Seven researchers receive NIH grants for ‘high-risk’ work

The five-year grants encourage scientists to explore bold approaches to major research challenges.

- By Krista Conger, Bruce Goldman, Erin Digitale, Amy Adams

Seven researchers at Stanford have received awards totaling $10.25 million from the National Institutes of Health to explore bold approaches to major research challenges.

The Stanford recipients are among 88 scientists nationwide to receive Pioneer, New Innovator, Transformative Research and Early Independence awards through the NIH’s High-Risk, High-Reward program. The awards total about $127 million and are supported by the NIH’s Common Fund.

“The program continues to support high-caliber investigators whose ideas stretch the boundaries of our scientific knowledge,” said NIH director Francis Collins, MD, PhD. “We welcome the newest cohort of outstanding scientists to the program and look forward to their valuable contributions.”

Six Stanford scientists received New Innovator Awards, and one received an Early Independence Award. Six of the recipients are from the School of Medicine, while the seventh is from the School of Humanities & Sciences.

Jason Andrews

New Innovator Award

The New Innovator Award provides up to $1.5 million over five years to fund innovative research by an investigator who has not yet received a research project grant or the equivalent from the NIH.

Jason Andrews, MD, assistant professor of infectious diseases, plans to use his award to study a new way of detecting tuberculosis by testing air samples in public spaces.

Tuberculosis affects 9.6 million people every year and causes 1.5 million deaths annually, making it the No. 1 cause of death by infectious disease. Resource-limited countries have traditionally tried to control TB by waiting until people show up in in a hospital, clinic or doctor’s office with symptoms, and to then test them for the disease. But infected individuals may be capable of transmitting TB to others for as much as a year before they’re diagnosed. Early screening of individuals would be ideal, but individual screening is costly and not sustainable in poor countries where the TB burden is greatest.

More than 80 percent of transmissions cannot be linked to close contacts among household members. Andrews intends to use custom-built air-sampling devices and highly sensitive molecular diagnostic techniques to study the utility of testing for TB in the air in public settings, such as schools, churches and public transit, in the hope of locating the “hot spots” where TB transmission occurs.

Andrews is a member of Stanford Bio-X.

Sean Bendall

Sean Bendall, PhD, assistant professor of pathology, will focus his grant on single-cell proteomics — an approach that provides a snapshot of a cell’s protein profile that can yield valuable information about its identity and function.

He will use the technique to study some of the earliest precursors of our blood and immune system cells in an effort to identify those that can customize and broaden hematopoietic stem cell therapies. Currently, about 20,000 such transplants are performed each year to reconstitute the immune systems of cancer patients who have received lethal doses of chemotherapy or radiation to treat their disease. Only about 1 percent of all cells transplanted, however, are true multipotent stem cells.

“Leveraging single-cell proteomic technologies that we have pioneered, we can capture cell identities and functional information on millions of individual cells in a single experiment,” said Bendall. “This will allow us to comprehensively characterize the nature of these most primitive cells and their function in human regenerative medicine, health and disease.”

Bendall is a member of Bio-X and of the Stanford Cancer Institute.

Alia Crum

Alia Crum, PhD, assistant professor of psychology, will use her award to continue examining the ways in which a person’s mindset alters their physiology and behavior. Her work is inspired by the placebo effect and looks at the ways in which a person’s mental state can elicit physical changes.

One example is in work she did examining nutrition labels. She took identical vanilla milkshakes and labelled them in two different ways — one low calorie and healthy, the other indulgent — then examined blood levels of a hormone that signals satiety.

What she found is that if people eat the same thing but think they are eating something very different, their blood hormone states reflect their expectations — not their meals. People who thought they were getting a low-calorie snack had hormone levels indicating that they weren’t done eating. Those who expected to be full felt full.

She carried out similar work with exercise. Simply by telling hotel maids their work counted as exercise was enough to elicit some of the benefits of an active lifestyle. Women who considered their work exercise lost weight, had lower blood pressure and had smaller hip-to-waist ratios.

