A Conversation with Harold Varmus ’61 & David Kessler ’73, hosted by Shirley Tilghman H’08
April 30, 2020
Nobel Prize-winner Harold Varmus ’61 joins Trustee Emeritus David Kessler ’73, for a discussion hosted by trustee Shirley Tilghman H’08.
Nobel Prize-winner Harold Varmus ’61 joins Trustee Emeritus David Kessler ’73, for a discussion hosted by trustee Shirley Tilghman H’08.
Biddy Martin (00:00:07):
At Amherst, David [Kessler] was part of the independent scholar program. He went on to earn a law degree at the University of Chicago before earning his medical degree from Harvard Medical School. Welcome, David, and thank you for being here. Dr. Harold Varmus, class ’61 was the co-recipient in 1989 of the Nobel Prize in Physiology of Medicine for studies of the genetic basis of cancer. He is the Louis Thomas University Professor of Medicine at the Meyer Cancer Center of Weill Cornell Medical Center in New York City. He's also Senior Associate Member of the New York Genome Center where he helps develop programs in cancer genomics. He's also adjunct professor at the Macaulay's Honors College at the City University of New York. Harold was Director of the National Cancer Institute for five years. He was President of Memorial Sloan Kettering Cancer Center for 10 years and Director of the National Institutes of Health for six years.
Biddy Martin (00:01:12):
He serves on numerous advisory groups for academic, governmental, philanthropic, and commercial institutions. He's authored hundreds of important scientific papers and five books, including a 2009 memoir entitled The Art and Politics of Science at Amherst. I'm pleased to say Harold Varmus majored in English and he went on to receive an MA in English literature from Harvard University before deciding to go into medicine at Columbia. Hosting and contributing to today's conversation is Amherst College trustee Shirley Tilghman, who is an honorary degree recipient from Amherst College in 2008. She's a professor of molecular biology and public affairs and president emerita of Princeton University. Shirley was a founding member of the national advisory council of the human genome project for the National Institutes of Health. She's received many, many awards as well, including a lifetime achievement award from the society for developmental biology. She serves on the Science Advisory Board or the Chan Zuckerberg initiative. She's director of the Broad Institute of MIT and is a Fellow of the Corporation of Harvard University. On Tuesday this week, just two days ago, she was selected by New Jersey's governor, Phil Murphy, to co-chair the state's restart and recovery commission, overseeing the timing and process of reopening the state after pandemic related closures. It's a great honor and a gift to have you all here. Take it away.
Biddy Martin (00:03:00):
Shirley Tilghman (00:03:03):
Thank you, Biddy, and good evening, everyone, who are listening to this and watching this podcast. I'm going to just launch right into some of the questions that I think are on many people's minds that our two experts have a great deal to say about. The first, I'm going to direct to Harold. This is not the first time that we heard the ’coronavirus.’ What did we know about coronaviruses before this pandemic and what do we need to learn about it now?
Harold Varum (00:03:42):
I think, Shirley, many people were surprised to learn that the so-called new virus was actually a member of a large virus class. There were hundreds of isolates that correspond to the term coronaviruses. They are named, as I think many people have recognized now, because of the glorious pictures that are on the news hour and other places, that coronaviruses have what looks like a crown of thorns around their entire spherical body. Those spikes on the surface that you see next to Judy Woodruff every night are proteins that the virus uses to enter cells. These many viruses inhabit a wide number of host species. They're not only found in human beings, although we know of at least four such viruses that have been causative agents of common colds as known for many years.
Harold Varmus (00:04:41):
But these viruses, as I think probably all of the listeners are aware, can be found in bats and pangolins and camels and tigers and many and many other animals. So that's one of their extraordinary features and it makes them at one level, somewhat akin to the influenza viruses that are also found in many species, and indeed their ability to hop from species to species and then infect human beings is one of the reasons they pose a risk to us. And indeed there have been at least a few other outbreaks, most famously the SARS outbreak and the MERS minor epidemic several years ago that have introduced coronaviruses to the general public. This one is different from the others in many regards. When you look at an evolutionary tree, you find that it's incredibly closely related to the SARS virus that was found in Southeast Asia 2003. A lot of what we've learned about this virus class has been one of many ways that science has prepared us for dealing with this epidemic. And I'm sure in due course we'll get into the issues of what that long history of studying coronaviruses has meant for this epidemic.
Shirley Tilghman (00:06:03):
What I'd like David to comment on is, despite what Harold has said, it seems that both the SARS and the MERS epidemics did not sort of produce a kind of canary-in-the-mine alert sign that would have made us better prepared for this. Why do you think that is?
