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Fostering Communication and Collaboration
The nihCatalyst A Publication fob NIH Intramural Scientists
National Institutes of Health i Office of the Director Volume 8, Issue 6 November-December 2000
NIH Research Festival Translational Research Running with the Genome: Jean Li d Cadet: NIH Gets To Work with the ‘Working Draft’ A Bridge at NIDA by Cynthia Delgado by Fran Pollner
he “working draft” se- r ean Lud Cadet is equally at home quence of the human I upstairs and downstairs in the genome, delivered to building that houses the NIDA in- T | the desktops of the biomedi- Jamural research program at the cal community this summer, Johns Hopkins University Bayview may become the most “dog- campus in Baltimore. eared” work-in-progress the On the fourth floor, Cadet runs the world has ever known. four labs that make up the Molecu- Unlike the first draft of a lar Neuropsychiatry Unit, of which medical text that requires cor- he is chief; and on the first floor, he rections and updates before directs NIDA’s clinical research pro- it is finally printed, the gram, overseeing the inpatient re- genome’s first draft is out search unit, the outpatient research there, and some NIH investi- program, an adolescent clinic that fo- gators are using it to make cuses on smoking new discoveries while oth- cessation, and the — ers are arranging the data to 70 currently active make the material even more clinical protocols meaningful as a resource to all of which are the research community. strategic use of the HGP’s data aided conducted on-site. Simultaneously, the working draft is the discovery of a new family of recep- Upstairs, research- constantly growing, as sequencing data Taste,” ers are charting tors (see “An Acquired page 6). pours in, nonstop, from centers around and figuring out the world. The working draft—which The ABCs of Sequencing ways to prevent—the neurodegen- was 85-90 percent complete when it was Stage 1 of the HGP involved studying erative effects of illicit daigs in the announced in June should be entirely organizing the from each chro- brains of mice. Downstairs, they are — and DNA filled in by year’s end. The finished prod- in a process as map- documenting cognitive and hemody- mosome known uct (see description below) is anticipated ping. For physical mapping, each chro- namic deficits induced by these drugs in the year 2003, Eric Green said at the mosome is broken up into larger or in the brains of long-term human us- NIH Research Festival plenary session smaller pieces and isolated as DNA ers—and the persistence of these on “The Utility of Whole Genome Se- continued on page 6 effects, thus far, despite up to one quences: Early Glimpses of the Se- month’s abstinence. quence-Based Era.” CONTENTS The paths between the first and Calling the human genome a “24-vol- fourth floors are well traveled, and 1 6 ume encyclopedia set volumes 1-22, Running Sequencing when Cadet’s working in one loca- — X, and Y,” Green, chief of NHGRI’s Ge- With the Genome anid an AcqiAcquired Taste tion, he’s never far from the other, nome Technology Branch and director either physically or mentally. The Jean Lud Cadet: 8-9 of the NIH Intramural Sequencing Cen- A Bridge at NIDA Eureka: hope is that the cellular and molecu- ter, presented an overview of the fun- Hepatitis A Vaccine lar mechanisms of toxicity unraveled Thioether Bond damentals of the Human Genome Project in the lab will be brought to bear on From the DDIR: Cyclodextrins (HGP). the prevention and treatment pro- Planning for Change Rounding out the session, NCBI’s Greg White Knights grams in the clinic. Schuler described the computational pro- 3 When he arrived at NIDA, in 1992, Awards and Events 10-15 grams rapidly being developed to tackle Cadet had an agenda: to identify the Recently Tenured the task of assimilating and utilizing the long-term neurological effects of data—and Nick Ryba, chief of the NIDCR Prion Profiler 16 continued on page 4 Reed Wickner Catalytic Questions Taste and Smell Unit, reported on how The NIH Catalyst From the Deputy Director for Intramural Research
Planning for Change in Biomedical Research
unning the NIH has been described as equiva- tegrate into tissues and organs, and how these or- lent to steering an aircraft carrier—you can- gans produce organisms that interact with their en- Rnot turn on a dime and you have to think vironments. way ahead to keep from running aground. Bio- To satisfy these scientific imperatives, we need medical research is entering an era of enormous resources to allow creation of new animal mod- change, and we all need to start thinking about els—housing transgenic mice alone is a major re- how these changes will affect how we will do re- source commitment—and the requirements for search in—the future. Scientists are by nature con- zebrafish and large animal models will be substan- servative “If it ain’t broke, don’t fix it!” is a favor- tial. We are currently planning a new central vi- ite phrase of many bench scientists in describing varium on campus that will provide the space and their experimental approaches. But even the most flexibility to support these models and resources conservative of us realize that the future will not for histopathology, genetic manipulation, behav- look like the present. What should the intramural ioral analysis, and special surgery. program at NIH be doing to stay one step ahead of We will also need resources to support high-reso- new developments in biomedical research? lution structural studies. Currently, the NIH intra- We will undoubtedly need to deal with the enor- mural program supports a dedicated X-ray beam mous quantities of data currently being loaded into line at Brookhaven and one at Argonne for our central databases: genome sequences; microarray crystallographers. We have also upgraded our high- gene expression analyses as a function of develop- resolution electron microscope facilities, which will ment, disease, tissue type, etc.; complete medical be housed in Building 50, and we are planning for records, including radiological and pathological im- larger and larger magnets for high-resolution NMR ages; and the entire world’s literature at our finger- studies of molecular structure. For clinical imaging tips. We need networks that allow quick and easy research, we have a shared in vivo NMR center, access to this information, soft- and the new animal imaging fa- ware that predigests information cility will open in 2001. These or displays it in ways that are What should the facilities will put intramural NIH meaningful to us, and appropri- at the forefront of the technol- ate computer terminals for all INTRAMURAL PRO- ogy needed to support our re- scientists at NIH. The leadership search. of NIH has been working with GRAM AT NIH BE The design of our new labora- Al Graeff, the director of the tory buildings reflects the chang- Center for Information Technol- DOING TO STAY ONE ing nature of biomedical re- ogy, and with IT staff in the In- STEP AHEAD OF NEW search. Each of the new build- stitutes and Centers to be sure ings on campus has a basic in- that the most flexible infrastruc- DEVELOPMENTS IN terstitial design, which means ture exists to support these sci- that all of the support utilities for entific demands. The Clinical BIOMEDICAL RE- the labs are on floors layered be- tween the lab floors. This will Center has taken the lead in de- SEARCH? veloping a state-of-the-art Clini- make it easy in the future to cal Research Information System change and maintain plumbing, (CRIS) to replace our outmoded electrical, and air supplies to the Medical Information System (MIS). This develop- labs without disrupting the laboratories themselves. ment takes money and talented individuals, and Other elements of new lab design include com- we are making good progress on both fronts. puter networking, electrical supply that meets the The scale of many of our laboratory activities is high energy needs of current equipment, and more also undergoing great change. For example, in the efficient heating and cooling systems. And all of 1940s and 1950s, we were content to purify an the new buildings bring natural light and more space enzyme and demonstrate an activity; in the 1960s to our researchers. The NIH Master Planning pro- and 1970s, we wanted to clone and sequence the cess has provided a mechanism for rational growth enzyme; in the 1980s and 1990s, we expected to and renovation of our campus, and we are cur-
do all of these and also crystallize it to determine rently considering other ways to meet our burgeon- structure, map the gene, and create a genetic model ing space needs. lacking or mutating the enzyme to determine its Finally, the vast power that these new research function. In the new millennium, no one is satis- tools give us also brings new responsibilities. Cur- fied with one enzyme—we want to characterize rent ethical concerns about clinical research are a the complete family of such enzymes, its whole direct result of our increasing ability to restructure evolutionary tree, and perhaps the entire pathway human genes and human bodies. Our planning for in which the enzyme resides. the future must include oversight systems to reas- In the not too distant future, we will be combin- sure both ourselves and the public that we are tak- ing physiological and molecular information to gain ing the right approaches and continuing to serve insight into how cells actually work, how they in- humanity. 2 —” .
