- Welcome to "The Minor Consult," where I speak with leaders shaping our world in diverse ways. I'm your host, Dr. Lloyd Minor, Dean of the Stanford School of Medicine, and Vice President for Medical Affairs at Stanford University. Today, in our "Big Idea" series, we're continuing to spotlight discoveries and innovations that transform how we live. Our guest is Lucy Shapiro, a trailblazing biologist, entrepreneur, and advocate with deep ties to Stanford Medicine. Over a career spanning more than five decades, Lucy revealed that even the simplest cells are remarkably organized and intelligent systems. This discovery reshaped modern biology and opened new paths for fighting infectious disease. Her impact extends far beyond the lab. She founded Stanford's Department of Developmental Biology, launched companies that created antibacterial and antifungal drugs, and advised US presidents on biological warfare and emerging infectious threats. This year, Lucy was honored with the Lasker-Koshland Award for special achievement in medical science, recognizing her extraordinary contributions to science and society. Lucy, welcome to "The Minor Consult."

- Oh, it's a pleasure being here.

- So maybe Lucy, let's start out at the beginning. You're an artist.

- Yes.

- You started really pursuing your interest in art, and then...

- Something happened.

- Were attracted to chemistry, and the rest is history. So, walk us through that. How did you get involved in what you're doing?

- I went to the High School of Music and Art in New York, and special high schools in New York are amazing. I come from a very musical family, played the piano from the age of four. But when it was time to go to high school, I decided, "Yes, music and art would be wonderful, but I wanted to paint." And so I taught myself how to draw and made a little humble set of drawings for the admissions meeting, and I got in, and it was fabulous. I think for a little kid raised in Brooklyn, New York with being ensconced in family in a little house, I suddenly was up there in the far reaches of Manhattan in Harlem with students from every walk of life. And it was transformative. And I loved the humanities and I loved painting. And then I went to Brooklyn College where I majored in fine arts and painting, but I minored in biology because I was part of a special honors program, I could more or less do whatever I wanted. In my senior year, a physical chemist at Rockefeller University named Ted Shedlovsky bought one of my paintings at a group show. And we got to talking. And it turned out that Ted had this thing about finding young people in the arts and trying to say "What we're doing in science is exciting and creative. Don't you wanna do that?" And I said, "Well, yeah, it's interesting." And he said: "I want you to take a course in organic chemistry." So I did. It was an honors course, and that's a whole nother story, which I won't go into. And Lloyd, I have to tell you that that changed my life. I was at that point writing my senior thesis on Dante and why he wrote in the vernacular and not Latin, and I was embedded in the Italian Renaissance, but suddenly I learned about this world that was invisible to me, and I actually thought it was the most beautiful thing I'd ever seen.

- That's wonderful.

- And what helped is that I have an eidetic memory. So I can picture something and my mind takes a photograph and I can recall it. I could get it back at any time. And I have the ability to move things around in space. So spatial organization has had an enormous impact on my science. So what happened then is Ted said, "Okay, go into a lab, learn what it's like being in a lab." So I joined what was called then the Jungle Biochemist in New York City. It was a lab run by Jerry Hurwitz, first at NYU, then at Albert Einstein College of Medicine, doing the enzymology and biochemistry of the new molecular biology. And then my department, in which I had gotten my PhD, invited me back as a faculty member. And I was given a great gift. Bernie Horecker was then chair of the Department of Molecular Biology at Albert Einstein College of Medicine. And he said, "Lucy, before you put a foot in the lab, take three months to just read and think and decide what big question do you want to work on for the rest of your life." Now that's a gift, that doesn't happen often. And so what I settled on was, and it all comes back to spatial orientation that I was interested in. What I settled on was how do you go from a linear genetic code to three-dimensional space? How do you build a three-dimensional cell or an organ? Where is that information and how is it transmitted? And so I read and I found a bug called Caulobacter. And this bug had asymetry, it had a structure, a stalk at one end and a flagellum at the other. And every time it divided, it gave you two different cells. I said, "Wow, this can be my hydrogen atom, the simplest cell I could find that did things that I wanted to understand." So I wanted to know how you got an asymmetric division, as well as how you built the structures. And little did I know then, but what I was really embarking on was how do stem cells do their thing? How do you get two different cells from one division? And Lloyd, that's the basis of all of developmental biology. And that was the plant that ultimately led me to Stanford and building a department of developmental biology. All the way back then. I was a kid, you know, I was 26 years old, and I knew that I wanted to take that cell completely apart as though it was my test tube. And a pivotal experiment in the lab was saying... and this actually was done at Stanford when we first moved here by a graduate student named Mike Laub, who's now a professor at MIT. And we said, "Well, you know, everybody, first of all believes that bacteria are a bag of enzymes." So I had one half of my lab understanding the architecture. The other half of the lab, which was Mike and other people, was, "Well, how do you turn genes on and off, really?" And we showed for the first time in a major science paper that the simple cell, as it goes through the cell cycle, has a hardwired program of turning genes on and off as it moves through the cell cycle, hundreds of genes. And we identified them all. And so this was the first indication that there is probably a logical genetic circuit in operation. At that point, a physicist named Harley McAdams, who happens to be my husband, and was working in the aerospace industry doing signaling from Earth to satellites who had moved with me to Stanford from Bell Labs, got extremely interested in what we were doing. And one day he announced, "You know, Lucy, this has got to be akin to an electrical circuit. The rules that apply to electrical circuitry are very logical. And let's see if a living cell does the same thing." And he said, "I'll make you a deal. I'll teach you Boolean algebra if you teach me genetics." And then we published a lead article again in science on the analogy between electrical circuitry and the regulatory circuitry that runs a bacterial cell. And I'll read you something.

