Episode 2 Transcript: Calling on Electrons

Introduction (00:03): Great science and engineering often begin with a singular hypothesis. But how does a lone spark of innovation become popular science? From Caltech, this is The Lonely Idea.

Rich Wolf, host (00:16): Welcome to The Lonely Idea. I'm your host Rich Wolf. Today, I'm here with my good friend, Jackie Barton. Jackie is a pioneer in the field of biochemical synthesis despite having attended a high school in New York that didn't offer courses in chemistry or calculus. Jackie, welcome to the program.

Jackie Barton, guest (00:32): Thanks, Rich.

Wolf (00:33): So Jackie, let's start by talking a little bit about you and getting to know you better. I have to let our listeners know that in addition to growing up in New York City, you grew up a Yankees fan. And would you tell, because I'm such a big baseball fan and a Yankees fan, would you tell our listeners a little bit about what it was like growing up in and rooting for the Yankees in New York?

Barton (00:50): Well, as I think you know, I lived my whole life in New York City until I moved here to Caltech. And so that was absolutely my world. And really when I was growing up, my dad was a Supreme Court judge in New York. And, his chambers were looking over Yankee stadium.

Wolf (01:16): Oh my.

Barton (01:16): And so, we would on a regular basis be able to look in and see the Yankees doing their thing from my dad's office. And, you know, my view of the world was clearly New York centric. And so I used to think that The World Series was always held in New York, right there in Yankee Stadium and it was just a matter of who was going to play them in any given year. That also dates me in terms of how old I am.

Wolf (01:43): Well, the Yankees had an incredible dynasty then. And it also is a testament to your New York roots. You not only grew up in New York, but you went to school in New York and later taught at two different universities in New York [including] Columbia. Could you tell us a bit about growing up in New York City and what that taught you in terms of your desire to want to become a scientist and how that was instructive for you?

Barton (02:07): Well. I can hail a cab anywhere in the world, which is a very useful thing. So I was brought up in New York and went first to an all-girls school, Riverdale Country School for Girls. And I went there through high school and then I went to Barnard College. At the time, Columbia did not take women, and I went to Barnard, which was an outstanding and still is an outstanding place to go to college. And then I worked first at Bell Labs because I was interested in checking out what industry was like and then Hunter College. And then I moved back to Columbia, after grad school. And I went there as well. So, I was completely New York centric. When I did my postdoc at Bell Labs, I even commuted. I always lived in the city and just went back and forth.

Barton (03:08): So the thing about New York and being involved in chemistry, was if you go to a girls' school at that time, I didn't take chemistry.

Wolf (03:21): They didn't teach chemistry in the girls' school?

Barton (03:24): They taught, there was some chemistry that was being had at the boys' school, which was just on the other side of the highway. But not at the girls' school. And so I didn't take chemistry in high school. But I did take math and I loved math. And in fact, when I was a junior in high school, Mrs. Rosenberg, my math teacher, first talked to the headmistress and then my parents had to come and talk to the headmistress because she wanted me to take math at the boys' school so that I could take calculus. So the girls' school was all about art and languages and all that good stuff. And the boys' school was about math and science.

Wolf (04:10): They didn't even offer calculus at the girls' school.

Barton (04:12): Correct. But Riverdale Country School was an outstanding school. It still is an outstanding school and now actually it's co-educational. But I in part helped to do that, because we convinced the headmistress that I should take calculus at the boys' school. And that was the beginning of my being in a room with 20 boys, which I did for much of my career thereafter.

Wolf (04:41): Let's talk a bit about that because when you and I were talking in advance, I said, Jackie, we should take a minute and talk about women in science. And I blanched because we don't have to talk about men in science. Why do we feel obliged to focus on women in science? Well, the reason we do is because there still is conscious and unconscious bias that exists. You felt it as a little girl.

Barton (05:03): Well, in fact, because of what I had, I was oblivious to it. This is the way it always was. And I in fact have as much unconscious bias as anybody else. That's an inevitability of what happens. But I was good at math and I enjoy doing math. And so, you know, I took math at the boys' school and then when I went to Barnard College, I took my first chemistry class and it was, and I loved the lab. I just loved it. And it was a way of bringing together my mathematical tools with thinking about the world and molecules in the molecular world and in that respect and structures. And so then I became incredibly excited about that.

