Stanford scientists awarded grants for innovative research

- By Bruce Goldman

Eight Stanford University scientists have received more than $17 million from the National Institutes of Health that will enable them to pursue innovative research in biomedicine.

They are among the recipients of 78 Pioneer, New Innovator, Transformative Research and Early Independence Awards presented by the NIH in 2013. The awards, which were announced today, aim to encourage high-risk, high-reward approaches to biomedical and behavioral research.

"These awards recognize and support the kind of creative thinking that has put Stanford on the map as the epicenter of innovation," said Lloyd Minor, MD, dean of the School of Medicine. "I would like to extend my congratulations to these eight scientists whose unconventional ideas are changing biomedicine."

This year, the NIH awarded approximately $123 million for 12 Pioneer Awards, 41 New Innovator Awards, 10 Transformative Research Awards and 15 Early Independence Awards (the only category in which Stanford is not represented).

"NIH is excited to continue support of visionary investigators, among all career stages, pursuing science with the potential to transform scientific fields and accelerate the translation of scientific research into improved health," said NIH director Francis Collins, MD, PhD.

MIchael Lin

Following are the names of the award recipients and descriptions of their research projects.

Pioneer Award

The NIH Director's Pioneer Award, now in its 10th year, carries a five-year, $2.5 million grant to be used in highly innovative approaches that have the potential to affect a broad area of biomedical or behavioral research.

Michael Lin, MD, PhD, assistant professor of pediatrics and of bioengineering, will use his Pioneer Award funding to continue developing a method to control a protein's activity with just the switch of a FLIP — a fluorescent light-inducible protein.

Lin's research group recently discovered a light-controlled, protein-protein interaction involving a protein called Dronpa, which changes shape on exposure to cyan (greenish-blue) light.

Using basic genetic manipulation, Lin's team creates a FLIP by fusing Dronpa to both ends of another protein. The two Dronpas then reach across the center protein and bind to each other, blocking binding sites on the center protein, rendering it inert. But shine cyan light on the FLIP and the shape-shifting Dronpas let go of each other, opening the binding sites on the sandwiched protein for chemical activity.

Catherine Blish

Lin said FLIPs could be used for precisely controlling protein activities in time and space in a wide range of applications.

New Innovator Awards

Three Stanford faculty members will receive New Innovator Awards, designed to fund innovative research by investigators who are within 10 years of completing their education or clinical residency, but who have not yet received an R01 grant, which is the most common mode of NIH funding, or another equivalent type of NIH support. Each award provides $1.5 million over five years.

Catherine Blish, MD, PhD, assistant professor of medicine, will use her New Innovator Award to explore ways of harnessing the immune system's natural-killer cells in order to fight viruses.

While vaccination has clearly been one of medicine's greatest success stories, many viral infections such as HIV and cytomegalovirus have eluded efforts to control them with vaccines — in great part because these pathogens can mutate quickly and evade the immune surveillance a vaccine generates. Natural-killer cells, which are a type of lymphocyte, can mount a rapid and thorough attack on virus-infected cells and, like other members of the lymphocyte family such as T-cells and B-cells, differentiate into long-lived "memory" cells in response to confrontation with a pathogen's structural features or a vaccine containing them.

Maximilian Diehn

Using an advanced technology called cytometry by time-of-flight, Blish's lab will characterize natural-killer cells on the basis of as many as 40 molecular features simultaneously, in order to identify particular populations of these cells most responsive to HIV, influenza and CMV. Knowing which natural-killer-cell subsets to stimulate should speed the development of better vaccines.

Maximilian Diehn, MD, PhD, assistant professor of radiation oncology, will use his award funding to develop a novel genomic method for noninvasive cancer screening.

Early detection of cancer via screening has been shown to lead to improved survival rates for several common malignancies. Lung cancer, for example, is the No. 1 cause of cancer deaths, and low-dose computed tomography screening has recently been shown to produce significant survival benefits in high-risk patients. However, about 95 percent of "positive" screening results detected by low-dose CT lung-cancer screenings are actually false positives, indicating that better methods are needed. An important screening goal is to detect as many cancers as possible while minimizing false-positive screening outcomes.