- Please.

- So, when I was awarded the National Medal of Science from Obama, this is what he said as to why he was awarding me this thing, he said: "That you showed, Lucy, that the bacterial cell is controlled by an integrated genetic circuit functioning in time and space that serves as a systems engineering paradigm underlying cell differentiation, and ultimately the generation of diversity in all forms of life." And that's what we did.

- That's wonderful. You know, you make it sound so easy in a sense, and that's the true mark of any, you know, consummate scientist or artist. But I know it wasn't, and I know you must have encountered, Lucy, a lot of hurdles, challenges along the way. What were some of the ones that stand out in your mind? And in particular, what can others learn from the way you encountered them?

- Well, okay, there were different kinds of challenges. One of them, which is really very interesting, has to deal with people's mindsets and what they assume to be true. Anytime you change a paradigm, it's not easy to get people to respond easily. The first thing we did was our work with circuitry really gave birth to the field of systems biology. And there were a lot of people who just didn't wanna think that way. You know, life was one thing, a circuit was another, but actually it's all the same. And so it was dealing with paradigm shifts. Another one was, we showed for the very first time, well now the second, because cell cycle proteins, cell division proteins were localized in the middle. But we showed that all the chemo receptors, and this was Janine Maddock, and Dickon Alley in the lab, amazing postdocs, showed that the chemo receptors were localized at one poll of the cell. Christine Jacobs-Wagner, who's now a professor here at Stanford, showed that regulatory kinases had specific addresses in the cell. And we clearly demonstrated that the simple bacterial cell was highly organized and an exquisite chemical machine. And again, another lead article in science, we did this both in Caulobacter and E.coli so people would believe us, and these papers were 90% control and 10% experiment. But it took five years to convince the academic community that bacteria didn't come from Mars, that they are part of our evolutionary path. And that in fact the simple cell is an exquisite chemical machine. And you know, I would give seminars and they would say, "Oh, artifact, it's gotta be artifact." And then I would give tons of data. "No, no, it's probably artifact." I remember one time at the pastor trying to convince them of this. It took five years. But we did get there, and now everyone assumes, "Well, of course we've always known that." So, that was one. Another kind of challenge, Lloyd, was after I finished my PhD, which was all biochemistry and enzymology, I had two PhD mentors, Tom August and Jerry Hurwitz, Jerry was the one who was a fierce, fierce academic and logical, exquisite biochemist, trained by Arthur Kornberg, by the way. And he said, "What are you gonna do now?" And I said, "Well, I'm gonna work on Caulobacter and do in vivo biochemistry." And he said, "Oh my God." He said, "You're gonna work on drek." You don't know what drek means, but in Yiddish, it's garbage. And he said, "How can you do this, after the exquisite training you've received?" I said, "I'm gonna use that exquisite training to go inside that cell and uncover what's going on in vivo." But that was a big hurdle, because I looked up to all my biochemistry mentors as gods. But what I did when I opened my own lab is I decided to apply for an NSF grant. And I couldn't possibly give my first tries and a grant to my biochemistry colleagues because it was not biochemistry. So I had followed the work of Dale Kaiser here at Stanford, and I sent him a letter, remember, there were no email, no computers. I sent him a letter and I said, "Dear Dale, you do not know me, but I am about to work on an unknown organism, and I'm gonna write my first grant, but I need help." And I asked him to send me one of his grants to the NSF, so I could read it and see how it's structured. And I put down with no hint of hubris, one that was preferably funded. And he sent me a grant.

