Graduate Schoollife allows Matt and his mentor, Wayne Hendrickson, Ph.D., <strong>University</strong> Professor, to determine how closely and strongly the ligand is adhering to the protein. They and their collaborators can then tinker with the ligand to improve the fit, which gives Matt a chance for some family bonding over the chemical bonding, as he discusses the data with his chemist father. The hope is that Matt’s work will help in the development of a ligand that binds strongly and specifically to the coat protein when introduced into the bloodstream and thereby prevents HIV from binding to its biological receptor on immune cells. Prashant Donthamsetti, left, and Hideaki Yano PHOTOGRAPH BY JORG MEYER 30 <strong>Columbia</strong>Medicine Spring 2012 Zach Carpenter, who is doing his thesis research with Raul Rabadan, Ph.D., assistant professor of biomedical informatics, and Adolfo Ferrando, Ph.D., assistant professor of pediatrics and of pathology & cell biology in the Institute for Cancer Genetics, is taking a bioinformatics approach to identify carcinogenic alterations in protein structure. Nucleotide sequencing of DNA from patients with a cancer, such as peripheral T-cell lymphoma, identifies mutations. Special computer programs, some of which Zach helped develop, can then suggest which mutations are functionally important and how they might affect the shape and orientation of important domains of the protein coded by the mutated gene. There is also the possibility of “in silico” drug screening, where computer programs can model the interactions of a library of drug structures with a protein domain of interest. Sitting at his desk, with nary a pipetter or cell culture dish in sight, Zach can meld the screening and design approaches to drug development. In the laboratory of Jonathan Javitch, M.D., Ph.D., the Lieber Professor of Experimental Therapeutics in Psychiatry and professor of pharmacology (in the <strong>Center</strong> for Molecular Recognition and in physiology & cellular biophysics), the focus is on proteins that mediate the actions and regulate the distribution of the important brain transmitter, dopamine. These proteins are key targets of drugs of abuse, such as cocaine, and of many drugs used to treat schizophrenia. Pharmacology graduate students Prashant Donthamsetti and Hideaki Yano are both focused on the dopamine D2 receptor to which antipsychotics bind. They use techniques such as bi-molecular fluorescence complementation to monitor the interaction of drugs with the receptor and of subunits of the receptor with each other and with proteins to which the activated receptors bind to lead to cellular effects. These techniques involve tagging components of the receptor complex with small molecules. When the components come close enough to one another for their respective tags to interact, fluorescence is emitted; thus, these are called proximity assays. Prashant, for example, is using these to try to understand why aripiprazole, an “atypical” antipsychotic, has different actions at the D2 receptor in different cellular contexts. Work such as that of Prashant and Hideaki addresses the issue of specificity of drug action, which is critical for thinking about the design of drugs with fewer side effects. Seth Robey, a second-year student in the laboratory of Robert Kass, Ph.D., the Hosack Professor of Pharmacology, Alumni Professor of Pharmacology (in Neuroscience), chair of the Department of Pharmacology, and vice dean for research at P&S, also uses fluorescence tagging to moni- Graduate students in pharmacology and molecular signaling use sophisticated techniques that will lay the groundwork for designing drugs. tor protein movement. His protein of interest is a channel in the membrane of heart cells whose conformational changes lead to ion fluxes that generate the cardiac action potential. Mutations in this channel are associated with serious cardiac arrhythmias, such as long QT syndrome. Seth is using voltage clamp fluorimetry, where the light output from the probe is affected by the molecular environment, to study these conformational changes and their regulation. He focuses on a region of the channel at which certain local anesthetics bind, so his studies hold the promise of improving our understanding of the molecular mechanism of action of this class of drug not only in the heart, where the drugs are used as antiarrythmics, but also in nerves, whose ion channels resemble those in the heart. Not uncharacteristically, Seth was placed on the path to these studies of intramolecular movement serendipitously. As an undergraduate biochemistry major, he sent out requests for research opportunities to numerous faculty, and the first offer was from a researcher in the biophysics of ion channels. Once Seth appreciated the potential of such studies to allow him to relate intramolecular events to cell physiology, he was hooked. And for Seth and these other pharmacology students, seeing the broad picture from molecule to disease state and treatment is powerfully attractive.
S & Alumni Marianne Wolff’52, Alumni Editor Peter Wortsman, Alumni Writer News¬es Biotech Stars Their biotech businesses are located within a two-mile radius in Westchester County, N.Y., but their influence extends far beyond. Page 37 32 37 40 42 44 Class Notes Alumni Profile Profiles in Giving Alumni in Print In Memoriam
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