COVID Webinar Series: Transcript of session with Melanie Ott, MD, PhD

KRIS REBILLOT: Talk about Remdesivir. 

MELANIE OTT: Yes, good morning, Kris. Thanks so much for having me. It’s, indeed, an exciting and, as you can imagine, very busy time for virologists and for the entire Gladstone Virology Institute.

Yes, Remdesivir is a drug that many have watched very closely to see how it does against the virus. And I think the news today from Gilead, itself, appears promising, that in their clinical trial that they see an efficacy here against COVID-19. I understand that there is a second trial from the NIAID, where we still need results from. This is actually the more important trial and the way that it actually compares the drug with… between untreated and non-treated patients, and I’m really eager to see the results. But at least there is some hope here, and we are… we’re certainly, you know, excited to see the full extent of the… of the clinical data.

KRIS:  Would this drug block replication?

MELANIE:  Yes, I think this is a drug that is… was, initially, developed against Ebola, and it targets an enzyme in the SARS-CoV-2 virus that’s called the polymerase.  This enzyme is actually amplifying viral genomes during the course of the infection, and, basically, allows the virus to amplify and to spread. Now, this is a very important step, obviously, and the idea and the evidence, currently, that we have is that that drug from Gilead directly interferes with this amplification.

KRIS:  Where are we now in the science and research?

MELANIE: I think we are very much at the beginning. I think the time that we are in very much reminds me of the beginning of the AIDS epidemic, you know, some 30 year ago. I think at the… like now, like then, we’re dealing with a completely new and deadly virus that jumped from animals to humans and we’re having to learn everything about it. So the point is that we are very similar stage, very much at the beginning.

But I think the big difference from the beginning of the AIDS epidemic and now is that we are doing science, really, in a different way today.  We are learning much faster, and we are… and we are sharing this knowledge much faster, and we’re also doing science in a different way today. I think back then, we had to go and work on each of the individual proteins, one-by-one. Now, we can… we can really take a more holistic approach and look at everything at the same time and generate a lot more data, and… because of the existing technology.

So I think it’s a… I think it’s a… as I said, a very… a very beginning time, but I think it’s, also, a very, you know, exciting times because we can accelerate so much faster.

KRIS:  Where is our biggest gap as far as understanding about the virus or what happens in our bodies?

MELANIE:  Yes, so the bottom line is that we have to understand everything about this coronavirus. There’s nothing specific about that virus that makes it different from other viruses. It’s a unique virus, but like any other virus, we have to understand how it’s been transmitted, how it replicates in the cells, and how it affects out body, how does it make… how it makes us sick.  And I think, you know, all this knowledge, ultimately, feeds into get a better testing, better treatments, and, ultimately, hopefully soon, a vaccine.

KRIS:  What is your reaction to states opening up, some more than others?

MELANIE:  Well, this is risky business. I think… I think it’s risky in the way that we cannot open up and repeat all the mistakes that we have done a few weeks back when we started sheltering in place. I think we want to wind back time, but we want to do it right this time. And I think what we need is really… we need to focus on three questions. We really need to focus on testing. And we need to, you know, identify people who are infected. We need to have reliable and frequent testing, so that we can do, you know, contact tracing and we have… we can isolate people who are being infected. This is, I think a cornerstone for opening up and for going back to a new normal, basically.

KRIS:  What degree of testing do you think is going to be needed to really get a handle on this?

MELANIE: I think we have to absolutely increase our current testing capacity.  I think the Governor has talked about some numbers that he thinks we should reach, in the 60,000s. And I think these are probably good guiding numbers. I think, currently, the point is that we are not there, and that we have to increase this capacity to whatever we can do. I think I see not only a bottleneck, currently, in the testing availability, I also see a bottleneck in the way how we prescribe testing. I think many people who would like to get tested cannot get tested, but at the same time, now, universities and blood banks are rolling out more systematic testing across the country to really do community-based testing independently of symptoms. And I think this is an important second arm to do what we can do to really get on top of this… you know, on top of this virus.

KRIS:  Do you think that there will be immunity to this, and what do you think of antibody testing and how useful that may or may not be?

