Host: Benjamin Thompson
Welcome back to the Nature Podcast. This week: a virtual chemical library identifies LSD-related antidepressants that lack the trip, and the latest on this year’s Nobel science winners. I’m Benjamin Thompson.
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Interviewer: Benjamin Thompson
Drugs like LSD or psilocybin – one of the key molecules in magic mushrooms – are probably best known for their ability to induce powerful hallucinations in people who take them. But these drugs are also of great interest to researchers because, in some cases, they’ve shown strong promise as antidepressants. Recently, a paper came out in Nature demonstrating a new way to virtually test millions of chemicals related to these psychedelics to help speed up the discovery of similar drugs that might have potential clinical uses. Drugs like LSD and psilocybin bind to a receptor in the brain called serotonin 5-HT2A, and so the team behind the work looked for other molecules that would do the same. They decided a promising starting point to work with would be compounds containing a structure called a tetrahydropyridine, as Bryan Roth, one of the authors of the work, explains.
Interviewee: Bryan Roth
Tetrahydropyridines are a sort of a core chemical scaffold that are seen in some drugs. So, LSD has part of it, but this particular class of drugs is underrepresented in most small molecule libraries that are used for physical screening or for computational screening.
Interviewer: Benjamin Thompson
Often when chemists test potential drugs against a molecular target, they do so using giant libraries of physical compounds, or do so virtually on a computer. But because they can be difficult to make, tetrahydropyridines are rarer than other compounds in existing libraries. So, what do you do if the library doesn’t have what you want? Well, in this case, the team decided to build their own, based entirely on molecules containing the tetrahydropyridine scaffold. They took advantage of recently developed methods that make these kinds of molecules easier to synthesise, and combined those with computational methods, to make a virtual library of molecules that could theoretically be made by a chemist in the lab. In total, their bespoke library contained 75 million virtual compounds that could be tested against the 5-HT2A receptor.
Interviewee: Bryan Roth
A key to this was actually developing the methodology whereby each of these molecules could be tested against the receptor virtually. And so, we had this opportunity to use this new chemistry, these new computational tools, basically just to see if we could find new chemical matter for the receptor, and the hope was that what we would find would be interesting and useful for something.
Interviewer: Benjamin Thompson
Building their bespoke library meant the team could test a huge amount of molecules in a huge amount of ways against the receptor.
Interviewee: Bryan Roth
So, each molecule is tested against the receptor in up to a million different conformations, so that with the 75-million-compound library, you end up with these huge, huge databases of potential drugs that interact with the receptor. And you end up with sort of like a gigantic Excel spreadsheet, and there are ways basically to rank those and winnow those out for the ones we think have the highest probability of success.
Interviewer: Benjamin Thompson
The team synthesised a handful of these chemicals in the real world, and went through an iterative process of testing them and tweaking them until they whittled down to just two. Tests in a dish showed that these molecules had low toxicity and looked like they could bind to the 5-HT2A receptor, but it wasn’t exactly clear what they might do, so the team tested them in mice.
Interviewee: Bryan Roth
And that’s when the surprises really started.
Interviewer: Benjamin Thompson
Bryan says he expected that these two molecules would have psychedelic effects, like other tetrahydropyridine-containing drugs that bind to the receptor, such as LSD.
Interviewee: Bryan Roth
But they don’t at up to very high doses, despite the fact that they got into the brain at very high levels and had basically good drug-like properties. Because most but not all drugs that activate this receptor are psychedelic, so it was not unprecedented, but it was a little surprising.
Interviewer: Benjamin Thompson
But how do you test whether or not a mouse is on a psychedelic trip?
Interviewee: Bryan Roth
So, there's one test that has been used since the 1960s – what's called the mouse head-twitch test – and it's very specific. Every known psychedelic drug that’s psychedelic in humans will induce a head-twitch response in mice, and our drugs were negative in that test, and they were negative and in several other tests.
