The Compatibility Gene, page 26
16. Chen, Y. et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–35 (2008).
17. González, A. Merck will end Seattle research, costing 240 jobs. Seattle Times (23 October 2008).
18. Brown, D. Maker of Vioxx is accused of deception. Washington Post (16 April 2008).
19. Schadt et al. Computational solutions.
20. Kaiser, J. Profile: Stephen Friend. The visionary. Science 335, 651–3 (2012).
21. Sacks, J. The Great Partnership: God, Science and the Search for Meaning (Hodder and Stoughton, 2011).
22. Samson, M. et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene. Nature 382, 722–5 (1996). Dean, M. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CCR5 structural gene. Science 273, 1856–62 (1996).
23. Huang, Y. et al. The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nature Medicine 2, 1240–43 (1996).
24. There is evidence that another factor is also able to protect haemophiliacs, but we still don’t know what that factor is.
25. Hutter, G. et al. Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. New England Journal of Medicine 360, 692–8 (2009).
26. Hetherington, S. et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359, 1121–2 (2002). Mallal, S. et al. Association between presence of HLA-B*5701, HLA-DR*07, and HLA-DQ*03 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359, 727–32 (2002).
27. Mallal, S., et al. HLA-B*5701 screening for hypersensitivity to abacavir. New England Journal of Medicine 358, 568–79 (2008).
28. Facts taken from the Canadian AIDS Treatment Information Exchange, CATIE, http://www.catie.ca.
29. Chessman, D. et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity. Immunity 28, 822–32 (2008).
30. Another possibility would be that the drug somehow lowers the threshold at which T cells get activated so they react when they shouldn’t – but if this is the case, it’s not clear why the drug-triggered T cell response is restricted to people with a particular HLA type.
31. Chessman et al. Human leukocyte antigen class I-restricted activation of CD8+ T cells provides the immunogenetic basis of a systemic drug hypersensitivity
32. Oppenheimer, S. Out of Eden: The Peopling of the World, revised paperback edn (Robinson, 2004). This is one of many books that discuss this vast and fascinating subject.
33. Cann, R. L., Stoneking, M. and Wilson, A. C. Mitochondrial DNA and human evolution. Nature 325, 31–6 (1987).
34. Jakobsson, M. et al. Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451, 998–1003 (2008). Li, J. Z. et al. Worldwide human relationships inferred from genome-wide patterns of variation. Science 319, 1100–1104 (2008). Sykes, B. The Seven Daughters of Eve (Bantam Press, 2001). The story of how our genes can be analysed to unravel our ancestry is lucidly told in this bestselling book.
35. Stix, G. Traces of a distant past. Scientific American 299, 56–63 (2008).
36. Abi-Rached, L. et al. The shaping of modern human immune systems by multiregional admixture with archaic humans. Science 334, 89–94 (2011).
37. Sanchez-Mazas, A. et al. Immunogenetics as a tool in anthropological studies. Immunology 133, 143–64 (2011). This paper includes many details about the relative frequencies of different HLA types across the world. Table 4 in this paper, for example, lists the four most frequent HLA types across ten different world regions.
38. Prugnolle, F. et al. Pathogen-driven selection and worldwide HLA class I diversity. Current Biology 15, 1022–7 (2005).
39. Belich, M. P. et al. Unusual HLA-B alleles in two tribes of Brazilian Indians. Nature 357, 326–9 (1992). Watkins, D. I. et al. New recombinant HLA-B alleles in a tribe of South American Amerindians indicate rapid evolution of MHC class I loci. Nature 357, 329–33 (1992).
40. Williams, R. C. and McAuley, J. E. HLA class I variation controlled for genetic admixture in the Gila River Indian community of Arizona: a model for the Paleo-Indians. Human Immunology 33, 39–46 (1992).
41. Sanchez-Mazas et al. Immunogenetics as a tool in anthropological studies.
42. This analysis was carried by the research group led by Professor Steven G. E. Marsh, Deputy Director of Research, Anthony Nolan Research Institute, Royal Free Hospital, London.
43. Poland, G. A., Ovsyannikova, I. G. and Jacobson, R. M. Genetics and immune responses to vaccines. In Genetic Susceptibility to Infectious Diseases, ed. Kaslow, R. A., McNicholl, J. M. and Hill, A. V. S. (Oxford University Press, 2008).
