November 27, l990 Vol. XLII No. 24 "The Second U.S. Deparrmenr of Health Best Thing and Human Services About Payday"

National lnsriru1es of Health e Recor, NIDDK Celebrates 40th Year With Focus on Future Discovery of CF Gene Spurs Windfall of Research

By Jane OcMouy

" SOLD OUT" read the banner pasced over the poster in a Crystal City horel lobby. Upstairs, the crowd had alread)1 filled a ball­ room. New arrivals spilled into adjacent rooms, where they crowded around TV monicors. The headliners for these sranding-room-ooly crowds were nor Madonna or Paul McCartney, buc che cystic fibrosis gene, ics mutation, Delta F508, and the cystic fibrosis trans­ membrane regulator (CFTR). Backing them up was the Molecule of 1989, the DNA poly­ merase, which helped make the lase cwo possible. The occasion was the 1990 North American and lnternaciona.1 Cystic Fibrosis Conference and the speakers, Dr . .Francis Col­ lins of the University of Michigan (Ann Arbor) and Drs. Lap-Chee Tsui and Jack Riordan of the Hospital for Sick Children in Toconco, were the three NIDDK grantees who only a year ago discovered the mutation that Dr. Griffin Rodgers, a mearcher in NlDDK's Laboratory of Chemical Biology, seanhe1 for u;ays to mat causes cystic fibrosis (CF) co occur in 70 per- sickle cell di;ease. See pages 8-13 for more 40th amiivusary feature stories and photographs. (See CF GENE, Page 6J NIDDK Clinical Research The Well-Beaten Path Between Bedside and Bench NIH To Observe World

By Ka1hy Kranzfelder AIDS Day, Nov. 30

I n her postcard co che National Institute of of studying an extreme form of a disorder is T he National Insticutes of Health will Diabetes and D igestive and Kidney Diseases, that a pattern of symptoms specific co the dis­ commemorate World AIDS Day on Friday, the woman wrote, "Please send me informa­ order tends to emerge. If invescigators looked Nov. 30. Officially, Dec. l (Saturday) has tion on your d iseases. I've been diagnosed only at milder forms of the disorder, such a been declared by the World Health Organiza­ wich all of chem." pattern might cake many more years and tion (WHO) Global Programme on AlDS as a Surely she was mistaken. Maybe she has resources co identify. day co focus on che concerns and problems of diabetes, perhaps with kidney complications, Taylor's group has been investigating severe women, co support programs chat specifically but could she also have a thyroid condition? insulin resistance type A, a syndrome chat promote the health of women and children, sickle cell disease? hepatitis? ulcers;, kidney often leads co non-insulin-dependent diabetes and co assist women in their crucial role in scones, gallstones, cystic fibrosis, and a long and is marked by dark, velvet-like rashes in AIDS prevention and care. The first World list of metabolic disorders? the folds of skin, called acanchosis nigricaos, AIDS Da)1 , held in December 1988, was pro­ Like che postcard's author, most people and, in young women, high androgen (cestos­ posed by che World St1mmic of Ministers of have no idea of the breadth of disorders being cerone) levels, leading to facial hair and Health on AIDS Prevention in recognition of studied by NIDDK scientists. NIDDK clini­ menstrual disorders. People with severe insulin the need for wide dissemination and exchange cal invescigacions involve hematologists, resistance have plenty of insulin circulating in of information and edt1cacional messages on endocrinologists, hepatologiscs, gascroencerolo­ their blood, bur defective insulin receptors AIDS prevention. giscs, pathologists, even neurologists. Varied prevent cells from responding efficiently co che The NIH World AIDS Day program, as these studies are, however, they have one hormone, which leads co impaired glucose "Women and AIDS," will be held at noon in thing in common: the constant traffic they metabolism. Investigators believe that high Lipsett Amphitheater, Bldg. JO. The pro­ create between bedside and bench. levels of insulin have adverse effects on some gram, cosponsored by the Office of AIDS organs, including the skin and ovaries, thus Research and the Fogarty International Genter, Severe Forms of Disorders Smdied causing chc acanchosis nigricans and will feature addresses by Dr. William F. hyperandrogenism. Raub, acting NIH director; Dr. Anthony S. NIDDK clinical studies, particularly into The dark rash can cause patients consider­ Fauci, NIH associate director for AlDS rare, severe forms of disease, have often given able distress and is often their main reason for research and director, NIAID; S. Denise insight into basic biological mechanisms. For seeking medical attention, said Taylor. A top­ Rouse, a commander in the PHS Commis­ example, studies of a severe form of insulin ical cream used co treat acne is frequencly sioned Corps; and LaShaun Evans, a woman resistance have led to an understanding of how effective in relieving acaothosis nigricans. living with HIV disease. healthy insulin receptors function. The changes caused by hyperandrogenism, Rouse has held various positions in the According co Dr. Simeon Taylor, chief of the NIDDK Diabetes Branch, the advancage

AIDS DAY 'Names' Quilt To Be Displayed During World AIDS Day at NIH (Continued from Page 1 ) Bureau of Health Care Delivery and Assistance The Names Project Foundation is respon­ than rwo football fields, included 1,920 at the Health Resources and Services Admin­ sible for the Names Project Quilt, a quiJc panels, and was seen by an estimated half mil­ istration. She was the recipient of a PHS made of thousands of 3 · x 6' panels, each one lion people. award in 1989, and an outstanding unit cita­ commemorating the life of someone who has The entire AIDS quilt returned to the tion for planning the National Conference on died from complications associated with rhe Washington area in Oetober 1988, having HJV Infection and AIDS among Racial and human immunodeficiency virus (HIV) char grown to 8,288 memorial panels when it was Ethnic Populations. In 1987 she was the causes AIDS. The idea of a quilt as an AIDS displayed on the Ellipse behind rhe White recipient of the Southern Christian Leadership memorial originated with Cleve Jones in House. le grew co more rhan 10,900 panels Coalition's Black Achievers of Alabama November 198'>. A year and a half larer, in when it was displayed for rhe last time, again Award. She holds a master's degree in public June 1987, he reamed up with several others on the Ellipse, rhe weekend of Oct. 6-8, health, in addition co her undergraduate to organize rhe Names Project Foundation. l 989. It has grown roo large to ever be dis­ degree in biology. She is presently on a special Jones, who served as executive director of the played in its entirety again. assignment co Community Health Care, Inc., Names project until lase spring, spoke at the The Names project estimates that more a federally funded health center in the District 1989 NIH commemoration of World AIDS than 2 million people have visited the quilt. of Columbia. Day. le presently weighs more than 14 tons, con­ Additionally, Rouse serves as the volunteer Two important goals of the Names project sists of more than 227,000 square feet, director of the D.C. Women's Council on relate well to the commemoration activities contains more than 4 miles of walkway fabric AIDS. The council, founded in 1987, is a pri­ planned at NIH-to confront individuals and and more than 78 miles of total seams. Paneh vate nonprofit organization dedicated to the governments with the urgency and enormity have been contributed from individuals in all prevention of HIV infection in women, as well of the AIDS pandemic and the need for a SO stares, Puerto Rico, rhe D istrict of Colum­ as providing compassionate support co women compassionate response, and, by revealing the bia, as weU as 23 countries, including names and the lives behind the global st,atis­ Australia, Belgium, 1srael, Italy, Uganda and tics, to build a powerful, positive, creative New Zea.land. symbol of remembrance worldwide. Materials in the quilt include afghans, cre­ The sections of the quilt displayed ac NIH mation ashes, dresses, flags, jeans, merit are part of more than 13,300 panels that com­ badges, scuffed animals and wedding rings­ prise it. The quilt, in its entirety, was first all representative of the diverse lives com­ displayed on Oct. 11, 1987, on rhe Capitol memorated by the quilt. Mall. At chat time, it covered a space larger

the Washingt0n Free Clinic, when she is nor spending "quality time" with her 9-year-old daughter or serving on the advisory committee of Po1itive Woman, a newsletter for HIV posi­ The NIH Record tive women. Evans, in a recent telephone Published biweekly at Bechesda, Md. , by che Edicorial S. Denise Rome interview, said, "Don't call me a victim, and Operations Branch, Division o( Public lnformacion, for rhe don't give me your sympathy-I feel good information of employees of the Narional Institutes of infected by HIV. "The council exists because abour myself, about my life, and about how I Health, Deparcmem o( J--le-,llth and Human Services, and AIDS is now one of the cop 10 causes of dearh am living with HIV disease." circulated to noncmployces by subscription only through for women in their childbearing years. The A Visible Symbol, a videotape produced by the Government Printing Office. The comem is reprimable without pennisslon. Pictures may be a,•ailable on request. proportion of female cases of AIDS in two the Names Project Foundation ro explain the Use of funds for printing rhis periodical has been approved D.C. wards significantly exceeds the national educational and memorial nature of the AJDS average," stated Rouse, who also serves as a by the director o( rhe Office of Management and Budget memorial quilt, will be shown during rhe through September 30, 199 l. "buddy" co several Black women, offering presentation. This film, shown during last them her friendship and support. year's World AIDS Day program, moved NIH Record Office Staff Correspondents: CC, Karen Riedel Rouse will talk about one of the council's many in the audience to tears. In addition, Dldg. 3 1. Room 20-03 several programs, rhe Sister Care Supporc Phone 496-2125 DCRT, Anita S. Ferguson sections of the A[DS quilt (see related story) FAX 402-1485 DRG, Sue Meadows Network. Sister Care, as its all-volunteer will be shown. The entire quilt contains more FIC, Louise Williams membership calls it, holds weekly support than l3,300 panels.-Marc Horowitz 0 Editor NCI, Pacricia A. Newman group meetings chat provide peer support, Richard McManus NCNR, Gerry Pollen companionship and information on how ro live NCRR, Poll>• Onderak with HIV for infected women. Segments of a Assistant Editor NE!, Linda Huss Anne Barber N H LBI, June Wyman soon-ro-be released film of a support group Subjects Needed for Herpes Study NIA, Carolyn Shanoff meeting will be shown. In the film, Rouse Staff Writer NIAIU, Ann C. London serves as facilitator for three HIV-infected \..aria Garnett NJAMS, Barbara W eldon women. NIAID is seeking healthy men and women, NICHO, Carol Florance ages 18 ro 45, with confirmed gcniral herpes Editorial Assisiant NIDCD, Gail Blau The film, renrarively named Women and Marilyn Berman NIDDK, Eileen Corrigan AIDS, is "real and strong," said Rouse, and for a placebo-concrolled study. You must have had genital herpes for more than 1 year to Th, NIH R«o,J reserves the right NIDR, Mary Daum "tells it like ir is. " One of the support group ro make c-orrcccions. change~. or NJEHS, Hugh J· Lee participants, Evans, will also speak at rhe qualify for this study. For more information, deletions in submitred copy in NIGMS, Wanda W arddell NIH commemoration. Evans, a 35-year-old · call 496-1836. 0 conformity with the policie-s of chc- NlNDS, Carol Rowan pope, and HHS. NLM, Roger L. Gilkeson single mother, is rhe HIV program director at page 3 The Record November 27, 1990

