Egyptian baboons and overlooked COVID genes

Tracking down the location of the mysterious land of Punt, and the genes we're ignoring in COVID cases.....
23 February 2021
Presented by Chris Smith
Production by Eva Higginbotham, Chris Smith.

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Baboon hieroglyphs

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This month: how a dose of magnesium can improve long-term memory, scientists scrutinise the world’s sourdough microbes, and evidence that we're overlooking important COVID-relevant genes. Plus, shark behaviour in low oxygen environments, and using baboon mummies to solve a mystery of ancient times...

In this episode

Baboon mummy

00:32 - Baboon mummies help locate the lost city Punt

Archaeological detective work to find a city of ancient Egypt

Baboon mummies help locate the lost city Punt
Nathaniel Dominy, Dartmouth College

Indiana Jones fans, this is a story you’ll love: archaeology, science and legend have all come together as Dartmouth College’s Nate Dominy tells Chris Smith how museum specimens of baboons from ancient Egypt have revealed to him the location of a lost city that was big business thousands of years ago. Okay, we're exaggerating slightly, but not much...

Nate - There are two mysteries, a mystery wrapped in a mystery. And the first involves baboons because baboons have a very large distribution across Subsaharan Africa. And generally across Africa, baboons are disliked. You rarely see baboons in any kind of statuary or carving or any kind of handicraft. Egypt, however, is the big exception because when you look at the entire arc of Egyptian history, you see that baboons have been revered, they've even been deified. They've been elevated into the Pantheon of Egyptian gods. So it's really quite a striking reversal to the general patterns across Subsaharan Africa. The puzzle for someone like me, who studies primates, is that baboons never lived in Egypt. The Holocene fossil record, which is the period of time of modern human habitation and agriculture and complex societies, is entirely devoid of any evidence of any primate whatsoever - let alone baboons.

Chris - Have we got physical specimens of baboons from that geography nevertheless? They must have encountered them because they defied them.

Nate - That's right. So we find baboons buried in human contexts. They were deliberately buried. The oldest evidence looks like it might've been a zoo. One young baboons is buried with a young person about age 12 or 13, suggesting status as a pet. And then at later periods, we get Royal mummification where the animals were actually wrapped in linens and interred in Royal tombs in the Valley of the Kings. And then in a still later period, during the Roman and Greek period, we get the period of animal cults where baboons and many other animals were mummified on a practically industrial scale. You get tens of thousands of animals being mummified during that period.

Chris - So therefore if you've got evidence of these animals being deified in that particular geography, you've got evidence of specimens of them being brought to that geography, but there's no evidence that they were naturally there, this argues that any baboons that are there were brought there by human activity and therefore the question must be from where?

Nate - Precisely. And the Egyptians, they have written records of importing baboons into Egypt. They have paintings and reliefs on their temple walls and tombs showing the importation of baboons from a distant place. And they tell us that place - the place was Punt. And that's the other mystery is, where was Punt?

Chris - So there's lots of references to a place, but that place no longer exists, and we don't know where it is?

Nate - Right. Historians have argued about Punt because it was terribly important because the Egyptians, typically when they wanted resources, they might go to war to get those resources. We know the Egyptians went to war with the Nubians, they went to war with the Hittites. But with the Puntites, they sent emissaries, they sent ambassadors, they sent diplomats. This was a very important trading partner for the ancient Egyptians, primarily because the Puntites produced very valuable incense that the Egyptians used for religious purposes. So the Egyptians were highly motivated to travel great distances to go to Punt for these exotic luxury goods, including baboons.

Chris - So how can you use our knowledge of baboons to work out where Punt is then?

Nate - Baboons are a really great animal system for this question because baboons drink water every day. And the water in your environment reflects the rainfall, and the chemical composition of water evaporates at different rates. And so when animals are drinking water on the landscape, they incorporate those chemical signatures, the oxygen stable isotopes in the water, and that incorporates into their bones and in their teeth and in their hair. And so you get this geographic fingerprint of where an animal has been living based on the kind of water and food it's been ingesting.

