Young, Eager and Scientific

By Kate Ledger

For 24 years, Hopkins has paid tribute to its beginning investigators, whose work breaks new pathways in science.

Award winner Greg Gato (left) in the lab with his mentor Jeremy Berg, head of Biophysics and Biophysical Chemistry.

Ask Paul Talalay what makes a medical center like Hopkins tick, and the J.J. Abel Distinguished Service Professor of Molecular Pharmacology doesn't miss a beat in his response: "The students are the heart and soul of this place," he states. "They're the journeymen of the entire scientific enterprise."

Talalay felt the same 24 years ago when he proposed that the institution devote a day annually to honor its scientists-in-training. That year, he began building a roster of endowed awards for each year's most outstanding student research projects. Today, Young Investigators' Day is an impressive spring ritual. In a packed auditorium, 15 awards named in memory of beloved Hopkins researchers are given to some 20 graduate students and postdoctoral fellows. All the budding scientists have produced "first-class, scholarly work," explains Theresa Shapiro, associate professor of clinical pharmacology, who chairs the committee of faculty judges. "These were projects in which the students had the ideas and executed the research."

What's clear is that the award-winning studies have been more than thesis projects; they've contributed new ideas and techniques to science. Take Gregory Gatto Jr. an M.D./Ph.D. student whose project earned one of two Michael A. Shanoff Awards. Gatto decided early on that he wanted to study protein structure with department chair Jeremy Berg. But during a biochemistry rotation with Stephen Gould, he hit on a question that fascinated him: how are proteins, created in the cytoplasm of the cell, delivered with exacting specificity to the organelles where they belong?

Part of the answer was known to involve an identity tag, called PTS1, that's attached to each protein like a license plate, and a receptor protein, called PEX5, that binds to it and helps with delivery. But Gatto's enterprising idea was to study the interaction between the Gould's proteins, using biophysical techniques from Berg's lab.

The first step was postulating a computer model of PEX5 and PTS1. Then, over painstaking months, he confirmed the accuracy of his model, capturing the proteins with X-ray crystallography and giving an unprecedented view of their interaction. The modeling and experimental successes were published in Proteins and Nature Structural Biology. The work has applications to disease. "Mutations in these proteins can cause metabolic disorders in early childhood," Gatto explains. He returned to the bench with an array of variously mutated PEX5 proteins, testing how one mutation over another would affect the binding. "Biophysics," he says, "gave us a window into this mechanism."

Another award-winning project tackled an innovative question about medical diagnoses. Taking a hiatus from the four-year M.D. track, Cliff Weiss was accepted into the highly selective Clinical Research Training Program, a venture funded by the National Institutes of Health. There, in the Laboratory of Cardiac Energetics, he became enthralled by the uses for magnetic resonance imaging of the heart and the cardiovascular system. MRI scans, Weiss learned, had been used to study inflammation within the body, but had not been used to detect the inflammation associated with atherosclerotic plaque. That inflammation is intimately involved with the initiation and development of atherosclerotic plaque from its very beginning to the occurrence of a heart attack or stroke. But no one had yet tried it to view the effect of atherosclerotic plaque in the coronary arteries, which from the first moment of attachment causes inflammation in the arterial wall. Could MRI be used to detect patients at risk for acute coronary disease, Weiss wondered?

His investigation, which extended for two years and bloomed into numerous projects, centered on high-resolution MRI scans of patients in three groups: those with known disease, those with elevated cholesterol, and those who were over 40 but otherwise healthy. Weiss compared the MRIs with serum markers that are associated with increased risk of cardiovascular events. What he found was that MRI could detect inflammation in vessel walls of apparently healthy people who were without risk factors for atherosclerosis. The imaging tool, he concluded, presents a new opportunity to detect early trouble. Weiss, who received the Paul Ehrlich Research Prize, presented his findings at the American College of Cardiology and at the American Heart Association.

In the lab of neuroscientist David Ginty, postdoctoral fellow Antonella Riccio seized upon a question that had baffled scientists for decades. How do developing sympathetic neurons, with their cell bodies located near the spinal cord and their long axons projecting nearly a meter away, receive signals that instruct them to survive? The going theory was that the molecular stimulus, nerve growth factor (NGF), bound outside the membrane and induced a cascade of signals that traveled all the way to the cell body. Riccio wasn't convinced: Too many steps, she thought. Too many opportunities for mistakes in a vital operation.

In search of a better theory, Riccio revived a little-known experimental technique from the early 1970s for studying developing neurons. Using a teflon chamber, she separated the cell body from the axon and stimulated the axon tip with NGF. She was surprised to find that NGF appeared inside the cell along with growth genes activated in the nucleus. NGF, she discovered, begins by binding to a receptor protein on the axon tip, but the two molecules are then engulfed in a lipid vessicle that travels intact to the nucleus of the cell. "It was a new explanation of the machinery," explains Riccio, who published the discovery in Science in 1997, and went on to describe the NGF receptor in Neuron and the anti-apopotic gene, called bcl-2, in a later issue of Science. The discoveries, ultimately may enable doctors to supplement neuron survival messages that are failing, as in diseases like Parkinson's and Alzheimer's. Riccio received the W. Barry Wood Jr. Award for her work.

The ceremony of Young Investigators' Day celebrates contributions like these, Talalay says. But he also notes that the awards augur future success. Recently, he tracked down the past winners of the Shanoff Award—the first honor he established when he conceived the program in 1978—and found that, almost to a person, they'd gone on to leadership roles in science around the country. Gatto, who learned of the legacy after hearing that he'd won the prize, was stunned. "It's a great honor," he says, adding, "I hope I can live up to it."