The Co-Evolution of Humans and Pathogens, Iowa City, Iowa, February 6, 2014

- [Sue Dulek] I want to acknowledge our university and community partners for today, University of Iowa Honors Program and the University of Iowa International Program. Both contribute vital time, talent and logistics to our organization. I also want to thank today's program sponsors, MidWestOne and DNA Technologies. Our work is made possible by the generous financial support of these sponsors. Our format today is what you always see here, includes introduction of the speaker, our speaker's remarks, followed by a question and answer period. You can write your questions on the cards at your table, they will be collected at the conclusion of Professor Kitchen's talk. Prior to introducing our speaker, I want to make note of a special opportunity arranged for and by the UI Honors Program, and our speaker today, Dr. Kitchen, will be offering an honors round table this evening for honors students at 6:00 p.m. at the south commons of the Blank Honors Center. The round table permits not only further discussion of today's remarks and questions and answers, but free pizza, so. And I am pleased to introduce Drew Kitchen, Professor Kitchen graduated from John Hopkins University in 2001, with a degree in biomedical engineering, after which he obtained a MS from the University of Oxford. He received an MS and PhD in anthropology from the University of Florida. Before joining the University of Iowa in 2012, Drew was a postdoc at the Center for Infectious Disease Dynamics at Penn State. His research interests are in human evolution and the evolution of pathogens, primarily viruses and bacteria, and the genetic study of ancient human migrations, generally, and the peopling of the Americas specifically. Please join me in welcoming Dr. Kitchen. - [Drew Kitchen] Thank you for that generous introduction, and thank you for inviting me to speak. This is a great opportunity, and I thank you for extending it. You'll have to excuse me, I'm currently suffering from an infection, which is quite ironic. It's always ironic when someone who studies infectious disease himself becomes sick. We take great pleasure in this irony as well. So I will be talking about some of my work on looking at the co-evolution of humans and their pathogens. I know this is a forum that's interested in international issues, and I hesitate to, I guess I should say, I apologize for not including the international impact of infectious disease in my title, though we will get to it. Alright, so co-evolution of humans and their pathogens. This brings together my two main research interests, alright, evolution of infectious disease and human population history. Infectious disease has played a critical and central role in human population history. Everything from the fall of the Roman Empire, facilitated possibly by Justinian's Plague, to the reorganization of European economies after the Black Death, to our susceptibility to HIV infection, mediated by an ancient pathogen closely related to endogenous retrovirus, which is a virus that has inserted itself into the genome, into a genome that infected chimpanzees millions of years ago. Alright, so infectious disease has been with us and played a critical and central role in human history and evolution throughout time. Now, the first thing we have to understand about infectious disease is that pathogens are a fact of life. Pathogens are organisms that cause disease in their hosts, alright, so you can have bacteria that are non-pathogenic, everyone carries bacteria. They help us metabolize food that we eat, for example, so everyone has bacteria in their gastrointestinal tract, we have bacteria that live on the surface of our bodies, but they aren't pathogenic until they actually cause disease. Now, pathogens are ubiquitous. Parasites and bacteria, I mean, sorry, viruses and bacteria are the most abundant life forms on Earth. That extends throughout the globe, so all of us, for example, carry more bacteria, we have more bacterial cells in our bodies than we have human cells. And each of those bacteria harbor viruses, so there are even more viruses than there are human cells, by orders of magnitude. So most of the DNA in life, most of the DNA in the world is actually viral DNA, and then bacterial DNA, and then organisms. So pathogens are everywhere. And by pathogens I'm talking about viruses and bacteria. Secondly, virus and bacteria have incredibly short generation times. Generation times for viruses can be on the order of minutes, all the way to the order of days, same for bacteria. If you think of humans, human generation times, we typically use somewhere around 25-30 years. Now, there's a researcher at Michigan State, Richard Lenski, who has been looking at bacterial evolution in a lab, and he has over 30,000, I believe now 40,000 bacterial generations sampled. So he accumulates mutations in these lines and freezes these bacteria. Now, 40,000 generations in human history would be on the order of a million years. Which means that bacteria, the population changing allows natural selection to work very, very efficiently and on short orders of time. Much faster than human evolution. Thirdly, genome structures, basic function of genome structures, differences in virus and bacteria, mean that viruses accumulate diversity rapidly. So they accumulate diversity per generation much quicker than organisms with double-stranded DNA genomes, which is what we have. Viruses can have RNA genomes, and viruses with RNA genomes mutate at a roughly one mutation per genome per replication. Things with double-stranded DNA genomes typically, roughly one mutation every thousand generations. Every 1,300 generations. So not only are you generating more diversity per generation, you have shorter generations. So these populations generate