The Priestley Address of 2015 Priestley Medalist Jacqueline K. Barton, given at the 249th ACS National Meeting, Denver, March 24, 2015.
First let me say how very honored I am to be receiving this award. I never imagined I would be in this position. And the American Chemical Society, the chemistry community, has already given me so very much. So thank you from the bottom of my heart.
Frequently when I travel to different chemistry departments, I end up talking with young people, and they ask about my career path. In fact, just before hearing about this award, I was at Penn State, and at the poster session, a young woman asked very straightforwardly, “So how did you get to be you?” Let’s be clear, it wasn’t by design. It was the result of a succession of accidents and opportunities. So I thought that would be the basis of my talk, an illustration of one career in chemistry. There are no recipes for getting here—just taking advantage of accidents and opportunities. But chemistry has an extraordinary number of options for careers, and I think it’s important for young people to understand that.
I never even took high school chemistry. I went to Riverdale Country School for Girls, and at that time the focus for young girls was on music, art and languages. Mrs. Rosenberg, my math teacher, insisted to the headmistress that I go up to the boys’ school for calculus. It was the beginning of my spending time in a room with lots of boys (something I still do); but at the time, for a teenager, it was an especially good thing!
It was at Barnard College, a women’s college within Columbia University, where I fell in love with chemistry, and especially being in the lab, carrying out chemical transformations and trying to figure out what I had made. I was taught physical chemistry by Bernice Segal, a strong woman with a booming voice who wrote as much back in your lab book as you had written in the first place. She had very high expectations for her students, and while we were all scared to death of her, we did our best to rise to meet those expectations. Watching Professor Segal in action, I thought maybe I would be a college teacher. I certainly didn’t think there was anything strange about women doing chemistry; after all at Barnard, a women’s college, doing chemistry was just fine.
So I crossed the street and went to graduate school at Columbia. I talked with Steve Lippard about metals and DNA, and I was hooked. Making transition-metal complexes that maybe could be the basis of new chemotherapeutics combined many of my interests. And after all, the DNA helix is a beautiful structure, and the three-dimensional structures in our molecular world were always appealing to me.
Steve told you a bit about my grad student days last year during his Priestley address. He too had high expectations for his students. But I decided in graduate school that I didn’t really want to be a high-powered professor at a high-powered university. Maybe I would try industry. After all, chemistry offers wide opportunities in industry.
I decided to do a postdoc at Bell Labs. At the time, Bell Labs was really an industrial research institute, a mecca for research. I worked with Bob Shulman using NMR to monitor cellular metabolism. It was the beginnings of MRI, an exciting time. But I learned also that I preferred a university setting, with lots of students and faces always changing. My postdoc was a short one (I didn’t want to do another Ph.D.), and made even shorter when I ran into Joe Dannenberg; Joe was a professor at Hunter College in New York City, with whom I had worked a couple of summers while at Barnard. Joe offered me a job at Hunter, and I took it. (To the young people out there putting together large packages and a complex research talk: I’m sorry, things were different in the ’80s!) The idea of doing some teaching and some research in my own lab was very appealing. Being a professor at Hunter College would give me options and represented a different kind of academic position—no less work, just different.
You will also note there is a theme here. I was very much a New York City kid. (I commuted to Bell Labs in New Jersey and then to Yale when Shulman moved there.) So the notion of an academic job on 68th and Park in and of itself was outstanding. I could teach and do research as well. I lived in the city and walked to work.
It turns out that when you become a professor, there are things you need to learn—whether you are at Hunter College or Barnard College or Caltech. You need to learn how to write lectures. You need to learn how to interact with your colleagues. And you need to learn how to write grants. I actually was awarded my first NIH grant while at Hunter. And I sincerely want to thank the National Institute of General Medical Sciences for funding me then and ever since.
I was interested in zinc ion interactions with DNA. DNA is a good ligand for zinc ion, both through the sugar-phosphate backbone and the bases. I carried out biophysical experiments to test DNA unwinding by zinc ions and simple complexes, and I included a control, a tris(phenanthroline) complex, where the zinc was coordinated by three bidentate phenanthroline chelates and therefore couldn’t directly coordinate the DNA. That complex, putatively the control, unwound DNA the most. But octahedral tris(chelate) complexes are chiral; they adopt left-handed and right-handed propeller-like structures. So it begged the question, Does one enantiomer bind DNA more tightly than the other? That’s a pretty straightforward thing to test: Dialyze DNA against the racemic mixture and ask if there is any optical activity outside the dialysis bag. If there is, then there is a preference inside the bag for the other enantiomer bound to DNA. The experiment worked, and we were off and running. We soon switched to ruthenium(II) and cobalt(III) complexes because they are inert to racemization and had interesting photophysical and photochemical properties.
