1. Carrington, M. and Walker, B. D. Immunogenetics of spontaneous control of HIV. Annual Review of Medicine 63, 131–45 (2012).
2. Connor, S. Mystery of Aids immunity may be solved. Independent (5 November 2010).
3. The first dating agency offering this service began operating in the Boston area in 2007, as reported widely across the news media. See, for example: Nuzzo, R. Do I smell sexy? Here’s a new reason to swap spit. LA Times (19 May 2008). However, the untimely death of the dating agency’s founder and president Eric Holzle, in 2011, aged just forty-seven, leaves this particular company’s future unclear.
1. Medawar, P. B. Memoir of a Thinking Radish (Oxford University Press, 1986).
2. Medawar, J. A Very Decided Preference: Life with Peter Medawar (W. W. Norton and Company, 1990).
3. Mitchison, N. A. Interview online (2004). Interview of Av Mitchision by Martin Raff, June 2004, available online at ‘Web of Stories’: http://www.webofstories.com/play/13795?o=MS.
4. Nandy, D. Sir Peter Medawar 1915–1987: A Personal Memoir (Runnymede Trust, 1988).
5. Medawar, J. A Very Decided Preference.
6. Ibid.
7. Bhishagratna, K. K. L. An English Translation of the Sushruta Samhita (J. N. Bose, 1907).
8. Moore, A. Frankenstein’s Cadillac. In Dodgem Logic, vol. 4, pp. 2–11 (Mad Love Publishing, 2010).
9. Jansson, S. Introduction to Frankenstein by Mary Shelley, 1831 Edition (Wordsworth Classics, 1999).
10. Gibson, T. and Medawar, P. B. The fate of skin homografts in man. Journal of Anatomy 77, 299–310, 294 (1943).
11. Medawar, P. B. The behaviour and fate of skin autografts and skin homografts in rabbits: a report to the War Wounds Committee of the Medical Research Council. Journal of Anatomy 78, 176–99 (1944).
12. Ibid., and Medawar, P. B. A second study of the behaviour and fate of skin homografts in rabbits: a report to the War Wounds Committee of the Medical Research Council. Journal of Anatomy 79, 157–76 (1945).
13. Medawar, P. B. Memoir of a Thinking Radish. Medawar, J. A Very Decided Preference.
14. Interview with Brigitte (Ita) Askonas, 29 May 2012.
15. Billingham, R. E., Brent, L. and Medawar, P. B. Actively acquired tolerance of foreign cells. Nature 172, 603–6 (1953).
16. Owen, R. D. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 102, 400–401 (1945).
17. Brent, L. Sunday’s Child? (Bank House Books, 2009).
18. E-mail correspondence with Leslie Brent, 1 June 2012.
19. Brent, L. Rupert Everett Billingham. 15 October 1921–16 November 2002: elected FRS 1961. Biographical Memoirs of Fellows of the Royal Society 51, 33–50 (2005).
20. Brent, L. Sunday’s Child?
21. Ibid.
22. Ibid.
23. Ibid.
24. Ibid.
25. Ibid.
26. Brent. Rupert Everett Billingham.
27. Medawar, J. A Very Decided Preference.
28. Medawar, P. B. Memoir of a Thinking Radish.
29. Interview with Leslie Brent, 10 December 2010.
30. Brent. Rupert Everett Billingham.
31. Billingham, R. E., Brent, L. and Medawar, P. B. Quantitative studies on tissue transplantation immunity. iii. Actively acquired tolerance. Philosophical Transactions of the Royal Society of London B Biological Sciences 239, 357–414 (1956).
32. In a letter dated 24 October 1960 to Josh Lederburg, who had won the Nobel Prize for Medicine or Physiology two years earlier, Medawar wrote: ‘Dear Joshua, I was absolutely delighted to get your telegram . . . I’m utterly delighted – with only the omissions of Ray Owen’s and Billingham and Brent’s names to make one regret the peremptory and arbitrary nature of these awards.’
33. Brent. Sunday’s Child?
34. Letter from Medawar to Owen, 24 October 1960, reproduced in Hansen, P. J. Medawar redux – an overview on the use of farm animal models to elucidate principles of reproductive immunology. American Journal of Reproductive Immunology 64, 225–30 (2010).
35. Richard Dawkins spoke about two scientists that inspire him, Darwin and Medawar, at the National Portrait Gallery, London, 14 June 2012.
36. Medawar, P. B. The phenomenon of man. In The Art of the Soluble, 71–84 (Methuen and Co., 1967).
37. Klein, J. Interview for ‘Web of Stories’, http://www.webofstories.com/play/15857. (2005).
38. Klein, J. Natural History of the Major Histocompatibility Complex (John Wiley and Sons, 1986).
39. Medawar, P. B. Peter Alfred Gorer (1907–1961). Biographical Memoirs of Fellows of the Royal Society 7, 95–109 (1961).
