Columbia Scientists Receive Prestigious New Innovator Awards from NIH

Four young faculty members at Columbia University have received prestigious “New Innovator” awards from the NIH’s High-Risk, High-Reward program:

• Vikram Gadagkar, PhD, assistant professor of neuroscience (Vagelos College of Physicians and Surgeons and the Zuckerman Institute)
• Jellert Gaublomme, PhD, assistant professor of biological sciences (and the Herbert Irving Comprehensive Cancer Center)
• Christopher Makinson, PhD, assistant professor of neurological sciences (in the Department of Neurology of the Vagelos College of Physicians and Surgeons, the Institute for Genomic Medicine, and the Columbia Stem Cell Initiative)
• Joanna Smeeton, PhD, the H.K. Corning Assistant Professor of Rehabilitation & Regenerative Medicine Research (Vagelos College of Physicians and Surgeons and the Columbia Stem Cell Initiative)

Awards from the program enable exceptionally creative scientists to push the boundaries of biomedical science and pursue ideas that, due to their inherent risk, may struggle to receive traditional funding despite their transformative potential.

This year, the High-Risk, High-Reward program issued 72 “New Innovator” awards to early career investigators.

Read more about each project below.

Judging others

In nearly every social interaction, we continually evaluate and make judgments about other people’s behaviors through their words, posture, or tone of voice. While neuroscience is making rapid progress on how the brain encodes one’s own behavior, little is known about how the brain’s neural circuits evaluate another individual’s actions for proper social responses. This lack of understanding presents a major obstacle to treating people with disorders of social evaluation, including autism spectrum disorder.

In his project, Vikram Gadagkar will look at the female songbird, which has evolved a specialized behavior and dedicated neural circuits to evaluate male song, to begin to understand how we evaluate the actions of others. These studies will address three fundamental questions: How does the brain encode an internal representation of others’ behavior? How does the brain evaluate the quality of others’ behavior? And how does the brain show a preference for the most desirable behavior in others?

The findings should provide insights into disorders characterized by deficits in social interactions, such as aphasias, agnosias, and autism.

Read more: The Female Songbird as a Novel Mechanistic Model for the Neural Basis of Social Evaluation

A path to better cancer drugs

Tumors evade the immune system by silencing T cells, which receive signals from cancer cells, stromal cells, macrophages, and the extracellular matrix, among others. But these influences are not captured by in vitro studies most often used during pharmaceutical screens to identify new therapeutic targets.

Identifying signals that silence the immune system can yield therapeutic breakthroughs, as evidenced by recent advances in immune checkpoint inhibition. Recently developed CRISPR screens are a powerful method to identify such signals, but typically these assays require cells to be isolated from their native tissue before analysis.

Jellert Gaublomme proposes to pioneer a CRISPR screening method that can be used in native tissue, enabling the selection of the most promising therapeutic targets.

He will prioritize studies of hepatocellular carcinoma, a deadly cancer with poor five-year survival in patients. Recent studies show that combination therapies in cancer can be more effective than single agents. By leveraging the proposed methods, he aims to prioritize the most promising combinations of therapeutic targets.

More information: Spatial mapping of pooled in vivo CRISPR screens in the tumor microenvironment

Building a brain in a dish

Put human stem cells in a dish, under the right conditions, and they will self-assemble into 3D neural tissues—brain organoids—that show remarkable similarities to the developing brain. As the closest cellular model to native human brain tissue available, brain organoids are an enormously powerful system for probing mechanisms of early (prenatal) brain development.

But brain organoid maturation stalls as it approaches later stages of development. Why might this be? The brain requires experience to develop and mature. Yet, current brain-in-a-dish approaches are unable to replicate this key aspect of development. In his project, Christopher Makinson will introduce synthetic "virtual" inputs to mimic this missing experience in order to drive later stages of human brain development.

If successful, Makinson’s lab will use the mature brain organoids to address fundamental questions about how the human brain develops and to uncover pathogenic mechanisms behind severe developmental epilepsies. This resource will also enable other researchers to use organoids to access some of the earliest, disease-relevant processes in disorders such as autism, intellectual disability, or schizophrenia.

More information: Unlocking the postnatal human brain using activity augmented organoids

Repairing joints

Joint injuries and diseases are the leading causes of disability worldwide because our joint tissues—the cartilage that cushions the bones and the ligaments that stabilize the joint—do not regenerate and heal.

Not all animals are so deficient. Zebrafish have an uncanny capacity for repairing joints, even catastrophic injuries, with new cartilage and fully integrated new ligaments to restore natural function.

The fish’s repair powers appear to lie in its stem cells, and in her project, Joanna Smeeton will try to identify the cells involved and understand how they work to regenerate complex 3D joint tissues. Zebrafish are popular model organisms with scientists, but zebrafish didn’t get much attention as models for osteoarthritis until Smeeton discovered that their joints are more similar to ours than previously believed.

In using zebrafish as a model, Smeeton will be able to see, trace, and manipulate progenitor cells during joint regeneration. The results of her studies may allow us to awaken similar cells in humans to improve the repair of joints damaged by injuries or degenerative diseases.

More information: Deciphering multi-scale differentiation and patterning cues driving whole craniofacial joint regeneration