Hard Drugs

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.

(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

Click here to view the episode transcript.

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

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/ 
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