Alter Takes a Lasker
his year’s Lamentation of the “C’s” T Lasker Required Course Award for clini- When it came to hepatitis he required course for clinical One undaunted, had to fight us principal investigators, Clinical cal medical re- , T search will be “Get out of the blood Research Training, will be repeated shared by You no-good crud ” on December 12, 2000, 12:00 pm- Harvey Alter, His words did thus befright us 4:00 pm in Building 10, Lipsett Am- chief of the in- phitheater. Harvey Alter was his name, fectious dis- The course was designed to ad- Bashing virus was his game eases section dress one of the essential standards A researcher unsurpassed and associate director of research in (Training and Education) recently Hefought us to the last. the Department of Transfusion approved by the NIH for conduct- CC And never lost his aim Medicine, and Michael Houghton, of ing clinical research in the intramu- ral research include the Chiron Corp. in Emeryville, Calif. Our extinction, number three program. Topics From his co-discoveiy of the Aus- Came after “A and “B ethical issues in human subjects re- tralia antigen to his uncovering of the Our brothers, all so retro search, roles and responsibilities of existence of a “non-A, non-B hepati- Were the first that Alter let go the investigator and institution, regu- tis vims” that was ultimately named Non-A, non-B, we were victim “C” latory issues, and clinical investiga- the hepatitis C virus, Alter’s tors and the mass media. groundbreaking hepatitis research We tried, in vein, to hide All principal investigators with a we’d thus reside spans more than 30 years. The Lasker Unknown, protocol approved through the So close andyet sofar- Award cites his pivotal role in ferret- Clinical Center are required to take Beyorid your PCR ing out the cause and drastically re- the course and successfully com- But Alter on us spied ducing the risk of transfusion-associ- plete an exam by March 1, 2001. ated hepatitis. Houghton was cited for Registration will be held from No- His work will surely end us his isolation of the hepatitis C virus. vember 1-30. To register, please And to our Maker send us visit the course website at Notwithstanding the fact that the Before God, we shall ask Her
is awarded by Duke to students who complete the required coursework. Awesome Foursome Prospective participants should hree of 60 new members elected into the Institute of Medicine in October consult with their institute or center T hail from NIH, and another is the cabinet member who oversees NIH: regarding the official training nomi- Dennis Charney, chief, Mood and Anxiety Disorder Research Program, NIMH nation procedure. Application dead- Steven Hyman, director, NIMH line is March 1, 2001. For more in- David Lipman, director, National Center for Biotechnology Information, Na- formation, visit the program website: tional Library of Medicine Donna Shalala, secretaiy, U.S. Department of Health and Human Services. cc duke/info.html . 3 Jean Lud Cadet continued from page 1 drug abuse. The literature on that subject, he says, was sparse. It’s less sparse today. Cadet and his colleagues have published extensively on the neurodegenerative effects of amphetamines and MDMA (Ecstasy), drugs of choice among adolescents today because “they’re cheap, accessible, and can be made very easily by any good chemist.” In cell culture and with transgenic mice that overexpress su- peroxide dismutase (SOD)—an enzyme that breaks down super- oxide radicals and is abnormal in such conditions as amyotrophic lateral sclerosis—the team has demonstrated that the toxicity as- sociated with methamphetamine and MDMA involves the pro- duction of superoxide radicals and can be offset by SOD. The Back to Back: Jean Lud Cadet transgenic mice are largely protected against the brain cell death wears two seamless hats— all the (in the cortex, striatum, and hippocampus) that typically accom- time— in his dual role as a basic panies drug exposure in other mice. science section chief (molecular Although SOD is too big a compound to gain easy access to neuropsychiatry) and clinical the brain, smaller SOD mimics have shown some promise in director of the NIDA IRP. experimental stroke models. Notwithstanding that the usefulness His introduction to NIH and of an antioxidant strategy in humans has yet to be proved. Ec- with it the realization that he stasy makers and users—who apparently read the relevant sci- wanted to spend his life in entific literature—have been observed at parties to combine the research came when he was a drug with an antioxidant vitamin cocktail. fourth-year medical student at New York’s Columbia University Biochemical changes in the brain consistent with cell death in College ofPhysicians and Surgeons and had a three-month humans have been observed in long-term users, Cadet notes, rotation at NIMH. He got his M.D. degree in 1979, undertook and could account for the cognitive impairment his team has two residency programs—one in psychiatry and one in in clinical studies to documented designed determine whether neurology—and then returned to NIH in 1984 as an NIMH abstinence reverses drug-related cognitive deficits. Thus far, little medical stafffellow and ward chief at St. Elizabeth’s Hospital change has been seen after a month of abstinence in studies in Washington. He then taught at Columbia before rejoining involving heavy users of cocaine and alcohol; clinical studies NIH in 1992— this time at NIDA as chief of the neuropsychia- involving amphetamine and Ecstasy users are anticipated next. try and neurotoxicology unit. He became acting chief of the Longer-term studies are needed but are problematic, Cadet molecular neuropsychiatry section thefollowing year and then chief when he was tenured a year later. He assumed the observes, because it is difficult, if not impossible, either to keep acting clinical directorship in 1994 and took on that study volunteers confined for longer than a month or to ensure permanent role in 1997. abstinence among a nonconfinecl population. One of the salient findings in the cognitive studies is that the constellation of defi- cits varies with the drug of abuse. Although all drugs exert their Two-thirds of the U-shaped addictive effects along the dopamine pathway, their cognitive , effects are played out in different regions of the brain—a fact four-story that should serve as a guide to tailor treatment programs, Cadet building that houses the says. “Everyone who comes in for treatment needs to be evalu- NIDA ated neurologically and neuropsychologically so that their thera- intramural peutic program can be planned around their particular impair- research ments. Someone with attention deficits, for instance, might need program in a focusing medication in order to process the information of- Baltimore fered in the program.” The fact that cocaine indeed causes cognitive deficits is only now beginning to be appreciated and is still not common knowl- lated to the cognition deficits we’re seeing,” Cadet adds, edge. “It’s very new information. Our study (1) is one of the few suggesting that therapies aimed at the one might also ben- to document clearly that this is the case,” Cadet notes, although, efit the other. he adds, people who have worked in the field with long-term Using cDNA arrays, Cadet and his team also hope to cocaine abusers have suspected as much for a while now. identify genes that are affected by chronic drug use, the In another study undertaken to establish a physical basis for better to get to precise mechanisms of toxicity and devise the increased risk of stroke among cocaine users, Cadet and treatment strategies specific to each of the drugs of abuse. colleagues measured cerebral blood flow using transcranial Dop- The brain is far too complex, he says, to imagine that one pler (TCD)—a “classical neurological approach.” The brain vas- pathway would cover all bases. culature and increased resistance to blood flow they found in References: Bolla, F.R. Funderburk, and Cadet. “Differential effects of their study population—chronic users in their 30s—resembled (1) K.I. J.L. cocaine and cocaine + alcohol on neurocognitive performance.” Neurol- that reported for people in their 60s and 70s and for patients ogy 54:2285-2292 (2000). with multi-infarct dementia. As in the study of cognitive deficits, (2) R.I. Herning, D.E. King, W.E. Better, and J.L. Cadet. “Neurovascu- no changes were seen in the study cohort after one month of lar deficits in cocaine abusers.” Neuropsychopharmacology 21:110-118 abstinence (2). “I think the blood flow abnormality is also re- (1999). 4 November — December 2000 Reed Wickner: Prion Profiler by Katie Farr IDDK’s Reed Wickner, one of of Wickner’s key insights kind of like the mathemat- NIH’s two newly elected mem- came as he was writing a ics of biology.” At the N bers of the prestigious National review article on the ele- same time, he says that he Academy of Sciences, does things a little ments in 1989—a time has made good use of his differently from the rest of the crowd. when he says “the inter- medical training. He ob- Wickner’s groundbreaking work estab- est in nonchromosomal served that what he is re- lished that certain elements in yeast are genetic elements in the ally studying is an infec- prions—an abnormal form of a protein yeast world . . . had tion of yeast. “I view [the capable of “infecting” normal molecules mostly died out.” Wickner prions] as parasites ... so of the protein and converting them to realized that two ele- that while other people the abnormal prion form. Mammalian ments, [LJRE31 and [PSI+], are looking for how this prions are believed to cause “mad cow” might really be yeast is an advantage to yeast, disease and Creutzfeldt-Iakob disease prions. So, he started I’m not always thinking of (CJD). working on [URE31, build- it in those terms.” Wickner’s route to basic science ing on “beautiful work” by Wickner says he would showed his preference for the road less Aigle and Lacroute who Fran Poiiner advise early career scien- traveled. As an undergraduate at Cornell, discovered it, with elegant Reed Wickner tists to do as he did and he was drawn to mathematics and experiments of his own. march to a different drum- earned his bachelor’s in that field. But In 1994, Wickner proposed three oft- mer. “I’m not sure this advice would be instead of pursuing math further, cited genetic criteria for calling some- what other people would give, but my Wickner decided to follow in his father’s thing a prion: 1) “Curing” a prion can advice is . . . don’t propose as your work footsteps to become a physician. While be reversed—the prion state can spon- when you become independent a linear in medical school, he was more in- taneously reappear after the phenotype continuation of what you’ve been do- trigued by the science behind the dis- has vanished; 2) An excess of the nor- ing as a postdoc. Propose to do some- ease than by the art of diagnosis. This mal protein can increase the chance of thing that is obviously your own.” This led to yet another career move—becom- prion appearance; and 3) The pheno- could mean applying the biochemical ing a postdoctoral scientist here at NIH. type of an organism with a prion is the or genetic techniques you have learned He studied en- same as the phe- to a new system, or staying with the same zyme biochemistry notype of a mu- organism, but addressing a new prob- with Herb Tabor, Very recent work from the tant in the gene lem. “It’s not easy to do,” he concedes, who, Wickner Wickner lab has found that for the protein. but postdocs should try to think beyond says, “taught me As Wickner has their immediate experiments toward the how to do sci- A PROTEIN CALLED MksI IS shown, [URE31 bigger picture. “You need to see some- ence.” Next came meets the three thing and see its interest and importance training with Jer- REQUIRED FOR THE TRANSFORMA- genetic criteria that other people don’t see.” ard Hurwitz at TION OF THE NORMAL