Wolf (05:49): Was there a curiosity about problem solving that led you to, because it sounds like something led you to math, math led you to chemistry, but was there something else innate that was going on that you enjoyed solving problems that you saw things in the world differently?

Barton (06:02): I loved solving problems.

Wolf (06:04): Puzzles?

Barton (06:09): I love doing problem sets. I just loved new problems all the time, and math offered that. And then chemistry offered that. But in a three dimensional context, which made it even more exciting. And I loved, and still do love, discovering new things about the way the world works. You know, it's the surprise of seeing something new that no one ever saw before. And that you didn't understand before. And then those are the data. And then you have to understand that and think about that. How did that work? And there's the problem solving.

Wolf (06:42): Did being at Barnard where there were only women, was that a positive or a negative in terms of your ability to pursue that desire to solve problems and study science?

Barton (06:51): So, the thing about Barnard College, and it's still true today, is it was the best of both worlds. And it is the best of both worlds. It's an undergraduate college in the context of a university. And so I had my first exposures to chemistry in the context of a small college. And many of my graduate students today attended small colleges all over the country. That's where they really get wonderful training. You get to run your own NMRs (nuclear magnetic resonance spectroscopy machines). You get to do all sorts of experiments and be exposed to all sorts of new things. That's a lot harder at a very large university. But the wonderful thing about Barnard and so there, I could do that. And yeah, it was all girls, and so I didn't notice and there wasn't anything wrong with me being the one raising my hand and suggesting something. And then once I had that experience, I could actually take graduate courses over across the street, over at Columbia, and be exposed to a great university and all that goes with that. And it turns out that Columbia was outstanding in terms of its chemistry. And so I was exposed and got to interact with all sorts of really outstanding professors.

Wolf (08:15): Was it fair to say that in that time period as a woman studying science, you didn't feel that different as a result of that?

Barton (08:23): Absolutely. And that's, and that's the point. So, when I was learning chemistry, everybody who was doing chemistry was a woman in the first place, and so that wasn't strange. But then when I went over across the street to Columbia, yeah, there weren't a lot of women graduate students. There was only one woman professor, and for a very short time, because she didn't get tenure. And so that's just the way it was. And you didn't think of anything being different. Now, I have to tell you, the thing of which I'm most proud in my career is actually that I have trained over 30 women that are now professors across the country.

Wolf (09:10): Wow.

Barton (09:10): And I think, you know, if there is a secret sauce, certainly the secret sauce to whatever success I have is in part because of all the young women I've had in my group. But partly their success, is because I would tell them don't worry about those guys. You know that will just distract you. Do the best that you can. Focus on your science. They win if you're being distracted by all of that. Don't have a chip. Just do your thing and don't worry about it. Be oblivious to it. I was oblivious to it, and I think that ended up being a success.

Wolf (09:54): I remember you telling me, we met 27 years ago, and I remember you talking to some grad students and I happened to be standing there and you were emphasizing data. And the one thing I think about with you, Jackie, is that you've always viewed data as the great equalizer. Men, women, old, young, what school you're at, it doesn't matter. Data is the great equalizer.

Barton (10:13): Who cares? It's all the data. It's all in the data. That's what's important. And get the best data that you can. And for young women it's important to just focus on the science. I used to say, and I actually got in some trouble for this, that the best thing that I could do for women in science is to do good science. That's what matters. That's what matters.

Wolf (10:38): I'm reminded of my great scientific hero and one of the reasons I became a scientist was because of the first person to win a Nobel Prize in two fields, two different fields. And of course that was Marie Curie. And there are so many things about what she did as a scientist that remind me of what you just said. Have there been people that influenced you in that way, male or female, where you thought: the way that person approached data or science or thinking about ideas had an impact on me?

Barton (11:05): It's everybody around here at Caltech. It's all the really great scientists that I know. It's all about the data, and it's all about asking questions that you don't know the answer to. Right? That's why we're here at Caltech.

