From Pipe Bombs to Viagra: Nobel Prize Winner’s Secrets Revealed - Lou Ignarro - #521

Please join my mailing list here 👉 https://briankeating.com/list to win a meteorite 💥 Lou Ignarro went from building pipe bombs as a curious teen to winning the Nobel Prize for discovering how a gas—nitric oxide—regulates blood flow, fuels Viagra, and revolutionized cardiovascular medicine. In this explosive conversation, we trace how one molecule transformed sex, science, and the story of human health. Key Takeaways: 00:00 Intro 00:55 The molecule that saves and kills 04:00 The invention of the X-ray 05:44 Nitroglycerin: explosive or life-saving drug? 11:07 Fine-tuning and Lou’s religious beliefs 14:38 Judging a book by its cover 16:56 The importance of curiosity 20:00 Thoughts on the Nobel Prize 24:58 What does Viagra do and how does it work? 32:10 The importance of collaboration in scientific research 35:15 Achieving the breakthrough discovery 41:02 What happens if a woman takes viagra? 42:55 Other applications of nitric oxide 47:57 Lou’s heart-healthy diet 52:41 Outro Additional resources: ➡️ Follow Lou Ignarro: ✖️ Twitter: https://x.com/drignarro 📚 Dr. NO by Lou Ignarro: https://a.co/d/gSarIKX ➡️ My new book: 📖 Into the Impossible Volume 2: Focus Like a Nobel Prize Winner: Lessons from Laureates to Concentrate Your Creativity and Ignite Your Career: https://a.co/d/hi50U9U ➡️ Follow me on your fav platforms: ✖️ Twitter: https://twitter.com/DrBrianKeating 🔔 YouTube: https://www.youtube.com/DrBrianKeating?sub_confirmation=1 📝 Join my mailing list: https://briankeating.com/list ✍️ Check out my blog: https://briankeating.com/cosmic-musings/ 🎙️ Follow my podcast: https://briankeating.com/podcast — Into the Impossible with Brian Keating is a podcast dedicated to all those who want to explore the universe within and beyond the known. Make sure to follow/subscribe so you never miss an episode! Learn more about your ad choices. Visit megaphone.fm/adchoices

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Brian Keating?

  If you saw today's guest walking down the street, you might think retired grandfather, industrial scientist, maybe a professor, but here's what you wouldn't guess. He once made illegal pipe bombs in his basement and then discovered the molecule that powers certain other things that instead of taking down buildings, it's responsible for a certain type of erection, shall we say. Viagra. He won the Nobel Prize and he rewrote medical textbooks. What's so wonderful about this man, Lou Ignarro, is he's written a book called Dr. No. It's about a magical molecule that's in your blood right now and may be deficient in some of the listeners and we'll talk about ways we can improve our life. So

• 0:40Brian Keating?

  today's episode might save your life. It may make your life better and it might improve your sex life. Welcome to the podcast, Dr. Lou Ignarro. How are you today, sir?

• 0:51Speaker 01

  Fine, great. Thanks, Brian. It's such a pleasure to be here.

• 0:54Brian Keating?

  It's really wonderful. I love this book. It's incredible. It really teaches you not exactly, you know, how to win a Nobel Prize, kind of the antidote to my book. You know, if my book and your book come together, it's like antimatter, you know, losing the Nobel Prize, yours is winning the Nobel Prize, but it tells you what it's like, what it feels like to have the curiosity that unintentionally took you all the way to Stockholm. So I want to ask you the first question. You share something delightful with Alfred Nobel, the father of the most famous prize on earth. I would say more people respect the Nobel Prize, especially the Peace Prize, but I actually am not as impressed by some of the

• 1:33Brian Keating?

  Peace Prize winners I am by you and other scientists. What binds you to Alfred Nobel? Talk about what the two of you have in common, besides the prize that is eponymously named after him.

• 1:45Speaker 01

  Well, I think the thing that we have both in common is that, you know, he was noted for many things. He had 175 patents, I think. One of them was for dynamite because he used nitroglycerin as the active explosive in dynamite, which made nitroglycerin actually a very safe explosive to use. And I never used nitroglycerin.

• 2:10Speaker 01

  In terms of an explosive, but when I was young, I started to use ordinary gunpowder to make explosives. And for the first few years of my young childhood, I made firecrackers, rocket fuels, bombs. I read all about Nobel's nitroglycerin, but luckily, luckily, I didn't take the time to try to make some nitroglycerin to see if I could improve my firecrackers.

• 2:33Brian Keating?

  Isn't it ironic, Dalu, that, maybe poetically ironic, that the molecule can kill you can also save your life? How do you react to that knowledge, once you discovered this incredible breakthrough?

• 2:44Speaker 01

  Well, it was surprising. You know, it was very surprising. Normally, one would not think that. However, you know, to be successful in life, and I learned that a long time ago, you need to think outside the box. You know, you have to be very curious about things. And with nitroglycerin, we knew that it was a powerful, powerful explosive. But during the time that nitroglycerin was used to make dynamite, the physicians in the community of Stockholm in the 1800s noted that people who breathed in the fumes of nitroglycerin, it's a volatile oil, were relieved of their heart pain, it lowered the blood pressure, and so on. And so, you know, I tried to reckon with that and tried

• 3:28Speaker 01

  to understand, how is it that an explosive can prevent an impending heart attack? And that was the start of my career. Because we discovered, and I can talk about it later if you wish, but we discovered the way nitroglycerin works in your body to lower the blood pressure is by being metabolized or converted to this magic molecule, nitric oxide, or NO. And that was the start of my career.

• 4:00Brian Keating?

