Eight scientists awarded NIH grants for high-risk, high-reward research

Eight School of Medicine researchers have been awarded High-Risk, High-Reward Research grants from the National Institutes of Health.

In all, the Stanford researchers will receive $32 million over the next five years to fund their investigations.The grants support high-risk research efforts with the potential to make a big impact in the biomedical sciences. This year, the NIH gave 89 awards totaling $282 million.

“We’re honored that the NIH has recognized the promise of the endeavors proposed by these gifted Stanford scientists,” said Lloyd Minor, MD, dean of the School of Medicine. “By stretching the limits of our biomedical understanding, our researchers are helping to realize Stanford Medicine’s goal of making health care more precise, predictive and proactive.”

Two of the Stanford scientists received Pioneer Awards, two received New Innovator Awards and four received Transformative Research Awards. The grant program is part of the NIH Common Fund.

Pioneer Award

The Pioneer Award provides up to $3.5 million, dispensed over five years, to investigators at all career levels to pursue new research directions and develop groundbreaking, high-impact approaches to a broad area of biomedical or behavioral science.

Christina Curtis, PhD, assistant professor of medicine and of genetics, plans to use her award to study how human tumors develop and to predict their progression. Her research focuses on understanding cancer systems biology, or the complex way in which many aspects of biology interact in healthy and diseased states. Akin to weather forecasting, the goal is to ultimately allow clinicians to anticipate how a tumor will behave over time, as well as to steer its course and tailor treatment options.

“Characterizing how a patient’s tumor changes over time, adapts to therapy and sometimes spreads to other tissues is challenging since this process often cannot be directly measured,” Curtis said. “Yet, learning cancer’s evolutionary rulebook will give us clues about a patient’s prognosis and is a necessary step toward the development of predictive models.”

To overcome these challenges, Curtis has developed powerful computational and statistical techniques to infer an evolutionary history of tumors by analyzing the patterns of mutations present in their genomes and comparing these with virtual tumors simulated under different scenarios. She is also working to measure tumor adaptation during development and tumor progression in real time by leveraging new methods to trace cell lineages.

Curtis is co-director of the Stanford Molecular Tumor Board and a member of the Stanford Cancer Institute, the Canary Center at Stanford for Cancer Early Detection and Stanford Bio-X.

Michelle Monje, MD, PhD, associate professor of neurology and neurological sciences, studies a group of deadly brain tumors called high-grade gliomas. Monje’s team recently discovered that gliomas grow in response to nervous system activity, and that the cancer cells depend on signals from healthy neurons to progress. 

Monje’s award will enable her to expand the tactics her team uses for studying how glioma cells form functional circuits with healthy brain cells: In studies of mice implanted with human gliomas, she plans to employ optogenetics, calcium imaging and measurements of membrane depolarization to map, monitor and control the circuit dynamics of high-grade gliomas as the disease evolves. 

High-grade gliomas are particularly difficult to treat. Monje’s team hypothesizes that understanding how the cancer cells connect to and cooperate with healthy brain cells will provide clues to new therapies.

“With this award, I’ll be building my lab’s electrophysiology and in vivo imaging capabilities to get a global view of how gliomas integrate into neural circuitry,” she said. “We hope to identify specific patterns of glioma circuit activity that could be therapeutically modified to give better outcomes for these intractable cancers.”

Monje is also a pediatric neuro-oncologist at Lucile Packard Children’s Hospital Stanford and a member of Stanford Bio-X, the Stanford Child Health Research Institute, the Stanford Institute for Stem Cell Biology and Regenerative Medicine, the Stanford Cancer Institute and the Stanford Neurosciences Institute.

New Innovator Award

Alistair Boettiger, PhD, assistant professor of developmental biology, received a New Innovator Award, which provides up to $1.5 million over five years to fund innovative research by investigators who are within 10 years of their final degree or clinical residency and who have not yet received a research project grant or the equivalent from the NIH.

Boettiger’s research explores how genomes fold within a cell’s nucleus to affect gene expression. 

“Like a book printed on origami, in which folding the pages changes the course of the story, the genomes of higher animals fold to connect or conceal different parts of this genetic blueprint to control cell behavior,” Boettiger said. “My lab is developing new microscopy approaches to observe this folding with detail never before achieved. This award will help us focus this technology on the developing embryos of diverse animal species to better understand the conserved mechanisms that shape genome organization and contribute to cell differentiation. It will also allow us to tap new genome-editing approaches to determine which sequences direct folding decisions.”

The ability to read and understand the distinct three-dimensional blueprints of a single cell will enable researchers to discern the links between an organism’s genome sequence, individual traits and the genetic aspects of health. 

Boettiger is a National Academy of Sciences Kavli Fellow, a Beckman Young Investigator and a member of Stanford Bio-X. 

Manish Saggar, PhD, assistant professor of psychiatry and behavioral sciences and director of the Brain Dynamics Lab at Stanford, focuses his research on developing computational methods to better understand how the human brain adapts from doing one thing to the next, both in people who have mental health problems and those who don’t.