- Great.

- And that started a friendship that lasted the rest of our lives.

- That's wonderful, that's wonderful.

- And I got the grant. I got my first grant.

- Congratulations. And many, many since then.

- And many, many, many.

- Yes.

- Yes, many, many more.

- Your work from its inception has had implications, important implications, Lucy, for antimicrobial resistance. And this is a topic that you focused a lot of your science on, and a lot of your writing for the public, for the broader public. Tell us about how your interest in that topic began and what your concerns are now.

- As time went on, and I was elected to the National Academy, fairly young, I somehow felt that maybe I had a bully pulpit. And I looked around the world, and I said, "Things are a mess." We had a perfect storm going on. We had antibiotic resistance rising enormously, and I knew what that meant. We had emerging infectious diseases coming in from everywhere, in many instances, due to the incipient climate change. We had drug companies who really did not see antibiotic discovery as something that was sustainable for them, rather than dealing with chronic ailments. You know, "Here, you take something, you get well, you're done." And also, it was very difficult. Now, at that point, coincidentally, I was also sitting on boards. I was sitting on the board of directors of Silicon Graphics, sitting on a board of directors of then SmithKline Beecham. And they started something called the Manhattan Project for New Antibiotics. And it didn't go very well. And it was too disperse, there were too many different things going on at once. And one of my colleagues, Steve Benkovic, was on the advisory board, and he's a visionary chemist. And I got Steve aside, and I said, "Look, Steve, we have to do something. This is not sustainable. We are gonna be back in 1907 soon, and children are gonna be dying all over the place because we will have no antibiotics." And especially, and this is where I'm going to introduce vaccines, we have to have more of that. And so Steve and I put our heads together and they said, "Let's do something completely different. Let's start by trying to make new anti-infectives based on a chemistry that isn't being used in drug design." And we looked at the periodic table and we said, "Right below carbon is boron." Now, boron is very reactive. We'd have to do some really clever chemistry. But what if we made small molecules as anti-infectives based on boron at the active site, not carbon. And so we said, "Oh, okay, we need some money." So we applied to DARPA.

- Right, right.

- We sent DARPA a two-page request, and based on, I don't know, hope, they gave us $1 million. And we went ahead. Steve and his guys, one of his great students, Steve Benkovic, built an entire panel of compounds based on boron, sent them to me at Stanford, and I had a whole panel of fungal pathogens and bacterial pathogens and viruses, and we had incredible activity. And I said, "Okay, now let's do the critical experiment." What you have to do is replace the boron with carbon. What happens? And we did it, and we lost all activity, which means that the boron mattered. So Steve and I pooled our resources and patented what we had. And then I started working with Stanford. And in fact, that led to Anacor, one of our companies. And we wound up with two FDA-approved drugs, which were later sold to Pfizer, the whole company for $5 billion. And it was one way of trying to deal with this. But getting back to antibiotic resistance, independent of trying to make new antibiotics, it's a losing game. Other than phage therapy, which is not dependent on the kinds of things that you have to do using antibiotics. And phage therapy is very, very hard to scale. You can save people's lives and you do by using phage therapy, but phages mutate, and it's not easy, but there's a whole industry trying to make this work now. But it's extremely difficult to scale. The problem with keeping designing new compounds is it's a losing game. The bugs are really smart. And they get around eventually anything we throw at them. And that leads me to my second point. And that is the way that we have to do this while preserving as much as we can of our antibiotics, it depends on vaccines. And this is what worries me so much as we are entering what I consider the era of pandemics. And it can be based on a virus, it can be based on bacteria, it can be based on fungus. And there is a pandemic of fungal infections in agriculture, and we have to really pay attention to all of this, as well as livestock and humans, vaccines are our vital weapon that we have, as scientists and physicians, to keep our global health safe. And... I think that the more we as scientists have the opportunity to speak to the public, we should do it, because as a consequence of COVID pandemic, you know, people are scared. And we do not live in a scientifically literate world, and there's no reason to expect that we should. Not everybody does understand everything, but we do understand people dying. We do understand pandemics. And people are scared. When people are scared, they want to hear something definitive. "Tell me what to do. What is the right thing to do and the wrong thing to do?" And because pandemics, and medicine, and science is something that changes with time, as you learn more. They are not definitive, "Yes, do this, no, don't do this." Everything has to be reconsidered in real time with the goal of saving lives. That's what we do. So we're now left with a population, and it's not just in the United States, it's everywhere, a population of frightened people. We didn't know what to do when COVID hit, we were blindsided. And there were goods, and there were bads. Fundamentally, the world managed to save many, many millions of lives. And at the core of that was vaccine. And so now I know one of the things, and I know you're probably gonna ask me about this because it matters. "What am I worried about now?" What I was worried about even before COVID hit, was pandemic, and interestingly enough, a little digression...

