CONVERSATIONS WITH GIANTS IN MEDICINE

A conversation with Lucy Shapiro

Lucy Shapiro, from , Chairman’s Honors Organic Chemistry. The is a renowned molecular and developmen- admin wanted to confirm my background tal biologist whose work has answered the in chemistry, and I mentioned signing up fundamental questions underlying the for general chemistry, but that I dropped genetic and molecular decision-making the course. Actually, I had forgotten to drop process that directs an asymmetric cell it officially, so I had to take the final. It was division yielding daughter cells with differ- multiple choice, so I circled all the Bs, and I ent cell fates. Shapiro’s (Figure 1) insights got a D grade. The woman who was listen- helped launch the field of , ing to me was horrified. Out of his office and more recently, her work has led to the came the chairman, Dr. Peach. He said, development of novel antifungal drugs. “Now, I’m curious,” and asked, “Can you do Tune in to the whole interview on the JCI this?” And I looked him in the eye and said, website at: https://www.jci.org/videos/cgms. “I’m very smart.” He said, “All right, that’s a JCI: Can you start by telling us about challenge.” That was probably the defining your parents and where you grew up? moment in my life. Shapiro: I grew up in , the Organic chemistry was like being child of Ukrainian immigrants. Although exposed to the most beautiful thing I had he never had formal schooling, my father ever seen. I have an eidetic memory, so if Figure 1. Lucy Shapiro. Photo credit: Christine I see a page or write something down, it’s taught me to play chess as a young child and Baker, Lotus Pod Design. instilled in me a love of literature. My moth- like taking a photograph. I can also move er, a first-generation American, was a music molecules around in three-dimensional teacher and a pianist. I am the eldest of three was local, free, and had space easily and see them. Obviously, those sisters. Enid, only 17 months younger than I, a brand-new experimental program: the abilities are a useful asset for the study was brain damaged at birth. From a very ear- Honors Program. I could take anything I of organic chemistry. Next, according to ly age, Enid was my responsibility because wanted, and I didn’t have to attend classes, Shedlovsky, I had to find a lab. I applied both my parents worked. Looking back on it, just work with faculty advisors, read, write for several technician jobs. One of them I did not have a carefree childhood. papers, and pass the finals. I had a double was with Tom August and Jerry Hurwitz I was destined to attend my local high major in fine arts and in biology. at NYU. At that time, Jerry had just codis- school, Manual Training, where only 5% of JCI: What did you think you were going covered the DNA-dependent RNA poly- the students went on to college. My parents to do next? merase. Working in that lab was an incred- suggested I pursue piano at New York’s High Shapiro: My goal was to become a ible experience. I remember I shared a bay School of Music and Art [now called Fiorello medical illustrator, and while in college, I with Jacques Monod, who had just won the LaGuardia High School of Music & Art and supported myself by illustrating course syl- Nobel Prize; he was doing a short sabbat- Performing Arts]. Everyone in my family was labi. I could have graduated in three and a ical with Jerry. His experiments weren’t musical, and I took piano lessons from the half years, and near that ending time, I was working because he continually dripped age of four. I really wanted to attend Music part of a group art show at Lever House. At his cigarette ashes into his test tubes. and Art, but I knew music was not my call- the show’s opening, I met Ted Shedlovsky, JCI: What made you decide to transition ing. So I taught myself to draw and took the a physical chemist from Rockefeller Uni- from research technician to PhD student? entrance exam in art. Every night after lights versity. He enjoyed finding creative young Shapiro: We got ahold of the RNA phage out, I got out a book called How to Draw [Jon people in the arts who he decided would F2 that Norton Zinder had just discovered, Gnagy] that I found at the local library, and do well in science, and he invited my hus- and Jerry and Tom wanted to know if there with my little flashlight on, I’d go through the band at the time and myself up to Woods was an RNA-dependent RNA polymerase. book. Fortunately, I had some talent. With Hole for a week. At the end of the time I In another defining moment in my life, my art portfolio in hand, I took the exam and was there, he urged me to take a course in I got ahold of the phage, grew it up, and was accepted. It was a family crisis. organic chemistry and then gain experi- infected E. coli with the F2 phage. After I was a good student. I loved math, ence working in a research lab. infection, I assayed for the polymerization and I had a biology teacher that really got I listened to Ted and dutifully went to of radioactive nucleotides into RNA from me intrigued. When it came time for col- the Chemistry Department office at Brook- an RNA template. I remember as though it lege, there was no way I could leave the lyn College to see about an organic chemis- were today standing in the counting room, city because I was embedded in my family. try course. The only thing available was the and with time after infection, goddamn it, I was making RNA. It was a Saturday, no one was around except Monod, and I ran and

Copyright: © 2019, American Society for Clinical Investigation. pulled him into the counting room, and I Reference information: J Clin Invest. 2019;129(8):2981–2982.https://doi.org/10.1172/JCI131492. said, “That is a new enzyme activity!” And

jci.org Volume 129 Number 8 August 2019 2981 CONVERSATIONS WITH GIANTS IN MEDICINE The Journal of Clinical Investigation