Chris - But what about if you do what you said, which is that there's evidence that there were animals being held in captivity in Egypt, will you not then see the signature of Egypt rather than the signature of where the animal came from written into those ratios?

Nate - Yes, that was a great risk of the project, that long-term captivity would produce a geographic signature associated with living in captivity in Egypt. And so we use different tissues, hair, bone teeth, which integrate drinking water and food over different intervals of the animal's life, and a large number of animals. For example, the baboons that we studied that were at the Petrie Museum in London, those animals uniformly showed us a signature that was consistent with a lifetime living in Egypt. And so we think the Egyptians may have had a husbandry program, they may have been breeding them in captivity. But we got very lucky - there was one animal at the British Museum that showed us a signature in the teeth that showed a distinctly foreign signature. It was unambiguously non-Egyptian.

Chris - So in order to work out where Punt must have been, are you reasoning then that if you triangulate the origins as written down in the teeth and other specimens of these baboons, that Punt must be somewhere relatively equidistant from these places, or close to where a lot of these animals were originating from, that that would give you a narrowed geography for where Punt was likely to be?

Nate - Exactly. So the Egyptians tell us that Punt was East and South of Egypt, and they tell us that you could reach it by land or sea. Problem is that East and South of Egypt - still a lot of open possibilities! And so what we can do is we can take baboons living in all of those competing areas - Somalia, Eritrea, Ethiopia, Yemen, Sudan, Uganda - we can take that baboons living in those areas now, and we can look at their chemical signatures and create a chemical map, if you will, of that region. And so then we can match the mummified specimens that are present at the British Museum to populations in those areas. And the great thing about our analysis is we could definitively rule out some places, and we showed a very strong match to animals living in Eritrea and Somalia today.

Chris - That would be, therefore, the most likely place where the animals were sourced from, but do not just think that it could just be that was a good hunting ground, and they were transported from there to wherever Punt was?

Nate - That's right. Punt was both a kingdom and an emporium on the coast. So there was a market town or port. And so we think the Egyptians would have pulled their ships up to the port and they may have purchased or traded for animals that were there in the port city. But the animals may have been sourced from farther inland, and that makes sense. We think the Puntites knew their market, they knew their consumers. And so they would have gathered animals from farther inland and brought them for trade with the Egyptians.

Chris - So how much narrower is the search for Punt now in the wake of what you've done?

Nate - Much narrower. For 150 years, scholars have been debating about the possibility of the Arabian peninsula. So Yemen has always been a strong contender for the location of Punt. Some authors have put it in Mozambique or Uganda. We can rule those places out. And we can say definitively that it was somewhere in Africa, on the horn of Africa, probably in Eritrea and Somalia. We can't distinguish between those two places, which are the two contending places that most scholars agree on.

Chris - And is there any way to nail it well and truly?

Nate - Yes, I think so. I think if we can turn to ancient DNA, maybe turn to some of the other tissues that were coming out of Punt, if they all start to point in the same place and corroborate each other, then we'll really have something. And obviously archeology is where we need to go. It'd be nice to dig in some of those areas. And if we can find the remains of these ancient places that'd be the clincher.

Yellow gene mutant drosophila

08:29 - Memory improves with magnesium

Magnesium supplements boost the long-term memory of flies

Memory improves with magnesium
Scott Waddell, University of Oxford

Now most of us would probably welcome a better memory if we were offered one. And believe it or not, a dose of magnesium might well be all that’s needed to make that happen, in flies at least! Scott Waddell, at the University of Oxford, is finding that magnesium supplements can boost long term memory. And he’s also uncovered a gene for a magnesium transporter protein that seems to be essential to the process, as he told Chris Smith...

