. RESEARCH IN NUCLEAR MEDICINE ‘U z @1 Nobel Laureates Foretell Future VI Based on Past Achievements ‘U z W hLNil@@@i1\11 @. @@h)\\@tndSolomonA. help diagnose and treat such diseases as prostate I l@CF'.@)11I)CL@11@c@citching adult—onset and ovariancancers. Otherlaureateshave used @ in thc 1@itcI @)@()@theyneversus radionuclides to study the fundamentals of neu pcclc(@1thcir n@ct@Ih()Ii@ii@@iuJic@using ‘3I—labeledropeptides, cellular communication mechanisms in'@@ilit'i\\OU1J @..purtI'IL@@(@lL@'\Cl()j)fllClltofahostofnev' and cholesterol receptors, which they foresee Icc1Ui@R)@1c@@..l@tL@t•N@flIlk1 “1@1I@\\observed that the will furtherthe understanding ofcancer and heart I,ftIR)ILtI\ C ii'@@@ii1inc1c@iicJ llin thcpancreasmore disease. Given the advances made so far,Newsline slowly in dia called on several Nobel laureates to discuss their betic patients. groundbreaking research with radionuclides, to I They specu predict the significance oftheir findings on further lated that the research and to speculate on the role nuclear I slower clear medicine imaging will play in future advances. ance was caused by the The Technique that Spawned a New binding of Erain Medicine radiolabeled Radioimmunoassay measures concentrations of insulin to an unknown substance by comparing the ratio of antibodies the substance's ability to disrupt antigen binding made by a to the already known disruptive actions of specific diabetic antibodies. Measurements are obtained by the patient's body use ofradionuclides such as ‘@‘Iand @°Cowhich in response to synthetic insulin facilitate the reaction ofa radioactive antigen with treatments. They found, however, a specific antibody.Radioimmunoassayhasbecome thatthistheorywasimpossibleto a useful prospective device to evaluate protein and prove because the immunologi enzyme binding to cells and to gauge the effec cal technology availableatthat tiveness ofvarious tracersin combating a wide van time was not capable of detecting ety ofdiseases. Ithas become the gold standardfor the tiny antibodies to which screening blood donations for hepatitis and has led insulin binds. Berson's and to the development of screening tests for prostate I Yalow'sneedforatechnologyto and ovarian cancers. Moreover, its ability to com jmeasurethe smallestbiological pare substances that bind to antibodies has led to substances inthe body resulted in widespread understanding about the interrelation @t1 their development of radioim ships between hormones in the body andthe mech Nobel prize winners who used munoassay, atechnique which has anisms which enable them to be released through radionuclides in their research (from hadatremendousinfluenceonthe out the body to combat foreign invaders. top, clockwise): Alfred Gilman, MD, way physicians practice modern Trained as a physicist at the University of Illi PhD, for his discovery of G-proteins; Joseph Goldstein, MD, and Michael S. medicine. nois, Yalow received the Nobel prize for Physiol Brown, MD, for their discovery of the Forthepastfourdecades,avast ogy or Medicine in 1977 alone because Berson, LDLreceptor;RosalynS. Yallow,PhD, number ofNobel prize winners her friend and colleague ofmore than 20 years, for her invention of radioimrnunoassay; in medicine have relied on died4 years earlier. In acknowledgingYalow's work, Martin Rodbell,MD, for hiswork on radionuclides for their discov the Nobel committee stated that radioimmunoas intercellular communications. eries, and they are now seeing say represented “anenormous development in hith theirresearch applied in ways that erto closed areas ofresearch?' Her colleagues agreed they never envisioned. Berson's and Yalow's the technique could provide the building blocks for radioimmunoassay technique has revolutionized exploring the workings ofeach hormone in the researchers' abilities to measure virtually all bio body. In fact, it contributed significantly to the work logic substances and opened up new doors to of Roger C. Guillemin, MD, PhD and Andrew V. 24N The Journalof Nuclear Medicine•Vol. 36 •No 10 •October 1995 RESEARCH IN NUCLEAR MEDICINE ____ — Schally, PhD—who shared the prize with Yalow parisons led to the discovery that cell receptors are in 1977—fortheirdiscovery thatthe neuropeptide not as passive as they appear. Rodbell and others somatostatin inhibited the release ofthe growth have found that when receptors are activated by hormone somatotropin in brain tumors. Guillemin radionuclides they are able to bind to hormones and Schally used radioimmunoassay to identify and then actually penetrate the cell membranes and synthesize three brainhormones thatareused to communicate information. Rodbell's discov by the hypothalamus to regulatethe release ofpitu eries have also revealed that receptors