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** We’ve paused the Works in Progress podcast feed, so head over to our dedicated Hard Drugs podcast feed to listen to future episodes, if you hadn’t subscribed there already! https://harddrugs.worksinprogress.co/ **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:Click here to read the episode transcript. Saloni’s substack newsletter: https://www.scientificdiscovery.dev/ Jacob’s blog: https://blog.jacobtrefethen.com/  Acknowledgements: Graham Bessellieu, video editorAbhishaike Mahajan, cover artAtalanta Arden-Miller, art directionDavid 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/s42003-024-06121-9Chokwassanasakulkit 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

** We’ve paused the Works in Progress podcast feed, so head over to our dedicated Hard Drugs podcast feed to listen to future episodes, if you hadn’t subscribed there already! https://harddrugs.worksinprogress.co/ ** GLP-1 drugs like Ozempic and Mounjaro have transformed the treatment of obesity as well as diabetes, can 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. 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, composerBlogs 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 & report 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

Alberta is the only part of the world that has people but not rats. Rats came to the new world on ships to New York, Boston and Philadelphia during the Industrial Revolution. From there they spread west at a rate of 24 kilometers a year and by 1950 they were on Alberta's border. But Albertans stopped them coming any further. In the US there is a culture that lives in dense cities, the women usually work, and yet they still have an average of six children each. The ultra-Orthodox have a number of pro-fertility norms, most of which wouldn't work for the secular world but some we could learn from. Sam, Pieter, and Aria discuss a handful of pieces in Issue 24 of Works in Progress. They talk land reclamation, vaccinating wild animals, the Squamish Nation's housing development in Vancouver and how The Glorious Revolution caused the Industrial Revolution. Buy your copy here: https://worksinprogress.co/print/

In the nineteenth century, cities often grew a thousandfold while increasing wages, the size of homes, and delivering great public goods like electricity and plumbing to their people. What made them so extraordinary? They had a hybrid of laissez-faire and top-down control. Landowners could build almost anything they liked but street networks were laid out with near-Soviet thoroughness decades in advance. Transport and utilities, meanwhile, ran as regulated monopolies. They were funded by users, turned a profit, but prices were controlled. Samuel, Ben and Aria discuss what made this system work and why it was dismantled.

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. 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 ProgressGraham Bessellieu, video editorAlice Edwards, captionsAbhishaike Mahajan, cover artAtalanta Arden-Miller, art directionDavid 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

The Trump administration wants to bolster traditional art. Their attempt to revive sculpture, a mass statue-building program, is doomed. America doesn’t have the sculptors, foundries, and workers to make hundreds of bronze or marble sculptures. North Korea would be in a much better position. Sam and Samuel sit down with our Art Director, Atalanta, a sculptor by training, and talk all things sculpture. They discuss how art education has become de-skilled, how sculpture has always been the best art form for mass production and the surprising places the tradition has been kept alive.

Generations of microbes evolve in hours, not millennia. By speeding up Darwin’s clock, scientists have watched evolution happen in real time, and it’s changed how we understand natural selection. You can see the images, graphs and read the article at https://worksinprogress.co/issue/the-evolution-of-bacteria-2/ And you can find the rest of Works in Progress at worksinprogress.co Words by Kevin Blake Read by Stuart Ritchie Music by David Hackett

Local government works best when areas can compete with each other and capture some of the upside of economic growth. Ben sits down with Judge Glock to discuss how well-structured local incentives helped make Loudoun County, Virginia, the global capital of data centers — and helped France build so many nuclear power stations. 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. Read Judge Glock's piece on why water in America is too clean here: https://worksinprogress.co/issue/the-gold-plating-of-american-water/

In 1965, married American women did 34 hours of housework weekly. By 2010, that had fallen to 18 hours. The dishwasher wasn’t the only cause, but it certainly helped. You can see the images, graphs and read the article at https://worksinprogress.co/issue/inventing-the-dishwasher/ And you can find the rest of Works in Progress at worksinprogress.co Words by Erin BraidRead by Stuart Ritchie Music by David Hackett

English prose has become much easier to read. But shorter sentences had little to do with it. You can see the images, graphs and read the article at https://worksinprogress.co/issue/the-logical-triumph-of-english/ And you can find the rest of Works in Progress at worksinprogress.co Words by Henry Oliver Read by Stuart Ritchie Music by David Hackett

Drug development has never been more expensive, in terms of output per dollar spent.  This trend, called Eroom's law, is surprising, considering incredible technological advances. Ben and Saloni talk to Ruxandra Teslo about why this has happened and what can be done about it. How can we reform clinical trials to make them more efficient and abundant? Why are so many pharma companies moving early trials to Australia? What's wrong with ethics boards and how can we fix them without compromising on safety?

Competition makes capitalism work. A new method for measuring it may be the holy grail of economic regulation.  You can see the images, graphs and read the article at https://worksinprogress.co/issue/how-to-spot-a-monopoly/ And you can find the rest of Works in Progress at worksinprogress.co Words by Brian Albrecht Read by Stuart Ritchie Music by David Hackett

We disinfect water before we drink it. Germicidal ultraviolet could make airborne disease as rare as those carried by water. You can see the images, graphs and read the article at https://worksinprogress.co/issue/the-death-rays-that-guard-life/ And you can find the rest of Works in Progress at worksinprogress.co Words by Gavriel Kleinwaks & Karam ElabdRead by Stuart Ritchie Music by David Hackett

You should freeze your eggs. Contrary to popular myth, egg freezing works very well and if you freeze your eggs in your twenties or early thirties, you have a very good chance of having a child. European leaders are looking to copy Australia's example and cut migration from boat-bound refugees but they are in danger of learning the wrong lessons. Offshore detention was the most widely publicized aspect of their refugee policy but it didn't work. Turnbacks were much cheaper and more effective. Ben, Aria and Pieter discuss different articles in the new issue of Works in Progress. They discuss how Britain lost its position as the world leader in nuclear power, why ASML is so successful, how envy killed the first bus, and how cool neo-traditional temples are. Buy your copy here: https://worksinprogress.co/print/

If we ever want to live in space, we need to work out a way of creating artificial gravity. You can see the images, graphs and read the article at https://worksinprogress.co/issue/inflatable-space-stations/ And you can find the rest of Works in Progress at worksinprogress.co Words by Angadh Nanjangud Read by Stuart Ritchie Music by David Hackett