lots of diversity over short periods of time, and they also have large population sizes, which allows them to adapt to other environments. And so pathogens are everywhere. They generate immense amounts of diversity, and they quickly adapt to their hosts. And they quickly adapt to new hosts, because they generate so much diversity over short periods of time, that they can eventually jump hosts. So one feature of viruses that we see a lot is host-jumping. So in context of human evolution, we have to understand that pathogens have always been with us. Ever since we had a common ancestor with single-celled organisms, that common ancestor probably had a virus infecting it. And so this is just a fact of life, for all global populations, whether they're human or other animal or plant. So that's the context in which we have to understand evolution of humans, in terms of the influence of pathogens on evolution. Now, humans have obviously evolved in response to pathogens. And there are ways we can look at the human response by looking at human genetics. We can look at signatures of selection in human genes in response to pathogens. So if you look at the global distribution of malarial, anti-malarial alleles, this is G6PD, which is glucose-six-phosphate dehydrogenase, and if you're deficient in it, you have anti-malarial, you have malaria resistance. However, this is off-set by having other associated diseases like anemia. And so, you wouldn't naturally have this, this would negatively selected for it, except in the presence of malaria. So if we look at places where there's endemic malaria, we see G6PD deficiency. So that's one strong signal of co-evolution of human populations with their pathogens. We can also look at what's called paleovirology. Now paleovirology sounds kind of interesting, we like to use funny figures for it. What it is is that viruses insert themselves, some viruses can insert themselves into your genome, so they become fossils at this point. And so we can look back and look for these remnants of these viruses in your genome and say "Ha ha, at some point in your history "as a species, or the populations, "you were infected by this type of virus." And so we can directly test, as opposed to the indirect tests of looking at alleles, resistance alleles to distributions, we can directly test and show that you were actually infected by this virus. And so we have things like human endogenous retroviruses that move, that are in all of our genomes here, and are moving around, currently moving around through our genomes. So this is indicative of an ancient retroviral infection in our species. We can also look at human genetics and see reductions in diversity that are caused by epidemics that decrease population sizes. And so we can think of things like Native American populations that were decimated after the, well, went through a post-Columbian collapse because Native American populations didn't have adaptive resistance, they didn't have herd immunity to infectious agents that were brought over by European colonists. We can posit that this reduction of population size, which is thought to be anywhere from two thirds to 90 percent, would reduce genetic diversity in its populations. And so we can look and see signatures of this. Now, one of the interesting things of this is that we can identify genes that are causing disease now, or are causing other phenotypic changes, that are the effect of past infections. So all current populations are living in the shadow of past infections that infected ancestors of these populations. For example, there's a deletion of 32 base pairs in the chemokine receptor five... sorry, chemokine receptor five gene, that's wide-spread in Europe, it's about ten percent frequency in Europe. Now, this probably arose in response to a past infection, infectious agent that used this receptor as a way of getting into the host cell. So it's posited that it may have been smallpox infection, that was endemic in Europe for thousands of years, perhaps, or it may have been bacterial infection like you're seeing in pestis. Now, why is this important now? Well, it's important because HIV uses the same receptor, and if your homozygous recessive, meaning you don't have this receptor, you don't have a working version of this receptor, then you are immune to HIV infection. So one percent of Europeans are homozygous recessive to this. So we're living in the past, living in the shadows of these past infections. So this allele is not a high frequency in any other populations, because it arose in Europe in the context of these epidemic diseases in the past. Now, pathogens also evolve in response to humans, right? Differences in humans, you know, our immune system adapts, then they have to adapt in response, human populations' ecologies change, we start living in larger groups, or we move between continents, or we start using antibiotics, and the pathogen populations evolve in response to that. And there's two ways that we generally look at this kind of response. One way is, we do lots of ecological modeling and we look at the epidemic profiles of infections like measles, for example, and through our mathematic models we can say, a population, to sustain an endemic level of infection, meaning that the infection goes through the population, and then it keeps cycling and stays around infecting new hosts, the population needs to be somewhere around 200 to 500,000 individuals. So if you want to know when measles entered human populations, we can look backwards in time and use archeological data or historical data and figure out when human populations in certain regions reached 200 to 500,000 and we can start looking for measles then. The descriptions of disease that looks like measles. So we can start thinking about that, looking backwards in time using the ecological, known