Hard Drugs

Computer chips have become dramatically cheaper over time. But the opposite seems to have happened in drug development. Since at least the 1950s, it’s become more and more expensive to develop new drugs. Scientists have coined this trend Eroom’s law.

In this episode, Jacob and Saloni investigate Eroom’s law. Why has it become so much more expensive to develop new drugs, despite massive technological advances? They chat about penicillin, CRISPR, billion-dollar research failures, and whether the last decade has been a turning point. Can AI help reverse the trend? Listen to find out!

Chapters:

• (00:00) - Introduction
• (02:53) - Eroom’s law trivia
• (12:33) - How much does it cost to develop a drug?
• (22:35) - The better than the Beatles problem
• (33:06) - From penicillin to modern clinical trials
• (42:01) - Have we picked the low-hanging fruit?
• (01:01:22) - Is Eroom’s law slowing down?
• (01:06:18) - Can AI reverse Eroom’s law?
• (01:15:09) - Conclusion

You can listen on Spotify, Apple Music, YouTube (https://youtu.be/aJ8girWzWJM), or wherever you get your podcasts.

Click here to read the episode transcript.

Hard Drugs is a podcast from Works in Progress about medical innovation presented by Saloni Dattani and Jacob Trefethen. Saloni Dattani is an editor at Works in Progress, a writer on global health and medical innovation, and an advisor to Coefficient Giving on clinical trial reform. Jacob Trefethen is the head of Life Sciences & Curing Diseases at the OpenAI Foundation.

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Acknowledgements:

• Graham Bessellieu, video editor
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David Hackett, composer

Articles

• Jack W. Scannell, Alex Blanckley, Helen Boldon and Brian Warrington (2012). Diagnosing the decline in pharmaceutical R&D efficiency. https://www.nature.com/articles/nrd3681
• Henry Grabowski, John Vernon and Lacy Glenn Thomas (1978). Estimating the effects of regulation on innovation: an international comparative analysis of the pharmaceutical industry. https://dukespace.lib.duke.edu/items/033ea8c0-a9bb-406d-bf85-5688c23c0f1f
• Stephanie Rennane, Lawrence Baker, and Andrew Mulcahy (2021). Estimating the Cost of Industry Investment in Drug Research and Development: A Review of Methods and Results. https://journals.sagepub.com/doi/10.1177/00469580211059731
• Michael S. Ringel, Jack W. Scannell, Mathias Baedeker and Ulrik Schulze (2020). Breaking Eroom’s Law. https://www.nature.com/articles/d41573-020-00059-3

Books

• Paul Offit (2007). Vaccinated: One Man’s Quest to Defeat the World’s Deadliest Diseases.

What if treating diseases was as simple as telling your cells to stop making a harmful protein? That’s the premise of siRNA, a technology that silences genes without changing DNA. Just a single dose of siRNA can last for months. Better, it can be reprogrammed to silence a different gene or mutation by simply switching its sequence.

In this episode, Jacob and Saloni explore why it took so long for siRNA to be turned into drugs, why most siRNA drugs so far have targeted liver diseases, and whether they could eventually be used to treat many diseases, from infections to heart disease to rare diseases to cancers.

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

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

Chapters:

• (00:00) - Introduction
• (09:58) - siRNA trivia
• (28:14) - The 20 year journey to make siRNA drugs
• (36:07) - Which diseases could siRNA treat?
• (50:45) - Programmable, long-lasting, scaleable drugs
• (54:32) - Can siRNA solve everything?
• (01:08:23) - Conclusion

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Acknowledgements:

• Graham Bessellieu, video editor
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David Hackett, composer

Articles

• Jacob Witten (2026). The kill switch for harmful genes. Works in Progress. https://worksinprogress.co/issue/the-kill-switch-for-harmful-genes/
• Virginie Baylot et al. (2024) Between hope and reality: treatment of genetic diseases through nucleic acid-based drugs. https://www.nature.com/articles/s42003-024-06121-9
• Chokwassanasakulkit et al. (2024) SiRNAs as antiviral drugs – Current status, therapeutic potential and challenges. https://doi.org/10.1016/j.antiviral.2024.106024
• Antonio Fontanellas et al. (2025) RNA-based therapies in liver metabolic diseases. https://doi.org/10.1136/gutjnl-2023-331742

GLP-1 drugs like Ozempic and Mounjaro have transformed the treatment of obesity as well as diabetes, help treat heart disease, kidney disease, sleep apnea, and maybe even Alzheimer’s. But they are far from the only medicine with more than one use. Aspirin, colchicine, minoxidil, and Viagra were all found to treat more conditions than expected, and about a third of drugs end up with a second approved use.

