Tuesday, May 12, 2020

Steven Cherry Hi, this is Steven Cherry for TTI/Vanguard.

The world has been concentrating on the epidemiology of the novel coronavirus and Covid-19, and with good reason. We need to know how far and how quickly the virus spreads, and which areas might safely come out of hibernation sooner rather than later.

But ultimately many of the most important questions lie at the level of the individual person.

Why does the disease overcome some people while it leaves others without symptoms entirely? What’s the role of co-morbidities such as obesity, diabetes, and heart disease? How much does it have to do with our immune systems—is there a perfect level of response, attacking the virus vigorously, but not too vigorously? Ultimately, are there genetic differences among people, such that we could predict who will likely get the virus, and at what severity, by looking at their DNA?

And finally, testing and immunity—does getting the disease render you safe to others who haven’t had it yet? Does it shield you from getting it again? Forever? Or could it return in a different, maybe worse form, the way chicken pox comes back as shingles? And what role can the study of genetics play in developing tests and a vaccine?

My guest today won’t have all the answers, but he is a great person to ask the questions of.

Dr. Robert C. Green is a Professor of Medicine at Harvard Medical School, a medical geneticist, and a physician–scientist, who directs the Genomes2People Research Program at Brigham and Women’s Hospital, the Broad Institute, and Harvard Medical School. His M.D. is from the University of Virginia, and he has as well a master’s degree in Public Health, specifically Epidemiology, from Emory University.

Robert, welcome to the podcast.

Robert Green Thanks, Steven. It’s great to be here.

Steven Cherry Robert, your area is preventive genomics and you’re a clinical geneticist. Those seem like two different things.

Robert Green Not so different for me, in that—but you’re right, the science of clinical genetics has been concerned with super-rare diseases in the past and mostly with making a diagnosis. So the classic patient is a child who is identified to have something unusual and the geneticist is called in to try to make a diagnosis, maybe help the family avoid having a second child with the same condition. But you know, genomics has exploded in every domain of medical science. And one of the areas is the degree to which genomics is going to allow us to anticipate, predict, and prevent even common diseases, all sorts of cancers, all sorts of cardiovascular disease, dementias like Alzheimer’s disease. And this brave new world is a world where we’ve been calling preventive genomics. And that’s what I’ve been focusing on most recently.

Steven Cherry Very cool. So what do we know about the genomic structure of SARS-CoV-2?

Robert Green Well, keeping in mind that I’m not a virologist or an immunologist, but I have been looking into some of this because so many people are fascinated and asking questions. We know that this is a particular kind of virus. We know that it is the coronavirus family, everybody’s heard. We know it’s different from the influenza virus that we’re familiar with in that it’s more contagious, it has a longer incubation time, and therefore, it’s got a much higher community-attack rate. And we also know that there is tremendous heterogeneity in terms of how people are impacted. You can have people who literally have no symptoms whatsoever with the infection, to people who have multi-organ systemic failure or two people who, of course, are overcome by the disease and don’t make it. So that’s one of the fascinating things about this, is how broad the symptomatology can be.

Steven Cherry Yeah, it, I guess, lodges in the lungs the way a lot of other infectious diseases do, but it seems to be able to ravage the entire body from head to toe.

Robert Green That’s right. It’s got a particular propensity probably through infection to come in through the nasal epithelial cells and the respiratory cells. But then, it’s very clear, as this has developed, that there are people who have different degrees of liver failure, different degrees of kidney failure, that have G.I. problems, that have brain problems—everything from stroke and seizures to just sort of the confusion that you would expect with such a severe illness—has conjunctivitis and inflammation in the eye membranes, people ... Back to the nose, people can lose their sense of smell, and not so long ago, really a surprising recognition that there can be people who have carditis, an inflammation of the heart itself with the virus. So it’s really got a protean set of presentations in addition to the obvious very severe pulmonary symptoms that people are aware of.

Steven Cherry It’s also been surprising people in terms of factors that might contribute to susceptibility. I mean, I was surprised to hear that blood type might contribute. And what else are we learning?

Robert Green Yeah, that’s right. I think, you know, it’s really important to sort of separate underlying medical vulnerability. And just to reiterate those that you mentioned before. Age seems to be the number one issue. So older people are at greater risk almost regardless of underlying disease and vulnerability. But then there’s a clear gradient where people with lung disease, diabetes, hypertension, immune deficiencies of various kinds, are at increased risk for severe symptoms and death. So that’s sort of the diseases that they have. But if you set that aside, you just sort of take a population of ostensibly healthy people, middle aged or even younger. Some of them, as we said, are getting really severe symptoms and some of them are getting very mild symptoms. And that’s really mysterious. Why is it that some of them are getting such severe attacks and others are doing so well?

