Breakthrough antivirals and fresh US grant cancellations

Summary

Science In Action – Breakthrough Antivirals and Fresh US Grant Cancellations

Date: March 27, 2025
Host: Roland Pease (BBC World Service)

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Main Theme and Purpose

This episode investigates two critical science stories: the development of groundbreaking antiviral drugs that could transform responses to current and future coronavirus pandemics, and the abrupt cancellation of major US federal grants supporting antiviral research post-COVID. The show also explores tantalizing new evidence of complex organic molecules on Mars and evolutionary science revealing what makes horses remarkable runners.

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Key Discussion Points and Insights

1. Antiviral Breakthroughs: New Hope for Pandemic Preparedness

[03:00–09:12]

• The Antiviral Discovery Challenge:

  • Antivirals effective against coronaviruses, particularly COVID-19, have been slow to develop.
  • Two promising antivirals have emerged, both at the preclinical stage, showing strong efficacy in cell cultures and animal models, but require further refinement and human trials.

• Innovative Screening Approach:

  • Johann Naitz's team at the Rega Institute, Leuven University, tested 350,000 candidate molecules using an automated robotic chemistry lab.
    • "Today, actually, we can on average test 25,000 molecules a day against a virus infection in cells ... that allowed us to test these 350,000 compounds and then from those, pick a few molecules that block the replication of the virus." — Johann Naitz [03:50]
  • The process involves using multi-well plates, robotic platforms, and automated microscopes to rapidly assess which compounds inhibit viral replication.

• The Novel “Achilles Heel” Approach:

  • Unlike existing antivirals that prevent the replication of viral genetic material or inhibit critical viral enzymes, the new compound blocks the assembly of new virus particles inside infected cells.
    • "By using this approach, we can basically identify novel ... Achilles heels of this virus ... putting [the components] together, the assembly into a infectious particle, is not happening." — Johann Naitz [06:10]

• Progress and Potential:

  • Tested in mice and hamsters, the new compound is as potent as nirmatrelvir (in Paxlovid).
  • Ongoing work is enhancing potency and extending its action to cover the family of coronaviruses, potentially preparing for "SARS-CoV-3."
    • "If it would have been right now in midst of the pandemic, I think the molecules that we have right now have the qualities to go into clinical trials in humans." — Johann Naitz [08:08]

Memorable Moment:

• Roland Pease marvels at how discovering vulnerabilities (“Achilles heels”) at later stages of the viral lifecycle could revolutionize antiviral strategies.

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2. US Grant Cancellations: Threat to Pandemic Readiness

[09:12–15:18]

• Sudden Federal Funding Cuts:

  • NIH abruptly terminated all COVID-related research grants, including the AVID Antiviral Drug Discovery Support program ($500 million supporting 9 consortia, such as the UK-US-led ASAP project).
    • "The end of the pandemic provides cause to terminate Covid related grant funds." — Official wording read by Caroline Freycinet [09:49]

• Consequences of Halting Projects:

  • Ed Griffin (Med Chemica) and Annette von Delft (Oxford) explain the challenge of stopping ongoing projects:
    • "It's a little bit like we've started building a bridge and we are halfway there. And ... it will be very difficult to complete this bridge without significant funding into the area. But you can't walk over a bridge that only has been half built." — Annette von Delft [11:34]

• Preparedness vs. Complacency:

  • Early-stage antiviral research is crucial to prevent outbreaks from becoming pandemics.
    • "Outbreaks are inevitable. Pandemics aren't. So if we can catch a virus ... really early and you can do that with antivirals, if you already have them ready to ship, you can catch it before it's a pandemic..." — Ed Griffin [10:44]
  • Private sector disincentivized to invest in antivirals for non-existent diseases—public funding thus vital.
    • "If there isn't a market now, why are you working on it? So this is where the AVID centres were particularly different because we're trying to get ahead of the game." — Ed Griffin [14:05]

• Salvaging Results:

  • Despite the funding cut, the ASAP team plans to share their rich datasets for wider benefit.
    • "We have generated very, very rich data sets. So it's something that we hope will help other people, maybe ourselves, but maybe others, to find drugs that will be effective against pandemics in the future." — Annette von Delft [14:47]

Notable Quote:

• Roland Pease observes the dangerous cycle: researchers unable to sustain slow, complex antiviral discovery unless crises are ongoing—a lesson from past pandemics.

