Nobel Award Stirs up Debate on Nitric Oxide Breakthrough
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news Nobel award stirs up debate on nitric oxide breakthrough [LONDON] The Nobel committee has once again sparked controversy, particularly in Britain, with the award this week of the 1998 8 prize for physiology or medicine to pharma- cologists Robert Furchgott, of the State Uni- versity of New York, Louis Ignarro, of the University of California, Los Angeles, and Ferid Murad, of University of Texas Medical SULLIVAN NADEL/PAT AP/ADAM School in Houston. No-one is disputing that the pioneering work of the three US researchers on nitric oxide as a signalling molecule in the cardio- vascular system (see box) deserves the recog- nition of the committee. But many feel that a The winners: Robert Furchgott (left), Louis Ignarro and Ferid Murad. fourth name should also have been recog- nized — that of Salvador Moncada, currently pharmacology”. Moncada’s achievements edged. But he believes that the prize is thor- director of the Wolfson Institute for Biomed- were recognized when he was elected as a oughly deserved by Furchgott — without ical Research at University College London. foreign associate of the National Academy of whom “the field would not even exist” — The controversy originates in 1987, when Sciences in 1994. The citation says that he and says that he had nominated both Furch- a paper by Ignarro confirming the identity “discovered that mammalian vascular tis- gott and Ignarro for the prize. of endothelium-derived relaxing factor sues generate nitric oxide that is biosynthe- More outspoken support for Moncada (EDRF) and nitric oxide, as had been sized from L-arginine. He elucidated the rel- comes from Nobel laureate Cesar Milstein of hypothesized separately by him and Furch- evance of this pathway as a universal trans- the MRC Laborato- UCL gott, appeared in the Proceedings of the duction mechanism for the regulation of cell ry of Molecular National Academy of Sciences (84, function and communication”. Biology in Cam- 9265–9269; 1987). Moncada expressed surprise on Monday bridge. Milstein The publication came six months after a (12 October) at the decision of the Nobel won the 1984 Nobel similar report in Nature by Moncada and committee to award the medicine prize to prize for his work on colleagues, working in London, who had Furchgott, Murad and Ignarro. His disap- monoclonal anti- already concluded that EDRF and nitric pointment was shared by Sir John Vane, joint bodies, and dug oxide were identical (see Nature 327, winner of the 1982 Nobel prize for his work deep into the nitric 524–526; 1987). Writing in the same issue of on prostaglandins. oxide literature fol- Nature, Paul Vanhoutte, then at the Mayo Although delighted that the committee lowing the award in Clinic in Rochester, Minnesota, acclaimed has recognized the importance of the nitric Moncada: disappointed 1996 of the presti- the finding as “the climax of one of the most oxide field, Vane expressed regret that Mon- at lack of recognition. gious Albert Lasker exciting sagas in vascular physiology and cada’s contributions were not acknowl- Medical Research Award to Furchgott and Murad. Hidden role of a gas of many parts Milstein argues on the basis of his investi- gations that Moncada was the first to take [LONDON] Interest in nitric of the blood vessel — was the gas could activate seriously the suggestion by Furchgott and oxide has exploded in recent intact (see Nature 288, guanylate cyclase, the Ignarro that EDRF might be identical with years due to the recognition 373–376; 1980). The enzyme that mediates the nitric oxide — and did the key experiments that the gas plays an implication was that a signal production of the signalling that made the earlier hypothesis physiologi- important role in many molecule was being released molecule cyclic GMP. cally meaningful. physiological processes, and by endothelial cells and Murad also showed that Characterizing the decision as “scan- that manipulating the nitric acting on the muscle cells, nitroglycerin and other dalous”, Milstein argues that the committee oxide signalling pathway can and Furchgott called the vasodilating drugs released made a serious blunder by excluding Monca- have major medical benefits. postulated molecule nitric oxide. But the da from the awards. But, only 30 years ago, the endothelium-derived relaxing physiological relevance of Milstein says he does not believe that the idea that a gas could have factor – EDRF. this discovery remained omission of Moncada will seriously damage biological functions would The link with nitric oxide unknown. The various links British research. But he regrets that this have seemed far-fetched. was not immediately in the story were only pulled research will not get the fillip it deserves, and In 1980, Robert Furchgott obvious. EDRF was highly together at a conference in admits that the omission leaves him “uneasy reported that acetylcholine labile, and