“Don Wiley spent his scientific career in the pursuit of excellence,” says Mervyn Turner, Senior Vice President, Worldwide Licensing and External Research, Merck Research Laboratories. “As someone who knew Don both personally and professionally, I think it is fitting that the Merck-Wiley Fellowships recognize excellence–excellence in the quality of graduate students in the interdisciplinary genetics and genomics, and molecular, cellular, and chemical biology training programs.”
On October 10, 2003, Turner presented the second-annual Merck/Wiley Fellowships to two MCB graduate students: Antonia Holway, a fourth-year graduate student in the laboratory of Matthew Michael, and Adam Castoreno, a fourth-year graduate student in the laboratory of Axel Nohturfft.
“Adam has proven himself to be an outstanding scientist and a fantastic problem solver,” says Axel Nohturfft, Assistant Professor of Molecular and Cellular Biology. “We’ve been studying the export and sorting of cholesterol from endosomes, exploring the system as a paradigm for the greater question of how cells control the distribution of lipids to maintain membrane homeostasis.”
In endosomes, the protein and lipid components of lipoproteins are hydrolyzed to small building blocks, which are then released. Cholesterol enters this pathway mostly as cholesteryl fatty acyl ester, which is hydrolyzed by an enzyme called acid lipase to produce cholesterol and fatty acid. While this pathway is now discussed in all textbooks, the regulation of cholesteryl ester hydrolysis and the mechanisms of cholesterol export from the endosomal system remain poorly understood.
“Adam has begun to reconstitute the endosomal production of cholesterol from cholesteryl ester and its subsequent export in vitro,” says Nohturfft. “His progress constitutes an enormous technical achievement. Moreover, his investment in assay development has been rewarded by some very interesting results on the regulation of cholesterol ester hydrolysis that have significantly improved our understanding of endosomal cholesterol metabolism. In fact, Adam’s work provides an explanation for the accumulation of cholesteryl esters in lysosomes of atherosclerotic foam cells. Because sixty percent of the population dies from atherosclerosis-related causes, this result is very important.”
Antonia Holway is studying the DNA damage response using C. elegans as a model system. She explains, “I began this project by characterizing mus-101, a known DNA damage response gene, and found that worms partially depleted of the protein by RNAi are healthy but sensitive to stresses such as drugs that damage DNA or inhibit replication.”
Based on this observation, Holway hypothesized that she could use the sensitized worms to identify genes that interact with mus-101, which are involved in the DNA damage response by simultaneously co-depleting the two genes by RNAi. “I conducted a screen to co-deplete mus-101 and most of the genes on Chromosome 1 then identified a small number of genes that displayed increased lethality when co-depleted with mus-101.”
“Toni is already a terrific scientist, armed with prodigious technical gifts as well as a sharp intellect and substantial creativity,” says Matt Michael, Assistant Professor of Molecular and Cellular Biology. “She has a very bright future ahead of her.”
Currently, Holway is focusing on one of these genes called slm-1. “Worms depleted of slm-1 are sensitive to DNA damaging agents,” she says. “This suggests that it plays a role in the DNA damage response.”
Slm-1 is a sumo ligase, suggesting that sumoylation of a certain protein or protein(s) is essential for tolerance of DNA damage. “I’m looking at this information in several ways, including the use of transgenic worms harboring an affinity tagged Sumo, in order to identify the target of slm-1 sumoylation during the DNA damage response.”
“Don Wiley made such significant contributions to this department and to the scientific community,” says Holway. “It is a great honor to receive this award in his memory.”
Candidates for the fellowships were nominated by their advisors and selected from a pool of graduate students from the Departments of Organismic and Evolutionary Biology, Molecular and Cellular Biology, and Chemistry. Candidates submitted a curriculum vita along with letters of recommendation from their thesis committees to a selection committee headed by the chair of the department, Andrew McMahon, Frank B. Baird, Jr., Professor of Science. Selection was based on these submissions and the candidate’s demonstrated productivity.
The Merck-Wiley Fellowships, established by Merck Research Laboratories, honor Professor Don Wiley and recognize excellence among graduate students, an ideal strongly endorsed by Wiley. The $500,000 award will provide support for two graduate students for their fourth and fifth years of study.