ecological profiles of disease, or we can look at the genetic evidence of these infectious agents, we can actually go out and look at their genomes, and look at the relationships between genomes of infectious agents, sample different places and different times, and then construct genealogies of how they're related to each other, and then figure out using molecular clocks when they arose, when they moved from one region to another. And so one of the coolest things about this is that we're actually looking at an infectious agent itself. A good example of this is that, if you look at lice, human lice are just one form of general sucking lice that infect other primates. And the relationships of those lice to each other are the same as the relationships between humans and other primates. So human head lice are most closely related to chimpanzee lice, which are most closely related to gorilla lice, right, in the same way that humans are most closely related to chimpanzees, which are most closely related to gorillas. This is another evidence of the fact that we're living in this kind of shadow of these past infections. So we inherit a lot of our infectious disease due to common ancestry. Lice are very interesting, you'll also note that there's one place where this tree, these two trees are the parasite and the host, don't match up. And that's human pubic lice. Humans got their pubic lice from gorillas a few million years ago, we have no idea how, it was probably because of some direct conflict. Lice typically have to eat every 24 hours or else they'll die, take a blood meal at 24 hours. So this had to be over a short period of time, possibly because our human ancestors were hunting gorillas, perhaps. That's just a hypothesis, but it is well established that human pubic lice are gorilla lice. Now, human pathogen load has changed over time. This is one of the most interesting things to me, and what most of my research focuses on, are some of these historical shifts in human pathogen load. What do I mean by pathogen load? I mean the diversity of pathogens that infect a species or a population. So anything from how many nematode infections there are to how many viruses are infecting you to how many bacteria. For the longest period of our evolution, humans were just another large-bodied mammal. Our pathogen load was similar to any other large-bodied mammal with the same social structures. Human populations were diffuse and small until we started getting things like agriculture. So things changed at agriculture. Jared Diamond has called agriculture the worst invention in human history because of this. Once you start getting agriculture, you're getting groups of people living together in larger groups, and they're living closer to animals. And so these larger groups then can sustain infections that would normally die out in small populations, they can sustain them more. So things that are infectious over short periods of time, to which you get complete immunity, or long-term immunity, these things would cycle through a population very quickly if you had small, diffuse populations, if you had large populations, there's always more susceptible people in the population. You also get lots of contact with non-human animals, you have some domestication of large livestock, and that increases the number of contacts you have with them which increases over time the probability that there will be a host-jump from those animals. So agriculture changes things. Urbanization takes the changes in agriculture and pushes them up a level. So you start getting central hubs, population densities increase, along with population density increasing, contact networks increase, the number of contact you have with other people increases, in larger populations you have people moving from central population to peripheral populations, you start getting interconnected webs. So you have more and more people connected. And so infections that are acute, short periods of time, when you're shedding virus, for example, these start entering populations and becoming endemic. So we started getting things like measles in this period. You also become sedentary. One of the side-effects of agriculture and urbanization is that you're shedding pathogens in your environment. You start getting things like contaminated water supplies. So you're shedding your environment and then you're staying in that environment, so whatever you shed there, I get tomorrow, because I'm in the same environment. Whereas if you're hunter-gatherer, you're moving around. Colonialism, large-scale movements of people around the globe changes things dramatically, because geography played a huge role in the distribution of pathogens. Population structure in humans meant that pathogens weren't jumping from one region to another as quickly, because humans weren't moving as far. So you get distinct distributions of things like Dengue Virus, where there's four different types, and they were distributed throughout equatorial regions. Once you start moving people between continents, you start moving viruses between continents, and bacteria between continents. So you have populations that were previously naive to these infections having these infections introduced, and then having dramatic epidemics in these populations. And now, we live in this globalized world in which infections jump between continents rapidly. We can look at global air traffic travel and we can predict, you know, central foci of where infections are going to occur, and where they're going to pass through. You get things like SARS moving from East Asia to Toronto within a couple days or weeks, you get things like H1N1, swine flu, moving through entire populations and around the globe rapidly. This wouldn't have happened prior to this modern, globalized age. Now, what are some examples of this? Like I