p53
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The most important sources for the finding of the first tumour-suppressor gene are the MIT conversation with Weinberg cited above and Natural Obsessions: striving to unlock the deepest secrets of the cancer cell, by Natalie Angier (Boston: Houghton Mifflin, 1999).
Chapter 8: p53 Reveals its True Colours
The epigraph from Francis Crick, co-discoverer with James Watson of the double-helix structure of DNA, comes from The Eighth Day of Creation, page 93.
Suzy Baker tells her story in S. J. Baker (2003), Redefining p53: Entering the Tumor Suppressor Era. Cell Cycle, Volume 2, pages 7-8.
Chapter 9: Master Switch
The epigraph from Matt Ridley comes from his book, Genome: the autobiography of a species in 23 chapters, page 271. Reprinted by permission of HarperCollins Publishers Ltd © 1999 Matt Ridley.
Besides the personal interviews, this chapter relied heavily on the book 25 Years of p53 Research, cited at the beginning of these notes.
Chapter 10: ‘Guardian of the Genome’
The epigraph from David Lane comes from his commentary, ‘Worrying about p53’, in Current Biology, Vol. 2 (1992), pages 581-583.
Chapter 11: Of Autumn Leaves and Cell Death
The epigraph comes from The Man Without Qualities, a novel by the Austrian Robert Musil, unfinished at the time of his death in 1942 and published posthumously (London: Pan Macmillan, 1997, translated by Sophie Wilkins and Burton Pike).
John Kerr’s own paper, ‘History of the events leading to the formulation of the apoptosis concept’, published in Toxicology, Volumes 181-182 (2002), pages 471-474, was a key resource.
The interview with Richard Lockshin appears in R. A. Lockshin (2008), Early work on apoptosis, an interview with Richard Lockshin. Cell Death and Differentiation, Volume 15, pages 1091–95.
Chapter 12: Of Mice and Men
The epigraph comes from The Eighth Day of Creation, page 73.
A key resource for this chapter was the archive of the Nobel Foundation, which awarded the 2007 Prize for Medicine to Mario Capecchi, Oliver Smithies and Martin Evans for their work on transgenic mice. See www.nobelprize.org/nobel_prizes/medicine/laureates/2007/
Another important source of information was the National Human Genome Research Institute. See www.genome.gov/10005834
Chapter 13:The Guardian’s Gatekeeper
The epigraph from Gerard Evan comes from my interview with him in Cambridge, England, in June 2012.
Besides the personal interviews, this chapter relied heavily on the book 25 Years of p53 Research, cited at the beginning of these notes. See especially Chapter 4: Gatekeepers of the Guardian: p53 regulation by post-translational modification, MDM2 and MDMX, by Geoffrey Wahl, Jayne Stommel, Kurt Krummel and Mark Wade.
Chapter 14: The Smoking Gun
The epigraph from Siddhartha Mukherjee comes from his book The Emperor of All Maladies: a biography of cancer, page 241. Reprinted by permission of HarperCollins Publishers © 2011 Siddhartha Mukherjee.
For information on Richard Doll and his research, I drew on two main sources: Life of A Revolutionary, by Jonathan Wood, a review of Conrad Keating’s biography of Doll that appeared as an ‘Oxford Science Blog’ from the University of Oxford on 11th November 2009, available at www.ox.ac.uk/media/science_blog/091111.html, and Doll’s paper in the British Medical Journal of 30th September 1950: ‘Smoking and carcinoma of the lung: preliminary report’ by Richard Doll and A. Bradford Hill.
Information on Angel Roffo is drawn from ‘Angel H Roffo: the forgotten father of experimental tobacco carcinogenesis’ by Robert Proctor (2006), in Bulletin of the World Health Organization, Volume 84, pages 494–96.
A rich source of information for this chapter was the wealth of original documents that the tobacco industry was obliged by US law to make public and which are available online at tobaccodocuments.org. See especially tobaccodocuments.org/profiles/roffo_ah.html and tobaccodocuments.org/atc/60359252.html#images
The Legacy Tobacco Documents Library, developed and managed by the University of California, San Francisco, also has more than 14 million documents available for scrutiny at http://legacy.library.ucsf.edu/
A key source for this chapter was the paper by Asaf Bitton and colleagues (including Stanton Glantz) in The Lancet of January 2005 (pages 531–540): ‘The p53 tumour suppressor gene and the tobacco industry: research, debate and conflict of interest’.