NIAID To Test New AIDS Vaccine in Humans

The NIAID has received FDA approval co proteins. NIAID, IMMUNO-Ag, and NCl begin human clinical trials of a new candidate scientists initiated a project co make a vaccine AIDS vaccine. The trials will cake place in with a recombinant gp 160 made by chis N IAID's AIDS Vaccine Evaluation Units process. located at several major medical centers around A monkey cell line was coinfected with two che country. This is the sixth AIDS vaccine recombinant vaccinia viruses, each acting sanctioned by the Food and Drug Adminisua­ solely as a carrier. One vaccinia carried the cion for human testing. gene for an enzyme from a bacterial virus. The vaccine (IMMUNO-Ag) consists of This enzyme, RNA polymerase, helps copy gpl60, the surface protein of che AIDS virus, DNA into RNA, which is then translated into made by recombinant DNA technology. This proteins. T he ocher vaccinia carried a "switch" particular recombinant gp 160 is novel because attached to the gene for gp 160. As RNA its chfee-dimensional shape marches that of polymerase was produced, it bound to the che gp 160 protein made by native HIV. Expe­ switch, initiating the production of gp 160 rience with ocher virus vaccines indicates that protein. Because this process all took place in this match may be important. a mammalian cell line, the recombinant "In many cases, retaining the native shape gp 160 protein was properly glycosylarcd: that of the viral molecule is crucial co a vaccine's is, sugar molecules were attached to its surface NIAID di,·ector Dr. Amhony S. Fa11ci recently ability co stimulate a strong immune in the same way as found on native HIV. received the First Inter11ational Chiron Prize Jo,· response," said NIAID director Dr. Anthony Thus vaccinia, a virus familiar co medical Biomedical Reiearch d11ri11g a ceremony in Rome, S. Fauci. "We don't know if this is true for science, was adapted to induce rhe production Italy. The honor was bestowed upon Fauci by the HIV molecules used in vaccines, but these of noninfectious HIV envelope proteins chat Smola Supwiore di Oncologia e Scienze Biomediche, clinical trials will help answer chis very impor­ could be purified and formulated into a vac­ in Genoa, Italy, and the Saro/a In1ernatio11ale di tant question cine.- Laurie K. Doepel 0 Onco/ogia e Medicine Sperimelllale. in Rome. The Scientists from NIA!D, the National Cancer irntitmiom honored Fauci for his scientifi, accom­ Institute, and IMMUNO-Ag of Vienna, Aus­ plishments in the field of basic and clinical tria, collaborated on preclinical development im1111mology . Fauci also received the degree of doctor of the vaccine. Seminar Series on Women's Health of medicine and su,-get)', hono,-is car/Sa, from the The phase l clinical scudy wi11 evaluate che Continues With Dec. 12 Session Universita di Roma , ·La Sapienza.•· in Rome. safety and immunogenicity of the vaccine and will be performed in two phases. In the first The second session in the seminar series phase, a low dose of vaccine (12.5 micro­ entitled "Women's Childbearing Years and grams) wi ll be evaluated: by random Beyond ," begins at 3:30 p.m. in Lipsett assignment, 20 volunteers will receive the real Amphitheater, Bldg. 10, on Dec. 12. vaccine and 10 will receive a dummy vaccine, The program for seminar JI is a multi­ or placebo. Neither the volunteers nor the disciplinary examination of the health and study physicians will know who is receiving behavior issues across the lifespan of women. which vaccine. Following an introduction by Dr. Vivian In the second phase, a high-dose (50-micro­ Pinn-Wiggins of Howard University, Dr. gram) vaccine preparation and placebo will be Nancy Adler of the U niversity of California at compared in a similar manner, with 20 volun­ San Francisco will present research findings teers receiving che real vaccine and 10 most relevant co women in their teenage years. receiving placebo. The high-dose study will Dr. Jennifer Niebyl of the University of Iowa begin l month after the low-dose phase, and Hospitals and Clinics will address health issues only if no serious toxicities are noted in the related to pregnancy and childbirth and Dr. earlier study. Each of the 60 volunteers will Sonja McKinlay will talk about menopause. be given a primary immunization and boosters Ors. Jane Norbeck of the University of Cal­ at 30 and 180 days and will be followed for a ifornia at San Francisco and Ruth Faden of total of approximately 30 months. Johns Hopkins University will lead the discus­ Volunteers muse be HIV-negative healthy sion that follows. rnen and women ages 18 co 60. A comprehen­ All those interested are urged co attend. Dr. \f/il!iam E. Paul, chief of the Laboratory of sive questionnaire and interview will be Until further notice, no rickets are required. Immunology, N IAID, was one of 24 interna- administered before admission to the study to Seating will be on a first-come, first-served l ionally renl)trned biomedical scientists who spoke determine chat neither the potential volunteer basis and this session will not be broadcast via recently at the frvington Institute for Medical nor his or her sex partners have identifiable closed-circuit television. Re.search 75th anniversary symposilfm "Irttmrmology high-risk behavior for H IV infection. Please check The NIH Record for future in the 2 1st Century·· in New York City. His Work on the IMMUNO-Ag vaccine began announcements about the remaining sessions theme was "Lymphokine.r: Molernlar Mediators of several years ago in the laboratory of Dr. (Feb. 6 and Apr. 3) of the 1990- 199 l the lm111une Response." The symposium focused 011 Bernard Moss, chief of NIAlD's Laboracory of women's health seminar series. 0 neil' studies that have led to an improved under­ Viral Diseases. He and his colleagues had standing of the basic funct iollS of the immrme syJtem and thefr implicatiom for the practice of medicine devised a new way co turn mammalian cells today and in the fNt1tre. into mini-factories for producing recombinant page 4 TheReaml November 27, 1990

CLINIC generation of cyclic AMP, which finally leads co a physiologic effect, for example, rhe excre­ (Continued from Page 1.J tion of phosphate ions in urine as occurs in however, are more difficult co reverse. "'Ic's kidney cells. like when you're in a boat that's fuU of water: This recepcor-G procein-effeccor system is it's easier co bail out the wacer after you've very specialized in che first phase, when hor­ plugged the hole," said Taylor. Thus, the first mones are bound by their uniquely specific seep is co reduce the patient's androgen level, receptors, and in che end, when che specific usually with estrogen and progescin. These physiologic effects are triggered. The middle hormones suppress the pituitary hormones chat steps involving G protein and effector action signal the ovarie~ to release androgen. Once are generic. The G protein chat binds co an the source of androgen is blocked, patients can activated parathyroid hormone receptor in the cry electrolysis co remove unwanted facial hair. kidney is indistinguishable from che G protein Losing weight also helps co reduce che mas­ chat binds ocher hormone receptors linked co culinizing effects of excess androgen. cyclic AMP production in liver cells, thyroid The cosmetic prnblems of severe insulin cells and myriad ocher cells. resistance can be profoundly dismrbing ro "If you were crying co discover the cause of patients, and Diabetes Branch scientists arc a disease of PTH resistance, you would not trying co understand the physiologic mecha­ likely be chinking che defect would occur in G nisms chat trigger these changes. The work of proteins, because if the resistance is unique co Taylor's group actually began with the discov­ PTH, }'Ou would look co che specific pares of ery of type A insulin resistance by NIDDK che pathway-in che beginning ac the PTH invescigacors Drs. Ron Kahn, Jesse Roch, and receptor, or possibly in the end where che Phillip Gorden in 1976. A steady flow of physiologic effect occurs," explained Spiegel. basic science insights has emerged from this Dr. Simeon Tay/{)r However, several common features in line of clinical research ever since. pseudohypopa[athyroidism---obesicy, short "In the past decade, we've made great his collaborators were che first co show chat stature and mental deficiency---cannoc be advances in learning how receptors work and chis syndrome, and possibly ocher thyroid hor­ explained by resistance to parathyroid hormone in identifying the genes chat encode for mone abnormalities, could be caused by alone; and ocher hormonal disorders in these insulin receptors," said Taylor. NIDDK scien­ receptor defects. individuals have come co light such as abnor­ tists have identified about 15 mutations "There is an increasing recognition chat mal thyroid and gonadal function. These associated with insulin resistance. As obstacles many endocrine problems studied ac NIDDK findings led Spiegel, who was working with co gene therapy are gradually overcome, these are caused by problems in receptors," said Dr. Gerald Aurbach in the 1970's, co look for findings may lead the way to curing insulin Weintraub. Since this early speculation, l l a point of convergence chat would cie these resistance and possibly preventing some forms separate molecular defects in che thyroid hor­ characteristics together. of diabetes. mone binding domain have been discovered, Aucbach, chief of NIDDK's Metabolic Dis­ Thyroid Hormone's Role Elucidated and at least four different thyroid hormone eases Branch, had already determined chat the receptors have been identified. "We have Dr. Bruce Weintraub, chief of NIDDK's defect had co occur ac or before the poi nc of learned chat the various forms of thyroid hor­ Molecular, Cellular, and Nutritional Endo­ cyclic AMP production in the cellular path­ mone receptors play an imporcanc role in crinology Branch, is studying hormones chat way, which ruled out the end of the pathway. regulate the thyroid gland. like che Diabetes growth, development, behavior and metabo­ Spiegel trained his attention on che G protein, lism," said Weintraub. Branch researchers, Weincraub's group has which had recently been discovered by found receptor defects chat interfere wich the NJDDK sciencisc Dr. Marcy Rodbell. "A Defective Cell Intermediaries Targeted body's ability to use vital hormones efficiently. defect in che PTH receptor would give a pic­ ture of unique PTH resistance," sai.d Spiegel, Weintraub has also focused on syndromes of Studies of hormone resistance by Dr. Allen severe hormone resistance before searcrung for Spiegel, chief of che Molecular Pachophysiol­ "but a defect in a common clement can give less severe, possibly more common hormonal ogy Branch, are also enhancing our abnormalities. understanding of the basic workings of the Generalized thyroid hormone resistance cell. Spiegel's investigations of pseudohypo­ (GTHR) is one such syndrome, in which thy­ parachyroidism helped establish chat inherited roid hormone fails co bind properly co ics diseases can be caused by defects in G pro­ intracellular receptor, leading co mencal retar­ teins, which serve as intermediaries between dation, accencion deficit, and impaired hormone receptors and effectors. Individuals growth. Earlier NJDDK research indicated with pseudohypoparachyroidism have short that chis hormone resistance is an inherited stature, bone abnormalities in hands, feet and syndrome caused by a generic mutation and face , obesity and mental retardation. has provided the first clearly genetic model for The cellular sequence of events involving G chc study of accencion deficit disorder, or proteins begins when a so-called first mes­ hyperactivity, in children. senger such as a hormone binds with a GTHR, like ocher hormone resistance syn­ receptor which then accaches co a G protein. dromes, has long balled physicians because The G protein carries a signal co an effector, che symptoms led doctors co believe patients often an enzyme, before shutting itself off. lacked thyroid hormone, yet blood cescs indi­ The effector sends ouc a second messenger co cated excess thyroid hormone. Weintraub and signal another sequence of events, often the Dr. Br11re Weintraub page 5 ~Record November 27, l990