Wolf (11:24): So let's jump into that. I feel like I could, there are a million things that I admire about you as a scientist and as a mother and as someone who enjoys good food and wine. And of course as a Yankees fan, we could go down a million paths, but you touched on the thing that you know is near and dear to my heart, which is the impact that you've had on chemistry and science in general. And in asking questions about that, I have to ask about the thing that pervades a lot of what you've done, which is electron transfer. Could you take a minute, because our audience is across all backgrounds, could you talk a little bit about electron transfer and where your lonely idea came from originally? And then maybe we'll delve a little deeper into that.

Barton (12:04): Okay. Well, the story starts, it's now a long time ago. It's now about 30 years ago. And, my group was interested, and still is in part, in looking at metal complexes that bind to DNA, that are associated with DNA. And we all know about cisplatin, which is a very important anti-tumor drug that's used as a major source of chemotherapy today. Cisplatin is a simple metal complex that binds to DNA. My group was interested in designing new complexes that bind to DNA and among the different complexes that we were looking at for all sorts of different reasons were some ruthenium compounds and some cobalt compounds.

Barton (12:54): And that all sounds maybe a little esoteric, but they were interesting compounds and they had interesting colors and characteristics that we could look at in terms of their binding to DNA. Now it turns out that while we were doing this other people like Henry Taube, and he got a Nobel Prize for this, Henry Taube was at Stanford at the time, he was looking at electron transfer reactions between ruthenium compounds and cobalt compounds. And when you're looking at electron transfer reactions, essentially you just want to have the electron be transferred from one metal to the other metal center. And it's sort of like an ant moving a bunch of elephants. The elephants are going to respond to that change in charge from one spot versus another. And there are all sorts of important characteristics that are associated with that. And electron transfer reactions are fundamental to how you and I breathe and eat our food and metabolize, how all sorts of circuits and batteries work.

Barton (14:04): So electron transfer reactions are fundamentally important. Okay, so now let's go back to our little ruthenium and cobalt complexes. So I had a postdoc in my research group. Now I'm at Columbia and we're looking at these metal complexes. And he also had, was good at reading the literature. His name is Vijay Kumar. He's a professor now at University of Connecticut. And, Vijay wondered whether or not he could do the same reaction that Henry Taube was doing so famously, but in the presence of DNA. And so he wanted to ask, what happens to these metal complexes in the presence of DNA? How does that affect the electron transfer reaction? Well, it turns out that in the presence of DNA, the electron transfer reaction is much more efficient, and that was a big surprise. And so I thought those were the data. It's more efficient.

Barton (15:03): So what's the explanation? How do you solve that puzzle? So I thought it was like the DNA was maybe like a railroad track and that the metal complexes would move along the railroad track and that would make them more efficiently find each other.

Wolf (15:18): Effectively a communication tool. A wire.

Barton (15:21): Oh, there you go. But now there's an alternative explanation and that's more like a wire. This was more like a railroad track. The wire analogy is to say that one metal complex is at one end of the DNA and it shoots the electron through the DNA to the other metal complexes that's bound in another spot. That was a crazy idea and I was sure that wasn't the explanation, but there was one way to check that out and that is attached to the metal to one end of the DNA and attach the other metal to the other end of the DNA.

Barton (15:55): See if it still works. If it still works, it's using it like a wire. So it turns out we did that, and it still worked. So now there was this crazy idea and now we're thinking, how is this actually working? So we had to understand that.

Wolf (16:15): Well then you must have also thought at the time that nature created this. Nature must have had a reason to have done this.

Barton (16:23): Yeah. So, so Rich, I'd love to have you in the lab. I'm getting there. Okay. So the next thing you say is, okay, well if this is true, how do you… while I was looking at this problem, a lot of labs were looking at electron transfer reactions through proteins. In fact, Harry Gray, my colleague here at Caltech was doing that at the time, and they were finding it very hard to do electron transfer through a protein.

Barton (16:58): But we were actually doing it incredibly quickly through the DNA. And so whether it was Harry's group or other groups, groups across the country were starting to say, "Jackie Barton's doing a really crazy experiment and there must be something wrong with it. It can't possibly be right." And so, we had to deal with that and focus on the data. So how do you show that it's going through the DNA and not, they said: maybe the DNA is bending, so the metal complexes could touch each other directly? Well, for that size metal complex, it doesn't make any sense, but we got to check that out. So, we put a little mistake in the DNA, a little barrier in the DNA, if you will. And if it was going through the DNA in the first place, now it won't work anymore. And in fact, that's what we found. And what we found was any time there was a mistake in the DNA, the electron couldn't be transferred. And if there wasn't a mistake in the DNA, it could be transferred. And so now I go over to Rich Wolf in Tech Transfer and say, "Rich, I've got something that allows me, electrically, to find out if there's a mistake in DNA."

