JHMI Office of Communications and Public Affairs

April 9, 2002

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2002 Young Investigators' Day Award Winners

Pamela Frischmeyer received the Michael A. Shanoff Research Award for her project "Nonstop decay: A novel mRNA surveillance mechanism," conducted with Hal Dietz, M.D. An M.D./Ph.D. candidate in the McKusick-Nathans Institute of Genetic Medicine, Frischmeyer has discovered how cells get rid of messenger-RNA that has no termination signal, so-called "nonstop" mRNA. The exosome, a complex of enzymes previously known to destroy non-coding RNAs, is responsible for recognizing and degrading this form of waste mRNA before a protein is made from it, Frischmeyer discovered with colleagues at the University of Arizona.

"We found that about one percent of the known genes of yeast and humans can make nonstop mRNA," says Frischmeyer, a graduate of the University of Iowa. "The nonstop decay mechanism is important and it's very different from the mechanism for cleaning up mRNAs that have early termination sequences (nonsense mRNAs) and normal mRNA."

The findings, published March 22, 2002, in two papers in the journal Science, reveal a new hypothesis: nonstop mRNAs are made throughout life, and their protein products may be important at certain stages of development or in certain tissues. Nonstop decay, the cell's way of destroying this mRNA, may begin only when the nonstop mRNAs and their encoded proteins are no longer needed, Frischmeyer suggests. Importantly, understanding nonstop mRNA clean-up may help efforts to improve and develop treatments for many genetic diseases that are caused by mutation or misreading of stop sequences in DNA, says Frischmeyer, originally from Carroll, IA.

Jacob Jones received the first Nupur Dinesh Thekdi Research Award for his project "A new paradigm for membrane protein biogenesis," conducted with Steve Gould, Ph.D. An M.D./Ph.D. candidate and a graduate of Duke University, Jones has helped explain how a tiny compartment called a peroxisome is created in cells. An organelle, the peroxisome has its own membrane, whose proper construction is vital but was not well understood.

Jones discovered that a specialized chaperone protein, PEX19, binds to multiple regions of newly made membrane proteins destined for this organelle. PEX19 protects the membrane proteins from the destabilizing effects of water and also delivers them to the peroxisome. "Our findings suggest an entirely new mechanism for the targeting and import of membrane proteins and may serve as a model for studying other systems," says Jones. The findings also help explain why mutations in the PEX19 gene cause the lethal inherited disease known as Zellweger syndrome.

Siew Loon Ooi received the Hans Joaquim Prochaska Research Award for her project "Yeast genetics on microarrays: Probing end-joining in S. cerevisiae," conducted with Jef Boeke, Ph.D. Ooi, a graduate of Beloit College in Wisconsin, developed a way to take advantage of molecular "barcodes" created by Dan Shoemaker of Rosetta Inpharmatics to reveal functional differences between all yeast mutants simultaneously. The barcodes, unique 20-base-long identifiers for each mutant, in theory allow the 4,600 plus mutants to be thrown together and then separated using microarray technology, and Ooi, a Ph.D. candidate in molecular biology and genetics, tested the idea by evaluating the mutants' abilities to fix double strand breaks in DNA.

The experiments revealed which strains' mutations adversely affected that repair mechanism, called nonhomologous end-joining. In addition to finding new genes involved in DNA repair, her work provides a method to search the yeast genome for genes of a particular function rather than sequence. "Siew Loon has truly propelled the lab into new areas and opened our minds to new ways of doing science," says Boeke.

Giovanni Traverso received the David Israel Macht Research Award for his project "Early detection of colorectal tumors through the examination of fecal DNA," conducted with Bert Vogelstein, M.D. and Kenneth Kinzler, Ph.D. Traverso's research, published recently in The Lancet and in The New England Journal of Medicine, documented development of tests to look for tell-tale genetic signs of colon cancer in stool samples. While these genetic changes had been identified by others in Vogelstein's laboratory a decade ago, problems in purifying the DNA and in reliably detecting the mutations in an excess of normal DNA molecules overwhelmed efforts to create a screening tool.

Traverso developed technology called Digital Protein Truncation (Dig-PT) that divides extracted DNA into separate, smaller portions so that mutated copies stand out. "Essentially, Dig-PT makes it possible to find the needle by dividing the haystack into very small, more manageable piles," explains Traverso, a Ph.D. candidate in the Human Genetics Program.