In this episode, Jacob and Saloni explore the idea of drug repurposing: taking a medicine made for one disease and finding it works against others. They trace how GLP-1 drugs emerged from an adorable Gila monster, why some drugs have multiple uses, why so many of those uses go untested, and how patents, competition, prizes, and platform trials shape whether we ever find them.

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

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

Chapters:

• (00:00) - Introduction
• (13:20) - The origins of GLP-1 drugs
• (46:07) - GLP-1s for everything?
• (01:03:33) - Promiscuous drugs
• (01:25:04) - Why isn't drug repurposing more common?
• (01:56:39) - How to fix the incentives

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Acknowledgements:

• Aria Babu, editor at Works in Progress
• Graham Bessellieu, video editor
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David Hackett, composer

Correction: Saloni misdescribed the mechanism of immortal time bias - it comes from the pre-prescription time being counted in the treatment group, not the control group.

Blogs

• Julia Rohrer (2018). The uncanny mountain: p-values between .01 and .10 are still a problem https://www.the100.ci/2018/02/15/the-uncanny-mountain-p-values-between-01-and-10-are-still-a-problem/
• Abhishaike Mahajan (2025). Mapping the off-target effects of every FDA-approved drug in existence (EvE Bio) https://www.owlposting.com/p/mapping-the-off-target-effects-of

Videos

• George Davey Smith (2026). Does the shingles vaccine prevent dementia? https://www.youtube.com/watch?v=qlTnnQytOJ0

Articles & reports

• Radwan Darwish et al. (2025). History of glucagon-like peptide-1 receptor agonists. https://doi.org/10.1016/j.phrs.2025.108045
• Brian L. Furman (2012). The development of Byetta (exenatide) from the venom of the Gila monster as an anti-diabetic agent. https://doi.org/10.1016/j.toxicon.2010.12.016
• Eric Budish, Maya M. Durvasula, Benjamin N. Roin, Heidi L. Williams (2026). Missing markets for innovation: evidence from new uses for existing drugs. NBER Working paper. https://www.nber.org/system/files/working_papers/w34222/w34222.pdf
• Babak Sahragardjoonegani, Reed F Beall, Aaron S Kesselheim, Aidan Hollis (2021). Repurposing existing drugs for new uses: a cohort study of the frequency of FDA-granted new indication exclusivities since 1997. https://pmc.ncbi.nlm.nih.gov/articles/PMC7780607/
• BMJ (2020). Covid-19: The inside story of the RECOVERY trial https://www.bmj.com/content/370/bmj.m2670
• Stephan Guyenet (2021). The future of weight loss https://worksinprogress.co/issue/the-future-of-weight-loss/
• Kevin Hickey, Erin Ward (2024). The Role of Patents and Regulatory Exclusivities in Drug Pricing https://www.congress.gov/crs-product/R46679
• Alex Kesin (2025). The three-thousand-year journey of colchicine https://worksinprogress.co/issue/the-three-thousand-year-journey-of-colchicine/
• Natália Coelho Mendonça (2024). The promise of SGLT2 inhibitors https://worksinprogress.co/issue/the-future-of-kidney-treatment/
• Samy Suissa, Laurent Azoulay (2012). Metformin and the risk of cancer: time-related biases in observational studies https://doi.org/10.2337/dc12-0788
• Nicholas Reville (2026). Proposing an NIH High-Leverage Trials (HILT) Program. Center for Addiction Science, Policy, and Research (CASPR) https://caspr.org/policy/papers/HILT/

Web

• Smithsonian’s National Zoo. Gila monster. https://nationalzoo.si.edu/animals/gila-monster

Malaria is caused not by a virus or bacterium, but by a complex, shape-shifting parasite that has evolved alongside us for millennia. This has made vaccine development a brutal challenge.

