Hard Drugs – Details, episodes & analysis

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Hard Drugs

Saloni Dattani & Jacob Trefethen

Science

Health & Fitness

Frequency: 1 episode/37d. Total Eps: 12

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.

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🇬🇧 Great Britain - science
29/07/2026
#84
🇬🇧 Great Britain - science
28/07/2026
#91
🇬🇧 Great Britain - science
27/07/2026
#66
🇬🇧 Great Britain - science
26/07/2026
#43
🇬🇧 Great Britain - science
24/06/2025
#89
🇬🇧 Great Britain - science
23/06/2025
#99
🇬🇧 Great Britain - science
22/06/2025
#91
🇬🇧 Great Britain - science
19/06/2025
#87
🇬🇧 Great Britain - science
18/06/2025
#71
🇺🇸 USA - science
18/06/2025
#84

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https://www.scientificdiscovery.dev/
22 shares
https://blog.jacobtrefethen.com/
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https://www.ebi.ac.uk/training/online/courses/alphafold/
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Score global : 68%

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Lenacapavir: The miracle drug that could end AIDS

Episode 1

Wednesday, June 11, 2025 • Duration 04:53:46

Lenacapavir is a new HIV drug that blocks infections with an efficacy rate of nearly 100%, and it could completely change the fight against HIV worldwide. Saloni and Jacob talk about the development and prospects for this new drug, as well as the history of HIV, the initial discovery of retroviruses, and how HIV was transformed from a death sentence to a manageable condition.

Hard Drugs is a new podcast from Works in Progress and Open Philanthropy about medical innovation presented by Saloni Dattani and Jacob Trefethen.

Chapters:

00:00 Intro
03:52 How was HIV discovered? Where did it come from, and how does it attack the body and cause AIDS?
38:10 Antiretrovirals: How did scientists develop breakthrough HIV drugs — from azidothymidine to protease inhibitors to PrEP?
1:51:35 How does prevention and treatment work today?
2:19:03 HIV’s capsid and the breakthrough of lenacapavir, the first-approved HIV capsid inhibitor
2:50:36 How to develop long-lasting treatments
3:14:45 Lenacapavir’s near 100% efficacy in clinical trials
3:48:40 The impact of global programs against HIV, and can we now end HIV?

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/

Books:

How to Survive a Plague — by David France (2016). [Mentioned as a history of the science and activism against the AIDS epidemic, and the protease-inhibitor breakthrough.] https://surviveaplague.com/
And the Band Played On — Randy Shilts (1987). [Mentioned as an account of the early years of AIDS.] https://us.macmillan.com/books/9780312374631/andthebandplayedon/
Drug development stories: From bench to bedside — Elsevier (2024). [Mentioned as containing a history of the development of lenacapavir] https://shop.elsevier.com/books/drug-discovery-stories/yu/978-0-443-23932-8

Retrospectives:

The development of antiretroviral therapy and its impact on the HIV-1/AIDS pandemic — Samuel Broder (2015). https://doi.org/10.1016/j.antiviral.2009.10.002
History of the discoveries of the first human retroviruses: HTLV-1 and HTLV-2 — Robert Gallo (2005). https://doi.org/10.1038/sj.onc.1208980
A Look at Long Acting Drugs — Anne de Bruyn Kops for Open Philanthropy (2025). https://bit.ly/long-acting-drugs-op
How To Save Twenty Million Lives, with Dr Mark Dybul — Statecraft (2023) https://www.statecraft.pub/p/saving-twenty-million-lives
The Road to Fortovase. A History of Saquinavir, the First Human Immunodeficiency Virus Protease Inhibitor — Redshaw et al. (2000) https://link.springer.com/chapter/10.1007/978-3-642-57092-6_1

Articles:

