The Compatibility Gene, page 25
19. It later turned out that this cell line didn’t actually have just one type of HLA-B. When sub-types were described afterwards so that each HLA allele could come in slightly different versions, the HLA-B*07 from this cell line turned out to include two different sub-types. This was described to me in e-mail correspondence with Jack Strominger, November 2011.
20. Discussion with Jim Kaufman, 27 May 2011.
21. Brewerton, D. All About Arthritis: Past, Present, Future (Harvard University Press, 1992). Chapter 20 of this book, entitled ‘The beauty of crystals’, contains a detailed discussion of the work by Bjorkman, Wiley and Strominger to get the crystal structure of HLA-A*02. The story is told from Bjorkman’s perspective and includes a long letter written to the author by Bjorkman, describing many details of the process. This letter was written just a few years after the work was published, so details would be well remembered. This also serves to show how quickly this work was known to be important.
22. Interview with Pamela Bjorkman, 12 May 2011.
23. Rolf M. Zinkernagel – Autobiography. Available at Nobelprize. org.
24. A great deal of important research has been omitted here. Venezuelan immunologist Baruj Benacerraf, working at Harvard, had studied the genetic requirements for immune responses and discovered the so-called immune response (Ir) gene in guinea pigs. Independently, Hugh McDevitt, working in the UK’s National Institute for Medical Research, London, showed that strains of mice would vary in their immune response. Benacerraff shared the 1980 Nobel Prize with Dausset and Snell. Snell shared the prize because his work with inbred strains of mice identified the genes that governed transplantation, which in turn made mice essential tools for probing the genetics of immune responses. Snell’s work took a long time to be recognized: in 1956 when asked how many colleagues understood his work on compatibility genes, he replied that he could easily count them without using all his fingers. McDevitt must have been closely considered for the Nobel Prize in 1980 and many immunologists have said that he thoroughly deserved to win.
25. Interview with Rolf Zinkernagel, 18 May 2011.
26. Doherty, P. The Beginner’s Guide to Winning the Nobel Prize (Columbia University Press, 2006).
27. Zinkernagel was experienced in doing this kind of experiment – to test how well cells are killed by immune cells. First, the cells that will be killed are filled with radioactivity. Then, as they get killed, their radioactive innards leak out into the surrounding liquid, indicating their death. Importantly, the number of cells killed is proportional to how radioactive the surrounding liquid gets.
28. Zinkernagel, R. M. Cellular immune recognition and the biological role of major transplantation antigens. Nobel lecture, 8 December 1996. This Nobel lecture gives a detailed and thorough account of Zinkernagel and Doherty’s experiments and also outlines their influences at the time.
29. Zinkernagel, R. M. and Doherty, P. C. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system. Nature 248, 701–2 (1974). Zinkernagel, R. M. and Doherty, P. C. Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis. Nature 251, 547–8 (1974).
30. Interview with Rolf Zinkernagel, 18 May 2011.
31. Interview with Peter Doherty, 16 May 2011.
32. Zinkernagel and Doherty. Restriction of in vitro T cell-mediated cytotoxicity.
33. Interview with Peter Doherty, 16 May 2011. Interview with Rolf Zinkernagel, 18 May 2011.
34. E-mail correspondence with Peter Doherty, 15 June 2011.
35. Doherty, P. C. and Zinkernagel, R. M. A biological role for the major histocompatibility antigens. Lancet 1, 1406–9 (1975).
36. Rebbeck, C. A., Thomas, R., Breen, M., Leroi, A. M. and Burt, A. Origins and evolution of a transmissible cancer. Evolution 63, 2340–49 (2009).
37. Interview with Peter Doherty, 16 May 2011.
38. Weiss, A. Discovering the TCR beta-chain by subtraction. Journal of Immunology 175, 2769–70 (2005). Much of the research behind the discovery of the T-cell receptor is not covered in depth in this book but is described succinctly in this brief overview by Art Weiss, where the key primary publications can be found also. Many great scientists played a role in the discovery of the T-cell receptor including Jim Allison, Ellis Reinherz, John Kappler and Philippa Marrack, who isolated antibodies that could detect the T-cell receptor. Mark Davis and Tak Mak’s work led to identification of the relevant genes.