40. Temple, R. Sir Peter Medawar. New Scientist 1405, 14–20 (1984).
41. Liz Simpson, as interviewed in the BBC TV Horizon documentary about Peter Medawar, broadcast in 1988.
42. Interview with Charles Medawar, 7 December 2010.
43. Ibid.
44. Stephen Jay Gould, Foreword to Medawar, P. B. The Strange Case of the Spotted Mice (Oxford University Press, 1996).
45. Interview with Liz Simpson, 3 December 2010.
46. Mitchison, N. A. Sir Peter Medawar (1915–1987). Nature 330, 112 (1987).
47. Interview with Av Mitchison, 30 March 2011. It is also of interest that Av’s mother, Naomi, was a distinguished writer and James Watson’s famous book The Double Helix is dedicated to her. Her brother was the famous Oxford geneticist J. B. S Haldane. Amongst other things, in 1933 J. B. S. Haldane postulated that transplant rejection was an immune reaction against alloantigens. Av’s father was a Labour Member of Parliament.
48. A BBC TV documentary about Peter Medawar, in the series Horizon, broadcast in 1988.
49. Medawar, J. A Very Decided Preference.
50. Interview with Charles Medawar, 7 December 2010.
51. Brent. Rupert Everett Billingham.
52. E-mail correspondence with Leslie Brent, 1 June 2012.
53. Smith, L. Sale of human organs should be legalised, say surgeons. Independent (5 January 2011).
1. E-mail correspondence with Leslie Brent, March 2011.
2. Over the centuries, many great thinkers stamped their mark on defining the causes of disease even though, arguably, little changed fundamentally. The ninth-century CE Arab physician Rhazes, for example, through careful observations of patients, realized that smallpox and measles were different. Contemporary thinking was that smallpox was caused by a kind of fermentation that removed excess moisture from blood. Rhazes made the important observation that survivors of smallpox would rarely get the disease again, a hallmark of immunity. He interpreted this as being because all excess blood moisture had been removed during the first bout of illness, so that a second attack couldn’t occur.
3. Horrox, R. The Black Death (Manchester University Press, 1994).
4. Silverstein, A. M. A History of Immunology, 2nd edn (Academic Press, 2009).
5. Debre, P. Louis Pasteur (The Johns Hopkins University Press, 2000).
6. Editorial. Boston Medical and Surgical Journal (1 March 1883).
7. The Life Millennium (Little, Brown and Company, 2000).
8. Burnet and Fenner were thinking specifically about how antibodies could be made. It was well established that in addition to white blood cells, our blood also contains soluble proteins called antibodies. These antibodies stick to and neutralize all kinds of germs and other potentially dangerous molecules. For Burnet and Fenner, and their contemporaries, the key problem lay in understanding how such antibodies could recognize so many different kinds of germs, while seemingly not triggering an attack on our own cells or tissue.
9. Fenner, F. Nature, Nurture and Chance: The Lives of Frank and Charles Fenner (Australian National University E Press, 2006).
10. Sweet, M. Obituary: Frank Fenner. British Medical Journal 341, 1218 (2010).
11. Interview with Elizabeth Dexter, MacFarlane Burnet’s daughter, 9 February 2011.
12. Burnet, F. M. Changing Patterns: An Atypical Biography (Heinemann, 1968).
13. Interview with Elizabeth Dexter, 9 February 2011.
14. Sexton, C. Burnet: A Life (Oxford University Press, 1999).
15. Ibid.
16. Burnet, Changing Patterns.
17. Ibid.
18. Ibid.
19. Interview with Elizabeth Dexter, 9 February 2011.
20. Ibid.
21. Burnet. Changing Patterns.
22. Sexton. Burnet: A Life.
23. Interview with Elizabeth Dexter, 9 February 2011.
24. Owen, R. D. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 102, 400–401 (1945).
25. Burnet, F. M. and Fenner, F. The Production of Antibodies, 2nd edn (Macmillan and Co., 1949).
26. Ibid.
27. Burnet. Changing Patterns.
28. Quoted in Soderqvist, T. Science as Autobiography: The Troubled Life of Niels Jerne (Yale University Press, 2003). This is a definitive and particularly thoughtful biography of Jerne. This biography uses a vast array of letters and interviews to paint a vivid picture of his life, with a great deal of interesting discussion and interpretion by the author.
29. Ibid.
30. Ibid.
31. Interview of Niels Jerne by Lewis Wolpert, recorded in 1987. It was not broadcast but is available from the online BBC archives. (The BBC archive states this was recorded in 1985, but the interview itself refers to 1987): http://www.bbc.co.uk/archive/scientists/10605.Shtml.
32. Ibid.
33. Ibid.
34. Ibid.
35. Ibid.
36. Burnet. Changing Patterns.
37. Burnet, F. M. A modification of Jerne’s theory of antibody production using the concept of clonal selection. The Australian Journal of Science 20, 67–9 (1957).
38. Hodgkin, P. D., Heath, W. R. and Baxter, A. G. The clonal selection theory: 50 years since the revolution. Nature Immunology 8, 1019–26 (2007).
39. Burnet, F. M. A modification of Jerne’s theory.
40. Burnet, F. M. The Clonal Selection Theory of Acquired Immunity (The Abraham Flexner Lectures of Vanderbilt University 1958) (Cambridge University Press, 1959).
41. Talmage, D. W. The acceptance and rejection of immunological concepts. Annual Review of Immunology 4, 1–11 (1986).
42. Hodgkin, Heath and Baxter. The clonal selection theory.
43. Talmage. The acceptance and rejection of immunological concepts.
44. Nossal, G. J. V. One cell – one antibody. In Immunology: The Making of a Modern Science, ed. Gallagher, R. B., Gilder, J., Nossal, G. J. V. and Salvatore, G. (Academic Press, 1995).
