Research Summary

My laboratory is interested in the logic of cell signaling systems: understanding how the networks of signaling proteins found in eukaryotic cells have evolved to allow cells to make complex behavioral decisions. We use two broad approaches to attack this problem. First we use biochemistry, cell biology, genetics, and computational biology to dissect the mechanisms of signaling proteins and networks. We are particularly interested in understanding how nature's toolkit of modular domains are recombined through evolution to generate new and diverse response behaviors. Second, we use synthetic biology: the redesign of biological systems. In particular, we are using various methods to create novel or modified signaling proteins and pathways, both to systematically understand network structure/function relationships and to develop engineered research tools and novel biotechnological and therapeutic applications.

Research Funding

  • September 10, 2021 - August 31, 2026 - Synthetic circuits that drive infiltration of therapeutic T cells into immunologically cold tumors , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U01CA265697
  • April 1, 2021 - March 31, 2026 - Synthetic epigenetic circuits: tunable cell fate switches controlled by dynamic and combinatorial inputs , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA253017
  • December 1, 2020 - November 30, 2025 - Recognizing the tumor ecosystem: Integrating stromal and cancer antigen signals to achieve precision recognition of solid tumors by CAR T cells , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA249018
  • September 24, 2019 - August 31, 2024 - UCSF Center for Synthetic Immunology: Tools to Reprogram the Immune System to Combat Cancer , Principal Investigator . Sponsor: NIH, Sponsor Award ID: U54CA244438
  • September 1, 2018 - July 31, 2023 - Protein Recognition in Signal Transduction , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA220257
  • September 20, 2017 - August 31, 2021 - Designer Tregs for restoring tolerance in patients with type 1 diabetes , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: UC4DK116264
  • September 23, 2014 - August 31, 2021 - Redesigning the T cell: Using Synthetic Biology to Engineer Therapeutic Cells , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01CA196277
  • September 1, 2010 - July 31, 2019 - Exploring Design Principles of Cellular Control Circuits , Principal Investigator . Sponsor: NIH, Sponsor Award ID: P50GM081879
  • January 1, 1997 - July 31, 2018 - Protein Recognition in Signal Transduction , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM055040
  • September 30, 2013 - May 31, 2018 - Harnessing CRISPR for Targeted and Inducible Epigenomic Reprogramming , Co-Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01DA036858
  • September 30, 2004 - July 31, 2015 - Cellular Control: Synthetic Signaling/Motility (RMI) , Principal Investigator . Sponsor: NIH, Sponsor Award ID: PN2EY016546
  • March 1, 1982 - May 31, 2015 - Bio-Organic Biomedical Mass Spectrometry Resource , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P41RR001614
  • February 1, 2001 - April 30, 2012 - Protein Interactions Regulating Cell Motility , Principal Investigator . Sponsor: NIH, Sponsor Award ID: R01GM062583
  • August 15, 2001 - July 31, 2007 - ASSEMBLY AND TARGETING OF NEURAL RECEPTORS AND CHANNELS , Co-Investigator . Sponsor: NIH, Sponsor Award ID: P50MH063981
  • September 30, 2004 - July 31, 2005 - Engineering Synthetic Cell Motility Systems (RMI) , Principal Investigator . Sponsor: NIH, Sponsor Award ID: PN1EY016546

Education

Harvard University, Cambridge, MA, AB, 1986, Chemistry
Mass. Institute of Technology, Cambridge, MA, PhD, 1991, Biochem & Biophysics
Yale University, New Haven, CT, Postdoc, 1992-1996, Biophysics & Biochem

