploited it for centuries, selectively breeding livestock and crops for desirable traits. But neither Darwin nor anybody else at the time could explain how traits were passed down from parents to offspring.

Inheritance was full of mysterious patterns: skin color tended to be a blend of the parents’, eye color could differ from either, and sex only matched one. How could such variation be explained? There were plenty of theories – including Darwin’s own provisional hypothesis of ‘pangenesis’, in which every cell in the body shed tiny particles called ‘gemmules’ that traveled to the reproductive organs and were passed to offspring – but nobody had persuasive evidence to support one over another.

Nobody, that is, except a little-known Austrian monk named Gregor Mendel. Mendel’s experiments with pea plants showed that inheritance depended on discrete factors transmitted from parents to offspring. Some traits, such as peas being wrinkled rather than smooth, could disappear and then pop up again in later generations – an impossibility if traits were a simple blend of both parents. Mendel’s work went unnoticed in his lifetime, but in 1900 three botanists independently rediscovered and confirmed his findings. By 1909 these factors had been given a name: genes. But the original meaning differed significantly from today’s. Wilhelm Johansen, who coined the term, explicitly rejected the idea that genes were physical particles, instead conceptualizing them as a chemical or physiological process.

The geneticist Thomas Hunt Morgan hypothesized that genes might either be a ‘chemical molecule’ or a ‘fluctuating amount of something’, but concluded: ‘I see at present no way of deciding’. By 1933, the confusion hadn’t resolved. Morgan wrote in his Nobel Prize lecture: ‘There is no consensus of opinion amongst geneticists as to what the genes are – whether they are real or purely fictitious’.

A common thread was the assumption that genetic information must be encoded in protein, not DNA. Proteins are made from long chains of simpler molecules called amino acids, joined in sequence like beads on a string. With 20 different amino acids for each position, like letters in an alphabet, even short protein sequences can produce an astronomical number of combinations. Meanwhile, the alphabet of DNA has only four ‘letters’, made from the four simpler molecules called nucleotides that join in sequence to make strands of DNA. Today, a four-letter alphabet may seem luxurious compared to the binary language of computers (1 and 0), but while information theory would eventually come to influence biologists’ thinking, this would not take hold for a few decades more.

Further, the best evidence suggested that the four letters of DNA were present in equal proportion in every organism, and arranged in repeated blocks. Such a monotonous molecule could be structural, but surely not informational. The physicist-turned-biologist Max Delbrück spoke for many at the time when he derided DNA as ‘so stupid a substance’.

For decades, geneticists remained stuck. To establish causality, they needed to show that a chemical induced predictable and hereditary changes in cells. The dream experiment would be to isolate and purify either DNA or protein from one organism, introduce it into another, and observe a heritable change. But living things could not take up genetic material from their environment – or so they thought. That assumption would be overturned by experiments with bacteria.

An unlikely answer

For much of the early twentieth century the study of bacterial variation and heredity was hopelessly confused. As late as 1942, the biologist Julian Huxley excluded bacteria from his theory uniting Mendelian genetics with Darwinian natural selection on the grounds that ‘they have no genes’. It seemed unlikely that bacteria had anything to offer genetics.

Then, in 1928, the British bacteriologist Frederick Griffith published a paper that shocked researchers around the world. Griffith was studying pneumococci, the bacteria responsible for pneumonia, and a promising new treatment called ‘serum therapy’ in which antibody-rich serum from patients who survived an infection could be used to treat others. But subtle differences between pneumococci rendered serum from one infection ineffective against others, so scientists categorized pneumococci into ‘serotypes’ (I, II, III, and IV). A pneumococcus’s type was fixed and inherited: it was genetic. The bacteria also differed in their colony shapes. Some produced smooth (‘S’) dome-shaped colonies, while others were rough (‘R’) and irregular. The S form was virulent and deadly, thanks to a slippery coat that protected it against our immune cells. But the R form, lacking this coat, rarely caused disease.

In his experiment, Griffith combined two bacterial strains that should have been harmless when mixed: live type I bacteria of the rough form, which didn’t cause disease, and heat-killed type II bacteria of the smooth form, which had once been virulent but were now inert. Injected into mice separately, neither was harmful. But together, the mixture proved unexpectedly deadly. Even more surprising, when Griffith isolated bacteria from the dead mice, he recovered live type II smooth pneumococci. Somehow, by coming into contact with the remains of the virulent dead bacteria, the harmless live bacteria had been ‘transformed’ to match the dead ones. And this change was not temporary: the transformed bacteria continued to produce descendants of the same type as they multiplied. It was heritable.

Immunologists were initially skeptical of Griffith’s work. Perhaps some small fraction of the virulent pneumococci hadn’t really been killed? But soon the experiment was confirmed independently by labs around the world.

Among those struck by Griffith’s experiment was Oswald Avery at The Rockefeller Institute. For 20 years, Avery had studied the immunology of pneumococci. After reading Griffith’s paper, he assigned trainees to investigate transformation. One was JL Alloway, who showed that transformation could also be brought about in vitro with chemical extracts from the killed smooth cells. By dissolving living cells and filtering out cellular fragments, Alloway extracted the ‘thick syrupy precipitate’ that contained whatever it was that was causing bacteria to change serotype. This mixture became known as the ‘transforming principle’.

Solving the puzzle

Avery had shown that the transforming principle caused hereditary changes. That meant it contained genes. If he could isolate the component responsible for transformation and determine its chemical composition, he’d finally have an answer to the long-sought question of what genes were made of.

But on the precipice of a major scientific breakthrough, progress suddenly stopped. Avery was diagnosed with Graves’ disease, a thyroid condition that exhausted him and gave him a tremor that made it difficult to perform experiments. After having his thyroid surgically removed he spent months recovering; when he finally returned to work, he shifted his research focus to newly discovered antibiotics.

When Avery came back to the question of the transforming principle eight years later, the field was largely unchanged. Why no other group swooped in during his absence remains a mystery. Perhaps geneticists were uninterested in working with bacteria, or bacteriologists had prioritized practical research into vaccines and antibiotics.

Whatever the reason, Avery began by refining the method to extract the transforming material with the help of scientists Colin MacLeod and Maclyn MacCarty. Their new process required vast quantities of bacterial culture: 75 liters of broth teeming with bacteria to obtain just 10 to 25 milligrams of transforming principle. They adapted a steam-driven kitchen cream separator to separate bacterial cells from the broth. Obviously, the device was not intended for handling pathogenic bacteria. Tiny gaps in the seals meant that its use filled the room with an invisible mist of potentially lethal pneumococci. Avery’s team had to construct a vessel that could contain and sterilize the machine before opening. The cake of bacteria it collected had to be handled with towels soaked in germicide, and the recovering Avery left the lab whenever it was being used.

Through this effort, the team purified a substance that had rich transforming activity. It contained a mixture of polysaccharides, proteins, RNA, and DNA. Next, they needed to work out which of these was responsible for transformation. Adding enzymes that inactivated proteins or polysaccharides did not stop the bacteria from transforming. But when they added an enzyme that destroyed DNA, transformation no longer occurred. That meant the transforming principle, and therefore the gene, was DNA.

The mood in the lab was electric. But Avery knew it would be an uphill battle to convince others that DNA, not protein, was the genetic material. Opponents would argue that minute traces of protein remained and these were what accounted for the transforming activity. Since it was impossible to prove a negative (that the samples were protein-free), Avery aimed to gather as much evidence as he could: chemical composition, enzyme inactivation, centrifugation, electrophoresis, and ultraviolet absorption. Every result converged on DNA.

In a letter Avery wrote to his brother, he overflowed with excitement about the implications of his discovery. ‘It touches genetics, enzyme chemistry, cell metabolism and carbohydrate synthesis, etc.’ But in his public addresses, he was cautious to a fault. ‘It’s lots of fun to blow bubbles – but it’s wiser to prick them yourself before someone else tries to’.

Avery, MacLeod, and McCarty’s paper was published in 1944. Reflecting Avery’s caution, the word ‘gene’ does not appear in the title, summary, or conclusion, and the paper ends by acknowledging that minute amounts of contaminants nevertheless could be the true source of the transforming activity. But the conclusion was unmistakeable: genes were made of DNA. The response to the paper was mixed: many praised Avery’s work, while some critics argued that contamination by protein could explain the results. But the burden of proof now rested on them to identify such a protein, and nobody was able to do so.

The molecule that changed everything

Avery’s experiment not only settled the question of the physical nature of genes, but also made it possible to ask a hundred more. How does DNA encode genetic information? Do other living organisms also use DNA, or just pneumococci? What is DNA’s molecular structure, and how does it replicate itself?

Hundreds of papers would be published on the nature of DNA over the following decades. Their authors are among the most celebrated scientists of the twentieth century, including the Nobel laureates Joshua Lederberg, who studied how bacteria can exchange DNA; Alfred Hershey and Martha Chase, who demonstrated that DNA, not protein, is transferred from bacteriophages to bacteria during viral infection; and of course Watson and Crick, who discovered the double helix structure of DNA.

Avery however never received a Nobel Prize, despite having been nominated 38 times. The Nobel committee, unaccustomed to Avery’s ‘restraint and self-criticism bordering on the neurotic’, as described by his protégé René Dubos, perhaps decided it best to wait for further confirmation. But Avery was already 65 when he published his DNA work, and died 11 years later; Nobels are not awarded posthumously. Avery’s work has received less notice than that of other geneticists, in large part because he never received science’s top prize. Nevertheless, it is the foundation upon which the last 75 years of genetic and biomedical research has been built.

DNA now dominates all facets of biomedical research. But perhaps the most important consequence of Avery’s investigations has been the recognition that all living things on Earth – from deep-sea algae to high-flying birds, sharks to iridescent beetles, disease-causing bacteria to humans – store their genes in the same way: in the twisting strands of DNA.

Kevin Blake is scientific editor at Washington University in St Louis.

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What explains recessions? Are they the product of boom-bust cycles? Do they follow cyclical or semi-cyclical patterns? Or are they best viewed by policymakers as being due to surprises changes in the global economy, which economists call ‘shocks’. These are the questions addressed in Tyler Goodspeed’s Recession: The Real Reasons Economies Shrink and What to Do About It.

Economists usually communicate new arguments and data in journal articles. In contrast, Recession is published by Basic Books, an imprint of Hachette, the third-largest publisher in the world. The book is rich with both historical anecdotes and biographical sketches of key players such as Irving Fisher and FA Hayek. Despite this, Goodspeed’s book is a serious, data-rich work.

At first glance, Goodspeed’s target is the popular understanding of a boom-and-bust cycle. Consider his vivid account of the crisis of 1873. Both popular and scholarly histories have attributed this recession to railway mania and the collapse of the Northern Pacific Railroad. Goodspeed instead points out the devastating role of a surprise that had nothing to do with economics or economic policy: the great grasshopper plagues of 1873-1876, during which a single locust swarm covered an area larger than California and devastated the very regions the railroad was supposed to open to European settlers.

Goodspeed’s first message is that macroeconomic events are not morality plays, nor always under policymaker control or influence. Jay Cooke’s vision of a railway connecting the Pacific northwest was not inherently flawed or hubristic. Nor were other nineteenth-century business busts such as the 1857 New York banking crisis associated with the collapse of Ohio Life. Instead these panics were, like that of 1873, each associated with an idiosyncratic confluence of factors.

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The intuitive account of recessions: payback for good times

Goodspeed is not just interested in confronting the kinds of explanations for mania, crashes, and panics seen either in history books or in journalist accounts. He wants to see if the data supports theoretical accounts of recessions that locate the cause of the downturn in the preceding expansion. His antagonists are two celebrated Austrians: first Friedrich Hayek, introduced early in the book as a prospective restaurant dishwasher as a young man in New York and whose prominent account of business cycles rivaled Keynes’s in the 1930s; and second, Joseph Schumpeter, who saw in recessions the opportunity to sort out the mistakes and misallocations of the boom. Goodspeed’s main goal in the 200 or so pages of the book is to ask whether the data supports these theories, or their modern variants, or whether it is consistent with a much simpler story.

The short answer is no, and this is Goodspeed’s second main message. The spine of the book is data on quarterly output for the UK and US. The UK data comes from the work of Steve Broadberry and coauthors. The US data stems from the National Bureau of Economic Research but Goodspeed has extended it back to 1700 and applied a consistent methodology to provide a continuous business cycle series for both countries.

Goodspeed shows that British and American expansions do not resemble Dorian Gray, looking beautiful but hiding an inevitable accumulation of malinvestments (objectively bad investments that are destined to fail) and distorted decisions (mistaken economic decisions taken on the basis of bad regulation or flawed prices) that make a correction inevitable. If they did so, he argues, one would expect that as expansions get longer they get more and more likely to end. In his data, however, the relationship between the age of an expansion and the probability of death is essentially zero. Nor do measures of increased investment during the boom correlate with the severity of a downturn. Nor do longer expansions have longer recessions after them.

This is why recessions remain essentially unpredictable. Any perceived regularity is likely to be a statistical illusion. Goodspeed shows that attempts to forecast recessions such as inversions of the yield curve (where long-dated government bonds have lower interest rates than short-dated ones) or the Sahm rule (which says a recession is likely underway if the unemployment rate spikes high above its recent lows for three months) are overfitted to US data and don’t work for the UK. The same proved to be true of the Phillips Curve, a strong correlation between unemployment and inflation that existed in British data between 1860 and 1960, which broke down after governments attempted to target it and fine tune the economy in the 1960s.

On top of all this, he finds no evidence that recessions are corrective. Reallocations tend to happen more aggressively during expansions not contractions, contrary to the arguments that Joseph Schumpeter famously made. Similarly, he finds that contrary to common belief recessions tend not to be contagious but rather are mostly patriotic, usually confined to a single country like the modest 2001 downturn in the US (which did not spread to the UK).

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Nothing new under the sun

The blurb provided by Niall Ferguson on the hardcover of the book proclaims that it is ‘truly revolutionary’. I would say that Goodspeed’s account is highly consistent with at least one strand of research in macroeconomics.

As Goodspeed makes very clear, his account of recessions has a direct antecedent in Milton Friedman’s so-called plucking model, which is not so much a model as an empirical observation that the path of the economy could just as well be described as a straight trend upwards, which sees negative deviations from the trends and recoveries back to the trend. In Friedman’s view, there is no special reason to see faster-growth periods as artificial booms or bubbles. The goal for policy makers, if Friedman’s model is true, is neither to burst bubbles nor to prevent booms from getting going, but simply to limit or prevent negative shocks and ameliorate their consequences.

Goodspeed’s historical case studies are also consistent with a much derided tradition in macroeconomics, known as real business-cycle theory, associated with economist Ed Prescott, who won the Nobel Prize in 2004 and died in 2022. In real business-cycle theory, the economy ticks along its regular path until it is hit by what real business-cycle theorists call ‘technology shocks’. Former US Treasury Secretary and Harvard President Larry Summers objected to these models because technology shocks were undefined. Goodspeed’s narrative accounts provide compelling examples of how shocks broadly understood can account for much business cycle behavior.

I recall being distinctly unimpressed by this emphasis on shocks as an undergraduate. Nonetheless, it is clear that until recent times, most economic fluctuations were caused by exogenous factors such as the climate. What Goodspeed emphasizes is that exogenous shocks have played an important role even into modern times.

For example, recent research has demonstrated the role of bank failures in explaining the depth of the Great Depression. Goodspeed notes that huge locust plagues like those of 1873 ravaged western and central states. By late 1931, one in six farms in this region was underwater. So while contemporaries blamed land speculation and irrational land booms, it is clear that exogenous shocks to the real economy lay behind part of the severe banking distress of the early 1930s. Again, Goodspeed notes that this wasn’t The Cause of the Great Depression. There was no one cause, ‘but rather a succession of overlapping and interacting shocks, often highly region-specific’.

Predicting such events is a fool’s errand. Rather, Goodspeed argues we should imagine several dice being rolled as if in a game of chance. A roll of one is a negative shock: a war or a coal-strike or a climatic shock. A recession might occur if we simultaneously roll three ones.

If you’re in a hole, stop digging

Not all shocks are necessarily exogenous in nature. Chapter 7, entitled ‘Firefighters and Arsonists’, notes that while policymakers can play a vital role in smoothing shocks and responding to a crisis, they have often themselves acted as arsonists.

The actions of the Federal Reserve during the Great Depression are a famous example. Wary of speculative finance, the Fed allowed the money supply to fall precipitously and failed to halt the banking collapse. The shock here was hardly exogenous to the economy itself but the type of unforced error that is sadly not unusual in the historical record.

Similarly, conventional accounts at the time of the Great Recession of 2008 emphasized financial malfeasance in the housing market with subprime mortgages being repackaged to unsuspecting lenders. But why should these issues in the banking sector produce a worldwide recession? Moralizing accounts that emphasize the greed of bankers can be politically and emotionally satisfying but they don’t explain the scale of the downturn. The vast majority of the homes built during the bubble between 2002-2006 turned out to be entirely consistent with subsequent demand.

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Goodspeed sees the 2008 recession as caused by a confluence of largely independent and to a degree avoidable shocks. There was a negative supply shock that saw the price of gasoline reach $5.86 per gallon in 2026 prices (at time of writing still an all-time real terms high). As a result, fertilizer prices also spiked. This energy-shock-induced slowdown began before distress in financial markets resulted in the collapse of Lehman Brothers. But this shock itself would not be nearly enough to explain what then happened.

Rather, as monetary economists such as Robert Hetzel and Scott Sumner have argued, monetary authorities then responded to this shock to prices by tightening policy at precisely the wrong time. In Spring and Summer 2008, the Fed failed to decisively lower interest rates in the face of declining economic activity. Goodspeed highlights the particular errors made by Alistair Darling in failing to agree to a US proposal to bail out Lehmans on the grounds that this would be importing the US contagion. Regardless of the rights or wrongs of that particular decision, Goodspeed’s account is consistent with those who see the crisis of 2008 as at least partly caused by a departure from the standard monetary policy procedures during the Great Moderation.

Prepared to get schooled in my Austrian perspective

It is worth asking how adherents of either FA Hayek’s Austrian business cycle theory, which says, effectively, that the bust is punishment for an unsustainable boom, or Hyman Minsky’s financial instability hypothesis, which says that highly financialized economies are inherently unstable, would react to his arguments.

The Austrians might challenge whether Goodspeed’s empirical tests map onto the theoretical objects they are meant to be testing. For example, Goodspeed’s data show that longer expansions don’t predict deeper or longer recessions. But the Austrian claim is subtler: it is comfortable with a short expansion generating more malinvestment than a long, sound-money expansion, if the short expansion is driven by massive credit inflation. The Austrian story is fundamentally microeconomic: it predicts distortions in specific investment decisions and the accumulation of these decisions across the economy produces macro-level effects. This is hard to test with Goodspeed’s data and without firm-level data on investment and capital decisions, it seems like the two views risk talking past each other.

The Minskyites would say that Goodspeed had proven them right. Goodspeed acknowledges that recoveries from a financial crisis or credit crunch tend to be slower. But it isn’t apparent from his framework or Friedman’s plucking model why this should be the case. If financial recessions are qualitatively different from other types of recession, this suggests that the state of the financial system at the time of the shock matters, meaning that Minsky’s concerns about financial fragility cannot be dismissed.

The data that Goodspeed has assembled is impressive but it covers just two countries. The experience of a broad set of countries might reveal still more of a role for financial overextension or capital market distortions. These responses notwithstanding, Goodspeed does pose important challenges for adherents of either Hayek or Minsky. If the empirical data Goodspeed offers is not an adequate test, then it becomes incumbent on them to at least propose tests which would offer a fair hearing for their theories. If they cannot do that, their theories risk becoming more metaphysics than economics.

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An end to boom and bust?

So, does Goodspeed’s book succeed in smiting the myth of the boom-bust cycle? Without doubt, he lays to rest many suppositions or beliefs many have about business cycles. The book is a great read and packs a lot of analysis into its 200 pages. The datawork of the book is itself an important contribution. While I don’t see Recession as the final word on this topic, readers will update their priors about the extent to which shocks to the economy such as the 2026 US-Iran conflict have been the key drivers of many economic downturns. In contrast, plausible and intuitive accounts that both non-specialists and specialists alike have offered for an endogenous business cycle, where booms sow the seeds of eventual busts, struggle to find support in his data.

Personally, Recession strengthened my prior beliefs that policymakers simply don’t have enough information to even distinguish between a robust expansion and a speculative bubble in real time, let alone the tools to safely tame any bubbles that they did find. Rule-based monetary policy, which allows market participants to form stable expectations about what its response will be, while still allowing flexibility in the event of shocks, might be the best we can hope for. Here Goodspeed’s advice is sensible: policymakers should first do no harm before thinking that they have the ability to entirely tame the business cycle.

Mark Koyama is professor of political economy at the Hamilton School, University of Florida.

Hard Drugs is a podcast from Works in Progress about medical innovation presented by Saloni Dattani and Jacob Trefethen.

Timestamps:

00:00 Introduction
05:08 Our favourite parasites
10:12 How to invent a vaccine during your PhD
34:18 Why is it called the R21 vaccine?
37:32 Moving from the bench to billions of doses
41:43 The vicious life cycle of malaria parasites
46:15 Malaria research IN MICE
53:03 The murderer in malaria research
55:51 Would you volunteer to get infected by malaria?
1:08:21 Why did the first malaria vaccine take so long?
1:18:26 Could we have had the vaccine sooner?
1:40:48 Vaccine versus vaccine: which one’s better?
1:46:53 If we did this again today, could we make better vaccines?
2:04:55 Conclusion and our reasons for pessimism and optimism

You can watch or listen on YouTube, Spotify, or Apple Podcasts.

Saloni’s substack newsletter:

https://www.scientificdiscovery.dev/

Jacob’s blog:

https://blog.jacobtrefethen.com/

Transcript

Saloni Dattani: I read that if just a single parasite makes it to the liver, it can cause an infection. Is that true?

Katharine Collins: Yeah, that’s right. And I think that’s the really tough challenge with Malaria.

Jacob Trefethen: The reality of this problem is the hardness of it is set by nature, and nature is a vicious test setter.

Katharine Collins: Adrian asked if I wanted to stay on, this was the PhD project that he pitched to me. I thought it sounded quite interesting to make a new vaccine. There was a lot of iteration. The first time I saw the particles under electron microscope that was really exciting.

Saloni Dattani: Would you participate in the challenge trial?

Katharine Collins: I would love to, but I really hate needles. I have to lie down. Otherwise I might faint. It’s kind of ironic for a vaccine developer.

Jacob Trefethen: There are people like Katharine Collins who invent entirely new vaccines that are now gonna be used by millions of children. You may know one of these people. You may become one of these people in the future.

Saloni Dattani: Malaria kills around 600,000 people a year. Most of them are young children in Sub-Saharan Africa. It’s caused by a parasite, not a bacterium or virus, and it’s spread by a mosquito. Until recently, the only control measures were insecticides and a handful of anti-malarial drugs. But in the last few years, we finally got effective vaccines.

Jacob Trefethen: Two malaria vaccines have now received WHO recommendations and are being rolled out across Africa. And for the first time ever, a human-infecting parasite has a vaccine.

Saloni Dattani: Getting here took longer than it should have. The first malaria vaccine was developed and tested in the nineties, but it’s spent 23 years in clinical trials and pilot tests before it was licensed and rolled out.

Jacob Trefethen: So in this episode, we’re going to cover the science of why malaria is so hard to vaccinate against, how the vaccines actually work, why it took so long, what we can do to speed up the rollout now, and what even better vaccines are being tested now for fewer doses and longer durability in the future.

Saloni Dattani: Today’s episode is special because we’re joined by Katharine Collins, who co-invented the second malaria vaccine during her PhD, and she can tell us what it was actually like from the inside. Welcome to Hard Drugs, hosted by me, Saloni Dattani, and Jacob Trefethen.

Okay, so we have some news today, right? Because Jacob, you have started a new job. Could you tell us about what you’re doing now?

Jacob Trefethen: I’m gainfully employed. I’m working at a new foundation making grants to science still, but from a different vantage point. It’s the OpenAI Foundation and we have been getting started in science, so it’s kind of exciting, a little bit different than my previous job which was at Coefficient Giving. And the previous job was quite fun. But you’ll have to ask around what my reputation was there, for example, Katharine, what was I like back then?

Katharine Collins: Jacob, you were the best manager I’ve ever had.

Jacob Trefethen: No no, we can’t include that! No, no. Expulsion! No, my biggest difficulty of changing jobs is that I don’t get to work with some of the wonderful people I worked back at Coefficient Giving with, like Chris Somerville, Ray Kennedy, Heather Youngs, Rafael Dib, Douglas Chukwu. Oh gosh. So many people, Aisling Leow. And guess who? Katharine Collins. Now the good news is that Katharine at least is here today.

Saloni Dattani: So Katharine is joining us from Coefficient Giving as well, and is a very special guest on today’s episode because she co-invented the second malaria vaccine.

Jacob Trefethen: Now we are lucky at Hard Drugs to have listeners around the world, and that means I’m going to start here with some insight into the British psyche. For those listening from other places, we have a guest on today who is an inventor and she’s also British. That means that she’s very reticent to take credit for things, even things she invented, so it took a lot of cajoling to get her onto this episode, though we knew if we could pull it off that our listeners would love it.