45. Nossal, G. J. Sir Gustav Nossal interviewed by Dr Max Blythe on 3 March 1987 and 1 April 1998. In Interviews with Australian Scientists (The Australian Academy of Scientists, 1998).
46. Nossal, G. J. and Lederberg, J. Antibody production by single cells. Nature 181, 1419–20 (1958).
47. Marchalonis, J. J. Burnet and Nossal: The impact on immunology of the Walter and Eliza Hall Institute. The Quarterly Review of Biology 69, 53–67 (1994).
48. Burnet, F. M. Genes, Dreams and Realities (Penguin Books, 1971). Burnet, F. M. Endurance of Life (Press Syndicate of the University of Cambridge, 1978).
49. Interview with Elizabeth Dexter, 9 February 2011.
50. Burnet. Endurance of Life.
51. Sexton. Burnet: A Life.
52. Talmage, D. W. Obituary: Frank Macfarlane Burnet 1899–1985. Journal of Immunology 136, 1528–9 (1986).
53. Brent, L. A History of Transplantation Immunology (Academic Press, 1997).
54. Miller, J. F. A. P. The discovery of thymus function. In Immunology: The Making of a Modern Science, ed. Gallagher et al.
55. Kincade, P. W. and Kelsoe, G. A birthday for B cells: Lymphopoiesis II, a scientific symposium honoring Max Cooper. Nature Immunology 4, 1155–7 (2003).
56. Or arguably over 150 years in the making, since Jenner first immunized a boy with smallpox.
57. Burnet. Changing Patterns.
58. Park, H. W. Germs and Tissues: Frank Macfarlane Burnet, Peter Brian Medawar, and the Immunological Conjuncture (Nova Science Publishers, 2010). This fifty-three-page monograph discusses in detail the approach of Burnet and Medawar.
1. Interview with Leslie Brent, 10 December 2010.
2. From James Watson in conversation with Brenda Maddox, 9 March 2011, London, organized by Intelligence Squared.
3. Brent, L. A History of Transplantation Immunology (Academic Press, 1997).
4. A definition of irreversible coma. Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. JAMA 205, 337–40 (1968).
5. The first succesful kidney transplant between living patients was performed in December 1954 at Brigham Hospital in Boston. This operation was performed between identical twins, which avoided the complication of an immune reaction effecting graft survival. For this and other work, the surgeon Joseph Murray won a Nobel Prize in 1990 along with Donnall Thomas, who developed bone-marrow transplantation as a cancer treatment.
6. Barnard, C. and Pepper, C. B. One Life (George G. Harrap and Co., 1969).
7. Ibid.
8. Ibid.
9. Time magazine. Cover story and feature article: Surgery: the ultimate operation. 15 December 1967.
10. Stark, T. Knife to the Heart: The Story of Transplant Surgery (Macmillan, 1996).
11. Congress. Life-sustaining Technologies and the Elderly (US Government Printing Office, 1987).
12. Rothman, D. J. Strangers at the Bedside: A History of How Law and Bioethics Transformed Medical Decision Making (Aldine de Gruyter, 2003).
13. Ibid.
14. Veatch, R. M. Transplantation Ethics (Georgetown University Press, 2000). This is a highly accessible and fascinating book that describes in far more detail than given here all the key issues around transplantation ethics, including more detailed views from different religious groups.
15. Caplan, A. L., Coelho D. H. (eds). The Ethics of Organ Transplants (Prometheus Books, 1998).
16. Numbers taken from the Mayo Clinic (US) and the National Health Service (UK), March 2011.
17. Speiser, P. and Smekal, F. G. Karl Landsteiner, trans. R. Rickett (Verlag Vienna, 1975).
18. Owen, R. Karl Landsteiner and the first human marker locus. Genetics 155, 995–8 (2000).
19. Gottlieb, A. M. Karl Landsteiner, the melancholy genius: his time and his colleagues, 1868–1943. Transfusion Medicine Reviews 12, 18–27 (1998). Karl Landsteiner’s life was complex, and this is an interesting introduction.
20. Speiser, P. and Smekal, F. G. Karl Landsteiner.
21. Medawar, P. B. The Uniqueness of the Individual (Methuen and Co., 1957).
22. Rous, P. Karl Landsteiner. 1868–1943. Obituary Notices of Fellows of the Royal Society 5, 294–324 (1947).
23. Speiser, P. and Smekal, F. G. Karl Landsteiner.
24. In England, the relative frequency of the different blood groups are approximately 47 per cent O, 42 per cent A, 9 per cent B, and only 3 per cent AB.
25. Gottlieb. Karl Landsteiner, the melancholy genius.
26. Speiser and Smekal. Karl Landsteiner.
27. Henig, R. M. A Monk and Two Peas: The Story of Gregor Mendel and the Discovery of Genetics (Weidenfeld and Nicolson, 2000). This is a great, easy-to-read telling of Gregor Mendel’s fascinating story.