In this episode, Jacob and Saloni are joined by Katharine Collins, who co-invented the second malaria vaccine, called R21, during her PhD. They discuss the gruelling process of reverse-engineering a vaccine and eureka moments along the way. They ask whether the biggest barriers to new vaccines are scientific or financial, and what it will take to finally eradicate one of natureʼs most vicious killers.

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/

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

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

Heart disease is the leading cause of death worldwide, but it’s also one of medicine’s biggest success stories. Since the 1950s, the risk of dying from cardiovascular disease has fallen dramatically, thanks to public health efforts, emergency care, medical innovation, and surgeries.

In this episode, Jacob and Saloni explore the cholesterol revolution: from statins discovered in fungi to new drugs that cut LDL cholesterol by 60% and last for months, driven by breakthroughs in genetics, monoclonal antibodies, RNA therapies, and modern medicinal chemistry. They talk about how cholesterol travels through the bloodstream, how it causes atherosclerosis and heart disease, and why it took nearly a century for scientists to form the consensus that lowering cholesterol saves lives.

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

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

Chapters:
0:00:00 Introduction
13:35 The decline in heart disease mortality
31:02 Surprising facts about cholesterol
55:40 The lipid hypothesis: 7 lines of evidence for the harms of LDL cholesterol
1:22:15 How cholesterol works
1:30:40 The discovery of statins
1:48:44 Should everyone be on statins?
1:57:10 PCSK9 drugs and beyond
2:22:56 Summary

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Acknowledgements:

• Aria Babu, editor at Works in Progress
• Graham Bessellieu, video editor
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David Hackett, composer

Works in Progress & Coefficient Giving

Correction: In the episode, Saloni makes an error in converting the number of heartbeats per lifetime. It is roughly 2.5 billion beats, not a trillion.

Books

• Daniel Steinberg (2007) The Cholesterol Wars.
• Jie Jack Li (2009) Triumph of the Heart: The Story of Statins.

Blog posts

• James Stein (2025) Lipid and lipoprotein basics series. https://jamesstein18.substack.com/p/part-i-lipid-and-lipoprotein-basics

Articles

• Akira Endo (2017) Discovery and Development of Statins https://doi.org/10.1177/1934578X1701200801
• Joseph L Goldstein, Michael S Brown (2010) History of discovery: The LDL receptor. https://pmc.ncbi.nlm.nih.gov/articles/PMC2740366/
• Patty W. Siri-Tarino and Ronald M. Krauss (2016) The early years of lipoprotein research: from discovery to clinical application https://pubmed.ncbi.nlm.nih.gov/27474223/
• Eun Ji Kim and Anthony S. Wierzbicki (2020) The history of proprotein convertase subtilisin kexin-9 inhibitors and their role in the treatment of cardiovascular disease https://pubmed.ncbi.nlm.nih.gov/32537117/
• Patrick W. Siri-Tarino et al. (2010) Saturated fat, carbohydrate, and cardiovascular disease. https://www.pnas.org/doi/10.1073/pnas.94.9.4312
• Saloni Dattani (2025) Death rates from cardiovascular disease have fallen dramatically — what were the breakthroughs behind this? https://ourworldindata.org/cardiovascular-deaths-decline
• Cholesterol Treatment Trialists’ (CTT) Collaboration (2010) Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. https://doi.org/10.1016/S0140-6736(10)61350-5
• E. J. Mills et al. (2011) Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. https://pubmed.ncbi.nlm.nih.gov/20934984/
• Julia Brandts and Kausik K. Ray (2023) Novel and future lipid-modulating therapies for the prevention of cardiovascular disease. https://www.nature.com/articles/s41569-023-00860-8

Videos

• Ninja Nerd (2018) Lipoprotein metabolism https://www.youtube.com/watch?v=wQY0xpwqPfQ

Hepatitis B is a tiny virus that causes hundreds of thousands of deaths from liver disease and cancer each year. The vaccine against it became the first of many milestones: it was the first viral protein subunit vaccine, the first recombinant vaccine, and the first vaccine to prevent a type of cancer.

