2022 Priestley Medalist Peter B. Dervan pioneered treating DNA as an organic molecule

In 1975, Peter B. Dervan, then an assistant professor of chemistry at the California Institute of Technology, switched his research focus from physical organic chemistry to DNA. That doesn’t sound remarkable unless you realize what tools weren’t available at the time. There was no easy way to synthesize DNA and no easy way to sequence it. There wasn’t even a high resolution crystal structure of the right-handed helix. Those all came later.

At the time, DNA was the domain of biologists and biochemists. It wasn’t something that organic chemists studied.

“Biology, to many people, was a forbidden zone, because the philosophy is you go after problems you can solve,” says Tadhg Begley, who did his PhD with Dervan between 1977 and 1982 and is now a professor of chemistry at Texas A&M University. “So much of biology seemed intractable to chemistry in terms of its complexity.”

Dervan changed that perspective. He treated DNA as an organic molecule that was fair game for organic chemists. In doing so, he laid the groundwork for the field that has come to be known as chemical biology.

“He was the first person to think about nucleic acids as a substrate for chemistry and how to design molecules that recognize DNA in a sequence-specific fashion,” says Alanna Schepartz, who did a postdoc with Dervan in the 1980s and is now a chemistry professor at the University of California, Berkeley.

“Peter made the case that a biological macromolecule—DNA—is really just a molecule, and we’re chemists, and we should be able to do chemistry on that molecule,” says Dennis A. Dougherty, a longtime colleague at Caltech. “Nowadays, it’s difficult to imagine that that would be a novel idea.”

Dervan’s “research into the chemistry of sequence-specific DNA recognition and cleavage established the utility of site-specific gene manipulation that paved the way for later genome-editing technologies, including CRISPR,” says Jennifer Doudna, a biochemist at UC Berkeley who received half of the Nobel Prize in Chemistry for helping develop CRISPR. “As a graduate student I read and loved Dervan’s elegant work on DNA binding and cutting, not suspecting that years later it would have direct relevance to my own research.”

In recognition of his pioneering contributions designing molecules that bind to specific DNA sequences, Dervan, the Bren Professor of Chemistry, Emeritus, at Caltech, is receiving the 2022 Priestley Medal, the highest honor bestowed by the American Chemical Society.

Early days

It wasn’t inevitable that Dervan would become an eminent scientist. The son of Irish immigrants, he had to avoid bullies in Boston’s Dorchester neighborhood, the tough, blue-collar community where his family lived. He managed to stay out of trouble and never got beaten up.

“I was a good kid, and I owed it to my parents to stay out of trouble,” he says. “I didn’t hide out in the house. I wasn’t a wussy, but I was just a quiet, serious kid. And they left me alone.”

He attended Boston College High School, a Catholic all-boys’ school. His 4 h of homework each night kept him busy. By participating in the science club, he discovered he had a knack for science and a love of chemistry. He won the first-year-student prize in the science fair for a project on the effects of radiation on yeast.

Dervan’s fellow students recognized his aptitude in chemistry. In his senior yearbook, he was described as “always a gentleman” and “a whiz in chemistry.”

“A lot of young people need to search around to find what their passion is going to be,” Dervan says. “I went to Boston College knowing that chemistry was what I wanted to do.”

While at Boston College, he participated in a summer research experience. It convinced him that he didn’t know enough yet to be an independent researcher. “It made great sense to me that I should go to grad school and I needed to keep learning.”

Dervan also wanted to see more of the US. So after graduating from Boston College in 1967, he chose to go to graduate school at the University of Wisconsin–Madison, where he worked with Jerome Berson, a physical organic chemist.

At the time, the specter of the Vietnam War loomed. After so many years of being the good boy, Dervan responded to what he calls the “existential threat” of the war by embracing risk. Feeling that the draft could render all those years of working hard and keeping out of trouble pointless, he took up skydiving on the weekends as a form of physical risk that he could control. He jumped more than 40 times.

When his draft status was reclassified, he returned to Dorchester to petition for a 12-month occupational deferment from the draft. After an impromptu organic chemistry lecture punctuated by Dervan waving his arms to illustrate how broken bonds move, the draft board granted his deferment.