Ure2 for being a prion. New York’s Albert [URE31 protein Einstein College of PROTEIN TO THE ABNORMAL also forms the Prize Protege Medicine, where characteristic ag- "IDDK postdoc Herman Edskes Wickner worked PRION FORM [URE3].TfflS IS gregates for N!has received the second an- on the purification which prions are nual Norman P. Salzman Memorial THE FIRST REPORT OF SUCH A and characteriza- famous. Award in Vi- tion of DNA poly- HELPER PROTEIN FOR PRION Very recent rology, an merase II. work from the award pre- FORMATION. But it was at NIH Wickner lab has sented by the where Wickner es- found that a pro- Foundation tablished his own lab as a principal in- tein called Mksl is required for the trans- for the NIH vestigator in yeast genetics. Many fac- formation of the normal Ure2 protein to for contribu- tors drew him back. Freedom from writ- the abnormal prion form [URE3](see box tions in basic ing grants and teaching affords him the to right). This is the first report of such virology luxury of doing experiments himself. a helper protein for prion formation. while work- Celia Hooper “I’ve been very lucky over the years to Identification of an analogous factor in ing at NIH or Herman Edskes have some really excellent postdocs, but animals could help researchers treat, or I also enjoy doing research myself. And perhaps even prevent, prion-induced Edskes received the award for his my impression from my friends in uni- disease. paper entitled “A protein required versities is they don’t really have time.” Refreshingly enthusiastic about his re- for prion generation: [URE31 induc- Pursuing the unusual has paid off for search, Wickner says the same force that tion requires the Ras-regulated Wickner. His lab studies non-Mendelian fueled the love of his undergrad major Mksl protein”—with special recog- genetic elements in budding yeast, now drives his work. “Mathematics is nition to the winner’s mentor, Reed which include RNA viruses, a plasmid what I really like—mathematics and Wickner. called 2pDNA, [PSI+], and [URE31. One physics. Genetics is very logical—it’s 5 — The NIH Catalyst • 8 Research Festival Running with the Genome continued from page 1 clones. These clones are char- to describe the hard polish- 1997, and the first multicellular genome, acterized and overlapped on ing of the sequence—getting the nematode Caenorhabditis elegans, one another by identifying re- additional sequence reads to in 1998. Earlier this year, a collabora- gions in common. The result- improve accuracy and cover tion between Celera Genomics, of ing “contigs” constitute a con- gaps— refinements that yield Rockville, Md., and the HGP resulted in tiguous segment of the start- a highly accurate sequence, the completion of the sequence for the ing DNA. “Like a jigsaw thereafter known as a “fin- fruit fly, Drosophila melanogaster. puzzle, the larger clones are ished” sequence. at first easier to put together Accomplishments of the The G5 into contigs than the smaller HGP to date include com- The complete working draft of the hu- clones,” said Green. plete sequencing of a num- man genome is expected by year’s end, Two DNA cloning systems ber of microbial genomes, in with a projected completion of the fin- have been instrumental to the addition to the first eukary- ished sequence in the year 2003- The HGP’s efforts to map the hu- otic organism, the common working draft of the mouse genome Eric Green man genome. In one, the brewer’s yeast reported in should be available early next year and larger pieces of cloned DNA are isolated as yeast artificial chromosomes (YACs); An Acquired Taste in the other, smaller pieces of cloned heximide has been mapped to a locus DNA are isolated as bacterial artificial by Nick Ryba, NIDCR at the distal end of chromosome 6, just chromosomes (BACs). “Each YAC pro- n collaboration with HHMI investi- where the T2R-5 gene is also found. vides multiple pages from one of the I gator Charles Zuker and his group at Moreover, nontaster mice have five mu- hypothetical chromosomal volumes, or, the University of California, San Diego tations in T2R-5, and these affect the roughly, chapter-size pieces of cloned (UCSD), we have used the “working sensitivity of the receptor in the cellu- DNA,” Green explained; each BAC clone draft” to help uncover a family of taste lar assay, strongly pointing to a genetic is approximately page-size. Because of receptors. explanation for a behavioral trait. larger size and availability, YACs play a Aversive reactions to bitter tastes pro- Why do many unrelated toxic com- dominant role in constructing the first- tects animals from ingesting toxic com- pounds taste bitter? It turns out that taste generation physical maps of the human pounds. But until human genome se- cells containing one T2R also express genome. quence information helped identify a most of the other Stage 2 of the HGP, Green continued, new family of receptors we had little T2R genes. The involves sequencing the organized idea how many chemically unrelated brain interprets information about DNA—using what is termed a “se- compounds could all taste bitter. patterns of cellu- quence-ready contig map,” or a series G-protein coupled receptors (GPCRs) lar activation of overlapping BACs that map to a cer- have been implicated in mediating bit- last year, the ability of rather than which tain region of a human chromosome ter taste, and humans to taste a specific bitter sub- receptor is in- to construct each human chromosome stance was genetically linked to a re- volved. This page by page. gion of chromosome (5pl5). The means that sub- The fundamentals of DNA sequenc- 5 NIDCR-UCSD group used tools such as stances activating ing—developed in 1977 by Fred Sanger, Nick Ryba open reading frame-finder coupled with different T2Rs are a British scientist who received his sec- BLASTp and hydrophobicity analysis to likely to taste similar. ond Nobel Prize in chemistry for work identify a new candidate GPCR (T2R-1) There is already considerable inter- in this field have not changed, but se- — in sequence from this interval. But what est in exploiting this information to efficiency has dramatically. quencing — was really exciting was that tBLASTn modify taste. For example, certain In one year, Green said, a single person searches of draft sequence indicated drugs for AIDS, heart disease, and de- can produce more than one million that T2R-1 was a member of a large pression taste so bad or so ruin the bases of sequence. “Shotgun sequenc- family of GPCRs clustered in just a few flavors of food that patients abandon ing” is the most commonly used method: regions of the genome, all implicated life-saving medications. But the main “BAC clones are selected and large in controlling bitter taste in mammals. focus of the NIDCR group will be try- amounts of DNA made (like taking a Using molecular biology techniques, ing to extend our knowledge of how page and making lots of xerox copies), we cloned homologous receptor genes taste works, ultimately to understand then randomly fragmented (putting from rodents and examined where T2Rs how information is encoded in the tongue, transmitted to the brain, and these pages in a paper shredder).” Thou- are expressed. As expected, for sen- decoded there to produce the familiar sands of these fragments are sequenced sory receptors, T2Rs were found in sub- sensations that contribute so much to and assembled by a computer program. sets of taste receptor cells. Then, using system, showed our everyday enjoyment. In this way, each fragment of the hu- a cell-based assay we that at least some T2Rs responded to For further information about T2Rs see man genome is essentially sequenced bitter-tasting compounds. For example, 6 November — December 2000 1 the finished sequence by 2005, ucts are distinguished from pre- Schuler emphasizes that the genome Green said. To meet the dead- dicted genes and their protein sequence provides a uniform frame of lines for the human genome products. The standard tool for reference (or coordinate sytem) for relat- sequence, five major sequenc- sequence analysis, BLAST (Basic ing the positions of disparate types of Local Alignment Search Tool), features, as ing centers, collectively known genomic such genes, mapped offers multiple searching options: markers, and common sequence varia- as “the G5,” were responsible “For example,” Schuler said, “sup- tions. for sequencing approximately pose you had a query protein and The team has also developed a “locus 85 percent of the human ge- its gene sequence. You could use identifier” and a program called “Refseq,” nome. About 12 other centers the software tBLASTn to scan the which aims to establish one sequence were responsible for sequenc- draft of the genome for any entry for each naturally occurring DNA, ing the rest. matches in humans or other organisms.” RNA, and protein molecule. Ill G5 are: The Alternatively, he added, one could use the University Se- Washington Genome genome to come up with predicted pro- quencing Center, St. Louis Getting There teins and make a searchable database fol- ccording to Francis Collins, Whitehead Institute for Biomedical lowed by a BLASTp search and compare Research/MIT Center for Genome Re- A NHGRI director and head of the results with the query protein. With a pre- Human Genome Project, the public search, Cambridge, Mass. dicted protein sequence, one could search working draft version of the human Baylor College of Medicine, Human for common protein domains to get infor- sequence can be found in its most Genome Sequencing Center, Houston mation about function or look at the per- useable forms at the following web H U.S Deparment of Energy Joint Ge- centage of conserved domains. sites: nome Institute, Walnut Creek, Calif. University of California at Santa The Sanger Centre, Hinxton, United GenBank Field Guide, Cruz: It’s a Blast! “One of the great things about the Ge- nome Project,” said Greg Schuler, NCBI staff scientist, “is that you don’t have to wait until it’s finished to start making use of the data.” Schuler and his NCBI colleagues are get- ting creative with the sequence data gen- erated by the HGP—data that are regu- larly downloaded within 24 hours from se- quencing centers into the public database, GenBank. Schuler and company are work- ing to make the system user-friendly and optimized for the needs of researchers. GenBank is equipped with several fea- tures that provide pertinent information on the quality of particular working draft se- Fran Pollner quences, such as redundancy, fragment number, and base quality scores. It also Modern Art and Science: Carmen Kaplan, special projects manager of the NIH allows users to look at different types of Office ofResearch Sendees, Office of Quality Management, at her post in the to Research Festival goers with on the updated, compre- sequence entries—for instance, by chro- Natcher lobby provide info hensive, web site. The redesign project took six months, she said, mosomes or large contigs. In many cases, user-friendly ORS was largely the work OQM's Dressell . Check it out at unique qualifiers are used to label data so and of Pam 7 Research Festival Eureka! And Beyond: , ^ , , TT T ™ _ by Margaret Coulombe Hard Lessons in Tech Transfer r udging from the experiences of a panel of HAV and was able to grow it in cell The Thioether Linkage I of NIH intramural investigators speak- culture. Purcell’s team was then able, by Frank Robey, an NIDCR senior investi- ing at the Research Festival in Octo- serial passage in cell culture, to generate a gator, described the novel | chemical pro- Jer, tech transfer can be a long journey, a live attenuated vims, which could be tested cess that he and colleagues Wolfgang short glide, or an uphill battle after the in nonhuman primates for development of Lindner and Ray Fields invented and that first heady thrill of discovery. vaccine in humans. others have brought to bear in such clini- At the October 12th minisymposium, the At this point, Purcell