While much of the COVID-19 research at Yale has focused on patient testing, other labs at the University are undertaking new research with the help of genetic sequencing to explore emerging questions about the virus.
Labs at the Yale Center for Genome Analysis are working to study two key areas of COVID-19 genomic research. One hurdle is to sequence the genome of the virus itself, SARS-CoV-2, in order to track the mutations in the virus. The other key focus is to explore the genes of infected patients. This analysis can be used to understand why some people get more severe symptoms than others, as well as, help with the development of new treatments in the future.
“By studying coronavirus, we can identify the unique genetic code,” said Shrikant Mane, director of the YCGA and the Keck Biotechnology Resource Laboratory. “The genetic code actually can say who is becoming ill, for example, and what type of illness they are having or what types of symptoms they are having, and whether all those symptoms are caused by the COVID-19 virus, and how the human immune system is responding.”
Mane’s group does work that includes the sequencing of the virus’ genome itself. They have recently started receiving samples from hospital patients in order to access the virus’ DNA. According to Mane, the sequencing itself is fairly straightforward, and they have not faced too many technical challenges on that front.
This sequencing work will be a part of a study that Mane’s lab is conducting, which is sponsored by the National Institutes of Health. He says they hope to collect about 1,000 patient samples and sequence the SARS-CoV-2 genome from them. This type of large scale work is critical in order to map the evolution of the virus.
“The virus keeps changing. It gets mutated very fast,” Mane said. “This virus has multiple genomes.”
By generating a collection of SARS-CoV-2 genomes in various locations around the world, scientists can figure out where different cases came from. For example, this information can be used to trace cases in hotspots like New York City to determine if they originated in Europe versus China. According to Mane, this process can also tell us about how the virus evolves as it spreads.
Researchers at Mane’s laboratory are also interested in the response of human cells when a person is infected. More specifically, they are looking for what genes are synthesized within cells, how the cell fights back and which of these attack methods are actually effective in combating the virus.
Mane’s group is not the only one using sequencing techniques to study the virus. Guilin Wang, the associate director of microarray research at the YCGA, is investigating why certain populations are more likely to get the virus and show severe symptoms. In order to answer this question, Wang’s team is sequencing the genomes of patients to hunt for genetic clues that might hint to why 20 percent of people react severely to the infection, while the rest are not even aware they were infected.
Similar work is being conducted at the laboratory of Ruth Montgomery, who is the director of the Yale Cytometry Time-Of-Flight Facility and associate dean for scientific affairs at the Yale School of Medicine. Her group is also starting to work with patient genomes in order to investigate similar questions as Wang’s laboratory.
“We will be sequencing the genomes of patients with severe COVID-19 infection. You can compare those to other people that don’t have a severe disease,” Montgomery said. “If we understand how the people who remain healthy are able to do that, that can help us guide therapeutics for the people who are more ill.”
Conducting research during a global pandemic, however, comes with the challenge of balancing physical distancing requirements while working in a lab, researchers said. Since such research is considered essential, scientists must adapt and find new ways to keep working.
In Wang’s laboratory, for example, only one person goes in at a time, since “everyone of us can perform the work independently.” They conduct as much work as they can, leave and then the next person comes in to finish what they started. Mane explained that at the YCGA, the only research being done is essential COVID-19-related work.
“One challenge is, of course, the biocontainment for the safety of the lab workers,” Montgomery said. “We have a great lab at Yale for biosafety level three experiments, but they are more demanding for the researchers. We have a lot of extra training in order to work in those spaces.”
While some Yale laboratories involved in COVID-19 testing are having trouble getting materials, Wang said that in his lab, their supply of reagents is stable for now. He admitted that “the thing we need the most is PPE — masks, gloves, etc.”
Despite the challenges being faced in this extreme situation, scientists have been working together to obtain and share new information. Mane said that this cooperation even extends beyond borders, “between the international institutes, not only the institutes in the US.”
Montgomery highlighted that many collaborative projects are taking place in order to compile this research effectively. The Genome Wide Association Study and the Yale Generations Project both involve gathering human genome sequences in order to study the variances in patient susceptibility and resistance. The Nextstrain project is involved with keeping track of how the SARS-CoV-2 genome itself changes over time and across the world, according to Montgomery.
“The international sharing of reagents and ideas and suggestions for new ways to approach the experiments has just been unreal,” Montgomery said. “Stuff going up on Twitter minutes after it’s produced in the lab, instead of months later in a journal. It’s astonishing. None of us have ever seen anything like it.”
She emphasized the uniqueness of the whole situation, which she believes has led to the increased collaboration. She said the speed of the work being done also stems from the fact that the whole world is battling this pandemic together, which has changed the way people view the research.
“I think people are not thinking of it as their normal scientific work and career advancement,” said Montgomery “I think there’s a real sense of shared urgency to investigate this illness and move forward.”
The Yale Center for Genome Analysis is located on West Campus.
Charlotte Zimmer | charlotte.zimmer@yale.edu