So I am very grateful for the willingness of our guests to be cajoled, but I should say upfront, as part of our ability to pull it off, that there are many other people involved in the story of malaria vaccines and of R21 in particular, who we won’t get to have on today, who took forward the vaccine into clinical trials, who did all the work to make sure it could get approved and used by kids around the world. So that’s my proviso, that’s the trade we had to make with our world famous inventor. With that in mind, enjoy.

Saloni Dattani: So I have a question for both of you, which is, do you have a favorite parasite?

What I didn’t realize until recently was that fungi and plants can also be parasites. And so a parasite could be a single celled organism. It could be an animal like a mosquito, vampire bats, hookworms. Or it could be fungi like the ringworm fungi. Or it could even be a plant, like mistletoe is a parasite.

Jacob Trefethen: What?!

Saloni Dattani: Yeah, mistletoe is a parasite. It attaches to other trees and extracts water and nutrients from them.

Jacob Trefethen: Gosh. And here I was. Okay. I think I have two answers. You brought up hookworm. Hookworm’s one of my answers, tape worm’s another one of my answers. I mean, tape tapeworms disgusting, obviously, but you just have to be impressed. They get so large.

Saloni Dattani: How large do they get?

Jacob Trefethen: Like, I don’t know, probably miles long. Joking.

Saloni Dattani: Wow.

Jacob Trefethen: They get feet long for sure. And maybe meters. I mean, I just think that’s crazy. It’s obviously gross, but luckily hookworms aren’t gross at all. All they do is hook onto the side of your gut and suck your blood. They come up, they sort of get up through your foot, sneak - their whole life cycle’s insane - they eventually get down into your gut and hook onto it and start sucking your blood. I mean, that’s pretty impressive.

Saloni Dattani: Is that why they’re called hookworms? Because they hook onto your gut?

Jacob Trefethen: You know, I’ve never thought of that. And the answer is probably yes, but I don’t know.

Saloni Dattani: And then are tape worms called that because they look like tape?

Jacob Trefethen: No, it’s actually ‘cause on the underside, they are sticky.

Saloni Dattani: Oh, wow.

Jacob Trefethen: That’s a joke. Sorry. That’s a joke. That’s a joke.

Saloni Dattani: Oh, you tricked me!

Jacob Trefethen: First trick of the episode!

Saloni Dattani: Okay. My favorite parasite also, well, I’m not impressed by this, I’m just so horrified by it that I have decided it’s also my favorite. And it’s Guinea worm, which is so horrible. And people ingest the worm larvae when they drink contaminated water. And the larvae get into your stomach, they get through your gut, and then they grow into worms that can reach up to a meter long. And they kind of crawl through your connective tissue and your joints, and then slowly erupt out of your legs - usually out of the skin, near your legs. And the emergence is also very slow. And the way that you remove the worm is by slowly winding the worm around a small stick, and if you go too fast, the worm snaps and dies, and that causes severe inflammation in your body.

Jacob Trefethen: That sounds like it was invented by Jigsaw from the series Saw as a patient to someone who was impatient or something. Okay, well thank you for that.

Saloni Dattani: Wait, wait, wait. The good news is though, we’ve almost eradicated it. Isn’t that great? So it used to cause like a million or more cases per year in the 1980s, and it turns out just cleaning up the water, filtering drinking water, or telling people not to drink from stagnant water can help prevent infections.

Jacob Trefethen: Do you know how near eradication we are?

Saloni Dattani: I think there were 10 cases reported in total last year.

Jacob Trefethen: Wow!

Katharine Collins: Wow. That’s incredible.

Saloni Dattani: Yeah, so from millions per year to 10. What about you Katharine?

Katharine Collins: Yeah, mine’s really boring. Mine’s the malaria parasite. I can’t say anything else after studying it for two decades.

Saloni Dattani: Yeah, it would be really surprising if you said something else.

Jacob Trefethen: Yeah, it would kind of be like adultery or something.

Saloni Dattani: In this episode we’re going to talk a lot about the two malaria vaccines that have been rolled out. The first one is called RTS,S and it was developed in the 1990s. The second was R21, it was invented by Katharine Collins, who’s here with us today, and it was based on the first one. So those are two names that we’re gonna refer to throughout the episode. RTS,S, the first malaria vaccine and R21, the second malaria vaccine.

I guess it’s easy to remember because the second one has two in it, R21, but just in case that is confusing; those are the two names that you’ve gotta remember. RTS,S, the first malaria vaccine and R21, the second.

Maybe let’s start with how you got into malaria research in the first place. What drew you into the field? Or how did you get into vaccine research?

Katharine Collins: I had done my undergraduate and my master’s degree in basic research and not in global health. I did various projects in different disease areas, but it was really about trying to understand the fundamentals and different signaling pathways and things like that. So I think one of my projects identified a protein interacted with another protein in a pathway. And while that was cool, and I loved science and it’s definitely where I’m supposed to be, but it I didn’t see how that was gonna have any direct impact on health in the near term.

I actually started looking for jobs, or how I could have an impact in global health, or how I could transition from science into global health work, and it wasn’t really clear. And then this job was advertised at Oxford University to work on malaria vaccine trials. And I thought, wow, that’s global health. I should just take that job, and or apply for that job, and that may open doors. And so I did. And I really loved working on malaria. It was instantly something I was really passionate about, really motivated to work on. It’s just a fascinating parasite.

So the job was a research assistant on malaria vaccine trials. So the Jenner institute at Oxford, where Adrian Hill’s group that I joined, they were testing a number of different candidates in malaria trials. And my job was to help coordinate those trials and to do all the immunology in the background.

Saloni Dattani: And then how did that turn into inventing a new vaccine?

Katharine Collins: Yes. Well, after being there for about a year, Adrian asked if I wanted to stay on, and do a PhD. The project idea was that Adrian had developed a vaccine that targeted the malaria parasites, whilst they were in the liver. It’d been shown to protect some people against infection, but it was quite a low level, I think it was 20% efficacy. So the idea was to combine this liver stage vaccine for the vaccine that could also prevent the malaria parasites before they get to the liver. So stop them invading the liver.

And the leading vaccine at that time targeted the parasites before they invaded the liver, and this was a circumsporozoite based vaccine called RTS,S, and it was developed by GSK. So he wanted me to work on making a newer version, an updated version of that vaccine.

Saloni Dattani: That’s so cool. I feel like compared to - so my PhD was very boring in comparison to this, and it makes me think that there’s actually -

Jacob Trefethen: Wait, Saloni, did you not invent a vaccine in your PhD?

Saloni Dattani: I know, I feel like people should know upfront that some PhDs are better than others. You know, some fields are better than others. So who else was involved in this? Did you have mentors, collaborators, rivals, or enemies?

Katharine Collins: I worked fairly alone in the lab. I did have a few people that were supporting the work as well. So my PhD supervisors were Adrian Hill and Sarah Gilbert. There were also a couple of postdocs and technicians and PhD students that helped me with various parts of the project over the years. For example, someone actually helped me vaccinate all the mice that we used for the preclinical experiments. And then I did the immunology myself.

Saloni Dattani: And Sarah Gilbert is the inventor of the AstraZeneca vaccine, is that right?

Katharine Collins: That’s right. Yeah.

Saloni Dattani: For COVID. Got it.

Katharine Collins: Yeah.

Saloni Dattani: And rivals?

Katharine Collins: Rivals, well, oh, you’re asking the good questions. I guess in the field at the time, there were lots of people trying to develop a malaria vaccine. I guess there was competition between the different groups to see who would get there first. And whilst I was working on it, RTS,S hadn’t crossed the finish line, but it was obviously way, way, way further ahead in development. So the expectation was that that vaccine would move forward and get approved first, and then R21 may follow.

Saloni Dattani: Right. And by that point, had the RTS,S patent already expired?

Katharine Collins: Yes, actually that’s right. So if I remember correctly, it was due to come off patent. And interestingly, that was essentially the starting place for learning how to make R21. So I reviewed that patent, I looked at how they’ve made RTS,S, and then I made a plan for how to go about making R21.

Saloni Dattani: Did that have enough information for like? What was that like?

Katharine Collins: So RTS,S is actually made with a lot of a protein on the surface of the Hep B virus. This is the Hep B surface antigen and that was needed to make it form the virus like particle, but it had quite an excess of Hep B surface antigen. So it’s actually a really good Hep B vaccine, and not a terribly good malaria vaccine. So my project was to see if we could remove some of that Hep B and actually make it a better malaria vaccine.

And we had established a plan for how we’re going to get there. So initially we wanted to just replicate the RTS,S process in the lab and then try a few different things to see if we could get the particle to form without this excess Hep B surface antigen. One approach was actually to just try and chop out some of the malaria protein out of the vaccine and remove some of the T-cell epitopes, which were in there, and a few other bits as well, and see if the smaller protein would be more able to form particles on its own. The other way was just to try and reduce the amount of extra Hep B that we were adding and see if it could form particles on its own that way, by using some of these newer yeast expression technologies to grow the protein and new methods to purify.

I think RTS,S had something like a 12 step purification process at least in the patent, and that might not be what they used anymore. But I wasn’t really interested in trying to set up this 12 step new process in an academic lab. You know, I’m not a biochemist. So I essentially looked at their process to understand what they had done and why, and then developed a purification process using a combination of some of those old methods and some of the newer technologies.

Saloni Dattani: I feel like my immediate question is why didn’t the developers of the RTS,S vaccine do that? Like if there were various steps that didn’t need to be included.

Katharine Collins: Yeah, I mean, they probably did. I mean, when they first patented what they were doing, it probably had this multi-step process. Maybe they had different process they were using lots of different methods, so they patented the whole process and I’m sure they probably optimized that as they scaled up and improved their manufacturing.

Jacob Trefethen: I wanna just get a more of a sense of what it feels like to be in the lab alone, toying with different steps of purification, and how long were you - did you feel sort of lost versus actually, it worked pretty quickly and you got, once you saw in the electron microscope, you’re like, oh God, it’s actually gonna work. Was that pretty quick or you were there for months, years? You’re tinkering. What did the invention process feel like?

Katharine Collins: Actually, I think I was interviewed by someone a while ago and I, my recollection is that it was very quick that I kind of give it a go and it worked.

Saloni Dattani: Wow.

Katharine Collins: And then I thought, now I thought, is this true? And I went back to my lab notebooks and I had a look through like the electronic notebooks and I had a look through and it wasn’t that quick. There was a lot of iteration, a lot of optimization that happened with every single stage.

So we were using yeast to express the protein and grow the protein, and there were four different strains we were testing, and then for each different strain, we picked multiple different colonies, and I screened all of these different colonies first to find the best expressing colonies, and then I started to try and purify it, to purify them. And I probably used multiple different techniques until I got something that looked substantial. So it wasn’t that quick. So I think it was a long time ago now, so my memory’s a bit optimistic maybe?

Saloni Dattani: So am I imagining right that it’s like, you have the instructions-ish from the patent and then you’re trying out different options, like different versions of the yeast, different versions of the purification process, and at each step trying to optimize which is the best one to go forward with or something like that? Or is that not the right way to think about it?

Katharine Collins: Yeah, that’s just about right. There are a lot of newer technologies available for purifying proteins and particles, so it’s kind of a process of looking at which steps could be replaced by newer technologies and going for something that was more modern and simpler, where that was possible, and where there wasn’t a newer technology, we were sticking with that whole process as well.

Saloni Dattani: So you were at the Jenner Institute, is that right?

Katharine Collins: That’s right.

Saloni Dattani: Do they have just people working on many different diseases and like trying to develop vaccines against all of them, or are there some areas that they focus on? Or, are lots of people doing this during their PhD?

Katharine Collins: I think developing a vaccine was rare, fairly novel at the time, or quite rare. So not a huge number of people were doing it. There were three PhDs I can remember that developed a vaccine during their PhD and I was one of them, but there may have been others as well.

But in terms of the structure at the Jenner Institute, there were different group leaders, or PIs, that have their focus area, and the Jenner Institute was generally open to having new people join the institute. And if there was space, they did actually join the physical lab space as well. So we had work going on on multiple diseases at the same time.

Jacob Trefethen: Okay. So you’re, you’re tinkering, you’re tinkering, you’re tinkering, you look under the electron microscope and then you test something in mice and it protects them from malaria. Did it feel like a eureka moment at any points of that step, or was it just iteration? Iteration, feels good, feels a bit better, feels a bit better?

Katharine Collins: No, definitely a few eureka moments. I mean, the first time I saw the particles under the electron microscope, that was really exciting, especially when I had used the process that we didn’t think that was possible. So by removing all the excess Hep B, that was really cool when we could see those, and they looked very similar to the Hep B particles. So it was it was really reassuring that we were doing something right.

Then the next push was to move that into a preclinical study, to inject mice and see if we get an immune response, and then if we can protect the mice as well. And whilst I was optimizing the process, the yield was really, really low of the particles. And I tried to concentrate it and it wasn’t easy to concentrate. So we ended up injecting an incredibly low dose into the mice and it was like, well, we might as well, we have the product, let’s just see what it does. And then it protected all the mice.

And so that was really exciting. We had gone for this dose that was dramatically lower than any other dose we normally test in the lab. And the vaccine I think 10 times lower than any other dose that had showed for RTS,S being tested in mice and that it worked. So that was really exciting. That was the one of the really exciting moments. Yeah.

Saloni Dattani: That’s super cool because if you have a lower dose, you can vaccinate more people with the same amount, right?

Katharine Collins: Yeah, exactly. And a tenfold lower dose, that’s huge. That’s not half the doubling the number of people. That’s a dramatic increase. But actually at the time there wasn’t a lot of information on how well dose in mice would translate to humans and if it would actually result in a lower dose human vaccine. We did later find out that it was easier to scale up.

Jacob Trefethen: So, interesting how the practical constraints - let’s say it had been effective but you would’ve needed five times more product. Is it possible you would’ve just dropped this lead and focused on something else ‘cause you couldn’t make enough, or what would’ve happened?

Katharine Collins: No, I was really early on in the purification process, in optimizing that. So it was just that, it was just of luck. But we had gone in with such a low dose to begin with. Maybe we would never have got to the low dose, that lower dose, if we haven’t had that constraint on the concentration of the product.

Jacob Trefethen: Okay. So all of this is happening in your PhD, was that 2010 to 2014? Is that right?

Katharine Collins: Yeah, well remembered!

Jacob Trefethen: So we now know, with the benefit of hindsight, that R21 works in kids, in humans, and it protects babies against malaria. And that took time to prove out any clinical trials, and there was - to give a spoiler to the audience, the R21 vaccine was actually approved a couple years ago for wide use.

Along that journey, you finished your PhD and you started doing other malaria research elsewhere. Did you, when you finished your PhD in 2014, did you have a feeling that, oh, I just invented a vaccine that’s gonna get used by millions of people? Or did it feel more like, okay, I’ve proven out that this might work and I’m gonna pass it on, but it’s, we’ll see. Yeah. What did it feel like?

Katharine Collins: I think most people in the field were quite skeptical about R21 in the early days. They couldn’t really see the point in making a vaccine that was so similar to RTS,S. And the initial results, kind of backed that up, that there was reasons for that skepticism. It didn’t look very different in the preclinical work, in the mice studies, there wasn’t a really strong reason to think that this was gonna save a lot of lives, when there was already a vaccine that was very similar.

Saloni Dattani: But the dosing was very different, right?

Katharine Collins: It was, and I think this is a lesson for vaccine developers, right? At the time, everybody was quite negative about R21. But if you think about things like being able to reduce dose, making it simpler and easier to manufacture, even small increases in immunogenicity, if you add all of those benefits together, you end up with a product that’s easier to deploy, a lot cheaper, and maybe easier to manufacture. So it can really have an impact, without just making a dramatically better vaccine in terms of efficacy.

Jacob Trefethen: It’s sort of scary though, ‘cause I think I, as a outsider who has never developed a vaccine, if I had seen the results from preclinical tests in animals and the results said, well, we can’t distinguish that this is better from RTS,S, I probably would’ve killed it. And yet now we know that it is much cheaper to produce and it’s more manufacturable and it’s longer durability. I mean, so it’s sort of terrifying. What was in the system that allowed this one to actually go forward and now it’s reaching people. You know, is it as contingent as it sounds to me?

Katharine Collins: Yeah. You know, I think this was - all the credit goes to Adrian Hill for pushing it forward and really finding out what it could do in people, right? I think so many people would’ve dropped the vaccine at this point. And another difference that we haven’t mentioned so far is that R21 also used a more scalable adjuvant, and I think that’s quite important for the supply argument as well.

Saloni Dattani: An adjuvant is another ingredient in the vaccine that strengthens its immune response?

Katharine Collins: Yeah. Yeah, absolutely.

Saloni Dattani: Alright, and so these were different between the two vaccines, and the R21 adjuvant was cheaper to produce and easier to scale up.

Katharine Collins: Yes, absolutely. Yeah. The adjuvant used with the, with RTS,S is a GSK adjuvant. It’s also used in another product, and yeah, much more difficult to scale, and much more limited supply.

Saloni Dattani: I remember reading that it comes from - that adjuvant comes from the tree bark of a South American tree. Is that right?

Katharine Collins: Yeah. And that comes from the bark of a Chilean - I can never get the name, pronounce the name right, is a Quillaja tree (Quillaja saponaria, soapbark).

Saloni Dattani: Does that mean that you have to get that tree to get the adjuvant? Is that why it’s difficult to scale up? And how come the second one is easier to scale up if they’re both from these trees?

Katharine Collins: So the supply limitation is the availability of the trees, the raw material, and also the purification process. So if you imagine you’re purifying all these products from the bark of the tree, or from the tree, and if you purify and throw away a lot - a lot of it away, it’s gonna be more expensive and harder to scale. They’ve improved the ways they’re producing the trees, so supply is increasing and it’s gonna be less of a limitation moving forward. And people are also working on synthetic versions and special, not sure the right word, aquaculture style (hydroponics) growing of these, of these trees and different methods of harvesting from them to get the components.

Saloni Dattani: Is it like someone shaving parts of a tree off and then doing some other, like, how does this all work?

Katharine Collins: I’ve never seen anybody do it that, and that’s kind of how I imagined it, taking the bark off. But other thing I should mention is you have to like harvest most of the tree or you have to kill the tree and that was the problem, and so I think they’ve changed the way that they actually harvest from the tree so they can keep growing as well in some instances. So you don’t just have to - it takes 25 years to get the tree and then you cut it down.

Jacob Trefethen: So you’re looking at your lab notes, Katharine?

Katharine Collins: Yeah, it’s fascinating. I’m glad I kept really good notes. It’s really interesting.

Jacob Trefethen: Are they dated?

Katharine Collins: Yeah.

Jacob Trefethen: What date are you looking at?

Katharine Collins: Um, troubleshooting the purification process, 23rd of the third, 2011.

Jacob Trefethen: Whoa.

Saloni Dattani: Wow. What were we doing in 2011?

Jacob Trefethen: Yeah, 23rd of the third.

Saloni Dattani: I was in school.

Jacob Trefethen: I was inventing vaccines, actually, Saloni.

Saloni Dattani: You didn’t tell me that.

Jacob Trefethen: Yeah, I try to keep it private.

Saloni Dattani: So what happened on that day?

Katharine Collins: I tested a few different methods and then the result: aggregation seen in sample.

Jacob Trefethen: Okay. Bad.

Katharine Collins: Second purification attempt: reduce aggregation.

Jacob Trefethen: I love it.

Saloni Dattani: Do you have any, um... random comments in there? Do people put in computerized doodles? Emoticons?

Katharine Collins: No. Definitely not, emojis didn’t exist then, Saloni!

Saloni Dattani: No, but emoticons did.

Katharine Collins: LOL.

Saloni Dattani: XD

Jacob Trefethen: Aggregated again, LOL. Wait, so how many experiments are you doing? Is this like every day you have new entries?

Katharine Collins: Yeah, yeah, yeah.

Jacob Trefethen: Wow.

Katharine Collins: No, every couple of days. So I guess I’m gonna test this and then it takes a few days to test and then... results: aggregation seen in sample.

Saloni Dattani: ROFL. Are there images of the RTS,S or R21 under the microscope? Should we- we should include one.

Jacob Trefethen: Well if you are up for it - us including some screenshots might be kind of fun for viewers. Oh my gosh, no. Sorry. We have thank goodness. We have to include this.

Saloni Dattani: Wow.

Jacob Trefethen: This is so cool. Whoa. Okay, great.

Saloni Dattani: Wow. They’re so cute.

Jacob Trefethen: Okay, listeners, so we are looking at two images here. On the left it looks like spots on someone’s skin, maybe measles. So talk us through the left here. Katharine, what are we looking at? Those beautiful circles. Wow.

Katharine Collins: So those, that’s a transmission electron micrograph of negatively stained R21 particles.

Jacob Trefethen: Oh my gosh, that’s so clear. They’re so clean. They’re so circular.

Saloni Dattani: They’re so blobby.

Jacob Trefethen: I mean, just to restate some of, and correct me if this is wrong, Katharine, but part of the reason why having these circles that look like viruses is so useful is that our immune system is really good at attacking circular viruses. So is that a fair statement?

Katharine Collins: Uh, yeah. So they’re easier to recognize by the immune response, definitely. That’s part of the theory behind virus type particles.

What reading this has just really made me realize how much I was reinventing the wheel. Like if this was anybody else making it, or company making it, you’d have had an expert in purification diving into this that would’ve been able to, I had to do all the research myself.

Jacob Trefethen: Oh my gosh. Wow.

Katharine Collins: Yeah. And figuring it out.

Jacob Trefethen: That’s so cool!

Saloni Dattani: Yeah, that’s even cooler.

Katharine Collins: You know I did have support. There were other people in the lab that I’d go to for advice, and I talked to Sarah and Adrian, but I was often figuring it out by myself, or at least that’s how I remember it.

Jacob Trefethen: It’s astonishing because I tend to, sometimes I feel myself getting skeptical about patents in particular, where the trade that society is making with inventors is that if you publish in public how you did something, then we will give you exclusivity for 20 years to do whatever what you want. Sometimes I’m like, well, hold on. How much are you actually gonna be able to learn from reading that? They’re probably gonna hide whatever they can and to get away with it. And what, how can you learn something from reading? You need to see someone do it, but you’re telling me you literally read the patents and then you just kept plugging away until you’ve simplified and fixed all of the stuff.

I mean, that’s awesome. That’s a one person show. And I’m like, wow. So knowledge in public is a extremely big deal.

Katharine Collins: Yeah. I think I managed to get it to the point that we could make it ensure that it works. And then there was a huge amount of work that happened by others to turn it into a GMP grade process. And even then that was a simplified or a shortcut version to get to a GMP product that was done by the clinical biomanufacturing facility in Oxford. They did an enormous amount of work to produce the first batch and then Serum got involved and they used all of their knowledge and knowhow to probably dramatically change the process.

Jacob Trefethen: So I wanna pause on that actually, ‘cause it’s my day job is I’m a funder and then now your day job is, you’re a funder, Katharine. And one thing that comes out from this story that’s really interesting is that a lot of universities where a lot of knowledge is generated and science is done, do not have facilities to produce the vaccines that you could take into humans safely, whereas Oxford does. Is that a fair statement? And do you think that that allows for a knowledge generation loop, which is unusually productive?

Katharine Collins: Yeah, absolutely. I think that’s definitely one of the big advantages of being in the Jenner Institute. Adrian had set up this clinical biomanufacturing facility and that meant he could really quickly iterate, he could design something in the lab with a student designing it, and then transfer it to the manufacturing facility and quickly produce a small batch.

Saloni Dattani: Does that mean we should have more Jenner Institutes doing other - can you scale that to work on more diseases or is it just really hard to do that?

Katharine Collins: No, no, I think that’s the way - people should be learning from that model. I think it’s not cheap to maintain a facility like that.

Saloni Dattani: I have another question, which is, why is it called R21?

Katharine Collins: Uh...

Saloni Dattani: Is that a very complicated story?

Katharine Collins: Um.. I can’t remember.

Jacob Trefethen: What?!

Saloni Dattani: Wow!

Katharine Collins: Adrian came up with a name and I think I remember asking him, and I think he said it was a 21st century version of a repeat region vaccine. The repeat region is the part of the CSP protein that’s included in RTS,S and R21, and that’s what the R stands for in RTS,S.

Saloni Dattani: Well, maybe you should ask him.

Katharine Collins: Yes, right now.

Jacob Trefethen: Alexander, why is it called penicillin? God, I just can’t remember. I can’t remember.

Katharine Collins: I’ve got an answer.

Jacob Trefethen: Oh, we have an answer.

Katharine Collins: So Adrian said it’s the 21st century presentation of the CSP repeat vaccine.

Saloni Dattani: So your earlier answer was basically correct.

Katharine Collins: Yeah.

Saloni Dattani: That’s great. It’s so funny to me that you thought that you had made it up, but you actually remembered it correctly.

