Six Stanford scientists have been awarded High-Risk, High-Reward Research program grants from the National Institutes of Health (NIH). These grants support “exceptionally creative scientists pursuing highly innovative research with the potential for broad impact in biomedical, behavioral, or social sciences within the NIH mission.”

The six awardees this year are Yousuf Khan, an instructor in the Department of Molecular and Cellular Physiology in the School of Medicine (Stanford Medicine); Kyle Daniels, assistant professor of genetics at Stanford Medicine; Theodore Roth, assistant professor of pathology at Stanford Medicine and an Arc Institute Innovation Investigator; Anne Brunet, the Michele and Timothy Barakett Professor of Genetics at Stanford Medicine; K.C. Huang, professor of bioengineering in the schools of Engineering and Medicine and of microbiology and immunology at Stanford Medicine; and Bianxiao Cui, the Job and Gertrude Tamaki Professor of Chemistry in the School of Humanities and Sciences.

The High-Risk, High-Reward Research Program is part of the NIH Common Fund. The goal of these grants is to encourage investigators to work on research that may otherwise face difficulties getting funded in more traditional ways.

Early Independence Award

The NIH Director's Early Independence Award bypasses the traditional post-doctoral training period by helping establish independent scientific careers for newly graduated scientists with the intellect, creativity, drive, and maturity to flourish independently.

Yousuf Khan works at the intersection of AI and molecular science, studying the function and influence of RNA beyond its most well-known role, as messenger between DNA and protein. Viewing RNA as the "dark matter" of the cell, Khan plans to use this grant to further his lab's research into the mechanisms of how RNAs fold, function, and exert themselves in the cell.

Khan studied the biophysics of molecules during his PhD, while also completing a master's in computational biology. He also worked alongside last year's winners of the Nobel Prize in chemistry, as a member of the AlphaFold team. “To me, it seemed the people working in these two arenas, wet lab science and computation, were not fully aligned with each other,” said Khan. “Leveraging both of these concurrent journeys, we hope to make groundbreaking discoveries in this nascent and burgeoning field of RNA biology.”

New Innovator Award

The NIH Director’s New Innovator Award supports exceptionally creative, early career investigators who propose innovative, high-impact projects.

This award will aid Kyle Gabriel Daniels’ efforts to engineer a synthetic immune system to treat cancer. The aim of the project is to create cell therapies that deploy various engineered immune cells – T cells, macrophages, and natural killer cells – to work together against cancer.

“This work is inspired by the function of the natural immune system, which coordinates the activities of many unique immune cell types to fight infections or cancer,” said Daniels. “We’re also really motivated by the success of cell therapies thus far, the need to make more effective cell therapies for difficult-to-treat cancers, and the emerging technologies – high-throughput synthetic biology, artificial intelligence – that now allow large-scale exploration of synthetic immune systems.”

Theodore Lee Roth’s lab builds tools to explore how genetic changes can drive cells to perform useful therapeutic functions – such as reinvigorating and reinfusing a cancer patient's own immune cells to clear difficult-to-treat solid and metastatic tumors. With this grant, the team will be investigating how to build complex patterns of genetic changes, or even new human genes, to allow human cells to evolve new functionality – similar to, and hopefully overcoming, how cancer cells change their own genomes to evolve their new, dangerous functions.

“We always try to take our initial inspiration from natural biology: How do natural systems solve problems? How do natural systems cure disease, or how do they break down in the face of the most challenging diseases such as cancer and neurodegeneration?” said Roth. “We then try to build technical systems in the lab to model, and ultimately therapeutically apply, this wondrous complexity of the natural living world to build curative genetic therapies for patients today.”

Pioneer Award

The NIH Director’s Pioneer Award supports extraordinarily creative scientists who propose bold approaches to addressing major challenges in biomedical and behavioral research.

In Anne Brunet’s lab, this grant will support research aimed at understanding how the distribution of nerves in organs responds to aging. Brunet’s lab has recently developed new methods to better understand the complex ways in which aging alters the functions of our organs. These include approaches that combine machine learning and spatial transcriptomics to determine the age of multiple cell types and establishing a new vertebrate model system for aging studies, the African killifish. The goal of this work, overall, is “resetting" organ function and coordination during aging.

“We want to leverage these tools – and develop new ones – to understand how the peripheral nervous system, which connects the brain to all organs, could set the tempo of aging,” said Brunet. “Our overarching goal is to identify new strategies to counter aging and age-related diseases.”

The colon has been studied extensively, but the small intestine remains largely uncharted, even though it is where nutrients are absorbed and many diseases, from Crohn’s to irritable bowel syndrome, take root. With the Pioneer Award, K.C. Huang and his lab will create the first comprehensive atlas of small-intestinal microbes, build synthetic communities that model how they protect us from pathogens, and develop precision tools to engineer these communities for health.

Huang compared current methods for gut investigation – using stool as a stand-in for the gut – to “studying the Amazon rainforest by only examining the driftwood that washes out to sea.” He hopes that focusing on the small intestine directly could unlock a new class of microbiome-based therapies to treat gastrointestinal and metabolic diseases.

“As a physicist-turned-biologist, I’m drawn to problems that are both technically daunting and profoundly impactful,” said Huang. “The small intestine is a frontier that has resisted exploration, but if we can understand and engineer this microbial ecosystem, we may be able to reshape human health at its foundation. That possibility – to reveal the unseen and turn it into something actionable for patients – is what drives me.”

Transformative Research

The NIH Director’s Transformative Research Award supports unconventional, paradigm-shifting research projects that are inherently risky and untested, and allows teams of principal investigators when appropriate.

Bianxiao Cui will use this grant to support research to uncover and target a newly identified survival mechanism of metastatic cancer cells: their dependence on nanoscale membrane curvature. The work will investigate how membrane curvature drives kinase activation, which can lead to cancer growth and metastasis, and develop therapeutic strategies that selectively block curvature-induced signaling. By doing so, the research seeks to create novel treatments that specifically eliminate metastatic cancer cells without harming normal or adherent cells.

“The motivation for this work comes from the urgent need to address the grim prognosis associated with metastatic cancer,” said Cui. “Discovering that nanoscale membrane curvature is an essential survival feature of detached cancer cells opens up a fundamentally different and promising therapeutic angle. We hope to translate this insight into therapies that can selectively eliminate metastatic cells.