28. Owen. Karl Landsteiner and the first human marker locus.
29. Beyond the A/B blood groups, the next most important issue in blood transfusions is the Rhesus factor. This was discovered in 1940 by US scientist Alexander Wiener, working with Landsteiner, who by that time had moved to New York’s Rockefeller Institute to avoid the political troubles in Europe. The factor is named for the Rhesus monkey, whose cells were studied initially, and refers to a single type of protein that you either do or don’t have on the surface of your red blood cells. Immune cells in someone who doesn’t possess the Rhesus protein will react to blood cells from somebody who does – they would, in other words, recognize the protein as ‘non-self’. There are many other differences between people that play a role in determining the success of blood transfusions, but the A/B blood groups and the Rhesus protein are the dominant factors.
30. Landsteiner, K. On individual differences in human blood. Nobel Lectures, Physiology or Medicine (1930).
31. Parham, P., Norman, P. J., Abi-Rached, L. and Guethlein, L. A. Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules. Philosophical Transactions of the Royal Society of London B Biological Sciences 367, 800–811 (2012).
32. The fact that red blood cells lack compatibility proteins does make it hard for our body to detect anything dangerous that could live inside red blood cells, such as the malaria parasite.
33. In more detail, for a haematopoietic stem cell (bone-marrow) transplant it is hoped to be able to match 10/10 alleles across HLA-A, -B, -C, -DRB1 and -DQB1. For solid organ transplantation, HLA-A, -B, -C, -DRB1 and -DQB1 are assessed, but often some level of mismatch is unavoidable. In that case, much effort is spent on ensuring the recipient does not already have antibodies that could trigger a reaction against any of the HLA proteins on the donor’s cells. Such antibodies could be present from exposure to other people’s HLA proteins from pregnancy, blood transfusions or an earlier transplant.
34. Roberts, J. P. et al. Effect of changing the priority for HLA matching on the rates and outcomes of kidney transplantation in minority groups. New England Journal of Medicine 350, 545–51 (2004).
35. Thorsby, E. A short history of HLA. Tissue Antigens 74, 101–16 (2009). For more details on the history of HLA, this paper is a superb entry point, being exceptionally thorough and clear, with all the big papers cited within. Before these genes were discovered in humans they were first found in mice. Early clues came from Bernard Amos. Born in Kent and then working in Peter Gorer’s laboratory in London, he showed that a mouse made antibodies against white blood cells from a different mouse strain, because of their different compatibility genes. This built on the pioneering work by Gorer and Snell that serologically defined the histocompatibility genes in mice, known as the H-2 system. Even though the mouse H-2 system was discovered before the HLA system, each came from parallel tracks of research using serology in each species. That is, HLA wasn’t discovered through a direct search for the equivalent of H-2 in humans.
36. Dausset, J. The HLA adventure. In History of HLA: Ten Recollections, ed. Terasaki, P. L. (UCLA Tissue Typing Laboratory, 1990).
37. Van Rood, J. J. HLA and I. Annual Review of Immunology 11, 1–28 (1993).
38. Interview with Jon van Rood, 15 July 2011.
39. Dausset. The HLA adventure. Jan Klein recalls visiting Dausset’s laboratory around 1958 and briefly discusses this on page 15 of his seminal book, Natural History of the Major Histocompatibility Complex (John Wiley and Sons, 1986).
40. Bodmer, W. and McKie, R. The Book of Man (Little, Brown and Company, 1994).
41. Interview with Sir Walter Bodmer, 25 May 2011.
42. Bodmer, J. and Bodmer, W. Rose Payne 1909–1999. With personal recollections by Julia and Walter Bodmer. Tissue Antigens 54, 102–5 (1999).
43. Dausset. The HLA adventure.
44. A brief history of the histocompatibility workshops is available online here: http://www.ihwg.org/about/history.Html.
45. At this meeting all fourteen groups used their improved techniques to test sera for reactivity against a common collection of cells isolated from forty-five different people.
46. Thorsby. A short history of HLA.
47. At the third HLA meeting, the teams tried to address the heredity of HLA by testing blood from eleven families, including some twins.
48. Thorsby. A short history of HLA.
49. Bodmer, W. F. HLA: what’s in a name? A commentary on HLA nomenclature development over the years. Tissue Antigens 49, 293–6 (1997).
50. Walford, R. L. First meeting WHO Leukocyte Nomenclature Committee, New York, September, 1968. In History of HLA: Ten Recollections, ed. Terasaki.
51. Class I MHC proteins are also made from two chains, but one of them, given the unwieldy name of beta-2-microglobulin, does not vary from person to person.
52. The contemporary formal way of writing out HLA types and sub-types is to use an initial asterisk separator followed by subsequent fields separated with colons. As an example, one allele can be specified precisely as, say, HLA-A*02:101:01:02N. However, this level of detail is rarely used in scientific papers exploring the basic biology of HLA genes and proteins. It is more common to simply use a simple designation of say, HLA-A*02 or B*57, which strictly speaking covers a set of a few HLA types that have minor variations. Scientists will sometimes write a specific HLA type as say, HLA-B57 instead of its formal name of HLA-B*57. The HLA-C alleles include the designation w, to avoid confusion with other proteins called C1, C2, C3 and so on. Hence they are termed HLA-Cw*01, -Cw*02, -Cw*03, etc., and again, scientists will commonly omit the asterisk and talk of Cw1, Cw2 and so on. The HLA nomenclature also includes longer designations to fully account for subtle variations and up to four sets of numbers can follow the basic allele designation. Full information is available online, along with some description of the history in naming the HLA system, at: http://hla.alleles.org/nomenclature/naming.html.