Wolf (18:22): I remember it like it was yesterday.

Barton (18:26): And it was, it was crazy, but it was very simple. That was the beginning of us starting GeneOhm Sciences.

Wolf (18:35): And before we delve into that, because I want to talk about your background as an entrepreneur, maybe let's talk a little bit more about how nature uses this. Because what an incredible thing. DNA is complicated. 3 billion base pairs from mommy and 3 billion from daddy in our genome. And yet nature figured out a way to communicate down its own backbone and to figure out there's something wrong. There's a mismatch. And there's diseases, like sickle cell anemia, where there's just one base that's off. And so somehow nature figured out how to do this. And what an incredible thing that you identified by running these experiments. And also by having people tell you this isn't gonna work. You identified this thing. So tell me more about what nature is doing.

Barton (19:17): Well, when we decided to do GeneOhm Sciences, it was because I didn't want to do it in my laboratory. My laboratory was for learning new things about the way the world works. And so this was now very powerful chemistry and we were learning more and more how powerful and how sensitive this chemistry was to mistakes in DNA, to lesions in DNA, to the changes in DNA that occur when you smoke too many cigarettes or you don't eat your broccoli, and DNA generates these mistakes and lesions. And so inevitably you have to ask whether or not nature has taken advantage of this because nature is the best chemist of us all. It takes advantage of everything, right? And it turns out, we have in you and I a whole portfolio of proteins that are constantly looking for mistakes in DNA, finding them, and fixing them.

Barton (20:18): And it turns out a subset of these proteins are proteins that have little iron pieces, iron co-factors in them. And these proteins are - the same characteristics of these proteins occur - in bacteria and in turn are in you and me. And if we get a mutation in one of these repair proteins, that leads to cancer. So these are very important proteins to us. But why do they have this little piece of iron in them? Now again, people said, it must be an ancestral relic. There was iron in the bacteria and now it's still there. Well, you know, it takes a lot of genes to make this little co-factor of iron and stick it in a protein and nature isn't going to expend all of that energy to do that for no reason. And it seemed to us that the good reason to have iron there was because this co-factor could do an electron transfer reaction.

Barton (21:23): And use it to find mistakes in DNA. And so, over the course of time, we now have found that lots of proteins involved in repair have these iron centers. And they're used for signaling as a first step in finding where that mistake is in the DNA and they're critically important. And if you have a mutation near where that iron is posited in one of these repair proteins, that's also associated with cancer. So they're critically important in that regard. Remarkably, as we move through this research, we've now found—others made the first determination of this and we found the role for it—that polymerases, the proteins that make DNA in each of our cells in you and me, also have these iron co-factors.

Wolf (22:18): So in the process of making the DNA, they're checking it along the way.

Barton (22:21): Absolutely. And they're using it for all sorts of fast signaling amongst these repair proteins, amongst these polymerases, to find the mistakes and fix them. So more and more proteins involved in processing DNA are being found every day to have these iron co-factors in them. And we think they're using them because of their redox activity to find mistakes in DNA.

Wolf (22:47): The other thing I love about this story is I know in your core you're an inorganic chemist, yet the whole world thinks you're a biochemist and you are a biochemist, obviously. But how neat that your background as a metal inorganic chemist led you to this discovery, and you were very daring in doing that.

Barton (23:04): But this is the story of basic research, right? So I've now told you the whole story. When I started this with Vijay Kumar, we were just looking at little metal complexes binding to DNA. And now, we're looking at polymerases. We're doing experiments with the (USC) Norris Cancer Center in terms of looking at mutations in patients and what the source of those mistakes are. Who knew that we'd be starting here looking at these simple metal complexes and now we're doing what we're doing? That's the nature of basic research. That's what makes it exciting.