  Soon we'll get to the discovery of the downstream effects, no pun intended, and urology, and then sexual reproductive health. And we'll certainly talk about all of that, because your discovery is very much consonant with what Alfred Nobel wanted, right? He wanted discoveries that would be for the betterment of all mankind. And nowadays, we say humankind, but he said mankind. And certainly, your discoveries benefit mankind. And it wasn't just to be airy-fairy, blue-sky research for no purpose, although sometimes the prize has gone to that. But you point out That the very first prize went to a medically relevant device that is also responsible for some of the most energetic phenomenon in the universe. So talk about the invention

• 4:42Brian Keating?

  of the x-ray and maybe how that was paradigmatic of how what Nobel really wanted, which is to have discoveries, inventions that would make the life on earth by human beings better.

• 4:53Speaker 01

  I haven't really thought about it that way. But Alfred Nobel was a technical, technological person. He's into technology, right? Developing explosives, all sorts of other things, but related to explosives. And so he wanted the Nobel Prize to be awarded to those individuals who not only made original first-time discoveries, but also that discovery has to have been shown to be of prime benefit to mankind, as you said. And so here we have x-rays, a new technology. Renkin is the one who got the Nobel Prize, I believe in physics, for that. He developed a technique. He even took x-ray photographs of his hands with rings

• 5:37Speaker 01

  on it and so on, and that's been published. So that epitomizes Nobel and the Nobel Prizes. Thanks for bringing that up.

• 5:44Brian Keating?

  Yeah, and he wanted it for peaceful purposes as well, and obviously established the Peace Prize. But, you know, you made a bomb as a kid, and obviously dynamite, you know, he was tortured by this epitaph that he read that turned out to be his brother. But in this Parisian newspaper, one day he saw that he had died. I think it was 1889, like five years before he died. And it said Alfred Nobel, the man who killed more people than any other, the merchant of death is dead. And I couldn't help thanking God or whoever, Mother Earth, if you will, that, you know, it wasn't uranium that made vascular dilation take place. Because if it had, you might have made an atom bomb as a kid. And I always think about how, and you talk about aspirin, and you talk about other molecules

• 6:28Brian Keating?

  in the book, but there are very many similarities between something that's inherently deadly, explosive perhaps in the case of, you know, or anesthetic, like nitrous oxide, which is not what we're going to talk about today. Talk about how just the mere- Arrangement, sometimes the exact same isomer. Maybe you can explain that. What is an isomer?

• 6:46Speaker 01

  Well, I mean, I wish I could talk an hour about chemistry.

• 6:49Brian Keating?

  Yeah, we can. We can talk as long as you like.

• 6:51Speaker 01

  Chemistry is amazing. And even if you're not a chemist, even if you're just a, you know, a plumber, it doesn't make any difference. You have to understand that molecules are made out of atoms. Atoms are tiny little structures. And but every, every molecule that you know of, no matter what it is, whether it's testosterone or whether it's a, a, a drug that reduces blood pressure or whatever it is, these molecules have atoms. And what's incredible about chemistry is you could change one atom, one of hundreds of atoms, or change where it's located in the molecule, and that gives you completely different chemical and biological properties. So that kind of study of chemistry is very exciting

• 7:36Speaker 01

  and very important and necessary for the development of novel therapeutic strategies.

• 7:41Brian Keating?

  Nitroglycerin is highly unstable, and that's part of what Alfred Nobel wanted to do with his dynamite, you know, which means power rock, I think. So talk about the difference in those two different explosive use on one hand and medical use. So the heart and artery dilation. What is actually the difference in the molecular kind of way that the body is utilizing nitroglycerin or nitric oxide?

• 8:02Speaker 01

  Well, in, in the explosive, nitroglycerin is, you know, it's a chemical. It's a thick liquid and it's very sensitive to, to air, to oxidation. It's very sensitive to movement. Anything, and if you hit, if you, if you have some nitroglycerin in a little tablet or something, if it's pure nitroglycerin and you hit it with a hammer, it'll blow your hand off and the hammer and everything else. It's very, very explosive. But yet, if you take the same nitroglycerin, but in much, much smaller amounts.

• 8:34Speaker 01

  And you put it in your mouth or under your tongue. It does not explode. Instead, it dissolves into your body fluids. And it is converted by enzymes to a different molecule called nitric oxide. And it turns out that the nitric oxide is not explosive, but it can relax your arteries, lower the blood pressure, increase blood flow and do many other things. So the same molecule can do different things depending upon how you use it.

• 9:07Speaker 02

  Hey, everybody. I'm usually the one that asks my guests to judge their books by their covers. But today I'm asking myself to judge my own book by its cover. My newest book, Focus Like a Nobel Prize Winner, is chock full of advice, life tips, and focus and productivity tips from nine of the world's greatest minds, Nobel laureates ranging from economics to peace to physics, of course. It launches September 9th, which is also my birthday. So go to Amazon and get a Kindle copy today.

• 9:35Brian Keating?

  It can also be a poison. But how does it work as a poison, but also signaling the neuronal, you know, the brain, basically, in order to enhance these different functions like relaxation and so forth? How does the body know, you know, when enough is enough and when too much is too much of a good thing?

• 9:51Speaker 01

  Like I said before, right? The nitroglycerin itself in the body doesn't do anything.

• 9:57Brian Keating?

  Right, right.

• 9:57Speaker 01

  It has to be converted to nitric oxide, which is a simple molecule. One atom of nitrogen, N. One molecule of oxygen, O. They hook together, you have NO. That's the molecule that does all these things in the brain, in the heart and in the blood vessels and so on. And in each of these organs, there are specific systems or processes that have receptors on them that nitric oxide is attracted to. So if nitric oxide is going to attract it to the arteries, the smooth muscle in the arteries, it relaxes it and that will lower the blood pressure. In the brain, nitric oxide can react with other kinds of receptors and actually

• 10:43Speaker 01

  Prevent the development of dementia and Alzheimer's disease, maybe even autism. And in different organs, it produces different effects. Because there are a bunch of different kinds of receptors in the different organs, all of which can react with this one simple molecule, nitric oxide. To me, that's very fascinating.

• 11:07Brian Keating?

