Arthur Riggs (geneticist)

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Arthur Riggs
Born
Arthur Dale Riggs

(1939-08-08)August 8, 1939
Modesto, California, U.S.
DiedMarch 23, 2022(2022-03-23) (aged 82)
Duarte, California, U.S.
NationalityAmerican
CitizenshipU.S.
Alma materUniversity of California, Riverside, California Institute of Technology
Scientific career
FieldsGenetics
InstitutionsBeckman Research Institute of City of Hope National Medical Center
Doctoral advisorHerschel K. Mitchell
Websitewww.cityofhope.org/people/riggs-arthur

Arthur Dale Riggs (August 8, 1939 – March 23, 2022)[1] was an American geneticist who worked with Genentech to express the first artificial gene in bacteria. His work was critical to the modern biotechnology industry because it was the first use of molecular techniques in commercial production of drugs[2] and enabled the large-scale manufacturing of protein drugs, including insulin. He was also a major factor in the origin of epigenetics.

Riggs was a professor of biology and, in 2014, founding director of the Diabetes & Metabolism Research Institute of City of Hope National Medical Center.[3] He was the founding dean of City of Hope's graduate school, the Irell & Manella Graduate School of Biological Sciences. He was also director emeritus of the Beckman Research Institute of City of Hope National Medical Center, which he headed from 2000 to 2007.[4] Riggs served on the board of trustees at the Keck Graduate Institute of Applied Life Sciences.[5][6] In 2006, Riggs was elected to the National Academy of Sciences.[7][8]

Early life and education[edit]

Riggs was born in Modesto, California, near his family's home in Ceres, California,[2][9] on August 8, 1939.[10] 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.[9][10]

Riggs earned his undergraduate degree in chemistry at University of California, Riverside in 1961.[10] He conducted his doctoral thesis work at the California Institute of Technology with Herschel K. Mitchell,[9][11] obtaining a Ph.D. in biochemistry in 1966.[12][13]

Mammalian DNA replication[edit]

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.[14][15] 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.[9]

Protein–DNA interaction[edit]

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.[2] However, Arthur Riggs was the first to purify usable quantities of a transcription factor protein, the lac repressor.[9] He and Suzanne Bourgeois[2] developed a nitrocellulose filter binding assay method that was much faster than existing methods of analysis.[16] Their work resulted in another well-known series of papers on the lac repressor and bacterial gene regulation,[9][16][17][18] opening up new areas of research and theory.[16]: 109 

City of Hope National Medical Center[edit]

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.[9] 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.[4]

Somatostatin and insulin[edit]

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.[9][19]

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.[2][20] 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.[21] 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.[9]

Next, the group produced a synthetic gene coding for human insulin, one that was about ten times larger than the somatostatin encoding.[9] They succeeded in producing artificial insulin in 1978. In 1979, Riggs received the Juvenile Diabetes Foundation Research Award for this work.[2][22]

DNA methylation, epigenetics and antibody engineering[edit]

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.[9] Through ongoing research he has helped to understand the mechanisms of DNA methylation and gene regulation.[23][24]

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."[25] 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.[26] 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.[27][28][29]

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".[9] Riggs continued to work on the epigenetic programming of the cell, designing proteins that can bind to DNA in highly specified ways, wherever desired.[30]

Administration[edit]

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)[31] and served as its founding dean from 1994 to 1998.[4]

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.[4]

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.[3]

Personal life[edit]

Riggs married Jane Riggs in 1960. Together, they had three children.[10]

Riggs died on March 23, 2022, at a hospital in Duarte, California. He was 82, and suffered lymphoma prior to his death.[1][10]

Awards[edit]

  • Distinguished Alumni Award, California Institute of Technology, 2008[32]
  • Elected to the National Academy of Sciences, 2006[7][8]
  • Technology Leadership Award, 2004[33]
  • Distinguished alumnus of University of California, Riverside, 1988[34]
  • Juvenile Diabetes Research Foundation Rumbough Award, 1979[35][36]

References[edit]

