 Good afternoon, everybody. Hello. Hi, and welcome, everyone. I'm Seema Kumar. I'm vice president for innovation, global health, and public policy and communications at Johnson & Johnson. It's a pleasure to welcome you all back after the break for our second conversation today. So our second conversation of the day explores how genomics is impacting global health. This is a critical topic for all of us. And today, the genome is actually bearing fruit. And producing treatments and cures for a bunch of different diseases, better, faster treatments, and also personalized treatments, more targeted treatments. And at J&J, we believe that this is an important era for us to find the genomic ways to cure diseases and to find treatments in global health broadly. So the conversation actually could not be more timely, because although we are going to discuss the impact of global health, the impact of genomics on global health more broadly, as it relates to chronic diseases, we're also going to pay some particular attention on how genomics has helped us understand the recent outbreak of the Ebola virus in West Africa. This is a topic that's at the forefront of many of us and, of course, has been covered extensively in the news. And it's important for us at Johnson & Johnson as we are racing to develop a vaccine to prevent the spread of the disease. Today, we're honored to have joining us for this conversation to distinguish researchers in the field of genomics. First is Dr. Pardis Sebedi. She is an associate professor at the Center for Systems Biology. OK, let's see. There we go. At Harvard University, Department of Organism and Evolutionary Biology. And in the Department of Humanology and Infectious Diseases at Harvard School of Public Health. And she's also a senior associate member of the Broad Institute at Harvard and MIT. She is a computational geneticist with expertise in studying genetic diversity. Dr. Sebedi's lab focuses on detecting and characterizing signals of natural selection in humans as well as pathogens. She completed her undergraduate degree at MIT and her PhD at Oxford as a Rhodes Scholar before returning to earn her medical degree at Harvard Medical School as a Soros Fellow. On a more personal note, Pardis and I actually worked at the same time at MIT at the Whitehead Institute under Eric Lander. So nice to see you again after all these years, Pardis. She is a World Economic Forum Young Global Leader, a Pop-Tech Science Fellow, a National Geographic Emerging Explorer. Wow, very impressive and even more impressive lead singer of the alternative rock band, Thousand Days. So maybe we'll hear from you as well in a different way. More recently, she was one of the senior authors of an August paper that was published in Science, which reported on the research of using genome sequencing to actually track the origin of the Ebola virus outbreak in West Africa. So let me just play a quick video about Pardis Sabati and then we'll actually have her come and join us on stage. Here we go. I'm Pardis Sabati. I'm an associate professor at Harvard University and the Broad Institute. My work is in computational genomics and infectious disease. And what that means is my lab develops methods, mathematical tests, and tools to mine genomic data to look for interesting patterns that might be important in how we respond to infectious diseases, such as how do some humans have resistance to diseases like malaria or Lassa fever or tuberculosis? How do those types of the microbes causing those infectious diseases develop resistance to the drugs that we give them, the vaccines, and to stay agents of morbidity and mortality throughout the world? And the type of work we do takes us to all corners of the world and also focuses on our lab here. And I like to say that I have one of the greatest jobs in the whole world, because I get to work in the university with talented undergraduates and graduate students and to teach. And I get to go to Africa and work with amazing collaborators, scientists, and physicians that are brilliant and also dedicated to understanding these diseases to help their populations. And so we are passionate about what we do. We have fun with the work we do, but we are committed. And so I love my line of work. And so on top of that, it's just such an honor and a pleasure to be recognized in the Smithsonian American Ingenuity issue. Thank you. Welcome, Sabeta Park. Come on up and come and join us on stage. And please take a seat while I introduce our second panelist. Our other panelist is Dr. Charles Rotimi. He's a chief and senior investigator in the metabolic, cardiovascular, and inflammatory disease genomics branch and director of the Center for Research on Genomics and Global Health at the National Human Genome Research Institute. His research actually has focused on identifying genetic, social, and lifestyle determinants of diseases of major public health importance. He believes that scientific activities operate within the larger context of society and is interested in how scientists document and describe the non-random patterns of human genetic variation and to link to disease risks. Previously, Dr. Rotimi was director of the National Human Genome Center at Howard University. He also helped established and currently serves as a president of the African Society of Human Genetics. Dr. Rotimi received his undergraduate degree in biochemistry from the University of Benin, a master's degree in health care administration from the University of Mississippi, and a master's degree and a doctoral degree in epidemiology from the University of Alabama at Birmingham School of Public Health. So let me now show a video about Dr. Rotimi. Here we go. My name is Charles Ngooma Rotimi. I'm the director of the Center for Research on Genomics and Global Health, and I'm also a senior investigator at the Heritage Research Branch at the Genome Institute at NIH. What is so appealing about understanding the human genome and understanding DNA structure and how it relates to health and disease is that it is really the basic instruction for who we are. Without it, there's really no us, and a lot of things around us will not be in existence. So I look at it as our history book, and it has captured our whole existence over time in the way that if we read it correctly, it will begin for maybe the first time to understand human history and also to understand human health and while some people get certain disease and others don't. The project we called Human Heritory Health in Africa was really started under the umbrella of the African Society of Human Genetics. I am the founding president and the current president of that society. We founded that project because we call it H3Africa because we wanted to make sure that genomics, the genomic revolution, did not fly over Africa as a lot of revolutions have done in the past. So we, as members of the African Society of Human Genetics, came together and said, how do we bring attention to the fact that we are unraveling this wonderful fundamental knowledge of human existence and human history? And Africa is the critical point in this human history. The work we are doing in Africa in terms of making sure that Africans are engaged in genomic research really cuts across the whole continent of Africa, from South to the North and East to the West. We are engaging young men and women in a way that we want to put in place fundamental tools and capacity for them to be able to be a part of this wonderful revolution that is going on in terms of genomics. In that regard, we are indeed, for my lab specifically, I'm interested in understanding the genetics of type two diabetes, hypertension and obesity. Thank you, please welcome up Dr. Rotimi. Thank you both very much for joining us. So the way we're gonna do this conversation now is first we'll ask the big question and then we'll start with each of you taking some time to answer that question. You first, parties, and then after that, you, Dr. Rotimi. And then we're gonna just have a discussion amongst ourselves and then we'll open it to the audience for a question. So with that, and