Full Interview: Screening for Treatments & Collaboration in the Science Community with Stephen P. Goff
By: Hannah Lin (CC '23)
Could you describe your research at the moment?
My lab has always worked on another family of viruses—retroviruses—and, of late, HIV, so with the pandemic coming, we were forced to close the lab, pretty much, to shut down all the work we normally do. But we were allowed to continue if there were projects that were related to the Sars-CoV-2 virus.
Two people in my lab chose to switch and start working on the virus, so they are continuing and have picked up on two projects that we thought were useful. Both of the projects were natural extensions of what we normally do with retroviruses, so they were projects that we chose because they were something that we could work on, where our lab expertise could be useful. Both of them have to do with screening chemical libraries for drugs—that’s the goal. One of the ways you can do that is by looking at a particular function of the virus and looking for inhibition of that function. We have a history of that—we’ve worked in the retrovirus world on an enzyme called reverse transcriptase, a key enzyme for the virus. In a way, the analogous replication enzyme for SARS-CoV-2 is an RNA polymerase that the virus encodes.
So one of the projects was to express the enzyme in bacteria where we could make a lot of it, and screen, in a very high throughput way, for inhibitors. Columbia has a very good high-throughput screening facility, and all you need to do is set up a very good assay that’s able to work on hundreds of thousands of samples, and test huge libraries of chemicals for potential inhibitors. So the project, really, has been to make large quantities of this polymerase, and now we’re ready to start screening chemical libraries for inhibitors. There are inhibitors already—one of the famous ones is Remdesivir, and I think it’s one of the drugs most likely to succeed out there being tested at the moment. Polymerase is a very natural target—it’s a good enzyme to inhibit, and I think there’s a very good chance that there will be very specific inhibitors that will be effective.
The other project that is being worked on in the lab is a more general system to allow screening, again, for inhibitors. One of the difficulties in working with a virus like this is that one of the simple things you would like to do is just infect cells in culture and test for drugs that would protect the cells or inhibit the virus. Working with this live virus is difficult—it’s under conditions called BSL-3, which are difficult conditions to work with because it’s a hazardous virus. So any situation where you can set up screens that don’t require a live virus and don’t require this level of biosafety is a big deal. The assay I told you about with purified enzyme is totally safe; it’s simply a viral enzyme and assays are just in vitro.
The other system that we’re trying to set up that is also safe and easy to work with is in cell culture, but it’s using a system called a replicon. So viruses like this—these RNA viruses—can not only spread by infecting cells, producing virus, but they can also replicate within a cell as an RNA molecule that is maintained within the cell at low copy number without killing the cell. What you do for that is to engineer a crippled version of the viral genome that can’t make particles, can’t spread from cell to cell, but can only replicate within a cell. So those replicon systems are very handy because you can test for inhibition of that replication, which reads out most of the important steps in the virus replication. It allows you to look for inhibitors of that in a safe way, where there’s no threat of virus and no need to handle it in a special facility.
Where’s the progress on that project right now?
We have built our genomes that we think are going to work as replicons. They’re based on very analogous ones that were generated 15 years ago for SARS—the original SARS. We hope they’ll work; we think they should work in the same way. So we’re just putting those into cells—probably tomorrow.
Are you going into the lab everyday?
I am not; I am staying at home. I can work here, pretty much, doing the things that I would be doing in lab. The two people—Yosef Sabo and Kenia de los Santo—who are working in the lab everyday on this project, I am only in contact with them by Zoom.
What are some misconceptions that you’ve seen regarding COVID-19, and how would you respond to or rectify those perspectives?
Boy, I don’t know what all the misconceptions could be out there. They come in all flavors. There are some people who are deniers, who don’t believe it exists or that it’s a problem, don’t believe it’s contagious, don’t believe they’re going to get it, not following the guidelines of keeping separate—I suppose that would be the worst. It’s a virus, it’s very contagious—that we know—and it has a pretty high frequency of being serious. It’s going to be around for a while, and it’s definitely a problem.
How have you seen the scientific environment change--I know you’re at home, but have you seen scientists’ attitudes or collaboration change?
In general, the biggest change is that everything has stopped. Everything that’s not this virus, in terms of all the science you could think of that’s going on in the whole country has stopped. So that’s a huge change. In terms of the work going on with the virus itself, I think it’s amazingly fast; people have really committed to rapid progress, and people are collaborating and sharing very openly, more than ever. And that’s been true pretty much everywhere in the world, in China and the US. China was very fast to publish the sequence of the virus, for example, which has been hugely helpful, and people are sharing plasmids and reagents very freely. So that’s been gratifying.
That’s really good to hear; building on that, what is your perspective on the future, not only for the research that you are participating in, but more broadly as well?
I can’t even begin to imagine the economic impact yet. It’s going to be drastic. In terms of treatments, they will be coming online as soon as we can manage. I think there will be inhibitors, drugs like these that we’re looking for. It’ll take months, maybe a year to get them approved and in common usage. There will be vaccines, not in too different a timeframe, probably; maybe a year and a half. It’s the kind of virus that’s very likely to not be so hard to make a vaccine, as has been for a virus like HIV. Another thing that will come very soon will be antibodies that are used as drugs, essentially, passive immunity. David Ho’s people at Columbia are focused on getting good monoclonal antibodies that will be used as therapies. So all those will come.
I think the distancing that we’re doing is slowly going to reduce the burden of the virus. Already, it’s encouraging the hospitals, which have been overloaded. We’re probably now seeing light at the end of the tunnel, and it’s likely that they’ll be able to handle the patient load. But it’s not going to be going away completely very fast with the way that we’re handling it in this country. There’s the potential for another wave of the virus to come; maybe soon, maybe in the fall. So I think we need to be prepared to live with this virus for a while until these vaccines and treatments kick in, maybe in a year.