The mysterious extinction of the dire wolf

Host: Benjamin Thompson

Welcome back to the Nature Podcast. In our first show of 2021, probing the extinct dire wolf’s DNA…

Host: Nick Howe

And what the UK’s science relationship with the EU will look like post-Brexit. I’m Nick Howe.

Host: Benjamin Thompson

And I’m Benjamin Thompson.

[Jingle]

Host: Nick Howe

America was once home to a massive species of wolf known as the dire wolf. They could reach nearly 70 kilograms, and they shared the land mass with several other now extinct mammals up until the Late Pleistocene when they all but vanished. Luckily there were lots of them and so they left an extensive mark in the fossil record. For instance, there have been thousands of them excavated from the famous La Brea tar pits in California alone. But why they went extinct and how they’re related to their modern wolf family is still up for debate. Along with his team, Laurent Frantz from Queen Mary University of London and the University of Munich turned to ancient DNA, recovering dozens of partially fossilised remains – subfossils as they’re known in the business – providing a clearer story of this ancient American predator. Reporter Geoff Marsh found out more.

Interviewee: Laurent Frantz

We’re talking about a time at which the climate was on average colder than we are now, with quite a few glacial periods where a large proportion of North America would have been covered by a very thick ice sheet, and everything that was living south of the Canadian-American border would have been living in a sort of dry and relatively warm environment. We have multiple predators around – the American lion and you have these sort of giant short-faced bears as well – but really the most common and the one that is the most ubiquitous is the dire wolf. And then later on, the grey wolf and the cayote, we don’t know exactly when but they were there before the dire wolf went extinct for sure, and probably tens of thousands of years before dire wolf and other mega-carnivores like the lion and the bear went extinct. So, I’m Laurent Frantz. I’m a professor of palaeogenomics at the University of Munich and a senior lecturer at Queen Mary University of London.

Interviewer: Geoff Marsh

So, I guess the big mystery is that we know for a time that dire wolves were sharing America with those other canids like the grey wolf and the cayote, but somehow the grey wolf kind of ended up as this top predator and the dire wolves ended up in evolution’s waste basket.

Interviewee: Laurent Frantz

I mean, in the end, things have reversed a little bit. Now, the grey wolf is almost extinct from North America and the one that’s found everywhere now in North America is the cayote, the smaller version that was maybe the outsider for a long time and seems to have come out as the winner in the end.

Interviewer: Geoff Marsh

Okay, so, really, what you’re interested in is how these dire wolves are related to these other wolf-like animals.

Interviewee: Laurent Frantz

So, for a long time, people have been looking at the morphology because this is all we had, and when you look at the morphology of a dire wolf, it’s just very strikingly similar to a wolf, and you can use fancy statistics and sort of 3D modelling of their skulls and put their skulls through scanners and compare the skulls to all these other canids, and when you’re comparing the skull’s teeth or other elements to other species, there’s a striking relationship between grey wolves and dire wolves. They look almost identical. It’s not really a shape difference but just a size difference, and that’s what led people to think they just are a species or subspecies. That’s what you see from a morphological perspective.

Interviewer: Geoff Marsh

Sure, but to properly resolve the story, you and your crew turned to ancient DNA, didn’t you?

Interviewee: Laurent Frantz

So, we turned to ancient DNA and also ancient proteomics. There’s not just only DNA that survived in these subfossils, also the proteins survived. It stays a lot longer than DNA and in fact, we managed to get some of these from the La Brea tar pits which are highly decorated material in which there is no DNA whatsoever. So, that gives you also an answer, and the answer we got from that specific sequence was that yes, they were different from grey wolves but it was really difficult to say more than that. You need genomes for this. So, we had 46 subfossil specimens from places like Tennessee and Wyoming. Of those 46, we only identified 5 that actually possessed enough DNA that we could sequence and reconstruct parts of their genome. We also sequenced genomes of African relatives to make sure that we had the genomes of all the closely related species, and then you use an algorithm to construct a tree, and then you could say, well, the dire wolf was actually extremely far away from the grey wolf. You can also use various methods to try to estimate how long ago were their ancestors living, so how long ago did they separate into two different species, and it was millions of years ago, and that was extremely surprising.

Interviewer: Geoff Marsh

What was it, 5 million years ago?

Interviewee: Laurent Frantz

5-7 million years ago, about. A large confidence interval, but still, a long time ago.

Interviewer: Geoff Marsh

And does that locate where the dire wolf originated?

Interviewee: Laurent Frantz

It does to some extent. It allows us to sort of think about what we call a biogeographic model. We think that the dire wolf was part of this lineage that was in America for millions of years, and most of its evolution took place in the Americas as opposed to all of the other living canids that live nowadays, even those that are in the Americas nowadays.

Interviewer: Geoff Marsh

So, like the cayote, the grey wolf, they came later, quite recently.

Interviewee: Laurent Frantz

They came later, much more recently, yes.

Interviewer: Geoff Marsh

You mentioned earlier, though, didn’t you, that the canids themselves, these wolf-like animals, they are kind of well-known for their interbreeding and their hybridisation, aren’t they, so how do we know that wasn’t going on in the dire wolves?