MELANIE:  Yeah, so I’m currently working at Gladstone on a… on a test that is directly testing for the virus, combined with, actually, contact tracing. And I think that’s very… that’s one important arm, currently. And, as you mentioned, the second important arm is that we not only look at the acute infection to see who is carrying the virus and shedding the virus currently, but we’re also looking into who has had the virus in the past, and who might be immune. And you might notice that I say ‘might,’ because we don’t really know whether the anti… the current antibody testing is really translating into immunity. And this an open question that we need to answer pretty fast. I think the other open question currently with the serology testing is that they have been rushed on the market very fast, and I think we have to a step back currently and really make sure that they have all the appropriate quality controls in place, so that we can trust the results.

KRIS:  Do we have ‘the test’ yet?

MELANIE:  I think there will be no the test because I think there’s different tests for different things. As I said, we can test acute patients mostly with nasal swabs for the existence of the virus in these swabs, and we can test in the blood patients who might have… or people who might have had the virus. So these are totally different approaches. They take different samples, they take different technology, and so they will be… they will have to be combined in the future to really get the full handle on the virus.

KRIS: When you read the literature, where do you think we are with vaccine development?

MELANIE:  Well, I think we are actually at an enormous pace, currently, with the vaccine development compared to other vaccines that we have developed in the past that takes years to do. And I think the reason why we are moving so fast... and most of the companies that are claiming, you know, early victory here are those that are going after the RNA of the virus. So this is… you know, since the virus genome sequence was deposited in early January by our colleagues in China, I think this genome has basically provided the basis for most of the research that’s currently ongoing and around the world. You can use it to develop diagnostics, you can use it to develop therapeutics, and you can use it to develop a vaccine.

And so what has happened is that that genomic sequence, which is just the information, the genomic information of the virus, was used to directly translate it into a vaccine. Usually, what we do is we might generate, you know, parts of the virus, and then produce them in a very specific way, and then inject them to generate immunity. But here, basically, this was bypassed, and we take the genomic information, inject it, and then let the body make all… do all the work. This is a wonderful concept and it was extremely fast, and that’s why people talking about maybe having something already on. But at this point, we don’t know if it works, because it has never worked before, it has never been used before, and so we don’t know if it’s going to work as we predict it will work.

KRIS:  It’s been in the press that healthcare workers who are exposed to this virus in a large degree are getting sick and sicker. Do you know the minimum amount of virus?

MELANIE:  This is a very good question, one that we dealing with a lot, because viral titers is what my daily life is all about. And so the answer is we don’t know how much virus you need to get infected, but what we know is that… or what we think we know is that the amount of the virus that you get in contact with might determine how sick you get. And so this is a good example of the healthcare workers that, in general, are getting more sick, and with… also, they’re young and healthy, and should not have, you know, any coexisting conditions or risk factors in that… in that way. And so one explanation is that they might get into touch with the virus, with higher loads of the virus. They might also inhale them more because they are in closer contact with patients, and so they get deeper into the lung and can establish infection there. So I would say the question... you know, I think that the amount of virus that you get in contact with might determine how severe of an infection you get, and, also, potentially where this infection is going to set shop in the body.

KRIS:  You were part of an international collaboration of researchers who were looking at some 69 drugs that have been shown to have some promise against COVID-19. What stage of that work are you on and how are you handling it?

MELANIE:  Yes, I think this is a really exciting collaboration that we have with my colleague, Nevan Krogan, at the Quantitative Biology Institute at UCF, and also part of Gladstone, and also an adjunct member at the Buck. And we have been, actually, working together for two years now in very close and coordinated fashion because our goal was to find host targeted therapies. And this is different from what I said before about the Gilead drug, which is really targeting a viral enzyme. We were interested to really look in the interaction between the virus and the host. And, here, it’s really important to remember that a virus cannot exist in a vacuum. It is very dependent on finding a host cell that it can hijack and then make… turn into little viral production factories.

