Pamela Silver Explained

Birth Name:Pamela Ann Silver
Thesis Year:1982
Thesis Url:http://www.worldcat.org/oclc/763038710
Thesis Title:Mechanisms of membrane assembly : studies on the association of an integral protein with biological membranes
Doctoral Advisor:William T. Wickner
Nationality:American
Fields:Synthetic biology
Systems biology
Workplaces:
Alma Mater:
Doctoral Students:Christina Agapakis[1]
Valerie Weiss
Spouses:)-->
Notable Students:Karmella Haynes
Jessica Polka
Anita Corbett

Pamela Ann Silver is an American cell and systems biologist and a bioengineer. She holds the Elliot T. and Onie H. Adams Professorship of Biochemistry and Systems Biology at Harvard Medical School in the Department of Systems Biology. Silver is one of the founding Core Faculty Members of the Wyss Institute for Biologically Inspired Engineering at Harvard University.[2] [3]

She has made contributions to other disciplines including cell and nuclear biology,[4] [5] [6] systems biology,[7] [8] RNA biology,[9] [10] [11] cancer therapeutics,[12] international policy research, and graduate education. Silver was the first director of the Harvard University Graduate Program in Systems Biology.[13] She serves as a member of the National Science Advisory Board for Biosecurity.[14]

Education and early life

Silver grew up in Atherton, California, where she attended Laurel and Encinal Elementary Schools. During this time, she was a winner of the IBM Math Competition, winning a slide rule[15] and received special recognition for her early aptitude in science. She attended Menlo Atherton High School and graduated from Castilleja School in Palo Alto. She received her B.A. in chemistry from the University of California, Santa Cruz and her PhD in Biological Chemistry from the University of California, Los Angeles in 1982 in the laboratory of William T. Wickner, working largely on the coat assembly of the M13 coliphage.[16] [17]

Career and research

Silver did her postdoctoral research with Mark Ptashne at Harvard University where she discovered one of the first nuclear localization sequences.[18] [19] She continued to study the mechanism of nuclear localization in her own lab as an assistant professor at Princeton University. During this time, she characterized the receptor for NLSs and discovered one of the first eukaryotic DnaJ chaperones.[20]

Silver continued in the area of Cell Biology upon moving to the Dana Farber Cancer Institute to hold the Claudia Adams Barr Investigatorship and to become Associate Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School and Dana-Farber. During this time, she was among the first to follow GFP-tagged proteins in living cells.[21] In addition, she initiated early studies in systems biology to examine interactions within the nucleus on a whole genome scale.[22] Together with Bill Sellers, she discovered molecules that block nuclear export[23] and formed the basis for a publicly traded company Karyopharm Therapeutics. She was promoted in 1997 to Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School and Dana-Farber.

In 2004, Silver moved to the newly formed Department of Systems Biology at Harvard Medical School as a Professor. Around this time, she worked closely with the Synthetic Biology Working Group at MIT and made the decision to move her research group into Synthetic Biology. She observed the motion of the carbon fixing organelles in photosynthetic bacteria.[24] She has worked extensively on designing modified bacteria to act as sensors for exposure to a drug[25] or inflammation[26] in the mammalian gut. She has served as the Director of an ARPA-E (DOE) project on electrofuels.

Her former students include Christina Agapakis,[1] Valerie Weiss, Karmella Haynes, Jessica Polka and Anita Corbett[27]

Synthetic Biology

Some of Silver's work in this area includes the engineering of: mammalian cells to remember and report past exposures to drugs and radiation,[28] [29] [30] robust computational circuits in embryonic stem cells and bacteria,[31] and synthetic switches to moderate gene silencing with the integration of novel therapeutic proteins.[32] [33] Silver's work sets the stage for the development of novel therapies for use in both humans and animals.

