Brianna Bibel, CSHL School of Biological Sciences
The COVID/SARS CoV2 Rapid Research Reports is a series of meetings organized by Cold Spring Harbor Laboratory (CSHL) that brings together scientists from around the world to discuss the very latest research on the novel coronavirus SARS-CoV-2 and the disease it causes, COVID-19. The series began in June 2020 and continues with the fifth installment this week.
Brianna “Bri” Bibel is a fifth-year graduate student in the CSHL School of Biological Sciences studying biochemistry and structural biology in Leemor Joshua-Tor’s lab. Bri is the scientist behind the popular blog, The Bumbling Biochemist and Instagram account @thebumblingbiochemist. Her style of explaining basic biochemical experiments is approachable, and appreciated by science teachers and young students alike. Here she guest writes for us, reflecting on the first three installments of the CSHL COVID meeting series.
The third COVID/SARS CoV2 Rapid Research Reports meeting was pretty doggone cool! And not just because we got to see videos of doggies being cute… Well, they weren’t only being cute – as University of Pennsylvania’s Cynthia Otto explained in one of the highlights of the August 25-26 meeting, they were being trained to sniff out the scent of COVID-19. As with the first two of this meeting series, the third meeting (virtually) brought together scientists from around the world to discuss the very latest findings about the novel coronavirus that’s captivated everyone from hard-core virologists to random grad students like me who, before this all struck, couldn’t recognize a coronavirus if it hit me in the face with its Spike protein!
What was especially great about this third meeting was that, unlike the first two meetings which featured only invited speakers (which, don’t get me wrong, was really awesome!), the third meeting featured speakers selected from submitted abstracts. Because of that, we got to learn more about viral proteins that haven’t gotten nearly as much attention as Spike, but which also offer tantalizing therapeutic targeting potential. Other exciting additions to this meeting were a virtual poster session and a roundtable discussion on convalescent plasma therapy. Here’s some of what I found the most fascinating.
Structural biology, molecular biology, and immunology
As with the previous two meetings, this one was broken up into sections by topic and first up was “Host-virus Interactions/Structure.” There were some great talks looking at which animals are likely susceptible to the virus based on the genetic similarity of their ACE2 receptors to our ACE2 receptor (which we know is the way this coronavirus is able to dock onto our cells). Minks definitely are susceptible to getting and spreading the disease, as we learned about from Wim van der Poel of Wageningen University, who told us about his work studying outbreaks of SARS-CoV-2 amongst farmed minks in the Netherlands. In his studies, he was able to genetically trace outbreaks amongst people, minks, and even wandering cats!
Yogesh Gupta, UT Health San Antonio
Those “host-virus interactions” talks were really interesting but, as a student in a structural biology lab, I was particularly excited by the “structure” half of the session. At the second meeting we heard a lot about the Spike protein and RdRp, the RNA-dependent RNA polymerase which the coronavirus uses to copy its genome. At this meeting, more of the coronavirus’ dozen or so Nsps (non-structural proteins) got their time in the spotlight. Yogesh Gupta of the University of Texas and Karla Satchell from Northwestern University each told us about their labs’ work studying the structure and function of the nsp16/nsp10 dimer. These two Nsps work together to help disguise the coronavirus’ RNAs from our immune system by adding a small chemical adornment called a methyl group to the viral RNAs’ cap, making the viral RNAs look more like host RNAs. Both labs had promising early findings on the potential to target these proteins for therapeutics, and Satchell explained how her work was open access so that other groups can use the crystal structures and biochemical data her lab has generated to come up with ideal drugs. You can learn more in their publications here and here.
The second session, “Coronavirus Biology,” continued the theme of “evading the immune system.” Nsp16/nsp10 helps the coronavirus evade innate viral RNA sensors, but our cells also have intricate signaling networks to pass along warnings from a number of other hints that something’s amiss. Often these pathways lead to the addition of sugar groups called ADP-ribose onto proteins. University of Kansas’ Yousef Alhammad told us about a specialized section of the coronavirus Nsp3 protein, called a macrodomain, which removes this distress-signal from proteins, effectively erasing the cell’s attempts to trigger protective pathways.