Interviewer: Benjamin Thompson
And while they didn’t share the hallucinogenic properties of some other drugs, these molecules did share something else.
Interviewee: Bryan Roth
So, we just basically just took a chance that maybe they would have antidepressant activity, and in a head-to-head comparison with the fluoxetine, which is the drug Prozac, they were 40-fold more potent at inducing an antidepressant-like response in the mice, and the effects lasted up to, I think, 21 days, which is a long time for a mouse.
Interviewer: Benjamin Thompson
There is a huge amount of research interest in developing drugs with antidepressant properties but without any associated hallucinogenic effects, and so the discovery of these two compounds has caused some excitement. Although it remains to be seen, of course, whether these effects will translate into humans. But for Bryan, while these finds are important, it’s the methods that the team developed which really hold promise. Virtual chemical libraries are expanding at an incredible rate, but there may be some advantages to creating your own relatively small bespoke library like this team did. I asked Bryden Le Bailly, a senior editor at the Nature journal, who handles papers on the interface between chemistry and biology for his thoughts on this approach.
Interviewee: Bryden Le Bailly
We’ve seen a huge increase in the size of virtual chemical libraries, running into the tens of billions these days. That doesn’t mean that they’re representative of the whole of chemical space and so, in this case, when you know that a part of a molecule known as a tetrahydropyridine will interact with serotonin receptors, then you basically are saying, ‘This is a really complex system. Let’s start from somewhere where we know there’s an interaction and go from there.’ That’s probably a lot better than if you take 11 billion molecules, of which a very, very small number contain that kind of structure, and just throwing everything at the wall and seeing what sticks. So, for example, you could think about leveraging this approach for another receptor of any kind, as long as you have a structure and as long as you have a key part of that molecule that you know will interact with that structure, you basically have two starting points there that you can effectively apply this kind of method, and you would hope that you would see some results.
Interviewer: Benjamin Thompson
And Bryan is on the same page. He thinks it could open the door to developing other drugs that target both the 5-HT2A receptor and the larger family of proteins it belongs to, which play roles in a variety of different diseases.
Interviewee: Bryan Roth
And so, the main takeaway for me, is not that, oh, we have a non-psychedelic drug that is antidepressant. I think that's awesome. But more generally, it really opens up the potential to use this approach really for all of the members of this family.
Interviewer: Benjamin Thompson
That was Bryan Roth from the University of North Carolina at Chapel Hill in the US. You also heard from Bryden Le Bailly, a senior editor at the journal Nature. To read Bryan’s paper, look out for a link in the show notes. Coming up, we’ll be hearing about the winners of this year’s science Nobel Prizes from Nature’s Flora Graham. Right now, though, Dan Fox is here with this week’s Research Highlights.
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Dan Fox
Ancient artificial island settlements called crannogs have proven a puzzle for archaeologists. But new DNA evidence suggests they served as larders, abattoirs – and perhaps even feasting sites for society’s elite. Crannogs can be found dotted in lakes in areas of northern Europe, including Scotland and Ireland, and date from more than 6,000 years ago up to the seventeenth century. The surviving islands are typically 30 metres in diameter and around 3 metres thick. To better understand life on these islands, a team of researchers took samples of sediment from in and around crannogs in Scotland and Ireland. Ancient DNA from these sediments suggested that humans once stored cereal crops and kept high-value livestock on crannogs. Other biomolecules and material from sediment cores suggested that crannogs were sites of butchery, food storage and perhaps ceremonial feasts. Uncover that research over in Antiquity.
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Dan Fox
Astronomers have spotted what might be the most luminous star ever observed. In 2020, scientists reported a peculiar object in a distant galaxy called the Sunburst Arc, whose exact nature wasn't understood. But now, researchers have used observations and modelling to potentially solve this mystery. They find that the object is probably a hot, massive star called a luminous blue variable star. The object, which they have named Godzilla, appears to be undergoing a particularly intense outburst, during which its size and brightness have dramatically increased. The recently launched James Webb Space Telescope is scheduled to observe Godzilla and should provide the astronomers with an improved image of the star, allowing for more detailed study. You can observe that research in Astronomy and Astrophysics.