I have a similar but very different story where I thought that my earliest memory ever was made up for a while and then I found video evidence of it being true. So my, so my earliest ever memory is of us, my family, going to the Grand Canyon and at the Grand Canyon I had a pink balloon and the only thing I remember is that I had this pink balloon and I dropped it down the Grand Canyon. And I remember mentioning this to a bunch of people afterwards and then eventually I was like, did that actually even happen at all? Like that just sounds like such a crazy story. Like why would I drop a balloon, that doesn’t sound like me? Like I was two, but it still doesn’t sound like me. I wouldn’t do that.

And then last year I found a video that my dad took of this whole trip that we took to the US when I was two. And in the video there’s a segment where I’m holding the balloon, the pink balloon. And in the background, you can hear my dad telling me to drop it down the Grand Canyon.

Jacob Trefethen: That is pretty much a clincher.

Saloni Dattani: I was like, wow. I finally feel so validated. But also it wasn’t me. I didn’t, I wouldn’t, I was just listening to my dad.

Jacob Trefethen: There’s a lot to unpack there.

Saloni Dattani: I was like, why would I litter?

Jacob Trefethen: Oh... Right?

Saloni Dattani: That’s not like me at all!

Jacob Trefethen: It’s all adding up now.

Saloni Dattani: Before we move on to the science of malaria, what happened after you invented the R21 vaccine and what happened after you finished your PhD?

Katharine Collins: Yeah, so after the vaccine was made, we then first tested it in a mouse model of malaria, and we showed that we could protect the mice against malaria, and this worked best when you used the right adjuvant. And I did a large number of studies in mice to really look at the dose that was needed, and that’s really where my PhD ended.

So once I developed the vaccine and we had shown that it worked in mice, Adrian was moving this forward into clinical trials. So I had the opportunity to stay at Oxford and continue working on the vaccine as it moved into the human clinical trials. But I’d finished my PhD, so I decided I wanted to move on and broaden my experience and learn some new skills.

I moved to work with James McCarthy in Brisbane and he had set up a model where you could infect people with malaria - this was a challenge trial - and evaluate the efficacy of drugs. And so I was working there on those studies and also developed a new challenge model as well. I then moved on to work in - on projects in the field, understanding malaria transmission more fully, and looking at interventions to interrupt malaria transmission. That work was mainly based in Burkina Faso and it was based out of a lab in the Netherlands.

Saloni Dattani: Hmm. And then how did you get from there to Coefficient?

Katharine Collins: Jacob hired me.

Saloni Dattani: Oh, wow!

Katharine Collins: No, I mean, it’s an interesting story. I wasn’t particularly looking to leave academia. I was loving the work I was doing, but obviously Coefficient Giving, or Open Philanthropy at the time, is a really exciting funding organization that’s quite innovative.

Saloni Dattani: And what happened to the vaccine after that?

Katharine Collins: So Adrian then took the vaccine forward into clinical trials and there were lots of other people involved in the development of the vaccine. All the investigators in Africa, the clinical investigators in Oxford, and also the Serum Institute who licensed the vaccine from Adrian and from Oxford, and worked with the team there to carry out the phase three trials and then obviously develop the final product.

Saloni Dattani: I think it’s sort of underappreciated just how many people work on these, like actually getting the testing and scaling up to people. It takes so many people and it makes me think also that it’s not just about funding, it’s also the number of people working on things like this.

Katharine Collins: Yeah, I mean, absolutely. I think this large number of people it takes is really important for me. I just played a very small role at the beginning and there’s such an enormous number of people that made this vaccine get to the finish line and have the impact it’s gonna have.

Jacob Trefethen: I think it’s time to get into the science of malaria. But before we move on, I’ll just, my reflection on this segment, is there gonna be a lot of people listening who - basically science nerds - who sometimes it may feel like the big things left to do in science while they’re all behind us. That’s why Saloni and Jacob talk about Gaston Ramon. You know, we’ve already had all these antibiotics invented. Oh, well and so, wouldn’t it have been cool to live back then and.

I think that’s entirely the wrong orientation. You know, there are people like Katharine Collins, who in 2010 to 2014, invent entirely new vaccines that are now gonna be used by millions of children. And yet, and she is right here. We got to talk to her right now. And you can too! You can work on important problems and there are many people who can benefit! And it’s just, it’s almost scary how sensitive to particular scientists at particular times a lot of this stuff is, and it’s very inspiring too.

So, Katharine, thank you so much for joining us.

Katharine Collins: Great to be here.

Saloni Dattani: All right, so how come it took so long to develop a malaria vaccine? And why are malaria vaccines so much harder to develop than vaccines against other diseases?

Katharine Collins: Malaria is caused by a parasite, which is quite different to a bacteria or a virus, it’s a lot more complex. And the malaria parasite actually moves- it has a really complicated lifecycle, and it moves through at least three different stages.

So it’s first injected into the body by the mosquito, and then travels from your skin into the liver. It develops in the liver for about seven days and then bursts out into your red blood cells in your bloodstream and it invades your red blood cells. The symptoms are caused by the parasites invading your red blood cells and then destroying them, and then it does this many times. Each cycle it produces many more parasites and so it invades many more red blood cells and that’s what causes the anemia. And then the parasites within the red blood cell, those infected red blood cells, can adhere to different tissues and that can cause problems for different organs as well.

Saloni Dattani: I read that if just a single parasite makes it to the liver, it can cause an infection. Is that true?

Katharine Collins: Yeah, that’s right. And that, I think that’s the really tough challenge with malaria, but you know, you can get hundreds or thousands of sporozoites from one bite. But I think you - we don’t think it’s many thousands, and you could have some immunity that gets rid of a lot of those, but just one has to get through the defenses, and that gets into the liver, and then in the liver they actually replicate so that it doesn’t stay as one parasite. It turns into many, many merozoites, and they then burst out of the liver cell and start invading blood cells. By the time you get to the blood, you’ve got many parasites again, and very quickly, they replicate and produce more.

Saloni Dattani: That makes me think, both of the vaccines are - the efficacy is much lower than many other vaccines. But if I think about it this way, that they’re trying to prevent even just one parasite from getting to the liver, then from that perspective, it sounds like they’re actually really effective at doing that, at least.

Katharine Collins: Yeah. Yeah, it’s a very high bar. Exactly. Yeah.

Saloni Dattani: Well, that’s terrifying. Just one parasite. So all of that makes it much harder than, let’s say, measles or flu, which are caused by viruses and where the vaccines are produced by killing or attenuating the virus.

Katharine Collins: So there are many reasons that it’s difficult to make a vaccine against malaria parasites. First is this really complex life cycle and then also the malaria parasite has been around since Egyptian times. So it’s evolved to evolve with the human immune system for a really long time, it’s learnt how to evade our immune responses really well. So every time our immune system is managed to attack the malaria parasite, or find a good way to get rid of it, it’s then evolved another mechanism to keep surviving.

There are lots and lots of redundant proteins in the parasites. So you think you can block something that’s important and then it just switches on a different protein instead and uses that. That’s been one of the reasons it’s been quite tricky.

Saloni Dattani: So the malaria parasite has a very complicated lifecycle. Does it, when it goes through these different stages, does it also change shape? What actually happens?

Katharine Collins: Yeah, it looks completely different at each stage. It starts with what we call a sporozoite that looks like a little eyelash when you look under the microscope, it’s a curve shape. Then when it invades the red blood cell, it’s called a merozoite; it’s like a round, almost cone shape. But not only does it look different, but it has different proteins on the surface. So a vaccine that works against one stage isn’t necessarily gonna work against another stage.

Saloni Dattani: Right. And that’s one thing that’s hard about developing a vaccine. Like, how do you pick which protein to use in the vaccine?

Katharine Collins: Yeah, absolutely. Yeah. You know, the approach is normally to look for a protein that’s really important. So you find out something that’s probably something that’s involved for an invasion or adhesion. So people would look at knocking out different proteins and seeing whether they’re critical for development. If you find something that’s essential, then that’s also gonna be a good target. And the other way is that people look for what’s most abundant on the parasite, or the pathogen in general, but that can often be a decoy. That’s an interesting one. Like sometimes the things that were abundant on the surface are there to misdirect the immune response.

Jacob Trefethen: Okay. So you’re taking these samples from mice and you’re learning a lot, it sounds like, from mice. So firstly, thank you to our mouse brethren. And Saloni, I know that you have written a lot about, in one of my favorite pieces that I read two years ago was about the invention of the malaria vaccine. And you wrote about how mice were originally domesticated in some sense, to be models for malaria. So how did that work?

Saloni Dattani: It starts out before mice, I think there were some animal models in the late 19th century, the first animal models for malaria were birds. And the way that scientists proved that malaria was spread by mosquitoes, was by using sparrows and infecting them with the blood of an infected human, and seeing whether it would transmit. And I think it seemed like there were some, there were a bunch of different birds that could get infected by malaria, but they just didn’t translate that well to what would happen in humans? So people tried developing drugs, like testing new drugs, in bird malaria, and they seemed to work there, but in humans they didn’t; they caused various side effects. And so they were trying to find different models.

There are also two other types of models used in between. One was monkeys; monkeys are really expensive and difficult to work with. And then the other was humans, right? Because in the 1920s, if I remember right, humans were used as a model to study malaria because people with syphilis could be treated by infecting them with malaria, because the bacteria doesn’t survive after the fevers that are caused by malaria.

Jacob Trefethen: It’s a bit like solving your aching thumb by chopping it off to me, but, okay.

Saloni Dattani: Would you rather get syphilis or malaria?

Jacob Trefethen: Ah, the eternal question. And my answer is I’m glad that we’re in the 21st century.

Saloni Dattani: Syphilis seems like it was really scary before antibiotics.

Jacob Trefethen: Yeah.

Saloni Dattani: Especially if you got neurosyphilis.

Jacob Trefethen: Yeah. The bacteria would worm its way up into your brain and stick around for years or decades.

Saloni Dattani: I’ve been to a medical museum in London called the Hunterian Museum, and they have exhibits of people who had syphilis at the time, and their skulls are filled with holes from the infection. It’s very scary.

Jacob Trefethen: Well, that’s a wonderful tangent, but I was wondering about, I was wondering if we could talk more about mice.

Saloni Dattani: Right. Okay, so mice, so we have the bird models that aren’t great. You have the monkey models that are really expensive, and the human models, which once you could treat syphilis with antibiotics, there was no longer an audience of people who were interested in being infected with malaria deliberately. So the next question was, let’s try to find a different animal model. Let’s try to find a rodent that can be infected by malaria.

And I think it took quite a while to find any rodents that were infected by malaria. There were two researchers that finally figured it out. I think they were two Belgian researchers who were in the Congo, and they were doing tests to see which animals mosquitoes had bitten, and that ruled out various animals nearby and it didn’t rule out rodents. So they thought maybe there’s something here, and they continued trying to look for rodents that were infected by malaria. And eventually they found a thicket rat (Grammomys dolichurus) that was infected with it.

This thicket rat was infected by a different strain of malaria called Plasmodium berghei, and that seems to be much more - like that’s just much easier to work with. I think at first, they also, they couldn’t replicate the whole lifecycle of the parasite in those thicket rats, because there were certain stages of the parasite’s lifecycle that needed a cooler temperature.

So when I was reading about this, it seemed like it took 16 years for them to work that out. It was several things. So the original research was just post World War II and then in the 1950s, various countries did large-scale malaria elimination programs and cut down on malaria research. And so all the people who were working on that stopped working on, or many of them did, stopped working on it, and then only then got interested again in it during the Vietnam War. So I think it was like partly that and partly just, historical contingency of which parasite they discovered. And did they look at their own lab notes from 16 years ago to see what the temperatures were in that forest where they found the first malaria infected rats. Goes to show how important lab notes are.

Jacob Trefethen: Sounds like mice can tell you something, and took a long time to get to a model that worked in the lab. But they can’t tell you everything, ‘cause mice aren’t humans, and they might mislead you sometimes.

Saloni Dattani: A mouse has never told me anything.

Jacob Trefethen: Speak for yourself. Well, I mean, that brings me onto a question I have, which is: are mice enough? If not, what’s the next step?

Katharine Collins: Well, so you could use non-human primates, but they aren’t the perfect model for malaria. There’s only one that gets infected, that could be affected with human malaria parasites, and so none of the models are perfect. So people don’t often do a lot of non-human primate work, but they can be used to answer specific questions. So then your next model is obviously humans.

Jacob Trefethen: Mm-hmm.

Saloni Dattani: And that makes sense because if you want to make a vaccine for humans, you probably wanna test it on humans.

Jacob Trefethen: Okay. So we’re segueing to humans. How did that begin? What were the first experiments in humans?

Saloni Dattani: So the first ones were the ones that were treatments for syphilis in the 1910s to forties. And then when penicillin was developed, it wasn’t necessary anymore. But then, after that, there were various experiments in prisoners in different parts of the US, I think. And what was interesting to me when I was reading about this was that - so the prisoners were volunteering for these experiments, but some of the prisoners were not just subjects in the experiments. Some of them were actually technicians and researchers, who helped in the experiments as well.

And one of the most famous ones is Nathan Leopold. Do you know, do you recognize that name?

Jacob Trefethen: Not me.

Saloni Dattani: So he was a - I know this because of a film that was inspired by his life. He was a murderer who murdered a friend, I think, a classmate of his. So with a friend of his, they both kidnapped and murdered one of their classmates while they were students at the University of Chicago. And while they were serving their sentences, Nathan Leopold, one of them, enrolled in one of the malaria research studies. And after that, he then became a technician, he started doing - like he was actually operating research as well.

And the reason that I know this is because that story inspired the Alfred Hitchcock film Rope, if you’ve seen that. Have you seen that?

Jacob Trefethen: I have not seen that.

Saloni Dattani: It’s a very good movie where, I mean, it’s the same-ish story. They’ve kind of changed what actually happened. But in the film, these two students decide to kidnap and kill one of their classmates for fun, essentially. And then they store him in a, what is it called? Like a box in their apartment. And they then host a party just hours after this murder, to basically show the fact that they could get away with it. And the whole film was taken in 10 shots, like 10 long segments that are just stitched together. And it’s an incredible film. Like very, very well made.

Jacob Trefethen: Wow. Okay, so...

Saloni Dattani: So how does this relate to malaria? Many prisoners would’ve been part of this malaria research in the mid 20th century, and they contributed to our understanding of various parts of the transmission process, I think.

And since then, we’ve continued studying malaria in humans in a type of study called a challenge trial, where you deliberately infect volunteers with mosquitoes with malaria. So I think in the past it was many mosquitoes per person and now it’s just five bites. Is that right?

Katharine Collins: Yeah. I guess there was work to improve and standardize the modern challenge trials. That’s where they landed on five mosquito bites that could reproducible infect the volunteers.

Saloni Dattani: So what happens in one of these experiments do you sit with. Do you put your hand into a jar that’s filled with mosquitoes or what? What’s the what’s it like?

Katharine Collins: No, the process is quite dull, actually. I guess you normally have to travel to somewhere where there’s a facility. And because these sort of things do contain mosquitoes infected with malaria, they’re usually under high containment, so then the volunteers need to pass into a contained containment area, and then a cup is often passed through a window into that room and they have a cup - it’s like a coffee cup - and it has gauze on the top and the mosquitoes will be inside. The lid will all be taped shut so they can’t escape, and then you place your arm on top of the cup and allow the five mosquitoes to bite you and say, a few minutes for feeding. And then they’ll have a look and see how many of those mosquitoes have fed on you.

So what they do is they take the cup of mosquitoes, they then look at them, each mosquito individually under the microscope. You can see whether it’s blood fed, because it’s got blood in its abdomen, in its belly. Then if it’s got blood in the belly, then look at the salivary glands and check that it had sporozoites in the salivary glands. And so you’re looking, five mosquitoes in that cup that fed. But so they count up how many did feed, then they’ll put more mosquitoes in a cup. So if you only need one more infected bite, they’ll put one more mosquito in, and then you can be bitten by that mosquito. If that one doesn’t bite you, then they take that one out, put another one in until you’ve had five infected bites.

Saloni Dattani: Oh, I see. That’s probably the most disgusting coffee cup I’ve heard of.

Jacob Trefethen: Not so tasty. These, these days, are the people who are putting their arms out, are they mostly undergrads somewhere or, yeah, what, who are the volunteers?

Katharine Collins: I think it depends where you do the trials. I think in Oxford it’s typically lots of students, but other people as well. But you, the students are often quite willing to get involved.

Jacob Trefethen: Legends.

Saloni Dattani: I saw a picture where it wasn’t a coffee cup, but it was a cup noodle box container.

Katharine Collins: Yeah or soup. And they’re often called, used as soup cups. They’re like, or ice cream containers, they’re that kind of large, larger size that would be used. That’s usually used to hold a lot more mosquitoes. It would’ve been a different study, probably.

Saloni Dattani: Oh, I see.

Jacob Trefethen: So you, in those challenge models, you are giving some of the students or other volunteers injections of vaccine, some of them placebo, and then they’re getting bitten.

Katharine Collins: Exactly. That’s right. Yeah.

Jacob Trefethen: Okay. And then what do you, how do you figure out the truth afterwards? You’re just seeing which one of them faint, or?

Katharine Collins: Once you’ve been challenged, you start following them up a couple of days later. So the parasites will be in the liver for seven days. You don’t have to monitor them too carefully in the beginning, but you still monitor them and check the parasites haven’t got into the liver, into the blood from the liver. And then you are monitoring quite closely from liver emergence. So once the parasites are entering the blood or you’re expecting them to, you can see them once or twice a day, up to twice a day, take their blood.

You can look under the microscope for the parasites, see if they’ve got the parasites in their blood, and you can also do molecular diagnostics as well, like PCR to look - it’s a much more sensitive method. So you can detect the parasites in the blood before they will make the people sick. And so you can treat them quite quickly and then you’ll know which volunteers have been protected and which haven’t.

Saloni Dattani: That’s very cool. And then now there are methods that are beyond mosquito bites. People directly inject volunteers with the parasite, is that right?

Katharine Collins: Yeah, there’s a couple of models. So the other models you would inject either cryopreserved sporozoites, that’s that first stage that goes into the liver. You can inject those intravenously, you can ship those anywhere in the world to do that type of study. The other model is injecting blood stage parasites. So both of these are greats and they can answer different questions.

Saloni Dattani: And these two vaccines, the RTS,S and R21, are for the first stage. So you’d want to be able to test it against the natural infection with the mosquito bite.

Katharine Collins: Yeah, definitely.

Jacob Trefethen: Saloni, I’ve got a question for you.

Saloni Dattani: Oh, what’s the question?

Jacob Trefethen: Would you have volunteered for one of these human challenge trials?

Saloni Dattani: I was thinking about this back when you asked who was volunteering in the studies because as I have described in the first episode we did, I once volunteered for an HIV vaccine trial, phase one trial. And I enjoyed it and I think I probably would.

I think the difficulty is that back when I did that, I was a student and I was very bored and I didn’t have anything to do in my free time anyway and I didn’t have a social life. And now I have a lot of stuff going on in my life, like I just have a lot of work.

Jacob Trefethen: By the way... congratulations.

Saloni Dattani: Thank you.

Jacob Trefethen: Me, I’m still alone, but I’ll get there.

Saloni Dattani: But I was thinking like, there are lots of different types of diseases that you might do a challenge trial for, right? Like you could do one for rhinovirus or like flu or cholera or I don’t know, what else is there - Shigella maybe, or something like that. And all of these sound very unappetizing to me. Like, I wouldn’t wanna do a challenge trial for any of those. Like the flu, the respiratory ones, I’m like, that’s just boring and someone else is gonna do them anyway. Probably the, that’s -

Jacob Trefethen: Amazing. I’m not gonna do that one. It’s boring. I want something harder!

Saloni Dattani: Right. And then the other, like cholera and shigella, I mean, diarrhea... I don’t want, that sounds horrible. And also I feel like I’m quite small and if I lose too much weight, there’ll be none of me left, and so I can’t do that one. So what I would do is a more dangerous pathogen, I think.

Jacob Trefethen: Okay, nice. Is malaria dangerous enough for you?

Saloni Dattani: That would make it worth it. I think so, yeah.

Jacob Trefethen: Okay. Even though malaria -

Saloni Dattani: Even though it’s treatable and stuff.

Jacob Trefethen: It’s treatable. Yeah. I mean, just in case listeners are thinking about it themselves and concerned; in the diarrhea ones, they do treat you. They don’t just leave you, they give you antibiotics. But yeah, those in order to get more of a signal, they don’t treat you in, within an hour, they’ll probably you within 12 hours or something. So it’s a - it’s not, you gotta go through some pain to get the gain.

Saloni Dattani: Well, I read that with the cholera vaccine challenge trials some people... actually, you know what? I’m not gonna finish that sentence.

Jacob Trefethen: Oh -

Saloni Dattani: It was about how much diarrhea they had. And you know what? I don’t actually wanna give people that image.

Jacob Trefethen: That’s.. you know what, Saloni? I think they’ve got it now.

So my question for malaria, Katharine, how sick do you get? Do you get sick at all or do you get treated as soon as there’s any risk of sickness or? What if you’re in, what happens?

Katharine Collins: I guess the idea is that they treat you before you develop any real symptoms. So you probably start to feel a bit fluey. You may get a headache, but because they’re monitoring your parasitemia so closely, the plan is to treat you before you get any really uncomfortable symptoms. By the time you get treatment, you could have some symptoms. I think people do typically get symptoms. They feel rough for a day or two, but that’s hopefully the extent of it.

Jacob Trefethen: I think that’s kind of cool. Yeah, I would do it. I mean, I haven’t done it, so you always have to take with a grain of salt, whatever I say now. The issue, yeah, I tried to volunteer for a trial recently and ended up getting swamped in the logistics. So your point Saloni, that it’s harder once you have a job? I’ve had that experience too.

It also depends where you live, whether there are trials around you that are convenient that you can participate in. So it comes down to those aspects as much as anything. But malaria sounds kind of fun. If you get, the drugs are great. You get, if you get feel a little bit sick, that will make me feel like I’ve done something for humanity and then I get treated, I’m up for that. Sounds good.

Saloni Dattani: And also you get to live in a cool quarantine hotel for a bit. No?

Jacob Trefethen: No, because -

Saloni Dattani: No?

Jacob Trefethen: It’s safe to walk outside. In England, right? There’s no, there’s no mosquitoes that bite you.

Saloni Dattani: So you are infected and then they’re just like, go on with your life. Yeah. And you just feel sick at home instead?

Katharine Collins: Yeah. They give you a little card to put in your wallet, which tells people what you have and what you need to be treated with in case something happens.

Jacob Trefethen: Oh, really?

Saloni Dattani: Okay. I’m not volunteering for this thing.

Katharine Collins: Emergencies, like if you ended up in hospital from a car crash or something, they would know that they should probably give you antimalarials now. The study’s over.

Saloni Dattani: No, I thought, I thought you’d be in a little quarantine hotel. I thought it was like a mini vacation but you’re sick.

Katharine Collins: No, I think maybe they do it differently in different places. So it depends maybe what type of trial you are in. So for the drug trials with malaria, because they actually let you develop parasitemia to a certain level, then they treat you. And then they want to measure the clearance rate of the parasites. So they want to sample you quite quickly and frequently after treatment. So for those, they do often do inpatient for your convenience, then they let you go once you are treated, so it could be just a couple of days.

Saloni Dattani: I think I’m thinking of the respiratory virus challenge trials where, because you could transmit it to someone else, they keep you in a facility.

Jacob Trefethen: Diarrhea as well, for the shigella one they keep you in. Yeah. I realized Katharine in that description though, one of the other reasons why people might not want to do it, which is you’re getting pinpricked constantly ‘cause people are taking a lot of blood samples. So that’s if you wanna get over needle phobia via exposure therapy, go for it!

Saloni Dattani: I feel like the way to - Exposure therapy is supposed to give you like a mild version where it’s like, oh, nothing actually happens when you get injections. This seems like it would actually scare you more!

Jacob Trefethen: Well, I did exposure therapy and nearly died.

Saloni Dattani: Would you participate in the challenge trial?

Katharine Collins: I would love to, but I really hate needles.

Jacob Trefethen: Oh, there we go! There we go!

Katharine Collins: It’s kind of ironic for a vaccine developer.

Jacob Trefethen: That’s so funny.

Katharine Collins: I’m terrified of getting vaccines. When I have, when I go to get a vaccine, I have to lie down to have a vaccine, I have to lie down with the blood taken, as otherwise I might faint. I think I have fainted in the past, that’s the problem.

Jacob Trefethen: Oh, wow.

Katharine Collins: And so, as you mentioned we take blood in these challenge trials, 10 to 15 times depending on when you get malaria. So I just couldn’t, I couldn’t cope with that. Unfortunately.

Jacob Trefethen: We must know our limits. Okay. So how come that’s not enough? Or is it enough? So let’s say you’ve taken a malaria vaccine through human challenge trials. You ready to license it, roll it out across different countries or not? I know the answer, but I’m curious.

Katharine Collins: Well, obviously no, I guess that’s not the target population. So you still need to find out if your vaccine’s gonna work in the people that it’s intended for, which would be children in Africa.

Saloni Dattani: Well, we have some vaccines that are approved just from challenge trials. Right? Like the typhoid vaccine.