Silvia Rouskin, Whitehead Institute
One of my favorite talks of the meeting was by the Whitehead Institute’s Silvia Rouskin. The coronavirus genome contains “recipes” for making different viral proteins, and the virus gets the cells’ protein-making complexes, ribosomes, to use these recipes to make their proteins. But instead of making each protein separately, the ribosomes make some of the viral proteins as continuous chains or “polyproteins” which the virus then cuts into individual proteins using its viral proteases. Rouskin told us about a way the virus can choose which proteins to make when by altering the shape of its RNA. A region of the coronavirus genome folds up into a knotty structure called a “frameshift element” that’s able to stall the ribosome long enough that it slips, causing it to backtrack a letter and add extra proteins onto the polypeptide chain its making. Rouskin used a technique she developed called DMS-MaPseq to figure out which RNA letters were bound to other letters inside of infected cells. This allowed her to find that the structure of a coronavirus’ frameshift element inside of cells is different from that predicted based on the structure of shorter, isolated RNA. And there isn’t just one structure - she showed that the RNA took on various different shapes (alternative conformations) with different propensities for inducing frameshifting. The ratios of the alternative conformations the RNA took depended on the cellular context, hinting that certain intracellular cues might help the virus regulate which proteins to make at which times.
“...even never-hospitalized people who have “fully recovered” from COVID-19 have some strange things going on with their immune system.”
In the third session, “Pathogenesis and the Immune Response” we got to hear from medical doctors, immunologists, and epidemiologists monitoring the generation and stability of immune responses to SARS-CoV-2 infections. In a really fascinating talk by a medical student from the University of Alabama at Birmingham named Jacob Files, we learned how even never-hospitalized people who have “fully recovered” from COVID-19 have some strange things going on with their immune system. When he examined blood samples from patients over time, he found signs that immune cells called T cells were still working harder than would be expected since their virus was presumably cleared. At this point, they still aren’t sure what the significance is, but definitely something to keep an eye on. See more in this article in the Journal of Clinical Investigation.
Roundtable discussion on convalescent plasma therapy
Cynthia Otto’s coronavirus-sniffing dogs may have stolen the show the first day, but the highlight of Day 2 for me was the roundtable discussion on the use of convalescent plasma (CP) therapy for patients with COVID-19. The session came just days after the FDA issued a controversial Emergency Use Authorization for this treatment, in which the cell-free part of the blood (called the plasma) from recovered patients is infused into sick patients. The rationale behind this strategy is that, among other things, anti-SARS-CoV-2 antibodies in the recovered patients’ sera can help block the virus from infecting more cells and doing more damage in the sick patient’s body.
Arturo Casadevall, Johns Hopkins School of Medicine
In the U.S., CP is a highly politicized issue but Arturo Casadevall from Johns Hopkins School of Medicine urged us to look past the hype and counter-hype to examine the data. And if there’s one person who knows that data well, it’s Casadevall. He led the early push for the testing of CP, which as he explained was no easy task. Nevertheless, he was able to put together a network of scientists and doctors who established an “expanded use” (EU) program through the Mayo Clinic. The EU program, though not set up as a controlled clinical trial, did allow doctors around the country to administer CP to severely ill patients – which they did in droves. In fact, the success of program had the downside of making it harder to enroll patients into controlled clinical trials, which made it harder to get the data needed to definitively say if CP is helpful. However, Casadevall showed us convincing signs based in part on analysis of data from the EU program that CP likely is helpful for some patients, especially if administered early and at “high doses” (sera containing high levels of protective antibodies). Read more about the analysis here.
“...one of the main reasons Casadevall is urging researching on CP [is because it] can be more easily deployed in developing countries.”
The other scientists on the panel, including Paul Bieniasz, Adrian Hayday, and Stanley Perlman, seemed optimistic about the potential of CP as well, but all stressed the need for more data – and from large randomized control trials so we can tell if effects are due to things like chance or the placebo effect. Since the treatment seems to help some people but not others, research is underway to try to figure out why this is and whether doctors can target the treatment to those most likely to benefit.
Speaking of benefitting, CP has the potential to potentially benefit large numbers of people who otherwise might go untreated. CP is often seen as a “stopgap measure” for addressing an emerging pandemic, before more targeted treatments are developed. But even once more targeted treatments (such as purified monocolonal antibodies) are available, they likely won’t be available to everyone; one of the main reasons Casadevall is urging research on CP is that, unlike extremely expensive and less stable monocolonal antibodies, CP can be more easily deployed in developing countries. The sincerity with which Casadevall spoke of his desire to help these underserved populations and the pain he felt over the polarization of the issue were palpable and stuck with me. I look forward to seeing the results of the controlled trials that are currently underway, and I hope that CP really is able to help patients around the world.
Although nothing can truly replace the experience of an in-person meeting, the third COVID/SARS CoV2 Rapid Research Reports meeting showed, once again, that virtual meetings can bring together scientists and allow them to disseminate their research to wide audiences as well as engage in fruitful discussions. It was an immense privilege to participate.
This post is part of a series. Go here for a summary of the first COVID meeting and here for the second meeting.
The next installment of the COVID/SARS CoV2 Rapid Research Reports series will take place on January 26-27, 2021.