Interviewee: Laurent Frantz

So, with genomes, you can actually test this, and so we could do the same thing with the dire wolf, and when you’re looking at the genus Canis, which is most of the canids that we think of today except not foxes, but cayotes, grey wolves, the dhole in southeast Asia but also the African wild dog and the jackals, there is gene flow all over the place. It seems like canids interbreed, they will separate into species, stay away for a few million years and then they’ll meet again somehow and then interbreed again, and then we see a lot of lineages that are almost equal hybrids between two species. So, what we were expecting was basically, okay, if you overlap with other canids for a long time, there will be some gene flow, and it turns out that the dire wolf actually didn’t really interbreed with either grey wolves or cayotes, which was also extremely surprising, even though they’re morphologically so similar.

Interviewer: Geoff Marsh

Well, one thing we can be quite certain about is that the dire wolf, along with lots of other megafauna, massive animals from the end of the Pleistocene, all went extinct. What does your genetic analysis do for our understanding of perhaps why the dire wolf didn’t make it through and yet the grey wolf and the cayotes did?

Interviewee: Laurent Frantz

It seems that there is one rule for this Canis species, one very important rule in their evolution is mix up with whatever is living there. So, if you arrive in a new environment then you can mix up with the species that live there, borrow a few genes and a few behaviours and sort of adapt yourself faster, or you can also do that with a new species coming in when there are changes in the environment. What we think maybe is happening is that the environments were changing quite rapidly at the end of the Pleistocene and so the dire wolf wasn’t able to actually adapt fast enough and it wasn’t able to adapt fast enough potentially because it wasn’t able to borrow these genes from these incoming species. And actually, it seems like the grey wolf has been able maybe to survive in some parts, like in Yellowstone Park where we see black grey wolves. These black grey wolves probably acquired this black coat colour through interbreeding, in this case, with dogs that came even later with humans, and that black colour seems to have been highly beneficial for them and maybe allowed them survive longer. So, the dire wolf didn’t have this potential mechanism. It seems to have broken maybe rule number one of surviving as a Canis species.

Interviewer: Geoff Marsh

Yeah, so they were these kind of really specialist top predators, maybe too specialist on these big prey, and because they stayed so isolated and didn’t mix up their genetic toolkit, they were stuck when things changed around them maybe.

Interviewee: Laurent Frantz

They were definitely too specialised. We have a lot of evidence for this. They were clearly big, they were clearly morphologically made for attacking large prey, so if large prey disappeared then that’s it. But you could think that maybe someone of your genes could have been surviving in these grey wolf populations that were living afterwards and, in a way, they would not have gone completely extinct the way they are now.

Interviewer: Geoff Marsh

One thing I thought was does the fact that they’ve been genetically isolated and yet they have this striking morphological resemblance of current wolves, does that say anything about the body plan of a wolf, because it strikes me that evolution has gone, ‘This is a brilliant, lethal blueprint. If it ain’t broke, don’t fix it.’ You hear that about the crocodilians, don’t you? They’re body plan hasn’t changed much for millions of years.

Interviewee: Laurent Frantz

So, yeah, this is something that we’ve been asking ourselves. Are we looking at a convergence between a grey wolf and a dire wolf, or are we actually looking at the ancestral form, right? This is this sort of form that has been around for a very long time because it’s so efficient. So, yeah, I think it speaks for that body plan as something really adaptive. But I think the grey wolf had something else. What’s interesting about the grey wolf is that it’s extremely plastic. They have what we call ecotypes. Some of them hunt bisons and some of them hunt rabbits, and they walk in teams or they are more solitary, they are widely different sizes and have widely different behaviours. It’s an incredibly plastic and sort of flexible species, so this plus that sort of killing body plan I think make it like an almost indestructible species.

Host: Nick Howe

That was Laurent Frantz. For more on those ancient apex predators, we’ll put a link to the paper in the show notes. And thanks to Yellowstone National Park’s sound library for some of those canid recordings you heard throughout the story.

Host: Benjamin Thompson

Now, this would normally be the time in the show for Coronapod, but there has been a lot of coronavirus related news recently, so we’ll be putting out a standalone episode later on in the week. Look out for that in your podcast feeds. Back to this show, though, and coming up later, we’ll be talking about the B-word, Brexit, and what the future of research in Europe looks like in a post-Brexit world. Right now, though, Dan Fox is here with the Research Highlights.

[Jingle]

Dan Fox

Pluto’s distinctive blue haze may be a result of an atmosphere rich in particles of frozen organic matter. Planetary scientists had thought that Pluto’s haze is formed by light-driven chemical reactions that yield complex organic compounds. But now, a team of researchers have proposed a chillier explanation. Using data from the New Horizons spacecraft among other sources, the team found that because of Pluto’s cold atmosphere, organic compounds condense readily in its skies. The resulting organic ice particles are likely a major contributor to Pluto’s haze. The authors think that organic ice particles could also explain the hazy skies of other distant objects, like Neptune’s largest moon, Triton. Chill out with that research over at Nature Astronomy.

[Jingle]

Dan Fox

Mice may not seem to be the most sensitive creatures, but researchers have mapped neurons in their brains that could be involved in empathy. The team of scientists first induced an emotion in one mouse. Then they allowed a second mouse to observe these emotions. In all of the observing mice, brain patterns varied with the emotion they witnessed. Mice witnessing another mouse in fear or pain or even gaining relief from pain mirrored those emotions in their brain circuitry. The researchers hope that their results could contribute to the development of psychiatric drugs to enhance empathy in people who lack it. Read that research in full in Science.

