. 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 for fast-tracking drugs that have already advanced sales of OctreoScan were a significant impetus for been approved in other countries. In the meantime, products boosting sales once the product was approved. Even though the like Myoview must still go through separate review processes synthetic peptide was approved around the same time in both in order to be distributed in Europe, Japan and the U.S. Europe and the U.S., its sales in this country are still lagging This past April, the fate of Myoview was seen as uncertain behind its sales abroad. when the FDA safety officer called and said herdepartmentwas still “waffling―on whether to write an approvable letter. In the The Somewhat Disjointed EuropeanUnion meantime,Amersham executives were toldthey neededto answer In 1992, the drug approval process became centralized for the chemistry reviewer's questions on a degradation study and members ofthe European Union (which includes the Western they also needed to revise Myoview's package insert. Europeancountries such as GreatBritain,FranceandGermany). Things started looking up in May, when Waterman and Radiopharmaceutical manufacturers still apply to a specific otherAmersham executives received word from the FDA safety country for approval—forinstanceHollandhandles most ofthe officer that an approval letter was in the works—althoughthe NDA'Sfor monoclonal antibodies—butthe Union coordinates letter still needed review by at least a dozen FDA officials before the approval for the rest ofits member countries. Although the it could be sent. On July 14, 1995, Amersham received an offi European Union was founded on the best intentions, “itis becom cial―Approvable―letterfrom the FDA accompanied by 10pages ing more like the FDA with its bureaucracies and regulations,― ofquestions and a request that an additional “Phase IV― clini said Doedens. Once a new drug is approved by one country, cal study be performed after approval. On August 22, Amer the other members have an opportunity to comment on the appli sham executives mailed offtheir response to the FDA'S ques cation when it reaches the Union, which can slow down the tions. It was more than 10,800 pages long. As ofpress time, process. What's more, the Union has set up more restrictive rules Myoview still had not received official FDA approval. There for promoting a product before it is approved. will probably be a few more rounds ofletters with questions and Perhaps the largest problem has centered around trying to requests before the process is finished. Watterman says they're get 16 countries to agree to one set of regulatory laws. Some hoping for approval by the end of this year—two years after countries have traditionally taken a much tougher stance on the FDA'Soriginal deadline. When Myoview will actually be regulating imaging agents than others. Holland and Finland, approved is still anyone's guess. for instance, had never regulated radiopharmaceuticals as Deborah Kotz

Nobel Laureates ropharmacology at the University of Texas Southwestern (Continuedfmm page 25N) Medical Center, is even more optimistic: “Weanticipate munications, he said, can allow cells to multiply wildly or dis knowing every molecule involved in G protein-mediated ease-causing pathogens to run rampant. transmembrane signaling—all of the hundreds of receptors, Although formally retired, Rodbell continues to do Gproteinsandeffectors.Wewillthusbeabletodecipherthe research on cellular communications and has firm views on complete wiring diagram for the signaling switchboard for where he thinks the field is heading. “Futureresearch will every cell. This knowledge will have enormous implications continue to focus on assessing cellular communications to for drug development and the rational treatment of disease.― show how the communications networks in similar cells are in fact very different' he said. For instance, cloned cells have A New Understandingof Cholesterol been found to have different internal structures and commu Using radionuclides for their research on cellular recep nication networks. “Wethink, and hope, that people are going tors, Michael S. Brown, MD and Joseph Goldstein, MD, from to follow our lead, and with the benefit of ever-improving the Molecular Genetics section at the University of Texas, imaging technologies, such as PET, gain better and better shared the 1985 Nobel prize for their discovery ofa low-den glimpses of the functioning of the intercellular communica sity lipoprotein receptor (LDLR) and its role in familial tions grid,―said Rodbell. Gilman, who currently serves as the hypercholesterolemia. “Whileknowledge of receptors sur Raymond Willie Distinguished Chair in Molecular Neu faced almost 50 years ago when investigators tried to con

