Scientific collaboration in the era of COVID-19
Researchers across MIT and neighboring institutions tackle COVID-19
As the COVID-19 pandemic continues its spread, the same questions that were raised at its emergence continue to be asked, with both hope and concern: When will a vaccine be developed? How can tests for both infection and immunity be widely administered? Why the broad range in individuals’ presentation of symptoms? In short — when will scientists know all the answers?
Researchers across MIT, working alongside scientists and clinicians from neighboring institutions and hospitals, are making broad and collaborative efforts to address these questions. Coming from a range of backgrounds — some virologists by training, others biophysicists — they are all applying their unique skill sets to tackle a single, unifying topic: SARS-CoV-2, the virus behind COVID-19.
Yet this scientific challenge is unique not only in the collaborative nature of the research being conducted, but also in its urgency and the pace of investigators’ efforts. With Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, estimating an unprecedentedly short 12-to-18-month timeline for vaccine development, and the parallel push for diagnostics and basic research, the scientific community is operating with unprecedented speed and intensity.
Alex Shalek, associate professor of chemistry and associate member of the Ragon Institute of MGH, MIT, and Harvard, is one of many MIT researchers tackling this challenge. His research group studies the dynamics of cellular communities, exploring how their composition and communication drive tissue-level properties. With expertise in host-pathogen interactions and immunology, the Shalek Lab was primed and ready to explore the pathogenesis of COVID-19.
In late April, a team from his lab and the Human Cell Atlas Lung Biological Network published a study in Cell examining the likely cellular targets of SARS-CoV-2. Using single-cell RNA sequencing (scRNAseq) data, the researchers identified specific cell types that co-express the genes for ACE2 — angiotensin-converting enzyme 2, the cell surface receptor to which SARS-CoV-2’s spike protein binds — and TMPRSS2 — an enzyme also involved in viral entry.
Shalek explained that scRNAseq relies on each mRNA transcript in a cell possessing a polyadenylated tail — a string of adenine nucleotides — which can uniformly and efficiently be captured using a common probe. Many viruses also contain polyadenylated stretches in their genome, allowing researchers to co-detect viral nucleic acids in host cells and, in turn, identify the cellular properties associated with high viral loads. The researchers discovered a striking association: ACE2 is an interferon-stimulated gene in certain human cells, meaning that SARS-CoV-2 may exploit the upregulation of ACE2 in response to interferons, a family of proteins typically released during antiviral responses.
Notably, all of the results revealed in the study came from data sets “created for completely different biological questions,” said Carly Zeigler, a graduate student in the Shalek Lab and the lead author of the paper. Because genomics technology can measure the expression of all the genetic material in a subject’s cell, researchers in the Shalek lab were able to quickly reanalyze data from past studies to study ACE2 and TMPRSS2. “This project was really enabled by a ton of data we could repurpose from other diseases and research questions that we were already working on,” Zeigler said.
The publication process for this paper was unique in many ways, Shalek added. The authors’ ability to conduct follow-up experiments and collect data in response to reviewer comments was unusually restricted, he said. As a result, they made an effort to be transparent with the limitations of the paper and “put things out with all the appropriate caveats.”
Researchers’ overarching priorities during the pandemic have also shifted from the norm, Shalek noted: “This has been a time where our main focus is not on writing papers,” he said, “but rather our goal is to rapidly generate essential data and share it with the public.”
Shalek’s is not the only lab at the Ragon Institute rapidly applying existing data and methodologies to study COVID-19. Bruce Walker, the founding director of the Ragon and a leader in the study of HIV infection, noted that “it’s been quite remarkable that what we’ve been doing related to HIV has been so directly applicable to this pandemic, and that we’ve been able to take platforms we have and immediately pivot them to work on this new virus.”
According to Walker, researchers across the Ragon have begun a whole array of COVID-19 research projects, with a particular emphasis on vaccines and diagnostics. Dan Barouch, a founding member of the Ragon, is developing a vaccine using genetic vectors taken from adenoviruses with inserts of the gene coding for SARS-CoV-2’s spike protein. The vaccine has already been shown to reduce viral loads in monkeys and is expected to enter clinical trials this fall. Its rapid pace of development was made possible by the Ragon’s existing HIV vaccine platform, Walker noted. Other researchers at the Ragon, including Harvard Professor of Biology Aaron Schmidt, are working to develop recombinant viral proteins that can be used in antibody detection assays to test for prior infection.