  Oh, it's incredibly fascinating and how the body is so attuned to tiny differentials. I mean, it's impossible. I mean, most of my audience, you know, is probably atheistic, as are most of your colleagues and most of your fellow laureates that I've interviewed. I would say 90% do not believe in God. But where do you come down? I mean, you mentioned God, your first wife wanted to be a nun, I think you mentioned. And you're an Irish Catholic boy. I was a, sorry, you're an Italian.

• 11:33Speaker 01

  Italian Catholic.

• 11:34Brian Keating?

  Roman Catholic. I was an Irish Catholic boy, but that's another story.

• 11:36Speaker 01

  I see.

• 11:37Brian Keating?

  Yeah, but tell me, tell me, Lou, do you ever think about these things? Fine tuning, we hear about this quite frequently without, you know, saying which way or another.

• 11:44Speaker 01

  No, no, no, no, no. Listen, I am kind of a believer and an atheist. You have to remember, my parents were Roman Catholic.

• 11:52Brian Keating?

  Yes.

• 11:53Speaker 01

  And so when I, at a young age, I went to church every Sunday. Friday, we couldn't eat meat and God knows what other things. On other days, I did, made my confirmation, Holy Communion confirmation, and I just went to church. And then at about 16, 17 years of age, I started to think, is there really a God? I mean, I believed that Jesus Christ did exist and so on and so forth. Maybe it got a little exaggerated, but I believed it and I thought it was a good thing. But I decided I'd rather play football and baseball than go to church. And that's what I did. And so for decades, I wouldn't go to go to church. But I have to tell you that somehow I'm still a believer.

• 12:36Speaker 01

  In other words, so many things have happened in my life where. I didn't think they would ever happen and they happen and I begin to believe that maybe there's an outside force that we or sense that we still don't understand physiologically, you know, and maybe, and maybe, you know, that's what we would consider as God, not being a person, but being some kind of influence. I never deface God. I never, I mean, I'll crack jokes about Jesus Christ, but I'll never use his name in vain. I just kind of leave that alone, you know, I just, I just leave it alone because I'm afraid that'll strike me dead if I say that.

• 13:16Brian Keating?

  Well, yeah, so to add another twist, this is your podcast, but I can't resist talking about my favorite subject, which is me. And I'm actually Jewish. I was born to two Jewish parents from the Bronx, not far from where you grew up, and they were, you know, immigrant, children of immigrants, just like your, your parents were. So I was, I grew up Jewish, my mother remarried, an Irish Catholic guy, and I became an altar boy rather than having a bar mitzvah.

• 13:38Speaker 01

  Wow.

• 13:39Brian Keating?

  And you'll read about it if you, if you get a chance to read my, my first book, Losing the Nobel Prize. But the reason I bring that up is because I, but one of my kids told me a joke the other day about these two Jewish guys are walking down the street and just speaking, by the way, about Jesus. And one of the Jewish men says, oh, you go vault, my, my son is dating a non-Jew. And the other one says, you think that's bad? My son converted to Christianity. And then, and then a heavenly voice breaks out and it says, you think that's bad? Jesus was a, is incredibly influential person in my life, even though I'm Jewish. So it's, it's beautiful that you mentioned. Okay. We're going to get to how explosives led to experiments, the kind of mindset that my audience will really appreciate, and how to teach your kids that curiosity is not

• 14:23Brian Keating?

  something that kills the cat as past prize winner, Los Angeles dweller Barry Barish, who's not, not too far from you in Santa Monica, my good friend Barry, he says that we teach too much to be afraid of curiosity. We remove the explosives from modern day chemistry sets. But before we get there, Lou, I do want to talk about your book and do what you're never supposed to do, which is to judge a book by its cover.

• 14:58Brian Keating?

  Dr. NO. Tell us about the title, the subtitle, and this cover illustration.

• 15:04Speaker 01

  Well, we have Dr. No. And the book is a memoir about my life, starting from childhood all the way to post Stockholm and the Nobel Prize. It's not a James Bond book. I just thought it was just fortuitous. The NO stands for nitric oxide. And oh, so Dr. No. I discovered nitric oxide, and so that's the appropriate title. But the book describes how the work led to a Nobel Prize, and also how it led to the development of very important drugs, one of them being Viagra. I did not develop the drug myself, because I'm not a pharmaceutical

• 15:47Speaker 01

  company. I didn't have $500 million to develop a drug, but I had the idea. I had the idea, which is published. Anybody can read it. Anybody can follow up on it. And Pfizer Pharmaceuticals, thank God, followed up on it and developed a drug that boosts your nitric oxide in the erectile tissue, in the male erectile tissue in the penis. And what happens is that that when you boost NO in the erectile tissue, you cause lots of vasodilation, engorgement with blood. Well, that's what an erection is. And so the FDA fast-tracked that drug, and in five years,

• 16:31Speaker 01

  became a drug, which is incredible. And because of that, I'm often referred to as the father of Viagra.

• 16:38Brian Keating?

  Very good. Well, there are worse things to be known for. And again, you make light of it, Lou, and I know you joke in the book that you were asked by Elton John, if you, Sir Elton John, who you love, if you ever use Viagra, and you hilariously told him, "No, I'm Italian, Elton." So I love that story.

• 16:54Speaker 01

  We had a great conversation.

• 16:56Brian Keating?

  He's a big part of this book, and I'll leave it to the reader to enjoy those many recollections of him throughout your life. And he was the kind of constant... The only character who's really with you from, you know, from early research, you know, as a postdoctoral fellow and so forth, up until the Nobel ceremony and beyond and working for Herbalife, right?

• 17:16Speaker 01

  Right, right, that's correct.

• 17:17Brian Keating?

  How do you go from being a Long Island kid like me, I was born in Stony Brook, you were born a little bit more west of there, but how do you go from a Long Island kid blowing stuff up to cracking one of biology's biggest mystery at the time?