In this episode, Jacob and Saloni follow the trail of strange jaundice outbreaks that scientists traced to a stealthy liver virus, how scientists turned one viral surface protein into a lifesaving shot for newborns, and how it was all built upon breakthroughs in immunology.

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

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

Chapters:
0:00:00 Introducing the hepatitis B vaccine
0:15:46 The mysterious trail of jaundice outbreaks
0:28:03 How a tiny virus causes cirrhosis and liver cancer
0:53:19 Maurice Hilleman's purified hep B vaccine
1:17:36 Turning the hep B vaccine recombinant
1:29:14 The impact of hep B vaccination
1:39:27 The 19th century battle for immunology
2:01:34 How the body makes an almost infinite number of antibodies
2:30:57 How subunit vaccines took over
2:45:33 Conclusion

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Books:

• Paul Offit (2007) Vaccinated: One Man's Quest to Defeat the World's Deadliest Diseases
• Arthur M Silverstein (2009) A history of immunology
• Ronald W Ellis (1993) Hepatitis B Vaccines in Clinical Practice
• Sally Smith Hughes (2011) Genentech: The beginnings of biotech

Articles:

• Timothy M. Block et al. (2016) A historical perspective on the discovery and elucidation of the hepatitis B virus https://doi.org/10.1016/j.antiviral.2016.04.012
• Naijuan Yao et al. (2022) Incidence of mother-to-child transmission of hepatitis B in relation to maternal peripartum antiviral prophylaxis: A systematic review and meta-analysis https://doi.org/10.1111/aogs.14448
• Jill Koshiol et al. (2019) Beasley’s 1981 paper: The power of a well-designed cohort study to drive liver cancer research and prevention https://pmc.ncbi.nlm.nih.gov/articles/PMC5866222/
• William J. McAleer et al. (1984) Human hepatitis B vaccine from recombinant yeast https://doi.org/10.1038/307178a0
• Chunfeng Qu et al. (2014) Efficacy of Neonatal HBV Vaccination on Liver Cancer and Other Liver Diseases over 30-Year Follow-up of the Qidong Hepatitis B Intervention Study: A Cluster Randomized Controlled Trial https://doi.org/10.1371/journal.pmed.1001774
• Anthony R Rees (2020) Understanding the human antibody repertoire https://doi.org/10.1080/19420862.2020.1729683

Correction: Urea was mentioned as a protein, but is actually the product of a protein breakdown process, not a protein itself.

Acknowledgements:

• Aria Babu, editor at Works in Progress
• Graham Bessellieu, video editor
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David Hackett, composer

Works in Progress & Coefficient Giving

Before vaccines became routine, they were risky experiments. In this episode, Jacob and Saloni travel back to the world of smallpox, cowpox, and cow-based “vaccine farms” to see how scientists stumbled toward the first vaccines against infectious diseases: smallpox, rabies, TB, polio, and more. Through the stories of milkmaids and aristocrats, secret lab notebooks, microscopes and cell culture, they explore how trial and error turned gruesome folk practices into the science of immunization, and how it all began with a single pustule.

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

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/

Books:

• Gerald Geison (1995) The private science of Louis Pasteur
• Thomas D. Brock (1998) Robert Koch: a life in medicine and bacteriology
• Mervyn Susser and Zena Stein (2009) Eras in epidemiology : the evolution of ideas
• Angela Leung (2011) Chapter: “Variolation” and vaccination in late Imperial China, ca. 1570–1911. History of vaccine development by Stanley Plotkin
• Florian Horaud (2011) Chapter: Viral vaccines and cell substrate. History of vaccine development by Stanley Plotkin
• Samuel Katz (2011) Chapter: The role of tissue culture in vaccine development. History of vaccine development by Stanley Plotkin
• Hervé Bazin (2011) Chapter: Pasteur and the birth of vaccines made in the laboratory. History of vaccine development by Stanley Plotkin

Articles:

• Andrew Shattock et al. (2024) Contribution of vaccination to improved survival and health: modelling 50 years of the Expanded Programme on Immunization https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00850-X/fulltext
• Saloni Dattani (2020) The story of Viktor Zhdanov https://worksinprogress.co/issue/the-story-of-viktor-zhdanov/
• José Esparza et al. (2020) Early smallpox vaccine manufacturing in the United States https://doi.org/10.1016/j.vaccine.2020.05.037
• Paula Gottdenker (1979) Francesco Redi and the fly experiments https://www.jstor.org/stable/44450950
• Donald Angus Gillies (2016) Establishing causality in medicine and Koch’s postulates
• Burt A Folkart (1993) Dr. Albert Sabin, Developer of Oral Polio Vaccine, Dies https://www.latimes.com/archives/la-xpm-1993-03-04-mn-283-story.html
• Saloni Dattani (2025) Measles leaves children vulnerable to other diseases for years https://ourworldindata.org/measles-increases-disease-risk

Acknowledgements:

• Aria Babu, editor at Works in Progress
• Graham Bessellieu, video editor
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David Hackett, composer

Works in Progress & Coefficient Giving

Artificial intelligence is transforming how we discover and develop new medicines. But how far can it really take us? In this episode, Jacob and Saloni trace the path of drug development from discovery to testing, manufacturing, and delivery. They explore where AI could speed things up, and where it still hits the limits of biology, data, and economics. They ask what it would take, beyond algorithms, to actually cure and eradicate diseases.

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

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/

Chapters:
0:00:00 Intro
0:09:56 Drug discovery
1:02:20 Animal models
1:49:09 Drug efficacy
2:32:56 Drug safety
2:58:29 Manufacturing and healthcare
3:43:23 R&D funding
4:00:56 Trust and ambition
4:16:01 Summary

Blogposts:

• Claus Wilke (2025) We still can’t predict much of anything in biology https://blog.genesmindsmachines.com/p/we-still-cant-predict-much-of-anything
• Elliot Hershberg (2025) What are virtual cells? https://centuryofbio.com/p/virtual-cell
• Jacob Trefethen (2025) Blog series. 1) What does AI progress mean for medical progress? https://blog.jacobtrefethen.com/ai-progress-medical-progress/ 2) AI will not suddenly lead to an Alzheimer’s cure https://blog.jacobtrefethen.com/ai-san-francisco/ 3) AI could help lead to an Alzheimer’s cure https://blog.jacobtrefethen.com/ai-optimism/

Articles:

• Wendi Yan (2024) Discovering an antimalarial drug in Mao’s China https://www.asimov.press/p/antimalarial-drug
• Jason Crawford (2020) Innovation is not linear https://worksinprogress.co/issue/innovation-is-not-linear/
• Shayla Love (2025) An ‘impossible’ disease outbreak in the Alps https://www.theatlantic.com/health/archive/2025/03/als-outbreak-montchavin-mystery/682096/
• Alex Telford (2024) Origins of the lab mouse https://www.asimov.press/p/lab-mouse
• Jonathan Karr et al. (2012) A whole-cell computational model predicts phenotype from genotype https://pmc.ncbi.nlm.nih.gov/articles/PMC3413483/
• Wen-Wei Liao et al. (2023) A draft human pangenome reference https://www.nature.com/articles/s41586-023-05896-x
• Per-Ola Carlsson (2025) Survival of transplanted allogeneic beta cells with no immunosuppression https://www.nejm.org/doi/pdf/10.1056/NEJMoa2503822
• Saloni Dattani (2024) Antipsychotic medications: a timeline of innovations and remaining challenges https://ourworldindata.org/antipsychotic-medications-timeline
• Saloni Dattani (2024) What was the Golden Age of antibiotics, and how can we spark a new one? https://ourworldindata.org/golden-age-antibiotics

Books:

• Sally Smith Hughes (2011) Genentech: The beginnings of biotech

Theses:

• Alvaro Schwalb (2025). Estimating the burden of Mycobacterium tuberculosis infection and the impact of population-wide screening for tuberculosis.

Acknowledgements:

• Aria Babu, editor at Works in Progress
• Graham Bessellieu, video editor
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David Hackett, composer

Works in Progress & Open Philanthropy

[Minor correction: Since the 1980s, malaria challenge trials no longer involve hundreds of bites; in the past, volunteers received many bites for the exposure part of the trial rather than the challenge part.]

