Six Stanford scientists have been awarded High-Risk, High-Reward Research program grants from the National Institutes of Health (NIH), which recognize “highly innovative scientists who propose visionary and broadly impactful behavioral and biomedical research projects.”

The six awards this year are Steven Banik, assistant professor of chemistry in the School of Humanities and Sciences; Polly Fordyce, associate professor of bioengineering in the schools of Engineering and Medicine and of genetics in the School of Medicine; Xiaojing Gao, assistant professor of chemical engineering in the School of Engineering; William Greenleaf, professor of genetics in the School of Medicine; Maia Kinnebrew, a postdoctoral fellow in biochemistry in the School of Medicine; and Stanley Qi, associate professor of bioengineering in the schools of Engineering and Medicine.

The High-Risk, High-Reward Research Program is part of the NIH Common Fund, which, according to the NIH’s press release, oversees programs that “pursue major opportunities and gaps in biomedical research that require trans-NIH collaboration to succeed.” The goal is to encourage investigators to work on research that may otherwise face difficulties getting funded in more traditional ways. This year, the NIH Common Fund awarded 85 High-Risk, High-Reward Research Awards, totaling approximately $187 million over five years (pending the availability of funds).

Pioneer Award

The NIH Director’s Pioneer Award challenges 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.

Polly Fordyce will use her Pioneer Award to solve a major problem in cancer immunotherapies. Despite their promise, it remains challenging to identify the molecules that stimulate the immune system to target cancer without collateral damage to healthy cells.

All cells are decorated with surface molecules that immune cells “sample” as they slide across cells throughout the body, and the forces applied during this sliding are critical for recognition. By developing tools that make it possible to probe how force impacts molecular interactions, the Fordyce lab hopes to uncover new information that will allow scientists to design better and safer therapies. Fordyce’s strategy involves building unique microfluidics-based platforms that allow researchers to perform thousands to millions of experiments in days rather than the decades needed with traditional techniques.

“We are trying to unlock a new physical understanding of how cells communicate with each other,” said Fordyce, who is also an institute scholar at Sarafan ChEM-H and a member of Stanford Bio-X, SPARK at Stanford, and the Wu Tsai Neurosciences Institute. “In future work, we hope this understanding can revolutionize personalized medicine.”

William Greenleaf’s award supports research on combinatorial cell state engineering, which takes advantage of the epigenome to direct how cells develop. The epigenome is like software to DNA’s hardware; it’s how our cells – which all have identical DNA – end up as all different types, such as neurons or red blood cells.

“Stanford is already the epicenter of technology development of two enabling methodological areas that have cellular state engineering ripe for transformative breakthroughs,” said Greenleaf, highlighting methods for precisely reprogramming the epigenome of a cell and methods for accurately comparing reprogrammed cells with unperturbed controls in great detail.

“Success in this ‘grand challenge’ would allow accurate derivation of any cell type in the human body for research of therapeutic applications, with an extended goal of developing methods for epigenetically faithful in vitro generation of entire organ systems,” said Greenleaf, who is also a member of Bio-X, the Maternal & Child Health Research Institute (MCHRI), the Stanford Cancer Institute, and the Wu Tsai Neurosciences Institute.

Stanley Qi will use his Pioneer Award to understand and ultimately engineer the locations of mRNA in cells. Molecules of mRNA, which comprise instructions for the cell to make proteins, are found in specialized compartments throughout the cell. Scientists know that mRNA localization is important in health; several diseases, like amyotrophic lateral sclerosis (ALS), involve changes in mRNA location. But without methods to precisely track mRNA, scientists have been unable to understand how localization is controlled or its role in disease.

Qi is combining CRISPR-based tools and machine learning to track and tune mRNA location in living cells in real time and decipher how localization impacts neuron function.

“Space and time govern the physics of life. One big difference between a bag of chemicals and a cell is the organization of molecules in space,” said Qi, who is also institute scholar at Sarafan ChEM-H and a member of Bio-X, the Stanford Cardiovascular Institute, the MCHRI, the Stanford Cancer Institute, and the Wu Tsai Neurosciences Institute. “This isn’t just academic curiosity; we believe unlocking this RNA space control could be a game-changer in understanding and tackling neurological diseases.”

New Innovator Award

The NIH Director’s New Innovator Award supports unusually innovative research from early career investigators who are within 10 years of their final degree or clinical residency and have not yet received a research project grant or equivalent NIH grant.

Steven Banik’s lab focuses on rewiring mammalian biology and chemical biotechnology development using molecular design and construction. Projects in the Banik lab combine chemical biology, protein engineering, cell and molecular biology to precisely manipulate the biological machines outside and inside of mammalian cells to reveal new biological principles. His New Innovator Award will support their efforts to map proteins which traverse between the extracellular space and lysosomes.

“Proteins which traffic to lysosomes serve as a primary means of communication between the extracellular space and a major signaling and metabolic hub,” said Banik, who is an institute scholar of Sarafan ChEM-H and a member of Bio-X and the Wu Tsai Human Performance Alliance. “Our ability to hijack a small number of these proteins forms the basis of a number of therapeutic modalities, the scope of which would be dramatically expanded by a greater knowledge of extracellular-to-lysosome communication.”

Banik and his lab will work toward applying their studies of biological mechanisms and pathways that can be co-opted by synthetic molecules and proteins with the aim to develop new therapeutic strategies for treating aging-related disorders, genetic diseases, and cancer.

Xiaojing Gao and his lab engineer biomolecules, molecular circuits, viral vectors, and cells, combining quantitative experimental analysis with computational simulation. Their work enables biomedical applications and basic biological discoveries.

The New Innovator Award will support Gao’s development of a platform for synthetic receptors that can be delivered into the body using mRNA and bestow human cells with novel sense-response capabilities – such as sensing a tumor microenvironment and selectively mobilizing immune cell there to attack cancer cells.

“I am motivated by the need to deliver the promise of synthetic biology-empowered ‘smart medicine,’ while ensuring that such solutions are accessible to the general public,” said Gao. “Imagine a future where redirecting one’s immune cells against cancer is as straightforward as getting a COVID vaccine shot.”

Gao is also a faculty fellow at Sarafan ChEM-H and a member of Bio-X, the Wu Tsai Human Performance Alliance, the Stanford Cancer Institute, and the Wu Tsai Neurosciences Institute.

Early Independence Award

The NIH Director’s Early Independence Award provides an opportunity for exceptional junior scientists who have recently received their doctoral degree or completed their medical residency to skip traditional postdoctoral training and move immediately into independent research positions.

Maia Kinnebrew researches how cells communicate with each other and their environment by testing how the membrane influences protein signaling. Specifically, she will use her award to investigate a cell-surface compartment called the primary cilium, which is gaining recognition as a critical regulator of human metabolic homeostasis.

“My research aims to determine how the lipid composition of both the cilia and plasma membranes regulate their sensory and signaling functions,” said Kinnebrew, who is also a Howard Hughes Medical Institute Hanna Gray Fellow. “This work will reveal new principles of membrane biology and uncover strategies to correct human developmental and metabolic diseases.”

The possible applications in medicine and the excitement of being at the forefront of an emerging field are part of what motivates Kinnebrew, who added, “I am also driven by working with students because I can share my passion for biology and inspire them to pursue scientific research.”