WIMM PI
Curriculum Vitae
Personal Data
Name Simon Davis
Nationality Australian
Present Position
Jul 1997-present: Wellcome Trust Senior Research Fellow in the Basic Biomedical Sciences, Nuffield Department of Clinical Medicine, The University of Oxford
Previous Positions
Feb-May 1986: Visiting Scholar, Medical School, University of California at San Diego, San Diego CA
Nov 1987-Dec 1994: Post-doctoral Research Fellow, MRC Cellular Immunology Unit, The University of Oxford
Jan 1995-Jun, 1997: Wellcome Trust Career Development Award Research Fellow, Nuffield Department of Clinical Medicine, The University of Oxford
Research Achievements
My career focus has been on the cell biology of the T-cell surface. I was initially interested in the problem of how recognition by cell surface receptors can be both weak and specific. The crystal structure of CD2, determined after we solved the problem of the inhibitory effect of glycosylation on protein crystallization, yielded the first view of a cell adhesion molecule. My subsequent work on CD2 revealed that ligand binding involves a novel form of protein recognition reliant on electrostatic- rather than geometric complementarity. The advent of genomics at the end of the 1990s also prompted us to consider the extent to which the T-cell surface was characterized. This was necessary, we argued, because the development of convincing models of cell surface biology would be hampered if important components laid undiscovered. We showed, using transcriptomics, that the composition of the resting T-cell surface was largely known, and produced the first insights into the overall complexity of a mammalian cell surface. My most significant achievement is the formulation of the kinetic-segregation (KS) model of T cell receptor (TCR) triggering, published with P.A. van der Merwe in 1996. At this time a new idea seemed clearly to be needed because existing triggering concepts were incompatible with the likely structure of the TCR. The new concept implied that TCR triggering is achieved by the size-dependent removal of phosphatase activity rather than the induction of kinase activity. The first evidence that the KS model could be extended to other molecules emerged later from our analysis of the crystal structure of an antibody superagonist complexed with CD28. Applying these ideas to the inhibitory receptor PD-1 immediately yielded new antibodies that switch off T-cell responses in vitro and in vivo, and are now licensed to industry. Finally, we have used resonance energy transfer assays to overturn the widespread notion that G protein-coupled receptors invariably homo- or hetero-oligomerize.
What are the Future Aims of Your Current Group?
Our goals in the next five years are (1) to determine whether or not the KS model is the correct theory of receptor triggering, (2) to determine how the signals generated immediately downstream of receptor triggering are integrated and produce distinct signaling outcomes, using a systems-based approach, and (3) to apply our thinking to the development of new therapeutic antibodies. We will use super-resolution imaging to try to visualize the receptor re-organization that we believe is at the heart of receptor triggering, at the scale we propose that it occurs, i.e. the single-molecule level. We have already shown that large phosphatases segregate very readily at cell contacts. We are particularly keen to show that receptor triggering, under certain conditions, is ligand independent because it will establish clear water between our thinking and all other theories of triggering, which require ligands to “do something” to the receptor. An additional important matter is to study the changes, if any, in the regulation of kinases in regions of contact from which phosphatases are excluded, and to extend our findings to native cell-cell contacts at super-resolution. The biophysical principles underpinning post-triggering signal integration and pathway specificity will be established by expressing all of the key proteins (of which there are ~60) likely to interact with phosphorylated receptors, measuring their interactions using SPR, and determining their expression levels using proteomics approaches. We will then simulate the entire system of interactions using computational models that we are developing with Omer Dushek (Pathology). We expect this to yield new biological concepts. Finally, we will build on the “proof-of-concept” we obtained by making inhibitory anti-PD-1 antibody superagonists by preparing new superagonists against other promising targets. We estimate that 50-100 proteins expressed by leukocytes could be targeted in this way, and we will choose ~20 of the most interesting. Our goal is to corner the market for this new class of therapeutic antibodies.
How do the aims of your research fit with the aims of the WIMM and Division of Medicine
Rather than taking clinical observations and working back to molecular causes and possible therapeutic solutions, we address important questions in human health by striving to understand the normal functioning of biological systems known to impact on disease processes. Rather than “translational medicine” our goal is to do “translatable biology”. Specifically, we are committed to understanding, at a very basic level, the most important processes at the heart of human immune responses. The potential of this approach, we think, is well illustrated by our work on superagonistic antibodies. It is well known that certain types of tyrosine-phosphorylated receptors, which include the TCR itself, have disproportionately large impacts on immune cell function. It is also known that antibodies directed at these receptors can have extremely potent effects in humans, as revealed by the unfortunate outcome of the clinical trial at Northwick Park in 2006. The questions are: why do these antibodies have such large effects in healthy immune systems and could we use an understanding of the mechanism as the basis of new therapeutics? Our structure of the complex of a superagonistic antibody with its cellular target, CD28, immediately suggested a general mechanism for antibody superagonism and implied that such antibodies could, in principle, be generated against a large number of receptors dependent on extrinsic tyrosine kinases. By targeting inhibitory rather than activating receptors we expected to be able to produce intrinsically safer superagonists. That we quickly succeeded in generating the predicted inhibitory agonists, and that these have already been taken up by industry, illustrates the speed with which a combination of good concepts and the right experiments can create opportunities for delivering potentially new types of healthcare. The risks inherent in not doing the necessary groundwork are, in turn, illustrated by the failure of the Northwick Park trial.