We also modeled (very crudely) the complexes on a DNA helix. If you partially intercalate one ligand between the base pairs, the two nonintercalated ligands will be positioned either in a left-handed orientation, conflicting with the right-handed helix, for the Λ isomer, or for the ∆ isomer in a right-handed orientation, matching the right-handed orientation of the DNA helix. The models thus explained the basis for the enantioselectivity and suggested experiments for how to improve it. The modeling also suggested that we look at Z-DNA, a left-handed DNA helix.
At some point, as this was becoming more interesting, Bob Shulman, my postdoc adviser, visited Hunter and heard about my experiments. When he returned to Yale, where he had moved from Bell Labs, he spoke with Lippard and thought he would suggest me as a possible faculty hire at Yale. When Steve asked me about the idea, I was surprised, but out of my mouth came the words, “I would really love a job at Columbia.” I hadn’t thought about it; the words just came out. My time at Hunter had taught me a great deal. My colleagues were wonderful and very supportive. But the experience at Hunter taught me that research was a key part of what I wanted to do, and I would have more time, more students with whom to work, and a greater focus on research at Columbia. Importantly, my time at Hunter gave me the ambition and probably the confidence to take on a position at Columbia. Maybe I did want to become a professor at a “high powered” place, if that meant I could focus on research. I applied the following week, interviewed soon after that, and was hired the afternoon of my interview.
Returning to Columbia as an assistant professor was special, and a little scary. By this time, Lippard had departed for MIT, and I occupied his old labs, my old lab as a graduate student. My now colleagues, people I had earlier addressed as “Professor,” were extremely supportive and wanted me to succeed, but in my mind, they were still my professors. I didn’t want to let anyone down, and, importantly, I didn’t want to waste anyone’s time. And as I now tell my students taking on faculty positions, “People want to be helpful, but everyone’s busy, and really they just want to do their own thing.”
One of my very special colleagues was Nick Turro. He was my department chair, but he also became a great collaborator. My first postdoc was someone who had applied to Nick, whom Nick suggested we take on jointly, Vijay Kumar. Vijay was outstanding and just the right personality to handle both Nick and me. With Nick’s help and instrumentation, we used photophysical studies to characterize the interactions of ruthenium phenanthroline complexes and DNA. Nick, who wrote the book, literally, on photochemistry, was teaching me things every day. It was grand. We used photophysics and photochemistry to probe different DNA conformations and develop sequence-specific DNA binding molecules. The design of octahedral metal complexes targeted to DNA sites goes on today in my lab, and the complexes we have currently that bind to single base mismatches may form the foundation for new therapeutics targeted to mismatch-repair-deficient cancers. I should add that the earliest experiments were carried out, along with Vijay, by a top bunch of grad students, in particular Adrienne Raphael, Avis Danishefsky, Jill Rehman, and Anna Marie Pyle. It takes courage to join the group of someone just starting out. They had courage, and creativity, and tremendous enthusiasm. I thank them all. This award is really because of them and those that followed.
There were many “firsts” for me at Columbia. I was the only woman on the chemistry faculty, and two years after I arrived, I was given tenure, making me the first woman to receive tenure in the chemistry department. I also became the first woman to receive the NSF Waterman Award. A few years later, I received the ACS Award in Pure Chemistry; that too was breaking the glass ceiling for women. In fact, C&EN published an editorial on the subject. I had mixed feelings about it. If we truly had made progress for women, there wouldn’t be a need for an editorial. In the subsequent 27 years, seven other women have received the ACS Award in Pure Chemistry. That’s some progress, but we are not quite done, not by a lot! And it’s really not about “firsts.” It’s about acceptance and respect, and a genuine focus on the chemistry.
The fact that there weren’t a lot of women in chemistry at the time and I was achieving some prominence created some pressures that I hadn’t counted on and still see to greater or lesser extents today with my own students. I was constantly asked to be on various committees, to travel to various meetings—much more so than my young male colleagues. I remember walking into a meeting at NAS and seeing only men with gray hair or no hair. I was sure I was in the wrong place, but I wasn’t. These many commitments could have easily become an enormous distraction. I learned how to say “No,” and how to pick my spots and opportunities. I frequently advise my female students who are in academic positions to be patient and focus on their science first. That’s how they can make the most difference. I have often said that the best thing that I can do for women in science is first to do good science. Let’s remember with our younger colleagues that the science should come first, and try not to take advantage of them because “we need a woman on the list.”