[Jingle]

Interviewer: Benjamin Thompson

Now, we haven’t touched on Brexit in the podcast for a while, but the process of the UK leaving the European Union has of course been a matter of some concern for researchers and scientific institutions for several years. Over the past few weeks, a lot of political moves happened and decisions were made that have clarified what the future might mean for science as a result of Brexit in the short term at least. Here to help me unpick what’s been going on is Lizzie Gibney who’s been following the Brexit process for a very long time. Lizzie, thank you so much for joining me today.

Interviewee: Lizzie Gibney

Thank you, Ben. Yes, it does feel like a long time.

Interviewer: Benjamin Thompson

Well, just to get us up to speed, what’s happened over the past few weeks?

Interviewee: Lizzie Gibney

So, the whole of 2020 was a transition period after the UK had technically left the EU already at the end of January last year, but then this transition period meant the real break was going to be on 31 December 2020. Now, thankfully, even though it came very, very close to the wire, there was a deal that was done on 24 December, on Christmas Eve, which meant that there was an avoidance of this no-deal, cliff-hanger situation that was the thing that had really scared a lot of people and would have had some really damaging impacts.

Interviewer: Benjamin Thompson

And this deal is quite expansive. I mean, it covers a lot of sectors. But let’s look at some of the science-specific things it contains, and I picked out a few that were of quite some concern to researchers over the years. The big one is funding, and the UK has been the recipient of a lot of research money from various EU schemes, and there were fears in the UK that there would be no more access to this funding in the future. What’s been going on here?

Interviewee: Lizzie Gibney

Yeah, so this is really good news and the point on which most scientists kind of reacted with a lot of relief. The UK is going to be able to stay part of the European research programme, so that was Horizon 2020 but starting in 2021 the new programme called Horizon Europe. So, that means that the UK will be able to get grants from that programme, so all the collaborative grants, but also those such as the European Research Council and the Marie Curie grants which are the individual ones. So, basically, it means that the UK will be able to stay part of those European research programmes pretty much as they were before. There are a few little tweaks. There’s one new programme called the European Innovation Council that the UK will be out of but in general, it’s really good news because it’s basically status quo.

Interviewer: Benjamin Thompson

And this pot of money is worth billions and billions of pounds. You say things are broadly similar but the devil of course is in the details, and the UK is now not a full member of these funding streams, it is an associate member. What does that mean in real terms?

Interviewee: Lizzie Gibney

Yeah, so an associate member is essentially somebody who isn’t a member of the EU but can take part on broadly the same terms as a member because the UK will be paying a certain amount of money into the overall pot with the understanding that it will take something similar out.

Interviewer: Benjamin Thompson

Well, that seems fairly straightforward then. When can UK researchers start applying for this money?

Interviewee: Lizzie Gibney

Well, one of the issues is that there is not actually an association agreement yet. So, part of this overall trade deal was to say that this associate membership status was going to happen, but that actually has to be signed off by a committee. That may be a rubber stamp process. We’re not entirely sure. The actual grants, the first grants that go out under Horizon Europe probably won’t be until March or April, so there’s a little few months of leeway, but it’s also possible that that scheme gets underway before this agreement is ready so that’s one potential little snag.

Interviewer: Benjamin Thompson

And you mentioned that the UK is paying money into this pot to then take it out again, and I can see arguments being made that that’s perhaps a bit strange, but it seems that these are very, very well established schemes and they have a lot of kudos and they’re very useful for helping things like collaborations.

Interviewee: Lizzie Gibney

Absolutely, so you’ll have grants like European Research Council grants that very top people within the EU compete for, and that is something you can’t really recreate within an individual country. So, staying part of that is incredibly important. And also, as you mentioned, collaboration, that’s something that is just very hard to replicate. When you have a system like this, you have all the networks that already exist and are working really, really well. It was actually that collaboration really over and above the funding itself that people were really, really scared about losing so they’re very, very happy to be able to keep.

Interviewer: Benjamin Thompson

Seemingly good news there, Lizzie, but after the Brexit vote, we saw a pretty significant drop in the number of UK researchers applying for European funding. Is there the expectation that applications will go up again now that they’re able to do so?

Interviewee: Lizzie Gibney

There’s certainty the hope. The strange thing really is that the UK never was out. There was never a change in its status so there was no real reason for UK participation and its level of funding to drop, but like drop it really did from 2016-2020, and that was just purely down to the uncertainty. People were saying, ‘Well, do we want to have UK researchers leading this programme when they might be out in a year, two years, three years?’ So, that created such a problem and now, in theory, there is stability, the UK is part of this programme, that should not happen anymore, but there’s also a bit of reputational damage. So, I think there’s going to be a real challenge there and a task for UK researchers to rebuild those networks and that kind of reputation that they have and try and regain the status that they previously had in the European programmes.

Interviewer: Benjamin Thompson

If we think about the scientific enterprise, of course funding is very, very important, but the lifeblood of science are the people who do it, right, the scientists themselves, and now that the UK has left the European Union, that unrestricted right to go and live and work between the two regions has ended, and of course that could affect people being able to go into labs and do research.

Interviewee: Lizzie Gibney

Broadly, the argument is that already you can have a scientist come in from the States or from China to the UK, to anywhere within Europe, and they will be able to take up their job – visas exist. But there is no longer that ease of travel, that kind of interchangeability where your country just doesn’t matter if you’re an EU citizen. So, there will be a lot of extra bureaucracy and that will obviously hamper things, but there are new visa systems that do exist, so it won’t be impossible. So, if you’re an EU citizen and you’re taking up a job in the UK, there will be a points-based system that means you’re kind of considered alongside scientists from the rest of the world and something called the Global Talent visa which is a particular scheme for scientists. And the other way around, again, it’s a little bit trickier because obviously you’ve got a whole different bunch of countries, you’ve got 27 more countries within the EU, and although they have some harmonisation over the rules for visas for scientists, there’s a little bit of difference still that exists between those countries. So, if you’re a UK scientist and you’re wanting to go and work in the EU, you’re going to have to look specifically at the country that you’re going to and figure out what kind of visa you’re going to need. It’s going to be a lot more difficult than it was before but not impossible.