• 17:28Speaker 01

  I think, you know, if I had to use the one key word, which I know you have used in your books and discussions with people, that would be curiosity. You know, I was, I was a kid, always very curious. How, how, how does a firecracker explode? You know, what's in it? Okay, so I discovered gunpowder and I discovered that gunpowder could do many other things besides just making a little noise, okay? And then other questions came up when I was in, actually in high school. Some of my neighbors would die at a very young age of a heart attack or stroke, 55 years old, 58 years old. Other neighbors would have lived to 90, they were perfectly healthy. Why?

• 18:13Speaker 01

  I'm curious, why? You know, and I would speak to the doctors in the community, they had no idea. So I came up with an idea that maybe the sick people, or I should say maybe the normal people, we all make a molecule that somehow prevents us from getting cardiovascular disease, but the ones who do get heart attacks and strokes don't make enough of this molecule or make it at all, and those who are healthy make a normal amount. Okay, so I stuck with that throughout graduate school, throughout medical school, in my early research career, I never forgot that. And I just, when we discovered, as I explained earlier, that nitroglycerin works in the

• 18:56Speaker 01

  body because it's converted to nitric oxide, I'm thinking, okay. Maybe nitric oxide is produced in our bodies. As a pharmacologist, I began to study the effects of nitric oxide, which is a gas, by the way, in the body, in animals and cells and so on. And that's when I discovered that N O lowers the blood pressure, increases blood flow, causes erections in animals and so on and so forth. And then I'm thinking, then I get to the next word besides curiosity, and that's imagination. I kept saying, imagine, Lou, if our bodies produced nitric oxide. Suppose our bodies produce nitric oxide. Wouldn't that be something?

• 19:38Speaker 01

  Because it would protect us against cardiovascular disease and also, you know, facilitate our sexual performance. And so I stuck with that. And in 1986, we discovered that our bodies do produce nitric oxide. And that's what got me to Stockholm. So in a nutshell.

• 19:59Brian Keating?

  It's amazing. There's so many questions I have and we'll get into some technical details. Again, don't be afraid to be technical. Over half the audience has advanced graduate degrees. As I said, you're the 22nd Nobel Prize winner to come on the podcast, even the second one in medicine or physiology. So I've had everybody on, even a Peace Prize winner and an economics prize winner, which we all know is not really a Nobel Prize. As Alfred Nobel wanted it. And I want to talk about your thoughts on the Nobel Prize itself, because a lot of my research and discussions with the Nobel Prize winners, you know, 22 now, has to do with what they might change if they had the opportunity to talk to Alfred Nobel. What would you want to tell Alfred about his prize? What it's become? And maybe how you might change it if it was the Ignar Prize.

• 20:45Speaker 01

  No, I think, I think he did an incredible job, you know? For one man to do this, he did this only a couple of weeks before he died in 1896, decided he died December 10th, 1896. And so every year, the Nobel Prizes are awarded on December 10th. I would tell him that he did a great thing. I especially like the fact that not only did someone have to make an important discovery. A unique discovery, but the discovery needs to be shown to be of benefit to humankind, right, as he called it mankind. I think that's important. There's so many esoteric discoveries,

• 21:26Speaker 01

  which could be fantastic, you know, fantastic. However, there are many prizes for that. So the Nobel Prize exclusively is for a discovery that has great benefit to humankind. I think he did the right thing with the categories, physics, chemistry, and he called it physiology or medicine, because he didn't want just physicians to get it. It's really the physiologists who do the research. Today, that's different. A lot of physicians or medical scientists, they do the research. But I think, and literature, I think was the right thing. Peace? I'm not sure about peace. I think there's been a few peace prizes, maybe that shouldn't have been awarded, but the criteria for peace is different. It's different.

• 22:09Speaker 01

  The criteria for peace is that the peace prize is awarded in a category or an event where the Nobel Committee wants to see further peace in that particular area. So they think that if they give the peace prize for that, there'll be an establishment of peace. Not always. No. Our current President Trump, which I will not get into, thinks, you know, if he can solve the problem with Israel and Iran and so on and so forth, he probably would deserve it if he can solve that problem. That's... Yeah, well, yeah. We have economics. Economics was a prize that Nobel did not intend. Okay, the economics prize is actually named after a bank.

• 22:50Speaker 01

  It's a Swedish bank in honor of Alfred Nobel, and I think that was started in the 1960s, which is a good prize. I think that's a good prize. But again, not many people understand economic sciences or what it means, and many of the, many of the themes that certain economists who have gotten the Nobel Prize have advocated...

• 23:14Speaker 01

  Turned out not to be so. So I like, I like the sciences.

• 23:18Brian Keating?

  Yeah, and then, you know, not that there haven't been some duds. I mean, literally, the Nobel Prize in 1912 in physics went to the guy who invented some system that regulates lighthouse lights. And, and that was decade before Albert Einstein won his Nobel Prize. In other words, they gave it to a guy for a lighthouse regulator, and that was in part because of their anti-Semitic orientation in the early years, which, you know, thankfully, they've gotten over, right? The medicine prize, you know, there, there have been a couple, like the lobotomy wasn't the greatest. I think, I mean, you're the expert, so who should I say?

• 23:51Speaker 01

  You're right. It's not all, most of them, the great.

• 23:53Brian Keating?

  Bloopers, right? There's been a couple of bloopers, as you might say.

• 23:57Speaker 01

  I think that in the most cases, that except for a couple of bloopers, I think the Nobel Prize in medicine is well deserved. But of course, there are other areas that deserve a Nobel Prize that have not, not gotten a Nobel Prize in medicine. There's so much progress being made in the life sciences. And there's only one Nobel Prize in medicine per year, and a maximum of three people within the one category can get the prize. So sometimes, you know, pride, they're left out. Not everyone who deserves it gets it.

• 24:30Brian Keating?

