Photo of Pamela A. Silver,  PhD

Pamela A. Silver, PhD

Harvard Medical School

Harvard Medical School
Phone: (617) 432-6401
Fax: (617) 432-6405

Pamela A. Silver, PhD

Harvard Medical School


  • Elliott T. and Onie H. Adams Professor of Biochemistry and Systems Biology, Systems Biology, Harvard Medical School


Research Abstract

My group focuses on several areas in systems and synthetic biology. We are trying to understand how groups of molecules and cells function together to generate spatial and temporal organization. At the same time, we are developing design principles to create complex biological systems. Some of the current research areas are summarized below. See our web site for more details and additional references.

1) Genome organization. Our studies of nuclear organization concern the spatial and temporal relationships between genes and other nuclear structures and their functional significance. It has become increasingly clear that the organization of genes within the nucleus plays an important role in cell identity and epigenetics. Recent work from our lab has included a genome-wide study of nuclear organization and generating a high-resolution map of gene location. In doing so, we made discoveries concerning the relationship between gene activation and repression. Current interests in the lab include studying the dynamic nature of the genome under different growth states and different cell types, throughout the cell cycle and in response to drugs in development as anti-cancer therapeutics. We also study the dynamics of post-transcriptional regulation and its relationship to the organization of the genome in response to drugs and diseases.

2) Pathways in Disease. Many signaling pathways employ spatial organization as a key part of their response to environmental stimuli. For example, the movement of key proteins in and out of the nucleus is often one of the downstream steps in signal response. We have taken advantage of this spatial organization to screen for small molecules and genes that affect signaling pathways and therapeutic targets. Currently, we are building on these findings to gain a more quantitative picture of how tumor cells respond to certain drugs. We employ a combination of high-resolution microscopy, genome association technology, modeling and cell-based screens.

3) Designing biological systems. Our goal is to both enhance our understanding of the principles of natural

biological design, and to develop tools and concepts for designing artificial organisms. In the long term, we hope to develop principles for building novel cells that act as sensors, memory devices, bio-computers, or energy producers, and to build novel subsystems such as proteins with designed properties. Current projects use the advanced operating system afforded by eukaryotes to create artificial proteins with therapeutic value, a cellular oscillator that could lead to pulsatile drug delivery, a cell division counter for analysis of aging, and manipulation/creation of metabolic pathways to produce bio-hydrogen as an economical energy source. These experiments use a combination of theoretical and experimental approaches.

