What motivates a creative scientific mind? How does an accomplished scientist pinpoint new subjects to explore? How is the field of chemical biology evolving? In this episode of Stereo Chemistry, C&EN executive editor Lisa Jarvis sits down with Broad Institute scientists and serial entrepreneurs David Liu and Stuart Schreiber, both pioneers in developing tools that use chemistry to explore biology, to probe those questions.
Read Stuart Schreiber’s Harvard Magazine article about discovering his family’s secrets at https://www.harvardmagazine.com/2019/07/dna-testing-schreiber
Sign up for C&EN’s weekly newsletter at bit.ly/chemnewsletter.
The following is an edited transcript of the episode. Interviews have been edited for length and clarity.
David Liu: I was in way over my head, I’d never seen organic chemistry before. And so after a lecture by Stuart on chair/boat cyclohexane conformers, I went up to him afterwards and asked him a question. And I remember it was a very poorly formed question, because what I was really trying to say was, “I have no idea what you’re talking about.”
Kerri Jansen: You’re listening to Stereo Chemistry. I’m your host, Kerri Jansen.
Attabey Rodríguez Benítez: And I’m Attabey Rodríguez Benítez.
Kerri: If you listened to our season preview, you already know that Attabey will be joining us as a cohost for this season of Stereo Chemistry.
Attabey: Hi, everyone!
Kerri: If you didn’t listen to the preview yet, that’s OK! We’ll catch you up.
Attabey: In this season of Stereo Chemistry, we’re featuring a lineup of sensational chemists in conversation with . . . each other.
Kerri: Each episode will pair up two chemists for a conversation about their science, their inspirations, and the future of their fields. This is the first of four episodes in this series. For more detail on the other episodes we have coming up, go check out that season preview after you finish this episode.
Attabey: I’m so excited for this episode because today we’re featuring a conversation between two scientists from my own field of chemical biology: David Liu and Stuart Schreiber. That was David you heard at the beginning of the episode, remembering an early encounter with organic chemistry.
Kerri: Yeah, I think it’s safe to say he’s no longer in over his head.
Attabey: Right. And many would credit Stuart with helping to found the field of chemical biology.
Kerri: C&EN executive editor Lisa Jarvis recently sat down with David and Stuart for a pretty wide-ranging interview, and we’re going to be sharing more of that conversation with you in this episode. Lisa is here in the Stereo Chemistry virtual studio with us now.
Lisa Jarvis: Thanks, Kerri. Yes, Attabey is right, Stuart is a pioneer of chemical biology—and later we’ll get into what exactly that means, but for right now let’s call it a field that develops chemical tools to answer biological questions.
Kerri: OK, we’re with you.
Lisa: Stuart and David both have developed different ways of trying to expand the universe of bioactive small molecules. There’s a long list of important biological pathways that Stuart has helped us to understand, as well as developed potential drugs for. And David’s fingerprints are all over a long list of technologies. The one that’s grabbing headlines these days is a type of gene editing called base editing. It allows fixes to the genome at the nucleotide level—say, changing an adenine to a guanine—and, if it works in humans, it could lead to treatments or even cures for many genetic diseases. They’ve both founded many, many biotech companies, too many for me to list here. And the similarities don’t stop there. They’re both professors at Harvard, and both have labs at the Broad Institute, which Stuart actually helped to found.
Kerri: OK, so I think we’re getting the point that these two have made a few contributions to science.
Lisa: Yeah, definitely. So in this episode, we’ll get a taste of their relationship as colleagues and friends, and spend a lot of our time learning about how they think about science—what motivates them to explore a new area of research, what science grabs their attention, and, in this COVID era, what they think of the relationship between science and society.
One thing I love about these two is that they’ve known each other since, well, David was a teenager. Let’s go back to David’s story from the beginning of the episode, when he found himself standing before Stuart with that poorly formed organic chemistry question—and also hear Stuart’s reaction.
Attabey: Yeah, I want to hear the rest of that story.
David Liu: What I was really trying to say was, I have no idea what you’re talking about. But I think I was trying to convey that I was investing great effort into trying to figure out what he was talking about.