  That's the most common thing I hear is that there's a thousand people that worked on a, you know, telescope project or the Large Hadron Collider, and only three people can win it. That leaves out a lot of people, and I, I discussed that in previous interviews. But yeah, two laureate, pretty much, they all agree that it should be modernized just to reflect how modern science is done. It's not done by three people. I mean, the list of acknowledgements in your book alone is like, takes up a page and a half. Not, not counting your wonderful wife. Okay, so let's, let's talk about the elephant in the room. What is nitric oxide's relevance to Viagra? How does it end up in Viagra? And what is its sort of unique chemical pathway? And again, don't be afraid to be technical.

• 25:09Speaker 01

  Okay, no, no, okay. So first of all, nitric oxide NO is a gas. It's an unstable gas. It has a half-life of about three seconds, which means it'll last in your body for no more than five seconds. So it can't be synthesized. It is synthesized in the body. That's what we discovered, but. Once it's synthesized, it has to produce its effect locally immediately. It can't be stored inside organelles. It can't be stored inside the cell like so many other signaling molecules and then released when necessary. No. The way nitric oxide works is that when it's needed, it's synthesized, released,

• 25:52Speaker 01

  and produces an effect literally within seconds, maybe even, you know, milliseconds. Okay, so you can't put NO in a pill. You can't put it in an elixir or a powder, nothing. So what can you give to boost your nitric oxide? Well, you can give certain chemicals that might have an NO attached to it with a bond. And then you take that drug and it go, it's then metabolized, let's say by an enzyme in a particular organ to release the NO locally. You know, that's possible. And there aren't, there are hardly any drugs like that on the market. Some have tried to make it to market, but they just were not effective enough.

• 26:37Speaker 01

  It's the technology that's the problem. But then there's, there are other ways. And this is how Viagra works. And Pfizer was very, the people at Pfizer were brilliant. So the way Viagra works is this. When nitric oxide is made, NO then stimulates the formation of another molecule in the body. It just happens to be called cyclic GMP. The name is, is not important. But NO works by elevating cyclic GMP, which is much more stable. So when you make the cyclic GMP, that lasts for a long time, minutes.

• 27:17Brian Keating?

  And that GMP that's-

• 27:18Speaker 01

  That makes you very smart.

• 27:19Brian Keating?

  That CGMP is what causes smooth muscle relaxation?

• 27:22Speaker 01

  That's exactly right. It's the CGMP that causes smooth muscle relaxation. So it's an indirect effect, not a direct effect of the nitric oxide. Okay, so now the way Viagra works is that it inhibits-

• 27:39Speaker 01

  An enzyme that rapidly degrades cyclic GMP. When you make signaling molecules and you have NO, NO raises cyclic GMP. You don't want the cyclic GMP to last forever. The effect will be too long.

• 27:54Brian Keating?

  It says on the bottle, if you have an erection for... It says on the bottle, if I'm told it said on the bottle, if you have an erection for more than five hours, call a doctor, but you know, some people would call, call the newspapers, but...

• 28:07Speaker 01

  No, I would call the doctor and say, "Thank you for prescribing it to me."

• 28:11Brian Keating?

  Now Lou, is this what's called PDE5 inhibition?

• 28:14Speaker 01

  Phosphodiesterase is the name of the enzyme that destroys cyclic GMP. And there are different isomers of PDE. The one that's present in the erectile tissue is PDE5. Okay, so imagine what would happen to erections if you gave an inhibitor of PDE5. You would cause the cyclic GMP to stay up and that brings on an erection. And that's especially important in the hundreds of, hundreds of millions of men who suffer from erectile dysfunction where they don't, they don't make enough NO. If you don't make enough NO, you don't make enough cyclic GMP. You make a small amount of cyclic GMP.

• 28:59Speaker 01

  But in the presence of Viagra, that cyclic GMP accumulates and you get a normal erection. So that's how that works.

• 29:07Brian Keating?

  Again, I'm a simple cosmologist, Lou, so please, please go gentle on me. But the question that I had is it sort of reminded me of these serotonin reuptake inhibitors and that you get depressed because you lose serotonin and there's something in your body that attacks the serotonin and gets rid of it. So you want to prevent that from being taken up so that the serotonin sticks around a little bit longer?

• 29:28Speaker 01

  Yeah, that's it, that's it. Yeah. One of the ways in which serotonin effect is eliminated or decreased is by not metabolism, by enzymes, but reuptake back into the nerve where it can't produce an effect. The serotonin produces an effect when it's released from the nerve, outside the nerve and goes to the other cells. So if you stimulate, if you have reuptake, you can, you can decrease the effect of serotonin. So the serotonin reuptake inhibitors enhance the effect, right, by keeping it outside the cell.

• 30:01Brian Keating?

  Other mechanisms that sort of have this serendipitous, counterintuitive mechanism by acting. I mean, an idiot like me would just attach some NO gas to a pill or just give it to me, you know, someone who needs to have an erection. Again, I don't use it, but, but the point is, Lou, I mean, the brute force method, as physicists love to approximate everything by a spherical cow, just give the guy some nitric oxide and, or, and be done with it. But you didn't do that. You kind of prevented from being uptake. Is, and Prozac and SSRIs work the same way. Are there other ways in, in biology that we can think about that the same kind of counterintuitive mechanisms might be thought to work? In other words, reuptake inhibitors, but essentially, or, or, or prevention of whatever you call that.

• 30:41Speaker 01

  Yeah, mechanistic degradation.

• 30:43Brian Keating?

  Degradation, sorry.