Monod said, “Bon. This is indeed very excit- have distinct cell fates. Caulobacter had the make policy. Furthermore, I founded a bio- ing. Now, you must call Professor Zinder characteristics I needed, so I sat down and tech company to design novel antiinfectives. and tell him what you’ve done.” Very rapid- wrote out a plan for the next 20 years of how I As a member of the board of directors of ly after that, Jerry said I should be a gradu- was going to dissect this cell from its genome large pharmaceutical firms and biotech com- ate student, and that became my thesis. My through to every structural and functional panies, I met a visionary biochemist named graduate course work centered on physics, change it went through during its cell cycle. Steve Benkovic (Penn State). It was with physical chemistry, and biochemistry. I realized that I couldn’t possibly just study Steve that the plan to build a novel class of JCI: You headed to a postdoc at Prince- each of these cell cycle events without under- small molecules, based on boron instead of ton with Walter Kauzmann? standing how they impacted one another. carbon at the active site, came to fruition. Shapiro: I decided that physical chem- Clearly, the cell had to be an integrated sys- Steve created a small molecule library, and istry was what I really wanted to do. Walter tem operating in time and space, and to me, I tested its activity against an array of cells Kauzmann at Princeton was doing just real- that was the beginning of systems biology. and pathogens. We had incredible activity ly beautiful work, and I didn’t apply any- JCI: After running departments at that was completely lost if we replaced the where else. But just when I was to arrive, Einstein and Columbia, you decamped to boron with carbon. Our very first step was he had to go on an immediate sabbatical for California to launch a new department of to patent our library. Some were specific family reasons. So I spent about six months developmental biology at Stanford. for yeast. None touched HeLa cells. Others in Julius Marmur’s lab at Einstein, and at Shapiro: I remember when I told Rich- were effective against different bacterial about that time, Bernard Horecker (chair- ard Axel that I was leaving New York and pathogens: Gram negative and Gram pos- man of molecular biology at Einstein) asked moving to Stanford, he looked at me and itive. Just at that time [2001], the anthrax me to come back as a faculty member. said, “Remember not to breathe any air you scare and everything dealing with bioter- It took me the weekend to say yes. can’t see.” We camped across the country — rorism was upon us. For Steve and me, that Horecker then did something amazing. He my husband is a Texan, and he said, “You’ve meant that Homeland Security was now proposed that I take three months to think got to see the country.” At that time, Harley very excited by what we had: compounds about what I should do for the rest of my life [McAdams] was a department head at Bell for anthrax and tularemia and other criti- in science. That was yet another defining Labs, a physicist. I really was very anxious cal pathogens. Most importantly, our com- moment because it gave me the freedom to about this decision to leave New York, but pounds were nontoxic to the host. think about important questions. I grappled to me, Stanford was a mecca. We formed a company called Anacor with the idea of positional information: a Harley got a job working in the aero- Pharmaceuticals, and it grew into a sizable cell knows where to put things in 3D space. space industry dealing with signaling from enterprise. We had on the market the first Cellular organization in time and space is earth to satellites. At one point, he came to new antifungal in 50 years with a novel inherited. So it must be encoded, but how? a seminar that Ira Herskowitz gave; at the mechanism of action. Another of our drugs How is the information from a genetic code end of Ira’s talk, he had on the board all was a topical effective in kids that have atop- translated into three-dimensional space these genes connected by arrows and bars ic dermatitis with streptococcus super infec- and remembered? and feedback loops, and few people could tion. We did a large trial with children with Also, there are cell divisions that give untangle the circuitry except Ira and Harley. eczema. It worked okay as an for you cells of different cell fate. Asymmetric By then, my incredible cadre of students and strep infection, but then the docs overseeing division is ultimately the fundamental basis postdocs had worked out a lot of the genet- the trials reported that the inflammation was of development and speciation. What do ic circuitry that ran the cell cycle and had going away, in many cases working as well we know about that first asymmetric divi- integrated positional information with reg- as a steroid ointment. Following a phase III sion in which you have to read the genomes ulatory feedback loops. Harley had an aha trial with our newly identified PDE4 inhibi- differently in the two cells? Given these moment in realizing a cell is run by an inte- tor, we sold Anacor to Pfizer, and Eucrisa is questions, I then had to find the right mod- grated system, not unlike electrical circuit- now on the market. el organism — a cell that was as simple as ry. He was hooked. He joined the faculty at We are now focusing our antifungal could be, yet demonstrated positional infor- Stanford, and we integrated our labs. library on agriculture; we’ve started a com- mation that yielded an asymmetric divi- JCI: You served as a White House advi- pany called Boragen, and it’s cooking. sion, every division, and yet could be easily sor on bioterrorism — how did that happen? JCI: If you couldn’t be a scientist, what manipulated genetically and biochemically. Shapiro: By 2000, we were facing a per- else do you think could have kept you JCI: So how did you land on Caulo- fect storm. Antibiotic resistance was growing engaged for a lifetime? bacter crescentus instead of, say, a polarized rapidly, pathogens were on the move across Shapiro: I love to paint, and I still do. But mammalian epithelial cell? the globe, and large pharmaceutical houses science is my life. I knew that when I took Shapiro: I thought that a mammalian cell were not focusing on making new that first organic chemistry course and then would be too complicated! In my innocence, or antifungals. I gave as many public talks as when I met Caulobacter. I simply want to fig- I thought a bacterial cell would be quite sim- I possibly could on antibiotic resistance and ure out the complete circuitry that makes a ple. In my reading, I hit upon Caulobacter, the emerging infectious disease threat. Also, living entity. And there is nothing, nothing this Gram-negative bug that exhibits polari- I knew the message had to be conveyed to that I’d rather do other than my science. ty and for which every division is asymmet- people in power in Washington, and so I even- ric. When it divides, the resulting daughters tually managed to speak with the people who Ushma S. Neill

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