Katharine Collins: Yeah, that’s right. Yeah, I think when the trial isn’t feasible to be done in the target population, there’s good arguments to try and get that efficacy signal from a challenge trial, and then they still need to get your safety data from the target population that you’re gonna use the vaccine in as well.

Jacob Trefethen: Okay. So we’ve talked about the second malaria vaccine, and we are talking about the animal models and the human challenge models for vaccines in general. Saloni, since you’ve written about the history of malaria, I’d love to hear, if you’re willing, what was the first malaria vaccine development timeline like? What were the steps there? What happened?

Saloni Dattani: I love how we’ve gone through this backwards, like we’re doing the Star Wars prequels or something.

Jacob Trefethen: But more entertaining.

Saloni Dattani: Well, I guess it’s a long story. So I think I probably wanna start with a quick summary of the whole development. I first got interested in this topic when I was reading about the news of the malaria vaccine being rolled out in 2021, and I wanted to write a blog post about it. So I was starting to write this blog post, and one of the first things that I learned was that it was actually developed in the ‘90s. And it really kind of shocked me and I was just thinking: what went wrong? Like, what happened? Why was it, why it didn’t only get released now, if it was developed so long ago? And a lot of my interest just stemmed from that curiosity and frustration, with how things could have taken so long.

The short version is that I think a lot of it is because of a lack of funding, infrastructure, and in some cases, also the regulatory changes and standards that there were. But I think the broader version is really, you know, this malaria vaccine essentially came out of research from the US Army. In the 1950s, almost every country was affected by malaria, and they used, there were large scale malaria eradication programs in the 1950s, mostly using insecticides like DDT. And those were very effective, like a lot of high income countries eliminated malaria in the 1950s with DDT and other control efforts.

And funding also declined, so there was no more reason for a lot of high income countries to do research on malaria, and a lot of the researchers who were previously doing it became operators and managers of this eradication program. So funding for research and development massively contracted, and that kind of stayed that way until really the 1960s, when the Vietnam War was happening, and the US Army was then once again facing malaria in Southeast Asia. But by then it was kind of drug resistant malaria. So there was once again, this need for research trying to develop new drugs that were effective against drug resistant malaria, but also potentially vaccines.

And so some researchers started working on this program to try to develop a malaria vaccine. And their names were Ruth Nussenzweig, Jerome Vanderberg and some of their colleagues. And what they did was, they first tried to build a proof of concept of the vaccine, so let’s see if you can protect mice by infecting them first with a killed version of the parasite. If you protect them with this killed version of the parasite, will they then be protected from another infection? And what they found was that yes, you could do that.

And, this eventually much later led to a different type of vaccine, which we might come back to later on, but it’s not really scalable. So the other option is let’s try to develop a subunit vaccine. From our previous episode on a history of vaccines and Hepatitis B, basically the idea here is that, instead of using the whole organism, the whole parasite as a vaccine, let’s try to find a few components, or maybe the one component, that is enough to stimulate an immune response. And so that’s what they tried to find and they sort of looked at these mice that they were protecting with this killed parasite and saw: what are they generating antibodies against? What is their immune response reacting against? And they found that that clustered around a protein called the circumsporozoite protein. That protein, it turned out, was gonna be a very good candidate for a vaccine. That was gonna be the main component of the vaccine.

So the initial attempts were to use that protein as the vaccine. If you remember back from our protein subunit vaccines episode, the Hepatitis B one, often just using a single protein in a vaccine is not very effective. And the reason for that is that, often when you have a whole pathogen being a vaccine, or when you’re exposed to a whole pathogen, there are many things about that pathogen that can stimulate your immune response. Whereas when it’s just one protein from that, that’s often not enough for your immune system to recognize that this is something that we need to react to. There are obviously lots of nuances there, but that’s kind of the simplified version.

So this initial vaccine, just using that one circumsporozoite, or CSP, protein, was not very effective. They only managed to protect one volunteer out of six in their first study. The way that you improve that, is often by adding an adjuvant. So an adjuvant boosts the immune response in some way, and so that’s kind of what they tried. They tried different adjuvants, they tried different formulations, and eventually they created this formulation. And I forget what each of the letters stands for. And this, the formulation was the RTS,S vaccine. And so Katharine, what does, what is this formulation made of?

Katharine Collins: So the formulation is made of parts of the malaria parasite and the Hep B virus. So the R stands for the repeat region, which is from the CS protein in the malaria parasite. The T is for the T cell epitopes that are from the same protein, and the S is from the Hep B surface antigen, and this is fused to that malaria protein. Then there’s the excess Hep B surface antigen I mentioned before that was needed for this to form a virus-like particle, and that’s the extra S so that makes the RTS,S.

Saloni Dattani: Unfortunately, by the ‘90s, there was no longer interest in funding it from Vietnam War era army research anymore, and they couldn’t scale up and continue that research. So they only found this adjuvant, that they ended up using, in the nineties. So at that point, we have a possibly more effective vaccine and they did another challenge trial to see how effective that would be. This time it was more effective, it was six out of seven people in the challenge trial that were protected from further infections.

And again, this, a seven person study sounds extremely small and it is, but that was one - this is a preliminary, pilot type of study, so this isn’t really the real deal, but it is still much better than any other study had shown so far. So this was a much more promising candidate for further research.

So what they did next was to do a field trial with many more participants. So they ran a field trial in The Gambia with 300 men, they vaccinated them with this candidate and with a placebo, and they looked at their rates of malaria infection afterwards. And in the group that received the vaccine, they had a 34% lower rate of malaria infections over the next four months. So that was the first field trial, and that was done in 1998.

And okay, this field trial looks not amazingly effective, but still effective in a way that no other vaccine candidate had been up to that point. And so the next step was really, let’s try to get this into real, clinical trials in the population that needs these vaccine, which are children. So they started with trials in older children, who were 6 to 11 years old, and then younger children, who were 1 to 4 years old, and then finally infants. This idea is called age deescalation. Basically you’re testing it first in children who are least likely to be affected by potential side effects, and then the infant group who are more vulnerable. You sort of wanna make sure that it works first in adults, and then in children, and then in infants.

But this process took a long time and they struggled to find funding at every stage of the process from what I read, and also needed to themselves set up clinical trial sites across Africa. Often there were just not clinics with the expertise to run clinical trials, or the equipment to do testing and things like that, and the researchers themselves had to fund some of that work, so it was a very long process. And then it eventually finished in 2015, the phase three trials ended at that point. That is, I think, much longer than the research process that we often have for vaccines today.

Jacob Trefethen: Though, luckily, I’m sure that meant it got approved in 2015.

Saloni Dattani: No!

Jacob Trefethen: No. What happened then?

Saloni Dattani: What happened then? Well, in 2015, the phase three results came in and the European Medicines Agency said, this looks safe and effective, but the World Health Organization didn’t recommend it for a large scale rollout. They asked for more pilot studies before they would do that.

And one of the reasons for that was that there were some, in post hoc analyses of the data, they found higher rates of meningitis in older children and higher rates of death in girls at two of the trial sites. And the World Health Organization, if I understand correctly, didn’t think that they were - those signs were causally related to the vaccine, but they wanted it to be ruled out, and so they asked for pilot studies.

The pilot studies took around four years to find funding for, and to get staffing for, and they finally launched in 2019. And then another two years into the pilot studies, there was enough data for the Data Safety Monitoring Board to look at the data, find no increased risk of these side effects, and then finally clear the vaccine for the World Health Organization’s endorsement in October, 2021. So that is 23 years after the first field trials.

Katharine Collins: The safety was one of the reasons, but that wasn’t the only reason, right? They, there was a lack of confidence in how effective the vaccine was. So it wasn’t the risk, it was about the risk benefit analysis. You know, it was only 36% effective in those phase three trials, and there was the safety signal.

Jacob Trefethen: The RTS,S vaccine was going up for EMA and WHO review in 2014, 2015. That was just about when you were finishing your PhD, working on the R21 vaccine. Katharine, so what was the feeling like in the malaria research community at that time? Did people have conflicting and different views, and there was a lot of debate? Was there consensus and surprise? What, what was it like?

Katharine Collins: I think everybody was really hopeful that the vaccine would get approved. I think there was definitely mixed opinions in the field about whether a vaccine that showed such low efficacy in the phase three trial should be rolled out and would actually be effective.

So I think what was really important and really key was the cost effectiveness modeling that was done with the data. And I think that was quite pivotal. And in that it really showed that even a poorly effective vaccine or suboptimal vaccine, most vaccines that have been used in children at the time had really high levels of efficacy, like 80, 90%. So it was a completely uncharted territory. But the modeling showed that even with this low level of efficacy, because there’s so much malaria, it could have quite dramatic impact and it would be cost effective.

I think that was a bit of a surprise to everybody. We’ve been aiming for this really high bar, and then all of a sudden there was this realization actually a quite a suboptimal tool could make a big difference. I think that was quite unfortunate and quite pivotal.

Jacob Trefethen: So what did it feel like when the WHO verdict came in that more studies were needed?

Katharine Collins: I think it was really disappointing. I think it’s a difficult decision that they had to make. This is really uncharted territory; a vaccine with really poor efficacy and this safety signal. So it’s a tough call for them to make, but I think people at the time and now still think there could have been a better way to resolve the safety signal issue.

And had they prepared better for understanding the public health impact of a vaccine that has this level of efficacy, maybe that messaging could have been different when they were trying to make the recommendations, if they understood the potential value more fully, maybe that would’ve have shifted the approach away from a pilot implementation program that took six years to conclude versus doing a much more rapid safety assessment.

Saloni Dattani: I guess I also, I feel like it’s a little bit surprising just because even the first field trials in 1997 and 1998 also showed fairly low efficacy, but they continued working on it and people probably should have been prepared by that point that, hey, this even though this isn’t a very highly effective vaccine, it probably will save a lot of lives. And so it’s surprising that that wasn’t enough to not require another study after that.

Katharine Collins: Yeah, I think you’re right, and what I’ve said just now is my recollection of the events at the time. This is a while ago and I wasn’t deeply involved in the process, so perhaps there was more preparation than that I was aware of, but it feels like that was the missing piece that people didn’t truly, at least the people I was talking to, didn’t truly appreciate the potential impact, global health impact, of this tool at the time.

And there were other consequences as well to delaying the rollout. So you’ll see GSK would be hoping that at the end of their phase three trial, they can scale up manufacture and start delivering the vaccine. They probably had a factory that was making it, but now there was gonna be this huge delay. What were they gonna do with the facilities that were producing the vaccine? And then what was that gonna mean for vaccine supply later on? All these knock on effects as well that in hindsight it’s easy to think differently about what we could have done differently. But I’m not sure it was so easy at the time, to be honest.

Jacob Trefethen: It’s also just like to state the obvious, so strange and messed up that the way that things currently work is that to get a scalable regulatory opinion, you end up relying on the EU and the WHO when, you know, over time we have to get to a world where kids in Ghana rely on regulators in Ghana, not these kind of more distant bodies. ‘Cause you could totally imagine, as happened with the next vaccine, R21, that some nations want to go ahead with vaccination campaigns, even if the WHO doesn’t agree and they absolutely should. So that’s another part of this story that’s a bit heart wrenching.

Saloni Dattani: I feel like there’s also a part of this that’s like what safety standards we’re used to here might be different. Like the cost benefit just might be very different and the willingness to take vaccine at an earlier stage might be different.

But I think there’s also another thing that kind of drew out the process, which was a lack of funding and a lack of infrastructure for clinical trials at the time. So especially in the early 2000s, there were very few trial sites in Africa where you could actually try to do research on the malaria vaccine at all. And it was only in the 2000s when malaria funding actually grew from various organizations like the President’s Malaria Initiative in the US, and Unitaid and the PATH’s Malaria Vaccine Initiative that was funded by the Gates Foundation and the Global Fund. And all of these appeared only in the mid-, early-2000s.

Until then, it would’ve been really difficult, I think, to get enough funding to set up these trial sites and to actually do the research. To me, when I think about it seems like mostly a failure of infrastructure and funding. And there are also these regulatory concerns, but if we’d had that sooner, we would’ve been able to test many other vaccines as well.

Katharine Collins: Yeah, I agree with that. I think that’s a really important point. I think, we take it for granted now that actually these clinical trial facilities are so well established, and the investigators there are so competent, that they can run their own trials, lead their own work. That wasn’t the case.

I remember the stories of the people leading the RTS,S work doing the draw of the sites that existed at the time, and injecting cash into a lot of these sites to bring them up to the standards that would be needed for their product development needs. So I think a lot of that work done by GSK has really benefited the rest of the malaria community and other development of other vaccines as well.

Jacob Trefethen: Okay. So there’s infrastructure, which is key, and also funding, as you mentioned, Saloni. So let’s say that there had been a big burst of funding back then that was even bigger than we saw. How would that have happened? Were there people proposing it?

Saloni Dattani: There were people proposing it, but they were proposing a different type of funding. Much of the funding that we’re talking about is sort of directed at specific groups to do the research, or to set up the trial sites, and things like that.

But in 2004, some economists, Michael Kremer and Rachel Glennerster proposed an Advanced Market Commitment, which is a different type of funding model to try to spur innovation and change the commercial incentives for vaccine development. So the general idea, of why did we need philanthropy and like foreign aid and all of these global health programs, is that there isn’t otherwise a commercial incentive to develop vaccines where it’s very small. The reason for that is that the people who are most affected by malaria are very poor and you can’t really sell vaccines at a high price because they wouldn’t be able to afford it.

So here the idea is, what if we could change those commercial incentives? And the Advanced Market Commitment is a way of doing that. So instead of directing funding at specific research groups, it’s actually a pool of funding that is only available to researchers or to manufacturers if they develop a successful vaccine in trials and they reach certain criteria. So Rachel Glennerster and Michael Kremer proposed this Advanced Market Commitment where they said we should have a commitment for around $3.2 billion in total, where you would pay per person who was vaccinated, for the first 200 million people, and you would pay about $13 per person. What this does is it actually incentivizes companies to develop a vaccine and take it to the finish line. Both invent-, both developing it and then also scaling it up because they’re only gonna get that payout per person they immunize.

So I think that is a really cool model that spurs commercial development and it’s very different from the type of funding that was actually done. But the problem was that that idea didn’t actually get taken up. And there were various reasons for that. One was that at the time people thought the malaria vaccine was just too technically difficult. It was too far away to be reality. So they didn’t want to use this new funding model that was proposed, for something that might not ever happen, and they thought that you, we have to have a lot more basic R&D before we’d have a product that could reach that standard. That also just made it more politically risky. People were like, well, we want something that will definitely or has a much higher chance of success. We want a proof of concept that this funding model could work.

And the other problem is that it’s hard, in a commitment like that, which is essentially this legal document that funders, in this case they would be countries - governments, or philanthropists agreeing to pay out a vaccine that meets these standards. It’s hard to decide what those standards are and what kinds of products would fit those criteria if you don’t have a malaria vaccine yet, and you don’t have like things that are late in the pipeline.

So instead of doing an Advanced Market Commitment for malaria, there was a different Advanced Market Commitment that was actually implemented, and that was for the pneumococcal vaccine. And so in 2009, various countries and the Gates Foundation came together to fund an Advanced Market Commitment to develop a new pneumococcal vaccine that would target the strains that were common in Africa and South Asia. Those strains were not included in the previous pneumococcal vaccines, but there was already a proof of concept that we have this, we have these other pneumococcal vaccines, it should be fairly easy to turn to make new ones against these strains. And it worked. So there were three companies, I think, that quickly developed these pneumococcal vaccines, took them through phase three trials and then manufactured them in bulk to get that payout from the commitment.

I personally think it feels like a very big missed opportunity to use it for malaria as well. But many people disagreed with that at the time.

Jacob Trefethen: Okay. Katharine, you were around. Do you think it would’ve worked back then?

Katharine Collins: I’m not sure. I think the limitations were scientific, biological, we had the problems with the adjuvants, we had lack of trial infrastructure. I’m not sure it would’ve made things go much faster.

Saloni Dattani: Well, it’s hard to say as well, because this was proposed in 2004. And so at that point, the RTS,S vaccine already existed and it already had like an efficacy of 30 something percent. And so if you were at the time, and you were trying to put this commitment together and you said, we’ll fund a vaccine that reaches these standards, probably you would, the standards that you would ask a vaccine to be developed for would be higher than the 30% I think.

So I think in that sense it would’ve been hard. What’s interesting though is that there was another paper in 2005 where they tried to model this explicitly, so trying to model the cost-effectiveness under different estimates of the efficacy. Like if it was 30%, how would it be cost effective? If it was 60%, et cetera? And this was a paper by also Rachel Glennerster, Michael Kremer, many other economists, Heidi Williams, and they found basically that it was, it would still be cost effective to fund an Advanced Market Commitment for a malaria vaccine, even if the efficacy was only 30%.

So I think to some degree there had been a bunch of thinking on this, but at the same time, I don’t think we know what the counterfactual is because I don’t think that other, there are enough other commercial companies that are developing malaria vaccines now that we can compare this to. Like the thing that is effective about the Advanced Market Commitment is that it gets people to enter the market that wouldn’t otherwise. And so it’s hard to know how that could have gone, I think.

Katharine Collins: I think that’s the bit that I agree with that there weren’t other people that were that far advanced in their vaccine. The only thing that has worked to date is a CSP based vaccine. There were people working on other types of vaccines at the time. But it’s not sure, because it’s not clear any of those would’ve made it either, or looked promising enough to advance.

Jacob Trefethen: So that’s a pull funding mechanism incentive to get to the finish line. Katharine, did it feel like more grant money, and more universities, and more companies wherever, would have made the difference if there was a hundred million more every year going into malaria vaccines? Or did it feel like the science and the infrastructure - you can’t rush that, and you actually just have to do it step by step?

Katharine Collins: That’s a very good question and, actually I, maybe I’m gonna change my opinion slightly and that there were other, with more funding available, there were other people doing great science at the time. So Simon Draper at the University of Oxford has developed a blood stage vaccine with RH5, and that work was happening at the same time on the lab bench next to me, when I was doing R21. But that was seriously underfunded, so there was - people had to prioritize what they were gonna support with their funding, there was limited funding. So the focus went on to CSP based vaccines and that’s what the Gates Foundation funded the RTS,S vaccine through MVI and the Gates Foundation didn’t fund blood stage.

There was only one funder at the time that was supporting that work, or one main funder, and that was USAID (United States Agency for International Development). Had there been more money, that work could have been accelerated. And you know, that’s shown now in a phase two trial that it gives good levels of efficacy, not as high as R21 and RTS,S, but there’s potential to combine that with R21. So that work could have been accelerated a lot quicker, had there been more funding around.

Jacob Trefethen: So just playing that out. So that, that result you just referenced, that was from about a year ago, was it? That was pretty recent. Right? Yeah. And so if that funding had happened a decade earlier, could that result have come about a decade earlier, do you think? Or is - that’s just a funding question really.

Katharine Collins: Yeah, I think the product was the one they were working on in the beginning.

Jacob Trefethen: No!!

Katharine Collins: Depressing.

Saloni Dattani: Wow. That is incredibly depressing.

Katharine Collins: I know, but I think credit has to go to Simon Draper and the funders that supported him and Lorraine Soisson at USAID, they kept that work going with quite limited budgets, and they’ve made it to the finish line, well, not to the finish line, but to the clinical trials now, and the efficacy trials.

Saloni Dattani: Wow, geez.

Jacob Trefethen: Thank you Simon. Thank you Lorraine, for believing against consensus and keeping it going.

Saloni Dattani: I have a question related to this because both these are different stages of the vaccine and so I’m wondering if you had a vaccine that combines the vaccines against both of these different stages, would you expect that to have a higher efficacy, and have people tried to do things like that?

Katharine Collins: Yeah, I think that was the original approach from Adrian, when I was making R21. He also had a liver stage vaccine. The other vaccine he had developed was the ME-TRAP vaccine (Multiple Epitope–Thrombospondin-Related Adhesion Protein), and that targeted the infected hepatocytes. His theory was that if you could reduce the number of sporozoites that get to the liver, then the liver stage vaccine would have an easier time finding and clearing out those liver cells. And that was valua - that was tested and it didn’t work, so that was a great theory that didn’t work.

Now people are looking at combining the CSP based vaccines with the blood stage vaccines that Simon Draper’s developed and others. There are lots of other people working on blood stage vaccines now as well. But the preclinical models are really difficult to evaluate all stages of the parasites in the same model and the combination of those vaccines. So we really have to get into humans, and that’s the work that Simon and Angela and his team are working on at the moment.

Saloni Dattani: Wow. And so that was also - could that have also been sped up by 10 years?

Katharine Collins: Yeah, that vaccine that they’re now putting into clinical trials with R21 was being developed at the same time as I was developing R21. So I know that could have gone quicker.

Saloni Dattani: This is crazy.

Jacob Trefethen: It wasn’t exactly hard to spot, it was right next to you on the lab next to you. I’m gonna cry.

Saloni Dattani: Geez.

Jacob Trefethen: I mean, so as someone who works in philanthropic funding, I think the main lesson here is just that funding in global health R&D is so tight that you have to make these prioritization decisions that are vicious and impossible. So we just - I mean, a more sane society would have more long-term government and philanthropic funding that was less correlated, more decision makers, more money total, so that you could get more shots on goal.

So I think, for anyone listening who is wondering what the solution is, I think that’s the most obvious general solution staring us in the face, and so I don’t wanna hide it. There’s obviously all these specifics we can get into that are more technical, but that one is just - is obvious. So we just have to say it out loud. Sorry!

Saloni Dattani: Geez.

Katharine Collins: No, I agree with that. I don’t disagree with the decisions that were made about what you had to prioritize at the time. I think they were tough decisions that people had to make. That had there been more money, we could have moved things a lot faster.

Saloni Dattani: I feel like what’s even more depressing about this is that... Despite all of that, malaria is still one of the more well-funded diseases in global health world, and there are various others that are large burdens and get tiny fractions of the funding.

Jacob Trefethen: I am wondering if we could just talk about the two vaccines already approved next to each other, and then what’s coming next after these two? What needs to be done next in the invention pipeline?

So RTS,S versus R21. I will tee this off by saying I don’t know that there’s - there are different comparisons you could make, but one fact just to state upfront is that neither has faced a rollout where tens of millions of children have received the vaccine, so perhaps the biggest problem is simply that there is not enough reach of either of them, let alone comparing between the two.

That said, what do we know about the data that has come in, about how they look? So there’s more data coming in every year, but what do we know so far about efficacy, about safety, and other factors? Katharine?

Katharine Collins: The headline efficacy figures from the phase three trials look quite different for the two vaccines. So RTS,S, we mentioned it was something like 36% an efficacy overall. And actually for the population that was used for the phase three trials for R21, that was most similar, the efficacy I think was 57% overall. And then for R21, the phase three result was something around 75%. I can’t remember the same, the exact numbers, so this looks like R21 may be a lot better.

But there’s some nuance and detail about how these trials were conducted, and where they were conducted, and when they were conducted, that means we can’t - we probably can’t directly compare these trial results. So I don’t think you can claim that R21 definitely has a higher level of efficacy. There were different things happening at the time; different other malaria interventions that were being used, like bed nets, or seasonal chemo-prevention drugs that were given to children every year, so those results aren’t directly comparable. So I think we have to try not to make that comparison unless we run a head-to-head trial.

What I think is interesting about the R21 data that’s starting to emerge is that it does - it may be more durable than RTS,S. So the decline of protection seems to be slightly slower. So it may, even if the efficacy isn’t much different, that peak protection they gets the, it may last a little bit longer, so that could make quite a big difference.

Jacob Trefethen: I see. So, but in both cases, your first shot, you’ll probably get it at five months old. Is that about right? And then you might get another, the ideal is you get one at five, one at six, one at seven months. And you’re saying that the immune response from R21 is lasting for longer after those first shots?

Katharine Collins: That’s right. That’s actually a fourth dose that’s given around 18 months.

Saloni Dattani: I think my takeaway from the difference between the two is mostly the manufacturing and the cost. Is that also how you see it? And are there any other differences? Why is there such a huge difference in the cost of both of these? And is that because of the dosing that we talked about at the start?

Katharine Collins: I guess, the other big difference is of the scalability of the vaccines. R21, it seems to be easier and cheaper to produce and that may be in part due to the lower dose and maybe also new technologies that have been used to produce the vaccine itself - so newer yeast expression systems and things like that. And also, the adjuvant that’s added to the vaccine.

As we mentioned earlier, that the adjuvant was really important for the RTS,S vaccine. We found the same with R21, only when we used a certain adjuvant did we see protection. And that the adjuvant that’s been chosen for R21 was Matrix-M and that doesn’t have the same supply limitations as AS01, and it’s slightly cheaper as well. So that makes it more scalable.

Jacob Trefethen: Yeah, I mean it’s funny, it’s not the property you’d think about first – scalability, and how that might have implications for cost and price. But last price that I saw for RTS,S was about €9 a dose and there are four doses. And then the last price I saw for R21 was the original price was 3.90 and it maybe has come down to $3? So we’re, we’re talking about a 3X, say, difference, which may not sound like much, but is decisive in a lot of these cost-effectiveness calculations because global health funding, there’s just not so much of it going around. So when you think of cost-effectiveness, it’s not just how effective are these vaccines, it’s how much it cost to actually deliver them to the kids who need them. So anything you can do to bring the numbers down is, it could change the equation.

