COVID-19 Research: Genomics, Rapid Execution & Funding

How Has Canada’s Research Community Responded to COVID-19?  

We are really kind of starting from scratch when it comes to this coronavirus. Now having said that, this is not the first coronavirus we have seen.  

There are four coronaviruses that can infect humans—these are common cold viruses that surely almost every Canadian has been infected with, so we are all coronavirus experienced in one way or another. There are three “high consequence” coronaviruses. Those include SARS, MERS and now SARS-Coronavirus-2. Of these coronaviruses, there are very few that have been extensively studied, at least in Canada. There are a couple of centres of excellence where they are studying things like MERS—places like VIDO-Intervac—where they have done excellent work on the MERS coronavirus. Having said that, a lot of virologists in Canada were mostly working on other viruses when this hit. 

One of the things that this pandemic has done is galvanized that community, and many of these virologists—whether there were working on HIV, Zika virus, West Nile or influenza—pivoted over to coronavirus, because there are a lot of basic skills that can be applied. Whether it is epidemiology, basic science or clinical research, that is one thing that has happened.  

The other thing that has happened has been across the broader research community. There have been individuals who have come forward with long-standing reputations and very storied careers in other fields—it could be oncology, neuroscience or engineering or any field related to biology and even sometimes physics. Those are all things that can be brought back to trying to understand this particular virus. I have met more investigators in other fields in the last six weeks than I have throughout my career, which has been great.  

How Can We Improve Collaboration Within Canada’s Research Community?  

I think where we can do better is really trying to coordinate these efforts. As you probably appreciate, the way science works in Canada there is somewhat of a competitive atmosphere, and that is partly because there are limited funds. To gain access to those funds there are competition, and there can be a race to publish certain results. That leads to an atmosphere where people remain a little bit closed—they hold their cards close to their chest, because they don’t want to give away too much.  

That is one thing that has changed with this particular pandemic. The spirit has really changed; individuals have really opened up. I’ve heard the phrase repeated many times by several people: it’s better to collaborate than compete, which is a huge relief because it wouldn’t help anybody to maintain a competitive attitude in this particular situation. That is very helpful. 

“It’s better to collaborate than compete, which is a huge relief because it wouldn’t help anybody to maintain a competitive attitude in this particular situation.”

But again, what has been lacking is a more coordinated effort. Part of that is due to many of us not knowing each other, especially across different disciplines. As an example, many engineers and virologists do not normally work together—and now there are clear opportunities and needs for them to work together. If that kind of approach could be coordinated, I think we would be further ahead. 

Why Has Your Research Focused on Isolating the Virus?  

Isolating the virus is a tool—a very important tool—that we now have to develop a number of medical countermeasures. That really starts with understanding the biology of the virus. Unless you have the virus in hand to use to infect cells and other models, it is difficult to understand what the potential druggable tests are and how the virus affects the host—whether that is a cell or an actual organism. Now we have the virus to be able to do that, and it is incredibly helpful—and it is not something we are doing alone.  

There are a lot of collaborators, both at the University of Toronto and other institutions, who have potential candidates for antivirals and vaccines. With the virus we are able to actually test those candidates and without it, we wouldn’t be able to even consider doing that.  

What Must We Focus On In Terms of Testing For COVID-19? 

To begin with, it was quite remarkable how quickly the first tests were developed. The primers were based on very early genomic sequences that were posted from China. That was incredibly helpful, because you can’t develop a detection test if you don’t know what the sequence of the virus is.  

It was very helpful to develop a PCR test—that’s a type of molecular rest that is commonly used for respiratory viruses, so that is helpful. We used a lot of infrastructure that we already had for things like influenza—doing detection for other respiratory viruses that circulate every year. It wasn’t as simple as puck and play, but we were able to implement tests that were more specific for SARS-Coronavirus-2, but by using a lot of the same platforms. That was very incredible, but we can definitely do better.  

We know that we have had issues with supply of different reagents and supplies of swabs, and then there is turnaround time. Someone might have a sample taken, and depending where you are getting tested it might take a day or a week to get results back. Those are some of the areas of improvement for the broader scientific community.  

Developing point-of-care tests is really key. Those are tests where you do not necessarily have to send the sample back to the lab. They’re more portable. You might even be able to do the testing right away and get results within an hour or two. You might also be able to take different types of samples—like spit or saliva as opposed to a swab. We are looking to see whether that is better or not—and it will be very important to make sure that whatever we do is not inferior to the current testing modality. That is key.  

“The other test that is important to develop is the serological testing, which is understanding whether somebody has antibodies.”

The other test that is important to develop—and people have made good headway on this—is the serological testing, which is understanding whether somebody has antibodies. This is not so much a detection test, but a test that tells you whether or not somebody has been potentially exposed. Not everybody might make antibodies, and we do not know who does and who does not, or how long they last. There are a lot of unknowns there, but it all starts with having a really good test for that. These are the advances that people are really focusing on right now from a diagnostic perspective.  