Carbon fixation and sustainability

Silver has characterized the carboxysome – the major carbon-fixing structure in cyanobacteria – to enhance photosynthetic efficiency[34] and carbon fixation.[35] She has also engineered cyanobacteria to more efficiently cycle carbon into high-value commodities and has shown that these bacteria can form sustainable consortia.[36] In a collaboration with Jessica Polka, Silver performed super-resolution microscopy of the β-carboxysome.[37]

Silver collaborated with Daniel Nocera at Harvard University to develop a device, called the "Bionic Leaf", that converts solar energy into fuel through a hybrid water-splitting catalyst system that leverages metabolically engineered bacteria.[38]

Gene regulation

Silver discovered a correlation between nuclear transport and gene regulation – she identified the first arginine methyltransferase, which plays a role in chromatin function and is important to the movement of RNA binding proteins between the nucleus and cytoplasm of cells. She also discovered previously unknown variations among ribosomes that led her to propose a unique specificity for the matching between ribosomes and the subsequent translation of mRNAs. Silver's finding has several implications for our understanding of how gene regulation impacts disease development, such as cancer.[39]

Awards and honors

Silver has been the recipient of an NSF Presidential Young Investigator Award, a Basil O’Connor Research Scholar of the March of Dimes, an Established Investigator of the American Heart Association, the NIH Directors Lecture, and NIH MERIT award, Innovation award at BIO, a Fellow of the Radcliffe Institute for Advanced Study, the Elliot T. and Onie H. Adams Professorship at Harvard Medical School and named the Top 20 Global Synthetic Biology Influencers. She sits on numerous advisory boards and has presented to members of the US Congress.

Silver was awarded the BBS Mentoring Award for Graduate Education at Harvard Medical School. She is also one of the founders of the International Genetically Engineered Machines competition (iGEM) and currently sits on the Board of iGEM.org. Silver founded and was the first Director of the Harvard University Graduate Program in Systems Biology. Silver was elected to the American Academy of Arts and Sciences in 2017[40] and the National Academy of Sciences in 2023.

