hello and welcome to pandemic live I'm your host Russ Altman and today I'm talking with Jean Lall Casanova of Rockefeller University about the genetic basis of the vulnerability to infectious diseases included including Kovan 19 which I'm sure is on all of our minds first a few comments I'm a professor of bioengineering genetics medicine and biomedical data science at Stanford University my research interest is in the application of computing AI and data science to problems in medicine I'm also and I think this is why I'm here today the editor of the annual review of biomedical data science and this is brought to you in part an entirety by the annual reviews organization I'm the host of a radio show called the future of everything which is also available on an iTunes podcast different from The Wall Street Journal podcast with a similar name unfortunate this discussion is part of the pandemic life an initiative to disseminate scientific ideas and findings that shed light on the Cova 19 pandemic pandemic Life is produced by the non profit publisher annual reviews as part of their commitment to bringing the knowledge and wisdom of the world's leading researchers to policymakers practitioners patients and the wide general public now over the last 25 years Jean Laurent Casanova has explored the genetic basis for a variety of severe infections that predispose otherwise healthy humans infants children adolescents and adults to a single type of infectious disease his work tells us that life threatening infectious diseases can be caused by what he calls inborn errors of immunity or ie eyes will try not to use too many abbreviations today along with his co-author and long-term collaborator Laura Abel Sean Laurent has published a terrific article recently in the annual review of pathology mechanisms of disease and it's entitled lethal infectious diseases as inborn errors of immunity toward a synthesis of the germ and genetic theories Jean Ron and I will discuss this work and how it relates to covert 19 now do send your questions in the Q&A box at the of the zoom window under the YouTube video or tweet them so that's three different ways zoom video YouTube video or tweet under the hash tag pound signed AR pandemic life we have a team of trained curators who will be looking at your questions and feeding them to me after my conversation begins with with genre so with that I think we'll start John the Ron thank you so much for being here Before we jump into covin 19 which of course many of us are interested in I think we should take a few minutes for you to give us some background on how and why genetics may play a role in the severity of infections is this a new idea how long has it been around what's the evidence for this kind of hypothesis Russ thank you for inviting me but you know if you ask me three four or five questions in a row I can't memorize them I won't be able to answer okay so let's try to ask questions one by one all right okay so the first gave us some of the hold on oh the first thing I want to say is - thank you okay the second thing I want to say is that is the first time I'm doing a webinar also the first time I'm on YouTube so I'm thrilled and also to some extent intimidated or worried okay now your third the third thing I want to say is to try to answer one of your many questions and perhaps it's best that I introduce myself I'm a professor of pediatrics and my lab has been testing the idea that severe catastrophic infections striking previously healthy children adolescents or young adults in the course of primary infection may result in some cases perhaps in many cases from single gene inborn errors of immunity that is monogenic disorders that are clinically silent until the patient is exposed to and infected with a particular microbe okay so that's what we've been doing for 25 years how did you get interested in this line of research as worthy of your time well you know so have a pediatrician and the the most common problem faced by pediatrician is childhood fever childhood infection no childhood death of fever and childhood death of infection so this is really a fundamental prom in Pediatrics and what is really striking is that for every pathogen virus bacterial fungus or a parasite children who suffer from severe clinical disease are actually infected by a microbe that is harmless in their relatives sometimes their siblings parents also the health care workers so it'd be the Enigma that is phased by pediatricians and internists to some extent is that for any given microorganism there is gigantic inter-individual variability in terms of the clinical manifestations of infection it ranges from silent infection in asymptomatic individuals to life-threatening and sometimes lethal disease what what varies from microbe - microbe is the proportion of silent versus life-threatening disease the proportions vary some microbes can kill less than one in ten million infected individuals these are very rare infections these microbes are typically commensals or sacrifice they're everywhere and they're harmless in most in the vast majority of people but in one in a million or one or ten million they can kill and at the other end of the spectrum you have viruses or other pathogens that can kill one percent ten percent sometimes twenty or thirty percent of infected individuals and in between you have everything microbes that can kill one percent 1% one in ten thousand one in hundred thousand so this is this inter individual clinical variability in the course of infection that I think is the fundamental infection enigma and that's the problem that my lab has been interested