said, this is my, these are my particularly focuses of research, are how have these events patterned genetic diversity in these pathogens, and what events in human history have caused epidemics, how have human behaviors changed that has allowed epidemics to occur, and what role do these epidemics then have in human evolution? Now, this is a field that people, prior to the 2000s, was very limited. Because we haven't had the availibility of genetic data that we do now, we get full genome sequences regularly, we have studies of thousands of viral genomes, whereas prior to the early 2000s, studies would be of individual genes, perhaps, of only dozens of individuals, now we can collect worldwide samples. We can do things like construct a phylogeny, which is a gene tree with a time component of yellow fever virus, that relates yellow fever in Africa and the New World, and we can look at this and say, the first branch of yellow fever is in East Africa, and the next branch of yellow fever comes out in West Africa and then we have eastern South America, and then western South America. And we can say that this happened, excuse me, roughly 500 years ago. So yellow fever was brought to the New World via the slave trade with Africa. We can see there exactly a human event that has correlated with the evolution of the pathogen, that has affected the pathogen diversity, and now we have an endemic yellow fever that's been, epidemic that's been in the New World for hundreds of years and is currently now spreading. Now this isn't my work, but this is something I find kind of classic in the field. So we're trying to reproduce this and look at what events in human history have patterned genetic diversity in different pathogens like this. One of the things I have worked on is microbacteria in tuberculosis, the cause invasion of tuberculosis infections. Now, what we did was we look at 48 globally-distributed genomes, genomes fromto the samples of tuberculosis, tuberculosis genomes, just a few million bases pairs, so it's roughly one thousandths the size of human genome, and we were able to, using two historical calibration points or periods in the history of tuberculosis infection, we were able to calibrate the rate of evolution of tuberculosis. One of these is that French Canadian fur traders introduced tuberculosis to Native American populations in Canada. So this is an after-effect of this colonization, this change in distribution. Prior to that, Native Americans wouldn't have had tuberculosis. Alright, we also had a laboratory strain, and what we found was really, really interesting, is that we found a global phylogeny of tuberculosis, and these are all the red, or European, tuberculosis. Native American tuberculosis clusters within this group, and the most interesting thing is that the tuberculosis strains that we have today are only about 2,000 years old. Most previous estimates, people thought tuberculosis was much, much older. We also found that tuberculosis infections spiked at the same time as human populations spiked. So roughly about the 18th century, 18th, 19th century, human population growth curves changed, became inflected, so we had this rapid period of growth. We saw the same thing in tuberculosis, to the point where now roughly one to two billion people on Earth are infected with tuberculosis, though most don't show disease, they're affected asymptomatically. And that's consistent with this population growth. So tuberculosis itself is expanding at the same rate because human populations are expanding at the same time. Now of course, tuberculosis is becoming multi-drug resistant in response to the wide-spread use of antibiotics to treat tuberculosis infections. So this is a nice story of co-evolution of human populations and their pathogens. Now, tuberculosis isn't the only wide-spread pathogen that has played a huge role in human evolution. Smallpox has played, has been endemic throughout the world for a long period of time, until the 1970s, when it was eliminated. This is often called the greatest humanitarian event, or I should say, drive in human history, it saved potentially hundreds of millions or billions of lives. Prior to that, smallpox was endemic and was an incredibly high source of mortality. Smallpox has been with us for a long period of time, you can look at Ramses here, an Egyptian Pharaoh, and there see smallpox, what looks like smallpox, legions on their face, so we can assume that smallpox has been with us for thousands of years. Now, when we looked at smallpox, we found that the smallpox genomes that are available, that are publicly available, there are roughly 48 of them. The smallpox that we see today is very, very recent. How can we explain this? Well, one explanation is that smallpox was evolving under high-selection pressures, to evade human immune systems, or to evade vaccination campaigns that were that were undertaken during the sampling period. So smallpox is rapidly evolving, and these strains that we saw up until the 1970s were under selective pressures that allow them to replace previously-existing strains that weren't as competitive. How much evidence is there for this? Well, if we look at the closely-related virus called Myxoma virus, which some of you may have heard of, Myxoma virus was a virus used by Australian populations to control rabbits. Rabbits were introduced to Australia and completely devastated their environment, and so the Australians, in one case, one of the same individuals that was involved in eradicating smallpox, Frank Fenner, drove the introduction of Myxoma virus to Australia. Now, Myxoma virus, which is also orthopox virus, evolves just as rapidly as smallpox, so it does seem that perhaps the vaccination campaign, or perhaps just the very nature of smallpox infections, and positive selection in them, drove the rapid evolution of