1 This interview features in the BBC TV programme The Pleasure of Finding Things Out, part of the Horizon series, archived online here: http://www.bbc.co.uk/iplayer/episode/p018dvyg/horizon-19811982-9-the-pleasure-of-finding-things-out. A transcript of the interview is also available in Jeffrey Robbins (ed.), The Pleasure of Finding Things Out: The Best Short Works of Richard P. Feynman (Penguin, 2001) – but from a transcript alone, you miss Feynman’s absorbing oratory skill. Feynman’s story is captured wonderfully in James Gleick, Genius: Richard Feynman and Modern Physics (Abacus, 1992).
2 Irwin, M. R., ‘Why sleep is important for health: a psychoneuroimmunology perspective’, Annual Review of Psychology 66, 143–72 (2015).
3 Dorshkind, K., Montecino-Rodriguez, E., & Signer, R. A., ‘The ageing immune system: is it ever too old to become young again?’, Nature Reviews Immunology 9, 57–62 (2009).
1 Bilalić, M., McLeod, P., & Gobet, F., ‘Inflexibility of experts – reality or myth? Quantifying the Einstellung effect in chess masters’, Cognitive Psychology 56, 73–102 (2008).
2 There are many experiments that show the ‘Einstellung’ effect – a significant field of research in its own right. A great entry point to this subject is Bilalić, M., & McLeod, P., ‘Why good thoughts block better ones’, Scientific American, 310, 74–9, March 2014.
3 Matzinger, P., ‘Charles Janeway, Jr, Obituary’, Journal of Clinical Investigation 112, 2 (2003).
4 Gayed, P. M., ‘Toward a modern synthesis of immunity: Charles A. Janeway Jr and the immunologist’s dirty little secret’, Yale Journal of Biology and Medicine 84, 131–8 (2011).
5 Janeway, C. A., Jr, ‘A trip through my life with an immunological theme’, Annual Review of Immunology 20, 1–28 (2002).
6 Ibid.
7 State of the world’s vaccines and immunization (third edition, World Health Organization Press, 2009).
8 Variolation is a term often used to describe inoculation with smallpox. Variolation can be defined as an application of a small dose of infection in a controlled manner, whereas vaccination can be distinguished from this as the use of dead or weakened infection. The terms inoculation, vaccination and immunization may also be given subtly different meanings. However, the various ways in which modern vaccines work makes, to my mind, specific definitions difficult for these terms and so I have used these terms interchangeably here.
9 Rhodes, J., The End of Plagues: The Global Battle against Infectious Disease (Palgrave Macmillan, 2013); De Gregorio, E., & Rappuoli, R., ‘From empiricism to rational design: a personal perspective of the evolution of vaccine development’, Nature Reviews Immunology 14, 505–514 (2014).
10 Silverstein, A. M., A History of Immunology (second edition, Academic Press, 2009).
11 A very brief history of the Royal Society is available online here: http://royalsociety.org/about-us/history/
12 Mead, R., A Discourse on the Small Pox and Measles (John Brindley, 1748). This book is by Richard Mead, the prominent London physician who carried out the inoculations of prisoners in 1721. The story of the royal experiment is told in Chapter Five, ‘Of the inoculation of the small pox’.
13 Before inoculating their own children, the Princess of Wales first paid to have five orphan children inoculated. The test on prisoners had involved only adults and she felt it important to test the safety of the procedure in other children, before her own.
14 It’s worth bearing in mind that celebrities influence public opinion quite independently of the prevailing orthodox view of, for example, relevant scientific bodies. One example is the story of Jenny McCarthy, former Playboy model and partner of actor Jim Carrey, who has claimed that her own son, Evan, developed autism as a result of vaccination. Her opinions reached a huge audience around 2007–9, for example by her appearing on Oprah Winfrey’s TV show. Her personal story is emotive and she has said: ‘my science is Evan. He’s at home. That’s my science.’ She has written several books herself, including Louder than Words: A Mother’s Journey in Healing Autism (Plume, 2008). Her story is also discussed in Mark A. Largent, Vaccine: The Debate in Modern America (Johns Hopkins University Press, 2012), 138–48.
15 Silverstein.
16 Jenner, E., An Inquiry Into the Causes and Effects of the Variolae Vaccinae: A disease discovered in some of the Western Counties of England, particularly Gloucestershire, and known by the name of the cow pox (1798). This landmark text has been republished many times and the full text is freely available on the web, such as here: http://www.bartleby.com/38/4/1.html.
17 The word vaccine was coined by surgeon Richard Dunning. The use of the word ‘vaccine’ in situations other than for the use of cowpox to protect against smallpox has been attributed to Louis Pasteur (1822–95).
18 The fact that smallpox was tackled on a global scale is important. ‘Probably the worst thing that ever happened to malaria in poor nations,’ journalist Tina Rosenberg has written, ‘was its eradication in rich ones’, quoted on p. 44 of Eula Biss’s wonderful book about vaccination, On Immunity (Graywolf Press, 2014).
19 Rhodes.
20 Although not known in 1920s, it was well established in 1989 that the immune system learns what our body is made of at an early age, so that it is then ready to attack anything else. This is discussed in much greater depth in my first book, The Compatibility Gene (Allen Lane, 2013).
21 Oakley, C. L., ‘Alexander Thomas Glenny. 1882–1965’, Biographical Memoirs of Fellows of the Royal Society 12, 162–80 (1966).
22 Oakley, C. L., ‘A. T. Glenny’, Nature 211, 1130 (1966).
23 Ibid.
24 Having been brought up in an especially conservative Christian household in which going to the theatre or concerts was forbidden, Glenny had little interest in anything outside work.
25 Marrack, P., McKee, A. S., & Munks, M. W., ‘Towards an understanding of the adjuvant action of aluminium’, Nature Reviews Immunology 9, 287–93 (2009).
26 Gura, T., ‘The Toll Road’, Yale Medicine 36, 28–36 (2002).
27 The Cold Spring Harbor Symposia on Quantitative Biology is a series of conferences which began in 1933. Many renowned scientists were present at the 1989 meeting, including Tasuku Honjo, Leroy Hood, John Inglis, Richard Klausner, Fritz Melchers, Gustav Nossal and Rolf Zinkernagel. Twenty photos from the meeting have been archived and are available online here: http://libgallery.cshl.edu/items/browse/tag/Immunological+Recognition. John Inglis, executive director of Cold Spring Harbor Press, has told me (email correspondence, 25 March 2015) that in his recollection, Janeway sent him the paper for inclusion in the meeting proceedings after the event and that at the meeting itself, he didn’t give a formal talk on the subject. He may have just discussed the ideas with people informally at the meeting itself.
28 Janeway, C. A., Jr, ‘Approaching the asymptote? Evolution and revolution in immunology’, Cold Spring Harbor Symposia on Quantitative Biology 54 Pt 1, 1–13 (1989).
29 Ibid.
30 Some scientists do not like the term ‘pattern recognition’, as this type of interaction between a protein and another molecule is usually called ‘molecular recognition’. Nevertheless, the term ‘pattern-recognition receptors’ remains in common use today.
31 Charles Janeway, with colleague Paul Travers, first published their textbook Immunobiology in 1994. This and all subsequent editions have been hugely successful. The ninth edition of this book – now titled Janeway’s Immunobiology – was published in 2016, updated by Kenneth Murphy and Casey Weaver.
32 George Bernard Shaw said this in a speech at a public dinner in London on 28 October 1930, to honour Albert Einstein. Excerpts from this speech are given in Michael Holroyd, ‘Albert Einstein, Universe Maker’, New York Times, 14 March 1991.
33 Calculated as 3 × 1004 = 3 × 108.
34 Calculated as seventy-two divisions in twenty-four hours (one every twenty minutes), leading to 272 offspring.
35 Essentially, this means that the process of evolution by natural selection happens much faster for viruses than for us. For some viruses, this is enhanced even further because the rate at which genetic variations occur when viruses reproduce is far greater than it is in us (because the machinery used to copy genetic material is less careful in some viruses). This works for viruses because any defective offspring that may arise have little consequence overall.
36 Janeway (1989).
37 Email correspondence with Leroy Hood (10 February 2015) and Jonathan Howard (12 February 2015), respectively.
38 Janeway (1989).
39 Medzhitov, R., ‘Pattern recognition theory and the launch of modern innate immunity’, The Journal of Immunology 191, 4473–4 (2013).
40 Interview with Ruslan Medzhitov, 31 March 2015.
41 Ibid.
42 Ibid.
43 Gura.
44 Interview with Ruslan Medzhitov, 31 March 2015.
45 Ibid.
46 Dahl, R., The Minpins (Puffin, 1991).
47 McKie, R., ‘Six Nobel prizes – what’s the fascination with the fruit fly?’, Observer, 8 October 2017. Available online here: https://www.theguardian.com/science/2017/oct/07/fruit-fly-fascination-nobel-prizes-genetics.
48 Interview with Jules Hoffmann, 7 April 2015.
49 Particularly inspirational to Hoffmann – and others – were Hans Boman’s discoveries through the 1970s and early 1980s which culminated in identifying antibacterial peptides in North America’s largest native silk moth, Hyalophora cecropia. Over 700 different antimicrobial peptides have since been isolated from mammals, as discussed by Jack L. Strominger in The Journal of Immunology 182, 6633–4 (2009). Hans Boman died on 3 December 2008.
50 Fehlbaum, P., et al., ‘Insect immunity. Septic injury of Drosophila induces the synthesis of a potent antifungal peptide with sequence homology to plant antifungal peptides’, Journal of Biological Chemistry 269, 33159–63 (1994).
51 O’Neill, L. A., Golenbock, D., & Bowie, A. G., ‘The history of toll-like receptors – redefining innate immunity’, Nature Reviews Immunology 13, 453–60 (2013). This scholarly and authorative article reviews, in depth, the sequence of events that led to the discovery of toll-like receptors.
52 Lemaitre, B., ‘The road to toll’, Nature Reviews Immunology 4, 521–7 (2004).
53 Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M., & Hoffmann, J. A., ‘The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults’, Cell 86, 973–83 (1996).
54 The three reviews of this paper, obtained by the journal Cell, are archived online by the first author Bruno Lemaitre. It is interesting that all three reviews were very encouraging although, as is nearly always the case with peer review, each scientist did demand several more experiments before they felt the work should be published. The reviews are available here: http://www.behinddiscoveries.com/toll/resources
55 Interview with Jules Hoffmann, 7 April 2015.
56 Ibid.
57 It’s certainly plausible that Medzhitov did have the data in hand already; there were clues as to what to look for from other immune receptor pathways (involving IL-1 and TNF). When seeking to clarify some of these details, one impartial immunologist replied to me that ‘it’s all a bit cloak and dagger, Dan’.
58 Medzhitov, R., Preston-Hurlburt, P., & Janeway, C. A., Jr, ‘A human homologue of the drosophila toll protein signals activation of adaptive immunity’, Nature 388, 394–7 (1997).
59 It’s important to note, however, that Barbara Baker’s work on the tobacco N gene, part of the plant’s innate defence, began before the work on flies discussed here. Baker’s research indicates a similarity in innate immunity defences even between mammals and plants.
60 Interview with Bruce Beutler, 21 April 2015.
61 A short autobiography by Beutler is available online at http://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/beutler-bio.html.
62 Interview with Bruce Beutler, 21 April 2015.
63 Ibid.
64 Ibid.
65 Beutler’s grandparents all moved to the USA to avoid persecution of Jews in Europe. Anti-Semitism shaped the ethos of his family and Beutler says, in autobiographical notes archived by the Nobel Committee, that ‘probably we all felt a need to excel partly because of these facts; to show that we were as good as the other children in our schools’.
66 Beutler Nobel autobiography.
67 Ibid.
68 Poltorak, A., et al., ‘Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene’, Science 282, 2085–8 (1998).
69 O’Neill (2013).
70 Qureshi, S. T., et al., ‘Endotoxin-tolerant mice have mutations in toll-like receptor 4 (Tlr4)’, The Journal of Experimental Medicine 189, 615–25 (1999).
71 Hoshino, K., et al., ‘Cutting edge: toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product’, The Journal of Immunology 162, 3749–52 (1999).
72 Beutler recounts how he heard the news in a telephone conversation with Adam Smith, editorial director of Nobel Media, recorded on the same day as the prize was announced, 3 October 2011: http://www.nobelprize.org/mediaplayer/index.php?id=1632.
73 Allison, J. P., Benoist, C., & Chervonsky, A. V., ‘Nobels: Toll pioneers deserve recognition’, Nature 479, 178 (2011).
74 Paul, W. E., & Germain, R. N., ‘Obituary: Charles A. Janeway Jr (1943–2003)’, Nature 423, 237 (2003).
75 Paul, W. E., ‘Endless fascination’, Annual Review of Immunology 32, 1–24 (2014).
76 Interview with Ruslan Medzhitov, 31 March 2015.
77 Interview with Jules Hoffmann, 7 April 2015.
78 Ezekowitz, A., et al., ‘Lawrence’s book review unfair to Hoffmann’, Current Biology 22, R482 (2012).
79 Lemaitre, B., An Essay on Science and Narcissism: How Do High-Ego Personalities Drive Research in Life Sciences? (Copy Media, 2016).
80 Cyranoski, D., ‘Profile: Innate ability’, Nature 450, 475–7 (2007).
81 It’s not clear why insects, for example, don’t have or need a more complex immune system akin to ours. Body size and longevity are sometimes invoked in explanations, or that, as anatomy evolved to be more complex, a more complicated immune defence also developed.
