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. Yamada T, Trentesaux C, Brunger JM, Xiao Y, Stevens AJ, Martyn I, Kasparek P, Shroff NP, Aguilar A, Bruneau BG, Boffelli D, Klein OD, Lim WA. Synthetic organizer cells guide development via spatial and biochemical instructions. Cell. 2025 Feb 06; 188(3):778-795.e18.  View on PubMed
  2. Reddy NR, Maachi H, Xiao Y, Simic MS, Yu W, Tonai Y, Cabanillas DA, Serrano-Wu E, Pauerstein PT, Tamaki W, Allen GM, Parent AV, Hebrok M, Lim WA. Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs. Science. 2024 Dec 06; 386(6726):eadl4793.  View on PubMed
  3. Simic MS, Watchmaker PB, Gupta S, Wang Y, Sagan SA, Duecker J, Shepherd C, Diebold D, Pineo-Cavanaugh P, Haegelin J, Zhu R, Ng B, Yu W, Tonai Y, Cardarelli L, Reddy NR, Sidhu SS, Troyanskaya O, Hauser SL, Wilson MR, Zamvil SS, Okada H, Lim WA. Programming tissue-sensing T cells that deliver therapies to the brain. Science. 2024 Dec 06; 386(6726):eadl4237.  View on PubMed
  4. Weinberg ZY, Soliman SS, Kim MS, Shah DH, Chen IP, Ott M, Lim WA, El-Samad H. De novo-designed minibinders expand the synthetic biology sensing repertoire. bioRxiv. 2024 Aug 29.  View on PubMed
  5. Kim MS, Bhargava HK, Shavey GE, Lim WA, El-Samad H, Ng AH. Degron-Based bioPROTACs for Controlling Signaling in CAR T Cells. ACS Synth Biol. 2024 Aug 16; 13(8):2313-2327.  View on PubMed
  6. Senthilnath Lakshmanachetty, Milos Simic, Jeffrey Haegelin, Payal Watchmaker, Haoyu Long, Jason Deucker, Robert Zhu, Chanelle Sheperd, Wei Yu, Ben Ng, Yuan Wang, Olga Troyanskaya, Lia Cardarelli, Sachdev Sidhu, Wendell Lim, Hideho Okada. DIPG-15. NOVEL CNS SENSING SYNNOTCH-CAR T CELLS FOR TARGETING DIFFUSE MIDLINE GLIOMA. Neuro-Oncology. 2024 Jun 18; 26(Supplement_4):0-0.  View on PubMed
  7. Kim MS, Bhargava HK, Shavey GE, Lim WA, El-Samad H, Ng AH. Degron-based bioPROTACs for controlling signaling in CAR T cells. bioRxiv. 2024 Feb 17.  View on PubMed
  8. Lim WA, Custodio R, Sunga M, Amoranto AJ, Sarmiento RF. General Characteristics and Design Taxonomy of Chatbots for COVID-19: Systematic Review. J Med Internet Res. 2024 01 05; 26:e43112.  View on PubMed
  9. Wong WW, Lim WA. Golden age of immunoengineering. Immunol Rev. 2023 11; 320(1):4-9.  View on PubMed
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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

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