What if you could design a protein never seen in nature? In this episode, Jacob and Saloni explore how researchers are using new tools like RFDiffusion, AlphaFold, and ProteinMPNN to ‘hallucinate’ entirely novel proteins: designing them from scratch to solve problems evolution hasn’t tackled. They talk about how these technologies could transform medicine, agriculture, and materials science. Along the way, they reflect on the surprising ways AI is changing the process of science itself.

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

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Courses:

• EMBL-EBI. AlphaFold: A practical guide https://www.ebi.ac.uk/training/online/courses/alphafold/

Articles:

• Tanja Kortemme (2024) De novo protein design—From new structures to programmable functions https://www.cell.com/cell/fulltext/S0092-8674(23)01402-2
• Jie Zhu et al. (2021) Protein Assembly by Design https://pubs.acs.org/doi/10.1021/acs.chemrev.1c00308

Lectures:

• Rosetta Commons (2024) Diffusion models for protein structure generation (and design) https://www.youtube.com/watch?v=OEnY2yA3jy8
• Rosetta Commons (2024) AlphaFold – ML for protein structure prediction https://www.youtube.com/watch?v=SVrn8_8aKO8
• Rosetta Commons (2024) MPNN – ML for protein sequence design https://www.youtube.com/watch?v=6z4XmUAwdNA

Acknowledgements:

• Aria Babu, editor at Works in Progress
• Graham Bessellieu, video editor
• Rachel Shu, on-site editor
• Anna Magpie, fact-checking
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David Hackett, composer

Works in Progress & Open Philanthropy

Nature didn’t evolve all the proteins we need, but maybe artificial intelligence can help. Jacob and Saloni explore how tools like AlphaFold and ProteinMPNN are helping researchers re-engineer proteins, to make them safer, more stable, and more effective. They talk about how new technologies could help make a long-sought vaccine against Strep A, which causes scarlet fever and rheumatic heart disease, and how similar tools have already led to breakthroughs against COVID and RSV.

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

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Courses:

• EMBL-EBI. AlphaFold: A practical guide https://www.ebi.ac.uk/training/online/courses/alphafold/

Articles:

• Monica Jain et al. (2022) Exosite binding modulates the specificity of the immunomodulatory enzyme ScpA, a C5a inactivating bacterial protease. https://pmc.ncbi.nlm.nih.gov/articles/PMC9464890/
• Jakki Cooney et al. (2008) Crystal structure of C5a peptidase https://www.rcsb.org/structure/3EIF
• Hui Li et al. (2017) Mutagenesis and immunological evaluation of group A streptococcal C5a peptidase as an antigen for vaccine development and as a carrier protein for glycoconjugate vaccine design https://pubs.rsc.org/en/content/articlelanding/2017/ra/c7ra07923k

Lectures:

• Rosetta Commons (2024) AlphaFold – ML for protein structure prediction https://www.youtube.com/watch?v=SVrn8_8aKO8
• Rosetta Commons (2024) MPNN – ML for protein sequence design https://www.youtube.com/watch?v=6z4XmUAwdNA

Acknowledgements:

• Aria Babu, editor at Works in Progress
• Graham Bessellieu, video editor
• Rachel Shu, on-site editor
• Anna Magpie, fact-checking
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David Hackett, composer

Works in Progress & Open Philanthropy

[Correction: The structure of RSV's prefusion F protein was initially determined by X-ray crystallography by Jason McLellan and colleagues, rather than cryo-electron microscopy, although the latter was used to visualize antibody binding and confirm its structure.]

A hundred years ago, insulin was scraped from pig pancreases. Today, it’s made by bacteria in giant tanks. In the second part of a mini series on proteins, drug development and AI, Saloni tells the story of how insulin went from a crude animal extract to the first genetically-engineered drug, kickstarting the biotech industry along the way.