44. Cartron, G. et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99, 754–8 (2002).
45. Chapman, M. A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467–72 (2011).
CHAPTER 7: MISSING SELF
1. E-mail correspondence from Rolf Kiessling, 5 September 2011.
2. Song lyric from ‘Anthem’, by Leonard Cohen, on the 1992 album The Future and the 2009 collection Live in London.
3. The use of animals in medical research is controversial for many of us. Throughout contemporary research in immunology, inbred mice have facilitated many major advances, such as Zinkernagel and Doherty’s Nobel-Prize-winning experiments that found a critical role for MHC proteins in the immunological detection of viruses. Today, hundreds of inbred strains of mice can be relatively easily purchased by appropriately licensed scientists. I am not advocating any particular view of this here other than the fact that it is absolutely right that the use of animals is always very carefully and critically questioned.
4. The phenomenon is known as ‘hybrid resistance’ because the F1 hybrid ‘resists’ bone-marrow transplants.
5. Cudkowicz, G. and Bennett, M. Peculiar immunobiology of bone marrow allografts. I. Graft rejection by irradiated responder mice. Journal of Experimental Medicine 134, 83–102 (1971).
6. Kiessling, R., Klein, E., Pross, H. and Wigzell, H. ‘Natural’ killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell. European Journal of Immunology 5, 117–21 (1975). Surprisingly, Kiessling published this landmark discovery in a relatively specialist European journal. When I asked about this in 2011, he said it was because he was fairly young and somewhat naive about the importance of maximizing exposure of one’s work by trying to publish in the world’s premiere journals. Herberman, R. B., Nunn, M. E. and Lavrin, D. H. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. I. Distribution of reactivity and specificity. International Journal of Cancer 16, 216–29 (1975).
7. Kiessling and Herberman are the scientists celebrated for the discovery of the Natural Killer cell. However, this immune cell had been studied earlier in a different context from 1968 to 1970 by Ian MacLennan and colleagues at the University of Birmingham.
8. Interview with Rolf Kiessling, 7 September 2011.
9. E-mail correspondence from Rolf Kiessling, 10 September 2011.
10. Ibid.
11. Ibid.
12. Interview with Rolf Kiessling, 7 September 2011.
13. Herberman arrived in Pittsburgh when the new Cancer Institute had a staff of two but by the time he stepped down as its director, in 2009, it employed over 3,000.
14. Peterkin, T. US cancer expert Ronald Herberman warns against children using mobile phones. Daily Telegraph (24 July 2008).
15. Timonen, T., Saksela, E., Ranki, A. and Hayry, P. Fractionation, morphological and functional characterization of effector cells responsible for human natural killer activity against cell-line targets. Cellular Immunology 48, 133–48 (1979).
16. Timonen, T., Ortaldo, J. R. and Herberman, R. B. Characteristics of human large granular lymphocytes and relationship to natural killer and K cells. Journal of Experimental Medicine 153, 569–82 (1981).
17. Kärre, K. How to recognize a foreign submarine. Immunological Reviews 155, 5–9 (1997).
18. Kärre, K. Natural killer cell recognition of missing self. Nature Immunology 9, 477–80 (2008).
19. Interview with Klas Kärre, 9 January, 2012.
20. Ibid.
21. Kärre. How to recognize a foreign submarine.
22. Cohen, G. B. et al. The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells. Immunity 10, 661–71 (1999).
23. Interview with Klas Kärre, 9 January, 2012.
24. Lanier, L. L. Missing self, NK cells, and The White Album. Journal of Immunology 174, 6565 (2005).
25. Kärre, K., Ljunggren, H. G., Piontek, G. and Kiessling, R. Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature 319, 675–8 (1986).
26. Ljunggren, H. G. and Kärre, K. In search of the ‘missing self’: MHC molecules and NK cell recognition. Immunology Today 11, 237–44 (1990).
27. Yokoyama, W. M. The search for the missing ‘missing-self’ receptor on natural killer cells. Scandinavian Journal of Immunology 55, 233–7 (2002).
