New NIH program funds scientific ‘innovators’ at Yale

In September, two Yale scientists won Director’s New Innovator Awards from the National Institutes of Health (NIH), part of the Roadmap for Medical Research Initiative launched by NIH Director Elias Zerhouni, M.D., to transform the nation’s medical research capabilities and speed the movement of research discoveries from the bench to the bedside.

David A. Spiegel, M.D., Ph.D., assistant professor of chemistry at Yale, and Derek K. Toomre, Ph.D., assistant professor of cell biology at the medical school, were among 30 recipients of the awards who were selected out of 2,100 applicants. A special evaluation process that engaged 262 experts from the scientific community identified the most highly competitive individuals in each pool.

This was the first year that New Innovator Awards were granted. The awards, which provide a total of $1.5 million in research support over 5 years, are reserved for investigators of exceptional promise who are just beginning their careers and have not yet received a regular research grant from the NIH.

“New investigators are the future of science, and innovative ideas are its lifeblood,” said Zerhouni in announcing the new grants.

Spiegel, a 2004 alumnus of Yale’s M.D./Ph.D. Program who went on to complete a postdoctoral fellowship at Harvard University, is developing a novel approach to using antibodies that normally recognize a single small molecule as a universal agent for targeting and destroying many different pathogens and various types of diseased cells.

For many years, physicians and scientists have used the small molecule 2,4-dinitrophenyl chloride, or DNP, to generate anti-DNP antibodies as a test of the status of the immune system.

“For no apparent reason, about 20 percent of people already have DNP antibodies in their system, and it is easy and harmless to induce DNP antibody production,” Spiegel explains. “Our task will be to rationally design DNP compounds that recognize pathogens and act as ‘magnets’ for the antibody.”

To do this, Spiegel is designing “bifunctional” molecular structures: one side will bind DNP antibodies, and the other will bind distinctive surface proteins on infected target cells, such as cells infected by HIV. These two-sided constructs will serve a function similar to that of the adapters placed on electrical cords, increasing the versatility of DNP antibodies by allowing them to “plug into” a wide variety of pathogens and infected cell types, thereby marking the cells for destruction by the immune system.

Spiegel theorizes that when infected cells, bacteria or viruses are exposed to his new compounds, they will be treated by the immune system as if they were coated with DNP, which will bring on a defensive attack of DNP antibodies.

With his award, Toomre and his colleagues are developing a new generation of microscopes that gives a clear close-up view of the inner life of the cell.

The cell cortex, a region that is a cell’s gateway to its environment, is abuzz with activity. It is the region where molecules are secreted, signaling complexes are assembled, cell-surface receptors are internalized and the cytoskeleton (the cell’s internal scaffolding) is remodeled.

Studies of the cell cortex are important for understanding secretion, cell migration, and signal transduction and downregulation—processes that go awry in diseases such as cancer and diabetes.

Toomre’s lab employs Total Internal Reflection Fluorescent Microscopy (TIRFM).

Using optical sleight of hand, TIRFM illuminates a very thin section of the lower cortical region of the cell (as thin as 50 nanometers) and provides exquisitely high signal-to-background images—so detailed that single molecules can be visualized.

The new, variable-angle TIRFM microscopes proposed by Toomre’s team will prevent artifacts created by conventional TIRFM equipment that can obscure the image and will also allow the depth of the light beam’s penetration to be rapidly varied.

These powerful new microscopes will permit researchers to observe membrane trafficking and signaling in three dimensions with unprecedented resolution.

Among other projects, Toomre’s group will apply this technology to understand the trafficking pathways that regulate insulin-stimulated delivery of glucose transporters to the cell surface—a process that is disrupted in type 2 diabetes.

Toomre, who joined the medical school faculty in 2004, earned his Ph.D. in 1997 at the University of California at San Diego and did postdoctoral research in Germany with Kai Simons, M.D., Ph.D., an internationally renowned cell biologist.