• 30:44Speaker 01

  You know, off the top of my head, I can't, you know, I can't think of many, but there, there are a number of different drugs that work by those mechanisms, either inhibiting an enzyme and therefore allowing the product of that enzyme to accumulate. There, there are drugs that can actually activate, perhaps, an enzyme to remove a product, especially if the product is toxic, for example, to, to inhibit toxicity of certain molecules, to treat, you know, arsenic poisoning, this poisoning, that poisoning. There's a lot of incredible research going on in that area. And now that we have AI, which we're not talking about, but with artificial intelligence, it's amazing how those programs can understand

• 31:27Speaker 01

  much faster than we can how to make a molecule that will do certain things that we'd like it to do. And it really helps the pharmaceutical companies in designing a drug. Because when I, I worked in, in a pharmaceutical company many years ago, that's how I started my career. And we didn't know how to do any of that. That was not available. So the chemists made a thousand drugs and we tested all of them. And the 10 that worked, we then, you know, did further studies to be sure they were safe. And then the two that did work, we would then file a new drug application and send it to the FDA. That's why it costs, you know, hundreds of millions of dollars to get a drug to market. That, that price is going to come down very soon.

• 32:10Brian Keating?

  Yeah, they say, you know, the the first pill costs a billion dollars. The second one goes down. Now Lou, take us into the lab. You're a brilliant raconteur storyteller, which is such a rare gift that you have. And I know you work at it hard as well. Take us back to the lab, Tulane and and and even afterwards, and then eventually at UCLA, our our neighbors to the north there. We are bigger now than UCLA. I can't believe it, at UCSD. But tell me, Lou, take us into the lab. This molecule lasts for seconds. Its half-life is seconds, and yet you proved it's real, it's reality, despite its ephemerality. You use chemical luminescence, bioassay, vasodilation curves. What did you do? And the role of these of this new technology at the time, I remember you describing

• 32:53Brian Keating?

  in the early 70s, late 60s, that you had to like borrow from this very taciturn guy at Tulane, or at the medical Veterans Administration, something like that. Tell us about the tool. Take us into the lab with a young Lou, and you making this breakthrough.

• 33:06Speaker 01

  Right. The most important point I want to make about the laboratory, one person can't do it by himself or herself. I mean, I'm talking about me. I needed help to make my discoveries. Yes, I had the idea. Yes, I was curious enough to to imagine all sorts of things, but I couldn't do everything myself. So many people I know try to do everything themselves, and it takes forever, and sometimes they don't they don't reach their goals. I, for example, as you brought up, the Veterans Administration Hospital at Tulane Medical Center, I needed to purify an enzyme protein. This is the protein that makes the cyclic GMP we talked about, okay?

• 33:49Speaker 01

  It was known, my my coworker, not not coworker, but co Nobel laureate Fred Murad, discovered that nitric oxide can activate an enzyme called G-cyclyase, and thereby elevate cyclic GMP. And that was not good enough for me. I had to try to understand how we did it. How could an unstable gas like nitric oxide activate a protein? How is that possible? That was unheard of. So the only way to study that is to purify the protein so that no other proteins are around it, okay? You have a homogeneous protein. So I didn't know how to do that. So I went next door, across the street, to the VA Hospital,

• 34:32Speaker 01

  where Andrew Shally, who later won a Nobel Prize, because he purified lots of

• 34:40Speaker 01

  Proteins and lots of peptides for other reasons. And after a lot of consternation and my begging, he allowed me to go into his lab and learn how to purify proteins. I took his methods, came back to my lab, purified the G-cyclase. And then we published 20 papers on the mechanism by which nitric oxide activates the G-cyclase to elevate cyclic GMP. I could not have done that at all without collaboration.

• 35:14Brian Keating?

  Yes, that's why I say in my book, no one goes to Stockholm by themselves, right? Okay, so Lou, this is an incredible story. Again, like I want to impress upon my audience how serendipitous this could be because it's not something that you went into knowing that you would discover this. And in fact, the mystery, the intellectual heresy that you were guilty of at first was involved this other molecule or ghost that people really didn't know about called EDRF, endothelium-derived relaxation factor. So in one universe, the one that you exist in, in the multiverse, the entire field of pharmacology is hunting for this mysterious life-giving substance called EDRF.

• 35:56Brian Keating?

  But in a completely parallel universe, chemists and environmental scientists have identified this toxic gas, nitric oxide, made me filed away as a pollutant, as a toxin, as something dangerous, a simple destructive component of smog, which you guys get a little more of in L.A. than we do in San Diego. Acid brain, connect these two worlds. How did your brain connect these disparate worlds? It was a heresy, Lou. Tell me about the moment of conception of that idea.

• 36:24Speaker 01

  That was, you know, the way you put it, it makes it even more exciting than I first thought. And actually, you know, you're right. So there was a fellow, his name is Robert Furchcott. He also shared in the prize, three of us shared this prize. So he didn't discover NO, but what he discovered is The mechanism by which another molecule in the body called acetylcholine, maybe you've heard of it, that's a vasodilator. And no one knew how that worked. And he discovered, actually by accident, that acetylcholine does not directly relax the smooth muscle in the artery, but rather it interacts first with the endothelial cells, which line the inside of the artery.

• 37:07Speaker 01

  The endothelial cells separate the blood flow from the smooth muscle. And what he discovered is that acetylcholine binds to the endothelial cell and stimulates it to make a relaxing factor. He tried to identify the relaxing factor. He couldn't. But he showed that it had a half-life of two or three seconds, but he couldn't identify it. And so when he published that in 1980, 1981, I'm looking at it. I had a meeting with my people in the lab. And we all looked at each other and said, "Maybe that's nitric oxide." You know, and I presented that to other people outside the lab, which I shouldn't have. And they said, "Ignarro, you're crazy.

• 37:52Speaker 01

  You're absolutely going off the deep end." Okay, so it was a hell of a series of experiments. One thing led to the next. We were able to stabilize, isolate, and chemically identify EDRF as our friend nitric oxide. And that was the first-class ticket to Stockholm, that discovery.

• 38:16Brian Keating?

  And a fellow laureate who also came from not far away from you, Queens, New York, Richard Feynman says, "The first principle of science is that you must not fool yourself. And the second principle is that you are the biggest fool." Not you, Lou, but experimentalists like you and me. In some sense, the burden of proof falls upon us that we have to be most suspicious of ourselves and maybe how we have made a mistake. So what was that aha moment, that wow-to-now moment that proved unequivocally that the biological action of EDRF and the chemical actions of nitric oxide were identical? Because just showing that two things have the same half-life, that's not enough, right?

