Arthur Riggs (geneticist)

Riggs was born in Modesto, California, near his family's home in Ceres, California, on August 8, 1939.{{cite news|title=Arthur Riggs, who helped develop diabetes treatment, dies at 82|url=https://www.washingtonpost.com/obituaries/2022/03/30/diabetes-research-arthur-riggs-dies/|first=Matt|last=Schudel|date=March 30, 2022|access-date=March 31, 2022|newspaper=The Washington Post}} After the family lost their farm during the Great Depression, they moved to San Bernardino, California, where Riggs attended San Bernardino High School. He helped his father, who managed a trailer park, to build and fix things. His mother, a nurse, gave him a chemistry set to encourage his interest in chemistry and biology.

Riggs earned his undergraduate degree in chemistry at University of California, Riverside in 1961. He conducted his doctoral thesis work at the California Institute of Technology with Herschel K. Mitchell,{{cite web|last1=Cohen|first1=Shirley K.|title=Interview with Herschel K. Mitchell (1913–2000)|url=http://oralhistories.library.caltech.edu/25/1/OH_Mitchell_H.pdf|access-date=June 2, 2015|website=Archives, California Institute of Technology|date=December 3, 1997}} obtaining a Ph.D. in biochemistry in 1966.{{cite web|title=Symposium Speakers|url=https://chem.ucr.edu/documents/history/50thanniv_speaker.pdf|website=50 Years Department of Chemistry|publisher=University of California, Riverside|access-date=June 2, 2015}}{{cite news|title=Three World-Renowned Researchers Appointed To Leadership Positions at City of Hope|url=http://www.prnewswire.com/news-releases/three-world-renowned-researchers-appointed-to-leadership-positions-at-city-of-hope-71858122.html|access-date=May 13, 2015|work=PRNewsWire|date=March 27, 2001}}

As graduate students at Caltech, he and Joel A. Huberman collaborated on work that later led to a classic paper on mammalian DNA replication, which was published in 1966.{{cite journal|last1=Huberman|first1=J. A.|last2=Riggs|first2=A. D.|title=Autoradiography of chromosomal DNA fibers from Chinese hamster cells|journal=Proceedings of the National Academy of Sciences of the United States of America|date=March 1, 1966|volume=55|issue=3|pages=599–606|doi=10.1073/pnas.55.3.599|pmid=5221245|pmc=224194|bibcode=1966PNAS...55..599H|doi-access=free}}{{cite journal|last1=Huberman|first1=JA|last2=Riggs|first2=AD|title=On the mechanism of DNA replication in mammalian chromosomes.|journal=Journal of Molecular Biology|date=March 14, 1968|volume=32|issue=2|pages=327–41|pmid=5689363|doi=10.1016/0022-2836(68)90013-2}} They wanted to use radioactive nucleotides to tag replicating DNA and then use photographic film to produce physical images that capture what happens during replication. Their advisors were not interested in the experiment when Huberman and Riggs proposed it, and the students continued the work on their own. Using their method, they were able to measure the rate of DNA replication. The results indicated that chromosomal DNA contained many sections, which replicated independently, and that replication occurred in both directions at each section's origin. The results were important and helped to extend scientists' understanding of mammalian DNA replication. Herschel Mitchell and Giuseppe Attardi, their advisors, felt that the papers should be published under Huberman and Riggs' names, without their advisors', because they had done the work independently.

