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  • Should everyone be taking statins?

    Should everyone be taking statins?
    Feb 27 2026
    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 Introduction13:35 The decline in heart disease mortality31:02 Surprising facts about cholesterol55:40 The lipid hypothesis: 7 lines of evidence for the harms of LDL cholesterol1:22:15 How cholesterol works1:30:40 The discovery of statins1:48:44 Should everyone be on statins?1:57:10 PCSK9 drugs and beyond2:22:56 Summary Saloni’s substack newsletter: https://www.scientificdiscovery.dev/Jacob’s blog: https://blog.jacobtrefethen.com/ Acknowledgements:Aria Babu, editor at Works in ProgressGraham Bessellieu, video editorAbhishaike Mahajan, cover artAtalanta Arden-Miller, art directionDavid Hackett, composerWorks in Progress & Coefficient GivingCorrection: 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.BooksDaniel Steinberg (2007) The Cholesterol Wars.Jie Jack Li (2009) Triumph of the Heart: The Story of Statins.Blog postsJames Stein (2025) Lipid and lipoprotein basics series. https://jamesstein18.substack.com/p/part-i-lipid-and-lipoprotein-basics ArticlesAkira 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.94.9.4312Saloni Dattani (2025) Death rates from cardiovascular disease have fallen dramatically — what were the breakthroughs behind this? https://ourworldindata.org/cardiovascular-deaths-declineCholesterol 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)61350-5E. 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/s41569-023-00860-8VideosNinja Nerd (2018) Lipoprotein metabolism https://www.youtube.com/watch?v=wQY0xpwqPfQ
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    2 Std. und 55 Min.
  • The first cancer vaccine

    The first cancer vaccine
    Dec 22 2025

    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
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    2 Std. und 59 Min.
  • The history of vaccines

    The history of vaccines
    Nov 26 2025

    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
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    2 Std. und 6 Min.
  • Will AI solve medicine?

    Will AI solve medicine?
    Oct 29 2025
    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 Std. und 35 Min.
  • The art of protein design with AI

    The art of protein design with AI
    Oct 15 2025

    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
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    1 Std.
  • Hacking proteins with AI

    Hacking proteins with AI
    Oct 1 2025

    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.]
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    55 Min.
  • 100 years of insulin in 15 minutes

    100 years of insulin in 15 minutes
    Sep 16 2025

    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
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    18 Min.
  • Proteins: Weird blobs that do important things

    Proteins: Weird blobs that do important things
    Sep 3 2025

    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]
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    20 Min.