- Please.

- And interestingly enough, in 2019, right before the pandemic hit, I was invited to address the US Senate Armed Services Committee in Washington on antibiotic resistance, on the generation of new infectious diseases and what the government should do, and the military should do to prepare our population. And I then told them that I was worried that we would have a global pandemic, but I thought it was gonna be flu, and not a clue that it was gonna be a coronavirus. Just a few months later, COVID hit. And as I said, we were blindsided. But now that we know and we understand what's going on, when I wake up at four in the morning, what am I worried about? I'm worried about bird flu. I'm worried about H5N1. And I recently wrote an article for the Bulletin of the Atomic Scientists that are not only worried about nuclear armageddon, but worried about pandemics. And we have here a very lethal virus that has jumped the species from birds to mammals all over the world. Not just on dairy farms, not just on cows, but all of our seals and elephant seals, and dolphins, deer, cats, mammals. And in the aquatic population, this virus is jumping from mammal to mammal. It has not yet jumped from human to human. It can infect human. And especially if the human gets infected from a bird. If a human gets infected from a cow, that virus is not as lethal. But from birds, it's bad news. And now it's the bird virus that's killing off the aquatic mammals. And my concern is that even as recently as a year ago, we were doing testing all over the place, testing in dairy farms, testing farm workers. You don't wanna just test people who are symptomatic, you wanna test people who are asymptomatic. And it was building into a pretty horrific story. And then bango, it's all stopped. The testing is minimal. Very little is coming out of the CDC, we're not allowed to talk to WHO. So we don't really know what's happening in many places. And the preparation of new vaccines is primarily going on in Europe, South America, Asia, and I'm very worried, and I think pandemic preparedness is something that we better wake up to. And so this is all leading to my final point, that we, as scientists and physicians, have to speak up, have to speak to people, to help people understand what's happening, allay fears, talk about what we can do in a positive way. And while at the same time dealing with disinformation. So it's a challenge, Lloyd. But it's a challenge that every one of us should take on with humility and with understanding of people's point of view.

- Exactly.

- And people's fears.

- Exactly.

- So it's a challenge, but one that we must step up to.

- Well, I, really Lucy, love the way you described that, particularly the emphasis on humility and meeting people where they are, and presenting the facts as we know them, recognizing that they change as we learn more. So overall then, greatest concern on the viral front and bird flu, maybe talk for just a moment about concerns you have with bacteria and fungal infections and, you know...

- Oh, okay, so-

- Where do you think we could have problems there?

- Okay, our big problem is climate change. And why is that our big problem, if we're worried about medicine? What's happening is even very, very small increases in centigrade are significant in Fahrenheit. And the vectors that carry the pathogens, bacterial pathogens, fungal pathogens, viral pathogens, are now learning to live in environments that are warming up. We have malaria in the Himalayas. We have chikungunya that used to be only down in the tropics, up in the Carolinas. We have a vast movement of mosquito vectors, ticks, fungus that's carried on spores, moving up into temperate zones and even arctic zones because of climate change. This is not something that people who worry about climate change and talk about climate change even refer to very much. I mean, they worry about flooding and they worry about weather patterns, all valid. But my worry is about the effect on pathogens. And that's why we're having this onslaught of quote, unquote "new pathogens and old pathogens in new places."