What Are Canada’s Priority Research Aras?  

In terms of really understanding what the priorities are in terms of research and medical countermeasures, it all starts with understanding the biology of the virus. The virus is relatively similar to SARS-Coronavirus-1, but there are phenotypic differences so the disease it causes in humans is somewhat different. This virus seems to transmit better and—we hope—it has a lower mortality than something like SARS-Coronavirus-1, and it certainly has a lower mortality than MERS. But understanding why that is is really important—so understanding the biology of the virus, what it’s doing in cells, which cellular proteins it’s interacting with, and which cellular proteins it’s stimulating. In other words, trying to understand the host’s immune response to it. Those are all key priorities.  

“This virus seems to transmit better and—we hope—it has a lower mortality than something like SARS-CoV-1, and it certainly has a lower mortality than MERS.”

By understanding that biology, you understand what the druggable targets are. If you understand what those targets are, you can help people develop screens for and a rational design for antivirals. They can design molecules to target either components of the virus or components of the host’s response that would mitigate infection. 

Understanding the biology and the host’s response has immense bearing on the vaccine. Vaccine development and understanding what the correlates of protection are is the only way to test vaccines. Those are a couple of key priorities that, in the coming months, will be highlighted.  

Will We See More Waves of COVID-19 Infections?  

The likelihood for this particular pandemic that there will be another spillover event of the exact same virus is quite low. Having said that, we don’t fully understand exactly where it came from.  

Most likely, the reservoir was a bat—but was it a bat to human transmission directly? Or is there an intermediate host out there that we’re not aware of? If we don’t understand what the intermediate host is, then there is a chance that there may be another reintroduction. That is probably the greatest risk, if we don’t pay attention to viral ecology as well.  

What Role Can Genomics Play in Data Sharing and Future Preparedness? 

Genomics plays a really crucial role, and it plays a very interesting role. The perspective is actually quite interesting, because you can look at the most minute cellular level, and the genomics at the cellular level are very insightful. By looking at how the viral components of the virus actually interact with the components of the cell, we can identify some potential druggable targets and means by which to interfere with host-viral relationship. Looking at genomics from that perspective is really key. 

And obviously, it goes beyond the gene—it can go to the transcriptome and the metabolome, and so on. There are quite a few systems—we call them systems biology in terms of understanding what is happening at the cellular level, particularly when a host cell and a virus interact—but there is whole other level, which is the population level. There are two sides to that story as well. There is the host side of the story, and then there is the viral side of the story—and both can be sequenced. We can get the genomic structure from both perspectives.  

“We have seen some elderly do well, and some young people do poorly. What is it about those two different hosts that determines their outcome?”

Humans are obviously incredibly diverse in some respects in terms of our genome—and I think that there’s a very good chance that if we do this properly and in a broad enough fashion, we might be able to answer some really key questions. We know that some people do poorly, because of their age and comorbidities—but we have also seen some elderly do well, and some young people do poorly. What is it about those two different hosts that determines their outcome? Understanding the host genome in the context of viral infection and outcome, or severity in disease, will be really important. 

Then there is the viral side of the story. If we are aware of the entire viral sequence over a range of different viruses—we’re talking about thousands, tens of thousands, perhaps even hundreds of thousands of viral sequences across the globe—then we will be able to make some important links in order to understand the relationships between those viruses. At this point, it looks very promising that we will gain some significant insight into viral activity and transmission if we do in-depth and broad enough analysis of the genome over time and geographic jurisdiction. 

The other thing that the viral genome can tell us—and I know I keep coming back to this because it is important—is looking at the components of the virus that are important for the vaccine response. There are parts of the virus called viral epitopes. If we understand, A, what the epitopes are—which are targets for the immune response that we are trying to solicit by using a vaccine—that’s a great starting point. But as vaccine trials get rolled out at the population level, chances are those epitopes will change, as the virus passes from one person to another. Genomics will be really key in terms of tracking that change and doing surveillance in terms of anticipating vaccine escape mutants. Similarly, for antivirals there is a risk of antiviral resistance—so if we have the viral genome at our fingertips we can hopefully dissipate some of that and intervene.  

“If there are changes to the genome we risk losing our ability to detect the virus.”

Lastly, we really need to know the viral genome in terms of diagnostics. We target the viral diagnostics against the viral genome, but if there are changes to the genome we risk losing our ability to detect the virus. That is why it’s important to do ongoing surveillance, verify our primers and our targets to make sure they will still detect the virus.   

What Role Can Genomics Play in Data Sharing and Future Preparedness?  

In terms of data sharing, there’s a significant role for genomics. It will be absolutely crucial that we share data across jurisdictions. If we, for example, are just looking at data within an institution, a city or a province, there will be a limited amount of information that we can glean from that. It may be difficult to make decisions based on that limited information.  