Scott - We teach flies by exposing them to an odour with a sugar reward, and you're effectively training them to expect to find food when they smell that odour. So when you give them a choice between the two odours, they preferentially run towards the one that they expect to find the food with

Chris - And how long does it take a fly to learn? I know how long it takes to train my dog - it depends if there's food involved! How long does it take to train a fly?

Scott - Well, actually only 1 2 minute session is sufficient to form memories that last for days.

Chris - And then you can come back literally days later and they will have remembered what you taught them?

Scott - Yes.

Chris - Goodness, and then how did you bring the magnesium into play then?

Scott - All we did was we fed the flies with food that contained a high magnesium concentration for a few days before we trained them and tested their memory.

Chris - How do you know that it isn't just the flavour? Cause if you're feeding them with something that makes them feel more motivated because they like it, they're in a good mood now, how do you disentangle that from it being actually a physiological effect on the brain biochemistry of the magnesium?

Scott - Magnesium is of course salty. So I guess one of the controls for that is that we fed other salts that were similar, like calcium strontium and they don't have the same effect.

Chris - So you give the flies, or some flies, supplementation with magnesium versus no magnesium. How does it affect their learning and memory then?

Scott - So funnily enough, their learning or their immediate memory seems to be completely the same, but in the flies that were supplemented with high magnesium levels, their long-term memory is better.

Chris - You've therefore got the observation that supplementing with magnesium has some kind of effect on recall or at least establishment of these memories, so then how did you explore that to find out what is underpinning that observation?

Scott - In parallel, we had been looking for genes that were involved in memory persistence in the fly and Yanying Wu, the person that did most of the work in my lab, had actually found a mutation in a magnesium transporter. And so we simply put these two things together - magnesium enhancement of memory, and a potential molecule that was involved in this. And we found out that it actually was involved

Chris - Where is that magnesium transporter expressed? Which bit of the fly brain is involved?

Scott - It's broadly expressed throughout the brain, but it's particularly abundant in a part of the brain that's called the mushroom body, which is a centre that has been previously implicated in memory formation.

Chris - Talk us through then what you think is actually happening with and without magnesium for the flies to have their ability to recall memories affected in this way.

Scott - To be honest, we don't really know why. All we know is that the level of magnesium in the cells, for example of the mushroom body, seems to be higher when we feed the flies magnesium. And that this transporter seems to be involved in allowing this memory enhancement to occur.

Chris - And if you knock out that transporter or temporarily deactivate it, do the flies lose their sensitivity to this magnesium effect?

Scott - Yes. So we can specifically take this molecule out of the mushroom body neurons and then the flies lose their normal extended memory, in addition to the magnesium enhanced memory.

Chris - And does that transporter pump magnesium in or does it pump magnesium out of the cell?

Scott - So this was a bit of a controversy in the field and our data suggests that actually it's involved in magnesium coming out of the cell.

Chris - Well, that sounds a bit strange then doesn't it? So giving more magnesium, nevertheless results in better memory recall - how do you square that circle?

Scott - Yeah, it seems very counterintuitive and this puzzled us a great deal. So when we started to look at using genetically encoded reporters, we were able to see that the magnesium levels seem to fluctuate over time. And that this transporter that we identified seems to be involved in the efflux phase of that transport. So we assume that there's a maintenance of a higher level that occurs that's dependent on this molecule.

Chris - Do you therefore think that high levels of magnesium facilitate learning in the first place, and that then you need it low in order to keep the memory there? Or do you think that in recalling a memory, you need a spike of magnesium, but then the level has to rapidly plummet in order for that message to be correctly expressed? I mean, how do you actually think it works?

Scott - I don't think we have that level of resolution to really give us an idea of specifically what's happening. That's actually one of the things that's somewhat dissatisfying with the study is that there's an awful lot left to do. And that's one of those things. We know clearly that this molecule is involved in maintaining the levels, but as you say, the higher levels giving rise to enhanced memory and the molecule being involved in actually kicking it out of the cells, doesn't really make intuitive sense.