53. Dausset. The HLA adventure.
54. Terasaki (ed.). History of HLA: Ten Recollections.
55. Two years prior to Dausset winning the Nobel Prize, van Rood won the Wolf Prize, a top prize awarded by Israel, along with Dausset and Snell. But for the Nobel Prize, his name was replaced by that of Baruch Benacerraf, who had earlier helped establish that there are genes that control immune responses, specifically the class II MHC genes.
56. Dausset. The HLA adventure.
57. Blueprints in the bloodstream. A BBC TV programme in the Horizon series, first broadcast in 1978.
58. Terasaki, P. L. History of HLA: a personalized view. In History of HLA: Ten Recollections, ed. Terasaki.
59. Hakim, N. S. and Papalois, V. E. (eds.). History of Organ and Cell Transplantation (Imperial College Press, 2003).
60. During the mid-1970s, some confusion arose because Terasaki’s research indicated that HLA-matching was less important for deceased than for living donors. But later results across many studies clarified that HLA-matching was always beneficial in kidney transplantation.
61. Crispe, I. N. The liver as a lymphoid organ. Annual Review of Immunology 27, 147–63 (2009). This is a thorough review about the immunology in the liver by one of the world’s experts in this subject.
62. Hornick, P. and Rose, R. (eds.). Transplantation Immunology: Methods and Protocols (Humana Press, 2010).
63. Laurance, J. Pig-to-human tissue transplants ‘imminent’. Independent (21 October 2011).
1. Interview with Peter Doherty, 16 May 2011.
2. Butterfield, F. A Harvard Professor’s baffling vanishing. New York Times (27 November 2001).
3. Harvard University Gazette (29 November 2001).
4. Who is a candidate for the Nobel Prize is generally a closely guarded secret. But people often do know, or assume, they are candidates through at least two routes. First, the Nobel Prize isn’t the first prize somebody will win, and often it is clear someone is being considered if they have previously won other big international prizes. Second, gossip can fly around that reviews of a person’s work are being solicited for their nomination and/or consideration by the relevant Nobel committee.
5. Feynman, R. There’s plenty of room at the bottom. Caltech Engineering and Science 23, 22–36 (1960).
6. Watson, J. D. and Crick, F. H. C. Molecular structure of nucleic acids. Nature 171, 737–8 (1953).
7. E-mail correspondence with Pamela Bjorkman, 13 July 2012.
8. Schlesinger, S. Oral history: Don Wiley. Interviews with Don Wiley, recorded by Sondra Schlesinger 1 and 5 April 1999. Available at: http://virologyhistory.wustl.edu/wiley.Htm.
9. E-mail correspondence with Jack Strominger, 15 November 2011.
10. Discussion with Jim Kaufman, 27 May 2011.
11. E-mail correspondence with Jim Kaufman, Cambridge University, May 2011.
12. Strominger, J. L. The tortuous journey of a biochemist to immunoland and what he found there. Annual Review of Immunology 24, 1–31 (2006).
13. Interview with Jack Strominger, 13 June 2011.
14. Strominger. The tortuous journey.
15. E-mail correspondence with Jack Strominger, 15 November 2011.
16. Peter Parham had worked at getting the crystal structure of an HLA protein for a relatively brief time. He lost enthusiasm when a protein sample that took a month to obtain was very quickly lost when Wiley’s lab took the sample for further purification. The anecdote emphasizes the essential quality that Pamela Bjorkman brought to the project: her dedication and hard work, which was needed to keep the project going over an incredibly long eight years. Getting a picture of HLA-A*02 was a long and arduous process. Parham remained enthusiastic about the work and discussed the project with Bjorkman often, especially at the time of writing up the paper when both were at Stanford University.
17. Interview with Pamela Bjorkman, 12 May 2011.
18. Beverley, P. and Naysmith, D. Obituary of Arnold Sanderson (1933–2011). Immunology News: The Newsletter of the British Society for Immunology 19.1, 10–12 (2012). Strominger’s procedure for obtaining the HLA protein had involved many other researchers, most notably Arnold Sanderson. Sanderson had a colourful career and worked alongside many great immunologists. This obituary mentions that he thought that his own best work was on bacterial cell-wall sugars and that he enjoyed horse racing.
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).
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).
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.
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).
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.
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).
38. Interview with Gary Beauchamp, 7 November 2011.
39. Reusch, T. B., Haberli, M. A., Aeschlimann, P. B. and Milinski, M. Female sticklebacks count alleles in a strategy of sexual selection explaining MHC polymorphism. Nature 414, 300–302 (2001).
40. Ibid.
41. Kurtz, J. et al. Major histocompatibility complex diversity influences parasite resistance and innate immunity in sticklebacks. Proceedings: Biological Science 271, 197–204 (2004).
42. In fact, human smell is more sensitive than we commonly acknowledge and many scientists, including Gary Beauchamp for example, think we use olfaction far more than we generally realize.
43. Rosenberg, L. T., Cooperman, D. and Payne, R. HLA and mate selection. Immunogenetics 17, 89–93 (1983).
44. Havlicek, J. and Roberts, S. C. MHC-correlated mate choice in humans: a review. Psychoneuroendocrinology 34, 497–512 (2009).
