Pamela Silver

Last updated
Pamela Silver
Born
Pamela Ann Silver
NationalityAmerican
Alma mater
Scientific career
Institutions
Thesis Mechanisms of membrane assembly : studies on the association of an integral protein with biological membranes  (1982)
Doctoral advisor William T. Wickner
Doctoral students Christina Agapakis, Valerie Weiss
Other notable students Karmella Haynes
Jessica Polka
Website silver.med.harvard.edu

Pamela A. 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.

Contents

She has made contributions to other disciplines including cell and nuclear biology, [1] [2] [3] systems biology, [4] [5] RNA biology, [6] [7] [8] cancer therapeutics, [9] international policy research, and graduate education. Silver was the first Director of the Harvard University Graduate Program in Systems Biology. She is a member of the National Science Advisory Board for Biosecurity. [10]

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 [11] 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 the laboratory of William T. Wickner, working largely on the coat assembly of the M13 coliphage. [12] [ citation needed ]

Career and research

Silver did her postdoctoral research with Mark Ptashne at Harvard University where she discovered one of the first nuclear localization sequences. [13] [14] 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. [15]

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. [16] In addition, she initiated early studies in systems biology to examine interactions within the nucleus on a whole genome scale. [17] Together with Bill Sellers, she discovered molecules that block nuclear export [18] 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. [19] She has worked extensively on designing modified bacteria to act as sensors for exposure to a drug [20] or inflammation [21] in the mammalian gut. She has served as the Director of an ARPA-E (DOE) project on electrofuels.

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, [22] [23] [24] robust computational circuits in embryonic stem cells and bacteria, [25] and synthetic switches to moderate gene silencing with the integration of novel therapeutic proteins. [26] [27] 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 [28] and carbon fixation. [29] She has also engineered cyanobacteria to more efficiently cycle carbon into high-value commodities and has shown that these bacteria can form sustainable consortia. [30] In a collaboration with Jessica Polka, Silver performed super-resolution microscopy of the β-carboxysome. [31]

The bionic leaf is a system for converting solar energy into liquid fuel developed by the labs of Daniel Nocera and Pamela Silver at Harvard. Bionic leaf.png
The bionic leaf is a system for converting solar energy into liquid fuel developed by the labs of Daniel Nocera and Pamela Silver at Harvard.

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. [32]

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. [33]

Awards

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 [34] and the National Academy of Sciences in 2023.