smallpox, just the same way as Myxoma virus was rapidly evolving to its rabbit host. Now, this story is also very interesting because just two years ago, scientists were able to pull smallpox from a epidemic grave, a grave that was, individuals were deposited during an epidemic in Yakutia which is in Siberia, 18th century. So over 200 years ago. Now, what's interesting about this, they were able to get smallpox DNA from this grave. So this is the oldest virus that I know of, that has had been sampled. It's certainly the oldest smallpox virus, which is variola virus is the virus name. What's interesting about this is that, if we look at our tree of pox viruses, smallpox, modern smallpox are all of these guys, right here, and they're closely related to each other. This ancient smallpox, this 18th century smallpox, lies outside of modern smallpox, which suggests that smallpox did actually evolve rapidly, and that smallpox is actively evolving in response to, perhaps, at least my hypothesis is, human vaccination campaigns. That's pretty exciting. The fact that we can see a virus that has a double-stranded DNA genome and is very large, which we think has a slow evolutionary, actually evolving in response to human population pressures. Now, if we change things up and we think about bacteria, bacteria have larger genomes, I posited at the beginning of the lecture that they may evolve slower because of some genome structures. So we wouldn't expect bacteria to evolve, perhaps, this rapidly in response to human behavioral changes, at least in terms of generating sequence diversity. But we do, actually, and so this is a phylogeny of, or gene tree of, global sample of the Shigella sonnei bacteria. Shigella sonnei bacteria cause dysentery, sever dysentery, and disease in human populations, and because you can't read this, I'll just describe this. The tree is, if blue is Europe and the rest of these colors here are South Asia and, for the most part, East Asia, and we have a timescale, and this is about 1950 right here, and this is 1700 here, so you can see that these samples all came out of Europe very, very recently, and spread around the world roughly in the last 50 years, post-World War II. And we actually do see an increase in Shigella sonnei infections in the developing world post-World War II, consistent with this. Now, why is this important? Well, first of all, it shows an epidemic that's moving from Europe to the rest of the world, and most people don't think of Europeans as moving infections, most people think of infections moving from equatorial regions into other populations, but this is a very, very interesting story, in that what happened, the hypothesis of what happened is that in all these developing countries post-World War II, or around the same time period, perhaps a little bit earlier than World War II, water supplies were centralized and cleaned. This is obviously a great advantage, eliminate pathogens in the water supply. What happened though, is that there was another naturally-occurring bacteria that had the same antigenic profile as Shigella sonnei. So essentially what it did-- but it did not cause severe disease. So essentially, individuals were getting infected with this and their immune systems were gaining immunity to this, and it was naturally vaccinating populations against Shigella sonnei. So once you cleaned the water supply, population immunity to Shigella sonnei was eliminated, and then you get the worldwide distribution of Europeans associated with development and World War II, and you get the introduction of Shigella sonnei from Europe, and then it was able to become an epidemic and gain a foothold in these populations. And so we now see bacteria evolving really, really rapidly in response to human behavioral changes, right? And we see this complication of aid and development having response in pathogen load, an unintended consequence of this. This story is even more interesting than I let on, because along with the spread, these black squares here are indicative of acquisition of drug-resistance in these strains, so not only did they spread around the world, but the strains that spread around the world quickly acquired drug resistance. Drug resistance is acquired very rapidly in bacterial populations because of widespread recombination and lateral gene transfer, horizontal gene transfer in bacteria. So they can pick up drug resistance rapidly from other bacteria, and a short generation times mean that selection works very, very rapidly, so that populations quickly adapt and become drug resistant. I do a lot of human genetic studies as well, so I'm going to shift things up a bit and talk about some of the studies I've looked at human diversity in response to virus infection. What I'm working on right now is this post-Columbian population crash in Native Americans. Quickly after Europeans explorers discovered the Americas, we start seeing and keep hearing accounts of population crashes in the New World. Populations crashed throughout the New World and we think it's because the introduction of measles, smallpox, tuberculosis from Europe into these populations, which never experienced these infections before, combined with the cataclysmic effect of Europeans actually disrupting social systems and urban environments, so that public health responses may not have been as effective as we would've thought of, thought of course we don't think of public health, nowadays we don't think of public health responses being effective in the past, there's some evidence that they would've. So the disruption of social networks and introduction of pathogens should've had, or we think had devastating consequences. However, we don't see genetic evidence of this, for the most part. Now, why do we think Native Americans would have been so adversely affected by these infectious