in for near more than 25 years great thank you so in your review article that I referenced in the introduction you outline three categories of inborn errors of immunity that contribute to the susceptibility for infection could you take a moment to review these three areas and perhaps give an example of what goes wrong or what is the genetic problem in in each of these three areas right so the the discovery that some genetic variations can underlie severe disease in the course of infection in a previously healthy individual that discovery followed three sets of studies corresponding to three steps that I'm gonna briefly try to explain to you the first group of inborn errors of immunity are often referred to as primary immunodeficiencies they were clinically described in the 50s and the genetic variations the mutations responsible for disease were deciphered from 1985 onward these patients typically missed a big component of host defense they lack a subset of leukocyte or a molecule produced by leukocytes that is of great importance against a variety of infectious agents therefore these patients early in life suffer from multiple recurrent infectious diseases sometimes even often infectious diseases that are unusual rare in the general population a good example are babies who like lymphocytes such as the famous child who spent years in a sterile bubble to provide Lemmo exactly to prevent him from being exposed to environmental pathogens so these are rare conditions we said that they're Mendelian meaning that they're caused by single gene lesions that are highly penetrant that is if you carry the at-risk genotype then you will display both the immunological consequences the lack of leukocytes subsets for example and the infectious consequences that themselves result from the illogical anomaly so these are the primary immunodeficiencies but you understand easily that this is very different clinically from say a cousin of yours who would have TB or a friend of yours who would have meningitis but would otherwise be normally resistant to infectious agents but still you know these primary immunodeficiency is provided proof of principle that in humans infectious diseases could be genetic okay so that is step one the second step is a series of studies that have focused on the what we call Mendelian infections these are clinical conditions that were described earlier for some of them earlier than the primary immunodeficiencies from 1946 onward these are patients who are vulnerable to one microbe only one and this unusual vulnerability to one relatively rare infection segregates in families like a Mendelian trait these infectious diseases are unusual because they're rare because they said they run in families literally as as a Mendelian trait and there are different types of Mendelian traits but they really run in families and these patients are otherwise paradoxically normally resistant to other infectious agents unlike patients with or deficiencies who as we've discussed earlier you know are prone to a variety of infections so these five there are five such Mendelian infections they were clinically described from 1946 onward and from 1996 onward the genes were cloned and the molecular basis of these very unusual Mendelian infections were discovered what's interesting with this small group of patients and I'm going to give you one example but what's interesting is that they provided proof of principle that infectious diseases striking otherwise healthy individuals normally resistant to other infectious agents could also be genetic so that was the second step you know getting closer to the situation with which you're familiar you know you're your uncle or your friend suffering from a common life-threatening infectious disease and I'm gonna give you one example of these five Mendelian infections it's a condition known as Mendelian susceptibility to microbial diseases this these children adults are or children adolescents or adults are fine until they develop severe disease caused by mycobacteria a group of bacteria that are the big witness in the environment or until they're vaccinated with the BCG vaccine against TB which is a live vaccine and that can also cause disease in these patients there are these patients suffer from inborn errors of gamma interferon immunity that is they carry mutations that prevent that that reduce or abolish the production of gamma interferon or the response to gamma interferon so what we've learned from this experiment of nature so to speak and from the other for Mendelian infections that we will not describe detail today is that there we're truly genetic disorders that can make people vulnerable to one micro and with high penetrance these are Mendelian disorders if you carry the genetic lesion you're prone to a particular infection so that's step number two the third step evolved from 2007 onward with the discovery that there were common infectious diseases in the general population that could be caused literally not only by the infectious agent but also by monogenic lesions inborn errors of immunity that do not display complete penetrance that is a child an adolescent or an adult with one severe infection with no medical history himself/herself or in his or her family that is this infection is not running in the family it's sporadic it's isolated and for a number of infectious diseases that we're going to discuss in a second monogenic inborn errors of immunity have been discovered so that is the third step and the the first I think discovery was published in 2007 with mutations in a pathway that underlie herpes simplex virus encephalitis this is a