Now, people been looking, well, I should just step back, Steven, and say the scientific community, like the frontline medical community, has reacted to this whole pandemic with unbelievable intensity, commitment, collaboration, cooperation and speed. I’ve never seen anything like it in the decades of my scientific career as the intensity with which scientists are working together and they’re working with within whatever domain they can. So in my domain of genetics, we’ve been looking at all the different possible reasons why some people could be more vulnerable than others, what you might call host vulnerability. Because we’re the host for the virus. And as you said, there is some early indication that blood type—that was one of the first indications that certain blood types might be more vulnerable. So, for example, studies from China and New York City were suggesting that a blood type—A as in “apple”—might increase susceptibility while O blood type—O as in “olive”—might be protective. And so that was sort of a very crude genetic distinction between different people.

And then there were other clues. So, for example, we’re pretty sure that the little spikes on the virus attach themselves to a specific protein called the ACE2 receptor. And that particular receptor, like all proteins, it has a genetic code. And it turns out that there is at least 17 different variations in humans of that genetic code. So we’ve already got some early evidence that two of those variations are more resistant to the virus hooking on to your cells. Now, in and of itself, that’s not terribly useful information. It’s not like we’re going to go and identify a few people have that variation, say, hey, it’s OK for you to go outside.

But there are parallels to, for example, HIV virus there and clues like this can help accelerate the discovery of treatments and vaccines. So you may remember in the HIV world that the CCR5-delta 32 variation that’s quite rare was also protective in the same way for HIV people. The virus couldn’t really hook on to people’s cells if you had that variation. And that’s really spurred research on HIV vaccines. And although we don’t have any yet, it’s a starting point. And then by the same token, these kinds of genetic variations might be clues on which the whole world could build some rapid progress for vaccines and treatments.

Steven Cherry You mentioned this, the intensity and speed with which scientists are working together on this, and I guess you mean globally. You’ve been involved in something called the Hosts Genetics Initiative.

Robert Green Yes, that’s right. That’s right. This is an initiative that was first organized from groups at the University of Helsinki and here in town at the Broad Institute. And it bears mentioning that, you know, people have generously donated their DNA to DNA biobanks all over the world, including our MassGeneral–Brigham biobank here in Boston, that has already over one hundred and twelve thousand people who had volunteered and who donated DNA and a subset of those we’ve already genotyped and sequenced. And what’s happening is that collections of biospecimens and collections of DNA that exist in multiple locations all over the world can be leveraged to try to find rapid answers around Covid.

The way it works is this in our health care system, in our MassGeneral–Brigham health care system, you know, these hundred thousand people, a certain percentage of them are getting sick with Covid, and that’s being put down in their medical records. And this DNA analysis we’ve done in the past is already linked to their medical records and they’ve already given broad consent for use of this information in scientific research. So we can quickly find the people who had severe symptomatology and, for example, compare them to the people who had mild symptomatology.

Now, even with one hundred thousand people in our Boston Biobank, it’s going to take us a while to get to the numbers we need to look at this with validity. So what do you do? You coordinate our biobank with somebody else’s biobank and somebody else’s biobank. And these colleagues around the world have just sort of self-aggregated into this remarkable consortium that is aggregating over 600 investigators, over 150 different teams, to try to pull these data together quickly. And so, again, I’m not exaggerating. I’ve never seen anything move this fast. I’ve never seen institutional review boards review protocols so fast. I’ve never seen people so unselfishly dedicate their staff. We have staff that we’ve pulled off of other funded projects and have put on these projects, as has everybody else. It’s pretty remarkable.

Steven Cherry So I guess I guess in part the goal is to create a common framework so that data could be more easily shared and compared, and aggregated, and disaggregated. It’s interesting to me that this large international group did its work using things like Zoom and Slack and Google Docs. Have these tools made a big difference?

Robert Green You’ve named them exactly what we’re using. That’s right. We are putting the documents together on Google Docs. We’re talking to each other on Slack and we’re having a weekly call every week on Zoom with several hundred people. So that’s it ... we’ve been using these, of course, in our small labs. We’ve been using them for smaller collaborations. But that’s exactly how it works.