Riggs moved to the Salk Institute to study protein–DNA interactions with Melvin Cohn as a postdoctoral fellow from 1966 to 1969. At the time, two proteins had been identified as binding to DNA and controlling gene expression: the lambda repressor and the lac repressor. Riggs worked on isolating the lac repressor by affinity chromatography. Walter Gilbert and Benno Müller-Hill were the first to successfully identify it, using a different technique. However, Arthur Riggs was the first to purify usable quantities of a transcription factor protein, the lac repressor. He and Suzanne Bourgeois developed a nitrocellulose filter binding assay method that was much faster than existing methods of analysis. Their work resulted in another well-known series of papers on the lac repressor and bacterial gene regulation,{{rp|72}}{{cite book|last1=Müller-Hill|first1=Benno|title=The lac Operon : a short history of a genetic paradigm|date=1996|publisher=Walter de Gruyter|location=New York|isbn=978-3-11-014830-5|url=https://books.google.com/books?id=sKFGttp2g2IC&pg=PA72|access-date=June 2, 2015}}{{cite journal|last1=Riggs|first1=Arthur D.|last2=Bourgeois|first2=Suzanne|title=On the assay, isolation and characterization of the lac repressor|journal=Journal of Molecular Biology|date=June 1968|volume=34|issue=2|pages=361–364|doi=10.1016/0022-2836(68)90260-X|pmid=4938551}}{{cite journal|last1=Riggs|first1=Arthur D.|last2=Bourgeois|first2=Suzanne|last3=Newby|first3=Ronald F.|last4=Cohn|first4=Melvin|title=DNA binding of the lac repressor|journal=Journal of Molecular Biology|date=June 1968|volume=34|issue=2|pages=365–368|doi=10.1016/0022-2836(68)90261-1|pmid=4938552}} opening up new areas of research and theory.{{rp|109}}

As a result of his interest in gene regulation in mammalian cells, Riggs became curious about X chromosome inactivation, in which one of the two copies of the X chromosome present in a female mammal is inactivated. One of its co-discoverers, Susumu Ohno, worked at the City of Hope National Medical Center. In 1969 Riggs joined the department of molecular biology at the City of Hope National Medical Center as an associate research scientist. He became a senior researcher in 1974, Associate Chair of the Division of Biology in 1979, and Chair of the Division of Biology in 1981.

Riggs continued to study the lac repressor and examined gene regulation in bacteria with Richard E. Dickerson, John Rosenberg, and Keiichi Itakura. They hoped to mix E. coli lac repressor with lac operator, crystallize it, and examine the protein–DNA binding of the crystals using high-resolution DNA methylation analysis. They were able to clone Itakura's lac operator and confirm that it would work in live bacteria, an important result. They also developed a method in which researchers add short "linkers" to DNA sequences and insert them into the bacterial genome.{{cite book|last1=Wu|first1=Ray|last2=Grossman|first2=Lawrence|last3=Moldave|first3=Kivie|title=Recombinant DNA Methodology Selected Methods in Enzymology|date=2014|publisher=Academic Press|isbn=978-1-4832-9597-8|url=https://books.google.com/books?id=s1GeBQAAQBAJ&pg=PA11}}

Riggs and Itakura collaborated with Herbert Boyer at Genentech, and used recombinant DNA technology to become the first to produce a human protein in E. coli.{{cite web|last=Hughes|first=Sally Smith|title=Arthur D. Riggs City of Hope's contribution to early Genentech research|url=http://digitalassets.lib.berkeley.edu/roho/ucb/text/riggs_arthur.pdf|website=Program in Bioscience and Biotechnology Studies|publisher=Regional Oral History office, Bancroft Library|date=2005}}{{cite book|last1=Hughes|first1=Sally Smith|title=Genentech : the beginnings of biotech|date=2013|publisher=University of Chicago Press|location=Chicago|isbn=978-0-226-04551-1|edition=Paperback}} Following the advice of Riggs and Itakura, the group successfully produced the hormone Somatostatin in 1977 as a proof of concept before they attempted to work with the more complicated insulin molecule.{{cite book|editor-last1=Gelijns|editor-first1=Annetine C.|editor-last2=Rosenberg|editor-first2=Nathan|editor-last3=Committee on Technological Innovation in Medicine, Institute of Medicine|title=The sources of innovation : universities and industry|date=1994|publisher=National Academy Press|location=Washington, D.C.|isbn=0-309-05189-4|chapter-url=http://www.nap.edu/openbook.php?isbn=0309051894&page=167|chapter=Incentives and Focus in University and Industrial Research: The Case of Synthetic Insulin|last=Stern|first=Scott|pages=[https://archive.org/details/sourcesofmedical0005unse/page/157 157–187]|url=https://archive.org/details/sourcesofmedical0005unse/page/157}} They were able to link somatostatin to a larger protein, beta-galactosidase, produce it in E. coli, isolate it, and then separate the somatostatin from the galactosidase. Somatostatin was the first mammalian hormone to be produced in a bacterium.