At that point, he felt he needed to give research his all. Rather than continuing to take physical risks, he instead took intellectual risks. Berson moved to Yale, and Dervan went with him. A golf player, Dervan now views the transition as a “mulligan” that allowed him to “tee it up again.” He asked himself, “Are you willing to take the risk of finding out that you’re not all that good?”

He threw himself into his research, spending 6–7 days a week in the lab. For his thesis, he did a four-pathway analysis of sigmatropic rearrangements of dipropenylcyclobutanes.

With a Yale PhD in hand, Dervan accepted a postdoctoral position with Eugene E. van Tamelen, a synthetic organic chemist at Stanford University. Soon after Dervan arrived at Stanford, universities started inviting him to give talks. He thought he was just practicing for when he would seriously go on the market in a year or two, but he received multiple offers. He accepted the offer from Caltech.

“I thought, for sure, I’ll go down there for 5 years, they’ll find out I’m not a genius like the rest of them, and I’ll get fired,” Dervan says. “I went to Caltech not worrying about whether I was going to get tenure.” That attitude gave him the freedom to go in a new direction.

Changing course

Dervan was hired at Caltech as a physical organic chemist. For the first few years, he studied the mechanisms of reactive intermediates such as 1,4-biradicals. Through his teaching, he came to realize that he wanted to change his focus.

He taught an advanced organic chemistry class using original papers and the Socratic method. In the class, he asked students to use the data from the papers to propose reaction mechanisms. As he taught the class, Dervan realized how much groundbreaking work in physical organic chemistry had been done decades before.

“I can’t do this for 40 years,” Dervan told himself. He decided he needed to do something radically different.

He chose to focus on molecular recognition. People such as Jean-Marie Lehn at the University of Strasbourg and Donald J. Cram at the University of California, Los Angeles, were already doing molecular recognition with host-guest systems, but they were working in organic solvents.

“If I study molecular recognition and I just do the next host-guest thing, I’m not going to distinguish my program,” Dervan remembers thinking. He decided that he needed to work with biological polymers in water, the solvent of life.

When he first started studying DNA, the tools for working with DNA at a molecular level didn’t yet exist. The field was completely open. “My idea was that I would go into this dark area and try to turn on the lights,” he says.

“I took this risky decision that was potentially career ending,” Dervan says. If the tools for studying DNA hadn’t materialized soon enough, he would have been unproductive and gotten fired, he says.

“I was pretty sure that he was going to do really well because he was such a brilliant, exciting colleague,” says Harry B. Gray, who was already on the faculty when Dervan joined Caltech. “His enthusiasm was so great that you just had to believe that he was going to do it.”

For his first foray into DNA research, Dervan and his group set out to make a bifunctional molecule that could recognize a DNA sequence and then cut it. Such a molecule would essentially function like a synthetic restriction enzyme.

They made (methidiumpropyl-EDTA)Fe(II) (MPE), which comprises the DNA intercalator methidium connected to the metal chelator ethylenediaminetetraacetic acid (EDTA) by a short linker. MPE nonspecifically binds and cleaves DNA at multiple locations. The construct became a useful tool to reveal the binding of other small molecules by seeing where MPE’s intercalation and cleavage were blocked.

But Dervan also wanted something that could bind to specific sequences. Peter G. Schultz, a graduate student with Dervan from 1979 to 1984 and now the CEO of Scripps Research, synthesized another bifunctional molecule, this time linking EDTA with the antibiotic distamycin, which consists of multiple methylpyrrole amino acids. The distamycin would bind to DNA rich in adenine and thymine, and the EDTA would cleave the DNA. John-Stephen Taylor, a Dervan postdoc in the early 1980s and now a chemistry professor at Washington University in St. Louis, did the polyacrylamide gel separation of the resulting DNA cleavage products.

They saw the pattern they expected for one DNA strand, with the cleavage next to the binding site. But when they sequenced the cleavage sites on the other DNA strand, they saw something unexpected. The cleavage pattern for the second strand was offset from the pattern on the first strand.

Taylor was puzzled, but Dervan immediately grasped the implication that the distamycin was binding in the minor groove of DNA, Taylor recalls. Dervan had a large model of DNA in his office, and his careful study of it was paying off. “Clearly, his mind was already prepared for the result,” Taylor says.

Dervan’s lab continued to study polyamides to bind to DNA in the minor groove. Using various combinations of pyrrole, hydroxypyrrole, and imidazole, his team could distinguish all four base pairs.