Steven Cherry A key question right now is how best to treat Covid patients. It seems E.R. physicians and nurses have learned a lot just in the field. For example, early on, the ventilator protocols they used were basically the same as for other respiratory illnesses. And now that they know that the best practices are quite different. But scientists like yourself also studying the role of genetics in treatment?

Robert Green Many people are. And, you know, I have to caveat this by saying I am not treating patients. My wife and my daughter are actually in the front lines. So I am hearing a lot about it. And I’ll tell you what I know. But there are peculiarities. For example, it turns out that the kind of lung disease that people get with Covid allows you to get rid of some of the CO2, even as your oxygen is falling. And what that means is the air hunger that people typically get when their oxygen is falling, which is signaled by the CO2 accumulation is not as present. And my colleagues in the emergency room are describing scenarios where they’re watching somebody talk on the telephone to their family—sit there and talk—looking perfectly normal while the oximeter shows their PO2, their oxygen level in their blood, is dropping to 90, to 85, to 80, to below 80, to the point where they suddenly pass out and then they’re in respiratory failure. So this is just one example of the way that E.R. docs and pulmonary specialists, in fact, all the clinicians on the frontlines have learned to anticipate this kind of rapid pulmonary decline.

And so there’s lots of nuances like this. I wouldn’t be in a position to name them all, but there’s lots of nuances like this where the clinicians who are taking care of patients are learning special ways of anticipating problems and special ways of managing problems. And you know, Steven, this is one of the nuances that kind of gets lost when we’re talking about when to go back to work and when to open up society and all of this, because we’re not just sheltering in place and wearing masks in order to push this out for some abstract reason. We’re buying time to figure out how to best manage patients so that when people get sick, they are treated better and better and they survive more. We were literally buying time for people to live longer because the medical system is less overwhelmed and is learning from every single case that comes through.

Steven Cherry Have scientists found any role of genetics when it comes to treatment?

Robert Green We’ve written a paper that we’ve submitted actually that we have proposed a sort of hypothetical set of advantages. If you had a system—which my group has been advocating for years—if you had a system where your DNA and my DNA was already available along with our electronic medical record and it was already integrated, then yes, I believe that there would be some distinct advantages. There would be certain kinds of rare diseases that would make you more susceptible to metabolic crises if you were in the intensive care with Covid. There would be certain kinds of genetic changes that would make you more likely to have a bad effect if you were intubated with a certain anesthesia drug. There would be certain kinds of genetic changes that would put your lungs at more risk for pulmonary failure and therefore you should probably be monitored more closely.

So it’s mostly hypothetical, Steven, because we don’t have that genetic information available in the day-to-day care of patients. But it’s just another example. I don’t want to take anything away from the severity of this pandemic. It’s horrible. It’s a life-changing once-in-a-generation sort of event. But this is a fast-moving pandemic and we are dealing with millions of deaths a day from the slow-moving pandemics of cancer, heart disease, and Alzheimer’s disease. And in all of these pandemics, fast and slow-moving. If we had genetic information integrated into our health care, I think we could do a better job of taking care of people every day.

Steven Cherry Let’s turn to testing. The antigen testing, that is for whether Covid-19 is active—that is, if a person currently has the disease—is very different from antibody or serologic testing—that is whether a person has been exposed to the disease and has developed antibodies for it. Why are they so different and why is the latter testing seemingly so much harder to get right?

Robert Green That’s exactly right. We’re really talking about two very different kinds of tests. The antigen testing or the testing for the virus is looking for the genetic signature of the virus itself. That’s where they’re sticking that swab up your nose or back your throat. They’re scraping it, they’re trying to get some virus on that swab. They then put that into buffers and then quickly reverse-transcribe it and see DNA, amplify it up through quantitative PCR, and—which is just a fancy way of saying they’re going to turn it from RNA into DNA and measure the amount. And if the amount is high enough, you’re positive. And so there that test is actually saying, yep, you’ve got virus in your nose and therefore you’re infected. And if it’s positive, that test is very reliable. I think you can believe it if you are positive for that PCR test. The trouble is, if it’s negative, it’s—and we think there maybe is somewhere between 10 and 30 percent false negatives—so that test needs to be continually improved. There seem to be people who have a lot of the virus residing in their nasopharynx and others that don’t. Maybe it’s in their gut or it’s deeper in their lungs. And so you don’t pick it up when you swab the nasopharynx. So that’s the PCR diagnostic test for viral infection.