you lots of ocher things going wrong." Schechter, Rodgers and collaboracors found petes with opiates for che same receptors, Spiegel's hypothesis was easy co test because chat hydroxyurea raised fecal hemoglobin levels caused only minor side effects in the study's che G protein is in all kinds of cells. He could cwo- co ten-fold in more than half the patients healthy control group. These observations sug­ measure amounts of G protein in easily acces­ they treated. This increase curbed by 25 per­ gest that patients with cirrhosis have increased sible red blood cells and skin tissue. "We cent the tendency of hemoglobin molecules ro levels of internally produced opiate-like found about a 50 percent deficiency in the polymerize, or link up in long chains, which substances. amount of G protein in pseudohypopara­ leads co the red cells' distortion, the hallmark Bergasa and her colleagues conducted a thyroid individuals as compared co controls of the hereditary blood disease. This "sick­ pilot study co see if another opiate-receptor and people with plain old hypoparachyroid­ ling" of red cells can lead to clogged blood antagonist, naloxone, would alleviate itching ism," said Spiegel. T hese initial results have vessels, causing excruciating pain, and, in caused by primary biliary cirrhosis. Naloxone now been extended co identification of specific severe cases, strokes and sudden death. is often used in hospital emergency wards co mutations in the gene for the G protein in Rodgers and Schechter believe that the awaken unconscious heroin abusers. individuals with pseudohypoparachyroidism. more they can reduce the polymerization tend­ Eight patients received either naloxone or Malfunctioning G proteins have since been ency, the fewer complications their patients saline infusions without being told which they suggested as suspects in causing some psychi­ will suffer. They are currently studying the were receiving. Scratching was chen measured atric illnesses, acromegaly and ocher endocrine potential of creating patients with hydroxyurea with a "scratch transducer," developed by rnmors, and the aging process. Given the in combination with erythropoiecin, an anti­ NJH's National Center for Research Resources' ubiquity of G proteins, scientists are very anemia drug. Anemia is another common Biomedical Engineering and Instrumentation interested in knowing all the functions and complication of sickle cell disease because sick­ Program, which recorded the vibrations of a influences· of these intracellular coupling pro- led red blood cells cend co "wear out" faster fingernail as it crossed skin. Naloxone reduced than normal red blood cells. scratching by 50 percent overall, according to Bergasa. She is now seeking additional Opiate Blockers May Relieve Itching patients with itching caused by liver disease co Another example of applying basic concepts further test the benefits of naloxone and to a clinical problem comes from the liver dis­ nalmefene. Bergasa has also gone back co rhe eases section of NIDDK's Digestive Diseases lab where she is studying how opiate systems Branch. Investigators here are exploring the behave in animal models of cholescatic liver problem of severe pruricus, or itching, associ­ disease. ated with obstructive liver disease (cholascasis) such as primary biliary cirrhosis in which bile Back to Basics secretion is impaired. The itching was originally thought to be Many other clinical investigations are under caused by the accumulation of bile acids way in NIDDK, yet they represent only part because skin biopsies from patients with cho­ of what goes on in the Division of Intramural lescasis showed high levels of bile sales. The Research. NlDDK has one of the largest, conventional therapy was co administer oral most varied basic science programs on campus. resins chat bound bile acids in the intestine While N IDDK clinical investigators often and increased their fecal excretion. "Anti­ hear words of gratitude from their patients, histamines have been prescribed, though they the basic scientists toil in relative obscurity to generally didn't work. Ultraviolet light has Dr. Allen Spiegel the general public. Most people are unaware of also been cried. In face, many treatments have the seemingly unimportant basic findings that been given in an attempt to relieve this dis­ underlie so many widely known clinical reins. About 16 different G proteins have been tressing symptom without any strong scientific therapies and discoveries. discovered ro date. rarionale," said Dr. Nora Bergasa of the liver To the world scientific community, diseases section. When all else fails and the however, NIDD K has a well established repu­ Basic Findings Lead to Sickle Cell Drug itching becomes incraccable, a liver transplan­ tation as an excremely productive and About as often as clinical findings demystify tation is the final option. influential basic research institution. Half a fundamental mechanisms, bench findings can Bergasa was working with section chief Dr. dozen Nobel laureares in chemistry and phys­ spur new treatment approaches. Such was che E. Anthony Jones on other research when they iolog}' or medicine since 1956 can trace roots case when NIDDK Laboratory of Chemical hypothesized chat chis form of pruritus might co the NIDDK Division of Intramural Biology researchers Drs. Griffin Rodgers and be mediated by opiate substances that are Research. 0 Alan Schechter and ochers decided co cry somehow present in increased amouncs or hydroxyurea, a widely used leukemia drug, co made more available co the brain in cholestatic treat sickle cell disease. liver disease. SIDS Seminar Set for Dec. 6 'The observation chat individuals with high "Opiate-like substances have been reported levels of fetal hemoglobin have mild sickle cell co accumulate in patients with chronic liver T he NIH Disease Prevention Seminar Series disease, combined with what molecular biolo­ disease, and pruritus is a recognized side effect will present, "SIDS: Working Toward Preven­ gists had learned about turning on fecal genes, of opiates such as morphine," Bergasa tive Strategies," on Thursday, Dec. 6, in led co the idea of increasing the levels of fecal explained. These findings, along with results Wilson Hall, Bldg. 1, at 11:30 a.m. Dr. hemoglobin in sickle cell patients co cry co of a study published in England, provide sup­ Marion Willinger, Center for Research for improve their clinical condition," said port for Bergasa's postulate. In the British Mothers and Children, NICHD, will make Rodgers. Hydroxyurea promised co "turn on" study, patients with cirrhosis had a reaction the presentation. All NlH employees are the fecal hemoglobin genes as desired, though similar to narcotic drug withdrawa.1 when they invited to attend. No preregistration is neces­ scientists do not fully understand how this were given nalmefrne, a powerful opiate­ sary. For more information, contact Janet happens. receptor antagonist. Nalmefene, which com- Wetmore, 496-1105. 0 page 6 The Record November 27, 1990

