** 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 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

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 Progress
• Graham Bessellieu, video editor
• Alice Edwards, captions
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David 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/