In true Stuart style, he stopped, gave me his full attention and said, in very tactful, clear, dispassionate, Stuart-like language, basically, that he was having difficulty understanding what I was talking about. He said something like—you know, these are the memories that you live with, sort of forever—he said something like, “I can see you’re really trying to understand this material. And it would really help me if you could convey more clearly what is the difficulty that you’re having.” So I remember that moment and will for the rest of my life. But you know, it made this great impression that here was a very famous organic chemist in the prime of his career who was stopping to help a lost freshman undergraduate figure out which way was up.
Stuart Schreiber: I wish I could remember that particular incident. I don’t. I have my own vivid memories of the early days of getting to know David.
Lisa (in interview): I’m sure it will make a lot of students feel good to know that you struggled a little bit in organic chemistry, David.
David Liu: I was so scared after my first organic chemistry exam, which was my first exam in college. And it was also the first time I, you know, lived away from home, etc. I remember calling my parents saying, “Well, everyone here is smarter than I am. I think I’ll still learn a lot. But you know, the days of being at the top of my class are over.”
Lisa (voice-over): Spoiler alert: David’s days as being at the top of his class were not over. He went on to graduate first in his class at Harvard and made a big impression within the chemistry community both as an undergrad doing research in chemistry Nobelist E.J. Corey’s lab, and later as a graduate student. The young David Liu started working in Peter Schultz’s lab, which at the time was at UC Berkeley. That’s where Stuart’s memories of David begin.
Stuart Schreiber: Well, my memories of getting to know David are pretty vivid and they start actually with a conversation with Pete Schultz. Pete had some really remarkable things to say about a young graduate student in his lab. And when Pete has, you know, advice like that, you tend to listen, because he’s a thoughtful and critical person. And yet, what I was hearing was just remarkable. So I went upstairs to talk to E.J. Corey. And E.J. said, “I know David Liu. David was in my lab.” And I heard for the second time, a series of remarkable statements about David. And I think at that time, David, you were like, a third-year graduate student.
David Liu: Yeah, I was, yeah.
Stuart Schreiber: And E.J. and I pretty much on the spot said, “OK, let’s recruit this guy to the Harvard Chemistry Department.” I don’t recall there being a single moment between the two of us of, you know, sort of the more standard thinking, well, he’s very young and like, has he done, you know, what, should he do a postdoc? No, it was like, you know, talents like that don’t come along very often. So let’s just go get him.
Lisa: And so they did.
Kerri: Is that Harvard’s typical hiring strategy? Give someone just out of graduate school the keys to their own lab?
Lisa: Definitely not. That tells you how special they thought David was. He told us that he didn’t even realize he was being recruited, and wasn’t even sure what direction he wanted to take an independent lab. And yet, this very first project—a method of using DNA sequences to generate libraries of nonnatural bioactive compounds—helped spur a field of research.
Attabey: And that tool is such a good example of how chemistry can inform biology, which can help expand the possibilities of chemistry. So, yeah, chemical biology is pretty cool.
Kerri: For the non–chemical biologists here, [cough] me, can we back up a second? You told us chemical biology is about making chemical tools to answer biological questions. But can we expand on that? What exactly is chemical biology?
Lisa: Oh, I’m glad you asked, Kerri, because I really do think it’s confusing to anyone outside of the field. And in fact, I asked Stuart and David to talk about that.
Lisa (in interview): I wondered if we could first just talk about the state of chemical biology because when I try to get writers to get a little more interested in writing on those topics, I think we all think of it as different things. And so I wondered if I could hear from each of you how you think of it, how do you define it to yourselves?
Stuart Schreiber: I think you’re right Lisa that the word chemical biology means different things to different people. But I actually think that’s part of the specialness of the field and its success. It has been, I think, more inclusive than many other fields, which tend to, you know, be very prescriptive. And I think the fact that just a lot of people identify themselves as chemical biologists, even though maybe they do very different things. So I think that’s a real plus of the field; I’m not worried about, like, what is the definition?
I think in my own mind, just reflecting my own interests, when I think of chemical biology. I think a really key issue for me is, as someone who’s interested in mechanism, including biological mechanism, and in science, where there’s so many challenges, distinguishing correlations from causality. And I think of chemical biology as this means to perturb systems. And only through perturbation can we ever distinguish correlation and causality. I give the example to my students—there are a number of examples—but one is like if you’re driving into work, and you see a flashing street sign that says accident ahead, you get frustrated because you know you’re probably going to be late. But we intuitively know not to get out of our car and unplug the street sign, it’s not going to have any difference, right? But that’s an experiment. That’s a perturbational experiment.