agents? Well, it's because of the unique evolutionary history of Native Americans. Specifically, the fact that Native Americans descend from a small, diffuse population. These populations, remember when I was talking about the modern human evolutionary changes, agriculture, the adoption of agriculture organization, colonization and globalization, Native American populations would've been small and disperse for a large period of time, so they wouldn't have been able to contain these crowd infections, that we call, like measles, and things. They would've burned out locally. So these populations wouldn't have contained these infections when they came over to the New World. Another thing is that these populations existed before they came to the Americas at high latitudes. At high latitudes, biodiversity is low and this is true for all levels of diversity, so pathogen diversity would've been low as well. You'd have had fewer things that were fewer Arboviruses, for example, mosquitoes don't over winter very well at high latitudes, so you wouldn't have sustained transmission of these infections. So they would've been living in an environment that didn't have many natural pathogens. Thirdly, only after a long time do you actually start getting large accumulations of people into cities in the New World, so they would've only been recently, had this occurred, it wouldn't have occurred in Beringia before they entered the New World. And so they wouldn't have had the pathogens, it was only after they moved out of these regions that they had large populations. And so they would've lost their pathogens when they were still in Beringia. Now, when they did introduce agriculture, when agriculture was developed in the New World, population health did decrease, but that was probably for nutritional reasons, for the most part, not because of crowd diseases. Most of what we think are crowd diseases are diseases that probably came from our livestock and jumped into humans. Native Americans didn't have the same large, mammalian livestock that Europeans had. They didn't have large numbers of llamas, for example, they didn't have cattle and pigs. And so they wouldn't have had these diseases that probably jumped from them, they would've had nutritional deficits that are associated with agriculture. And so they would've been suffering from some of these nutritional deficits as well, when Europeans brought over their crowd diseases and introduced them to Native Americans. What this meant is that these populations didn't have any adaptive immunity. Human populations for example, I mean European populations for example, in which measles were endemic, had these infections as childhood infections. Most of the population had been infected and then recovered, and therefore were immune to it. So these infections were mostly childhood infections. These populations would've been completely susceptible. So everyone would've infected with these, and so the entire population at the same time would've been experiencing infection. So that's one major change. And so, when we look at nuclear genetics of Native Americans, we don't see much of a reduction. At least so far, we haven't seen a reduction in population size. So we can look at the relatedness of individuals and we can infer how many individuals were in the ancestry by taking two individuals, for example, and saying "How long, how far back do we have to go "to trace your ancestry?" If we have to go very far back to having a common ancestor, that means the population is probably large. If you go only a short time back, then your population is probably small. So we can use that same principle to look at human genetic diversity, and look back through time. And this plot, which is unpublished and just recently found with some undergraduate research fellows, we can see the Native American population, thousands of years ago, increasing because of the adoption of agriculture, and then massively plummeting. So this is relative population size and it's on a log scale, so this is about 10,000, this is 100,000. So populations were up, nearly a million, and then rapidly declined. And this is some of the first evidence for a post-Columbian decrease in population size in Native Americans due to infection. And so we have human populations responding to infection and evolving in certain ways, so these populations become very diffuse and population number decline very rapidly. And this is quite interesting, so this is just from Mesoamerica, where we think it would've been the most intense force of infection. You also have some of the largest populations in the New World as well. Now I'm going to shift to something slightly different, I promised that I would end on talking about human lice, which are always, everyone always lights up and smiles about this. Humans have, like I said, we have two different species of lice, we have pubic lice and head lice but we have two different kinds of head lice, alright? Head lice and then clothing lice. Clothing lice are just a different morphotype of head lice. They've evolved from head lice. Now, we can use these differences to look at a key feature that we think of as a modern human feature. And that's the origin of clothing. Now, why would we look to lice for seeing the origin of clothing? Well, because clothing doesn't persist for very long in the archeological record. Organic material decays rapidly. So we don't have much evidence for the material origins of clothing. So we have needles that go maybe 40,000 years ago, and then we have hide scrapers 700,000 years ago, and we can look at genes that are associated with skin color, so positive selection, roughly 1.2 million years ago, we can infer that humans lost their body hair 1.2 million years ago, and that by 700,000 years ago, humans were scraping hides for something. We don't know if