Newswise — Four Harvard Medical School scientists are among 86 recipients nationwide honored by the National Institutes of Health High-Risk, High-Reward Research Program.

Neuroscientist Jeffrey Macklis and geneticist David Sinclair are recipients of the NIH Director’s Pioneer Award, which challenges investigators at all career levels to pursue new research directions and develop high-impact approaches to a broad area of biomedical and behavioral science.

Healthcare policy researcher Sherri Rose is a recipient of the New Innovator Award, which 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.

Healthcare policy researcher Zirui Song is a recipient of an Early Independence Award, which 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.

The awards recognize unconventional approaches to major challenges in biomedical research and honor exceptionally creative scientists pursuing high-risk, high-impact research. The program accelerates scientific discovery by supporting high-risk research proposals that may not fare well in the traditional peer review process despite their potential to advance the field.

“I continually point to this program as an example of the creative and revolutionary research NIH supports,” said NIH Director Francis Collins. "The quality of the investigators and the impact their research has on the biomedical field is extraordinary."

Macklis, who is the Max and Anne Wien Professor of Life Sciences in the HMS Department of Stem Cell and Regenerative Biology, Harvard Medical School professor of neurology at the Massachusetts General Hospital, and a faculty member of the Center for Brain Science at Harvard University, explores how neurons of the cerebral cortex develop and communicate with each other as well as ways to regenerate neurons affected by disease. Specifically, the Macklis laboratory focuses on unraveling the biology and molecular mechanisms of neuronal generation and degeneration and how neurons form their long-distance connections and circuitry. Macklis and his team are particularly interested in the precisely assembled diversity of the neuronal circuitry of the cerebral cortex and how this diversity and precision enables high-level sensation, movement, thought and behavior. Importantly, Macklis and colleagues explore how perturbations in these processes can lead to neurodevelopmental, neurodegenerative, and psychiatric conditions, such as autism spectrum disorders, intellectual disabilities, ALS (Lou Gehrig’s disease) and schizophrenia among others. Macklis’ Pioneer Award work directly investigates the biology and function of the molecular machinery—proteins and RNAs—of the distinct and diverse regions of the neuron known as “growth cones.” Growth cones are hand-like sensing structures at the end of neuronal axons responsible for controlling the assembly of the brain’s exquisitely precise circuitry. Growth cones are critical decision-makers that probe their surroundings to detect signals and determine how, whether and when to form connections—or synapses—with other neurons.

Rose, an associate professor of health care policy at Harvard Medical School. Her work focuses on developing and integrating innovative statistical approaches to improve public health. Broadly, Rose’s methodological research uses nonparametric machine learning as a way to tease out cause-effect relationships and predict outcomes in health and biomedical data. Within the field of health policy, Rose works on risk adjustment, comparative effectiveness research, and health program impact evaluation. She also co-leads the Health Policy Data Science Lab and coauthored the first book on machine learning for causal inference.

Sinclair is a professor of genetics and co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School. He is best known for his work toward unraveling the mechanism of aging and his efforts to develop therapies that prevent cellular degeneration, DNA damage and slow down the process of aging and aging-related disease. The primary focus of Sinclair’s laboratory is understanding the role of sirtuin genes in disease development and aging, with associated interests in chromatin, energy metabolism, mitochondria, learning and memory, neurodegeneration and cancer. Most recently, research led by Sinclair showed that feeding mice a compound known as nicotinamide mononucleotide (NMN) may avert and reverse cellular DNA damage, slowing down aging in mice.

Song is assistant professor of health care policy at Harvard Medical School and an internal medicine physician at Massachusetts General Hospital. His research occurs at the intersection of medicine and economics. Specifically, Song’s work focuses on strategies to improve the value of health care spending, including changes in provider payment, incentives for quality improvement and financing of insurance markets. The goal of Song’s research is to is to generate rigorous evidence to inform health policies and delivery system reform efforts that can have a positive impact on population health.

The High Risk, High Reward program is part of the NIH Common Fund, which supports a series of exceptionally high-impact programs that cross NIH institutes and centers. Common Fund programs pursue major opportunities and gaps in biomedical research that require trans-NIH collaboration to succeed.

In addition to the Pioneer, Early Independence and New Innovator awards, the program also administers the Transformative Research Awards, which promotes cross-cutting, interdisciplinary approaches and are open to individuals and teams of investigators who propose research that could potentially create or challenge existing paradigms.

For 2017, the NIH is giving 12 Pioneer awards, 55 New Innovator awards, 8 Transformative Research awards, and 11 Early Independence awards.

The 2017 awards, totaling nearly $263 million, represent contributions from the NIH Common Fund; National Institute of General Medical Sciences; National Institute of Mental Health; National Center for Complementary and Integrative Health; and National Institute of Dental and Craniofacial Research.