candidate 1986 when Furchgott and about the way that recognition is being given could contract or relax the molecules, such as Louis Ignarro, who had been at the level of major prizes, and in terms of smooth muscle surrounding prostacyclin and other working independently of careers and publications”. blood vessels, but that this prostanoids, were soon ruled each other, hypothesized that Not all researchers are as critical. relaxation only occurred if out. But in the 1970s Ferid EDRF and nitric oxide were Jonathan Stamler, of Duke University Med- the endothelium — the lining Murad had discovered that identical. R. H. ical Center in North Carolina, who also works on nitric oxide in the cardiovascular NATURE | VOL 395 | 15 OCTOBER 1998 | www.nature.com 625 Nature © Macmillan Publishers Ltd 1998 news system, says he is very pleased that the work of Furchgott, Ignarro and Murad has been Physicists rewarded for recognized. Stamler accepts that Moncada “had the vision to appreciate the field in the broader ‘fractional electrons’ sense and to shoulder the burden of later research”. But he believes that earlier work had Physics laureates: AP already opened the way for the later discover- Robert Laughlin (left) ies, as the Nobel committee has recognized. shortly after hearing of8 Solomon Snyder of Johns Hopkins Uni- his award, Daniel Tsui versity in Baltimore, Maryland, says he (centre) and Horst agrees with this interpretation, and accepts Störmer. that the committee would have done much scholarly work before making its decision. He says the medical significance of Murad’s work on nitroglycerin is enormous. Murad showed that the active metabolite of [LONDON] This year’s Nobel prize for physics In 1980 Klaus von Klitzing found that, nitroglycerin is nitric oxide, leading drug has been awarded to the researchers who first when the charge carriers are confined within a companies to search for other drugs that observed and explained the fractional quan- very thin conducting film (that is, in two could release the gas. tum Hall effect. This is the effect in which an dimensions), the magnitude of the Hall cur- Ironically, Alfred Nobel, the inventor of electric current within a two-dimensional rent (or, equivalently, the conductance of the dynamite — in which the explosiveness of conducting material appears to be made up material) no longer varies smoothly with mag- nitroglycerin is kept in check by a porous of charge carriers bearing a fraction of the netic-field strength at very low temperatures. material composed of diatoms — was charge on an electron. Instead, the conductance varies with field ordered by his doctor to “eat” nitroglycerin Horst Störmer of Columbia University, strength in a series of abrupt steps. In other for a heart condition, but refused to take it. New York, and Bell Laboratories, and Daniel words, the conductance is quantized: it Nitroglycerin is a potent drug now used in Tsui of Princeton University, who both saw changes in integral multiples of the funda- the treatment of angina. Just 0.5 mg placed the effect experimentally in 1982, share the mental quantum unit of conductance, e2/h under the tongue can make a patient suffering prize with Robert Laughlin of Stanford Uni- (where e is the charge on the electron and h is an angina attack feel better within minutes, versity, California, who provided a theoreti- Planck’s constant). due to the dilation of the affected blood vessels. cal explanation shortly afterwards. The fractional quantum Hall effect repre- It is now clear that nitric oxide is the The standard Hall effect is the lateral sents a deeper puzzle, since it seems to reveal major determinant of blood pressure. But its deflection of moving charge carriers — an a change in the nature of the fundamental medical significance does not stop there. In electric current — in a magnetic field. It was particles. Much the same can be said of 1992 Snyder and colleagues showed that discovered in 1879 by Edwin Hall, and today superconductivity, in which electrons nitric oxide synthase (NOS), the enzyme that provides the basis for determining the charge appear to attract one another (or, more produces nitric oxide, is expressed in neu- and density of charge carriers in a semicon- properly, to show bosonic instead of fermi- rons in the penis and that nitric oxide medi- ductor (electrons and holes are deflected in onic behaviour), and of superfluidity, in ates erectile function. Rory Howlett different directions). which the atoms of the superfluid no longer generate viscosity. The FQHE was seen by Tsui and Störmer for the transport of a two-dimensional elec- Theoretical chemistry makes its mark tron ‘gas’ in a semiconductor heterostructure [LONDON] The award of the Nobel prize for electronic band structures fabricated by Art Gossard, now at the Univer- chemistry to Walter Kohn of the University of solids, and also in sity of California at Santa Barbara. On apply- of California at Santa Barbara and John liquid-state physics.