I'm gonna hand you the clicker because you can move through your slides. I'll put it over here first. Okay, there we go. So the big question I think that we wanted both of you to sort of think about and give us your thoughts on is, you know, what are the big opportunities, the promises and the challenges of bringing genomics to clinical care, not only in the developed world, but in particular in areas of the world that are still developing. So, parties, do you wanna first start us off? Sure, yeah, so this is really nice and I was telling Charles that I have known about him for about 20 years since the early in my graduate school. So this is an honor to be on the stage here at the Smithsonian and to be here with him and to be with you, we've known each other for so long. So thank you so much for taking the time for allowing us and for allowing me to be here. And while actually I did a lot of my early work in human genetics, actually very close to the type of work the child does, of late I've been really focused in infectious disease. And so I'll kind of be giving a little bit of a different angle of how genomics is not just something important in understanding our own genomes and how we evolve and change and how it drives different medical disease or relationships with individuals, but also how we can use it to investigate the genomes of other organisms on earth and particularly the infectious diseases that we combat again. And so I'll sort of just start here with this slide. It's a picture that I took in May of this past year in Nigeria at Redeemer's University, which is right outside of Lagos. And if I can, right there is Christian Happy, Dr. Happy. I've worked with him for many, many years. He's an extraordinary scientist, we've been working in Nigeria for a very long time, born in Cameroon. He's the dean of the university and we've worked together in malaria for many years before and on a disease called Lassa fever for the last six, seven years. Right in the middle there is Dr. Shikomar Khan. He's from Sierra Leone. He passed away, unfortunately, to Ebola in the midst of this outbreak. But he, Dr. Happy, Dr. Khan, and Dada Nyadeh is from Senegal. We're really partners that we came together and we had an idea that we wanted to develop a genomic center of excellence that was based in Nigeria, but with branches in Sierra Leone and Senegal to really help develop the next generation of scientists in Africa to carry out diagnostic surveillance and research in infectious disease. And this is supported by the NIH as well as by the World Bank and part of it was a graduate program in this area. And we are very excited and we met for this meeting in May but this is something that's been in the works for a very long time. And the reason that this has come to be is actually, this is a picture that kind of gives you a sense of why were we there. So for those of you that maybe by now might recognize this, this is actually the Ebola virus. This is an image of the Ebola virus. But it's drawn into a picture that Stephen Geyer in my lab took while flying over the Congo River. And so he transformed through the clouds out of his airplane. He saw the Congo River. And as we published a paper up, he transformed the Congo River into the image of the Ebola virus. And the paper that we were publishing a few years ago as a perspective in science was called Emerging Disease or Diagnosis. And in essence, the individuals that were standing on the steps with me I'd been working for, for some of them for almost a decade. And we had basically by, we'd been working in malaria, we'd been working in Lassa fever. And as we worked on these diseases, the more we went into the villages, into the cities that we were working on, we began to recognize that diseases like Lassa virus and like Ebola may not actually be new. And they may not be rare the way we think about them. They may not be these emerging threats. They may actually be circulating in clinics and in villages in Africa, as well as in different parts of the world, different viruses like these may be circulating. And so this picture is a way of capturing that if we looked from a different angle and we looked, you know, from the right perspective, would we recognize that these diseases are actually not emerging? They're not new or rare, but they're circulating and have been for decades, hundreds of years, maybe even millennia. And so within that context, it's something we've been thinking about for a very long time. But while we were while we were developing plans to do this type of work, the Ebola outbreak started. And it was, you know, first cases are believed to be in December, but it was the sort of declared as an epidemic in Guinea in March of 2014. And at that time, Dr. Khan, who's now in this picture right in the middle here, you know, spoke to us as did Christian Happy and said, we have to be prepared. We have to make sure that we can diagnose and surveil for Ebola if it comes into our countries. And so we immediately worked with them to get the diagnostics on ground. We'd been working for about six years on Lassa virus, which is another biosafety level four virus. We already had the labs in place that had very high standards of safety and security and all the things in place to do this kind of work. And we just made sure we had assays that could pick up Ebola. And so Christian and Steven and my group here went over and met Augustine and Dr. Khan and Mamboo and Symbirion, our group out there. And they worked to basically get prepared. They put the diagnostics in place, began to do surveillance, enhance the abilities to work on more samples in case we were to get an influx. We brought much, much more personal protective gear and helped to establish that. And basically, and they went back, they had a lot of cases and they did a big scan in all of March and I think even late at February. None of them had Ebola on them. In April again, it was all clear. In May it was all clear. But on May 25th, I diagnosed the first case. And so this is Augustine in the lab. This is the personal protective gear that he wears within the lab. And we have a very, really nice facility there. And he diagnosed the first case using these PCR-based diagnostics based on the genome sequence. Identified the first case of Ebola in Sierra Leone. And I'll actually hold here before I get into this point. But basically, one of the things that we talk about, actually when we talk about what happened there, was we said, well, that was exactly the kind of thing that should have happened, which is that we were on ground, we've been doing surveillance, we're able to detect cases that were coming into the country when that first case emerged on May 25th. We were able to detect the individual, say that they have Ebola, place them an award that has a high level of standards. This is an award that's been designated and designed in order to be safe. And there was no incident that happened within that no individual's getting infected, everything was in position. And we have an extraordinary contact tracing team that went out to the villages and were able to look to see were there any other contacts. The problem was that by May 25th, when we detected this case, it wasn't the first instance. We weren't detecting the first case of Ebola. We were detecting an avalanche, a tidal wave that was coming into the country, right? That first case to happen in Guinea at the border of Liberia and in Sierra Leone. By the time that it came into Sierra Leone, it didn't be going on for many, many months, almost six months of this thing percolating in neighboring countries. And when it came in, it came in, our first detection was with 14 different people coming in simultaneously, that it happened two weeks before in a village three hours away. Those people were infected with two different versions of the virus already. So it had been mutating enough that it was two distinct versions of the virus coming in. And before we could even blink, this thing had already been moving across the country. So Nigeria being the opposite example or being a different example of a