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3. Mars Organics: Ancient Hints of Life

[17:32–24:58]

• Curiosity Rover’s Surprising Find:

  • Caroline Freycinet (Institut Pierre Simon Laplace) describes how Curiosity's SAM instrument reanalyzed drilled clay samples from Mars (collected in 2013).
    • "Having those fragile compounds preserved for 3.7 billion years at the surface of Mars, it gives a lot of hope that if life ever appeared or existed at this time, the residue of this life would be preserved until today." — Caroline Freycinet [21:19]

• What Was Discovered:

  • Complex carbon-chain molecules (alkanes of 10–12 carbons) detected, larger than previously found Martian molecules.
  • Likely degraded products of fatty acids, common both in life and in non-biological chemistry.

• Interpreting the Findings:

  • The distinction between chemical and biological origins remains unresolved; both could produce such molecules.
    • "We have no way today ... to differentiate between a chemical origin or a biological origin of those fatty acids. It can be chemical, it can be biological. It will give the same fatty acids." — Caroline Freycinet [23:18]

• Reserves and Future Plans:

  • One more pristine Martian sample (“doggy bag”) remains for a future, carefully optimized experiment.

Notable Moment:

• Freycinet’s reflection: "It's a lot of patience, but it's also a lot of excitement ... we are living on all these small successes that we obtain in the lab..." [24:21]

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4. Horse Genetics: Evolution’s Endurance ‘Hack’

[24:58–32:08]

• The Evolution of the Horse:

  • Gianni Castiglioni (Vanderbilt University) explains how horses’ unique mutation allows for exceptional endurance, vital for both escaping predators and their later domestication by humans.
    • "They have so much mitochondria densely packed into their muscle cells, ... really at the physiological limit of how much oxygen you can take in and how much energy you can produce." — Gianni Castiglioni [26:18]

• The Mutation's Impact:

  • A single critical mutation at first appeared “broken,” but instead gives rise to a special form of protein, enabled by further compensatory mutations. This allowed horses to efficiently prevent cellular damage from high oxygen use during intense activity.
    • "We originally thought this protein was broken, that this gene was broken in horses. This is the majesty of evolution. Through trial and error, it will find these really elegant ways to kill two birds with one stone." — Gianni Castiglioni [27:55 and 02:34, repeated for emphasis]

• Broader Implications:

  • Similar mutations in humans often cause disease. Studying the horses’ “genetic patch” could offer new therapeutic ideas for human genetic disorders.
    • "We're not going to take horse genes and put them into you. We're just going to use the design principles that nature has produced and kind of steal that blueprint for our own purposes." — Gianni Castiglioni [32:08]

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Timestamps of Important Segments

• Antiviral Discoveries: [03:00–09:12]
• US Grant Cancellations & Research Risks: [09:12–15:18]
• Mars Organics and Origin of Life: [17:32–24:58]
• Horse Evolutionary Mutation: [24:58–32:08]

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Notable Quotes & Memorable Moments

• "Outbreaks are inevitable, pandemics aren't. ... The only advantage we can have is by being prepared."
  — Ed Griffin [10:44]
• "You can't walk over a bridge that only has been half built."
  — Annette von Delft [11:34]
• "This is the majesty of evolution. Through trial and error, it will find these really elegant ways to kill two birds with one stone."
  — Gianni Castiglioni [27:55]
• "Having those fragile compounds preserved for 3.7 billion years at the surface of Mars ... gives a lot of hope that if life ever appeared or existed at this time, the residue of this life would be preserved until today."
  — Caroline Freycinet [21:19]

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Overall Tone & Style

The conversation maintains a measured, inquisitive, and occasionally wry tone, reflecting both the excitement of scientific discovery and the frustration at bureaucratic setbacks. The scientists, while hopeful and passionate, express concern about the loss of momentum in pandemic preparedness and the slow, incremental nature of both scientific and policy progress.

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Summary Flow

Listeners are guided from the cutting edge of antiviral drug discovery (and the systemic challenges it faces with grant cancellations), to the edge of our solar system and the very beginnings of life, back down to Earth for lessons from evolution. The episode seamlessly intertwines urgent biomedical challenges with awe-inspiring cosmic curiosity and the relentless logic of natural selection, showing the breadth—and the vulnerability—of scientific progress.

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For listeners seeking more, visit the Science In Action webpage to explore past episodes and further resources.

Transcript

[Roland Pease]

This BBC podcast is supported by ads outside the uk.