relatively I wouldn't say a common infection but it is not a rare infection it unfortunately strikes maybe one in 10,000 children herpes simplex virus is in almost a bigot as virus people are infected they typically have gingiva stomatitis and when there are recurrences they develop herpes lab jelly's but in you know one in 10,000 children the virus doesn't stop in what we call the trigeminal ganglia near you know in front of the ear here the virus and fertile goes to the brain and causes encephalitis well it was discovered from 2007 onward that this sporadic tragic disease can be caused by inborn errors that impair immunity of neurons in the brain against herpes simplex encephalitis so these are the three steps from 1985 onward that led from you know the baby bubble as you say the severe primary immunodeficiency kids vulnerable to everything to the discovery of sporadic isolated infectious diseases of humankind being caused by monogenic inborn errors of immunity with incomplete penetrance well well thank you very much that's a beautiful setup now to give us a kind of a more deeper understanding of the the set up for what you now know I'm going to ask which is what is your sense now of the situation with Kovac 19 and the possibility that there are the same kinds of processes happening in the current pandemic well Russ this is a of course an important question a timely question also night around 95% of the severe cases of kovat are probably accounted for by age or pre-existing comorbidities or both it seems weather in Asia in Europe in the Middle East in the Americas that most people who is Co vide severe pneumonia people who require oxygen and admission to an intensive care unit most of them are older than 50 or 60 or 70 years and most of them have one two or three comorbidities metabolic disorders cardiovascular disorders or pulmonary conditions so that does not translate immediately into molecular cellular or immunological terms but we understand from this epidemiological description that aging sick frail individuals are more vulnerable to SARS coronavirus than previously healthy young people now in that context it still is surprising and even shocking that one to five percent of the severe cases are younger than 50 years of age and do not display any overt medical condition that can be someone who would be running the marathon in October 2019 and now in April 20 2020 he or she is in the intensive care unit intubated and ventilated so that's the problem that we're trying to tackle and as you suggest this problem is very similar to the problems that our lab and other labs have tackled in the last 30 years someone who would have severe flu for no reason or someone who would have severe tuberculosis and nail or severe purpose encephalitis as we've discussed and now it is someone with severe kovat for no apparent reason so that's the problem we want to tackle the way we want to tackle this problem yeah you want to ask a question I'm sorry I'm very long you know I'm long and worried language in French in French I would be much more concise but you know I don't think you can learn French fast enough to interview me well I can tell you I would be extremely pretty concise if I were to try to speak French but actually I was going to ask I think the question you were about to answer which is you have tracked down in your career similar associations so what kind of data needs to be collected in order for you and your colleagues to get started on understanding if this does in fact have the the genetic influences that you suspect in May right so I've told you but the problem too is the hypothesis but you you've just said the hypothesis the hypothesis that severe kovaydin previously healthy young people can be genetic single gene inborn errors of immunity with incomplete penetrance okay that's another you're asking me what's the third step which is the approach so because these are relatively rare patients we decided with Helen sue at the NIH early on in February to try to collect patients to recruit patients all over the world and to team up with colleagues in Asia Oceania Africa Europe and the Americas why well because what we've learned from the previous studies of infectious diseases is that there is what we call in or jargon genetic heterogeneity that is for a given infection there can be mutations in different genes so for example a patient with severe could be in New York City may be mutated in gene a and there's another patient mutated in gene a in Tokyo Japan and a third in Sydney Australia so the only way to suspect that gene a may be causative of severe kovat is to have these three patients because then with three patients with even the same gene the likelihood that the gene can be responsible for severe disease is much higher than if you have only one patient mutated in that gene so we've decided early on to start an international consortium which we've designated as the covered human genetic effort and the website is by the way human kovin human genetic effort calm and we are organized in a very simple manner there are hundreds of hospitals worldwide that recruit and consent patients they take a blood sample and DNA is extracted and the DNA is sequenced by a sequencing hub that is regional there are already I think thirty more than 30 sequencing hubs Japan Australia and the Middle East in Europe in the Americas and these sequencing hubs analyzed the data of the patients in their region but also they work together so that all exomes and genomes from patients worldwide can be analyzed together in order again as I stressed earlier to increase the chance of detecting