cal and co-workers uses as detecting acute deep vein I Office of Technology Transfer (OTT) pre- sought a potential commercial partner to thrombi and diagnosing and treating non- | sented a panel of scientists whose bright develop a live attenuated hepatitis A vac- small-cell lung cancer. ideas (Eureka!) turned into commercial cine and settled on SmithKline Beecham. Robey, a chemist whose focus is AIDS products and cash for the investigators, In a collaborative effort by Purcell’s group, vaccine research and immunology, de- the labs, and the federal piggy bank. Ac- the Walter Reed Army Institute of Research, veloped an “enabling” technology—one cording to OTT, more than 1,200 licens- and SmithKline Beecham, the HM175 strain that can be used in many diverse appli- ing agreements have been signed since of HAV was adapted to grow cations, often to speed up 1993- A 1998 General Accounting Office in a cell type suitable for vac- product design. In 1986, (GAO) report on the technology transfer cine development (MRC-5 Robey and colleagues cre- activities of six major U.S. government cells). By then, however, ated a method to place a agencies stated that, since 1996, NIH has SmithKline Beecham was thioether bond at any po- generated 95 percent of the total royalties more interested in develop- sition in a synthetic pep- received ($102 million) by the federal gov- ing an inactivated vaccine tide—a doorway to new ernment. and was working closely with realms in chemistry. Pat- a strain of HAV provided by ented in 199T Robey’s in- Serendipity in Science: scientists in Switzerland. vention has found its way The Hepatitis A Vaccine Purcell asked SmithKline into multiple diagnostic Robert Purcell, chief of the Hepatitis Beecham if it would compare and therapeutic products, Viruses Section in NIAID’s Laboratory of the HM175 strain with the some of which have been Infectious Diseases (LID), opened the sym- Swiss strain for suitability as approved by the FDA. He posium. His tale, spanning nearly 20 years, an inactivated vaccine. SKB is quick to emphasize, Frank Robey began with discovery of the hepatitis A agreed and found that the however, that while he virus (HAV) in 1973 by postdoc Steve HM175 strain was a better inactivated vac- provided the novel chemistry underlying Feinstone, now with FDA’s CBER. Using cine candidate than the Swiss HAV. They emerging patents, the creative use of the immune-electron microscopic techniques subsequently dropped the Swiss option and linkage and the development of the prod- developed by LID’s Albert Kapikian to vi- pursued an inactivated vaccine with the ucts drew on the hard work and ingenu- sualize transmissible gastroenteritis, HM175 strain in collaboration with Purcell’s ity of others. Feinstone was able to see HAV structure group. The leading group to capitalize on and went on to develop a Over the next decade, Robey’s thioether bond technology so far diagnostic test for hepatitis members of Purcell’s lab is a New Hampshire-based biotechnol- A. He also obtained 20 se- cloned and sequenced wild- ogy company, Diatide, Inc. Richard Dean rum samples from another type and attenuated HAV and John Lister-James, working at Diatide, study on post-transfusion strain HM175 and mapped have now spun the bond into three prod- hepatitis at NIH and, with the location of mutations im- ucts and multiple patents of their own. his colleagues in the LID and portant for allowing the vi- Diatide’s first product that makes use Harvey Alter in the CC ms to grow in cell culture of Robey’s peptide-based thioether bond Blood Bank, discovered and that attenuated viru- is called AcuTect®, a diagnostic imaging non-A, non-B hepatitis lence. kit for detecting fresh (acute) blood plate- (hepatitis C). In all, the researchers in let clots in the deep veins in the legs and Despite the break- Purcell’s lab have applied for pelvic area. AcuTect® was approved on throughs in visualization more than 60 patents and fast track by the FDA and is now in Phase and diagnosis, isolation of have secured 21, 10 of which III clinical trials for imaging obstructions the vims and production in culture (the relate to the hepatitis A vaccine; some of in carotid arteries. NeoTect®, a second first steps toward preparation of a vaccine) these are held jointly with SmithKline Diatide product, binds to somatostatin proved fruitless. Then, serendipity played Beecham. receptors that are overexpressed on sev- a hand. In 1976, Ian Gust, an Australian PI In 1991, the HM175 strain of HAV be- eral epithelial-derived cancers, permitting, on sabbatical in Purcell’s lab, moved the came the first licensed hepatitis A vaccine for example, X-ray detection of this can- lab closer to success when he brought in (licensed first in Switzerland), and it was cer in the lung. Neotide®, a third Diatide stool samples he had collected from a fam- licensed in 1995 in the United States. It is product, uses Robey’s thioether bond as ily in Australia that had developed hepati- currently one of two licensed hepatitis A the linker to attach a therapeutic beta- tis A from eating raw mussels. vaccines in the United States (the other is emitting radioisotope, Rhenium-188, to The strain of HAV recovered from the manufactured by Merck Laboratories). somatostatin, which then binds to and family’s stools, dubbed hepatitis A vims Despite the challenges and potholes on kills malignant tumors overexpressing the strain HM175, turned out to be critical to the road to discovery, this line of research, somatostatin receptor and kills them. the subsequent development of the vac- Purcell concluded with a smile, “has been Now in Phase I/II trials, Neotide® has cine because in 1981 Richard Daemer, also very good to the lab, which,” he added, “is been shown in preclinical animal testing now at CBER, isolated the HM175 strain now pursuing hepatitis C and E vaccines.” to have an extremely high success rate in 8 November — December 2000 targeting and shrinking or eliminating non- covery, Winding Road to Use!” unmodified, natural hormones small-cell cancers in lung. as an object lesson in the pit- orally to humans. Birth control Beyond these three “eldest children,” falls of patenting. pills based on natural hormones numerous other compounds are now be- Pitha’s discovery involved are an example of how this pro- ing developed. Robey’s method of chemi- the small carbohydrate com- cess could be turned to a revo- cal ligation has become a standard in the pound cyclodextrin, which he lutionary application. field of peptide chemistry and often is was using to try to improve The potential was not lost used to ligate large peptides together to the solubility of another com- upon many watchful eyes. form even larger proteinlike moieties. pound. His “eureka” moment “Others recognized the lucrative Robey’s current research focuses on the came when he realized that outcome of my discovery,” he utility of such peptide linkages in con- cyclodextrin must be chemi- noted. Within 10 years of Pitha’s structing potential AIDS vaccine compo- cally modified to make full use first patent filing in 1983, other nents. “Using this technology, we have of its capsulelike structure. individuals had filed 600 related made peptide polymers, or peptomers, Modified cyclodextrin had the patents, some of which should that act as unique immunogens for mak- potential to molecularly en- have been challenged, he ing antibodies to target peptide confor- capsulate other chemicals, muses, but were not. There mations in large proteins. Often times, a drugs, or even food flavor were also problems arising from synthetic peptide will not have any de- compounds. licenses granted to small com- tectable conformation, but we’ve ob- Pitha’s thoughts went imme- panies that not only did not de- served that after it’s been polymerized, diately to the desirability of velop any products but blocked the peptide then contains constraints encapsulating steroid hor- other companies from doing so. that often mimic those found for the mones. Two things brought steroids to Frustrated companies called for a federal peptide in the native protein. We are try- mind: his own experience with testoster- investigation; people lost their jobs; and ing to be extremely creative with one shots and his recollection of a profes- Pitha’s patents became “hot potatoes.” One peptomer technology,” Robey said in an sor of his in Switzerland in the 1930s who’d patent was involved in an interference interview with the Catalyst. been given tons of porcine testicular tis- case that was not decided for more than “Since we do not know the overall con- sue and told to find a hormone that could 10 years. formation of the HIV envelope protein or be administered orally. “Can you imagine Despite the morass of patenting diffi- conformations of its subfragments, we are such a mess?” Pitha commented. culties, Pitha points to the positive out- using the peptomer technology as a shot His research path clear, Pitha soon dis- comes of his journey. As a result of his in the dark to go after certain conserved covered that cyclodextrin derivatives lent work, a whole new class of cyclodextrins regions of gp 120. We are finding this excellent solubility to a variety of steroids; is available commercially. The principles approach to be quite successful. We model that the encapsulation resulted in full re- of his invention are now so widely ac- and then we immunize with these con- lease; and that the process and carrier were cepted as to be ubiquitous—though no formationally constrained subfragments.” safe. He obtained good results with estra- one knows that he developed them—and, Many of the conformations in the en- diol, progesterone, and testosterone. He most significantly, many therapeutic ap- velope are highly conserved, Robey notes, was, in fact, his first test subject. He made plications are on the horizon. “There is,” and he is in the process of making vari- it possible for the first time to administer he said, “great satisfaction in that.” H ous components of the HIV envelope that can produce antibodies to “recognize all or most strains of the virus as it mutates.” Who Was that White Knight? His method, he says, is “geared toward here’s an invisible clause attached to exclusive licenses negotiated between the something that is very broadly cross-re- TNIH Office of Technology Transfer (OTT) and its industrial partners. It’s called the active and cheap to make something that — White Knight clause, and it’s a voluntary, unwritten but verbally sealed agreement that can cover the poorer populations in Af- the involved company will “do good" in relation to the exclusivity of its newly ac- rica and Asia if it ever comes to that level quired license to what presumably will be a profit maker. of development.” The White Knight program was created five years ago by OTT director Maria Freire in the course of discussions with a small, family-owned business—named White Knight. Cyclodextrins: “It was during the time of the Ebola vims outbreak,” Freire recalls, “and during the Victims of Their Own Success? negotiations, I suggested that they donate their product—gowns coated with a viral The path to transforming methodolo- barrier—to the Centers for Disease Control for use overseas.” Although those particular gies and therapeutics is not always strewn transactions did not actually come to fmition, the company’s name lived on in the with patents, royalties, and glory. concept of the White Knight that crystallized in Freire’s mind. It was based on the “this is are other things than financial terms in “To start with,” advised Josef Pitha, “you notion, she says, that NIH and there business deals to be considered.” need three ‘eurekas!’