So, Nevan and I, we have started a joint program called BioFulcrum, where we look at multiple viruses and their host interactions. And it is really a combination of the expertise of our two labs, him being really an expert in something called mass spectrometry where you can look at the proteins and identify all of the host proteins that are making contact with the virus in the cell. And my lab has focused on generating advanced technology to actually study viruses and cells. So we create little mini organs in a dish, and then infect these many organs called organoids to find a better way to really predict how these viruses are going to act in the real organ in the patient. And so by combining these two things, him identifying the factors and us testing whether the factors are important and what role the factors are playing in the infection, we have established a whole platform where we’re looking at multiple viruses comparing their dependencies on the host cells, and actually using these shared dependencies as targets for new therapeutics.

KRIS:  I understand that as far as the work on COVID-19, you’ve actually created organoids… lungs [?], which seems like it’s really an important thing to do because this coronavirus does really impact the lungs, right?

MELANIE:  Yes, absolutely. So I think they’re the reason why my lab was… became so early interested in studying SARS-CoV-2 was that we had certain tools in the lab that I thought were really relevant for studying this virus. One was this collaboration with Nevan and this platform that we had established. But, second, was that we had, within this collaboration, just started to study influenza virus in lung organoids, and this was very promising. We have established together, also with Jennifer Doudna’s lab and her CRISPR technology, you know, ways how we can inactivate these individual mechanisms in the cells that throw a lifeline for the virus. And so we thought that we could use this knowledge and these lung organoids and this technology to immediately translate it to SARS-CoV-2, and that’s what we’re doing currently.

KRIS:  What does it take to set up a lab where there is live viruses happening?

MELANIE:  Well, that involves a lot. Thank you for that question because that’s what keeps me up day and night, or it has kept me up day and night for the last two months. It is not easy to establish a lab like this. You need a very high biocontainment level, everything is regulated. You enter the… the laboratory has to be built in a certain way so that there is no air coming out of the lab into the outside. And, also, everything that is in the lab cannot leave that lab unless it goes through an autoclave, which is basically high temperature oven that kills everything when it goes through this. So there are certain, you know, logistics and facility, you know, requirements, but there’s also a lot of paperwork that is involved to, you know, establish standard operating procedures that will be strictly followed, so that there’s absolutely no risk for anybody in that laboratory to get infected. And  I think the basics is that we work with respirators and whole body suits. It really looks a little bit like a moon landing when you were in there. But since it is a respiratory virus, you really cannot, you know, be around the virus and not be protected in a very systematic way.

Now, a lot of people think, is it really safe to work in there? And I keep telling… I keep saying that I’m convinced that it’s currently more safe to work in this laboratory with all the protections and precautions that we take than it is to go actually to the grocery store around the corner currently.

KRIS:  So when you go to the grocery store, what do you do?

MELANIE:  I put my mask on and I wash my hands after.

KRIS:  There was an article in the New York Times this weekend that talked about the future of pandemics and that we’re probably not done with them for sure, and that there are efforts to develop drugs and vaccines that are pan antivirals. What do you think of pan treatments and could your work contribute to that?

MELANIE:  Yes, we hope so. I think that’s the goal. I think that’s why we started the BioFulcrum effort two years ago, with the dedicated, you know, goal to develop pan antivirals. And the reason why we thought the host is a good target for this is because we have learned through our ongoing studies with Nevan and in my lab that there is actually a lot of overlap of these factors in the cell that are important for viruses. Also, viruses are very different. They look different. They occupy different spaces in the cell. They still need energy to replicate. They need… you know, they need certain nucleic acids to build more genomes. So there’s a lot of bottom line that we can… that we find is actually common between these viruses. And they have to deal with a lot of immunity and restriction factors in the cells. And so I think our approach was to take advantage of these… of these shared pathways that we.. that we target, and so then with the hope that a future virus about which we don’t know yet at that time, much at the beginning, what would also follow the same principle and require these factors and would respond to these drugs. So I think we’re 100% aligned with this article that you mentioned.

I think the Remdesivir study is also a pan antiviral in some sense, because it was developed against another virus, and is currently being used, you know, against SARS CoV-2. And we have other examples. I think HIV drugs have been used for… against, you know, COVID-19, and so there’s a lot of… you know, a lot of effort currently ongoing to see what we can borrow from other viruses and can translate it now to this current virus.