genetic homogeneity so um before I ask my next question let me remind the listeners that if you have a question you can post it on the zoom on the YouTube comments or at the hashtag AR pandemic live I know there are some questions coming in we will get to those in about six minutes and 49 seconds but my next question on on that note is are you this is a very exciting consortium that you've assembled and and we are all rooting for you to find out if you if we can give clinicians information about those who might be at greater risk is the consortium focusing on these young folks that you refer to less than 50 no existing comorbidities or is it a broader that's even including the older patients no we really try to recruit young previously healthy patients no comorbidity and younger than 50 years now you you may say rightly well 50 is arbitrary what's the difference between someone age 49 and 51 true there's no difference and in addition you know at a given age people can be very different people age in different ways so it's a threshold that is convenient but it's arbitrary therefore if a clinician somewhere sees a patient age 60 or 70 who was in great shape and all of a sudden has severe cough it'd you know that patient could be enrolled as well so as you know I'm a little bit of a geneticist myself and we as we always worry about the interaction between metics and the environment and so I'm wondering in this effort if there are plans either well underway or just still in the planning process to evaluate potential environmental factors in these young people that could also contribute to the severity of the infection well environmental variables may account for inter population differences you know you can think yet yes maybe the epidemic will take a different term in a quarter in Iceland that's plausible but you know these differences are unlikely to account for inter-individual variability in a given region within Iceland or within Ecuador for example are there so that's that's very interesting and I I'm actually a little bit surprised by that it's a because there is these possibilities that specific exposures in the diet or specific histories of other infectious disease in the past which I would generally put under the category of environmental it seems to me possible that those micro differences that could be different within within a population but obviously I don't I don't I haven't done this work and it's so it's interesting for me to hear that you believe that within it within it within a cohort but you with enough numbers you'll be able to average out those effects I guess that's the argument Oh Russ I think I think we misunderstand each other I misunderstood your question so I'm not saying that the history of the individual does not matter it may very well matter as you rightly point out the history of previous infections by other coronaviruses for example may be beneficial or detrimental when the host is infected by SARS coronavirus - that's unknown right okay and I agree that for example the corona virus SARS one that was limited to China you know it may be that in China people who had previously been infected with the sarkodie one may be the course of Sasuke v2 infection is going to be better or worse that's unknown but it's possible I'm with you here good thank you the we're gonna be going to questions from the audience in a moment but I also wanted to ask and I'm a little bit embarrassed to ask this question because I do research as well and the research timescale is never satisfying to the public future don't ask me a question about the future I am compelled to ask you in the name of our people listening could you give us any sense of timeline yes let me look at my crystal ball and give me a second all right well no I I got no answer okay I understand and I accept that answer so I for those who are wondering about timelines people work as hard as they can but in science you can't predict when the insights and when the observations come that are going to give you the answer so I totally understand my colleagues hesitancy to answer anything about timeline it sounds like they're working extremely hard and that's really all we can ask Thank You Russ Russ Russ we're scientists we're neither magicians nor politicians okay we're doing our best we're working hard but I I can predict the future thank you so we do have some questions I'm now going to go a little bit early because they look good from Adam we have the question is your research showing potentially that only certain genetic mutations could predispose someone to a potentially lethal kovin 19 result I'm not sure do you ask me a question this is from Adam yeah he's in our he's in the audience and he wants to know I guess would your research discover a genetic mutation if it was strongly correlated with lethality of kovat oh yes so you know strongly correlated with lethality or severity of CO vid would imply that we have two or more cases probably dozens of cases that is dozens of patients carrying mutations in a given gene that that is an optimistic scenario because it suggests that there is high genetic homogeneity that we could find many patients carrying mutations in the same gene it is possible and then Adam followed up with a much more specific question about whether it's possible that existing mutations that are known to predispose for other diseases like retinal blastoma or other kind of phenotypes are they at more are they more likely to be the ones that we find or is it possible that we're gonna find something entirely new so retinal blastoma it's hard to see a connection but we have to be humble