45. Ober, C. et al. HLA and mate choice in humans. American Journal of Human Genetics 61, 497–504 (1997).
46. Interview with Gary Beauchamp, 7 November 2011.
1. Carla Shatz and her colleague Helen Blau discuss how they were hired and other interesting aspects of their career in a short film, Pioneers of Science, produced in 2010 by Stanford University, available here: http://www.youtube.com/watch?v=3tC1LneCuFs.
2. Gewin, V. Movers: Carla Shatz, director, BioX, Stanford University, Stanford, California. Nature 447, 610 (2007).
3. Interview with Carla Shatz, 23 November 2011.
4. http://www.youtube.com/watch?v=3tC1LneCuFs.
5. Interview with Carla Shatz, 23 November 2011.
6. Joly, E., Mucke, L. and Oldstone, M. B. Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science 253, 1283–5 (1991).
7. Simpson, E. A historical perspective on immunological privilege. Immunology Review 213, 12–22 (2006).
8. Interview with Carla Shatz, 23 November 2011.
9. Ho, V. M., Lee, J. A. and Martin, K. C. The cell biology of synaptic plasticity. Science 334, 623–8 (2011).
10. How the brain works can’t be studied without animal models, unfortunately. The key thing about the brain is the way in which the neural cells are connected to each other. So if isolated cells were studied, the essential nature of the brain would be lost. Cats have been especially important in studying synaptic circuits involved in vision, because they have eyes facing the front, use binocular vision, and the layout of their visual system is similar to ours. Undoubtedly, scientists carry out this kind of research in the most humane way possible, with animals being anesthetized, for example, and as few animals as possible being used.
11. Hubel, D. and Wiesel, T. Brain and Visual Perception: The Story of a 25-year Collaboration (Oxford University Press, 2005).
12. A fascinating insight into this work is discussed in David Hubel’s Nobel Lecture, given on 8 December 1981 at the Karolinska Institute, which can be viewed at: http://www.nobelprize.org/mediaplayer/index.php?id=1605andview=1.
13. Hubel and Wiesel. Brain and Visual Perception.
14. Ibid.
15. Olby, R. Francis Crick: Hunter of Life’s Secrets (Cold Spring Harbor Laboratory Press, 2008).
16. Hubel and Wiesel. Brain and Visual Perception.
17. In a more holistic sense, consciousness is obviously what sets aside a brain from a computer, but we have little idea how that works or even what it is: it’s the biggest unknown.
18. Corriveau, R. A., Huh, G. S. and Shatz, C. J. Regulation of class I MHC gene expression in the developing and mature CNS by neural activity. Neuron 21, 505–20 (1998).
19. Interview with Carla Shatz, 23 November 2011.
20. Huh, G. S. et al. Functional requirement for class I MHC in CNS development and plasticity. Science 290, 2155–9 (2000).
21. Marcus, A. and Oransky, I. Science publishing: the paper is not sacred. Nature 480, 449–50 (2011).
22. Purcell, S. M. et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748–52 (2009). Stefansson, H. et al. Common variants conferring risk of schizophrenia. Nature 460, 744–7 (2009).
23. Wright, P., Nimgaonkar, V., R. G. and Murray, R. M. HLA and psychiatric disease. In HLA in Health and Disease, ed. Lechler, R. and Warrens, A. (Academic Press, 2000).
24. Numbers are taken from from Narcolepsy UK, where far more information is also available: http://www.narcolepsy.org.uk/.
25. Hor, H. et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nature Genetics 42, 786–9 (2010).
26. Cvetkovic-Lopes, V. et al. Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. Journal of Clinical Investigation 120, 713–19 (2010).
27. Boulanger, L. M. and Shatz, C. J. Immune signalling in neural development, synaptic plasticity and disease. Nature Reviews Neuroscience 5, 521–31 (2004).
28. McConnell, M. J., Huang, Y. H., Datwani, A. and Shatz, C. J. H2-K(b) and H2-D(b) regulate cerebellar long-term depression and limit motor learning. Proceedings of the National Academy of Sciences USA 106, 6784–9 (2009).
29. Neuroscience 2011, Washington, DC, 12–16 November 2011: http://www.sfn.org/am2011/home.aspx.
30. Abstracts from all the presentations of this meeting are available online through the Society for Neuroscience and many tens of these abstracts discuss immune-system genes or proteins in various aspects of brain research.
31. Tang, S. C. et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proceedings of the National Academy of Sciences USA 104, 13798–803 (2007).
32. Allan, S. M., Tyrrell, P. J. and Rothwell, N. J. Interleukin-1 and neuronal injury. Nature Reviews Immunology 5, 629–40 (2005).
33. Interview with Carla Shatz, 23 November 2011.
34. Irwin, M. R. and Cole, S. W. Reciprocal regulation of the neural and innate immune systems. Nature Reviews Immunology 11, 625–32 (2011).
35. Gleeson, M. et al. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nature Reviews Immunology 11, 607–15 (2011).
36. Paul, W. E. and Seder, R. A. Lymphocyte responses and cytokines. Cell 76, 241–51 (1994). This paper was influential for scientists thinking about the similarities in how immune cells and neurons work. Mike Norcross, then working with Ron Germain at the National Institute of Health, had earlier suggested the terminology of an ‘immune synapse’ to decsribe the contact a T cell makes with other cells, but the paper by Paul and Seder reached a much wider audience.