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[Annette von Delft]

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All so that he can help students, staff and teachers stay healthy and focused. Call 1-800-granger click grainger.com or just stop by Granger for the ones who get it done. Welcome to Science in Action from the BBC World Service with me Roland Pease. Later in the programme, Molecular hints of life. Perhaps once on Mars, having those fragile.

[Caroline Freycinet]

Compounds preserved for 3.7 billion years at the surface of Mars, it gives a lot of hope that if life ever existed at this time today we could be able to see those molecules so.

[Roland Pease]

Tantalizing and the mutation that maybe made horses extra muscly.

[Gianni Castiglioni]

We originally thought this protein was broken, that this gene was broken in horses. This is the majesty of evolution. Through trial and error, it will find these really elegant ways to kill two birds with one stone.

[Roland Pease]

Keep listening. Antivirals, it seems, are like proverbial London buses. You wait years for something new to tackle Covid like coronaviruses and then two show up at the same time. They're both at the pre clinical stage, shown to be effective in cell cultures and animals, but with loads more development and human trials needed if they're ever to be used. But what a difference it would have made if effective and accessible antivirals had been available five years ago. As SARS CoV2 started spread across the globe, however, it's extraordinarily hard to find the perfect compounds that will halt the viral life cycle by essentially throwing chemical grit into the infection's molecular replication machinery. For Johann Nait, leader of one of the successful teams, that meant testing 350,000 candidate compounds. And that starts with an extraordinary bio secure robotic chemistry lab.

[Johann Naitz]

Today, actually, we can on average test 25,000 molecules a day against a virus infection in cells. And so that allowed us to test these 350,000 compounds and then from those, pick a few molecules that block the replication of the virus. And that's then basically we call that a hit.

[Roland Pease]

So it's quite a blind sort of search. This must involve robots and what tiny little cells containing tissue samples. You infect them, you put in different compounds into each of them and then see which ones the virus replicates in.

[Johann Naitz]

Indeed. Right. So we use these plastic plates with 384 wells and we fill them with cells, we add the virus and we also add the test compound. And then the virus is basically replicating on the cells. And we can then do, by fully automated microscopes in that robotic platform, we can then do the readout, that's all happening automatically. That can even happen on Christmas evening, in the mid of the night, hopefully, then identify a few of these molecules that block the replication of the virus.

[Roland Pease]

And would you find a good one, is that it?

[Ed Griffin]

Or.

[Roland Pease]

I think there's presumably further steps of chemistry to try and see if you can improve it.

[Johann Naitz]

We work very intensively here at Leuven University with the center for Drug Design and Discovery. So step by step together with the chemist in a close effort, we increased the potency. And at a certain step, if you have molecules that are sufficiently potent against the virus and have no adverse effects on the host cell, then we started basically using these molecules as what we call chemical tools to try to identify what the mechanism is by which they block the replication of the virus. Because, I mean, that's, that's the important part.

[Roland Pease]

So I absolutely wanted to talk about this because this is one of the things I found very interesting in your work. So, as you say, the existing antivirals for Covid either stop the RNA genetic material being replicated, which is a good idea, or there's this enzyme, which sort of Allows it to use all its toolkits, its molecular toolkit, to take over a cell. And those are the ones which exist. Yours seems to work at a much later stage in this whole virus replication stage, where the components that have been made in a cell cannot assemble into a new virus.

[Johann Naitz]

Absolutely. So that's the cool things. By using this approach, we can basically identify novel, what I would call the Achilles heels of this virus. And indeed, that's happening at the later step. So basically, the building blocks are being produced within the cell, but then putting that together, the assembly into a infectious particle, is not happening.

[Roland Pease]

I mean, it's. For me, it's part of the whole viral lifecycle I find so fascinating, is that these are molecules that pack themselves into their own suitcase and then sort of take the trip to the next cell. And the idea that you can block that sort of process. How effective is your antiviral compared to, you know, the ones that are already there?

[Johann Naitz]

For now, we have only tested the molecule in animal infection models in mice and in hamsters. And, well, it's difficult to compare, of course, side by side. But let's say that as a reference molecule, we used nirmatrilvir, which is the active component of paxlovid, and it shows, let's say, more or less, the same potency as that molecule. Of course, it's in mice, it's in hamsters, and. But I should also say that the molecule that we now report in this paper that is being published in Nature, that this is kind of an intermediate molecule. So since then, we have been continuing, of course, between submitting this manuscript, we have been working hard for it to improve the potency, and by now we have molecules that are even more potent than the one that we publish in this paper.