Wolf (23:41): It seems like that, I think you're being generous to basic research, because I do feel like there's something special that happens here at Caltech. There's something that's unbridled. Was there an aspect of being here that enabled you to do it more freely?

Barton (23:56): I think being here, I don't have to be an inorganic chemist or a biochemist. I'm a chemist. I'm a scientist and I interact and collaborate with people across the campus and across the world. And in part because I'm at Caltech, I'm able to do that. I did experiments with Ahmed Zewail, who was down the hall and a dear friend of mine, looking at the rate of electron transfer through DNA. And then we're also doing experiments now with physicians. So, you can look at a whole range of different kinds of things. And I think that is a very important part of Caltech.

Wolf (24:44): It's funny you say that because I suspect that if I asked you in casual cocktail conversation, what do you do, you would say you're a scientist first before you'd ever say a chemist.

Barton (24:53): Absolutely.

Wolf (24:53): A lot of Caltechers are that way.

Barton (24:55): Absolutely.

Wolf (24:55): So you touched on something else that I don't want to let go because you've also been a successful entrepreneur. But a lot of people probably don't realize I was there at the time. You had not no interest, but making money was not an interest. And in fact, it was a little bit getting you kicking and screaming because you thought, if I can do good with this, I want to do it. But this can't be about making money, this has to be about helping patients and about coming up with a new way of interrogating DNA. Yet you took to it like everything else.

Barton (25:31): I remember having to promise to you that I shouldn't, I wouldn't, tell anybody that I wasn't interested in making money.

Wolf (25:41): Exactly. So, but you were incredibly successful. And also, I saw a side of you that I had not seen before, which was a side that was working in an operating environment and helping to drive science for a product. And you had two students at the time, but one in particular who was incredibly helpful in that regard. Could you talk a bit about that relationship and what your experience was as an entrepreneur?

Barton (26:03): As I said before, I thought this was really powerful chemistry and that it could be used to develop a whole range of new diagnostics, and I wanted to see that happen. But that was not the sort of thing that should happen in my lab because we're interested in basic research. We're not interested in making money. We're interested in learning new things, and so it has a different goal. And then, one of my students, who had gone off and done a postdoc, he came back to me. This was Erik Holmlin. Your friend is as well as mine and said, I'm ready to do it. I'm ready to help start GeneOhm Sciences. And I wasn't going to do it unless I had people that I knew who were outstanding that were involved. Because the one thing that I had learned and really had learned from my husband Peter Dervan, who's also an outstanding chemist and who was very much an entrepreneur, he was one of the scientific founders of Gilead. In starting companies, Peter had always taught me that what matters is having outstanding people involved. So when Erik said he wanted to do it, and then another one of my former students, Shana Kelly, said she was interested in doing it. I had it.

Wolf (27:37): It clicked.

Barton (27:37): It clicked. It was going to work.

Wolf (27:40): It doesn't matter whether it's the science or the company, people are the key factor.

Barton (27:45): In everything, in absolutely everything. That's what's most important. And that's what's special about Caltech as well, the outstanding people, the outstanding students we have here.

Wolf (27:54): What is the secret sauce to hiring?

Barton (27:56): I have one criterion. Did they knock my socks off? It's the way they think about a problem. And having that courage and that interest in the data and seeing what the data are telling them. And if they knock your socks off, then you want to hire them.

Wolf (28:16): I love that it's not the specific field. You're not going after an organic [chemist], we need to fill a hole of an organic chemist. You're looking for hunters, for idea generators.

Barton (28:24): We're looking for people. Absolutely. I want them to tell me what's the next wall to climb? What's the next mountain to climb? What is the next great area to go into? They should be defining it. Not me. Mine are the ideas from 10, 20 years ago. I want the next great idea.

Wolf (28:47): Well, Jackie, you're very modest and why don't we use that as an opportunity to thank you very much for being on this session of The Lonely Idea. I can't think of a better way to close than on that note about people in hiring and what makes Caltech so great. Thank you very much for time.

Barton (29:01): Thank you.

Closing (29:03): The Lonely Idea is produced at Caltech. Learn more about Caltech innovators and their research on our website at www.caltech.edu, or connect with Caltech on Facebook, Twitter, Instagram, and YouTube.