. Not just one—first To a very large degree, OTT’s business partners have agreed: Approximately 80 the discovery, then a patent attorney who percent of the exclusive licensees participate in what Freire considers a “voluntary will research and write up the proper payback to the community in recognition of the taxpayer’s contribution.” White Knight patent, and, last, a business person who offerings have included informational web sites, indigent access to health facilities, has the capabilities and the intent to get vaccines for schools, and drugs for clinical trials. the product to the market.” Among the more recent White Knight deeds was participation by company scientists The former chief of the Section on Mac- in the physically demanding as well as exhilarating year 2000 Alaska AIDS ride (see romolecular Chemistry at the NIA Geron- People Recently Tenured sions that develop in the prostate appear strik- Jeff Green received his M.D. in 1981 from Vanessa Hirsch obtained a D. V.M. in 1977 ingly similar to human prostate intraepithelial McGill University in Montreal and residency and a Masters of Veterinary Science in pa- neoplasia and progress to invasive carcino- training in pediatrics at the Children ’s Hos- thology in 1981 from the University of mas. A significant number of these lesions pital ofPhiladelphia. Hejoined the NIH Clini- Saskatchewan in Saskatoon. She became a develop ras mutations, as occurs in a subset cal Center in 1984 as a clinical geneticsfel- diplomate ofthe American College of Veteri- of human prostate cancers. Although most low and subsequently became an NCI bio- nary Pathologists in 1984 and obtained a transgenic mammary tumors do not harbor technologypostdoctoralfellow in the labora- Doctor of Science degree at the Harvard ras mutations, amplification of ki-ras occurs tory of the late George Khoury. After an ap- School of Pu blic Health in Boston in 1988. during tumor progression. We have demon- pointment as an investigator in the Labora- Afterfour years as a research assistant pro- strated the functional significance of this find- tory of Molecular Oncology at FCRDC, he fessor at Georgetown University in Washing- ing by crossing the C3(l)/Tag mice with ki- joined the Laboratory of Cell Regulation and ton, D C., she joined the Laboratory of In- ras knockout mice. The resulting mice show Carcinogenesis, NCI, in 1997, where he has fectious Diseases in 1992 and is now a se- delayed tumor development. We have also served as the head of the Transgenic Onco- nior investigator in the Laboratory of Mo- demonstrated that expression of genesis Group. lecular Microbiology, NIA1D. the transgene in the mammary The use of transgenic animals My research focuses on the pathogenesis gland is not responsive to es- for modeling human diseases of AIDS and the development of a vaccine trogen and, as with human has been the primary focus of for HIV-1, using simian immunodeficiency breast cancer, expression of es- the work in my laboratory. My virus (SIV) infection of monkeys as an ani- trogen receptor a is lost during early interests involved the phe- mal model. SIV induces an immunodefi- tumor progression. notypic and molecular charac- ciency syndrome in macaque monkeys that Our work has also demon- terization of transgenic mice car- is remarkably similar to that in HIV-infected strated that there is a biphasic rying the human T-cell lympho- humans. alteration in the apoptotic re- trophic virus (HTLV-1)- tax gene. Although HIV-1 infection of humans is sponse in the transformed cells The tax mice were shown to de- fatal, the disease course is highly variable, during the development of velop perineural tumors with ranging from asymptomatic survival for more mammary cancer in the C3(l)/ similarities to human neurofibro- than 15 years to progression to AIDS within Tag mice: Rates of apoptosis rise mas, as well as inflammatory lesions in the two years of infection. The level at which during the preinvasive phase, but fall during salivary and lacrimal glands leading to ab- plasma viremia stabilizes after primary in- the transition to invasive carcinomas. Our lab normalities similar to those found in human fection is a highly significant prognostic in- has demonstrated that the bax gene appears Sjogren’s syndrome. Further analyses of these dicator of subsequent disease course. This to be a critical regulator of the early pro- transgenic animals also demonstrated in vivo suggests that host immune mechanisms are apoptotic response in die mammary tumors that the tax gene can upregulate important critical in the control of viremia. Studies in C3(l)/Tag mice lacking bax have an acceler- growth regulators, including granulocyte my lab have shown that SIV-infected ated rate of tumor formation. macrophage colony stimulating factor, the macaques also exhibit variable disease Currently, I serve as the principal investi- interleukin-2 receptor, and nerve growth fac- course and that viral load is a strong predic- gator of the NCI Mouse Models of Mammary tor. tor of disease progression. Cancer Collective, which is part of the na- With my growing interest in hormone-re- My lab is investigating host and viral fac- Models of Human Cancer tional NCI Mouse to the variable disease lated malignant disease, I became intent on tors that contribute Consortium. The NCI Mouse Collective is a developing a transgenic model for human course in SIV infection of macaques. We re- community of 25 highly interactive NIH in- prostate cancer. To reach this goal, our lab cently demonstrated that the susceptibility vestigators seeking to advance the under- designed a targeting vector using the C3(l) of peripheral CD4+ T cells to viral infection cancer through animal standing of breast predictive primary component of the rat prostate in 5' flanking in culture is highly of models. after their inocula- region. This led to the first transgenic model viremia in these animals With support from the Collective, my lab proportion of for prostate cancer that was driven by the tion with SIV. The relative is expanding research using cDNA microarray the expression of large and small T-antigen (Tag) CD4+ T cells, their level of activation, or technologies to define genetic pathways and from the SV40 early region. Interestingly, level of expression of the major SIV co-re- identify new genes in mammary and pros- female transgenic mice carrying the same ceptor, CCR5, does not explain the major tate tumor development. We are comparing transgene develop mammary cancer that differences in susceptibility. This result sug- the expression profiles of tumors from sev- that exhibits many important features observed gests there are other host cell factors eral major transgenic mouse models of mam- establishment of persistent breast cancer. Although Tag is not contribute to the in human breast can- mary cancer with those of human to AIDS. etiologically involved in human prostate or viral replication and progression cer, as part of the validation process for I also investigating the origins of pri- breast cancer, its mechanism of transforma- am mouse models of human disease. In addi- remem- tion involves the inactivation of two impor- mate lentiviruses. It is important to tion, we are continuing to use transgenic an Asian tant tumor suppressor genes, Rb and p53. ber that SIV infection of macaques, to test several therapeutic approaches models artificial. SIVs originate in pri- The loss of these tumor suppressors has been monkey, is to mammary and prostate cancer including including sooty implicated in many human cancers, includ- mates of African origin, chemoprevention and antiangiogenesis green mon- ing prostate and breast cancer. Thus, Tag- mangabeys (SIVsm) and African array technologies to agents. We are using the first induced transgenic oncogenesis may involve keys (SIVagm). My lab characterized uncover mechanisms of action for these three spe- relevant pathways for human cancer devel- SIVsm isolate, SIV strains from agents. opment. cies of African green monkeys, the sole SIV Our goals in this work and for the future SIV from Transgenic prostate and mammary cancer from Sykes' monkeys (SIVsyk), and of transgenic emphasize development new L’Hoest monkeys and suntailed monkeys lesions in these mice develop over a very and models for prostate and mammary cancer genetic re- predictable time course. We have taken ad- (SIVihoest and SIVsun). A close targeting vectors and the development of new SIV from the latter two vantage of this fact to define histopathologi- lationship between to improve heterologous gene ex- strategies despite their long-term (over cal and molecular changes that occur at par- monkeys, pression in vivo. separation, sup- ticular stages of tumor formation. The le- 10,000 years) geographic 70 November — December 2000 r ports the hypothesis that the pri- (MVA), we demonstrated that the identification of a candidate susceptibil- mate lentiviruses co-evolved in vaccination with MVA express- ity locus for human prostate cancer on the African monkeys over the last ing SIV genes resulted in sig- X chromosome (HPC-X). million years. Interestingly, nificant modulation of viremia In 1992, we developed the comparative SIVIhoest and SIVsun are geneti- and improved survival when genomic hybridization (CGH) technique to cally most closely related to animals were challenged with identify chromosomal regions that are altered SIVmnd from mandrills, despite SIV. in cancer. At NHGRI, we are focusing on the fact that mandrills and In one study of MVA express- the identification of genes that are affected L’Hoest monkeys are only dis- ing SIV Gag-pol proteins, by genomic alterations, particularly high- tantly related. Recently, we char- rhesus macaques received four level DNA amplifications that often take Fran Pollner SIV immunizations with the re- place in genetically cells. acterized from redcapped Vanessa Hirsch MVA unstable cancer In mangabeys ( Cercocebus torqua- combinant virus or nonrecom- collaboration with other investigators, we tus torquatus) and drill (Mandillus leuco- binant MVA as a control. Gag-specific cyto- have identified several genes whose in- phaeus) and mandrill monkeys (Mandillus toxic T lymphocyte (CTL) responses were de- creased expression as a result of gene am- sphinx). We have found that many of these tected in all experimentally immunized plification may drive cancer progression and SIV isolates induce AIDS in Asian monkeys. macaques, with levels peaking after the sec- the development of therapy resistance. These Despite serologic evidence of widespread ond immunization. After challenge with include androgen receptor gene amplifica- SIV infection in African monkeys, AIDS-like pathogenic SIV, all macaques became in- tion in prostate cancer, and AIB1 and the disease is observed only in macaques. SIVsm fected; however, viral load was lower in MVA- ribosomal protein S6 kinase, which are am- infection of sooty mangabey monkeys is as- gag-pol-immunized macaques than in the plified in breast cancer. We are now using a ymptomatic, whereas inoculation of this control macaques. The level at which CTL combination of high-resolution DNA chip same virus strain into macaques results in stabilized after resolution of primary viremia technologies, such as CGH and cDNA AIDS. My lab demonstrated a similar phe- correlated inversely with plasma viral load microarray analyses, to rapidly identify am- nomenon with SlVagm in African green mon- set point. Most importantly, the magnitude plified and overexpressed genes throughout keys and macaques. This species-specificity of reduction in viremia was predicted by the the genome. Such genes may contribute to of virulence allows us to examine underly- magnitude of the vaccine-elicited CTL re- the clonal progression of cancer and pro- ing mechanisms of attenuation in the natu- sponse prior to SIV challenge. vide targets for therapy. ral host species and is a focus of my patho- In summary, these studies demonstrate that In the postgenomic era, translating gene genesis studies. recombinant MVA-SIV as a sole immunogen discoveries into clinical applications will be We recently evaluated plasma viral load generates a robust CTL response in macaques an increasingly important challenge. We re- and expression of SIV in