Interviewer: Benjamin Thompson

Well, let’s think about one of the other key parts of science. Obviously, we’ve got funding, we’ve got people, but of course data is really, really at the core of scientific research, and the free flow of data between countries in the EU really was making research a lot more straightforward I would imagine in many, many cases, but yet again things are different as of now.

Interviewee: Lizzie Gibney

Yes, data, everyone’s nerdy but very, very important favourite topic. So, the free flow of data from the EU to the UK and vice versa was completely possible previously as an EU member state. Now, it’s a bit different.

Interviewer: Benjamin Thompson

So, now we have the UK’s data regulations on one side and the EU’s data regulations on the other, and I’m guessing this is what’s making things potentially a bit difficult when it comes to data sharing.

Interviewee: Lizzie Gibney

So, the UK’s rules are not very different from the EU’s because they were based on exactly the same directive, but there’s a process that the UK has to undergo for the EU to ensure that is still the case and it’s called adequacies. So, there’s an adequacy decision that everyone’s still waiting on. If that comes through then in theory this free flow of personal data, which is obviously very important for things like clinical trials, patient data, then we should be able to continue with the status quo where that data flows freely. But we’re still waiting on it and obviously now Brexit has happened, the UK is no longer a member state, so the way around this for now is that the transition period, at least when it comes to data, has been extended. So, there’s going to be another six months of acting as if the UK, when it comes to data, were still part of the EU.

Interviewer: Benjamin Thompson

And if a decision can’t be reached then what sort of areas of research could that impact?

Interviewee: Lizzie Gibney

Well, the big one would be clinical trials. I mean, you have a lot of trials that happen between countries that have patients in several European countries and maybe are headed up by an institution in the UK, and in that kind of situation you might be in a position where you have to be transferring that patient data from, say, France or Germany to the UK, and that will no longer be able to happen smoothly. You might need to redraft your contracts, you’ll have an awful lot more bureaucracy, so that could potentially be a big issue.

Interviewer: Benjamin Thompson

Well, Lizzie, they’re some of the more broad issues that people have been talking about. Let’s maybe expand it out then. What are scientists saying about this deal? I mean, are they happy?

Interviewee: Lizzie Gibney

So, I think probably relief was the greatest emotion that people felt. We really didn’t know right up until the last minute if there was going to be any kind of a deal at all. So, the fact that not only was there a deal and that this deal actually meant that the UK would stay part of the European research programmes, which is something that people have been campaigning on for years, that was something that made people very, very happy, and the kind of potential huge damage of Brexit, the worst damage, was not done. I think there’s also just a huge amount of regret, though. Researchers really are an international bunch and almost none wanted to leave the EU. And then maybe a little bit of trepidation because we don’t really know if the UK is going to be able to regain that really prominent position that it had in Horizon 2020 before Brexit started. So, regret, relief and some trepidation, I would say.

Host: Benjamin Thompson

Lizzie Gibney there who’s written a news explainer on all the topics we’ve touched on today and more. You’ll find a link to that in the show notes.

Host: Nick Howe

Finally on the show, it’s time for the weekly Briefing chat where we discuss a couple of articles that have been highlighted in the Nature Briefing. Ben, what have you got this week?

Host: Benjamin Thompson

Well, Nick, we’re going to head to the Moon for my story today, and it’s a story that’s published in Nature, and it’s a very exciting time to be a lunar researchers because there’s a bunch of missions scheduled to go to the Moon in the next few years and some of these missions will be visiting the poles for the first time, and these are very, very interesting areas for science.

Host: Nick Howe

And what makes these areas so interesting?

Host: Benjamin Thompson

Well, that’s a great question, Nick, and the answer is water or ice, I guess, because this water is frozen, that’s tucked away in some of the craters there. And as I say, this water is of great interest to researchers but there’s been a bit of a dilemma. There’s kind of two schools of thought. Some researchers want to sort of go up there and get hold of it quickly and have a look and see what’s going on inside it. It might offer clues, for example, as to when water first appeared on the Moon or on Earth. But there’s another school of thought of if people just go up there and start sort of digging it up and maybe bringing it back to Earth, that it could be contaminated by the very experiments set to go and have a look at it.

Host: Nick Howe

And I suppose the risk with contamination is it may muddy future research and maybe we won’t be able to understand it as well as we could have if we hadn’t contaminated it.

Host: Benjamin Thompson

I think that’s right, Nick, but as I say, there’s a lot of debate going on in this area but there’s some reports that have either just come out or are coming out which are aiming to tidy things up. One is from the US National Academies of Science, Engineering and Medicine, which says that space agencies need to prioritise what science they want from the lunar poles in order to explore them effectively. And this other group, the international Committee of Space Research, which outlines the best practices for space exploration, is evaluating what’s going on, and they’re going to decide in the forthcoming months whether to issue new guidelines for spacecraft going to the Moon, and it’s thought that NASA and other space agencies will follow COSPAR’s decision on how to visit the Moon responsibly.