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References

  1. ↑ Jason A Kahana; Bruce J Schnapp; Pamela A Silver (October 10, 1995). "Kinetics of spindle pole body separation in budding yeast". Proceedings of the National Academy of Sciences. 92 (21): 9707–9711. Bibcode:1995PNAS...92.9707K. doi: 10.1073/pnas.92.21.9707 . PMC   40871 . PMID   7568202.
  2. ↑ PA Silver; LP Keegan; M Ptashine (October 1, 1984). "Amino terminus of the yeast GAL4 gene product is sufficient for nuclear localization". Proceedings of the National Academy of Sciences. 81 (19): 5951–5. Bibcode:1984PNAS...81.5951S. doi: 10.1073/pnas.81.19.5951 . PMC   391836 . PMID   6091123.
  3. ↑ Casolari, J.M.; Brown, C.R.; Komili, S.; West, J.; Hieronymus, H. & Silver, P.A. (May 14, 2004). "Genome-wide localization of the nuclear transport machinery reveals coupling of transcriptional status and nuclear organization". Cell. 117 (4): 427–439. doi: 10.1016/s0092-8674(04)00448-9 . PMID   15137937. S2CID   8932425.
  4. ↑ 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 (July 15, 2005). "Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forehead protein FoxA1". Cell. 122 (1): 33–43. doi: 10.1016/j.cell.2005.05.008 . PMID   16009131. S2CID   16841542 . Retrieved May 6, 2015.
  5. ↑ Haley Hieronymus; Pamela A Silver (February 1, 2003). "Genome-wide analysis of RNA-protein interactions illustrates specificity of the mRNA export machinery". Nature Genetics. 33 (2): 155–161. doi:10.1038/ng1080. PMID   12524544. S2CID   25722385.
  6. ↑ Michael J Moore; Qingqing Wang; Caleb J Kennedy; Pamela A Silver (August 20, 2010). "An alternative splicing network links cell-cycle control to apoptosis". Cell. 142 (4): 625–636. doi:10.1016/j.cell.2010.07.019. PMC   2924962 . PMID   20705336.
  7. ↑ Elisa C Shen; Michael F Henry; Valerie H Weiss; Sandro R Valentini; Pamela A Silver; Margaret S Lee (March 1, 1998). "Arginine methylation facilitates the nuclear export of hnRNP proteins". Genes & Development. 12 (5): 679–691. doi:10.1101/gad.12.5.679. PMC   316575 . PMID   9499403.
  8. ↑ Margaret S Lee; Michael Henry; Pamela A Silver (May 15, 1996). "A protein that shuttles between the nucleus and the cytoplasm is an important mediator of RNA export". Genes & Development. 10 (10): 1233–1246. doi: 10.1101/gad.10.10.1233 . PMID   8675010.
  9. ↑ Tweeny R Kau; Frank Schroeder; Shivapriya Ramaswamy; Cheryl L Wojciechowski; Jean J Zhao; Thomas M Roberts; Jon Clardy; William R Sellers; Pamela A Silver (December 31, 2003). "A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells". Cancer Cell. 4 (6): 463–476. doi: 10.1016/S1535-6108(03)00303-9 . PMID   14706338.
  10. ↑ "National Science Advisory Board for Biosecurity (NSABB)". Office of Science Policy. Retrieved January 16, 2021.
  11. ↑ "Harvard's Pamela Silver recalls journey from Silicon Valley to synthetic biology". Harvard Gazette. May 16, 2017. Retrieved January 19, 2019.
  12. ↑ 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. doi:10.1016/0092-8674(81)90052-0. ISSN   0092-8674. PMID   7026042. S2CID   24764847.
  13. ↑ Silver, P.; Keegan, L. & Ptashne, M. (1984). "The amino terminus of the yeast GAL4 gene product is sufficient for nuclear localization". Proc. Natl. Acad. Sci. USA. 81 (19): 5951–5. Bibcode:1984PNAS...81.5951S. doi: 10.1073/pnas.81.19.5951 . PMC   391836 . PMID   6091123.
  14. ↑ Silver, P.; Chiang, A. & Sadler, I. (1988). "Mutations affecting localization and production of a yeast nuclear protein". Genes & Development. 2 (6): 707–17. doi: 10.1101/gad.2.6.707 . PMID   3138162.
  15. ↑ Blumberg, H. & Silver, P. (1991). "SCJ1, a DNAJ homologue that alters protein sorting in yeast". Nature. 349 (6310): 627–30. doi:10.1038/349627a0. PMID   2000136. S2CID   4358892.
  16. ↑ Kahana, J.; Schnapp, B. & Silver, P. (1995). "Kinetics of spindle pole body separation in budding yeast". Proc. Natl. Acad. Sci. 92 (21): 9707–9711. Bibcode:1995PNAS...92.9707K. doi: 10.1073/pnas.92.21.9707 . PMC   40871 . PMID   7568202.
  17. ↑ Casolari, J.; Brown, CR; Komili, S.; West, J.; Hieronymus, H. & Silver, PA. (2004). "Genome-wide localization of the nuclear transport machinery reveals coupling of transcriptional status and nuclear organization". Cell. 117 (4): 427–439. doi: 10.1016/s0092-8674(04)00448-9 . PMID   15137937. S2CID   8932425.
