A Push for Biomedical Innovation:

Three Chan Zuckerberg Biohub Stories

The Chan Zuckerberg Biohub Initiative springs from a basic goal: “to make fundamental discoveries and develop new technologies that will enable doctors to cure, prevent, or manage all diseases during our children’s lifetime.” To that end, the Initiative awards money to scientists from three institutions — UC–San Francisco, UC-Berkeley, and Stanford — for leading biomedical research projects. Stanford is always well-represented; Catherine Blish, Euan Ashley, and David Relman are among recent recipients.

Catherine Blish

The Diversity of Immune Responses

Catherine Blish, MD, PhD, is an associate professor of infectious diseases with a research background in immunology. Her project explores how the innate immune system copes with the diversity of viruses it encounters. As she explains, many people study the diversity of the adaptive host-immune response, but there’s also an “underappreciated” diversity within the viruses that infect us.

“So the question is, how does an immune cell recognize a bunch of different viruses?” Blish asks. “And what features of that recognition are common among viruses? If we know that, we can figure out how to target the responses that will best fight the viruses.”

Blish is looking at the innate immune system (specifically the natural killer cells and the monocytes) and how it recognizes patterns and diverse strains. She aims to figure out how those common recognition patterns can be used to “come up with new, more broadly reactive approaches to vaccination.”

This research, which Blish calls “high risk, high reward,” has an ultimate goal of creating designer vaccines. One major goal is a universal vaccine that protects against all strains of the flu for several years.

The high reward part is clear, but why exactly is this high risk? Blish explains: “We’re studying cells of the innate immune system that one normally doesn’t try to generate vaccines from, so we have a lot of underlying biology to understand before we can actually bring this to the clinic.” She adds, “But that’s also what makes it more fun; it’s a new approach.”

Her Biohub award is a five-year conceptually oriented grant. Since the award was presented in 2017, Blish has made significant progress. Her team is working on three viruses: HIV, influenza, and dengue; As she puts it, “We’re getting close to understanding the specific receptors on natural killer cells that are required for recognizing HIV-infected cells.” They’ve also “identified a number of mechanisms by which natural killer (or NK) cells recognize influenza-infected cells.” She adds, “Some pathways are similar between the two viruses and some are different. So that’s been exciting.”

She’s optimistic about the results of her work. “We’re learning about fundamental immunologic mechanisms,” she says. “That will help in the future as we think about therapeutics and vaccines.”

Euan Ashley

Genes and Genetic Variants in the Heart

Euan Ashley, MBChB, DPhil, professor of cardiovascular medicine and genetics, came to Stanford from the United Kingdom 14 years ago. He’s excited by the possibilities of his Biohub award, which he calls “a really fantastic opportunity” for better understanding the heart. His grant’s ultimate goal is to “understand at a much deeper level how genes and genetic variants interact in heart development, health, and disease.” This understanding, he believes, will “allow us to target disease more precisely.”

Ashley’s grant proposal began as a collaborative effort. He and colleagues like James Priest, MD, assistant professor of pediatric cardiology at Stanford (as well as other investigators at Stanford, UCSF, and UC-Berkeley), tried to figure out “where we could really make an advance that wouldn’t have been possible without this award.” They ended with the goal of better understanding the heart at multiple levels, and in particular how this understanding could be “elevated by the use of new approaches such as artificial intelligence.”

The group, then, will focus on three investigations: The team at UCSF will work together with the Stanford group on deep learning, which is a form of artificial intelligence particularly suitable for interpreting images and videos. It can be trained to recognize areas of the heart from ultrasound and MRI scans and identify abnormalities, some of which might not be visible to the human eye.

The UC Berkeley team will be studying genetic variants. Ashley explains that in the past researchers usually had to confine themselves to studying a single variant at a time, but that “doesn’t get close to understanding the complexity of a biological system” in which potentially thousands of variants interact. The UC Berkeley team will attempt to “model combinations of genetic variants” and get closer to understanding the complexity of the genetic control of the heart.

Finally, Ashley’s team at Stanford will be looking at the smaller picture: single cells. Their aim is to “look at and characterize individual single cells: measure their size, their shape, their distensibility, and then connect that to the genetic changes that we noted in the first and second parts of the grant.”

Ashley plans to take full advantage of the Biohub community and its resources, including sequencing resources and a community of investigators regularly presenting their work to one another. As he puts it, “I love collaboration and I love the interdisciplinary nature of the Biohub.”

David Relman

The Interaction of Microbial Communities

David Relman, MD, Thomas C. and Joan M. Merigan Professor of Medicine and professor of microbiology and immunology, has been working for two decades on the microbiome. He adds, “What I love about my work is the discovery of unrecognized diversity and function in the microbial world (where the vast majority of biological diversity has arisen) and unraveling the interwoven relationships between microbes and humans.”

When Relman applied to the Chan Zuckerberg Biohub Initiative, leaders created a Microbiome Initiative with several faculty at Stanford, UCSF, and UC-Berkeley, in addition to Relman. The point of the initiative — and Relman’s work — is to bring investigators together to better understand the “key properties of native microbial communities in the human body” and how they “confer and support health.” Relman and his collaborators hope this will allow doctors and scientists to someday create synthetic communities in the lab that can be used therapeutically.

To that end, over at least three years, Relman and his collaborators — Michael Fischbach (bioengineering), KC Huang (bioengineering), and Justin Sonnenburg (microbiology and immunology) at Stanford, as well as colleagues at UC-Berkeley and UCSF — plan to use robotics, anaerobic microbial cultivation technology, mass spectrometry, and ecological theory to explore the microbial communities of humans.

An important feature of these microbial communities is how community members interact with each other and with their host. These interactions will be “a major focus” of the teams’ research. Relman in particular will, as he explains, “lend expertise in studying stability and resilience, explore the use of new technology to study the human small intestine, and apply some of our findings from and to human subjects and patients.”

Relman appreciates the Biohub’s “emphasis on group efforts, shared skills, and transdisciplinary thinking,” adding, “This approach in some ways mirrors the workings of the microbial communities that we study: cooperation, shared resources and products, and diversity. We’re hoping that we can produce benefits for our community (of humans) that match even a small portion of the benefits that our microbial communities provide to us!”