See also the interview with Glantz in Frontline: Inside the Tobacco Deal. Available at www.pbs.org/wgbh/pages/frontline/shows/settlement/interviews/glantz.html. Copyright © 1995–2014 WGBH Education Foundation. See also The Cigarette Papers, edited by Stanton A. Glantz et al., 1998 (University of California Press)
For the p53 database see http://p53.iarc.fr/
Chapter 15: Following the Fingerprints
The quotation by Isaac Asimov, American biochemist and science writer, used for the epigraph is of unknown origin, but widely used.
For this chapter I relied on two key documents: ‘A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma’ by Douglas E. Brash et al., in PNAS, Vol. 88, pages 10124–28, November 1991 and ‘Sunlight and Skin Cancer’ by David J. Leffell and Douglas E. Brash, in Scientific American, Vol. 275, 52–59, reproduced with permission copyright © 1996 Scientific American, inc. All Rights Reserved.
Chapter 16: Cancer in the Family
The epigraph from Patricia Prolla comes from my interview with her, Porto Alegre, Brazil, 2012.
Chapter 17: The Tropeiro Connection?
The epigraph is from the Polish-born physicist Marie Curie, famed for her pioneering work on radioactivity in the early 20th century.
Chapter 18: Jekyll and Hyde
The epigraph from James Watson, American molecular biologist best known as co-discoverer with Francis Crick of the double-helix structure of DNA, comes from The Eighth Day of Creation, page 27.
An important reference document for this chapter was ‘Mutant p53 Gain-of-Function in Cancer’ by Moshe Oren and Varda Rotter, in Cold Spring Harbor Perspectives in Biology, 2010, Volume 2, a001107. Available at cshperspectives.com/content/2/2/a001107.full
For the information on Stanley Prusiner, I relied on the archive of the Nobel Foundation, which awarded him the Prize for Medicine in 1997. See www.nobelprize.org/nobel_prizes/medicine/laureates/1997
Other key references were two papers, published simultaneously in the same journal, Cell, Volume 119, 2004, by Tyler Jacks and Gigi Lozano and their colleagues: ‘Mutant p53 Gain of Function in Two Mouse Models of Li-Fraumeni Syndrome’ by Kenneth P Olive et al. (847–860) and ‘Gain of Function of a p53 Hot Spot Mutation in a Mouse Model of Li-Fraumeni Syndrome’ by Gene A Lang et al. (861–872).
See also ‘Mutant p53: one name, many proteins’ by William A. Freed-Pastor and Carol Prives, in Genes and Development, 2012, Volume 26, 1268–86.
Chapter 19: Cancer and Ageing – a Balancing Act?
The epigraph from John Maddox, editor emeritus of Nature, comes from his introduction to The Eighth Day of Creation by Horace Freeland Judson, page xii.
Key sources for this chapter were ‘Using Mice to Examine p53 Function in Cancer, Aging, and Longevity’ by Lawrence A. Donehower, Cold Spring Harbor Perspectives in Biology, 2009, 1:a001081, see http://cshperspectives.cshlp.org; ‘Two faces of p53: aging and tumour suppression’ by Francis Rodier et al. in Nucleic Acids Research, 2007, Vol. 35, pages 7475–84; ‘Modulation of mammalian life span by the short isoform of p53’ by Bernhard Maier et al. Genes and Development, 2004, Volume 18, pages 306-19. Video recording of Dr Brian Kennedy, CEO of the Buck Institute for Research on Aging in Novato, California, in conversation with Judith Campisi, 5th February 2013, available at http://vimeo.com/58981629.
Chapter 20:The Treatment Revolution
The epigraph comes from Sharon Begley’s article ‘The Cancer Killer’ in Newsweek, January 13, 1997.
This chapter relied heavily on t
he book p53 in the clinic, edited by Pierre Hainaut, Magali Olivier and Klas Wiman (Dordrecht, Netherlands: Springer, 2013).
Other important sources were:
p53-based Cancer Therapy by David P. Lane, Chit Fang Cheok and Sonia Lain, in Cold Spring Harbor Perspectives in Biology, 2010, 2: a001222. See http://cshperspectives.cshlp.org.
‘Cancer Specific Viruses and the Development of ONYX- 015’ by Frank McCormick, in Cancer Biology & Therapy 2, Suppl. 1, 2003, 157-160.
‘Clinical Trials with Oncolytic Adenovirus in China’ by Wang Yu and Hu Fang, in Current Cancer Drug Targets, 2007, 7, 659–670.
‘MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines’ by Hege O. Ohnstad et al. in BMC Cancer 2011, 11, 211.
‘An evaluation of small-molecule p53 activators as chemoprotectants ameliorating adverse effects of anticancer drugs in normal cells’ by Ingeborg M. M. van Leeuwen et al. in Cell Cycle, 2012, 11, 1851-61.