Catherine Huang received the Martin and Carol Macht Research Award for her project "New insights into the trypanosome RNA editing complex," conducted with Barbara Sollner-Webb, Ph.D. By studying components of the trypanosome RNA editing complex individually, Huang has helped identify which components of the editing complex perform which duties, pulling together some key concepts about the complex, which inserts and removes uracil residues from precursors of messenger RNA.

Her combined papers show that the different parts of the editing complex depend on each other for proper assembly and function. Even though the removal and insertion processes are somewhat distinct, she found that having a common complex catalyze both processes improves control and accuracy. Huang, who grew up in Silver Spring, MD, discovered the excitement of science in high school and went to college at Case Western Reserve University. She is a Ph.D. candidate in biological chemistry.

Wei Lu received the Alicia Showalter Reynolds Research Award for his project "Site-specific incorporation of a phosphotyrosine mimetic reveals a role for tyrosine phosphorylation of SHP-2 in cell signaling," conducted with Philip Cole, M.D., Ph.D. A graduate of the East China University of Chemical Technology in Shanghai, Lu studies regulation of enzymes that add phosphate groups to tyrosine residues of proteins, an activity crucial in cells' signaling pathways.

Through a series of experiments, Lu designed and created a mimic of phosphotyrosine, incorporated it into a phosphorylation enzyme called SHP-2 and tested the change's effects on the enzyme's activity. Published in Molecular Cell in 2001, his results solve a longstanding question about how SHP-2 turns on phosphatase activity and should be useful for unraveling other mysteries of tyrosine phosphorylation, says Cole. Lu is a Ph.D. candidate in the department of pharmacology and molecular sciences.

Emily Corse received the Mette Strand Research Award for her project "Envelope protein localization and coronavirus budding at Golgi membranes," conducted with Carolyn Machamer, Ph.D. Studying a type of virus that assembles at intracellular membranes rather than at the cell surface, Corse has revealed the workings of a small protein that helps make the virus's "envelope." Instrumental in assembling the virus, this "E" protein may do so by interacting with the "Golgi scaffold," a complex of several proteins whose function is still controversial.

Corse, who grew up in Charleston, MO, and went to college at the University of Wisconsin-Madison, says she has been curious about biology for a long time. "Doing research seems like a natural and satisfying extension of my curiosity. I was attracted to Carolyn's lab because of the diverse and creative ways she chooses to approach a scientific question," says Corse, a Ph.D. candidate in cell biology.

Hee Jung Chung received a Paul Ehrlich Research Award for her project "Regulation of glutamate receptor function and synaptic plasticity by PDZ ligand phosphorylation," conducted with Richard Huganir, Ph.D. Knowing that receptors for the neurotransmitter glutamate play critical roles in the brain, Chung studied processes that regulate the interaction of these receptors with "PDZ" domains, segments of scaffolding and signaling proteins found in neuronal synapses.

She discovered that phosphorylation of the PDZ-binding areas of glutamate receptor subunits regulates the receptor's interaction with PDZ-containing proteins. This phosphorylation also rapidly changes the receptor's function during synaptic plasticity, including during long-term depression, a neuronal process critical for learning and memory.

Born in Seoul, Korea, Chung received a bachelor's degree from Cornell University prior to coming to Hopkins. "I perceive this award not only as an achievement but also as a reminder of the importance of becoming a better scientist and person," says Chung, who will graduate in May with a Ph.D. in neuroscience.

Joseph Lawler received a Paul Ehrlich Research Award for his project "Identifying prime numbers with a DNA computer," conducted with Jef Boeke, Ph.D. Completely unrelated to his thesis work, and performed during a break from his clinical training, Lawler's development of a DNA computer that could find prime numbers represents a significant advance in the field -- the advent of multiplication with DNA.

Lawler decided on the framework for the computer -- how to code numbers using nucleic acids, how to create an operation (reaction) that would multiply those numbers and give the right answers, and how to determine what those answers were -- and made it work. "Can one perform multiplication using a computer made out of silicon instead of DNA?" asks Lawler. "Yes, but now that we can multiply with DNA, the next question is in what contexts can a DNA computer be used to assist a silicon-based computer?"

Lawler went to Queens College and then entered Hopkins' M.D./Ph.D. program in cellular and molecular medicine. "I chose Hopkins because of its outstanding reputation for clinical and basic research and for the flexibility it offers its students in charting their career path," he says.