success story in the New York Times talk today about the declaration of clear, that was an extraordinary example of two labs in the same city that the individual came in that both were able to detect the Ebola. So Christian Happy as well as Sunday Amalabu's lab, both were able to do that detection, immediately detected, move quickly to do all of the contact tracing. And so Sierra Leone, Kenema where we work was well positioned, but it was three hours away from where the incident happened. It was right on the border, so cases were coming in constantly. And before we knew it, basically we were flooded. And there was this hospital that could handle 20 patients with Ebola, which is outstanding, had to deal with 80 coming in at a time, right? And more and more people coming in. And so as a result of this, and this is the last thing, is that we've been doing a lot and there's been a lot of success stories on what's going on with Ebola. But within this, Dr. Khan, as well as a number of other nurses and hospital staff at Kenema have passed on. And so obviously this is incredibly personal to us. This is not where we want the story to end. In fact, I've just met with the Khan family and we have a lot of big plans for the future to make sure that we stem this outbreak as it is now, that we make sure that we support the families of all the individuals. So today we've sort of put out a call for, or yesterday we put out a call for an Ebola Heroes Fund that we created to support the families of all these individuals in Kenema who have had their primary breadwinners pass on and who've lost their lives while dealing with Ebola and also across this epidemic. But to also build up enhanced training for the future because we do believe that actually with good diagnostics in place and good procedures in place, genomics can help us to identify, understand these viruses before they become these global threats the way they are. We have to start by first stopping this epidemic, but then there are many lessons that can be learned to make sure that it never happens again. Thank you. Thank you, parties. And we'll dive into it a little bit more. But first I want to also give the opportunity for Charles to have the place over to you to give your version, your answer to the big question. Yeah, I think for me to answer the big question, I have to sort of come start from my own history in the sense of growing up in Nigeria and having to do my initial training there in biochemistry. I remember those days, we can only talk about one gene at a time and the structure of DNA, we were so fascinated by that point. So coming out of the way to the point where we can sequence genomes, multiple genomes on a day, I really do feel like a kid in the candy store in terms of my own work, in terms of genomics. But two things have motivated my career over time and that is basically the fact that I grew up in a developing country and I immigrated to the United States, to the University of Mississippi where I met my wife and where I was actually socialized to the American culture. And it was there that I first observed the concept of head disparity. And I began to understand that a certain group of people in the United States are at higher risk for certain diseases compared to others of the US citizens. And for me, I really didn't understand why that would be. And I started asking questions like is it possible that a group of people can selectively just inherit by genes and therefore be at higher risk? I did not think that was a plausible kind of answer to that kind of question. So I started to ask more questions, why is this going? So I was socializing in certain part of the United States and that started to clue me into the whole concept of public health, how do we begin to answer this kind of questions? The other thing that has also motivated my own career is again coming back to the fact that I grew up in developed countries. I've always wanted to make sure that the best science that we do, wherever we do it, that it's applicable to all world populations, that all world populations benefit from this concept. So those two things have indeed shaped my career over time. In terms of the head disparity story, I noticed along with the fact that there were different distributions in head disparity, in terms of risk. I also noticed that then in African-Americans that there was a clustering of what we call metabolic disorders, as when you find a diabetic, you tend to find a hypertensive, you tend to find somebody who's heavy, and you know, so all of these things tend to, and you also tend to find somebody who have a risk-lippy profile. So all of these things were coming together in my head and I was saying this indeed needs some answer and some investigation, and those two things have indeed shaped my career over time. So, one of the, how do we go past that? So for me, the whole concept of genomics, really the best way I look at it is that it's a history book. It's a history book that has captured our experiences of our ancestors over many, many years, and it has done this, I say, in an unbiased way. And we are just beginning to have the right tools to understand this story in the way that we are going to inform human history, or we are informing human history and human health, in a way that we couldn't do in the past. But the challenge that we face is that are we going to interpret this book in an unbiased manner, given that it has been captured, the information has been captured unbiasedly. So I am very interested in what I call the junction of society and genomics. How do we interpret human genetic variation in a way that would do not reinforce old notions of ourselves in terms of distinct racial groups and things like that? How do we understand human genetic variation? And how do we appreciate the fact that when you use world like black, you actually distort the distribution of human genetic variation? Because what you may find among the Maasai, you may not find among the Eurobats, but all of these individuals will be classified as black. The Ebola experience is a very good one. And another experience that was provided earlier was the issue of the APOL-1 in terms of kidney disease. That variant is almost absent in Europe and in Asians. And it's quite common in African-Americans and Africans. But to call it an African variant is a misnomer because it is not. It's not the characteristics of being African. It's the characteristics of having survived in an environment where sleeping sickness and trapezoid masses was the dangerous thing. So those are some of the things that I think we have to monitor and we have to be very sensitive to as we bring genomics to different parts of the world. The other thing that I'm very, very interested in is this diversity. Our diversity is not an illusion. We need to study. There's a reason why we look the way we look and there's a reason why sitting disease vary in certain populations. It could be due to environmental factors. It could be to genetic factors. But most likely it's probably the result of these two things, gene and environment, that drives quite a bit of this phenomenon. So those are some of the promises. But I put this slide here also in terms of cell phone. Some of my colleagues, in terms of when the cell phone first came, people were saying, oh, don't take cell phone to Africa because Africans can't afford it. I can tell you today that cell phone probably has saved Africa in a very, very significant way. And Africans actually use cell phones probably more than a whole lot of other parts of the world today. So we need to be careful how we deploy or how we even think people can gain access to technology and how they can use it and whether they can afford it or not. The beauty about the cell phone, it's a really interesting technology. The initial investment to get one actually varies. You can buy a very sophisticated phone. You can buy a very cheap phone, but it does the same thing. There's the ability to communicate. And you pay as you use it. See, if you have $1, you buy $1 worth. If you have $10, you buy $10 worth. So it really frees up