Honors & Awards

  • 1982
    Westinghouse Science Talent Search
  • 1986
    Blumberg Creative Science Award, Harvard College
  • 1988-1991
    Howard Hughes Medical Institute Predoctoral Fellowship
  • 1992-1994
    Helen Hay Whitney Foundation Postdoctoral Fellowship
  • 1994-1996
    Patrick & Catherine W. Donaghue Foundation Postdoctoral Fellowship
  • 1997
    Burroughs Wellcome Fund New Investigator in the Pharmacological Sciences
  • 1997
    Searle Foundation Scholar
  • 1997
    David and Lucille Packard Fellow in Science and Engineering
  • 2001
    Kirsch Foundation Medical Investigator
  • 2005-present
    Board of Advisors, Burroughs Wellcome Fund Scientific Interfaces Program
  • 2005
    Plenary Lecturer, Proteins Gordon Conference
  • 2006
    Rogers Family Foundation Award
  • 2006-present
    Board of Scientific Counselors, National Cancer Institute
  • 2009
    Keynote Speaker, National Academies Keck Futures Initiative, Synthetic Biology Conf.
  • 2009
    National Academies Committee, “A New Biology for the 21st Century”
  • 2010
    Hans Neurath Award, Protein Society
  • 2011
    NSF Synthetic Aesthetics Fellow, exchange between scientists and artists/designers
  • 2012
    Wired SmartList: 50 people who will change the world
  • 2012
    Frederic M. Richards Memorial Lecture