Next, the group produced a synthetic gene coding for human insulin, one that was about ten times larger than the somatostatin encoding. They succeeded in producing artificial insulin in 1978. In 1979, Riggs received the Juvenile Diabetes Foundation Research Award for this work.{{cite web|title=First Successful Laboratory Production of Human Insulin Announced|url=http://www.gene.com/media/press-releases/4160/1978-09-06/first-successful-laboratory-production-o|access-date=June 3, 2015|website=Genentech|date=September 6, 1978|archive-date=September 27, 2016|archive-url=https://web.archive.org/web/20160927073029/http://www.gene.com/media/press-releases/4160/1978-09-06/first-successful-laboratory-production-o|url-status=dead}}

In 1973, Riggs hypothesized that X chromosome inactivation might act in ways analogous to restriction enzyme complexes such as E. coli. He eventually published a theoretical paper on the topic that correctly predicted a key mechanism for DNA methylation epigenetics. Through ongoing research he has helped to understand the mechanisms of DNA methylation and gene regulation.{{cite journal|last1=Razin|first1=A|last2=Riggs|first2=AD|title=DNA methylation and gene function.|journal=Science|date=November 7, 1980|volume=210|issue=4470|pages=604–10|pmid=6254144|doi=10.1126/science.6254144|bibcode=1980Sci...210..604R}}{{cite journal|last1=Riggs|first1=AD|last2=Jones|first2=PA|title=5-methylcytosine, gene regulation, and cancer.|journal=Advances in Cancer Research|date=1983|volume=40|pages=1–30|doi=10.1016/S0065-230X(08)60678-8|pmid=6197868|isbn=978-0-12-006640-7}}

In the 1980s, Riggs became convinced that the type of splicing approach used with recombinant DNA also could be used to produce antibodies. Riggs worked with Shmuel Cabilly on "fundamental technology required for the artificial synthesis of antibody molecules."{{cite news|last1=Meland|first1=Marius|title=Judge Dismisses MedImmune's Patent Suit Vs. Genentech|url=http://www.law360.com/articles/1355/judge-dismisses-medimmune-s-patent-suit-vs-genentech|access-date=May 13, 2015|work=Law360|date=April 24, 2004}} Once again, Riggs and his group characterized the genes for antibodies and cloned them into bacteria. They were able to describe and patent a method for making humanized monoclonal antibodies, using mouse antibodies.{{cite journal|last1=Storz|first1=Ulrich|title=The Cabilly patents|journal=mAbs|date=October 30, 2014|volume=4|issue=2|pages=274–280|doi=10.4161/mabs.4.2.19253|pmc=3361663|pmid=22453097}} They created a gene sequence that would "trick" or induce bacteria into manufacturing humanized antibodies rather than mouse antibodies. This technology has been used to produce "smart" cancer drugs such as Herceptin, Rituxan and Avastin.{{cite news|last1=Lewis|first1=Wayne|title=Art Riggs: Smart cancer drugs and how they came to be|url=http://breakthroughs.cityofhope.org/art-riggs-smart-cancer-drugs|access-date=May 13, 2015|work=City of Hope Breakthroughs|date=June 10, 2013|archive-url=https://web.archive.org/web/20150329093237/http://breakthroughs.cityofhope.org/art-riggs-smart-cancer-drugs|archive-date=March 29, 2015|url-status=dead}}{{cite journal|last1=Cabilly|first1=Shmuel|last2=Riggs|first2=Arthur D.|title=Immunoglobulin transcripts and molecular history of a hybridoma that produces antibody to carcinoembryonic antigen|journal=Gene|date=January 1985|volume=40|issue=1|pages=157–161|doi=10.1016/0378-1119(85)90037-X|pmid=3937766}}{{cite journal|last1=Cabilly|first1=S|last2=Riggs|first2=AD|last3=Pande|first3=H|last4=Shively|first4=JE|last5=Holmes|first5=WE|last6=Rey|first6=M|last7=Perry|first7=LJ|last8=Wetzel|first8=R|last9=Heyneker|first9=HL|title=Generation of antibody activity from immunoglobulin polypeptide chains produced in Escherichia coli.|journal=Proceedings of the National Academy of Sciences of the United States of America|date=June 1984|volume=81|issue=11|pages=3273–7|pmid=6374653|doi=10.1073/pnas.81.11.3273|pmc=345489|bibcode=1984PNAS...81.3273C|doi-access=free}}