39. Hedrick, S. M., Cohen, D. I., Nielsen, E. A. and Davis, M. M. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature 308, 149–53 (1984). Hedrick, S. M., Nielsen, E. A., Kavaler, J., Cohen, D. I. and Davis, M. M. Sequence relationships between putative T-cell receptor polypeptides and immunoglobulins. Nature 308, 153–8 (1984).
40. Discussion with Mark Davis, 2 November 2011.
41. Marx, J. L. Likely T cell receptor gene cloned. Science 221, 1278–9 (1983).
42. Hedrick, Cohen, Nielsen and Davis. Isolation of cDNA clones. Yanagi, Y. et al. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature 308, 145–9 (1984). Mark Davis had done his work with mouse cells and, independently, Tak Mak in Canada cloned a T-cell receptor gene from human cells.
43. Alain Townsend’s PhD supervisor was Brigitte (Ita) Askonas, who had made many seminal contributions to immunology. A very large number of well-known immunologists trained with Askonas. Her obituary, by Bridget Ogilvie, is published in the Guardian, 10 January 2013.
44. Interview with Andrew McMichael, 4 July 2011.
45. Townsend, A. R., Gotch, F. M. and Davey, J. Cytotoxic T cells recognize fragments of the influenza nucleoprotein. Cell 42, 457–67 (1985).
46. Townsend, A. R. et al. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell 44, 959–68 (1986).
47. Interview with Alain Townsend, 25 May 2011.
48. Interview with Andrew McMichael, 4 July 2011.
49. Interview with Alain Townsend, 25 May 2011.
50. Galileo, G. Sidereus Nuncius (or The Starry Messenger) (1610). The original edition in New Latin is rare and worth hundreds of thousands of pounds. Various English translations are available, some free online.
51. E-mail correspondence with Peter Doherty, 15 June 2011.
52. In e-mail correspondence on 4 October 2011, Jack Strominger said that, while he didn’t want to take anything away from Bjorkman and others, he ‘never felt that Saper has gotten his fair share of credit for what turned out to be such an important paper’. Indeed Saper has missed out on the limelight for this work, compared with the others involved. He was second author of the original paper in Nature and was the first author of the longer, more detailed description of the structure of HLA-A*02 published later in 1991, while Strominger was on sabbatical leave in Oxford. The paper is: Saper, M. A., Bjorkman, P. J., and Wiley, D. C. Refined structure of the human histocompatibility antigen HLA-A2 at 2. 6 Å resolution. Journal of Molecular Biology 219, 277–319 (1991). Eminent immunologist Peter Parham called this second paper ‘masterfully encyclopaedic’.
53. Bjorkman, P. J. Finding the groove. Nature Immunology 7, 787–9 (2006). In this article, Pamela Bjorkman details how the structure of HLA-A*02 was elucidated.
54. Parham, P. Putting a face to MHC restriction. Journal of Immunology 174, 3–5 (2005).
55. Braunstein, N. S. and Germain, R. N. Allele-specific control of Ia molecule surface expression and conformation: implications for a general model of Ia structure-function relationships. Proceedings of the National Academy of Sciences USA 84, 2921–5 (1987). This paper, which slightly pre-dates the publication of the structure of the class I MHC protein HLA-A*02, did show a schematic view of how class II MHC protein would look, as predicted from many biochemical experiments. It got many essential features right, although of course the atomic-scale crystal structure of HLA-A*02 provided the definitive and iconic view.
56. Bjorkman, P. J. et al. Structure of the human class I histocompatibility antigen, HLA-A2. Nature 329, 506–12 (1987).
57. Bjorkman, P. J. et al. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329, 512–18 (1987).
58. The valuable Canadian Gairdner award in 1994 included Wiley and Bjorkman but out left Strominger. Two years later, the Paul Ehrlich Prize, another major international award, included Bjorkman and Strominger and left out Wiley. Then, to complete all possible pairings, the Japan Prize, with its cash prize of around US $450,000, was given to Wiley and Strominger in 1999, leaving out Bjorkman. Scientists usually say in public that such prizes aren’t overly important and certainly aren’t anybody’s focus, and it is true that the vast majority of successful scientists start with the drive and curiosity to find things out, not to become famous. On the other hand, there is considerable money and fame at stake with these international prizes, and a sprinkling of fairy dust from a Nobel can trigger global celebrity status (at least until the next one is awarded). Bjorkman, like many other scientists, says that prizes are great for highlighting discoveries widely but she also says there may be too many. Strominger suggests that recognition should be spread more widely because so much outstanding work is being done, in part because of the huge technical advances made in the past few decades. He thinks it might be better if each person could only win one big international award to spread the glory more widely. Zinkernagel says that the impact of prizes depends on one’s character; for decent people, they won’t change anything: ‘They cause a problem only for people who are anyway intolerant.’