it was for clothing, it may have been for shelter, but the material evidence for clothing is very scarce. And so we can think about looking at the origins of clothing lice and saying clothing lice couldn't have arose before the niche of clothing arose. And so we can look at this as an inferential way of looking at how human parasites have responded to this innovation in human behavior. When we do a human genetic analysis of this, a population genetic analysis of this, we see that this is the distribution of possible times in which clothing lice arose. It's quite large, and we're looking at, right now we're trying to revise this by looking at genome sequences of lice, so these are just from a few genes, but our best estimate is roughly 170,000 years ago. So long before the first reliable dates for needles, and long after the first dates for hide scraping. But well before humans left Africa. So humans were wearing clothing before they left Africa. Now, I'll see if anyone asks the question that I always get asked, so I won't give it away yet, I'll do this in the question period. And so this is quite interesting, that prior to expansion out of Africa, humans were wearing clothing. We've been kind of showing off our duds for the last 170,000 years. We can also look at human lice and see other events in human history. There's one really interesting event that's been all over the media in the last, or several events in the last four years. That is the introgression of archaic human DNA into modern humans. Alright, so the interbreeding of some modern human populations with Neanderthals, and interbreeding with modern humans in some Denisovan populations, and the possible interbreeding of other archaic humans with each other. What does this have to do with lice? We know that humans picked up pubic lice from gorillas, is it possible that humans may have picked up some of their other lice from other archaic hominids? We expect that each lineage of primates has, well at least each lineage of ape, has their own lice, so why wouldn't archaic humans have their own lice that are distinct from modern human lice? In fact, when we look at the distribution of diversity in modern human lice, we see that there's one clade that we call Type A, and that's found throughout the world, and then we see an expansion about 100,000 years ago. Now if you look at Type B, this is found mostly in Europe, in places that Europeans have colonized, and we find C in Africa and in Central Asia. One spot in the Himalayas. And these date back to the same relative ages that we see for divergences between lineages that led to modern humans and lineages that led to Neanderthals and other archaic humans. And so we can posit that all these diverse lineages of lice, did they all arise on population that's ancestral to modern humans? And so they're all modern human lice but they have old divergences? Or did they arise on different archaic humans and then jump over to modern humans when humans interacted with them? And in D, what we find when we do all this is that when we do a simulation study, we do find that this model here, where you have lice diverging in Asia on some putative, archaic human, and lice diverging in Europe on some putative, archaic human, we'd mostly think of Neanderthals, and this could be Denisovans for example, we see introgression, so this is the best explanation here, is archaic lice jumping to humans when humans were encountering them roughly, anywhere from 25 to 100,000 years ago. So shortly after out of Africa. So we're working on this right now, I'm writing this up, so this is quite interesting and clearly an example where lice, the parasites themselves can tell us about human history. The next step in my research is going to be looking at human microbiomes. Human microbiomes are the bacteria that exist, that are commensal, that live with you and help you metabolize food or displace potential pathogenic species. They change over time and change in response to human behaviors. So anytime you take antibiotics, you're killing off parts of your microbiome, any time your diet changes, your microbiome changes as well. And this happens on a day-to-day basis, we're finding out. Now one of the biggest events in human history, of course, is agriculture, when diets when from being very wide, lots of foodstuffs, to very narrow. And we expect that your microbiome would've changed. This event also, as I said before, is associated with decreases in human and community health. So we want to look at these ancient microbiomes by looking at ancient human fecal remains called Coprolites. We know that agriculture began in the American Southwest roughly 3,400 years ago, and this is a population curve, so we know Native American populations increased. And so we know all this happened, so we're hoping to go out and collect fecal remains. They're much easier to get than you would imagine, than skeletal remains, most museums are perfectly happy that you can go out and sample them. They're very abundant in the environment. And look at this. Not only are we going to look at the human fecal remains, we're interested in looking at dog and associated animal fecal remains, and seeing if there are pathogens that have been shared between these species. Here's just some examples of these fecal remains. They're all dried. So this isn't that rough. And with that, thank you for inviting me, I hope you enjoyed my talk, and I'm looking forward to your questions. - [Sue Dulek] First question here is: what made the Justinian Plague and the Black Death so particularly rapid and devastating? Was there something novel about those pathogens, or was it primarily facilitated by human practices? - [Drew Kitchen] That's a very good question. Right now, we have one genome from each of the plagues and the Black Death genome looks like modern