people to be able to use that technology. To the point now, farmers use it to call trucks to come and pick up their crops in different possible. So the question is, genomics has the potential to come up with this kind of technology in a way that things that require refrigeration right now may not necessarily need it. And therefore we may be in a position to have better diagnostic and cheaper tools that developing countries can have. And I think for me that is exciting about genomics. So that's sort of the promise. What are the challenges? Right now the way genomics is currently deployed. I think you heard this in the previous section of panel is that most of the genomics that is currently done right now is done in Europeans and to some extent Asian populations. Okay, but this diagram here represents what I call the workhorse of how we are trying to do genomics to understand disease, what we call genome-wide association studies. If you look at the distribution of how this is being deployed and used, you'll see that most of it is being done in European populations. Therefore most of your understanding that we have right now in terms of genetic variants and disease is coming from European population. That doesn't make it bad. It just make it incomplete. And that is where I think we have to make sure that we engage the world population. And that brings me to this slide here, which to me represents, I call it a lifetime achievement for me and for a lot of our colleagues, including Eric Green here, who's director of our institute. And that is the Human Heritage and Health in Africa project, which is co-sponsored by the WECOM Trust and the NIH. And right now to the tune of about 75 million dollars, this project alone is changing the landscape of genomics on the continent of Africa. And it's giving young men and women the necessary tools that they're going to need to begin to appreciate and do genomics to answer questions that are relevant to that continent. So the footprint of H3 Africa is really across the whole continent and it has the potential to actually put in place the necessary infrastructure to do this work. The part of the challenge here is we have to be able to engage communities and we have to engage communities at their own place. And I always say, please don't engage a community unless you want to hear what they have to say. So don't pretend that you're engaging them just for the sake of it because they might tell you things that will surprise you or that may want to make you change your study. So there's also the issue of informed consent and the issue of language. How do you communicate some of these concepts? The challenge I always throw out to my genetic colleagues how do you explain Fando effect or haplotype to your mother? Those are really big challenge if we are actually going to get the concept the informed consent of individuals we have to challenge ourselves to make sure that we explain some of this concept. We don't have to use the same words. Like in the African culture, people may not use genes but they are very conscious of inheritance. They understand that concept in a way so we need to tap into those local understandings in a way that we can communicate with individuals. And then one of the things I always say is that in terms of data sharing and things that I wish is the hallmark of genomics we need to do it in a way that is equitable. Scientists in developing countries may not have the tools to run as fast as scientists in the Western countries. Therefore, if we are giving a scientist in the Western countries six months to analyze their data before they release it, we may need to double that for people in Africa or South America. Just because of lack of infrastructure and maybe the technical know how to be able to adjust those data. So those are some of the challenges that we face. And I look forward to answering your questions. Thank you, thank you Charles. So parties, I'm gonna turn my first question to you. Back to Ebola. So you were able to, your recent paper in science got a lot of attention. You were able to trace the origin of the outbreak using genomics. So can you talk to us a little bit about how you were able to do that? How genomics was able to do that? Sure, so just as a background, we in the lab that we have in Sierra Leone at the kind of a government hospital, we had it set up so that the diagnostics happen and then as soon as, so you'll take a blood sample, you'll run the diagnostics if they have Ebola or don't have Ebola. And then there's a, you have to kind of take a larger volume and then there's a good amount that's sort of discardable or discarded. We call it clinical access. And obviously in the Ebola outbreak, you're not gonna be doing consenting and all this other kinds of things. So you wanna be able to just get clinical access just to sequence the virus. And so that's how we set it up. So we set it aside. You have a sample of the blood and the serum that we take of it. And you can put a solution into it to deactivate the virus. And it worked very closely with a lot of the biosecurity level. Four labs here to create protocols that allow you to do that. So as part of the H3Africa grant, we actually have funds to put sequencing machines in to Nigeria and as well now through support, through USAID, we might be able to move that to also Senegal and Sierra Leone as well. And Illumina is going to be donating machines. So that's the aim of moving it all the way into country. But for now, given that we have the deactivation, we could send the samples back to the United States where we sequenced them. And what we ended up doing is we sequenced from the first three weeks of the outbreak, 78 different patient samples. That was about 70% of the samples that came in at that time. And since we've been doing surveillance, we think we have a pretty good snapshot of what's going on. And what we then did is we sequenced the samples. And one thing that's important about the way we sequenced the samples and the new technology, this great technology that's available now that we talked about in the last session as well, is that you can do just deep dives of the information. So we not only, we don't capture just one sample of the virus circulating in an individual, we get 2,000-fold coverage. Meaning that the virus is not just one virus within you. The virus is mutating and changing within you as well. And there's a population of viruses that are infecting your body. And so we can actually get a large snapshot and find even the small new strains that are emerging within an infection. And so within that, we found about 300 mutations that separate the virus, what we call the West African strain from all previous outbreaks. We found about 55 mutations that have become fixed just within this period of time. And again, we only have a snapshot at this point, just a three-week snapshot. And we found over 250 mutations that were actually percolating within individual infections, within hosts. And that's actually that incredibly high-resolution data allows you to begin to understand these transmissions. So in addition to the 78 individuals that we had gotten samples from, there were three that had been previously published and made available from Guinea, from early in the outbreak. And so the kinds of things we could see is we can see that if you look at all of the outbreaks in the past and then compare the strains within this outbreak that we're looking at, you can see that this is all one transmission. So you can see that all of them are so genetically similar that it appears to be one single event from the likely natural reservoir that is spreading between individuals. And those little mutations that are popping up because it's such high-resolution, you can actually use that to give information of who passed the virus to who. And you can see these intense sort of transmission chains happening. There's one that we talk about in our paper where you see a healthcare worker who then infected another healthcare worker as well as an ambulance driver. That driver happened to go across to a different district and then