28. Yokoyama, W. M., Jacobs, L. B., Kanagawa, O., Shevach, E. M. and Cohen, D. I. A murine T lymphocyte antigen belongs to a supergene family of type II integral membrane proteins. Journal of Immunology 143, 1379–86 (1989).
29. Yokoyama. The search for the missing ‘missing-self’ receptor on natural killer cells.
30. Interview with Wayne Yokoyama, 3 October 2011.
31. Ibid.
32. Ibid.
33. Over twenty years on from this basic discovery, my own research team uses super-resolving microscopes to visualize this killing machinery and to work out in detail how the inhibitory receptors regulate it. The hope is that, eventually, drugs can be designed to influence where and when NK cells kill. Such drugs could be used in many medical treatments including helping target an attack on cancerous or virus-infected cells.
34. The Nobel Assembly at Karolinska Institutet awards the Nobel Prize in Physiology or Medicine. Nominations are evaluated by the Medical Nobel Committee, chaired by Klas Kärre in 2009 and 2010. Details can be accessed here: http://www.nobelprizemedicine.org/?page_id=326.
35. Colonna, M. and Samaridis, J. Cloning of immunoglobulin-superfamily members associated with HLA-C and HLA-B recognition by human natural killer cells. Science 268, 405–8 (1995). Wagtmann, N. et al. Molecular clones of the p58 NK cell receptor reveal immunoglobulin-related molecules with diversity in both the extra-and intracellular domains. Immunity 2, 439–49 (1995).
36. Scientists can not only add individual genes or proteins into mice, they can also include human cells. Hepatitis B and C viruses can’t infect mouse liver cells as another example of the problem, but this could be solved by transplanting human liver into mice either directly or by using human stem cells in mice.
37. Khakoo, S. I. et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 305, 872–4 (2004).
38. Ge, D. et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461, 399–401 (2009).
39. Khakoo et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection.
40. An alternative possibility is that the activating version of NK cell receptors might detect a specific viral peptide presented by an HLA protein, perhaps one from a common virus that we’ve evolved a specific defence against. Yet another possibility is that we make our own special peptide when under attack, and that gets recognized by an activating NK cell receptor to trigger an immune response. All in all, it’s here that we hit an edge to our knowledge.
41. Bashirova, A. A., Thomas, R. and Carrington, M. HLA/KIR restraint of HIV: surviving the fittest. Annual Review of Immunology 29, 295–317 (2011).
42. Alter, G. et al. HIV-1 adaptation to NK-cell-mediated immune pressure. Nature 476, 96–100 (2011).
43. The modern overall view of NK cells is that they decide whether or not to kill another cell depending on the balance of signals received through their activating and inhibitory receptors, and Kärre’s original hypothesis stands as one strategy this process facilitates.
CHAPTER 8: SEX AND SMELLY T-SHIRTS
1. Rimmel, E. The Book of Perfumes (Chapman and Hall, 1864). This book was a bestseller and was reprinted countless times. Various formats are readily available. Eugène Rimmel founded the brand ‘Rimmel’ with his father.
2. Turin, L. The Secret of Scent: Adventures in Perfume and the Science of Smell (Faber and Faber, 2006). Luca Turin advocates a specific view of how smell works. He suggests that how a molecule smells is determined by the frequencies at which different chemical bonds vibrate. His view is not widely accepted, in large part because there isn’t a clear process that is established by which this information could be ‘read’ by our nose. A more conventional view is that shapes of different molecules are what is detected by our receptors for smell.
3. Luca Turin mentions his own analysis of this perfume in his TED talk, available online at: http://www.ted.com/talks/luca_turin_on_the_science_of_scent.html.
4. Turin. The Secret of Scent.
5. Medawar, P. B. The Uniqueness of the Individual (Basic Books, 1957).
6. Yamazaki, K. et al. Control of mating preferences in mice by genes in the major histocompatibility complex. Journal of Experimental Medicine 144, 1324–5 (1976).