If we want genomics to really impact decision making, there needs to be data sharing. Obviously, there are a number of very important considerations around privacy, but also cost and infrastructure. How do we curate the data so that it is consistent? It has to be quality data. But if we make those investments in infrastructure, that would be a very high-yield proposal. 

“Genomics will be very important in terms of being able to track the virus through communities and populations.”

In terms of preparedness, genomics plays a very important role. Right now, we are in the first wave of the pandemic and we anticipate further viral activity—whether it comes as a second wave or a smaller outburst. Genomics will be very important in terms of being able to track the virus through communities and populations. It may even help us with surveillance in anticipation of further waves. It is quite key to have the information now, rather than waiting to generate it later, because it will only be useful if we can apply it to mitigate further spread.  

What Lessons Must We Learn From This Epidemic to Strengthen Our Preparedness In the Future?  

One of the ways that we can be better prepared, especially in terms of policy, is not to change the policies that are in existence but to have a good regulatory framework in Canada to do this work in a safe and responsible manner. However, it could be done more quickly. Having said that, I’ve never seen anything so quick as what I’ve experienced with this—in terms of research ethics and legal, we have moved incredibly quickly. But if we could do it at a more accelerated pace, we would be better off. I think the way to do that is to have pre-existing agreements. That connects to what I spoke about earlier: having a coordinated approach. People are already working together and sharing re-agents and data protocols, and that has been incredibly helpful. To be able to pivot to a new agent makes it a lot more nimble process that we can be incredibly effective. 

“I’ve never seen anything so quick as what I’ve experienced with this—in terms of research ethics and legal, we have moved incredibly quickly.”

Instead of working in a timeline of weeks, which is already better than existing timelines which is usually months, we’ve definitely taken a step in the right direction. But if—instead of over six to eight weeks—it could be possible to have certain things happen in the span of a week or so. At a small scale we’ve been able to do that, but I do not know that we’ve been able to do that at a larger scale. I think pre-existing agreements would enable that at a larger scale.  

One of the things that is important to realize is that there’s been a lot of attention around funding for this particular pandemic—but this is an area that has actually been chronically underfunded for a very long time. Basic science and virology is something that has been quite limited in terms of funding and support. Appreciating that, generally speaking, there is a limited impact in the way that these viruses impact people’s health day to day. Admittedly, thing that actually impact Canadians’ health generally speaking are influenza viruses, HIV, or non-viral causes along the lines of cardiovascular disease and oncology. But we write this in our grants every time: there will be an epidemic, possibly a pandemic, and this research will become incredibly relevant. Unfortunately, we’ve become complacent between pandemics and we saw this with SARS, we’ve seen this with other viruses. We are paying the price for that complacency. That may sound harsh, but I want to underscore that. Because again, in 12 months or 24 months, when this is behind us, we will forget about the ongoing need for research especially during interpandemic periods, and we will find ourselves in this situation again.  

What Silver Lining Have You Seen Through This Crisis?  

In terms of the silver lining, I think what has heartened me and what has kept me going is the fact that there has been so much openness and collaboration. I have never seen people rally together like this. I think if we continue with that momentum, we will be able to make a significant difference. I don’t want, at the end of this, for us to lose that particular momentum, because the collaboration has been incredibly productive. We’ve galvanized and we need to consolidate that. 

That is one of the silver linings that has come out of this, and there is no reason that we can’t continue to work together in the same fashion. Much in the same way as there is no reason we cannot continue to be as kind and supportive of each other as we have during this. I do think there will be a long-lasting effect.  

What is a Contrarian View You Hold on This Crisis?  

In terms of an interesting perspective on this virus, this is a small, tiny little molecular machines that has effectively brought to the world to its knees. To me it is a fascinating concept. To me, this virus is not necessarily the problem. It is a natural phenomenon that was very quietly residing in its natural habitat, most likely a bat, and really it is human activity that caused this entire pandemic.  

I certainly don’t want to lay the blame at the feet of the individuals who have been infected by this virus. That is by no means what I’m trying to imply. But what I do want to point to is the bigger picture. As we encroach on natural habitats, we increase the likelihood that we will encounter or be exposed to viruses that normally we would not be exposed to. That is one thing. That’s the spillover event. But because of unfettered global travel, we very effectively spread this virus around the world in a very short period of time. 

“As we encroach on natural habitats, we increase the likelihood that we will encounter or be exposed to viruses that normally we would not be exposed to.”

We need to think about how our behaviour really allowed some of this to happen, because again, if we want to mitigate this in the future, we have to take some responsibility and accountability. I know that that is a somewhat unusual perspective, but I really do view the virus as a very efficient molecular machine that is part of the natural world. It’s a fascinating part of the natural world, and we need to appreciate our own role in terms of this pandemic.