82 This was suggested by Rolf Zinkernagel speaking at the 64th Lindau Nobel Laureate Meeting, 1 July 2014, and is recounted by Jules Hoffmann in an interview recorded at that meeting, available online here: http://www.dw.de/tomorrow-today-the-science-magazine-2014-07-07/e-17717966-9798.
83 Interview with Jules Hoffmann, 7 April 2015.
84 Rees, M., Our Final Century (William Heinemann, 2003).
85 Marrack et al.
86 De Gregorio & Rappuoli.
87 Beutler Nobel autobiography.
88 Interview with Luke O’Neill, 16 March 2016.
89 Interview with Ruslan Medzhitov, 31 March 2015.
1 Koestler, A., The Act of Creation (Hutchinson, 1964).
2 Nussenzweig, M. C., & Mellman, I., ‘Ralph Steinman (1943–2011)’, Nature 478, 460 (2011).
3 Steinman, R. M., ‘Dendritic cells: understanding immunogenicity’, European Journal of Immunology 37 Suppl 1, S53–60 (2007).
4 Steinman, R. M., & Cohn, Z. A., ‘The interaction of soluble horseradish peroxidase with mouse peritoneal macrophages in vitro’, The Journal of Cell Biology 55, 186–204 (1972).
5 Mosier, D. E., ‘A requirement for two cell types for antibody formation in vitro’, Science 158, 1573–5 (1967). This is the first paper clearly showing the need for so-called accessory cells in an immune reaction. The observation was made by studying the reaction of mouse immune cells against red blood cells from sheep.
6 Jolles, S., ‘Paul Langerhans’, Journal of Clinical Pathology 55, 243 (2002).
7 Steinman, R. M., & Cohn, Z. A., ‘Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution’, The Journal of Experimental Medicine 137, 1142–62 (1973).
8 Simons, D. J., & Chabris, C. F., ‘Gorillas in our midst: sustained inattentional blindness for dynamic events’, Perception 28, 1059–74 (1999).
9 The Invisible Gorilla video is available online here: http://www.theinvisiblegorilla.com/gorilla_experiment.html
10 Drew, T., Vo, M. L., & Wolfe, J. M., ‘The invisible gorilla strikes again: sustained inattentional blindness in expert observers’, Psychological Science 24, 1848–53 (2013).
11 Snyder, L. J., Eye of the Beholder: Johannes Vermeer, Antoni van Leeuwenhoek, and the Reinvention of Seeing (W. W. Norton, 2015).
12 Lindquist, R. L., et al., ‘Visualizing dendritic cell networks in vivo’, Nature Immunology 5, 1243–50 (2004).
13 The origin of this quote is unclear. Albert Szent-Györgyi used the line in his 1957 book Bioenergetics but he used quotation marks, indicating he borrowed the line from elsewhere. He won the Nobel Prize in Physiology or Medicine in 1937.
14 Steinman, R. M., ‘Endocytosis and the discovery of dendritic cells’ in Moberg, C. L. (ed.), Entering an Unseen World (Rockefeller University Press, 2012).
15 Pollack, A., ‘George Palade, Nobel Winner for Work Inspiring Modern Cell Biology, Dies at 95’, New York Times, 9 October 2008.
16 Porter, K. R., Claude, A., & Fullam, E. F., ‘A Study of Tissue Culture Cells by Electron Microscopy: Methods and Preliminary Observations’, The Journal of Experimental Medicine 81, 233–46 (1945).
17 Moberg, C. L., Entering an Unseen World: A Founding Laboratory and Origins of Modern Cell Biology 1910–1974 (Rockefeller University Press, 2012).
18 Steinman, R. M., ‘Dendritic cells: from the fabric of immunology’, Clinical and Investigative Medicine 27, 231–6 (2004).
19 Steinman’s children were interviewed by Dan Woog for the article ‘Remembering Ralph Steinman’, published online 26 October 2011, in a blog, available here: http://06880danwoog.com/2011/10/26/remembering-ralph-steinman/.
20 Albert Claude had earlier established the basic process of using a centrifuge to separate parts of cells. Claude’s first experiments with a centrifuge were carried out in 1937 and he obtained four crude fractions of cells, for example, in 1941. Claude shared the Nobel Prize in Physiology or Medicine, in 1974, with Palade and de Duve. Swedish scientist Theodor Svedberg developed the scientific use of centrifugation before this, showing that the method could be used to separate out different protein molecules. In 1926, the Nobel Prize in Chemistry was awarded to Svedberg for this work.
21 De Duve, C., ‘Exploring cells with a centrifuge’ (Nobel Lecture, 1974). Available online here: http://www.nobelprize.org/nobel_prizes/medicine/laureates/1974/duve-lecture.pdf
22 Nussenzweig, M. C., ‘Ralph Steinman and the discovery of dendritic cells’ (Nobel Lecture, 2011). Available online here: http://www.nobelprize.org/nobel_prizes/medicine/laureates/2011/steinman_lecture.pdf
23 Gordon, S., ‘Elie Metchnikoff: father of natural immunity’, European Journal of Immunology 38, 3257–64 (2008).
24 Metchnikoff, I., ‘Nobel Lecture 1908’ in Nobel Lectures in Physiology or Medicine 1901–1921 (Elsevier, 1967).
25 Vikhanski, L., Immunity: How Elie Metchnikoff Changed the Course of Modern Medicine (Chicago Review Press, 2016).
26 Metchnikoff, O., Life of Elie Metchnikoff (translated from French) (Houghton Mifflin Company, 1921).
27 Metchnikoff (1967).
28 Vikhanski.
29 Ibid.
30 Ambrose, C. T., ‘The Osler slide, a demonstration of phagocytosis from 1876 Reports of phagocytosis before Metchnikoff’s 1880 paper’, Cellular Immunology 240, 1–4 (2006).
31 Paul, W. E., ‘Bridging innate and adaptive immunity’, Cell 147, 1212–15 (2011).
32 Tirrell, M., Langreth, R., & Flinn, R., ‘Nobel laureate treating own cancer dies before award announced’, Bloomberg Business (4 October 2011). Available online here: http://www.bloomberg.com/news/articles/2011-10-03/nobel-laureate-ralph-steinman-dies-3-days-before-prize-announced.
33 Guy Raz interviews Adam Steinman, Ralph’s son, broadcast on National Public Radio, 3 October 2011. Available online: http://www.npr.org/2011/10/03/141019170/son-of-nobel-winner-remembers-his-father.
34 Nussenzweig, M. C., & Steinman, R. M., ‘Contribution of dendritic cells to stimulation of the murine syngeneic mixed leukocyte reaction’, The Journal of Experimental Medicine 151, 1196–212 (1980); Nussenzweig, M. C., Steinman, R. M., Gutchinov, B., & Cohn, Z. A., ‘Dendritic cells are accessory cells for the development of anti-trinitrophenyl cytotoxic T lymphocytes’, The Journal of Experimental Medicine 152, 1070–84 (1980).
35 Nussenzweig, M. C., Steinman, R. M., Witmer, M. D., & Gutchinov, B., ‘A monoclonal antibody specific for mouse dendritic cells’, Proceedings of the National Academy of Sciences USA 79, 161–5 (1982).
36 Van Voorhis, W. C., et al., ‘Relative efficacy of human monocytes and dendritic cells as accessory cells for T cell replication’, The Journal of Experimental Medicine 158, 174–91 (1983); Steinman, R. M., Gutchinov, B., Witmer, M. D., & Nussenzweig, M. C., ‘Dendritic cells are the principal stimulators of the primary mixed leukocyte reaction in mice’, The Journal of Experimental Medicine 157, 613–27 (1983). In experiments reported in these papers in 1983, Steinman studied different kinds of immune reaction, including the reaction which occurs when blood cells from different people are mixed together. It’s a reaction that can happen in a bone-marrow transplant situation if certain genes aren’t well matched. The magnitude of the immune response, or how powerful the reaction is, can be monitored in several ways, such as testing how well the immune cells multiply to increase in number. Steinman’s team showed that dendritic cells were at least 100–300 times more potent in triggering this kind of immune reaction, in comparison to any other immune cell.
37 Van Voorhis, W. C., Hair, L. S., Steinman, R. M., & Kaplan, G., ‘Human dendritic cells. Enrichment and characterization from peripheral blood’, The Journal of Experimental Medicine 155, 1172–87 (1982).
38 Steinman (2004). Like many scientists who trained in Ralph Steinman’s lab, Gerold Schuler went on to have his own stellar career in science. He become a head of department at Universitätsklinikum Erlangen, Germany, and has made many contributions in exploring the potential medical use of dendritic cells.
39 Schuler, G., & Steinman, R. M., ‘Murine epidermal Langerhans cells mature into potent immunostimulatory dendritic cells in vitro’, The Journal of Experimental Medicine 161, 526–46 (1985).
40 Today, each dendritic-cell meeting attracts about 1,000 participants. The first meeting was held in Japan, 1990, as a satellite meeting. The second, held in the Netherlands in 1992, was a specific meeting dedicated to dendritic cells. This second meeting had 220 participants and fifteen invited speakers.
41 T cells which have a receptor which can easily trigger a reaction against healthy cells have been killed off (in the thymus) so that T cells in the lymph node do not react to the body’s own components.
42 Often given less attention than, say, cancer or HIV, parasites affect well over a billion people and cause huge social and economic problems, arguably trapping some whole countries in poverty.
43 Anthony, R. M., Rutitzky, L. I., Urban, J. F., Jr, Stadecker, M. J., & Gause, W. C., ‘Protective immune mechanisms in helminth infection’, Nature Reviews Immunology 7, 975–9 (2007).
44 Kapsenberg, M. L., ‘Dendritic-cell control of pathogen-driven T-cell polarization’, Nature Reviews Immunology 3, 984–93 (2003).
45 Reis e Sousa, C., ‘Dendritic cells in a mature age’, Nature Reviews Immunology 6, 476–83 (2006). Essentially, I have described the basic model for how dendritic cells work in the body to trigger an immune reaction but many exceptions and details are discussed, for example, in this academic article.
46 Lamott, A., Bird by Bird: Some Instructions on Writing and Life (Pantheon Books, 1994).
47 Formally, there are class I and class II versions of the MHC proteins. Class I proteins are found on nearly all types of cells, but class II proteins are found only on some types of immune cells – known as antigen-presenting cells. The antigen-presenting cells include macrophages and dendritic cells and these are the types of cells able to trigger immune responses. Dendritic cells are the most potent antigen-presenting cells.
48 Davis, D. M., The Compatibility Gene (Allen Lane, 2013).
49 An additional signal that guides immune cell behaviour comes from soluble factors – cytokines – and this is sometimes referred to as Signal Three. Cytokines will be discussed in more detail in the next chapter.
50 The co-stimulation of T cells is a complex field in its own right. For a more detailed analysis of this topic, see Chen, L., & Flies, D. B., ‘Molecular mechanisms of T cell co-stimulation and co-inhibition’, Nature Reviews Immunology 13, 227–42 (2013).
51 Like so much of immunology, there are exceptions to this statement. These same ‘co-stimulatory proteins’ can also engage inhibitory receptors on T cells to switch them off. The thinking here is that this serves to end the immune response after some time. In other words, the co-stimulatory proteins initially help switch on T cells, but in time they are also involved in switching T cells off when an immune response is no longer needed.
52 Ralph Steinman recalls the motivation behind his work on dendritic cells in an interview for the journal Immunological Reviews, recorded in March 2010. It is available online here: https://www.youtube.com/watch?v=BAn8wEpURtE.
53 Kool, M., et al., ‘Cutting edge: alum adjuvant stimulates inflammatory dendritic cells through activation of the NALP3 inflammasome’, The Journal of Immunology 181, 3755–9 (2008).
54 Interview with Kayo Inaba upon winning the 2014 L’Oréal-UNESCO Award for Asia-Pacific. Video available online here: https://youtube.com/watch?v=pd2tSDy8A3s.
55 In Japan, before working with Steinman, she had already studied dendritic cells and independently discovered their ability to trigger immune responses.
56 Inaba, K., Metlay, J. P., Crowley, M. T., & Steinman, R. M., ‘Dendritic cells pulsed with protein antigens in vitro can prime antigen-specific, MHC-restricted T cells in situ’, The Journal of Experimental Medicine 172, 631–40 (1990).
57 In 2013, one in seven researchers in Japan was female, compared to more than one in three in the UK, for example, as reported in ‘Strengthening Japan’s Research Capacity’, from Kyoto University Gender Equality Promotion Center, available online here: http://www.cwr.kyoto-u.ac.jp/english/introduction.php. The original source of these data is quoted in this report (but available only in Japanese): http://www.stat.go.jp/data/kagaku/kekka/topics/topics80.htm. The topic is also discussed in the Japan Times here: http://www.japantimes.co.jp/news/2014/04/15/national/japans-scientists-just-14-female/#.VZ5fmcvbJaQ.
58 Palucka, K., & Banchereau, J., ‘Cancer immunotherapy via dendritic cells’, Nature Reviews Cancer 12, 265–77 (2012).
59 Engber, D., ‘Is the cure for cancer inside you?’, New York Times Magazine, 21 December 2012.
60 The problem is that if you accidently get exposed to your own blood cells that have been treated in some way, they could cause problems, whereas blood cells from somebody else would normally be destroyed on account of the genetic differences, like in a transplant situation.