infected another set of individuals. And you can see those mutations passing from individual to individual. So you begin to create what we call a family tree, but it's a family tree of the virus and it shows you exactly how the virus is spreading between individuals. We have about a thousand samples that we've collected since. During the outbreak there's been new challenges to get those samples and for everyone to agree and allow us to begin sequencing those samples, but they have been collected in a way that doesn't affect response. And we hope to get those and begin sequencing those now to understand also what the virus has been doing since and we may talk about that too, but in addition to all this surveillance and transmission, there's very important information about the virus itself and how it affects diagnostics, vaccines and therapies that we need to know. Yeah. So just to follow up question to that, which is you said there were a lot of lessons learned. Obviously, right now the focus is on preventing and containing the outbreak. But how can genome, what were the lessons learned and how can genomics help in the future? Sure. Well, I mean, again, right now we're writing a piece about a little bit about what happened in Nigeria and the lesson learned there is if you have diagnostics in a city available and that you can detect the first case early on and that, I mean, in addition to the diagnostics, that's the one piece and these are diagnostics based on genomic sequence, right? That in coordination with all of the other outstanding work that happened amongst the, the Lagos City government and all of that and the Gates Foundation had a major hand in that. All of those pieces together were able to contain. And that this is not something, it shouldn't be an expected of these things will happen and we won't have control actually. The viruses are pretty simple. They have a genome. If we can begin to identify what they look like and really get a capture of this, we can actually do this kind of surveillance and so that's what it tells you and Senegal was able to do the same thing in the same city. So the lesson really learned is actually this idea that if we are able to do better genomic surveillance in real time in every country, one of the things that one of the points we're gonna make in this piece that we're writing is actually that in the United States, right? We can talk about, oh, you know, we're talking about a different country. United States, there's actually only one lab that's designated to test for Ebola. So you can see that you get these incidences where you say there's a suspected case in New Mexico. There's a suspected case in Texas. Why are they suspected cases for days? Because we have to then get the sample, put it in a box, wrap it up, put it on a plane, ship it to the CDC, and that's where they do the diagnosis. That kind of, if Ebola was to come to the United States, that's not gonna work. And so we're gonna have to rapidly turn around and try to regroup and otherwise what we can do, and this is a regulatory thing. My lab can do that diagnosis. We're just not allowed to. And so these are the kinds of things that we need to reshape and rethink. We need to position ourselves to do this kind of diagnostic routinely. And it will both help the patient on the ground get that information immediately, and also help the entire public health sector to understand and be able to move to contact tracing. Thank you. Charles, now why did you decide to work in the field of genomics? And especially what did you find was some of the most challenging research that you've undertaken or faced, especially as it relates to chronic diseases in African populations? Yeah. My initial inclination really was from trying to understand why disease vary across different populations. Again, going back to the whole concept of head disparity. I remember when I was doing my post-doctorial work at Loma Linda University in California, I was actually studying, I was working with a specialist in who was studying Alzheimer's disease. It was one afternoon I was reading, because I know after my post-doctorial, we need to get a job that pays real money at some point. So I was, usually at the end of the day, I'll go through the back of different publications to see what has been advertised, what kind of job. So I saw this ad from a Loyola University in Chicago from Richard Cooper, who I consider my mentor today, or who is my mentor today. The job description was such that I actually picked up the phone immediately and I called him and I said, did you write this for me? And he just said, I'll write the word for you, I'll see your ad. Because what the ad said was, he is looking for somebody who is interested in understanding why hypertension vary so much from rural Africa to the black nations of the Caribbean to the United States. He said, how do we use that migration design to understand the risk factors for hypertension and therefore begin to share light on the very high rate of hypertension among African Americans. So basically we wanted to study the African diaspora. So Africans in Africa and Africans that have moved out, you know, voluntarily and otherwise. So when we did that study, we enrolled about 10,000 individuals and we showed very clearly that the rate of hypertension vary dramatically across individuals that you would call African ancestry or black. So for example, in rural Nigeria, among the Europe as that we studied, hypertension was 7%. When you move just two hours to Ibadan Lagos, hypertension rose to about 16%. Then you come to the nations of the Caribbean, St. Lucia, Barbados and Jamaica, hypertension was about 26%. And among African Americans it was about 34, 35%. So you can see there are almost a monotonous increase as you move from rural Africa among individuals who share very recent ancestry to different parts of the world. What was really interesting to me as somebody who studied epidemiology was that gradient that you saw, we were able to explain about 60% of it by looking at how much salt you consume, how heavy you are and level of physical activity. But after that study, we also realized immediately that we couldn't explain all of the variants. So I started thinking, what are other factors that may be going here? As you go across this African diaspora population, you also see varying degree of admixture. What do I mean by that? That is individuals who have now interacted and have all strings from different ancestral background that have been separated over a long period of time. For example, in the concept of African Americans, you do see admixture in terms of European and also West African and sometimes Native Americans and sometimes Asians. So you have this different constellation of ancestry. How do we begin to use that to explain some of the variants that were there? So that also brought my interest in the way in terms of genetics. So how do we begin to bring genetics to bear on the same question? So I started, again, ramping up in the way in terms of genetics and how to do this. So my very first study was really the study of families in Nigeria and also African Americans to begin to see how do we explain heritability? Do we even get a good estimate of heritability for hypertension in these various populations? And from there, we started addressing the questions of the Iranian angiotensin system, what are the variants in these systems that may be able to explain. I remember when I was doing that work, there was a very widely publicized study of angiotensin, the angiotensin gene, which is a part of the Iranian angiotensin system. That shows that there's a particular variant there that was a very high frequency in African ancestry individuals. All of us thought that this was going to help us to explain maybe the differential response to things like salt intake that we see. And that this may help us explain some of the disparity that we see in hypertension. So I quickly ran to Nigeria, we collected blood samples, we brought it back here and we typed that particular variant. And it turned out that it was actually true. It was