David Kessler (00:06:26):
I think if you look at the epidemiology of both MERS and SARS, the fatality rate, the degree of infectivity, the human to human transmission, sort of waned after the initial outbreak. I mean, I went back yesterday in talking to the people who are developing monoclonal antibodies against, COVID-19. The good news is there's a lot of experience and they were working and doing these monoclonal antibodies. This is true also, certainly, for the Oxford group on their adenovirus vector vaccine. They were doing trials in the mid-East, and there wasn't enough epidemic to even continue to test those agents effectively. It didn't really hit us. I think if you ask Harold what people were really worried about, the virologists that I know and talk to, they were losing sleep. They expected a pandemic to come, but it was going to be influenza. It wasn't gonna be a coronavirus. I think that mistake or that lack of insight because when we saw the coronavirus, people were really focused on influenza being the overwhelming virus and not coronavirus.
Shirley Tilghman (00:08:14):
Harold, you wanted to add something?
Harold Varmus (00:08:16):
I'm going to go back to your question about preparedness. There's really two kinds of answers here to deal with this question of the difference with SARS and MERS. The first has to do with the question of anticipation. You know, David's right, there's been more concerned about flu in general in most virological circles, but we all recognize that there are lots of viruses out there that can cause a lot of damage. And it's not just flu that keeps most virologists up. Highly virulent viruses like ebola, the recurrence of coronaviruses because we know there've been a lot of coronavirus, but one of the things that society has failed to do, despite repeated warnings from scientists every time we have a pandemic, is to get our surveillance case together.
Harold Varmus (00:09:05):
We have incredible tools now for looking very widely at what's in animals, what's in the environment, what is the causative agent of some unexpected illness occurring in some remote place. There are so-called high throughput ways using remarkable sequencing technologies to look anywhere that you see signs of disease or unusual virus spread and find out what's out there. This surveillance mechanism, which wouldn't be incredibly expensive, has been proposed over and over again. We've not done anything about it. The other question though, the other side of this question is how is this different from MERS and SARS? And one very important thing I think we'll come back to, has to do with the course of infection. I think it's important to separate infection from disease because especially in the case of this virus, infection is followed by several days in which people don't feel symptomatic, maybe two days, maybe six days, maybe 28 days. And during that period people have a lot of virus, a very high virus titer as we refer to it, in the upper respiratory tract, in the nose, in the mouth, in saliva. People can just be speaking and they spew out droplets, some of which are very small and can float very slowly
Biddy Martin (00:10:24):
[inaudible ]vectors of transmission in a way that I think is quite different from what was true of MERS and SARS, which tended to cause disease more quickly. Without this prelude period, in which people are feeling pretty good and transmitting virus.
David Kessler (00:10:38):
Therefore, because of what Harold said, the infectivity is less, I think because that asymptomatic period puts everyone at much greater risk.
Shirley Tilghman (00:10:54):
So the question I was going to ask David is how unusual is this asymptomatic period for this coronavirus? It seems to me that, that there are two curiosities here for someone who's not an epidemiologist or a virologist. One is the degree to which asymptomatic people seem to be contributing to the spread of the virus. The other is the invulnerability of children.
Shirley Tilghman (00:11:24):
With influenza, the two populations that are most vulnerable are the very young and the very old. With this virus, it seems that the very young are relatively protected from infection. Why is that? Do we know anything about that?
David Kessler (00:11:40):
Let me take the children as a pediatrician and Harold is a virologist can maybe talk about viral shedding and being asymptomatic. Shirley, I don't think we know yet the full story of how this affects children. There are two very conflicting views today. Switzerland--and please don't do this, for the grandparents who are listening, please don't follow what I'm about to say, because I have some concerns about it, but the chief epidemiologists in Switzerland say it's okay to hug your grandchild if that child is under ten. They did not encourage family gatherings. The German epidemiologists jumped on that. I don't think, that doesn't quite make sense to me. We are starting to see, and we have to worked this out, in young children, this kawasaki-like disease that that's basically a hyper immune stimulated disease in young children that we think may be associated with this virus. That we're just beginning to see cases, certainly in Italy and elsewhere, and we haven't worked that out. I think the answer is we don't fully understand the story when it comes to children. Harold, do you want to go ahead?
David Kessler (00:13:28):
It has greater concerns. I mean, because it's a constellation of symptoms that you do see after certain viral illnesses that are not the virus but the actual immune stimulatory effects that are associated with this virus. I think it's very early, but I think when you look at coronavirus, I almost see this course, this disease as two phases. And again, I think it's very early, but it's very important for how we're going to therapeutically approach this disease, right? You talked about the asymptomatic period prior to the onset of symptoms, but even with the onset of symptoms, you have certainly this viral phase of fever and cough.