‘Cyclotherapy: opening a therapeutic window in cancer treatment’ by Ingeborg M. M. van Leeuwen, in Oncotarget, 2012, 3, 596–600.
Talk by Gerard Evan, entitled ‘Cancer isn’t mysterious’, to staff at Cancer Research UK in September 2012. Available at www.frequency.com/video/cruk-passion-ta/59881838.
Acknowledgements
This book might never have got off the ground if the Pathological Society of Great Britain and Ireland had not been prepared to support the proposition that even the toughest science deserves a popular audience. I am extremely grateful for their financial contribution to my research, and for the enthusiasm of the board for the project. In particular I should like to thank Peter Hall, who first suggested this book and who sat with me for a couple of days in his office at Queen’s University, Belfast, drawing up a timeline for the history of p53, and Alastair Burt and Simon Herrington, who championed the idea with the Path Soc committee.
My sincere thanks are due also to the following people: Anna Day of Dundee University, who got the project under way; The Society of Authors, whose research bursary enabled me to set off on my travels; my agent, Donald Winchester of Watson Little Ltd, for his quiet encouragement, sure instinct and always good advice; Jim Martin of Bloomsbury Sigma for his enthusiasm and commitment to the story and my editor Caroline Taggart for her keen eyes and good suggestions; Suzanne Cherney, one of the best editors WHO ever had, for her skilful reading of the manuscript and excellent comments (and as much as anything for the long friendship and the laughter); my friend and fellow writer Claire Bell for her support during the writing and wise feedback at a critical moment; my translators in Brazil, Fernanda Paschoal Fortes (who introduced me to caipirinhas!) and Henrique Campos Galvão; and Elizabeth Garret for her generous hospitality at the perfect writer’s retreat, Cliff Cottage on the ragged Aberdeenshire coast. Special thanks are due also to my partner, Fred Bridgland, whose constant support, listening ear and understanding of a fellow writer’s obsession are deeply appreciated.
I am hugely grateful to the many scientists who gave me their time and shared with me something of their personal journeys in science and the highs and lows of their research. Among them I owe a particular debt of gratitude to Pierre Hainaut, without whose advice, guidance and readiness to clarify some extremely complex science from time to time I would have struggled mightily. My understanding of the p53 story was greatly enhanced by conversation and communication with a number of people whose names do not appear in these pages, and to whom I extend my thanks. They include Walter Bodmer, Jean-Christophe Bourdon, Xin Lu, David Meek, Thea Tlsty, Karen Vousden and Geoff Wahl. I am grateful also to the following for their kind permission to use short quotations of theirs from other sources: Suzy Baker, Bill Bryson, Judith Campisi, Richard Lockshin, Matt Ridley and Bob Weinberg.
Finally, I should like to express my special thanks to Luana Locke, John Berkeley and the families affected by Li-Fraumeni syndrome in Brazil whose poignant stories of life in the shadow of cancer shift the focus of attention from the scientists’ laboratories to the outside world, and serve to underline just how important p53 research is to us all.
Sue Armstrong, August 2014
Endnotes
1. A free database of references to papers on life sciences and biomedical topics set up in 1996]
2. When the electron microscope was developed in 1931, virus particles could be seen for the first time.
3. ‘A virus is nothing but a package of genes inside some proteins. So whether it’s alive or not is kind of debatable. It’s either a kind of a complex chemical or a very simple life form,’ says Jeffery Taubenberger, Senior Investigator in the Laboratory of Infectious Diseases at the National Institute for Allergy and Infectious Diseases, Bethesda, Maryland.
4. A postdoctoral scholar (‘postdoc’) is an individual with a doctoral degree who’s engaged in a temporary period of mentored research and/or scholarly training in order to acquire the professional skills needed for his or her future career.
5. The others were teams led by Mariano Barbacid at the National Cancer Institute, Bethesda, and Michael Wigler at Cold Spring Harbor.
6. A somatic mutation is a mutation in a mature cell that has occurred spontaneously during the course of life, as opposed to a mutation that is inherited and will be present in all the cells, both normal and cancerous.
7. The read-out of a procedure that looks at isolated bits of DNA.
8. In fact, the first ever transgenic mouse was created in 1982 by Richard Palmiter and Ralph Brinster working at the Universities of Washington and Pennsylvania respectively. But genetic modification was made a great deal easier and more precise by the technology that won Capecchi and Smithies their Nobel Prize.
9. A lipoprotein is a combination of a fat and protein molecule. The protein helps to transport fat to where it is needed in the body.
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