TWiV 1363: A Cauldron of Bats

Weather and virus appreciation

0:00This Week in Virology, the podcast about viruses, the kind that make you sick.

0:10From Microbe TV, this is TWIV, This Week in Virology, episode 1363, recorded on October 2nd, 2026. I'm Vincent Racaniello, listening to the podcast, All About Viruses. Joining me today from Montreal, Canada, Angela Mingarelli. Hello, everyone. You didn't talk about the weather, Vincent. Anyway, I'll talk about the weather. What's the weather in New York? Because here,

0:42it is 17C, 62F. I had to Google that, obviously, because I don't... And it's raining. It's kind of overcast. I'm sitting in front of the window. It's a little bit gloomy. It's warm here. It's 29C and cloudy. So it's warmed up a bit. Yeah, it's warm. Wow. Also joining us from Western Massachusetts, Alan Dove. Good to be here. And here in Western Mass, it is also 29C, which is 85 Fahrenheit. Cloudy, chance of rain tonight. So it's a little one day of extra summer,

1:17and then we return to our regularly scheduled season of autumn tomorrow, apparently. Yeah, we have fake autumns and fake summer ends and all that stuff. So a few weeks ago, it got cold. I had to turn the heat on. Yeah. Oh, really? And now, yes, last night I had the windows open. It was great. Sleeping with windows open is the best, especially if there are no animal noises outside. That's too muggy here for... Yeah, it's muggy. Yeah. Yeah. I had to... Actually, we had... Previously, we had the heat on, and then this morning I flipped it back to AC.

1:51I haven't had AC or heat in like three weeks. I've been neutral housed, just windows, which is nice. I feel happy. When I have the heat and the AC off, I feel like I'm saving money. Yes. Helping the environment, right? And it doesn't last very long, but it will last for a while. So anyway, so it's funny. I think TWIV is now a three-person show, or mostly. Right.

2:16So here we go. If you enjoy these programs, we would love to have your support to produce them. You can go to microbe.tv slash contribute. You know, what do we do on these programs? We talk about science, and we talk about the papers mainly. So it's a pretty... I guess you would say low-level, not high-level, right? Low-level discussion. Yeah. You can... Buffin. Yeah. Right. Yeah, it's granular. Right. But we go from... I feel like we go from high-level to granular. Yes, we try. We try and explain things.

2:48And you can always send in questions if you don't understand that. You can send them to TWIV at microbe.tv. But if you'd like to support us, we'd love your help, microbe.tv slash contribute. There's one news item today. Tomorrow, October 3rd, and Kathy put this in the notes, is Virus Appreciation Day. And some people are going to say, what? Why should I appreciate viruses? Actually, there is a website called daysoftheyear.com, and you can find every day what's going on.

3:20And so, yes, in fact, there is a Virus Appreciation Day. It's been an unofficial holiday for over 20 years, and its purpose is rather than celebrate harmful infections. It focuses on educating the public about the complex role viruses play in nature evolution and scientific medical advancement, such as molecular biology, vaccine development, and gene therapy, and highlights ongoing work of medical science in fighting and treating viral disease. So here at TWIV, it's every week is

3:52Virus Appreciation Week. We talk about viruses twice a week, actually, on TWIV, and sometimes more. Who knows? So I understand that. It's to celebrate how interesting they are and how much people work on them, and they can be beneficial too. But we have two papers today for you that I think you will

Anthropogenic fingerprint on infectious diseases

4:17enjoy very much. And the first one was published in Nature. So Alan's going to have to go all the way to the end of the article for the affiliations. And the title is The Anthropogenic Fingerprint on Emerging Infectious Diseases. And they did an interesting thing with co-authors here. It's three of them contributed equally. So two co-first authors, Rory Gibb and Sadie Ryan, and then the senior author is Colin Carlson, and apparently

4:49they all contributed equally. And as Vincent said, since it's Nature, the list of affiliations is at the end, and end has a few different definitions. But right. So in this case, the list of affiliations could be a separate book. I could just say they're from everywhere, but I will actually go through them. University College London, University of Florida, Gainesville, University of KwaZulu, Natal, Durban, South Africa, University of Washington, Seattle, Washington State, University in

5:19Pullman, University of Sydney, Trinity College, Dublin, University of Oklahoma in Norman, Universidad de las Americas, Santiago, Chile, University of Idaho, Moscow, that's Moscow, Idaho, Tulane University in New Orleans, Cary Institute of Ecosystem Studies in Millbrook, New York, Georgetown University in Washington, D.C., London School of Hygiene and Tropical Medicine, Mahidol University in Bangkok, University of Oxford, Liverpool School of Tropical Medicine, Columbia University, Boston University School of Public Health, Natural History Museum,

5:54in London, Universidad Internacional, S.E.K. in Quito, Ecuador, Instituto Nacional de Biodiversidad, Inabio, in Quito, Vangeningen University and Research in the Netherlands, Administración Nacional de Laboratorios e Institutos de Salud, ANLIS in Pergamino, Argentina, University of Cape Town, University of Melbourne, and Yale University School of Public Health in New Haven.

6:24Okay. Very good. Yeah. It's a lot of, it's because there's a lot of data from different places. You're going to see why it's, the group is from everywhere. Now in the title, the word. Everyone but Canada. Sorry. They don't have any infectious diseases there? Is that the idea? Oh, we'll talk about that once we talk about the paper, but yeah. The word in the title, Anthropocene, maybe some of you haven't encountered it. Yeah. This is kind of an unofficial geologic time interval describing when human activity has been kind of the dominant influence on the Earth's climate and ecosystems, right?

6:57So it's unofficial. It's not like Pleistocene and all that stuff, right? Well, it's currently unofficial, but there have been discussions about making it official because it meets a lot of the requirements to be an epoch. There has to be a clear starting point. There has to be, you know, a defining set of features and there are some clear starting points. You know, we're doing things to the planet that people will be able, or whatever, will be able to detect if the technology exists millions of years from now.

7:29I think that word you used was right, an epoch. I would say it's an epoch, epoch. Yes. Because we're screwing up things here. So this paper is all about trying to find drivers of infectious diseases, you know, human-related drivers. And, you know, there have been lots of outbreaks. They cite them, zoonoses of all sorts and other infections. And we think human-driven environmental changes are doing a lot of things to promote these.

8:02They're increasing animal susceptibility to infection, more opportunities for animal-to-human transmission, which, of course, is a zoonotic spillover, more outbreaks. And because there have been a number of these emerging infections recently, you know, people have been thinking about what kind of ecological and social interventions could mitigate these drivers of disease. And we pay a lot of attention to curbing wildlife trade, right, and trying to avoid deforestation.

8:35But there are other options, you know, reducing greenhouse gas emissions, that reduces climate change, ecosystem restoration, human and livestock vaccination, and then better point-of-care diagnostics and clinical care, surveillance systems that look not only at people but animals and biosecurity. So they say in the introduction here, we think all of these are important, but actually we

9:05don't have much data. We don't really know. Right. I mean, the problem is we know all of these things are good for a lot of reasons. You know, reducing greenhouse gas emissions is good because it will long-term reduce the climate change that we've signed up for. You know, these public health interventions are going to save human lives. That's all great. And we think, based on first principles, that this will cut down on the risk of spillovers because, you know, if people are seeing a doctor regularly and things are properly, you

9:39know, accounted for, then you're less likely to let things get out of control. But we don't actually have data showing what the requirements are for a spillover or what's driving the spillovers, you know, what's going to work best. Well, and this is also assuming that you have access to a healthcare provider, which we'll go into in this paper. Yes, exactly right. Anyway, so this has been written about before, obviously, and things like community, so anthropogenic

10:13effects have effects on community diversity, pathogen diversity, infection dynamics, both in wildlife and in arthropod vectors, and ecosystem degradation and biodiversity loss tends to increase wildlife disease prevalence. But the net effects of all these things are unpredictable and probably context-specific, as you will see today. Yeah, and to be clear, that's what I meant by the lack of data.

10:44We have tons of data on, you know, this causes this, but we don't know what the big, you know, what's the most important thing in this particular case. And also, it's complicated because human-wildlife contact patterns and social vulnerabilities vary between landscapes and populations. And so, as you'll see in the end, this kind of study is probably not sensitive enough because you've got to look at a specific disease.

11:15But anyway, there have been studies that have showed that there are geographic hotspots of human disease emergence. They correlate with social, ecological factors like land use, change, agricultural expanse and biodiversity hotspots, global travel. But, and this is a key point, the first confirmed human infections, especially in a large outbreak, may not reflect the factors that lead to wider landscapes of infection risk, right? So, you know, and also data on these emergence events are biased towards better resource settings

11:54where you can identify the pathogen. And they're typically away from rural and marginalized populations that have the burden of zoonotic and vector-borne diseases, right? In rural areas where H5N1 mostly spills over, there's very little clinical support to look at that. But we do have more and more geo-referenced outbreak data sets for many of these diseases, and that's what they took advantage of in this study. They have geo-referenced human outbreak data for 32 infectious diseases.

12:30These include bat viruses with epidemic and pandemic potential, rodent-borne pathogens, mosquito-borne arboviruses, and other zoonotic diseases like melioidosis, Cremean Congo hemorrhagic fever, and even malaria, plasmodium nolzai. And so what they wanted to look at here was what are the drivers of outbreak risk? And so they only include outbreak records that are associated with some level of environmental influence

13:03that we know of, right? And they collect data from published scientific data sets from National Notifiable Disease Surveillance Systems from the continental U.S., Brazil, and Argentina. And the whole data set has 58,319 unique outbreaks across 169 countries from 1910 to 2022. So I have a question. Is it only me? Okay, so they said as of, I think it's what, 50 degrees north of the latitude line.

13:35But then you look at figure one, which those of you that want to open the paper can see this. Canada is completely just blank. It's not even that there's, and that's not true because we have had detected outbreaks, so I'm not sure why they didn't include any in Canada, because even in Europe, it does seem more sparse. Because Northern Africa also has zero, which is probably a reporting. Russia has nothing. It's probably either a reporting problem or they didn't include those data because Canada for sure has available data sets. So I don't know why they didn't include that.

14:06I thought it was a little bit odd, especially Europe. Like Spain has nothing. The U.K. only has one little point. And like we know that there's been outbreaks there, especially in Northern Africa. So I thought that was a little bit odd. But anyway. Yeah, I noticed as well. I looked at the map. I was like, oh, yeah, that's a lot. Wait a second. Yeah. Some of these gaps make sense. Like Northern Africa. Okay, that's most likely a data collection problem. But Canada, you're right, really, really stuck out. Initially, I thought Australia was blank, but it's got some spots.