KRIS:  Where is the research on T cells? Antibodies are fine, but limited in their effect. So can you give us a little tutorial about T cells?

MELANIE:  Yes, absolutely. I think my research is mainly focused on the infected cell, and that’s the innate immune response that… as the question correctly points out. And… but, eventually, these innate responses call in the adaptive arm of immunity, which is our dedicated immune cells, T cells, B cells, macrophages, and others. And I think T cells are a very important part of this because they provide important help for the B cells to actually generate the antibodies, and they also directly destroy the infected cell when they recognize it. And the adaptive immunity is really something that can go very specifically after the infected cell. So that’s something that a vaccine is trying to harness and to improve.

We know… we start to understand more about T cells, especially, also, in the severe disease because we know that the immune system is likely responsible, in part, for causing this severe lung disease. So there’s a lot of effort currently been focused on understanding what’s happening in the lung and what might tip the immune system to an overreaction versus an appropriate reaction.

And I think one thing is that we… you know, we’re learning these things now, maybe at a slower pace than we wish, but we need access to T cells and, you know, blood samples from patients currently in the clinic, and there has been huge studies being set up for this. For this, you need, you know, appropriate institutional permits and study protocols. You cannot just take something and study it. You have to… this is highly regulated. These have been set up.

Now, the good news is in California, we have not enough patients that we can enroll in this because we’re doing extremely well in flattening the curve, and in New York, people are overwhelmed to actually do systematic studies currently because of the need. So I think this will balance out in the long run, but I think we will learn a lot more about the immune response in the T cell in the coming weeks.

KRIS:  Is there anything I can do to make my T cells happy so that if I get infected, they’ll be ready? What can I do to get my innate immune system geared up?

MELANIE:  I think you can stay healthy. You can nurture yourself and make sure that you are in the best shape ever. Gut I think, most importantly, to prevent infection, you have to follow the guidelines. You have to watch your hands, you have to wear a mask in public, and you have to keep your distance so that your T cells are as little engaged as possible.

KRIS:  And you think that we’re going to be doing the hygiene and social distancing and masks for a while?

MELANIE:  I think it will be part of our reopening strategy and maybe also of our new normal as long as we don’t have a vaccine and potentially also not really effective therapeutics. So I expect to have these guidelines around for a while.

KRIS:  I’m going to get back to the biology and the physiology of COVID-19 and what goes on in the cells. The virus hijacks proteins, and then proteins start replicating. There’s a lot of connections between all these proteins. Am I correct in that there’s a lot to understand here?

MELANIE:  Oh, yes. There’s an amazing amount of complexity here, you know, that… that really shows us that the virus is really a master manipulator in the cell and in the body. And I think we have to understand it on a cellular level, but also on an organismal level, where we really understand how... you know, in the cellular level, we know what the virus does to a cell when you… when the cell enters, but we can also learn what it does to the neighboring cells that might get all its guards up and prevent infection.

So we currently are really doing these infections in the cell at a single level, where we can sequence the genomes or the genes that are being expressed in these cells on a really whole genome scale. So we know all of the factors that are going up and all of the factors that are going down in a cell when it becomes infected, but also in a cell that sits next to the infected cell and does not become infected. And that cell is almost more important for us to study because we want to know what effectively is actually preventing the infection in this cell. So there’s an enormous amount of complexity already going on in a relatively simple dish that I study in the laboratory. But when you then go into a mouse or into a patient, I think then you see how that cellular level is interacting with the surrounding and what compensatory mechanisms might be at play to either fight the virus or to help the virus.

KRIS:  There have been some controversy about various drugs that either show promise or don’t. I’m thinking specifically of ACE inhibitors that people take for high blood pressure. Does the complexity of what’s going inside the cell explain some of the up and down responses from some of these drugs?