and agnostic a more you know obvious example are the inborn errors that underlie pneumonia caused by related viruses not corona viruses but influenza virus or Rhino virus so there are already examples of viral pneumonia severe viral pneumonia that is genetic these errors could also underlie severe it could be that's possible yeah so I think that so in fact Anna from the audience asked the question about whether it is possible that there are other specific viruses who's up who's pattern of severity would correlate with the patterns of severity that we see with kovin well I think that the SARS coronavirus 2 is the most virulent virus since 1918 in terms of pneumonia so there is no recent example yes there's a couple of questions I'm sure you're familiar with bio banking efforts in the world and in particular the UK biobank which follows 500,000 residents of the UK and has both genetic information and some clinical information they recently decided to release information about the subset of 500,000 patients I'm sorry the subset of 500,000 participants in the UK biobank who have been infected by kovat I'm wondering if that represents a useful the question is from the audience does that represent a useful resource for your consortium yes I think UK biobank is an extraordinary gift to humankind and this is really a wonderful resource I wish there were more equivalent resources worldwide and for our studies of tuberculosis in the past we've we've used UK biobank with success and when they released the COBIT information last week since that day we've been analysing almost day and night the UK biobank so we're working on it another question interesting question they're all interesting is you mentioned that you're focusing on young people with no core mobility because it seems to be a much more complex issue for the elderly but this person asks might there be genetic damage accruing over age throughout the lifetime of a elderly individual damage to their DNA that actually does cause their increased susceptibility to the disease yes it is it is plausible another good example is zoster everybody most people are infected with the varicella zoster virus in childhood they have varicella but then the virus is latent but from the age of 50 years onward zoster appears and you know it's an indicator unfortunately of the inevitable aging of human organisms and I think the same applies to of it well somebody was listening very carefully to your useful summary of the three different categories of inborn deficient deficiencies of immunity and their question is is it possible that this is a polygenic process in the sense that we don't find one gene but it's the interaction between several genes that causes this increased susceptibility and if so would your consortium be able to detect that so the monogenic disorders that do not display complete penetrance and that have been discouraged from 2007 onward by definition in fact literally are not monogenic because incomplete penetrance implies the involvement of other genes perhaps a second locus perhaps - and perhaps more so what we're searching is the main driver the monotonic lesions but we certainly do not exclude the possible contribution of a second hit or a third or a fourth you know but we start by trying to identify the key lesion the key variation the key genetic disorder so there's a very practical question um if a mutation is discovered through your consortium or for the efforts of others can you imagine what kind of practical impact it would have for clinicians dealing with treatment and prevention or perhaps how has it affected it in the other examples previously well that's another great question you know I can answer in two ways the first answer is a general answer it is that the first step in medicine in medical research is to understand because once you understand a mechanism of disease you can start thinking rationally about ways to prevent or treat it okay that's a general abstract answer but it's validated by 200 years of medical research the second more specific answer is as you suggest based on previous examples and here we're going to discuss again Mendelian susceptibility to micro battle diseases these patients are vulnerable to micro bacteria because they don't make enough gamma interferon or their cells do not respond well to gamma interferon well it turned out that gamma interferon is a medicine that's been on the market for 40 years and that you can buy at the corner of the strip so the identification of the genetic and images of Mendelian susceptibility to mathematical disease immediately provided a way to prevent micro battle disease or treated in this page you know it's very similar to insulin for the diabetic patient you essentially provide the component that the organism does not produce in sufficient amount near Ida I'm not saying that in three months we're gonna have a chimera coulis component for Kumud I'm just saying that it's a rational approach to try to understand the mechanism of severe corvid and that by analogy with other genetic disorders that may at some stage lead to preventive and therapeutic advances yes and if I could add as you know people are now beginning to worry about how do we how do we reengage society and obviously if we had these very valuable biomarkers or indicators of who's at particular risk we could come up with a plan where they get some special treatments a management special management of their situation because we now know if this information becomes available that they would be at increased risk so that really does make perfect sense as a public health as well as a personal health