Publications from Harvard Catalyst Profiles

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  • Lee J, Vernet A, Redfield K, Lu S, Ghiran IC, Way JC, Silver PA. Rational Design of a Bifunctional AND-Gate Ligand To Modulate Cell-Cell Interactions. ACS Synth Biol 2019. PubMed
  • Hsu BB, Gibson TE, Yeliseyev V, Liu Q, Lyon L, Bry L, Silver PA, Gerber GK. Dynamic Modulation of the Gut Microbiota and Metabolome by Bacteriophages in a Mouse Model. Cell Host Microbe 2019; 25:803-814.e5. PubMed
  • Brown DM, Chan YA, Desai PJ, Grzesik P, Oldfield LM, Vashee S, Way JC, Silver PA, Glass JI. Efficient size-independent chromosome delivery from yeast to cultured cell lines. Nucleic Acids Res 2016. PubMed
  • Lee JW, Gyorgy A, Cameron DE, Pyenson N, Choi KR, Way JC, Silver PA, Del Vecchio D, Collins JJ. Creating Single-Copy Genetic Circuits. Mol Cell 2016; 63:329-36. PubMed
  • Boeke JD, Church G, Hessel A, Kelley NJ, Arkin A, Cai Y, Carlson R, Chakravarti A, Cornish VW, Holt L, Isaacs FJ, Kuiken T, Lajoie M, Lessor T, Lunshof J, Maurano MT, Mitchell LA, Rine J, Rosser S, Sanjana NE, Silver PA, Valle D, Wang H, Way JC, Yang L. GENOME ENGINEERING. The Genome Project-Write. Science 2016; 353:126-7. PubMed
  • Burrill DR, Vernet A, Collins JJ, Silver PA, Way JC. Targeted erythropoietin selectively stimulates red blood cell expansion in vivo. Proc Natl Acad Sci U S A 2016. PubMed
  • Biteen JS, Blainey PC, Cardon ZG, Chun M, Church GM, Dorrestein PC, Fraser SE, Gilbert JA, Jansson JK, Knight R, Miller JF, Ozcan A, Prather KA, Quake SR, Ruby EG, Silver PA, Taha S, van den Engh G, Weiss PS, Wong GC, Wright AT, Young TD. Tools for the Microbiome: Nano and Beyond. ACS Nano 2016; 10:6-37. PubMed
  • Chang ZL, Silver PA, Chen YY. Identification and selective expansion of functionally superior T cells expressing chimeric antigen receptors. J Transl Med 2015; 13:161. PubMed
  • Robinson-Mosher A, Chen JH, Way J, Silver PA. Designing cell-targeted therapeutic proteins reveals the interplay between domain connectivity and cell binding. Biophys J 2014; 107:2456-66. PubMed
  • Green AA, Silver PA, Collins JJ, Yin P. Toehold switches: de-novo-designed regulators of gene expression. Cell 2014; 159:925-39. PubMed
  • Kotula JW, Kerns SJ, Shaket LA, Siraj L, Collins JJ, Way JC, Silver PA. Programmable bacteria detect and record an environmental signal in the mammalian gut. Proc Natl Acad Sci U S A 2014; 111:4838-43. PubMed
  • Lienert F, Torella JP, Chen JH, Norsworthy M, Richardson RR, Silver PA. Two- and three-input TALE-based AND logic computation in embryonic stem cells. Nucleic Acids Res 2013; 41:9967-75. PubMed
  • Wintermute EH, Lieberman TD, Silver PA. An objective function exploiting suboptimal solutions in metabolic networks. BMC Syst Biol 2013; 7:98. PubMed
  • Chen AH, Silver PA. Designing biological compartmentalization. Trends Cell Biol 2012; 22:662-70. PubMed
  • Delebecque CJ, Silver PA, Lindner AB. Designing and using RNA scaffolds to assemble proteins in vivo. Nat Protoc 2012; 7:1797-807. PubMed
  • Adelmant G, Calkins AS, Garg BK, Card JD, Askenazi M, Miron A, Sobhian B, Zhang Y, Nakatani Y, Silver PA, Iglehart JD, Marto JA, Lazaro JB. DNA ends alter the molecular composition and localization of Ku multicomponent complexes. Mol Cell Proteomics 2012; 11:411-21. PubMed
  • Burrill DR, Inniss MC, Boyle PM, Silver PA. Synthetic memory circuits for tracking human cell fate. Genes Dev 2012; 26:1486-97. PubMed
  • Chen AJ, Paik JH, Zhang H, Shukla SA, Mortensen R, Hu J, Ying H, Hu B, Hurt J, Farny N, Dong C, Xiao Y, Wang YA, Silver PA, Chin L, Vasudevan S, Depinho RA. STAR RNA-binding protein Quaking suppresses cancer via stabilization of specific miRNA. Genes Dev 2012; 26:1459-72. PubMed
  • Senapedis WT, Kennedy CJ, Boyle PM, Silver PA. Whole genome siRNA cell-based screen links mitochondria to Akt signaling network through uncoupling of electron transport chain. Mol Biol Cell 2011. PubMed
  • Wang Q, Silver PA. Genome-wide RNAi screen discovers functional coupling of alternative splicing and cell cycle control to apoptosis regulation. Cell Cycle 2010; 9:4419-21. PubMed
  • Aldaye FA, Senapedis WT, Silver PA, Way JC. A structurally tunable DNA-based extracellular matrix. J Am Chem Soc 2010; 132:14727-9. PubMed
  • Moore MJ, Wang Q, Kennedy CJ, Silver PA. An alternative splicing network links cell-cycle control to apoptosis. Cell 2010; 142:625-36. PubMed
  • Silver PA. Knowing when to change: reprogramming (my) life. Nat Cell Biol 2010; 12:730. PubMed
