K. Christopher Garcia
Alma materTulane University, Johns Hopkins University
Scientific career
Fieldsstructural biology
InstitutionsStanford University
Doctoral advisorMario Amzel
Other academic advisorsDavid Goeddel, Tony Kossiakoff, Ian Wilson

K. Christopher Garcia is an American scientist known for his research on the molecular and structural biology of cell surface receptors. Garcia is a professor in the Departments of Molecular and Cellular Physiology and Structural Biology at the Stanford University School of Medicine,[1] an Investigator of the Howard Hughes Medical Institute[2] and a member of the National Academies of Science and Medicine.[3][4] In addition to his role at Stanford, Garcia is a co-founder of several biotechnology companies, including Alexo Therapeutics,[5] Surrozen,[6] and 3T Biosciences.[7]

Education

Garcia earned his B.S. in biochemistry from Tulane University. He attended graduate school at the Johns Hopkins University School of Medicine, where he received his Ph.D. in Biophysics under the mentorship of L. Mario Amzel. After receiving his Ph.D., Garcia conducted postdoctoral research at Genentech in the laboratories of David Goeddel and Tony Kossiakoff, where he immersed himself in the nascent technologies of protein engineering and recombinant protein expression, and then at The Scripps Research Institute in the laboratory of Ian Wilson.

Research career

Garcia's research integrates approaches in structural biology, biochemistry and protein engineering to understand how cell surface receptors sense environmental cues through the engagement of extracellular ligands, and transduce signals. The overarching theme of the laboratory is to elucidate the structural and mechanistic basis of receptor activation in systems relevant to human disease, and to exploit this information to design and engineer new molecules with therapeutic properties. Thus there is a close integration of basic science discovery with translation. Garcia's laboratory at Stanford has published numerous scientific articles describing the molecular structure and signaling mechanisms of proteins important for immunity, neurobiology and development.[8] According to data from Google Scholar, Garcia's publication record yields an h-factor of 105 as of February 2023.[9]

Antigen recognition

Garcia's earliest research as a graduate student at Johns Hopkins University focused on understanding how anti-idiotyopic antibodies recognize peptide antigens.[10] As a postdoctoral scholar at The Scripps Research Institute, Garcia conducted a groundbreaking study that revealed how T cells of the immune system survey peptides presented by major histocompatibility complex proteins (MHC), thus allowing them to distinguish between "self" and "non-self". Garcia's research led to the first visualization of a T cell receptor (TCR) bound to a peptide-MHC (pMHC) complex and was published in the journal Science in 1996.[11] Garcia's 1996 article on the TCR-MHC interaction has had broad impact in the fields of immunology and immunotherapy.[12]

At Stanford University, the Garcia Laboratory reported the structure of the pre-B cell receptor (pre-BCR) in 2007, which revealed how pre-BCRs oligomerize to signal in the absence of antigen.[13] Garcia's group has also authored several additional landmark articles exploring various aspects of TCR-pMHC interactions, including the first structure of a γδ TCR-pMHC complex,[14] the molecular basis for dual recognition of "self" and "foreign" MHCs by TCRs,[15] insights into the germline basis of TCR/MHC interactions,[16][17] the extent of cross-reactivity in the TCR repertoire,[18][19] and elucidation of the structural trigger for TCR signaling.[20] In Garcia's most recent work, his lab developed a peptide-MHC library technology that has enabled the discovery of antigens for orphan T cell receptors, such as those resident in tumors. This technology also enabled a breakthrough in understanding how signaling is initiated by pMHC engagement.

Cytokine signaling

Garcia's research has established how structural and biophysical principles govern receptor binding and signal activation in many different cytokine systems. Key findings include determination of the first crystal structures of the following cytokine family members in complex with their surface receptors: gp130 family (IL-6),[21] common gamma (γc) family (IL-2),[22] Type I Interferons (IFNα2/IFNω)[23] and Type III Interferons.[24] The Garcia Laboratory has also determined crystal structures of many other major cytokine-receptor complexes including those of IL-1, IL-4, IL-13, IL-15, IL-17, IL-23, LIF and CNTF. These structures have revealed a wide range of binding topologies and architectures, and demonstrate how convergent evolution has provided many solutions for cytokine receptors to transduce signals across the cell membrane. In addition to molecular studies of cytokines, Garcia's group has also used directed evolution to engineer high affinity cytokine variants (IL-2, IL-4, IFN-λ) with improved therapeutic properties.[25][24][26]

