Four Scientists Win High-Risk, High-Reward Grants from NIH

Four scientists at Columbia University Vagelos College of Physicians and Surgeons were awarded grants from NIH’s prestigious High-Risk High-Reward program, created to support unconventional approaches to major challenges in biomedical and behavioral research.

Three scientists—Jennifer Small-Saunders, Department of Medicine; Dian Yang, Department of Molecular Pharmacology & Therapeutics; and Sara Zaccara, Department of Systems Biology—received New Innovator Awards, which support unusually innovative research from early-career investigators.

Alex Dranovsky, Department of Psychiatry, received a Transformative Research Award, which funds research that could create new paradigms or challenge existing ones.

Read more about each project below.

New Innovator Awards

Jennifer Small-Saunders, MD, PhD

Assistant Professor of Medicine (Infectious Diseases)

"Epigenetic drivers of quiescence in artemisinin-resistant Plasmodium falciparum malaria"

Malaria parasites are getting increasingly better at resisting an essential drug, artemisinin, imperiling global malaria treatment and control. Small-Saunders has recently uncovered hidden parasite biology that could potentially lead to a new class of antimalarials.

One way that drug-resistant malaria parasites can evade artemisinin is by switching into a quiescent, inactive state and reawakening after the drug washes away. Small-Saunders has discovered that parasites can make the switch by tapping into an epigenetic mechanism, tRNA modification reprogramming, that can rapidly alter the composition of proteins within the parasite.

Parasites may take advantage of other epigenetic mechanisms, including non-coding RNAs, that are known to regulate quiescence in cancer cells and bacteria. By harnessing techniques from these other fields, Small-Saunders will identify these non-coding RNAs and other epigenetic pathways that can lead to quiescence in drug-resistant parasites.

The work should identify parasite vulnerabilities that can be leveraged into the development of new antimalarials to combat one of the deadliest global diseases.

Dian Yang, PhD

Assistant Professor of Molecular Pharmacology and Therapeutics

"Towards a Comprehensive, Spatiotemporal Roadmap of Cancer Metastasis"

Cancer metastasis causes 8 million deaths each year around the world, but the process by which cancer spreads is still largely hidden.

Several features of metastasis have posed significant challenges to researchers: metastasis can be driven by random and rare events that can unfold over years, and its progression across different locations in the body, along with varying microenvironments, can induce further changes in cancer cells.

Deciphering the dynamics, spatial context, and molecular nature of each step during metastasis is critical to understanding this lethal phase of tumor evolution and developing effective therapeutic strategies.

To overcome these challenges, Dian Yang, an expert in developing molecular recording technologies to capture cell lineage history, will develop cutting-edge technologies to trace the entire course of metastasis in small cell lung cancer, one of the most metastatic and lethal types of cancer.

The effort should generate a blueprint of metastatic progression of small cell lung cancer, offering insights for future therapeutic development. More broadly, this work may create a template for studying the progression of other cancer types, enabling a holistic understanding of tumor evolution.

Sara Zaccara, PhD

Assistant Professor of Systems Biology

"Programmable depletion and rescue platform to screen dynamic regulatory events during cellular differentiation"

As stem cells develop into mature cells with defined responsibilities, specific gene expression programs are activated at precise times to control the cells’ development. Timing is critical, but how the cell keeps everything coordinated is still unclear.

Zaccara proposes that specialized RNA degradation complexes are involved in controlling the decay of specific mRNA subclasses at precise times; however, the decay happens too fast for current technologies to detect.

To test her idea, Zaccara will create a programmable depletion and rescue strategy to control the expression level of components of the mRNA degradation machinery with a precise time resolution. By combining this technology with a high-resolution imaging system, she can accurately determine the specific impact of any perturbed components on the fast-occurring RNA decay process and cellular differentiation.

The research also has the potential to overturn the current view of how mRNA decay is regulated. And because the system can be applied to any biological process, it may become an important tool for a wide range of biologists studying dynamic processes that are now hard to detect.

Transformative Research Award

Alex Dranovsky, MD, PhD

Associate Professor of Psychiatry

"Astrocytes as the integrators of neuromodulator signals"

Astrocytes are by some accounts the most common cell in the brain. Astrocytes have been historically viewed as support cells for neurons, though new studies show that astrocytes receive signals from neurons and send their own signals in response, suggesting they are active participants in neural circuits.

Dranovsky will lead a team of Columbia and outside investigators to explore the provocative possibility that astrocytes play a bigger role in brain function than previously thought. The new study will determine if throughout the brain, astrocytes integrate information from multiple neural modulator systems. The investigators will use state of the art techniques and develop new ones to determine how astrocytes are affected by neuromodulators and how these effects impact circuit functions and behavior.

Stress and aging have a notable effect on astrocytes, and neuromodulator systems are the best-established targets for neurologic and psychiatric medications. Therefore, this work may help explain how these factors contribute to neurological and psychiatric diseases and has important and broad implications for treating brain disorders. The researchers will use their new techniques to explore how stress and aging affect the ability of astrocytes to integrate neuromodulator signals and alter brain circuit function and behavior.