Lisa (voice-over): Stuart offered a more concrete example of why it’s important to have tools to test this correlation/causation question: the case of good and bad cholesterol. We’ve known for decades that high levels of LDL, or “bad” cholesterol, are associated with an increased risk of heart disease, and higher levels of HDL, or “good” cholesterol, are associated with protection from heart disease. But it took years of testing drugs that either lowered bad cholesterol or raised good cholesterol to prove LDL causes the disease, whereas HDL is simply correlated with it.
Stuart: That’s because it’s a biomarker; it’s a correlation of cardiovascular disease. So chemical biology just provides these amazing tools of all sorts to interrogate biological systems in that way.
David Liu: Yeah, Stuart said it beautifully. I totally agree with him. You know, I think we do benefit from still feeling like a community in that, despite the fact that chemical biology these days has come to include everything from using chemistry to illuminate biology, to using aspects of biology to advance chemistry, to performing chemistry on the genome, that we all still enjoy and are stimulated by, are very curious about all of these fields, all of these approaches to using lessons from life to exploring biology. And to me, that’s really what makes chemical biology special; it feels more like a philosophy than it does a set of problems.
Lisa: One thing that strikes me is that big drug companies now like to talk about how they’ve built up chemical biology expertise. That feels like a shift to me. Probably one driven by the many transformational tools coming out of labs like David and Stuart’s. Both of these scientists have made huge contributions to the field that have been the basis of many, many biotech companies. So I wondered what all of this has meant for the students in their labs.
Lisa (in interview): Does it feel to you like the field has a different kind of profile now? Do you find your students being more often pursued by industry than in the past?
David Liu: Yeah, you know, maybe I’ll take this one first, because Stuart may be too modest to say a few things that I’ll say, which is, you know, I think it’s largely the prominence of chemical biology and the transition in viewing chemical biology students as really choice recruits for not only biotech companies, but pharmaceutical companies, really, in my opinion began when some of the luminary chemical biologists—namely, Stuart Schreiber, Peter Schultz, and their contemporaries—began training students who were so incredible in their intellect and their dedication, that I think pharma companies and biotech companies that, you know, initially might have been viewed as taking a risk hiring them quickly realized those students ended up becoming stars at the companies and the leadership ranks were populated quickly with trainees from those labs. And the culture change, I think, grew out of those labs, demonstrating that some of the most creative and productive contributors to the molecular science industries came from chemical biology labs.
And I definitely agree with what you’re saying that, you know, it used to be that students who joined chemical biology labs, I think, had an insecurity that perhaps they would be less hirable by industry than those who trained in traditional synthetic organic chemistry labs. And now I see a complete sea change that chemical biology students have no problem getting hired by a large variety of industries, appealing to a large variety of academic departments as well.
Stuart Schreiber: I would say the transition was slow, and it’s been over decades. But it is exactly as David describes. I don’t think our students think so much anymore about this issue, whereas there was a period of time when, you know, students might feel that if they were in chemical biology, they had to really stress the synthetic organic chemistry elements of their chemical biology. I don’t think any of them think that way now. I think most of them are more concerned with whether they can show that they are really good problem solvers, you know? They know how to tackle a difficult problem and solve it, right? And that that’s how they’ll be judged.
Lisa: Speaking of solving difficult problems, one big problem that is still front of mind for everyone right now is ending the global pandemic. And it turns out, that’s one that chemical biologists are playing a role in, too. Stuart and David were both part of an informal group called Scientists to Stop COVID-19 that, behind the scenes, acted as a filter for government officials as they tried to parse the flood of COVID research popping up on preprint servers like bioRxiv. Basically they were trying to distill down the mass of options, whether potential treatments or vaccine technologies, to the ones most likely to succeed. And then they also offered guidance on masking and testing, which Stuart and David lament was not followed. They shared what that experience taught them about the tricky intersection of science and politics.
Attabey: But how did David and Stuart get involved in this group?