61 Steenhuysen, J., & Nichols, M., ‘Insight: Nobel winner’s last big experiment: Himself’, Reuters, 6 October 2011.
62 Engber.
63 Gravitz, L., ‘A fight for life that united a field’, Nature 478, 163–4 (2011).
64 Steenhuysen & Nichols.
65 Gravitz.
66 Steenhuysen & Nichols.
67 Engber.
68 Steenhuysen & Nichols.
69 Engber.
70 Ibid.
71 Steinman (2011).
72 Interview with Andrew MacDonald, 24 August 2015.
73 Tirrell et al.
74 Palucka & Banchereau.
75 Interview with Christian Münz, 28 August 2015.
76 Ibid.
1 Bresalier, M., ‘80 years ago today: MRC researchers discover viral cause of flu’, Guardian, 8 July 2013.
2 I wrote about Macfarlane Burnet’s life and work in detail in Chapter Two of The Compatibility Gene (Allen Lane, 2013).
3 Watts, G., ‘Jean Lindenmann’, Lancet 385, 850 (2015).
4 Ibid.
5 There are lots of places where any scientific journey could be said to have begun: much started with Aristotle, or Darwin, for example. There were hints of cytokines in experiments performed before Lindenmann and Isaacs but because of the depth of their work, and the lucidity of their ideas, they are widely regarded as discoverers of the first cytokine.
6 Andrewes, C. H., ‘Alick Isaacs. 1921–1967’, Biographical Memoirs of Fellows of the Royal Society 13, 205–21 (1967).
7 Edelhart, M., Interferon: The New Hope for Cancer (Orbis, 1982).
8 Findlay, G. M., & MacCallum, F. O., ‘An interference phenomenon in relation to yellow fever and other viruses’, Journal of Pathology and Bacteriology 44, 405–24 (1937).
9 In detail, they used a virus that was inactivated by heat, so that it couldn’t replicate on its own. And they used so-called red blood cell ghosts, which are red blood cells with the haemoglobin removed, so that the cells appear clearer in electron microscope pictures.
10 Pieters, T., Interferon: The Science and Selling of a Miracle Drug (Routledge, 2005).
11 Lindenmann, J., ‘Preface’ in Edelhart.
12 Isaacs, A., & Lindenmann, J., ‘Virus interference. I. The interferon’, Proceedings of the Royal Society of London. Series B, Biological sciences 147, 258–67 (1957); Isaacs, A., Lindenmann, J., & Valentine, R. C., ‘Virus interference. II. Some properties of interferon’, Proceedings of the Royal Society of London. Series B, Biological sciences 147, 268–73 (1957).
13 Pieters.
14 One eminent US scientist who doubted Lindenmann’s and Isaacs’ early evidence for interferon was Howard Temin. An expert in viruses, he went on to share the 1975 Nobel Prize in Physiology or Medicine – with Renato Dulbecco and David Baltimore – for the discovery of reverse transcriptase, a crucial enzyme for many viruses, e. g. HIV. This enzyme refuted a long-standing dogma that information encoded on DNA can be transfered to RNA, but not the other way around. Just like interferon, many scientists doubted the discovery of reverse transcriptase at first.
15 Pieters.
16 Edelhart.
17 Pieters.
18 Hall, S. S., A Commotion in the Blood: Life, Death, and the Immune System (Henry Holt and Company, 1997).
19 Ibid.
20 Interview with Leslie Brent, 23 October 2015.
21 Brent, L., ‘Susanna Isaacs Elmhirst obituary’, Guardian, 29 April 2010.
22 Hall.
23 Pieters.
24 Hall.
25 Isaacs, A., & Burke, D. C., ‘Interferon: A possible check to virus infections’, New Scientist 4, 109–11 (1958).
26 Derek Burke recounts the story of interferon in an online article, ‘The Discovery of Interferon, the First Cytokine, by Alick Isaacs and Jean Lindenmann in 1957’, posted on 14 February 2009, available here: http://brainimmune.com/the-discovery-of-interferon-the-first-cytokine-by-alick-isaacs-and-jean-lindenmann-in-1957/.
27 Pieters.
28 Andrewes.
29 Cantell, K., The Story of Interferon: The Ups and Downs in the Life of a Scientist (World Scientific Publishing Co., 1998).
30 Hall.
31 Only a few viruses can sometimes cause cancer in humans, and these include human papilloma virus (HPV), Epstein–Barr virus (EBV) and human T-lymphotropic virus 1 (HTLV-1). Most people infected with these viruses do not develop cancer.
32 Gresser, I., & Bourali, C., ‘Exogenous interferon and inducers of interferon in the treatment Balb-c mice inoculated with RC19 tumour cells’, Nature 223, 844–5 (1969).
33 Hall.
34 Gresser, I., ‘Production of interferon by suspensions of human leucocytes’, Proceedings of the Society for Experimental Biology and Medicine 108, 799–803 (1961).
35 Cantell.
36 Ibid.
37 Ibid.
38 Pieters.
39 Cantell.
40 At one time, Cantell was flown to Cuba and got to meet Fidel Castro, who set up a Cuban research institute focused on interferon.
41 ‘The Big IF in Cancer’, Time, 31 March 1980.
42 Interview with Jordan Gutterman, 18 January 2016.
43 Gutterman and Lasker would chat on the phone three or four times a week. Once, Lasker phoned Gutterman at around midnight and she wanted to know about prostate cancer. Gutterman was asleep but stirred to answer the phone. ‘Tell me what you know about prostate cancer,’ Lasker said. Half asleep, Gutterman simply replied: ‘It’s more common in men.’
44 Cantell.
45 The chief reason that interferon was hard to purify was that it was only secreted from cells in tiny amounts. This is a characteristic of all cytokines, and that very small quantities still have strong effects in the body.
46 Cantell.
47 Ibid.
48 Herbert Boyer and Stanley Cohen first reported bacteria with genetic information from a different species in 1973. In their case, frog DNA was inserted into bacteria. Before this, in 1972, Paul Berg had combined DNA from different species into what is termed recombinant DNA molecules. Boyer was one of the co-founders of the biotech company Genentech.
49 Human insulin, initially sold as Humulin, was manufactored by Eli Lilly under licence from Genentech. FDA approval was given five months after the application was made, instead of the normal twenty to thirty months; see Lawrence Altman, ‘A new insulin given approval for use in US’, New York Times, 30 October 1982.
50 This uses a type of enzyme called reverse transcriptase, which can convert RNA into DNA, discovered by Howard Temin at the University of Wisconsin–Madison and, independently, by David Baltimore at MIT; the same Howard Temin who had doubted the existence of interferon at first.
51 Nagata, S., et al., ‘Synthesis in E. coli of a polypeptide with human leukocyte interferon activity’, Nature 284, 316–20 (1980).
52 Cantell.
53 Other co-founders of Biogen included Phillip Sharp from MIT, and Nobel laureate Walter Gilbert from Harvard University.
54 Cantell.
55 Ibid.
56 ‘The Big IF in Cancer’, Time, 31 March 1980.
57 Panem, S., The Interferon Crusade (Brookings Institution, 1984).
58 Dickson, D., ‘Deaths halt interferon trials in France’, Science 218, 772 (1982).
59 Panem.
60 Ahmed, S., & Rai, K. R., ‘Interferon in the treatment of hairy-cell leukemia’, Best Practice and Research Clinical Haematology 16, 69–81 (2003).
61 Taniguchi, T., Fujii-Kuriyama, Y., & Muramatsu, M., ‘Molecular cloning of human interferon cDNA’, Proceedings of the National Academy of Sciences USA 77, 4003–6 (1980).
62 Sorg, C., ‘Lymphokines, monokines, cytokines’, Chemical Immunology 49, 82–9 (1990).
63 Interview with Werner Müller, 11 January 2016.
64 Atwood, M., Moral Disorder (Bloomsbury, 2006).
65 Cytokines are hormones in the sense that they are soluble factors produced by one cell which then affect the behaviour of other cells. Characteristics of some cytokines, however, are not usually attributed to hormones: some cytokines act relatively locally in the body; for example, a few are bound to the surface of cells rather than released into the bulk liquid environment, and some cytokines can be produced by many different types of cells.
66 McNab, F., Mayer-Barber, K., Sher, A., Wack, A., & O’Garra, A., ‘Type I interferons in infectious disease’, Nature Reviews Immunology 15, 87–103 (2015).
67 Yan, N., & Chen, Z. J., ‘Intrinsic antiviral immunity’, Nature Immunology 13, 214–22 (2012).
68 Everitt, A. R., et al., ‘IFITM3 restricts the morbidity and mortality associated with influenza’, Nature 484, 519–23 (2012).
69 Ibid.
70 Zhang, Y. H., et al., ‘Interferon-induced transmembrane protein-3 genetic variant rs12252–C is associated with severe influenza in Chinese individuals’, Nature Communications 4, 1418 (2013).
71 Ibid.
72 Interview with Peter Openshaw, 5 January 2016.
73 Chesarino, N. M., McMichael, T. M., & Yount, J. S., ‘E3 Ubiquitin Ligase NEDD4 Promotes Influenza Virus Infection by Decreasing Levels of the Antiviral Protein IFITM3’, PLoS Pathogens 11, e1005095 (2015).
74 If the same enzyme was targeted in humans, there could be side effects because this type of enzyme is involved in the degradation of many other protein molecules, not just the one encoded for in the IFITM3 gene.
75 Obviously, any statements I make regarding medical treatments should not be taken as explicit advice for one’s own medical care. This book describes general principles and ideas which hopefully help one’s understanding of the science behind health issues, but this is not a substitute for specific advice from a physician or general practitioner. More information about the use of interferon in cancer therapies is available here, from Cancer Research UK: http://www.cancerresearchuk.org/about-cancer/cancers-in-general/treatment/cancer-drugs/interferon.
76 Zitvogel, L., Galluzzi, L., Kepp, O., Smyth, M. J., & Kroemer, G., ‘Type I interferons in anticancer immunity’, Nature Reviews Immunology 15, 405–14 (2015).
77 Ibid.
78 Red blood cells are an exception; they are the only cells in our body that can’t produce or respond to a cytokine.
79 Email correspondence with Salim Khakoo, 2 February 2017.
80 Rusinova, I., et al., ‘Interferome v2.0: an updated database of annotated interferon-regulated genes’, Nucleic Acids Research 41, D1040–6 (2013).
81 The stories of how many cytokines were discovered are discussed in detail across several chapters in Smith, K. A. (ed.), A Living History of Immunology. Frontiers in Immunology 6, 502 (2015).
82 The interleukins have been discovered at a rate of about one per year over the last decade, and we were at IL-23 in 2001, for example.
83 Dinarello, C. A., ‘Immunological and inflammatory functions of the interleukin-1 family’, Annual Review of Immunology 27, 519–50 (2009).
84 You may have come across the importance of neutrophils if you or someone you know has had neutropenia. Caused by cancer and some cancer therapies, neutropenia is essentially having low numbers of neutrophils, making a person more susceptible to infections.
85 Brinkmann, V., et al., ‘Neutrophil extracellular traps kill bacteria’, Science 303, 1532–5 (2004).
86 Kolaczkowska, E., & Kubes, P., ‘Neutrophil recruitment and function in health and inflammation’, Nature Reviews Immunology 13, 159–75 (2013).
87 IL-2 has been important in thousands of research studies; in Robert Gallo’s lab at the National Institutes of Health, for example, it allowed the isolation of HIV from T cells.
88 Howard, M., & O’Garra, A., ‘Biological properties of interleukin 10’, Immunology Today 13, 198–200 (1992).
89 Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K., & Muller, W., ‘Interleukin-10–deficient mice develop chronic enterocolitis’, Cell 75, 263–74 (1993).
90 The charity Crohn’s and Colitis UK provides details on these diseases: http://www.crohnsandcolitis.org.uk/
91 ‘Partnership for Public Service, Dr Steven Rosenberg: Saving lives through important breakthroughs in cancer treatment’, Washington Post, 6 May 2015.
92 Fox, T., ‘The federal employee of the year’, Washington Post, 7 October 2015.
93 Rosenberg’s high status is emphasised by the fact that in 1985, he was the cancer expert on the surgical team who operated on President Reagan. At a press conference, it was Rosenberg who said the words which became the headline for newspapers around the world: ‘The president has cancer’. Others on the team presented the details of the president’s condition, but Rosenberg thought it important to use the word cancer, to demystify the word itself and to make the disease less isolating.
94 Hall.
95 Rosenberg, S. A., & Barry, J. M., The Transformed Cell: Unlocking the Mysteries of Cancer (Orion, 1992).
96 Ibid.
97 Rosenberg goes on to say: ‘Now am I going to achieve that goal, I think it’s very unlikely. But can I put a dent into that goal, I think so.’ He says this in an interview in 2007, for Roadtrip Nation, a series of videos in which young people interview people who made careers from things they love. A clip from Rosenberg’s interview is available online here: https://www.youtube.com/watch?v=iNc_nY6nUoI.
98 Rosenberg & Barry.
99 It is possible that small numbers of cancer cells are dealt with more commonly by our immune system without us being aware of it – and we’re not aware of it.
100 Rosenberg & Barry.
101 Ibid.
102 Ibid.
103 Hall.
104 In all the scientific reports discussing this case, Linda Taylor is given the pseudonym Linda Granger, to protect her identity, but she is named as Linda Taylor in some more recent presentations of her case, including the 2015 PBS TV documentary Cancer: The Emperor of all Maladies.