14:37And then I realized, well, you know, the interior of Australia kind of is blank. So it sort of makes sense that there's – you detect these the odd – and Russia is just this vast open space. And yeah, like a couple of countries in Europe, that's true. That's Spain, Portugal, just – it seems very unlikely that there's nothing. It's kind of odd. But anyway. And they have collaborators from there. Didn't – Right. I actually know. I think the ones that you said were from South America. I don't think any of them were from Spain.

15:08Oh, yeah. There's nobody from Spain, of Portugal. It's true. I think there's somewhere. And nobody from Canada, maybe. Exactly. Maybe it's just – maybe that's why. Anyway. So let me tell you how they analyzed all these data. So they have a framework. So they want to know the socio-environmental drivers of spatial outbreak intensity. Okay. So they use a case-controlled design. So they're comparing contemporary outbreak locations. It's after 1980 with population-weighted background location. And at each location, they extract 16 covariates from geospatial data sets.

15:44And they fall into five categories. They have detection processes like motorized travel time to healthcare. That's a really big one. Urban land cover, socioeconomic factors like livestock, density, relative social vulnerability, ecosystem structure. That includes spatial, vegetation, heterogeneity, forest cover, cropland cover, et cetera. Land use change in intensity, forest loss, cropland expansion, urban expansion, and climate change, the change in annual temperature and precipitation.

16:17Okay. Now, for the statistics. I want to talk about this for five minutes because there's this sentence here that drove me crazy. We used Bayesian geospatial logistic regression models to test the linear contribution of these covariates to outbreak risk. What does that mean? Of course. How else would you do it? Yeah. How else would they do it? So logistic regression is a pretty standard tool for a binary outcome, right? Outbreak or no outbreak at a location. It answers the question, given these covariates that I just told you, what's the probability

16:51of an outbreak here? And you output the odds ratio saying how much each driver increases the risk. That's pretty straightforward, right? The Bayesian part, instead of saying the effect of deforestation is X, you say the effect is probably in this distribution with this much uncertainty, right? And that's being really honest, right? Because you can never say what it is exactly. Then there's the geospatial part, which accounts for the fact that nearby locations aren't

17:22independent, right? Dengue in Vietnam correlates with Dengue in Cambodia, right? Regular logistic regression assumes independence. So here we have to do geospatial stuff. And finally, what's unique about this study is the spatially structured random intercepts. So I had to look this up because I don't know it. So you fit your model with these- I'm glad that I wasn't the only one very lost reading certain sections. I didn't want to just roll off the names, so I wanted to look into it.

17:53So you fit a model with your covariates, but the prediction will still be wrong in certain regions. Instead of asking why, you add a spatial effect that basically captures this variation, okay? And so let's say in Kenya and Brazil, after accounting for everything else, Kenya still has more reported outbreaks than your model predicts. So you give it a spatial effect of plus two, say, and Brazil has fewer than predicted, you give it a minus 1.5. So you're building this into the whole system to account for these.

18:24I'm pretty sure this is a very fancy term for fudge factor. Yes, it is. Exactly what it is. This is the correction you have to apply to make this work. The correction, basically. Yeah. That's exactly right. Okay. So what do they find? First of all, the first section is called outbreaks. Outbreak hotspots are detected by or shaped by detection biases, okay? So they estimate the overall effects of these anthropogenic drivers across all diseases for

18:55the whole data set. And in many of these areas, the unexplained spatial variation exceeds the size of all the covariant effects, especially in the U.S. and Brazil, where they have really good surveillance. That's the problem. And so basically, this is because they have better data and better resourced health systems, infrastructures, diagnostic laboratories for determining where outbreaks are happening, right?

19:25They find that outbreak event risk increases with higher levels of forest cover, landscape fragmentation, and livestock density. So that's what they found. And you can feel that that's probably right. And then their findings align with this idea that infectious diseases tend to emerge in zones of frequent contact among people, livestock, and wildlife. But the intensity and the clustering of human-driven impacts varies geographically.

20:01And that produces distinct regional syndromes of outbreak risk. For example, in East Asia and Pacific, most anthropogenic pressures are correlated tightly in space, but it's the opposite in sub-Saharan Africa. It's a spatial thing, right? Okay, so that's one thing. What they conclude from this part is that the geographic differences in the drivers are influenced by each region's particular set of diseases,

20:32the anthropogenic pressures, and reporting processes. And they say unpacking these requires shifting towards more granular disease system-specific inference. So that tells me this idea of looking at everything for a common driver is not working, right? You've got to look at every disease independently, and each one's going to be different, which is an important conclusion.

Outbreak drivers differ across diseases

20:54Okay. All right, next section is called Outbreak Drivers Differ Between Disease Systems, which is just what they were talking about that you have to do. They developed disease-specific geospatial models for these 31 diseases. And so across all of the diseases, they find, again, widespread evidence of systematic reporting biases. And the most—but aside from that, the most prevalent or the most significant, in fact,

21:24effects were of increasing urban land cover. So, right, acidification. Yep. It's 20 out of the 30 diseases. And proximity to the nearest health facility is a huge driver of outbreaks, 15 out of 23 tested. Just think about that. There's not something I think about, how far you are from the nearest hospital, right? But if you're not close enough to get diagnosed or tested, you're going to spread. Yeah. That's true. If you live three hours away and you're feeling sick, or you don't even have a car to go,

21:59because a lot of these people won't even have cars. There's no way for them to access health care. Yeah. So they will continue to be sick and they will infect other people and it will just spread. Right. For about half of the diseases they looked at, the outbreak risk is more fragmented in—resulted—sorry, the outbreak risk increased, higher outbreak risk, and more fragmented in forested landscapes. Mm-hmm.

22:30Okay. For a quarter of the diseases, outbreak risk was strongly linked to long-term changes in annual precipitation. So remember, a quarter, that's 8 out of 31, so nothing in common. And so areas that are experiencing climate drying trends were at higher risk of outbreaks of several vector and waterborne diseases. And they think that these—that long-term drying events may be increasing underlying societal or landscape susceptibility that triggers outbreaks.

23:04Well, and it's also going to— So I was thinking— Sorry, go ahead, Luke, Alan. But it's also going to shift vector dynamics. Sure. I mean, I think of West Nile, you get a drought and the mosquitoes aren't able to feed on the birds because the birds left and so they feed on the people and you get, you know. Yeah. And the storing of water. So like I was actually reading about this in droughts where people, when there's a drought, you store all of your water in these huge— Exactly, yes. Like buckets or whatever, whatever they're called. And then that is a breeding ground now for all of these vectors.

23:35Exactly. Yeah, that's right. Like huge cisterns. That's right. Or when like Rift Valley fever, a lot of the outbreaks are post a drought because the rainfall is so intense and then it pools on the ground. And then all of the vectors, all of these—it's 80s, I think? Or is it? I don't know for Valley fever. I don't remember which mosquito it is. But same thing happens where they're pooling on the ground, then all of the mosquitoes, the floor, the ground doesn't drain fast enough. And then there's an outbreak because the eggs are normally like dried, which I didn't actually know. I was reading about this.

24:06The eggs can just stay, mosquito eggs, dry in the ground. And then once water hits them, they just explode. So continuing with this, relationships with land use, biodiversity, temperature, and socioeconomic factors were found less commonly across diseases, and they were much more variable. And, for example, deforestation, right, is considered one of the primary drivers, but they found impacts of forest loss in just a few of their systems, which for me is weird because two viruses immediately come to mind, which are the outbreaks are a consequence of deforestation or land change.

24:50So there's the original Nipah outbreak in Malaysia, which was a consequence of deforestation. And then the Argentine hemorrhage fever virus emergence in Argentina was because they were getting rid of the pampas, which is a grassy area to plant corn, and that's changing the land use. So that's my bias. That's how these two come to mind. But they're saying very few systems. Right. And that gets at really a core aspect of this paper versus the way we – I think the same way.

25:30I'm like, well, what about this? What about this? Yes, yes. But they're seeing those things, but they're not seeing them as the majority. So this is taking the big picture. Yeah. You know, is that often a driver? Well, no, but it can be. Yeah, it can be. Exactly right. Right. What else here? So climate warming was, we think, is a driver for most diseases, but they found effects of long-term temperature change for only a few diseases.

26:02Okay. And also disentangling the influence of social vulnerability from correlated detection biases, they said, is impossible at this big scale. Can't do it. And they say that it's unclear how much the limited detectability of certain drivers reflects a true absence of causal relationships versus a consequence of little data or spatial and temporal misalignments between infection and detection and environmental data.

26:34So basically, they can't disentangle urban reporting biases from the influences of urban built environments and climates and population density and disease transmission. Their models also detected numerous well-known or strongly suspected drivers, okay, which they say validates our approach. For example, pig density and climate change trends were known drivers of Japanese encephalitis outbreaks and the effect of drying on dengue virus outbreaks.

27:13Increased risk of avian influenza outbreaks in areas with higher poultry density. Forest loss increases the risk of MPOX and zoonotic malaria. And fragmented forest cover drives outbreaks of arboviruses that emerge at human forest ecotones.

27:34All right. Then they have another section called shared drivers differ by pathogen transmission modes. And they say prevailing narratives about disease emergence focus on the impacts of individual drivers. But outbreak risks typically arise from several things acting together, not just one thing. So, in fact, I said, you know, forest clearance was responsible for the NEPA. But actually, there was also an El Nino event that contributed to it and other things as well.

28:05So it's never one thing. So they wanted to look at the shared drivers with their transmission model. So across all the diseases, this is what they find. There were large increases in outbreak risk with higher levels of landscape fragmentation and forest cover. Weaker increases in risks with higher biodiversity intactness and moderate decreases in risk in more socially vulnerable settings. So you have different effects of these environmental changes.

28:37Certain drivers, they note, co-occur frequently overall, principally urban cover and healthcare access, and to a lesser extent, fragmented vegetation and forest cover. And as far as transmission goes, which was the heading title, the magnitude of driver effects differ substantially by transmission. So zoonotic diseases transmitted by arthropods to humans are more strongly sensitive to ecosystem drivers and climate drying, okay, reinforcing the importance of ecotonal fragmented and urbanizing landscapes as critical points for these outbreaks.

29:20And so they suggest, you know, strategies that regulate the financial actors most responsible for extractive land use may have greater potential to mitigate these diseases. Basically, the companies that want to make a lot of money, you have to get them to back off, and good luck with that. Yeah. Now, in contrast, directly transmitted zoonoses like Ebola, MERS, MPOX, they have less evidence for consistent directional effects and very little evidence of sharing drivers among the different diseases.