Zefeng Wang received a Paul Ehrlich Research Award for his project "Studying trypanosome gene function with RNA interference," conducted with Paul Englund, Ph.D. Using a technique he learned during a summer course in 1999 at Woods Hole Marine Biological Laboratory in Massachusetts, Wang knocked a gene down instead of out in the parasite Trypanosoma brucei, whose mitochondrial DNA forms a unique network of thousands of interlocking circles of DNA. "The gene we're studying is essential, so classic knockout will never reveal its function," says Wang, a graduate of Tsinghua University in Beijing.

The technique, called RNA interference, leads to a gradual decrease in a gene's expression, and hence its protein's function, revealing the gene's effects. By knocking down the gene for topoisomerase II, Wang, a Ph.D. candidate in biological chemistry, discovered that the enzyme attaches newly-made rings of DNA to the periphery of the network, known as kinetoplast DNA. With Mark Drew and James Morris, Wang also developed a new vector to induce stable expression of RNA interference into the parasite, an advance adopted by others in the field.

Haining Zhong received a Paul Ehrlich Research Award for his project "Assembly and stoichiometry of heteromeric cyclic nucleotide-gated channels," conducted with King-Wai Yau, Ph.D. Essentially single-handedly, Zhong made some important and fundamental discoveries about how ion channels are put together, particularly those channels involved in detecting light in the eye and odorants in the nose. A graduate of Tsinghua University in Beijing, Zhong showed how the different parts of these "cyclic nucleotide-gated" ion channels come together to form the correct complex with the correct ratio of its parts -- the alpha and beta subunits.

After discovering that an unusual region on the alpha subunit actually interacts with itself, Zhong uncovered evidence that this self-reactive region is responsible for organizing the channel correctly. His findings have also led him to suggest that the channel is made of three alpha and one beta subunits, instead of two-and-two as widely believed. Zhong, a Ph.D. candidate in neuroscience, will be corresponding author for two papers reporting the findings.

Hyung Chun received the Ivor and Colette Royston Predoctoral Research Award for his project "Novel inherited caspase-8 mutation in autoimmune lymphoproliferative syndrome," conducted with Michael Lenardo, M.D., of the National Institute of Allergy and Infectious Disease. Chun worked to find the genetic mutation responsible for disease in a few individuals with a rare immune system disorder called autoimmune lymphoproliferative syndrome. The discovery of mutations in the gene for caspase-8 that caused their disease also revealed a new role for the caspase-8 protein in regulating immune system function and may help lead to better treatments for these patients, says Chun, who was born in Seoul.

An M.D. candidate who was sponsored for the award by H. Franklin Herlong, M.D., Chun will be returning to Harvard, where he obtained his bachelor's degree, for his residency in radiation oncology. "My early scrutiny of biological processes helped establish one of my primary motivations for entering the field of medicine -- to seek discoveries through scientific research that will enhance patient care," he says.

Brad St. Croix, Ph.D., received the Ivor and Colette Royston Postdoctoral Research Award for his project "Genes expressed in human tumor epithelium," conducted with Kenneth Kinzler, Ph.D. St. Croix, a postdoctoral fellow in oncology, developed the techniques and methods to analyze differences in gene expression between normal and cancerous tissue.

Using these methods to examine the endothelial cells that line blood vessels, St. Croix found 79 transcripts expressed differently in tumor versus normal endothelial tissue, 46 of those to a greater extent in tumor. These genes are likely to provide targets for blocking angiogenesis, tumors' critical process of creating new blood vessels, says Canada native St. Croix, a graduate of the University of British Columbia and the University of Toronto. Published in Science in August 2000, the work supports the idea that gene expression analysis can be used to "fingerprint" cancer tissue, leading to new insights into what makes cancers different from normal tissues.

Lisa Korn, M.D., received the Helen B. Taussig Research Award for her project "Is screening for osteoporosis associated with fewer hip fractures," conducted with Linda Fried, M.D., MPH. While osteoporosis increases the risk of hip fracture, and the bone-weakening condition can be detected and treated before fractures happen, guidelines disagree on whether people should be screened, says Korn, who grew up in White Plains, NY, and went to Harvard for college and medical school.

By analyzing available data on about 3,000 people, Korn discovered that screening for osteoporosis in people over age 65 was associated with 40 percent fewer hip fractures compared to usual primary care. "Although the study wasn't randomized, the results suggest screening for osteoporosis in people over age 65 may be beneficial," says Korn, a postdoctoral fellow in the Robert Wood Johnson Clinical Scholar Program and the department of medicine.