David Kessler (00:14:36):
And then sometime around day eight, nine, 10, sometimes the second week, in some individuals, they crash. They have increasing [inaudible] requirements. They have difficulty, increasing shortness of breath. They end up being intubated, put on a ventilator, many of them several days later. We don't fully understand this second phase of this disease because it's the second phase of this disease that overwhelms the lungs. Is it the reaction of the lung tissue to the virus? Is it a viral toxicity? Is it a hyper stimulation of the immune system? Is it due to [inaudible]? Is it due to even the ventilator? We haven't sorted this out. The good news and the real good news, cause it would certainly be reminiscent, to me, going back 30 years, when we've had the first drugs on HIV, the announcement yesterday on remdesivir that showed biological activity. Clearly that's the first antiviral. If that will work, and hopefully we'll find other drugs for other targets and combination therapy of maybe multiple antivirals, it maybe likely that they work early. But we also are going to need to have drugs for this second phase. And again, I don't think we know the mechanism. It may be IL-6. I think we have to think about combination therapy and understand the course of this disease.
Harold Varmus (00:16:27):
Before we get back to therapy, which I think we should discuss in somewhat more detail, let me get back to your original question for this segment about kids. Two points I'd like to make. The first is that we simply haven't done enough testing of people who don't have symptoms because of the shortage of available tests for the virus to know the answer to your question about why kids clearly have less of the now garden variety version of COVID-19. We just haven't tested that many children to see whether they're getting infected less frequently. They clearly they have less clinical disease but why that is not apparent. The second issue has to do with things that David was speaking about and that has to do with our failure to understand fully the pathogenesis of this disease. We still don't know because we haven't tested enough people.
Harold Varmus (00:17:22):
How many people actually get sick? We don't know why certain people get sicker than others. We know that there is a clear age dependency that the older you are, the more obese, the more likely that you are to get severely ill. There are a number of other so-called comorbidities, hypertension, diabetes, and a few others. But what's even more interesting and striking is that there are a number of aspects of this disease which are totally unexpected. You can see in people who seem to be virtually asymptomatic, diffuse shading of the lung fields on chest x-ray. We don't fully understand what's going on there. People are frequently experiencing low oxygen, as David mentioned, without feeling short of breath because they're getting rid of their carbon dioxide because of the way this virus seems to affect the lungs. And then there are a lot of other manifestations of the disease including strokes and circulatory insufficiency in several organs, disorders of the kidney that are apparently caused by this virus or by the immune response to it that are very unusual. We just don't understand enough about why kids in particular don't seem to have disease and we don't know what the epidemiology of infection is. And it's important in this conversation to make a clear distinction between being infected with the virus and producing virus and being a carrier and actually having symptoms and being said to have COVID-19, the disease.
Shirley Tilghman (00:19:01):
I mean an issue that clearly is dominating the national discussion about this pandemic is the need for intensive testing. So the question I would ask both of you is why in the most scientifically advanced country in the world are we finding it's so challenging to develop the kind of testing capacity that we need to do, the two things that I think both of you have been talking about, to identify who has the disease, who is carrying the virus and who is carrying it in the population with asymptomatic.
Harold Varmus (00:19:42):
Let me start this one. And I think the word testing, first of all, has to be modified in every case by what you're testing for. When we say the word testing, what most of us are referring to is testing for the virus, but there is a whole other category of testing that David and I both want to say something about which is testing for a host's response to the virus. We're looking for antibodies that say, yes, this person has been infected at some time in the past. When you're testing for virus, you know, traditionally in virololgy--and I think this is a teachable moment as they say, for letting the people who are dialed in today to know something about the history of testing for viruses. What was done traditionally is you go to the site of disease, the lungs, the respiratory tract, and you see if there's a living particle we call a virus particle, which can infect cells and destroy them, copy and multiply itself.
Harold Varmus (00:20:43):
No longer do we do that routinely. What we do is we look with much more sensitive techniques that have been developed over many years of being molecular biologists, as all of us are. And that involves simply being able to detect the so-called chromosome of the virus, which in this case is a very long strand of RNA. We have methods. Some of them are from your terms like polymerase chain reaction, PCR and those methods allow us to see even very, very small numbers of a virus, particles that contain the viral genome. The reason we don't have enough testing going on is testing for viruses, incredibly important, it tells you who's infectious, who might be able to transmit this virus to somebody else. And we don't have enough, not because we didn't identify the virus quickly. Indeed, compare the speed of which we found this virus just a couple of weeks after the first cases appeared and the speed at which we had a complete count of the nucleotide sequence of the genome just a couple of weeks. Extraordinary. But there was a defect in the supply chain, the of tests, people were being unreceptive to the idea of using someone else's test. And we really failed to understand the epidemiology of this disease despite this incredibly powerful set of tools we have for being able to test the viral genome and say that there are virus particles there. But we'll come back to the serologic testing later.
