The global biomedical effort to understand and stop the novel coronavirus may be the largest such collaboration in history. Yale researchers and clinicians have played an integral role, pivoting from their other projects to team up and scale up at breathtaking speed.
“Everything I am going to tell you about today—none of it existed three weeks ago,” said Ellen F. Foxman, MD, PhD, assistant professor of laboratory medicine and immunobiology, on March 31.
“We are very lucky as scientists to have the privilege of action to address this pandemic,” said Ruth R. Montgomery, PhD, professor of medicine and associate dean for scientific affairs.
Does this patient have COVID-19 now? Did they get it in the past? Those questions are key, Foxman said. Knowing COVID-19’s true fatality rate requires knowing how many people contract the disease, including those who remain asymptomatic. But she reminded the audience that the U.S. effort to test for the virus has proceeded in fits and starts since mid-February, when the Centers for Disease Control and Prevention (CDC) revealed problems with its test kit.
Yale rose to the challenge with unprecedented speed. Within days of the CDC announcement, Albert Ko, MD, professor of epidemiology and of medicine, and chair of the Department of Epidemiology of Microbial Diseases at Yale School of Public Health; Saad B. Omer, MBBS, MPH, PhD, director of the Yale Institute for Global Health, Susan Dwight Bliss Professor of Epidemiology of Microbial Diseases, and professor of medicine; and Akiko Iwasaki, PhD, Waldemar Von Zedtwitz Professor of Immunobiology and of Molecular, Cellular, and Developmental Biology, founded the Yale COVID-19 Working Group. Among other activities, this group has been instrumental in supporting the Yale New Haven Hospital Clinical Virology Laboratory as it works to circumvent roadblocks to testing during the pandemic.
Developing a much-needed coronavirus test
Thanks to immense effort by the staff of the lab, led by its director Marie-Louise Landry, MD, professor of laboratory medicine and of medicine (infectious diseases), as well as collaborating labs from the COVID-19 working group, Yale’s new in-house polymerase chain reaction (PCR) coronavirus test went live March 13—a process that normally takes months, Foxman said.
Despite repeated supply-chain interruptions, the clinical virology lab is now using the Yale platform to test 400 people a day for the novel coronavirus. In addition, the Yale New Haven Hospital (YNHH) laboratory recently went live with a rapid test by the commercial supplier Cepheid, which can provide results in about an hour. At present this allows YNHH to run an additional 100 tests per day.
Essential to building this testing capacity was the lab of Nathan Grubaugh, PhD, assistant professor of epidemiology (microbial diseases) in the School of Public Health. Collaborating with Landry’s lab, Grubaugh’s team generated virus standards and controls that Landry’s lab needed to get emergency use authorization from the Food and Drug Administration, and which Grubaugh has now shared with diagnostic labs across the country.
Grubaugh is also an expert on properties of the Zika virus, and he described how he had changed his research focus in the past few weeks from studying Zika to investigating how the novel coronavirus spreads. Using a tool called genomic epidemiology that is ordinarily used to analyze and map mosquito-borne viruses like Zika, Grubaugh and his lab group are combining information about viral genetics with epidemiological and travel data. What they have found links Connecticut’s outbreak to that of Washington state, lending weight to a hypothesis that domestic spread has outweighed international transmission in Connecticut.
Learning from patients
As patients begin to crowd Yale New Haven Health System medical wards, the ways each responds to the virus provides crucial clues to defeating it. Spearheaded by Ko, and supported by the COVID-19 Working Group, Yale researchers have been enrolling and following cohorts of patients and healthcare workers since March 22, investigating the transmission and pathogenesis of COVID-19, and building a research biorepository, or a library of clinical specimens. It consists of clinical samples drawn every 1-3 days from hundreds of inpatients and health care workers, and will be an invaluable resource for researchers.
Iwasaki, who has become a familiar public voice via social and traditional media through her extensive outreach about the coronavirus, is using her lab to train workers so they can be certified to work with infectious virus. Iwasaki is also involved in a host of collaborative coronavirus research projects, include creating a mouse model of COVID-19, developing a serological assay and a home test kit, studying candidate drugs, and working to describe COVID-19 patients’ peculiar blood cell counts.
