NOBELFÖRSAMLINGEN KAROLINSKA INSTITUTET
THE NOBEL ASSEMBLY AT KAROLINSKA INSTITUTET
October 12, 1998
The Nobel Assembly at Karolinska Institutet has today decided to award
the Nobel Prize in Physiology or Medicine for 1998 jointly to
Robert F. Furchgott, Louis J. Ignarro and Ferid Murad
for their discoveries concerning "nitric oxide as a signalling molecule in the cardiovascular system".
Nitric oxide (NO) is a gas that transmits signals in the organism. Signal transmission by a gas that is produced by one cell, penetrates through membranes and regulates the function of another cell represents an entirely new principle for signalling in biological systems. The discoverers of NO as a signal molecule are awarded this year's Nobel Prize.
Robert F Furchgott, pharmacologist in New York, studied the effect of drugs on blood vessels but often achieved contradictory results. The same drug sometimes caused a contraction and at other occasions a dilatation. Furchgott wondered if the variation could depend on whether the surface cells (the endothelium) inside the blood vessels were intact or damaged. In 1980, he demonstrated in an ingenious experiment that acetylcholine dilated blood vessels only if the endothelium was intact. He concluded that blood vessels are dilated because the endothelial cells produce an unknown signal molecule that makes vascular smooth muscle cells relax. He called this signal molecule EDRF, the endothelium-derived relaxing factor, and his findings led to a quest to identify the factor.
Ferid Murad, MD and pharmacologist now in Houston, analyzed how nitroglycerin and related vasodilating compounds act and discovered in 1977 that they release nitric oxide, which relaxes smooth muscle cells. He was fascinated by the concept that a gas could regulate important cellular functions and speculated that endogenous factors such as hormones might also act through NO. However, there was no experimental evidence to support this idea at the time.
Louis J Ignarro, pharmacologist in Los Angeles, participated in the quest for EDRF's chemical nature. He performed a brilliant series of analyses and concluded in 1986, together with and independently of Robert Furchgott, that EDRF was identical to NO. The problem was solved and Furchgott's endothelial factor identified.
When Furchgott and Ignarro presented their conclusions at a conference in July, 1986, it elicited an avalanche of research activities in many different laboratories around the world. This was the first discovery that a gas can act as a signal molecule in the organism.
Nitric oxide protects the heart, stimulates the brain, kills bacteria, etc.
It was a sensation that this simple, common air pollutant, which is formed when nitrogen burns, for instance in automobile exhaust fumes, could exert important functions in the organism. It was particularly surprising since NO is totally different from any other known signal molecule and so unstable that it is converted to nitrate and nitrite within 10 seconds. NO was known to be produced in bacteria but this simple molecule was not expected to be important in higher animals such as mammals.
Further research results rapidly confirmed that NO is a signal molecule of key importance for the cardiovascular system and it was also found to exert a series of other functions. We know today that NO acts as a signal molecule in the nervous system, as a weapon against infections, as a regulator of blood pressure and as a gatekeeper of blood flow to different organs. NO is present in most living creatures and made by many different types of cells.
- When NO is produced by the innermost cell layer of the arteries, the endothelium, it rapidly spreads through the cell membranes to the underlying muscle cells. Their contraction is turned off by NO, resulting in a dilatation of the arteries. In this way, NO controls the blood pressure and its distribution. It also prevents the formation of thrombi.
- When NO is formed in nerve cells, it spreads rapidly in all directions, activating all cells in the vicinity. This can modulate many functions, from behaviour to gastrointestinal motility.
- When NO is produced in white blood cells (such as macrophages), huge quantities are achieved and become toxic to invading bacteria and parasites.
Importance in medicine today and tomorrow
Heart: In atherosclerosis, the endothelium has a reduced capacity to produce NO. However, NO can be furnished by treatment with nitroglycerin. Large efforts in drug discovery are currently aimed at generating more powerful and selective cardiac drugs based on the new knowledge of NO as a signal molecule.
Shock: Bacterial infections can lead to sepsis and circulatory shock. In this situation, NO plays a harmful role. White blood cells react to bacterial products by releasing enormous amounts of NO that dilate the blood vessels. The blood pressure drops and the patient may become unconscious. In this situation, inhibitors of NO synthesis may be useful in intensive care treatment.
Lungs: Intensive care patients can be treated by inhalation of NO gas. This has provided good results and even saved lives. For instance, NO gas has been used to reduce dangerously high blood pressure in the lungs of infants. But the dosage is critical since the gas can be toxic at high concentrations.
Cancer: White blood cells use NO not only to kill infectious agents such as bacteria, fungi and parasites, but also to defend the host against tumours. Scientists are currently testing whether NO can be used to stop the growth of tumours since this gas can induce programmed cell death, apoptosis.
Impotence: NO can initiate erection of the penis by dilating the blood vessels to the erectile bodies. This knowledge has already led to the development of new drugs against impotence.
Diagnostic analyses: Inflammatory diseases can be revealed by analysing the production of NO from e.g. lungs and intestines. This is used for diagnosing asthma, colitis, and other diseases.
NO is important for the olfactory sense and our capacity to recognise different scents. It may even be important for our memory.
Alfred Nobel invented dynamite, a product in which the explosion-prone nitroglycerin is curbed by being absorbed in kieselguhr, a porous soil rich in shells of diatoms. When Nobel was taken ill with heart disease, his doctor prescribed nitroglycerin. Nobel refused to take it, knowing that it caused headache and ruling out that it could eliminate chest pain. In a letter, Nobel wrote: It is ironical that I am now ordered by my physician to eat nitroglycerin. It has been known since last century that the explosive, nitroglycerin, has beneficial effects against chest pain. However, it would take 100 years until it was clarified that nitroglycerin acts by releasing NO gas.