One very good thing came from serving on national committees in Washington, because it was there that I got to know Peter Dervan, my husband now for 25 years. So the chemistry community gave me something else, the love of my life. Peter has always been on the faculty at Caltech, arguably the best chemistry department in the country. So in 1989 I gave up my NYC roots and moved to Caltech. I will always love Columbia and my colleagues there. It’s where I grew up, but it was time to go, to be with Peter and his son, Andrew.
The move came with a whole new set of pressures. There already was one tenured woman in the Division of Chemistry & Chemical Engineering but not more than a handful across the campus. I also worried that I would be viewed first as Peter’s wife. Peter and I agreed not to collaborate and not to serve on each other’s student committees. Caltech was quite different than Columbia, and there were things I needed to learn. Being a part of Caltech, now for 25 years, has been so very rewarding. And serving as chair of the division, following in the shoes of some extraordinary chemists, has been a very gratifying opportunity. I should add that I’ve been lucky to have very special faculty colleagues not only at Caltech but also at Columbia and Hunter, and they have been great mentors to me. Ron Breslow, Gilbert Stork, Harry Gray, Jack Roberts are not only great chemists, but they taught me much about the chemistry community and the importance of contributing, both within the university and more generally.
Quite soon after I joined the Caltech faculty, Peter and I in fact did collaborate on a major natural product synthesis, our daughter, Elizabeth. Having children is the best thing in the whole world, and as I tell all my students, something not to be missed. But it totally changes your life. I was lucky to have a husband who, as a chemist himself, understood. I want to thank Andrew and Elizabeth for both being here tonight and for all the happiness they have given us. Being part of their evolution into the wonderful people they are is really what it is all about, more than any paper I could write. I should mention that we always had a daytime nanny in the house, Natividad Loeza. She’s been with us for 25 years—even though the kids are gone, I kept the nanny! And at work, also for 25 years, Mo Renta has helped to keep things afloat. Having a support system is critically important.
Before I moved to Caltech, Vijay Kumar, my shared postdoc with Nick Turro, carried out an interesting experiment. I’ve noticed that experiments initiated by my students are usually the best ones! We had been working with polypyridyl ruthenium complexes and cobalt complexes, and Henry Taube had shown that outer-sphere electron-transfer reactions could be easily monitored between these complexes. So Vijay asked, “What happens in the presence of DNA?” What he found was that DNA made the electron-transfer reactions more facile. I was sure that the reaction was faster because of facilitated diffusion of the complexes along the DNA helix, bringing them together. We just needed to test an alternative possibility: that electron transfer might occur between the complexes over a distance. As more experiments were carried out, the idea of long-range electron transfer became more plausible, based on the data. Then I moved to Caltech, and one of my new postdocs, Cathy Murphy, and colleagues carried out one more experiment that really pointed to that conclusion. They had tethered a stacked ruthenium intercalator, the dppz complex, to one end of a DNA helix, and a rhodium intercalator to the other end; in the presence of DNA, the ruthenium luminescence was quenched.
The result was striking. Coupled with lots of controls, the result indicated fast electron transfer over 34 Å, a result that was distinctly different in timescale and distance than that seen with comparable donors and acceptors across proteins. But should that be surprising? DNA, with its π-stacked aromatic heterocycles is completely different chemically from proteins or from the smaller σ-bonded systems that were being investigated at the time. The result sparked enormous controversy. Even C&EN got in the act. What became clear, as with any very interesting result, was that we needed to follow it up with more data, more experiments to characterize the system.
Critics suggested that maybe it wasn’t electron transfer at all, maybe it was energy transfer. We used biochemical methods to show that you could carry out a chemical transformation, oxidation, to damage DNA from a distance through DNA charge transport. Maybe the DNA was bending so that the two ends came together? So we introduced a bend in the DNA and showed that the destacking at the bend actually inhibited the long-range reaction. We also introduced a mismatch in DNA, a subtle perturbation but enough to interrupt stacking and turn off the electron transfer. Megan Núñez then showed long-range oxidative damage over 200 Å, extraordinary molecular distances. “Maybe it’s something funny about those metal complexes!” said the skeptics. Shana Kelley showed, using modified bases, that long-range electron transfer could proceed easily through the DNA base stack to a modified adenine from guanine.
The controversy really led us to do better and better experiments. But it was hard on my students, and on me. Cathy Murphy, Michelle Arkin, Dan Hall, Eric Stemp, Erik Holmlin, Megan Núñez, Shana Kelley, what an outstanding, fearless bunch. And these were very difficult experiments. I remember at group meeting explaining that what was important were the data, that we should think of better experiments each day to answer each concern and explore the scope of the chemistry. The sensitivity of the reaction to coupling to and across the base stack was remarkable, but that made the experiments more challenging, requiring careful synthesis and characterization. And maybe that’s why other labs, not quite so concerned with maintaining the well-stacked duplex, found different results with different assemblies. But the data are what the data are, and we just focused on the chemistry.