Lay Summary of Research
Immunology consists of the study of white blood cells, how they protect humans and other animals from infectious agents and possibly from cancer, and how, in an over-zealous state, these cells turn on us, giving us e.g. diabetes or arthritis. It’s known that white blood cells express on their surfaces hundreds of different proteins called “receptors”, that play a major role in directing their protective functions. The dark secret at the heat of immunology is that we still don’t understand how even the best-known and most important of these receptors perform their functions. We originated, and are now testing, the idea that these receptors act in ensemble-like ways, and that the key to how they function depends on how they are distributed across the cell surface. Our idea is that changes in the distribution alter the local balance in the activities of the receptors. A major goal of our work is to use groundbreaking new microscopy-based methods for studying receptor distribution at the single protein level in live cells; already we are seeing hints of the changes in distribution we predicted would have to occur if our theory is correct. In other work, we are trying to understand at the whole-cell or “system” level, how the activities of surface receptors are integrated and interpreted by the cell. Our approach is based on “ground-up” measurements of the properties of each one of >1000 possible interactions the receptors engage in. This work is taking us into new frontiers in biology that may require us to re-formulate our thinking about how cells function. Finally, we are trying to apply all these ideas to the development of new types of drugs that might help us to treat diseases like diabetes and arthritis. Our approach depends on being able to alter receptor organization specifically and artificially, and in model systems we are already able to switch off immune responses.
All Publications Over the Past 5 Years
James JR, Davis SJ (2007) Reply to: BRET analysis of GPCR oligomerization: newer does not mean better. Nat Methods 4, 4
Nettleship JE, Aplin R, Radu Aricescu A, Evans EJ, Davis SJ, Crispin M, Owens RJ (2007) Analysis of variable N-glycosylation site occupancy in glycoproteins by liquid chromatography electrospray ionization mass spectrometry. Anal Biochem 361, 149-151
Kearney A, Avramovic A, Castro MA, Carmo AM, Davis SJ, van der Merwe PA (2007) The contribution of conformational adjustments and long-range electrostatic forces to the CD2/CD58 interaction. J Biol Chem 282, 13160-13166
Chang VT, Crispin M, Aricescu AR, Harvey DJ, Nettleship JE, Fennelly JA, Yu C, Boles KS, Evans EJ, Stuart DI, Dwek RA, Jones EY, Owens RJ, Davis SJ (2007) Glycoprotein structural genomics: solving the glycosylation problem. Structure 15, 267-273
Petrovas C, Price DA, Mattapallil J, Ambrozak DR, Geldmacher C, Cecchinato V, Vaccari M, Tryniszewska E, Gostick E, Roederer M, Douek DC, Morgan SH, Davis SJ, Franchini G, Koup RA. (2007) SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection. Blood 110, 928-936
Berlanga O, Bori-Sanz T, James JR, Frampton J, Davis SJ, Tomlinson MG, Watson SP (2007) Glycoprotein VI oligomerization in cell lines and platelets. J Thromb Haemost 5, 1026-1033
Crispin M, Aricescu AR, Chang VT, Jones EY, Stuart DI, Dwek RA, Davis SJ, Harvey DJ (2007) Disruption of alpha-mannosidase processing induces non-canonical hybrid-type glycosylation. FEBS Lett 581, 1963-1968
Chirifu M, Hayashi C, Nakamura T, Toma S, Shuto T, Kai H, Yamagata Y, Davis SJ, Ikemizu S (2007) Crystal structure of the IL-15-IL-15Ralpha complex, a cytokine-receptor unit presented in trans. Nat Immunol 8, 1001-1007
James JR, Davis SJ (2007) Reply to: Experimental challenge to a 'rigorous' BRET analysis of GPCR oligomerization. Nat Methods 4, 601
Aricescu AR, Siebold C, Choudhuri K, Chang VT, Lu W, Davis SJ, van der Merwe PA, Jones EY. (2007) Structure of a tyrosine phosphatase adhesive interaction reveals a spacer-clamp mechanism. Science 317, 1217-20.
Hene L, Sreenu VB, Vuong MT, Abidi SH, Sutton JK, Rowland-Jones SL, Davis SJ, Evans EJ (2007) Deep analysis of cellular transcriptomes - LongSAGE versus classic MPSS. BMC Genomics 8, 333.
James JR, White SS, Clarke RW, Johansen AM, Dunne PD, Sleep DL, Fitzgerald WJ, Davis SJ, Klenerman D. (2007) Single-molecule level analysis of the subunit composition of the T cell receptor on live T cells. Proc Natl Acad Sci U S A. 104, 17662-7.