Host: Nick Howe

And how might one visit the Moon responsibly? How do you avoid this contamination?

Host: Benjamin Thompson

Well, one of the areas of concern is water vapour that comes out of rockets as they’re flying around, and there is some concern that that would land on the water and really make it difficult to work out what’s going on. Now, some researchers say, ‘Hey, that’s just landing on the top layer, don’t worry about it,’ but others are more concerned. So, one of the ways that this might be avoided is by, well, very careful writing of lists.

Host: Nick Howe

Very careful writing of lists? You need to give me more.

Host: Benjamin Thompson

Okay, so, at the moment, this international Committee on Space Research, their guidelines suggest that nations keep a list of all the organic materials – carbon, composites, paints, adhesives – aboard missions that are going to the Moon, and that helps scientists work out, ‘Well, that was actually brought there, so if we’ve found it, it may have come from ourselves.’ And the thought is that these lists might be expanded to keep a list of gases that could be emitted from rockets or life-support systems, and that would help sort of pull those out of the data and know what’s contamination and what isn’t.

Host: Nick Howe

And I wonder as well, is there a risk that these things have already been contaminated? How do we know that what’s there now hasn’t been sullied by previous Moon missions?

Host: Benjamin Thompson

Well, you’re absolutely right, Nick. It appears that the Moon’s polar ice has already been contaminated by past missions, but I think this is more of a far-sighted thing to help future researchers get more of a clear idea of the past by avoiding contamination.

Host: Nick Howe

Well, hopefully with the future Moon missions we’ll see this come to light. Sticking with a kind of space theme, I’ve also been looking at, well, not the Moon but stuff orbiting the Earth, and this is a spy satellite.

Host: Benjamin Thompson

Right, I mean, I don’t know where you’re going to go with this one, Nick, to be honest with you. What’s going on with spy satellites?

Host: Nick Howe

Well, it’s not really what’s going on now, it’s what has been going on in the past and, as I’m sure many people are aware, during the Cold War, the US in particular had many such spy satellites orbiting the Earth in order to look at their potential enemies, places like the USSR. But later on, these spy satellites were actually used for a lot of important environmental work and that’s what this article in The New York Times has been looking at.

Host: Benjamin Thompson

Well, yeah, I mean, I guess these satellites have or had some pretty amazing optics and very, very precise cameras and what have you, so I guess they were being used to look at the Earth in really fine detail.

Host: Nick Howe

Exactly, I mean, if you want to see if someone’s got a rocket base or a weapon or something like that, then you need really good resolution and really good images from your satellites, and later on, after the USSR collapsed, these satellites were still floating around and various agencies in the US were trying to find a use for them. And this story that is, as I said, in The New York Times, focuses on Dr Linda Zall who seems to have been really important in this, and she worked for the CIA and she’d previously worked using satellites and other aerial imagery for scientific work and then in the CIA she put together a team called Medea that really worked very hard to get this wealth of data, wealth of images, and put it to use to investigate how the climate and how the environment is changing over time.

Host: Benjamin Thompson

Well, Nick, the CIA by its very existence is a fairly secretive organisation from what I understand about it. How was this data used? Was this sort of released into the public sphere or was it kept internal?

Host: Nick Howe

So, a bit of both, really. So, some of this data came out much later after it had been declassified, other bits were actually given to the public to be used and, as I said, this was a push in the 90s after the Soviet Union collapsed, and there was a wonder in the US about why they were spending so much money on these satellites, and this idea actually promoted by Dr Linda Zall to look at the environment was an interesting way to use these satellites, make it worth their while for them to still be there and get a really good understanding of it. So, she doesn’t appear on any of the papers that actually came out because she was working for the CIA and it’s a very secretive organisation, but the article in The New York Times estimates that probably hundreds of papers have relied on data from these spy satellites that were released to the public.

Host: Benjamin Thompson

Wow, I mean, what sort of things were they looking at then? What were these papers about?

Host: Nick Howe

Well, one interesting thing about how satellites work is a lot of them have a north to south rotation. They go from the top to the bottom or the bottom to the top of the planet because that way you can cover a lot of the Earth. But what that means is they actually spend quite a lot of time going over the Arctic and the Antarctic, and that isn’t actually of much interest to people spying on people, but it’s of great interest to environmental scientists who could use such images to work out how much ice has been lost or how ice is changing in those regions. And other example which was quite striking in the article is it looked at the difference between the extent of the Aral Sea over time, and you can see that over quite a long period it has shrunk quite dramatically.

Host: Benjamin Thompson

Goodness, I mean, where does this go next then, Nick, do you think? You said some of this work had been declassified. Is there more data to come out and what’s the future of these satellites, do we know?

Host: Nick Howe

Unsurprisingly, it’s not hugely clear because they are still kind of secretive. The programme itself, Medea, has been shuttered. It was shuttered in 2015 and only now has Dr Linda Zall been able to talk about her involvement in it. So, what the future is is not quite clear, but it doesn’t seem like the recent Trump administration has been interested in this sort of climate change work, but perhaps with the Biden administration there may be interest in looking at some of these other images that are maybe in the CIA, or who knows what information they’ve got. But it seems that in the past there has been a wealth of data that has been really useful for environmental scientists.

Host: Benjamin Thompson

Well, fantastic, thanks, Nick. That’s a super interesting story. Listeners, if you’d like to know more about both of the stories we discussed, you’ll find links to them in today’s show notes.