He intends to use his New Innovator Award to develop a computational framework for modeling how an individual’s brain activity changes over time. 

“I propose to take already collected neuroimaging data from individuals who are diagnosed with either major depression or ADHD and use these new modeling techniques to capture clinically meaningful insights about changes in the brain’s intrinsic activity without averaging data across space, time or individuals,” Saggar said.

This new computational framework could both be used for developing biologically grounded stratification of mental illnesses and as a test bed for developing future treatments and personalized care for patients, he said.

Saggar is a member of Stanford Bio-X, the Stanford Child Health Research Institute and the Stanford Neurosciences Institute.

Transformative Research Award

The award supports individuals or teams proposing projects that are inherently risky and untested, but that have the potential to create new paradigms and may require large budgets.

Karl Deisseroth, MD, PhD, professor of bioengineering and of psychiatry and behavior sciences and the D.H. Chen Professor, and Anne Brunet, PhD, professor of genetics and the Michele and Timothy Barakett Endowed Professor, will use their five-year, $13.75 million award to advance the basic science of how the brain and the aging process control each other.

They intend to develop new technologies for collecting brainwide, neuronal activity signals at cellular resolution across the entire life span of a vertebrate animal from the beginning of its life until its death.

“We expect these new technologies and follow-on basic science discoveries to be directly pertinent to major societal problems facing the United States and the world,” said Deisseroth, whose research focuses on developing molecular and cellular tools to observe, perturb and re-engineer brain circuits. “Aging leads to a decline in cognitive abilities, even in healthy individuals, and is the leading risk factor for conditions such as Alzheimer’s disease. Meanwhile, the median age of the human population continues to rise on all continents.”

Brunet’s work concerns the molecular mechanisms of aging and longevity, with a particular emphasis on the nervous system. “We’re looking to identify ways to observe changes in the brain during aging,” she said. “We’ve pioneered genetic and genome-editing tools to transform a short-lived vertebrate, the African killifish, into a premier model organism for studying aging and age-related diseases such as Alzheimer’s disease. We feel that this system is ideally suited to discover new neuronal networks that respond to aging and can regulate its pace.”

Deisseroth and Brunet are members of Stanford Bio-X and the Stanford Neurosciences Institute. Additionally, Brunet is a member of the Stanford Cancer Institute and the Stanford Cardiovascular Institute and co-director of the Stanford Glenn Center for the Biology of Aging. Deisseroth co-directs the Stanford “Cracking the Neural Code” program and is a Howard Hughes Medical Institute investigator.

Roger Kornberg, PhD, professor of structural biology and the Mrs. George A. Winzer Professor in Medicine, won the 2007 Nobel Prize in chemistry for his pivotal research into the transcription process by which genetic information residing on chromosomal DNA is copied in the form of mobile molecules of RNA. He plans to use his five-year, $7.5 million award to focus on chromosomal structure at a high level of resolution.

“The 3-D structure of chromosomes is the richest unexplored territory in cell science,” Kornberg said. "Chromosomes are large, dynamic, complex and fundamental, underlying cell differentiation, cell physiology and disease. They are also enigmatic, exhibiting at the same time structural heterogeneity and order, physical flexibility and rigidity, and functional activity and silencing.” 

He intends to probe and dispel these mysteries by determining chromosome structure at 10- to 20-nanometer resolution. “Our approach is applicable to chromosomes in all physiologic states, at all stages of the cell division cycle,” he said.

Kornberg is a member of Stanford Bio-X.

Alice Ting, PhD, professor of genetics and of biology, develops technologies to map out cells and delineate the signals and circuits that give rise to cell function. Ting’s research harnesses a variety of molecular approaches and protein engineering tactics to detect, measure and manipulate specific molecules that could play crucial roles in cell and animal behavior.

Ting and her collaborators at Harvard, MIT and the University of Southern California have received a Transformative Research Award for a project that seeks to understand how different organ systems communicate with one another to affect each other’s functions. The scientists aim to decipher the exact molecules that traverse multiple organ systems to facilitate “cross-talk,” and understand how one tissue might influence another. To tag and track molecules of interest in the body, the group will use an enzyme called TurboID, which Ting created in her lab in the fall of 2017.

TurboID carries a special marker engineered to stick to the molecules in its immediate proximity. The marker provides a traceable “tag” that allows scientists to track where the labeled molecules go in the body. 

“The idea is, tag a wide range of molecules found in a single type of tissue, such as fat, and subsequently look for those tagged molecules in a different tissue, such as muscle,” Ting said. Those with the tag will have come from the fat and can be further investigated to understand any functional significance. The grant totals more than $8 million, of which about $637,000 will be funneled directly to Stanford to support Ting’s continuing efforts to develop and refine the TurboID enzyme and proximity-labeling technology.

Ting is a member of Stanford Bio-X, the Stanford Child Health Research Institute, Stanford Cancer Institute, Stanford ChEM-H and Stanford Neurosciences Institute.