Lisa: Well, it began with a member of the venture capital community asking a few prominent scientists—ones he felt would be willing to put politics aside—to hop on a videoconference. I’ll let Stuart describe it.
Stuart Schreiber: What happened was, we said sure, and we’ve all been reading, you know, bioRxiv every day, every paper coming out on this topic. And so he said they’ll be about 30 people will show up. And that very first meeting many hundreds, maybe reaching 1,000 people showed up. And to our surprise, we noticed that there were a lot of well-known people from the White House, governors, members of Congress, mayors, members of the entertainment industry, you know, NBA, PGA, NHL, Major League Baseball, etc. And that I think after that we said, we need to get real serious about this if this sort of grassroots, you know, notion and an opportunity to, to integrate science with policy makers. I know, I speak for myself, I think David’s the same, there was a 9 month period or more where I think it was the vast majority of everything we did,we just sort of put everything else aside, and we were constantly, and it does continue to this day; I know I’m contacted by members of that world.
David Liu: In this early spring of 2020, when it became apparent that the world was going to change in a major way, everybody was trying to do their part. And scientists, I think, recognize that we’re in a position to be able to help sort through the massive amount of information enabled by advances in information-sharing technologies and social media and preprint servers. And that the public and policy makers were going to have a real challenge to separate the wheat from the chaff, to even understand that even 10 well-designed studies can come to different conclusions, but you can extract the lessons to arrive at consensus opinions.
Stuart Schreiber: The train wreck, I think we saw coming was that there were just so many possibilities out there. And so we would spend a lot of time together to get clear ideas.
David Liu: You know, I think we learned the reality that those logistical challenges, while surmountable, become in effect insurmountable when politics are introduced at a level that makes every decision paralyzed. It’s a real lesson for us, unresolved problem and a lesson for us to work on for the future pandemics.
Lisa (in interview): I wondered what the last, you know, 2 years, little less, has taught you about just sort of the public’s perception of how science is done.
David Liu: Well, first, it’s always, I think, dangerous to ask scientists about their view of the perception of science, because we’re not an unbiased party, and even the experiences we have with the people around us are highly filtered. We live in nonrepresentative communities—nonrepresentative of the entire country, nonrepresentative of the entire world.
But I’d like to hope and the optimistic side of me thinks that if nothing else, the pandemic served as a reminder to the general public that some of the biggest challenges that we face and will face ultimately will boil down to science, and the potential solutions will come from science. At least that’s what I hope.
Stuart Schreiber: I share David’s hope. It ought to be that way. But, of course, the verdict is still out. We’re at a strange time societally. And I think, you know, we have to really work hard to continue to get the rest of the world to understand the value of science. We can’t take it for granted.
Kerri: We’re going to take a short break, and when we come back, we’ll hear from David and Stuart about what research captivates them—and how their science teaches them about themselves.
Gina Vitale: Hi everyone, Gina Vitale here. I’m an assistant editor at C&EN. And I’m here to remind you about a great way to stay up to date with the latest news from the world of chemistry and chemical engineering: our weekly newsletter.
The newsletter delivers the best of C&EN to your inbox every week. You’ll get the most important research findings, the emerging trends you need to know to get ahead, plus the latest jobs and career insights. And also some really cool extra content, like Periodic Graphics in collaboration with the science illustration website Compound Interest. Or Chemistry in Pictures, which showcases the beauty of the central science.
You can sign up for our newsletter at bit.ly/chemnewsletter. Just point us to your inbox, and we’ll take it from there.
Again, that link is bit.ly/chemnewsletter. And now, back to the show.
Attabey: So in the first part of this episode, we heard about some of the contributions David and Stuart have made to science and society. Their work has really covered a lot of territory.
Kerri: Right: helping to establish a new field of science in chemical biology, inventing new technologies, discovering drugs, starting biotech companies, and pitching in to be steady voices to policy makers amid the pandemic.
Attabey: Those two sure are busy.
Lisa: Seriously. And hopefully it’s clear that David and Stuart are constantly pondering new questions—ones that very often open up whole new veins of research. I wanted to hear about how these two expansive minds come up with new ideas—like, when you’re someone who is curious about so many different things, how do you decide what to do next? How do you set your priorities? It turns out that asking this question opened up its own vein of exploration in our conversation—one that became deeply personal.