For recognizing the major groove of DNA, Dervan and his colleagues focused on oligonucleotides that bind to DNA to form a triple helix. Heinz Moser, a postdoc with Dervan in the mid-1980s and now executive director for global discovery chemistry at Novartis, did the early work on the triple-helix approach.

“When I joined his group, he only spent about 10 min with me to explain what I should do,” Moser says. In those 10 min, Dervan told Moser that they should be able to specifically recognize double-stranded DNA sequences by using a short oligonucleotide that binds to the DNA and forms a triple helix. Moser didn’t even know triple helices existed. “I matured as a scientist tremendously because I was thrown in the cold water and had to learn how to swim,” Moser says. Six months later, after many failures and with support from Dervan and his group, Moser got the triple-helix approach to work.

As Dervan and his mentees continued to develop DNA recognition, they increasingly moved toward using their bifunctional molecules for biological applications. Anna K. Mapp, a postdoc with Dervan from 1997 to 2000, and Aseem Z. Ansari, a postdoc with Mark Ptashne at Harvard University, developed artificial transcription factors, molecules that regulate gene expression. Ansari, now at St. Jude Children’s Research Hospital, continued to collaborate with Dervan after starting his independent career at UW–Madison. Mapp’s time in Dervan’s lab “changed entirely the trajectory of what I was interested in,” she says.

When Amanda Hargrove, now a chemistry professor at Duke University, was a postdoc with Dervan in the early 2010s, the group was working toward applying DNA-binding polyamide molecules to mouse models of disease. The team focused on blocking the transcription of the androgen receptor as a way to slow the growth of prostate cancer. “It was a really exciting time to be there,” she says.

Even in the face of other methods of DNA recognition and gene modulation and editing, such as RNA interference and CRISPR, a place remains for the polyamides that Dervan’s lab pioneered, Ansari says. “Small molecules that can target the genome and can be delivered systemically will still be incredibly valuable in ways that CRISPR will not,” Ansari says.

Popular destination

Dervan paved the way for what became chemical biology, but he doesn’t consider himself a founder of the field. His lab was instead the “incubator” lab, he says. In those early days, it was “Chemical biology” with a capital C and a lowercase b, he says.

“I was learning the biology as I went along, and the methods weren’t big enough to do the big B,” Dervan says. “When I was starting out, you couldn’t sequence 10 letters of an oligonucleotide.”

The early successes made Dervan’s lab a popular destination for organic chemists looking to pivot to biological applications. Multiple group alumni say that they were inspired to join his lab after hearing him give a talk about the DNA work.

“If you were interested in what we now call chemical biology and you were coming from a really strong place and wanted to go to a really strong place, Peter was like a beacon,” says Samuel Gellman, who did a postdoc with Dervan in the mid-1980s and is now a chemistry professor at UW–Madison.

“Being able to expand the ideas of organic chemistry into this biologically important molecule was super exciting,” says Eric T. Kool, who did a postdoc with Dervan in the late 1980s and is now a chemistry professor at Stanford University. “Peter’s enthusiasm about and communication skills about it really are what won me over.” In Dervan’s lab, Kool designed new molecules that expanded the sequences that could be recognized by triple helices.

Dervan was “a pioneer in modular design; his compounds combined recognition with chemical reactivity,” says Laura L. Kiessling, who was a postdoc with Dervan from 1989 to 1991 and is now a chemistry professor at the Massachusetts Institute of Technology.

The field has evolved since then. “I would no longer be a card-carrying chemical biologist today,” Dervan says. “Today’s modern successful chemical biologist is a biologist. They are steeply taught both experimentally and intellectually how to do biology. I never had that training.”

Dervan fostered a collegial environment in his lab. He had a hands-off approach to mentoring that gave his students and postdocs a sense of ownership over their projects. It also encouraged them to help one another.

“There wasn’t a culture in the lab of shooting down ideas. There was a culture of making things better,” says Martha Oakley, a chemistry professor at Indiana University Bloomington who was a graduate student with Dervan in the early 1990s. “There was a lot of back and forth, and people would give you good ideas,” she says. “You were never made to feel like an idiot.”