• 38:53Speaker 01

  No, no, no, no. We showed that they had the same half-life, but also if you study the nitric oxide separately, added to isolated blood vessels in a variety of preparations, you can see that NO produces a relaxation effect with a certain profile, lasts a couple of seconds and so on. We were able to make enough EDRF using acetylcholine to release it from a perfused artery to drip on another blood vessel, and we saw relaxation, okay? And we compared the NO to the EDRF, and they were identical. But that's not good enough. That's not good enough. You have to show chemically that they're identical.

• 39:36Speaker 01

  So I had to come up with an assay, oh, God, an assay that revealed that EDRF was NO. So because I studied nitric oxide for 10 or 12 years prior to that, I knew that NO could react with hemoglobin and change its light absorption spectrum. What that means is if you record the light emission in a spectrophotometer, that's what we call it, or a colorimeter, if that's something you understand better. Hemoglobin produces one spectrum, but if you react the hemoglobin with nitric oxide, this was known years before. Chemists did that for no apparent reason that I know. They showed that nitric ceal hemoglobin,

• 40:21Speaker 01

  the product of that reaction, produces a different spectrum. And I said, ah, let's react NO with hemoglobin and reproduce that spectrum. We did. And then, let's add EDRF to the hemoglobin. That was a tough experiment, to see if the EDRF can shift the spectrum to the same way that NO did. And it did. And that was our chemical identification. I don't know if you can see it here, but if you look at this graph right here, that shows you the spectra from that experiment. I had to put that on the wall. My wife tried to stop me, but I said, nope, I'm putting that on the wall.

• 41:01Brian Keating?

  Wow. Well, you know, you deserve it. You deserve that. And your model trains, Lou. No one can take that away from you. Okay. What happens if a woman takes Viagra? Because certainly they need NO in the bloodstream as well as males.

• 41:14Speaker 01

  Of course. You know, you ask a great question, and I have no experience with Viagra myself, nor do I have any experience giving it to a woman. But I do have a lot of friends who have tried that because they've asked me the same question. Well, let me explain in a nutshell. It is so easy, but yet no product has been marketed like this, which if I was younger and had some money, I would have, I would have, I would start up a company that would develop pills for women. Women have erectile tissue also. In fact, it's even more sensitive than men. It's called the clitoris. That's where all the erectile tissue is. Any tactile stimulation or, you know,

• 41:58Speaker 01

  thinking about sex and so on stimulates that erectile tissue, and that causes lubrication and all sorts of other things, and increases the desire, of course, to want to have sex in women. So to make a long story short, Viagra absolutely works in women. What appears to be the case, not that many clinical trials published, is that they need double the dose. So instead of a 50-milligram dose in men, they take 100 milligrams, which is perfectly safe. 200 milligrams is perfectly safe in a man or woman. And so from, based on what I've heard and what I've read in JAMA and other medical journals, is that the Viagra does do that. It increases the sensitivity of the area

• 42:43Speaker 01

  so that, you know, the women want to have sex. So it works the same way as men, except, you know, anatomically, there's a slight, obviously, a slight difference in the effect. But it does work.

• 42:55Brian Keating?

  Now, I started the podcast in 2020 in earnest, and that was during the beginning of the COVID pandemic. And you point out the applications in the afterword to this book, which I assume you wrote during the COVID pandemic, at least part of it, that either Viagra or nitric oxide itself could be used in some sense. Can you talk about, you know, what these other applications are? I mean, can people benefit, you know, it couldn't have other benefits? The same way that it turned out that we had these serendipitous benefits of other chemicals, like these weight loss peptides that people are taking. They're finding that people give up on addictions like biting their fingernails or gambling, you know, from taking a peptide, a GLP-1, right?

• 43:36Brian Keating?

  So are there other serendipitous benefits of Viagra or nitric oxide?

• 43:41Speaker 01

  Yes, there are. Again, you can't give NO by itself because of its chemical properties. However, there's some, there's a lot of effort on the part of biotech companies to develop drugs that stimulate NO in certain regions of the brain and so on. Some of that's going on actually at Scripps Clinic in UCSD. Stuart Lipton and his colleagues are looking at this, trying to find ways to boost nitric oxide or direct it into a different pathway to produce beneficial effects, like preventing or reducing the development of dementia, Alzheimer's disease, autism, for example. Nitric oxide seems to have a very good inhibitory effect on prediabetes.

• 44:25Speaker 01

  It affects certain enzyme systems where you could actually delay or prevent the establishment of pathways that could lead to diabetes. So that's called prediabetes. So there are a number of different areas, you know, that are being looked at. The problem with the nitric oxide is it's damn chemistry. It's so unstable that unique new methods have to be found to boost your own nitric oxide. Okay? You have to boost your own nitric oxide. And we still don't know all of the physiology about our own nitric oxide. But we've made a hell of a lot of progress in 20 years. I could tell you that.

• 45:09Brian Keating?

  Do you think someday it could be used as, you know, prophylactic? Ironically, given its use in Viagra, you know, for the opposite? Or maybe, you know, you need a prophylactic there too, I suppose. Could it be used like aspirin? You know, people take a baby aspirin every day. You see it in some sense being, you know, put in the water supply. I mean, let's let our minds roam free. I mean, from bombs to making peace.

• 45:30Speaker 01

  I think Viagra is a good example. Viagra is not used only to treat erectile dysfunction or to increase, you know, sensory perception and so on. Viagra is used in a number of different ways. Remember I told you earlier Viagra boosts the effects of nitric oxide indirectly. It boosts the effects of cycle GMP, which is what produces the effects of nitric oxide. And so Viagra has been used even in infants, in newborns, to prevent what is called pulmonary hypertension. Many infants are born with pulmonary hypertension, high blood pressure in the lungs, and these infants can die from that.