Wnt signaling

In 2012, Garcia's laboratory determined the crystal structure of a Wnt protein in complex with its cellular receptor, Frizzled.[27] The Wnt-Frizzled structure indicated that Wnts utilize a post-translational lipid modification to directly engage the Frizzled extracellular domain, which represents a highly unusual binding mode among soluble ligands. Garcia's study revealed a striking, donut-shaped architecture adopted by the Wnt-Frizzled complex that adorns the cover of the July 6th, 2012 issue of Science.[27] More recently, Garcia's laboratory reported a breakthrough in being able to recapitulate canonical Wnt signaling using water-soluble bispecific ligands that dimerize Frizzled and Lrp6, which has important implications for the development of therapeutics for regenerative medicine.[28]

Notch signaling

In 2015 and 2017, Garcia published articles in Science describing the first atomic-level visualizations of Notch signaling complexes.[29][30] Garcia's group used directed evolution to strengthen low-affinity interactions between the receptor Notch1 and ligands Delta-like 4 (DLL4) and Jagged1 (Jag1) as a means of stabilizing the complexes for co-crystallization. Notch1-DLL4 and Notch1-Jag1 structures were determined by x-ray crystallography and revealed long, narrow binding interfaces assisted by multiple O-linked fucose and glucose modifications on Notch1. O-linked glycans are rarely observed at protein-protein interfaces, and their presence at the Notch-ligand interface explained how changes in glycosylation state influence Notch signaling activity. Garcia's 2017 publication also established that Notch-ligand interactions form catch bonds, and that Delta-like and Jagged ligands have different mechanical force thresholds for Notch receptor activation.[30]

GPCR signaling

In 2015, the Garcia Laboratory reported the x-ray crystal structure of the virally encoded G-protein coupled receptor (GPCR), US28, bound to its chemokine ligand, fractalkine (CX3CL1).[31] The US28-Fractalkine structure was one of the first reports to visualize a protein ligand bound to a GPCR, and revealed that the globular "head" of fractalkine docks onto the extracellular loops of US28, while fractalkine's flexible N-terminal "tail" threads into a cavity in the center of US28 as a means of fine-tuning its downstream signaling activity. In more recent studies, the lab has engineered biased chemokine ligands and shown that GPCR activation is governed by ligands that induce shape changes rather than highly specific bonding chemistries.[32]

Cancer immunotherapy

Garcia has conducted several studies targeting cellular receptors for applications in cancer immunotherapy. In 2013, Garcia's group developed high affinity antagonists of the receptor CD47 that potently enhance the antitumor effects of established therapeutic antibodies.[33] Garcia later determined that the therapeutic effects of CD47 blockade require combination therapy with checkpoint blockade antibodies in immunocompetent hosts, thus proving that CD47-based therapy relies upon stimulation of the adaptive immune system.[34] Garcia's lab published the creation of an "orthogonal" IL-2 receptor complex to enable the selective delivery of IL-2 signals to engineered T cells during adoptive cell therapy.[35] They also reported a new technology using yeast-displayed peptide-MHC molecules to identify tumor antigens recognized by Tumor Infiltrating Lymphocytes.[36]

Video highlights

Garcia has published descriptions of several research findings online in the form of videos.[37][38]

Awards

  • March of Dimes Basil O’Connor Award (1999)
  • Frederick J. Terman Junior Faculty Award (1999)
  • Rita Allen Foundation Scholar (1999)[39]
  • American Heart Association New Investigator Award (1999)
  • Cancer Research Institute New Investigator Award (2000)
  • Pew Scholar (2001)[40]
  • Keck Distinguished Medical Scholar (2002)[41]
  • Established Investigator of the American Heart Association (2004)
  • Elected to National Academy of Sciences (2012)[3]
  • NIH MERIT award (2013)
  • Member of Mathematical Sciences Jury for the Infosys Prize (2015)
  • Elected to National Academy of Medicine (2016)[4]

Personal life

Garcia is a competitive long-distance runner and has run more than 120 ultramarathons, including several 100-mile races.