[Roland Pease]

That's very interesting because I wanted to sort of move on to what happens next. As well as your paper in Nature, there's one from the company J and J.

[Johann Naitz]

Yes.

[Roland Pease]

Which seems to be actually quite coincidentally similar to the one you're doing. But I get the feeling there's not a lot of activity in developing antivirals for Covid or for the next pandemic. Is anyone going to take up the work that you're doing to make it into something that you can test in a proper clinical trial?

[Johann Naitz]

Well, if it would have been right now, in midst of the pandemic, I think the molecules that we have right now have the qualities to go into clinical trials in humans. They're very, very potent, very, very safe. And so that's the exercise that we're doing right now is to make sure that they are active against the whole family, as far as we can see of coronaviruses, not only with the aim to have it active against SARS CoV2, but also, for example, against SARS CoV3, if such virus would emerge. It's just at the time, basically the day that you know what the gen, that teams can start working on a vaccine, but then it may take a year before you can basically use your vaccine. So indeed, in this first month and year of a pandemic, you need something to protect the people most at risk, the high risk patients, but perhaps also doctors and nurses that work with these patients. And if you then have a pill that you can, for example, take once or twice a day and give it to people that have the first symptoms, you will basically block this disease to further evolve and you will protect those most at risk.

[Roland Pease]

Johann Naitz of the REHGA Institute for Medical Research in Leuven. Details of both his candidate antiviral and the JJ one are set out in Nature this week. Now, I thought we'd get through one week without talking about the rapid changes in federal site support in the usa. But as I was preparing for that interview, wondering about the ecosystem for developing vital new antivirals, Nature and Science magazines reported the axing of all Covid related research.

[Johann Naitz]

There.

[Roland Pease]

Here's the wording handed down to the National Institutes of Health.

[Caroline Freycinet]

The end of the pandemic provides cause to terminate Covid related grant funds.

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These grant funds were issued for a.

[Caroline Freycinet]

Limited to ameliorate the effects of the pandemic. Now that the pandemic is over, the.

[Roland Pease]

Grant funds are no longer necessary. Among the programmes summarily axed a half billion dollar program called AVID Antiviral Drug Discovery Support, supporting nine independent consortia to do the kind of work that Johan does. And all halted within a day, some of them international. For example, asap, a project taking advantage of AI in antiviral discovery. It's led from the Sloan Kettering Institute for Cancer Research in New York, but includes in the UK Annette von Delft of Oxford University and Ed Griffin of the drug's discovery company Med Chemica, who says the focus is is not the past pandemic, but the next one.

[Ed Griffin]

Outbreaks are inevitable, pandemics aren't. So if we can catch a virus that crosses over into the human population really, really early and you can do that with antivirals, if you already have them ready to ship, you can catch it before it's a pandemic. It's the only advantage we can have is by being prepared.

[Roland Pease]

And you have heard quite specifically the project that you're involved in, this one called asap, that has been cut. Is that confirmed?

[Annette von Delft]

Yes, we just had a meeting today. We as the whole centre, ASAP is the consortium that we're working in, that stands for AI Driven Structure Enabled Antiviral Platform, that our funding has been terminated.

[Roland Pease]

Where does that leave the work that you've done up to this point?

[Annette von Delft]

It's a little bit like we've started building a bridge and we are halfway there. And yeah, it will be very difficult to complete this bridge without significant funding into the area. But you can't walk over a bridge that only has been half built.

[Roland Pease]

I mean, we were talking just earlier to Johann Nait about a candidate antiviral that he's developed with his team and it's taken five years. These things are so complex. You can't just turn this kind of work on and off.

[Annette von Delft]

Yeah, and I think that really highlights the rationale for being prepared. As you correctly said, antiviral discovery does take a long time. We have to show that the new drug works against the like range of viruses, but we also have to show very importantly that this is a safe drug to give. And that takes a huge amount of effort and long timescales as well. And we will have to bring these compounds to a stage where they are ready to be tested in humans in the case of a pandemic. So we'll have to start much earlier than kind of hearing about the virus being in humans already. So yeah, I think it is going to be very important for humanity that we have molecules that are ready to be tested in case of a future pandemic?

[Roland Pease]

Ed, is this a kind of illustration of the fact that antivirals are, I don't know, are there a Cinderella part of the pharmacy business?