the frequency in Africans it was almost double that of Europeans. But it was not related to blood pressure. We couldn't really get a very good understanding of that. And it did not help us to understand one of the phenomenon that has been expressed before in the past. And that is that maybe the high rate of hypertension among African Americans is due to the slave trade, having to survive the middle passage. That individuals who were able to survive their horrible experience, that's in humanity to mind that we engaged in, actually may have selected on the ability to retain salt. Because most of one of the daily conditions was a little like depleting diseases like diarrhea. But we could not use this data to substantiate that. So that hypothesis, it may look appealing, but genetics so far is not supporting it in the same. So those are some of the things that really engage me in terms of trying to use genetics to understand these various diseases. So are there key lessons that you have learned through all of your research that you can talk a little bit about? Yes, I think one of the key for me, we study different diseases. One of the key things is that when you want to engage community, and you want to engage them for a long period of time, you need to understand where that community is coming from and how your research is going to impact or not impact them and don't over promise what your research can or what it can deliver. But I also know that sometimes by bringing in lengths of genetics to bear on a disease that you may actually increase the level of stigmatization of that disease you are not careful. For example, we are in Ethiopia right now, we are studying a disease called podoconiosis. It's really a disease of poverty. It's almost 100% preventable if you were sure. How do people get it? People get it because they don't wear shoes and they go to farm and they farm with their bare foot and they have this exposure to frankly sand, from volcanic frankly sand that cause the initial insult to the skin and causes this massive inflammatory response and the legs waste up. It's like elephantiasis but it's not due to infection. It's actually due to a physical insult to the skin that goes into the lymphatic systems. Now the disease, you cannot hide it. It's there and people as young as eight years of age get it. So when you study that disease, people over the years know that this disease tend to be traveling in families. Not everybody in those communities get the disease. Although it's preventable by wearing shoes but not everybody who is exposed get the disease. So when we started saying we wanted to study, people say, oh, no, no, no, we don't want to participate because this could lead to stigmatization and we also reinforce the notion that this is really genetic. There's nothing they can do about it. People don't marry into those families and so for me, the lessons that we learned there was that we needed to be, you may mean good but that's not enough. You really need to know where the community is coming from and how that disease is perceived in that community and the intervention that you are bringing in or the study they are bringing in, that it is consistent, that you are not doing more hard than good, so it's quite challenging. And the other real big thing I've learned over the years in doing the work in developing countries is that the playing field is not balanced. I come from NIH, I have my lab, I can do the things I want to do but the investigator in Nigeria or in Ghana or Uganda doesn't have the same infrastructure. So we have to make sure that as we, I'm not saying slow down research but we can run and work depending on how we want to make sure that we bring the whole world along in terms of doing genomic research. So we need to make sure that we engage all communities not just as participants but also as scientists. That's a great, great, great thought. So parties, you said in your video that you began to study genomes, not just human genomes but then genomes of microbes and tuberculosis you mentioned, for example. So how does genomics help in that respect in terms of public health priorities that we face in many developing nations? Whether it's tuberculosis, Ebola, other infectious diseases. Yeah, I mean I think that in my mind, and sorry I need to pep it up a little bit. I think I feel like everything I'm saying is just like, and that's sad. So I'm gonna try to be a little more peppy. Anne was a ball of energy so I'm gonna try to take a tip from Anne. I mean, genomics is amazing and NH3Africa is just such an extraordinary example of the kind of impacts that it can have and it's only when it's just beginning but as Anne described too, we are on the precipice of a really exciting time and it can have an impact in both communicable and non-communicable diseases. And in fact, actually I think in some of these communicable diseases like tuberculosis, HIV is where there's this tremendous impact. A lot of people say, well, what are we gonna learn from the human genetics? And I think there's a lot we can learn and you first have to understand underlying genetics to get to the point that you can then develop the therapies that are based on it, develop the interventions that are based on it. But when it comes to the microbes actually, we can implement right away because when you actually say we can detect these different microbes, that makes a major impact just in the case of lasophever. So I'll tell you a little about lasophever I work on. That's a disease that's like, is another deadly disease right now that fatality rates that we do see in Sierra Leone around 84% amongst hospitalized cases. Extraordinarily, but there are treatments that if identified, if the virus has identified it when it's just right starting, right? When it's just to the point, same thing with HIV, the earlier you pick up these things, the more the interventions can work. So you can, there's a drug called ribovirin in a study 25 years ago, it was shown that from fatality rates of 55%, if you diagnose and treat within the first six days of that, of the sort of, even in the symptomology, that you can reduce the fatality to 5%, that's an enormous impact. These are the kinds of things we can do. Actually, if we get better and better at detecting these microbes, we have a much larger chance at developing interventions. And of course, those microbes are gonna, them continue to evolve as well, and they're gonna try to develop drug resistance. But genomics will get us to the bottom of how is it changing? How is it mutating? What's it trying to do? And we've got a tool in our toolkit that the microbes don't have themselves. And it really is very much predicated on understanding the genome of those microbes and what they're doing. So what message do you have for young scientists who are entering into this field? Both of you. It's an exciting time. It's a kidney candy store is exactly right. I did the early work. So, you know, I started my PhD in 19, or my research basically kind of path in 1993, and my PhD in some 1997 period. And back then it was one meeting. It's just as Charles said, it was like one thing at a time. My entire master's thesis was four mutations I tested and 300 people, and it took me the better part of a year to get that done. And now you could do that million fold in an afternoon. So it's a great time to be in the field. Yeah, for me, I think the lesson or the message to young investigators is really to be patient and to acquire the necessary skills to be able to be competitive in the whatever area of research or investigation that you want to do. There is really no substitute for you being able, she won't be able to do what she's doing today if she doesn't have the scientific skills to be able to achieve that. So it is imperative for us to make sure our young men and women have the necessary skills and determination, really, to be able to succeed in this, not just in genomics, in just about anything you do in life, you have to have the right set of tools. And then it is the responsibility of society that these laboratories, that these young men and