105 Rosenberg & Barry.
106 Rosenberg, S. A., et al., ‘Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer’, New England Journal of Medicine 313, 1485–92 (1985).
107 Rosenberg & Barry.
108 Before Rosenberg knew that Taylor’s treatment had worked, he also treated another patient, given the pseudonym James Jensen. Rosenberg says in his autobiography that he ‘felt desperate, as desperate as I have ever felt in my life’, and he pushed Jensen even harder than he did Taylor, giving him even more infusions of immune cells as well as high doses of IL-2. Jensen’s tumours never disappeared, and he eventually died from his cancer, but his tumours did shrink in response to Rosenberg’s effort.
109 Rosenberg was on the front cover of Newsweek on 19 December 1985. His success was also the lead news item on NBC and ABC news on TV, and front-page news in newspapers across the USA, Europe, China and Japan.
110 Schmeck, H. M., Jr, ‘Cautious optimism is voiced about test cancer therapy’, New York Times, 6 December 1985.
111 Rosenberg & Barry.
112 Burns, K., Cancer: The Emperor of All Maladies (PBS TV, 2015).
113 Rosenberg, S. A., ‘IL-2: the first effective immunotherapy for human cancer’, The Journal of Immunology 192, 5451–8 (2014).
114 Rosenberg & Barry.
115 Ibid.
116 Coventry, B. J., & Ashdown, M. L., ‘The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses’, Cancer Management and Research 4, 215–21 (2012).
1 Feldmann, M., ‘Translating molecular insights in autoimmunity into effective therapy’, Annual Review of Immunology 27, 1–27 (2009).
2 Ibid.
3 Interview with Marc Feldmann, 22 February 2016.
4 Feldmann (2009).
5 Interview with Marc Feldmann, 22 February 2016.
6 Interview with Werner Müller, 11 January 2016.
7 Dinarello, C. A., ‘Historical insights into cytokines’, European Journal of Immunology 37 Suppl 1, S34–45 (2007).
8 Auron, P. E., et al., ‘Nucleotide sequence of human monocyte interleukin 1 precursor cDNA’, Proceedings of the National Academy of Sciences USA 81, 7907–11 (1984).
9 Email correspondence with Werner Müller, 13 January 2016.
10 Lachman, L. B., ‘Summary of the Fourth International Lymphokine Workshop’, Lymphokine Research 4, 51–7 (1985).
11 Interview with Werner Müller, 11 January 2016.
12 Ibid.
13 Lachman.
14 Gannes, S., ‘Striking it rich in biotech’, Fortune Magazine, 9 November 1987. Available online here: http://archive.fortune.com/magazines/fortune/fortune_archive/1987/11/09/69810/index.htm.
15 Interview with Werner Müller, 11 January 2016.
16 Lachman.
17 March, C. J., et al., ‘Cloning, sequence and expression of two distinct human interleukin-1 complementary DNAs’, Nature 315, 641–7 (1985).
18 Wolff, S. M., et al., ‘Clone controversy at Immunex’, Nature 319, 270 (1986).
19 Marshall, E., ‘Battle ends in $21 million settlement’, Science 274, 911 (1996).
20 Ibid.
21 Ibid.
22 ‘Immunex to Pay $21 Million To Cistron to Settle Lawsuit’, Wall Street Journal, 4 November 1996. Available online here: http://www.wsj.com/articles/SB847060346541962500.
23 Marshall.
24 Hamilton, D. P., ‘Amgen Confirms Cash, Stock Deal to Acquire Smaller Rival Immunex’, Wall Street Journal, 18 December 2001. Available online here: http://www.wsj.com/articles/SB1008606575817774000.
25 Feldmann (2009).
26 Bottazzo, G. F., Pujol-Borrell, R., Hanafusa, T., & Feldmann, M., ‘Role of aberrant HLA-DR expression and antigen presentation in induction of endocrine autoimmunity’, Lancet 2, 1115–19 (1983).
27 Interview with Marc Feldmann, 22 February 2016.
28 Data on the prevalence of rheumatoid arthritis is available from the Centers for Disease Control and Prevention, a part of the US Department of Health and Human Services, online here http://www.cdc.gov/arthritis/basics/rheumatoid.htm.
29 Eyre, S., et al., ‘High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis’, Nature Genetics 44, 1336–40 (2012).
30 Heliovaara, M., et al., ‘Coffee consumption, rheumatoid factor, and the risk of rheumatoid arthritis’, Annals of the Rheumatic Diseases 59, 631–5 (2000).
31 Lee, Y. H., Bae, S. C., & Song, G. G., ‘Coffee or tea consumption and the risk of rheumatoid arthritis: a meta-analysis’, Clinical Rheumatology 33, 1575–83 (2014).
32 Feldmann (2009).
33 Uganda became independent in 1962.
34 ‘Spotlight: Ravinder Maini – A Career in Research. An interview with Ravinder Maini’ published on 28 March 2014, in three parts: the first part is available online here: https://www.youtube.com/watch?v=ZJ53ApfoiD8.
35 Interview with Marc Feldmann, 22 February 2016.
36 Interview with Ravinder Maini, 15 February 2016.
37 Feldmann and Maini weren’t the only ones doing this kind of research at the time. Several different research groups across the globe had set out to determine the cytokines present in a diseased joint, often using different methods.
38 TNF-α should have a simpler name, just another numbered interleukin, IL-something, but just like interferon, it was discovered and named before the interleukin classification was in place and its cumbersome name has stuck.
39 Buchan, G., et al., ‘Interleukin-1 and tumour necrosis factor mRNA expression in rheumatoid arthritis: prolonged production of IL-1 alpha’, Clinical and Experimental Immunology 73, 449–55 (1988).
40 Carswell, E. A., et al., ‘An endotoxin-induced serum factor that causes necrosis of tumors’, Proceedings of the National Academy of Sciences USA 72, 3666–70 (1975).
41 Vilček, J., Love and Science: A Memoir (Seven Stories Press, 2016).
42 In 1938, with the security of Jews in Czechoslovakia already in doubt, his family hatched a plan to leave young Vilček with a family in Holland. The plan never materialised. If it had done, Vilček would have suffered the same fate as the Jewish Dutch family he would have been staying with, and they did not survive the Holocaust.
43 While the nuns could not have been Nazi sympathisers – they helped Jewish children – government regulations for the orphanage required Vilček to be taught loyalty to the Nazis.
44 Vilček (2016).
45 Ibid.
46 This was a view advocated by Stalin’s confidant Trofim Lysenko, who claimed that seeds treated with moisture and cold grew better in the Russian frost, and that this benefit passed on to future generations of seeds. Lysenko’s theories are nowadays widely regarded as wrong. Scientists who produced, or faked, evidence to support his ideas were favoured with rewards, recognition and research funding. There is, however, relatively recent evidence that some genetic changes caused by the environment can be passed on from one generation to the next; the emerging field of epigenetics. This does not mean that Lysenko’s ideas were right, because the effects are small and limited. Scientist and broadcaster Adam Rutherford warns against over-hyping epigenetics to a mystical level, in ‘Beware the pseudo gene genies’, Guardian, 19 July 2015. Available online here: https://www.theguardian.com/science/2015/jul/19/epigenetics-dna–darwin-adam-rutherford.
47 Vilček, J., ‘From IFN to TNF: a journey into realms of lore’, Nature Immunology 10, 555–7 (2009). In this article, Vilček recalls meeting Isaacs in 1958. But in discussion with him on 4 February 2016, he now thinks it must have been in 1957, as that was the year he graduated in Bratislava.
48 Interview with Jan Vilček, 4 February 2016.
49 Vilček, J., ‘An interferon-like substance released from tickborne encephalitis virus-infected chick embryo fibroblast cells’, Nature 187, 73–4 (1960).
50 He didn’t like the restrictions on travel that the communist country imposed on him, and had had been called in for a few interviews with the secret police, but says it was his wife who really pushed him to defect.
51 Interview with Jan Vilček, 4 February 2016.
52 Perez-Penauug, R., ‘Research Scientist Gives $105 Million to NYU’, New York Times, 12 August 2005.
53 Interview with Jan Vilček, 4 February 2016.
54 When winning the prestigious Albert Lasker Basic Medical Research Award for this work, César Milstein and Georges Köhler publicly stated that ‘both the conception and execution of the work was the result of close collaboration between us with the skilled technical assistance of Shirley Howe’.
55 Köhler, G., & Milstein, C., ‘Continuous cultures of fused cells secreting antibody of predefined specificity’, Nature 256, 495–7 (1975).
56 Margulies, D. H., ‘Monoclonal antibodies: producing magic bullets by somatic cell hybridization’, The Journal of Immunology 174, 2451–2 (2005).
57 The original agreement with Centocor was based on Vilček producing an antibody against interferon which the company planned to develop into a diagnostic test for levels of interferon in, for example, a blood sample.
58 Vilček was very surprised when he first arrived in New York that he had to obtain all of his own funding to do research. In communist Czechoslovakia, there were many shortages of equipment and suchlike, but each researcher was at least given money for their research, without having to write specific grant applications.
59 With Vilček, Junming Le also shared in the royalties that arose from the anti-TNFα antibody. Le set up the Iris and Junming Le Foundation in 2006, to support various medical and health activities.
60 Marks, L. V., The Lock and Key of Medicine: Monoclonal Antibodies and the Transformation of Healthcare (Yale University Press, 2015).
61 Beutler, B., Milsark, I. W., & Cerami, A. C., ‘Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin’, Science 229, 869–71 (1985).
62 Lagu, T., et al., ‘Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007’, Critical Care Medicine 40, 754–61 (2012).
63 Marks, L., ‘The birth pangs of monoclonal antibody therapeutics: the failure and legacy of Centoxin’, mAbs 4, 403–12 (2012).
64 John Ghrayeb and his team at Centocor did this work, using methods established in 1983–5 by several research teams working independently, involving academic labs in Cambridge (UK), Stanford and Toronto, as well as the US company Becton-Dickinson in California.
65 Vilček (2009).
66 Ibid.
67 Brennan, F. M., Chantry, D., Jackson, A., Maini, R., & Feldmann, M., ‘Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis’, Lancet 2, 244–7 (1989).
68 Interview with Marc Feldmann, 22 February 2016.
69 Williams, R. O., Feldmann, M., & Maini, R. N., ‘Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis’, Proceedings of the National Academy of Sciences USA 89, 9784–8 (1992).
70 As well as work that Feldmann was directly involved with, another line of evidence in support of his ideas came from George Kollias and his colleagues in Greece. They showed that mice genetically engineered to produce human TNFα would develop an inflammation in their joints, consistent with the idea that this cytokine was very important in arthritis.
71 Feldmann (2009).
72 Interview with Jan Vilček, 4 February 2016.
73 Interview with Ravinder Maini, 15 February 2016.
74 Ibid.
75 Feldmann (2009).
76 Feldmann, M., ‘Development of anti-TNF therapy for rheumatoid arthritis’, Nature Reviews Immunology 2, 364–71 (2002).
77 Interview with Jan Vilček, 4 February 2016.
78 Interview with Ravinder Maini, 15 February 2016.
79 Feldmann (2009).
80 Ibid.
81 Interview with Marc Feldmann, 22 February 2016.
82 Vilček (2016).
83 The company obtained approval to use Remicade first for Crohn’s disease, a chronic inflammation in the intestine, and then later for rheumatoid arthritis. No new treatments for Crohn’s disease had been approved for decades. So Crohn’s disease qualified as being a relatively rare disease with few treatment options, which meant that fewer people were required to be tested in a clinical trial before the drug was approved. The paucity of treatments also meant that regulatory review of the drug was prioritised. Overall, this meant that the cost of getting the drug approved for Crohn’s disease was far less than getting it approved for rheumatoid arthritis.
84 Morrow, D. J., ‘Johnson & Johnson to Acquire Centocor’, New York Times, 22 July 1999.
85 Vilček (2016).
86 Feldmann (2009).
87 Feldmann (2002).
88 There are several ways in which fully human antibodies can be made. One way is to use mice which have been modified so that their antibody-making genes have been replaced with human genes. However, Humira, a fully human anti-TNFα antibody approved in the USA in 2002, was made in a different way, using viruses that invade bacteria, by a technique called phage display.
89 Number of users taken from the official website for Remicade: http://www.remicade.com/.
90 White, E. B., Here is New York (Harper & Bros., 1949).
91 Vilček (2016).
92 Interview with Ravinder Maini, 15 February 2016.
93 Choy, E. H., Kavanaugh, A. F., & Jones, S. A., ‘The problem of choice: current biologic agents and future prospects in RA’, Nature Reviews Rheumatology 9, 154–63 (2013).
94 Winthrop, K. L., & Chiller, T., ‘Preventing and treating biologic-associated opportunistic infections’, Nature Reviews Rheumatology 5, 405–10 (2009).
95 Choy et al.
96 ‘Spotlight: Ravinder Maini – A Career in Research. An interview with Ravinder Maini’ published on 28 March 2014, in three parts: the first part is available online here: https://www.youtube.com/watch?v=ZJ53ApfoiD8.
97 Another reason that this may happen for some versions of anti-TNFα therapy is that the body begins to produce antibodies against the therapeutic antibody, which stop it from working.
98 Occasionally, patients with Crohn’s disease have come off treatment with anti-TNFα therapy and not relapsed, but this is rare and the reasons are not understood.