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

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Books:

• Genentech: The beginnings of biotech by Sally Smith Hughes

Articles:

• FDA (2007). Celebrating a Milestone: FDA's Approval of First Genetically-Engineered Product https://fda.report/media/110447/Celebrating-a-Milestone--FDA%27s-Approval-of-the-First-Genetircally-Engineered-Product.pdf
• Genentech (2016). Cloning Insulin https://www.gene.com/stories/cloning-insulin
• Arthur Riggs (2020). Making, Cloning, and the Expression of Human Insulin Genes in Bacteria: The Path to Humulin https://academic.oup.com/edrv/article/42/3/374/6042201

Podcasts:

• Novo Nordisk (Ozempic) by the Acquired podcast https://www.acquired.fm/episodes/novo-nordisk-ozempic

Acknowledgements:

• Aria Babu, editor at Works in Progress
• Adrian Bradley, on-site producer
• Anna Magpie, fact-checking
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David Hackett, composer

Works in Progress & Open Philanthropy

This episode kicks off a mini-series on proteins, drug development and AI. Saloni and Jacob explore the world of proteins, including how proteins fold into complex shapes, why that complexity matters and how crowded and dynamic the inside of a cell really is; and they exchange surprising statistics about proteins.

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

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/

Books:

• Ron Milo and Rob Phillips. Biology by the numbers https://book.bionumbers.org/
• Carl Ivar Branden and John Tooze (1999) Introduction to protein structure https://www.taylorfrancis.com/books/mono/10.1201/9781136969898/introduction-protein-structure-john-tooze-carl-ivar-branden

Articles:

• Niko McCarty (2023). Biology is a burrito. https://www.asimov.press/p/burrito-biology
• Rhiannon Morris, Katrina Black, and Elliott Stollar (2022) Uncovering protein function: from classification to complexes. https://pmc.ncbi.nlm.nih.gov/articles/PMC9400073/
• Victor Muñoz and Michele Cerminara (2016) When fast is better: protein folding fundamentals and mechanisms from ultrafast approaches https://portlandpress.com/biochemj/article/473/17/2545/49248/When-fast-is-better-protein-folding-fundamentals

Image credits:

• Chang et al. (2012) Egg white in organic electronics. https://spie.org/news/4149-egg-white-in-organic-electronics [diagram of egg white denaturing and cross-linking]
• John Kendrew’s model of myoglobin’s structure; via Carl Ivar Branden and John Tooze (1999) Introduction to protein structure.
• Carl Ivar Branden and John Tooze (1999) Introduction to protein structure. [diagram of amino acids and protein structure]
• Ron Milo and Rob Phillips. Which is bigger, mRNA or the protein it codes for? https://book.bionumbers.org/which-is-bigger-mrna-or-the-protein-it-codes-for/ [diagram of myoglobin mRNA vs protein]
• Scitable (2014). Microtubules and Filaments. https://www.nature.com/scitable/topicpage/microtubules-and-filaments-14052932/ [diagram of microtubules]

Lenacapavir is a new HIV drug that blocks infections with an efficacy rate of nearly 100%, and it could completely change the fight against HIV worldwide. Saloni and Jacob talk about the development and prospects for this new drug, as well as the history of HIV, the initial discovery of retroviruses, and how HIV was transformed from a death sentence to a manageable condition.

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

Chapters:

00:00 Intro
03:52 How was HIV discovered? Where did it come from, and how does it attack the body and cause AIDS?
38:10 Antiretrovirals: How did scientists develop breakthrough HIV drugs — from azidothymidine to protease inhibitors to PrEP?
1:51:35 How does prevention and treatment work today?
2:19:03 HIV’s capsid and the breakthrough of lenacapavir, the first-approved HIV capsid inhibitor
2:50:36 How to develop long-lasting treatments
3:14:45 Lenacapavir’s near 100% efficacy in clinical trials
3:48:40 The impact of global programs against HIV, and can we now end HIV?

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Books:

• How to Survive a Plague — by David France (2016). [Mentioned as a history of the science and activism against the AIDS epidemic, and the protease-inhibitor breakthrough.] https://surviveaplague.com/
• And the Band Played On — Randy Shilts (1987). [Mentioned as an account of the early years of AIDS.] https://us.macmillan.com/books/9780312374631/andthebandplayedon/
• Drug development stories: From bench to bedside — Elsevier (2024). [Mentioned as containing a history of the development of lenacapavir] https://shop.elsevier.com/books/drug-discovery-stories/yu/978-0-443-23932-8

Retrospectives:

• The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic — Samuel Broder (2015). https://doi.org/10.1016/j.antiviral.2009.10.002
• History of the discoveries of the first human retroviruses: HTLV-1 and HTLV-2 — Robert Gallo (2005). https://doi.org/10.1038/sj.onc.1208980
• A Look at Long Acting Drugs — Anne de Bruyn Kops for Open Philanthropy (2025). https://bit.ly/long-acting-drugs-op
• How To Save Twenty Million Lives, with Dr Mark Dybul — Statecraft (2023) https://www.statecraft.pub/p/saving-twenty-million-lives
• The Road to Fortovase. A History of Saquinavir, the First Human Immunodeficiency Virus Protease Inhibitor — Redshaw et al. (2000) https://link.springer.com/chapter/10.1007/978-3-642-57092-6_1

Articles:

• The origin of genetic diversity in HIV-1 — Smyth et al. (2012). [Mentioned as a review about HIV’s recombination, which described it as “a primitive form of sexual reproduction”] https://www.sciencedirect.com/science/article/pii/S0168170212002122
• PF74 Reinforces the HIV-1 Capsid To Impair Reverse Transcription-Induced Uncoating — Rankovic et al. (2018) https://doi.org/10.1128/JVI.00845-18
• Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons — Kelley et al. (2024) https://www.nejm.org/doi/full/10.1056/NEJMoa2411858
• Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women — Bekker et al. (2024) https://www.nejm.org/doi/10.1056/NEJMoa2407001
• The evolution of HIV-1 and the origin of AIDS — Sharp and Hahn (2010) https://doi.org/10.1098/rstb.2010.0031
• Pathogenic mechanisms of HIV disease — Moir et al. (2011) https://doi.org/10.1146/annurev-pathol-011110-130254
• Estimating per-act HIV transmission risk: a systematic review — Patel et al. (2012) https://journals.lww.com/aidsonline/fulltext/2014/06190/Estimating_per_act_HIV_transmission_risk__a.14.aspx
• The structural biology of HIV-1: mechanistic and therapeutic insights — Engelman and Cherepanov (2012) https://doi.org/10.1038/nrmicro2747
• Challenges and opportunities in the development of complex generic long-acting injectable drug products — O’Brien et al. (2021) https://doi.org/10.1016/j.jconrel.2021.06.017
• Making a “Miracle” HIV Medicine — Nahas (2025) https://press.asimov.com/articles/hiv-medicine
• Highly active antiretroviral therapy transformed the lives of people with HIV — Dattani (2024) https://ourworldindata.org/data-insights/highly-active-antiretroviral-therapy-transformed-the-lives-of-people-with-hiv

Videos:

• Mini-Lecture Series: HIV Capsid Inhibitors: Mechanism of Action — David Spach, National HIV Curriculum (2024) https://www.youtube.com/watch?v=iZ9KDxV5Zbs&ab_channel=NationalHIVCurriculum

Image credits:

• Mini-Lecture Series: HIV Capsid Inhibitors: Mechanism of Action — David Spach, National HIV Curriculum (2024) [Multiple diagrams of HIV capsid and lenacapavir’s effect.]
• Saloni Dattani; Our World in Data (2024) Highly active antiretroviral therapy transformed the lives of people with HIV. [Graph of decline in HIV/AIDS mortality after HAART was introduced.]
• Engelman and Cherepanov (2012). The structural biology of HIV-1: mechanistic and therapeutic insights. [Diagram of HIV’s entry into the cell.]
• Susan Moir, Tae-Wook Chun, Anthony S Fauci (2011). Pathogenic mechanisms of HIV disease. [Diagram of HIV replication rates over time, contrasting acute and chronic infection.]
• Saloni Dattani, adapted from Patel et al. (2014). Estimating per-act HIV transmission risk: a systematic review. [Bar chart of risks of contracting HIV from different sources when unprotected.]
• Thomas Splettstoesser under CC-BY. [Diagram of HIV’s internal structure.]
• Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women — Bekker et al. (2024) [Chart of lenacapavir’s efficacy.]
• Our World in Data based on Joint United Nations Programme on HIV/AIDS (2024). [Chart of global HIV deaths over time.]

Acknowledgements:

• Douglas Chukwu, researcher at Open Philanthropy
• Sanela Rankovic, Acting Instructor at the Institute for...