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Host: Benjamin Thompson
It’s Nobels week this week so, as is tradition here on the Nature Podcast, Flora Graham, senior editor of the Nature Briefing, joins me to discuss this year’s winners. Flora, how are you doing today?
Flora Graham
Great, always happy on Nobels week.
Host: Benjamin Thompson
Well, very happy that you’re here, as always, Flora. So, maybe we’ll work through the winners in order then, and so let’s start on Monday with the announcement of the Nobel Prize in Physiology or Medicine, which went to Svante Pääbo, a geneticist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.
Flora Graham
Yeah, the Nobels are always exciting. I mean, celebrating these triumphs of discovery is always a cheerful and fun activity. But I think this win really had everybody smiling in the newsroom because the amount of really fascinating creative work that we've had the opportunity to write about that came out of Svante Pääbo’s work has just been such a joy to explore.
Host: Benjamin Thompson
Yeah, and this really sort of centres on his pioneering studies of human evolution and developing methods to sequence and analyse DNA from ancient hominin fossils that could be, I don't know, tens of thousands of years old and damaged by the elements, or contaminated with sequences from microorganisms or modern humans, for example. What sorts of things are these techniques been used for?
Flora Graham
Yeah, for me, one of the most spectacular findings that came out of Pääbo’s and his colleagues’ work has got to be taking this tiny, tiny little piece of a finger bone, 40,000 years old, and isolating the DNA from that and finding it's not from Neanderthals, it's not from Homo sapiens, but it's from a whole new group of hominins that was named the Denisovans. I mean, what could be more exciting?
Host: Benjamin Thompson
Well, absolutely right. And the techniques have also been used to sequence the Neanderthal genome as well, which led to defining that Neanderthals and Homo sapiens interbred and that perhaps up to 4% of the genome of modern humans of European or Asian descent could be traced back to the Neanderthals. So, it really gives us a sense of maybe the journey that humanity has been on.
Flora Graham
And we've found these very interesting individual cases, like someone who had one parent was a Neanderthal and one parent was a Denisovan. So, we're able to kind of start to fine-tune this to really look at what these individual people's lives might have been like.
Host: Benjamin Thompson
And it's not just looking back, Flora. It seems like this work has some implications for looking forward for modern medicine as well.
Flora Graham
You're right. I mean, the proportion of the human genome that contains this archaic DNA is quite small, but they seem to punch above their weight in the sense of contributing to the risks of diseases like schizophrenia, for example, or even severe COVID-19.
Host: Benjamin Thompson
Well, one of the games, Flora, we like to play each year is how did the person find out that they'd won the prize? And in this case, for Pääbo, it's been reported that he didn't believe it. He thought it was very much an elaborate prank by his colleagues, which obviously turned out to not be the case. But his colleagues also celebrated his victory in maybe a fairly unique way.
Flora Graham
Yeah, there's a quite jolly video of him getting chucked into the pond at the Max Planck Institute where he works, and it's a pretty green pond, so it's maybe more of a punishment than a celebration.
Host: Benjamin Thompson
Well, congratulations to him. Let's keep going, Flora. Let's move on to Tuesday and the Nobel Prize in Physics, which was shared between three scientists: Alain Aspect, John Clauser and Anton Zeilinger.
Flora Graham
That’s right, and they've shed light on an issue that really sits at the heart of quantum mechanics, which is this concept that Einstein called ‘spooky action at a distance’, which is that widely separated particles that are entangled on a quantum level can kind of instantaneously communicate with each other, although no communication takes place and there's no kind of hidden information that was always there.