  18. ↑ Kau, TR; Schroeder, F; Wojciechowski, C.; Zhou, JJ; Roberts, T.; Clardy, J; Sellers, W & Silver, PA. (2003). "A chemical genetic screen for inhibitors of regulated export of a Forkhead transcription factor in tumor cells". Cancer Cell. 4 (6): 463–476. doi: 10.1016/s1535-6108(03)00303-9 . PMID   14706338.
  19. ↑ Savage D, Afonso B, Silver PA (2010). "Spatially ordered dynamics of the bacterial carbon fixation machinery". Science. 327 (5970): 1258–61. Bibcode:2010Sci...327.1258S. doi:10.1126/science.1186090. PMID   20203050. S2CID   36685539.
  20. ↑ 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. Bibcode:2014PNAS..111.4838K. doi: 10.1073/pnas.1321321111 . PMC   3977281 . PMID   24639514.
  21. ↑ 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. doi:10.1038/nbt.3879. ISSN   1546-1696. PMC   5658125 . PMID   28553941.
  22. ↑ Ajo-Franklin, CM; Drubin, DA; Eskin, J.; Gee, E.; Landgraf, D.; Philips, I. & Silver, PA. (September 15, 2007). "Rational design of memory in eukaryotic cells". Genes & Development. 21 (18): 2271–2276. doi:10.1101/gad.1586107. PMC   1973140 . PMID   17875664.
  23. ↑ Burrill D, Silver PA (2011). "Synthetic circuit identifies sub-populations with sustained memory of DNA damage". Genes & Development. 25 (5): 434–439. doi:10.1101/gad.1994911. PMC   3049284 . PMID   21363961.
  24. ↑ Burrill DR, Inniss MC, Boyle PM, Silver PA (July 1, 2012). "Synthetic memory circuits for tracking human cell fate". Genes & Development. 26 (13): 1486–1497. doi:10.1101/gad.189035.112. PMC   3403016 . PMID   22751502.
  25. ↑ Robinson-Mosher A, Chen JH, Way J, Silver PA (November 18, 2014). "Designing cell-targeted therapeutic proteins reveals the interplay between domain connectivity and cell binding". Biophysical Journal. 107 (10): 2456–2466. Bibcode:2014BpJ...107.2456R. doi:10.1016/j.bpj.2014.10.007. PMC   4241446 . PMID   25418314.
  26. ↑ Haynes KA, Silver PA (August 5, 2011). "Synthetic reversal of epigenetic silencing". Journal of Biological Chemistry. 286 (31): 27176–27182. doi: 10.1074/jbc.C111.229567 . PMC   3149311 . PMID   21669865.
  27. ↑ Alexander A. Green; Pamela A. Silver; James J. Collins & Peng Yin (November 6, 2014). "Toehold Switches: De-Novo-Designed Regulators of Gene Expression" (PDF). Cell. 159 (4): 925–39. doi:10.1016/j.cell.2014.10.002. PMC   4265554 . PMID   25417166 . Retrieved May 7, 2015.
  28. ↑ Ducat DC, Avelar-Rivas JA, Way JC, Silver PA (April 2012). "Rerouting carbon flux to enhance photosynthetic productivity". Applied and Environmental Microbiology. 78 (8): 2660–2668. Bibcode:2012ApEnM..78.2660D. doi:10.1128/AEM.07901-11. PMC   3318813 . PMID   22307292.
  29. ↑ Ducat DC, Silver PA (August 2012). "Improving carbon pathways". Current Opinion in Chemical Biology. 16 (3–4): 337–344. doi:10.1016/j.cbpa.2012.05.002. PMC   3424341 . PMID   22647231.
  30. ↑ Polka J, Silver PA (December 1, 2013). "Building synthetic cellular organization". Molecular Biology of the Cell. 24 (23): 3585–3587. doi:10.1091/mbc.E13-03-0155. PMC   3842987 . PMID   24288075.
  31. ↑ Niederhuber, Matthew J.; Lambert, Talley J.; Yapp, Clarence; Silver, Pamela A.; Polka, Jessica K. (October 1, 2017). "Superresolution microscopy of the β-carboxysome reveals a homogeneous matrix". Molecular Biology of the Cell. 28 (20): 2734–2745. doi:10.1091/mbc.E17-01-0069. ISSN   1939-4586. PMC   5620380 . PMID   28963440.
  32. ↑ Torella JP, Gagliardi CJ, Chen JS, Bediako DK, Colon B, Way JC, SIlver PA, Nocera DG (February 24, 2015). "Efficient solar-to-fuels production from a hybrid microbial-water-splitting catalyst system". Proceedings of the National Academy of Sciences. 112 (8): 2337–2342. Bibcode:2015PNAS..112.2337T. doi: 10.1073/pnas.1424872112 . PMC   4345567 . PMID   25675518.
  33. ↑ Yu MC, Lamming DW, Eskin JA, Sinclair DA, Silver PA (December 1, 2006). "The role of arginine methylation in formation of silent chromatin". Genes & Development. 20 (23): 3249–3254. doi:10.1101/gad.1495206. PMC   1686602 . PMID   17158743.
  34. ↑ "Newly Elected Fellows". www.amacad.org. Retrieved May 1, 2017.
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