29:56They say maybe because we don't have a lot of outbreaks, but also there are really different ecologies and life cycles and human exposure pathways here. So the conclusion of this paragraph, they say, these findings do not support the idea that one size fits all ecological interventions would be broadly protective against epidemic and pandemic threats. This isn't that surprising? Do you guys think that's surprising finding? Yeah. I mean, I was going to say this at the end, but my overall message from this is none of these are shocking me.

30:33Yeah. No. No, it's not a shock, really. Maybe the last part when we get to that. I was slightly surprised by that. Yeah. So what would be a one-size-all thing, like global regulations on deforestation and agriculture? Right. They're saying this is not going to help overall. It may help in some specific instances, but not everywhere. If you just do that, it's not going to solve the emerging infectious disease problem. But what would help, they say, ecosystem-based surveillance and risk prevention programs are the most scientifically supported option to reduce.

31:03Spillover risk and improve outbreak detection. Right.

Healthcare access and outbreak detection

31:09Okay. The last section is healthcare access supports detection and response. They say, you know, even though we have a lot of data, the study is limited still.

31:24And we have a lot of reporting biases. They say detection and reporting biases are a pervasive worldwide phenomenon. It cuts across spatial scales and low-to-high-income settings. Many of the highest-concerned pathogens, like bat-borne epidemic viruses, have the lowest availability of data. And so it's probably under-detection rather than fewer spillover events. And they say previous studies have suggested up to half of all Ebola outbreaks might never be identified.

31:58They happen, and we never detect them. So they say this illustrates an underappreciated lever for intervention. If you improve access to healthcare in underserved rural and remote communities, that can help control outbreaks, which is what we kind of hinted at before. In much of the world, it takes over a day to reach a healthcare facility. And there's, I mean, us here, like, what? Ten minutes for us, right?

32:28Right, right. We're so spoiled. It's true. We might have to sit in the waiting room for a whole day or 12 hours, some of us. Yeah, that's a different problem. But at least you're there. And if it was urgent, you would be taken. Yeah. And when you do get to these facilities, they may not be able to diagnose you, right? Outbreaks that start further from healthcare centers are less likely to be detected, treated, diagnosed, and are more likely to grow into epidemics.

32:58And so here are the numbers. For most of the diseases, outbreak event reports cluster near clinics. The outbreak odds decline by a median of 32% for each additional hour's motorized travel time from the nearest healthcare facility. And to be clear, that does not mean that if you close down the clinics, the outbreaks will go away. No. No. They will get worse because you have nowhere to go. Yes, they'll get worse. You just won't see them. So, yeah.

33:29I thought that was pretty striking, 32% per hour of driving. Yeah. Considering what you were saying about most people don't even have, you know, within a day's trip, some of them can't even make it. It just shows how many are probably unreported. Yeah. It's an eye-opener, I think. I didn't know that before. Anyway, they conclude that investing in new infrastructure, lowering social and economic barriers to access would ensure, you know, timely diagnosis, treatment, and prevention for underserved communities,

34:01and increase the odds of outbreak detection. We also need to improve global surveillance at human nature interfaces, paired syndromic and serological surveillance.

34:15And that would help address the data gaps in this study. So, there you go. Yeah. So, you were most surprised by the healthcare access, Angela? Yeah. I mean, now that I hear it, it seems obvious, but I never stopped to think about how much that would bias the reporting, because people just physically can't get to a healthcare provider. Yeah. And it seems very naive for me not to think about that, because I have access to healthcare providers, but this is because I live in Canada. So, yeah, but, I mean, we talk a lot about data gaps when we talk about emerging diseases, and we say, you know, lack of data, lack of data.

34:54But it was, for me, too, it was like, oh, yeah, of course that's why lack of data, because lack of access to healthcare in these wide swaths of territory. And to see that quantified, I think, is a really important contribution. Mm-hmm. Yeah. So, there's no, overall, no strong common thing for everything. But there are individual, and obviously this healthcare issue is one of them, and there are other anthropogenic issues, but they tend to be disease- and geographically specific.

35:28Right? Well, and we're losing- There's no one thing. Like, temporal dynamics of seasonality and transmission dynamics and weather, like, in this case, I think it was very binary. It was like, is it presence or lack of infection or, let's say, outbreak in this country? Obviously, to your point, every different disease state is influenced by different factors. That seasonality is also huge that we miss here. But I thought the main finding about the healthcare, for me, that was, like, the most interesting finding of the paper.

36:00Yeah. My conclusion is the one way that you could eliminate these outbreaks is to get rid of humans. Yes. We would stop having spillovers into humans if there weren't any. And also, we would stop the anthropogenic stuff that is driving- Yes, that would certainly stop. It's kind of an extreme solution. Yes. Well, we may do it to ourselves in the long run. When the bears take over after us, they're going to wonder where all these diseases are coming from. The bears. Yeah. Is that what it's going to come at? I don't know. I'm just-

36:31Or the cephalopods. Yeah. I mean, as I say, I'm not shocked by any of these results. And- but it- it really helps to contextualize a lot of them and to say that there's not going to be one straightforward thing, but that there are many things that we can do and that will have effects on various aspects of the problem. But I think surveillance is an important one.

37:02Yes. At key interfaces, they know, right? It's really important. And the way to get that- I don't think we do enough of that. The way to get that done is, and this is the hard answer, healthcare access. Mm-hmm. Yes. You know, and the DRC Ebola outbreak is an interesting illustration, right? Yep. So they have healthcare access. The people who got sick went to the clinic. They did an Ebola test, and it was negative because it was a different Ebola virus. And they sent them back home where they then proceeded to infect the rest of their family.

37:34So you have to have the right healthcare also. You have to have the right diagnostic test. Mm-hmm. I guess there's a lesson there, right? Well, I guess it's also the doctors to know- If there are four Ebola viruses, you can test them all. Yeah, well, symptoms, even if it's negative, if you see that people have symptoms that are very similar to Ebola, you would think that they might think, oh, maybe this is just a different, something similar, but not exactly the same, you would think. So I asked John Dye that, who's got experience with Bundibushu. He says the early days of Ebola and Lassa overlap in symptoms.

38:06You can't tell them apart. And this is an area where Lassa fever is prevalent. So they thought it was Lassa, in which case there's no human-to-human transmission. They say, go home, you'll get better, or die, you know, whichever. So aggressive. It's true, though, yeah. Well, unfortunately, it's true. You know, there's a high fatality rate with Lassa. There's nothing you can do about it so far.

Genomics and longevity in myotis bats

38:29All right.

Genomics and longevity in myotis bats

38:30So our second paper actually has to do with this, right? Because we're talking about bats now, which are sources of spillovers, and this is a nature paper also, insights into longevity and virus-driven adaptation from myotis bat genomes. And the authors, two co-first authors, Juan Vasquez and Elise Lauterberg, and three co-corresponding authors, Lucie Etienne, David Ennard, and Peter Sudmont.

38:59And once again, thank you, Nature. We go to the end of the paper. Actually, it's at the bottom of the first page. Or no, that's right. This one they put at the bottom of the first page. I think it has to do... No, this is just as long. Well, anyway, the group is from University of California, Berkeley, University of Arizona, Tucson, Université de Lyon in France, CNRS, Strasbourg, California Department of Fish and Wildlife in Sacramento, California State Polytechnic University in Humboldt, Arcata, California, University of Michigan, Ann Arbor, Smith College in Northampton, Berkeley City

39:33College in Berkeley, Bat Conservation International in Austin, Texas, Stony Brook University in New York, and Bat Survey Solutions in Tucson.

39:45Wow, that's an interesting name for a company. Bat Survey Solutions, yes. I wonder if their vehicles are the Batmobile. Yeah.

39:56Okay, bats. We talk a lot about bats because they are sources of... They have a lot of viruses and sometimes they spill into humans. Nature has been publishing a lot of bats recently. Yeah. Like, Emmett Teeling also just had another bat paper where they published 42 new bat genomes, which is really cool. Oh, cool. That's another group of people should check out. Yeah. And I saved this for Angela because she's interested. You've done some bat experiments, right? It's true. I'm writing a bat paper right now. Cool. All right. So, bats are numerous.

40:2720% of all known mammals, very phenotypically diverse. They emerged 60 million years ago. And so, there's a lot of diversification. And they have some interesting traits, including longevity, viral tolerance, and immune defenses. And the topic of this paper is the genus Myotis, which emerged 33 million years ago. 139 species on six continents and a lot of ecological diversity.

41:00You didn't work on Myotis, did you, Angela? Actually, well, I have a data set of Myotis that I'm also looking at, an RNA-seq data set. But it's not mine. It was generated by another group. But just to add, you said 20% of all mammals. But there's over 1,500 species of bats. And 139 of those are Myotis. But there's 1,500 just for context. So, people can think there's a lot of bat species. They're highly- Yeah. Myotis is the largest genus within bats. But there are many other genera.

41:30Between bats and rodents, that's 60% of mammals. It's like everything. Everything is a bat and a rodent, basically. Yes. What are humans? What percent of mammals are humans? Like 0.1%? I don't know. I don't know what you go by. By numbers? By species? We're only one species, right? We're one species. Yeah. It would be less, well under a percent. We're just a plague. Yeah. The Myotis are interesting because they have a big variation in lifespan. A six-fold difference between the longest-lived, which is Myotis brandi, 42 years.

42:02Oh, my God. 42 years. And the shortest is seven years. And these two, that's Myotis nigricansin, they diverged 10.6 million years ago. Which is, when you think about it, not very long. 10 million years and their lifespans are that different. It's very, very abnormal. Yeah, and there's this rule in biology that lifespan correlates with body size. Elephants live a long time. Mice don't live so long. Bats break this, right?

42:33You've got these little bats flying around living for 42 years. That doesn't fit the curve. They break it. But so do naked mole rats. Naked mole rat also breaks it, yes. They do as well. They break it also, yeah. It's called an elementary scaling. They live a long time. They do. But they have special things that we can talk about later. They have special, like, elephants. There's Pitot's paradox, which the paper discusses that we can talk about as well. Yeah, yeah. All right, so this paper is about Myotis. They're doing genomics and some cell culture experiments. So they make cells from the bats.

43:05So there's a mix of both, okay? And what they're looking at are the phenotypic adaptations that contribute to the lifespan and immune phenotypes of these bats. So they have skin punches and they make cell lines from several North American species, including the M. lucifugus, the longest lived. They make, all right, so this is a very cool part here. They have haplotype-resolved chromosome-scale genomic assemblies for eight species.