David Kessler (00:22:20):
I think that if you look at the root of the delay, why did we lose a month or five or six weeks, till we were able to get testing to begin to get ramped up, is that if you look what happened, CDC decided, as it does many times, not to take the WHO tests. They were going to develop their own diagnostic. The FDA went in and saw from the beginning that there were contamination problems with the way CDC was making that diagnostic. So when it sent out these tests kits, they didn't work. There were problems. And I think both agencies really didn't get the urgency, certainly in February and even early March. These are generally, and certainly my old agencies are pretty conservative
David Kessler (00:23:33):
"small c" scientific agency, likes to get things right. It said to CDC, you know, there were problems, but no one got the fact the house was on fire. It took weeks for someone to say, hold it. We have a national emergency. Now, once that happened, things shifted. But I really think that we underestimated, I mean, certainly CDC and FDA now, there were those, if you look at the emails that have come out, there were those who were literally screaming at the top of their lungs in their emails, that this is coming, this is coming. Shut down. But, I think CDC and FDA for that five, six-week period before they figured this out, we're just flatfooted. And I regret to say that. I understand why testing is so important. Can I just go over to make sure everyone understands why--and let's stay with what Harold's talking about testing for the virus itself.
David Kessler (00:24:45):
In the absence of a vaccine and the absence of a therapy, what is this about? There's an infected person, there's a susceptible person and for the virus to be transmitted, there needs to be an effective contact. The only tools we have, I mean really when it comes down to it, is can we reduce the number of infected people. Well, if they're asymptomatic and they don't even know they're infected, you've got to test them, you take them out of the system, but in order to take them out of the system to quarantine them or isolate them, you need that test. The other tool we have is just to reduce the contacts we have with each other. In the absence of a vaccine,
David Kessler (00:25:33):
that's all we have now. Those two tools, for the last 200 years, are very effective public health tools, but you can't reduce the number of infected people without testing. As much as it was a mistake not to have testing early on, and we became overwhelmed because we really weren't able to contain this virus early on. We didn't have the testing to take those isolated cases and shut them down. Now testing has become equally important because we have no idea how many infected people there are out there. And I don't know how you open up. Maybe [signal lost].
Harold Varmus (00:26:32):
Someone's sending you you've talked too long. I didn't do it. Not me.
Shirley Tilghman (00:26:46):
While we try and get David back, David has said that the magic word 'vaccine,' which of course is something that is on everybody's mind, but before we talk about the vaccine, I think it would be very important to talk about what do we know about the human immune response to this virus that would suggest that a vaccine would actually be successful. Harold.
Harold Varmus (00:27:11):
This is an incredibly important, maybe the most important question we can discuss tonight. Let me say first of all that we are deeply ignorant of the potential for making a vaccine [inaudible], because we need to recognize that although we know there are antibodies produced in response to this virus and to infection by it, we don't actually know whether those viruses have the potential in all cases to either reduce the effects of a virus infection or to prevent infection entirely, which is the common principle objective of making a vaccine. But there are some encouraging signs. First of all, we know that some patients who have antibodies actually have antibodies that neutralize, that inactivate the virus. We know this because we can take the serum from a person who's been infected and we can show that that serum will prevent the virus from infecting cells in laboratory cultures.
Harold Varmus (00:28:16):
So that's encouraging. Secondly, people have identified specific components of those antibodies and shown that they are highly effective in blocking infection. Third, people have done experiments in primates, other nonhuman primates showing that antibodies can protect against infection. And then you can actually make a vaccine that works in rhesus monkeys that protects against infectious challenge. We also can observe that patients do clear the infection, how the immune system is doing a lot of things, as David has already mentioned. We know that the immune system appears to play a pretty intense role late in the disease when the disease is particularly severe. We don't know exactly what the lethal components of that reaction might be, but it seems to be a reaction that includes some attack on the virus itself because virus titers become very low and eventually people who had the infection and have recovered are free of any evidence of carrying a live virus.
Harold Varmus (00:29:25):
So all those things point to the idea that the immune system can control this infection. Now there are two questions. How well does it do that? How long does the recovered patient remain resistant to reinfection? And those are really important things we need to learn because they're going to inform how we approach vaccine development. And secondly, they're going to give us an idea about how long we're going to be dealing with the virus called SARS COV-2. Some epidemics go away and we don't hear about the virus very much again, if at all. In this situation, we just don't know whether we're going to be seeing this virus SARS COV-2, or some closely to the related version of this virus that's undergone a few mutations, call it SARS COV-3 and 4 and 5 in subsequent years because the immune system doesn't have a good memory for this kind of agent.
Shirley Tilghman (00:30:30):
So Harold, are there urgent experiments that need to be done to develop answers to those questions as the vaccinologist are developing an effective vaccine?
Harold Varmus (00:30:43):
They're huge numbers of questions, some of which could be approached simply with the tools that we already have, questions we've been thinking about such as the true transmissibility, the true prevalence of the virus. And what we need to do there is scale up the availability of tests. We have this point, a pretty good system for testing people who have symptoms, to see if they have COVID-19. But we do have, methods thanks to a number of amazing developments in the world of genomics and other kinds of molecular biology, some remarkable new ways to go about screening large numbers of patients who seem perfectly well to find out how many people in the population in New York and in Sioux falls and California have actually been exposed to this specific virus.
