KATHLEEN DURKIN I’m Kathleen Durkin of Columbia’s Zuckerman Institute.
DEVIN POWELL And I’m Devin Powell of the Zuckerman Institute.
KATHLEEN Welcome to Lab in the Time of Coronavirus, a podcast that looks at scientists pivoting their work to combat this pandemic.
DEVIN Today we’re going to be talking to some researchers who are putting the virus under the microscope — quite literally. They’re part of an enormous team that’s working on a treatment for people infected with COVID.
KATHLEEN And as you can imagine, a lot of people are very motivated to make this treatment happen sooner rather than later.
DAVID HO We have a massive mobilization of the scientific community to address this threat that is likely to persist for quite a period of time.
DEVIN Dr. Ho and his colleagues have shifted their focus from AIDS to COVID-19. They’re working around the clock to develop a treatment.
DAVID We remain open while many other laboratories are shut down. So a good portion of the team simply moved into the dormitories and they just live here, cranking away day and night.
KATHLEEN One member of that team — who is still living in his own apartment — is scientist Larry Shapiro, PhD, a principal investigator at Columbia’s Zuckerman Institute. Larry is an expert in the structures of molecules, with years of experience investigating viruses.
LARRY SHAPIRO For 10 years or 15 years I’ve been doing HIV, and everything from HIV transfers to this. But the worldwide effort on CoV-2 dwarfs the worldwide effort in response to HIV. People around the world work all day long working on this and really in remarkable unison. It’s truly exciting, the kind of joint effort that I think has never been seen before for any scientific project.
We think that we’ve found a novel immune evasion strategy that’s employed by coronavirus that hasn’t been seen before, and if you understand the tricks the virus is using, then you can think up ways to get around those tricks.
KATHLEEN So what exactly is the treatment? The team is laying the groundwork for treating COVID patients with antibodies. Antibodies are molecules that your immune system naturally makes to fight off viruses.
DEVIN The idea is to inject sick patients with antibodies. And the process of developing this treatment starts with collecting antibodies from people who have already had COVID-19 and recovered.
LARRY David Ho’s group has found that the people who have horrible courses of the disease, who are on the ventilator for a month and are chronically infected, have by far the best antibodies, which is probably not surprising because they’ve had a long time for those antibodies to develop. Antibody development is like a little mini-evolution that happens in the body, and it happens over time.
DAVID We are isolating antibodies from convalescent patients, and we have been amazingly successful in doing that. In just around two months time we pulled out some of the most powerful antibodies that exist right now. The idea is that these antibodies could serve as drugs. They are very powerful in shutting down the replication of the virus. In addition they could serve as prophylactics as well, so we could give the antibody to people who are at risk or who have been exposed to but have not come down with the disease, and hopefully block the occurrence of disease.
KATHLEEN This antibody therapy isn’t the same thing as a vaccine.
DAVID It’s not as nice as a vaccine, where maybe one or several shots, and you’re protected. We would have to give it repeatedly if there are repeated exposures. But it could make it to the clinic and show protection a little faster than vaccines.
DEVIN And Kathleen while we’re talking about antibodies, I think you’ve had a personal experience with antibodies recently. Would you feel comfortable sharing that?
KATHLEEN Sure would. I tested positive for COVID antibodies. I barely even recall having COVID symptoms, but I guess that tells us a lot about how the disease presents.
DEVIN Antibodies can neutralize a virus by sticking to its surface.
KATHLEEN But not all antibodies are effective at stopping a virus, even when they stick. Only some can actually block the virus from attacking, which is why Larry is taking a closer look at the antibodies discovered by Dr. Ho and his team.
LARRY We have the antibodies. We can make those antibodies and then test them for their properties. Do they neutralize the virus and at what concentration do they prevent the virus from working? Only some small percentage of those will be very potent neutralizers. For the potent neutralizers we’ll map them to where they bind.
KATHLEEN The team has been focusing on antibodies that attack COVID-19’s spike protein. You’ve seen this protein in drawings of the coronavirus.
DEVIN It sticks out all over the place from the virus’s surface. It gives the virus that crown-like appearance that gives the virus its name. “Corona” means “crown”.
LARRY The spike protein fuses the membrane of the virus with the cell, and if you can interfere with those processes then you can neutralize the virus. There’s a very interesting connection to neuroscience here.