Katharine Collins: Yeah. And just going back to the delivery schedule you mentioned earlier Jacob, which is giving doses of the vaccine at five, six, and seven months. And then there’s this booster dose or final dose that’s given around a year later, and none of these time points are actually aligned with the schedule for other infant vaccines. So what this means in reality is that children and their parents and caregivers have to travel for each of these visits at another time. And what we’re finding is that people are not showing up for all of their doses of vaccine, and so if they’re not getting the full course, it’s gonna reduce the effectiveness of both of these vaccines.

Jacob Trefethen: Right. If you have to travel three months in a row, but you are busy taking care of your other kids or you’re at work, or, I mean, it’s, you can see how you might miss a dose. And then if that happens, then whatever we saw in the clinical trial may not reflect the reality of what kids are getting protected, so more work to do there.

Okay. So those are two vaccines and they’re imperfect, but they are helpful for kids. Do you think they’re good enough, Katharine?

Saloni Dattani: If we did this again today, could we make better vaccines?

Katharine Collins: Uh, yeah, I think well, oh gosh. Wow. That’s a tough one. I think...

Saloni Dattani: I mean, scientifically, not in terms of the funding or trials or anything like that.

Katharine Collins: Yeah, I think we have better techniques and technologies for developing vaccines. Structured-guided design, reverse vaccinology, computational protein design, things that you’ve talked about in your previous podcast episodes, where we really try and understand more specifically what type of immune response you want to generate. So you can take the whole protein that you think is important, and show that to the immune system, but it might generate a mixture of helpful responses and unhelpful responses.

So using these more sophisticated techniques, we can try and understand which parts are really helpful, and design the proteins or the antigens to really elicit those responses more carefully and more specifically. So using those techniques, people are already doing this. They’re working on trying to make better CSP vaccines, better blood stage vaccines, and also vaccines that target the transmission blocking stage as well.

Saloni Dattani: But why were you hesitant before?

Katharine Collins: It’s not clear that any of those will actually be any better. So I think there was a really interesting paper published by the Protein Design Institute by Neil King, someone that we support and think is an incredible institute for using computational design to really improve vaccine antigens. And they tried to make better versions of R21, and I can’t remember what the paper showed exactly now, but there were many candidates they assessed and they used this incredible methodology to try and improve the vaccines, but none of them looked substantially better than R21.

Saloni Dattani: What do you think of the whole sporozoite vaccines where scientists were just irradiating the whole parasite at the early stage and injecting that as a whole? I think they were doing that in the ‘70s, and that seems like in that research it was pretty effective and some people are continuing to work on it.

Katharine Collins: Yeah, absolutely. I think those are some of the first data that really stimulated the vaccine development community. They showed really early on, decades ago, that you could protect people by using these irradiated sporozoites, and that work continued.

So a company called Sanaria, with Steve Hoffman and others, developed the PfSPZ vaccine, and this worked really well with three doses in people in the US, so people who had no experience with malaria infections before. But when they ultimately got this into children in Africa who had had malaria infections in the past, the vaccines didn’t work very well, so that hasn’t moved forward for that population.

There’s actually been some really interesting work more recently that they’ve used genetically attenuated parasites. So instead of irradiating the parasites and then using them, they’ve made them so that they can’t survive beyond the liver stage, but importantly, if these parasites live to the end of the liver stage, then they’re really protective. And there was a recent study where they showed that a single dose of this vaccine provided really high levels of protection in their challenge trial.

But again, this was in people that haven’t been exposed to malaria before, so while this looks really exciting at the moment, it still needs to be tested in the field, in people who have been exposed to malaria, and then ultimately in children as well. But it’s really exciting. It’s pretty game changing if you can get a single dose vaccine to protect against malaria; we’ve never seen that before.

But the challenge with these parasites is that they need to be stored in liquid nitrogen, so you can’t just kill them like we have done in the past with other whole pathogen vaccines. They need to be viable, they need to be able to survive in the liver, and that’s gonna be quite challenging for delivery in Africa, because there aren’t liquid nitrogen facilities everywhere.

Saloni Dattani: Why does it have to be so cold?

Katharine Collins: That’s the way of putting them in stasis.

Saloni Dattani: Is it just preserving them?

Katharine Collins: Preserving them, yeah. So that they can be woken up. They’ve either got to be kept alive until you inject them, or you can try and cryo-preserve them in a way that they could be thawed, and then they’d still be viable.

Saloni Dattani: What if someone found a different way to preserve them for a long time? Are there other options? Can you like freeze frame a vaccine?

Katharine Collins: No. The - no?

Saloni Dattani: I have no idea. I feel, well, I’ve been watching a lot of Pokémon and Team Rocket has all of these crazy tools and equipment to do things.

Jacob Trefethen: We can learn from them.

Saloni Dattani: I feel like they would have a laser beam that could just freeze someone in place.

Katharine Collins: That would be cool, yeah.

Jacob Trefethen: Let’s take a note. Let, let’s look into that, I think that could be pretty interesting.

Katharine Collins: I know a funder that’s just started there.

Jacob Trefethen: Yeah. Yeah. Let me just, actually I’ve already got too much in my laser beam column, someone else is gonna have fund that one. But...

Saloni Dattani: Also this laser beam thing that could freeze - could be used much more widely than just malaria research.

Jacob Trefethen: You could zap people miles away. It’s interesting I don’t hear people talking about this more given how important it could be.

Saloni Dattani: Yeah!

Jacob Trefethen: Now on our current technologies, boring, so it sounds like - my sort of takeaways from this section are that when people talk about vaccines, the thing you always hear about is efficacy. COVID vaccine is 90% efficacious, blah, blah, blah, blah, blah. But that is one number.

Firstly, that number does not bake in to the public narrative, duration. It does not matter if something is 90% efficacious and lasts for three months, if it then decays. Secondly, it doesn’t bake in cost. What’s the manufacturability of this? How widespread is it gonna be in a global health context? But then in addition, it doesn’t bake in how many doses do you need? And, in a context where people might not be - they’re juggling a lot, may not come back for a second, third, or fourth dose; getting down from four to three, three to two or two to one is just an incredibly big deal, not for scientists, but for people in the real world who’re actually gonna be taking these vaccines.

So Katharine, is that a fair summary?

Katharine Collins: Yeah, absolutely. Spot on.

Saloni Dattani: It reminds me of, you know the HPV vaccine, where it was originally a three dose vaccine, and then it turned out that actually one dose was really effective. But it took a really long time for them to change the recommendation on how many doses people needed. And now that they have that new recommendation that you only need one dose, you can actually scale it up much more widely than before.

Jacob Trefethen: So, Katharine, if you had to make a guess, I’m gonna put you on the spot: in 10 years will we have an approved vaccine in use, which is, say, two doses for kids?

Katharine Collins: 10 years, I think, two doses is too high a bar. I think we can get to three.

Jacob Trefethen: Mm.

Katharine Collins: I think we can get to a more durable and a more protective vaccine with three doses.

Saloni Dattani: What’s the - what are the barriers to making it happen?

Katharine Collins: I don’t know. Maybe I wanna change my answer there. I think 10 years, I would put it 60% chance we can get to two doses.

Jacob Trefethen: Okay. But it’s all to play for, you’re saying it really could go either way.

Katharine Collins: Yeah, it’s not a done deal. I think 60% chance we can get to two doses, like 90% chance we’re gonna have a better vaccine.

Jacob Trefethen: Okay.

Katharine Collins: Three doses, 90%. That’s too high, 80%.

Jacob Trefethen: Okay. So you’re saying we’ve got to plug away and get to a better vaccine than even the one you invented.

Katharine Collins: Definitely! R21 is suboptimal. It can have impact like we’ve discussed, but it’s not a game changing vaccine. The delivery challenges, the durability - that all needs to be solved.

Saloni Dattani: Hmm.

Jacob Trefethen: Okay. So challenge number one then. So you’re saying there’s a good chance if we really push for it, we can get to a better vaccine. Maybe it’s three doses, maybe it’s longer duration, and then - but we have to also be aiming at the same time for even further improvement for kids, and that’s hopefully getting to perhaps two doses, perhaps, you know, transmission blocking, that kind of thing.

Katharine Collins: Yeah, absolutely.

Jacob Trefethen: So it’s all to play for. Okay. Saloni, how are you feeling at the end of this section?

Saloni Dattani: This makes me sad. I feel like it’s so sad that one, our technology has improved so much, but it doesn’t seem to have made that much of a difference in terms of the efficacy – except for this one vaccine, which is really hard to scale up because you need to cryo-preserve the sporozoite stage, which means that it sort of rules it out being used widely. And the third thing, is that there were like various vaccines that are in late stages of trials right now that could have been in late stages 10 years ago. It’s just the combination of all of that is just incredibly depressing to me.

Jacob Trefethen: Yeah. Well, can I try and cheer you up?

Saloni Dattani: Yes.

Jacob Trefethen: Just to reorient to how many lives a vaccine can save. That is even imperfect. You know, if R21 or RTS,S - I mean R21 seems more likely now - could scale up to more children who need it, tens of thousands of children’s lives would be saved already. And then Katharine is telling us that within 10 years, we have a good shot at an improved vaccine that’s even better, so that is gonna matter to a lot of children.

And science, the reality of this problem is the hardness of it is set by nature, and nature is a vicious, vicious, test setter sometimes. The fact we’ve got this far, I mean, that is pretty impressive and we have a ways to go, but there’s a line of sight to improvement, even if not to the absolute a hundred percent blocking one dose thing.

Saloni Dattani: I mean, I’m happy for the children who are getting these vaccines, but it’s just that counterfactual. It’s just very hard to get out of your head.

Jacob Trefethen: Yeah. Yeah. So, Katharine, as you look to the next 10 years, how do you feel?

Katharine Collins: I’m optimistic. I think we can do better. I think we’ve got great people doing incredible work, great new tools and more people thinking about the problem end to end. So more people thinking more about more than just efficacy, with all the other criteria you raised that we should be considering. More developers are now aware of all of those things to consider in the development pathway, and so I think there’s a lot of hope.

Saloni Dattani: There’s also the current rollout, right? That we could scale up.

Katharine Collins: Yeah, I think that’s a tough one. I think it’s a really difficult funding environment, so we don’t have enough donor support to provide R21 and RTS,S or the countries that would like it, that would need it, and are requesting from Gavi. So if we had more support coming from the different donor countries.

Jacob Trefethen: The UK’s cutting back, US cutting back, Japan’s cutting back.

Saloni Dattani: Germany as well. What I read from a report, talking about the situation at the time, two years ago, was back then, both of the vaccines had been pre-qualified from by the World Health Organization and they were being rolled out and they estimated that it would take another 12 years after that for all children under three in the countries with high malaria prevalence to be vaccinated. And another 2.5 million children were expected to die being unvaccinated from malaria, and the main constraints to increasing the number of children who were vaccinated fast was a lack of funding.

And I remember reading this and finding it surprising in one sense that this was the only constraint. But also, I think, after everything that we talked about, thinking that it was actually not that surprising and just very depressing. But the fact that if you had a few more billion dollars of funding for Gavi, which supports vaccination in countries around the world, you could vaccinate enough children to save another 300,000 lives.

The other thing that was interesting to me about this was that one of the reasons that there was this funding constraint was that one of the countries with the highest burdens of malaria was Nigeria. And Nigeria had just increased its GDP enough to be placed in a higher threshold, of a higher income country, according to Gavi, and that meant that they were no longer eligible for financial support to purchase these vaccines, and that meant that a lot of children would go unvaccinated, and that the cost was just so much higher after just passing this threshold. It seemed very bad to me that that was the case.

But there is some good news, which is that there was another deal where the price of R21 was reduced from $4 to $3 per dose, and that would save around $90 million and help vaccinate another 7 million children.

Jacob Trefethen: So all in all, what do you each wish that donors and funders and other decision makers understood about vaccine development that they’re getting wrong?

Saloni Dattani: I mean, I think it’s one of these situations where actually throwing money at the problem would make a difference. And that is something that people might find surprising in other fields, but here, funding Gavi would actually go a pretty long way. Or funding the other types of malaria vaccine research would go a long way. I think that’s quite surprising to people.

Katharine Collins: I think we should really be learning from our experience with RTS,S and R21. And the biggest problem, with both those vaccines, is getting all of the doses into the children, that they need. So thinking more carefully about how you develop a product that’s deliverable, earlier on in development, could have such a dramatic impact on the impact the vaccine can actually have. And I don’t think the researchers doing the work, the ones running the very first trials in humans, are thinking about that enough.

Jacob Trefethen: Right? It’s less pizzaz-y, but actually testing different delivery schedules in the clinical trials can have these incredible downstream effects of what gets recommended for millions of kids.

Katharine Collins: And maybe it’s not fair to put that all on the researchers and the developers actually, I think. They’re asking for funding to do the work. Funding’s tight and limited, funders will give you the bare minimum, to do the bare minimum. So you can only test one schedule, and so you have to go with what you have the data on already, or what already looks promising instead of exploring what the other options could be. To me, that’s also on the funders to really understand that as well.

Saloni Dattani: I think another thing is - that people may not know is just how important it is to have clinical trial infrastructure, to have better ways of running trials more efficiently, but also just more sites, more people doing these tests, being able to test multiple vaccines and not having the situation where people have to prioritize funding for one vaccine over the other, at the expense of testing the others as well.

Katharine Collins: But I think there’s also another part to the story as well in that, with malaria, everybody knows about malaria. The burden’s really well known. So as soon as a malaria vaccine was developed, countries were asking for it. They knew they had a problem, they wanted the vaccine and they’re pushing to roll it out to protect people, so those vaccines can have an impact.

But there are other vaccines that we’ve tried to develop in the past where we didn’t have good data on the burden in all the countries that possibly needed it. And so I think the Hib vaccine was a good example. It was developed, it was ready to be used, but countries didn’t know they had a problem. So it was this huge delay in rollout. There’s so much more that needs to be done when you’re thinking about developing a vaccine, beyond just developing the product, thinking about how it’s gonna reach people, and how people are gonna understand whether they need the vaccine, what the demand is.

Jacob Trefethen: That was quite an episode. That is our first episode where we had a expert interviewee with us the entire time. Thank you so much, Katharine. And now it’s time to conclude with what some of the things, what are some of the things we learned or that stuck out to us from this episode?

And I’m gonna start. Number one, how much you can learn from patents. It turns out that there are people who read them and then they tweak them, and then they change them, and then they make new inventions. I mean, that really gave me hope for public knowledge again.

Saloni Dattani: That was really cool to hear about.

Jacob Trefethen: Saloni, what did you, what stuck with you?

Saloni Dattani: So I had a bunch of thoughts. The first one, which I was thinking about before we started recording was that, and this is a very unpopular opinion, but some PhDs are just better than others and some fields are better than others too. I know it’s controversial, but I think more students should go into infectious diseases, and should go into vaccine development. And I have many thoughts about which fields should move into those, but I won’t name them - they’ll probably, they’ll know who they are.

The other was that I thought it was really interesting to hear about the Jenner Institute, and how it was set up in such a way that there was a manufacturing facility that researchers could work with, and they could learn from that stage of the process in manufacturing. And I thought maybe more institutes should be set up like this, where you can see the both the basic research and the translation and the manufacturing happening in the same place, and learn from these different stages. That I thought was a really cool thing to learn about.

The other that stuck with me throughout this episode was that malaria is very complicated, especially compared to the other pathogens that we’ve talked about in previous episodes. It has many different stages of its lifecycle, it changes shape. It’s harder to develop vaccines for malaria than for many other diseases. And there were various parts of that process that were just very tricky to do scientifically. It was hard to find good animal models that helped replicate what the disease would be like in humans.

The next was that a lot of the research funding for malaria was affected by priorities that high income countries had. So in the 1950s during the global Malaria eradication program, the funding for research dried up and a lot of researchers were made program operators in the eradication program, and that stalled research until the Vietnam War, where the US Army troops were facing potentially drug resistant malaria, and there was now a renewed need for research into new malaria drugs, but also malaria vaccines. And that is where the RTS,S vaccine originally came from, was research from people who were working on that during the Vietnam War. So that stood out to me as well, that we sort of think of research happening in the lab, but it’s really actually influenced by all of these much broader considerations, and the historical context, and things like that, that I think people don’t appreciate enough.

Katharine Collins: So the first one for me is probably the cost, scalability, and deliverability are actually really important. People should think about them earlier in the process. I think it’s clear from the R21 and RTS,S experiences that the vaccines could have much greater impact if those things were considered earlier.

Saloni Dattani: I also thought that just within that process, it’s not just the broader concerns, but at every stage of vaccine development, these things are really important. Like how you develop the adjuvants and how expensive those are, or how that affects the efficacy of the vaccines, and how accessible they might be later on as well. And then things like, how does the dosing of the vaccine that’s being developed affect how easy it is to scale it up, across countries, or across millions of children, I think is something that people underappreciate. And then similarly, the vaccination schedules - the fact that the malaria vaccine is taken at different ages than other childhood vaccines, and how that affects uptake of the vaccines, is something that was new to me. And just this idea of making things more efficient at all of these stages could be really important.

I’ve been reading the book The Origins of Efficiency by Brian Potter, and one of the key things that stood out to me from that book was just how much progress we’ve made in medicine, but also engineering, and all parts of life were from improving the efficiency of things that people have already discovered, and that that stage can often make the difference between something that is possible versus something that’s actually used by millions of people, and I think that’s actually a huge part of the picture.

The other thing that I have always been thinking about is just how different things could have been. Like what others, what other alternative universe we could have lived in, if things were different. And the key things that I think about here are: one, how things would be different if there was more funding. And second, how different things would be if there was better infrastructure for running clinical trials.

And we talked about a bunch of examples of how that could have been different. So one, that probably would’ve sped up the developments of the RTS,S vaccine, the first malaria vaccine. Having the clinical trials sites set up earlier, that would’ve made a difference. Having more funding, that would’ve made a difference. But then we also talked about other vaccine candidates for malaria, and how more funding for that research could have changed the picture and sped up the trials for those vaccines. And then finally, the rollout of the malaria vaccines that have already been approved could be sped up with more funding. And that funding was the constraint, and still is the constraint, to getting that out to more children.

And I think that often people think of this as purely a scientific problem, but I think that’s not the case, and that in many situations when we’re talking about diseases that affect people and poor countries, often commercial incentives, and funding, and the historical context and all of these things actually have a very big impact.

Katharine Collins: I think it’s really easy to look back and think about how things could have been done differently with hindsight. But it’s really important to remember that these were really uncharted times for this type of vaccine, and it’s really quite amazing what was achieved over the time. Obviously, we all wish things could have been done faster and can keep going faster in the future, but it is quite remarkable what was achieved. But I think it’s important that we do look back. I think we should all be looking at the experiences of the past and learning from them so we can improve what we’re doing as we’re developing future vaccines; learn from those mistakes.

And you know, now as a funder, I’m trying to take a lot of those lessons and those experiences and apply them to the development of next gen malaria vaccines and Strep A (Group A Streptococcus) vaccines and any other products we end up working on at Coefficient Giving.

Saloni Dattani: What you just mentioned, made me realize that the alternative universe that we could have lived in: it could have been faster, but it also could have been slower, and I hadn’t thought about that.

Jacob Trefethen: I think my main takeaway from looking backwards into the past today is about the present and about the future. And it’s that we live at a time of scientific wonder. We - people who invented world-changing technology are among us today. Invention is often a process of building on other people’s work, tinkering, tinkering in the lab, and taking care of those lab notebooks, looking in an electron microscope, trying an experiment, changing what you started with, trying another experiment. And these people are heroes.

They’re real people. Sometimes you can even get them to come on your podcast, thank you very much, Katharine. And to anyone listening, you may know one of these people, and society may not recognize it yet, and they’re still inventing and they’re still trying stuff. You may become one of these people in the future. And when it comes to science, we are all in this together. We’re trying to figure out what is true and what we should do next.

So I just wanna end by saying, Katharine, thank you very much. This was very enjoyable and I’m very excited about everything that comes next.

Katharine Collins: Thank you. It’s been great to be here. Great to chat.

Saloni Dattani: If you enjoyed this episode, you should rate us on Spotify or Apple or wherever you listen to this and share it with everyone you know, including any parasites that you are currently infected with.

Jacob Trefethen: Maybe they are heroes too, you never know, they could contribute in their own way. Please share this one in particular with anyone who’s considering starting a PhD.

Saloni Dattani: Yes!

Jacob Trefethen: Great. See you next time everyone!

Saloni Dattani: Bye!

Jacob Trefethen: Bye!

Katharine Collins: Bye!

Show Notes

Acknowledgements:

• Aria Babu, editor at Works in Progress

• Graham Bessellieu, video editor

• Alice Edwards, captions

• Abhishaike Mahajan, cover art

• Atalanta Arden-Miller, art direction

• David Hackett, composer
  

Works in Progress & Coefficient Giving

Thesis

• Katharine Collins (2014). R21, a novel particle based vaccine for a multi-component approach to malaria vaccination.
  

Books

• R. Killick-Kendrick (2012). Rodent Malaria.

• Michael Kremer and Rachel Glennerster (2004). Strong Medicine: Creating Incentives for Pharmaceutical Research on Neglected Diseases.
  

Articles and reports

• Saloni Dattani (2023). Why we didn’t get a malaria vaccine sooner. https://worksinprogress.co/issue/why-we-didnt-get-a-malaria-vaccine-sooner/

• Jerome P Vanderberg (2010). Reflections on Early Malaria Vaccine Studies, the First Successful Human Malaria Vaccination, and Beyond https://pmc.ncbi.nlm.nih.gov/articles/PMC2637529/

• Pratik Pawar (2022). It Took 35 years to Get a Malaria Vaccine. Why? https://undark.org/2022/05/25/it-took-35-years-to-get-a-malaria-vaccine-why/

• Ernst R. Berndt, Rachel Glennerster, Michael R. Kremer, Jean Lee, Ruth Levine, Georg Weizsacker & Heidi Williams (2005) Advanced Purchase Commitments for a Malaria Vaccine: Estimating Costs and Effectiveness. https://www.nber.org/papers/w11288

• Ryan Duncombe, Karam Elabd and Justin Sandefur (2024). Avoiding Another Lost Decade on Malaria Vaccines https://www.cgdev.org/publication/avoiding-another-lost-decade-malaria-vaccines

I recently visited Washington DC, for the first time since I was a boy. Visiting Washington in person is like seeing the Mona Lisa: one has experienced it so many times in reproduction that it is almost eerie to see the real thing. I found the experience fascinating, and I have tried to write down a few of my thoughts and impressions.

Each of the monumental buildings of Washington sits on its own city block, with a border of lawn separating it from the street, like a great roast turkey sitting alone on a silver dish. This quality of distinctness and separateness is a common aspiration of nineteenth-century design, but it was hard for Europeans to achieve amidst their dense and historically layered cities. In London, tremendous monumental buildings are piled up along crowded narrow streets and chaotic traffic islands, like the British Museum on Great Russell Street and the Palace of Westminster on Parliament Square. Not so in Washington, where every grand building rests calmly at the end of a long perspective. This certainly does give the city dignity, though perhaps it loses something of vitality at the same time.

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The buildings themselves are distinctive too. For one thing, most of them are faced in marble. Marble was used extensively for monuments in ancient Rome, but it has not been the dominant building stone in any great city of Europe since then, and in fact very few of Europe’s major buildings feature much exterior marble. Indeed I believe there is only one significant marble structure in London, the Marble Arch, whose material was so distinctive the building was named for it. In every European city the dominant building stone is limestone, or sandstone if limestone is unavailable, or granite if neither is. But because Washington was built so late in history, when transport costs had fallen, the Americans could access the wonderful building marbles of Georgia and Vermont, and create the world’s first marble city since antiquity.

Marble is favored by sculptors because of a feature called subsurface scattering. What this means is that marble is slightly translucent: sunlight not only illumines its surface, but a millimeter or so of its depth, creating a softly luminous quality in certain lights. Human flesh also has this feature, whence arises the special appeal of marble for sculptors of the human figure. I had read about subsurface scattering before, but I had never engaged seriously with the idea and slightly suspected it of being a pious canard. But in Washington, I became a believer. The monuments of Washington do seem to glow softly in the brilliant southern light: this does give them a sensuous quality, which becomes almost overwhelming when a whole city is built this way. I am not sure I am a good enough photographer to capture this effect, but I think you can see something of it in the contrast between the colonnade of the Jefferson Monument (Vermont marble) and the Church of the Madeleine in Paris (Lutetian limestone).

Washington’s monuments are stylistically unusual, too. For monumental architecture, the Americans traditionally favored the neoclassical style, drawn from Greco-Roman antiquity. Many people think of neoclassicism as, so to speak, the official style of Western civilization. There is an element of truth in this, but quite a limited one. When Europeans began to draw on ancient precedents in the Renaissance, they did so loosely and freely, and each country did so in its own way, such that French, German, Spanish and Italian Renaissance styles are highly distinct from each other. These national renaissance traditions continued in various forms for over three centuries. There was then a brief period of international neoclassicism in the late eighteenth and early nineteenth centuries, after which European architects mostly returned to their national idioms.