Early blood data suggest, for example, that patients who do worst tend to have lower white blood cell counts compared to those who do well enough to go home. Montgomery is studying other such signals in COVID-19 patients’ blood and tissue samples, working to identify how COVID-19 patients’ differing immune responses correlate with their susceptibility to the disease. Using advanced CyTOF technology that allows researchers to detect dozens of biomarkers at once, Montgomery’s team is examining cells from the airways of patients at 10 national sites, then sharing what they learn on the NIH-funded portal ImmPort.org.
Better information on biomarkers of protective versus damaging immune responses, Iwasaki explained, could help doctors predict whose condition is likeliest to deteriorate and use that knowledge for better therapeutic targeting.
Such therapies remain largely experimental at the moment. But Yale researchers are racing to discover new vulnerabilities in both the virus and its human host that could serve as targets for medications or vaccines. Craig B. Wilen, MD, PhD, assistant professor of laboratory medicine and of immunobiology, discussed his lab’s efforts to identify human genes that may promote infection by the coronavirus in hopes that some of them could be targeted by drugs.
Probing the properties of a mysterious virus
The novel coronavirus remains difficult and dangerous to handle. Brett Lindenbach PhD, associate professor of microbial pathogenesis and of comparative medicine, is developing genetic tools to dissect the virus, in part in order to make it safer to work with. Among his goals is to make a “replicon” of the virus that can replicate within cells but not spread. One way of doing that, he explained, is to target essential viral genes for deletion, such as the gene encoding the spike glycoprotein, which the virus uses to enter human cells. Lindenbach's lab is also collaborating with Iwasaki and Wilen to create a mouse-adapted version of the virus
The spike protein, which sticks out prominently on the viral surface, is an obvious target for a vaccine, said Walther Mothes, PhD, professor of microbial pathogenesis. But it is a challenge to work with. The protein has several possible arrangements, or conformations, some of which conceal its crucial binding site. It can also protect itself from antibody binding with a structure called a glycan shield—a familiar trick used by HIV. Mothes’ group is using techniques established to study HIV to monitor how antibodies interact with SARS-CoV-2’s spike proteins’ various conformations. In collaboration with Lindenbach, Mothes is also using imaging studies to track where the virus travels in the respiratory tract both before and after antibodies have attached.
To sort out which health care workers have already had the disease and recovered from it, an antibody test is needed, Foxman said. YNHH is evaluating three such tests. The hospital is also considering a trial of treating COVID-19 patients with the antibody-rich plasma of others who have recovered.
Yale’s coronavirus research efforts extend well beyond the medical school. Eli P. Fenichel, PhD, Knoblauch Family Professor of Natural Resource Economics at the Yale School of Forestry & Environmental Studies, discussed his models of the not-so-benign side effects of social distancing. Though measures such as closing schools may sound to many like a no-brainer, that action could cost lives if closures force health care workers to stay home and care for children, pulling them away from patients who need them. Other unintended consequences could include increased rates of domestic violence, substance abuse, and dropping out of school. What Fenichel learns could lead to better policy decisions.
Caring for the sick
At the center of the whirlwind are, of course, the human beings stricken by the virus. With the number of critically ill COVID-19 patients at YNHH rising, consolidating hospital critical-care capacity is paramount. Leading that effort is Jonathan M. Siner, MD, associate professor of medicine and medical director of the medical intensive care unit. The hospital is preparing to receive COVID-19 patients in isolation wards, non-medical critical care units, and, as a last resort, operating rooms and post-operative care units.
“Staffing, equipment, and space challenges,” Siner said, “are really disproportionate to anything anybody has seen before.”
Not in short supply, at least, are readiness, willpower, and a spirit of collaboration. Physicians previously engaged in critical-care research are now pivoting to clinical care, Siner said, while the section of Pulmonary, Critical Care, and Sleep Medicine is coordinating with other critical care departments whose staff stand ready to help.
When Iwasaki asked her own lab staff for a couple of volunteers to run clinical tests, she said, “essentially everyone wanted to contribute.” They are now working in shifts around the clock, she said: “I am really, really proud and honored to be working with these amazing people.”