In 2009, Riggs published on studies conducted with Gerd Pfeifer on the "methylome" of the genome of a human B cell, examining the DNA methylation pattern of the entire genome in an attempt to find patterns of the epigenetic mark 5-methylcytosine. DNA methylation is believed to pass information from parent cells to daughter cells, functioning as a secondary, high-fidelity information encoding system. The blood donated for the isolation of the B cells was that of Riggs himself. "It could have been anyone's DNA, but as a pioneer in DNA methylation epigenetics, there is something special to me about it being my methylome".{{cite journal|last1=Mossman|first1=Kaspar D.|title=Profile of Arthur D. Riggs|journal=Proceedings of the National Academy of Sciences|date=March 23, 2010|volume=107|issue=12|pages=5269–5271|doi=10.1073/pnas.1001339107|pmid=20332218|pmc=2851768|bibcode=2010PNAS..107.5269M|doi-access=free}} Riggs continued to work on the epigenetic programming of the cell, designing proteins that can bind to DNA in highly specified ways, wherever desired.{{cite news|last1=Lewis |first1=Wayne |title=Art Riggs: A groundbreaking scientist looks to the future |url=http://breakthroughs.cityofhope.org/art-riggs-future/4939 |archive-url=https://web.archive.org/web/20130623103252/http://breakthroughs.cityofhope.org/art-riggs-future/4939/ |url-status=dead |archive-date=June 23, 2013 |work=City of Hope Breakthroughs |date=June 17, 2013 }}

Riggs was closely involved in institutional expansion at City of Hope. In the 1990s, he helped establish the City of Hope Graduate School of Biological Sciences (renamed the Irell & Manella Graduate School of Biological Sciences as of May 15, 2009){{cite web|title=Irell & Manella Graduate School of Biological Sciences|url=http://www.irell.com/assets/htmldocuments/IM_COH_brochure.pdf|website=Irell & Manella|access-date=June 4, 2015}} and served as its founding dean from 1994 to 1998.

During Riggs' time as chair of the Division of Biology (1981–2000), City of Hope restructured in response to a $10 million grant from the Arnold and Mabel Beckman Foundation and established the Beckman Research Institute of City of Hope. From its establishment in 1983, Riggs was chair of the Division of Biology of the Beckman Research Institute. From 2000 to 2007, he served as director of the Beckman Research Institute.

In 2014, City of Hope opened a new Diabetes & Metabolism Research Institute, building on its existing diabetes research program, with Riggs as the institute's first director.{{cite news|last1=White |first1=Nicole |title=City of Hope unveils new Diabetes and Metabolism Research Institute |url=http://www.cityofhope.org/city-of-hope-unveils-new-diabetes-research-institute |archive-url=https://web.archive.org/web/20150315035842/http://cityofhope.org/city-of-hope-unveils-new-diabetes-research-institute |url-status=dead |archive-date=March 15, 2015 |access-date=June 4, 2015 |work=City of Hope Press Releases |date=November 14, 2014 }}

Riggs married Jane Riggs in 1960. Together, they had three children.