intervention now we have many questions from people this is actually very exciting from people around the world we have somebody in Lombardy Italy we have somebody from Brazil and the questions are similar which is what are the chances in your assessment that there are country or geographically of geography of origin specific genetic mutations that are leading to higher rates in Italy or in Brazil or in any place in the world versus that being a function of other non-genetic factors so that's that's a yet another great question you know I hesitate to stick my neck out here because if I follow my instinct I would say that the inborn errors of immunity underlying the severe forms of kovat are probably equally distributed you know across ancestries in the past people would say across ethnicities that that would be my instinct because I think that we're searching mostly for rare variations that are highly pain and I would be inclined to think so however we may have surprises and it may very well be that in some ins histories there are more common variants that have a greater impact because they are enriched in that particular group of people in that particular ancestry or conversely defeated so you know I'm not gonna take any bet yes there was a kind of a related question that came up which is we've been talking about mostly about genetic variations that increase the risk of the disease somebody asked is it possible that you will learn that there are certain genetic backgrounds that get protected from the disease absolutely well another fascinating question it is not proven yet but I think there's every reason to believe and in fact to hope that some individuals exposed to the virus again and again for example the sparrows of someone who ends up in the intensive care unit or healthcare workers with insufficient protections would remain seronegative that is would not even be infected by the virus despite repeated exposure these people naturally resistant to the infection itself if they are identified would perhaps be genetically resistant and there are examples for two viruses the norovirus that cause gastrointestinal lesions individuals homozygous for a variation in the gym called fut2 are naturally resistant the virus simply cannot enter the intestinal epithelial cells another well-known example is a mutation in ccr5 these individuals when carrying two copies that are mutator of ccr5 are naturally resistant to the human immunodeficiency virus so there are already two examples and you know there might be humans genetically resistant to the source code of the virus to we're trying we're trying to detect these individuals and if they exist we'll try to find the genetic underpinnings the the questions that are coming in are extremely excited about the consortium that you described the international collaboration it's very inspiring I think and one question very simple as how is it going with respect to sample collection and are you at the hundreds or thousands or where are we in that process they just what we're asking about the numbers so you know I cannot speak on behalf of my friends and colleagues in Japan or Australia or elsewhere but in Paris we've already enrolled a hundred patients and we've already sequenced about 50 in New York we've enrolled fewer patients but it's also progressing is it harder to get research done in New York you know the reason I'm asking is we have lots of research happening at Stanford University our curve has been flattened pretty effectively and so now we have this it's not really a problem it's good news people are not as sick but we also don't have as many patients as we thought we would to do clinical research so there are some drug trials and some diagnostic and therapeutic trials that are actually stalling a little bit because this is good news I just want to stress that I am not complaining but we're not having the patients that we were expecting I think there might be an opposite problem in New York and of course Rockefeller universities in New York where it was my impression that for the last few weeks people have been so much just trying to get on top of helping these patients I'm just wondering has it been possible to get any research done in New York well yes we've recruited patients and we collaborate closely with University Hospitals in the city you know I think most if not all institutions in New York have teamed up with us and with the New York genome Center Tom maniatis who's the current head of the New York genome Center has agreed to sequence the genome of these severe unexplained young cases for us so they form one of the sequencing hubs and and I think perhaps the final question before we close up is there's a lot of questions about whether you're looking at drug response and the genetics of drug response as part of this study no we we we haven't so far decided to tackle this other important problem so listen I think that this has been wonderful I want to thank all of you for joining us I want to thank dr. cousin over for joining us we hope you enjoyed it we hope this was useful and science-based because that really was our goal you can find this and other episodes of pandemic live at WWE annual weekend make sure I say this correctly WWE annual reviews all one word dot org where you can also find Jean Lawrence review article that we've referenced and remember to join me on the future of everything on podcast or Sirius XM if you're interested doctor Casanova thank you so much for your time and for your work ruse thank you so much for your invitation this ends the formal portion of our program I'm going to leave the zoom
