A new episode of our podcast, “Show Me the Science,” has been posted. At present, these podcast episodes are highlighting research and patient care on the Washington University Medical Campus as our scientists and clinicians confront the COVID-19 pandemic.
Even before the first case of COVID-19 was reported in the United States, Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine, started setting the stage with Sean Whelan, PhD, the Marvin A. Brennecke Distinguished Professor of Molecular Microbiology, for scientists at the university to study the virus. Whelan had just arrived in St. Louis to begin his new role as head of the Department of Molecular Microbiology and didn’t even have an operational laboratory when the two scientists jumped into the breach and started work to equip and certify a Biosafety Level III laboratory, where researchers could study SARS-CoV-2.
Since those early days of improvising to get funding and equipment in place, the researchers not only have studied the novel coronavirus, they’ve made a less dangerous form of the virus that has allowed a wider circle of scientists to study it. And after discovering that SARS-CoV-2 does not naturally infect mice, they used a viral vector to temporarily make the mice susceptible to the virus, enabling scientists to learn more about how it behaves in an animal model. Diamond and Whelan also have played a role in efforts to develop new vaccines, including a nasal vaccine that prevents infection in mice.
The podcast, “Show Me the Science,” is produced by the Office of Medical Public Affairs at Washington University School of Medicine in St. Louis.
Jim Dryden (host): Hello and welcome to “Show Me the Science,” conversations about science and health with the people of Washington University School of Medicine in St. Louis, Missouri, the Show-Me State. As we continue to detail Washington University’s response to the COVID-19 pandemic, we take a trip into the laboratory.
Michael S. Diamond, MD, PhD: Our goal, I think, initially, was to get the virus, to grow the virus, and the first thing we were going to do as part of studies was to generate antibodies against this and a screen for antibodies with therapeutic capacity. That was one of the first things that — one of our goals.
Dryden: Michael Diamond has specialized in the study of new and emerging viruses, and he began studying the virus that causes COVID-19 even before the first case was reported in the United States. Early on, he teamed with Sean Whelan, the new head of the Department of Molecular Microbiology, to build lab space where it would be safe to study the virus. Whelan says they needed space that could be certified as a BSL-3 lab. That stands for Biological Safety Level Three. And it requires workers to wear personal protective equipment, including respirators. It also requires special ventilation in the room, locked doors, and other safety measures designed to prevent inhalation of the potentially deadly virus. As they started their work, Whelan says, there was a fair amount of improvisation involved as he and Diamond gathered resources for a lab and worked to coordinate research efforts around the Medical Campus.
Sean Whelan, PhD: Maybe I can share a little bit of a personal perspective. I arrived in St. Louis on the 4th of January 2020 and ran into Mike shortly thereafter here on campus and asked Mike, “Are you interested in this coronavirus that’s emerging in Wuhan, China?” And Mike indicated that he was also interested in working on this virus. And I think that was an early stage of the outbreak where I don’t think — I certainly didn’t expect this pandemic to become what it became. I hoped that it would be contained in much the same way that SARS was, but it certainly seemed like something interesting was happening.
Diamond: Yeah. And my recollection is that we had some conversation, and then we went to Sean’s temporary office upstairs. And after we agreed that this was possibly a problem and possibly important, what would it take for us to study it? And then we looked at each other and realized that we had space but not equipment or all of the resources necessary. And my recollection of the conversation was, “Sean, we would need to really upgrade this very quickly.” And Sean said, “Yes, let’s do it now.” We had to acquire the virus, so I took care of that through my contacts at the CDC. We knew there would be some paperwork, which there was. And then the second thing was Sean and I visited the space that we planned to work on, and it was a space that was left over from a former investigator who worked on SARS. And essentially, it was empty, except for some very antiquated biosafety cabinets. We went down to my laboratory and decided which equipment we could move up to that laboratory, and then also what we had to actually purchase.
Dryden: So it was improvisation at some level.
Diamond: Yes. And we had a lot of help from Sean’s administrator, Sharon Janoski, who knew how to get things done and knew where to get stuff. And also from that technical group, there’s a freezer story as well that helped us — maybe Sean can talk about that. So the summary is once we decided to do it, we mobilized to take some equipment from us in medicine downstairs and then get new equipment and refit and retrofit that facility to get it approved to do SARS-CoV-2 work very quickly.
Whelan: Yeah. It was a case of beg, steal and borrow. Christina Stallings, in my department, had actually ordered a minus 80 freezer that I actually managed to co-op so that we could install it in the BL3 lab, because it was here and was waiting to be installed, and Christina was gracious enough to allow us to use it so that we could actually work with this virus.
Dryden: So you’re putting together this lab to study this virus that you don’t know very much about. Did you know, for instance, at the time, Dr. Diamond, that you couldn’t infect mice with it?