Nobel Prize Awarded to Scientists for Nitric Oxide Discoveries
Nitric oxide was named "Molecule of the Year" in 1992 by the journal Science, but it took another 6 years for those responsible for the major discoveries surrounding it to win the Nobel Prize. Three US scientists—Robert F. Furchgott, PhD, Louis J. Ignarro, PhD, and Ferid Murad, MD, PhD—will receive the 1998 Nobel Prize for Physiology and Medicine on December 10, 1998, in Stockholm, Sweden.
The discovery of nitric oxide's signaling role in the cardiovascular and nervous systems is now nearly 20 years old, but its clinical use is only beginning. Dr Furchgott, a distinguished professor of pharmacology at the State University of New York (SUNY) at Brooklyn, began the studies that led to the identification of nitric oxide as a biological agent in 1980. At that time, he was trying to reconcile the contradictory effects drugs had on blood vessels. He concluded that endothelial cells produce an unknown signal molecule that makes vascular smooth muscle cells relax. He called the signal molecule EDRF, or endothelium-derived relaxing factor.
In unrelated experiments, Dr Murad, now chairman of the integrative biology department at the University of Texas Medical School at Houston, was analyzing how nitroglycerin works. In 1977, while at the University of Virginia, he found that nitrates release nitric oxide, which relaxes smooth muscle cells, resulting in vasodilation. He was fascinated that the colorless, odorless gas could act as a signaling molecule.
Dr Ignarro, now a professor of pharmacology at UCLA School of Medicine in Los Angeles, California, through a series of analyses concluded in 1986 that EDRF was identical to nitric oxide. His work, done independently and together with that of Dr Furchgott, prompted an increase in research activities in many areas of the world.
The Nobel committee could recognize only 3 scientists, and their decision not to name Salvador Moncada, PhD, a professor at University College London, as one of the awardees provoked some comment. The controversy was similar to that when the Albert Lasker Awards were announced in 1996. At that time, Drs Murad and Furchgott were the awardees, and omission of Drs Ignarro and Moncada aroused comment. However, Dr Moncada has made no protest. Michael E. DeBakey, MD, chairman emeritus of the Lasker Award jury, said Murad and Furchgott received that prize because the work represents "a fundamental finding affecting the circulation. It is a fundamental and important observation."
Dr Furchgott, 82, said he was mildly surprised to have won the Nobel prize because most such prizes go to more popular areas, such as molecular research. He described himself as an old-fashioned pharmacologist.
Dr Murad, 62, who had held his University of Texas position only 18 months when the prize was announced, said he had been called by the secretary of the Nobel committee at 4 AM Central Standard Time. He rushed upstairs to shower and don a coat and tie before photographers appeared at the door.
"It's fantastic to recognized by one's peers," he said. "I'd like to share this with so many of the trainees who have worked with me over the years.
What the Nobel prize recognized was the scientists' dogged efforts to prove that nitric oxide, an endogenous gas and also a free radical, could have this kind of crucial biological effect. Research has proven the crucial role the gas plays in such fundamental biological processes as regulation of blood pressure, functioning and malfunctioning of the immune system, and activation of mechanisms in the central nervous system affecting everything from gastric motility to memory to behavior.
Long known only as an air pollutant, nitric oxide and its related enzymes could one day provide the basis for the development of drugs that could treat everything from Alzheimer's disease to high blood pressure. Its inhibition could play a role in treatment of sepsis and dangerous hypotension, and the ability to increase its activity might lead to a treatment for hypertension.
Each of the recipients of this year's Nobel prize has a distinguished career in research. Dr Furchgott, born June 4, 1916, in Charleston, SC, received his BS from the University of North Carolina and his PhD in biochemistry at Northwestern University in Chicago, Ill. He began his career at SUNY-Brooklyn in 1956 and has continued there ever since. He holds honorary doctorates at several universities and is the recipient of numerous awards other than the Lasker and the Nobel.
Dr Murad, born September 14, 1936, in Whiting, Ind, received his undergraduate degree from DePauw University in Greencastle, Ind. His MD and PhD in pharmacology were received from Western Reserve University School of Medicine in Cleveland, Ohio. He did his residency at Massachusetts General Hospital in Boston. He served as professor and director of clinical research at the University of Virginia School of Medicine in Charlottesville and was director of the division of clinical pharmacology there from 1975 to 1981.
From Virginia, Dr Murad went to Stanford University in California in 1981, where he was a professor of internal medicine and pharmacology until 1989. He served as chief of medicine at the Palo Alto Veterans Administration Medical Center from 1981 until 1986. In 1990, he became vice president for pharmaceutical research and development at Abbott Laboratories in Illinois and served as an adjunct professor in the department of pharmacology at Northwestern University Medical School in Chicago. In 1993, he started his own biotech firm, called Molecular Geriatrics Corporation, in Lake Bluff, Ill, but he left the post of president there to return to academia at the University of Texas at Houston in 1997.
Dr Ignarro was born May 31, 1941, in Brooklyn, NY. He obtained his BA in pharmacy at Columbia University in New York, NY, and his PhD in pharmacology at the University of Minnesota. From 1979 to 1985, he was a professor in the department of pharmacology at Tulane University School of Medicine in New Orleans, La. In 1985, he joined the faculty of the department of pharmacology at UCLA, where he is currently a professor. Dr Ignarro was out of the country when the Nobel award was announced.