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Priestley Medal address 2022: Skydiving into the interface of chemistry and biology

by Peter B. Dervan, 2022 Priestley Medalist
March 20, 2022 | A version of this story appeared in Volume 100, Issue 10
Peter Dervan on the Caltech campus.

Credit: Thomas Alleman Photography


A version of this essay will be presented at the American Chemical Society Spring 2022 meeting by 2022 Priestley Medal winner Peter B. Dervan, the Bren Professor of Chemistry, Emeritus, at the California Institute of Technology.

Let me extend my deepest thanks to the American Chemical Society. It is a very special honor to be included among the Priestley Medalists, many of whom are my teachers and scientific heroes. I am grateful to my students and mentors who helped me along the way.


Priestley Medal address 2022: Skydiving into the interface of chemistry and biology

Tonight I will take you on my journey from Boston to Pasadena. I will discuss the importance of luck, my early education, graduate school at the University of Wisconsin–Madison and Yale University, becoming a California Institute of Technology assistant professor at age 28, the impact of teaching on my research direction, embracing risk and crossing the divide between chemistry and biology, venturing outside the academic ivory tower, and national service.

My parents emigrated from Ireland. They came over in the early 1920s, before the Great Depression. Life must have been hard. Our family of six lived in Dorchester, a working-class suburb of Boston. One important value at our home was to focus on education. In the 1950s, science was admired in America. Jonas Salk had developed a safe and effective vaccine for polio, saving thousands of children from being disabled or confined to an iron lung.

In 1957, when I was 12 years old, the Soviet Union launched Sputnik, a satellite the size of a basketball that weighed about 184 lb (84 kg). The US government calculated that the Russian rockets were bigger than ours! There could be a science and engineering gap between the US and the Soviet Union. I believe this crisis was one of the best things that ever happened to America. It certainly impacted my generation. Young people were encouraged to pursue careers in science and engineering, and fellowships to do so were plentiful.

My high school experience was formative. Boston College High School was a college-preparatory school. We took 4 years of Latin and 2 years of Greek, along with German, math, chemistry, and physics—the whole deal. I carried out my first science project as a freshman and I loved it. With 4 h of homework every evening, I learned how to study and how to learn. I was prepared to succeed in college, and I feel I have been coasting downhill ever since.

I then attended Boston College as a chemistry major and have great memories doing undergraduate research in the summer before my senior year. I discovered the fun of not knowing the result of an experiment. It was like going to the racetrack! Thank you to the National Science Foundation for those undergraduate summer research fellowships.

From Boston to Wisconsin, Yale, and Stanford

For graduate school, I wanted a break from New England and to see the country, starting with the Midwest. I chose the University of Wisconsin–Madison. I was very happy there. But there were clouds on the horizon. The year was 1967, and the Vietnam War was escalating; the draft was ramping up.

I was one of five students to join Jerry Berson’s group that year at Wisconsin. All of us had graduate fellowships from the National Institutes of Health or NSF. In those days the federal agencies awarded the funds to the students, not the professors, and we voted with our feet to join the best labs. There were exciting mechanistic puzzles to sort out. I chose a project testing the limits of the Woodward-Hoffmann rules: an analysis of the four pathways for the 1,3-sigmatropic rearrangement.

A big unknown when I started graduate school was whether my fellow students and I would be drafted for the Vietnam War. Our class was told that we could go to graduate school for 1 year and then we would likely be called up. The attrition in our first-year class was staggering, a 50% dropout in 1 year.

Near the end of my first year, I received a letter to report to my local Selective Service board for a physical exam, a first step to military assignment. I traveled to Dorchester and appealed in person. They wanted to know why I thought I should continue my deferment. So I told them what I was working on. I think my exuberance, with my hands rotating antarafacial versus suprafacial to explain sigmatropic rearrangements, astonished them. I got a 1-year deferment!

Subsequently, in an effort to make the draft appear more fair, the government then introduced the draft lottery to rank who to draft. My random number corresponding to my birthday came above the cutoff, meaning I could complete graduate school. Talk about good luck.

In those first 2 years in Madison, I was distracted by the existential threat of Vietnam. I took up skydiving on the weekends, jumping with an old Korean War surplus parachute. My skydiving ended in 1969, when Berson decided to accept an offer to move to Yale. We packed our bags and drove to New Haven, Connecticut, for a new start.

