***
Such screens have still to be widely validated and refined before they reach the clinic. However, many scientists working on the front line of p53 believe we are on the threshold of a golden age in cancer prevention and cure. In coming years we should expect to see:
• gene therapy become routine treatment for cancer as researchers perfect the technique for modifying viruses as delivery vehicles (dozens of people with diverse genetic disorders have already been treated successfully);
• more widespread use of genetic analysis of tumours, and the status of p53 being used to determine the best course of treatment and to predict outcomes and long-term prognosis;
• a dramatic decrease in side effects of cancer therapy as treatment becomes more accurately and exclusively targeted at tumour cells, and as strategies such as cyclotherapy are used to protect the body’s normal cells;
• a variety of p53-based drugs for use in different circumstances that are able to manipulate the tumour-suppressor pathway to kill cancer cells.
‘I’m very, very optimistic,’ said Gerard Evan. ‘I think we’re going to see dramatic shifts in our ability to treat and contain human cancers over the next 10, 15, 20 years.’ And he added, perhaps provocatively, ‘My daughter is 22 and my son is 21, and I can pretty confidently say they will never, ever have to worry about dying from cancer.’
Dramatis Personae
Note: these thumbnail biographies do not include all the people mentioned in this book, but are intended as an aide-memoire to some key players whose names appear frequently and sometimes out of context.
EVAN, GERARD
A scientist with Cancer Research UK (CRUK), now based at Cambridge University as Professor of Biochemistry. An early enthusiast for the use of mouse models to find out how things work in living organisms, he is renowned as an original thinker whose work frequently challenges mainstream thinking. We meet him first in Chapter 1, making the provocative comments about the rarity of cancer.
HAINAUT, PIERRE
Based at the World Health Organization’s International Agency for Research on Cancer (IARC) in Lyon, France, for many years, Hainaut ran the mutant p53 database – a detailed record of all the different mutants appearing in the literature and how they behave. A natural-born detective, he has a special interest in tracing the distribution and pattern of disease caused by mutant p53 among people throughout the world.
HALL, PETER
A Professor of Pathology and close colleague of one of p53’s discoverers, David Lane, at Dundee University, Scotland, in the 1990s. p53 has been one of Hall’s main research interests. Especially renowned for the maverick experiment he cooked up with Lane in a Dundee pub to test the effects of radiation on p53 in living organisms.
KNUDSON, ALFRED
The US-based cancer geneticist who first hypothesised the presence in our cells of genes whose job is to protect us from cancer. The ‘two-hit’ hypothesis of 1971, which grew out of Knudson’s work with children with the eye tumour retinoblastoma, changed forever the way in which cancer biologists viewed the process of tumour formation.
LANE, DAVID
A central character in the story of p53 as one of four people who, working entirely independently, discovered the gene in 1979. Lane was then at the ICRF (Imperial Cancer Research Fund, now known as Cancer Research UK) in London. At Dundee University in the 1990s, he built one of the largest communities of scientists working on p53 anywhere in the world. Responsible, among many other things, for dubbing p53 ‘Guardian of the Genome’.
LEVINE, ARNIE
The Princeton-based scientist who discovered p53 independently but at the same time as David Lane and two others in 1979. Levine’s lab has been a hub of p53 research ever since and has been involved in many of the most important discoveries about the function of the gene.
OREN, MOSHE
One of the first people, in 1984, to make a clone – an exact replica – of p53 from which endless copies could be made for research. Among many other important contributions to the field, Oren also discovered p53’s role in apoptosis (cell suicide) and, along with Arnie Levine and Carol Prives, helped to uncover the mechanism that keeps the powerful p53 under strict control in our cells.
PRIVES, CAROL
A Columbia University-based scientist who, in collaboration with Bert Vogelstein, discovered that p53 works as a master switch in our cells, turning other genes on and off in response to signals. Involved also, along with Moshe Oren and Arnie Levine, in discovering the mechanism that keeps the powerful p53 itself under strict control in our cells. Prives is among a number of key researchers at the core of the p53 community.