Harold Varmus (00:31:36):
I hope that we'll be able to sort that out pretty soon. Secondly, we're going to be able to do the testing on such a large scale, because of things that have happened in world's very different from studying infectious disease, the worlds of genomics, and so-called high-throughput DNA sequencing where machines have made it possible to test literally millions of people a day to get a much better picture of how much of the population is infected and able to transmit virus with time. We'll be able to do large scale tests for antibodies to tell us whether people have actually been infected in the past. And we'll eventually get a picture of the demographic of this virus that will allow us to feel more confident about whether we should be opening up our economy.
Shirley Tilghman (00:32:40):
One of the most recent studies was done by the New York public health department that did a survey of 3000 New Yorkers and discovered that roughly 20% of the population of a random selection of the population within New York City showed signs of having been exposed to the virus. Upstate, it was much lower. That's hardly surprising given that the city is the epicenter of this pandemic. How, as a new Yorker, Harold, how does 20% feel to you?
Harold Varmus (00:33:19):
Well, first of all, I have to question the result a little bit. It's not entirely clear that the test was perfectly accurate. There've been a lot of tests put out in the market because the FDA agreed that these tests could be used fairly widely without being subjected to the kind of evaluation that they normally would be subjected to. And many have found that many of these tests are unreliable with large numbers of false positives and false negatives. Secondly, the population of 3000 that were selected for testing were not a totally random population. They were people who asked for tests. So let's say those 3000 people were asked in shopping malls and other marketplaces, so they're not a random population. They were people who were more likely to be out, either flaunting the rules or just doing the shopping that's within the rules, but they weren't the people who were confined at home. So there's probably an overestimate, even if you believe the task was accurate. Nevertheless, let's come back to the question of New York. Let's assume for a moment the 20% number is correct. What we're all looking for, of course, is enough immunity in the population to believe that we've established what's called herd immunity, where so many people have effective antibodies against the virus that the virus simply can't any longer spread through the population, in fact others who might be susceptible to its effects. And you generally thought to need about 70 to 80% of the population to be infected to establish this thing we call herd immunity. And we're nowhere near that yet. And that's of course in the epicenter of this epidemic. And everywhere else in the country, the numbers are closer to 2 to 5%. So when Tony Fauci says, make no mistake, if you let down all of these, behaviors that have been shielding us from a wider spread of infection over the next few months, there's going to be a recurrent increase in the number of people who were infected, the number of people who get sick.
David Kessler (00:35:44):
And that's why as you go and let down these restrictions and as people have more contacts, testing and contact tracing become even more important, right? Because what we did was we took our number, that reproduction number, whatever it is by sheltering in place, we reduce that. By stopping to shelter in place, we're going to increase it. The only way we can keep it under control by not sheltering in place is testing and contact trace.
Harold Varmus (00:36:22):
I think it's important for people to understand that there is another step involved when you move from what we currently have, which is most of us, like me up here in my house in the Hudson Valley. I'm pretty much confined to one person that seems to be amiable most of the time, and that's fine, to a time when more of us are back in society and being tested regularly to see whether we've contracted the virus and should go into quarantine because the adjacent step to identifying me and telling me to go into quarantine for two weeks is asking me who I've been in touch with, and not just by Zoom, but by real human contact and may have infected. That's going to require a whole set of caseworkers that our country doesn't really have at the moment. We're going to need people who can go and interview folks who've been identified by this mass testing and then go to the contacts and appropriately approach them. We're going to need to harness a large cohort of people do this kind of thing, and I think this might be a good time for us to consider some fairly radical steps that are not unlike what FDR did during the depression. Take people who are out of work put them to work, learn these basic social skills to do contact tracing, give them a salary because we've got to get our money moving again. We haven't said much about the social, economic and legal effects of all this. I know that other nights, but it's so closely tied to the kinds of things that we as medical scientists are thinking about that I think really has to be connected to the kinds of epidemiological protocols that we're discussing.
David Kessler (00:38:10):
I don't think we fully understand the extent of the viral burden in the United States. We are 4% of the world's population but we have some 25% of the cases that we can talk about reporting. But in part because of world travel, because we got hit on both coasts, people coming from Asia, people coming from Europe, we have the highest epidemiological curves in the world.
Harold Varmus (00:38:41):
I think it's interesting to think about that, David, because you know, the fact that we're wealthy and move around and you're out there, we're very social, this may make us very different than people in Africa and parts of South America and parts of Asia who you might think traditionally would be the ones who get the hardest hit. They're going to be hit later on, but the virus has to come to them. They're not out getting the virus, they don't have as many visitors coming to their countries. And our affluence has probably hurt us here. You look at where has this epidemic been dealt most acutely. In Europe, in wealthy parts of Asia and the US and there's a sociological aspect of that's important.