I guess when there is major change in life, it is an opportunity to take stock and pivot. At Yale I became very serious about my research and doubled my hours in the lab. I loved talking with Berson at the blackboard about new results. When the experimental data were confounding, Berson taught me the joy of the unexpected finding! He became my first mentor and role model.

Equipped with my PhD from Yale and an NIH postdoctoral fellowship, I resumed my westward migration in late 1972 and drove from Connecticut to California to join Eugene van Tamelen’s synthetic group at Stanford University. Shortly after I arrived, the phone in the lab began to ring and I was asked to give talks at the University of California, Berkeley; the University of California, Los Angeles; and Caltech. Without asking, I was on the academic job market. I never wrote a letter applying for an academic position. I had no research proposals. But I received offers to join Caltech and UCLA as an assistant professor that fall. I was 28 years old. Sorry, graduate students and postdocs on the academic job market today; 1973 was a very different time.

On to Caltech and DNA

When I arrived in Pasadena, California, the organic professors were Jack Roberts, Bob Ireland, and Bob Bergman. They were all incredibly supportive. I was replacing George Hammond, a renowned pioneer in photochemistry.

My first teaching assignment at Caltech was an advanced organic chemistry course for the first-year graduate students. This was an opportunity to learn my field, physical organic chemistry, by teaching the material. There was no advanced textbook in 1973, so I had my students read the original Journal of the American Chemical Society (JACS) papers of pioneers Roberts, Saul Winstein, and Bill Doering. Intuitively, I taught in Socratic style, presenting data from the research papers on the board first and then soliciting and debating with the class all possible mechanistic interpretations of the data. It was exhilarating. I loved teaching, and my knowledge of my field was becoming deeper and broader.

My research group embarked on measuring the relative rates of rotation, cleavage, and closure of tetramethylene, the parent 1,4 biradical. Our papers in JACS settled a long-standing debate between experiment and theory. That said, teaching advanced organic chemistry at Caltech made me realize that many of the breakthrough papers in physical organic chemistry had been written over the preceding 20 years. With 40 years of research in front of me, I needed to move in a new direction. It seemed that the field of molecular recognition had promise. We thought we might distinguish our program by studying specific ensembles of noncovalent bonds in water.

Believing that an important goal of synthetic chemistry is the discovery or invention of new properties, we turned our attention to the interface of chemistry and biology. In the design of molecules with function, we wanted to emphasize simplicity in both structures and syntheses. And when designing molecules for purposes never achieved before, the chance of failure was high. We might need multiple shots on goal.

There were early role models that set the stage for this new direction. Ronald Breslow was interested in understanding the principles of enzyme catalysis. His approach was to build artificial systems to mimic nature’s catalysts. Jean-Marie Lehn and Don Cram were demonstrating structure-specific selective interactions of host-guest chemistry in organic solvents.

My research group at Caltech decided to focus on the molecular recognition of double-helical DNA. There was a risk that we were too early. Neither DNA sequencing nor reliable methods to synthesize DNA were available in 1975. An X-ray crystal structure of right-handed double-helical DNA would not be published until 6 years later.

The structure of ferrous methidiumpropyl-EDTA and an illustration showing intercalation into DNA and conversation of dioxygen to hydroxyl radical.
Credit: Peter Dervan
(Methidiumpropyl-EDTA)FeII contains two separate domains, the DNA intercalator methidium and ethylenediaminetetraacetic acid–FeII. The complex cleaves DNA through iron-mediated reduction of oxygen to hydroxyl radical.

In addition, in 1975 there was a chasm between chemistry and biology. Chemists with precise knowledge of all the atoms in natural product architectures looked with dismay at the imprecise world of biology. Some of my colleagues worried that my new career path might take me off a cliff.

Our first effort at molecular recognition was the design of a bis(intercalator), bismethidiumspermine, by graduate student Michael Becker. From labor-intensive Scatchard plots and viscometric titrations, we determined that the dimer had a DNA binding site size of four base pairs and an affinity for calf thymus DNA that was 10,000 times as much as that of the monomer. For this bis(intercalator), the spacer would lie in the minor groove of the DNA. We imagined that modifying the linker could play a role in controlling the specificity of next-generation molecules bound to specific sequences of DNA. This work was presented in my tenure talk at Harvard University. R. B. Woodward was in the front row and seemed to enjoy it.