tissues of naturally that mediates protection from high levels of cently developed the tissue microarray and experimentally infected African green viremia after SIV challenge. The effectiveness (TMA) technology to conduct rapid, large- monkeys. A wide range in viral load was of recombinant MVA in the macaque sug- scale analyses of promising candidate genes observed among healthy African green mon- gests that MVA-based vaccines warrant evalu- in hundreds or thousands of clinical tumor keys, ranging from undetectable to concen- ation for preventing AIDS in humans. specimens. Up to 1,000 tiny “tissue spots” trations similar to those observed in HIV- originating from different patients can be ar- infected humans or SIV-infected macaques. Olli Kallioniemi received his M.D. in 1985 rayed on a single microscope slide. We are Therefore, containment of viremia is an un- and Ph D. in 1988 from the University of applying the TMA slides to study the role of likely explanation for nonpathogenicity of Tampere in Finland. After residency train- novel genes and proteins in thousands of SlVagm in its natural host. A major focus of ing in laboratory medicine, he did tissue specimens from different cancer types, future studies will be virologic and immu- postdoctoral work at the University of Cali- associating molecular findings with clinical nologic characterization of experimental fornia, San Francisco, and then returned to and treatment outcome information. Such SlVagm infection of African green monkeys the University of Tampere, where he became “genome-scale translational research” will be vs. the susceptible pigtailed macaque host. a professor ofcancergenetics beforejoining important to identify the most promising di- Determining how host species coexist with NHGR1 in 1996. He is now a senior investi- agnostic and therapeutic gene targets from their naturally occurring lentiviral infections gator in the Cancer Genetics Branch and the genomic data now becoming available. will aid us in understanding the pathogen- head ofthe Translational Genomics Section. esis of HIV infection in humans. My interest is in the molecular Thomas Kristie received his Ph.D. from the The development of a vac- basis of human breast and pros- Committee on Virology at the University of cine for AIDS is the other focus tate cancer and strategies and Chicago in 1986 and didpostdoctoral work of my research. Although anti- technologies to translate basic with Phillip Sharp at the Centerfor Cancer retroviral therapy has had a sig- research findings into clinical ap- Research, Massachusetts Institute ofTechnol- nificant effect on the survival plications. Our research focuses ogy. He joined the NIA1D Laboratory of Vi- of HIV-infected patients, treat- on the discovery of inherited ral Diseases in 1993 and is now a senior ment is costly and prone to the germ-line alterations, as well as investigator in the Molecular Genetics Sec- emergence of drug-resistant vi- somatic genetic events and gene tion. ral mutants. Thus the develop- expression changes involved in My laboratory is interested in the molecu- ment of safe, realistic, and ef- tumor progression. lar biology of herpes simplex vims (HSV), fective vaccine strategies is es- In the area of genetic predis- specifically focusing on the biochemical sential. Unfortunately, many of position, I have collaborated mechanisms of viral gene expression and the vaccine approaches tested with investigators in Scan- transcriptional control of the viral lytic-la- thus far have resulted in only partial protec- dinavia on genetic epidemiological studies tent cycle. tion from infection in primate models of AIDS. of breast and prostate cancer. Using genetic HSV is a human pathogen affecting a large My lab has been developing a vaccine linkage analysis of cancer families, we re- percentage of the population. After a pri- using live viral vectors to prime a cell-medi- cently identified a putative third major lo- mary infection, the vims remains latent in ated immune response. Using a highly at- cus, at 13q21-q22, for breast cancer suscep- the sensory neurons of the individual until tenuated, modified vaccinia virus Ankara tibility. Our laboratory was also involved in complex stimuli such as stress, hormonal 11 The NIH Catalyst People Recently Tenured alterations, or tissue damage re- , the regulation of cellular and ers of the epithelia and cause benign warts, j | activate viral replication. During k _ N— viral processes. or papillomas. In some cases these lesions the lytic cycle, the immediate early A second area of interest can progress to malignant carcinomas, the (IE) genes of HSV are controlled in the laboratory is the un- most notable of which is ceivical cancer. The by a complex viral regulatory en- usual specific proteolytic pro- papillomaviruses also have an interesting bi- hancer that provides the frame- cessing of the Cl factor. The ology: The virus infects basal epithelial cells work for the assembly of macro- precursor protein is cleaved and maintains its genome as an episome molecular complexes. Our focus at a series of 20-amino-acid within these persistently infected cells. Viral has been on determining the com- repeats in the central domain DNA amplification and capsid antigen pro- ponents, interactions, and func- to generate a family of poly- duction occur only in the differentiated lay- Fran Pollner tions of the various polypeptides peptides. The product poly- ers of a stratified epithelium. The Tom Kristie involved. peptides do not segregate, papillomaviruses encode oncogenes that in- As a postdoctoral fellow, I worked on iden- however, suggesting that proteolysis is a terfere with host cell growth control to en- tifying and purifying Cl factor, a critical host unique mechanism for regulating the ac- able the virus to replicate in nondividing, dif- cell component of the enhancer complex. tivity of the protein. We have determined ferentiated cells. After arriving at NIH, I began cloning and that the Cl factor itself contains an auto- My research has focused on the molecular characterizing this protein. Cl factor is a catalytic activity that is responsible for pro- mechanisms by which two papillomavirus unique transcription factor produced as a 230- cessing of the reiterations. We are now fo- proteins control the viral life cycle. The viral kDa protein and is proteolytically processed cusing on demonstrating our hypothesis, El protein is required to initiate episomal vi- into a family of polypeptides. In a series of namely that processing regulates the pro- ral DNA replication. The E2 proteins regu- studies, my laboratory has defined the inter- tein-protein interactions and, therefore, the late viral transcription, DNA replication, and actions of the Cl factor with each primary functional activity of the Cl factor. genome segregation. My colleagues and I component of the HSV enhancer complex Our interest in this area led to the devel- have defined the structure, function, and in- and demonstrated that it is both the coordi- opment of a genetic screen for the isola- teractions of these proteins. nator of the enhanceasome assembly and a tion and characterization of novel site-spe- A few years ago we identified an additional transcriptional coactivator. We have also iso- cific proteases. Site-specific proteolysis function for the E2 protein. We showed that lated a relatively large bank of cellular pro- plays significant roles in the regulation of the E2 protein and viral genomes are bound teins that interact with various domains of many basic normal and disease processes, to mitotic chromosomes in dividing cells. E2 Cl. We are now characterizing these to de- including: links the genomes to the host chromosomes termine the normal functions of the Cl fac- The control of cholesterol to ensure that they are not lost tor in mammalian cells. metabolism by proteolytic as the cells divide, and that they One of the most interesting and critical regulation of transcription fac- are segregated equally to daugh- questions in herpesvirus biology is the tor SREB ter cells. This finding defines the mechanism for establishment of and reacti- The cleavage of amyloid mechanism by which episomal vation from the latent state. Considering the precursor protein (APP), which viruses maintain and segregate cell-specificity of latency and the cell stimuli may affect the development of their genomes in persistently in- that reactivate the vims, we think cellular Alzheimer’s disease fected cells. We are currently try- factors probably play the most significant role The intricate pathway of ing to identify the chromosomal in the lytic-latent switch. It is also likely that proteolytic targeting resulting factor to which E2 binds and to the regulation of the IE genes would be a in cell apoptosis determine whether it is a com- primary target in reactivation. Models for the a model protease, mon target of other episomal vi- Using my Alison McBride reactivation of HSV from the latent state pro- laboratory developed a system ruses. pose either that 1) reactivation proceeds capable of selectively isolating a rare pro- We have also found phosphorylation of E2 through a viral gene expression pattern dis- tease of modest activity from a complex regulates its degradation by the proteasome tinct from the lytic phase or that 2) reactiva- cDNA pool. We are now involved in sev- and modulates episomal viral genome copy tion is due to coordinated activation of tran- eral collaborative efforts to identify and iso- number. Our current hypothesis is that E2 scription of the five IE genes by cellular tran- late novel site-specific proteases in a vari- phosphorylation is cell cycle-specific and scription factors. ety of biological systems. regulates genome segregation by determin- My laboratory has demonstrated that al- ing the amount of E2 bound to mitotic chro- though the Cl protein is localized in the Alison McBride received a Ph.D.from the mosomes. High concentrations of E2 protein nucleus of most cell types, it is uniquely se- Imperial Cancer Research Fund and Uni- can be observed in the differentiated cells of questered in the cytoplasm of sensory neu- versity ofLondon, U.K., in 1986. She was a a papilloma that amplify viral DNA, and we rons. In the mouse model, conditions that postdoctoral fellow and Investigator with are testing whether E2 has yet another role reactivate the vims from latency also result Peter Howley in NCI and joined NIA1D in in regulating vegetative viral DNA replication. in rapid relocation of Cl to the nucleus. This 1994. She is now a senior investigator in In addition to these molecular approaches, observation and our work on Cl functions the Laboratory of Viral Diseases, N1A1D. we have developed two biological systems led us to propose that the Cl factor is a criti- I am interested in the strategies that vi- with which to study the role of the El and E2 cal component of the signaling mechanism ruses have developed to manipulate key proteins. The study of the complete that initiates viral reactivation. host cell factors at different stages of the papillomavirus life cycle is difficult because We are now using biochemical and genetic virus life cycle. Such studies have helped it requires keratinocyte differentiation. We approaches to find how Cl factor is seques- characterize many fundamental regulatory have developed an animal model in which tered as well as the signaling pathway(s) for pathways in eukaryotic cells, such as DNA organotypic rafts are generated from bovine activation of Cl transport. In addition to de- replication, gene expression, cell cycle con- or human keratinocytes and are grafted onto termining the role of Cl -interacting proteins, trol, and signal transduction. immune-compromised mice. When trans- we have been developing animal models, in- Since joining NIH, I have studied the fected with viral DNA, the grafts develop into cluding Cl domain-specific knockout mice papillomaviruses. These are small viruses papilloma-like