Shirley Tilghman (00:39:22):
So what I'm hearing, I think from both of you, is an answer potentially to probably the most common question that I'm getting on my Google doc here of questions that are being submitted by people who were viewing this, and that is, what is it going to take for us to be able to come out of our sheltering. And what I think I'm hearing, David, you saying very clearly that we have to have extraordinarily expanded testing capacity and contact tracing or we are going to be back in shelter again as we are now. Is that accurate?
Harold Varmus (00:40:06):
We lost you again, David. We lost you. So let me just say one thing in addition to what you just said What you said is very true. But there's one other thing that we as a society are going to have a very hard time coping with. And that is, it's not just having these extreme measures of either sheltering in place or having a lot of testing and contact tracing. We're going to have to have a change in habits, no handshaking, wearing of masks, gloves, being conscious of contacts and ways you might transmit the virus. And this is going to be in place for quite a while until we have one of roughly three things. Either we're going to have good treatment. That'll mean you don't usually die if you get this infection and people are going to be less risk averse if they're just not going to care about wearing a mask if they can be treated with an effective drug. Second, we might have herd immunity eventually. That will entail, at least an undercurrent circumstances, a lot of loss of life before we get there in my opinion. And the third is of course, the most obvious, and that's to have a vaccine. I do think that there's a reasonable chance we'll have a vaccine, but everybody keeps saying it'll be in 12 to 18 months. And yet of course we don't know whether we actually will have one, number one, how good it is or whether it'll be that quick. If we look at the history of production of vaccines, there aren't very many vaccines that've been brought to market into a wide population in such a brief period of time. We do have much better technologies. There are vaccine candidates that have been put into people very, very swiftly after this virus was identified. So I'm encouraged by that, but we also know that if we have to use a traditional kind of a vaccine that it could be two or three years before we have one. And that's a very long time in modern life.
Shirley Tilghman (00:42:04):
Can I asked you a question that one of our viewers sent in, which is I think an interesting one, which is, is there any evidence that coronavirus is mutating in the way that influenza mutates, which would put us in a position of having to create a new vaccine every few years?
Harold Varmus (00:42:23):
Maybe I should answer that as a virologist. These two viruses are quite different. For one thing, the coronavirus chromosome is one piece of RNA, whereas the influenza chromosome is in eight pieces of RNA and those pieces can get shuffled very easily. And furthermore, mutation rate for the two viruses seem to be quite different, but the influenza rate appreciably higher than the rate for the coronavirus. So, we know that mutations occur. In fact, it's one of the reasons we can do such interesting studies of the evolution of this virus. How it came from SARS COV-1 to become SARS COV-2, how we can distinguish not just strains that were in Europe that came to the States or strains that were in China that came to the States, but how, within a single community, based on just one or two changes in the 30,000 nucleotide genome, you can tell who got the virus from whom. That's going to be very important very shortly because we're going to be asking, I predict within the next several months, where there's someone who seems to have the appearance a second infection with SARS COV-2 has had a recurrence of the original infection or has been infected by somebody else who has a slightly different strain of virus. And we can tell from these subtle differences in the genome, which is the case. And I think people have to reflect on the power of modern science to be able to distinguish between an example of the virus that has only one or two differences in that 30,000 nucleotide chain.
Shirley Tilghman (00:44:14):
So Harold, a number of questions are coming in about an understandable anxiety about the reliability of tests, not just the RTPCR tests for the presence of the virus, but the serology tests and how are we going to get to a point where we have confidence that we have a test that will give us a highly accurate reading?
Harold Varmus (00:44:40):
Well, let me take the two kinds of tests separately. Tests for the virus are most likely to fail because there simply wasn't enough virus on the swab or the sample that was used for the examination. And that's just a biological variation that we're going to have to deal with by sampling people twice or three times rather than just once and because people will be infected and the virus won't be detected for reasons that are understandable. Those tests in general are quite reliable with a pretty high rate of a pretty low rate of false negativity at extremely low rates of false positivity. But with respect to the serological tests, the issue is more difficult. And you can imagine that without being a sophisticated scientist or an immunologist, why that might be. I've already mentioned that there are lots of other coronaviruses. If you're testing for coronavirus antibody in the blood, which is what you're usually doing, with a so-called serological test, if you've been infected with one of these other coronaviruses, the cause of the common cold and the test that you're using is not designed to be specific for this current virus, SARS COV-2. It's possible to have a false positive because you're detecting the residual of an infection that occurred years ago with one of these fairly benign human coronaviruses, and for other reasons, false negatives are also possible. It's going to be important to have careful regulatory oversight of the tests that come in common use. I understand why federal agencies might've been eager to get some tests into play and curtailed some of the usual regulatory oversight, but eventually a few tests will emerge as the most effective. It's quite easy to construct samples that we know do and don't have viral antibodies to be sure that the tests are being done properly and give a very low number of false negatives and false positives. But I think it's also important to stress, and I like to do this repeatedly, that when you're testing for antibody against the virus, you may have a very reliable test that tells you whether or not that person has been infected with SARS COV-2 in the past. But it doesn't tell you necessarily whether that person is truly immune to reinfection unless you have a way to show the antibodies that are actually neutralizing the activity of the virus.
