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The 1982 Nobel Prize in Medicine Recognizes the Impact of Prostaglandin Research by S The 1982 Nobel Prize in Medicine Recognizes the Impact of Prostaglandin Research by S. K. Bergstrom, B. 1. Samuelsson, and J. R. Vasse L, . .. L-.-4a .4. ..4 J4)”f ifi ,-84 i~umoer iz Marcn IY, IYU4 The 1982 Nobel prize in physiology or Bergstrom, Samuelsson, and Vane medicine was shared by Sune K. Berg- were awarded the 1982 prize for their strom, age 66, and Bengt I. Samuelsson, discoveries involving prostaglandins age 48, both of the Karolinska Institute, (PCS) and related substances.7 As is Stockholm, Sweden, and by John R. often the case, they previously shared (in Vane, age 55, Wellcome Research 1977) the Albert Lasker Basic Medical Foundation, Beckenham, England. Research Awards Previous reports on Nobel prizes l-s PCS, of which there are many types, used citation analysis to provide a docu- are hormone-like fatty acids. They are mentary account of the field represent- formed in the membranes of cells ed. Recently, we ampliiied these discus- throughout the body—especially during sions by using research front data to times of illness, stress, or injury.g PCS determine the place the award-winning affect the nervous, reproductive, gastro- work occupies on the worldwide map of intestinal, and renal systems, as well as science. Briefly, research fronts are the regulation of body fluids and tem- identified by groups of current papers perature and the body’s defense mecha- that cite clusters of earlier, “core” nisms, such as inflammation. papers.4 PCS were first discovered in 1930 by We are covering the 1982 awards in two gynecologists, Raphael Kurzrok and five separate essays. The fiist dealt with Charles C. Lleb, both of Columbia Uni- the work of physics laureate Kenneth G. versity. 10 They observed a marked re- Wilson.5 The second focused on the sponsiveness of uterine smooth muscle work of chemistry prizewinner Aaron to an as yet unidentified substance in Klug.b Future essays will cover the semen. 11 However, they believed that prizes in economics and in literature. the activity they were measuring was due Before discussing the 1982 prize in to acetylcholine. It was Ulf S. von Euler, medicine, let me reiterate that citation Karolinska Institute, who first realized analysis cannot predict Nobel laureates. that this bioactivity was not due to any It is true that citation analysis can help known mediator or catalyst. 12By 1935, identify those individuals of Nobel class. von Euler showed that the mysterious And co-citation analysis does provide a substance in semen affected numerous modeling technique for forecasting the types of smooth muscles, and could growth and development of specialties lower the blood pressure of laboratory or disciplines. Indeed, we have seen that animals. 13,14 At that time, von Euler research front analysis helps identify the thought its presence in semen resulted fields that are eventually acknowledged from its production in the prostate. with a Nobel prize. But without confi- Thus, he named the compound “prosta- dential information it would be difficult glandin. “15 It was Von Euler who, in to predict which field or individual will 1947, urged Bergstrom to take up the be recognized in a particular year. formidable task of characterizing prosta- 77 glandin’s chemical structure. lb Signifi- former paper showed that PGs were in- cantly, von Euler shared a 1970 Nobel activated in a few seconds upon passage prize with Julius Axelrod, National Insti- through the pulmonary circulation. The tutes of Health, Bethesda, Maryland, latter paper reported the discovery of an and Bernard Katz, University College, unidentified substance that caused con- London, for work on neurotransmitters. tractions in strips of aorta material from Bergstrom quickly demonstrated that laboratory rabbits. Vane and Piper also the active principle in PGs was a new found that anti-inflammatory agents, type of highly active, lipid-soluble, un- such as aspirin, inhibited the release of saturated fatty acid. 17 Later known as PGS.29 arachidonic acid, th~ chain of hydrocar- Acting on these and other results, in bon molecules forms part of the struc- 1973 Samuelsson coauthored a paper ture of cellular membranes. It took with Mats Hamberg, Karolinska, show- Bergstrom and his coUeagues about ten ing that an endoperoxide compound is years to isolate pure crystals of two types formed as an intermediate step in the of PG. 18-21 In 1962, he and his Col- process of prostaglandin synthesis.