lesions that synthesize infec- to aid analysis of the roles of the Cl factor in that infect and replicate in the stratified lay- tious viral particles. This allows genetic analy- 12 — November — December 2000 I ses of the viral functions required for the In light of potential pharmacologic paral- ety and growth hormone deficiencies, I docu- lytic cycle. It also allows us to study DNA lels between pediatric and adult anxiety dis- mented a longitudinal association between segregation and persistence in an animal orders, I have examined the psychobiology anxiety in young girls and growth deficits model. of pediatric anxiety. Following work in adult from childhood into adulthood. Certain papillomaviruses are associated panic disorder, my initial studies found that Similarly, adult studies document associa- with the development of cervical cancer, and children with respiratory illnesses, such as tions among stress-induced anxiety, the hy- inactivation of El and E2 gene functions (by asthma associated with dyspnea, faced a pothalamic-pituitary-adrenal axis (HPA), and viral genome integration) is thought to play higher risk of separation anxiety disorder hippocampal function. I demonstrated spa- a role in malignant progression. Because El than did children with other illnesses. My tial memory deficits and elevated cortisol in and E2 are crucial for viral DNA replication, subsequent work, funded by extramural children with anxiety disorders. Because spa- it has been difficult to determine whether it grants from NIMH, demonstrated that chil- tial deficits, HPA activity, and some forms of is the absence of these gene products or the dren with separation anxiety disorder ex- anxiety could each relate to hippocampal integration event per se that is important in hibit the same set of respiratory abnormali- dysfunction, I developed fMRI methods for carcinogenesis. To study this process, we ties that are classically found in adult panic assessing hippocampal activity across devel- have developed a system that allows analy- disorder. These include heightened dyspnea, opment using a spatial navigation paradigm. sis of the effect of mutations in El and E2 on chaotic breathing, and height- With these methods, I am now biological indicators of malignant progres- ened respiratory response to testing the hypothesis that en- sion, in the absence of integration. C0 2 inhalation. hanced HPA activity in child- We hope that our study of the Because SSRIs ameliorate hood anxiety is associated with papillomavirus El and E2 proteins will con- such breathing abnormalities in both reduced memory-based tinue to provide important insights into the panic disorder, I designed a navigation ability and reduced pathogenesis of papillomavirus infection. study to test the hypothesis that hippocampal activation during This knowledge will be useful in designing SSRIs ameliorate these abnor- navigation. We also plan to pur- strategies to intervene in the viral life cycle malities in separation anxiety sue this hypothesis in our in- and could lead to prevention or treatment disorder. Through related psy- tramural lab. of papillomavirus-associated diseases. Our chophysiological projects con- Finally, studies among adults studies will also provide insights into mecha- ducted within the context of this find that abnormalities in im- nisms of transcriptional regulation and dif- study, I am examining the hy- pulse control and emotion regu- ferentiation-dependent regulation of epithe- pothesis, based on animal studies, that anti- lation each show unique associations with lial gene expression. A detailed understand- depressants exeit more consistent effects on distinct brain asymmetry profiles in poste- ing of the mechanism of papillomavirus DNA innate than learned aspects of fear. We are rior regions engaged by perceptual tasks. I replication and segregation could lead to the planning studies in the NIMH intramural documented parallel associations with dis- development of a new generation of persis- program to examine the effects of SSRIs on orders of impulse control and emotional tent extrachromosomal vectors that may have learned and innate fears in children and ado- regulation in children, using cognitive and applications for gene therapy and genetic lescents. electrophysiological indices of posterior brain immunization. My prior studies found that only a subset asymmetry. of children with separation anxiety disorder This work in turn led to a series of fMRI Daniel Pine received his M.D. degree from exhibits respiratory characteristics of panic studies examining developmental variations the University of Chicago-Pritzker School of characteristics that also identify adults with in brain regions engaged by emotional per- Medicine and did his postgraduate training familial forms of panic disorder. Hence, this ception tasks. In each of these projects, and at New York’s Columbia University before subgroup of children may manifest a poten- in proposed projects in the NIMH intramu- becoming afaculty member in the College of tially heritable, respiratory-based suscepti- ral program, I plan to continue illustrating Physicians and Surgeons there. He is now bility to panic disorder, a hypothesis I have how findings from adult psychiatry inform head of the Section on Developmental Psy- pursued through other NIMH-funded research on treatments and risk factors for chopathology and Affective Neuroscience, in projects. childhood psychiatric disorders. the Program on Mood andAnxiety Disorders, Supporting this hypothesis, I conducted NIMH. a longitudinal study showing that most adult Patricia Rosa obtained her doctorate in My research interests pursue two comple- panic attacks are preceded by a childhood 1980from the Institute ofMolecular Biology mentary avenues. First, I am an active inves- history of separation anxiety disorder, though at the University of Oregon in Eugene. After tigator in pediatric psychopharmacology. most children with separation anxiety dis- postdocs at Washington University in St. Louis Second, I am testing hypotheses on brain- order do not develop panic. To further test and the Research Institute of Scripps Clinic behavior associations in childhood psycho- the hypothesis, I developed a portable ap- in La Jolla, Calif., Rosa joined NIAID's Labo- pathology. ratory Microbial Structure and Function, paratus for assessing C0 2 sensitivity in chil- of My interest in pediatric psychopharmacol- dren. Our group has used this apparatus to Rocky Mountain Laboratories, in Hamilton, ogy developed while I was a member of the begin comparing respiratory parameters in Mont. She is now a senior investigator at Department of Psychiatry at Columbia Uni- children of normal parents and parents with RML 's Laboratory ofHuman Bacterial Patho- versity. The effectiveness of medications with three types of disorders: panic, depressive, genesis. selective serotonin reuptake inhibiting activity and anxiety disorders other than panic. In In a broad sense, I am interested in how (SSRIs) in adult anxiety disorders led our further support of the central hypothesis, the the phenotype of a cell at any particular time group to conduct an open trial of SSRIs for study is based on a sample in which there is reflects both its genetic structure and the en- childhood anxiety disorders. Results from this a strong familial association between adult vironment in which it is located. This inter- study in turn led to our participation in a panic disorder and childhood separation est probably began with an epigenetics multisite, randomized, controlled trial of SSRIs anxiety disorder. course that I took as an undergraduate and in 128 children with a pediatric anxiety dis- Beyond studies on anxiety disorders, I has taken various forms in graduate and order. This study established the robust effi- have extended to children other adult work postdoctoral studies. Since coming to Rocky cacy and safety of SSRIs in children with on brain-behavior associations. For example, Mountain Labs, my research has focused on anxiety disorders. based on the association between adult anxi- Borrelia burgdorferi, the spirochete that 13 The NIH Catalyst People Recently Tenured causes Lyme disease. Features of research in my lab. The prac- seven genes and two pseudogenes within this relatively simple bacterium tical consequence of B. 75 kb of sequence. We found that in a sig- and its infectious cycle present a burgdorferi s odd genome is nificant number of patients, mutant alleles good system in which to study that genetic tools and methods arise by recombination or gene conversion the adaptive responses of a bac- developed for more typical occurring between the glucocerebrosidase terial pathogen to its vector and bacteria do not work in B. gene and its nearby pseudogene. We discov- host environments. All steps of burgdorferi, so we have de- ered that these recombinations can occur at this infectious cycle can be re- veloped basic tools with which a variety of sites throughout the gene and produced in the laboratory, mak- to undertake genetic studies in by different mechanisms of recombination. ing it accessible to scientific in- this bacterium. In addition to recombination events within vestigation. Celia Hooper We have recently succeeded and around the glucocerebrosidase locus, the Maintenance of B. burgdorferi Patricia Rosa in inactivating genes in patho- actions of contiguous genes, environmental in nature requires efficient trans- genic strains of B. burgdorferi. factors, and modifying genes may contrib- mission between the tick vector and the This represents a significant advance because ute to the phenotypes observed. We are ac- mammalian host. Like many bacterial patho- until now, no one had been able to intro- tively exploring these possibilities via tran- gens, B. burgdorferi must cope with a chang- duce mutations into a wild-type background, scriptional studies of the contiguous genes ing array of environmental conditions to per- impeding analysis of the phenotype of mu- in the region, transcriptional arrays and sist, proliferate, and be transmitted between tant spirochetes in the infectious cycle. mouse models. hosts. My lab and others have found good Although the genetic system of B. Our active clinical service investigates the evidence for differential gene expression by burgdorferi is rudimentary and far from el- natural history and spectrum of manifesta- borreliae in these disparate settings. Yet, it egant, it still provides a powerful tool with tions in Gaucher disease. We focus on pa- is unknown how B. burgdorferi senses its which to explore the unique structure of the tients with atypical or extreme phenotypes, environment and orchestrates appropriate borreliae genome and to study the adaptive because they may reflect the involvement adaptive responses. What environmental sig- responses of a bacterial pathogen to its vec- of other genes or modifiers. Two fascinating nals define the tick vs. the mammal and in- tor and host environments. phenotypes I am investigating include duce the appropriate bacterial response? Gaucher patients with parkinsonian symp- How does B burgdorferi sense these sig- Ellen Sidransky received her M.D. from toms and patients with hydrocephalus and nals and transduce them? Which proteins are Tulane University in New Orleans in 1981. cardiovascular involvement. Genotypic made in different places or at different stages She trained in pediatrics at Children ’s Me- analyses reveal that patients in the first group of the infectious cycle, and what are their morial Hospital-Northwestern University in have many different Gaucher mutations, functions? What features of the spirochete Chicago, III., and in clinical genetics at the while the latter appear to share a common or the infection are pertinent to pathogenic- NIH Interinstitute Genetics Training Pro- genotype. In addition, a knockout mouse ity? Our broad objective is to use a molecu- gram. She joined the Clinical Neuroscience model of