Host: Nick Howe

And if you want even more stories like this delivered straight to your inbox then make sure you sign up to the Nature Briefing. Once again, head over to the show notes where’ll you find a link where you can do so.

Host: Benjamin Thompson

That’s all for the show. Don’t forget to look out later in the week for the next edition of Coronapod. In the meantime, I’ve been Benjamin Thompson.

Host: Nick Howe

And I’ve been Nick Howe. Thanks for listening.

Host: Benjamin Thompson

Hi, listeners – Benjamin here. It’s our first Coronapod of the year and we have a lot to discuss, so once again we’re putting the show out as a standalone podcast. Noah Baker is here of course, and making his Coronapod debut is freelance reporter Elie Dolgin. Hello to you both.

Elie Dolgin

Hey guys. Thanks for having me.

Noah Baker

Hi, Ben. Hi, Elie. Indeed, an awful lot to talk about at the beginning of 2021. I feel like we took a break over the holidays and the world moved at a pace that I can barely keep up with and we have to try to catch up now.

Host: Benjamin Thompson

Oh, definitely. But before we get into that, Elie, you’ve written for Nature news many times and you’ve appeared on the podcast a bunch over the years but for people who aren’t familiar with your voice, what’s your beat? What do you cover?

Elie Dolgin

Broadly speaking, biomedical research and drug discovery. I kind of missed some of the early days of the coronavirus outbreak because I was busy watching my kids, but I’ve been playing a little bit of catchup as the vaccine rollout has been happening and so now just my life is all vaccines all the time.

Host: Benjamin Thompson

Well, that does seem like a very apt place to start. There’s a lot going on in the vaccine sphere but, broadly speaking, where are we right now?

Noah Baker

We have found ourselves in a position now where approved for emergency use we have vaccines based on RNA, we have vaccines based on a viral vector, this adenovirus vector and there’s another one of those as well, and we’ve got live attenuated vaccines which are these kind of very classic, I suppose is maybe a word I’m going to use but perhaps not the ideal word to use, but a classic sort of weakened version of the coronavirus itself which is being rolled out and data is being gathered about those as we speak. But these RNA vaccines that have, up until the pandemic, never been approved before for use really seem to have taken the lead in terms of the vaccines that have been rolled out, and that’s something that you’ve been looking into in quite a lot of detail.

Elie Dolgin

Yeah, actually, so about a year and a half ago, I wrote a story for Nature Outlook where I got to visit the manufacturing facility that Moderna had just built here in Boston on the outskirts of the city, and when I met with the chief medical officer actually most of the discussion was around cancer. It wasn’t really around infectious diseases. I mean, they had brought most of the infectious disease vaccines built around RNA into the clinic more than anyone else, but going into the pandemic there were literally I think I counted 12 programmes that had ever gone into phase I. Moderna launched a phase II in December of 2019 and then the coronavirus happens and all of a sudden, now there are at least six – by my last count – RNA vaccines in the clinic to now having been proven to be approximately 95% effective and others that are presumably going to have similar levels of efficacy. So, it’s been just an incredible explosion and boomtime for the technology.

Noah Baker

Yeah, I think it’s strange how world events can change research priorities, and it’s something that we’ve certainly talked about a lot on Coronapod so far, and these RNA vaccines have had this big boost because of this necessity, and part of the reason that they in particular have had a boost is because part of the fundamental advantage of RNA as a vaccine platform is it’s fast to develop a new vaccine, right, and that’s one of their big advantages. I think it might be worthwhile, Elie, if you could just take us through a little bit about the kind of fundamentals of how this platform works and why that’s proven so useful in this scenario.

Elie Dolgin

The basic idea is that instead of delivering a bit of the virus or the whole virus to the body, you actually just give it the RNA recipe for making the proteins that you want the immune system to recognise and destroy. And so, the ability to synthesise RNA and the speed and ease of that is what’s really the advantage of this platform, and it could best be seen by the fact that Moderna, going back to January 2020 about a year ago, when the sequence was posted for the novel coronavirus out of China, they were able to design, synthesise and manufacture a vaccine candidate in days, literally four days, and then they were doing mouse experiments weeks later and within two months or so they were already in phase I testing in humans. And so the pandemic responsiveness ability with RNA is incredible and there’s just never been a technology platform like this for dealing with novel infections.

Noah Baker

And that kind of speed to synthesise RNA, that’s been around for a little bit of time, but there’s this other sort of key functionality for these types of vaccines that was required which is what to put them in to get them inside the body, and in this case it’s in what’s called lipid nanoparticles. Elie, can you tell us what they are?

Elie Dolgin

Yeah, I mean, RNA is an inherently unstable molecule and so the challenge is getting a way to deliver it into the cells in a way that it stays intact, gets to the protein manufacturing system of the cell so that it can produce the proteins to train the immune system. And so the key really was finding these essentially little fat bubbles that could serve as that delivery vehicle, and this was a technology that was really first developed in a different area of drug development and that field had developed this delivery system, these lipid nanoparticles. And then in 2012, a team at Novartis was the first to kind of borrow that technology and try it with the RNA vaccines, and it worked really well, and so that kind of laid the groundwork for all of the vaccines that are being built around RNA today. They are all going into these lipid nanoparticles.

Host: Benjamin Thompson

I mean, so incredibly rapid, as you say, and clearly it’s worked because we do have two efficacious vaccines that have been rolled out, but it’s not 100% rosy, right? I think we need to be careful there that these vaccines are not without their issues.