Host: Benjamin Thompson
Yeah, that's right. We talk about this in the podcast sometimes, this entanglement thing, that if you alter one particle, in this case, I guess, a photon of light, the other one instantly gets changed as well, and so this is quite central to things like quantum computing, for example. And from what I understand, this win kind of builds on theoretical work that was done back in the 1960s.
Flora Graham
Yeah, unsurprisingly, people were very hesitant to believe this quality that seems to arise from the mathematics, which is that you can have a system that is acting as one that's so widely separated. So, of course, the natural reaction is to say, ‘Oh no, those properties that are being revealed at that moment, they've always been there, we just somehow couldn't measure them or we couldn't access them,’ rather than what quantum physics predicts, which is that the quality of the other, the matching pair, is only defined at the instant that you measure it. So, what happened was in the 60s, a physicist named John Bell came up with a mathematical test to actually reveal, is it true that these particles always had these kinds of hidden variables that were always there but we just couldn't see them, or is it genuinely acquiring that property at the moment of measurement? And what this Nobel Prize really recognises are practical experiments that reveal what they call Bell's inequality, which really show that, yes, this quantum entanglement is really happening.
Host: Benjamin Thompson
And what have you heard from the winners then about their award?
Flora Graham
I think one thing that really impressed me about Zeilinger’s speech accepting the prize was how much he'd paid tribute to the early-career scientists he'd worked with. I don't think there's a Nobel Prize winner, or rarely, that doesn't pay tribute to the many, many colleagues that have contributed to their win, but he really emphasised that the young people he's worked with have been pivotal to his success.
Host: Benjamin Thompson
Well, lastly then, Flora, let’s shift forward to today, in fact just a few short hours ago, and the chemistry prize was awarded and shared between Barry Sharpless, and this is his second chemistry Nobel win it’s worth pointing out, Morten Meldal and Carolyn Bertozzi.
Flora Graham
Yeah, they have all been recognised for something that is called ‘click’ chemistry or a subset of click chemistry called bioorthogonal chemistry, and really what these are, are ways of joining molecules quickly and without kind of unwanted by-products.
Host: Benjamin Thompson
Yeah, and from what I understand, Sharpless coined the term click chemistry, and both he and Meldal independently came up with this way to click together two molecules then – an azide and an alkyne – with relative ease in this kind of strong, irreversible way, which is in contrast to some of the weaker lock-and-key interactions, for example, you see between biomolecules. And this has been applied to a host of different molecules in different situations, from modifying plastics through to making pharmaceuticals.
Flora Graham
Yeah, and Bertozzi built on click chemistry as well and took it in a slightly different direction. She really innovated how to map the surface of living cells for these specific polymers called glycans without disturbing the function of the cells. And she developed a method to do that, which she called bioorthogonal reactions, and those are now used widely as well.
Host: Benjamin Thompson
Yeah, and they're similar but different. Copper, as I understand it, was quite central to Sharpless’s and Meldal’s discovery, but of course copper is poisonous, so Bertozzi worked out a way to make the click happen without needing copper. And what's key is this can be used without disturbing cellular functions, so it allows things like visualising cellular processes, and it's being used to aid cancer drug development, for example.
Flora Graham
Yeah, and she says that the best is yet to come. She says that the field of click chemistry is really in its early stages, and she predicts a lot more new reactions will be discovered.
Host: Benjamin Thompson
Well, Flora, let’s leave it there then for another year. Thank you so much for joining me. And listeners, head over to the show notes where you can find links to all of Nature’s coverage of this year’s winners. That’s all for this week’s show. But before I go, just a quick heads up for all you keen photographers out there. Nature’s annual #ScientistAtWork photo competition is now open. If you have a great photo of a scientist at work, head over to the show notes, where you’ll find a link to where you can enter and find out all the relevant terms and conditions. And of course, as always, you can keep in touch with us on Twitter – we’re @NaturePodcast – or you can send us an email to podcast@nature.com. I’m Benjamin Thompson. Thanks for listening.