PROFILE Profile of Arthur D. Riggs molecular biologist and pioneer in “They had a better understanding of the field of DNA methylation how science really worked,” he says. “But Aepigenetics, Arthur Riggs was as far as the fundamentals, as far as the elected to the National Academy chemistry knowledge, my physics and of Sciences in 2006. Riggs and his col- mathematical background, I found that I leagues were the first to produce human was actually able to compete very well.” insulin in Escherichia coli. He is also Riggs’s graduate school mentor was known for his work on mammalian DNA Herschel (H.K.) Mitchell. “I chose him replication, protein-DNA interactions, because I enjoyed playing basketball, and and the production of recombinant he was the coach of an intramural bas- antibodies. ketball team,” Riggs says. Riggs has spent most of his career as a Mitchell specialized in the devel- researcher, and later the director, at the opmental genetics of Drosophila. Riggs Beckman Research Institute of the City studied Drosophila for a few years, of Hope National Medical Center, a but then switched to a project designed National Institutes of Health sponsored to determine the size of a Mycoplasma cancer center in Duarte, California. genome. His current work focuses primarily on “Mitchell’s policy was to allow his stu- mammalian epigenetics. dents to do anything they wanted,” says Riggs’ Inaugural Article, published in Riggs. “Most professors at Caltech the January 22, 2009 issue of PNAS (1), allowed a lot of freedom to their stu- investigates genome-wide DNA methyl- Arthur Riggs. dents, but we were expected to do out- fi ation. Speci cally, he and his colleagues standing work, and that was the situation examined at high resolution the pattern in “Helping my father was a great learn- with Mitchell.” DNA of 5-methylcytosine, an epigenetic ing experience,” says Riggs. “But I also Just as Riggs began to write his doctoral mark formed by the enzymatic addition of remember sometimes telling my father thesis, he and fellow student Joel a methyl group to cytosine in double- that I had homework to do in order to Huberman decided to do an experiment stranded DNA after replication. Among avoid digging ditches. I would then read that combined their areas of expertise. a number of possible functions, DNA science fiction rather than do my home- They wanted to label replicating DNA methylation is thought to help pass in- work. But I was always a good student with pulses of radioactive nucleotides and formation with high fidelity from parent and the science classes at San Bernardino expose photographic film to the DNA so cells to daughter cells, providing an in- High School were quite good.” that they might get a physical picture of formation coding system in addition to For college he went to the nearby what happens during replication. Their that of the primary nucleotide sequence. branch of the University of California, supervisors told them not to bother, but These epigenetic marks are thought to Riverside. the students were undeterred. lock genes in an inactive state and help “ “Joel and I didn’t exactly sneak in,” he stable maintenance of cell phenotype. In After I took a class in organic chem- istry, I decided to be a chemistry major,” adds, “but we did come in at night and did the article, the authors describe the DNA “ the experiment anyway. Then we had to methylation pattern of the genome of a Riggs says. You have to do some mental manipulations when you’re thinking put it in the freezer for 3 months. I went human B cell. Riggs conducted this work back to working on my thesis, and Joel in collaboration with Gerd Pfeifer after about organic compounds and their syn- thesis. It was fun for me, and I was good went back to his other project. But the stepping down from an eight-year stint ” at it. Spatial relations are apparently results were spectacular. as director of the Beckman Research In fact, once their supervisors saw the Institute. one of my talents. I wound up being the ” results, they gave their full support. best in the class. “ From Science Fiction to Science He also took enough biology course- These experiments led to better un- derstanding of mammalian DNA repli- Riggs was born in Modesto, in central work to get a double major in biology and ” chemistry, and although he did not com- cation, Riggs says. The investigators California, to parents who lost their farm learned that chromosomal DNA was in the Great Depression and moved to plete the thesis requirement, he found himself gravitating toward biochemistry as composed of many sections that re- San Bernardino in southern California. plicated independently and that, at each his graduation neared in 1960. His mother, a nurse, encouraged his section’s origin, replication forks pro- He applied to and was accepted