Diamond: No, we didn’t know that at all at that point in time. We didn’t know that until substantially later. Our goal, I think, initially, was to get the virus, to grow the virus, and the first thing we were going to do as part of studies that I had a collaboration with, a group at Vanderbilt, was to generate antibodies against this and a screen for antibodies with therapeutic capacity. That was one of the first things that — one of our goals. And we cobbled together some funding to support it, along with a lot of departmental funding. So Sean essentially paid for all of the funding to develop the resources. And then we also got support from the institution, from WashU, from the dean and from donors to actually do the experiments.
Dryden: And did that all come before the March lockdown, or is this happening while things are closing down?
Diamond: So, Sean, do you remember when we got the virus? I think we got it in mid-February, didn’t we?
Whelan: No, you got the virus very late January, I thought.
Diamond: Oh, maybe you’re right, maybe it was late January.
Whelan: Yeah. I thought you got virus around the 26th. In fact, when the virus arrived, we were rushing to just get the lab certified and the hood certified, so we could start to do the work.
Diamond: Right. Now I remember correctly. Basically, we got the virus, had to stick it in the freezer and lock the freezer until the rest of the room was ready.
Dryden: They had to ready the room because it needed to be certified at a BSL-3 level before the research could begin.
Whelan: And at the same time, we had — so in the intervening time, the sequence of the virus had been released. And so we had ordered, the day the sequence was released, we’d ordered versions of the surface protein of the virus to be synthesized by gene synthesis companies. And we got those about the same time as we got the virus. And I remember walking around campus one Friday afternoon distributing little aliquots of DNA of this viral spike protein to colleagues, including Daved Fremont in Pathology & Immunology, and saying, “Here, this is what we’ve got.” And other people had begun to start to get reagents together. And so I think at that time we figured out that we needed to have a discussion amongst all interested parties on campus. And so Mike and I started this weekly meeting that the only slot on our calendars that seemed to work was 8 o’clock on a Monday morning. And I have to say, I’m not really at my best at 8 o’clock on a Monday morning [laughter]. But that became the slot that we had our weekly COVID discussions. That was incredibly helpful, actually.
Diamond: Yeah. So my lab, fortunately, had some expertise in coronavirus work. So we had some postdocs and senior people who during their PhDs had done significant studies on either the original SARS-CoV-1 or other coronaviruses, animal coronaviruses such as mouse hepatitis virus. So we had some inkling on how to grow it, but we also knew that the virus was not necessarily stable. But once we had stocks of the viruses, then we had the opportunity to do a number of things. One is just to screen for antibodies that could neutralize it. The second is to help evaluate and validate — Sean’s had developed an assay pretty rapidly based on some of his prior work with VSV, making chimeric viruses with spike proteins from coronaviruses. He had done this with SARS-1 and with MERS, and then developed very rapidly, as he’ll tell you, the one for SARS-CoV-2. But we were able to then compare data across platforms and show that his neutralization assay was actually quite faithful to ones with live infectious virus, which has been very important.
Dryden: In other words, they didn’t always have to use the live, real virus to figure out how it infected cells.
Diamond: And then we were able to then start doing studies in mice. And the first series of studies that we did, of course, we put the virus in mice and nothing happened. And the virus didn’t replicate at all. And of course, as we were doing this, others were also reporting this. And that’s when we started to think about, “OK, how are we going to get this to work in mice?”
Dryden: Yeah so, Dr. Whelan, you essentially took the part of the virus that infects and stuck it onto something that was less dangerous.
Whelan: Yeah. That is a vaccine for use in humans for Ebola virus. And that vaccine is based upon a livestock pathogen vesicular stomatitis virus, where the surface of the virus was engineered so that it looks like the surface of Ebola virus. And so that was the basis for what we were trying to do, except with SARS-CoV-2. So make the outside of this livestock pathogen look like SARS-CoV-2. I actually didn’t have a lab here at the time. My lab was still moving from Harvard Med School to St. Louis, and they showed up about a week before the lockdown happened. But we were able to successfully construct, and we were then able to select from that a very efficiently replicating virus that had the spike of SARS-CoV-2 on the outside but was this innocuous livestock pathogen on the inside.
Dryden: How important was it that you had had experience with other viruses like Ebola, like Zika? I mean, does that help with something novel like this, or because this was a novel virus, did you have to start from scratch?
Whelan: I think having that experience clearly helps. Because with every new virus, there’s always some nuance about how to actually work with the virus. Even just simply growing the virus in cell culture. And I think having people around with that experience really contributed a great deal to being able to hit the ground running.
Dryden: Yeah. I guess, on one hand, it seems like a long time to be in this weird way of living that we’ve been in since last March, but on the other hand, when you think about the progress that has been made in labs like yours, it’s pretty breakneck speed.