[Ed Griffin]

Well, there's been huge success over the last 30 years in developing new antivirals for existing diseases, but that takes time. As a science, we've managed to make great progress on hiv, we've made great progress on hepatitis C, but those are existing diseases. When we talk about being prepared for the next pandemic, we have to have multiple drugs ready to go, ready to be tested, so that you can test different ones when a new viral threat arrives. If you leave it to when the virus is actually on your doorstep, you just can't do it in time.

[Roland Pease]

Is this something that could be left to the pharmaceutical industry itself? Because if they succeed, they make a huge profit, so they're presumably good incentives for them.

[Ed Griffin]

Well, the problem is if it's a disease that doesn't exist at the moment within the pharmaceutical industry, it's very hard to argue why are you working on that and not on a disease that's already there?

[Roland Pease]

You want a market?

[Gianni Castiglioni]

Yeah.

[Ed Griffin]

If there isn't a market now, why are you working on it? So this is where the AVID centres were particularly different because we're trying to get ahead of the game. But actually the early research is relatively inexpensive, so it makes good sense to spend a little bit now to save yourself a huge amount potentially in the future. And we're talking about money. This is people, the people. Consequences of the last pandemic were appalling. And what we're trying to do is say, well, we don't have to do that. Again, this is a choice. We can choose to be better prepared. So it's frustrating to us because that's what we've been spending our time doing.

[Annette von Delft]

I think we are actually incredibly proud of the results that we have achieved over the last three years as part of this ASAP AVID center. And we have generated very, very rich data sets. So it's something that we hope will help other people, maybe ourselves, but maybe others, to find drugs that will be effective against pandemics in the future. And we are planning to put all this data out there so that it is usable even if our current effort is paused.

[Roland Pease]

Annette von Delft and Ed Griffin wondering how to keep critical research going ahead of the next globe threatening outbreak. In fact, it was almost exactly five years ago we had another medicinal chemist on the program who'd been working since SARS 1 on potential coronavirus antivirals, but with no meaningful support. And we saw how that ended. You can find that edition and all the others on the Science in action [e-mail].

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This is the story of the 1.

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[Roland Pease]

But now science in action is going to fly you off to Mars, where another robotic chemistry lab on NASA's rover Curiosity has discovered intriguing organic. That's carbon based molecules which, well, they've set the wires abuzz yet again with thoughts of life on the red planet. Caroline Frestinet is the, shall we say, lab manager responsible for running the experiments across tens of millions of kilometers of separation.

[Caroline Freycinet]

We cannot be there on Mars, so we have to design and build an instrument that will work by itself on Mars. It was 20 years ago, this step for Curiosity and then we have to operate it on Mars and we get used to it. After 13 years on Mars, we know how to talk to it and we understand when the instrument talks to us, but it's still super difficult to understand the data because it's Mars and Mars is talking to us, but it's speaking Martian and we have to decipher what it says.

[Roland Pease]

Now what interests me about this new report is that you've gone back to old samples. You collected these samples, I think 12 years ago.

[Caroline Freycinet]

Yeah.

[Roland Pease]

Yeah. So were you bored or was there a reason why you went back and said, I want to take a second look?

[Caroline Freycinet]

That's a good question. The samples was indeed drilled in 2013. Then we did some analysis. We've spent a lot of time at this specific location because it was interesting. We wanted to stay more, but we had to move from it. It was found to contain a lot of clays. The layers of the clays, they accumulate molecules and when the clay dries out, it protects the organics that are trapped within it. It was formed 3.7 billion years ago at the surface of Mars, but it was covered with sediments at the time it was formed and it was buried within the surface. And a buried sample, it's protected from the harsh radiation that sterilize the surface of Mars. So it's a double protection, clays and buried. We kept some samples within our instruments, within the SAM instrument, the sample analysis at Mars. Those samples that we call our doggy bags. We knew that we had an interesting sample on board and that we had time to develop some new method, very innovative methods to run on this specific sample. And that's what we did during a couple of years in our labs after landing on Mars. Right. We developed this new and innovative method to make sure that we would see more of the compounds that are present in the sample.

[Roland Pease]

So even though the instrument was designed and built, I guess 20 years ago.

[Caroline Freycinet]

Yes.

[Roland Pease]

You were able to sort of redesign the way you were using it remotely. But you had to experiment, test it all out in your own labs in Paris.