Chris - And I have to ask you, do you take extra magnesium? Have you got a pot of Epsom salts on your desk, do you spoon feed yourself Epsom salts and stay near a toilet in order to gain the benefit of extra memory?

Scott - So it's funny you say that, I've been considering it, I haven't started yet. I knew you were going to ask me that!

Chris - Well, off the back of this interview, I'm now considering it. But as I say, I will remain proximal to the toilet because it has quite a strong osmotic laxative effect, doesn't it?

Scott - Yeah. Well, what my former colleague that actually did some of the initial studies in rodents does take daily magnesium. He's a smart person. It might work.

Sourdough bread

14:56 - Sourdough microbiome revealed

How the diversity of microbes in sourdough starters can affect the flavour and rise of the bread

Sourdough microbiome revealed
Elizabeth Landis, Tufts University and Angela Oliverio, The University of Colorado, Boulder

During the pandemic a lot of us took up baking, especially bread, and in particular sourdough bread. This is the oldest form of breadmaking and requires the use of what’s called a sourdough starter - essentially water mixed with flour and allowed to pick up yeasts and bacteria from the air so it ferments. The sourdough starter is what makes the bread rise. And now, scientists have collected over 600 sourdough starter samples from people’s kitchens across the USA and other parts of the world to find out which microbes are making it into people’s bread, and the effects different combinations of yeasts and bacteria might have on the final taste. Eva Higginbotham spoke with Angela Oliverio from The University of Colorado, Boulder, and Elizabeth Landis, who’s at Tufts…

Elizabeth - The first thing that we wanted to know was mainly just what microbes are in sourdough, because though people are fermenting flour and water in homes and bakeries all over the world, we really didn't have an idea of what microbes were in home fermentations of sourdough.

Eva - So what did you do?

Elizabeth - So the first thing that we did is we partnered with Rob Dunn's lab at North Carolina State University. They asked people to fill out a survey where they told us about their sourdoughs - so everything from where they lived and what type of home they had to whether they kept their sourdough starter in the fridge or at room temperature, and even down to whether or not they had pets in their homes. So they were telling us about the parameters around their sourdough starter. And then we asked people to send us samples of their sourdough so that we could sequence the microbes that are there and also culture some of those microbes to later do experiments with.

Eva - Angela, you also worked on this project. What did you do once you received the samples?

Angela - Yeah, so we actually extracted the DNA in those samples and used gene sequencing to look at what bacteria and fungi, and particularly yeast, were present in those samples. So we found a lot of different microbes, probably not surprising to any bakers out there we found a lot of Saccharomyces cerevisiae - it was definitely a dominate yeast. But we also found other more interesting or niche yeasts that are known to be associated with sourdough samples that you wouldn't be able to go out and buy at a store. And then we also found a lot of different species of lactic acid bacteria, Lactobacillus sanfranciscensis - which I bet that you can probably guess how that was named! -was the dominant bacteria in most sourdoughs where it occurred. And we found that within starters, there were often only one dominant species or bacterial species.

Eva - So there wasn't that much diversity within each individual sourdough starter, but there was quite a bit of diversity between different ones?

Angela - Exactly, yeah.

Eva - Did you find any patterns? Was it like some bits of the US have this dominant species versus other bits, or across the world were there differences?

Angela - Yeah, so we did look into this because some quintessential sourdough lore is that the sourdough is going to be different depending on where you are geographically, but we didn't find that taxonomic composition was correlated with geographic distance in the US at all. So it was overall a pretty poor predictor explaining any of the variation that we found across sourdough starters.

Eva - So if it isn't geography that's making a difference, what is making a difference between the different starters?

Angela - Great question! So we actually tested 33 types of metadata. It included things like the age of the starter, what sort of flour you were using in your starter - so like rye or wheat - and then a bunch of other sort of home characteristics. And then we also collected climatic factors, but altogether those predictors really only accounted for a little bit less than 10% of the overall variation in community composition.

Eva - I see, so is it still something of a mystery then how the diversity is generated?

