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

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. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. Li AW, Lim WA. Engineering cytokines and cytokine circuits. Science. 2020 11 27; 370(6520):1034-1035.  View on PubMed
  7. 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
  8. Toda S, McKeithan WL, Hakkinen TJ, Lopez P, Klein OD, Lim WA. Engineering synthetic morphogen systems that can program multicellular patterning. Science. 2020 10 16; 370(6514):327-331.  View on PubMed
  9. Chen YY, Lim W, Levings M, Blazar B, Krenciute G, Wong W, Lehner M. What is the Optimal Design-Build-Test Cycle for Clinically Relevant Synthetic CAR T Cell Therapies? Cell Syst. 2020 09 23; 11(3):212-214.  View on PubMed
  10. Dannenfelser R, Allen GM, VanderSluis B, Koegel AK, Levinson S, Stark SR, Yao V, Tadych A, Troyanskaya OG, Lim WA. Discriminatory Power of Combinatorial Antigen Recognition in Cancer T Cell Therapies. Cell Syst. 2020 09 23; 11(3):215-228.e5.  View on PubMed
  11. Joseph H. Choe, Jasper Z. Williams, Wendell A. Lim. Engineering T Cells to Treat Cancer: The Convergence of Immuno-Oncology and Synthetic Biology. Annual Review of Cancer Biology. 2020 Mar 9; 4(1):121-139.  View on PubMed
  12. Payal Watchmaker, Joseph Choe, Diego Carrera, Ryan Gilbert, Wei Yu, Kira Downey, Kole Roybal, Wendell Lim, Hideho Okada. IMMU-21. SEQUENTIAL TWO-RECEPTOR PRIMING CAR SYSTEM TO OVERCOME HETEROGENEOUS ANTIGEN EXPRESSION. Neuro-Oncology. 2019 Nov 11; 21(Supplement_6):vi123-vi123.  View on PubMed
  13. Yu W, Marshall WF, Metzger RJ, Brakeman PR, Morsut L, Lim W, Mostov KE. Simple Rules Determine Distinct Patterns of Branching Morphogenesis. Cell Syst. 2019 09 25; 9(3):221-227.  View on PubMed
  14. Gerardin J, Reddy NR, Lim WA. The Design Principles of Biochemical Timers: Circuits that Discriminate between Transient and Sustained Stimulation. Cell Syst. 2019 09 25; 9(3):297-308.e2.  View on PubMed
  15. Bugaj LJ, Lim WA. High-throughput multicolor optogenetics in microwell plates. Nat Protoc. 2019 07; 14(7):2205-2228.  View on PubMed
  16. Toda S, Frankel NW, Lim WA. Engineering cell-cell communication networks: programming multicellular behaviors. Curr Opin Chem Biol. 2019 10; 52:31-38.  View on PubMed
  17. Satoshi Toda, Jonathan M. Brunger, Wendell A. Lim. Synthetic Development: Learning to Program Multicellular Self-Organization. Current Opinion in Systems Biology. 2019 Apr 1; 14(Nature 459 2009):41-49.  View on PubMed
  18. Payal Watchmaker, Joseph Choe, Diego Carrera, Kira Downey, Maryam Shahin, Kole Roybal, Wendell Lim, Hideho Okada. IMMU-57. SEQUENTIAL TWO-RECEPTOR PRIMING CAR SYSTEM TO OVERCOME HETEROGENEOUS ANTIGEN EXPRESSION. Neuro-Oncology. 2018 Nov 5; 20(suppl_6):vi134-vi134.  View on PubMed
  19. Bugaj LJ, Sabnis AJ, Mitchell A, Garbarino JE, Toettcher JE, Bivona TG, Lim WA. Cancer mutations and targeted drugs can disrupt dynamic signal encoding by the Ras-Erk pathway. Science. 2018 08 31; 361(6405).  View on PubMed
  20. Toda S, Blauch LR, Tang SKY, Morsut L, Lim WA. Programming self-organizing multicellular structures with synthetic cell-cell signaling. Science. 2018 07 13; 361(6398):156-162.  View on PubMed

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