43:38So haplotype-resolved means they have, they can tell the parental origin of the DNA sequences. Most sequencing is all homogenized. So, you know, half your genome is from one parent, half the other. You can never tell unless you go to the trouble of doing haplotype-resolved, which means you get the mother and the father sequences together. That's really great. And it can tell you all sorts of things about inheritance. These are incredible genome sequences.

44:09They're almost 99% complete. They have, they find 20,869 protein-coding genes. And they say these are the, these are some of the most contiguous mammalian assemblies so far. And they did long read sequencing, which helped. As opposed to a lot of people through short read. Yeah. But the haplotype-resolved is really, really important. I really. I think they're the first ones to do that in bats.

44:39I mean, as long. Yeah. I've read a lot of bad papers, but I don't know. I've never seen a bad paper that has done that, which is really cool. Yeah.

44:48Okay. So they have 44 chromosomes. And they say the whole species, well, everything they looked at is 44 chromosomes, which they say is amazing for a genus of over six continents and 33 million years of their emergence. They all have the same number of chromosomes. So I take their word for it because I never thought about that before. No. It's true.

45:13Also, they find lots of variation among the genomes, right? They have structural variants, including inversions, duplications, translocations. They're pretty common. Base changes, of course. They find between 6,000 and 8,000 structural variants per genome relative to the rest of the group. That doesn't mean a lot to you, but they're different. Okay. They're different. There's a lot of structural variation occurring in the context of what they say is a highly constrained

45:45karyotype, 44 chromosomes, yet there's all kinds of stuff going on.

45:50All right. Now we're going to talk about a single gene, PKR, protein carnase RNA activated, which we have all known about for years. And this is an interferon-stimulated gene that is a sensor of double-stranded RNA, and double-stranded RNA produced during virus infection. And when it senses it, it shuts down protein synthesis as a way of stopping. The infection, a really powerful antiviral protein. And every virus genome has some kind of antagonist to PKR, because if you don't, you're out of

46:26business, basically. It's been previously shown that the PKR gene has been duplicated in certain myotis species. And so they said, okay, let's take a look at our sequences. And they have a number of organizations here. They have chromosomes with a single copy of PKR. That's PKR2. They have sequences with two tandemly duplicated copies, PKR1 and 2.

46:56And then they have three duplicates, PKR and PKR1-2, which is only in myotis californicus. So one, two, or three copies of the PKR gene, first of all. And they want to look at the evolutionary history of these duplications. Basically, they find that PKR2 is the ancestral copy. And PKR1 originated from a single duplication event at the root of the myotis genus.

47:28So these haplotypes, the duplicated and the unduplicated, have been segregating for tens of millions of years in these animals.

47:41Okay. They want to know now. Let's do some functional biochemistry. They want to know, why do you need multiple? Do they act additively? Are they synergistic? Or do they interfere with each other? So they make cell lines. They start with HeLa cells where the PKR gene has been knocked out. And then they can put in one or two or three PKRs that are coupled with GFP, I believe,

48:12so that they can assay PKR expression. So if you, a flag, not GFP, sorry.

48:21PKR plus, PKR1 plus 2 doesn't change the protein expression levels. Then they want to know, how about cell viability? Because we know that when PKR is activated by double-stranded RNA, it makes cells go into apoptosis. And so they find that viability is only infected at a high dose.

48:45And using a translational assay, they find that PKR1 plus 2 together leads to an immediate, intermediate translation, shut down, no synergism, nor inhibition of the duplicates. They also tested PKR1 plus 2 co-expression on infection by two viruses, VSV and synbis virus. So PKR1 plus 2 restricted viral infections to a similar extent.

49:17PKR1 forms homodimers, but PKR1 plus 2 does not, does not form heterodimers. And so they say maybe since the duplication, the divergence has been at the protein-protein interface, so you don't get any heterodimers formed. So they don't find any dominant negative effects, no synergistic effects, but they're additive in their cell functions, in their assays. But what's interesting here is that with high PKR doses, there's cell toxicity.

49:52And so they say maybe there's a trade-off between duplication. So in other mammals, we don't see duplication. So maybe it's because of the toxicity of PKR that somehow the bats have learned to deal with, right? And maybe bats need to have to because they need to defend against viruses, right? Or more so than other. I think there's another gene, Apobex, are extensively duplicated in bats, and much more so than in any other species, again, consistent with this viral.

50:23Bats also altogether don't have Pyin sensing that sends DNA. They lack it altogether. At least multiple species. They lack DNA sensors? Mm-hmm. Like the Pyin family? P-Y-H-I-N. I forget how to say that. Or Pyin. However you say that. But it's a DNA sensor, and in certain bats, it's actually been completely lost. What about sting and that stuff? Is that there? They do have sting intact. It's dampened. There's a paper that shows that. There's dampened sting activation, but it is intact, at least in the species looked at.

50:53Because the thing with bats is that bat is not equal to bat. There's over 1,500 species, and in all the species that we look at, there seem to be differences. Yeah, yeah. So maybe it's evolutionary pressures of their environment, because obviously they're in almost every single continent except for Antarctica. So, and it's interesting because this whole paper is about myotis. And I was thinking about it because, so myotis is a new world bat. So there's kind of bats that are split in, like, ying chiropteron, like yang chiroptera.

51:24And the old world bats and the new world bats. So myotis is a new world. And all of the old world bats, which are like the Rosettus, the Hippociterus bats, the Rhinolophus, the Horseshoe bats, those are all the main reservoirs for the most lethal pathogens that we know in humans. So, like, phyloviruses, like the Marburg, Ebola, there's a presumptive reservoir, but Ebola, phylo, Hennepa virus, coronaviruses, the beta coronaviruses, all of those are in old world bats.

51:55So it's interesting that even some of these things, you know, are in these new world bats, but maybe it's very distinct in an old world bat, which people don't study as much because they're not as readily accessible. Some people in Southeast Asia are now currently doing that. And also there's differences between fruit bats and insectivorous bats, like their physiology, the viruses they carry. So I think it's interesting what this paper shows, but I don't know what that means. I guess when we get into further on into the paper, when they start talking about DNA, like certain proteins that interact with DNA viruses, which is interesting because most of these viruses that infect bats

52:36are RNA viruses are RNA viruses, not DNA viruses. So I don't know what this means. So what, so I had a question about myotis.

52:52It's gone. They're all over, mostly, well, not only North America, but they're pretty ubiquitous across continents as well. They're just, a lot of them, the lucificus is in Europe and in North America is very, it's extended across. Do we know any, any viruses that have spilled over from myotis? Not as far as I know. So I did, I remember looking into this actually for one of the classes I had to do in my PhD, where it was, I was looking at North American bats to see,

53:23like as reservoirs of potentially pathogenic viruses, because this was like five years ago, post-COVID. And they have a lot of alpha coronaviruses, but they don't, as far as the sampling that has been done, at least the myotis and the big brown bat, the e-fuscus, they don't have any pathogenic viruses to humans thus far. Like we don't know if, if they possibly could, but as far as we know, they, they don't. So if I look up in the sky at dusk and I see a little bat, is that probably a myotis?

53:55It could be a myotis, it could be a big brown bat, which is a e-fuscus, which is like a little bit bigger than a myotis. So is a myotis a little brown bat, basically? Kind of. Or is that something? It's like, well, a little brown bat, I forget, is lucificus? Let me check. So a little brown bat is a specific species. Yeah. Yeah, a little brown bat is myotis lucificus. Exactly, it is. So yes, if you look up, little brown bat is myotis lucificus, and big brown bat is eptesicus fuscus. And it's, but they're both very, like, it's called big brown bat, but it weighs like 18 grams.

54:26So it's smaller than a mouse. If you don't see them side by side, you probably won't know whether you're looking at a big brown or a little brown. No, not at all. But they, but yeah, they're, they're very ubiquitous across all of North America. They just don't, as far as we know, carry viruses that infect humans. Well, it's a fair point, right? I should lie. I'm lying. Rabies, yes, right. I'm lying. I forgot rabies. Oh, myotis carries rabies? Yes, they have lysoviruses as well. So I should, I take back what I said. For coronaviruses, not yet. We haven't found any that are pathogenic in humans, but there are definitely lysoviruses that can infect humans.

55:01But let me, let me understand this. So when you, when a human gets rabies, so you can get rabies from a dog or a raccoon or a bat. So it's all the same virus, right? There are different lysoviruses that are in bats. If all of them are replicated in humans, I actually don't know. But there is a lysovirus, I forget what it's called, rabies one or something like that. Will, it is in bats and it can infect humans. But there are other lysoviruses that I don't know if they all infect humans. I'm not sure, actually.

55:32But there are multiple that bats carry. So when a human gets a rabies from an animal, did that animal ultimately get it from a bat? Not necessarily. Or it could be another animal, right? It could be a different reservoir. There could be different intermediate hosts. But it is true that bats are some of the canonical reservoirs of rabies. But, I mean, so are raccoons in Canada, for example. Do the raccoons always get it from a bat? Who knows? It could also be from another raccoon. Yeah, yeah, of course.

56:03Would they have maybe... Like the bat would have had to get it from summer, which would be another bat. And then where does that get it from? The environment, right? It's just like in the environment, so... Now, raccoons, though, get very sick from rabies, right? They do. So I think raccoons are accidental hosts. It's not necessarily the reservoir, yeah. So is the bat the reservoir or the main reservoir? Well, we think so because they don't have pathogenic disease in the same way that other animals do. At least those that we have seen.

56:35They can carry it and not have the very aggressive neurological symptoms. Not that all bats are immune to it. Like some bats can still have rabies, for sure.

56:47But at least not like us or like a dog or a raccoon. If you wake up one morning, Angela, and there's a bat in your bedroom, what should you do? Catch it and have it tested for rabies? Or just get a rabies vaccine? Well, if it hasn't bit you, then you don't necessarily need to get a rabies vaccine. I mean, the thing is, is that if you go to the doctors and nothing has bitten you, you won't get... They won't give you prophylactic rabies normally. Really? Only if they see... Yeah, only if they see a wound. But I would try to catch it. Or you can call animal control if you don't want to catch it.

57:19But try to get it out of your house as fast as possible. Please don't injure it because it didn't do anything wrong in its eyes. It's not the bat's fault. Exactly. Don't kill it, please.