Schultz started working with Dervan as an undergraduate at Caltech and continued through graduate school. He started out studying the biradical reactive intermediates and switched to DNA. “I was very fortunate to work for Peter because he gave me a real problem. He didn’t fool around with ‘Here’s a starter problem,’ ” Schultz says. “Peter was pretty hands off in the lab. If you didn’t need guidance, Peter really didn’t micromanage you.”

Group alumni recall Dervan’s push for unimpeachable data. “There were a lot of conversations in the lab about the requirement that Peter had to get the perfect gel,” says Scott Strobel, a Dervan graduate student from 1987 to 1992 and now the provost at Yale University. “You look at the data in those papers, and there is nothing ambiguous about interpreting what’s in those data.”

“We would never cut and slice a gel. If there was a lane that didn’t run perfectly, in my group you had to rerun that,” Dervan says. “I’m sure the students thought I was the biggest jerk in the whole world that I made people run gels three or four times. Then I knew the data was reproducible.”

“There were definitely complaints about it at the time,” Schepartz says. In retrospect, as a principal investigator herself now, “I know how important that exercise was because it ensured that nothing published was wrong or simply an artifact. It also taught everyone in the lab about the importance of data quality.”

Beyond the lab

In addition to his research, Dervan has served the science community beyond Caltech. Shortly after Dervan’s election to the National Academy of Sciences in 1986, Michael Riordan recruited him to become one of the founders of what became Gilead Sciences. The company was going to focus on antisense oligonucleotides. “I wasn’t working on antisense at the time, although the triple-helix stuff probably had that element to it,” Dervan says. “He picked me reputationally.”

Dervan turned Riordan down the first time he asked. “People don’t remember that in 1987, if you were a serious scholar, particularly at Caltech, you would never get involved in a start-up,” Dervan says. When Riordan tried again, Dervan agreed to join the company as a founder. His main role was as a member of the scientific advisory board. “I took a chance that people would look at me a little funny for having gotten involved with a biotech start-up,” he says. He remained a member of Gilead’s scientific advisory board until 2013.

Dervan also served on the Scientific Advisory Board of the Welch Foundation from 1988 to 2021, including 7 years as chair. When he was chair, Dervan increased the representation of women on the SAB by appointing four women. They were not the first women to serve on the SAB, but it was the first time there had been that many women on the SAB simultaneously.

Catherine Murphy, a chemistry professor at the University of Illinois Urbana-Champaign, is one of those women. She served as vice-chair with Dervan and became chair when he retired. Dervan is “a great role model because he always seems like he’s having fun,” Murphy says. “When you’re with a person who has a positive attitude, it just makes you think, ‘Let’s do this thing.’ ”

And Dervan’s service didn’t stop there. From 2008 to 2017, he was a member of the Board of Trustees at Yale University. During Dervan’s term on the board of trustees, Strobel was Yale’s vice president for west campus planning and program development. Strobel would bounce ideas off Dervan in Dervan’s capacity as a scientist on the board.

“Peter’s a positive, visionary person who calls it straight but at the same time does it in a way that is mentoring and nurturing as opposed to devastating and destroying,” Strobel says. “He very much encouraged all aspects of the management of the university along this path of getting us to a major investment in the sciences with a plan for what we’re going to do.”

In his late 60s, Dervan started planning for his retirement. “I decided that it’s hard for a human being to know when they’ve lost their fastball,” he says. “I think I knew already at age 65 that I would give my laboratory space back to the institute around age 72, 73, 74, cognizant that I had this extraordinary spouse who was younger than me and still very active in her career.” His extraordinary spouse is Jacqueline K. Barton, also a Caltech chemistry professor and recipient of the 2015 Priestley Medal (see box).

A teaching experience underscored for Dervan that the time for retirement was approaching. He has always prided himself on his board work. “I love a piece of white chalk and real slate, and I could do beautiful board work,” he says. “For years, when I would lecture both in sophomore organic chemistry and in my advanced organic courses, the board work was, to be immodest, really, really good. And I think, to be honest, that’s the speed at which students can actually grasp the material.”

In the last 5 years he was teaching, students still gave him good teaching evaluations for his lectures, but they also noted that the quality of his board work was deteriorating. Structures still looked good, but words were becoming less legible. Dervan says, “That’s an example, just in terms of my own personal standards of excellence, that I made the right decision.”