David Liu: The best part of being an academic—and maybe the only real reason to be an academic, as opposed to many other things one could do in the sciences, or outside of the sciences, in intellectual pursuits, etc.—is to have the freedom to work with these incredibly talented trainees, but working on problems in areas that are of interest to us, us collectively. So with respect to sort of how to choose science areas, for me, and I suspect for Stuart it’s really been driven by curiosity and where we think the biggest advances can be made. But the most interesting problems are . . . it’s never been, for me, you know, what would make a great company. Because if you’ve chosen a really interesting problem, you know, if it turns out to have the kind of impact that you were hoping, then the company creation opportunities tend to come naturally.
Stuart Schreiber: For me, it’s always been, like, somehow, somewhere along the way, something happens, and you just think, “That’s awesome. That’s amazing. Like, how does that happen?” You know, s0o it’s the excitement about a mystery.
At this moment, the one that fascinates me is the one that I’m probably too old to ever study now. But I do know finally, the answer to the question, which a lot of students ask me, if you were to start all over again, what would you do? Like, is there a problem more interesting and fascinating than the question of “What is consciousness?” You know, how is it that we know that we are, you know, we have a self-awareness? You know, there’s not a little homunculus in the brain that’s, you know, running a movie for us. I mean, like, how does that happen? Right? So it’s always something like that. And then asking, how would I answer that question?
Attabey: I have a hunch he’d go looking for answers in chemical biology.
Lisa: I think you’re definitely on the right track. Stuart might claim he’s too old to get to the bottom of consciousness—though, side note, I would never count that curious mind out. But he spends a lot of time pondering this question of what makes us, well, us. Part of that preoccupation comes from a deeply personal experience he recently had. I asked him a sort of off the cuff question about what research he admires, and it took us further down that path.
Lisa (in interview): I’m wondering what science is going on outside of your own labs that you feel really excited about?
Stuart Schreiber: I can tell you two that come to mind right away. So one is our ability to study the history of humans that comes from the ability to sequence archaic genomes—you know, 100,000-year-old bones—and then to analyze them and to see, you know, that we introgressed with Neanderthals and Denisovans. And that we picked up—you know, the number one risk allele for severe COVID? It’s an introgressed Neanderthal gene. So these are medically relevant. But more important from my point of view, they just tell us who we are, where we come from. The peopling of Americas was a subject of a Nature paper earlier this year, just absolutely astonishing to see.
I think I know why it’s so fascinating to me; it is an offshoot of another personal interest of genetic genealogy, which, you know, happily gave me one of the most joyful experiences of my life and figuring out like, “Who am I?” and “Where do I come from?” The other one I’ve kind of hinted that it’s still early days, but I . . . We still have no clue how this wetware creates, and then ultimately in humans, creates consciousness. So I find this really fascinating. And so to me, this is just an amazing area that is sort of ripe for modern approaches.
Lisa (in interview): Stuart, you referenced having done your own genealogy, and throughout our conversation it’s felt like you’ve made a number of allusions to things that sort of captivate you, motivate you, in terms of knowing who we are. Maybe you can tell us a little bit about doing your own genome.
Stuart Schreiber: What I can say is that I had—I thought I had—a knowledge of who I am and where I come from. And it all got turned upside down in multiple ways. And not just me, but my mother and not knowing you know, where she came from, and who she is and, and so that is . . I describe it as a surreal phase that moves into an unmoored phase. And I feel like I’m a very moored person in general, but not at this period.
Attabey: It sounds like something very serious happened here.
Lisa: Yeah, this is something Stuart has written about and talked a bit about in various venues. After his mom died of Alzheimer’s, Stuart and his brother wanted to know if they had a higher risk of getting the disease. So they did what a lot of us have done: they bought 23andMe kits to test their DNA. When their results came back, Stuart learned that the man he thought was his biological father . . . wasn’t. He wrote a very personal and thoughtful article in Harvard’s alumni magazine about his experience.
Kerri: We’ll link to that article in this episode’s show notes. In it, Stuart writes about at first feeling numb, then experiencing deep emotional turmoil, and then becoming intrigued by solving the mystery of his heritage. He turned his problem-solving skills as a scientist to uncovering the truth of his family.