David Kessler (00:47:33):
All our experience, and again, I agree with Harold, that we don't know the clinical question about clinical immunity. There's certainly a reason to believe that neutralizing antibodies may confer. We don't know how long, but certainly on past
Harold Varmus (00:47:56):
we went over this when you were having trouble with your, with your microphone.
Shirley Tilghman (00:48:01):
But David, maybe you can speak to the question about the reliability of the test. I mean, what role do the regulatory agencies have in ensuring that when an employer is testing their employees, that their test is good, reliable and will give accurate results?
David Kessler (00:48:34):
[audio feed unavailable]
Shirley Tilghman (00:48:49):
Hold that thought, David, until we figure out how your sound. So, Harold, this profoundly important question about distinguishing people who have antibodies that are simply against the virus but not neutralizing, and those that are neutralizing, how, how are we going to be able to tell the difference in a population study?
Harold Varmus (00:49:24):
That's a really good question. I think it's going to be based on if we can figure out which proteins in the virus are targets that result in neutralization of the ability of the virus to infect, if there's a good antibody against them. Then we'll have a pretty good idea because well, for example, I mentioned earlier these spikes on the virus surface that mediate the interaction of the virus with the host cells. We actually know already based on work done with the SARS virus that exactly which part of that protein is required for the virus to enter cells by binding to a cell protein that is on the surface of the cell. And we will have I think very soon, tests that are based on the ability of that patient to have produced an antibody which attacks that part of the virus surface. And those will be probably authenticated as tests that are neutralizing. And there may be other antibodies that are neutralizing as well. There's a lot of interest in some of the other many surprisingly many proteins that are made by this virus and some of those proteins help to make the virus structure intact. And you can imagine that the antibody that attacks those proteins would be a legitimate target for an antibiotic that basically blocks the capacity of the virus to enter new cells.
Shirley Tilghman (00:51:02):
So are you optimistic about a vaccine?
Harold Varmus (00:51:06):
I think we'll have one eventually. I think it may take longer than 12 months to 15 or 20 or 20 months. But you know, I think it's reasonable. It's reasonable to be somewhat optimistic. The problem of course is that even a year, year and a half is a pretty long time in our society. And given the effects of this epidemic on our social lives, and especially on our economy, I don't think we can't wait that much time. Even if we have a good outcome, a good vaccine, a year or a year and a half from now, we still have a national emergency because we have to get back doing some of the things that we do. And you know, the effects on mental health, the effects on people's income, their attitudes toward life. It's not my latte I'm worried about, I'm worried about collapse of society in a much more dramatic way. And we've got to figure out ways to live with the virus still circulating. Many people still susceptible to virus infection in a way that's compatible with at least a reasonably effective economy. And the country will come back eventually. But you know, this whole episode is going to have an effect on our country that is similar to what happened during the great depression in the thirties.
Shirley Tilghman (00:52:33):
So what do you make of the experiment that they're doing in Sweden right now where they have made the decision not to sequester, to basically allow society to continue, but to sequester those who they identify as vulnerable, which are individuals over the age of 65 and those who have underlying health vulnerabilities. What do you make of that experiment?
Harold Varmus (00:52:59):
I think it's something we deeply need to understand much more profoundly. That means of course going in there and doing the things we've been talking about, testing everybody for virus, testing them for serological responses there, the evidence that the infection has occurred. It's easier from a political point of view initially at least to say everybody should sequester inside not knowing who's really vulnerable. I'm sure of it in Sweden. I mean, we know they have cases, they have people who died. But they minimize the risks in a way that probably would be seen acceptable to most people. And I think we simply need to do some epidemiological and sociological studies to find out how people were reacting. We can say that they didn't apply all the strictures that have been applied in the US and in some European countries, but we really need to know what people did as opposed to what they were told to do. Because I think we may find that there, you know, you can't sit in Sweden and be oblivious to what's happening in the rest of the world. They have newspapers, they have TV shows, they go on the internet. And I suspect a lot of people, you know, we see movies on the news hour of folks wandering around on the on the Dockside in Stockholm. And it all looks jolly in the sunshine. But I suspect that the people are being a lot more cautious than we think and that there are obeying social restrictions that are not usual.
Shirley Tilghman (00:54:44):
So one of the statistics that I've heard is that the actual death rate among individuals who do not have some underlying health problem is very, very low. Is that something that is likely to hold up?