CF GENE (Continued from Page 1) cent of the 30,000 Americans who have the disease. Recently, the three researchers and their colleagues succeeded in correcting the CF defect i11 vitro by replacing it with a normal gene. Their work has energized conference attendees, who attentively examine slide after slide of DNA and Souchern blots, hoping co decipher whether rhe CFTR protein plays a role in the faulty ion transport char can cause the lungs of CF patients to clog with mucus, and whether drugs such as DNase, which breaks down the mucus in test cubes, will provide safe and effective treatment. CF research wasn't always like this. NIDDK scientist emeritus Dr. Paul Di Sant'Agnese discovered an abnormality in the swear of CF patients, leading tO the first diag­ nosric test for CF in 1953. In the next decade, NlDDK-traincd scientists made Nobel Prize­ winning discoveries that would make the eventual identification of the gene possible: Dr. Arthur Kornberg discovered the enzyme that could copy DNA; Dr. Christian Anfinsen A young patient t·eceives sweat test to detennine whether he has cystic fibrosis. identified che mechanisms of protein folding;· and Dr. Marshall Nirenberg helped unravel the code chat DNA uses to translate itself into 150,000,000 base pairs. But by 1988, unidentified; what is that something?" Collins the protein building blocks of the body. researchers knew chat the CF gene lay some­ queries. "The chloride channel doesn't seem co Then for some years, CF seemed stalled in a where between cwo markers, MET and J3. 11. be the issue, but maybe regulation of it is." sleepy backwater of research. Luckily, and Thar narrowed the terri cory co 2,000,000 base Researchers currently assume that several largely through NJH support, scientific cools pairs, making a systematic search possible. domains regulate the movement of sodium and were being developed that would change that: Using DNA probes from a library of CF swear chloride across the epithelial membrane. NlDDK-supporced researcher Dr. Paul Quin­ glands developed by Riordan, Tsui began to ton used greatly refined techniques for "walk" that segment of the chromosome with Search for Diabetes Genes Sparked by CF Success culturing and studying cells and their func­ overlapping segments of DNA in search of the tions co report chat the sweat gland duccs of CF trait, covering lengths of 20,000 bases at a The success of CF research has generated its CF patients did not allow normal chloride time. Meanwhile, Collins and the University own clones. Ocher scientists were encouraged transport. Simultaneously, geneticists were of Michigan team used an analogous tech­ co begin cracking the genes responsible for developing new methods co srudy genes, the nique, gene "jumping," which covered both insulin-dependent and non-insulin­ blueprints of proteins. Now cystic fibrosis 100,000 base pairs at a rime. Jn effect, Col­ dependent diabetes (NIDDM). NIDDM, research is advancing by coupling basic lins' team could scout the territory rapidly, believed co begin from the interaction of mul­ research in cell biology with recombinant looking for broad signs, knowing that Tsui's tiple genes and environmental triggers, DNA technology. Methods such as restriction team was following up, scrutinizing all che presents a particularly complex genetic puzzle. fragment length polymorphism (RFLP) anal­ nooks and crannies. Jc is that very complexity chat has intrigued ysis and gene walking and jumping, As they narrowed the field, the Collins molecular biologists such as NIDDK's Dr. techniques chat once might have seemed sci­ team mapped a promising region, using Simeon Taylor and Dr. Graeme Bell, a Uni­ ence fiction fantasies, are yielding answers. probes and pulsed field gel electrophoresis, versity of Chicago researcher and a member of Using RfLP analysis, for example, scientists while the Tsui ream screened thousands of the NlDDK-supporced team at the University are able co cut sequences of chemical bases in probes from a chromosome 7 library co label of California ac San Francisco (UCSF) chat DNA structure with restriction enzymes co the section of the chromosome near the CF cloned the insulin gene in 1979. A physician create a gene library. With chis technique, gene. With chis combined persistence and friend at UCSF began co educate him about NJDDK-supporced researcher Tsui and col­ inventiveness, they brought home the prize. diabetes while he shared his knowledge of bio­ leagues began co identify markers linked co "Finding the gene opened a botdeneck," chemistry and molecular biology in a mutual the disease, narrowing its location co the long Collins cold the crowd at the CF conference. effort to "see what we could do with this arm of chromosome 7. By mid-1987, several Since then, scientists in several labs have coop­ information." research teams had submitted proposals for erated co identify other mutations of CFIR, What Bell, now working with his own NIDDK support to find the gene, and totaling 50 to date. Collins and Tsui have ream, has done with the information has NlDDK staff facilitated a collaboration already succeeded in replacing a defective gene revitalized research in glucose metabolism. between Tsui in Canada and Collins in Michi­ with a normal one in a cell culture system. Research has shown chat glucose transporters gan chat resulted in their cooperative hunt. They are also trying co understand how che are likely co be involved in rhe pathology of Even for seasoned researchers, the task was gene and its protein function. diabetes, and by cloning and sequencing the daunting: chromosome 7 contained "The protein is there co pump something DNA encoding the proteins in a family of page 7 'Ire Record November 27, 1990

"' ·. y ·ir ·-·· l ~"- , glucose transporters, Bell's team has put I . . ' Ii I l .:· • • , • •••• I l c:-i;.., "faces" on chem, helping to illuminate their ...... •·· . - ~. 1-• . ., specific roles in glucose metabolism. "There ...; ~- ,,,,. are five proteins chat are able to cransporc --- glucose across the plasma membrane," Bell explains. "We now know the sequences of all of chem, so it's like having a signature." Ocher benefits accrue when molecular tech­ niques are applied co che physiological problems of a specific disease. Knowing the identity of each protein allows scientists co develop specific antibodies for each and co study each in isolation. A protein's precise molecular identity provides a base for more sophisticated assays co measure it, and researchers are then able co work with small amouncs of tissue from human subjects under various metabolic conditions. "You can use an RNA sample, and do a needle biopsy for fat On Oct. 22, the NIDDK EEO advisory commiltee presented a $375 check to Andrew Tart/er, executive and for muscle," Bell says, in some instances director of the Children's lnn, marking the l,w evellt celebrating the imtitute's 40th a11niversa,y. Seated are bypassing animal studies and providing infor­ (front row, from I) Karen Howard, Tart/er and Mmy Ja11e Zanz1JWJki. Seated i11 back row are (from I) mation chat applies directly co people. Dorothy Banks, Lois Lipsett (cochair), Ludlow McKay, James Scherbemke, Nancy Cumm111gJ (cocharr), "Molecular approaches allow a greater range of Rao Thotakura and Sharon Frazier. experiments," with more applications for clini­ cians, he says. Currently, Bell's lab is using cwo Research Subjects Needed NIMH Needs Volunteers approaches to identify genes that contribute to diabetes susceptibility. In one direction, they Earn up to $378 for participating in a psy­ The Laboratory of Psychology and Psycho­ continue to clone candidate genes expressed in chopharmacology experiment relating co the pathology, N IMH, is seeking healthy women beta cells and in insulin target tissues such as effects of commonly prescribed drugs. Mini­ and men between the ages of 20 and 45 co muscle, adipose tissue, and the liver. A second mum time required over a 7-week period. participate as control subjects in studies of approach chat appears to be paying off is to Must be between ages 21 and 50, in good cognitive processes in different types of mental ignore assumptions about gene produces char health , and not active-duty military. For more illness. No drugs or invasive procedures are might be involved and to look for DNA information, call 295-097 2 weekdays between involved. Volunteers will be paid. For infor­ markers using segregation analysis. 9 a.m. and 12 noon, Uniformed Services mation, call 496-7674 between 9 a.m. and Building on NIDDK-supporced work done University. D 4:30 p.m., Monday-Thursday. 0 by emeritus researcher Dr. Stefan Fajans at the University of Michigan in Ann Arbor, Bell's group has been studying a large family with Maturity Onset Diabetes of che Young (MODY). This form of non-insulin-dependent diabetes has a clear mode of inheritance, Bell explains, allowing the same kind of generic experimentation used co identify DNA markers for cystic fibrosis. They've already identified a DNA marker rightly linked co the MODY gene in one fam­ ily, Bell says. Working with Dr. William Knowler's group at the NIDDK labs in Phoe­ nix, Bell's ream is now trying co determine if chis marker might be responsible for diabetes in other families by looking at DNA samples from 100 Pima Jndians. Developing more generic data will help his ream develop a strategy for cloning the diabetes genes. Encouraged by research successes expedited by scientific cooperation, CF patients have begun to anticipate treatment, prevention, and cure. Diabetes patients have been watching, N!DDK ce/eb,·ated its 40th anniversary with a di1111er in September at the National Naval Medical Com­ coo. They hope it won't be long before Bell mand CommisJioned Officers' Cl11b. Seated are (from I) Dr. Daniel]. KoJhlandjr., guest speaker an.I and his colleagues can do the same for editor of Science magazine, Dr. William F. Ra11b. acting director of NIH. and Mrs. Raub. Standing are chem. D (/ram I) NIDDK director Dr. Phillip Gorden, Mrs. Gorden, assistallt secretary for health Dr. James 0 . Ma.ron, Mrs. Mason . and Dr. j ohn T. Farrar, chaimum of the Digestive Disease National Coalition and host of the event. page 8 The Record November 27. 1990