  • Afonso B, Silver PA, Ajo-Franklin CM. A synthetic circuit for selectively arresting daughter cells to create aging populations. Nucleic Acids Res 2010; 38:2727-35. PubMed
  • Taylor ND, Way JC, Silver PA, Cironi P. Anti-glycophorin single-chain Fv fusion to low-affinity mutant erythropoietin improves red blood cell-lineage specificity. Protein Eng. Des. Sel. 2010; 23:251-60. PubMed
  • Savage DF, Afonso B, Chen AH, Silver PA. Spatially ordered dynamics of the bacterial carbon fixation machinery. Science 2010; 327:1258-61. PubMed
  • Burrill DR, Silver PA. Making cellular memories. Cell 2010; 140:13-8. PubMed
  • Agapakis CM, Silver PA. Modular electron transfer circuits for synthetic biology: insulation of an engineered biohydrogen pathway. 2010; 1:413-8. PubMed
  • Haynes KA, Silver PA. Eukaryotic systems broaden the scope of synthetic biology. J Cell Biol 2009; 187:589-96. PubMed
  • Farny NG, Kedersha NL, Silver PA. Metazoan stress granule assembly is mediated by P-eIF2alpha-dependent and -independent mechanisms. RNA 2009; 15:1814-21. PubMed
  • Boyle PM,Silver PA. Harnessing nature's toolbox: regulatory elements for synthetic biology. J R Soc Interface 2009; 6 Suppl 4:S535-46. PubMed
  • Agapakis CM, Silver PA. Synthetic biology: exploring and exploiting genetic modularity through the design of novel biological networks. Mol Biosyst 2009; 5:704-13. PubMed
  • Hurt JA,Obar RA,Zhai B,Farny NG,Gygi SP,Silver PA. A conserved CCCH-type zinc finger protein regulates mRNA nuclear adenylation and export. J Cell Biol 2009; 185:265-77. PubMed
  • Lee SI,Dudley AM,Drubin D,Silver PA,Krogan NJ,Pe'er D,Koller D. Learning a prior on regulatory potential from eQTL data. PLoS Genet 2009; 5:e1000358. PubMed
  • Swinburne IA,Miguez DG,Landgraf D,Silver PA. Intron length increases oscillatory periods of gene expression in animal cells. Genes Dev 2008; 22:2342-6. PubMed
  • Hurt JA,Silver PA. mRNA nuclear export and human disease. Dis Model Mech 2008; 1:103-8. PubMed
  • Cironi P, Swinburne IA, Silver PA. Enhancement of cell type specificity by quantitative modulation of a chimeric ligand. J Biol Chem 2008; 283:8469-76. PubMed
  • Swinburne IA, Silver PA. Intron delays and transcriptional timing during development. Dev Cell 2008; 14:324-30. PubMed
  • Brown CR, Kennedy CJ, Delmar VA, Forbes DJ, Silver PA. Global histone acetylation induces functional genomic reorganization at mammalian nuclear pore complexes. Genes Dev 2008; 22:627-39. PubMed
  • Moore MJ, Silver PA. Global analysis of mRNA splicing. RNA 2008; 14:197-203. PubMed
  • Komili S, Silver PA. Coupling and coordination in gene expression processes: a systems biology view. Nat Rev Genet 2008; 9:38-48. PubMed
  • Farny NG, Hurt JA, Silver PA. Definition of global and transcript-specific mRNA export pathways in metazoans. Genes Dev 2008; 22:66-78. PubMed
  • Frietze S, Lupien M, Silver PA, Brown M. CARM1 regulates estrogen-stimulated breast cancer growth through up-regulation of E2F1. Cancer Res 2008; 68:301-6. PubMed
  • Komili S, Farny NG, Roth FP, Silver PA. Functional specificity among ribosomal proteins regulates gene expression. Cell 2007; 131:557-71. PubMed
  • Ajo-Franklin CM, Drubin DA, Eskin JA, Gee EP, Landgraf D, Phillips I, Silver PA. Rational design of memory in eukaryotic cells. Genes Dev 2007; 21:2271-6. PubMed
  • McKee AE, Silver PA. Systems perspectives on mRNA processing. Cell Res 2007; 17:581-90. PubMed
  • Drubin DA, Way JC, Silver PA. Designing biological systems. Genes Dev 2007; 21:242-54. PubMed
  • Moore MJ, Schwartzfarb EM, Silver PA, Yu MC. Differential recruitment of the splicing machinery during transcription predicts genome-wide patterns of mRNA splicing. Mol Cell 2006; 24:903-15. PubMed
  • Yu MC, Lamming DW, Eskin JA, Sinclair DA, Silver PA. The role of protein arginine methylation in the formation of silent chromatin. Genes Dev 2006; 20:3249-54. PubMed
  • Carroll JS, Meyer CA, Song J, Li W, Geistlinger TR, Eeckhoute J, Brodsky AS, Keeton EK, Fertuck KC, Hall GF, Wang Q, Bekiranov S, Sementchenko V, Fox EA, Silver PA, Gingeras TR, Liu XS, Brown M. Genome-wide analysis of estrogen receptor binding sites. Nat Genet 2006; 38:1289-97. PubMed
  • Auld KL, Brown CR, Casolari JM, Komili S, Silver PA. Genomic association of the proteasome demonstrates overlapping gene regulatory activity with transcription factor substrates. Mol Cell 2006; 21:861-71. PubMed
  • Tsankov AM, Brown CR, Yu MC, Win MZ, Silver PA, Casolari JM. Communication between levels of transcriptional control improves robustness and adaptivity. Mol Syst Biol 2006; 2:65. PubMed