plague, that we see that has re-occured in the 18th century and that is still actually segregating in, for example, rodent populations. So that was probably, you know, there's no genetic difference between those populations, so that was the human population living so densely in rat-infested areas where there were lots of fleas, and the fact that the plague quickly became Pneumonic Plague so it was spread by human contact, it was human mediated. Human to human contact. It was probably the same in the Justinian Plague, we know far less about Justinian's Plague than we do Black Death, just because the historical records aren't as full, and we still know where the Black Death cemeteries are much better than we know, for example, where Justinian mass graves would be. Good question. - [Sue Dulek] Here's a question that I thought I'd ask before I ask some of the others, and that is, the question is, what is a genome? - [Drew Kitchen] That's a good question, maybe I should've started off with that. The genome is a collection of genes that are packaged together and inherited, and so it's just a collection of all the genetic material. So human genome, we have 23 chromosomes with 23 different bits of it. We also have a mitochondrial genome, those are the genes that exist in the mitochondria, and that constitutes our entire genome. There's different genomes for, you know, genome structures change throughout organisms. All higher animals and plants have double-stranded DNA genomes, meaning they have two strands of DNA that are linked together via hydrogen bonds. Now viruses can have RNA genomes, RNA that exists in our cells is mostly messenger RNA or ribosomal RNA. Their genomes can actually be formed as RNA, they can have single-stranded or double-stranded RNA genomes, they can also have single-stranded DNA genomes as well. And their genomes can exist as one unit, so instead of ours having 23 pairs, they could have one unit just linear genomes that can be circular or they can have also segmented genomes, so the kind of chromosomes like we think of them. So does that help? - [Sue Dulek] Then there were two or three related questions, and I'll ask both of 'em and perhaps the answer's quite similar. Given the rapid evolution of viruses and bacteria, how is it possible for any antibiotic or antiviral drug to be effective, and how to insights about the evolution of pathogens affect the production of drugs used to treat them? - [Drew Kitchen] Those are great questions, and perhaps I'm, I'll give a pessimistic note, is that most antibiotics, for many class of antibiotics, there's naturally existing alleles in bacterial populations that provide resistance to these. So many antibiotics that are used individually will have, resistance in pathogen populations will increase. So bacterial pathogens will quickly acquire antibiotic resistance, either from mutations within populations, but for the most part, from getting alleles from other bacteria species that have resistance. One way to avoid resistance is to use a multi-drug approach. So we've seen this in HIV infections, where you use multiple different antiretrovirals at the same time. The probability then that any, the probability of drug resistance arising to all five drugs at the same time is therefore decreased, because if the drugs use different pathways, interrupt different pathways, then we have to have multiple different resistance alleles exist in the same pathogen, for example. So this delays the acquisition of drug resistance. So if you were to do something like prescribe multiple antibiotics to bacteria populations, if the bacteria population has some resistance to one antibiotic, it may not have resistance to others. But if we do this serially, we just use this antibiotic until it gains resistance, and then we use another antibiotic until it gains resistance then we're actually selecting from pathogens that have time to serially get resistance, acquire resistance. Now some resistance alleles have costs. Which means that if we stop using antibiotics, those bacteria that have the resistance alleles to those antibiotics will be out-competed by natural populations. So the natural populations will then lose resistance, because of the cost. The cost is no long out-weighed by the benefit of having resistance to the antibiotic, 'cause you're not using the antibiotic. So there's some hope that we can just take antibiotics off the market, stop using them. And this is the idea behind these, like, end of the line, last resort antibiotics. Physicians have lists where you typically don't choose this antibiotic first, because you want to hold it in reserve in case the other antibiotics don't work. - [Sue Dulek] The time has come to conclude today's program, and again on behalf of the Iowa City Formulations I want to thank Professor Kitchen for his talk today on the co-evolution of humans and pathogens. I also want to thank the sponsors, the University of Iowa International Programs and the University of Iowa's Honors Program for their generous support. Again, we thank our financial sponsors, MidWestOne and Integrated DNA Technologies. Drew, as a small token of our appreciation, we present you with this coveted, very coveted Iowa City Foreign Relations mug. Thank you very much for joining us, and give another hand to Dr. Kitchen. - [Drew Kitchen] Thank you. - [Sue Dulek] Last but not least, should you wish to become an I.C.F.R.C. member or support the programs with a tax-deductible contribution, please visit us at the back of the hall or call us at 319-335-0351, or you may mail donations directly to the I.C.F.R.C. at 1120 University Capitol Centre, Iowa City, 52242, again thank you very much and that's the end of our program today. - [Narrator] You're watching City Channel Four, on TV, online, on demand, on Facebook, and now on the go on your mobile device.