YALE JOURNAL OF BIOLOGY AND MEDICINE 76 (2003), pp. 133-138.Copyrght@2004. All nghts reserved.

FOCUS ON YALE MEDICINE

New Frontiers in Molecular Pharmacology andMedicine: A Celebration

Ellen Wittmack and Wenya Linda Bi

Yale University School of Medicine, New Haven, Connecticut

On October 24, 2003, the Yale Schoolof Medicine inaugurated its new wing forthe Department of Pharmacology with astar-studded symposium titled "NewFrontiers in Molecular Pharmacology andMedicine." In the world of academia, thisis as close as one gets to red carpet Oscarquality spectatorship. The roster beganwith Tony Hunter of the Salk Institute,Joan Steitz of Yale, Jack Dixon of UCSD,Robert Weinberg of MIT, JosephGoldstein of University of TexasSouthwestern and winner of the 1985Nobel Prize in Medicine, Stuart Schreiberof Harvard, and ended with PaulGreengard of Rockefeller University andwinner of the 2000 Nobel Prize inPhysiology.

HISTORICAL PERSPECTIVES ONYALE PHARMACOLOGY

The Department of Pharmacology atYale has a renowned history since itsinception in the 1940s by William Salter.Most notably, it has led the world in thestudy of cancer chemotherapy and neu-ropharmacology. Indeed, modem cancer

chemotherapy took flight at Yale in 1942when Alfred Gilman and Louis Goodmandiscovered the first anticancer drug forlymphoma when they demonstrated theeffects of nitrogen mustard in reducingtransplanted lymphosarcoma in mice(Gilman et al., 1963).

In 1953, Arnold Welch came to Yalefrom Oxford to become the departmentalchair. He took over an anemic departmentand began to recruit young scientists whowould prove to be the best in the country.John Vane shared the Nobel Prize in 1982for his work on prostaglandins and prosta-cyclin and the mechanism of action ofaspirin. William Prusoff discovered thefirst specific antiviral drug to be used inman, 5-Iododeoxyuridine (IUdR) for thetreatment of ocular herpes and later foundthe first drug against human immunodefi-ciency virus, 3'-deoxythymidin-2'-ene(d4T) (Lin TS et al., 1987). In neurophar-macology, Jack Cooper, Robert Roth, andFloyd Bloom led the research effort andwrote the Biochemical Basis ofNeuropharmacology in 1970, a book thatis in its Ninth Edition and can still be

c To whom all correspondence should be addressed: Wenya Linda Bi, Yale School ofMedicine, 367 Cedar Street, New Haven, CT 06510. E-mail: linda.bi@yale.edu.

133

134 Wittmack and Bi:- History of Yale pharmacology

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In 1967, Murdoch Ritchie wasappointed Chairman of the department andworked in collaboration with WilliamDouglas on the firing properties of non-medullated afferent fibers and with PaulGreengard on the mode of action of localanesthetics. Greengard went on to sharethe Nobel Prize in 2000 with ArvidCarlsson and Eric Kandel for his work ondopamine and other "slow" transmitterswhich act by protein phosphorylation andallow signal transduction in the nervoussystem. Alan Sartorelli, John Perkins, andLen Kaczmarek also served in as chairmenof the department until the arrival ofJoseph Schlessinger in 2001.

OLD THEMES, NEW IDEAS

As Alan Sartorelli puts it,"Pharmacology is the study of drugsbut that can be accomplished in many,almost any, ways." Indeed, YalePharmacology is becoming increasingly

multidisciplinary in this goal. The depart-ment today emphasizes a number of dif-ferent areas including neurochemistry,neurophysiology, psychopharmacology,viral and microbial chemotherapy andclinical pharmacology. In addition, there isongoing research into the mechanismsbehind signal transduction, carcinogene-sis, drug resistance, and differentiation.

Joseph Schlessinger joined thePharmacology department as Chairman in2001. Schlessinger heads a team ofdynamic researchers focusing on manydifferent areas of pharmacology - manyof whom use signaling in order to addressquestions in either cancer or neuropharma-cology. Investigators involved in signalingare Anton Bennett, William Sessa, EliasLolis, and Barbara Ehrlich. Bennett isinterested in the role protein tyrosine phos-phatases play in cellular processes such asmitogenesis, apoptosis, cell movementand differentiation. Sessa focuses on howendothelial nitric oxide synthase is regu-lated in the context of normal physiologyand in disease and the application of pro-

Wittmack and Bi: History of Yale pharmacology 135

teomics to discover new targets to regulateblood vessel function. The structure-func-tion relationships of chemokines is beinginvestigated by Lolis, while Ehrlich isinterested in the mechanisms behind cellregulation of intracellular calcium concen-tration.

In the area of signaling and neu-ropharmacology, Angus Nairn works onthe characterization of the basal gangliaphosphoprotein DARPP-32 and the possi-bility of developing drugs that specificallyaffect phosphoproteins or their targets. YaHa uses x-ray diffraction to study howmembrane proteins carry out complex bio-logical functions on the surface of neu-ronal cells and how changes in these pro-teins cause neurodegeneration. Jim Howestudies glutamate receptors, Gary Rudnickfocuses on neurotransmitter transport, andLen Kaczmarek's research aims to under-stand the nature of the biochemicalchanges that occur in neurons. PriscillaDannies examines the process by whichprotein hormones and neuropeptides areconcentrated into secretory granules.