MELANIE:  Yes, I think it really is a perfect illustration that viruses and medicines affect the whole body, and that there is a complex interaction, and that we have to look at the whole thing instead of just, you know, a singular aspect of it. With ACE-2, it’s really interesting because ACE-2 is the receptor of the virus. It really allows the virus to enter the body and to enter the cell and to set shop and produce viral factories. But at the same time, we also know that in the lung, it is an important anti-inflammatory protein and is important, actually, for lung health. So we also know that if you take ACE inhibitors, you have a compensatory upregulation of that receptor in the lung.

So I think the controversy, currently, is that you want to, you know, inhibit the virus to enter the cells, and maybe these inhibitors could play a role there, but you also inhibit, basically, an important lung pathway that could help you deal with the infection better. And then on top of it, the drug might upregulate this, which is good because it contributes to lung health, but it might be bad because it enhances the entry of the virus, and that’s the big concern.

However, so far, the studies… this is just a theoretical concern. I mean, some studies have started to look at, you know, seeing whether patients on ACE-2 inhibitor, or ACE inhibitors are doing better or worse in the clinic, and there is, to my knowledge, not a conclusive study published currently.

So I would say that it’s very important before stopping any medication because becoming… because you become concerned or panic, I think the important thing is really to work with your doctor, discuss this with your doctor, and if there is any indication for a switch, do this very slowly because you don’t… you want to avoid getting into uncontrollable hypertension because of the withdrawal of the drug.

So I think, currently, the evidence is there especially in… or is on the radar and people are looking into it. The data, so far, doesn’t show a huge difference between people who are taking ACE inhibitors or not, but this has not been systematically studied.

KRIS:  There have also been some scary stories about young, healthy people who get infected with COVID-19, and then they have really big strokes. What’s going on there?

MELANIE:  Yes, I think there is absolutely an emerging picture of the virus interfering or interacting with the blood clotting system in a very specific manner. This is not totally new, whereas viruses… other viruses are doing it, too, but the question is, is this at an unprecedental, level and is this really something that the virus is doing uniquely, or is it just a byproduct of the inflammation that is ongoing?

So the blood clotting system is currently under, you know, I would say, intense scrutiny, and I… we really have to find out what, exactly, is going on there. Again, this is a very complex system that you do not want to mess with, unless you know exactly what you’re doing. And the key for us is really to study this better and to see what we can do about it. I understand that doctors in New York are thinking that maybe some of the severe disease they were seeing in patients is also connected to some microinfarction in the lung, and are playing around with levels of heparin, which is an anti-clotting medicine, to see whether that improves, actually, the breathing problem that some people have. That is definitely an area of intense investigation not only in the central nervous system but also in the lung, or event in… I think we’re seeing even some vascular symptoms in extremities and legs or in feet.

KRIS:  Does this virus mutate very quickly?

MELANIE:  Yes, I think mutations is a very important part of any virus because a virus always has a propensity to introduce little arrows into its genome through the polymerase that I mentioned very much at the beginning. And so these random mutations can become very important in the long run when there’s a selective pressure. So, for example, when I say viruses can develop resistance against drugs relatively fast, especially if it’s a drug that targets a particular factor in the virus directly, because then these random mutations occur, and those that refer resistance to a drug will then grow out and become the dominant viral strain. So far, for this virus, I think the common assumption is that it does not have a very high mutagenic rate. So the error rate of its polymerase is not as high as other error rates from other viruses. But it has very unique features where it can actually use recombination and grabbing genetic material from other viruses or from other genetic sources to incorporate into its genome. So it’s a very, very, interesting virus.

We have, so far, when we look at the sequences of the virus across the world, and their central databases where all the sequences are being deposited, not seen a huge diversity. We know that there are certain hotspots in the genome where things are happening more rapidly. Things are deleted or changes occur in the genetic code. But, so far, it has not shown a very high…  not a very high mutagenic rate, and, also, it hasn’t shown a certain direction in where it’s going. But this is… this might change, as I said, if we put some selection pressure onto this virus in the form of growing immunity in the population, a vaccine, or potential therapeutics that might cause emergence of mutant strains.

KRIS:  For right now, the fact that it seems so stable, that’s a good thing, right?