59. Doherty, P. A Light History of Hot Air (Melbourne University Press, 2008).
CHAPTER 5: DIFFERENCES BETWEEN US THAT MATTER
1. Guthrie’s spirit lives on in the likes of singer-songwriter Billy Bragg in the UK and the band Wilco in the US, who teamed up in the late 1990s to record new songs using Guthrie’s lyrics stored in archives kept by his daughter Nora. Bragg says Guthrie was the greatest American lyrical poet of the twentieth century. Bragg, B. Forward in Woody Guthrie: A Life (Faber and Faber, 1999).
2. Nash, M. Memories of Woody Guthrie. The New York Times (9 February 2003).
3. Klein, J. Woody Guthrie: A Life, revised edn (Faber and Faber, 1999).
4. Ibid.
5. Ibid.
6. Dylan, B. Chronicles: Volume One (Simon and Schuster, 2004).
7. Details of the annual Woody Guthrie Folk Festival are at http://www.woodyguthrie.com.
8. MacDonald, M. E. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. The Huntington’s Disease Collaborative Research Group. Cell 72, 971–83 (1993).
9. Walker, F. O. Huntington’s disease. Lancet 369, 218–28 (2007).
10. Gordon Brown interviewed by Piers Morgan on Piers Morgan’s Life Stories, first broadcast in the UK on 14 February 2010, ITV1.
11. Data from the World Health Organization, accessed June 2011: http://www.who.int/en.
12. Lilly, F., Boyse, E. A. and Old, L. J. Genetic basis of susceptibility to viral leukaemogenesis. Lancet 2, 1207–9 (1964). McDevitt, H. O. and Bodmer, W. F. HL-A, immune-response genes, and disease. Lancet 1, 1269–75 (1974).
13. Bodmer, W. and Bonilla, C. Common and rare variants in multifactorial susceptibility to common diseases. Nature Genetics 40, 695–701 (2008).
14. Bodmer, W. F. Genetic factors in Hodgkin’s disease: association with a disease-susceptibility locus (DSA) in the HL-A region. National Cancer Institute Monographs 36, 127–34 (1973).
15. Schlosstein, L., Terasaki, P. I., Bluestone, R. and Pearson, C. M. High association of an HL-A antigen, W27, with ankylosing spondylitis. New England Journal of Medicine 288, 704–6 (1973).
16. Terasaki, P. I. History of HLA: a personalised view. In History of HLA: Ten Recollections, ed. Terasaki, P. I. (UCLA Tissue Typing Laboratory, 1990).
17. Brewerton, D. A. et al. Ankylosing spondylitis and HL-A 27. Lancet 1, 904–7 (1973).
18. Terasaki. History of HLA.
19. Brewerton, D. All about Arthritis: Past, Present, Future (Harvard University Press, 1995). Chapter 18 of this book, ‘The race for answers’, describes Brewerton’s view of how HLA became linked to disease, especially the work that linked HLA-B*27 to various diseases.
20. Interview with Derrick Brewerton, 5 July 2011.
21. Brewerton, D. A. Discovery: HLA and disease. Current Opinion in Rheumatology 15, 369–73 (2003). Brewerton gives here a personal account of his role in the early discoveries of the links between HLA and disease.
22. Ibid.
23. Interview with Derrick Brewerton, 5 July 2011.
24. Blueprints in the bloodstream. A BBC TV programme in the Horizon series, first broadcast in 1978.
25. Brewerton. All about Arthritis.
26. Brewerton. Discovery: HLA and disease.
27. Brewerton. All about Arthritis
28. Brewerton, D. Felpham Beach (Beach Publishers, 2011).
29. Interview with Derrick Brewerton, 5 July 2011.
30. Kaslow, R. A. et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nature Medicine 2, 405–11 (1996).
31. Migueles, S. A. et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proceedings of the National Academy of Sciences USA 97, 2709–14 (2000).
32. Fellay, J. et al. A whole-genome association study of major determinants for host control of HIV-1. Science 317, 944–7 (2007).