High Blood Pressure ls Maiw Culprit • NIDDK Celebrates 4 Blacks Struck by High Rate of Kidney Disease By Mary Harris Four hours a day, 3 days a week, and prob­ accounted for 29 percent-more than double ably for the rest of his life, 39-year-old J oe their representation in the U.S. population, Henderson Jr. goes co his "job" ac Walcer which is only 12 percent. Mose patients with Reed Army Medical Center's dialysis clinic. kidney failure have access co treatment­ There he is joined co a machine that removes dialysis and transplantation-through the his blood a pine ac a cime, cleans it, and Medicare program administered by the Health returns it to his body. Care Financing Adminisrracion (HCFA). Joe Henderson's kidneys don't work. His According to a report from the U.S. Renal job is dialysis, and it keeps him alive. Maybe Data System, an NIDDK-supporced program, long enough co receive a donated kidney. treatment for chronic kidney failure cost more Maybe noc. than $5.4 billion in 1988. "Kidney failure is no· longer fatal, thanks co The four main causes of kidney failure ace maintenance dialysis and kidney cransplanca­ diabetes, hypertension, glomerulonephricis and tion," said Dr. Lawrence Agodoa, who directs polycyscic kidney disease. Blacks are ac higher NIDDK's research program in chronic kidney risk than whites for all causes except polycys­ failure and treats patients with kidney disease cic kidney disease, but researchers are finding ac Walter Reed Army Medical Center. " Bue chat Blacks are hie especially hard by high even with these effective creacments, most blood pressure, which they tend co get at a people with chronic kidney failure have a younger age than whites. Between ages 25 to vastly shortened lifespan, with survival rares 44, Blacks have nearly 20 times the race of comparable co chose for pros race, colon and kidney failure from high blood pressure as lung cancers." whites, and between ages 45 co 64, their risk The main reason for this shortened survival is about 11 times higher. is heart disease. Heare-related problems were "High blood pressure is basically what did the immediate cause of death in 65 percent of my kidneys in," said Joe Henderson. " My feet kidney failure patients who died in L988. and legs started swelling, so I went co the Kidney failure patient receives hemodialysis. "Some of che deaths were due to an acceleraced doctor." By the time Henderson found ouc he buildup of cholesterol in che arteries," said had high blood pressure, his kidneys bad Agodoa. Bue cholesterol is nor the heart's only already been severely damaged. Fifteen years Liver Transplantation Becomes enemy. Because dialysis is not a perfect later he had kidney failure. replacement for the kidneys, patients with By Jim focdham kidney failure muse control the amount of Kidney Failure Caused by High Blood Pressure potassium-rich foods they eat. Too much or New Cases Per Million Population Liver transplantation is heroic surgery chat coo little potassium can disrupt the heart's 150 -.------, offers patients with fatal forms of liver disease rhythm, causing sudden heart failure. a new chance co pursue a full and active life. · Under normal conditions, the kidneys, This ultimate step in che treatment of liver nestled on each side of the body under the rib failure is excepciona.lly difficulc surgery that cage, remove waste and regulate blood pres­ only recencly has evolved from an experimental sure. They also balance body fluids and sales and often disappointing procedure into an and release erychropoietin, a hormone chat established, usually successful, treatment. cells the bone marrow co produce red blood 50 -,....------, More than 2, 100 liver transplants were per­ cells. formed in 1989 in 79 hospitals in the United The filtering units of cbe kidney, called Whites States, almost double che number done 3 years glomeruli, arc made up of clusters of micro­ ago, and more than 20 times che number done scopic blood vessels. When these units are o~------' 10 years ago. In face, more than half of all damaged by a disease such as diabetes or high 1982 1987 liver transplants have been done in the last 2 blood pressure, the remaining healchy units years. work harder co compensate for the loss. As che Before the landmark 1983 NIH Consensus As creacmenc for high blood pressure has disease progresses, more units are destroyed improved, death races for stroke and heart dis­ Development Conference on Liver Transplanta­ until the kidneys are working at only 5 or 10 tion, fewer than 350 livers had been grafted in ease have declined. In concrasc, kidney failure percent of capacity. Ac chis point, a person is che U.S. Ac chat meeting, the consensus panel due co high blood pressure is on che rise, par­ diagnosed with end-stage kidney disease, or concluded chat "liver cransplantacion is a ticularly in Blacks. As one researcher pointed kidney failure, and muse have dialysis or a therapeutic modality for end-stage liver disease out, doccors know how to protect che heart kidney transplant co survive. that deserves broader application," and in the and brain from hypertension but not the During 1988, 172,506 people in the kidneys. years since, this life-saving therapy has come United States were treated for kidney failure. An NIDDK research initiative on kidney of age. More than 36,000 were newly diagnosed This important achievement began wich disease in Blacks is aimed at filling chis gap of cases- nearly a 9 percent increase over 1987. information. "We need co find out why Blacks crucial research on experimental animals in the Whites accounted for 67 percent of chose 1950's and 1960's. By rhe early L960's, the treated for kidney failure, and Blacks (See BLOOD PRESSURE, Page 10} first extended survival after I iver transplanta- page 9 The Record November 27, 1990

tOth Anniversary NIDDK Researchers Probe Causes of Diabetes, Obesity By Joan Chamberlain Luggage in hand, Dr. Peter Bennett hurries "In the Pimas, insulin resistance shows into one last meeting at NIH before leaving strong familial clustering, independent of for the airport. In an unmistakably British obesity. Also, the Pimas rend co cluster into accent, he jokes about the 120-degree wel­ three groups- with low, medium and high come awaiting him in Phoenix, Ariz., where levels of insulin resistance--rather than in the he oversees an NIDDK intramural research typical bell-shaped distribution. This three­ program in diabetes. Bennett went ro Phoenix pronged pattern of insulin resistance suggests 25 years ago ro organize the firs t epi­ that in the Pimas there may be a major auro­ demiologic research on diabetes in the Pima somal gene inherited in a codominant Indians. As chief of NIDDK's Phoenix Epi­ manner," said Bogardus. That is, a person demiology and Clinical Research Branch, he could inherit two copies of a normal gene, leads a team of researchers v,iho continue to enabling a normal response to insulin; two search for the causes and treatment of insulin abnormal genes, resulting in severe insulin resistance, obesity and diabetes in the Pimas. resistance; or one of each, causing moderate Pima Indians have the highest race of diabe­ insulin resistance. tes in the world: 50 percent of adults ages 35 Bolstering the case for a generic basis of and older have non-insulin-dependent (also insulin resistance is a recent study conducted known as type II or adult onset) diabetes, the by NIDDK researcher Dr. Dave Pettitt, show­ most common form of the disease. Although ing chat Pima children have insulin resistance diabetes was rare in the Pimas early this cen­ decades before the onset of diabetes. In a tury, it had become common by the 1950's. study comparing 439 nondiabetic Pima In just the last decade, incidence has climbed youngsters ages 6 co 19 with age-matched by 50 percent. Diabetes is caused by a defect in the body's abil icy co convert food co energy, a process chat depends on the hormone insulin. People with non-insulin-dependent diabetes produce insulio, but cheir cells do not respond to the hormone efficiently. This condition, called insulin resistance, often precedes diabetes, Established Therapy making it a strong risk factor for the disease. To regulate glucose levels in the blood, the pancreas releases more and more insulin. Even­ cion in dogs was achieved using the anti­ tually, though, the pancreas can no longer rejection agent azathioprine, with one dog keep up with the body's demand for insulin, surviving more than 10 years. and diabetes secs in. Treatment consists of The first liver transplant in man was per­ weight loss through diet and exercise and, in some cases, insulin injections or oral drugs formed in 1963 by NIDDK grantee Dr. that lower blood glucose. Bue even with treat­ Thomas E. Starzl at the Colorado Medical School in Denver. During the next 20 years, ment, diabetes slowly damages nerves and about 540 of the operations were done at four small blood vessels and, in time, often leads major medical centers in the U.S. and in to heart, kidney, nerve and eye disease. Europe. Long-term survival of patients who Genes Contribute to Diabetes underwent the surgery was uncommon. Nearly 300 of rhe transplants done in the U.S. were NIDDK researchers believe that genes play performed by Starzl, who in February 1981 a major role in diabetes and have been study­ moved to the University of Pittsburgh School ing insulin resistance as a key co of Medicine to establish a transplant program understanding what goes wrong with glucose Dr. Peter Bennett directJ NIDDK's Phoenix Epi­ at the Presbyterian-University Hospital. metabolism. Insulin resistance worsens as a demiology and Clinical ReJearch Branch. There, in 1984, Starzl did the first human person gains weight, bur cells' sluggish combined heart-liver transplant. response co insulin has more to do with genes white children from Rochester, Minn., Pima In the beginning, successes were few, bur than obesity. children had blood insulin levels 15 to 20 per­ Starzl and his colleagues persisted, gradually "We're interested in insulin resistance cent higher than their Midwestern peers. improving the surgical technique and means of because non-insulin-dependent diabetes is Diabetes is most common in offspring who controlling rejection. Eventually survival rates clearly a genetic disease. Since insulin resist­ have two diabetic patents, less so in those improved. The challenge and excitement ance is one of the early abnormalities seen in with one diabetic parent, and least common in surrounding liver transplantation attracted tal­ the disease, it's natural co ask if insulin resist­ chose with nondiabecic parents. Another risk ented young investigators to the field. The ance is also generically determined, and several factor is diabetes during pregnancy. Offspring work of Starzl and his many young trainees pieces of evidence suggest that it is," said Dr. of a diabetic mother are much more likely to evemually led to successful surgical techniques Clifton Bogardus Ill, chief of the clinical dia­ develop diabetes than the offspring of a (See LIVER, Page 10) betes and nutrition section. (See DIABETES, Page U J page lO The Record Novtmber 27, 1990