Elie Dolgin

Oh, absolutely. I mean, the vaccines that exist are expensive because the lipid nanoparticle technology and the RNA synthesis itself is not cheap to manufacture. They require this cold chain storage, especially with the Pfizer-BioNTech vaccine which has to be kept at these arctic-level conditions of -70, but even the Moderna one currently requires freezer temperatures. They’re fairly reactogenic, is the term that’s used. It’s the side effects that you get when you get the shot in your arm. Something like 80% of all the participants in the Moderna trial had some kind of systemic reaction, things like headaches and fevers and general muscle pain and malaise, so really feeling quite icky, things that would knock you out for a day or so, but it is a transient thing, and actually, it’s a sign that the vaccine is working, ironically. But it’s not ideal. And just the manufacturing capacity is limited, so if we’re going to vaccinate all 7 plus billion people in this world, we’re going to need other platforms, things that will work, be affordable and be stable within the healthcare systems around the world.

Noah Baker

And I think almost all pharmaceuticals, no matter what you look at, vaccines or treatments or drugs, there will be a list of cost-benefits for everything. There’s always going to be some pros and some cons. But these are particularly important to think about in the context of these vaccine rollouts right now because some of the downsides, I suppose, of RNA-based technology in particular could have a really big impact in, for example, how many people are willing to take up vaccines at a time when there is this sort of vague, underlying, bubbling concern amongst many people that perhaps because these vaccines are being developed so fast something may have gone awry which, of course, we’ve discussed is not really the case in this case, but that is a concern, and the fact that they could illicit things that could cause fear or worry among the populous, if they see them being more reactive. And additionally, because they have these side effects, in order to get around that, these vaccines need to be given in two lower doses to reduce those side effects, but then having a two-dose vaccine regimen we know can cause problems because people may miss their second dose or they may not get back there in time for their second dose, and it opens up a whole can of worms which certainly we’ve discussed in the UK a lot recently about what the correct dosing regimen should be. And these are all really important questions for right now.

Elie Dolgin

Yeah, and just one small thing, the two-dose regimen, it’s not entirely about side effects. A lot of it is actually just about building enough immunity because we know that the second shot really does help lead to many more antibodies, and that’s true with a lot of vaccine platforms but it’s especially true with these RNA vaccines and, as I go into in this feature that I have in this week’s issue of Nature, there are other ways of designing the RNA vaccines in ways that the vaccine kind of copies itself, and that can help you both lower the dose because you don’t need to introduce as much because it’s going to make more copies inside the cell, and also because that copying process makes it look more like a virus, a natural infection, the immune system responds in kind of a stronger and broader way. And so, there are mechanisms in the works to improve upon the technology but in the here and now, definitely we need to be looking at other vaccine platforms.

Host: Benjamin Thompson

And each of these platforms, each type of vaccine, has it’s individual costs and benefits. We’ve talked about some for the RNA vaccines there. So, there’s still a need for other vaccines to be developed using different platforms to plug the gaps, if you will. But testing new vaccines is becoming more difficult.

Elie Dolgin

Absolutely. The challenge now, actually, is that because the first vaccines were so effective, it’s how do you test these other vaccines and show that they work to a similar degree in a way that’s ethical and feasible because you can’t really run a placebo-controlled trial for much longer, at least in many of those countries where the vaccines are now available because first of all, it’s just problematic to start giving people placebos when they could be getting what’s known to be an effective vaccine, and who would ever sign up for that kind of trial knowing that they have a chance of getting a dummy shot instead of just going and lining up for the actual thing.

Noah Baker

So, what do you do? How do you get around that problem because scientists need to get around that problem and they are.

Elie Dolgin

Well, so, there is a brief window right now where you can still run a placebo-controlled trial, largely by enrolling people who aren’t yet eligible for vaccination under the national programmes. So, maybe you don’t target doctors and nurses who are getting the real shots, but there’s still plenty of people who don’t want to wait 3-6 months and would readily sign up for a trial. Or, you hinted at this earlier, they don’t like the risks associated with the RNA vaccines and so they’re just more willing to give a protein-based vaccine or a viral vector vaccine a chance, even if there’s a risk of getting a placebo. But as one source told me, the window is closing on that, and so the future moves to different kinds of designs where what we need is either some kind of biomarker, levels of an antibody, say, in the blood, that would indicate, okay, you’re protected and we don’t need to run a field efficacy trial to show that it actually does lead to less disease, and many scientists are frantically trying to figure out what that marker would be. That’s currently how vaccines for the seasonal flu or for rabies are assessed, but you need some level of confidence that we can do that for coronavirus. That’s probably where things are heading, but it needs to be proven.

Noah Baker

And then I guess that there’s a couple of other options, but one that we’ve talked about on Coronapod is to use what’s called human challenge trials where you can deliberately infect a willing contributor to a trial with the coronavirus so you can directly and measurably assess the efficacy of the vaccine.

Elie Dolgin

It’s a much smaller trial. It’s a much faster trial. And not only that, it would also actually get at this earlier thing I was talking about, the biomarker protection. You could really directly test that because everything is controlled in a challenge trial. And I think almost everyone agrees that on a scientific level, it’s fantastic. The problems are on the ethics, and different ethicists have different attitudes, different countries and regulators have different approaches, so I know it’s in the works over there in the UK but I just don’t see it happening in the US. I don’t think the FDA would allow it and for whatever cultural reasons, a lot of the experts are just a lot more cautious here. And the problem is that we don’t have a good rescue treatment. If we knew that anyone who got infected through a challenge trial could be rapidly cured with drug x, okay, fine, let’s go ahead. But until that therapy has been discovered or proven, it’s going to remain a controversial approach.