• 46:15Speaker 01

  And so about 20 years ago, someone else discovered that if you give these infants nitric oxide gas by inhalation, small amounts, it can save these infants' lives and turn them from literally a purple color right after birth to bright pink, you know, within 30 seconds. So NO does that. And now we've found, not we, not me, we meaning the scientific community, Viagra can produce similar effects.

• 46:48Speaker 01

  A low dose of Viagra plus a low dose of nitric oxide by inhalation produces remarkable effects in these infants. And now Viagra with the NO is also being used to treat adult respiratory disorders where NO alone doesn't work. So, and many people, many physicians are trying to use Viagra in other formats, again, to try to boost NO to see if, if the Viagra could be effective in either preventing or particular pathological condition from getting worse. It's, we're in the middle of all that now. So biological, medical research is very different than, let's say, a discovery in physics.

• 47:32Speaker 01

  When somebody makes discovery in physics, oh, that's it. It's completely understandable and, you know, you get a Nobel Prize. But in medicine, my God, you gotta go through a thousand hurdles.

• 47:46Brian Keating?

  Yeah, we don't have lawyers over us, right? We don't have lawyers, we don't have FDA, NIH.

• 47:53Speaker 01

  Exactly.

• 47:54Brian Keating?

  Hopefully the-

• 47:55Speaker 01

  You don't need FDA approval.

• 47:56Brian Keating?

  That's right. But we don't blow up as many people as you almost blew up as a kid. Well, from, from that, before we wrap up, you know, you just talked about the benefits to infants, but, but you have a remarkable regimen that you actually predict. You're 84, you just celebrated your 84th birthday, congratulations, you should-

• 48:14Speaker 01

  Thank you.

• 48:15Brian Keating?

  To 120, as, as we say. But tell me, Lou, what is the reason that you still eat certain foods, like arginine-rich foods? And where can people get that and follow the, the Lou diet? Free of charge. We're giving you not, this is not medical advice from me, I'm a doctor, but not like Lou. So tell people, Lou, what are some basics that people should follow to be like you and run marathons and stuff?

• 48:34Speaker 01

  It's so basic. I try to point this out in my book. I'm ready to publish another book where I really point this out called No More Heart Disease. I take advantage of the discovery that I made. I mean, I really believe in it. Nitric oxide. We know, I've already told you, that NO can prevent heart attacks, stroke, diabetes, you name it, okay? What we now know from the work of not only my lab, but mainly other labs. If you eat certain foods and you engage in physical activity, get your body moving, your body makes enormous amounts of nitric oxide. So eating foods rich in antioxidants, like certain vegetables and fruits that are dark in color.

• 49:17Speaker 01

  Chemically, the darker the vegetable and fruit, the more antioxidant it has. That's why people should eat fruits and vegetables. Antioxidants raise nitric oxide. Remember I told you, NO is unstable, especially in air. Anything that is oxidizing will take out NO. So if you give an antioxidant, by definition, you boost NO. So foods like that work. I like arginine supplements because the only way your body makes nitric oxide is by converting the amino acid arginine to nitric oxide, believe it or not. And where is arginine? What foods? Protein. Protein, protein, protein.

• 50:00Speaker 01

  It could be eggs, it could be meat, it could be fish. My favorite is fish because fish is healthy and a solid protein. Plus you get all the polyunsaturated fatty acids. I'll stop there with the foods, but exercise. You know, 5,000 years ago, people said, and it's been recorded, that exercise is extremely important for your health. Nobody knew why. Now we think we know at least one reason. Whenever you move your body around, you make your endothelial cells in the arteries make nitric oxide in order to widen the blood vessels.

• 50:39Speaker 01

  To make more blood flow occur to deliver oxygen and nutrients to your working muscle. But that same nitric oxide works to keep your cardiovascular system and your brain healthy. It's a no-brainer. Healthy diet, physical activity makes NO, and that's what I do. And hopefully I live to 104. We'll see.

• 51:00Brian Keating?

  Yeah, maybe 120. That's what I think. Yeah, your Twitter account, which we'll link to, it says, you know, eat healthy, save your brain. It's a no-brainer. Okay, Lou, so as we begin to wrap up, you've been so generous with your time. You once built this bomb to make a crater in a pier in Long Island. But you ended up blowing a crater in our understanding of biology in the 20th century and beyond. So I want to ask you advice to curious kids, parents of curious kids, and any young person who's listening, or old person who's listening that's been inspired by you. What would you want a young Lou to take away from your story?

• 51:38Speaker 01

  Well, I think that, you know, you need to be curious, raise a lot of questions, ask simple questions like I did. You know, why do people get a heart attack? Why do so many people not get heart attack? You have a rash. What causes a rash? What can we do to get rid of the rash? What causes people to become senile with dementia at such a young age? What can we do to reverse that, prevent that? So I like to ask questions that we have no answers for yet. And, you know, that's kind of like thinking outside the box. Sometimes it's difficult to do that. People like to follow in the footsteps of others.

• 52:21Speaker 01

  But I always say that you need to create your own footsteps. You know, I mean, there's a quote by Ralph Waldo Emerson, which I want to say, and that is, "Do not go where the path may lead. Go instead where there is no path and leave a trail."

• 52:40Speaker 01

  That's what I recommend.

• 52:41Brian Keating?

  And Lou, you're a living proof that what seems explosive may someday become healing if handled wisely by proper minds, proper curious minds. Well, Lou, this has been a phenomenal treat for me and my listeners. I know the people want to read more about you and your life story. Get the book, Dr. No. Follow Lou on all social media. He's got a YouTube channel too. I love it. We'll put some shorts in there and clips from the YouTube channel. Lou, thank you so much. Maybe you'll get me to run my first marathon someday. I'm not quite ready yet, though.

• 53:14Speaker 01

  Thanks, Brian. This has been fantastic. Thank you so much.

• 53:17Brian Keating?

  Thank you.