  1. ^ a b "In Memoriam: Research pioneer Arthur D. Riggs, 82, developed the technology that led to the first human synthetic insulin to treat diabetes | City of Hope". www.cityofhope.org. May 11, 2022.
  2. ^ a b c d e f Hughes, Sally Smith (2005). "Arthur D. Riggs City of Hope's contribution to early Genentech research" (PDF). Program in Bioscience and Biotechnology Studies. Regional Oral History office, Bancroft Library.
  3. ^ a b White, Nicole (November 14, 2014). "City of Hope unveils new Diabetes and Metabolism Research Institute". City of Hope Press Releases. Archived from the original on March 15, 2015. Retrieved June 4, 2015.
  4. ^ a b c d "Arthur D. Riggs, Ph.D." City of Hope. Retrieved May 13, 2015.
  5. ^ Peterson's graduate programs in the biological sciences 2012 (46th ed.). Lawrenceville, NJ: Peterson's. 2012. ISBN 978-0-7689-3282-9.
  6. ^ "Arthur D. Riggs". Keck Graduate Institute. Archived from the original on May 18, 2015. Retrieved May 13, 2015.
  7. ^ a b "Arthur D. Riggs". www.nasonline.org. National Academy of Sciences. Retrieved April 1, 2022.
  8. ^ a b "Arthur Riggs Elected to National Academy of Sciences". City of Hope. April 25, 2006. Archived from the original (web.archive.org) on May 27, 2008. Retrieved April 1, 2022.
  9. ^ a b c d e f g h i j k l Mossman, Kaspar D. (March 23, 2010). "Profile of Arthur D. Riggs". Proceedings of the National Academy of Sciences. 107 (12): 5269–5271. Bibcode:2010PNAS..107.5269M. doi:10.1073/pnas.1001339107. PMC 2851768. PMID 20332218.
  10. ^ a b c d e Schudel, Matt (March 30, 2022). "Arthur Riggs, who helped develop diabetes treatment, dies at 82". The Washington Post. Retrieved March 31, 2022.
  11. ^ Cohen, Shirley K. (December 3, 1997). "Interview with Herschel K. Mitchell (1913–2000)" (PDF). Archives, California Institute of Technology. Retrieved June 2, 2015.
  12. ^ "Symposium Speakers" (PDF). 50 Years Department of Chemistry. University of California, Riverside. Retrieved June 2, 2015.
  13. ^ "Three World-Renowned Researchers Appointed To Leadership Positions at City of Hope". PRNewsWire. March 27, 2001. Retrieved May 13, 2015.
  14. ^ Huberman, J. A.; Riggs, A. D. (March 1, 1966). "Autoradiography of chromosomal DNA fibers from Chinese hamster cells". Proceedings of the National Academy of Sciences of the United States of America. 55 (3): 599–606. Bibcode:1966PNAS...55..599H. doi:10.1073/pnas.55.3.599. PMC 224194. PMID 5221245.
  15. ^ Huberman, JA; Riggs, AD (March 14, 1968). "On the mechanism of DNA replication in mammalian chromosomes". Journal of Molecular Biology. 32 (2): 327–41. doi:10.1016/0022-2836(68)90013-2. PMID 5689363.
  16. ^ a b c : 72 Müller-Hill, Benno (1996). The lac Operon : a short history of a genetic paradigm. New York: Walter de Gruyter. ISBN 978-3-11-014830-5. Retrieved June 2, 2015.
  17. ^ Riggs, Arthur D.; Bourgeois, Suzanne (June 1968). "On the assay, isolation and characterization of the lac repressor". Journal of Molecular Biology. 34 (2): 361–364. doi:10.1016/0022-2836(68)90260-X. PMID 4938551.
  18. ^ Riggs, Arthur D.; Bourgeois, Suzanne; Newby, Ronald F.; Cohn, Melvin (June 1968). "DNA binding of the lac repressor". Journal of Molecular Biology. 34 (2): 365–368. doi:10.1016/0022-2836(68)90261-1. PMID 4938552.
  19. ^ Wu, Ray; Grossman, Lawrence; Moldave, Kivie (2014). Recombinant DNA Methodology Selected Methods in Enzymology. Academic Press. ISBN 978-1-4832-9597-8.