Diamond: Yeah. I would say that. And continues to be. That there’s just remarkable — every time there’s a new twist and turn, there’s continually — the global scientific effort is moving pretty quickly. To sort of reiterate what Sean had said, we had four different things that were really important to us that allowed us to get going. One is that we had people in the lab who had previous coronavirus experience, especially Brett Case, who is a postdoc who did his work with Mark Denison’s laboratory at Vanderbilt. Then we also had a pathology fellow in my lab, Adam Bailey, who had really done a lot of work on designing RNA-based tests for viruses. We also had people who are experts in vaccine development, and I had somebody in my lab who worked on adenovirus vaccines. And then we were able to partner with David Curiel’s lab rapidly to generate a vaccine construct, but also to generate adenoviruses to deliver to mice to establish a new mouse model. And then I had people in the lab who were experts in mouse models against many viruses. And so we were certainly able to sort of address the problem: “That didn’t work the first time around, what do we do now? How do we move on very quickly?” And then we’ve also worked on several emerging viruses and sort of gone through this. Not quite at this breakneck speed and not quite with the pandemic, but I started my lab working on West Nile, we then worked on Chikungunya virus, then Zika came along, and this is now the fourth wave of really new significant virus that’s caused epidemics and pandemics. So we sort of understand what are the things that we need to do, and the timeline has just become incredibly compressed, obviously.
Dryden: A lot of us have gotten shots now of the Pfizer, Moderna, Johnson & Johnson vaccines. But you’re also developing more vaccines between the two of you. Is there going to be a need for new and different vaccines moving forward? And what’s different about the vaccines that you guys are working on at the moment?
Diamond: So I can say two things. One is we’re developing an intranasal vaccine, which would generate mucosal immunity. And none of the existing vaccines do that, although there is some evidence now that perhaps the very, very robust immunogenic ones, like Pfizer, Moderna, do have some protection against transmission. But the other ones probably don’t. And it’s not clear how well they’ll work against variant viruses with regard to transmission. So we think there’s a route for this. Now, the other thing I would say is that, although we move very quickly, we certainly didn’t move as quickly as Pfizer, Moderna or J&J, and part of that is that we did not have the infrastructure here at WashU to do that. There still is room for vaccine improvement, there’s still room for ones that can be developed for the developing world.
Whelan: I think there’s also concern about what’s going to happen in the future and to what extent we need to be thinking about next-generation vaccines. And whilst we can probably readily adapt the RNA platforms to do that, some of the limitations are the costs and the distribution. So generating much lower-cost vaccines that can be used globally I think is critical.
Diamond: And Sean and I have some other new ideas in how to actually make it even better, which we’re going to start to test. And I think once we do that, then this issue about cost will really be important in the developing world. I mean, right now we may have 15% or 20% of the people completed vaccination and more having had a single dose. But that is certainly not the case in the vast majority of the world at this point in time.
Dryden: Right. And if the disease is allowed to continue spreading in the developing world, then eventually some of those variants might get through the Pfizer and the Moderna platforms that some of us have been vaccinated with already. We’ve got to take care of the whole world, or we can’t take care of ourselves in the long run.
Diamond: Correct. Because if you have a third of the world not vaccinated, percolating variants, then they’re going to return.
Whelan: Yep. And soon.
Dryden: And does that mean that we should all look forward to needing boosters, or is this going to become an annual thing like the flu shot?
Whelan: I think this is inevitable, that we’re going to have to monitor this virus. And I think we’re going to require additional vaccines. I think there’s some optimism, but it won’t be every year. But some of that is also going to depend on the extent of other species that are also infectable and infected by this virus, in which the virus is multiplying and then coming back into humans.
Diamond: Yeah. It’s much easier to get rid of viruses that only infect humans. But when they are zoonotic, then they not only can go there and hide and percolate, but they can change. And so that’s why smallpox in some ways was easy because it was really obligate human. But other viruses, which can jump species, it’s extraordinarily difficult to eradicate.
Dryden: One final question for you: Where do we go from here? The last 12 months have been incredible. What happens now?
Diamond: I think there’s a couple of things on our side — I mean, I don’t know if the question is WashU-related or if the question is generally related, but on the WashU side, we have plans now to expand our pandemic preparedness at the experimental research level by expanding our BSL-3 facilities campuswide, for doing basically standard molecular and cellular work as well as animal-based work. We have a commitment to build a vaccine center. And so this will also allow us to be prepared to generate new discoveries, not only related to SARS-CoV-2, but as we anticipate that this won’t be the last of the microbial agents that lead to new epidemics and pandemics.
Whelan: I would like to just add to that. I think that the research that happens here at WashU on emerging pathogens and also on drug-resistant microbes, two really significant threats to human health, is second to none.
Dryden: In less than a year, Whelan, Diamond and a team of researchers have developed vaccines, including a nasal vaccine that now is in early human trials. They’ve also created model viruses, allowing researchers at Washington University and around the world to study how the SARS-CoV-2 virus infects cells without actually having to use the potentially deadly virus itself. And Whelan and Diamond say they’re continuing to race to find ways to get the pandemic under control, and then to keep COVID-19 under control. But it remains a race between the evolving virus and the vaccines and therapies that they and others are developing.
“Show Me the Science” is a production of the Office of Medical Public Affairs at Washington University School of Medicine in St. Louis. The goal of this project is to keep you informed and maybe teach you some things that will give you hope. If you’ve enjoyed what you heard, please remember to subscribe and tell your friends. Thank you for tuning in. I’m Jim Dryden. Stay safe.
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