KATHLEEN Larry has spent a lot of time studying the nervous system, specifically how sacks of chemicals, called vesicles, fuse with brain cells to propagate neural activity.
LARRY When you look at vesicles that fuse inside of cells that contain neurotransmitters and fuse with the plasma membrane, it’s also mediated by the same mechanism as viral fusion.
DEVIN Finding antibodies that prevent the spike protein from working isn’t easy. That’s because viruses have lots of tricks up their sleeves for avoiding antibodies.
LARRY Viruses evade immunity. They’ve co-evolved with our immune system to learn how to escape from it. Like flu or HIV, the world champion of immune evasion. Thus far there hasn’t been a successful HIV vaccine because of that immune evasion. One evasion mechanism that is used by many but not all viruses is that the protein actually changes its shape. There are conformational states that hide the virus surface.
KATHLEEN To get a detailed look at COVID’s evasion tactics, the team used a technique called cryo-EM or cryo-electron microscopy. Electron microscopy is a microscope that uses a beam of electrons as its light source. Researchers can view samples at near- atomic resolution. This technique makes it possible to scan the spike protein, atom by atom.
LARRY We can look at whole native molecules, and see all the gymnastics that the molecule does. We think that we’ve found a novel immune evasion strategy that’s employed by coronavirus that hasn’t been seen before, and if you understand the tricks the virus is using, then you can think up ways to get around those tricks. There are a lot of antibodies that will recognize the coronavirus spike protein, but they won’t neutralize its function. And so we have started to, I think, answer the question of why some of these antibodies that recognize don’t neutralize. And with that knowledge we think we can start to get around that.
DEVIN But even with this knowledge, finding one antibody that neutralizes COVID is not going to be enough. That’s because viruses have a tendency to mutate.
KATHLEEN When a virus mutates, an antibody may no longer be able to recognize it or to neutralize it. That’s why Larry and his team hope to develop cocktails that contain three antibodies.
LARRY A single antibody can be escaped easily, but a combination of three is almost impossible to escape. The probabilities go down exponentially as you have additional spots that would require mutations. We have our first set now of antibodies that are binding all over the spike, which is very cool.
DEVIN Given the obvious urgency of the situation, David Ho and his team are trying to fast-track the development of these antibodies into usable treatments.
DAVID We’re planning how to develop them into products. And that normally is a several year process. But before I spoke to you I was in the midst of making plans and dealing with people about how to shorten that timeline from where we are today to filing a so-called IND, which is Investigation of New Drug application to the FDA in four months. Now that’s never been done before, but in this pandemic it’s being done for our antibodies, other people’s antibodies, other people’s drugs, other people’s vaccines. Everyone is moving with tremendous speed.
KATHLEEN The current goal is to help those infected with COVID. But Larry hopes that what they’re learning today may help protect humanity from other outbreaks in the future.
LARRY The current COVID-19 pathogen, it’s the third coronavirus that in the last 20 years has come out to cause a major epidemic of deadly disease. We had SARS, we had MERS, and so these coronaviruses are clearly dangerous. They’re very dangerous. This may well not be the last one. There are antibodies that cross over between all three of these deadly coronaviruses, so in principle it might be possible to develop a pan-coronavirus vaccine. But this is a long-term effort. This is something that will go on for years, but the idea here has been moved forward because of the current pandemic.
KATHLEEN Thanks for listening to Lab in the Time of Coronavirus. Take a look at the show notes for links to all the things we discussed. You can find all of our episodes at https://zuckermaninstitute.columbia.edu or on iTunes. Take a moment to rate and review us on iTunes. That makes it easier for other people to find us.
DEVIN Special thanks to Rui Costa, Jennifer Farris, the researchers who sat down with us for this episode, and the entire Zuckerman team. The music was provided, as usual, by Miguel Zenón, Jazz Artist-in-Residence at the Zuckerman Institute. If you have thoughts or questions, you can find us on Twitter and Instagram @ZuckermanBrain. But before we wrap up this episode, Kathleen I think you have one last question for our researchers.
KATHLEEN What is the first thing you plan to do post-pandemic?
DAVID I think just going out and having a nice meal in a nice restaurant.
Note: This transcript has been edited for clarity.