Notes and References

  1. Christina. Agapakis. Biological Design Principles for Synthetic Biology. PhD. 1011273718. 2011. . harvard.edu. Harvard University.
  2. https://web.archive.org/web/20100906100857/http://wyss.harvard.edu/viewpage/128/pamela-silver Silver profile page, Wyss Institute
  3. https://web.archive.org/web/20050905082003/http://sysbio.med.harvard.edu/phd/index.html Systems Biology PhD Program
  4. Jason A Kahana. Bruce J Schnapp. Pamela A Silver. Kinetics of spindle pole body separation in budding yeast. Proceedings of the National Academy of Sciences. October 10, 1995. 92. 21. 9707–9711. 7568202. 10.1073/pnas.92.21.9707. 40871. 1995PNAS...92.9707K. free.
  5. PA Silver. LP Keegan. M Ptashine. Amino terminus of the yeast GAL4 gene product is sufficient for nuclear localization. Proceedings of the National Academy of Sciences. October 1, 1984. 81. 19. 5951–5. 6091123. 10.1073/pnas.81.19.5951. 391836. 1984PNAS...81.5951S. free.
  6. Casolari, J.M.. Brown, C.R.. Komili, S.. West, J.. Hieronymus, H.. Silver, P.A.. amp. Genome-wide localization of the nuclear transport machinery reveals coupling of transcriptional status and nuclear organization. Cell. May 14, 2004. 117. 4. 427–439. 15137937. 10.1016/s0092-8674(04)00448-9. 8932425. free.
  7. Jason S Carroll. X Shirley Liu. Alexander S Brodsky. Wei Li. Clifford A Meyer. Anna J Szary. Jerome Eeckhoute. Wenlin Shao. Eli V Hestermann. Timothy R Geistlinger. Edward A Fox. Pamela A Silver. Myles Brown. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forehead protein FoxA1. Cell. July 15, 2005. 122. 1. 33–43. 10.1016/j.cell.2005.05.008. 16009131. 16841542. free.
  8. Haley Hieronymus. Pamela A Silver. Genome-wide analysis of RNA-protein interactions illustrates specificity of the mRNA export machinery. Nature Genetics. February 1, 2003. 33. 2. 155–161. 10.1038/ng1080. 12524544. 25722385.
  9. Michael J Moore. Qingqing Wang. Caleb J Kennedy. Pamela A Silver. An alternative splicing network links cell-cycle control to apoptosis. Cell. August 20, 2010. 142. 4. 625–636. 10.1016/j.cell.2010.07.019. 20705336. 2924962.
  10. Elisa C Shen. Michael F Henry. Valerie H Weiss. Sandro R Valentini. Pamela A Silver. Margaret S Lee. Arginine methylation facilitates the nuclear export of hnRNP proteins. Genes & Development. March 1, 1998. 12. 5. 679–691. 9499403. 10.1101/gad.12.5.679. 316575.
  11. Margaret S Lee. Michael Henry. Pamela A Silver. A protein that shuttles between the nucleus and the cytoplasm is an important mediator of RNA export. Genes & Development. May 15, 1996. 10. 10. 1233–1246. 10.1101/gad.10.10.1233. 8675010. free.
  12. Tweeny R Kau. Frank Schroeder. Shivapriya Ramaswamy. Cheryl L Wojciechowski. Jean J Zhao. Thomas M Roberts. Jon Clardy. Jon Clardy. William R Sellers. Pamela A Silver. A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell. December 31, 2003. 4. 6. 463–476. 10.1016/S1535-6108(03)00303-9. 14706338. free.
  13. http://sysbiophd.harvard.edu
  14. Web site: National Science Advisory Board for Biosecurity (NSABB). 2021-01-16. Office of Science Policy. en-US.
  15. Web site: Harvard's Pamela Silver recalls journey from Silicon Valley to synthetic biology. 2017-05-16. Harvard Gazette. 2019-01-19.
  16. Silver. P.. Watts. C.. Wickner. W.. August 1981. Membrane assembly from purified components. I. Isolated M13 procoat does not require ribosomes or soluble proteins for processing by membranes. Cell. 25. 2. 341–345. 0092-8674. 7026042. 10.1016/0092-8674(81)90052-0. 24764847.
  17. PhD. Pamela Ann. Silver. 763038710. Mechanisms of membrane assembly : studies on the association of an integral protein with biological membranes. . University of California, Los Angeles. 1982.
  18. Silver, P. . Keegan, L. . Ptashne, M. . amp . The amino terminus of the yeast GAL4 gene product is sufficient for nuclear localization . Proc. Natl. Acad. Sci. USA . 1984 . 81 . 19 . 5951–5 . 10.1073/pnas.81.19.5951 . 6091123 . 391836. 1984PNAS...81.5951S . free .
  19. Silver, P. . Chiang, A. . Sadler, I. . amp . Mutations affecting localization and production of a yeast nuclear protein . Genes & Development . 1988 . 2 . 6 . 707–17. 10.1101/gad.2.6.707 . 3138162 . free .
  20. Blumberg, H. . Silver, P. . amp . SCJ1, a DNAJ homologue that alters protein sorting in yeast . Nature . 1991 . 349 . 6310 . 627–30 . 10.1038/349627a0 . 2000136. 4358892 .
  21. Kahana, J. . Schnapp, B. . Silver, P. . amp . Kinetics of spindle pole body separation in budding yeast . Proc. Natl. Acad. Sci. . 1995 . 92 . 21 . 9707–9711 . 10.1073/pnas.92.21.9707 . 7568202 . 40871. 1995PNAS...92.9707K . free .