Schimanski LM, Drakesmith H, Talbott C, Horne K, James JR, Davis SJ, Sweetland E, Bastin J, Cowley D, Townsend AR. (2008) Ferroportin: Lack of evidence for multimers. Blood Cells Mol Dis. 40, 360-9.
Abidi SH, Dong T, Vuong MT, Sreenu VB, Rowland-Jones SL, Evans EJ, Davis SJ. (2008) Differential remodeling of a T-cell transcriptome following CD8- versus CD3-induced signaling. Cell Res. 18, 641-8.
Evans EJ, Hene L, Vuong M, Abidi HS, Davis SJ. (2009) Transcriptome-based identification of candidate membrane proteins. Methods Mol Biol. 528,37-56.
Gonçalves CM, Castro MA, Henriques T, Oliveira MI, Pinheiro HC, Oliveira C, Sreenu VB, Evans EJ, Davis SJ, Moreira A, Carmo AM. (2009) Molecular cloning and analysis of SSc5D, a new member of the scavenger receptor cysteine-rich superfamily. Mol Immunol. 46, 2585-96.
Crispin M, Chang VT, Harvey DJ, Dwek RA, Evans EJ, Stuart DI, Jones EY, Lord JM, Spooner RA, Davis SJ. (2009) A human embryonic kidney 293T cell line mutated at the Golgi alpha-mannosidase II locus. J Biol Chem. 284, 21684-95.
Dunne PD, Fernandes RA, McColl J, Yoon JW, James JR, Davis SJ, Klenerman D. (2009) DySCo: quantitating associations of membrane proteins using two-color single-molecule tracking. Biophys J. 97, L5-7.
Watson AA, Christou CM, James JR, Fenton-May AE, Moncayo GE, Mistry AR, Davis SJ, Gilbert RJ, Chakera A, O'Callaghan CA. (2009) The platelet receptor CLEC-2 is active as a dimer. Biochemistry. 48, 10988-96.
van der Merwe PA, Dunne PD, Klenerman D, Davis SJ. (2010) Taking T cells beyond the diffraction limit. Nat Immunol. 2010 11, 51-2.
Sonnen AF, Yu C, Evans EJ, Stuart DI, Davis SJ, Gilbert RJ. (2010) Domain Metastability: A Molecular Basis for Immunoglobulin Deposition? J Mol Biol. 399, 207-13
Davis SJ, Crispin MD (2010) Solutions to the glycosylation problem for low- and high-throughput structural glycoproteomics. In Functional and Structural Proteomics of Glycoproteins R.J. Owens and J.E. Nettleship, Springer Science, in press.
Fernandes RA, Yu C, Carmo AM, Evans EJ, van der Merwe PA, Davis SJ (2010) What controls T-cell receptor phosphorylation? Cell 142, 668-9.
Davis SJ, van der Merwe PA (2011) Lck and the nature of the TCR trigger. Trends in Immunol. 32, 1-5.
Brackenridge S, Evans EJ, Toebes M, Goonetilleke N, Liu MK, di Gleria K, Schumacher TN, Davis SJ, McMichael AJ, Gillespie GM. (2011) An Early HIV Mutation within an HLA-B*57-Restricted T Cell Epitope Abrogates Binding to the Killer Inhibitory Receptor 3DL1. J Virol. 85, 5415-22.
Yu C, Sonnen AF, George R, Dessailly BH, Stagg LJ, Evans EJ, Orengo CA, Stuart DI, Ladbury JE, Ikemizu S, Gilbert RJ, Davis SJ. (2011) Rigid-body ligand recognition drives cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor triggering. J Biol Chem. 286, 6685-96.
Yu C, Crispin M, Sonnen AF, Harvey DJ, Chang VT, Evans EJ, Scanlan CN, Stuart DI, Gilbert RJ, Davis SJ. (2011) Use of the α-mannosidase I inhibitor kifunensine allows the crystallization of apo CTLA-4 homodimer produced in long-term cultures of Chinese hamster ovary cells. Acta Crystallogr Sect F Struct Biol Cryst Commun. 67, 785-9.
Bamberger M, Santos AM, Oliveira MI, Gonçalves CM, James JR, Moreira A, Lozano F, Davis SJ, Carmo AM. (2011) A new pathway of CD5-mediated T-cell inhibition dependent on inhibitory FYN phosphorylation. J Biol Chem. 286, 30324-36.
James JR, McColl J, Oliveira MI, Dunne PD, Huang E, Jansson A, Nilsson P, Sleep DL, Gonçalves C, Morgan SH, Felce JH, Mahen R, Fernandes RA, Carmo AM, Klenerman D, Davis SJ. (2011) The T-cell receptor triggering apparatus is composed of monovalent or monomeric proteins. J Biol Chem. 286, 31993-2001.