Overcoming COVID-19 and future pandemics: new tools to control viral threats

Virologists at the Morgridge Institute for Research are committed to fundamental research about viruses and disease that can set the foundation for targeted and purposeful solutions.

In light of the COVID-19 pandemic, Morgridge Investigators Paul Ahlquist and Tony Gitter joined CEO Brad Schwartz in a webinar on June 2nd where they discussed COVID-19 and the broader context of viral pandemics and how we respond to them.

The following abridged transcript highlights a few main takeaways from the discussion. A recording of the webinar can be viewed in full above.

Brad Schwartz
Brad Schwartz

Brad Schwartz: Our scientific programs have been addressing questions of virology ever since the institute started. I think it’s important that we think about this pandemic that we’re facing right now in the broader context of viruses and how they enter into our society, and then how we respond to them.

What was the reaction in the virology community, when SARS-CoV-2 began to emerge, and we saw it evolving into a pandemic?

Paul Ahlquist: Well, I think first and foremost, the virology community, just like the general public, quickly began to realize that this was the public health event of the century, and that it demanded a massive response in all spheres, across public health and medicine and the economy and other areas. The second, parallel reaction was that this was this pandemic was exactly what many researchers and public health officials have predicted for years.

The COVID-19 pandemic is not just a unique incident. It’s just one step in a series of dangerous virus emergences from before: 1918 influenza, HIV, Ebola virus, the earlier SARS and MERS, Zika virus and many others.

We also have to expect future pandemics similar to COVID-19. The emergence of dangerous new viruses is actually accelerating for multiple well understood reasons, including the fact that the human population density is increasing significantly. We have increasing encroachment on wild habitats that are the sources of these new viruses, increasing international travel and trade and so forth. So again, this is a continuum that has preceded COVID-19 and will assuredly extend beyond it.

Schwartz: That’s a very important point. And I think that certainly SARS in 2003, and MERS in 2012 got our attention, but it did not turn into the global pandemic that we’re seeing now. In the big picture, should virologists just focus on the coronavirus that we’re dealing with now, or should our focus be broader?

Tony Gitter: There’s two ways that we should think about this. On one hand, in the very short term, we are living in the middle of an ongoing pandemic. So certainly, scientists should be thinking and are currently thinking about how can we use the best scientific tools that we have available to end this pandemic as quickly as possible? How can we develop vaccines, how can we develop treatments against this specific coronavirus that’s emerged?

Virologists do expect that under current conditions, we will see future viral pandemics emerge. Without the ability to know whether it will be influenza, coronavirus, or something else, it really does demand that as virologists think about what the next steps are, and continue their ongoing work toward those next steps, we need to have a much broader and more general strategy for protecting ourselves against those new viral pandemics.

Paul Ahlquist
Paul Ahlquist

Ahlquist: We can’t predict in advance what kind of virus are going to be problematic in the future. We’ve had several recent coronavirus events as we’ve been saying, but it’s instructive to recognize that prior to the emergence of SARS, coronaviruses were well known to infect humans, but they were only known to cause very mild cold like symptoms. So, no one was worried about coronaviruses. And one might have easily relegated them to something that didn’t merit much study. The same is true for retroviruses before the emergence of HIV, for influenza before the 1918 pandemic. We’re continually surprised to seeing what we had thought were potentially innocuous virus groups turn out to be the source of major disruptions and disease and death. The viral threats to humanity are in fact extremely diverse. And our response in building knowledge and our tools also needs to be broad-based and correspondingly powerful.

Schwartz: That’s a very important point because currently, our antiviral drugs, and certainly our vaccines—each one of them is very specific for a given virus. And yet, we can’t predict if there’s going to be another virus that emerges, and which virus might cause the next pandemic. If we’re always having to react, is there a better way we can be ready to protect society in the future?

Gitter: The current approach, as we’ve seen, requires tailoring a solution for each new virus. By way of analogy, it says if this new virus is a locked door, and we have a new lock that emerges, and scientists are now scrambling to find the perfect special key that fits that brand-new lock that we haven’t seen before, and that key needs to be tailored to that one single virus. There’s a real scramble and race to figure out what the solution will be to unlock this door. So how can we come up with a different model for opening that locked door, because we don’t know what the lock will look like in advance?

To complete the analogy, we’re looking for something more powerful in general—like a crowbar that can burst through the door—where we don’t have to know what the details of that lock look like. We can use some alternative way to have a general effect of general treatments against the next virus.

Ahlquist: For many common bacteria, we already have antibiotics that work against many pathogenic bacteria because they target conserved processes that are common to all of those bacteria. Unfortunately, we don’t have such broad-spectrum antivirals generally now. To achieve a similar broad-spectrum level of virus control (Tony’s crowbar analogy), we’re trying to build a much fuller understanding of how viruses work, and identifying features and processes that are conserved across large groups of viruses. By targeting these broadly shared features, we can develop broad-spectrum antivirals that inhibit not just one but a whole group of viruses.

Developing a collection of tools like that, a toolbox of such broad-spectrum agents, would give us a much better chance of dealing with new emerging viruses. There’d be a good chance that one or more of these existing broad-spectrum tools would work against a new virus, either individually or perhaps even more powerfully in combination with multiple such drugs.

Schwartz: What are you doing in the John and Jeanne Rowe Center for Research in Virology at the Morgridge Institute to help develop these more powerful tools, and how widespread are such efforts around the world?