BLOOD PRESSURE sive drugs co prevent rejection, they are freed data presenced in chis article. The data system (Continued from Page 8 ) from dialysis and tend to have an improved began collecting and analyzing data in 1988 quality of life, close ro chat experienced before with the help of the HCFA and is now the seem more vulnerable co renal injury from rhe onset of kidney disease. largest database on kidney disease in the U.S. high blood pressure, if some drugs are better In 1989, 8,882 people got their wish for a Current studies are comparing patient and than others in preventing blood pressure­ new kidney. Unforcunacely, another 14,669 related renal injury in Blacks, and if che target were still waiting. Kidney donations have not For many, tramplantation improves blood pressure should be lower for Blacks than kept pace with need, so most patients wait a whites," said D r. Gary Striker, director of quality of life. year or more for a kidney transplant, accord­ NlDDK's Division of Kidney, Urologic, and ing co che U.S. Renal Dara Sysrem. graft survival considering severity of illness at Hematologic Diseases. Henderson does nor wane a kidney trans­ People with kidney failure must decide, the onset of treatment; prognosis based on plant. "Maybe if I was to get worse I would with the help of cheir docrors and families, renal biopsy results; and quality of life of think about it," he said. But even if he which crearment---dialysis or rransplancation­ patients treated with erychropoiecin, which wanted a transplant, he would not accept a relieves the anemia of kidney failure. is besc for them. Factors such as age, other ill­ kidney from a family member. "It would be nesses, emotional support of family and These and ocher NIDDK-supporred studies coo much co put on them. What if they got will improve the understanding of kidney dis­ friends, religious beliefs and cruse in the medi­ sick and died, and I was still alive? I couldn't ease and, one day, will lead to the treatment cal profession influence a patient's decision. live with that." Dialysis is a life-saving procedure and the and prevention of kidney failure. 0 But for patients who receive a transplant, treatment choice of most chronic kidney the success race is encouraging. Blacks and failure patients. Hemodialysis, done three LIVER whites who received a transplant in 1987 had rimes a week, uses a machine connected to a about the same 2-year survival. Up to 96 per­ (Continued from Page 9 ) special filter to remove, clean and return the cent of patients who received a kidney from a and methods of fo1lowup care to prevent rejec­ patient's blood minus wastes. Various forms of living relative and up to 93 percent of those tion that have made liver transplantation a peritoneal dialysis, done three times a week co who received a kidney from a deceased, unre­ well-accepted, effective therapy for advanced four times a day; depending on che form, use lated donor lived at least 2 years. liver disease. the patient's abdominal wall co filter wastes Grafe survival, or survival of the new Over the years, Starzl has trained hundreds from che bloodstream into a solution in che kidney, is lower in Blacks than whites regard­ of rransplanc surgeons from dozens of coun­ abdomen. The waste-filled fluid is periodically less of whether the kidney came from a living cries, including most of the liver transplant relative or deceased, unrelated donor. surgeons in the U.S. According to Dr. Oscar Blacks and whites differ in treatment Researchers do nor know why some patients Salvatierra Jr., past president of the United choice and results. keep a transplant when ochers who seem as Network for Organ Sharing (UNOS), Starzl well matched reject the transplant. Why graft "has concribuced more co the field of trans­ survival is lower in Blacks compared co whites plantation than any ocher individual." (UNOS replaced wich a clean solution. Surgery is is the national voluntary organization that sets required co insert a permanent device chat is nor well understood, but researchers are beginning to find genetic clues. standards of quality in organ procurement, allows easy access co the bloodstream for . distribution, data collection, testing and hemodialysis or the abdominal cavity for per­ A donor kidney is matched with a recipient on che basis of six aocigens, or tissue types, patient access.) itoneal dialysis. All dialysis patients must cut The liver is the largest of the body's organs down on calories, fluids, protein and sales. found on che HLA gene of each person. These antigens are pare of the immune system and and is essential to life. It acts as a chemical Side effects of dialysis include blood clots have been linked co kidney rejection. Accord­ factory, regulating the blood levels and dis­ and infections of the access site and the ing to Agodoa, "Grafe survival is best when tribution of nutrients. The liver synthesizes abdominal wall in peritoneal dialysis. New all six antigens match. The next best is when glucose for energy and produces proteins for hemodialysis patients can also experience head­ five of six match. Beyond char, graft survival metabolic functions. The liver makes most of ache, nausea, muscle cramps, anorexia, the clotting factors chat prevent a person from dizziness and seizures. is similar for four or fewer matching antigens. bleeding co death. It also metabolizes drugs Blacks most often ope co remain on dialysis, and toxins and secretes fluids such as bile that possibly because they rend co do well on it. Researchers have found rhat Blacks have a more diverse generic makeup and a wider aid in digestion. Without a viable liver, a per­ Among Blacks with kidney failure at the end range of HLA antigens than whites. This son would soon die. Liver transplantation is of 1988, 86 percent were on dialysis compared the only alternative. to 69 percent of their white counterparts. diversity decreases the chances of finding a donor kidne)' with matching antigens. Transplanting a liver is a monumental chal­ Blacks on dialysis have fewer complications lenge that draws on all of a surgeon's skill and chat require hospicalizacion, and they live Finding Answers intelligence. The operation on the liver reci p­ longer than whites on dialysis. According co ient can cake 10 hours or longer, during Henderson, "It's not a physically active life, In recommendations co NJDDK, a panel of which the surgeon often works blind, suturing but I don't have any noticeable problems. If I researchers in epidemiology, genetics, immu­ many vessels behind the large, awkward didn't cell you that I was on dialysis, you nogenecics, hypertension and nephrology has organ, and coping with numerous other wouldn't know. I feel well and I have adjusted called for more studies, including a clinical technical difficulties and complications. well to the diet and regular visits to the trial to help answer questions about kidney Important advances in liver replacement dialysis center." disease in hypertensive Blacks. The NIDDK is have included development of more effective Kidney transplantation has important now planning a pilot clinical trial that will surgical techniques for the management of bile advantages over dialysis that, for many people, cesc the feasibility of a full-scale study of duct connections and the introduction of the outweigh che risk of organ rejection, infection, kidney disease in hypertensive Blacks. "veno-venous bypass," which allows blood that osteoporosis and kidney damage. Although The NIDDK is also supporting the U.S. would normally go co the liver to circulate to transplant patients muse cake immunosuppres- Renal Data System, the source of most of tbe the ocher organs while the liver is being page 11 The Record November 27, 1990

action and efficacy, and seems to have fewer Ac present, che survival races of patients side effects. Scientists believe it may also receiving new livers are about 7 5 to 80 per­ prove to offer ocher advantages, such as per­ cent at l year and 60 co 65 percent ac 5 years. mirci ng use of lower doses of prednisone, Researchers hope, however, chat long-cerm improving survival and che quality of life of survival soon will be increased through transplant recipients. advances in immunosuppressive therapy co Another advance in antirejeccion therapy has scop rejection, developments in surgical tech­ been the use of monoclonal antibodies against nology, and through improved preservation certain lymphocytes. These help reverse rejec­ that yields better matches of donor organs and tion, bur they have been found to induce · better functioning grafts in recipients. allergic reactions when used repeatedly. Ac One of the most urgent and difficult prob­ present their use is limited to episodes of lems facing liver transplantation in the U.S. is severe rejection. shortage of organs. While the number of livers Unlike kidney transplantation, where transplanted increases each year, so does the kidney dialysis can usually maintain rhe waiting list of patients who need the opera­ patient's life until surgery, liver cransplanra­ tion. In a recent month, more than a thousand cion is generally an emergency operation in people were waiting. Ir is estimated that a Dr. Thomas Starzl, pioneer of liver tramplamation which a critical factor is the limited time char quarrer of chem will die before a donor is a donor liver can be preserved. Until just a found . Ac the same rime, only a small propor­ removed. few years ago, a cold storage solution could tion of the livers chat could be donated are A basic problem encountered in organ preserve a donor liver for about 8 hours or so. obtained. UNOS and numerous other volun­ transplantation is the natural tendency of the There was a vital need to find better methods tary health organizations are conducting body's immune system co reject the donor to excend preservation time of donor livers campaigns to encourage Americans co donate organ. Since the beginnings of organ replace­ before transplantation. organs at their death (call 800-24-DONOR). ment, scientists have searched for safe and In the lace l980's, NIDDK grantees Dr. There is hope chat some day the need for effective methods of suppressing che immune Folkcrc 0. Belzer and Dr. James Southard ac donor organs might be less urgent as artificial response. Ac first, irradiation and bone mar­ che University of Wisconsin developed and Livers are developed, as researchers gain exped­ row rransplanrarion were tried, but were tested a new solution chat can preserve a donor ence implanting portions of liver from living unsuccessful. Since chen, scientists have liver for up co 20 hours. The invescigacors donors, and as improved therapies prevent focused their efforts co prevent graft rejection cesced the new solution, known as "UW" complications of liver disease, reducing the on the use of either drugs or antibodies. solution (for the University of Wisconsin), on need for organ replacement. D The drug azachioprine was first used hundreds of donor livers and found char the clinically in 1962 and marked the beginning average preservation rime was nearly double DIABETES of the modern era of immunosuppression. that for the standard solution. The researchers (Continued from Page 9 J Nearly two decades passed before another also found rhac the livers preserved with UW drug, cyclosporine A, was found to be more mother with normal glucose tolerance during survived ac a significanrly higher race. effective than azarhioprine in suppressing pregnancy, even if chat mother later develops immune response. By the 1980's, cyclosporine diabetes. had become the mainstay of therapy co prevent NIDDK researchers chink the genetic defect transplant rejection, although it was necessary underlying insulin resistance might be found to combine it with prednisone, an anci­ in che pathway co che activation of glycogen inflammarory corticosteroid hormone. synthase, an enzyme necessary for normal Scientists soon found, however, that toxic glucose metabolism. "Jn normal people, most effects, particularly to the kidneys, occur when glucose is taken up by the skeletal muscle," cyclosporine A is given in a high-dose, two­ said Bogardus. "The cell does one of cwo drug regimen. So in recent years, many cen­ things with glucose: either it burns it­ ters have used three-drug regimens char oxidizes it to carbon dioxide and warer--or it combine lower-dose cyclosporine A with pred­ scores it as glycogen. In an insulin-resisrant nisone and azachioprine co prevent rejection. person, there are probably defects in both This approach is highly successful compared these pathways, but the most serious defect is in the glycogen storage pathway. We don't co early efforts to suppress immunity, but problems remain. Amounts of the drugs char think che generic defect is in the glycogen can be used are consrrai ned by toxic effects on synthase molecule itself, but we've found sig­ nificant abnormalities in che insulin regulation viral organs, and thus make ir difficult to bal­ of one of the enzymes back from glycogen syn­ ance the risks of infection from immunosup­ Live,· Transplantatio11 pression against the need to prevent graft thase-glycogen synthase phosphatase." Doctors have long known char obesity adds rejeccion. Extended preservation time provides impor­ co the problem of insulin resistance and the For this reason, researchers are excited over tant benefits for the safety of patients, the chances of getting diabetes. Often a modest the prospects of a new immunosuppressive timing of surgery, better coordination of sur­ JO-pound weight loss can increase a person's drug known as FK506, a natural product of gical teams, and cross-marching between sensitivity co insulin, even forestalling diabe­ soil fungi, chat is now being tested at several donor and recipient. The added time also tes. On the other hand, as an insulin-resistant transplant centers in a clinical trial sponsored allows for organ retrieval from more distant person gains weight, insulin resistance by the manufacturer, Fujisawa Pharmaceutical locations, and it permits more preparation increases. NlDDK researchers speculate chat Company, Led. , of Japan. So far, the drug time for staff in anesthesia, nursing, operating appears co rival cyclosporine A in its mode of room, blood bank and intensive care units. (Continued on Page 1.2} page 12 The Record November 27, 1990