References

  1. ↑ Stanford Medicine Profiles - Chris Garcia
  2. ↑ Howard Hughes Medical Institute Scientists - K. Christopher Garcia
  3. 1 2 Proceedings of the National Academy of Sciences - Member Details, K. Christopher Garcia
  4. 1 2 Press release (2016) - National Academy of Medicine elects 79 new members
  5. ↑ Pitchbook Profile of Alexo Therapeutics
  6. ↑ Yahoo Finance - Surrozen Launches Into Regenerative Medicine
  7. ↑ Farr, Christina (2017-10-04). "Peter Thiel and Sean Parker are financing a secretive cancer-fighting start-up, source says". CNBC. Retrieved 2018-08-28.
  8. ↑ PubMed - articles authored by Garcia, KC
  9. ↑ Google Scholar Citations for K. Christopher Garcia
  10. ↑ Three-dimensional structure of an angiotensin II-Fab complex at 3 A: hormone recognition by an anti-idiotypic antibody, Science (1992)
  11. ↑ An αβ T Cell Receptor Structure at 2.5 Å and Its Orientation in the TCR-MHC Complex, Science (1996)
  12. ↑ Google Scholar citations of "An alpha-beta T cell receptor structure at 2.5 microns and its orientation in the TCRMHC complex"
  13. ↑ Structural Insight into Pre-B Cell Receptor Function, Science (2007)
  14. ↑ Structure of a γδ T Cell Receptor in Complex with the Nonclassical MHC T22, Science (2005)
  15. ↑ Colf, Leremy A.; Bankovich, Alexander J.; Hanick, Nicole A.; Bowerman, Natalie A.; Jones, Lindsay L.; Kranz, David M.; Garcia, K. Christopher (2007). "How a Single T Cell Receptor Recognizes Both Self and Foreign MHC". Cell. 129 (1): 135–146. doi:10.1016/j.cell.2007.01.048. PMID 17418792. S2CID 13979698.
  16. ↑ Feng, Dan; Bond, Christopher J.; Ely, Lauren K.; Maynard, Jennifer; Garcia, K. Christopher (September 2007). "Structural evidence for a germline-encoded T cell receptor-major histocompatibility complex interaction 'codon'". Nature Immunology. 8 (9): 975–983. doi:10.1038/ni1502. ISSN 1529-2908. PMID 17694060. S2CID 9902244.
  17. ↑ Sharon, Eilon; Sibener, Leah V.; Battle, Alexis; Fraser, Hunter B.; Garcia, K. Christopher; Pritchard, Jonathan K. (September 2016). "Genetic variation in MHC proteins is associated with T cell receptor expression biases". Nature Genetics. 48 (9): 995–1002. doi:10.1038/ng.3625. ISSN 1546-1718. PMC 5010864. PMID 27479906.
  18. ↑ Birnbaum, Michael E.; Mendoza, Juan L.; Sethi, Dhruv K.; Dong, Shen; Glanville, Jacob; Dobbins, Jessica; Özkan, Engin; Davis, Mark M.; Wucherpfennig, Kai W.; Garcia, K. Christopher (2014). "Deconstructing the Peptide-MHC Specificity of T Cell Recognition". Cell. 157 (5): 1073–1087. doi:10.1016/j.cell.2014.03.047. PMC 4071348. PMID 24855945.
  19. ↑ Lightsources.org Stanford researchers discover immune system's rules of engagement
  20. ↑ Sibener, Leah V.; Fernandes, Ricardo A.; Kolawole, Elizabeth M.; Carbone, Catherine B.; Liu, Fan; McAffee, Darren; Birnbaum, Michael E.; Yang, Xinbo; Su, Laura F. (2018-07-26). "Isolation of a Structural Mechanism for Uncoupling T Cell Receptor Signaling from Peptide-MHC Binding". Cell. 174 (3): 672–687.e27. doi:10.1016/j.cell.2018.06.017. ISSN 1097-4172. PMC 6140336. PMID 30053426.
  21. ↑ Hexameric Structure and Assembly of the Interleukin-6/IL-6 α-Receptor/gp130 Complex, Science (2003)
  22. ↑ Structure of the Quaternary Complex of Interleukin-2 with Its α, ß, and γc Receptors, Science (2005)