MELANIE:  It’s very good news. It’s very good news, also for the development of a vaccine. Because a virus that has very high mutagenic rates and variability in it sequences are much harder to capture in a vaccine, or, also, in our own body, to develop, you know, really effective neutralizing immunity against it.

KRIS:  Do you have any comment on the president’s cut of NIH funds to the EcoHealth Alliance?

MELANIE:  Well, I have a lot to say about this, in general. I’ll probably keep it short here. I think the point is that if we want a vaccine fast, and we want medication fast, we have to fund science. And I think this is not what seems to be happening in this administration here. This principle is not being understood very well. I think the specific effect on this… you know, cutting the research in China, I think, is politically, you know, informed or motivated. I think there’s… this is a very, very, valid research line, because it really helps us understand what is happening in the bat, which is the origin of the coronavirus, the current coronavirus and former coronaviruses, and, in general, is a hotbed for viruses. So this work has led to our understanding that there is hundreds or thousands of coronaviruses in bats that we don’t understand.  It has also informed us to show that this coronavirus has a very close relationship to an existing bat coronavirus that has been sequenced previously, but only because we had scientists working on this. And I think going to the root cause of these viruses, which is the animal host, and finding the intermediate host for these viruses, is absolutely important for us to be better prepared for the future, and to, actually, also, cut, you know, the current pandemic.

KRIS:  Because, as we talked earlier, there’s more coming, right?

MELANIE:  Well, I think if you look at the current frequencies of outbreaks that we have every probably five years, currently, I mean, starting with SARS-1, going to MERS, looking at the Ebola outbreaks, looking at Zika a few years ago, now SARS-CoV-2, I think we can anticipate that this rhythm is going to continue and potentially accelerate. I think this is because we have a much more connected world, and a much more crowded world, also, in terms of transmission.  And I think we will have to deal with these outbreaks in the future, and, hopefully, we will be better prepared. And cutting for initiatives like this is shortsighted.

KRIS:  What is herd immunity? In your opinion, where do we need to get to, to have herd immunity?

MELANIE:  Yes, we have to get to very high numbers to get herd immunity. So herd immunity is basically the fact that when a virus is circulating in a population, people will get sick and they will eventually develop immunity against it. And if enough people in the community have developed immunity, then we have… the virus cannot spread anymore. That’s actually very effective. This is happening when we vaccinate people. We basically generate herd immunity. But we also know from our recent, you know, experiences from people who do not want to get vaccinated that if that level falls under a certain threshold, the herd immunity doesn’t work anymore. So, initially, people who don’t take vaccinations will be protected because of the herd immunity, but eventually, this will fall off if enough people are not participating in these efforts. So this is basically a natural vaccination that we see with a viral infection, where people… where enough people in the community have developed immunity, or antibodies, or whatever the correlate is, to prevent infection and so that the virus cannot be transmitted anymore. And we know that these levels, this is very much dependent on the capability of the virus to infect other people. It’s the so-called R nought factor. We think it’s about two for this virus. And so we calculate that about 50% of the population or more, 50- to 60% of the population, will have to be immune in order to make herd immunity the main driver of, you know, prevention of infection. We are far away from this number.

KRIS:  You talked about some interesting things that are happening other places where they’re tracking the virus through sewage systems… what’s that about?

MELANIE:  Yeah, I mean, everybody… I think tracking is really important. I think that’s why we’re developing at Gladstone a test where we connect our test directly with a mobile phone, so that the mobile phone processor… the lens, is basically the diagnostic… you know, is ready the… the the essay. The processor is managing the whole thing. And the GPS is helping to locate, actually, where the test was done. And so that’s similar to what has been tried now with Facebook and other major… or Google, to see whether we can have a much better, you know, tracking system of people with symptoms or with positive tests.