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The upshot of this is that the quantum of strictly neoclassical architecture in most European cities is actually very small. The most iconic form of classical architecture is the detached portico (the temple front with columns and a gable). I have had a go at counting detached porticos in the old city of Rome, in some sense the ‘world capital’ of classical architecture. I have found only two unambiguous examples, on the Pantheon and the Temple of Portunus, both of them survivors from antiquity. In Washington, by contrast, there are detached porticos in front of most major buildings, including, starting from the top, the Capitol, the White House, the Supreme Court, the Jefferson Monument, the National Gallery, and the Treasury Building.

This leads me to the curious idea that what Americans think of as traditional European architecture – marble neoclassicism – is actually characteristic of Washington in a way that it is not, and has never been, characteristic of any city of post-antique Europe. In the late nineteenth and early twentieth centuries, American thinkers worried that their architects were copying European precedents rather than developing a national style of their own. But perhaps, in their fervor to emulate European antiquity, they had developed an American national style after all.

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I find longhaul flights extremely tedious, so I distract myself by watching films. Returning from Washington I watched Dune: Part One and Dune: Part Two, in which families of aristocratic spacemen compete to rule a Middle Eastern-themed planet called Arrakis. I enjoyed this very much, and I was fascinated by the architecture of the sets. There was something of the Sumerians, something of Boullée’s neoclassicism, a dash of Brazilian modernism, elements from Hindu temple architecture, lots of Islamic motifs, and maybe something of the Mayans, but all pared back, horizontal, massive and monochrome, blended together very harmoniously, plausibly futuristic and ancient at the same time.

The designer of all this seems to be one Patrice Vermette, who has no historical or architectural training at all, having studied communications at Concordia University in Montreal. The star of Dune, an actor called Timothee Chalamet, recently generated something of a rumpus by criticizing the fustiness of opera and ballet. I find it pleasing that among his colleagues he has a historicist designer of some genius, who can draw upon a wide range of fusty sources with virtuosity.

Samuel Hughes is an editor at Works in Progress.

In the twentieth century, Christian and Jewish religious architecture was reshaped by modernism. Most new churches and synagogues today are built in modern styles; almost no new Gothic cathedrals have been built since the nineteenth century. Hindu architecture did not undergo the same process. Temple architecture is governed by ancient canons known as the Shilpa Shastras, which define the classical style of Hindu temple architecture. In the twentieth century, many Hindu communities continued to aspire to this style, while sometimes using modern materials for reasons of cost. As these communities have become more prosperous, they have tended to adhere to the these Shastras even more closely: modern affluence has enabled a more faithful embodiment of architectural tradition rather than a departure from it. Today, these monumental projects form the world’s foremost living tradition of masonry architecture, united to vast global supply chains and great feats of logistics and engineering.

To understand the Hindu temple, one must invert the modern conception of a public building. A temple is not an auditorium designed primarily for the convenience of a human audience: it is a residence of God, who is manifested on Earth through a consecrated image (mūrti) accommodated in the temple. Within Hindu theology, the sacred image is not a statue, but God’s living presence, which the architecture of the temple is designed to revere. Its scale, masonry, and ornamentation collectively aim at creating a residence befitting the majesty of God, while generating the peace and tranquility associated with the divine.

Temple architecture normally follows rules set out in the Shastras, architectural treatises composed between the fifth and fifteenth centuries. The Shastras function both as artistic guidelines and rigorous algorithms. The measurements of the temple’s components, from the height of the plinth to the curve of the shikara (the tower or spire), are calculated to correspond to the geometries of certain constellations.

The Shastras also rigorously govern construction methods. The basic structure of most large modern buildings is a steel or reinforced concrete frame: if stone is present at all, it is merely a surface cladding. In Hindu temples, by contrast, the structure is still formed of massive load-bearing stones. While steel is sometimes introduced in foundations and structural cores to meet modern seismic standards, the governing structural logic remains resolutely premodern. Stability is achieved through the compressive strength of stone and through complex interlocking jointing systems, including mortise-and-tenon-like connections.

This approach prioritizes longevity over speed. Steel frames are strong, but they often succumb to corrosion over time. This is one reason why many office buildings have a design working life of 50 years, after which they are sometimes replaced. Load-bearing masonry is slow to build, but it is extraordinarily durable. Temples built today could stand for thousands of years, vanishing only when their stones are worn away by the wind and the rain.

Perhaps the most striking innovation in recent temple architecture is the labor model. The construction of a modern temple can be a complex hybrid of high-tech manufacturing, hereditary craftsmanship, and devotional volunteerism. Stone is sourced from quarries around the world, especially Tuscany, Bulgaria and Rajasthan. It is shipped to workshops in India, where intricate carving is executed by professionals. These artisans often come from lineages of stone carvers who have preserved these skills for centuries.

The carved stones are then shipped to the construction site, a massive logistical puzzle involving tens of thousands of numbered pieces. Their assembly operates on a unique collaborative model: the more technical work is generally executed by professionals, but other tasks are performed by a host of volunteers. The construction process itself is often viewed as a form of worship: tools are sanctified and prayers mark critical stages, ensuring the sacred character of the temple is maintained throughout its creation. This integration of hereditary skill with devotional energy creates a site that can feel less like a construction zone and more like a festival.

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Here are seven examples of this living tradition. They are particularly impressive buildings, but they are not fundamentally exceptional: smaller and simpler temples in the same style are being built today in thousands of towns and villages across India.

1. Shri Swaminarayan Akshardham

Gandhinagar, Gujarat, India

Construction: 1979–1992

The BAPS Swaminarayan Akshardham in Gandhinagar is a pivotal building in modern Hindu architecture. Constructed over a period of 13 years, it is built from 6,000 tons of pink sandstone from Rajasthan, chosen for its durability and aesthetic warmth. Standing 108 feet tall, 240 feet long, and 131 feet wide, the structure is a complex assembly of 97 intricately carved pillars, 17 domes, 220 stone beams, and 256 statues representing the breadth of the Hindu spiritual pantheon.

The interior layout is designed to facilitate the dissemination of knowledge. The upper floor gallery houses a comprehensive series of paintings illustrating the biography of Bhagwan Swaminarayan, a visual text that makes his life and philosophy accessible. The lower floor serves as a repository for historical relics – personal objects used by Swaminarayan and preserved by his followers.

2. BAPS Hindu Mandir

Abu Dhabi, United Arab Emirates

Construction: 2019–2024

The BAPS Hindu Mandir in Abu Dhabi is the first traditional Hindu stone temple in the Middle East (‘mandir’ means ‘temple’ in Hindi). Built on land gifted by Sheikh Mohamed bin Zayed Al Nahyan, the temple was constructed using pink sandstone from Rajasthan for the exterior and Italian marble for the interiors. The temple features seven towering shikharas (spires), housing seven revered deities from across India, as well as representing the seven emirates of the UAE. Upon entering, visitors encounter streams representing the holy rivers Ganga and Yamuna, while a beam of light symbolizes the mythological Saraswati River.

Construction in the desert environment presented specific engineering challenges. The temple is the first traditional Hindu temple to undergo complete digital modeling and seismic simulation to ensure resilience against local geological conditions. The foundation utilizes a concrete pour reinforced with fly ash to reduce its carbon footprint.

Inside, 402 uniquely carved marble pillars support the structure, which includes a ‘Dome of Harmony’ depicting the five elements of nature and a central ‘Dome of Peace’. A notable feature is the stone-carving symbolism. While Hindu narratives adorn the exterior, to reinforce the message of Vasudhaiva Kutumbakam (‘the world is one family’), the carvings also depict moral stories from Arabian, Mayan, Greek, and other ancient civilizations.

3. BAPS Shri Swaminarayan Mandir

London, United Kingdom

Construction: 1992–1995

Popularly known in Britain as the ‘Neasden Temple’, the BAPS Shri Swaminarayan Mandir was the first traditional Hindu stone temple in Europe. Constructed in less than three years, the temple required five thousand tonnes of Italian Carrara marble and Bulgarian limestone. The limestone was specifically selected for its density and durability to withstand London’s damp climate and urban pollution. The stone was shipped to India for carving, after which over 26,300 pieces were shipped to London. The specific architectural layout corresponds to the Revati Nakshatra, a lunar constellation in Hindu astrology, ensuring the design aligns with precise spatial and auspicious parameters.

The foundation itself marked a complex engineering event. At the time, it was one of the largest single concrete pours in the UK, creating a massive raft capable of supporting the immense load of the stone superstructure. The project was financed entirely by the local community through grassroots efforts, including sponsored walks and aluminum can recycling campaigns. Over 3,000 local volunteers worked on the construction itself. Beyond its function as a place of worship, the complex regularly hosts school visits and features exhibitions on Hinduism and community outreach programs. Visitors have included royalty and prime ministers.

4. Swaminarayan Akshardham

New Delhi, India

Construction: 2000–2005

Dedicated to Bhagwan Swaminarayan, BAPS Swaminarayan Akshardham is a significant example of contemporary traditional stonework. Rising 141 feet, spanning 356 feet in length and 316 feet in width, the temple was completed in five years through a collaboration of 11,000 artisans and 8,000 volunteers. More than 300 million volunteer hours went into making the complex. The temple was originally envisioned by Yogiji Maharaj (1892–1971) as a temple on the banks of the sacred River Yamuna, and completed under the leadership of his successor, Pramukh Swami Maharaj (1921–2016).

The structure rests upon the Gajendra Peeth, a three thousand ton plinth featuring 148 sculpted elephants. These depict storied elephants from various texts and pay homage to the foundational support of the animal kingdom.

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Above them rises the temple’s intricately carved outer wall, the largest such wall built in India in eight centuries. It depicts animals like lions and elephants, followed by floral motifs, culminating in a layer adorned with various sculptures of deities and sages. The temple itself incorporates 20,000 statues across its 234 pillars and nine ornate domes. The pillars and ceilings depict various incidents and virtues from the life of Bhagwan Swaminarayan. The complex extends beyond the sanctuary to include educational facilities, featuring exhibitions, a cultural boat ride, and a multimedia water show depicting events from the Upanishads, some of the central Hindu religious texts.

5. Pramukh Swami Maharaj Smruti Mandir

Sarangpur, Gujarat, India

Construction: 2018–2023

The Pramukh Swami Maharaj Smruti Mandir represents a specific category of Hindu temple architecture known as a Smruti Mandir, or memorial shrine. Located in Sarangpur, this temple marks the cremation site of Pramukh Swami Maharaj (1921–2016), a significant figure in modern Hinduism who oversaw the construction of more than 1,200 temples, including the Akshardham complexes. Within Hindu traditions, sites associated with the final rites of enlightened spiritual leaders and virtuous figures are sacred spaces.

The temple is constructed entirely from pristine white Makrana marble, the celebrated Rajasthan stone used in the Taj Mahal. It features a single central dome and detailed carvings that illustrate the narrative of the guru’s life and global travels. The temple functions as a canopy over the specific site of the funeral rites. The original cremation spot has been preserved in its raw state within a transparent casing alongside the ashes, allowing visitors to view the ground directly. The current spiritual head, Mahant Swami Maharaj, inaugurated the temple with the stated objectives of fostering peace, faith, and the fulfillment of personal wishes.

6. BAPS Shri Swaminarayan Mandir

Chino Hills, California, United States

Construction: 2004–2012

The BAPS Shri Swaminarayan Mandir in Chino Hills presents a specific engineering application: reconciling the rigidity of traditional stone architecture with the safety requirements of a high-risk seismic zone. Located in the San Bernardino region, an area known for frequent tectonic activity, this structure is the first traditional Hindu temple designed with a base-isolation system. The exterior features pink sandstone from Rajasthan; the interior uses white Italian marble from Carrara.

To protect this brittle stone assembly from ground motion, the structure rests on a system of 40 base isolators – consisting of steel plates stacked with a viscous liquid – which mechanically separate the upper temple from its foundation. This mechanism is designed to allow the heavy edifice to shift laterally during an earthquake, effectively enabling it to ‘float’ independently of the ground. Engineers and architects refer to this configuration as the ‘floating mandir’.

The project required navigating complex regulatory and height restrictions. Temple representatives engaged with local officials and residents to explain the cultural and religious significance of the traditional spires to secure approval. Beyond the temple itself, the complex includes a cultural center, which houses a museum dedicated to the history and details of Hindu architecture. The site operates largely on solar energy, merging traditional aesthetics with modern ecological standards.

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7. Birla Mandir

Kolkata, West Bengal, India

Construction: 1970–1996

The Birla Mandir in Kolkata was sponsored by the industrialist Birla family, whose name it bears. The construction took 26 years. While the temple is consecrated to the Hindu deities Lord Krishna and his consort Radha, the complex also houses shrines for other major deities including Shiva, Durga, and Shakti.

Constructed from white marble and cream-colored sandstone, the edifice reflects a synthesis of regional aesthetics. It draws primary inspiration from the Lingaraj Temple in Bhubaneswar while incorporating elements of Rajasthani architecture and modern styling. The design principles are rooted in the Brihat Samhita, an ancient Sanskrit text that outlines precise standards for temple architecture and iconography. Standing 160 feet tall on a raised platform – a classical feature intended to separate the sacred space from the street – the structure is a defining landmark of the Kolkata cityscape.

The temple’s interior and exterior are notable for their didactic ornamentation. Intricate carvings depict pictorial narratives from Hindu philosophy and scenes from scriptures like the Bhagavad Gita. The project sustained a hired workforce of artisans from the city of Muzaffarpur in Bihar for over two decades, playing a crucial role in preserving traditional masonry skills.

Tilak Parekh is a researcher of religion and anthropology at the University of Cambridge.

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The phones we carry around in our pockets have two million times more memory and are thousands of times faster than the room-sized computers that guided the Apollo mission to the Moon. This incredible shrinking act has been driven by our ability to make transistors smaller and smaller.

Each transistor is a microscopic switch that can alternate between a one and a zero, the basic language of all computing. Billions are packed onto tiny silicon chips called semiconductors. The more transistors that fit onto a chip, the more logic and memory circuits it holds, and the more it can do.

Advanced semiconductors are, arguably, the most important technology in the world. Over the last five years, they have even emerged as a geopolitical flashpoint between the US and China. But for all this rivalry, any country or company that hopes to manufacture semiconductors is dependent on a single firm: ASML. Dubbed ‘a relatively obscure Dutch company’ by the BBC in 2020, ASML makes the only machines in the world capable of stenciling the transistors onto chips with the precision necessary to fit billions on a 30-centimeter wafer.

These machines are roughly the size of double-decker buses. To ship one requires 40 freight containers, three cargo planes, and 20 trucks. They are the world’s most complex objects. Each contains over one hundred thousand components, all of which have to be perfectly calibrated for the machine to produce light consistently at the right wavelength.

While ASML is now the sole supplier of these machines, and will be for some time to come, it started out as a laggard in the chipmaking industry. Overtaking its competition required many things rarely associated with European companies: close collaboration with the American government, selling large stakes to foreign competitors, and a huge gamble on an unproven technology.

Let there be light

The key to ASML’s success is a technology called photolithography (sometimes just called lithography). The technique involves transferring a pattern onto a semiconductor wafer by exposing it to light. In the 1950s, the first chipmakers had tried to draw these patterns by hand, but anything that physically touches the wafer scratches it, dirties it, or warps the pattern. Scientists working independently for Bell Labs and the US military realized that they could use light to print identical patterns without making physical contact with the wafer.

To make chips, engineers start with a thin wafer of semiconductor material, usually silicon. This wafer is coated with a chemical called photoresist, which reacts when exposed to light. In photolithography, light is projected through a detailed pattern onto the photoresist-coated wafer, softening the exposed areas. The wafer is washed to remove any softened areas, revealing the silicon underneath. It is then moved to an etching machine that blasts it with charged chlorine or bromine gas, carving the desired pattern into the exposed silicon. These features are later filled with metal, such as tungsten and copper, to connect the transistor to power. These etched layers then combine into an intricate network of transistors.

Over time, the semiconductor manufacturing ecosystem has developed increasingly sophisticated etching using ever smaller wavelengths of light. Smaller wavelengths diffract less, allowing the light to travel in straighter lines and print sharper, tinier details without blurring. These allow for more precise pattern projections that, in turn, allow smaller and more densely packed transistors.

Early lithography relied on mercury vapor lamps that were similar to streetlights, while more modern machines rely on lasers created using argon and fluorine gases. By 2010, such lasers made it possible to create a 22-nanometer feature through multiple exposures using a 193-nanometer wavelength.

The most advanced version of this technology, extreme ultraviolet lithography, is used to make the very smallest chips. The smallest in 2025 were marketed as three nanometers, roughly 25,000 times thinner than a human hair.

To make them, a droplet of liquid tin is released into a chamber and hit with a single pulse of light, which melts and flattens it. As the droplet continues to fall, a second, more powerful pulse vaporizes the tin, creating an extremely hot plasma that emits light at the narrow wavelengths needed for extreme ultraviolet lithography. The light beam is then concentrated by reflecting it across a series of slightly concave mirrors so flawless that, if scaled to the size of Germany, their imperfections would be measured in millimeters. Engineers need to use mirrors, rather than the glass lenses used in standard lithography, as almost all solid materials absorb light at such short wavelengths.

The light eventually hits the mask, which contains the pattern to be printed on the chip. As the pattern on the mask is usually several times larger than what is wanted on the chip, the light is then reflected by a second system of mirrors.

After the light reflects from the mask, it carries the pattern as a bundle of rays spreading out from each point. The next mirrors tip these rays inward so that, instead of spreading widely, they reunite over a shorter distance. When the rays from each point come together sooner, the picture they form is physically smaller. By repeating this with several carefully shaped mirrors, engineers shrink the pattern by a fixed amount while keeping it in focus. After being shrunk four times, it hits the wafer.

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The great shrinking act

Longer wavelengths act like a blunt chisel, suitable for rough shaping, but they struggle to capture finer details. The longer light waves are larger relative to the tiny features on the reticle that they must reflect from. When a wave meets something smaller than itself, it naturally spreads and bends around its edges instead of casting a sharp shadow. To create the same details, the blunt chisel needs to go over the same spot a number of times (creating blurrier edges). Lithography had to take wavelengths all the way to the extreme ultraviolet range to achieve the high resolution patterning needed for cutting-edge process nodes.

Wavelengths as low as 13.5 nanometers can achieve more precise patterns in a single exposure. In fact, extreme ultraviolet lithography can combine three or four photolithography patterning cycles into a single one on a seven-nanometer node. Without EUV, producing five-nanometer nodes might require as many as one hundred different steps.

Extreme ultraviolet lithography was able to produce more accurate patterns on wafers than older techniques even if they were used multiple times.

Today, ASML dominates the overall market for lithography and has an effective monopoly in extreme ultraviolet lithography. Its EUV machines sell for more than $120 million. With a market capitalization of over $400 billion, ASML is one of Europe’s most valuable companies. But it wasn’t always like this.

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Origins

ASML started off life within Philips, the Dutch consumer electronics giant. During the 1970s, Philips had roughly 20 percent of the global electronics market and was a major chipmaker. In this era, lithography machines used wavelengths of over 400 nanometers to pattern 1,000-nanometer features. The industry struggled to shrink features without losing accuracy or letting dust and flaws creep in. Philips began to work on its own prototype, drawing on its expertise in optics and precision mechanics. By the early 1980s, the project was running into trouble. The company was looking to cut costs and engineers estimated that they would need over $280 million in today’s money to finish the machine’s development and production.

In 1984, Philips spun out Advanced Semiconductor Materials Lithography (which later dropped the full name in favor of its acronym) as a joint venture with ASM International, a Dutch conglomerate that sold equipment to the semiconductor industry. The business originally struggled. It had no market share and no brand recognition. Its first product, the PAS 2000, was a commercial failure. The machine used oil pressure, like that in power steering, to move the table that held the wafer during exposure, rather than electric motors. This made it smooth and precise, but it was prone to leaking. At the first conference ASML attended, one industry executive told them: ‘The race has already been run. There’s no room for you here.’ ASML switched back to electric motors.

The company took an unusual approach from the outset. While Japanese giants Nikon and Canon were vertically integrated, ASML outsourced key components like optics and motors so that it could focus on assembling and optimizing the final machine. Given this outsourcing, it made sense for ASML to embrace a modular design with clearly defined subsystems. This approach was mocked in European manufacturing circles. German engineers warned ASML’s leadership that they were ‘asking for trouble’ and would ‘lose all control’ if they didn’t make critical components themselves. But ASML had no choice: it lacked the capital, expertise, and time to build these subsystems from scratch.

By 1988, ASML was on the verge of collapse. ASM International had already pulled out, and Philips considered shutting it down. It was saved by a single Philips board member, Gerd Lorenz, who was particularly worried about Europe’s growing dependence on Asia for strategic technology. Lorenz argued that Europe needed a stake in chip manufacturing. This was enough to convince Philips to give ASML more time, but didn’t fix its fundamental problem: it was still an inferior supplier with no competitive edge.

ASML used the time it was given to develop the PAS 5500, released in 1991 and the company’s first commercial breakout. While Nikon’s contemporary photolithography system was more precise, ASML’s modular design meant that machines could be fixed quickly on site. This reduced downtime and, by making it easy to replace parts when they broke, it was possible to extend the machine’s life. This was a key factor that led John Kelly, IBM’s director of semiconductor R&D, to push IBM to order the PAS 5500 over the Japanese machines. ASML had gone global.

The first breakthroughs

ASML’s success depended on two projects in the late 1990s and 2000s that gave it a huge advantage in research and development. The first was a public-private partnership, started in 1997, called the Extreme Ultraviolet Limited Liability Company. The Extreme Ultraviolet Limited Liability Company began life as a rescue mission. Before 1997, basic semiconductor research was carried out in a small handful of research labs, all dependent on government grants.

The original program for EUV research was a ‘virtual national lab’ that combined Lawrence Livermore National Laboratory, Sandia National Laboratories, and the Lawrence Berkeley National Laboratory. Each covered a different component: Livermore focused on mirrors and optics, Sandia on the light source and systems engineering, and Berkeley on advanced equipment for testing. But in 1996, Department of Energy budget cuts had placed the virtual national lab program on the chopping block.

Intel, then the undisputed world leader in microprocessors, was keen to preserve the work and spearheaded the creation of the Extreme Ultraviolet Limited Liability Company, the largest public-private partnership of its kind in the history of the US Department of Energy. During its six-year life, the company invested over $270 million into extreme ultraviolet lithography development, funded by the sale of shares to member companies, giving them a right of first refusal to purchase the photolithography tools being produced.

The company initially restricted membership to American firms. ASML, along with its main Japanese rivals, Canon and Nikon, was initially barred from membership.

The only established semiconductor equipment manufacturer to join the partnership from the beginning was Silicon Valley Group, which had a market share of just 5 percent to ASML’s 20 percent. Fearing the danger of being reliant on such a small manufacturer, the rest of the companies involved concluded that it would be better to open up to foreign firms, rather than risk ceding the entire market.

ASML was allowed to participate so long as it committed to establish a research center in the US and source 55 percent of components for the systems sold in the US from American suppliers. In practice, this commitment was never enforced. Its Japanese competitors were never allowed to join, due to widespread fear in the US of Japanese competition.

The program built up a vast base of intellectual property and process knowledge. These types of public-private partnerships typically grant the participating companies a non-exclusive license to use the intellectual property generated, but in this case the companies in partnership got complete ownership.

In 2001, ASML acquired Silicon Valley Group after it ran into cash flow difficulties, making ASML the sole surviving equipment manufacturer in the partnership. When the consortium produced the first full-scale extreme ultraviolet lithography prototype – the Engineering Test Stand – ASML stood alone at the vanguard of lithography. This was the first demonstration that 13.5-nanometer light could print dense features on a chip.

By the time the Engineering Test Stand was built, the program had already proved that it was possible to generate extreme ultraviolet light reliably, which let engineers start building mirrors and lenses that could be used in real production tools. To solve outstanding questions, such as how to boost the throughput of their machines or increase the power of their light sources in production settings, ASML needed to test its machines in environments close to the real world. But no chipmakers were willing to shoulder a project so large and risky at such an early stage.

The second project essential to ASML’s success was the Belgium-based Interuniversity Microelectronics Centre (IMEC), a research organization that collects machines from different companies and allows researchers to test them in semi-real environments while protecting the companies’ intellectual property.

As potential customers began to consider different options for next generation lithography technologies, ASML used IMEC to promote its extreme ultraviolet lithography prototype. Topping ASML’s target list was TSMC, which today is the world’s largest semiconductor foundry. Founded in 1987, TSMC’s history had been intertwined with ASML’s since its birth: Philips, ASML’s former parent, owned a 27.5 percent stake in it. Seeing ASML’s machinery exhibited at IMEC was what led TSMC to partner with ASML in EUV development.

By contrast, Canon and Nikon were tight-lipped about their research and made little effort to cooperate with outside companies. While this theoretically allowed them to maintain greater control over their work, and capture more of the value chain, it also made them solely responsible for simultaneously solving a bewildering array of fundamental physics problems, while assuming all the financial risk of doing so.