[Caroline Freycinet]

Exactly, in Paris and elsewhere in the world. It's an international collaboration.

[Roland Pease]

I mean, you found these carbon based molecules, I guess you were hoping for that.

[Caroline Freycinet]

We were hoping for that. But it's still a surprise to find so big molecules. They are made of 10, 11 and 12 carbon and in a linear chain. It was not a surprise to find organics. We did find already Organics in 2015, in 2018 in the same area. But those were at the time very small molecules composed of maximum six carbon. And also they were ring molecules.

[Roland Pease]

And they're more stable.

[Caroline Freycinet]

I guess they are way more stable. And in this new discovery, having those fragile compounds preserved for 3.7 billion years at the surface of Mars, it gives a lot of hope that if life ever appeared or existed at this time, the residue of this life would be preserved until today. And today, by picking a sample on Mars, we could be able to see those molecules.

[Roland Pease]

So I mean, these carbon molecules, they're alkanes, which are about the simplest form of organic molecule you can get. I mean, are they the original molecules do you think that you've sampled, or are they degradation products or something else? Or did you know, did something happen to them in the experiment that you were doing?

[Caroline Freycinet]

In our experiment, in a SAM experiment, we heat up the sample up to 850 degrees C. And by heating this sample, we make some chemistry. So the detecting molecules may not be the ones that are originally present in the sample. So we did a lot of experiments in our labs to try to get back to the original compounds that are present in MERS sample. And the most possible probable ones would be fatty acids.

[Roland Pease]

They sound biological, but I guess not necessarily. I mean, is that really encouraging in the idea that these might have a biological origin?

[Caroline Freycinet]

Yeah, it's very encouraging, but it doesn't sound that biological because we know how to form them in a completely chemical way. We know chemical pathways that will form fatty acids. We do find fatty acids on meteorites, and we know that life did not form them. It was a completely chemical synthesis. However, what's very intriguing is that those molecules, those fatty acids, are also decomposition products of bacterial membranes, all type of membranes. And we have no way today with the results we have to differentiate between a chemical origin or a biological origin of those fatty acids. It can be chemical, it can be biological. It will give the same fatty acids.

[Roland Pease]

Sounds frustrating. Have you got any samples left? I mean, could you redesign the experiments yet again to get, I don't know, some better clues?

[Caroline Freycinet]

We still have one more that is present in our SAM instrument. There is one SAM Cumberland doggy bag that we still have to analyze. A pristine sample that has not been analyzed until today.

[Roland Pease]

And you don't want to make a mistake?

[Caroline Freycinet]

We don't. We want to make the perfect experiment. We want to design in our labs the perfect experiment to try to answer the question of the origin of the fatty acid.

[Roland Pease]

I have to say, the work you do sounds fascinating, but it must require a lot of patience to wait for the moment.

[Caroline Freycinet]

It's a lot of patience, but it's also a lot of excitement. And there are different steps in the space mission, so there are small results all along, and then one big result sometime like the one of today. But we are living on all these small successes that we obtain in the lab, and also we work in different missions in parallel. It's not only Mars, but we want to go further in the solar system. The Dragonfly mission to Titan, a moon of Saturn. We are currently building the instrument, so it's a different stage, and all of them are super interesting.

[Roland Pease]

Caroline Freycinet, cosmic chemist at the Institute. Pierre Simon Laplace, with the stamina of a horse, ready for the longest of treks. An analogy I've chosen quite deliberately, if clumsily, because US researchers have uncovered an unlikely mutation that happened millions of years ago that separates horses from all other mammals in giving them the capacity to run and run and run. A galloping evolutionary success story, you might say. Gene hunter Gianni Castiglioni vaulted all the hurdles to see what made horses so useful to our ancestors.

[Gianni Castiglioni]

Our ancestors really seized on them for their athletic talent right during all these domestication processes thousands of years ago. But the starting point Was produced by natural selection. 50 million years or so of predators trying to catch horses can. And horses became better and better at escaping, running faster, having longer endurance. They have remarkably huge lungs, heart, they have over 200,000 kilometers of capillaries. So they have this incredible ability to take in oxygen. They actually go through nearly 400 liters of oxygen every minute when they're running. And yet, despite this incredible ability to deliver oxygen to muscle tissues, the muscles still cannot get enough. And that's because they have just so much energy production capability, ability, which requires oxygen. They have so much mitochondria densely packed into their muscle cells, which is the part of your cell that produces energy. They're really at the physiological limit of how much oxygen you can take in and how much energy you can produce.

