MAGIC MOLECULE

October 12, 1998
	Robert Furchgott, Ferid Murad, and Louis Ignarro were awarded the Nobel Prize for their research on the effects of nitric oxide on blood vessels. Elizabeth Farnsworth talks to Dr. John Cooke of Stanford University about the scientists' contributions to medical science.

Oct. 9, 1998: A discussion of Nobel Prize-winning author José Saramago May 7, 1998: A look at the demand for Viagra. March 9, 1998: A conversation with Nobel Prize Winner in Literature Toni Morrison Oct. 15, 1997: Nobel Prize winner in Physics Steven Chu. Oct. 10, 1997: A discussion with Nobel Peace Prize Winner Jody Williams. Oct. 4, 1996: A discussion on the 1996 Nobel Prize for Literature Winner Wislawa Szymborska. Browse the Online NewsHour's coverage of science.   Winners of the Nobel Prize from 1900-1998 Swedish Academy The Nobel Channel, a site dedicated to this history of the Nobel prize	ELIZABETH FARNSWORTH: The prize this year went to three American scientists for their discoveries about the role of nitric oxide in regulating blood vessels. The laureates are Robert Furchgott of the State University of New York in Brooklyn; Ferid Murad of the University of Texas Medical School in Houston; and Louis Ignarro of the University of California Los Angeles School of Medicine. And with me now to explain their work is Dr. John Cooke, Director of Vascular Medicine at the Stanford University School of Medicine. Thanks for being with us. JOHN COOKE, Stanford University School of Medicine: My pleasure. ELIZABETH FARNSWORTH: This was a bit of a scientific mystery story, wasn't it? Explain their discovery. JOHN COOKE: This was a great story. Bob Furchgott was in his laboratory and found that the blood vessel was doing something extraordinary. There was something it was releasing that was causing the vessel to relax. With a lot of work, he discovered that this relaxing factor was coming from the lining of the vessel - the endothelium - relaxing factor he tried to characterize here, but was so short-lived he really couldn't get a handle on it. And it wasn't until six years later actually that it was discovered to be nitric oxide. So for a short time there - for six years - it was called Endothelium Derived Relaxing Factor, or EDRF, because no one knew what it was. ELIZABETH FARNSWORTH: And how did they discover it was nitric oxide? And, by the way, what is nitric oxide?
	A gas that affects blood vessels.
	JOHN COOKE: Nitric oxide, NO - I'll refer to it as NO - is a simple molecule, has two atoms - nitrogen and oxygen. But it does an incredible array of things. ELIZABETH FARNSWORTH: First of all, it's a gas, right? JOHN COOKE: It's a gas. ELIZABETH FARNSWORTH: We know it as the byproduct of the automobile exhaust fume, but this is also inside of our bodies? JOHN COOKE: Yes. Our blood vessels make nitric oxide. It's a potent facile dilator, and this is how it was discovered, because it has this characteristic of relaxing blood vessels. ELIZABETH FARNSWORTH: Okay now we've got some pictures. Let's look at blood vessels and explain what we're seeing and what it is that these scientists discovered and got a Nobel Prize for. JOHN COOKE: Okay. This is - we're in our laboratory. We're looking at a rabbit iliac artery, a blood vessel, by video microscopy, and you can see this blood vessel is - it's contracted to norepenephrine. It's alive. It's functioning. It can contract and relax. Now what we do is we pass a little bit of flow through it, and you can see that the vessel relaxes in response to that flow. ELIZABETH FARNSWORTH: And by relax, you mean it gets bigger. JOHN COOKE: It gets bigger. The endothelium, the lining of the vessel, is able to sense that flow and - ELIZABETH FARNSWORTH: The flow of - JOHN COOKE: The flow of blood - through the vessel - and in response to that, the vessel relaxes. ELIZABETH FARNSWORTH: But where's the nitric oxide come in? JOHN COOKE: The nitric oxide is coming from the endothelium. The endothelium responds to the blood flow through it by releasing nitric oxide. ELIZABETH FARNSWORTH: Okay. Why was this such a big deal? I noticed that the Nobel assembly that released the prize in their press release said it was sensational.
	A scientific sensation.