Angela - Yeah, so we really started with more of the abiotic factors. But we also know that interactions amongst taxa also shape outcomes. And when we were looking at the data, we found some interesting correlative trends between different starter species. So for example, there were a couple of lactic acid bacteria that seemed to co-occur often together. Then Liz designed a series of experiments to look at the interactions between different yeast and bacterial taxa.

Eva - So Liz, what did you do to study the interaction between the different microbes in each starter?

Elizabeth - So we first autoclaved flour and tried to reduce the microbial load that was in the flour itself and mixed it with water and made these really controlled sourdoughs, where we had just one yeast and just one bacteria. And we tried that with all of the most abundant bacteria and yeast that we cultured from sourdough and found that generally we see the same patterns of microbes being able to grow together in the lab as we see in the world.

Eva - Did each of those different starters that you created behave differently in some way?

Elizabeth - We took a subset of 40 starters and looked for differences in the aromas of those doughs. So we partnered with an expert sensory panel and they did both sensory analysis and chemistry on those samples to determine differences in aroma, and then we looked at also the way that the dough rises over time.

Angela - We detected 123 volatile organic compounds. So those are basically the different compounds that sourdough starters are releasing, and those are thought as a way to capture what's contributing to the flavour profile of sourdough. So the sensory analysis yielded 14 dominant notes across the subset of 40 starters that were selected. And we're talking pretty expected notes such as yeasty, vinegary, but some pretty interesting notes as well, including acetic sour, green apple, fermented sour. We might've had one that was like toasted corn chips.

Eva - Are these like specialists smellers who smell the different starters and can say, "Oh, this is definitely apple"?

Angela - Exactly.

Eva - Okay. And were you able to match up then different combinations of microbes with different aromas and ,ultimately I guess, with the different tastes that the bread would have?

Angela - Right, yeah. So we didn't go as far as actually baking any bread, but we were able to link the functional outputs to what microbes were found in particular starters. I think it's a really cool proof of concept to show that these particular microbes really do yield a very specific sensory output. And this group of microbes was also directly linked to dough rise rates, which is just another functional output.

Ocean and an island

22:20 - Shark behaviour changing due to climate change

As oxygen minimum zones enlarge in the ocean, sharks are more at risk of getting caught up in fishing lines

Shark behaviour changing due to climate change
David Sims, Marine Biological Association Laboratory

There are regions in our oceans called “oxygen minimum zones”. They extend from about 200m below the surface to more than a kilometre down. They occur where abundances of sinking surface material cause a surge in decomposition processes, which consumes the available oxygen. David Sims, from the Marine Biological Association Laboratory in Plymouth, is interested in how larger predators, like sharks that routinely dive to over 1500 metres to feed on deep-dwelling squid and octopus, are coping with the fact that - propelled by climate change - these oxygen minimum zones are enlarging. This, he’s finding, is pushing the fish closer to the surface for more of the time, making them more likely to fall victim to human long-line fishing, as he explained to Chris Smith...

David - In this particular piece of work we did we were tracking blue sharks. And blue sharks can get up to about four metres long, and we attach electronic tags onto their fins, which can record not only where they are in the ocean - as they come towards the surface we can get direct satellite locations of where they are - but we can also use other tags which record the depth at which they're swimming. And so we tend to find that blue sharks spend most of their time in the top sort of 200 metre of the water column, but then during the day they undertake these deeper dives down to 400, 600 metres depth. And so the ones we tracked and tagged in the central Atlantic, so the Azores islands and further West towards the US and Canadian coast, we fitted those with electronic tags. And then using satellites, and on our laptops back in the laboratory, we were able to follow almost in near real time their movements. The blue sharks that we were tracking in normal oxygen waters were diving down to over 1500 metres to increase their foraging opportunities in deep water - squids and octopus. When they encountered this oxygen minimum zone those deep dives that they would have been doing just got shallower.

Chris - If they're not making those deep dives, does that mean the sharks are going hungry?