As you said, the other kind of testing is what we hope to have soon, which is serological testing or antibody testing. This is a test for specific antibodies that your own body is making in response to the virus. And there are dozens of companies rushing to make these. They there are EUAs—emergency use authorizations—from the FDA to all these companies. So they’re able to produce them with very little validation data. It’s a necessary Wild West, but Steven, it’s a Wild West. We don’t know the accuracy of all these tests by far yet. And there’s pretty good data that’s kind of in the opposite direction here. So if you’re negative on the antibody test, you’re probably still vulnerable if you’re positive. It’s not quite clear yet whether you’re protected or not because you could be—it could be a false positive or you could have antibodies to an earlier virus that wasn’t the Coronavirus that got a so-called cross-reacted with this particular test.

So everybody’s struggling with this. But eventually, eventually, the antibody test is going to give us really good insight into who’s been had it and is presumably at least temporarily immune to re-catching it. Now, all of these statements are said with humility at this point, because we really don’t know how much immunity is conferred. We really don’t know, if it is conferred, how long it lasts. And we really don’t know if you can, after a certain period of time, catch the same virus again or next year catch a slightly mutated version of the same virus, like with influenza.

Steven Cherry What would it take to know the answers to those questions with more than a presumption?

Robert Green It really takes the kind of trials that actually everyone is jumping into action and doing, you know, in my hospital, for example, at Brigham and Women’s. There is a tremendous there’s an actual data mart, they call it. There is an actual committee adjudicating hundreds of research studies to make sure that they don’t unnecessarily overlap and that they’re working collaboratively together. And so blood samples are being taken and analyzed. Symptoms are being recorded, bioinformaticians are scraping data from the emergence from the electronic medical record and from the emergency rooms. Samples are being donated—even in the midst of being super-sick with this illness, people are being asked if they will donate samples and they’re saying, yes.

You know, if ever there was sort of a nobility to participating in research both in the past where we have these DNA biobanks already available and in the present crisis where sick people are thinking about other people than themselves. This is really bringing out the best in our scientists and in our patients. It’s amazing.

Steven Cherry That is great to hear. Finally, what role does genomics play in developing a vaccine?

Robert Green Well, it plays a major role. And again, I won’t present myself as an expert in this arena. But in general terms, the idea is that you create something in your body that actually gets in the way of the virus, either attaching on, or the virus replicating. So either it never gets into you in the first place or once it gets into you, you’ve essentially disabled it.

And one of the most obvious areas is this spike I mentioned in the beginning because we know that that’s the mechanism by which it attaches to the cell. We know it attaches—the spike specifically attaches to this receptor. So, for example, one of many strategies is that you develop a vaccine that looks like the spike. So your body makes an antibody to that spike and that antibodies now circulating around in your body. And when the virus comes along, it says “Aha! Here’s what I was built to respond to!” And it goes after that spike in it, you know, covers it, or it blocks it or it destroys it, or allows your body to destroy it.

But there are I think at last count there were over 90 different vaccine strategies that were being pursued. And some of them are quite sophisticated. Some of them are really, really interesting. This is bringing out creativity at the same time that is bringing out so much cooperation with people.

Steven Cherry Experts in public medicine have been warning that it will take 12, 18, maybe even more months, to develop a vaccine. But that seems based on our experience of diseases of years ago without maybe some of the new tools and technologies that we have and maybe also the greater collaboration we spoke of. Is there any reason to hope that maybe it won’t take that long this time around? And I don’t mean just new and better ways to communicate and share and analyze data. But for example, is there a role for gene editing using CRISPR or something else?

Robert Green Let me answer the first part as best I can. More based on just the news that you and I are both seeing than any special knowledge. But luckily there were a couple of groups that were already so sophisticated in developing special vaccine technologies, particularly for RNA viruses that they had a jump on this. So there is some hope that they will develop potentially effective viruses faster than that typical 18–24 months. So, yes, there’s hope on that.

Now as to the gene editing, I think gene editing has turned out to be this all-purpose tool in the laboratory that helps in many, many ways. So, for example, if you created a particular—if you wanted to create a particular protein that had certain confirmations or that had certain antigenic properties that you would then use in your vaccine, you know, gene editing is a potent tool to help you create that. So absolutely, gene editing is, I think, here to stay. It’s in the workflow of almost every advanced biotechnical group working on things. I don’t think we’re talking about gene editing in the sense of gene-editing human beings to be resistant or gene editing something like that. But we’re definitely talking about gene editing as a workhorse tool in the production of treatments and vaccines.