  20. ^ Hughes, Sally Smith (2013). Genentech : the beginnings of biotech (Paperback ed.). Chicago: University of Chicago Press. ISBN 978-0-226-04551-1.
  21. ^ Stern, Scott (1994). "Incentives and Focus in University and Industrial Research: The Case of Synthetic Insulin". In Gelijns, Annetine C.; Rosenberg, Nathan; Committee on Technological Innovation in Medicine, Institute of Medicine (eds.). The sources of innovation : universities and industry. Washington, D.C.: National Academy Press. pp. 157–187. ISBN 0-309-05189-4.
  22. ^ "First Successful Laboratory Production of Human Insulin Announced". Genentech. September 6, 1978. Archived from the original on September 27, 2016. Retrieved June 3, 2015.
  23. ^ Razin, A; Riggs, AD (November 7, 1980). "DNA methylation and gene function". Science. 210 (4470): 604–10. Bibcode:1980Sci...210..604R. doi:10.1126/science.6254144. PMID 6254144.
  24. ^ Riggs, AD; Jones, PA (1983). "5-methylcytosine, gene regulation, and cancer". Advances in Cancer Research. 40: 1–30. doi:10.1016/S0065-230X(08)60678-8. ISBN 978-0-12-006640-7. PMID 6197868.
  25. ^ Meland, Marius (April 24, 2004). "Judge Dismisses MedImmune's Patent Suit Vs. Genentech". Law360. Retrieved May 13, 2015.
  26. ^ Storz, Ulrich (October 30, 2014). "The Cabilly patents". mAbs. 4 (2): 274–280. doi:10.4161/mabs.4.2.19253. PMC 3361663. PMID 22453097.
  27. ^ Lewis, Wayne (June 10, 2013). "Art Riggs: Smart cancer drugs and how they came to be". City of Hope Breakthroughs. Archived from the original on March 29, 2015. Retrieved May 13, 2015.
  28. ^ Cabilly, Shmuel; Riggs, Arthur D. (January 1985). "Immunoglobulin transcripts and molecular history of a hybridoma that produces antibody to carcinoembryonic antigen". Gene. 40 (1): 157–161. doi:10.1016/0378-1119(85)90037-X. PMID 3937766.
  29. ^ Cabilly, S; Riggs, AD; Pande, H; Shively, JE; Holmes, WE; Rey, M; Perry, LJ; Wetzel, R; Heyneker, HL (June 1984). "Generation of antibody activity from immunoglobulin polypeptide chains produced in Escherichia coli". Proceedings of the National Academy of Sciences of the United States of America. 81 (11): 3273–7. Bibcode:1984PNAS...81.3273C. doi:10.1073/pnas.81.11.3273. PMC 345489. PMID 6374653.
  30. ^ Lewis, Wayne (June 17, 2013). "Art Riggs: A groundbreaking scientist looks to the future". City of Hope Breakthroughs. Archived from the original on June 23, 2013.
  31. ^ "Irell & Manella Graduate School of Biological Sciences" (PDF). Irell & Manella. Retrieved June 4, 2015.
  32. ^ Scahill, Jacqueline (February 14, 2008). "Distinguished Alumni Named". Caltech Media Relations. Retrieved June 4, 2015.
  33. ^ "Awards, Appointments, Announcements". J Natl Cancer Inst. 96 (18): 1357. 2004. doi:10.1093/jnci/96.18.1357.
  34. ^ "Alumni Awards of Distinction". Alumni Association. University of California, Riverside. Archived from the original on June 13, 2010. Retrieved June 2, 2015.
  35. ^ Mulvey, Alexandra (March 14, 2022). "100, 100: Genetically Engineered Human Insulin Created". JDRF. Retrieved April 1, 2022. 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.....
  36. ^ Dutta, Sanjoy (March 2022). "JDRF Mourns the Passing of Arthur Riggs, Ph.D." JDRF. Retrieved April 1, 2022. 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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