There was an outstanding group of biophysical chemists in the nucleic acid field, and I found inspiration from the pioneering work in ligand-DNA interactions by Don Crothers and Claude Hélène. Our research group at Caltech brought synthetic chemistry to the field, and I felt warmly accepted by this international community. I recall vividly one meeting held at the Pontifical Academy of Sciences in Vatican City in 1986. We gave lectures in a small room with beautiful and well-preserved frescoes on the ceiling. Afterward we had an audience with Pope John Paul II. My dear departed Irish mother would have been so proud.

Back in my lab we became inspired by the natural product bleomycin, which cuts DNA in a reaction dependent on iron(II) and oxygen. Graduate student Bob Hertzberg attached ethylenediaminetetraacetic acid–FeII (EDTA∙Fe) to the DNA intercalator methidium and created a DNA-cleaving molecule, (methidiumpropyl-EDTA)FeII (MPE∙Fe). Since methidium had no sequence preferences, MPE∙Fe could cut DNA everywhere. From a design point of view, we had constructed a bifunctional molecule with two separate structural domains, one for recognition and one for cleavage. This would turn out to be a useful tool for footprinting small molecules on DNA and analyzing chromatin structure.

Illustration showing how DNA cleavage can be assessed using gel sequencing, along with a structure of ferrous distamycin-EDTA and illustration of DNA.
Credit: Peter Dervan
Distamycin linked to ethylenediaminetetraacetic acid–FeII [DE•Fe(II)] (bottom left) binds a 150-base-pair fragment of DNA and oxidatively cleaves at specific sites (bottom right). The specificity of binding can be analyzed on sequencing gels (top). Binding orientation and groove location at each site are revealed by the location of the cleavage pattern.

Proximity-induced cleavage

The next step in the lab was to create molecules that would bind and cleave DNA at specific sequences. The crescent-shaped natural product distamycin, known to bind DNA regions rich in adenine (A) and thymine (T), incorporates three N-methylpyrrolecarboxamide (Py) aromatic amino acids. Graduate student Peter Schultz and postdoc John Taylor attached EDTA∙Fe to distamycin. Thus they created a sequence-specific DNA-cleaving molecule, distamycin-EDTA∙Fe (DE∙Fe). By analyzing the cleavage sites on an end-labeled DNA fragment, they found that DE∙Fe bound multiple sites, each four to five base-pair stretches rich in A-T sequence composition. The three to four DNA strand scissions flanking each site were consistent with a cleavage mechanism involving a short-lived diffusible oxidizing species, most likely hydroxyl radical.


The DNA used for these experiments was a homogeneous restriction fragment, typically 150 base pairs in size. It is essentially a linear library of DNA sites addressed by a specific phosphorus-32 label on one end. The affinity cleavage method, based on proximity-induced cleavage, allows rank ordering of DNA binding sites by synthetic ligands in an unbiased experiment. In addition, the cleavage pattern on opposite DNA strands reveals the orientation of the molecule at each site, in the minor groove asymmetric on the 3′ side and major groove on the 5′ side. Taken together, specific binding site sequences, groove location, and orientation for multiple sites on DNA are all revealed in a single screening experiment.

Minor-groove recognition of DNA, and the pairing rules

DNA double helix
Credit: Peter Dervan
Compounds synthesized by combining imidazole (Im, red), 3-hydroxypyrrole (Hp, yellow), and N-methylpyrrolecarboxamide (Py, white), into asymmetrical pairs of Im/Py, Hp/Py, Py/Hp, and Py/Im bind to and distinguish guanine-cytosine, cytosine-guanine, thymine-adenine, and adenine-thymine base pairs in the minor groove of DNA (blue).

With the affinity cleaving method for screening and the logic of incremental change afforded through synthesis, the stage was set to discover or invent new aromatic rings to take us beyond A-T-rich tracts. Graduate student Warren Wade changed one ring from a pyrrole to an imidazole (Im) and synthesized the three-ring oligomer ImPyPy-EDTA∙Fe. From the affinity cleaving screen he discovered that Im paired with Py could distinguish a guanine-cytosine (G∙C) pair from a C∙G pair and both from A∙T and T∙A base pairs. David Wemmer and his coworkers at UC Berkeley provided nuclear magnetic resonance (NMR) structural proof of the model. Graduate student Milan Mrksich then connected two three-ring polyamide heterodimers with a diaminobutyric acid turn unit to create a hairpin structure that increased the affinity and specificity of binding.