99 Marks (2015).
100 The last line of Milstein’s and Köhler’s paper on the culture of hybridoma cells for the production of monoclonal antibodies, published in Nature in 1975, simply reads: ‘Such cultures could be valuable for medical and industrial use.’ In its simplicity, this is reminiscent of another classic ending to a scientific paper: Watson’s and Crick’s famous line in their description of the double helix structure of DNA, published in Nature in 1973, which reads: ‘It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.’
101 Dorner, T., Radbruch, A., & Burmester, G. R., ‘B-cell-directed therapies for autoimmune disease’, Nature Reviews Rheumatology 5, 433–41 (2009).
102 The World Health Organization’s list of essential medicines can be downloaded here: http://www.who.int/medicines/services/essmedicines_def/en/.
103 Battella, S., Cox, M. C., Santoni, A., & Palmieri, G., ‘Natural killer (NK) cells and anti-tumor therapeutic mAb: unexplored interactions’, Journal of Leukocyte Biology 99, 87–96 (2016).
104 Rudnicka, D., et al., ‘Rituximab causes a polarization of B cells that augments its therapeutic function in NK-cell-mediated antibody-dependent cellular cytotoxicity’, Blood 121, 4694–702 (2013).
105 ‘Drug trial victim’s “hell” months’, BBC News online, http://news.bbc.co.uk/1/hi/health/5121824.stm.
106 Vince, G., ‘UK drug trial disaster – the official report’, New Scientist, 25 May 2006.
107 Horvath, C. J., & Milton, M. N., ‘The TeGenero incident and the Duff Report conclusions: a series of unfortunate events or an avoidable event?’, Toxicologic Pathology 37, 372–83 (2009).
1 Strominger, J. L., ‘The tortuous journey of a biochemist to immunoland and what he found there’, Annual Review of Immunology 24, 1–31 (2006).
2 Bauer, S., et al., ‘Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA’, Science 285, 727–9 (1999).
3 Van der Zee, J., ‘Heating the patient: a promising approach?’, Annals of Oncology 13, 1173–84 (2002).
4 Shen, R. N., Hornback, N. B., Shidnia, H., Shupe, R. E., & Brahmi, Z., ‘Whole-body hyperthermia decreases lung metastases in lung tumor-bearing mice, possibly via a mechanism involving natural killer cells’, Journal of Clinical Immunology 7, 246–53 (1987).
5 Kokolus, K. M., et al., ‘Baseline tumor growth and immune control in laboratory mice are significantly influenced by subthermoneutral housing temperature’, Proceedings of the National Academy of Sciences USA 110, 20176–81 (2013).
6 Evans, S. S., Repasky, E. A., & Fisher, D. T., ‘Fever and the thermal regulation of immunity: the immune system feels the heat’, Nature Reviews Immunology 15, 335–49 (2015).
7 Elinav, E., et al., ‘Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms’, Nature Reviews Cancer 13, 759–71 (2013).
8 Zelenay, S., et al., ‘Cyclooxygenase-Dependent Tumor Growth through Evasion of Immunity’, Cell 162, 1257–70 (2015).
9 Groh, V., Wu, J., Yee, C., & Spies, T., ‘Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation’, Nature 419, 734–8 (2002).
10 Deng, W., et al., ‘Antitumor immunity. A shed NKG2D ligand that promotes natural killer cell activation and tumor rejection’, Science 348, 136–9 (2015).
11 Evans et al.
12 Ibid.
13 Ibid.
14 Lafrance, A., ‘A cultural history of the fever’, Atlantic, 16 September 2015.
15 Evans et al.
16 Rice, P., et al., ‘Febrile-range hyperthermia augments neutrophil accumulation and enhances lung injury in experimental gram-negative bacterial pneumonia’, The Journal of Immunology 174, 3676–85 (2005).
17 In some situations a fever warrants medical attention, such as a fever in a newborn baby. There is plenty of advice on the Internet about fevers but stick to web pages, such as those from the National Health Service in the UK, which present the consensus scientific view.
18 Woolf, V., On Being Ill (Hogarth Press, 1930).
19 Interview with Luke O’Neill, 16 March 2016.
20 Kalinski, P., ‘Regulation of immune responses by prostaglandin E2’, The Journal of Immunology 188, 21–8 (2012).
21 Furuyashiki, T., & Narumiya, S., ‘Stress responses: the contribution of prostaglandin E(2) and its receptors’, Nature Reviews Endocrinology 7, 163–75 (2011).
22 According to the International Aspirin Foundation, aspirin is one of the mostly widely used pharmaceutical drugs in the world, with 100 billion tablets’-worth being produced every year. The story of aspirin is, of course, fascinating in its own right, worthy of a whole book. Briefly, the active ingredient of aspirin is a synthetic version of a chemical found in the willow tree (and other plants). In 1823, a form of aspirin was isolated from willow bark. The pharmaceutical company Bayer made a synthetic version in 1897 and clinical trials began. Aspirin was launched in 1899 and was arguably the first ever drug produced from the pharmaceutical industry. In the 1930s, Bayer’s patents ran out and aspirin became a generic drug. Beginning in 1969, a series of experiments by John Vane working in London, UK, established that aspirin inhibited the production of prostaglandins. Vane tells the story in his Nobel Lecture from 1982, online here: http://www.nobelprize.org/mediaplayer/index.php?id=1615
23 Slocumb, C. H., ‘Philip Showalter Hench, 1896–1965. In Memoriam’, Arthritis and Rheumatism 8, 573–6 (1965).
24 Hench, P. S., ‘The reversibility of certain rheumatic and non-rheumatic conditions by the use of cortisone or of the pituitary adrenocorticotropic hormone’ (Nobel Lecture, 1950) in Nobel Lectures, Physiology or Medicine 1942–1962 (Elsevier, 1964).
25 Tata, J. R., ‘One hundred years of hormones’, EMBO Reports 6, 490–6 (2005).
26 Reichstein also worked out a way to synthesise vitamin C, which helped lead to its mass production. Kendall also isolated hormones from the thyroid, including thyroxine, sometimes known as T4.
27 Reichstein, T., ‘Chemistry of the Adrenal Cortex Hormones’ (Nobel Lecture, 1950) in Nobel Lectures, Physiology or Medicine 1942–1962 (Elsevier, 1964).
28 Kendall, E. C., Cortisone: Memoirs of a Hormone Hunter (Charles Scribner’s Sons, 1971).
29 Rooke, T., The Quest for Cortisone (Michigan State University Press, 2012).
30 Hench.
31 Saenger, A. K., ‘Discovery of the wonder drug: from cows to cortisone. The effects of the adrenal cortical hormone 17–hydroxy-11–dehydrocorticosterone (Compound E) on the acute phase of rheumatic fever; preliminary report. Mayo Clinic Proceedings 1949;24:277–97’, Clinical Chemistry 56, 1349–50 (2010).
32 Le Fanu, J., The Rise and Fall of Modern Medicine (revised edition, Abacus, 2011).
33 Rooke.
34 Ibid.
35 Ibid.
36 Hench.
37 Rooke.
38 Le Fanu.
39 Rooke.
40 Le Fanu.
41 Cortisol is a steroid hormone in the glucocorticoid family, not to be confused with anabolic steroids which are different and are related to the male sex hormone testosterone. Anabolic steroids increase muscle growth and are sometimes illegally used in bodybuilding and sports. Anabolic steroids can also be used therapeutically, to stimulate muscle growth in chronic wasting diseases and in some cases, to help treat breast cancer.
42 Chrousos, G. P., ‘Stress and disorders of the stress system’, Nature Reviews Endocrinology 5, 374–81 (2009).
43 Both cortisone and cortisol are produced as hormones by the adrenal gland in the body: the addition of a hydrogen atom converts cortisone to cortisol, and cortisol is the more potent, or active, version of the hormone.
44 Maisel, A. Q., The Hormone Quest (Random House, 1965).
45 ‘MRC Streptomycin in Tuberculosis Trials Committee. Streptomycin treatment of pulmonary tuberculosis’, British Medical Journal 2, 769–82 (1948).
46 Interview with David Ray, 15 April 2016.
47 Paget, S. A., Lockshin, M. D., & Loebl, S., The Hospital for Special Surgery Rheumatoid Arthritis Handbook (John Wiley & Sons, 2002).
48 High levels of cortisol can induce symptoms known as Cushing’s syndrome. As well as muscle weakness, fatigue and weight gain, these symptoms also can include thinning skin, reddish-purple marks on arms and legs, low libido and fat deposits in the face. As well as these symptoms developing in people taking cortisol or one of its derivatives as a medicine for a long period of time, they can also arise where a tumour develops in one of the body’s glands that produce stress hormones.
49 Rooke.
50 The 153 boxes of items collected by Philip Hench about the history of yellow fever are stored at the University of Virginia. The archive also includes many personal items, such as photographs of Philip Hench with his wife Mary in Havana, and many personal letters and telegrams. Some items have been digitised and are available online here: https://search.lib.virginia.edu/catalog/uva-lib:2513789.
51 Kendall.
52 Selye, H., ‘A syndrome produced by diverse nocuous agents’, Nature 138 (1936).
53 Hans Selye was nominated for a Nobel Prize for many years, by at least seventeen different individuals, but he never won. Details archived here in the ‘Nomination Database’ at nobelprize.org. Nobel Media AB 2014. http://www.nobelprize.org/nomination/archive/show_people.php?id=8395
54 ‘Obituary. Dr Hans Selye dies in Montreal; studied effects of stress on body’, New York Times, 22 October 1982.
55 Fink, G., ‘In retrospect: Eighty years of stress’, Nature 539, 175–6 (2016).
56 Selye, H., The Stress of Life (McGraw-Hill, 1956).
57 ‘Obituary’, New York Times, 22 October 1982.
58 Ibid.
59 There is great diversity in what the word ‘stress’ applies to, and although some aspects of these different stressors are the same, there are also differences. Stress due to divorce doesn’t have the same impact on the body as, for example, stress due to being stuck in a traffic jam, and the situation is even more complicated because everyone responds differently to any given stressor. Nevertheless, there is common ground in the particular hormones involved in stress and because of this, a modern definition of stress includes it being something that stimulates the so-called hypothalamic-pituitary-adrenal axis, which leads to the production of cortisol.
60 Gamble, K. L., Berry, R., Frank, S. J., & Young, M. E., ‘Circadian clock control of endocrine factors’, Nature Reviews Endocrinology 10, 466–75 (2014).
61 Webster, J. I., Tonelli, L., & Sternberg, E. M., ‘Neuroendocrine regulation of immunity’, Annual Review of Immunology 20, 125–63 (2002).
62 Ironson, G., et al., ‘Posttraumatic stress symptoms, intrusive thoughts, loss, and immune function after Hurricane Andrew’, Psychosomatic Medicine 59, 128–41 (1997).
63 Padgett, D. A., & Glaser, R., ‘How stress influences the immune response’, Trends in Immunology 24, 444–8 (2003).
64 I write this as fact, not in advocacy for animal experiments, which is a complex issue widely debated elsewhere.
65 Glaser, R., & Kiecolt-Glaser, J. K., ‘Stress-induced immune dysfunction: implications for health’, Nature Reviews Immunology 5, 243–51 (2005).
66 Rodriguez-Galan, M. C., et al., ‘Immunocompetence of macrophages in rats exposed to Candida albicans infection and stress’, American Journal of Physiology. Cell Physiology 284, C111–18 (2003).
67 Vedhara, K., et al., ‘Chronic stress in elderly carers of dementia patients and antibody response to influenza vaccination’, Lancet 353, 627–31 (1999).
68 Leserman, J., et al., ‘Progression to AIDS: the effects of stress, depressive symptoms, and social support’, Psychosomatic Medicine 61, 397–406 (1999).
69 Cole, S. W., Kemeny, M. E., Taylor, S. E., Visscher, B. R., & Fahey, J. L., ‘Accelerated course of human immunodeficiency virus infection in gay men who conceal their homosexual identity’, Psychosomatic Medicine 58, 219–31 (1996).
70 Glaser & Kiecolt-Glaser.
71 Brod, S., Rattazzi, L., Piras, G., & D’Acquisto, F., ‘“As above, so below” examining the interplay between emotion and the immune system’, Immunology 143, 311–18 (2014).
72 Pesce, M., et al., ‘Positive correlation between serum interleukin-1beta and state anger in rugby athletes’, Aggressive Behaviour 39, 141–8 (2013).
73 Hayashi, T., et al., ‘Laughter up-regulates the genes related to NK cell activity in diabetes’, Biomedical Research 28, 281–5 (2007).
74 Not much is understood about laughter in general, a complex social interaction that we share with all mammals. See, for example, a TED talk by Sophie Scott on ‘Why we laugh’: https://www.ted.com/talks/sophie_scott_why_we_laugh?language=en.
75 Fransen, M., Nairn, L., Winstanley, J., Lam, P., & Edmonds, J., ‘Physical activity for osteoarthritis management: a randomized controlled clinical trial evaluating hydrotherapy or Tai Chi classes’, Arthritis and Rheumatism 57, 407–14 (2007).
76 Yang, Y., et al., ‘Effects of a traditional Taiji/Qigong curriculum on older adults’ immune response to influenza vaccine’, Medicine and Sport Science 52, 64–76 (2008).
77 Ho, R. T., et al., ‘The effect of t’ai chi exercise on immunity and infections: a systematic review of controlled trials’, Journal of Alternative and Complementary Medicine 19, 389–96 (2013).