(Continued from Page U J the added fat causes muscle cells to enlarge, increasing the distance between capillaries chat carry insulin to its site of action. The type of muscle fiber a person inherits may also play a role in insulin resistance, according co Bogardus. "The two major classes of muscle fibers are type l and type 2, and each fiber type has different metabolic charac­ teristics. For example, a type 2 fiber is more insulin resistant than a rype 1 fiber. Also, the amount of each fiber that an individual has appears to be genetically determined. A person who inherits a lot of type 1 fibers, for exam­ ple, would make a good long-distance runner, while a person born with a lot of type 2 fibers would make a good weight lifter." Dr. Eric Ravussin of the Phoenix branch has been exploring metabolic rate in muscle. "In che past, muscle has been quire neglected because in resting conditions it doesn't require a lot of energy per unit of weight. Yet, it's a large tissue mass, about 30 or 40 percent of your weight. One observation that we have D,·. Clifton Bogard11J Ill coume/J Pima volunteer at NIDDK reJearch clinic. made is chat overall metabolic rate is related to muscle metabolic rate; char is, che dif­ ods of feast. D uring the periods of famine, studies in children. So much research in this ferences in metabolic race among people might, babies who were better at storing fat were field has compared obese ro nonobese people reside in muscle tissue." more likely co survive--they were more thrifty in cross-sectional studies. The problem is that in their metabol ism. Over the centuries, there obesity is so heterogenous. When you compare Studies of Metabolic Rate Shed Light was a natural selection for this th rifty gene or obese ro nonobese people, you can't learn Obesity, another risk factor for diabetes, is group of genes, which may turn out co be the much because everything tends to normalize in common in che Pimas, who are about 30 per­ same gene for d iabetes and low metabolic race. response co weight gain: your metabolic rate cent heavier than che general U.S. population. "We have observed under very standardized goes up, beyond che increase in body weight. Like insulin resistance, obesity appears co have conditions chat people who are better at burn­ You also start to burn more fat when you strong genetic influences. For example, family ing fat are less likely ro gain weight. We've reach the obese state, thus correcting for che members are likely co share the same meta­ found char there are differences among people initial defect." bolic rate. In studies using highly sensitive 111 the fuel mix they oxidize and that these Diabetes Causes W ide Range of Complications equipment co measure energy expenditure, the Phoenix invesrigacors found char rhe risk of Often a modest 10-pound weight loss can Living with diabetes has become a part of gaining 22 pounds over a 4-year period was increase a person's sensitivity to insulin, even everyday life for the Pima Indians. Young eight times higher in individuals whose res­ people talk about when, nor if, they will get ting metabolic races were lowest. forestalling diabetes. ic. They know all too well chat once they have Despite the strong role of genes, environ­ diabetes, they are likely co lose their eyesight, mental factors also play a role in weight gain, differences run in fami lies. Now we're study­ kidneys or a limb ro the disease. Some will and dietary changes over the years have clearly ing che enzyme lipoprotein lipase co try to lose all three. added to the Pimas' obesity problem. The tra­ understand rhe mechanism of high versus low "People used to say the Pimas don't have ditional Pima diet consisted of high­ fat oxidation. There are possible differences in carbohydrare, low-fat, high-fiber foods such as the activity of lipoprotein lipase in muscle maize, pumpkins, beans, gourds, and fruits versus fat tissue, which might explain dif­ supplemented by rabbit, deer, and fish. By ferences in fat deposition and oxidation. If you 1969, however, this diet had been replaced by have a high activity of rhi.s enzyme in your fat a high-fat, hig h-calorie diet, with the average tissue and a low activity in your muscle, you Pima woman between ages 25 and 44 earing are going ro direct ingested fat directly to fat 3,163 calories a day. The average intake for a tissue," Ravussi n explained. woman in che same age group in che U.S. 1n the 25 years since NIDDK scientists population is 1,600 calories a day. began studying the health problems of the "It's difficult co understand why a disease Pima Indians, researchers have gained valuable like diabetes is so prevalent if it is not linked insights into the biological mechanisms under­ ro a survival advantage. Io fact, a low meta­ lying diabetes and obesity. Such longitudinal bolic rate has probably been a survival and prospective studies are essential in obesity advantage for centuries," said Ravussin. "The research. "We need more prospective srudies 'thrifty gene' hypothesis suggests char, in the co learn what happens before the obese state past, populations like the Pima Indians have when the damage is already done," said Rav­ The Sonora De.rert is the traditional homeland of been subjected co periods of famine and peri- ussin. "We need longitudinal studies and the Pima fodians. page 13 The Record November 27, 1990

the race of diabetic complications chat Cauca­ sians do, but clearly they get nephropathy in abundance and recinopathy at least as fre­ quently as Caucasian populations. They also have a high race of amputations, although we haven't followed neuropachy as closely. Bue for reasons we don't understand, the Pimas don't ·have as high an incidence of h~art disease as might be expected, and which diabetes often causes,·• Bennecc explained. The research of Dr. William Knowler, chief of the diabetes and arthritis epidemiology sec­ tion in Phoenix, and ochers has shown that blood pressure is a predictor of many com­ plications of diabetes. As a result, doctors now focus more attention on controlling their patients' blood pressure co prevent complications. The longer a person lives with diabetes, the greater the chances of developing severe com­ plications. Because d iabeces strikes the Pi mas so early in life, they are as likely co suffer serious kidney and ere problems as a person who has type 1 or insulin-dependent diabetes. This less common form of diabetes, which D1·. William Know/er examines Pima volunteer's eyes for signs of diabetic retinopathy . usually occurs in children, is caused by an be due to high glucose levels rather than small simple." aucoimmune attack on the insulin-producing blood vessel disease, which rakes longer ro Following their hunch char one or two cells of the pancreas. develop," said Knowler. genes play a key role, the Phoenix team and "Jf Pima Indians who have diabetes lived 20 While the Phoenix researchers know that their collaborators have begun a large-scale years after the onset of che disease, we esti­ diabetes is a genetic disease, the nwnber of search of DNA from families with diabetes. mate that half would develop nephropathy­ genes involved may remain a mystery for a As their attention turns co finding the diabe­ kidney disease chat is marked by an abnormal while. In Knowler's view, "It's likely rhac one tes genes, che researchers foresee a rime when amount of protein in the urine. The actual gene has very large influence on insulin they may be able co identify persons who are percentage who have nephropachy is less than a resistance, and there may be ocher genes char susceptible co the disease and prevent it from influence rhe beta cell's abilicr co cope with gaining a foothold. They speak of gene "A low metabolic rate has probably been a insulin resistance. There is also evidence that therapy as a cure on the horizon. For many mrvival advantage for centuries. " genes influence which persons with diabetes Pima Indians, however, the prospects for - Dr. Eric Ravussin ger nephropathy. Bue I don't believe chat one genetic rherapy are still coo distant. For chem, or two genes will explain everything about the NIH research can be appreciated most for the causes of diabetes, because the patterns of dia­ good medical care it has given chem in the chis, however, because so many people with betes inheritance in families are just not char past 25 years. nephropachy have already died," said Knowler. "The real rragedy of nephroparhy is chat it leads co kidney failure, which means that a person must go on dialysis or have kidney transplantation. In a community of 5,000 to 6,000 Pimas, berween 60 to 80 people are liv­ ing on dialysis at any given rime. Thar's an astronomical number of people on dialysis compared to anywhere else," said Knowler. To learn how diabetes damages the kidneys, researchers from the Phoenix group, Stanford University and the Cleveland Clinic are study­ ing kidney function in che Pimas before and after diabetes begins. Early findings suggest rhac diabetes quickly disrupts the way the kidney's filtering units, the glomeruli, filter particles such as protein. "Normally, the glomerulus acts like a screen char lets water and waste produces filter through but holds back mosr of the protein. Early in the course of diabetes, we are seeing changes in che size of che pores of the screen, so chat more protein filters through. This may Aerial view of NIDDK research facility 011 the campus of the Phoenix Indian Medical Center page 14 The Record November 27, 1990

Employee Counseling Service Starts 1990-91 Lectures FAES Announces Spring Classes