At the floor of the minor groove of the DNA double helix, a G∙C base pair has an –NH2 steric bump at the edge, while a T∙A base pair presents a cleft between the thymine O2 and adenine C2. Guided by this simple bump-and-hole model, graduate students Sarah White, Jason Szewczyk, and Eldon Baird reasoned that 3-hydroxypyrrole (Hp), when paired with Py, should specifically bind a T∙A base pair. And so we demonstrated that four unsymmetrical ring pairs (Im/Py, Py/Im, Hp/Py, and Py/Hp) in the minor groove distinguish the four DNA base pairs, completing a programmable chemical language to read different sequences of the double helix. We referred to this modular code for minor-groove recognition of DNA as the “pairing rules.”

Major-groove recognition of DNA by triple-helix formation

In 1987, postdoc Heinz Moser demonstrated that a pyrimidine oligodeoxyribonucleotide-EDTA∙Fe could bind in the major groove of DNA by triple-helix formation with exquisite sensitivity to single-base mismatches. In a formal sense, this was a second chemical language, utilizing Hoogsteen pairing in the major groove by the third strand, for recognition of the double helix by isomorphous base triplets, T∙A∙T and C∙G∙C. For oligonucleotides targeting 15-base-pair sites, one could imagine that pyrimidine probes equipped with DNA-cleaving moieties could be useful tools for cutting chromosomes. Graduate student Scott Strobel demonstrated that this chemical approach could cut single sites in megabase-size DNA, including human chromosomes.

Then graduate student Tom Povsic and Strobel demonstrated that attachment of the electrophile N-bromoacetyl at the 5′ end of pyrimidine oligodeoxyribonucleotide affords alkylation of a single guanine (at N7) located two base pairs to the 5′ side of a local triple-helical complex. N-Bromoacetyldeoxyribonucleotides could bind adjacent inverted purine tracks on double-helical DNA by triple-helix formation and alkylate single guanine positions on opposite strands in megabase-size yeast DNA in 85% yield. In 1992, we wrote that “it is not unthinkable that quantitative reactions targeted to single atoms in the human genome . . . should be possible by strictly chemical methods” (J. Am. Chem. Soc., DOI: 10.1021/ja00041a005). We could not have anticipated that the genetically encoded CRISPR-Cas system characterized some 20 years later would revolutionize genome editing and human medicine.

Credit: Peter Dervan
A pyrimidine strand forms a triple helix with DNA (right) by binding through Hoogsteen hydrogen bonds in the major groove to the purine strand in the DNA double helix, creating base triplets.
Illustration showing normal DNA base pairs along with base triplets formed to create a triple helix of DNA and a pyrimidine strand.
Credit: Peter Dervan
A pyrimidine strand forms a triple helix with DNA (right) by binding through Hoogsteen hydrogen bonds in the major groove to the purine strand in the DNA double helix, creating base triplets.

The Dervan group

The graduate students at Caltech who worked in my lab were outstanding. Young people in their 20s are always hopeful, and anything seems possible. I gave the students independence in their projects, coupled with abundant support and encouragement. We published most of our work as full papers in JACS. We included primary data such as sequencing gels in the JACS papers to inform readers how we interpreted the results. Certainly, creativity is important in research. That said, execution in closing the problem was highly valued. “Put the puck in the net,” I would say. We learned to embrace failure. Setbacks made us smarter over time.

Credit: Courtesy of Peter Dervan
Alumni from Peter Dervan’s group gather for a reunion at the California Institute of Technology before the American Chemical Society’s spring 2016 meeting.
Large group of people.
Credit: Courtesy of Peter Dervan
Alumni from Peter Dervan’s group gather for a reunion at the California Institute of Technology before the American Chemical Society’s spring 2016 meeting.

As our early papers were rpublished, some of the best graduate students in the world from top organic groups wrote letters to join the group at Caltech for postdoctoral research. All the postdocs arrived with fellowships, and many were aiming for an academic research position. Our group became an “incubator lab” for training the next generation of organic chemists who would go on to be pioneers at the interface of chemistry, biology, and medicine. As I look at the careers of the Dervan group alumni, in addition to seeing over 65 academic research leaders, I find among them CEOs, provosts, biotech company founders, and editors in chief of major American Chemical Society journals. A significant number of the graduate students went on to obtain medical degrees or law degrees for distinguished careers in medicine, law, and venture capital investment.