Noah Baker

In terms of developing these new vaccines, having dozens would be very useful and we know that, but is this just a case of shortening the time until everyone in the world can get a jab or is this a longer-term problem? Is it the reality that actually, three vaccines that work would be fine, it just might take a lot longer to get them to everyone because of manufacturing delays and all that sort of stuff, and actually this discussion that we’re having is just about shortening the pandemic. In ten years’ time it’s not going to matter if we have three vaccines or a thousand vaccines. We’ve got a vaccine and we can get it to places.

Elie Dolgin

I think that’s right. It is about shortening the time. Even under the most ambitious timetables, the goals are to get something like 20% of the developing world vaccinated by the end of this year. That’s nowhere near what’s needed to get herd immunity so anything we can do to speed that up and to not further drive the economic disparities between different parts of the world would be advantageous. But also, in the long run, you need a vaccine that works for your healthcare system, and something that requires storage at -70° and is going to cost US$30-40 a shots and require two shots, that’s just not going to fly as a long-term strategy, assuming that you need boosters every so often. So, part of it is speed and part of it is also ensuring that every part of the world has something that’s affordable and works within their system.

Noah Baker

And I guess one other question which is really relevant to a lot of the discussion right now is how long all of these vaccines will be effective because we know that there are a couple of really highly publicised new strains of coronavirus, one in the UK, one in South Africa, are particularly changing the transmission dynamics and there’s a lot of kind of questions about what this might mean for these vaccines that have been developed using, in the case of RNA, spike proteins from one strain and that spike protein might be slightly different now, and is that enough of a change for the vaccines to be rendered less effective? Where are we on that? Do you have any insight there, Elie?

Elie Dolgin

The latest thinking, as I understand it, is that the variant that came out of the UK, while making the virus much more transmissible, is not thought to affect the efficacy of the vaccine. But the one that emerged in South Africa is a bit more problematic, and studies involving antibodies in the laboratory do suggest that it does weaken the response. It won’t completely render the vaccines useless because you develop what’s called a polyclonal response, so because the vaccines deliver the entire spike protein to the body, the immune system responds at a number of different points along the spike, and the mutation found in this variant from South Africa perhaps would impact just one of those sites. But if things keep mutating, in theory, it could really render the vaccines pretty useless. But fortunately, the RNA platform, because it’s so adjustable and modifiable and can be rapidly changed, in theory it could be updated in a matter of weeks and we could have coronavirus vaccine 2.0 that is now protective against that variant and then when a new variant arrives, we kind of have to keep iterating and improving upon it, and so then it starts to look a lot like your seasonal flu vaccine, and I know that some people are even talking about basically in the future, you’ll go for your annual flu-COVID vaccine and they’ll both be packaged together.

Noah Baker

And one assumes that by this point there has been the biomarker you discussed before, for the vaccine efficacy, that has been established so every time vaccine 2.0 or 3.0 gets created, we don’t have to go back through clinical trials each time, which means that you can have something akin to the seasonal flu vaccine.

Elie Dolgin

Exactly, you just give it to a bunch of healthy volunteers, you ensure safety every time, you make sure that it’s producing high enough antibody titers to be protective, and you could be deploying it within months of making it, really.

Noah Baker

So, this future you describe, it sounds rosy. Maybe it’s just because in my head getting a vaccine just makes me really happy as a concept because I’ve been thinking about it for so long, but it does kind of hinge on the huge development and money and time that’s been thrown into vaccines because of the pandemic being sustained somewhat. Do you think that as the pandemic starts to wane, and I’m going to just say that as if it’s a certainty, that there will be enough kind of put into these kind of RNA vaccines to continue the progress that they have made so far, to allow for this future that you describe.

Elie Dolgin

I’m going to give you an on the one hand, on the other, kind of answer, if that’s okay. On the one hand, vaccines and infectious diseases remain not huge money-makers necessarily, so that would work against the technology and any start-up that’s trying to raise capital to build a new RNA vaccine company. But on the other hand, all the investment, both scientifically but also in terms of manufacturing capacity, companies like Moderna and Pfizer and all these other companies, they’ve built massive manufacturing plants to enable the COVID response, and it means that everything they do in the future using this technology and for other infectious diseases becomes cheaper and easier to do. You can already sort of see some hints that interest in infectious diseases writ large is growing. Just this week, Moderna announced a few new programmes for HIV, flu and Nipah virus. I spoke to the CEO of BioNTech. They had always been really focused on cancer but now, thanks to both all the investments they made around the coronavirus vaccine and, I should say, the billions of dollars that they’re going to get in returns from all the sales, they have the ability to start thinking more broadly about other infectious diseases. So, I think, at least among the big companies, they’re going to keep at it. I think it will grow.

Host: Benjamin Thompson

Well, let’s leave it there both. It does seem that there are reasons for cautious optimism as we move into 2021. Elie, you’ve written a couple of articles for Nature about RNA vaccines and the bumps in the road for testing new vaccines. I’ll put links to both of those in this week’s show notes, and I hope you’ll join us again in future. Elie and Noah, thank you so much.

Elie Dolgin

Thank you guys. It’s been fun.

Noah Baker

Thanks so much, Ben, and thanks, Elie.