Since almost all of the parts in ASML’s machines are made by other companies, it has become master of a sprawling supply chain of over five thousand companies. It has diversified its suppliers over the years in a very deliberate way: 80 percent of its spending goes to companies across Europe and the Middle East (notably not the US, despite prior agreements), which reduces the risk of potential export restrictions, tariffs, and other geopolitical risks that may face critical suppliers based in the US or Asia. It also aims for its suppliers to make no more than 25 percent of their revenue from ASML, to force them not to become overreliant on the volatile semiconductor market.

While most of its components come from a large number of small suppliers, ASML has formed deep bonds with its biggest suppliers. It acquired a 24.9 percent stake in optics manufacturer Zeiss. Peter Leibinger, vice chairman of laser manufacturer Trumpf, has said that ASML and Trumpf are a ‘virtually merged company’.

Winning the war

Extreme ultraviolet lithography would not become a successful commercial technology until 2018, over 20 years after the creation of the Extreme Ultraviolet Limited Liability Company and 34 years after IMEC was founded. In the meantime, it was consuming more and more resources. By 2015, ASML was spending more than $1 billion a year on R&D, more than double its 2010 total. According to some estimates, by 2014, the industry had collectively invested over $20 billion in extreme ultraviolet lithography, with no guarantee of any return.

ASML was able to continue pouring money into this black hole partly because it had already beaten its competitors. By 2010, it had two thirds of the overall lithography market and was the dominant supplier for the rapidly growing smartphone market, with deep ties to Intel, Samsung, and TSMC. It had secured this position by winning the decisive technical battle of the 2000s.

At the start of the millennium, the entire semiconductor industry hit a physical wall. Circuits had been getting steadily smaller for decades by simply switching to shorter wavelengths, but the standard 193-nanometer light (roughly one five-hundredth of the thickness of a human hair) was too blunt to draw smaller circuits.

Nikon tried to solve this by developing a new light source with a smaller wavelength of 157 nanometers. But this shorter wavelength light was absorbed and distorted by standard glass, forcing Nikon to build lenses out of calcium fluoride, a rare, brittle crystal that was expensive to polish and prone to cracking under heat. The industry poured hundreds of millions of dollars into this ‘dry’ lithography path, only to find the manufacturing challenges insurmountable.

ASML’s partnerships helped it avoid this dead end. TSMC researcher Burn Lin had advised them to switch to a technology called immersion lithography. ASML continued to use 193-nanometer light but placed a layer of water between the lens and the silicon wafer. Just as a straw appears bent and magnified when placed in a glass of water, the water in the machine bent the light waves, sharpening the focus and allowing smaller circuits to be printed without needing new lenses.

ASML compounded this advantage by introducing a revolutionary machine architecture called TWINSCAN. In older machines, the light source would sit idle while the machine stopped to measure the surface of the silicon wafer to ensure it was flat. ASML replaced this with a dual-stage system: a massive machine with two tables would measure one wafer in the background while another was being printed simultaneously. This eliminated the dead time in the manufacturing process, allowing chipmakers to produce significantly more chips per hour. By the time Nikon abandoned its 157-nanometer project in 2005, ASML had become the industry standard, with 53.2 percent of the market.

ASML’s machines were so much better than the competition that it could charge nearly twice as much for them: $55 million versus $30 million for the comparable Nikon device.

But even this was not enough. While ASML was beginning to ship prototype EUV machines to IMEC from 2006 onwards, they were so slow and prone to breaking down that they were commercially useless. In 2012, ASML, still reeling from the global financial crisis, was struggling to continue financing its EUV efforts.

In a drastic move – part desperate attempt to keep the company’s research efforts afloat and part strategic bet to win the EUV market once and for all – the ASML leadership launched a co-investment program that sold 23 percent of the company to its three largest customers: Intel, TSMC and Samsung.

The funding also allowed ASML to complete a $2.5 billion acquisition of one of its suppliers, Cymer, which produces lithography light sources. The acquisition allowed ASML to invest in Cymer’s R&D efforts to perfect its soft X-ray light source, which involved hitting fast-moving droplets of tin with such force that they lost electrons, but precisely enough that this did not shed so much debris that it coated the mirrors. They accomplished this by moving from a single pulse to two separate laser pulses: the pre-pulse would shape the droplet and the main pulse would generate the plasma. This improved efficiency and stability.

ASML’s close partnership with TSMC proved especially critical. In 2014, TSMC launched its first chip for Apple, which was now its largest customer and was putting pressure on the chipmaker to produce higher performance chips than its existing machinery was capable of. It had become urgent for ASML to complete a commercial EUV machine.

The two companies worked so closely together that Anthony Yen, the Division Director at TSMC responsible for overseeing EUV development, described them as ‘one team’. ASML and TSMC engineers on the ground worked tirelessly, troubleshooting and iterating until they had reached the necessary throughput: 500 wafers a day for a month.

During this period, the joint team redesigned both the tin-droplet generator and the way the laser hit each droplet. The new setup produced droplets that were about half the original size while still yielding the same ultraviolet energy. Smaller droplets throw off far less debris when vaporized, which slows the rate at which tin builds up on the collector mirror. Because the mirror degrades more slowly, it needs fewer replacements, keeping the machine up and running for longer stretches.

The partnership was a win for ASML, as it was able to work through some of its key engineering and commercialization challenges. It also helped TSMC become an early adopter of the most cutting-edge technology. By 2019, TSMC was ramping up mass production of its seven-nanometer process and the first phones with EUV chips were being sold by the end of the year.

Meanwhile, competitor firms like Nikon, which had never believed as strongly in extreme ultraviolet lithography, effectively gave up. In its 2013 annual report, Nikon noted that its own EUV progress had not proceeded as planned, and it was not mentioned in an annual report again. With ASML pulling ahead on R&D and locking up key customer demand, and with competitors struggling to justify their own R&D spending in the wake of the financial crisis, ASML became the last company standing in the race to commercialize the technology.

The importance of tacit knowledge

Early on, ASML cultivated a culture that was more risk tolerant than other players in the industry. It promoted high-potential talent early and had a track record of retaining key employees for decades. Much of this is a product of its challenging early years. ASML needed the talent of its younger generation to save the company, so it was more willing to promote and empower them quickly.

For example, Martin Van Den Brink joined ASML in 1984. Within 18 months, aged 29, he became one of two people promoted to lead the development of one of the company’s early flagship projects. He carried on working at ASML for his entire career, serving as president and chief technical officer until his retirement in 2024. This practice was far less common among ASML’s Japanese rivals, who were more hierarchical and tended to reward seniority over performance.

Retaining the best workers is especially crucial in an area like photolithography, where a huge amount of tacit knowledge is used to assemble its machines. An ASML engineer once told He Rongming, the founder of Shanghai Micro Electronics Equipment, one of China’s top ASML competitors, that the company wouldn’t be able to replicate ASML’s products even if it had the blueprints. He suggested that ASML’s products reflected ‘decades, if not centuries’ of knowledge and experience. ASML’s Chinese competitors have systematically attempted to hire former ASML engineers, and there is at least one documented case of a former ASML employee unlawfully handing over proprietary information. But none of this appears to have narrowed the gap.

A European giant

ASML is a rare example of a European tech giant. Its success was the result of transatlantic cooperation, not continental parochialism. Had the company not joined a program funded by US chipmakers, Canon and Nikon would likely still dominate a less advanced lithography industry.

Cooperation with other companies was just as important. While vertical integration gave Nikon and Canon total control, it capped their innovation at the limits of their internal resources. In a system exceeding one hundred thousand components, that ceiling proved fatal. ASML’s modular approach allowed it to import cutting-edge physics by acquiring Cymer and investing in Zeiss, while distributing the risk to customers like Intel and TSMC. This strategy created a collective engine that outspent and outpaced every rival attempting to shoulder the burden alone.

This took a great deal of courage. ASML sank billions of dollars into the development and commercialization of EUV technology, with no guarantee that it would ever work. As late as the 2010s, many semiconductor experts doubted that the technology could be successfully commercialized. Now it is the most important technology in the world.

But ASML, and by extension the continent, cannot stand still. As ASML enjoys its place as an indispensable pillar in one of the world’s most important industries, others are working to create a new paradigm in chip technology. Moore’s Law probably doesn’t end here, and in a matter of years, five nanometers won’t be small enough.

Neil Hacker runs partnerships at Isometric. Follow him on Twitter.

A few days after Sasse’s interview, in April 2026, Revolution Medicines announced Phase 3 trial results for daraxonrasib showing the drug had roughly doubled survival in patients with metastatic pancreatic cancer compared to standard chemotherapy. For a disease where median survival has long been measured in months and where little had changed for decades, that result represents a genuine turning point.

But the significance extends beyond pancreatic cancer. Daraxonrasib is among the first drugs in an emerging generation designed to target RAS, a protein implicated in roughly a quarter of all human cancers and long considered beyond reach, in all its mutant forms. And it belongs to a broader class of medicines, molecular glues, that are beginning to show what becomes possible when drugs no longer depend on finding a ready-made pocket in their target. Several compounds in this class are now in clinical development, each probing a different protein that previous generations of drugs could not touch.

Pancreatic cancer: a tough nut to crack

Pancreatic cancer has the highest mortality rate of all major cancers. Although its five-year survival rate has improved from roughly 4 percent in the mid-1990s to around 13 percent today, it remains among the deadliest of all cancer types.

Survival is so poor partially because pancreatic cancer is typically diagnosed late: the pancreas sits deep in the abdomen, symptoms are vague and late to appear, and by the time most patients are diagnosed, the cancer has already spread. This feature has earned pancreatic cancer the name ‘silent killer’. Metastatic cases, where the tumor has already spread to other organs, represent more than half of all new diagnoses. For these patients in particular there has been minimal improvement in outcomes over recent decades, with just 2 to 3 percent still alive five years after their diagnosis.

For decades, no fundamentally new and effective treatments for metastatic cancer emerged. That changed in 2011, when a wave of innovation began transforming the field. At the heart of this renaissance are immunotherapies: drugs that harness the body’s own immune system to fight cancer. Among them are checkpoint inhibitors, which work by releasing the natural brakes on immune activity, and CAR-T therapies, a new class of anti-cancer wonder treatments which engineer a patient’s own immune cells into precision cancer-fighting weapons.

These treatments have redrawn the boundaries of what is possible in oncology. In metastatic melanoma (the most serious type of skin cancer), immunotherapy has produced results once thought unimaginable: from only 25 percent survival after one year twenty years ago to 50 percent survival after 10 years now. Unfortunately, metastatic pancreatic cancer is particularly good at protecting itself against immune attack and has thus remained beyond the reach of this newer wave of drugs.

Pancreatic tumors build a shield around themselves to evade immune attack. They are surrounded by a dense, scar-like layer of tissue that physically blocks a patient’s immune cells from entering the tumor. As a result, checkpoint inhibitors, which work by reactivating immune responses, often have little effect. CAR-T therapies also struggle to penetrate this physical barrier. Even when immune cells do manage to get inside, the tumor creates a hostile environment that weakens them. It does this by attracting suppressive immune cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and by releasing molecules that dampen immune function.

There is a further problem that compounds this. Immunotherapy tends to work best against genetically ‘noisy’ tumors: cancers with many mutations that generate abnormal surface proteins, known as neoantigens, which help the immune system recognise the cell as foreign. Melanoma is a classic example. Driven by UV-induced DNA damage, it often carries a heavy mutational burden and is therefore more susceptible to immune attack. Pancreatic tumors, by contrast, are comparatively quiet. They contain fewer mutations, and can remain largely hidden from immune surveillance.

Yet despite these disadvantages, pancreatic cancer has one feature that should, in theory, make it highly targetable: KRAS mutations, which are found in more than 90 percent of cases. A mutation this common, and so central to the cancer’s biology, ought to be a gift to drug developers: a clear and identifiable target around which therapies could be designed. In practice, however, it proved far more difficult.

Targeting RAS

The genomic revolution promised, among other things, that we would crack cancer. When the Human Genome Project concluded in 2003, the optimism was intoxicating. If cancer was fundamentally a disease of mutated DNA, then sequencing that DNA would tell us exactly what to target and how. What researchers hoped is that we would be able to find the broken gene, design a drug to block its protein, and shut the cancer down. Precision medicine, we were told, would transform oncology by swapping the bluntness of the old chemotherapy approaches into something more like a guided missile.

More than twenty years later, the progress has been mediocre. Two problems have stood in the way of realizing the genomic promise. The first is evolution: tumors have genomes that can change rapidly, and under the selective pressure of a targeted drug, resistant clones can emerge and allow the cancer to adapt around the treatment. The second problem is even more fundamental: many of the mutations that drive cancer produce proteins that simply cannot be targeted by conventional drugs.

RAS is one such example. RAS is a molecular switch. In its normal state, it cycles between an active ‘on’ position and an inactive ‘off’ position. When a cell receives a signal to grow or divide, RAS flips on, relays the message downstream through a cascade of other proteins, and then switches itself off again. It is, under normal circumstances, a tightly regulated relay station.

Cancer hijacks this system through mutations, which are small but catastrophic in their effect: they lock RAS permanently in the ‘on’ position. Cells receive a continuous, unrelenting instruction to proliferate, regardless of what the rest of the body is telling them.

For over two decades, RAS carried one of the most dispiriting labels in drug discovery: undruggable. This was not for want of understanding. RAS is in fact one of the most studied proteins in cancer biology, mutated in roughly 25 percent of all human cancers, and in over 90 percent of pancreatic cancers. In lung adenocarcinoma and colorectal cancer, the figure sits between 30 and 45 percent. The problem lies in the fundamental geometry of the protein.

Most cancer drugs are small molecules or compounds precisely shaped to slip into a pocket or groove on a target protein, jamming its function the way a foreign key might get stuck in a lock. This approach depends entirely on the protein offering a suitable cavity to exploit. But RAS’s surface is unusually smooth and chemically inhospitable, presenting none of the clear binding sites that drug designers look for.

In 2013 researchers demonstrated that small molecules could, in fact, bind to a specific mutant version of RAS called G12C. This particular mutation creates a small pocket that does not exist in the normal protein. The biochemist Kevan Shokat at the University of California, San Francisco, showed that certain compounds could lock into this pocket and trap K-Ras in its inactive state.

From that insight emerged the first generation of RAS drugs: sotorasib and adagrasib, both of which bind to and ‘switch off’ the G12C-mutated RAS protein. Sotorasib received FDA approval in 2021 for RAS G12C-mutated non-small-cell lung cancer. It was also, for pancreatic cancer patients, largely useless. The G12C mutation is common in lung cancer but rare in pancreatic cancer, accounting for only around 1 percent of cases. The vast majority of pancreatic tumors carry a different RAS mutation entirely, that does not form such a cavity in the protein.

Molecular glue

Molecular glues entered cancer medicine before they had a name. In the late 1990s, thalidomide, a drug infamous for causing birth defects decades earlier, showed unexpected activity against multiple myeloma. Its analogue lenalidomide was approved for multiple myeloma in 2006 and became one of the defining drugs in the disease. Only later, beginning with the identification of cereblon as thalidomide’s target in 2010, did scientists realise that these drugs worked as molecular glues.

Molecular glues take a different approach from most small molecule drugs. Rather than binding a pocket, they create new connections between proteins. A molecular glue binds to the surface of one protein and, in doing so, alters that surface’s chemistry just enough that a second protein is now attracted to it. The two proteins, which might never normally interact, are held together by the glue acting as a chemical intermediary, for example by adding new contact points, or bridging surfaces that would otherwise repel or ignore each other. Because this strategy doesn’t depend on finding a pre-existing cavity, it opens up proteins that have long been considered beyond reach.

After the mechanism of molecular glues was understood, scientists started to think about targeting RAS. But progress required more than understanding molecular glues in principle. Scientists had to recognise that Cyclophilin A, a protein that is common in human cells but with no prior connection to cancer, could serve as a bridging partner, and that a small molecule might hold it against RAS. Seeing whether that was even possible required advances in cryo-electron microscopy, a technique can capture the fleeting, multi-protein assemblies that a molecular glue would need to stabilise. Only once the interface between RAS and Cyclophilin A was mapped precisely enough could a bridging compound be designed.

Daraxonrasib is that compound. It binds Cyclophilin A first, and the two form a combined unit whose reshaped surface fits snugly against the active form of RAS, locking the three components together. Cyclophilin A then simply takes up space, blocking RAS from making contact with its downstream partners.

In the Phase 3 trial, patients treated with daraxonrasib experienced a median overall survival of 13.2 months, roughly twice as long as those who received standard chemotherapy: just a prolonging of survival, not a cure. But for a disease that was otherwise so untreatable, doubling survival with a daily pill rather than intravenous chemotherapy is, by the standards of pancreatic cancer, a genuine advance.

The limits of targeted therapy

Daraxonrasib’s clinical success has been real, but resistance inevitably emerges. Analysis of patients treated with the drug has already revealed the tumor’s counter-moves. Some cancers acquire mutations at positions on the RAS protein itself, such as Y64, that physically prevent the molecular glue from forming the complex with Cyclophilin A. Still others amplify copies of KRAS itself, or activate parallel signaling pathways, rerouting growth signals through channels the drug cannot reach.

Because resistance to any single agent is essentially guaranteed, the future lies in combinations: hitting multiple vulnerabilities simultaneously, or switching strategies as the tumor evolves. But doing that well requires being able to test new approaches quickly and in small, targeted patient populations. This sits uneasily with a regulatory framework built around several rounds of trials in multiple patients. Matching the right drug to the right mutation in the right patient, in something close to real time, will require that framework to change. One important idea is making small-scale Phase I investigator initiated trials much easier to carry out.

The broader lesson of this era, though, is one of optimism. As well as RAS, the cancer field has scored another win against a previously ‘undruggable’ target, PI3Kα, another commonly mutated protein in cancer. Inavolisib, which both inhibits and destroys the mutant form of the protein, roughly doubled progression-free survival in PIK3CA-mutated advanced breast cancer when added to standard treatment. The assumption that certain targets are simply beyond reach has repeatedly turned out to be wrong.

They discuss which public goods local government is best placed to provide, why America has better housing outcomes than its reputation suggests, and when national government needs to constrain local power.

You can also watch the rest of the episode on Apple Podcasts, Spotify, and YouTube.

You can read Judge Glock’s piece on why water in America is too clean here.

The list below is a sample of topics. We also want to broaden the types of pieces we publish. The historical case study has become our staple, and we’ll keep running them. But some of our best early work took other forms, like Stephan Guyenet’s 2021 feature on semaglutide, or Keller Scholl’s diary of a Zika vaccine trial. We’d like to do more pieces like those: more narrative journalism, more diaries, and more reporting. If you have an alternative format in mind, please pitch it.

Writers interested in pitching should email wip-pitches@stripe.com with a brief introduction, the pitch in question, and a few paragraphs setting out the argument and the evidence behind it. Our pitching guide can be found here. It is worth reading carefully, as our requirements are not those of other publications.

The importance of cheap capital. Scotland got rich in the 1700s and 1800s due to good banking institutions. China researches and invests at impressive rates today, in part due to restrictions on where capital can be invested, and on consumption spending. Europe has fallen behind American growth since 2010, perhaps because banking has prevented the flow of credit. Capital matters a lot. Are these stories true? What does it tell us about what poor or stagnant economies should do differently?

Did Prohibition work? Alcohol prohibition in the United States is remembered as a failure, but alcohol consumption did fall sharply, and its impact on health outcomes, traffic accidents, and domestic violence was probably not trivial. Did it work after all? Were any of its benefits enduring?

A history of the Stein-Hardenberg reforms. In the early nineteenth century, Germany’s economic life was largely organized around serfdom, the guilds, and a complicated structure of jurisdictions inherited from the late Middle Ages. After Prussia’s defeat by Napoleon in 1806, two chief ministers, Karl vom Stein and Karl August von Hardenberg, embarked on an enormous program of reform. Within a few years, serfdom had been abolished, land reformed, the guilds crushed, local government established, and the foundations of industrialization laid. We’d love to read a good history on this episode, of the kind we published on the Hanseatic League.

How Emmanuel Macron undermined the French growth machine. Until the late 2010s, French physical growth was legendary. It built highways, high-speed rail, industrial areas, homes, and energy infrastructure at a pace to inspire envy. But since Macron reformed local property taxes in 2018, this growth machine seems to have disappeared. What happened? What did the reform change, why, and is there a path back?

The Korea divergence. North and South Korea shared a language, culture, and economic base in 1945, and by some measures the North was more industrialized as late as the 1960s. It’s one of the most striking natural experiments in development economics. How similar were they really, how quickly did the gap open, and how large is it now?

North Korean baby bust. We’d also like an article on North Korean birth rates, which seem to be falling rapidly, although probably less quickly than in the rest of East Asia. What does North Korea’s trajectory imply for the prevailing explanations of the “baby bust”?

The spread of tipping. Over the past ten years, a practice once confined to American restaurants has migrated to coffee shops and hamburger stands around much of the world. The cause seems to have been Square’s payment terminals, which made soliciting tips convenient and the default option. But was this inevitable? In particular, we’d like a piece that tells this history from the inside: what led to the design choice, and how important was terminal design really?

What happened to Polish fracking? Europe has large reserves of shale gas. It is often argued that the lack of exploitation is due to regulatory obstacles: many European countries banned fracking over the last ten years. But Poland has reserves, started drilling in 2010, granted licenses to foreign producers, and still didn’t extract any gas. Why?

Modern architecture in Bhutan. After the Second World War, modernist architectural styles became dominant around the world. There is only one exception: the mountain kingdom of Bhutan. Still today, every normal house, flat and office block is built in the old style of Bhutan, with deep eaves, colorful brackets, and timber-mullioned windows. How did this happen? What challenges have Bhutanese builders faced as a result? How is Bhutan’s unique trajectory seen by its people today?

How to make an anti-addiction drug. Addiction was treated as a moral failing long after it was understood to be a neurological condition. But now many anti-addiction medicines are available, including methadone, buprenorphine, and naltrexone. How have addiction medicines been developed, and how do the different ones work? Are there more coming through the pipeline?

How gas turbines became so efficient. Few artifacts of modern civilization are as optimized as the gas turbine. This efficiency rests on a long accumulation of innovations: single-crystal blades, ceramic coatings, internal air cooling, computational fluid dynamics, and ever-higher firing temperatures. Who deserves credit for these improvements? More importantly: how much further could we go?

The world’s most successful land reform. Plots in both the Indian and Pakistani Punjab are efficient squares, contrasting starkly with the inefficient customary strips that predominate across the rest of the subcontinent. This, plus historic irrigation schemes, explain why it is the region’s breadbasket. How did Victorian-era governors and post-WW2 Indian farmers pull this huge reform off?

Cycling in the Netherlands. It is well known that the Dutch are keen cyclists: they are about ten times more likely to travel by bicycle than the French, British or Spanish, let alone Americans or Australians. But the explanations standardly given for this are obviously inadequate: the Netherlands may be flat and temperate, but it is hardly unique in this. Why, then, has cycling ended up playing a completely different role in Dutch life than it has in almost any other modern society?

The long wait for RNAi crops. RNA interference, which is the cell’s natural mechanism for silencing genes, was first observed in plants in the 1980s, and has been understood well enough to engineer for decades. But the first RNAi-based pesticide only cleared EPA approval in 2023. What applications could it have in agriculture?

Medical specialization. South Korea has become the world leader in cosmetic dermatology, Turkey in hair transplants, Spain in IVF. Are these concentrations accidental or do they reflect regulation, funding or agglomeration? How did these clusters emerge, and what can they tell us about how medical innovation and expertise develop?

Inflation, disorder, and social trust. Countries around the world are seeing upswings of extremist politics and populism. Is this all down to inflation? This article would go through the historic links between inflation and social and political disorder. Did inflation contribute to Nazi Germany? Did inflation end the Soviet Union? Might it have ended the Roman Empire? Can the price system be sustained in the face of high inflation today?

Embrapa and R&D in the developing world. Brazil’s agricultural research corporation transformed the cerrado – a vast tropical savanna once considered unfit for farming – into one of the world’s most productive agricultural regions. How was Embrapa set up, and what did it do? What does it tell us about publicly funded R&D in low- and middle-income countries?

The brain’s locked door. The blood-brain barrier keeps pathogens and toxins out of the brain with remarkable efficiency, as well as nearly every drug we try to send to it. That makes it incredibly hard to develop safe and effective treatments for conditions like Alzheimer’s, Parkinson’s, and brain tumors. How do we crack it?

Making dynamic pricing work. People dislike surge pricing. But the practice to which it belongs is among the most useful mechanisms in modern commerce. Charging different prices to different buyers widens access to goods, allocates them toward those who value them most, and sustains markets that would otherwise be too small to serve. We would love to read a piece on the subject, either on notable historical episodes or an account of technical advances that have made modern surge pricing possible.

Why don’t we have a syphilis vaccine? Syphilis is one of the oldest diseases recorded, and is rising again across wealthy countries. Untreated, it can cause blindness, cardiovascular disease, brain damage, and in fetuses, stillbirth or severe disability. But we still have no vaccine. Why?