David Kessler (00:55:05):
We don't have enough data, Shirley, to say what the death rate is. In the last day or two there were increasing reports that the death rate is maybe one and a half times to two times the number of deaths that we think it is. Just too early. The reporting is not been scrutinized to know what the actual death rate is.
Harold Varmus (00:55:37):
That is absolutely correct. But I also think that Shirley's right, the evidence is pretty strong to suggest that the, the kind of factors you're considering, which is the people. I have acquaintances who have underlying conditions who died fairly suddenly and would have normally been considered to have died of their underlying cancer or heart disease who were found to be positive for the COVID virus. And now being called COVID deaths probably were COVID deaths. And we see that by looking at the difference between the expected number of deaths and the real number. I still think that comorbidity is a huge issue and we don't really understand why that is. It's also true in influenza and other infections that have low mortality rates.
Shirley Tilghman (00:56:35):
We're very close to the end of our time. I want to ask a question that has come across from our viewers which is what do we need to learn from this one to protect ourselves more effectively from the next one? And the additional part of the question is, what are the other pathogens out there lurking that we should be paying a lot of attention to?
Harold Varmus (00:57:05):
David, can you try that?
David Kessler (00:57:08):
I think that one of the things we learned is that leadership is very important. Certainly from the beginning when there is intelligence of a significant threat out there that you have to go look at the experts from the beginning, take center stage, call it the way it is.
Harold Varmus (00:57:39):
Obviously, having a strong government response to an outbreak is critically important and we would all endorsed the idea, at least all of us on this call I think, would endorse the idea that we've had abysmal leadership from the top on this occasion. But there are some specific scientific issues that this pandemic brings up. Perhaps the most fundamental is taking more seriously the kinds of recommendations that the scientific community and the public health officials always make after a pandemic. And I think because of the magnitude of this one as opposed to the relatively modest impact that even the influenza epidemic of 2009 and certainly outbreaks like Ebola outbreak and SARS and MERS, which had pretty marginal effects on the US produced. This one will really make us reflect on the wisdom of an investment of even hundreds of billions to prevent the kinds of disaster we're seeing which are costing us trillions. The second thing is that we are developing tests with new methods and possibly vaccines and therapeutics with new methods that should inspire us to have platforms for developing new tests that are rigorous more quickly and for developing new ways to control outbreaks regardless of what the organisms might be. I think it's very difficult for us to say what the next pandemic is going to be. It Will probably be a virus. But you know, we were pretty well equipped for identifying viruses quickly. In general, we seem to be encountering viruses that belong at least to viral classes. We know something about. That's good. It's a good argument for investing in fundamental virology just as we were prepared for HIV because we had invested hundreds of millions of dollars in the study of that virus class, the retroviruses before year two, we had invested a fair amount of money in the study of coronaviruses, which were known to be widespread in the animal kingdom. And that did help to prepare us even though it doesn't feel like we were prepared. But we at least knew enough to recognize this virus and many of the things it does, and we're remembering that the only drug that's shown any signs of efficacy so far, remdesivir is a kind of an agent which was developed to interfere with the enzymes required to copy the RNA chromosomes of RNA viruses of animals. Let me stop there, I see times getting late.
David Kessler (01:00:33):
CDC used to be the gold standard. There's a agency that we all look to and what we see is that investments not only at CDC and local public health agencies, that's taken a hit over the last decade or so.
Shirley Tilghman (01:00:56):
Yeah. So leadership, public health, basic science, all of those are the things that we're going to need to invest in going forward.
David Kessler (01:01:07):
And just to add, there's one other point and that is we also need deep wells of patience right now. There is no doubt that as we lift these restrictions, if we increase our contacts, no matter what the testing, no matter what the contact tracing is, we go back to having the same number of contacts that we had in our cities, in our close spaces, were going to have very significant another wave. We need to have deep wells of patience..
Shirley Tilghman (01:01:54):
Thank you both. And David, I am so sorry that we had trouble with your audio. It was wonderful to see you and hear you when we could. And Harold, thank you so much for being a part of this. And perhaps on the note that we have been talking about for the last a minute or so, perhaps it's appropriate in bringing Biddy back to conclude this session to point out that five of the six nations that have overcome this pandemic most successfully in the world, five of the six are led by women. And with that, Biddy, I'm going to turn it back to you.
Biddy Martin (01:02:39):
Well, Shirley, that puts a lot of pressure on me, but also on you. Thank you so much. I want to apologize to you three and also to all of our audience for the technical difficulties. I'm sure it was terribly frustrating. And I'm really sorry, but thank you so much for being available, for all that we learned tonight and thanks to the audience for your attendance and your questions. There will be two more programs next week, which we'll make sure you're aware of. And all technical difficulties will have been fixed, and David Kessler will have any opportunity that he wishes to have to speak at great length on every subject that came up tonight. Thank you all so much. Goodnight. Thank you.