  23. ↑ Thomas, Christoph (2011). "Structural Linkage between Ligand Discrimination and Receptor Activation by Type I Interferons". Cell. 146 (4): 621–632. doi:10.1016/j.cell.2011.06.048. PMC 3166218. PMID 21854986.
  24. 1 2 The IFN-λ-IFN-λR1-IL-10Rβ Complex Reveals Structural Features Underlying Type III IFN Functional Plasticity, Immunity (2017)
  25. ↑ Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'
  26. ↑ Junttila, Ilkka S.; Creusot, Remi J.; Moraga, Ignacio; Bates, Darren L.; Wong, Michael T.; Alonso, Michael N.; Suhoski, Megan M.; Lupardus, Patrick; Meier-Schellersheim, Martin (December 2012). "Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines". Nature Chemical Biology. 8 (12): 990–998. doi:10.1038/nchembio.1096. ISSN 1552-4469. PMC 3508151. PMID 23103943.
  27. 1 2 Structural basis of Wnt recognition by Frizzled, Science (2012)
  28. ↑ Janda, Claudia Y.; Dang, Luke T.; You, Changjiang; Chang, Junlei; de Lau, Wim; Zhong, Zhendong A.; Yan, Kelley S.; Marecic, Owen; Siepe, Dirk (2017-05-11). "Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling". Nature. 545 (7653): 234–237. doi:10.1038/nature22306. ISSN 1476-4687. PMC 5815871. PMID 28467818.
  29. ↑ Structural basis for Notch1 engagement of Delta-like 4, Science (2015)
  30. 1 2 Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity
  31. ↑ Structural basis for chemokine recognition and activation of a viral G protein–coupled receptor, Science (2015)
  32. ↑ Miles, Timothy F.; Spiess, Katja; Jude, Kevin M.; Tsutsumi, Naotaka; Burg, John S.; Ingram, Jessica R.; Waghray, Deepa; Hjorto, Gertrud M.; Larsen, Olav (2018-06-08). "Viral GPCR US28 can signal in response to chemokine agonists of nearly unlimited structural degeneracy". eLife. 7. doi:10.7554/eLife.35850. ISSN 2050-084X. PMC 5993540. PMID 29882741.
  33. ↑ Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies, Science (2013)
  34. ↑ Durable antitumor responses to CD47 blockade require adaptive immune stimulation, PNAS (2016)
  35. ↑ Sockolosky, Jonathan T.; Trotta, Eleonora; Parisi, Giulia; Picton, Lora; Su, Leon L.; Le, Alan C.; Chhabra, Akanksha; Silveria, Stephanie L.; George, Benson M. (2018-03-02). "Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes". Science (Submitted manuscript). 359 (6379): 1037–1042. doi:10.1126/science.aar3246. ISSN 1095-9203. PMC 5947856. PMID 29496879.
  36. ↑ Gee, Marvin H.; Han, Arnold; Lofgren, Shane M.; Beausang, John F.; Mendoza, Juan L.; Birnbaum, Michael E.; Bethune, Michael T.; Fischer, Suzanne; Yang, Xinbo (2018-01-25). "Antigen Identification for Orphan T Cell Receptors Expressed on Tumor-Infiltrating Lymphocytes". Cell. 172 (3): 549–563.e16. doi:10.1016/j.cell.2017.11.043. ISSN 1097-4172. PMC 5786495. PMID 29275860.
  37. ↑ Cell Press (2011-08-03), Interferons—Provoking Distinct Signals through the Same Receptor, retrieved 2018-09-19
  38. ↑ Cell Press (2014-01-16), "Extracellular Architecture of the SYG-1/SYG-2 Adhesion Complex Instructs Synaptogenesis", Cell, 156 (3): 482–494, doi:10.1016/j.cell.2014.01.004, PMC 3962013, PMID 24485456, retrieved 2018-09-19
  39. ↑ Rita Allen Foundation
  40. ↑ Pew Trusts
  41. ↑ Philanthropy News Digest
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