78 Ibid.
79 Ibid.
80 Ibid.
81 Morgan, N., Irwin, M. R., Chung, M., & Wang, C., ‘The effects of mind–body therapies on the immune system: meta-analysis’, PLoS One 9, e100903 (2014).
82 The NIH and NHS discuss the effects of t’ai chi here: https://nccih.nih.gov/health/taichi/introduction.htm and http://www.nhs.uk/Livewell/fitness/Pages/taichi.aspx.
83 Bhattacharya, A., McCutcheon, E. P., Shvartz, E., & Greenleaf, J. E., ‘Body acceleration distribution and O2 uptake in humans during running and jumping’, Journal of Applied Physiology: Respiratory, Environmental and Exercise Physiology 49, 881–7 (1980).
84 Briskin, S., & LaBotz, M., ‘Trampoline safety in childhood and adolescence’, Pediatrics 130, 774–9 (2012).
85 Saxon, W., ‘Elvin Kabat, 85, Microbiologist Known for Work in Immunology’, New York Times, 22 June 2000.
86 Wax, R., A Mindfulness Guide for the Frazzled (Penguin, 2016).
87 Goyal, M., et al., ‘Meditation programs for psychological stress and well-being: a systematic review and meta-analysis’, JAMA Internal Medicine 174, 357–68 (2014).
88 Kuyken, W., et al., ‘Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomised controlled trial’, Lancet 386, 63–73 (2015).
89 Pickert, K., ‘The art of being mindful’, Time, 3 February 2014.
90 Black, D. S., & Slavich, G. M., ‘Mindfulness meditation and the immune system: a systematic review of randomized controlled trials’, Annals of the New York Academy of Sciences (2016).
91 Ibid.
92 O’Leary, K., O’Neill, S., & Dockray, S., ‘A systematic review of the effects of mindfulness interventions on cortisol’, Journal of Health Psychology (2015).
1 Loudon, A. S., ‘Circadian biology: a 2.5 billion-year-old clock’, Current Biology 22, R570–1 (2012).
2 Cutolo, M., ‘Chronobiology and the treatment of rheumatoid arthritis’, Current Opinion in Rheumatology 24, 312–18 (2012).
3 Foster, R. G., & Kreitzman, L., The Rhythms of Life: The Biological Clocks That Control the Daily Lives of Every Living Thing (Profile Books, 2004).
4 Folkard, S., Lombardi, D. A., & Spencer, M. B., ‘Estimating the circadian rhythm in the risk of occupational injuries and accidents’, Chronobiology International 23, 1181–92 (2006).
5 Foster & Kreitzman (2004).
6 Foster, R. G., & Kreitzman, L., ‘The rhythms of life: what your body clock means to you!’, Experimental Physiology 99, 599–606 (2014).
7 Wright, M. C., et al., ‘Time of day effects on the incidence of anesthetic adverse events’, Quality & Safety in Health Care 15, 258–63 (2006).
8 Bellet, M. M., et al., ‘Circadian clock regulates the host response to salmonella’, American Journal of Physiology. Cell Physiology 110, 9897–902 (2013).
9 Gibbs, J., et al., ‘An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action’, Nature Medicine 20, 919–26 (2014).
10 Scheiermann, C., Kunisaki, Y., & Frenette, P. S., ‘Circadian control of the immune system’, Nature Reviews Immunology 13, 190–8 (2013).
11 Email correspondence with David Ray, 20 April 2016.
12 Email correspondence with Eleanor Riley, 27 May 2016, and Robert Sinden, 10–11 June 2016.
13 Sinden, R. E., Butcher, G. A., Billker, O., & Fleck, S. L., ‘Regulation of infectivity of Plasmodium to the mosquito vector’, Advances in Parasitology 38, 53–117 (1996).
14 Interview with Andrew Loudon, 6 May 2016.
15 Till Roenneberg, speaking at the Euroscience Open Forum, 27 July 2016. Roenneberg is a leading sleep researcher at the Ludwig Maximilian University of Munich, and is also the author of Internal time: Chronotypes, Social Jet Lag, and Why You’re So Tired (Harvard University Press, 2012).
16 Durrington, H. J., Farrow, S. N., Loudon, A. S., & Ray, D. W., ‘The circadian clock and asthma’, Thorax 69, 90–2 (2014).
17 Foster & Kreitzman (2004).
18 Cutolo.
19 Foster & Kreitzman (2004).
20 Litinski, M., Scheer, F. A., & Shea, S. A., ‘Influence of the Circadian System on Disease Severity’, Sleep Medicine Clinics 4, 143–63 (2009).
21 Filipski, E., et al., ‘Effects of chronic jet lag on tumor progression in mice’, Cancer Research 64, 7879–85 (2004).
22 Grundy, A., et al., ‘Increased risk of breast cancer associated with long-term shift work in Canada’, Occupational and Environmental Medicine 70, 831–8 (2013).
23 The UK’s National Health Service discusses the issue here: http://www.nhs.uk/news/2013/07July/Pages/Long-term-night-shifts-can-double-breast-cancer-risk.aspx.
24 Cuesta, M., Boudreau, P., Dubeau-Laramee, G., Cermakian, N., & Boivin, D. B., ‘Simulated Night Shift Disrupts Circadian Rhythms of Immune Functions in Humans’, The Journal of Immunology 196, 2466–75 (2016).
25 Foster, R. G., et al., ‘Circadian photoreception in the retinally degenerate mouse (rd/rd)’, Journal of Comparitive Physiology A 169, 39–50 (1991).
26 Russell Foster interviewed by Marie McNeely, for ‘People behind the science’, 7 March 2016, available online here: http://www.peoplebehindthescience.com/dr-russell-foster/.
27 Freedman, M. S., et al., ‘Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors’, Science 284, 502–4 (1999); Lucas, R. J., Freedman, M. S., Munoz, M., Garcia-Fernandez, J. M., & Foster, R. G., ‘Regulation of the mammalian pineal by non-rod, non-cone, ocular photoreceptors’, Science 284, 505–7 (1999).
28 ‘Newswalk: Sleep scientist Russell Foster on how he stopped seeing life in black and white’, Newsweek, 6 May 2015.
29 O’Neill, J. S., & Reddy, A. B., ‘Circadian clocks in human red blood cells’, Nature 469, 498–503 (2011).
30 Barger, L. K., et al., ‘Prevalence of sleep deficiency and use of hypnotic drugs in astronauts before, during, and after spaceflight: an observational study’, Lancet Neurol 13, 904–12 (2014).
31 Crucian, B. E., et al., ‘Plasma cytokine concentrations indicate that in vivo hormonal regulation of immunity is altered during long-duration spaceflight’, Journal of Interferon and Cytokine Research 34, 778–86 (2014).
32 Crucian, B., et al., ‘Alterations in adaptive immunity persist during long-duration spaceflight’, npj Microgravity 1, 15013 (2015).
33 Exposure to radiation is predicted to cause a slight increase in an astronaut’s lifetime risk of cancer, but this prediction is based on, for example, the occurrence of cancer in survivors of the atomic bomb in Japan, which is not directly comparable.
34 Chang, K., ‘Beings not made for space’, New York Times, 27 January 2014.
35 Interview with Brian Crucian, 24 June 2016.
36 Mehta, S. K., et al., ‘Reactivation of latent viruses is associated with increased plasma cytokines in astronauts’, Cytokine 61, 205–9 (2013).
37 Crucian, B., et al., ‘A case of persistent skin rash and rhinitis with immune system dysregulation onboard the International Space Station’, Journal of Allergy and Clinical Immunology: In Practice 4, 759–762 (2016).
38 Ibid.
39 Ibid.
40 Interview with Brian Crucian, 24 June 2016.
41 Ibid.
42 Durrington et al.
43 Wallace, A., Chinn, D., & Rubin, G., ‘Taking simvastatin in the morning compared with in the evening: randomised controlled trial’, The British Medical Journal 327, 788 (2003).
44 Zhang, R., Lahens, N. F., Ballance, H. I., Hughes, M. E., & Hogenesch, J. B., ‘A circadian gene expression atlas in mammals: implications for biology and medicine’, Proceedings of the National Academy of Sciences USA 111, 16219–24 (2014).
45 Brown, M. T., & Bussell, J. K., ‘Medication adherence: WHO cares?’, Mayo Clinic Proceedings 86, 304–14 (2011).
46 Lin, S., et al., ‘Stretchable Hydrogel Electronics and Devices’, Advanced Materials (2015).
47 In some countries, of course, reaching people in need of a vaccine is still a challenge, never mind vaccinating them at a particular time of day. A blog by Jo Revill, chief executive of the British Society for Immunology, ‘Polio vaccination: Real world challenges and solutions’, 7 June 2016, highlights the difficulties in delivering the polio vaccine to everyone who needs it in remote locations, available online here: http://britsocimmblog.org/polio-vaccination/.
48 Phillips, A. C., Gallagher, S., Carroll, D., & Drayson, M., ‘Preliminary evidence that morning vaccination is associated with an enhanced antibody response in men’, Psychophysiology 45, 663–6 (2008).
49 There are many hints that the immune system does behave slightly differently in men and women. For example, some autoimmune diseases are more frequent in women. This may relate to the effects of hormones on the immune system but research to test this is difficult because gender-based differences could also arise from any number of social, economic or cultural factors.
50 Karabay, O., et al., ‘Influence of circadian rhythm on the efficacy of the hepatitis B vaccination’, Vaccine 26, 1143–4 (2008).
51 Silver, A. C., Arjona, A., Walker, W. E., & Fikrig, E., ‘The circadian clock controls toll-like receptor 9–mediated innate and adaptive immunity’, Immunity 36, 251–61 (2012).
52 ‘Global Health and Aging’, a report from the National Institute on Aging (USA) and World Health Organization, available online here: https://www.nia.nih.gov/research/publication/global-health-and-aging/preface.
53 The Office for National Statistics produces annual population data for the UK, available online here: https://www.ons.gov.uk/peoplepopulationandcommunity/populationandmigration/populationestimates. The charity Age UK also produce a monthly collection of statistics about elderly people, available online here: http://www.ageuk.org.uk/professional-resources-home/.
54 Shaw, A. C., Goldstein, D. R., & Montgomery, R. R., ‘Age-dependent dysregulation of innate immunity’, Nature Reviews Immunology 13, 875–87 (2013).
55 Dorshkind, K., Montecino-Rodriguez, E., & Signer, R. A., ‘The ageing immune system: is it ever too old to become young again?’, Nature Reviews Immunology 9, 57–62 (2009).
56 Treanor, J. J., et al., ‘Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains’, Clinical Infectious Diseases: An official publication of the Infectious Diseases Society of America 55, 951–9 (2012).
57 By midlife, the telomeres of our DNA are roughly half as short as they were at birth, and by sixty-five, our telomeres have shrunk to be half as short again.
58 Harley, C. B., ‘Telomerase and cancer therapeutics’, Nature Reviews Cancer 8, 167–79 (2008).
59 Blackburn, E., & Epel, E., The Telomere Effect: A Revolutionary Approach to Living Younger, Healthier, Longer (Orion Spring, 2017).
60 Carlson, L. E., et al., ‘Mindfulness-based cancer recovery and supportive-expressive therapy maintain telomere length relative to controls in distressed breast cancer survivors’, Cancer 121, 476–84 (2015).
61 There are many different subtypes of apoptosis and understanding cell death is an important area of contemporary research.
62 Munoz-Espin, D., & Serrano, M., ‘Cellular senescence: from physiology to pathology’, Nature Reviews Molecular Cell Biology 15, 482–96 (2014).
63 Baker, D. J., et al., ‘Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders’, Nature 479, 232–6 (2011).
64 Kirkwood, T. B., & Austad, S. N., ‘Why do we age?’, Nature 408, 233–8 (2000).
65 Shaw et al.
66 Discussion with Steve Marsh, 29 April 2016.
67 Sapey, E., et al., ‘Phosphoinositide 3–kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence’, Blood 123, 239–48 (2014).
68 Shaw et al.
69 Jamieson, B. D., et al., ‘Generation of functional thymocytes in the human adult’, Immunity 10, 569–75 (1999).
70 Interview with Janet Lord, 23 June 2016.
71 Mark Davis was one of the pioneers who worked out how T cells detect signs of disease in the body and his work on this is discussed in more detail in my first book, The Compatibility Gene (Allen Lane, 2013).
72 Brodin, P., et al., ‘Variation in the human immune system is largely driven by non-heritable influences’, Cell 160, 37–47 (2015).
73 Brodin, P., & Davis, M. M., ‘Human immune system variation’, Nature Reviews Immunology 17, 21–9 (2017).
74 Furman, D., et al., ‘Cytomegalovirus infection enhances the immune response to influenza’, Science Translational Medicine 7, 281ra243 (2015).
75 Leng, J., et al., ‘Efficacy of a vaccine that links viral epitopes to flagellin in protecting aged mice from influenza viral infection’, Vaccine 29, 8147–55 (2011).
76 Taylor, D. N., et al., ‘Induction of a potent immune response in the elderly using the TLR-5 agonist, flagellin, with a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125, STF2. HA1 SI)’, Vaccine 29, 4897–902 (2011).
77 Long, J. E., et al., ‘Morning vaccination enhances antibody response over afternoon vaccination: A cluster-randomised trial’, Vaccine 34, 2679–85 (2016).