Lisa: Yes, and, ultimately, it helped Stuart understand a lot about his childhood and relationship with the man who raised him. And, as he told us, it also opened doors, and only reinforced this fascination with the question of who we humans are and where we come from.
Stuart: So I go on these pilgrimages, I meet family, and it’s just joyful. It’s amazing. And I do think that this has just carried over to say well, like, why stop there? We now have the technology to know about all of us all the way back. Right now we can go 100,000 years back; pretty soon, I think we’ll go back to the split—you know, we’re learning about the multiple waves out of Africa, back into Africa. It’s this voracious appetite for knowing who we are. And for me, it took something personal to get, but it, you know, it’ll be with me now the rest of my life, no doubt.
David Liu: It’s too bad your listeners can’t see the huge grin on my face. Because every time I hear Stuart talk about this story, his story, it’s just so inspiring to me for many reasons. I think it reminds me, reminds all of us, I’m sure it reminds Stuart how connected we all are. How, despite the easy emphasis these days on our differences, that we’re so similar in so many ways.
And, you know, hopefully Stuart won’t mind me sharing a story that directly interfaces with some of his recount just now. But Stuart is an incredibly moored person 99.99% of the time; in fact, the only time I’ve ever heard him have a sort of quiver in his voice was when he called me. I got a call out of the blue and Stuart said, simply, “David, I’m feeling unmoored right now.” That was the words he used. And he explained to me what he had learned about his family history. And, you know, I just remember being filled with all sorts of thoughts, including how touched I was that Stuart was sharing this adventure that he was about to embark on with me. And I remember my response to him, which, you know, I continue to feel very strongly this day, which was, “Well, Stuart, how incredibly fortunate we all are, that your biological mother and biological father met and had the opportunity to create you so that you, your science, and the fields that, that have grown from your work, and the societal benefits that have come from your passions, could live to see the light of day.”
Stuart Schreiber: Thank you, David, you’re very kind.
Lisa: To me, the cerebral, compassionate way Stuart is processing this—finding joy in a family secret, and using it to push further into these questions of self—feels so indicative of who Stuart is as a scientist and human.
Attabey: I love this idea that there are so many ways for science—and for chemical biology in particular—to tell us about who we are, whether that means where we came from or what makes us human beings “human.”
Lisa: Indeed. Stuart says he would focus on this area if he could do it all over again, but I have a feeling there’s still a chance to see some of this work transitioned out of his personal life and into the lab.
Kerri: Or maybe some young chemical biologist will be inspired to pursue those questions.
Lisa: Maybe! Speaking of questioning who we are, I’m going to let Stuart leave us with some thoughts for any young scientists out there worried
Stuart Schreiber: Probably David and I both have experienced along the way people either telling us that we can’t do something because we’re not trained, or we don’t know. And then also, we become judged as to whether we’re contributing to chemistry or not, I told you my thoughts on that one. If you’re a chemist, and you’re trained in chemistry, and you find something that strikes your curiosity and your passion and you advance knowledge, it’s chemistry, by definition. Chemistry evolves and it evolves through the actions of chemists.
Lisa: If you want to hear more good advice from these scientists, a good place to start is David’s brilliant keynote address at C&EN’s 2018 Talented 12 symposium, where he talked about his path to scientific success and what he’s learned along the way about being a researcher and mentor. It’s a poignant talk, I’d encourage listeners to check it out—you can find a video of his talk on C&EN’s website.
Kerri: C&EN reporter Ryan Cross also wrote a great profile of David, and you can learn more about Stuart’s life and career in our coverage of the many awards he’s received over the years—we’ll link to all those stories in the show notes.
This episode was written by Lisa Jarvis and produced by me, Kerri Jansen. Story editing by Michael McCoy and Amanda Yarnell. Production assistance from Gina Vitale. The music in this episode was “Different Kind of Love—Instrumental Version” and “Something New—Instrumental Version” by Anthony Lazaro. The promo music was “Plain Loafer” by Kevin MacLeod.
Stereo Chemistry is the official podcast of Chemical & Engineering News. C&EN is an independent news outlet published by the American Chemical Society.
Attabey: Thanks for listening!