[Roland Pease]

And am I right that part of the question there is that when you burn oxygen, you end up with chemical species in your cells which are quite damaging. And so they've got around that somehow. Is that part of the story?

[Gianni Castiglioni]

Yeah, that's exactly it. So we've made a deal with the devil life billions of years ago, where we use oxygen to produce energy. It's fantastic. But we essentially have a slow burning fire in our bodies. When you set a fire, you are oxidizing the wood and you produce light, you produce heat. Those are forms of energy. And that's what our body does. We harness the energy. But in a fire, you know, something's getting burned and something's getting damaged. Unlike a fire, our bodies are able to recover from the damaging effects. And so what horses have done is they're able to make this fire even bigger and they're able to prevent it from causing any damage. So it's this twofold ability they've enhanced just through a single mutation.

[Roland Pease]

It's quite so extraordinary. You say that this is a mutation that affects one protein, but affects it so dramatically that it's had this sort of transformational effect.

[Gianni Castiglioni]

Yes, exactly. This is the majesty of evolution, so to speak, where through trial and error, it will find these really elegant ways to kill two birds with one stone. And it is nothing like what we, what we thought. We originally thought this, this protein was broken, that this gene was broken in horses. We did experiments, it turned out it wasn't the case. So we had to reformulate what was going on and dig deep into the literature and figured out this might actually be one of these very rare cases through this very convoluted mechanism, as you, as you said, and that, that ended up being the case.

[Roland Pease]

So this really was an advantage in.

[Gianni Castiglioni]

This case, we know from the fossil record of horses. It's a textbook, literally a textbook example of evolution where the fossils are almost a stepwise progression. They show how horses went from a dog sized ancestor all the way up to the modern horse. So we know that the trajectory that evolution was pushing them in. And so when we see this mutation, and it's not just the one mutation, the mutation would have been lethal on its own. We see other mutations that co evolved that compensate for that and really produce something greater than the sum of its parts. And it's this coordination that really screams to us. Natural selection was pushing on this. This is not a random thing. This was important for their evolution.

[Roland Pease]

I mean, it sounds like such a happy accident. This takes us into some complex biology, but I think it's worth doing. The mutation you describe should have meant that this critical protein wasn't being produced at all. But instead the cell had some way of getting around this, having a fix, and then the resultant form of this protein had sort of superpowers.

[Gianni Castiglioni]

Yes, that, that's exactly it. So we know from mouse models, if you get rid of this gene entirely, the mice die shortly after they're born. And this mutation should have done that to the horses. That's not the case. A mutation does not destroy the gene and the protein. There is some kind of phenomenon as if this never happened. It's treating it as if this is not even there. A good kind of analogy or metaphor for this is, you know, the genetic instructions you have in your body. It's a code for something. It tells your cells what to do. You need to have one set of instructions that codes for something. But very much like during wartime, the codes can change as you need to. You can shift what they encode for. That's what the horses are doing. They're using this very, very rare and old trick that people have only really seen in viruses where you can take this back door and kind of hack the genome, hack the code to encode for something different.

[Roland Pease]

I mean, it sounds like it's a sort of a biochemical patch that keeps this protein working. There are a lot of genetic diseases which are because of mutations. And I'm just wondering whether you see similar mutations, let's say, in humans, where there isn't the patch, people get ill. But you've learned something from this that may be a route to a treatment.

[Gianni Castiglioni]

It's hard to believe, but 10 to 15% of all disease in humans is caused by this type of mutation where spontaneously the gene gets inactivated and it's no longer functional. And that leads to all kinds of problems, as you might imagine. So there's intense clinical interest nowadays in the last few years. Well, how do we prevent this from happening? How do we recode the instructions to not dictate inactivation or breaking a gene, but something different that has a neutral net outcome? And so we found a completely different gene in horses. We have this gene as well. We're thinking we can take that as a starting point and then we can try to deliver it into disease models of, you know, some of the more infamous diseases caused by this, such as muscular dystrophy. We're not going to take horse genes and put them into you. We're just going to use the design principles that that nature has produced and kind of steal that blueprint for our own purposes.

[Roland Pease]

Johnny Castiglione of Vanderbilt University getting us to the finishing line. His paper is in science. We are science in action. That's me, Roman Peace and producer Emily Bird. We'll be back in the BBC starting gate next week for another race through research.

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