David - I don't think so because, in these oxygen minimum zones, what's interesting is perhaps not only the shark is limited by that low oxygen, but also that's the case for their prey species as well. Blue sharks are feeding on pelagic fishes - these are surface dwelling fishes, and they're probably also limited in diving. So it could be that above these oxygen minimum zones, prey is actually aggregated. And so it might be that these become sort of shark feeding hotspots, and the sharks might actually remain more in these areas than in others.

Chris - Does that mean that they're potentially in contention with other animals that are feeding on those prey or in contention with each other, or even in contention with us?

David - Obviously they're competing with other predators there such as tunas and swordfish and other sharks, of course, but one trick the blue shark might have up its sleeve is that one thing we did notice from this dive data in these oxygen minimum zones was that they did occasionally go very deep into potentially low oxygen water, very low oxygen. So it could be that the blue shark has an advantage in perhaps being able to hold its breath and do some deep dives, perhaps down to a thousand metres - those were some of the dives we mentioned, 750 metres. It could be that they're able to exploit prey which is hypoxia tolerant, in other words is tolerant to low oxygen conditions. And we know that many of the cephalopods, those squids and octopuses, there are species which are very tolerant to low oxygen. They have adaptations that allow them to remain in these low oxygen areas. So it could be the blue shark has an edge, but of course the other part of your question was, well, what about humans? How do they fit into the equation? Well, for that, I suppose we've got to think about the shooting fish in a barrel. If there's less water in the barrel, it's easier to shoot those fish. And that's what seems to be happening above these oxygen minimum zones. Blue sharks are becoming compressed into that shallower water. And so surface fisheries, such as longline fisheries, pose a much greater threat to the shark because their susceptibility to capture will be increased if they aggregate above these oxygen minimum zones,

Chris - It's a somewhat sombre message that you're conveying then. Obviously interesting observation that the sharks have changed their behaviour in this way, but it is bringing them into greater contention with human fisheries, therefore they're already vulnerable. They're going to become more vulnerable. What's the implication of what you found then? Is it basically curtains or is there something we can do about this?

David - There are things we can do. I think that there's room for optimism here because although we found in this study that the fishing effort and the fishing intensity was much higher above the oxygen minimum zone, and we found that catches were twice as high as they were in normal oxygenated waters. So there is a problem here in as much that more blue sharks are being caught than we would otherwise predict. The fishes know that they're perhaps easier to catch, and so they tend to go there. I think there is optimism because there can be of course management measures one can make to reduce the catches of sharks. These can be quotas for example, where sharks have to be put back if so many more is caught than is allowed. It could be that there are gear improvements. Ocean dwelling, ocean going sharks are notoriously susceptible to bycatch - in other words, being caught on these very long lines. These lines extend for about 100 kilometres each with about 1200 baited hooks. And there are thousands of these vessels around the ocean. So there's huge pressure. If gear can be improved to reduce the bycatch of sharks then that might be one way we reduce these catches. But I guess one thing that this study does point towards is the need for spatial management. It could be that as the oceans continue warming in the future due to climate change that we are going to have to think very seriously about mitigating the deoxygenation that we're seeing in the oceans, and which we'll continue by managing fisheries in those particular areas. So where we see that shark hotspot above that blob of low oxygen water, we're going to have to start to manage fisheries in that area itself, perhaps excluding them for certain times of the year when the sharks are there.

CGI images of DNA double helix

29:05 - Overlooked COVID genes

Evidence that there are important genes in COVID that are being ignored in the literature

Overlooked COVID genes
Thomas Stroeger, Northwestern University

The pandemic has predictably led to a massive surge in scientific papers on the topic of COVID. Some journals report that their submission rates are up hundreds of percent. But is the science we’re doing comprehensive, or are there stones repeatedly being left unturned? Northwestern University’s Thomas Stoeger has found that this appears to be the case when it comes to the genetics of COVID disease, as he explained to Chris Smith…

Thomas - There is a beautiful resource curated by the National Institutes of Health which, for each publication, tells other scientists, what are the genes that have in this publication. And we filtered this for all the publications around COVID-19.

