Straddling Disciplines to Improve Human Health
Andrew McGuire, Biochemist and Cell Biologist
Dr. Andrew “Andy” McGuire hesitates to classify himself as an expert in any particular scientific discipline. “I kind of learn what I need to learn as I come across the problems I’m working on,” he said.
So, while his work identifies structures of important viral proteins and discerns how the immune system recognizes and responds to those proteins, he doesn’t think of himself as a structural biologist, or as an immunologist.
“Structural biology is pretty intense — you have to be an expert in that, and I’m not,” he said. And “I hear a real immunologist talk and I feel like I don’t even know what they're talking about.”
Nonetheless, in just a few years, the McGuire Lab has identified structural vulnerabilities of key proteins on the surface of several impactful viruses. By prodding the immune system to create antibodies that bind vulnerable portions of those proteins, McGuire has also identified ways to render the viruses ineffective.
“There is a lot of emphasis in my work on structures and antibodies,” McGuire said, “but the ultimate goal is to use what we learn from those to try and make vaccines, or better vaccines.”
The idea of controlling cells enthralled McGuire as soon as an influential high school biology teacher in his hometown of Goderich, Ontario, introduced the concept. McGuire vividly recalls learning that one could deliver genes to cells and make those cells look or act differently. “I just thought that was extremely cool,” he said.
McGuire learned to manipulate proteins and yeast cells — workhorses of cell biology labs — as a student at the University of Guelph. McGuire loved working with yeast. “It’s really easy to manipulate, it grows fast, there are tons of research tools out there, you can do a lot pretty quickly and learn quite a bit,” he said.
However, when he considered his next professional steps, he realized that his passion didn’t lie in yeast. “Infectious disease and human health: I thought that was even cooler,” he said. Therefore, as a postdoctoral fellow, he began applying several of the experimental tricks he’d learned working on yeast cells to the study of HIV.
HIV, like many other viruses, has sophisticated strategies to evade detection, neutralization, and destruction. McGuire and his colleagues identify weaknesses in viruses and then trigger immune cells to create antibodies that exploit those vulnerabilities. A question McGuire often asks first is: Which portion or form of a viral protein will trigger immune cells to produce an effective, virus-neutralizing antibody? Identifying such a region and then introducing it via a vaccine enables the immune system to prepare for and blunt the impact of the virus.
One of McGuire’s first successes after joining Fred Hutchinson Cancer Center’s faculty was isolating a human antibody that binds and neutralizes Epstein-Barr virus, or EBV, a virus originally linked to a childhood cancer in East Africa. EBV is most recognizable as the cause of mononucleosis (better known as mono), and it’s increasingly associated with multiple sclerosis.
“It’d be like discovering fire, it’d be a massive game-changer.”
Subsequently, he and several colleagues demonstrated that administering the antibody to animals prevents EBV infection. Encouraged by that result, they developed several vaccine candidates that elicit antibodies capable of neutralizing EBV infection.
McGuire attributes his lab’s rapid progress on EBV to the arrival of enabling technologies and his collaborators. (McGuire’s long list of collaborations is due, in small part, to his dog Beauregard, the lab’s fuzzician scientist and a frequent presence in McGuire’s office on the Hutch campus. McGuire said, “He’s a great recruitment tool! People stop by just to see him”.)
Two of those key collaborators are structural biologists Dr. Marie Pancera and Dr. David Veesler at Fred Hutch and the University of Washington, respectively: “That was a great example of a collaboration,” he said, explaining that Pancera solved the structure of the antibody on its own and Veesler determined the structure of the antibody bound to the EBV protein.
“It led to other collaborations focused on SARS-CoV-2,” the virus that causes COVID-19, he said. “That’s the beauty of being not only at the Hutch but in Seattle where there are a lot of really great researchers and a really great community.”
Indeed, early in the pandemic the McGuire, Pancera and Stamatatos labs collectively identified a highly effective antibody from a person infected with SARS-CoV-2. Later, the same cross-disciplinary team identified a single antibody that neutralizes the alpha, delta, gamma and omicron variants of SARS-CoV-2, the related coronavirus behind the 2003 SARS outbreak, and even a SARS-like coronavirus from bats. These types of “broadly neutralizing” antibodies that can neutralize many strains of a virus will be critical if, as predicted, SARS-CoV-2 continues to evolve.
Broadly neutralizing antibodies are also critical in the fight against HIV. Surface proteins on HIV regularly adopt new, disguised versions of themselves that immune cells can’t recognize, despite being exposed to a portion of a previous variant. Therefore, in collaboration with the Stamatatos Lab and others, McGuire is tricking immune cells into creating potent antibodies that bind and disrupt a wide variety of HIV strains in laboratory tests.
In short, McGuire and his colleagues use a sequence of tricks to stimulate the extremely small subset of immune cells that are poised to create broadly neutralizing antibodies. Effective stimulation leads the rare cells to duplicate and occupy locations in the body such as lymph nodes; here these cells cluster together, get exposed to more (and more varied forms of) virus, and begin to evolve and generate increasingly more effective antibodies. Such broadly neutralizing antibodies would protect individuals against both current and future strains of HIV and, in doing so, save tens of millions of lives.
“It’d be like discovering fire,” McGuire said. “It’d be a massive game-changer.”
In the meantime, McGuire is both motivated and rewarded by the scientific process: “You’re always learning. That’s kind of why I’m here.”
— By Gabe Murphy, August 22, 2022
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