The invention of super glue. Cyanoacrylate, also known as super glue, was discovered by accident, dismissed, and rediscovered. Its extremely adhesive properties make it used across industries: in medicine to repair wounds and blood vessels, in forensics to lift fingerprints at crime scenes, and in the home to fix crockery in kitchen drawers. What’s the story behind super glue?

How the World Bank prevented a famine. International development institutions are typically slow-moving, long-horizon lenders. But in 2017, during Somalia’s worst drought in decades, the World Bank and other organizations deployed emergency financing fast enough to help avert a large-scale famine. What did they do?

The versatility of plastic. Plastic is one of humanity’s great creations. It extends the shelf life of food, reduces the weight and emissions of transport, and has made everything from clothing to electronics and construction materials more durable and affordable. How were plastics developed, and how did they become so widely used?

The CDC’s disease detectives. The Epidemic Intelligence Service has been training field epidemiologists and deploying them to outbreaks since 1951, including smallpox, Ebola, and COVID. What has it accomplished and how?

Where’s my p53 cancer drug? p53 is the most important protein in protecting us against cancer, and half of all solid tumors develop mutations in it. Restoring its function is probably the most obvious target in oncology. So why, decades after the discovery, do we still have no effective drugs against it? What makes p53 so hard to target, and what strategies could help to tackle it?

How the Serum Institute became the world’s largest vaccine factory. In 1966, a horse-breeder in Pune started extracting serum from his animals to make biological products. Today the company he founded supplies vaccines to more than 170 countries and was a key part of the global COVID-19 response. How did it come to dominate the market?

When Germany was the world’s scientific engine. For roughly a century from the 1820s onward, the German-speaking world produced a remarkable concentration of scientific talent across physics, chemistry, mathematics, medicine, and philosophy. What created the conditions in the first place? Was it specific institutions – such as the Humboldtian research university, the academies, the seminar system – or state patronage, the fragmentation of German principalities, or something else entirely?

Bonds for R&D. Governments borrow to build infrastructure on the logic that future generations will benefit and should help pay. The same argument could apply to basic research, but R&D is rarely funded this way. Could long-term government bonds be earmarked for research and development work?

This is the last week to apply to Invisible College, our week-long seminar in Cambridge in August. If you are 18–22 years old, bright, ambitious, and interested in ideas: apply! Applications close on Friday 8th May.

The first gene therapy for deafness earns FDA approval. About sixty percent of all babies born deaf have some underlying genetic cause, and mutations in the OTOF gene account for between 2 and 8 percent of them. That gene encodes a protein called otoferlin, which enables hair cells inside the ear to transmit messages into the brain.

The OTOF gene is quite long, though, stretching about 90,000 bases of DNA. This means it’s too long to ‘package’ inside a single viral capsid for delivery. Regeneron, the company that developed the therapy, therefore decided to split up the gene, package each piece separately, and then deliver each half in its own viral capsid. The therapy was injected directly into the fluid-filled space of the inner ear, called the perilymph.

In one study with 12 children – all of whom were unable ‘to hear a gas-powered lawn mower’ before starting therapy – six could hear soft whispering without any hearing aids after 24 weeks of the therapy, and three others developed normal hearing. Besides being the first gene therapy for deafness, this is ‘also the first dual-AAV [adeno-associated viral capsid] therapy to be approved by the FDA’, writes Veera Rajagopal. The drug will be given away for free to patients in the United States, according to a Regeneron press release.

Does hair loss treatment actually work now? A new oral drug for hair loss actually seems to work, which feels surprising in a field that’s been plagued by scams and overblown claims for decades. Until now, there have been only a few approved treatments: oral finasteride (only for men, but coming with side effects like sexual dysfunction) and topical minoxidil (for men and women, applied to the scalp, with effects that are not long-lasting).

Now, Veradermics reports their drug, VDPHL01, grew around 30 additional hairs per square centimeter over six months compared to roughly 7 in the placebo group in a late-stage trial, and around 80 percent of participants reported improvement. The drug is a reformulated version of minoxidil engineered for slower, steadier release: standard oral minoxidil has a half-life of only a few hours; the idea now is to keep levels consistently high enough for continuous regrowth without reaching toxic levels. A second confirmatory trial in men is expected to report by the end of the year, which could result in FDA approval if it’s successful. There’s also an ongoing trial in women, where the options are even more limited.

Scientists watched a protein fold in real-time. A protein moves between its folded and unfolded forms in less than one-millionth of a second. For a new study, researchers captured this transition in real time for eight small proteins. They measured each protein’s folding by attaching red and green fluorescent dyes to amino acids that sit far apart when unfolded but come together when folded. As the dyes get closer, the green dye transfers energy to the red dye instead of emitting its own light. Whereas an unfolded protein will emit roughly equal numbers of green and red photons, a folded protein will emit mostly red photons. After watching these proteins fold, using high-powered microscopes, the scientists discovered (surprisingly) that large proteins fold faster than small ones. The smaller proteins had shorter waiting times – meaning they flip back and forth between states more frequently – but larger proteins had shorter transition times, meaning they completed folds faster once the process had begun. The largest protein transitioned in 0.7 microseconds, compared to 3.1 for the smallest. Evolution has probably optimized larger proteins to fold more efficiently via cooperativity, where one part of the protein coaxes another part to snap into place.

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Researchers recreate snake venom with organoids, to help research into anti-venoms. Snakebites kill 50,000 people each year in India alone. Computational biologists are using AI tools, such as RFdiffusion, to design proteins that can neutralize a few toxins in snake venom, and which don’t need refrigeration, but so far they only work against select proteins in the venom rather than the whole cocktail. To make antivenom today, scientists physically milk a snake by pressing on its venom glands so that it bites down and releases venom into a container. Then, they inject small, non-lethal doses of that venom into a horse, whose immune system produces the antibodies that are turned into the final antivenom. There are many ways to make this process far better!

In 2020, for example, Dutch researchers made organoids – spherical clusters of tissue grown from stem cells – for front-fanged snakes, including Elapidae and vipers. The nice part about these organoids is that they actually make venom that is chemically identical to the venoms made by living snakes. But for several years, nobody was able to make organoids for non-front-fanged snakes, which constitute about 70 percent of all snake species on Earth. These snakes have a different gland anatomy — they produce venom in a place called Duvernoy’s gland, which is smaller and harder to access than the venom glands of vipers and elapids, and extracting stem cells from it requires anesthetizing the snakes first. Recently, though, English scientists figured it out.

A new preprint describes how to make venom-producing organoids for snakes from the Colubridae family, which is the largest snake family on Earth and includes king, rat, and garter snakes. These organoids only make a tiny amount of venom (you’d need hundreds or thousands of them just to make enough to inject a single horse), but will be a useful starting point for basic research into antivenom design.

How long can you clone mice for? Scientists cloned a mouse for the first time in 1997 by taking a cell from an adult animal and injecting it into an egg lacking a nucleus. The egg, after being stimulated with chemicals, began to divide and gave rise to a mouse which was a genetic copy of the original animal.

Now the same research group have published a paper showing how they kept cloning the mice, repeatedly, for a period of 20 years. One might suspect that a lack of genetic diversity would make the animals non-viable (after all, that’s what happened to royal dynasties in which brothers married sisters or cousins). But instead, the researchers found that the cloning success rate stayed basically flat through 40 generations, but then started to fall.

The experiment ended after 58 generations, when the scientists could no longer clone the mouse. ‘By generation 57, the cloned mice had acquired over 3400 single-base changes relative to the starting mouse, whereas 62 generations of natural reproduction (in an inbred mouse strain) had accumulated 752’, writes Merrick Pierson Smela, a geneticist. ‘In other words, cloning caused 3.1 times more single-nucleotide mutations per generation than natural reproduction’. The mice also lost an entire X chromosome between generation 25 and 45, which was never regained.

Some ask ‘Where’s my flying car?’ but I ask ‘Where’s my omnibus p53 cancer drug?’ p53 is the body’s most important protein for protecting us against cancer. Roughly half of all solid cancers develop mutations in it that prevent tumor cell death, promote tumor growth, and prevent DNA damage repair. So why don’t we have effective drugs against it?

Unfortunately, there are thousands of different p53 mutations, and most work by changing the protein’s shape rather than knocking out a specific function, which makes it hard to fix with a drug. What’s worse is that mutant p53 is harder for cells to break down, so it builds up in high levels in cancer cells; drugs have a lot of dysfunctional protein to overcome.

Progress in p53 drug development seems to have been pretty hard. But some mutants are easier to target than others – like the Y220C mutant of p53, which is shaped with a pocket that a small molecule can slot into. That’s what some researchers have been targeting. A new phase 1 trial shows a proof-of-concept that this strategy can work using rezatapopt, a new compound that binds to the Y220C mutant p53 and reduces its levels in patients’ blood.

Although itʼs promising, this mutation is only carried by around 1 percent of p53 mutant tumors! And there’s still more to do to demonstrate its efficacy; various previous attempts at p53 drugs have failed in late-stage clinical trials. It’s a difficult problem, but one that would be hugely impactful if solved. Let’s hope this is a successful step towards it.

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Roughly a third of approved antibody drugs bind to proteins they’re not meant to. Monoclonal antibodies are used in medical treatment for various conditions including many cancers, and are generally described as extremely precise drugs that lock onto a single target – which is true, relative to other drugs – but it turns out that some also bind to unintended targets.

A new study screened 74 antibodies that were FDA-approved or in clinical studies against over 6,000 human proteins. The authors found that 28 percent bound to at least one unintended target, which could cause unexpected side effects or reduce the efficacy of the drugs, although that wasn’t tested directly. On the bright side, the authors showed that inducing just one or two mutations to the antibody were enough to remove these off-target bindings without touching the intended ones. This kind of early systematic screening isn’t standard practice yet, but it could probably help find better antibody candidates and reduce failure rates in clinical trials.

US science agencies have money but aren’t spending it. A new analysis tracking real-time spending data finds that NSF is issuing new grants roughly 70 percent slower than its historical pace, NIH about 50 percent slower than before, and the National Cancer Institute particularly bad at 79 percent slower. While Congress actually held firm on science budgets, the current administration has been slow-walking the actual disbursement of funds to researchers, as it did in FY2025 before advocacy pressure forced a correction.

To make it easier to understand these slowdowns, Jordan Dworkin, Saloni’s colleague at Coefficient Giving, built sciencespending.org, a public tracker of grant-making pace across five major agencies. The problem is worse than just delays, because unspent NIH funds expire at the end of the fiscal year and go back to the Treasury, which means that money may never reach researchers.

Eugene Braunwald, probably the most important figure in modern cardiology, died on April 22nd at age 96. It’s hard to overstate his influence. Before his work in the 1970s, a heart attack was treated with sedation and bed rest: the prevailing view was that once muscle was dying, little could be done. Braunwald overturned this by showing that the amount of damage from a heart attack depended on the balance between oxygen supply and demand in the heart, and that one could act fast to shift this balance and rescue threatened muscle. The idea became known as ‘time is muscle’ and underpins almost all modern reperfusion therapy: clot-busting drugs, angioplasty, and stenting, which help clear arteries and deliver oxygen to the heart quickly.

He also defined the mechanics of hypertrophic cardiomyopathy (a condition where the heart muscle thickens and obstructs blood flow), and in 1984, he founded the TIMI study group, which has since run over 70 randomized trials shaping standard care for heart attacks, heart failure, and diabetes.

Over the course of his career, the share of patients who died within a month after having the most severe type of heart attack fell roughly three-fold – from a 30-day mortality rate of around 17 percent to around 6 percent; much of that is attributable to treatments based on his research.

It’s striking how recent all of this is: the idea that a heart attack was something you could actively treat is only about 50 years old! (Part of the reason is that people hadnʼt invented ways to study the mechanics of the living heart without killing the patient until the mid-20th century.)

Invisible College is a residential seminar in a Cambridge college, run by the Works in Progress team and hosted from 17-22 August 2026. Our aim is to give our students a serious introduction to important ideas, and to put them in touch with other unusually thoughtful and ambitious people their age.

During the week, attendees will take part in lectures, lightning talks, and group work on some of the topics that matter most to us from spatial economics and the Industrial Revolution to scientific fraud:

• Stuart Ritchie will explain how science is broken by fraud, bias, and hype, how to spot them, and how to make science work again.

• Tim Leunig will explain why dense cities are often the most productive: division of labour, transport and infrastructure, and why urban containment can be so costly.

• Anton Howes will explain how England went from being a European laggard in 1550 to by far the world’s leader 150 years later.

• Jenny Read will explain why robotic dexterity matters, why it’s so difficult to achieve, and give an overview of the newest research.

• Matt Clifford will explain how to future-proof your career against artificial intelligence.

• Laura Ryan will make the case that scientific progress is driven by scientific institutions.

• and much more!

We’ll also host dinner and drinks, and social activities including a pub quiz, a barbecue, and punting down the river. It is free to attend, including food and accommodation. To attend, you must be aged 18–22 in August. You do not need to be a current university student: the main requirement is that you are curious, intellectually serious, and eager to learn.

To apply, simply fill out this very short application form.

If you have any questions, check our FAQs, and feel free to email me (Ben Southwood) at bswud@stripe.com. Applications close on Friday 8th May.

We look forward to hearing from you!

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For the mothers of the baby boom, pediatrician Benjamin Spock’s child care handbook was a practical, confidence-boosting essential. Originally published in 1946 as The Common Sense Book of Baby and Child Care, Dr Spock’s baby book sold more than 500,000 copies in its first six months. By the time the second edition came out in 1957, with the simplified title Baby and Child Care, Dr Spock was selling a million copies a year. My mother, who was 24 when I arrived in 1960, still remembers the book’s reassuring tone.

‘You know more than you think you do’, the author told readers. ‘We know for a fact’, he wrote with medical authority, ‘that the natural loving care that kindly parents give to their children is a hundred times more valuable than their knowing how to pin a diaper on just right’.

Dr Spock went on to provide detailed instructions on the practical intricacies of parenthood, including diapers. Buy at least two dozen, he counseled, more if you aren’t washing them daily. Six dozen would cover all contingencies. With a diagram, he showed how to fold a diaper and explained how to position it on a boy versus a girl. ‘When you put in the pin’, he advised, ‘slip two fingers of the other hand between the baby and the diaper to prevent sticking him’. The book covered when to change the diapers and what to do with the dirties.

You want a covered pail partially filled with water to put used diapers in as soon as removed. If it contains soap or detergent, this helps in removing stains. Be sure the soap is well dissolved, to prevent lumps of soap from remaining in the diapers later. When you remove a soiled diaper, scrape the movement off into the toilet with a knife, or rinse it by holding it in the toilet while you flush it (hold tight).

You wash the diapers with mild soap or mild detergent in [the] washing machine or washtub (dissolve the soap well first), and rinse 2 or 3 or 4 times. The number of rinsings depends on how soon the water gets clear and on how delicate the baby’s skin is. If your baby’s skin isn’t sensitive, 2 rinsings may be enough.

On this subject, the 1957 edition contains two telling differences from the original. In 1946, Dr Spock recommended the knife method to those without flush toilets. And starting with the second edition, he advised new parents to buy an automatic washer and dryer if they could possibly afford them. ‘They save hours of work each week, and precious energy’, he wrote. ‘Energy’ in this case referred not to electricity or gas but to maternal stamina.

Disposable diapers did exist, but they accounted for a mere one percent of US diaper changes. They were expensive, specialty products and not that great. ‘The full-sized ones are rather bulky’, noted Dr Spock. ‘The small ones that fit into a waterproof cover do not absorb as much urine as a cloth diaper and do not retain a bowel movement as well’. Disposables were mostly used for travel, when washing diapers wasn’t an option.

But even as the second edition of Baby and Child Care was hitting bookstores and supermarket racks, change was afoot. After buying Charmin Paper Company in 1957, Procter & Gamble began looking for ideas for new paper products.

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Motivated by the less pleasant aspects of spending time with his new grandchild, the company’s director of exploratory development, Victor Mills, suggested disposable diapers. After analyzing existing products and conducting consumer research, P&G created a dedicated diaper research group.

The research this group conducted, like that of its successors and competitors, wasn’t glamorous. It didn’t advance basic science. It wasn’t even an obvious route to profit. (One percent of the market!) It was a high-stakes gamble that required solving difficult engineering problems. How that happened represents the kind of hidden progress that leads to everyday abundance.

P&G’s first design flopped. Tested in the extreme heat of a Dallas summer, the pleated absorbent pad with plastic pants made babies miserable and left them with heat rashes. Starting over, the group had a one piece diaper ready for testing in March 1959. With an improved rayon moisture barrier between the baby and the absorbent tissue wadding, the new diaper was softer and more comfortable. An initial test of 37,000 hand-assembled prototypes went well, with about two thirds of the parents deeming the disposables as good or better than cloth. The next step was mass production.

Designing one well-functioning disposable was hard enough. Turning out hundreds a minute was practically impossible. ‘I think it was the most complex production operation the company had ever faced’, an engineer recalled.

There was no standard equipment. We had to design the entire production line from the ground up. It seemed a simple task to take three sheets of material – plastic back sheet, absorbent wadding, and water repellent top sheet – fold them in a zigzag pattern and glue them together. But glue applicators dripped glue. The wadding generated dust. Together they formed sticky balls and smears which fouled the equipment. The machinery could run only a few minutes before having to be shut down and cleaned.

Eventually, the diaper team mastered the process. In December 1961, Pampers went on the market in Peoria, Illinois. Once again, the test failed.

This time mothers liked the diapers. But the price was way too high for a single use item: ten cents a diaper, equivalent to about one dollar today. By contrast, diaper delivery services, which served about five percent of the market, charged no more than five cents a diaper. Home laundry costs ran to one or two cents.

Lowering the price of a diaper required much larger volumes. Aiming at about six cents a diaper, P&G engineers spent several years developing what Harvard Business School’s Michael E. Porter described as ‘a highly sophisticated block-long, continuous-process machine that could assemble diapers at speeds of up to a remarkable 400 a minute’. After successfully testing Pampers at 5.5 cents each, P&G began a national rollout in 1966. By 1973, disposables accounted for 42 percent of the US diaper market.

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A noteworthy success was in Puerto Rico, which Pampers entered in 1972. Although incomes were significantly lower than in the continental US, the island’s poverty actually favored disposables. Many families lacked easy access to washing machines, and line drying diapers was tough in the humid climate. ‘Puerto Rico became one of the most successful Pampers markets’, records Oscar Schisgall in Eyes on Tomorrow, a corporate history of P&G. Disposable diapers turned out to be a particular boon to poor families.

The success of Pampers drew competitors into the growing market. ‘Any diaper maker that carved out a modest market share against Procter & Gamble could expect sales to triple as a result of sheer market growth’, write business historians Thomas Heinrich and Bob Batchelor in Kotex, Kleenex, Huggies, a history of Kimberly-Clark. But there was a catch. The bulky diapers took up so much space on shelves that stores rarely stocked more than two brands, plus maybe a discounted private label. Second place meant profits, third place disaster.

Most entrants gave up within a few years. Scott Paper abandoned the market in 1971. International Paper exited in 1972. Union Carbide left in 1977. Johnson & Johnson held on until 1981. J&J was adept at marketing baby products but couldn’t get its machines to turn out diapers fast enough to keep prices competitive.

Kimberly-Clark was the exception. The company that had introduced the world to Kleenex tissues and Kotex feminine pads, both completely new concepts in the 1920s, created a disposable diaper called Kimbies. It featured tape fasteners and an unusual triangular fold. Buyers liked the tape fasteners, which Pampers soon copied, but complained that the weirdly folded diapers leaked. After a disastrous switch in the glue affixing the cover lining to the pad, Kimbies began losing shelf space to J&J. In 1975, the company decided the only way to survive in the diaper business was to start over with a better design.

The new diapers, introduced as Kleenex Huggies in December 1977, were elasticized along the edge of the crotch to prevent leaks. Manufacturing them was a complicated process requiring custom-designed machines. Heinrich and Batchelor write:

A tissue machine combined layers of absorbent padding into sheets of varying thickness to form the wings and the crotch section, which was 15 percent thicker than the edges. Once the sheet had been cut into individual hourglass shapes, the latter received an elastic band at the crotch section and were combined with the cover and backing sheet to form the diaper.

Huggies had tapes that could be refastened without tearing the plastic cover, an annoyance I remember from my days as a teenage babysitter. Like P&G’s premium Luvs, which included similar features, Huggies cost about 30 percent more than regular disposables. But consumers were willing to pay more for higher quality diapers.

‘At a time of rampant inflation, declining real wages, and economic uncertainty, consumers flocked from Johnson & Johnson’s moderately priced diapers to the Huggies and Luvs premium brands’, write Heinrich and Batchelor. As Huggies expanded nationally, J&J sales cratered.

The following decade saw fierce competition between the two remaining diaper giants, with Huggies eventually becoming the market leader. In the mid-1980s, P&G and Kimberly-Clark replaced paper wadding with superabsorbent polymers (SAPs) that trap water like particles in a net. As manufacturers learned how to work with these wonder materials, disposable diapers got thinner and better.

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‘In the early eighties’, wrote Malcolm Gladwell in a 2001 New Yorker feature, ‘they were three times bulkier than they are now, thicker and substantially wider in the crotch. But in the mid-eighties Huggies and Procter & Gamble’s Pampers were reduced in bulk by fifty percent; in the mid-nineties they shrank by a third or so; in the next few years they may shrink still more’.

As diapers got slimmer, they took up less space in trucks and on shelves. Shipping costs dropped, allowing fewer factories farther apart. More shelf space permitted greater variety. ‘We cut the cost of trucking in half’, Ralph Drayer, P&G’s former logistics chief, told Gladwell. ‘We cut the cost of storage in half. We cut handling in half, and we cut the cost of the store shelf in half, which is probably the most expensive space in the whole chain’.

In 1987, Huggies got an unexpected boost from a cameo in the Coen Brothers farce Raising Arizona. It starred Nicolas Cage as a convenience store robber who marries Holly Hunter’s police photographer after she takes his mug shot. Needing diapers for the baby they’ve swiped from a family of quintuplets, Cage’s character hits a convenience store, grabbing a huge package of Huggies and waving a pistol (unloaded). ‘Wake up, son!’, he drawls to the young clerk, who looks up from perusing Juggs magazine. ‘I’ll be taking these Huggies and [shrug], uh whatever cash you got’. The filmmakers picked Huggies, Ethan Coen told a journalist, because ‘it sounded funnier than any other brand name’.

Meanwhile, Kimberly-Clark was secretly working on a product that would shock competitors: disposable training pants for toddlers. It wasn’t a new idea, but the execution was tricky, requiring enough side elasticity to allow little hands to pull up their britches without adult help. What Heinrich and Batchelor describe as ‘an innovative synthetic fabric’ was the key. Huggies Pull-Ups Training Pants debuted in 1989, completely blindsiding Procter & Gamble. ‘Huggies Pull-Ups in fact reigned unchallenged for the next three years, capturing 9 percent of the diaper market and generating more than $200 million in annual sales for Kimberly-Clark,’ write Heinrich and Batchelor.[ref 1] In 1992, a smaller competitor, Drypers, finally introduced a rival product.

By this time, disposable diapers had become a nursery necessity, commanding some 95 percent of the diaper market in the United States, Canada, Japan, and most of Europe. (The UK and Netherlands lagged by about a decade.) It was time for a backlash.

In the late 1980s and early 1990s, US environmentalists proposed restrictions on disposable diapers. Florida, Pennsylvania, and Vermont considered outright bans, while bills elsewhere would have exempted only disposables whose materials were biodegradable. New Hampshire’s legislature considered a ten cent tax on every diaper. In California, a 1990 bill supported by the Sierra Club would have required a package label declaring that ‘single-use disposable diapers pose significant environmental problems and costs when disposed. The state of California recommends that you consider reusable diapers for your daily diaper needs’. New York legislators proposed a similarly reproachful label.

None of these laws passed. In part, they failed because their environmental claims were disputed. Research by William Rathje, a University of Arizona archaeologist who spent decades analyzing the contents of landfills, found that disposable diapers made up less than two percent of US trash.

Others pointed to the complexities of measuring environmental harms across the entire diaper lifecycle, which would include water needed for irrigating cotton fields and washing dirty diapers. There were ‘too many ambiguities’ to declare disposables an environmental no-no, said Allen Hershkowitz of the Natural Resources Defense Council, which remained neutral on the issue.

Nonsense, responded green critics. Hershkowitz wasn’t a reliable source, Fred Munson of Greenpeace told the Los Angeles Times. ‘He has a kid and uses disposables’, said Munson, ‘and I personally think he is trying to placate his conscience’.

It was a petty ad hominem, but it contained a truth. Punitive bans, warning labels, and diaper taxes were doomed not because of wonky arguments about landfill contents and lifecycle analysis but because normal people love disposable diapers. Few parents would willingly return to diaper pails and daily loads of diaper laundry. Threaten their Huggies and you’re likely to find yourself out of office.

‘As a mother’, wrote humorist Erma Bombeck in a 1990 syndicated column. ‘I’d rather do away with foam cups and have hot coffee poured into both my hands than do away with disposable diapers’.

Virginia Postrel is a contributing editor and author at Works in Progress.