30N The Journalof Nuclear Medicine•Vol. 36 •No 10 •October 1995 ceptualize substances' interaction with cells and subsequent receptor can be raised through drugs and a low cholesterol cellular reactions to the substances, it has only been in the diet?' John M. Dietzschy, MD, who has also researched LDL past 15 years that specific radiopharmaceuticals have been receptors, said future advances will enable scientists to “tella developed to interact with receptors,― said H. William drug company how to design new medical treatments. In the Strauss, MD, of the division of nuclear medicine at Stanford next 10 years, we'll be able to develop and test medicines to University School of Medicine. improve the receptors and lower cholesterol levels in Brown and Goldstein specifically used radionuclides such humans.― as 125!to detect defects or inadequacies on LDL receptors Regardless ofwhether these Nobel laureates are the benefi which can cause an excessive increase in blood cholesterol ciaries ofpast research or the visionaries of future advances, levels leading to premature arteriosclerosis. The receptors or both, their discoveries will inevitably have a lasting impact work by stimulating transcription, which enables the cell to on the practice of modern medicine. Where, for example, control levels of plasma cholesterol circulating throughout would nuclear medicine be at the present time without the the body. Brown and Goldstein found that the LDL receptor radioisotopes that Glenn T. Seaborg and John J. Livingood is a transmembrane protein in the cell that mediates the themselves Nobel laureates—discovered in the late 1930s uptake and the degradation of plasma cholesterol through and early 1940s at Berkeley? “Ourmotivation in searching tiny sacs located in the cells called lysosomes. Experts in the for new radioisotopes was simply the fascination of exploring field say Brown's and Goldstein's discovery represents an an exciting new frontier of science,―said Seaborg in a recent enormous development in furthering the understanding of Journal ofthe American MedicalAssociation article. Echo hypercholesterolemia. It also sheds insight on why choles ing the sentiments ofother Nobel laureates, he said, “wevery terol levels vary among individuals independent oftheir diets. often cannot predict the practical applications of basic sci In an interview with The New York Times, Goldstein ence discoveries, but we can predict that some applications observed that future research will point “tothe importance of will occur later to the enduring benefit of mankind.― this receptor in the control of blood cholesterol and how the Brendan M. Peter

Clarification

The September Newsline article titled, “InvestigatingCher National Cancer Institute, plus assistance provided by the nobyl-InducedThyroid Cancer@Politics vs. Science―discussed Agency for International Development) and other countries, some ofthe efforts to study persons exposed to radiation from a number ofwhich, including the United States, have bilateral the Chernobyl nuclearpowerplant accident and suggested that agreements with one or more ofthe former Soviet republics. the effectiveness ofthe studies was compromised because of Formal and informal communications andmeetings between personal or national reluctance to cooperate with other par and among these participants have led to mutual under ticipants. These efforts could be facilitated by increased com standings and consensus on many ofthe scientific and pro munication among the various participants in the several pro grammatic issues involved in an effort to avoid overlap and jects underway in Belarus, Russia and the Ukraine. The duplication ofprojects, personnel and patients, and to maxi comments were not intended to be critical ofthe several pro mize resources. Multinational cooperation always is a chal jects orto suggest thatdifficulties were impeding the progress lenge, but the benefits to be derived from these studies out ofparticipating organizations. The numberofprivate, national weigh any ofthe difficulties noted in the September Newsline and international organizations that seek to assist those who article. I commend the efforts ofthe various groups to obtain have suffered because ofthis accident is large and includes needed scientific data and to provide support for the children the World Health Organization, the European Union, Japan, ofChernobyl. It is my hope that this additional perspective Germany, Italy, France, Finland, Canada,The Netherlands, the will add balance to the impressions previously presented. United States(including studies supportedjointlyby the Depart —ConradNagle, MD, ment ofEnergy, the Nuclear Regulatory Commission and the Editor,Newsline

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