57:31So if you weren't bitten, you don't need to capture it for testing then, right? No, even with tics though, I think now in the United States, before people used to take their tics in to see if it had like burgdorferi, burly burgdorferi, but I don't think people are doing that anymore. I think it's like the protocol has changed. But anyway... Yeah, RFK said we don't have to worry about tics. Yeah, which is crazy because Lyme disease is very prevalent. I think with doctors who are, you know, listening to appropriate input instead of RFK, the standard

58:06now is to presume if you've been bitten by a tic, then you are probably infected with whatever the local, you know, Lyme or what have you.

58:16All right, next set of experiments. I think these are very cool now. So they want to look at what viruses have done to shape the myotis genomes. So they're going to look for signatures in what they call virus interacting proteins. These are bat proteins that interact in various ways with viruses. They can be proviral. So like a receptor in a bat would be for a virus would be proviral.

58:47So it's supporting virus infection. Or it could be an antiviral protein like an interferon. Or it could be both, right? So they look at positive selection. In other words, what proteins in their genome sequences in the myotis have been positively selected using a program for that?

Viral interactions and genetic adaptation

59:10And they say, like other mammals, the myotis genome show an enrichment for adaptation of VIPs, virus interacting proteins, right? Because they should be positively selected because they're protective. So they didn't say how they define the VEPS, which I thought was a little bit weird. I wasn't sure if it was in other mammals. There's virus interacting proteins that we know are their signatures that are always there. But they didn't actually say if it was bat specific. And if it's bat specific, how did they make this library of proteins?

59:45Which they don't have a reference or anything. So I'm not sure if maybe you guys thought of it. No, I don't see that either. No, it's a good question. Because I don't think it's bat specific. I think it must be like some mammalian data set that they're using. Yeah. Yeah, they have this data set, and it's referenced 24, 5,527 manually curated VIPs, which are defined as host proteins, that have at least one experimentally verified physical interaction with a viral protein with RNA or DNA.

1:00:16Okay, so it's like mammalian, spanning mammalian mammals. Okay. But also they've been experimentally. It's a lot of VIPs. It's a lot. 5,500. All right, so then they repeat this. So basically, they find that VIPs are positively selected.

1:00:32They're enriched for changes at the VIPs. Okay, so then they repeat it using a gene set restricted to VIPs with experimental evidence of pro or antiviral effects. And therefore, you have some fitness data. You say this gene has a fitness effect. So they see an even stronger elevation in the ratio of positive selection in these pro-viral or antiviral VIPs that have been shown to be active, right? And so basically, this is consistent with viral interaction as a cause of enrichment for positive

1:01:08selection in these VIPs. And then they wanted to say, what about other bats? Do you see these same patterns? So they look for this across bats more generally, and they find it in a data set of 47 publicly available non-myotis bat genomes. Okay. So now they say, you know, we've got people have data that bats may respond differently to DNA and RNA viruses.

1:01:38So they wanted to take a look at it. So they compared the enrichment of positive selection in VIPs that interact only with DNA viruses and VIPs that interact only with RNA viruses. And they find that VIP adaptation in myotis and also in these other bats is driven by selection only in DNA VIPs. And not for RNA. There's no evidence for genome-wide enrichment in VIPs that interact with RNA viruses.

1:02:11This was a big surprise to me. Me too. It was a surprise to me, yes. But they're myotis bats and not reservoirs of a lot of the RNA viruses. Yeah, yeah, right. We think about, when we think about viruses in bats. So they don't carry those viruses. So maybe these bats carry more DNA viruses. We don't know. Maybe. If you don't look. So that's a fair point. Yeah. We'll never know. Yeah. All right. So then next, they say, okay, we looked at these VIPs for basically protein changes that lead to adaptation.

1:02:41But it can also happen by gene copy number changes, right? We saw PKR duplicated and triplicated. So they wanted to ask if VIPs are enriched among genes that are recently gained or lost in myotis. VIP, and what they find is that VIP genes were more likely to have undergone expansions or contractions on at least one branch of the myotis family, and that this pattern is driven

1:03:11only by copy number changes in RNA VIPs, not by changes in DNA VIPs, all right? So they see evidence for copy number changes in VIPs, but only the ones that interact with RNA viruses. So basically, you have adaptations to both DNA and RNA viruses. For the DNA viruses, you have changes in the sequences of the VIPs, and then for RNA viruses, you have copy number changes in the VIPs.

1:03:42Now, in humans, go ahead. Which could mean that these are two different strategies for dealing with two different types of viruses? Maybe when you're adapting to DNA viruses, you need to change the protein. And when you're adapting to RNA viruses, you just need more.

1:04:02I don't know. I would like to know which VIPs, because they're very broadly talking about all these VIPs and whatever, but like, which ones? It seems like it's odd that they would have actually mentioned. I don't know. It could be in the sub-data, you know? I don't know. They might put lists there. Yeah, I'm sure you could drill down into the... That's right. Maybe I'll go work. Okay. So in humans, VIP adaptation is driven by RNA VIPs, not by DNA VIPs, which also surprises me, because we have lots of DNA viruses, right?

1:04:34So then they want to look in other mammals. They look at four other large mammalian clades, okay? Primates, glaries, ingulata, and carnivora. So other mammalian orders show a mix of adaptation in both RNA and DNA VIPs. None show the absence of genome-wide enrichment in RNA VIPs that they've just found in the myotis. So that seems to be unique so far. So what's working for bats isn't working for anybody else. No, it doesn't seem to be.

1:05:05And maybe, but as Angela would say, it's myotis. Maybe it's different than other bats, right? Yeah. So I think you have to be careful about making a bat-generalized conclusion. Exactly. Bat is not equal to bat. Everyone that's in bat research knows that. And we love to say that in my lab. My supervisor loves to say that. Because it's true. We have a lot of data now on different bats, and a lot of it is not overlapping. Some of it is, but even goes to show now these new genomes where we're seeing things that we didn't see before. And we have, with the BAT1K project that Emma Teeling is running, she's trying to sequence

1:05:39over a hundred, no, sorry, a thousand bat genomes. And they now have, I think, over 150. And there's a plethora of differences between each genome. It's cool. It's really cool. But it's not, I think generalizing is very difficult. And we shouldn't, necessarily. Right. All right. Now we're going to look at body size and lifespan. All right. So bats, as we've already mentioned, they have, they're the longest lived clade of mammals after you correct for body size.

1:06:10They have an 11-fold range of lifespans within a 650-fold range of body size. And myotus, in particular, have this whole range. So bats are an exception to this idea of allometric scaling, that there's a positive correlation of longevity with body size that we've already mentioned. But they say this hasn't been tested phylogenetically. So we're going to do that now because we have these eight genome sequences.

1:06:42So they modeled the evolution of body size and lifespan independently across a super tree of a thousand mammals. And they generally see agreement between evolutionary patterns of body size and lifespan. You've got your whales, you've got your elephants, you've got your primates.

1:07:01So the largest and most rapid changes in lifespan across mammals are in bats. They found some of the largest and most rapid changes in bats. And they say it's largely independent between species and genera. Bats experience a 40% greater increase in lifespan per 1% increase in body size compared with non-bat mammals, for example, 0.2% increase in lifespan versus 0.159% increase per 1% increase

1:07:34in mass.

1:07:36In myotus, they saw some of the fastest increases in lifespan relative to their most recent ancestor. As you can measure the change in lifespan over divergent time. So basically, myotus bats and their ancestors have some of the most extreme increases in lifespan among mammals, despite similar allometric lifespan scaling of bats and mammals after phylogenetic correction. All right. Okay. So bats live a long time and they're not huge.

1:08:08All right. So then they look, they try and find some evidence for this.

1:08:15You know, body size has other implications for other things like cancer risk is lower in big mammals like elephants and whales. Cancer risk scales proportionally to both body size and lifespan within species. But there's no correlation between body size, lifespan, and cancer risk across species. And that's Pitot's paradox, which suggests that species with more cells or longer lifespans

1:08:47have adapted to reduce their cancer risks. Is that what you wanted to talk about? So we have to talk about elephants. Well, elephants are so cool because elephants have 20 copies of TP53, which is the guardian of the genome, as we know, and they have, so that's 40 alleles where humans and other mammals have one. So they've actually shown in vitro, which I went like down a little bit of a rabbit hole that, um, sorry, elephant cells versus human cells. If you irradiate them, the elephant cells will apoptose significantly faster than human cells

1:09:19or other mammalian cells because they, the DNA damage, they kind of sense DNA damage and right away clear out the dead cells as opposed to trying to repair, which I think is so fascinating. I guess when you have, but then if you think about it, the energetic cost of clearing out that many cells in the size of an elephant is actually crazy instead of repairing. Cause the repairing is, is energetically costly, but I, I would think that making a new cell is more energetically costly than repairing, but maybe I'm, I'm wrong.

1:09:52Uh, but yes, whales also have similar strategies to, to elephants and the naked mole rat as well, actually, which is not as large. So it's not as, not as large as an elephant. Not as large, not even close, but they also have interesting strategies. Yeah. So I mean the, the fundamental problem here is mammalian cells, um, an elephant cell and a human cell aren't that different in size, you know, compared to the output. Um, so an elephant has a whole lot more cells than a human, which means statistically the odds of an elephant having a tumor arise are much, much higher, but orders of magnitude

1:10:27higher somewhere in the body and humans, you know, tumors arise all the time or, or cells become cancerous all the time in our bodies and the immune system surveils and takes them out. Uh, but the scale of that, that would have to happen in an elephant is so much bigger that they would have to have adapted in order to grow large. This is Pito's paradox is that, you know, from one species to the next, um, you see this, you know, cancer risk is not scaling with body size. So what's interesting in bats, I don't remember if they go into this that much in this paper,

1:11:02but bats are extremely small, like we're talking about, very long lived. Um, but they don't have, the incidence of cancer in bats is, I want to say, I don't want to say zero, but almost zero. I have never read any, any literature in cancer in a bat. So they're extremely old and they just don't get cancer. So I'm not saying that no bat has ever not had cancer. Maybe there is, maybe there are a few, but even in captive colonies and things like that, bats just don't seem to get cancer, which I think is so interesting on it in itself.

1:11:34And they don't really go into that in this paper, but they could considering now, you know, they could look at tumor suppressing genes. We're going to have a theory about why bats don't get cancer. Yes, for sure. But to be clear, bats almost certainly do get cancer. We just haven't seen it yet. It's true. We don't want to start another one of those myths like sharks don't get cancer because sharks totally get cancer. It's less common than we would expect in bats. Exactly. Well, the cells are cleared before they become a tumor.

1:12:05That's basically it, right? No, of course. They mutate all the time. They just don't become, well, we don't know. As far as we know, we haven't sampled sufficiently, but.