~ leagues at Karolinska reported the Another paper by Samuelsson and sev- chemical structure of three PGs.ZZ It was eral Karolinska colleagues, published in this crucial breakthrough for which 1974, reported the isolation of two endo- Bergstrom was recognized by the Nobel peroxides, and elucidated their struc- committee.7 ture.sl These endoperoxides caused One of the coauthors of the landmark blood platelets to clump together, or ag- 1962 paper was Bergstrom’s student, gregate. They also caused a strip of rab- Bengt SamueLsson, who subsequently bit aorta to contract—although hun- participated in the structural elucidation dreds of times less strongly than the of other types of PGs. In 1962, Samuels- “rabbit-aorta contracting substance” son, Bergstrom, and others also collabo- found by Vane and Piper.zg,sl Later that rated on procedures by which all known same year, the results of an investigation prostaglandins can be isolated and iden- by Samuelsson and Hamberg on the oxy- tified.23 A year later, Samuelsson genation of arachidonic acid in human reported improvements in these pro- platelets provided evidence that endo- cedures, z’1and in 1964 he and Krister peroxides play a direct role in the regula- Green, Karolinska, succeeded in tion of cellular functions.sz We reported developing a method of quantifying the this paper as one of the 1974 articles production of PGs in the body by most cited during 1974. s3 ThM type of measuring their metabolites—the prod- study, incidentally, has proved to be one ucts of their breakdown-in blood or of the strongest predictive indicators urine.zs That same year, Samuelsson derived from chronological citation again collaborated with Bergstrom, as studies. well as with Henry Danielson, Karolin- Hamberg, Samuelsson, and Jan Svens- ska, on a detailed elucidation of the ox- son, also of Karolinska, next went on to ygenation of arachidonic acid .26 show that PG synthesis stops almost After setting up his own laboratory, completely at the endoperoxide stage Samuelsson began a series of investiga- when aspirin or indomethacin, an tions into the formation of PGs, and aspirin-like drug, is taken.~ In early their consumption by enzymes after only 1975, Samuelsson and colleagues report- a few minutes of existence. zTThis direc- ed the results of a further study into the tion was suggested in part by a 1967 mechanism of action of endoperoxides paperzB coauthored by John R. Vane in platelet aggregation. JS By mid-1975, and Sergio H. Ferreira, University of Samuelsson’s years of research on PG in- S%o Paulo, Brazil, and a 1969 paperzq by termediates bore fruit in a breakthrough Vane and Priscilla J. Piper, then of paper entitled “Thromboxanes: a new Royal College of Surgeons, London. The group of biologically active compounds 78 derived from prostaglandin endoperox- 25 most-cited papers of 1971.42 The dk- ides. ”sb Coauthored with Hamberg and covery of the basis of aspirin’s therapeu- Svensson, the paper reported the discov- tic activity is one of the major accom- ery of thromboxane A2, the unstable in- plishments for which Vane was cited by termediate formed during the conver- the Nobel committee, which credited sion of prostaglandin G2 into thrombox- him with providing a powerful approach ane B2. From the time of its publication to understanding the possible role PGs through 1983, it has received 1,330 cita- play in a variety of biological events, in- tions, according to Science Citation In- cluding, for example, rheumatoid arthri- dex@ (SCF ). This paper was featured as tis.dd a Citation Classic’” last year in Current Vane’s other major accomplishment Contents@ /Life Sciences.37 Thrombox- cited by the Nobel committee was his ane A2 proved to be the mysterious discovery of prostacyclin and its proper- substance that so powerfully contracted ties. Prostacyclin is also a PG derived rabbh aorta tissue and caused blood from arachidonic acid, but has the oppo- platelets to clump together, as reported site effect of thromboxane—rather than in the 1974 paper on the isolation and promoting the aggregation of platelets, structure of two new endoperoxides.Jl it inhibits their clumping together. 44 While Samuelsson studied and clar- Thromboxane and prostacyclin carry on ified the biological processes of PG for- a delicate balancing act to regulate clot mation, Vane was investigating the role formation. They are under study for PGs play in the body. The 1967 paper on possible use in the prevention of heart the disappearance of PGs in the pulmo- disease and stroke. nary circulation,zs a Citation Classic ,38 As already indicated by data for spe- also confirmed that PGs are released cific papers, it is somewhat redundant to into the venous bloodstream when the say that these scientists are highly cited. spleen contracts. As a direct result of his Bergstrom’s work, collectively, has been interest in the release and fate of PGs cited at least 3,600 times since 1955. He in the body, and of his discovery of the was among the 250 most-cited primary rabbit-aorta contracting substance in authors for the period from 1961 1969,2$’Vane was led to the idea that as- through 1975.4S Among his most-cited pirin might interfere with the biosynthe- works, Bergstrom’s earliest papers deal sis of PGs.39 In a 1971 article in Nature with rat liver bile acidsdG and steroids.’4T New Bio[ogy, he clearly demonstrated By 1959, however, he had published a this inhibition in cell-free preparations, paper on the effects of an infusion of and proposed that the therapeutic ef- prostaglandin E in volunteer subjects,da fects of aspirin and aspirin-like drugs are coauthored with von Euler and several due to their ability to inhibit the enzymes other Karolinska colleagues.
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