The origin of genetic diversity in HIV-1 — Smyth et al. (2012). [Mentioned as a review about HIV’s recombination, which described it as “a primitive form of sexual reproduction”] https://www.sciencedirect.com/science/article/pii/S0168170212002122
PF74 Reinforces the HIV-1 Capsid To Impair Reverse Transcription-Induced Uncoating — Rankovic et al. (2018) https://doi.org/10.1128/JVI.00845-18
Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons — Kelley et al. (2024) https://www.nejm.org/doi/full/10.1056/NEJMoa2411858
Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women — Bekker et al. (2024) https://www.nejm.org/doi/10.1056/NEJMoa2407001
The evolution of HIV-1 and the origin of AIDS — Sharp and Hahn (2010) https://doi.org/10.1098/rstb.2010.0031
Pathogenic mechanisms of HIV disease — Moir et al. (2011) https://doi.org/10.1146/annurev-pathol-011110-130254
Estimating per-act HIV transmission risk: a systematic review — Patel et al. (2012) https://journals.lww.com/aidsonline/fulltext/2014/06190/Estimating_per_act_HIV_transmission_risk__a.14.aspx
The structural biology of HIV-1: mechanistic and therapeutic insights — Engelman and Cherepanov (2012) https://doi.org/10.1038/nrmicro2747
Challenges and opportunities in the development of complex generic long-acting injectable drug products — O’Brien et al. (2021) https://doi.org/10.1016/j.jconrel.2021.06.017
Making a “Miracle” HIV Medicine — Nahas (2025) https://press.asimov.com/articles/hiv-medicine
Highly active antiretroviral therapy transformed the lives of people with HIV — Dattani (2024) https://ourworldindata.org/data-insights/highly-active-antiretroviral-therapy-transformed-the-lives-of-people-with-hiv

Videos:

Mini-Lecture Series: HIV Capsid Inhibitors: Mechanism of Action — David Spach, National HIV Curriculum (2024) https://www.youtube.com/watch?v=iZ9KDxV5Zbs&ab_channel=NationalHIVCurriculum

Image credits:

Mini-Lecture Series: HIV Capsid Inhibitors: Mechanism of Action — David Spach, National HIV Curriculum (2024) [Multiple diagrams of HIV capsid and lenacapavir’s effect.]
Saloni Dattani; Our World in Data (2024) Highly active antiretroviral therapy transformed the lives of people with HIV. [Graph of decline in HIV/AIDS mortality after HAART was introduced.]
Engelman and Cherepanov (2012). The structural biology of HIV-1: mechanistic and therapeutic insights. [Diagram of HIV’s entry into the cell.]
Susan Moir, Tae-Wook Chun, Anthony S Fauci (2011). Pathogenic mechanisms of HIV disease. [Diagram of HIV replication rates over time, contrasting acute and chronic infection.]
Saloni Dattani, adapted from Patel et al. (2014). Estimating per-act HIV transmission risk: a systematic review. [Bar chart of risks of contracting HIV from different sources when unprotected.]
Thomas Splettstoesser under CC-BY. [Diagram of HIV’s internal structure.]
Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women — Bekker et al. (2024) [Chart of lenacapavir’s efficacy.]
Our World in Data based on Joint United Nations Programme on HIV/AIDS (2024). [Chart of global HIV deaths over time.]

Acknowledgements:

Douglas Chukwu, researcher at Open Philanthropy
Sanela Rankovic, Acting Instructor at the Institute for...

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Are miracle drugs hiding in plain sight?

Episode 11

Friday, July 24, 2026 • Duration 02:31:43

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

Inventing the second malaria vaccine with Katharine Collins

Episode 10

Wednesday, May 27, 2026 • Duration 02:15:08

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

Should everyone be taking statins?

Episode 9

Friday, February 27, 2026 • Duration 02:54:47

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

The first cancer vaccine

Episode 8

Monday, December 22, 2025 • Duration 02:58:47

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

The history of vaccines

Episode 7

Wednesday, November 26, 2025 • Duration 02:06:23

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

Will AI solve medicine?

Episode 6

Wednesday, October 29, 2025 • Duration 04:34:48

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 Intro
0:09:56 Drug discovery
1:02:20 Animal models
1:49:09 Drug efficacy
2:32:56 Drug safety
2:58:29 Manufacturing and healthcare
3:43:23 R&D funding
4:00:56 Trust and ambition
4:16:01 Summary

Blogposts:

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 3) AI could help lead to an Alzheimer’s cure

The art of protein design with AI

Episode 5

Wednesday, October 15, 2025 • Duration 01:00:21

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

Hacking proteins with AI

Episode 4

Wednesday, October 1, 2025 • Duration 54:36

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:

Hard Drugs – Details, episodes & analysis

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Hard Drugs – Details, episodes & analysis

Podcast details

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