Cancer resistance and DNA damage repair

1:12:14Bat oncology is still a very young field. So the authors say, okay, these, these bats live a long time. So are, can we see effects on genes involved with cancer as, as a, as a consequence of that, right? So they, they look for such genes. They find an average of 4%, 5.4%, 20% of protein coding genes have at least one region of the positive or negative selection. These are genes involved in the cancer processes, and these are enriched for pathways in immunity,

1:12:50cancer, and aging. So they quantify the proportion of cancer-associated pathways over-represented among genes under positive selection throughout these myotis sequences. So among genes under positive selection, most of them within the, in the Arctic myotis were enriched for cancer hallmark pathways, all right? And so genes involved in generations of cancers. So they see significant enrichments in representation of cancer-associated pathways in many of the

1:13:27lineages that have the greatest lifespan. So again, the bats with the greatest lifespan have significant enrichments in these cancer-associated pathways. The longest-lived bat, right, M. lucifugus, had an over-representation of pathways associated with DNA double-stranded break repair, all right? So DNA double-stranded breaks happen all the time, and the cell doesn't like it.

1:13:59And if one way, as Angela has already mentioned, you could repair it, or you could just make the cell die, because it's going to lead to genotoxicity, right? Your cell's going to be messed up when you break the DNA. So they say, maybe M. lucifugus has an enhanced response to DNA double-stranded breaks relative to other bats. So they tested that, actually. They have skin fibroblasts from lucifugus, and they test their response to neocarzinostatin,

1:14:30NCS, which is a radiomimetic agent. So it mimics radiation in breaking DNA. It induces double-stranded breaks. So they add these to myotis and three non-myotis bat fibroblasts, okay? At low doses of this compound, NCS, the lucifugus was the only species with sensitivity after 24 hours. In other words, the cells die. They drop in viability.

1:15:01They have apoptosis. It's the same thing that Angela said happens in elephants, right? They're really sensitive to DNA damage. And at high doses of NCS, the lucifugus cells have the highest level of apoptosis and the greatest drop in viability of all the bats tested. So it would have been... Sorry, are you going to finish your thought? Let me finish it. This is consistent with other long-lived species where they've done similar experiments, elephants, naked mole rats, and bowhead whales. Longevity is associated with an increased ability to clear out damaged cells.

1:15:34Okay, go ahead. So this is very cool, but I thought it would be even more interesting if they had, because this is readily available, a human cell line or a mouse cell line or something in parallel, because this is like the lucificus bat compared to the other bats. But it would be really nice to see compared to another mammal, because I think it would be even more striking. Because maybe the lucificus is already extremely like outlier, let's say, compared to the other bats, but where do humans and mice and all of these other animals fall?

1:16:04I think that would have been nice to see. I would have included elephants and humans. Yes, for sure. Yeah, elephants also. So you get the extremes, right? Yeah. To see where my otis falls. Yeah. Yeah.

1:16:16Okay. So there's a difference in sensing and responding to double-stranded DNA. So they want to... Double-stranded DNA breaks. They want to know what genes are involved with this. So they do RNA-seq after 6 and 18 hours of treatment with this drug, NCS. At 6 hours, these are lucifugus cells. They see upregulation of genes associated with cell cycle arrest and cell death. Okay? So we know the drug is killing the cells, and this explains how, right?

1:16:49It's arresting the cell cycle, and it's inducing apoptosis. And downregulation of genes in pathways associated with cell division, growth, DNA damage, repair, and synthesis. All right? That's at 6 hours. At 18 hours, you get upregulation of genes in pathways associated with cell stress responses and continued downregulation of the cell cycle. So basically, the cells are stopping to divide, and they're undergoing apoptosis. The greatest, the strongest pathway enrichment, though, in this RNA-seq data from DNA-damaged

1:17:25cells are genes associated with the innate immune response.

1:17:32And they name a number of these. So what is going on here? Well, so there's an overlap. They say the innate response has evolved to respond to viruses, but they also protect you against double-stranded DNA breaks and subsequently cancer. So they call this pleiotropy with DNA VIPs. And in fact, they look at that, and they see an enrichment for genes that are differentially expressed after NCS treatment among the DNA VIPs only.

1:18:02So those NCS-induced genes are the DNA VIPs. There's an enrichment there anyway.

1:18:10So selection of the innate immune response, they suggest, may drive agonistic pleiotropy in aging-associated traits like DNA damage response and cicecal regulation. So the idea is that bats have been assaulted with viruses. They've evolved. Evolution has provided them with strong innate immune systems. And at the same time, those also gave them longevity and anti-cancer properties. That's the idea. And maybe gave them longevity because of anti-cancer properties.

1:18:42Exactly. That's probably part of it, right? Yeah, yeah, sure. But there's other things too, I'm sure, right? Sure. And this is all in fibroblasts. Imagine in other cell types and immune cells and things like this is just a punch biopsy from the skin. So I wonder. Yeah, it's true. It's like you wouldn't necessarily have, it's as innate immune system. I don't even know what fibroblasts, like what does that mean for a fibroblast? But it's still really fascinating. But I wonder, it would be cool to see it on hematopoietic cells as well. Yeah.

1:19:12But I ask too much.

1:19:14So we have here, we have eight almost complete genomes. We have differences in responses to DNA and RNA viruses, protein changes versus duplication. And we have this overlap, which they say, here's their last sentence, traits such as cancer risk, cellular homeostasis, and antiviral response have evolved in tandem due to pleiotropic selection at coinciding points in the evolutionary history of bats. That's pretty cool. Now, yeah, it's one type of bat and it's fibroblasts only.

1:19:46That's a star, right? You got to start somewhere. No, for sure. It's really cool. I think all bat research, I'm for all bat research. I don't hate on any of it. But it is becoming more and more prevalent. This month only, I think Nature had like two or three bat articles, just Nature, which is exciting for me because I'm hoping to submit one of my papers soon. So you would agree that bats are very successful, right? They're 20% of all mammals. That's pretty successful. But rodents are even more successful, right?

1:20:17They are. Nobody studies rodents. Or very few people study rodents. I mean, or everybody studies rodents, I dare say, because mice- Everybody. We do study rodents more than you would expect because we study mice. I mean, our mice and rats, people use mice and rats. And ferrets, ferrets aren't rodents. Ferrets aren't rodents, yeah. Those are their own things. These bats are wild bats. Of course. Mice that are studied mostly are lab mice and they are not. So I would be interested to know- Of course. You know, I guess mice don't live particularly long, right?

1:20:51No. Compared to other things, right? So there's nothing interesting there. Well, and people study rats and mice a lot, but how many other rodents do they study? Yeah, there are lots of others. You know, 60% of all mammals and we look at two species and- It's true. It's true. Yeah. Okay. Anyway, that's a cool paper. Did you like it? Very, very, very cool paper. It was very cool. Both papers, actually, I enjoyed today a lot.

Emails on Anthony Fauci and AI

1:21:19Okay. Let me do a couple of emails.

1:21:23All right. Let me take the first one. It's a short one. Vicky writes, I'm a huge fan of all things microbe TV. I've been listening to since, was it December 2019 when Vincent said there's a pneumonia in China that could be a problem? It was actually December. Yeah, it was December. Or maybe January. I don't remember. 2020. What's going on with the idea that Tony Fauci should be sued? This just seems insane to me. Sincerely, Vicky. Thank you, Vicky. No one has brought this up.

1:21:55It is insane. He's being persecuted by the Republicans for purely political purposes. And I'm sure Alan will weigh in. But my view of this is, Tony Fauci has spent his life working for people in public health. He's only done good things. And during the pandemic, he, like others, made some mistakes. And so now people want to vilify him for that. And particularly Rand Paul is pissed at him because Tony Fauci told Rand Paul at a hearing some time ago that Rand Paul didn't know what he was talking about.

1:22:27And now Rand Paul wants to get back at him. And so he had that hearing recently where he took the fifth over and over because Fauci was pardoned by Joe Biden. But the pardon only works up until the time of the pardon. Anything you do after that, you can be prosecuted by. They want to trip him up on telling a lie or something because they want to get him. But there's no reason that anyone should go after Tony Fauci. Any other thoughts? Tony Fauci is a national treasure. And, I mean, he spoke the truth during the pandemic to the best that he knew it and did way more than his job.

1:23:07The director of NIAID was never, ever supposed to be thrust into the public spotlight as the, you know, voice of reason in a pandemic. That's supposed to be the CDC director and the Surgeon General. Unfortunately, those two were, I'm just not on the job at that time. And, you know, the problem was by speaking the truth at that time during the end of the Trump, of the first Trump administration, that made Trump look like an idiot.

1:23:39And so Republicans who were on the MAGA side all want Tony Fauci tarred and feathered because he made Trump look like an idiot, which, you know, is just, you made the leaves look green. You know, it just, yeah. Alan, could you take the next one? Sure. Torsten writes, Hi all. Brianne's concerning pick, the generative AI learning penalty, evidence from Chinese secondary education in TWIF 1355, which supports fears of declining ability when learning too much on, leaning too much on AI, made me think of this article, which looks like it has some good answers.

1:24:20Articles titled, I'm a father of three who studies the impact of artificial intelligence. This is what parents need to know about AI. And in particular, teach both, test both, the author, Daniel Susskind, conveys, paraphrased by ChatGPT, or I'll be all day, and I'm going to paraphrase this because I'm not going to quote ChatGPT on the show, that this draws a parallel to the electronic calculator in the 1970s, and everybody thought at that time that kids would never be able to understand math if they relied on the calculator.

1:24:53And so what was ultimately concluded was we should teach kids how to do basic arithmetic without a calculator, and we should also teach them how to use calculators to do math, because there's a lot that you can teach when they're not going into the nitty gritty of long division. You can move on to more advanced concepts. So that's the teach both, test both approach. And ends up advocating doing the same thing with AI, teaching with the phones disconnected and then with them reconnected.

1:25:29A letter concludes, Daniel Susskind writes it in more detail and also links to the Cockcroft report. He also has other interesting suggestions. Thank you, Torsten. Well, in my class, we have exams in class, so they can't use AI to answer the questions. They can use it for other things, but they're not graded on it, so they still have to learn. But I understand that kids get assignments, they take them home, and they can do them with AI. Which is why teachers have to adapt, well, they have to adapt their teaching strategies, right?

1:26:00Which do things in class as opposed to giving them homework to take home, things that aren't crucial or very necessary for, you know, like extra accessory work. But, yeah, in class instead of— I remember getting math problems to take home, right? So now you could just give it to AI, right? And they'd do it for you. Yeah, you'll have to do those in class. You have to. You're not going to learn if you do that. You've got to do it yourself, right? Yeah. Yeah.