- New places, sure.

- And in many instances, we've never been exposed to them, so we have no antibodies and it's very difficult to deal with. Our physicians have never seen all of these cases of either chikungunya, or dengue, or, you know, Zika. This was all new. But it's been coming in wave after wave after wave. And it's climate change. It's the Aedes aegypti mosquito that brings in most of these guys, but it's also ticks, which are changing all over the United States and moving up North.

- Lucy, I had the privilege of joining you and your family in New York recently for the Lasker Award ceremony, and it was a wonderful event and lovely remarks, which are available on the Lasker website about your many scientific contributions as well as publications and PNAS and other journals about your career.

- Yeah, we've got an awful lot of publicity,

- Very well-deserved publicity. What are you most proud of as you look on your accomplishments in the many things you focused on in your career? What are you most proud of?

- You know, oddly enough, I'm most proud of building an interdisciplinary lab at Stanford. Of being part of starting Bio-X, beautiful work done by Jim Spudich and Steve Chu, and several, several others. And bringing together people from physics, applied physics, all forms of engineering into our lab in the medical school. And being able to not only ask unique questions, but solve problems that we didn't even know were out there. And for example, at our group meetings with this lab full of people from every discipline you can imagine, every week we had one person talk about their work. If a physicist was talking about the work that she was doing in modeling some complicated circuit, she had to know, and it struck everybody in the room with a new language so we could talk to each other. And this went on, Lloyd, for almost 15 years with people getting PhDs in electrical engineering and physics and cell biology and developmental biology, all from one lab. And that, I believe, changed the way in which we do the exploration of the living world and understanding the chemical logic of life. I think that's what I'm most proud of.

- That's wonderful. Well, you've done everyone, certainly at Stanford, but around the world, a service by showing how interdisciplinary science can be done, is done, and how powerful it is.

- Right, right.

- Lucy, I'd like to close with two questions that I ask all of my guests. And first, what do you think are the most important qualities for a leader, and in particular for pioneering groundbreaking science and advancing that science to the benefit of humanity?

- You know, I have an odd answer to that. What I've learned is it's critical that you listen to people. That you listen to people at all levels, that you listen to a beginning graduate student, that you listen to the president of your university, hear what they're really thinking. Try to understand what they know and what they're comfortable with not knowing. And again, I will use that word, humility again, everybody has something to offer. And being a leader, you must be able to deeply delve into other people's minds, and share with them your own passion, and joy, and fun for being in science and medicine, and help them with what they do well, help them bloom. And so to me, being a leader is being human and receptive and kind.

- Indeed. Very, very well-stated. And then finally, what gives you hope for the future?

- I think what gives me hope for the future is that we're facing many, many challenges right now. Challenges that none of us expected to ever face. And this will make us stronger. We will figure out ways of doing what we have to do. I think, and I may be wrong in this, but I think that rather than becoming isolationist, we are going to integrate more deeply with the rest of the world. And it's not just sharing grants, it's sharing our anxieties, our hopes, our breakthroughs. And if we make a breakthrough here in the United States but can't communicate what we're doing to the WHO, it's gonna get out. We're all human. We talk to each other. We all absolutely love what we're doing. And we must work as a single village, not just individual countries.

- Well, you've stated it so well, and thank you. Thank you for all you do, for what all you have done and all you are doing. And thank you for being a guest today. This has been a wonderful conversation.

- I've enjoyed every minute of it, Lloyd, and I've enjoyed working with you. It's been a pleasure for all these years.

- Well, it's been a pleasure for me, and, of course, you played a big role in bringing me here, and I'm so grateful for that. Thank you.

- I won that one.

- Thank you so much.

- You're welcome.

- And thank you for listening to "The Minor Consult" with me, Stanford School of Medicine, Dean Lloyd Minor. I hope you enjoyed today's discussion with Lucy Shapiro, award-winning scientist, entrepreneur, and advocate. Please send your questions by email to "The Minor Consult" at theminorconsult.com and check out our website, theminorconsult.com for updates, episodes, and more. To get the latest episodes of "The Minor Consult," subscribe on Apple Podcasts, Spotify, or wherever you listen. Thank you so much for joining me today. I look forward to our next episode. Until then, stay safe, stay well, and be kind.