  22. Casolari, J. . Brown, CR . Komili, S. . West, J. . Hieronymus, H. . Silver, PA. . amp . Genome-wide localization of the nuclear transport machinery reveals coupling of transcriptional status and nuclear organization . 2004 . Cell . 117 . 4 . 427–439 . 10.1016/s0092-8674(04)00448-9 . 15137937. 8932425 . free .
  23. Kau, TR . Schroeder, F . Wojciechowski, C. . Zhou, JJ . Roberts, T. . Clardy, J . Sellers, W . Silver, PA. . amp . A chemical genetic screen for inhibitors of regulated export of a Forkhead transcription factor in tumor cells . 2003 . Cancer Cell . 4 . 6 . 463–476. 10.1016/s1535-6108(03)00303-9 . 14706338 . free .
  24. Savage D, Afonso B, Silver PA . Spatially ordered dynamics of the bacterial carbon fixation machinery . 2010 . Science . 327 . 5970 . 1258–61. 10.1126/science.1186090 . 20203050. 2010Sci...327.1258S . 36685539 .
  25. Kotula JW, Kerns SJ, Shaket LA, Siraj L, Collins JJ, Way JC, SIlver PA. April 1, 2014. Programmable bacteria detect and record an environmental signal in the mammalian gut. Proceedings of the National Academy of Sciences. 111. 13. 4838–4843. 10.1073/pnas.1321321111. 3977281. 24639514. 2014PNAS..111.4838K. free.
  26. Riglar. David T.. Giessen. Tobias W.. Baym. Michael. Kerns. S. Jordan. Niederhuber. Matthew J.. Bronson. Roderick T.. Kotula. Jonathan W.. Gerber. Georg K.. Way. Jeffrey C.. July 2017. Engineered bacteria can function in the mammalian gut long-term as live diagnostics of inflammation. Nature Biotechnology. 35. 7. 653–658. 10.1038/nbt.3879. 1546-1696. 5658125. 28553941.
  27. Web site: Nature Awards give mentors the recognition, funding, and 'street cred' they need . Anon. 2019 . 2023-05-02 . springernature.com.
  28. Ajo-Franklin, CM. Drubin, DA. Eskin, J.. Gee, E.. Landgraf, D.. Philips, I.. Silver, PA.. amp. Rational design of memory in eukaryotic cells. Genes & Development. September 15, 2007. 21. 18. 2271–2276. 17875664. 10.1101/gad.1586107. 1973140.
  29. Burrill D, Silver PA. amp. Synthetic circuit identifies sub-populations with sustained memory of DNA damage. Genes & Development. 2011. 25. 5. 434–439. 10.1101/gad.1994911. 3049284. 21363961.
  30. Burrill DR, Inniss MC, Boyle PM, Silver PA. amp. Synthetic memory circuits for tracking human cell fate. Genes & Development. July 1, 2012. 26. 13. 1486–1497. 22751502. 10.1101/gad.189035.112. 3403016.
  31. Robinson-Mosher A, Chen JH, Way J, Silver PA. Designing cell-targeted therapeutic proteins reveals the interplay between domain connectivity and cell binding. Biophysical Journal. November 18, 2014. 107. 10. 2456–2466. 10.1016/j.bpj.2014.10.007. 25418314. 4241446. 2014BpJ...107.2456R.
  32. Haynes KA, Silver PA. Synthetic reversal of epigenetic silencing. Journal of Biological Chemistry. August 5, 2011. 286. 31. 27176–27182. 10.1074/jbc.C111.229567. 21669865. 3149311. free.
  33. Alexander A. Green. Pamela A. Silver. James J. Collins. Peng Yin. amp. Toehold Switches: De-Novo-Designed Regulators of Gene Expression. Cell. November 6, 2014. 159. 4. 925–39. 10.1016/j.cell.2014.10.002. 7 May 2015. 25417166. 4265554.
  34. Ducat DC, Avelar-Rivas JA, Way JC, Silver PA. Rerouting carbon flux to enhance photosynthetic productivity. Applied and Environmental Microbiology. April 2012. 78. 8. 2660–2668. 10.1128/AEM.07901-11. 22307292. 3318813. 2012ApEnM..78.2660D.
  35. Ducat DC, Silver PA. Improving carbon pathways. Current Opinion in Chemical Biology. August 2012. 16. 3–4. 337–344. 10.1016/j.cbpa.2012.05.002. 22647231. 3424341.
  36. Polka J, Silver PA. Building synthetic cellular organization. Molecular Biology of the Cell. December 1, 2013. 24. 23. 3585–3587. 10.1091/mbc.E13-03-0155. 3842987. 24288075.
  37. Niederhuber. Matthew J.. Lambert. Talley J.. Yapp. Clarence. Silver. Pamela A.. Polka. Jessica K.. 2017-10-01. Superresolution microscopy of the β-carboxysome reveals a homogeneous matrix. Molecular Biology of the Cell. 28. 20. 2734–2745. 10.1091/mbc.E17-01-0069. 1939-4586. 5620380. 28963440.
  38. Torella JP, Gagliardi CJ, Chen JS, Bediako DK, Colon B, Way JC, SIlver PA, Nocera DG. Efficient solar-to-fuels production from a hybrid microbial-water-splitting catalyst system. Proceedings of the National Academy of Sciences. February 24, 2015. 112. 8. 2337–2342. 10.1073/pnas.1424872112. 25675518. 4345567. 2015PNAS..112.2337T. free.
  39. Yu MC, Lamming DW, Eskin JA, Sinclair DA, Silver PA. amp. The role of arginine methylation in formation of silent chromatin. Genes & Development. December 1, 2006. 20. 23. 3249–3254. 17158743. 10.1101/gad.1495206. 1686602.
  40. Web site: Newly Elected Fellows. www.amacad.org. 2017-05-01.

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