are selec italy hormones which help curb the growth of tive in the proteins that they receive and can even malignant lesions. Since 1978, Schally's research alter the way they receive certain proteins. “The has been focused almost exclusively on develop cytoskeletal network,―said Rodbell, “isa big ing hormonaltreatmentsforprostate,ovarian,breast part ofthe weblike cellular communications sys and braincancers. Inhis recent work on braincan tems ofthe cell. The cytoskeleton works like a com cer, he used the somatostatin analogs ‘2Rc,@°Rcplicated subway grid:the vesicles ridealong a com and ‘6Rcwhich can cross the blood-brain barrier plex circuitry ofrails which help determine the and shrink brain malignancies that have highly health and functioning ofthe cell. A change in expressed somatostatin receptors. the circuitry ofthe subway route means that Yalow envisions that radioimmunoassay will there is a change in the ability ofthe cell to ward continue to shed new light on the minute workings offdisease in the future.―A breakdown in com ofthe human body: “Webegan using radiolabeled (Continuedon page 30N) materials in our studies, and the research of the future is going to continue to utilize the enzyme labels that researchers are employing now. This NuclearMedicineStandsonthe Shouldersof Giants means that all the hormones and other chemical The following Nobel laureates made discoveriesthat laid the foundation substances in the body will eventually be studied for nuclear medicine as it is applied today. and understood.―While Schally declined to spec 1901-p . WilhelmROntgen 1935-P...JamesChadwick ulate on the future, he acknowledges that his and Guillemin's discoveries have resulted in an explo 1903-P. HenriBecquerel 1936-P . CarlAnderson sion of hormonal therapies “gearedtowards PierreCurie 1938-P . EnricoFermi treating cancer patients without the harmful side MarieCurie 1939-P . ErnestLawrence effects of chemotherapy.― 1906-P . JosephThomson 1943-C . GeorgC.de Hevesy The Futureof Cellular Communication 1908-C...SirErnestRutherford 1944-C... OttoHahn A manwho has spentthe majorityofhis research 1911-C. MarieS.Curie 1946-M. HermannMuller career at the National Institutes of Health Sci ence in Research Triangle Park, North Carolina, 1918-P...MaxPlanck 1951-C. GlennT.Seaborg@ MartinRodbell,MD—co-winnerofthe 1994prize 1921-C . FrederickSoddy Edwin McMillan for Physiology or Medicine—didpioneering work 1921-P . AlbertEinstein 1956-P . John Bardeen on cellular communication mechanisms. This ledtothediscoveryofG-proteinsbyAlfredGilman, 1922-P . NielsBohr WalterBrattain MD, PhD, at the University ofTexas Southwest 1924-M. William Einthoven WilliamShockley em Medical Center in Dallas who sharedthe prize 1927-P . ArthurComptom 1959-P . EmilioSegre with Rodbell. Rodbell's work postulated that G proteins attachto receptors on the surface ofa cell CharlesWilson 1961-P . Robert Hofstadter andrelayinformation aboutthe functions of neigh 1934-C . HaroldC. Urey 1968-P . Luis Alvarez boring cells. 1935-C . Frederic Joliot 1977-M . Rosalyn S. Yalow Rodbell speculated thatthe G-proteins occurred intheformofmultimers(suchasactin),whichare IreneJoliot-Cune RogerGuillemin part ofthe cytoskeleton ofthe cell. With the help AndrewSchally ofPET nuclear imaging devices, Rodbell and his p= Physics;C= Chemistry;M= Medicine. associates have been able to peer at the structure ofthe cytoskeletal network. They used radionu 5ReprintedfromthehistoricaldocumentsofWilliamG.Myershousedin clides to compare the ability ofcertain hormones theSNMArchivesinReston,VA. to enhance cellularcommunication, andthese com Newsline 25N RadiopharmaceuticalApproval drugs before they joined the Union. Great Britain had very (Continuedfrom page 22N) strict regulatory laws, and Germany went as far as to regulate Europe. The product can be advertised in medical journals PET radiopharmaceuticals, which the FDA is now consider and sold to physicians and hospitals; what's more, it is usually ing. covered by health insurance. For the future, the FDA is currently looking into an world Incomparing the approvalprocess for OctreoScan in Europe wide cooperation of sorts. It is participating in an interna versus the U.S., Doedens said there was little difference in terms tional conference on harmonization next month in which ofthe reviewer's questions and the approval time (19 months agency representatives will meet with Asian and European in the U.S. versus 14 months in Holland). “Themajor differ drug regulatory officials, as well as technical experts in the ence' he said, “isthat it was possible to get preapproval sales pharmaceutical industry, to see if they can establish some in Europe, which is not allowed in the U.S.―Doedens said common guidelines