Steven Cherry It does occur to me that people have for a while now had an idea of getting rid of malaria by introducing mosquitoes that can’t reproduce, creating those mosquitoes with CRISPR. If you could create a version of the virus that does a poor job of replicating in the body—that would be a way to create a kind of immunity or vaccine.

Robert Green Well, that’s right. And you know, there’s precedent for that. Weakened viruses are live—live viruses are used in vaccines all the time. They’re weakened and modified in ways that don’t harm the human being typically, but do create the immunological response to protect you from infection with the bad virus. So that’s absolutely one of the principles. And you can use a lot of different techniques for doing that, including various degrees of modification of a virus that could include gene editing these days for sure.

Steven Cherry So overall, are you optimistic about the next three or six or twelve months or pessimistic?

Robert Green I wish we had a better national response to this. I wish we had ... We’re not arguing on a national level about the value of science. I wish we didn’t have conspiracy theories arising and dividing us. I wish that we were in some manner more aligned around the importance of evidence-based information and science as a value for our society. But I hope ... I’m not ... Overall I’m optimistic because I believe this is a teachable moment for America and the world, that those societies that prepared, those societies that were organized, the societies that had long-term vision, that believe their scientists—have done so much better than we have, and those societies that were not as well prepared.

And I’m extremely optimistic that this once-in-a-generation crisis will give us the flexibility to transform ourselves. I mean, just to pick one example, Steven, how long have we been talking about telemedicine? How long have we been saying, “You know, half of medical visits could be conducted over the telephone or by videoconference?” And yet we had barely moved in this direction at all. And I think that what we’re seeing now every single day is that doctors have, en masse, transformed their practice to telemedicine practices, reimbursers have—insurance companies have had to say, of course, we’re going to reimburse these trends, these telemedicine visits.

So you’ve got this sudden transformative change in the way we practice medicine. And I can’t see us going backward from that. And I think we’re going to see that in education. I think we’re going to see that in the workplace. I think we’re going to see that in politics if we can get past the objections to voting by mail. There is a possibility that this crisis brings positive transformation that we’ve needed for a long time and a lot of different societal areas.

Steven Cherry Not least of those, this will make us better prepared for the next pandemic. 

Robert Green Absolutely. Absolutely.

Steven Cherry Well, Robert, I myself, I’m not entirely sure if I’m an optimist or a pessimist, but I’m greatly encouraged by the work being done behind the scenes, largely out of the eyesight of the public and journalists, by doctors and scientists and researchers, especially those special individuals who all three such as yourself. Thank you for your work and for giving us this time today.

Robert Green Thank you so much for having me and good luck to you.

Steven Cherry We’ve been speaking with Dr. Robert Green, a medical geneticist and physician–scientist at the Harvard Medical School, about the roles genetics and genomics play in understanding the Coronavirus and in treating Covid-19. This interview was recorded March 9, 2020. Our audio recording and engineering was done remotely by Gotham Podcast Studio. Our music is by Chad Crouch.

For TTI/Vanguard, I’m Steven Cherry.

This interview was recorded May 9, 2020.

Audio engineering by Gotham Podcast Studio, New York, N.Y.

Music by Chad Crouch

We welcome your comments @ttivanguard and @techwiseconv

Note: Transcripts are created for the convenience of our readers and listeners. The authoritative record of TTI/Vanguard’s audio programming is the audio version.

Resources

Geneticist says DNA testing should be part of everyday healthcare

Of Known Significance: A Clinical OMICs conversation with the director of Genomes2People, Robert Green, M.D., MPH

Preventive Genomics Clinic

Keywords: genetics, genomics, Coronavirus, Covid-19, CRISPR, DNA, medical records, data, Robert Green, Steven Cherry, TTI/Vanguard, technology

Author: Steven Cherry

Director of TTI/Vanguard, “a unique forum for senior-level executives that links strategic technology planning to business success. In private conferences that are part classroom, part think-tank, and part laboratory, its members—corporate and government leaders, entrepreneurs, researchers, and academics—explore emerging and potentially disruptive technologies.”

Twenty years experience as a technology journalist and editor, at the Association for Computing Machinery (ACM), and the Institute for Electrical and Electronic Engineers (IEEE). Founded the award-winning podcast series, Techwise Conversations covering tech news, tech careers and education, and the engineering lifestyle. Teaches an intensive writing class as an adjunct instructor at NYU. Previously taught essay writing and creative writing at The College of New Rochelle.

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