1:26:30Well, I'm glad I'm mature and learned already. Yeah, there's nothing left to learn at your age. There's a lot left, but, well, the basic stuff, well, listen, even without AI, I was never good at math.

Immune responses to COVID vaccines

1:26:47Angela, can you take the next one, Charles? Charles writes, Hello, Twivers. It is 72F, 22C, and a very pleasant evening in Chapel Hill. A welcome break after a string of hot days. Today I received the updated Moderna mRNA COVID vaccines, and it raised a question about the timing of the immune response. As I understand it, when the immune response meets an antigen for the first time, it generally takes about two weeks to mount a strong enough response to at least reduce the severity of disease. I also understand that the updated vaccine spike protein shares many epitopes with earlier formulations while presenting some new ones.

1:27:23My hypothesis is that the shared epitopes will trigger a rapid recall response of existing memory B and T cells within days, while the novel epitopes will follow something closer to the standard two-week primary timeline. Is that a fair picture? I also wonder whether immune imprinting complicates it. Imprinting might favor memory B cells that cross-react with the new variant over naive B cells that recognize its new epitopes. Alternatively, memory B cells might re-enter germinal centers and adapt to the new epitopes over time.

1:27:54As I write this, I am listening to an album I had not pulled from my vinyl collection for a very long time. Buffalo Springfield's self-titled compilation released on ATCO Records in 1973. Thank you for the education and the entertainment, P.L. Charles Fisher. Freedom from responsibility is not liberty, it is childhood.

1:28:16Cute.

1:28:18So as the immunologist, Angela, what do you think? I was going to say, I don't know a lot about B cells, so I'm not even going to try to answer the B cell question. But for sure, so the way they describe, yes, when you get the vaccine, your cells will start making spike protein. That spike protein will be presented to T cells. T cells will then, if they're naive, then they will activate against that spike protein, and then some of them will become memory cells. They will live long in your tissue.

1:28:48Same thing with B cells. They'll also live long in your tissue. The difference is that B cells will make lots of antibodies against that epitope, so whatever the epitope is. So if you're getting a new vaccine that has different epitopes, then you will also have different B cells responding that will also now make antibodies against those specific epitopes. And you'll also have more T cells responding, because if the epitope is distinct, you'll have a huge T cell pool of naive T cells that will make new T cells. So naive will become activated, and then they will also become memory cells.

1:29:20So the germinal center part, I'm not going to address, because that I don't actually know. Memory B cells normally don't reenter germinal centers, as far as I know, to adapt to the new epitope. I don't know what they mean by that, but germinal centers are normally naive B cells that are then activating, and then they're proliferating. But I'm not a B cell biologist, so I'm not going to pretend to know. So when you have somatic hypermutation, do memory cells come into the germinal center to do that, or those are just primary B cells?

1:29:54So with B cells, I don't actually know if B cells, memory B cells are in germinal centers, I'm not going to lie. We talk so much about T cells, I should know more about B cells. Cindy would know. All right, we'll leave this for Brianne. I'm going to keep this in here, and Brianne will answer, because I don't know the answer. And I will note, my understanding of particularly the COVID-19 vaccine is that the T cell response tends to be against much more conserved epitopes, which are probably not changed between the new and old vaccines.

1:30:27And so your T cell response is going to be most likely the same thing as before, and the B cell response would be the primary difference.

1:30:36Yeah. Buffalo Springfield, very interesting group. You know, that was Stephen Stills and Neil Young. Yep. Okay. And it was really... Before my time, but I actually knew that. Good group, but they couldn't get along. They had different musical styles, so eventually Neil Young, the band broke up, and then Stephen Stills formed Crosby, Stills, and Nash, which was a huge hit.

1:31:07But they didn't have a lead guitarist to go on tour, so they took back Neil Young and made Crosby, Stills, and Nash, and Young. Which sounds more like a law firm than a rock group. Yeah, it does. So the problem was that Stephen Stills and David Crosby and Graham Nash had very different musical styles from Neil Young. They were precise, right on the beat, extremely perfect tone and everything, and Neil Young was the complete opposite.

1:31:39If you ever listened to Neil Young with Crazy Horse, the tone, they're off-key sometimes. They are dragging the pace on purpose to make it really a heavy sound, and that's why Neil Young left, and he said, I can't handle this CSN anyway. So it's a very interesting story. Thank you, Charles, for that. So you could say something was happening there, but what it was wasn't exactly clear. That was their big hit. Yes. Something happened in here, yes. You got that bing, bing in the beginning, and you know the song.

1:32:10Bing, bing, bing. Oh, very cool.

Global nitrogen cycle and agriculture

1:32:12That was Neil Young plucking his, I think, Les Gibson 1958 guitar. I shouldn't know all this. I should know science more. Well, you are a boomer. This is your music, so that's fine. My music, that's right. I know both. Yeah, I like both. Greg writes, I will understand if you decline to read this letter because it's mostly a response to a letter you read on TWIV 1357. That was a response to my letter on TWIV 1355 about aspects of the global nitrogen cycle.

1:32:45I think this is perfect to have this dueling letters. I have since exchanged emails with the letter writer, Dr. Weaver, but if any TWIVers are interested in my response to his comments, about my comments, please read on. So this was all started by, I think I picked a paper on the discovery of the nitroplast, this nitrogen-fixing organelle. It's discovered for the first time in a eukaryote. All the other nitrogen-fixation biologically is by bacteria and by human processes.

1:33:21And I made the comment that half of our nitrogen in us was made by the Haber-Bosch process, which goes to make fertilizer, and that's when the letters started coming. Okay, photovoltaic-powered production of nitrogen fertilizer, highlighted by Dr. Weaver, so he suggested using solar power instead of the Haber-Bosch, which is high heat and pressure, would likely be vastly better than nitrogen fertilizer produced with fossil fuels by Haber-Bosch.

1:33:52But comparing the energy needed for breaking the nitrogen bonds in an industrial facility to biological nitrogen fixation occurring adjacent to or in the crop roots is an incomplete energy analysis. This comparison does not count the energy required to obtain raw materials for ammonia manufacture or to transport the nitrogen fertilizer from the production facility to the farm fields or the inefficiencies of transferring the nitrogen fertilizer into the corn and wheat, which results in nitrogen contamination of surface and groundwaters and production of greenhouse gas.

1:34:27Biological nitrogen fixation associated with legumes occurs near or in the crop root nodules, so there are fewer losses to the environment and there is no transportation cost. A full life cycle study is probably needed to sort out trade-offs between PV ammonia,

1:34:47photovoltaic ammonia, and legume-produced nitrogen or livestock feed. But the point of my letter was to call attention to a larger gain in efficiency that can occur when we reduce dependence on grain-fed livestock. While it is generally true, as Dr. Weaver noted, that nearly all the world's arable land is currently in crop production, much of that land is used to grow feed grains for livestock. Much of the nitrogen fed to livestock is excreted, lost to surface and groundwater,

1:35:20volatilized as ammonia, and converted to N2O. What is that, nitric oxide? Nitrous oxide. Nitrous oxide. Human consumption of plant-based proteins avoids all these inefficiencies and much of the environmental loss. Crop varieties for human consumption typically have lower yields than feed grain varieties, so shifting away from grain-fed livestock to plant-based diets would require more cropland for human food, but this increase would be more than offset by a reduced need to grow feed grains for livestock.

1:35:55Poor and Namacek 2018 estimated that an unlikely global shift to vegan diets would result in a 19% reduction in the need for arable cropland and an abandonment of all pasture land. I don't advocate for everyone to adopt a vegan diet. Pastures and grazing lands can produce nutrient-dense food and protein for human consumption by relying on biological nitrogen fixation in legumes in the pasture vegetation rather than fertilizer nitrogen from the Haber-Bosch process.

1:36:27Many grazing lands and pastures are not suitable for cultivation, and in such setting, pasture-raised livestock does not utilize land that could otherwise be used for producing human food crops. Human dependence on Haber-Bosch-derived nitrogen currently involves large inefficiencies in the feed grain-to-animal-to-human system that can be reduced when people shift their diets to consume more plant-based protein and or more pasture-raised animal products and less feed grain-produced animal protein.

1:36:58I suspect that Dixon-Depaumier's criticisms of the current U.S. agricultural system revolved around the overemphasis on livestock-raised feed grains and the associated inefficiencies. Thank you for all you do to inform the public on virology and other topics. And Gregory is an Associate Professor Emeritus at the University of Illinois, Urbana-Champaign. I understood that, Gregory. Thank you. I did slightly, 50%.

1:37:29I have to reread. But you know, you're not going to change, in a major way, the diets of people. First of all, many low-income countries highly depend on protein, right? And they're not going to switch to other things. And some of the most populous countries in the world are big consumers of animal-based protein. Although that has shifted with economic development.

1:38:02In fact, meat consumption goes up with economic development. That's not an argument against economic development because public health also improves and a lot of other things improve. But if we could kind of decouple some of that and get people to continue with maybe some of the traditional diets that are, yeah, there's some meat, but it's not hamburgers three times a day. It's, you know, you have some meat and you have a whole curry to go with it.

1:38:29That would be an improvement. And of course, you know, if we had fewer people, that would be a major improvement.

1:38:38Well, that's going to happen naturally. Well, one way or another, there will be fewer. Earth rates are low and have been low for a while. So our population in the world has peaked for sure and will start declining significantly over the next 50 years. The population of China is predicted to go down to 600 million. Down to. Yeah. And some countries have negative birth rates already, which is good. Which a lot of people are wringing their hands about. And I'm thinking, well, that's moving the right direction as far as I'm concerned.

1:39:09I think it's fine. Yeah, I mean, the Earth cannot sustain much more than 8 billion people. And to be clear, there are going to be major societal issues that come up with that because we've built our entire modern world around a presumption of endless growth. But that we know is not sustainable. And if we are now having fewer people born, then that's great. And we can figure out how to adapt to that instead of, you know, just out reproducing the planet.

1:39:42Anyway, thanks for that, Greg. We appreciate it. And that's an interesting series of letters.

Picks of the week

1:39:48Let's do some picks of the week. Oh, Angela, what do you have for us today? This is a great pick, Angela. So, I mean, obviously, because of my veterinary background, I love animals. And birds, my pick is just birds. So I feel like a lot of people, birds are underappreciated by a lot of people of how interesting they are and how many very cool things they have about them, their physiology, their anatomy, their immune system. So I wanted to just highlight some very cool things about birds.