women are going to work, are well equipped, and that they have access to the best to do this kind of work and that they are actually well supported. For example, again, going back to my own whole experience, a lot of developing country scientists end up in Europe and America, not because they don't want to do work in their home countries, is because they don't necessarily have the right infrastructure to be able to do the kind of science that they want to do. So how do we begin to change that? That is why, again, I go back to the H3Africa project, which is really one of the real thing there is, African investors are being funded directly so that they can do this work, but there is still a challenge that these labs have to be developed, and the local universities and government have to pick up this. NIH and the Wellcome Trust are not going to change biomedical research in Nigeria or Ghana or over there. They can support it. The local government and the scientists and the business environment has to step up and make sure that the right infrastructure are available for young men and women to be able to do work locally so that it doesn't end up like a charge routine in the NIH, but an NIH maybe in Lagos or in Accra or in Johannesburg. Thank you. Now we have some questions from the audiences. So the first question is, what specific or common social determinants of health have the largest impact on public health over time and across generations? Would one of you want to take that? Social, common, specific or common social determinants of health that have the largest impact on public health over time and over generation. I can try that. You can try that one. You want to take it? Yeah, okay, go ahead. Social impact on health, in terms of health disparity, right. For me, I think we really need to look back and look at the rate of incarceration in the United States for African-American young men. When you look at that, I believe that is one of the most single important disruption of health and economic well-being for that community. And there is no gene that I'm going to be able to find today or tomorrow that can have as much impact on the health of African-American young men. And subsequently in terms of their own family, then if we are able to change that social determinant of health, we just published a study recently in hypertension where we showed that African-American boys who grew up with both parents had much lower blood pressure as an adult compared to those who did not grow up with either parents. That level of blood pressure change is about the same you get from drug treatments. That is a phenomenon. And society needs to look at how you can change that around. You don't even need to buy a pill to have that kind of effect. So for me, those are some of the really important social determinants of health. Thank you. Question for you. So how can we apply our understanding of host-pathogen interaction at the genomic level to disrupt the co-evolution of pathogen? For example, host specificity of malaria, as an example. There's this one. So, yeah, okay, so let me just think about it for a second. So, host-pathogen co-evolutions are very interesting topic. A lot of people are interested in. I always say it's very, it's complicated. I haven't even figured out the host or the pathogen yet to quite understand the host-pathogen co-evolution. But we do recognize, here's an example, and I can talk about malaria, but maybe I'll talk about Ebola because that's all I seem to know how to talk about now. We've done a lot of studies with you, Samrit, on non-human primates, as well as we've done a lot of work in clinical samples of the, of Lassa virus in both humans and in rodents, and with this deep 2000X coverage. And the kinds of things that we can see is, for example, that the virus is mutating, and it's mutating within hosts. So, in these time courses they do with the primates, they're testing an individual primate that they sample across many, many time points. And what we can see is actually that the virus is changing and it's changing in real time over the course of infection. And that, in general, there's a skew in the distribution of what the virus is doing than what you would expect, where there are more changes, there are more changes that happen to be functional, meaning they, in this case, functional is determined by changing the amino acids. There are more changes than you expect in the GP proteins of both Lassa virus and Ebola virus, which is the protein that is responding to our immune system. And that, in the case of Lassa virus, when we did the analysis, those changes seem to be happening in predicted epitopes, in predicted things that are responding to the immune system. So we can see these things in real time. We can see how the virus is changing and trying to evolve itself to essentially what looks to us like immune escape. And these are the kinds of things that we can model and understand, and also as we develop our vaccines and our antibody therapies, we have to consider that and design therapies that are going to be robust to the kinds of changes the virus is gonna make. And so those are the types of ways that that information is very important and there is this interaction and where we have to consider it in our therapies. Thank you. Question for you. So how do you expect genomic research to advance? Given the challenges of infrastructure and capabilities in Sub-Saharan African countries and what's required to help genomics and the field of genomics advance in countries, in the African continent? I think what is expected is really to, for the local authorities and businesses to build on initiatives like the H3 Africa and other is not just the only initiative. There are other initiatives like that to build on this in a very substantial way. And I think the local government, what I call, look, I'm not talking about national governments, have to realize the importance of research to economic development and wellbeing of the citizens. Right now, I think research is seen as something that costs money that really doesn't bring in, which is a very wrong way of looking at research, giving how research drive economic development in different parts of the world. Recent analysis of how genomics is influencing the United States economy, you can argue against that kind of impact. So I think the critical thing is really for these nations to recognize the central role of putting the right infrastructure in place. And when you do put the right structure in place, in terms of laboratories, they don't just support genomics, they support biomedical research in general. And then you begin to get young people excited about wanting to do work in the local environment and also being able to have a good life when you do that work. Nobody wants to be a scientist and you can't provide for your family. Your kids cannot go to good schools. So I think there has to be a recognition by local government and the businesses to know that it is important for us to put the necessary infrastructure in place. For example, I say, what is the excuse that a country as wealthy as Nigeria has, for example, not to be able to have an isolation laboratory like what the CDC has in a sense. Why can't we have that? I don't think it's really an issue of money. I think it's an issue of priority in a sense. So there are some instances where it's really an issue of money, but sometimes it's just issue of priority. How do we put things in place to make sure that we encourage the right type of behavior and the right type of interactions? Thank you. So this is sort of a related question and for both of you. So with projects like H3Africa, how do you see the genomic research of genetic medicine community collaborating with public health authorities and others to create and implement programs that sort of achieve the triple aims. That's no cost, effective, efficient care. And the question also is are anthropologists and social scientists and others being engaged so that you can create effective and sustainable change? Two deep questions. Do you want to start Charles and then