Team of top researchers prepares for endemic COVID-19

$15M Howard Hughes Medical Institute grant shared by 8 scientists at Fred Hutch and UW
photos of Drs. Erick Matsen, Trevor Bedford, Jesse Bloom and Harmit Malik
Four prominent Howard Hughes Medical Institute Investigators at Fred Hutchinson Cancer Research Center, (left to right) Drs. Erick Matsen, Trevor Bedford, Jesse Bloom and Harmit Malik, along with four HHMI Investigators at UW, are sharing a three-year, $15 million grant for research on COVID-19. Photo by Robert Hood / Fred Hutch News Service

Virus experts at Fred Hutchinson Cancer Research Center and the University of Washington are starting to explore new avenues of research focused on the anticipated transformation of COVID-19 from a fast-growing pandemic to a more stable, endemic disease.

The Howard Hughes Medical Institute, which supports more than 250 “HHMI Investigators” at research institutions across the U.S., has awarded $15 million for a project involving eight of those investigators — four at Fred Hutch and four at UW.

Over the next three years, the team members will work on finding innovative approaches to tracking, preventing and treating the disease as it settles in among a global population that, immunologically speaking, is becoming more accustomed to this unwanted viral newcomer.

“People sometimes understand endemic to mean mild, and it doesn’t really mean that,” said Dr. Jesse Bloom, one of the four Hutch scientists sharing the HHMI grant. “People may think of the viruses that cause the common cold as endemic, but seasonal influenza is also an endemic virus that causes notable outbreaks every year.”

There is one key difference between the first years of the COVID-19 pandemic and what is anticipated as the virus become endemic, Bloom explained: Most of the world’s population will have developed some immunity to it through vaccination, infection, or both.

“It is not going to be sweeping through an immunologically naïve population, as happens during a pandemic,” he said.

His lab has carried out pathbreaking work in tracking and understanding the potential effects of mutations in the genome of SARS-CoV-2, the coronavirus responsible for the pandemic. His method of cataloging these genetic changes is known as “deep mutational scanning.”

Since early 2020, Bloom and the other HHMI Investigators at the Hutch and UW have been acting primarily as scientific first responders, pivoting from their day-to-day roles in basic research or virology. The new, three-year grant will encourage them to explore the dynamics of SARS-CoV-2 over a longer time horizon.

In addition to Bloom, the other Fred Hutch HHMI Investigators sharing the grant are Drs. Trevor Bedford, Harmit Malik and Erick Matsen.

Working on complementary projects with them are four HHMI Investigators at UW: Drs. David Baker, Joseph Mougous, Jay Shendure and David Veesler.

Keeping up with COVID-19 virus mutations

Veesler was one of a handful of structural biologists in the world who were studying the spike structure of coronaviruses before SARS-CoV-2 emerged, and he has played a critical role in guiding the quick response to develop vaccines and therapeutics targeting the spikes of the pandemic strain. In this project, he’ll be working with Bloom to keep apace of the effects of mutations in that virus’ genome, while Matsen will be developing computer algorithms to help anticipate the effects of changes in the years ahead.

Meanwhile, computational virologist Bedford will continue ongoing efforts with UW’s genetic sequencing expert Shendure to improve the real-time tracking of COVID-19 and its variants, monitoring differences that may emerge during its spread through populations as the pandemic becomes endemic.

Hutch evolutionary biologist Malik will use the grant to study ways to bolster the body’s innate immune system against SARS-CoV-2. Sometimes likened to the first line of defense, the components of the innate immune system respond quickly to the presence of viruses to unleash an array of antiviral enzymes.

If antibodies are the guided missiles of immunity, the enzymes of the innate immune system — which evolved when most of life gurgled in swamps — are clubs and spears. Their primitive role is to ward off viruses long enough that slower-acting T cells and antibodies of the adaptive immune system — which developed more recently among vertebrates — can be rolled out effectively.

Fine-tuning innate immune defenses

An expert in how antiviral defenses change over millennia, Malik, along with his long-term collaborator Dr. Michael Emerman, have previously shown that innate immunity’s powerful responders do make evolutionary adjustments that make them more effective against specific viral threats. They just do it slowly, since these changes need to transmit over many host generations.

He and his colleagues will be working on ways to accelerate the evolutionary rate of innovation to tweak our innate immune defenses in the lab, making them more effective and efficient against SARS-CoV-2 and related viruses.

“Our approach is to test many evolutionary alternatives of the innate antiviral proteins, faster than nature could, and redirect them towards cellular compartments where coronaviruses do their business,” he said.

Malik’s work will complement efforts of UW microbiologist Mougous and structural biochemist Baker — who leads UW’s Institute for Protein Design — to find ways to select and reengineer innate immune proteins and ferry them to sites where they might provide the body with coronavirus countermeasures.

All eight researchers were previously named HHMI Investigators, with Bedford, Matsen and Veesler named just last year. With that title comes support of roughly $9 million over their seven-year terms. HHMI’s Investigator program stresses that it allows recipients to pursue scientific questions of their own choosing, investing in “people, not projects.” The COVID-19 grant comes in addition to their Investigator support.

'Different from the norm'

In that sense, these special COVID-19 grants are a departure for the organization, which was created in 1953 by the aviation pioneer and industrialist Howard Hughes. Dr. Dennis McKearin, a senior scientific officer of HHMI based in Chevy Chase, Maryland, works as a liaison with the investigators working at their various institutions across the U.S. He said that grants targeting a specific pathogen, in this case, SARS-CoV-2, are indeed “different from the norm.”

McKearin added that the Fred Hutch and UW investigators he knows “are amazingly strong” scientists. “Their prior work has been recognized in multiple ways, and I expect the same will be true with the results from this project,” he said.

In addition to the funds provided to the Hutch and UW, HHMI is supporting SARS-CoV-2 research with $10 million for similar collaborative effort at The Rockefeller University in New York, and with $10 million for two different projects at Yale University.

These research efforts, now underway, are a prelude to a different HHMI program, called the Emerging Pathogens Initiative, that will fund research designed to prepare the scientific community for future pandemics. Awards totaling $250 million will support research into “the origins, mechanisms, and evolution” of microbes that could threaten human health. The first awards in that program will be announced this summer. 

Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs. 

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