Ahlquist: Our group is defining the molecular mechanisms of key virus replication processes. And one aspect of this work among others, that has strong antiviral promise is identifying host cell factors on which viruses depend.

Using genetics and biochemistry, we and others have shown that virus replication depends on numerous host genes. For example, for one advanced model system that we’re studying, we’ve systematically tested the entire cellular genome. And we’ve already identified over 150 separate host genes in many different functional pathways that are required for viral replication. Some of these host functions and pathways appear to be required by many different viruses. So, identifying and modulating those widely used factors and pathways can be a basis for broad spectrum antivirals that would deny the replication ability of many different pathogens.

Anthony Gitter
Anthony Gitter

Gitter: That’s really been a central focus of some of my research as well as, because we know that the virus depends so much on human cells and human proteins to do its work. How can we use computational methods to try to identify which of those human proteins (the host factors that Paul mentioned) are most promising to go after next as targets for these broad-spectrum antivirals?

We are able to map out which viral proteins can directly interface with, or combine with, or work directly with specific human proteins in the human cells that are being infected by the virus. By tracking these protein-protein relationships, we can see that this particular viral protein has a direct effect upon some human protein. And we can also study which human proteins are being activated upon viral infection, and ends up combining to form maps or what we call networks of different protein relationships.

My group has put a lot of attention to thinking about how to use these networks, where we can see that the viral protein communicates with a human protein, which reacts with different human proteins, and build up these relationships. So then the computational challenges come in and that we want to think about how to use that network information to prioritize which host factors, which human proteins have the most appeal as drug targets.

Ahlquist: Genes and other biological components act in very complex systems in networks. And you can’t understand the function of these processes and their outcomes by studying just one gene at a time any more than you could understand a novel by studying one word at a time. So, these computational approaches now are very important in letting us envision and navigate the operation of these complex biological systems. Computation has become a very important new kind of microscope for biology and biomedicine to understand the processes that we’re studying.

Schwartz: I think that that those approaches that both of you have talked about certainly makes sense in a long-term approach to virology. But I think a lot of people in our society are saying, “well that’s all very well and good, but look what’s happening now.” And people may say, “why are you continuing to focus on a long term approach?”

Ahlquist: As everyone knows, in just a few months COVID-19 has already claimed in the US 100,000 lives—more than the Vietnam and Korean wars combined. It’s cost us trillions of dollars. And it threatens every aspect of our economy from small businesses to major industries like airlines. Underscored by HIV, by Ebola, by many other recent virus outbreaks in the last decades, this is a pivotal wake up call for public health.

We need to recognize the obvious lessons that viruses represent one of the greatest threats to public health and also one of the greatest threats to global economic and security interests. So, just as we as a country have responded to other potentially devastating challenges, and, and we’re struggling now to collectively grow in response to crucial social issues, in this case, also, we need to step up with a vigorous and dedicated long term plan fully commensurate with the scale of the issue.

If we don’t want to be living under the continuing threat of another COVID-19, or the next HIV, or the next even faster, spreading Ebola virus train that might be more deadly, we need a broad based “Space Race” type of approach against viruses. To do otherwise, we’d be irresponsible, and the cost will be small compared to the trillions of dollars that we’ve already lost to COVID-19. Now fortunately, recent advances in virology and in associated fields provide very exciting foundations as we’ve been saying for powerful next steps to understand and control viruses. So, we can be very confident that investments in these critical areas will pay off well for society.

Gitter: Certainly, both Paul and I are maintaining a big picture long term approach, while simultaneously asking ourselves what can we do with the tools and the skill sets and expertise that our labs have. Both of us have taken this opportunity to do whatever we can to have short term effects and use our existing skill sets toward this particular pandemic to try to shorten the duration any way we can, but it really is not lost on us that we need to be prepared for the next pandemics and need to be thinking about these alternative approaches. So that we’re not always caught in this scramble; and that if another COVID-19 like pandemic were to strike, we’re not going to be forced into physical distancing or social distancing for quite so long—we’re not going to need to have the same sort of societal disruptions.

We’re not going to be able to extinguish viruses worldwide. That’s certainly not the goal. But we’re going to be ready so that the consequences aren’t so dire if these long-term research plans succeed.

Schwartz: Well we’re reaching the end of our time, I want to thank everybody for attending. A couple of points I want to make:

I hope it’s evident why it’s so important to do basic fundamental research and really understand the underpinnings of how things work. Because once you figure out how something works and you’ve got the information right, you can be much more targeted in your approach to it—and unlike the viruses, we can actually be purposeful.

The second thing is, this virus is going to be with us for a while. And it’s important that all of us continue to be attentive to it, and that we continue to do our part in society to help get past it. And that I would say will take many forms. So one, you should continue being curious, and continue learning things. Number two, if you have an opportunity to participate in a study, that is investigating preventative therapy or a treatment, I would urge to think seriously about participating. Number three, if you find the work that any institution is doing important and interesting, you should think about learning more about supporting them in ways that will help them.

And also, please realize that most of the funding for ongoing research in this and all sorts of other important areas comes from the federal government. And it’s important that your elected representatives hear from you, and that they know that ongoing research is important to you and it’s something that you feel should be supported. So there are lots of ways that regular, everyone in society can have a role in not only getting the better of the current virus, but also preventing appropriately fighting whatever comes out in the future.