33. Interview with Bruce Walker, 14 September 2011.
34. Lok, C. Vaccines: his best shot. Nature 473, 439–41 (2011).
35. Interview with Bruce Walker, 14 September 2011.
36. A variation on the often-quoted theme in Spider-Man comic books and movies, ‘with great power comes great responsibility’.
37. Details of support from Mark and Lisa Schwartz are available in a press release from Mass General Hospital on 30 July 2008, entitled ‘MGH receives $8.5 million grant from Schwartz Foundation to expand HIV/AIDS work in Africa’, available here: http://www.massgeneral.org/about/pressrelease.aspx?id=1039. The Bill and Melinda Gates Foundation provides enormous resource and support for HIV research, and details are available at their web pages here: http://www.gatesfoundation.org/Pages/home.aspx.
38. Pereyra, F. et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330, 1551–7 (2010). McMichael, A. J. and Jones, E. Y. Genetics. First-class control of HIV-1. Science 330, 1488–90 (2010).
39. Kaslow, R. A. et al. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection.
40. Migueles et al. HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long-term non-progressors.
41. E-mail correspondence with Mary Carrington, 12 March 2012. To be precise, statistical significance depends on how many individuals are in the study – the CCR5 locus shows up if very large cohorts (n = thousands) are employed.
42. Bjorkman, P. J. et al. The foreign antigen binding site and T cell recognition regions of class I histocompatibility antigens. Nature 329, 512–18 (1987).
43. Interview with Andrew McMichael, 4 July 2011.
44. Evans, D. M. et al. Interaction between ERAP1 and HLA-B*27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B*27 in disease susceptibility. Nature Genetics (2011). This paper shows that the gene involved in directing peptides into HLA proteins was not associated with the rare form of ankylosing spondylitis in which patients don’t have B*27. This is strong evidence that B*27 is involved in causing this auto-immune disease because of its role in presenting peptides to T cells. Allen, R. L., O’Callaghan, C. A., McMichael, A. J. and Bowness, P. Cutting edge: HLA-B*27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. Journal of Immunology 162, 5045–8 (1999). There are other possibilities to why B*27 causes this auto-immune disease. For example, this paper suggests that B*27 may adopt an unusual configuration in which two B*27 proteins stick together at cell surfaces. But this remains a controversial idea; another frontier of compatibility research.
45. Hill, A. V. et al. Molecular analysis of the association of HLA-B53 and resistance to severe malaria. Nature 360, 434–9 (1992).
CHAPTER 6: A PATH TO NEW MEDICINE
1. Interview with Rolf Zinkernagel, 18 May 2011.
2. Germain, R. Ron Germain: towards a grand unified theory. Interview by Amy Maxmen. Journal of Experimental Medicine 207, 266–7 (2010).
3. Genome-wide association studies: understanding the genetics of common disease. A symposium report published by the Academy of Medical Sciences, London, July 2009.
4. Schadt, E. E. Molecular networks as sensors and drivers of common human diseases. Nature 461, 218–23 (2009).
5. Friend, S. H. Something in common. Science Translational Medicine 2, 40ed46, http://stm.sciencemag.org (2010).
6. Interview with Eric Schadt, 23 August 2011.
7. Ibid.
8. Moukheiber, Z. Gene bully. Forbes magazine (9 July 2001). The article is available here: http://www.forbes.com/forbes/2001/0709/074.html.
9. Interview with Eric Schadt, 23 August 2011.
10. Ibid.
11. Suggested by Peter Parham in e-mail correspondence, 28 March 2012.
12. Medawar, P. B. The Future of Man: The Reith Lectures 1959 (Methuen and Co., 1960).
13. Schadt, E. E., Linderman, M. D., Sorenson, J., Lee, L. and Nolan, G. P. Computational solutions to large-scale data management and analysis. Nature Reviews Genetics 11, 647–57 (2010).
14. Friend, S. H. Achievements of the past year. In Sage Bionetworks, available at: http://fora.tv/2011/04/15/Stephen_Friend_Achievements_of_the_Past_Year (2011).
15. This brief tale by Borges is widely available on the internet, in a translation by Andrew Hurley: https://notes.utk.edu/bio/greenberg.nsf/0/f2d03252295e0d0585256e120009adab?OpenDocument. Further tales are published in Fictions or the larger earlier collection entitled Collected Fictions, both published by Penguin. I’m grateful to Jorge Carneiro, head of the Theoretical Immunology Group at the Gulbenkian Institute of Science, Portugal, for bringing this work to my attention.