78 Interview with Janet Lord, 23 June 2016.
79 Interview with Akhilesh Reddy, 1 August 2016.
80 Interview with Janet Lord, 23 June 2016.
81 Interview with Arne Akbar, 29 April 2016.
82 Aldrin, B., & Abraham, K., No Dream is Too High: Life Lessons From a Man Who Walked on the Moon (National Geographic, 2016).
1 ‘Autoimmune disease’, Nature Biotechnology 18 Suppl, IT7–9 (2000).
2 Davis, D. M., The Compatibility Gene (Allen Lane, 2013).
3 Anderson, W., & Mackay, I. R., Intolerant Bodies: A Short History of Autoimmunity (Johns Hopkins University Press, 2014).
4 Mackay, I. R., ‘Travels and travails of autoimmunity: a historical journey from discovery to rediscovery’, Autoimmunity Reviews 9, A251–8 (2010).
5 Aoki, C. A., et al., ‘NOD mice and autoimmunity’, Autoimmunity Reviews 4, 373–9 (2005).
6 Interview with Shimon Sakaguchi, 14 July 2016.
7 Nishizuka, Y., & Sakakura, T., ‘Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice’, Science 166, 753–5 (1969).
8 Kojima, A., & Prehn, R. T., ‘Genetic susceptibility to post-thymectomy autoimmune diseases in mice’, Immunogenetics 14, 15–27 (1981).
9 Interview with Shimon Sakaguchi, 14 July 2016.
10 Sakaguchi, S., Takahashi, T., & Nishizuka, Y., ‘Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis’, The Journal of Experimental Medicine 156, 1577–86 (1982).
11 Germain, R. N., ‘Special regulatory T-cell review: A rose by any other name: from suppressor T cells to Tregs, approbation to unbridled enthusiasm’, Immunology 123, 20–7 (2008).
12 Benacerraf, B., ‘Obituary: Richard Gershon, 1932–1983’, The Journal of Immunology 131, 3096–7 (1983).
13 Gershon, R. K., Cohen, P., Hencin, R., & Liebhaber, S. A., ‘Suppressor T cells’, The Journal of Immunology 108, 586–90 (1972).
14 Interview with Shimon Sakaguchi, 14 July 2016.
15 Benacerraf.
16 Waggoner, W. H., ‘Dr Richard Gershon, leader in research on immune system’, New York Times, 13 July 1983.
17 Germain.
18 Interview with Shimon Sakaguchi, 14 July 2016.
19 Ibid.
20 The famous opening line of The Go-Between by L. P. Hartley (Hamish Hamilton, 1953).
21 Kronenberg, M., et al., ‘RNA transcripts for I-J polypeptides are apparently not encoded between the I-A and I-E subregions of the murine major histocompatibility complex’, Proceedings of the National Academy of Sciences USA 80, 5704–8 (1983).
22 Germain.
23 Green, D. R., & Webb, D. R., ‘Saying the “S” word in public’, Immunology Today 14, 523–5 (1993).
24 Bloom, B. R., Salgame, P., & Diamond, B., ‘Revisiting and revising suppressor T cells’, Immunology Today 13, 131–6 (1992).
25 Interview with Fiona Powrie, 16 September 2016.
26 Powrie, F., & Mason, D., ‘OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset’, The Journal of Experimental Medicine 172, 1701–8 (1990).
27 This was useful to do because mice were studied far more commonly than rats and there were many more tools available for studying the mouse immune system.
28 Powrie, F., Leach, M. W., Mauze, S., Caddle, L. B., & Coffman, R. L., ‘Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice’, International Immunology 5, 1461–71 (1993).
29 Morrissey, P. J., Charrier, K., Braddy, S., Liggitt, D., & Watson, J. D., ‘CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells’, The Journal of Experimental Medicine 178, 237–44 (1993).
30 Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., & Toda, M., ‘Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases’, The Journal of Immunology 155, 1151–64 (1995).
31 This discovery has become one of the most highly cited papers in The Journal of Immunology, published since 1916, as noted here: http://www.jimmunol.org/site/misc/Centennial/MostCitedPub.html.
32 Shevach, E. M., ‘Special regulatory T cell review: How I became a T suppressor/regulatory cell maven’, Immunology 123, 3–5 (2008).
33 Shevach had long-term funding from the NIH and so was not reliant on each new idea first needing approval by peer review, as would be the case if his work was funded solely through grant applications.
34 Shevach served as the editor-in-chief at The Journal of Immunology from 1987 to 1992. He describes why he took on the post, and the challenges of being a scientific editor, in an interview for the American Association of Immunologists recorded on 16 December 2015, available online here: https://vimeo.com/158976383. In this interview, Shevach emphasises how it’s important that an editor operates in an impersonal way. As editor, he was not keen to discuss papers with scientists informally over the phone and a policy of the journal at the time was to not publish its phone number. But of course, it was well known that he was the editor and scientists who had their paper rejected by the journal would sometimes even call his home to complain about it. Later the journal published its phone number prominently, so that aggrieved scientists wouldn’t call Shevach or his family at home.
35 Interview with Shimon Sakaguchi, 14 July 2016.
36 Thornton, A. M., & Shevach, E. M., ‘CD4+CD25+ immuno-regulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production’, The Journal of Experimental Medicine 188, 287–96 (1998); Takahashi, T., et al., ‘Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state’, International Immunology 10, 1969–80 (1998).
37 Shevach, E. M., ‘The resurrection of T cell-mediated suppression’, The Journal of Immunology 186, 3805–7 (2011).
38 Shevach, E. M., ‘Certified professionals: CD4(+)CD25(+) suppressor T cells’, The Journal of Experimental Medicine 193, F41–6 (2001).
39 Germain.
40 Ibid.
41 Another view, used in some scientific publications, is that suppressor T cells were not just renamed. Rather, they were cells with specific characteristics which were proved to not exist. With this view, regulatory T cells are not the same as suppressor T cells, but rather cells with different traits, which do exist.
42 In 2016, I asked Sakaguchi if he preferred working on an idea that went against the dogma of the time, or did he prefer it once everyone else had caught up and it became a mainstream research area. He replied that it’s nice that everyone else now realises the importance of regulatory T cells, but on the other hand, when only a few scientists believed in them, it was very easy to follow everything that was going on. ‘Now, I can’t follow all the publications.’
43 Russell, L. B., ‘The Mouse House: a brief history of the ORNL mouse-genetics program, 1947–2009’, Mutation Research 753, 69–90 (2013).
44 Ramsdell, F., & Ziegler, S. F., ‘FOXP3 and scurfy: how it all began’, Nature Reviews Immunology 14, 343–9 (2014).
45 Godfrey, V. L., Wilkinson, J. E., Rinchik, E. M., & Russell, L. B., ‘Fatal lymphoreticular disease in the scurfy (sf) mouse requires T cells that mature in a sf thymic environment: potential model for thymic education’, Proceedings of the National Academy of Sciences USA 88, 5528–32 (1991).
46 Brunkow, M. E., et al., ‘Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse’, Nature Genetics 27, 68–73 (2001).
47 Ramsdell & Ziegler.
48 Bennett, C. L., et al., ‘The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3’, Nature Genetics 27, 20–1 (2001).
49 Sakaguchi, S., Wing, K., & Miyara, M., ‘Regulatory T cells – a brief history and perspective’, European Journal of Immunology 37 Suppl 1, S116–23 (2007).
50 These three scientists together were rewarded for their work with the prestigious 2017 Crafoord Prize, awarded by the the Royal Swedish Academy of Sciences, for which the prize money is 6 million Swedish krona (approximately £550,000): http://www.crafoordprize.se/press/arkivpressreleases/thecrafoordprizeinpolyarthritis2017.5.470b0073156f7766c064a8.html.
51 Hori, S., Nomura, T., & Sakaguchi, S., ‘Control of regulatory T cell development by the transcription factor Foxp3’, Science 299, 1057–61 (2003); Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y., ‘Foxp3 programs the development and function of CD4+CD25+ regulatory T cells’, Nature Immunology 4, 330–6 (2003); Khattri, R., Cox, T., Yasayko, S. A., & Ramsdell, F., ‘An essential role for Scurfin in CD4+CD25+ T regulatory cells’, Nature Immunology 4, 337–42 (2003).
52 Ramsdell & Ziegler.
53 Fiona Powrie’s lecture at the Academy of Medical Sciences, London, 2 December 2014, in memory of Jean Shanks. Available online here: https://www.youtube.com/watch?v=rvEdEw0CU80.
54 Sender, R., Fuchs, S., & Milo, R., ‘Revised Estimates for the Number of Human and Bacteria Cells in the Body’, PLoS Biology 14, e1002533 (2016).
55 Zeevi, D., Korem, T., & Segal, E., ‘Talking about cross-talk: the immune system and the microbiome’, Genome Biology 17, 50 (2016).
56 Arpaia, N., & Rudensky, A. Y., ‘Microbial metabolites control gut inflammatory responses’, Proceedings of the National Academy of Sciences USA 111, 2058–9 (2014).
57 Chang, P. V., Hao, L., Offermanns, S., & Medzhitov, R., ‘The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition’, Proceedings of the National Academy of Sciences USA 111, 2247–52 (2014).
58 Chan, J. K., et al., ‘Alarmins: awaiting a clinical response’, Journal of Clinical Investigation 122, 2711–19 (2012).
59 A BBC documentary about Polly Matzinger, Turned On By Danger, was broadcast in 1997, in the Horizon series.
60 Matzinger, P., ‘Tolerance, danger, and the extended family’, Annual Review of Immunology 12, 991–1045 (1994).
61 Discussion with Polly Matzinger, 14 December 2011.
62 Silverstein, A. M., ‘Immunological tolerance’, Science 272, 1405–8 (1996).
63 Cooper, G., ‘Clever bunny’, Independent, 17 April 1997.
64 Matzinger, P., & Mirkwood, G., ‘In a fully H-2 incompatible chimera, T cells of donor origin can respond to minor histocompatibility antigens in association with either donor or host H-2 type’, The Journal of Experimental Medicine 148, 84–92 (1978).
65 Vance, R. E., ‘Cutting edge commentary: a Copernican revolution? Doubts about the danger theory’, The Journal of Immunology 165, 1725–8 (2000).
66 Schiering, C., et al., ‘The alarmin IL-33 promotes regulatory T-cell function in the intestine’, Nature 513, 564–8 (2014).
67 Martin, N. T., & Martin, M. U., ‘Interleukin 33 is a guardian of barriers and a local alarmin’, Nature Immunology 17, 122–31 (2016).
68 Aune, D., et al., ‘Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies’, The British Medical Journal 343, d6617 (2011).
69 Bollrath, J., & Powrie, F., ‘Feed your Tregs more fiber’, Science 341, 463–4 (2013).
70 Furusawa, Y., et al., ‘Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells’, Nature 504, 446–50 (2013); Arpaia, N., et al., ‘Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation’, Nature 504, 451–5 (2013).
71 Ohnmacht, C., et al., ‘The microbiota regulates type 2 immunity through RORgammat(+) T cells’, Science 349, 989–93 (2015).
72 Strachan, D. P., ‘Hay fever, hygiene, and household size’, The British Medical Journal 299, 1259–60 (1989).
73 Chatila, T. A., ‘Innate Immunity in Asthma’, New England Journal of Medicine 375, 477–9 (2016).
74 Stein, M. M., et al., ‘Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children’, New England Journal of Medicine 375, 411–21 (2016).
75 Ibid.
76 Tanner, L., ‘Can house dust explain why Amish protected from asthma?’, Washington Post, 3 August 2016.
77 Blaser, M., Missing Microbes: How Killing Bacteria Creates Modern Plagues (Oneworld Publications, 2014).
78 Korpela, K., et al., ‘Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children’, Nature Communications 7, 10410 (2016).
79 Ortqvist, A. K., et al., ‘Antibiotics in fetal and early life and subsequent childhood asthma: nationwide population based study with sibling analysis’, The British Medical Journal 349, g6979 (2014).
80 Vatanen, T., et al., ‘Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans’, Cell 165, 842–53 (2016).
81 Hofer, U., ‘Microbiome: Is LPS the key to the hygiene hypothesis?’, Nature Reviews Microbiology 14, 334–5 (2016).
82 Bollrath & Powrie.
83 As Gabriel Núñez from the University of Michigan puts it: ‘The use of probiotics in the clinic has been often associated with controversial or negative results. In my view, these disappointing results reflect the fact that the choice of probiotics has largely relied on empirical results with little or no scientific rationale for the selection of specific bacterial species or strains.’ In Underhill, D. M., Gordon, S., Imhof, B. A., Núnez, G., & Bousso, P., ‘Elie Metchnikoff (1845–1916): celebrating 100 years of cellular immunology and beyond’, Nature Reviews Immunology (2016).
84 Steidler, L., et al., ‘Treatment of murine colitis by Lactococcus lactis secreting interleukin-10’, Science 289, 1352–5 (2000).
85 Horowitz, A., et al., ‘Genetic and environmental determinants of human NK cell diversity revealed by mass cytometry’, Science Translational Medicine 5, 208ra145 (2013).
1 Grady, D., ‘Harnessing the immune system to fight cancer’, New York Times, 30 July 2016.
2 Sharma, P., & Allison, J. P., ‘The future of immune checkpoint therapy’, Science 348, 56–61 (2015).
3 Sharon Belvin, speaking in ‘Advancing the next wave of cancer therapy’, a video from the Cancer Research Insitute, New York. Available online here: http://www.cancerresearch.org/news-publications/video-gallery/advancing-the-next-wave-of-cancer-therapy.