Selected Publications

  1. Zhang J, Tsukui T, Wu X, Brito A, Trumble JM, Caraballo JC, Allen GM, Zavala-Solorio J, Zhang C, Paw J, Lim WA, Geng J, Kutskova Y, Freund A, Kolumam G, Sheppard D, Cohen RL. An immune-based tool platform for in vivo cell clearance. Life Sci Alliance. 2023 08; 6(8).  View on PubMed
  2. Lee JC, Brien HJ, Walton BL, Eidman ZM, Toda S, Lim WA, Brunger JM. Instructional materials that control cellular activity through synthetic Notch receptors. Biomaterials. 2023 06; 297:122099.  View on PubMed
  3. Gupta S, Simic M, Sagan SA, Shepherd C, Duecker J, Sobel RA, Dandekar R, Wu GF, Wu W, Pak JE, Hauser SL, Lim W, Wilson MR, Zamvil SS. CAR-T Cell-Mediated B-Cell Depletion in Central Nervous System Autoimmunity. Neurol Neuroimmunol Neuroinflamm. 2023 03; 10(2).  View on PubMed
  4. Trentesaux C, Yamada T, Klein OD, Lim WA. Harnessing synthetic biology to engineer organoids and tissues. Cell Stem Cell. 2023 01 05; 30(1):10-19.  View on PubMed
  5. Allen GM, Frankel NW, Reddy NR, Bhargava HK, Yoshida MA, Stark SR, Purl M, Lee J, Yee JL, Yu W, Li AW, Garcia KC, El-Samad H, Roybal KT, Spitzer MH, Lim WA. Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science. 2022 12 16; 378(6625):eaba1624.  View on PubMed
  6. Stevens AJ, Harris AR, Gerdts J, Kim KH, Trentesaux C, Ramirez JT, McKeithan WL, Fattahi F, Klein OD, Fletcher DA, Lim WA. Programming multicellular assembly with synthetic cell adhesion molecules. Nature. 2023 02; 614(7946):144-152.  View on PubMed
  7. Daniels KG, Wang S, Simic MS, Bhargava HK, Capponi S, Tonai Y, Yu W, Bianco S, Lim WA. Decoding CAR T cell phenotype using combinatorial signaling motif libraries and machine learning. Science. 2022 12 16; 378(6625):1194-1200.  View on PubMed
  8. Sasha Gupta, Milos Simic, Sharon Sagan, Jason Duecker, Chanelle Shepherd, Raymond Sobel, Stephen Hauser, Wendell Lim, Michael Wilson, Scott Zamvil. CAR-T Cell-Mediated B Cell Depletion in Central Nervous System Autoimmunity. Neurology. 2022 Dec 5; 99(23 Supplement 2):s32-s32.  View on PubMed
  9. Lim WA. The emerging era of cell engineering: Harnessing the modularity of cells to program complex biological function. Science. 2022 11 25; 378(6622):848-852.  View on PubMed
  10. Payal Watchmaker, Milos Simic, David Diebold, Psalm Pineo-Cavanaugh, Jason Deucker, Wei Yu, Wendell Lim, Hideho Okada. EXTH-33. PRIMING OF SYNNOTCH CAR T CELLS VIA CNS-SPECIFIC ANTIGEN ALLOWS SPATIAL AND TEMPORAL REGULATION OF CAR EXPRESSION, EFFECTIVE HOMING AND PERSISTENCE OF T CELLS IN THE CNS. Neuro-Oncology. 2022 Nov 14; 24(Supplement_7):vii216-vii216.  View on PubMed
  11. Allen GM, Lim WA. Rethinking cancer targeting strategies in the era of smart cell therapeutics. Nat Rev Cancer. 2022 12; 22(12):693-702.  View on PubMed
  12. Shangying Wang, Kyle G. Daniels, Sara Capponi, Wendell Lim, Simone Bianco. Deep-learning-based analysis of combinatorial synthetic T-cell receptor libraries. Biophysical Journal. 2022 Feb 1; 121(3):165a.  View on PubMed
  13. Choe JH, Watchmaker PB, Simic MS, Gilbert RD, Li AW, Krasnow NA, Downey KM, Yu W, Carrera DA, Celli A, Cho J, Briones JD, Duecker JM, Goretsky YE, Dannenfelser R, Cardarelli L, Troyanskaya O, Sidhu SS, Roybal KT, Okada H, Lim WA. SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma. Sci Transl Med. 2021 04 28; 13(591).  View on PubMed
  14. O'Donoghue GP, Bugaj LJ, Anderson W, Daniels KG, Rawlings DJ, Lim WA. T cells selectively filter oscillatory signals on the minutes timescale. Proc Natl Acad Sci U S A. 2021 03 02; 118(9).  View on PubMed
  15. Hernandez-Lopez RA, Yu W, Cabral KA, Creasey OA, Lopez Pazmino MDP, Tonai Y, De Guzman A, Mäkelä A, Saksela K, Gartner ZJ, Lim WA. T cell circuits that sense antigen density with an ultrasensitive threshold. Science. 2021 03 12; 371(6534):1166-1171.  View on PubMed
  16. Qi LS, Larson MH, Gilbert LA, Doudna JA, Weissman JS, Arkin AP, Lim WA. Repurposing CRISPR as an RNA-guided platform for sequence-specific control of gene expression. Cell. 2021 Feb 04; 184(3):844.  View on PubMed
  17. Huang X, Williams JZ, Chang R, Li Z, Burnett CE, Hernandez-Lopez R, Setiady I, Gai E, Patterson DM, Yu W, Roybal KT, Lim WA, Desai TA. DNA scaffolds enable efficient and tunable functionalization of biomaterials for immune cell modulation. Nat Nanotechnol. 2021 02; 16(2):214-223.  View on PubMed
  18. Li AW, Lim WA. Engineering cytokines and cytokine circuits. Science. 2020 11 27; 370(6520):1034-1035.  View on PubMed
  19. Williams JZ, Allen GM, Shah D, Sterin IS, Kim KH, Garcia VP, Shavey GE, Yu W, Puig-Saus C, Tsoi J, Ribas A, Roybal KT, Lim WA. Precise T cell recognition programs designed by transcriptionally linking multiple receptors. Science. 2020 11 27; 370(6520):1099-1104.  View on PubMed
  20. Payal Watchmaker, Joseph Choe, Milos Simic, Ryan Gilbert, Aileen li, Nira Krasnow, Diego Carrera, Wei Yu, Kira Downey, Anna Celli, Juhyun Cho, Jessica Briones, Ruth Dannenfelser, Lia Cardarelli, Sachdev Sidhu, Kole Roybal, Wendell Lim, Hideho Okada. IMMU-33. MULTI-ANTIGEN RECOGNITION CIRCUITS OVERCOME CHALLENGES OF SPECIFICITY, HETEROGENEITY, AND DURABILITY IN T-CELL THERAPY FOR GLIOBLASTOMA. Neuro-Oncology. 2020 Nov 9; 22(Supplement_2):ii111-ii112.  View on PubMed

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