Colin Garvie, Ph.D., received the W. Barry Wood, Jr., Research Award for his project "Structural insights into the regulation of DNA binding of Ets-1," conducted with Cynthia Wolberger, Ph.D. A postdoctoral fellow in biophysics and biophysical chemistry, Garvie solved five complex crystal structures to see exactly how two transcriptions factors (Ets-1 and Pax5) interact with each other and with DNA to regulate expression of a gene involved in development of B-cells. Each structure a daunting task and an accomplishment in itself, the combination of the structures revealed a never-before-seen aspect of gene regulation: one DNA-binding protein directly influencing the DNA-binding contacts of another.

"Understanding how the activity of transcription factors is regulated is an essential step in understanding how genes themselves are regulated," says Garvie, who holds degrees from the University of Glasgow and the University of Leeds.

Mark Levis, M.D., Ph.D., received the Daniel Nathans Research Award for his project "A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo," conducted with Donald Small, M.D., Ph.D. Levis developed and tested a new anti-cancer agent, known as CEP-701, that has now entered clinical trials in human patients.

The new agent interferes with signaling through a receptor called FLT3 (pronounced "flit three"), originally cloned by the Small lab. FLT3 signals by adding phosphate groups to itself and to other proteins on tyrosines, one building block of proteins. In up to 40 percent of patients with acute myeloid leukemia, FLT3 is activated because of mutations in the gene, and those mutations are linked to a poorer prognosis, says Levis, who holds degrees from the University of California-Berkeley and UC-San Francisco.

A postdoctoral fellow in oncology, Levis helped tremendously in translating findings with cell lines into new experiments on patient samples and his work has hastened the advent of the clinical tests of the new drug, says Small.

Charles Henrikson, M.D., MPH, received the Alfred Blalock Research Award for his project "Chest pain relief by nitroglycerin: Predictive value for coronary artery disease," conducted with Nisha Chandra-Strobos, M.D. Henrikson launched a study of nearly 500 patients at Bayview to test whether nitroglycerin's effect on chest pain really helps indicate the source of the pain.

"'The pain got better with nitroglycerin' is a common phrase on rounds, and is often used to convince the listener that the pain is cardiac in origin," says Henrikson, a cardiology fellow originally from Albany, NY. "However, nitro is used for other types of pain, too. We found that chest pain relief with nitroglycerin has no diagnostic value, in stark contrast to the prevailing wisdom."

Henrikson attended college at Yale and received his M.D. from Columbia, where he also did his residency. Now officially in the "research" phase of his fellowship at Hopkins, Henrikson is doing basic laboratory research with Eduardo Marban.

Chris Janetopoulos, Ph.D., received the Albert Lehninger Research Award for his project "The monitoring of heterotrimeric G-protein activation in living cells," conducted with Peter Devreotes, Ph.D. In studies with amoeba, Janetopoulos developed a way to visualize how and when G-proteins are activated during the critters' sensing of chemical attractants. He labeled the three subunits of the G-protein with fluorescent markers to see when subunits were close together and when they were separated, a sign of activation. Unexpectedly, he found that G-proteins are active (their subunits are separated) as long as receptors on the amoeba's surface bind the attractant.

The technique should be useful for studying G-proteins' behavior in mammalian cells, too, and it could be used to find agents that activate or inhibit signaling pathways that involve G-proteins. "G-proteins are used in signal transduction pathways in animal cells in response to such diverse stimuli as light, odorants, hormones and neurotransmitters," says Janetopoulos. "Many of these pathways are involved in disease and could be targets for drug development."

A native of Brookfield, IL, Janetopoulos received his B.A. from Augustana College in Illinois and his Ph.D. from Texas A&M. He is currently an American Cancer Society Fellow in the department of cell biology.

Taylor Sohn, M.D., received the A. McGehee Harvey Research Award for her project called "A human genotoxicity assay? High-throughput measurement of p53 responses," conducted with Scott Kern, M.D. Sohn created a line of human cancer cells that includes a p53-specific reporter system, allowing her to identify agents that increase levels of p53. She tested conventional chemotherapy agents, ionizing radiation and more than 16,000 small compounds for their ability to increase levels of p53, an activity that may indicate utility against cancer. The p53-reporting cells may also be useful for identifying cancer-causing agents among drugs and in the environment, says Sohn, a native of Old Bridge, NJ, and graduate of Rutgers University.

Her experiences with basic science have led to a goal of a career in academic general surgery, says Sohn, who became a postdoctoral fellow in Kern's lab after completing her medical doctorate and three years of her surgical residency at Hopkins. "In the long-term, I'd like to have a career where I could take care of surgical patients on a day-to-day basis while pursuing the clinical and basic science research that may benefit patients in the future," she says.





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