My colleagues in the Division of Chemistry and Chemical Engineering at Caltech were fabulous! Since 1976, six have received the Priestley Medal: Linus Pauling, Jack Roberts, George Hammond, Harry Gray, Ahmed Zewail, and Jacqueline Barton. In early days, Norm Davidson’s group taught us how to run sequencing gels. Doug Rees and his student Clara Kielkopf taught us how to crystallize ImHpPyPy:DNA for high-resolution X-ray crystal structures.

Roberts always supported me on a scientific and personal level. He was an early pioneer in physical organic chemistry, including teaching the field the power of NMR. But I was influenced by Roberts in other ways. It was clear he valued institutions like Caltech, the American Chemical Society, DuPont, the National Academy of Sciences, and the American Philosophical Society. He invested his personal time for their benefit.

In 1987, I received a visit to my office from Michael Riordan, of Menlo Ventures, to help found Gilead Sciences. In 1988, Norm Hackerman asked me to join the Scientific Advisory Board of the Robert A. Welch Foundation. I decided that my research would not suffer, if I took the time, as Roberts did, to serve something bigger than myself. I combined research and teaching with service for more than 3 decades, including serving as a trustee of Yale University from 2008 to 2017.

Another Caltech mentor was Arnold O. Beckman, inventor of the pH meter and founder of Beckman Instruments. As a longtime trustee at Caltech and philanthropist, he taught me the importance of giving back. I must say, in the early 1980s, the laboratory space for organic chemistry was decades old and worn. In 1985, Beckman provided renovated laboratories for all the organic chemists. The Crellin and Church buildings became the Arnold and Mabel Beckman Laboratory of Chemical Synthesis. I was taken by Beckman’s modesty and simplicity of life despite his wealth and business success. He embraced a code of conduct of “Don’t take yourself too seriously,” which may be the most important piece of advice ever.

I learned much through my experiences on the Scientific Advisory Board (SAB) of the Robert A. Welch Foundation for the past 33 years. I looked forward to annual meetings in Houston with chemistry heavy hitters Norm Hackerman, E. J. Corey, Bill Lipscomb, Glenn Seaborg, Yuan Lee, Joe Goldstein, Marye Anne Fox, Ahmed Zewail, Peter Schultz, and Roger Kornberg while advising the foundation on the distribution of more than $20 million per year to basic research in chemistry, biochemistry, and chemical engineering in Texas. During the past 7 years, I was also chair of the SAB. I recruited chemistry stars Jim Skinner, W. E. Moerner, Xiaowei Zhuang, Jennifer Doudna, Melanie Sanford, Cathy Murphy, Geoff Coates, and Kevan Shokat. Murphy succeeded me as chair this year upon my retirement. I wish every state in America would have its own Welch Foundation, funding basic research in chemistry for the benefit of humankind.

In summary, I have talked about the importance of serendipity in a scientific journey. For me it was Sputnik, the draft lottery, and Caltech. There is no playbook. My past will not predict your future.


I have talked about the importance of mentors. Here is the secret: you may not get to choose them! More likely, they will choose you, and you need to be ready to recognize the gift.

I have talked about the importance of embracing risk and failure. I skydived into the chemistry-biology divide. It could have been career ending. New methods necessary for experimental success arrived just in time. I would emphasize that our program was basic research—fundamental discovery, with no urgency for a timeline regarding translational impact. Throughout 45 years of research, the National Institute of General Medical Sciences supported our program at Caltech, for which I am profoundly grateful.

I have talked about the value of service. In 1987, Caltech was an ivory tower, and serious scientists committed to fundamental contributions did not get involved with biotech start-ups. That changed a decade later, and university technology transfer became a positive good. Most in this room this evening cannot believe that it was not always this way in universities.

Two men and two women wearing formal clothing.
Credit: Courtesy of Peter Dervan
Peter Dervan (far right) with, from left, his son, Andrew Dervan; daughter, Elizabeth Dervan; and wife, Jackie Barton.

Finally, the most important thing I will tell you tonight is the importance of family. I am grateful to my academic family, the Dervan group alumni, and my Caltech colleagues. But a life journey must be shared. My love, Jackie, has been my friend, adviser, and partner. My children, Andrew and Elizabeth, inspire and teach me every day. I became a better teacher in the classroom due to being a father. I became more patient and empathetic to the needs of the undergraduates and the stresses they experience daily in academics as I imagined my own kids in the classroom.

I hope I have connected the dots on my path to the Priestley, not unlike how chemical bonds connect different atoms to form a unique structure. For the students reading this story, have the courage to be true to yourself, and be prepared for unanticipated good outcomes in life and in research in chemistry.


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