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The winners: Robert Furchgott (left), Louis Ignarro and Ferid Murad. Credit: AP/ADAM NADEL/PAT SULLIVAN

The Nobel committee has once again sparked controversy, particularly in Britain, with the award this week of the 1998 prize for physiology or medicine to pharmacologists Robert Furchgott, of the State University of New York, Louis Ignarro, of the University of California, Los Angeles, and Ferid Murad, of University of Texas Medical 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 cardiovascular system (see box) deserves the recognition of the committee. But many feel that a fourth name should also have been recognized — that of Salvador Moncada, currently director of the Wolfson Institute for Biomedical Research at University College London.

Moncada: disappointed at lack of recognition. Credit: UCL

The controversy originates in 1987, when a paper by Ignarro confirming the identity of endothelium-derived relaxing factor (EDRF) and nitric oxide, as had been hypothesized separately by him and Furchgott, appeared in the Proceedings of the National Academy of Sciences (84, 9265-9269; 1987).

The publication came six months after a similar report in Nature by Moncada and colleagues, working in London, who had already concluded that EDRF and nitric oxide were identical (see Nature 327 524–526; 1987). Writing in the same issue of Nature, Paul Vanhoutte, then at the Mayo Clinic in Rochester, Minnesota, acclaimed the finding as “the climax of one of the most exciting sagas in vascular physiology and pharmacology”. Moncada's achievements were recognized when he was elected as a foreign associate of the National Academy of Sciences in 1994. The citation says that he “discovered that mammalian vascular tissues generate nitric oxide that is biosynthesized from L-arginine. He elucidated the relevance of this pathway as a universal transduction mechanism for the regulation of cell function and communication”.

Moncada expressed surprise on Monday (12 October) at the decision of the Nobel committee to award the medicine prize to Furchgott, Murad and Ignarro. His disappointment was shared by Sir John Vane, joint winner of the 1982 Nobel prize for his work on prostaglandins.

Although delighted that the committee has recognized the importance of the nitric oxide field, Vane expressed regret that Moncada's contributions were not acknowledged. But he believes that the prize is thoroughly deserved by Furchgott — without whom “the field would not even exist” — and says that he had nominated both Furchgott and Ignarro for the prize.

More outspoken support for Moncada comes from Nobel laureate Cesar Milstein of the MRC Laboratory of Molecular Biology in Cambridge. Milstein won the 1984 Nobel prize for his work on monoclonal antibodies, and dug deep into the nitric oxide literature following the award in 1996 of the prestigious Albert Lasker Medical Research Award to Furchgott and Murad.

Milstein argues on the basis of his investigations that Moncada was the first to take seriously the suggestion by Furchgott and Ignarro that EDRF might be identical with nitric oxide — and did the key experiments that made the earlier hypothesis physiologically meaningful.

Characterizing the decision as “scandalous”, Milstein argues that the committee made a serious blunder by excluding Moncada from the awards.

Milstein says he does not believe that the omission of Moncada will seriously damage British research. But he regrets that this research will not get the fillip it deserves, and admits that the omission leaves him “uneasy about the way that recognition is being given at the level of major prizes, and in terms of careers and publications”.

Not all researchers are as critical. Jonathan Stamler, of Duke University Medical Center in North Carolina, who also works on nitric oxide in the cardiovascular system, says he is very pleased that the work of Furchgott, Ignarro and Murad has been recognized.

Stamler accepts that Moncada “had the vision to appreciate the field in the broader sense and to shoulder the burden of later research”. But he believes that earlier work had already opened the way for the later discoveries, as the Nobel committee has recognized.

Solomon Snyder of Johns Hopkins University in Baltimore, Maryland, says he agrees with this interpretation, and accepts 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 nitroglycerin is nitric oxide, leading drug companies to search for other drugs that could release the gas.

Ironically, Alfred Nobel, the inventor of dynamite — in which the explosiveness of nitroglycerin is kept in check by a porous material composed of diatoms — was ordered by his doctor to “eat” nitroglycerin for a heart condition, but refused to take it.

Nitroglycerin is a potent drug now used in the treatment of angina. Just 0.5 mg placed under the tongue can make a patient suffering an angina attack feel better within minutes, due to the dilation of the affected blood vessels.

It is now clear that nitric oxide is the major determinant of blood pressure. But its medical significance does not stop there. In 1992 Snyder and colleagues showed that nitric oxide synthase (NOS), the enzyme that produces nitric oxide, is expressed in neurons in the penis and that nitric oxide mediates erectile function.