Among the Pharmacology facultymembers that study cancer are KarenAnderson, David Calderwood, Yung-ChiCheng, and Alan Sartorelli. Anderson does

research that interfaces signaling and can-cer by developing an understanding ofenzymatic reactions and receptor-ligandinteractions at a molecular level.Calderwood, the newest recruit toPharmacology, studies molecular controlof integrin signaling as intergrins regulatecell adhesion, growth and migration.Cheng focuses on cancer and viralchemotherapy and studies the functionalroles and properties of virus-specific pro-teins in order to design selective antiviralcompounds. DiGiovanni leads theresearch on the molecular signaling under-lying breast cancer and its treatment.Sartorelli's lab studies the mechanism ofaction behind multi-drug resistance andDNA base methylating and chloroethylat-ing agents.

DIRECTIONS FOR THE FUTURE

The symposium "New Frontiers inMolecular Pharmacology" was a celebra-tion of the new areas that exist in pharma-cological research. Tony Hunter openedthe symposium with a talk entitled"Signaling by Phosphorylation in the Ageof Genomics." In 1979 the Hunter lab dis-covered the phosphorylation of tyrosine

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136 Wittmack and Bi: History of Yale pharmacology

residues, leading to role of tyrosine kinas-es in signal transduction and cell growthand development.

Joan Steitz then discussed SnoRNPbiogenesis in mammalian cells and themechanism behind the release of thesnoRNA from the intron before process-ing. The Steitz lab is interested in thestructure and function of small ribonucle-oprotein complexes.

Jack Dixon is interested in the inter-action between bacterial pathogens andmammalian signal transduction systems.He spoke on the Yersina effector YopT, aprotein that is assembled and injected outof bacteria into mammalian cells. YopTcleaves Rho GTPases from the membranecausing disruption of the actin cytoskele-ton in host cells.

Bob Weinberg provided insight to thegroup on his labs research on telomerase,an enzyme that cleaves the telomeres atthe end of chromosomes in cancer cells.

This enzyme is a target in cancer therapybecause the preservation of the telomeresin the cancer cells allow for immortalizedproliferation.

Joseph Goldstein, recipient of the1985 Nobel Prize with Michael Brown fortheir discoveries concerning the regulationof cholesterol metabolism, spoke about hisresearch on regulated intramembrane pro-teolysis. Together, Dr. Brown andGoldstein discovered that cell surfacereceptors mediate the uptake of low-densi-ty lipoprotein and their research has led totreatment and prevention of atherosclero-SiS.

Stuart Schreiber spoke on the need touse small molecules to understand thechromatin signaling network. His labfocuses on development and application ofdiversity-oriented organic synthesis andthe development of ChemBank, a suite ofinformatic tools and federated databases

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Yale alumnus Paul Greengard's lec-ture, "Signal Integration in the Brain," wasa fitting way to wrap up a symposium cel-ebrating Yale Pharmacology - past andpresent. Greengard integrated the story ofdopamine signaling pathways in the cen-tral nervous system and its application tomajor neurological and psychiatric disor-ders such as Parkinson's disease, schizo-phrenia, attention deficit hyperactivity dis-order, and drug abuse. Greengard and hisproteges have beautifully developed thedopamine story at Yale and RockefellerUniversity over the past three decades. Inparticular, he focused on a molecule calledDopamine and cAMP Regulated Phospho-Protein with molecular weight = 32 kD(DARPP-32) which is located at a critical

junction point in the integration and differ-ential regulation of dopamine signalingpathways. Greengard concluded his talkwith the summary that "DARPP-32 playsan essential role in mediating the actionsand interactions of numerous neurotrans-mitters, therapeutic agents and drugs ofabuse in many brain regions, including theneostriatum, hippocampus, and cerebralcortex."

With the 21st century comes a needfor academic research in pharmacology toexpand the traditional borders and findnew ways to address biological questions."New Frontiers in MolecularPharmacology and Medicine" highlighteda few of the exciting angles that can beused in order to conquer disease. With anew chairman, new laboratory space, andfour new assistant professors, the depart-

138 Wittmack and Bi: History of Yale pharmacology

ment of Pharmacology at Yale is well pre-pared to continue making strong contribu-tions in the field of pharmacology.

LITERATURE CITED1. Gilman A. The initial clinical trial of nitro-gen mustard. Am J Surg. 1963;105:574-8.1963.

2. Lin TS, Schinazi RF, and Prusoff WH.Potent and selective in vitro activity of 3'-

deoxythymidin-2'-ene (3'-deoxy-2',3'-dide-hydrothymidine) against human immunod-eficiency virus. Biochem Pharmacol.1987;36:2713-8.

3. Welch A. Reminiscences in pharmacology:auld acquaintance ne'er forgot. Ann RevPharmacol Toxicol. 1985;25:1-26.