1:40:18First of all, they're dinosaurs. So technically, the clade that they are nested in is within the theropod dinosaurs. So we are literally living amongst dinosaurs. And they also, some like fun anatomical facts, they don't have a diaphragm. So they don't have like a thorax and an abdomen. They have something called the saloma. And it's this big cavity. They also have air sacs, which a lot of people don't know. It's very cool. So they have a pneumatized skeleton. So their bones aren't hollow, as a lot of people think.

1:40:50They actually just have like big pockets of air. And they have these air sacs that are within their long bones that if a bird actually breaks a bone, it can get a pneumothorax. So it can actually have problems breathing because that directly connects to its lungs. They can also have like pathogens, can grow within their air sacs, and they can have lots of different problems. But air sacs are very cool. It obviously, having a light pneumatized skeleton gives them lift to be able to fly. Um, they can also see in UV, which is very, very cool. So how we see birds is not how they see each other.

1:41:22People think pigeons just look very plain. No, pigeons to other pigeons look way cooler than we can see. Um, and then also what's really cool is that talking about intensive farming, um, a lot of people think if you were to want to have a fertilized hen every day, let's say you wanted to have eggs that were fertilized, uh, you wouldn't need to have the rooster with the hen every day because the female hens oviduct. So similar to the, like when a woman has like an ovary with like a fallopian tube and then

1:41:53a uterus, well, they have oviducts. And if you inseminate one of the hens, they will, they have this little receptacle in, it is called the, um, sperm storage tubules where the sperm can actually live for a month and inseminate. So, so sorry, fertilize an egg every single day for an entire month, which I think is so evolutionarily cool that they only need to see the male once a month and they can have fertilized eggs, chicks every single day. They can, they can lay an egg that will become a chick.

1:42:25Uh, and there's like a special pH inside of this, these little tubules that's distinct to be able to sustain the sperm there. And then as for their immune systems, they're also really cool. So they have nucleated red blood cells. They never use, lose their nucleus, their red blood cells, like we in mammals do. So our red blood cells are enucleated, but birds always have nuclei in their red blood cells. They also have these cells that are kind of like most similar to a neutrophil. They're called heterophils, but they're kind of a mix between a neutrophil and an eosinophil.

1:42:56And they're extremely divergent among different birds. It's like when you look at different bird species, all of their immune cells look so different, even between species. So kind of like bats where bird is not equal to bird. So, um, and they don't have lymph nodes necessarily. They do have the bursa fabricius, which is where B cells actually come from, which is also very cool. And my last point is actually a paper that came out in science a few months ago, two months ago, I did a journal club last week on it, uh, by Lissowski and all.

1:43:29And there they show that pigeons have super peragnetic macrophages in their liver, where they basically clodernate, deplete these pigeons. So they give them clodernate. So the macrophages take up these liposomes, they die. And they see that on cloudy days, the pigeons can't home properly to where they need to go. So on sunny days, they can get there without these macrophages, which is also crazy. We still don't understand how pigeons and birds know where to go because this is a 19 kilometer distance they have to fly.

1:44:00And if it's sunny without the macrophages, they can get there. But if it's cloudy and they don't have these macrophages, they can't get there, which is this paper is wild. So people should go check it out. If you write super peragnetic macrophages pigeon, you'll find it. It's a science paper. So all's to say, birds are really cool. Yes. You picked pigeons. I picked pigeons last time because pigeons are cool too. They're a bird. No, I saw that paper when it came out in science. I didn't read the whole thing, but I was like, oh my gosh, they found the compass.

1:44:31They finally found the pigeon compass. Because that's been a mystery since probably the dawn of human history is how do pigeons find their way home, right? But we don't know still. So they didn't go into the mechanism as to, they showed that there were like nerve bundles in the liver around where these macrophages are, but it's still, think about that. Wait, how does a macrophage tell the brain which direction to go in? That they still don't know. So there's still huge research gaps. And why in the liver?

1:45:01Why would this? They also have them in the spleen. So it's not only in the liver, they also have them in the spleen and they did clodronate full body. So they didn't rule out that it couldn't be a different population. There were just more of them in the liver. So they thought that they were the most interesting population, but they have them in the spleen too. So who knows? And they have like some magnetite on their beak. There's this whole other thing about like beaks that have magnetite that they think is involved with magnetoreception. Birds are crazy.

1:45:31Yeah.

1:45:33And I actually came to the conclusion a number of years ago, I, I grew up, you know, in my grandmother had a house in the woods and they always had bird feeders around and there were so many different kinds of birds. And as a kid, it was like, yeah, birds, just like, I don't know what those are. Um, and then as an adult, I now live in a house that's in the woods and we put out a bird feeder. Oh my gosh, birds are so cool. So I think there's a maturity aspect. You reach a certain age and you suddenly realize, oh wow, you can really appreciate that.

1:46:05That's true. Well, and there's about this whole migration thing. One last point. The bar-tailed godwit is a bird that can fly over 13,000 kilometers. This has been recorded. So it goes from Alaska to New Zealand without stopping. So this bird is not stopping. They showed that it did not stop for 13,000 kilometers. I think it took like 11 days or something like that. But imagine the, the physiological adaptations that these birds have that we don't fully understand to be able to do something like that.

1:46:36And how does it know to get from Alaska? Because a lot of people try to say that they use landmarks and that they're seeing where they're going, but in the middle of the ocean, there's nothing. So this is not, no. My gosh, don't they need to drink a water? They don't. And energy. They don't drink. Yeah, exactly. Well, they use, supposedly they do fat loading. They know that they fat load before they fly. I see. Up to 40% of their body weight. But the fact that they don't drink water is extremely impressive. And 13,000 kilometers, that's a long, I don't care how fat you get, that's a long way to

1:47:09go on one load. On one huge meal. They do a lot of soaring, I guess, right? They must. They must use air currents. But even so, like not stopping or drinking or eating anything for 11 days is a feat. Well, the good thing is they can poop on the fly, you know? Well, yes. But they're not even eating, so their digestive tract will be empty within like a few hours. No in-flight meals on that journey. Yeah. That's very cool. Okay. Thank you, Angela. Alan, what do you have for us?

1:47:39This is also somewhat animal-related, and I have visited this site before, and in fact, we bought three of these shirts and we bought others. So as people know, I volunteer, my family and I volunteer at the local animal shelter. Lately, we've been fostering kittens.

1:47:57And they have, seasonally, they come out with different t-shirts, you know, just as fundraiser and for the staff to wear and that kind of thing. And they really outdid themselves with the Halloween batch this year. So you can go there and order these Halloween-themed animal shirts that I think are just absolutely adorable. All three of us now have the one with the skeletal hand booping the nose of the black cat. That's very cute. Yeah.

1:48:28And there's a lot of other stuff you can get there. I like this one, Be Humane. This is great. Yes, Be Humane is one of their long-standing ones. I like it very much. And they have dog-themed stuff, too. You've got, you know, dogs in Halloween costumes. Not pictures of them, but little cartoons of dogs trick-or-treating. It's very cool. So cute. I just bought Be Humane. I got a black long-sleeved t-shirt. Excellent. So they don't actually charge, oh yeah, $29 and they want a donation.

1:48:59Okay, got it. That's cool. All right. My pick is a book by Jeff Hawkins called A Thousand Brains. I just finished reading it and I was having a conversation with Claude about AI and I said, can you recommend some books for me to understand where this came from? And this is one of the books that it recommended to me. So Jeff Hawkins actually was one of the co-founders of the Palm Pilot. You remember that? Yeah. Oh, wow. I haven't heard that.

1:49:30So he made a lot of money with that, but he always wanted to be a neuroscientist. So he started a bunch of neuroscience institutes. And this is partly the result of their research. They don't do wet experiments as far as I can tell, but it's all thinking and computer simulations. But this book is really good because the first part, he tells you about the brain.

1:49:56And the idea, first of all, there's an old brain and a new brain. So our neocortex is a relatively recent evolutionary invention. And our neocortex does all the great things that are humans. That humans do, right? All the creative stuff and the thinking and all of that. And the old brain, which has been there for a long time, is responsible for motor stuff, right? That's important. But it's also the crap like murder and deviousness and lying, all the bad things that people do.

1:50:27It's our old brain. And he talks about why that is because you needed that to survive. And he said, unfortunately, it's still with us, you know? So that's a very – and also this idea that the neocortex is made of columns of neurons. And each of those are a separate unit. And each column receives input from a different patch, a patch of your eye, from the olfactory, your skin, and so forth. And his idea is that the neocortex remembers frames of reference for everything.

1:50:58It's all the same. And really interesting theory. Then part two is about machine intelligence. And the first part is why there's no I in AI. Because he says none of this is intelligent. And he's right. He says it's not intelligent. It's just spitting things back at you. And he talks about this idea that AI is going to destroy humanity. And he puts a good argument for why this is pretty nonsensical. And I like that very much. And the last part is a little about human intelligence and, you know, where we're heading and so forth.

1:51:33He's got one part called estate planning for humanity. You know, he makes these interesting proposals about, you know, what if we mess up Earth? What are we going to do? And so anyway, it's really good. He's a PhD in neuroscience. And it's very refreshingly written. There's one point where it says people say that AI are going to destroy humanity. And he'll be like, I don't understand why people are saying that for this reason. And he goes through it all. So I liked it very much.

1:52:03And I wrote him yesterday to thank him. And he actually responded right away. So he's just a regular person. And I like this idea very much. So a thousand brains. I have to get it. Cool. I really like it.

1:52:20I can send you my copy. How's that? Oh, that's perfect. I mean, no, bring it to ASTMH. ASTMH. Yeah, okay. Bring it to ASTMH. You can give it to me in vivo. Give it to me in vivo. All right. That's TWIV 1363. You can find the show notes at microbe.tv slash TWIV. You can send us questions, comments, picks of the week to TWIV at microbe.tv. And if you enjoy these programs, we'd love your support. Microbe.tv slash contribute.

1:52:52Angela Mingarelli is at McGill University Immune Vet on Blue Sky. Thank you, Angela. Thank you so much. This was really fun.

1:53:02Alan Dove is at alandove.com, turbidplack.com. Thank you, Alan. Thank you. It's always a pleasure. I'm Vincent Racaniello. You can find me at microbe.tv. I'd like to thank the American Society for Virology and the American Society for Microbiology for their support of TWIV, Ronald Jenkins for their music, and Jolene Ramsey for the timestamps. You've been listening to This Week in Virology. Thanks for joining us. We'll be back next week. Another TWIV is viral.

1:53:32This Week in Virology