4 ‘A Scientist’s Dream Fulfilled: Harnessing the Immune System to Fight Cancer’, National Public Radio, USA, 9 June 2016. Available online here: http://www.npr.org/sections/health-shots/2016/06/09/480435066/a-scientists-dream-fulfilled-harnessing-the-immune-system-to-fight-cancer.
5 Her physician, Jedd Wolchok, asked Allison to come and visit her in his clinic.
6 Video made to celebrate and describe the research which received the 2015 Lasker DeBakey Clinical Medical Research Award, published on 7 September 2015. Available online here: https://www.youtube.com/watch?v=W8fUAvENkCo&feature=youtu.be.
7 Gross, L., ‘Intradermal Immunization of C3H Mice against a Sarcoma That Originated in an Animal of the Same Line’, Cancer Research 3, 326–33 (1943).
8 Earlier than this, in the 1930s and early 1940s, Peter Gorer, George Snell and others, showed that tumours taken from one mouse would be killed when implanted in a different (unrelated) mouse, but their framework for thinking about this was in terms of transplant rejection, rather than a specific immune response against cancer.
9 Shankaran, V., et al., ‘IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity’, Nature 410, 1107–11 (2001).
10 Coulie, P. G., Van den Eynde, B. J., van der Bruggen, P., & Boon, T., ‘Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy’, Nature Reviews Cancer 14, 135–46 (2014).
11 Radiation therapy was introduced soon after, in 1896, which was more easily administered and offered more consistent results. This was probably one of the reasons that Coley’s toxins were not used or studied as widely as they might have been at another time.
12 Engelking, C., ‘Germ of an idea: William Coley’s cancer-killing toxins’, Discover Magazine, April 2016.
13 Cancer Research UK, ‘What is Coley’s toxins treatment for cancer?’ Available online here: http://www.cancerresearchuk.org/about-cancer/cancers-in-general/cancer-questions/coleys-toxins-cancer-treatment.
14 ‘Science Webinar: Targeting Cancer Pathways, Part 5: Understanding Immune Checkpoints’, 19 January 2016. Available online: http://webinar.sciencemag.org/webinar/archive/part-5–targeting-cancer-pathways.
15 Video made to celebrate and describe the research which received the 2015 Lasker DeBakey Clinical Medical Research Award, published on 7 September 2015. Available online here: https://www.youtube.com/watch?v=W8fUAvENkCo&feature=youtu.be.
16 ‘The Journal of Clinical Investigations’ Conversations with Giants in Medicine: James Allison’, 4 January 2016. Available online here: https://www.youtube.com/watch?v=yCi0bUDR7KA.
17 A line attributed to the Chinese philosopher Lao Tzu.
18 Without this second signal from co-stimulatory proteins to signify the presence of germs, T cells that receive a signal through their T cell receptor don’t just not react, they become desensitised, or anergic, so that they are unable to participate in an immune response. This helps safeguard T cells from reacting to healthy cells and tissues. Ronald Schwartz and Marc Jenkins at the National Institutes of Health in the USA, as well as many others, established this.
19 Grady.
20 Brunet, J. F., et al., ‘A new member of the immunoglobulin superfamily – CTLA-4’, Nature 328, 267–70 (1987).
21 Bluestone, J. A., ‘CTLA-4Ig is finally making it: a personal perspective’, American Journal of Transplantation 5, 423–4 (2005).
22 Prasad, V., ‘The Folly of Big Science Awards’, New York Times, 3 October 2015.
23 Littman, D. R., ‘Releasing the Brakes on Cancer Immunotherapy’, Cell 162, 1186–90 (2015).
24 Price, P., ‘Tested: A reboot for the immune system’, Popular Science, 15 March 2010.
25 Walunas, T. L., et al., ‘CTLA-4 can function as a negative regulator of T cell activation’, Immunity 1, 405–13 (1994).
26 Interview with Jeffrey Bluestone, 23 November 2016.
27 Laurie Glimcher and Abul Abbas.
28 Interview with Jeffrey Bluestone, 23 November 2016.
29 Discussion with Matthew ‘Max’ Krummel, 21 September 2016.
30 Interview with Matthew ‘Max’ Krummel, 28 October 2016.
31 Krummel, M. F., & Allison, J. P., ‘CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation’, The Journal of Experimental Medicine 182, 459–65 (1995).
32 A technical detail here is that Bluestone’s and Allison’s teams tried to resolve this issue by comparing what happened when they used different forms of the antibody, including fragments of it, so-called Fab fragments, which are unlikely to trigger the receptor and more likely to block it.
33 Tivol, E. A., et al., ‘Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4’, Immunity 3, 541–7 (1995); Waterhouse, P., et al., ‘Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4’, Science 270, 985–8 (1995).
34 Krummel, M. F., Sullivan, T. J., & Allison, J. P., ‘Superantigen responses and co-stimulation: CD28 and CTLA-4 have opposing effects on T cell expansion in vitro and in vivo’, International Immunology 8, 519–23 (1996).
35 Allison, J. P., ‘Checkpoints’, Cell 162, 1202–5 (2015).
36 Leach, D. R., Krummel, M. F., & Allison, J. P., ‘Enhancement of antitumor immunity by CTLA-4 blockade’, Science 271, 1734–6 (1996).
37 ‘The Journal of Clinical Investigations’ Conversations with Giants in Medicine: James Allison’, 4 January 2016. Available online here: https://www.youtube.com/watch?v=yCi0bUDR7KA.
38 Allison.
39 ‘The 2013 Novartis Prize for Clinical Immunology’, Cancer Immunology Research 1, 285–7 (2013).
40 Video made to celebrate and describe the research which received the 2015 Lasker DeBakey Clinical Medical Research Award, published on 7 September 2015. Available online here: https://www.youtube.com/watch?v=W8fUAvENkCo&feature=youtu.be.
41 ‘The Journal of Clinical Investigations’ Conversations with Giants in Medicine: James Allison’, 4 January 2016. Available online here: https://www.youtube.com/watch?v=yCi0bUDR7KA.
42 Littman.
43 Ibid.
44 Hoos, A., ‘Development of immuno-oncology drugs – from CTLA4 to PD1 to the next generations’, Nature Reviews Drug Discovery 15, 235–47 (2016).
45 Wolchok, J. D., et al., ‘Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria’, Clinical Cancer Research 15, 7412–20 (2009).
46 Hoos.
47 Littman.
48 Hoos.
49 ‘OncoImmune Announces Option and License Agreement with Pfizer Inc.’, company announcement, 15 September 2016. Available online here: http://announce.ft.com/detail?dockey=600–201609150900BIZWIRE_USPRX_____BW5151–1.
50 Morse, A., ‘Bristol to Acquire Medarex’, Wall Street Journal, 23 July 2009.
51 Hodi, F. S., et al., ‘Improved survival with ipilimumab in patients with metastatic melanoma’, New England Journal of Medicine 363, 711–23 (2010).
52 Schadendorf, D., et al., ‘Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma’, Journal of Clinical Oncology 33, 1889–94 (2015).
53 Sondak, V. K., Smalley, K. S., Kudchadkar, R., Grippon, S., & Kirkpatrick, P., ‘Ipilimumab’, Nature Reviews Drug Discovery 10, 411–12 (2011).
54 Sales of Yervoy in 2015 reported by Bristol-Myers Squibb are available online here: https://www.bms.com/ourcompany/Pages/keyfacts.aspx.
55 Hoos.
56 Video made to celebrate and describe the research which received the 2015 Lasker DeBakey Clinical Medical Research Award, published on 7 September 2015. Available online here: https://www.youtube.com/watch?v=W8fUAvENkCo&feature=youtu.be.
57 Ishida, Y., Agata, Y., Shibahara, K., & Honjo, T., ‘Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death’, EMBO Journal 11, 3887–95 (1992).
58 Nishimura, H., Nose, M., Hiai, H., Minato, N., & Honjo, T., ‘Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor’, Immunity 11, 141–51 (1999).
59 Okazaki, T., & Honjo, T., ‘PD-1 and PD-1 ligands: from discovery to clinical application’, International Immunology 19, 813–24 (2007).
60 Hoos.
61 Robert, C., et al., ‘Pembrolizumab versus Ipilimumab in Advanced Melanoma’, New England Journal of Medicine 372, 2521–32 (2015).
62 Ansell, S. M., et al., ‘PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma’, New England Journal of Medicine 372, 311–19 (2015).
63 Long, E. O., ‘Negative signaling by inhibitory receptors: the NK cell paradigm’, Immunolical Reviews 224, 70–84 (2008).
64 Interview with Eric Vivier, 4 October 2016.
65 Meng, X., Huang, Z., Teng, F., Xing, L., & Yu, J., ‘Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy’, Cancer Treatment Reviews 41, 868–76 (2015).
66 Qureshi, O. S., et al., ‘Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4’, Science 332, 600–3 (2011).
67 Schneider, H., et al., ‘Reversal of the TCR stop signal by CTLA-4’, Science 313, 1972–5 (2006).
68 Davis, D. M., ‘Mechanisms and functions for the duration of intercellular contacts made by lymphocytes’, Nature Reviews Immunology 9, 543–55 (2009).
69 Email correspondence with Christopher Rudd, 25 October 2016.
70 Schneider, H., & Rudd, C. E., ‘Diverse mechanisms regulate the surface expression of immunotherapeutic target ctla-4’, Frontiers in Immunology 5, 619 (2014).
71 Moynihan, K. D., et al., ‘Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses’, Nature Medicine (2016).
72 Sean Parker is interviewed in ‘NBC Dateline On Assignment: Hacking Cancer’, 22 May 2016. Available online here: http://www.nbcnews.com/feature/on-assignment/hacking-cancer-n575756.
73 Tom Hanks interviewed for 1WMN TV in ‘Sean Parker and the Parker Foundation Launch the Parker Institute For Cancer Immunotherapy’, 14 April 2016. Available online here: https://www.youtube.com/watch?v=guVIGDc4z6o.
74 Cha, A. E., ‘Sean Parker, Silicon Valley’s bad boy genius, wants to kick the *!$% out of cancer’, Washington Post, 15 April 2016.
75 Leaf, C., ‘Can Sean Parker hack cancer?’, Fortune magazine, 22 April 2016. Available online here: http://fortune.com/digital-health-sean-parker-cancer/.
76 Parker, S., ‘Sean Parker: Philanthropy for Hackers’, Wall Street Journal, 26 June 2015.
77 Interview with Lewis Lanier, 8 November 2016.
78 Interview with Jeffrey Bluestone, 23 November 2016.
79 Interview with Lewis Lanier, 8 November 2016.
80 Jeff Bluestone said this during a speech at Dreamtalk, ‘Using Yourself to Beat Cancer and How We Will Beat Zika’, 16 October 2016. Available online here: https://www.youtube.com/watch?v=eXAcSloGVGA.
81 Rosenberg, S. A., & Restifo, N. P., ‘Adoptive cell transfer as personalized immunotherapy for human cancer’, Science 348, 62–8 (2015).
82 Porter, D. L., Levine, B. L., Kalos, M., Bagg, A., & June, C. H., ‘Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia’, New England Journal of Medicine 365, 725–33 (2011).
83 Zelig Eshar first published the use of T cells genetically modified to contain an antibody-like receptor in 1989, and this was soon followed by work from Leroy Hood and colleagues, published in 1990. Eshar, from the Weizmann Institute in Israel, continued to develop CAR T cells and was influenced by a year-long sabbatical he took in 1990 to work with Steven Rosenberg at the National Institutes of Health, USA.
84 Gill, S., & June, C. H., ‘Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies’, Immunological Reviews 263, 68–89 (2015).
85 Anonymous, ‘Penn Medicine Patient Perspective: I was sure the war was on. I was sure CLL cells were dying’, 10 August 2011. Available online here: http://www.uphs.upenn.edu/news/News_Releases/2011/08/t-cells/perspective.html.
86 Ellebrecht, C. T., et al., ‘Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease’, Science 353, 179–84 (2016).
87 Using, for example, the revolutionary genome-editing tool known as CRISPR–Cas9. Doudna, J., & Sternberg, S., A Crack in Creation: The New Power to Control Evolution (The Bodley Head, 2017).
88 Brynner, R., & Stephens, T., Dark Remedy: The Impact of Thalidomide and its Rival as a Vital Medicine (Basic Books, 2001).
89 Soon after, in the 1970s, other drugs proved to be more effective. The World Health Organization does not recommend the use of thalidomide for leprosy but sadly, some thalidomide babies are still born each year due to inappropriate use of the drug. Details are here: http://www.who.int/lep/research/thalidomide/en/.
90 Zeldis, J. B., Knight, R., Hussein, M., Chopra, R., & Muller, G., ‘A review of the history, properties, and use of the immunomodulatory compound lenalidomide’, Annals of the New York Academy of Sciences 1222, 76–82 (2011).
91 Lagrue, K., Carisey, A., Morgan, D. J., Chopra, R., & Davis, D. M., ‘Lenalidomide augments actin remodeling and lowers NK-cell activation thresholds’, Blood 126, 50–60 (2015).
92 Many lessons can be learnt from how the world reacted to the 2013–16 outbreak of Ebola. Several articles and books discuss this, such as Evans, N. G., Smith, T. C., & Majumder, M. S. (eds), Ebola’s Message (MIT Press, 2016).