Gaucher disease generated with a lar genetic approach to answer these ques- Branch at NIMH in 1988 and is now a se- null allele led me to recognize an analogous tions and elucidate the mechanisms of ad- nior investigator leading the Unit on Clini- human phenotype—a neonatal lethal form aptation and variation in B. burgdorferi over cal Genetics. of Gaucher disease. Affected patients die with the course of the infectious cycle. My laboratory integrates basic and clini- hydrops fetalis in utero or shortly after birth. Our current knowledge of B burgdorferi cal research in a “bench-to-bedside” ap- Since our original description of this pheno- at the molecular level represents an inter- proach, focusing on Gaucher disease, the type, dozens of additional cases have been esting paradox; we have the sequence of most common of the sphingolipidoses. I use identified. the entire genome, but we know very little Gaucher disease, which has a broad spec- I also discovered that null allele mice and about the functions of most of the encoded trum of symptoms, as a prototype for other severely affected human patients have proteins. Although we have identified sev- disorders affecting the nervous system. Most skin ultrastructural abnormalities and altered eral B. burgdorferi genes whose expression of these inherited disorders are character- epidermal barrier function secondary to the or putative function suggest that they are ized by a wide range of presentations, yet deficiency of epidermal glucocerebrosidase. important in the infectious cycle, we do not the factors contributing to this heterogene- This skin abnormality may serve as a valu- know the actual biological roles or signifi- ity are often elusive. My clinical, biochemi- able clinical tool, enabling early differentia- cance of their protein products. cal, and molecular studies of humans and tion of different Gaucher phenotypes. Ongoing and future studies are designed animals are designed to understand this het- Another challenge has been to understand to test the roles of these genes and their prod- erogeneity and to improve therapy. the development of neuronopathic Gaucher ucts in the infectious cycle and to identify My principal research aim is to understand disease. Because this and other aspects of additional genes that allow spirochetes to genotype-phenotype relationships in the pathology of Gaucher disease are not adapt, persist, and be transmitted between Gaucher disease and other in- adequately explained by gluco- ticks and mammals. We also want to under- herited disorders affecting the cerebroside accumulation, stand regulation of these genes and their nervous system. Our clinical and we are also exploring the sig- roles in pathogenesis. A major thrust of our molecular studies of more than nificance of an alternate sub- work is to analyze the phenotypes of spe- 200 patients have shown that strate, glucosylsphingosine, that cific gene mutants in the context of the natu- there is significant genotypic het- we found elevated in brains of ral infectious cycle. erogeneity among clinically simi- patients and mice with neuro- B. burgdorferi is structurally and geneti- lar patients. Moreover, patients nopathic Gaucher disease. cally quite dissimilar from other bacteria, with the same genotype can In working to improve treat- having a small linear chromosome and a have different disease manifes- ment for Gaucher disease, I large number of linear and circular plasmids. tations. participate in a collaborative How these DNA molecules replicate, why Our recent work revealed that effort to test chemical modifi- the genome is segmented, and the functional the region surrounding the hu- cations of recombinantly pro- significance of this unique structure are not man glucocerebrosidase gene on chromo- duced glucocerebrosidase. Modifications in- polyethylene well understood and are another focus of some lq21 is particularly gene-rich, with clude using molecules such as 14 — November— December 2000 glycol to prolong circulation of the enzyme. NIH on the role of Gs pathways We now appreciate that the This may permit lower dosage and drug cost, in osteoblast differentiation. We Gsa gene ( GNAS1) has multiple reduce antigenicity, and make it easier and also showed that heterozygous alternative promoters. We have more convenient to administer the enzyme inactivating mutations of the recently identified the fourth to patients. We are also investigating more same gene lead to Albright he- one of these that is imprinted, efficient production of the enzyme from new reditary osteodystrophy (AHO), and we believe this promoter transgenic sources, as well as the use of in- characterized by obesity, skel- region is critical for the tissue- hibitors of glycolipid synthesis. etal defects, and, in some cases, specific imprinting of Gsa. In Many of the approaches used in our stud- mental deficits. Interestingly, ma- patients with renal resistance to ies of Gaucher disease will also be applied ternal transmission of these mu- parathyroid hormone in the to another group of inherited disorders tations also leads to multihor- Fran Pollner absence of AHO (PHPIb), this congenital disorders of glycosylation mone resistance (pseudohypo- Lee Weinstein region has a paternal-specific (CDG)—in collaboration with Donna parathyroidism type la, PHPIa) whereas pa- imprinting pattern in both parental alleles. Krasnewich of NHGR1. These disorders in- ternal transmission does not (pseudopseudo- Therefore, PHPIb is caused by a GNAS1 im- volve defective assembly of NTb-linked oli- hypoparathyroidism, PPHP). printing defect that presumably leads to de- gosaccharides. Patients with CDG show di- Using a Gsa knockout mouse model, we creased Gsa expression in renal proximal verse symptoms; including cerebellar abnor- have shown that Gsa is imprinted in a tis- tubules. Analysis of this region provides a malities, malformations of facial features, gas- sue-specific manner—maternally expressed useful diagnostic tool for the evaluation of trointestinal disease, and profound delays in in some tissues (such as renal proximal tu- patients who present with parathyroid hor- psychomotor development. CDG provides bules, the site of parathyroid hormone ac- mone resistance. an opportunity to investigate the elusive cor- tion) but biallelically expressed in most other In the future, we hope to determine the relation between clinical manifestation and tissues. This provides a likely explanation mechanisms by which Gsa is imprinted in a the molecular mechanism of the metabolic for the variable clinical presentation in AHO tissue-specific manner and by which imprint- defect. patients (PHPIa vs. PPHP). We also showed ing of GNAS1 is established and maintained. The results of our genotype-phenotype that Gsa plays a major role in energy and We also plan to study the physiological roles studies provide evidence that even well-char- glucose metabolism. Specifically, maternal of Gsa in greater detail by examining mice acterized Mendelian disorders are not nec- vs. paternal transmission of a heterozygous with loss of Gsa in specific tissues. We hope essarily “simple.” I believe that investigations knockout leads to opposite effects on en- these studies will provide important insights into the mechanisms contributing to the het- ergy metabolism and fat accumulation. How- into the mechanism of genomic imprinting erogeneity encountered in these disorders ever, all heterozygous mice have increased and the role of Gs signaling in metabolism will ultimately enable us to discover the sensitivity to insulin in vivo. and hormone action. H “magic in the web of it.” Moreover, the strat- egies, experience, and knowledge gained through this work may be helpful in under- Opening Day at the Cybercafe standing and treating other hereditary dis- eases, including more “complex” neurologic and psychiatric illnesses. Lee Weinstein received his M.D. from New York’s Columbia University College ofPhysi- cians and Surgeons in 1983 and did a medi- cine residency at Montefiore Hospital in New York before joining the Metabolic Diseases Branch ofNIDDK in 1986. He is now a se- nior investigator in that branch. I am interested in G protein signaling and hormone action. My research at NIDDK has examined the role of G protein genetic de- photos by Celia Hooper fects in hormonal disorders. Our work has A Good Time Was Had By AIL: (left) Malissa . . . (left) Charles Sanders, president focused on the heterotrimeric G protein (Gs) Murray, technical IRTA in the NIDDK lab of of the board of the Foundation for that couples receptors to the enzyme Derek Le Roith, shares a Cybercafe table and the NIH, unveiled a plaque honory adenylyl cyclase, which catalyzes the gen- a laugh with Joan Schwartz, NINDS section ing Harold Varmus (right), eration of intracellular cyclic adenosine chief and OIR assistant director . . . and Cybercafe enthusiast. monophosphate (cAMP). The Gs a-subunit (Gsa) is ubiquitously expressed and is re- ormer NIH director Harold Varmus, whose advocacy laid the groundwork quired for the intracellular cAMP response F for the cultivation of graduate programs at NIH, returned in a blaze of good to hormones and other extracellular signal- cheer September 18 to participate in the opening ceremony of the Graduate ing molecules. Lounge. Located a few steps below the Building 10 lobby coffee bar, the In my early work at NIH, my colleagues Cybercafe offers comfortable seating around small tables, corner spots for and I showed that mutations that produce a constitutively active Gsa protein are present more private conversations, and, soon, free web access. The furnishings were in a mosaic distribution in patients with the the gift of Fisher Scientific International, Inc., and its CEO, Paul Montrone, McCune-Albright syndrome, which is char- who serves as treasurer of the Foundation for the NIH. acterized by hyperpigmented skin lesions, Envisioned as a place for NIH’s graduate students and other trainees to focal skeletal lesions (fibrous dysplasia), and mingle, the lounge is open to all; graduate students, however, have priority on endocrine hyperfunction. This observation reserving space for special events. provided the impetus for ongoing studies at 15 The NIH Catalyst Call for Catalytic Reactions n this issue, we are I asking for your reactions 1) What do you think the Intramural Research Program should be doing to stay one step in four areas: keeping ahead of new developments in biomedical research? ahead of research ad- vances, tapping into the human genome, tech transfer, and ways to improve the Catalyst. 2) Give us your rants and raves regarding your experience tapping the working draft of the Send your responses on human genome. What has worked well? What new tools would make it easier for scientists these topics or com- to use the data? ments on other intramu- ral research concerns to us via e-mail: In Future Issues... Health Disparities 4) The Catalyst staff and editorial advisory board meet in early December. Do you have any suggestions for us for improving the Catalyst—more coverage in certain areas, less in others, Angiogenesis a new type of feature? _ Research Fest Tidbits The NIH Catalyst is pub- PuBUSHER Scientific Editor Editorial Advisory Board lished bi-monthly for and by Michael Gottesman Celia Hooper Jorge Carrasquillo, CC the intramural scientists at Deputy Director David Davies, NIDDK NIH. Address correspon- for Intramural Research, OD Managing Editor Dale Graham, CIT dence to Building 2, Room Fran Pollner Hynda Kleinman, NIDCR 2W23, NIH, Bethesda, MD Editors Elise Kohn, NCI 20892. Ph: (301) 402-1449; John I. Gallin Copy Editor Susan Leitman, CC fax: (301) 402-4303; Director, Warren Grant Magnuson Shauna Roberts Bernard Moss, NIAID e-mail: U.S. Department of Health and Human Services Public Health Service National Institutes of Health Building 2, Room 2W23 Bethesda, Maryland 20892 ® Printed on 50% recycled content paper and can be recycled as office white paper.