Pardis? You can, sure, follow? Really, if I understand the question correctly, it's really how do we bring multiple disciplines together to make sure that we really reap the fruits of genomics? Yes. But also bringing it in a low cost, effective and efficient manner in those types of settings. Right. I think it's going to vary and it's going to depend on the specific thing that we are talking about. Some issues, like what we already see in terms of cancer treatment, are going to be driven by just that phenomenon. But there might be also understandings that lend themselves to public care. Let's say, for example, newborn screening. If we are able to develop a panel that replaces the current way we do newborn screening that can be deployed to different countries in a way that you don't need refrigeration, you don't need, you know, it's just a small box sitting somewhere and we can test it. That can revolutionize newborn screening in a way that is currently not doable in a sense. So I think it depends on the technology, it depends on the disease, and it depends on how the genomics is interacting or the crossroad of that genomic finding and society. I think that's really what is going to determine how it plays out at the public health level. Curtis? Yeah, no, I think that's absolutely right. Then there are so many ways in which really good genomics can change the way care. And newborn screening and even your preconception screening, all of that kind of thing is exceptionally important in care. Things like, you know, early testing for PKU, for example, fetal ketonuria, which is a metabolic disorder that can be devastating if not caught early. These are the kind of tremendous ways that it doesn't just lower cost and lower efficiency, but it transforms the lives of many. And from the standpoint of infectious disease, it's the same thing of early detection has an extraordinary impact on outcomes. And there are ways that right now we're seeing it. Unfortunately, you don't wanna be doing it during an outbreak, but the outbreak has galvanized a lot of different partners to think about what's the cheapest, closest bedside that diagnostic that we can get for these different things. So, and in all honesty, genomics is core and foundational for so many key parts of clinical care. I just wanted to just follow up a little bit. Again, the disease I spoke to you about earlier, they're called podoconiosis. It's also a very good example of how we have been able to use the genetic concept. You don't necessarily have to have that variant. What we've done in this disease in Ethiopia is that we were able to show that the risk, if you have a sibling that has a disease, the risk that another sibling in that family will have a disease is six-fold. So, we were able to show that to the community and we were able to show that to the NGO that helps to distribute shoes in that community. So, by giving them that kind of information based on genetic principles of family history, we are now able to prioritize limited number of shoes that come into that community in a way that the high-risk families get the shoes first. So, that's really the junction of genetics and public health in a very, very practical sense. So, one last question for both of you. If you gaze into the crystal ball and look at what the future, the real, real post-genomic era looks like, what do you see happen in 2025? Will there be a reduction in healthcare disparity? Will there be a new era where we can solve public health problems quickly? What do you see? What do you predict that world is gonna look like? Because we have mobile health technologies, we have changes happening... I'll take it from the micro-upside and maybe take it from the human side. From the micro-upside, I think that we will get to the point where we will have a really strong genomic surveillance program across the world, where when you go into the... where you get that cough in the middle of the winter and you wonder, what is it? Or am I gonna get it? Or who has it? You could actually get to the point where you could know immediately. And that's a huge thing because when you come in, the differential diagnosis for something that makes you ill is very, very long and there's no way to know. And so we have this huge advantage that the microbes don't have. We've got this information technology. We need to use it. It's not as simple or else it would be done because what we find is the more we look, we have this microbiome, we've got all sorts of microbes that are interacting with us, some good, some not good. So we're gonna have to go through and they'll probably take that decade to be able to really figure out what's the pathogen, what are the passengers, how do we do this? But at that point, we can get to that point where every individual may be in their home. Every time they get a cough, they just do their own little swab and then they know what they have. And that would be extraordinary and it'll probably require mobile technologies and all of these other kinds of things. You may just have it on your phone. So that's a world we can get to and I think it's a really exciting place. One thing I actually just, I hate leaving questions unanswered and I realize I didn't really get to that. The social part of the other question, I think it plays into this, which is that absolutely all those other sectors are really important and involved. We see in our outbreak response that while the diagnostics and the clinical care are important, so much of this sits on trust. When we talked about healthcare disparities, the biggest thing I think is also trust in the system. Where we have an issue in Africa right now is that you need to build trust. You need to know that if someone's telling you that you're quarantined in the site that you're in, that that's because it's the best place for you to be. Not the worst place, we're not creating a barrier to get you locked out from the outside world. We're creating an environment in which we're gonna help you and make you cared for. So I think it's very important that you get people from all of these different sectors working together. Right now, we're working with architects who think about infection control. We're working with epidemiologists who think about contact tracing. All of this is just one component of a larger puzzle and so not only do we need to get our genomics stronger, but we need to get our collaborative network stronger so that every aspect is considered, this is not the prerogative of any one domain. But genomics is moving very, very quickly and can be galvanizing in a lot of ways if used the right way. Thank you. Yeah, again, from the human perspective, I think that genomics is just like any tool. If you use it well, people will benefit from it. If you don't use it well, you will cause harm. In a sense, so if you sort of look in the future, I can see all of this playing out. But the challenge for us is to make sure that the good, fire seed, whatever consequences will come in terms of genomics. One of the things that I worry about personally is as we begin to use genomics to inform drug development, for example, are we doing that comprehensively enough that all human populations will benefit from the new drugs that we're going to develop? Because they are gonna be based on understanding of the distribution of genetic variation. And are we going to not deal with certain variation because they are not present in the United States, for example? So are we going to exacerbate her disparity as we do this? But we don't have to if we pay attention to it. So it's really not a characteristics of genomics. It's a characteristics of how we deploy things. And genomics may be a victim of that also unless we guide against it. Well, thank you both very much for a very engaging conversation and sharing your insight. Thank you. This brings us to the end of this conversation. Eric, was there any other announcement that needed to be made? 645. Yes, we have a reception that starts at 645. We have a next program. The next program is here, and then 645, yes. Thank you all very much. Thank you. Thank you. Thank you.