Now, one thing is that we know that the virus is not only, you know, exhaled through the respiratory, inhaled and exhaled through the respiratory tract, but it also gets into other organ systems. One of it is the gut. Many patients very early on have also complained about intestinal symptoms. And we know that the gut can become infected and that virus is being shedded. We don’t know if that is actually infectious virus. It looks as if there’s no infectious virus in stool, which is good because that interrupts all the oral fecal transmission that happens with other types of viruses. However, we detect tons of virus in the stool and other… and, also, in urine. And so the idea is that, you know, sewage is something that is being tracked for many indicators and quality controls. The City of Paris has started to track the virus in there, and they could show preliminary results showing that this might be an additional means to see how high the virus is actually distributed, or how prevalent the virus is in the community that the sewage is being taken from. So, yes, these are unconventional methods but, I think, on a population-based method, may be something that could be useful in the future.

KRIS:  Is getting some good marks for how they’ve responded to this. Can you compare the different approaches? What do you have to say about that?

MELANIE:  Yes, I think Germany was hit very early. I think with the patient in Munich that was very early infected and actually served, I think, as a distributor in Europe for a significant line of infections. And they… I think the lessons we can learn from Germany is (a) they have developed a test very early, very, very early, and they distributed it to everybody. I think our testing delay came to the point… was partially due to the centralization of the testing, initially, in Atlanta, which was a bottleneck that we overcame very fast, but still delayed us. I think the testing is done very progressively and actively on a population basis, currently. And they also have a very good medical and research system there that they have put into play, you know, on all fronts, like we do here in the US. And  I think their political system is different. I think they have, like us, states and the federal level, but I think the federal response was much more coordinated and also trusted by the population, so that all the measures and social distancing is strictly followed.

So Germany, currently, is actually playing a little bit with fire, because they will be the front riders of opening up the country. They were planning on starting limited school attendance on Monday, but, actually, got sued on Friday against it and had to lock it down. So there is still a lot of debate there whether they are too early, but they are confident that they have the virus under control currently, also because they have incredibly low fatality rates that really stand out around the world. But I think there’s still a debate whether they’re a little bit on the early side, but it will be important for us to watch.

KRIS:  Do you have any general guidance on how do you proceed with loved ones?

MELANIE:  I know it is very difficult at this moment, because from the strictly scientific side, I have to tell you that we don’t know what is happening and how protective the immunity will be, and whether we can tell people with positive serology or a positive history that they are not going to become infected again and they will not spreading the virus to somebody else again. But I would say from a scientific standpoint, from, you know… from my personal standpoint, I would say that we have a reasonable assumption that some form of immunity will be developed immediately after. I think we would have probably many more cases of repeated infection than are currently being investigated to do this. My assumption is that the contact with the virus is inducing immunity to a certain extent, at least for the short term.

The big question is really how long this will last. We know from other coronaviruses that some do induce longer-lasting immunity and some don’t. And so I think also back to your question from the beginning, is the severity of the infection playing a role here? Is the location where the infection has happened playing a role here? And is playing age a role, also? Because we know, in general, that if you’re older in vaccines and infections, you build less of an immune shield that is less effective.  So I think there’s many factors here. From the strictly scientific point, I think we don’t know at the current point what is happening and how protective the immunity is. From a common sense standpoint, I think there’s some immunity, but we will have to see how strong and how long it lasts.

KRIS:  So people are just going to have to make their own decisions based on their own health.

MELANIE:  I would say follow the guidelines, currently, and try to be as responsible in the way of social distancing as you can. I know it’s extremely hard with grandchildren and our loved ones, but I told my parents that they cannot have their two young kids currently in the house, and they’re very upset with me. And I don’t know if they follow it, because they’re in Germany, but I sure hope they do.

KRIS:  What do you think about keeping schools closed?

MELANIE:  I thought that the school closure was a very important part of our sheltering in place and doing it early was important. I know we know this from former epidemics, where short school closures were really the benchmark for success, basically. And I think especially with this virus, where we know that the young people often asymptomatically carry it but spread the virus, I think schools are probably a very, very difficult center of circulation, of viral transmission. And I think we have to watch this very closely, how are we going to reopen and how are we going back to a normal here. But I think it will be… because you have to just imagine crowded classrooms, or in college, dorms, and lunch rooms, and all this. I think this is really the perfect place where the virus is going to spread.

KRIS:  What can you say about obesity and COVID-19?