Now the data are taking us into the cell to see how nature may also take advantage of this chemistry. It started with experiments by Liz Boon on base excision repair proteins in collaboration with a former postdoc, Sheila David. We are finding that these proteins containing redox-active 4Fe-4S clusters can carry out redox signaling through the DNA helix and that DNA signaling may serve as a first step in how many repair proteins find the damage that they need to repair. Amie Boal spearheaded genetic experiments to test these ideas inside the cell. My lab now is studying a whole family of DNA-processing enzymes that contain redox-active 4Fe-4S clusters, and more DNA-binding proteins are being found all the time with these redox cofactors. Even polymerases. We have much to learn as to how the cell may harness this chemistry. That was clear from the data, and all the more so the more data we obtain.
Shana Kelley, along with Mike Hill, also explored some electrochemistry in DNA films. Here too we needed to show that electron transfer was through the helix, not between helices, so Shana and Mike introduced a base mismatch, perturbing the path, and in so doing turning off the electron transfer. But in carrying out that control, what they had found was a remarkably sensitive diagnostic for DNA mismatches.
With Erik Holmlin, Shana, and Mike, we soon spun out a company, GeneOhm Sciences. (Sonya Franklin gets credit for the great name!) Developing these new sensors on a practical basis was better carried out in an industrial setting, not an academic lab. And a career in chemistry actually offers the chance to do both! We created jobs, worked on technology development, and in a few short years, GeneOhm Sciences was acquired by BD Diagnostics. It actually broke my heart, because I thought this DNA electrochemistry could be the basis for a completely new platform in DNA diagnostics. I still think that!
It is really remarkable how very many general professional opportunities chemistry affords. And in just one career, I have had the chance to be involved in chemistry from many vantage points. Over the past 22 years, I have also been involved in a very large global chemical company, Dow Chemical Co., where I have been a member of its board of directors. It’s been an honor and privilege for me to participate in Dow, and to see how innovation, hard work, and creativity can lead to new materials, new applications, new geographies, and new businesses. It’s very much chemistry in action!
Recently I served on the ACS Commission for Graduate Education, and I was struck by how few options graduate students think they have. Getting a Ph.D. doesn’t mean you are just on the path for a university research job. Academic jobs mean lots of different things: university research, a small liberal arts college, maybe even teaching teachers! And the academic career is just a small part of chemistry. As chemists, we have a chance to be involved in a vast array of enterprises: pharmaceuticals, agriculture, biotechnology, sustainability. These are all areas that require chemists. I once said (and got in some trouble for it) that in the future there would be more chemists but fewer chemistry departments. But that doesn’t mean the opportunities for chemists are shrinking. Quite the contrary, the applications, the fields that chemistry touches, that require a molecular understanding, are in fact expanding all the time.
That’s why, when my students ask if there is still a viable career path for them, either in academics or in industry, I’m optimistic. It is true that grants are becoming more difficult to get, and academic positions in research universities are highly competitive, requiring that great paper and articulating that great idea. Industrial positions are very competitive as well, and all positions require real commitment and hard work. But we still need chemists, and in more arenas: liberal arts colleges, environmental labs, biotech start-ups, government. We need to do a better job in advising our students about the many options available.
So I’ve shown you one career path. That’s how I got to be me. Mine may have been a nontraditional career path, but really they are all nontraditional. I have an extraordinary job that allows me to interact with bright young people, come up with ideas, and learn new things about the way the world works. In fact, the best thing about my job, of which I am most proud, is actually not the papers I have written but the students I have trained. I have had the privilege of watching them grow up and become such extraordinary independent scientists. I have watched many become professors, but also some now work in pharma, in biotech. Others are in start-ups, venture capital, even consulting and the law. Participating in the development of these young scientists, wherever they go, is the best part of what we do. And so, thank you also to everyone in my scientific family.
Let me add my most important “thank you”—to Elizabeth, Andrew, and Peter. I couldn’t be “me” without you.
So let me end by asking a favor of all of you, this great community of chemists, from industry and academics, men and women, many of my friends. The next time you are at a social occasion and someone asks what you do, and you say “chemistry,” and they say, “ugh,” please stop and tell them what you do, in English: What you work on, what you are excited about, whether it’s making the colors on the monitor of their computer, the insulation for their house, the statins they take at night, or teaching the next generation of physicians organic chemistry. It’s all chemistry, and the larger community needs to understand the important role chemistry plays not just in my life but in all of our lives. So let’s raise a glass to good chemistry!