37. Poo, W. J., Conrad, L. and Janeway, C. A., Jr. Receptor-directed focusing of lymphokine release by helper T cells. Nature 332, 378–80 (1988).
38. Monks, C. R., Freiberg, B. A., Kupfer, H., Sciaky, N. and Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–6 (1998).
39. Davis, D. M. Intrigue at the immune synapse. Scientific American 294, 48–55 (2006). My discussion of Avi Kupfer’s research in this book is similar to my article about his work, published in Scientific American.
40. E-mail correspondence with Anton van der Merwe, 15 November 2004.
41. Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221–7 (1999).
42. Davis, D. M. et al. The human natural killer cell immune synapse. Proceedings of the National Academy of Sciences USA 96, 15062–7 (1999).
43. Davis, D. M. and Sowinski, S. Membrane nanotubes: dynamic long-distance connections between animal cells. Nature Reviews Molecular Cell Biology 9, 431–6 (2008).
44. Sowinski, S. et al. Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nature Cell Biology 10, 211–19 (2008).
45. Gousset, K. et al. Prions hijack tunnelling nanotubes for intercellular spread. Nature Cell Biology 11, 328–36 (2009).
46. Kwok, R. Cell biology: the new cell anatomy. Nature 480, 26–8 (2011).
47. Hubel, D. Eye, Brain and Vision (Scientific American Library, 1988).
1. Billington, W. D. The immunological problem of pregnancy: 50 years with the hope of progress. A tribute to Peter Medawar. Journal of Reproductive Immunology 60, 1–11 (2003). Medawar, P. B. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symposia of the Society for Experimental Biology 7, 320–38 (1953).
2. Medawar, P. B. Some immunological and endocrinological problems.
3. Moffett-King, A. Natural killer cells and pregnancy. Nature Reviews Immunology 2, 656–63 (2002).
4. Ibid.
5. Billingham, R. E. Transplantation immunity and the maternal-fetal relation (part one). New England Journal of Medicine 270, 667–72 (1964). Billingham, R. E. Transplantation immunity and the maternal–fetal relation (continued: part 2). New England Journal of Medicine 270, 720–25 (1964).
6. Apps, R. et al. Human leucocyte antigen (HLA) expression of primary trophoblast cells and placental cell lines, determined using single antigen beads to characterize allotype specificities of anti-HLA antibodies. Immunology 127, 26–39 (2009).
7. An hour-long interview with Charlie Loke filmed by Alan Macfarlane on 22 February 2007 is available in archives held at the University of Cambridge. In this wide-ranging interview, Loke discusses his background, personal life and some of his work in the immunology of pregnancy. The full interview is available online: http://www.dspace.cam.ac.uk/handle/1810/194470.
8. Moffett, A. Charlie Loke: contributions from Tennis Court Road – past, present and future. Placenta 24 Suppl. A, S4-9 (2003).
9. http://www.dspace.cam.ac.uk/handle/1810/194470.
10. Moffett. Charlie Loke.
11. Interview with Ashley Moffett, 19 January 2012.
12. Moffett. Charlie Loke.
13. Interview with Ashley Moffett, 19 January 2012.
14. Ashley Moffett’s work at this time uses her married name, King. After divorce, she used Moffett-King for a few publications and then later her maiden name, Moffett. At the time she was going through her divorce, she was particularly worried about being able to carry on with her top-level research career while raising three children as a single mother. At a dinner, she happened to sit across from a very famous female scientist who she knew also had children and was divorced. So she asked her how she coped, and the woman replied very clearly: ‘Come on, Ashley, of course it’s much easier to deal with three children compared with having to cope with three children and a husband.’
15. Interview with Ashley Moffett, 19 January 2012.
16. Ibid.
17. Ibid.
18. King, A., Wellings, V., Gardner, L. and Loke, Y. W. Immunocytochemical characterization of the unusual large granular lymphocytes in human endometrium throughout the menstrual cycle. Human Immunology 24, 195–205 (1989).
19. Interview with Ashley Moffett, 19 January 2012.
20. Bulmer, J. N., Morrison, L., Longfellow, M., Ritson, A. and Pace, D. Granulated lymphocytes in human endometrium: histochemical and immunohistochemical studies. Human Reproduction 6, 791–8 (1991). Starkey, P. M., Sargent, I. L. and Redman, C. W. Cell populations in human early pregnancy decidua: characterization and isolation of large granular lymphocytes by flow cytometry. Immunology 65, 129–34 (1988).
21. Interview with Phyllis Starkey MP by Richard Reece, published in the Biochemist magazine, June 2006, available here: http://www.biochemist.org/bio/02803/0049/028030049.pdf.
22. Interview with Ashley Moffett, 19 January 2012.
23. Clements, C. S. et al. Crystal structure of HLA-G: a non-classical MHC class I molecule expressed at the fetal–maternal interface. Proceedings of the National Academy of Sciences USA 102, 3360–65 (2005).