by the interest in biology and chemistry and gave ceeded in both directions (2). PhD program in biochemistry at the him a chemistry set at age 10. From the experiment, the students were “ California Institute of Technology (Cal- I thoroughly enjoyed mixing reagents able to measure the rate of DNA repli- tech, Pasadena, CA). and getting changes in color and carbon cation. Despite the importance of the ” “ “My plan was to use my chemistry dioxide release, he recalls. That and findings, Mitchell and Guiseppe Attardi, fi knowledge and talent to make new dis- reading science ction got me enthusi- Huberman’s supervisor, insisted on leav- astic about science in junior high school.” coveries about how organisms and bio- ” ing their names off the resulting papers, His father built and managed a mobile logical systems work, he says. because both supervisors had initially said home trailer park in San Bernardino, not to do the work. designing the electrical and plumbing Expected to Be Outstanding systems, as well as doing most of the At Caltech, Riggs felt that he was not as construction work. The elder Riggs also sophisticated as the students trained at fl This is a Profile of a recently elected member of the Na- designed, built, and ew small autogyro academic powerhouses like Harvard or tional Academy of Sciences to accompany the member’s airplanes as a hobby. Stanford. Inaugural Article on page 671 in issue 3 of volume 106. www.pnas.org/cgi/doi/10.1073/pnas.1001339107 PNAS | March 23, 2010 | vol. 107 | no. 12 | 5269–5271 Downloaded by guest on October 2, 2021 “I’m not sure that advisors would be that do high-resolution analysis of protein– To produce insulin was then a relatively generous these days,” Riggs observes. DNA binding.” straightforward task (8). The crystallography project led Riggs to “We used the same method, simply Gene Regulation and Inactivation work with Herbert Boyer at the University writing out—and then making—agene After finishing his PhD in 1966, Riggs took of California, San Francisco. Soon after coding for human insulin,” Riggs says. “But a postdoctoral job under Melvin Cohn at Riggs began this collaboration, Boyer the insulin was composed of two peptide fi the Salk Institute (San Diego, CA). cofounded Genentech, which funded chains that had to be joined [by disul de In collaboration with Susan Bourgeois, much of the research they conducted bonds]. Together they were about 10 times Riggs was the first to study protein–DNA larger than the somatostatin.” together. interactions by using a purified tran- There was tremendous media interest in With Herbert Heyneker, a postdoc in scription factor, the lac repressor. At the the somatostatin and insulin projects (9). Boyer’s lab, Riggs and his colleagues cloned time, only two proteins that bind to DNA Riggs, Boyer, and Itakura were also the lac operator made by Itakura and con- and control gene expression had been competing with other groups after the ducted experiments to determine whether detected in cell extracts: the lambda re- same goal, trying to clone the human the operator actually worked in live bac- pressor and the lac repressor. His re- gene for insulin. teria. It did, which was a landmark result search group was the first to isolate a One competing group was led by that the researchers published in Nature (5). useful quantity of either (3, 4). Walter Gilbert at Harvard University “I was able to obtain milligram (Cambridge, MA) and another other amounts of pure lac repressor—enabling “These experiments led was led by William Rutter and Howard study of the first transcription factor Goodman at University of California, protein,” he says. “That was, in its time, a to better understanding San Francisco. Stephen Hall chronicled major accomplishment.” the competition in a 1987 book, Invisible As Riggs began to consider establishing of mammalian DNA Frontiers: The Race to Synthesize a his ownlab,heturnedtowardtheregulation Human Gene (10). of gene transcription in mammalian cells. replication.” Despite the media and commercial He was particularly fascinated by attention, Riggs continued his research on X chromosome inactivation, in which X chromosome inactivation and con- one copy of the X chromosome—either the Riggs and colleagues also developed the tinued to work with Genentech. maternal or the paternal—is randomly “linker” method (6), widely adopted “I did not actively work in other start- turned off in each cell in the body of a thereafter, in which researchers add short up companies or even as an advisor for mammalian female. links of DNA-containing sites recognized other companies,” he says. “I had a con- That interest in X chromosome inacti- by restriction enzymes to the DNA se- tract to do work for Genentech until vation attracted him to the City of Hope’s quence they wish to clone.