In an effort to bring together the expertise of not only the Ragon’s Harvard, MIT, and MGH researchers, but also investigators at neighboring institutions and hospitals, Walker co-founded the Massachusetts Consortium on Pathogen Readiness (MassCPR) alongside Arlene Sharpe, department chair of immunology at Harvard Medical School. With scientists from institutions across the state — many from MIT — the consortium has proven “really transformational in terms of the collaborations that it’s facilitated and the synergy that it’s created by getting people from different areas to bring their ideas and perspectives to the table,” said Walker. As of mid-May, the MassCPR had donated over $16.5 million to COVID-19 research projects, including many led by MIT researchers such as Lee Gehrke and Feng Zhang.
“Science in a lot of places is very siloed,” Shalek noted. “MIT’s a particularly collaborative place and we’re a particularly collaborative lab, but this has been something where many scientists around the world have really turned out to try and tackle coronavirus together, and you see an incredible groundswell of excitement around this with people actively trying to figure out how they can help.”
Efforts by MIT researchers to study COVID-19 extend even beyond the broad efforts by researchers in the MassCPR and Ragon. Katharina Ribbeck, assistant professor of bioengineering, recently received a grant from the National Science Foundation (NSF), using their Rapid Response Research (RAPID) funding mechanism, to explore the biochemical role of mucus polymers in SARS-CoV-2 entry.
“Mucus was long considered to be mainly a physical barrier that prevents access of microbes to the underlying epithelium,” said Ribbeck, “but now a different picture is emerging… that the barrier is really highly active and directly interacts with and actually regulates microbial behavior and physiology.”
Ribbeck’s lab specializes in the study of mucins, bottle-brush-shaped polymers found in mucus that display a broad assortment of complex sugars known as glycans, which can interact with immunological factors and pathogens. Several viruses associate with and infect the epithelium by binding to sugar molecules on receptors displayed on the epithelium, she explained. For certain viruses, “this binding to sugar molecules can be prevented or suppressed in part by mucin polymers, which display molecules with similar chemical makeup at a further distance from the epithelium,” in turn acting as “decoys.”
Using her lab’s NSF RAPID funding, Ribbeck now hopes to identify the role of mucus in COVID-19 pathogenesis, as well as the mechanisms by which SARS-CoV-2 binds to and transports through mucus. Her lab is also interested in exploring biochemical differences between severely symptomatic and asymptomatic patients, to better understand the mechanisms behind the variation in COVID-19 disease presentation.
The Shalek Lab is similarly interested in exploring differences in disease severity, recently having begun a collaboration with Boston Children’s Hospital researcher and former lab postdoc José Ordovas-Montanes to compare disease pathogenesis in pediatric and adult cohorts.
Again and again, the investigators involved in COVID-19 research remarked on the collaborative spirit and drive present across all of the scientific community.
Because “there are so many people coming from so many backgrounds… to tackle this problem,” Shalek said, “you’re able to do these things on timescales that you would’ve never imagined before.” He noted that, in the process of publishing his lab’s Cell paper, many of the final pieces of data included in the manuscript came from scientists across the globe; for instance, their collaborators in France contributed to protein analysis on tissue extracts.
According to Walker, the Ragon Institute as a whole was originally established to counter the siloed nature of scientific research, which typically makes it “very hard to bring all scientific knowledge to bear against a specific problem.” Across the Ragon and particularly in the face of the current pandemic, Walker said, “we really embrace this notion of cross-fertilization by cross-disciplinary interaction.”
Researchers also emphasized the need to continue infectious disease and outbreak preparedness work even after the COVID-19 pandemic reaches its end. The MassCPR’s stated mission is to not only address the crisis at hand but also to “better position the Consortium for potential future outbreaks.”
Ultimately, for all of the current and future challenges and questions raised by the pandemic, “the degree of collaboration and coordination, and the openness with which the entire global scientific community is moving forward here, is truly astounding,” said Shalek. “It’s been amazing to see what the scientific community can do when they put their mind to it.”