24. Geraghty, D. E., Koller, B. H. and Orr, H. T. A human major histocompatibility complex class I gene that encodes a protein with a shortened cytoplasmic segment. Proceedings of the National Academy of Sciences USA 84, 9145–9 (1987). Kovats, S. et al. A class I antigen, HLA-G, expressed in human trophoblasts. Science 248, 220–23 (1990). Ellis, S. A., Palmer, M. S. and McMichael, A. J. Human trophoblast and the choriocarcinoma cell line BeWo express a truncated HLA Class I molecule. Journal of Immunology 144, 731–5 (1990).
25. Apps, R., Gardner, L. and Moffett, A. A critical look at HLA-G. Trends in Immunology 29, 313–21 (2008).
26. Davis, D. M. et al. Impaired spontaneous endocytosis of HLA-G. European Journal of Immunology 27, 2714–19 (1997).
27. Rouas-Freiss, N., Goncalves, R. M., Menier, C., Dausset, J. and Carosella, E. D. Direct evidence to support the role of HLA-G in protecting the fetus from maternal uterine natural killer cytolysis. Proceedings of the National Academy of Sciences USA 94, 11520–25 (1997). Pazmany, L. et al. Protection from natural killer cell-mediated lysis by HLA-G expression on target cells. Science 274, 792–5 (1996). Soderstrom, K., Corliss, B., Lanier, L. L. and Phillips, J. H. CD94/NKG2 is the predominant inhibitory receptor involved in recognition of HLA-G by decidual and peripheral blood NK cells. Journal of Immunology 159, 1072–5 (1997). Ponte, M. et al. Inhibitory receptors sensing HLA-G1 molecules in pregnancy: decidua-associated natural killer cells express LIR-1 and CD94/NKG2A and acquire p49, an HLA-G1-specific receptor. Proceedings of the National Academy of Sciences USA 96, 5674–9 (1999).
28. In detail, HLA-G can also work indirectly, through HLA-E. Expression of HLA-G allows HLA-E to get to the cell surface and HLA-E can then also be involved in inhibiting NK cells from killing trophoblast cells.
29. Kopcow, H. D. et al. Human decidual NK cells form immature activating synapses and are not cytotoxic. Proceedings of the National Academy of Sciences USA 102, 15563–8 (2005).
30. Koopman, L. A. et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. Journal of Experimental Medicine 198, 1201–12 (2003).
31. Hanna, J. et al. Decidual NK cells regulate key developmental processes at the human fetal–maternal interface. Nature Medicine 12, 1065–74 (2006).
32. Croy, B. A. et al. Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling. Reproduction 126, 149–60 (2003).
33. Guimond, M. J., Wang, B. and Croy, B. A. Engraftment of bone marrow from severe combined immunodeficient (SCID) mice reverses the reproductive deficits in natural killer cell-deficient tg epsilon 26 mice. Journal of Experimental Medicine 187, 217–23 (1998).
34. Hanna, J. and Mandelboim, O. When killers become helpers. Trends in Immunology 28, 201–6 (2007).
35. Koopman et al. Human decidual natural killer cells.
36. Madeja, Z. et al. Paternal MHC expression on mouse trophoblast affects uterine vascularization and fetal growth. Proceedings of the National Academy of Sciences USA 108, 4012–17 (2011).
37. Interview with Ashley Moffett, 19 January 2012. E-mail correspondence with Ofer Mandelboim, 24 January 2012.
38. Carosella, E. D., Moreau, P., Lemaoult, J. and Rouas-Freiss, N. HLA-G: from biology to clinical benefits. Trends in immunology 29, 125–32 (2008). Paul, P., et al. HLA-G expression in melanoma: a way for tumor cells to escape from immunosurveillance. Proceedings of the National Academy of Sciences USA 95, 4510–15 (1998).
39. Carosella, E. D., Favier, B., Rouas-Freiss, N., Moreau, P. and Lemaoult, J. Beyond the increasing complexity of the immunomodulatory HLA-G molecule. Blood 111, 4862–70 (2008).
40. Hiby, S. E. et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. Journal of Experimental Medicine 200, 957–65 (2004).
41. Ibid.
42. Further details on recurrent miscarriage are available from the Royal College of Obstetricians and Gynaecologists in London, UK, here: http://www.rcog.org.uk/womens-health/clinical-guidance/couples-recurrent-miscarriage-what-rcog-guideline-means-you.
43. Hiby, S. E. et al. Association of maternal killer-cell immunoglobulin-like receptors and parental HLA-C genotypes with recurrent miscarriage. Human Reproduction 23, 972–6 (2008).
44. Ibid.
45. Hiby, S. E. et al. Maternal activating KIRs protect against human reproductive failure mediated by fetal HLA-C2. Journal of Clinical Investigation 120, 4102–10 (2010).
46. Taken from an interview with Isaac Asimov in 1990, available on the CD Science Fiction Writers, published by the British Library, 2011.
47. Tang, A. W., Alfirevic, Z. and Quenby, S. Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review. Human Reproduction 26, 1971–80 (2011).
48. Tang, A. W. and Quenby, S. Recent thoughts on management and prevention of recurrent early pregnancy loss. Current Opinion in Obstetrics and Gynecology 22, 446–51 (2010).
49. Hogan, M. C. et al. Maternal mortality for 181 countries, 1980–2008: a systematic analysis of progress towards Millennium Development Goal 5. Lancet 375, 1609–23 (2010).