Elizabeth Sattely

Diehn's group will make use of insights gained from high-throughput resequencing of cancer genomes to develop a noninvasive approach for detecting cancers at early stages. If this approach proves successful, the method could be extended to nearly any cancer type and might ultimately allow screening for most common cancers using a single test.

Elizabeth Sattely, PhD, assistant professor of chemical engineering, will apply her New Innovator award to understanding the molecular mechanisms that help make vegetables like cabbage, broccoli and kale so beneficial to human health.

Over the next five years, she will focus on how the microbes in our gut digest and process the plant molecules we eat into the nutrients that nourish our body. In nature, these molecules are part of the plant's immune response against pathogens. In our bodies, gut bacteria activate or alter the bioavailability of these plant compounds, including the anti-inflammatory isoflavonoids and chemopreventive glucosinolates.

Thomas Rando

Why do different gut microbes vary dramatically in their ability to make plant nutrients available to the human host? Sattely plans to find out by identifying the gut bacterial genes responsible for metabolizing drug-like chemicals from plants, and will collaborate with the lab of Justin Sonnenburg, PhD, assistant professor of microbiology and immunology, to show how altering these genes can affect nutrient uptake by the host. To anyone who's ever heard mom say, "Eat your vegetables," Sattely's NIH grant will help to show exactly why she was right.

Transformative Research Awards

These awards, open to both individuals and teams of investigators, were created to support research projects that have the potential to create or overturn fundamental paradigms. The amount of these five-year awards varies.

Tony Wyss-Coray

Thomas Rando, MD, PhD, professor of neurology, and Tony Wyss-Coray, PhD, professor of neurology and a senior research career scientist at the Veterans Affairs Palo Alto Health Care System, have received a $4.26 million award to explore the basis for physical activity's robust positive effect on cognitive function.

Aging is associated with a progressive decline in cognitive ability, the consequences of which can be enormous for individuals and society. Muscle is increasingly understood to be a secretory tissue with effects on bone structure, metabolism and blood vessel formation.

Using innovative experimental models and tools, the Rando and Wyss-Coray teams will test the idea that factors produced in exercised muscle are secreted into the circulation, where they gain access to the brain and induce cognitive benefits. In particular, the researchers will investigate the mechanisms by which the profile of factors secreted by muscle tissue changes during exercise.

David Relman

Further, they will identify the neural cells whose behavior is modified by those secreted factors and that mediate the effects those factors induce during exercise, as well as afterward. The results of these endeavors may drastically alter current thinking about exercise's beneficial effects on the brain cells' function and regeneration, remodeling of neuronal circuitry, and cognition itself.

David Relman, MD, the Thomas C. and Joan M. Merigan Professor and professor of microbiology and immunology and chief of infectious diseases at the VA-Palo Alto, and Susan Holmes, PhD, the John Henry Samter University Fellow in Undergraduate Education and professor of statistics, will use their $6.2 million in funding to examine the effects of perturbations in humans' microbial ecology.

Humans have co-evolved with complex, dynamic internal microbial communities that play essential roles in nutrition, metabolism, immunity and numerous other aspects of our physiology. Exposure to antibiotics or other chemicals, as well as dietary shifts, can disturb or destabilize the microbial communities that dwell in the gut, with potentially severe and sustained negative impacts on health, including allergic disease, pathogen invasion, obesity and various chronic inflammatory disorders.

Susan Holmes

The investigators will monitor the microbial ecosystems of healthy humans before, during and after several types of planned disturbance, such as changes in diet or antibiotic administration. They will apply novel mathematical methods to the data generated from these clinical experiments and identify features associated with future stability or recovery from these disturbances, with the goal of predicting disease and restoring health.

Writers Bruce Goldman, Louis Bergeron and Tom Abate contributed to this report.

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2023 ISSUE 3

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