Riggs died on March 23, 2022, at a hospital in Duarte, California. He was 82, and suffered lymphoma prior to his death.

• Distinguished Alumni Award, California Institute of Technology, 2008{{cite news|last1=Scahill|first1=Jacqueline|title=Distinguished Alumni Named|url=http://www.caltech.edu/news/distinguished-alumni-named-1387|access-date=June 4, 2015|work=Caltech Media Relations|date=February 14, 2008}}
• Elected to the National Academy of Sciences, 2006{{cite web |title=Arthur D. Riggs |url=http://www.nasonline.org/member-directory/members/20012492.html |website=www.nasonline.org |publisher=National Academy of Sciences |access-date=April 1, 2022}}{{cite web |title=Arthur Riggs Elected to National Academy of Sciences |url=http://www.cityofhope.org/Media/ReleasesMedSci/RiggsNationalAcademy042506MS.htm |publisher=City of Hope |access-date=April 1, 2022 |archive-url=https://web.archive.org/web/20080527185241/http://www.cityofhope.org:80/Media/ReleasesMedSci/RiggsNationalAcademy042506MS.htm |archive-date=May 27, 2008 |format=web.archive.org |date=April 25, 2006 |url-status=dead}}
• Technology Leadership Award, 2004{{cite journal|title=Awards, Appointments, Announcements|journal=J Natl Cancer Inst|date=2004|volume=96|issue=18|page=1357|doi=10.1093/jnci/96.18.1357}}
• Distinguished alumnus of University of California, Riverside, 1988{{cite web|title=Alumni Awards of Distinction |url=http://www.alumni.ucr.edu/Page.aspx?pid=379 |archive-url=https://web.archive.org/web/20100613012137/http://www.alumni.ucr.edu/Page.aspx?pid=379 |url-status=dead |archive-date=June 13, 2010 |website=Alumni Association |publisher=University of California, Riverside |access-date=June 2, 2015 }}
• Juvenile Diabetes Research Foundation Rumbough Award, 1979{{cite web |last1=Mulvey |first1=Alexandra |title=100, 100: Genetically Engineered Human Insulin Created |url=https://www.jdrf.org/blog/2022/03/14/100-100-genetically-engineered-human-insulin-created/ |publisher=JDRF |access-date=April 1, 2022 |date=March 14, 2022 |quote=The City of Hope-Genentech team prevailed in the summer of 1978 —for which we gave the David Rumbough Award in 1979 to Arthur Riggs, Ph.D., David Goeddel, Ph.D., Keiichi Itakura, Ph.D., Roberto Crea, Ph.D., and Dennis Kleid, Ph.D.....}}{{cite web |last1=Dutta |first1=Sanjoy |title=JDRF Mourns the Passing of Arthur Riggs, Ph.D. |url=https://www.jdrf.org/press-releases/jdrf-mourns-passing-arthur-riggs-ph-d/ |website=JDRF |access-date=April 1, 2022 |date=March 2022 |quote=In honor of this groundbreaking work, JDRF bestowed its renowned David Rumbough Award in 1979 to Riggs and four others, for making human insulin a reality for the diabetes community...}}

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Category:1939 births

Category:2022 deaths

Category:Members of the United States National Academy of Sciences

Category:California Institute of Technology alumni

Category:University of California, Riverside alumni

Category:American geneticists

Category:Genentech people

Category:Fellows of the American Academy of Microbiology

Category:History of biotechnology

Category:People from Modesto, California

Category:People from San Bernardino, California

Category:Scientists from California

Category:City of Hope National Medical Center