Chris - Well, there's been a lot of publications hasn't there. I mean, we've never seen a tsunami of work like this on one particular topic all at once. How many papers did that therefore entail? And how many genes did you end up considering?

Thomas - We considered 10000 publications, everything that was out at that time. And we had an eye at all 20000 protein coding human genes, and we spotted roughly 4000 of them in publications.

Chris - Right, so what we've got here is a list of all the genes that keep getting a hit and you know roughly how many genes there are in the human genome, so you can ask how often do each of the genes in the human genome get talked about in the context of coronavirus infection?

Thomas - Absolutely.

Chris - I'll take a guess that the number one hit was the gene for ACE 2 - Angiotensin Converting Enzyme 2, which is the target that the virus uses to bind onto ourselves and get in and infect in the first place. Would that be a reasonable guess?

Thomas - Spot on that's absolutely correct. So this is basically the first place with the most publications.

Chris - And what comes next?

Thomas - It's genes that encode for proteins that signal from one cell to another that there's some virus infection going on.

Chris - How does this help us? And why have you actually done this? Because presumably one could just go and do a look up on a database and see if a particular gene has been looked at in the context of coronavirus and then research it. So what were you actually trying to flush out?

Thomas - We were looking for things that are not expected. So the of top hits are very expected and that is very reassuring because that means scientists do something that makes a lot of sense in the context of COVID-19. But then we got surprised by comparing the rest of the 4,000 genes to COVID-19 physiology. Since the Human Genome Project it's possible to do some experiments that query our genes at once, for instance all the genes that go up or down in the activity following infection with COVID-19. And we considered a few of those experiments. And in total, this is another list of 2000 genes. And we found that those 4000 genes and these 2000 genes rarely overlap. So the top ones kind of overlap, but the majority of the 4000 genes in the COVID-19 literature, they are not represented in these 2000 genes for which there's a very strong evidence that they relate to COVID-19.

Chris - Well, that's quite a striking finding, isn't it? Because what you're saying is that when you ask which genes actually change a lot when someone's infected with coronavirus and then ask, are these the ones we're looking at, you find that with a few rare examples, we're ignoring them.

Thomas - Absolutely.

Chris - Oh dear!

Thomas - But what these genes are really doing in the context of COVID-19 no one knows

Chris - How did we end up sidetracked in this way then, where we focused our attention on 4000 genes, but potentially ignored 2000 others that are doing possibly quite important things and don't overlap with that 4000 we've concentrated on?

Thomas - Science is really difficult and people have found again and again, that scientists at first start revealing those findings that are the least difficult. And along these lines we found that the genes which are being published in the COVID-19 literature are genes which could already be studied very well by approaches that existed in the 1980s and 1990s.

Chris - It's almost like a big game of Scrabble, isn't it? Where once someone starts putting down some letters in one part of the board, everyone then jumps on that bit and makes loads of words in that area. And it means that there are other fertile parts of the board that often get underplayed, and that's sort of what's happened here. Do you think we therefore need more studies like yours when we've got a course of work ongoing like this to highlight fertile areas so people's attention is refocused on things that they may have missed?

Thomas - I believe it's part of the puzzle. And we certainly do hope that studies like ours motivate further research and actually also provide other research starting points for their own exploration.

Chris - What do you think we need to do about this then? Do we need to have a regular program of approaching the genetic space in the way that you have with this paper so that we keep signposting people that overlooked or under appreciated possible bits of the genetic landscape, so that attention is focused back on those areas where that there might be some fruit that can be harvested?

Thomas - Absolutely. It would be my hope. There have been some initiatives starting outside of COVID-19 to explore some of those genes that we know to be important for disease, but no one is following them up. But still these initiatives, they dwarf compared to the bulk of the support that researchers can get elsewhere.

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