	JOHN COOKE: Well, it's a great discovery and it's going to have tremendous ramifications in American medicine - in medicine throughout the world. Nitric oxide is - as I said - a potent facile dilator. It controls blood flow. It controls our vascular resistance - blood pressure - so that when you have - when you're making sufficient amounts if nitric oxide, your blood vessels are relaxed, your blood pressure is low. If you're not making enough or it's inactivated, you make - your blood vessels become contracted and your blood pressure rises. So this is an important feature of the blood vessels - ability to control its own diameter. ELIZABETH FARNSWORTH: Until these discoveries that they made - and these were mostly in the early 80s and mid-80s, right? JOHN COOKE: That's right. ELIZABETH FARNSWORTH: Nobody knew exactly - I mean, we knew that nitroglycerine could help prevent a heart attack. JOHN COOKE: Yes. ELIZABETH FARNSWORTH: Right. But you didn't realize that it was causing the release of nitric oxide? JOHN COOKE: Well, that work - actually, that work was done by Ferid Murad, and Murad was able to show that nitroglycerine and these other agents worked by causing - by releasing nitric oxide and stimulating an enzyme in the vessel wall called guanalade cyclase. And then Ignarro, the third individual that received the prize, discovered that NO donors increased - NO increased the cyclic GNP - the second messenger in the blood vessel to cause the relaxation, so together these three individuals worked out the whole pathway of how nitric oxide induces facile dilation, relaxes blood vessels. ELIZABETH FARNSWORTH: Okay. So tell us some of the implications. For example, in your field you're a cardiovascular doctor. Do you try to get more nitric oxide into people who are, for example, having their - that are, for example, having hardening of the arteries?
	Treatment for arteriosclerosis.
	JOHN COOKE: Well, as you mentioned, Elizabeth, nitroglycerine is something that releases nitric oxide and relaxes people's vessels, and that can improve their blood pressure; it can relieve their chest pain by opening up their heart vessels and improving flow. Normally, in a person who does not have hardening of the arteries, your blood vessels make sufficient amounts of nitric oxide so you obviously don't need to take the medicine. So there's two ways that you can improve the status of someone that has hardening of the arteries. You can give nitric oxide - nitroglycerin in a pill, or you can improve the release of nitric oxide from the blood vessels themselves and enhance the body's ability to make nitric oxide, or protect nitric oxide from being broken down. ELIZABETH FARNSWORTH: And that's what you're doing in your lab here, basically building on your research? JOHN COOKE: That's right. We've - we're basically - they've built a very strong foundation to move into new applications now for cardiovascular disease and for other fields as well. My own work suggests that nitric oxide can - is our self-defense system against athrosclerosis. You see, the endothelial lining of the vessel is like Teflon. It keeps things from sticking to the vessel wall. The reason it has this property of Teflon is because it releases nitric oxide, so it's a non-sticky surface because it's releasing nitric oxide, which not only relaxes the blood vessel but also prevents things from sticking to the vessel. ELIZABETH FARNSWORTH: Now, the wires about this today all mentioned that the research led to the medication Viagra too, which can help people with impotence. How does that work?
	A myriad of other medical uses.
	JOHN COOKE: Well, Viagra assists the action of nitric oxide. As I mentioned to you earlier, nitric oxide causes a second messenger to be produced, this cyclic GNP, and Viagra prevents the breakdown of cyclic GNP, so it magnifies the effect of nitric oxide. Well, as I mentioned to you, nitric oxide is a potent facile dilator, and facile dilation increased blood flow - ELIZABETH FARNSWORTH: And by that you mean it makes the - it causes the relaxation of the blood vessels. JOHN COOKE: That's right. It relaxes blood vessels. And maletumescence - it requires increased blood flow for that, so this is why Viagra works. It improves blood flow to that part of the body. ELIZABETH FARNSWORTH: And another use, I noticed, is for babies, what we used to call blue babies, babies that are in respiratory failure. JOHN COOKE: Yes, that's right. ELIZABETH FARNSWORTH: How does this nitric oxide help babies? JOHN COOKE: Well, what they do for children that have this problem is they try to improve the blood flow to the lung and they do that actually by putting the nitric oxide gas in the oxygen that the children are inhaling, small amounts, very small amounts, because it's very powerful, and those small amounts of nitric oxide will cause the lung vessels to open up, improving lung blood flow and improving the oxygenation of the blood, getting more oxygen in the blood for the baby. ELIZABETH FARNSWORTH: What about halting tumor growth? I saw some indication that perhaps nitric oxide could even help with cancer. JOHN COOKE: Right. I think it was Ferid Murad that mentioned that today - and what he's referring to is the fact that nitric oxide is part of the body's self-defense mechanism. I mentioned hardening of the arteries but it also defends against bacteria. It also defends against tumor cells. NO in high concentrations can actually halt the growth of cells or can halt bacterial growth, so it's a defense against infection, it's a defense against tumor, it's a defense against hardening of the arteries. ELIZABETH FARNSWORTH: And just briefly, is there a down side to this, people should be worried about getting too much NO, right? Nitric oxide can be dangerous?
	Too much of a good thing.
	JOHN COOKE: Nitric oxide is dangerous under certain circumstances, but these are very unusual sepsis. When the body is confronted by overwhelming infection, the body in response to that makes a lot of nitric oxide and that can cause the blood pressure to drop. ELIZABETH FARNSWORTH: And just at the very end here, it's not nitrous oxide, which we know as laughing gas. It's quite different, isn't it? JOHN COOKE: Nitric oxide is NO. Nitrous oxide is something different. But it's also a gas, and it also causes blood vessels to relax. Nitric oxide is somewhat different. ELIZABETH FARNSWORTH: Well, Dr. Cooke, thanks very much. JOHN COOKE: My pleasure, Elizabeth.