Elizabeth Egan

Elizabeth Egan, MD, PhD, assistant professor of pediatrics, will use her grant to study genetic characteristics that influence human susceptibility to malaria. Malaria drugs are losing effectiveness as the malaria-causing parasite, P. falciparum, develops resistance to them. Instead of targeting vulnerabilities of the parasite, which can evolve to avoid attack, Egan’s team wants to understand how host factors influence the parasite’s biology. Findings from these studies may ultimately lead to the development of drugs that strengthen humans’ inherent defenses against malaria.

The malaria parasite causes illness when it invades red blood cells, and physicians know that some people with certain genetic traits — such as those who carry one copy of the gene for the blood disease sickle cell anemia — are naturally more resistant to malaria. However, because red blood cells lose their genome and nucleus before they mature, it is difficult to study the genetics of the cells.

To avoid this problem, Egan’s team will use a concept known as forward genetic screening: They will generate many blood-forming stem cells with different genetic changes, induce them to mature into red blood cells, and test how well the various cells can be infected by the malaria parasite. Their studies will then explore exactly what mechanisms in the red blood cells enable infection by the parasite, ultimately aiming to provide insights for creating new antimalarial medications.

Egan is a member of the Stanford Child Health Research Institute.

Polly Fordyce

Polly Fordyce, PhD, assistant professor of genetics and of bioengineering, specializes in developing new instrumentation and assays for making quantitative, systems-scale biophysical measurements of molecular interactions.

She will use the funds from her award to build upon a method her lab recently developed for producing small beads with unique color characteristics. A goal is to expand this palette to encompass thousands of easily differentiated color codes. These beads can be linked to different types of molecules in a way that uniquely associates a given type of attached molecule to a particular color code, allowing myriad molecules and their interactions to be simultaneously tracked by imaging tiny amounts of material with a microscope in the same amount of time it takes to measure a single interaction.

By linking thousands of different, short protein pieces, or peptides, to the beads, Fordyce hopes to learn more about how proteins interact with one another inside cells. Similarly, attaching thousands of small nucleotide sequences to these beads should permit the development of new ways of extracting information from single-cell sequencing.

Fordyce is a member of Bio-X and Stanford ChEM-H.

Anshul Kundaje

Anshul Kundaje, PhD, assistant professor of genetics and of computer science, will use his New Innovator Award to harness the power of vast biological data sets to understand how gene expression is regulated in healthy and diseased cells. In particular, he is working to develop new machine-learning approaches based on deep neural networks to decode the noncoding portion of the human genome and identify disease-associated genetic variation.

“The deluge of functional genomic data provides a unique opportunity to leverage new, deep-learning approaches to decode cellular function,” said Kundaje. “The methods we develop will be highly generalizable to several problems in genomics and will contribute to the foundation for a paradigm shift in computational genomics.”

Kundaje is a recipient of the 2014 Alfred Sloan Fellowship and was the lead computational analyst for the Encyclopedia of DNA Elements, or ENCODE, project and the Roadmap Epigenomics Project. He is also a member of Bio-X and of the Stanford Neurosciences Institute.

Aashish Manglik

Early Independence Award

Aashish Manglik received an Early Independence Award, which supports promising young investigators with up to $1.25 million over five years. The awards are meant to allow exceptional early career scientists to more quickly assume independent research positions by eliminating or shortening the traditional postdoctoral training period.

Manglik, MD, PhD, instructor of molecular and cellular physiology, focuses on decoding the molecular basis of transmembrane signaling and transport in order to understand how cells recognize and respond to their extracellular environment.

He intends to direct his NIH funding toward the study of ferroportin, the key transporter in the body responsible for regulating iron levels in the blood. Ferroportin, in turn, is regulated by a hormone called hepcidin, which previous research has shown binds to and degrades ferroportin in the presence of high serum iron levels. Ferroportin or hepcidin dysfunction can result in hemochromatosis, also known as iron overload, or various anemias.

There are no approved therapeutics that work by altering ferroportin or hepcidin levels, activities or interactions. Manglik’s work aims to understand how ferroportin works at the most basic level in order to produce new knowledge and new reagents that may lead to drugs capable of treating hemochromatosis or anemia by inducing favorable changes in the ferroportin-hepcidin pathway.

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2023 ISSUE 3

Exploring ways AI is applied to health care