The FAES Graduate School at N IH The theme for the 1990-91 Employee Making Money Count: film and discussion, announces the schedule of courses for the Counseling Services Guest lecture Series, T hursday, Feb. 21, Little Theater, Bldg. 10. spring semester. The evening classes sponsored "Intersections: Healrh and Illness Issues in rhe March by the Foundation for Advanced Education in Workplace," cemers around work and health the Sciences wi ll be given on the NIH issues and the impact of health srressors on rhe "The Ocher Side of Wellness: Dealing With Chronic Illness," Carol Weiss and Ano campus. workplace. Topics include the varied issues Mahony, Thursday, Mar. 14, Coof. Rm. 4, Tuition is $50 per credit hour, and courses and interests char come to the attention of Bldg. 31 . may be taken for credit or audit. Courses that ECS throughout the year and that speak to the Fight For Your Life: Survival Techniques in Liv­ qualify for institute support as training should eclectic needs of the NIH community. ing With Cancer: film and discussion, be cleared with the supervisors and admin­ Each month ECS will present a lecture one istrative officers as soon as possible. Thursday, Mar. 21, Little Theater, Bldg. 10. week and a fi lm and small group d iscussion Courses are offered in biochemistry, biol­ the next week. April ogy, b iotechnology, chemistry, computer All sessions will meet from noon until "Anger in the Workplace," Dr. Dale Berman, science, marhemarics, medicine, pharmacol­ p.m. on the dates indicated below. Wednesday, Apr. 11, Conf. Rm. 4, Bldg. ogy, immunology, m icrobiology, psychology, December 3 L. psychiatry, statistics, languages, administra• "Drawing the Line: Drug and Alcohol Recov­ Defusing Hostility: film and discussion, Thurs­ rion and courses of general interest. ery and Relapse Issues in rhe Workplace," Dr. day, Apr. 18, Lit tle Theater, Bldg. 10. It is often possible ro transfer credits earned George Kolodner, Thursday, Dec. 13, Conf. co ocher institutions for degree work, and Rm. 4, Bldg. 31. May many courses are approved for AMA category \'(/orking The Program: film and discussion, "Walking the Tightrope: Balancing Out l credit. Thursday, Dec. 27, Li erle Theater, Bldg. lO. Work and Family Life Health Issues," Dr. Classes will begin J an. 28, and regisrradon Michael Bowler, Thurs.day, May l l, Conf. will be held from Jan. 14 through 18. Spring January Rm. 4, Bldg. 31. schedules will be available mid-December in 'Taking Control: Depression and Anxiety Dis­ Vital Ba/a11ce: Work a11d Family Conflicts: film the graduate school office in Bldg. 60, Suite orders in the W orkplace," Dr. Norman and discussion, Thursday, May 16, Little The­ 230, the foundat ion bookstore, Bldg. 10, Wilson, Thursday, Jan. 24, Conf. Rm. 4, ater, Bldg. 10. Rm. B 1110 l and the business office in Bldg. Bldg. 31. 10, Rm. B 1Cl8. To have a schedule sent call June Dealing With DepreJJion: film and discussion, 496-7977. 0 Thursday, Jan. 24, Little Theater, Bldg. 10. "'Changing Currents: Dealing Wich Dis­ abilities in rhe Workplace," Dr. Dave Gray Lecture on 'Seeing Diseases' February and panel, Thursday, June 13, Conf. Rm. 4, "Financial Health: The Psychology of Money Bldg. 31. Dr. Sander L. Gilman, currently NLM's and Money Management," Olive Mellon, Disabilities: film and discussion , Thursday, visiting hisrorical scholar, will present an Wednesday, Feb. 14, Conf. Rm. 7, Bldg. 31. June 20, Little Theater, Bldg. 10. illustrated lecture on "Seeing Diseases: Visual Sources and the Meaoing of History," Dec. 5, at 3:30 p.m. in the Lister Hill Auditonum, Bldg. 38A. AJJ are invited. Human Rights Day Observed Gilman is on leave from Cornell University, where he is professor of humane studies and professor of psychiatry. His numerous publica­ The NIH medical scientists committee is tions reflect a long-term interest in the sponsoring rwo short films, The Colors of Hope portrayal of disease in art t hroughout history. and You Could Be A"ested to observe Human He is the author of Difference and Pathology: Rights Day. The films, which are produced b y Stereotypes of Sexuality, Race, and Madness the human rights organization Amnesty Inter­ ( 1985 ); and Disease a11d Representation: Images of national, will be shown Dec. 10, 12:30- 1:30 Illness from Madness to A IDS ( 1988). p.m. in rhe Visitor Information Center, Bldg. For further information call 496- 5405. 0 10. NIH'ers and their guests are invited to attend. Refreshments wi II be served. N IGMS director Dr. R111h L. Kirschstein (c) meets Toastmasters To Honor Mylander Human Rights Day commemorates the with NIH Merit Award n,cipiems Crystal Jenkim anniversary of the passage of the United ( I), an administrative assistant, a11d Marcia The NIH Toastmasters Club will hold its Nations Universal Declaration of Human Cohn, a grants management specialiJt. annual Communication Achievement Award Rights. The medical scientists committee is an ceremony Dec. 7 at noon in Wilson Hall, NIH employee group affiliated with Amnesty Madrigal Singers To Perform Bldg. I. This year's recipient is Maureen Internacional that works for the release of pris­ The NIH R&W Madrigal Singers will pres­ Myl ander, special assistant for health informa­ oners of conscience worldwide. The commitree ent a program of sacred and secular works tion in OD's Office of Communications. She is meets every Thursday from 12:30 to 1:30 from the 16th century, mostly from Eng land, also the author of the book, The Healthy Male, p .m. in Bldg. 10, Rm. B1D25. For more followed by a 20th century segment featuring and a former member of the NJH Toastmas­ information, call Dr. Pat McK inley, works by British composer Ralph Vaughan ters Club. 496-9291. 0 Williams and American songster Mel Torme. Everyone is invited co attend. For more The program will be given in Masur information, call Jasper Cummings, Auditorium, Tuesday, Dec. 11 at 12 noon. 0 496-5635. 0 page 15 The Record November 27, 1990

TRAINING TIPS Friends Offer NLM Calendar NIH Historian To Address Science Writers Guild, Dec. 4 A colorful 1991 National Library of Medi­ The NIH Training Cencer of the Division cine wall calendar-featuring 12 ill uscracions, of Personnel Management offers the following: mostly drawn from the library's historical col­ The first transfer of foreign genes into humans and che first clinical crial of gene Co11rses and Prograrm Starting Dates lections-is now available from the Friends of the National Library of Medicine, 1527 therapy are recent examples of NIH's promi­ Management and Supervisory 496-63 71 Wisconsin Ave., NW, Washington, DC nent role in making medical history. As head Efficient Reading for Professionals 12/13 20007. of NIH's Historical Office aod curator of the Working le Our 1/7 The price is $ 10 per calendar ($8 for mem­ DeWitt Sceccen Jr. Museum of Medical Good Starts: Transition Planning 1110 bers of the Friends and staff of NIH and Research at N IH, Dr. Victoria Harden plays a How To Write and Publish Scientific Papers 1114 key role in documenting and preserving NIH 's Time Management 1/16 Managing Workforce Div

Second Trial To Start Soon Former CC Surgical Wing Becomes Animal Facility Gene Therapy Approved for Melanoma Patients Bldg. lOA, the 5-level round structure for­ The NIH has received final approval from With the addition of the TNF gene, we hope merly housing the surgical wing of the NIH FDA ro begin the first study using human co enhance the ability of T ILs co destroy Clinical Center, was dedicated on Nov. 6 as gene therapy to treat cancer. rumor cells. " N IH's newest, scace-of-che-arc laboratory ani­ Drs. Steven A. Rosenberg and R. Michael This crial will be the first to apply gene mal facility. The new rodent and rabbit unit Blaese of NCI, and Dr. W . French Anderson therapy co cancer, which, in its many forms, will consolidate most of che 33 animal holding of NHLBI expect to treat the first patiems affects millions of people. and procedure rooms scattered throughout che next month. These patients have advanced On Sepe. 14, under the leadership of Clinical Center. melanoma, a skin cancer for which there is no Blaese, the research team of Anderson, A large g roup of NIH investigators, admin­ effective treatment. The scientists have Rosenberg, and another NCI investigator, Dr. istrators and laboratory animal care staff received approval co treat up co 50 patients Kenneth W. Culver, began a srndy using toured the new faci lity after the dedication with this disease. human gene therapy co rreac an extremely ceremony and ribbon cutting. "This approach that uses gene therapy co rare, inherited immune system disorder known Opening of the unit, scheduled for Febru­ creat patients with advanced cancer is experi­ as adenosine deaminase (ADA) deficiency dis­ ary, is pare of NI H's concentrated effort co mental and in an early srage of development," ease. The first patient in char study was a obtain accreditation of the entire NIH intra­ said Rosenberg, who leads the study. 4-year-old girl who received a transfusion of mural animal research program by the Patients in chis study will receive transfu­ her own white blood cells chat had been American Association for Accredicacion of Lab­ sions of special cancer-killing cells called altered in rhe laboratory by insertion of the oratory Animal Care. rumor-infiltrating lymphocyces, or TILs, chat human ADA gene. "le is fortunate that a move of the surgery have been altered in the laboratory by inser­ This patient lacks a crucial enzyme for co new, technologically advanced facilities was tion of che human gene for rumor necrosis immune system functioning known as ADA. already under way when the need co consoli­ ·factor (TNF). T he NIH scientists grow che Untreated, ADA deficiency disease often date che animal faci lities became clear," said gene-altered T!Ls in the laboratory for 4 co 6 results in death within the first years of life. Dr. Edward Rall, NIH deputy director for weeks before returning chem co the patient by _ Foreign genes cannot be direccly inserted J. intramural research. Renovations began in transfusion. into the cell, but certain viruses have the abil­ TILs are white blood cells char have ity to enter the cell and insert their genes into 1987. A committee of the intramural scientists migrated from ocher parts of che body co rhe the cell's DNA. In both the cancer and the who will use che facility rook pare in the cancer sire. After invading the rumor, they ADA deficiency trials, the virus that is used design decisions. The shared facility will be develop the ability to target and destroy the ro deliver the gene has been crippled so chat it managed by the Veterinary Resources Pro­ tumor tissue from which they were derived . cannot reproduce in the patient. gram, NCRR; participating JCDs will share in Since 1987, Rosenberg has been using "Ultimately, this new technique could lead operating expenses. unaltered TILs to treat cancer. Only about half co the use of gene therapy co correct or ame­ The unit has 49 animal holding rooms and the patients with advanced melanoma show liorate a wide range of diseases, including L5 research procedure rooms. le is equipped some improvement after therapy with cancers ocher than melanoma; heart disease; with computer-monitored environmental and unaltered T!Ls. diabetes; and ocher inherited disorders such as air circulation controls, radioisoto_pe rooms, "There has been a need to improve chis hemophilia and cystic fibrosis," Rosenberg and the latest technology for maintaining the therapy, and one way may be wirh the addi­ said. 0 health and well-being of the animals. tion of the TNF gene," said Rosenberg. "In mice, TNF is one of the most powerful antitu.mor agents we have seen. Humans, however, cannot tolerate the large doses neces­ sary co achieve this potent cancer-killing effect," he added. TNF is a protein that is produced by the body in the course of bacterial infections. Although initially recognized for its cancer­ killing activity in mice, TNF also regulates inflammation and immunity by signaling the body co repair injuries and fight infection. However, if TNF is active in the body for coo long, it can cause shock and body wasting. Ac the tumor sire, TNF appears to work effectively b)• cutting off the developing blood supply in chat region. By using TILs co target the tumor and carry the TNF gene directly to the tumor sire, scientists hope co maximize the gene's benefit and also minimize the A tour of the new Bldg . .JOA rodent ,md rabbit 1111it followed the ribbon rnlling by Dr. J. Edwa1·d Rall potential roxicity chat could result if TNF (r), NIH deputy dfrector for intramural research, along with (from I) Dr. Richard Wyatt. NIH anistal/1 were distributed chroughom the body. director for intramural affairs; Dr. Robert A. Whitney Jr. , director, NCRR; D,·. Wayne O'Brien. man­ Said Rosenberg, "At chis rime, we are giv­ ager of the new facility; J erry Lawson. Division of Engineering Services; and Dr. Stepherz Potkay, director, ing Tlls chat have some anticancer aetivicy. Veterinary Resources Program, NCRR. U.S GOVERNMENT PRINTING OfflCE t9'J0-26t-tl7/2000}