MELANIE:  It’s interesting, because my lab has a longstanding interest in, actually, fat metabolism and how it interacts with viruses, and we have learned quite a bit about it, that, you know, fat is actually a dependency factor, or can be, supporting the virus. It’s also a huge energy bowl, where the virus can access energy for its own replication. And we know from Nevan’s study that there is interaction of the virus or the viral proteins directly with the fat machinery in the cell. We don’t know if that is the reason why this is a risk factor, but it’s definitely something that we’re following up on. I think the other big question that needs to be addressed here is whether, you know, just the lung health, breathing functions are playing a role here, you know, dependent on body weight, whether that is just a more practical explanation for this… for this dependency.

KRIS:  It also seems like men are at higher risk for death and for serious complications. Is there any explanation for that?

MELANIE:  Well, there’s lots of speculation around this, because this has emerged relatively early in the pandemic already from colleagues in China. They published this beginning of the year that they see more elderly men in severe conditions than women. And that was, I think numbers that were double or half of, you know, the men or the women side. And that has held through.  And I think there’s… you know, thinking about the immune system and hormones, we know that women, in general, might have a stronger immune system also because of their pregnancy, you know, and the need to protect the baby. But they, also, we know, have the stronger tendency to have autoimmune diseases, so the tradeoff might be that you have a stronger immune system, but, also, maybe, more propensity to for the immune system to overreact. This does not seem to be the case here in this pandemic, so we don’t know. A lot of people have argued that even women post-menopausal, without, you know, the necessary protection of the female hormones are doing better than men. So they discard the hormonal explanation and squarely put it on, you know, men having more, you know, risk factors, and, in general, smoke more and have other more unhealthy habits, but that also doesn’t seem to explain it.

I’m just throwing out one interesting fact, is that ACE-2, the receptor, is actually located on the X chromosome, where we have, of course, two copies in women and one in men. And we’re just sort of trying.. starting to figure out whether there is really any, you know, difference here that could be explained, that could be explaining the difference that we’ve seen in the clinic.

KRIS:  When you look at this virus, is there anything that keeps you up at night?

MELANIE:  Well, I’m… I’m, actually, kept up at night a lot these days by many things, and I must say that the science is really that that drives, you know, most of these sleepless nights. And I think it is both an extremely urgent time that we’re having, but, also, an extremely, you know, important time as a virologist, and the way that we understand this virus in a record speed, and in the way that we establish and conduct collaborations, and the way how we, you know, try to move this forward. It’s really not a thinking of, ‘Oh, I do this next week.’ It’s really, ‘I do this in the next minute.’ And I think this urgency is driving everybody in the field. It’s not only virologists who are working on it. I would everybody has shifted, every scientists who I have spoken to has shifted part of their programs, and trying to contribute what they can contribute in their expertise. And, I mean, the 69… or the international consortium with the 69 drugs is an incredible example of this.  Most of these people are not virologists. They are experts in certain… in lung biology, in pharmacology, in structural biology, in many different aspects, and they all have come together to just focus on these… on this virus, and their proteins, and how they interact with the cell in order to develop something that is useful for the clinic, in, hopefully, no time.

KRIS:  You cared for patients during the HIV epidemic, right?

MELANIE:  Yes.

KRIS:  Does that experience form what you do now or what you think up now?

MELANIE:  Well, I was a neurologist in Frankfurt at the time of… in the early 90s, when we were really at the peak of the AIDS epidemic, and no treatment. I was running an intensive care unit in neurology, and many of my patients were HIV-positive and end-stage AIDS, and they all died. Nothing I could do. I had even nurses infected on the ward and dying, and it was a very, very dramatic time. I think what… the pictures that I see from New York remind me very much of that time. At that time, I decided I wanted to become part of the solution, I wanted to learn more about the virus, and, basically, switched. Moved to New York, did a Ph.D. in virology and HIV, and the plan was to go back to the clinic and become a physician scientist. But my experience in the lab was so profound that I got hooked to science and I never returned to the clinic. And I would say times like this are justifying these decisions because I think there’s a lot we have to do and a lot that keeps us up at night.