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 PasteurThomas D. Brock (1998) Robert Koch: a life in medicine and bacteriologyMervyn Susser and Zena Stein (2009) Eras in epidemiology : the evolution of ideasAngela Leung (2011) Chapter: “Variolation” and vaccination in late Imperial China, ca. 1570–1911. History of vaccine development by Stanley PlotkinFlorian Horaud (2011) Chapter: Viral vaccines and cell substrate. History of vaccine development by Stanley PlotkinSamuel Katz (2011) Chapter: The role of tissue culture in vaccine development. History of vaccine development by Stanley PlotkinHervé Bazin (2011) Chapter: Pasteur and the birth of vaccines made in the laboratory. History of vaccine development by Stanley PlotkinArticles: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 postulatesBurt 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 ProgressGraham Bessellieu, video editorAbhishaike Mahajan, cover artAtalanta Arden-Miller, art directionDavid Hackett, composerWorks in Progress & Coefficient Giving
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2:06:23
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2:06:23
Will AI solve medicine?
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 Intro0:09:56 Drug discovery1:02:20 Animal models1:49:09 Drug efficacy2:32:56 Drug safety2:58:29 Manufacturing and healthcare3:43:23 R&D funding4:00:56 Trust and ambition4:16:01 SummaryBlogposts: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 biotechTheses: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 ProgressGraham Bessellieu, video editorAbhishaike Mahajan, cover artAtalanta Arden-Miller, art directionDavid Hackett, composerWorks 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.]
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4:34:48
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4:34:48
The art of protein design with AI
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 ProgressGraham Bessellieu, video editorRachel Shu, on-site editorAnna Magpie, fact-checkingAbhishaike Mahajan, cover artAtalanta Arden-Miller, art directionDavid Hackett, composerWorks in Progress & Open Philanthropy
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1:00:21
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1:00:21
Hacking proteins with AI
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 ProgressGraham Bessellieu, video editorRachel Shu, on-site editorAnna Magpie, fact-checkingAbhishaike Mahajan, cover artAtalanta Arden-Miller, art directionDavid Hackett, composerWorks 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.]
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54:36
100 years of insulin in 15 minutes
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 HughesArticles: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 ProgressAdrian Bradley, on-site producerAnna Magpie, fact-checkingAbhishaike Mahajan, cover artAtalanta Arden-Miller, art directionDavid Hackett, composerWorks in Progress & Open Philanthropy
Hard Drugs is a show by Saloni Dattani and Jacob Trefethen about medical innovation: how to speed it up, how to scale it up, and how to make sure lifesaving tools reach the people who need them the most. It is brought to you by Works in Progress and Coefficient Giving.
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