7. Another member of their team, Tony Zayas, also noticed that mice had preferences for whom they mated with.
8. Thomas, L. Lives of a Cell: Notes of a Biology Watcher (Penguin, 1978).
9. Ibid.
10. Anonymous. Effects of sexual activity on beard growth in man. Nature 226, 869–70 (1970).
11. McClintock, M. K. Menstrual synchrony and suppression. Nature 229, 244–5 (1971).
12. Yang, Z. and Schank, J. C. Women do not synchronize their menstrual cycles. Human Nature 17, 434–47 (2006).
13. Beauchamp, G. K., Yamazaki, K. and Boyse, E. A. The chemosensory recognition of genetic individuality. Scientific American 253, 86–92 (1985).
14. Interview with Gary Beauchamp, 7 November 2011. Bard, J., Beauchamp, G. K. and Goldberg, E. H. Obituary: Edward A. Boyse. Nature Immunology 8, 1011–12 (2007).
15. Singh, P. B., Brown, R. E. and Roser, B. MHC antigens in urine as olfactory recognition cues. Nature 327, 161–4 (1987).
16. Manning, C. J., Wakeland, E. K. and Potts, W. K. Communal nesting patterns in mice implicate MHC genes in kin recognition. Nature 360, 581–3 (1992).
17. Potts, W. K., Manning, C. J. and Wakeland, E. K. Mating patterns in seminatural populations of mice influenced by MHC genotype. Nature 352, 619–21 (1991).
18. E-mail correspondence with Jon van Rood, 17 October 2011.
19. Wedekind, C., Seebeck, T., Bettens, F. and Paepke, A. J. MHC-dependent mate preferences in humans. Proceedings: Biological Sciences 260, 245–9 (1995).
20. Widmer, T. Der Schnüffeltest sticht unangenehm in die Nase (The sniffing test gets up people’s noses). Berner Zeitung (1993).
21. E-mail correspondence with Claus Wedekind, 14 October 2011.
22. Interview with Claus Wedekind, 12 October 2011.
23. Reviews and correspondence between Wedekind and the journal Nature dating from 1 and 20 September 1994. Papers and original faxes passed on to me by Claus Wedekind, October 2011.
24. Interview with Claus Wedekind, 12 October 2011.
25. Letter from Professor William D. Hamilton, Department of Zoology, Oxford University, to Claus Wedekind, 6 December 1994. Hamilton died in 2000 and is often said to have been one of the world’s leading evolutionary theorists of the twentieth century. Richard Dawkins, author of landmark books The Selfish Gene and The God Delusion, says that Hamilton was a great inspiration to him and has called him the greatest Darwinian since Darwin.
26. Ibid.
27. Richardson, S. Scent of a man. Discover magazine (February 1996). Available online here: http://discovermagazine.com/1996/feb/scentofaman699.
28. Interview with Claus Wedekind, 12 October 2011.
29. Testing a radical theory. Nature Neuroscience 7, 315 (2004). This sentiment has been attributed to James Randi in many places, although I’m not sure of its original source. Of relevance here, it was used in an editorial piece published in the top journal Nature Neuroscience when discussing data published in that journal which disagreed with Luca Turin’s theory of smell.
30. Hedrick, P. and Loeschcke, V. MHC and mate selection in humans? Trends in Ecology and Evolution 11, 24 (1996).
31. Wedekind, C. and Seebeck, T. Reply from C. Wedekind and T. Seebeck. Trends in Ecology and Evolution 11, 24–5 (1996).
32. Interview with Claus Wedekind, 12 October 2011.
33. Roberts, S. C., Gosling, L. M., Carter, V. and Petrie, M. MHC-correlated odour preferences in humans and the use of oral contraceptives. Proceedings: Biological Sciences 275, 2715–22 (2008).
34. Jacob, S., McClintock, M. K., Zelano, B. and Ober, C. Paternally inherited HLA alleles are associated with women’s choice of male odor. Nature Genetics 30, 175–9 (2002).
35. Potts, W. K. Wisdom through immunogenetics. Nature Genetics 30, 130–31 (2002).
36. Leinders-Zufall, T., Ishii, T., Mombaerts, P., Zufall, F. and Boehm, T. Structural requirements for the activation of vomeronasal sensory neurons by MHC peptides. Nature Neuroscience 12, 1551–8 (2009).
37. Kwak, J., Willse, A., Preti, G., Yamazaki, K. and Beauchamp, G. K. In search of the chemical basis for MHC odourtypes. Proceedings: Biological Sciences 277, 2417–25 (2010).