ROTTER, VARDA
Based at the Weizmann Institute in Israel, Rotter was one of the earliest researchers to recognise that p53, when mutated, does not simply lose the ability to function as a tumour suppressor; very often the mutant acts to promote the growth of a tumour. Rotter is famed for having stuck to her guns, even when her analysis was challenged by some of the best brains in the community, and today hers is the mainstream view.
VOGELSTEIN, BERT
Trained as a medical doctor at Johns Hopkins in Baltimore, Vogelstein’s experience treating children with cancer led him to molecular-biology research. The first person to investigate p53 in human cancers, he has been involved in many key discoveries about the function of the gene, including its role as a tumour suppressor and a master switch.
WEINBERG, ROBERT
Eminent US scientist involved since the early days of the molecular-biology revolution in uncovering the genetic basis of cancer. Best known for his discoveries of the first human oncogene (or cancer-promoting gene) and the first tumour suppressor. Weinberg has spent most of his working life at the Massachusetts Institute of Technology (MIT) and is the author, with Doug Hanahan, of a seminal paper, ‘The Hallmarks of Cancer’, which defines the key characteristics of all cancer cells.
WYLLIE, ANDREW
Trained as a pathologist, Wyllie was a PhD student at Aberdeen University in Scotland when ‘programmed cell death’, or cell suicide, emerged from rarefied fields into mainstream biology and was given the name ‘apoptosis’. His was one of two groups of researchers who simultaneously discovered that apoptosis is one of the programmes p53 is able to trigger in response to cellular stress in real life, not just in cell cultures in Petri dishes.
Glossary
Allele: One of a pair of genes that occupy the same site on a chromosome. All genes come in pairs: you inherit one allele of each gene from your mother and one from your father.
Antibody: Antibodies are the soldiers of the immune system; they move freely in the blood, seeking out invaders such as bacteria and viruses and flagging them up for destruction. Antibodies are tailor-made by the immune system to recognise and attach to specific targets, which makes them excellent tools for ‘finding’ target molecules in researchers’ laboratory experiments.
Apoptosis: Programmed cell death, or cell suicide.
Bacteriophage: A virus which targets and infects bacteria.
Carcinogen: A substance capable of causing cancer.
Carcinoma: A type of cancer that starts in the epithelial cells that form the outer membranes of all the organs, tubes and cavities in our bodies, and include our skin. At least 80 per cent of cancers are carcinomas (see also sarcoma, leukaemia, lymphoma).
Cell culture: A laboratory process in which cells are maintained and grown outside the body in specially designed containers, such as test tubes and Petri dishes, and under precisely controlled conditions of temperature, humidity, nutrition and freedom from contamination.
Cell line: A cell culture developed from a single cell and therefore consisting of cells with a uniform genetic make-up.
Cell-cycle checkpoint: The checkpoints mark the end of each phase in the multi-phase process of cell division. At each checkpoint, ‘quality control’ has the chance to verify that the process has been accurately completed before allowing the cell to proceed
to the next phase.
Checkpoint: See cell-cycle checkpoint.
Codon: A sequence of three consecutive nucleotides (the basic building blocks of DNA) on a gene that together form a unit. These units dictate which amino acids are to be used to create the protein that will carry out the function of the gene.
Clone: In the context of this book, a gene that is produced artificially from another gene, of which it is an identical copy.
DNA: Deoxyribonucleic acid, the material inside the nucleus of the cells of living organisms that carries genetic information.
Expression: The process by which an activated gene makes a protein or other product that carries out the function of that gene in the cell. If a gene is ‘over-expressed’, it implies there is an over-abundance of protein in the cell.
Gain of function: An expression used in reference to a genetic mutation that changes the gene product (e.g. protein) in such a way that it gains a new and abnormal function (see also loss of function).
‘Hallmarks of Cancer’: A seminal paper written by Robert Weinberg and Doug Hanahan in 2000 that describes the six characteristics common to all cancers, of whatever organ or origin. They revised the ‘Hallmarks’ in 2011, adding four more general principles.
Large T antigen: The gene in the DNA of the monkey virus SV40 that is responsible for causing cancer in the cells of the host species it infects.
Leukaemia: Cancer of the white blood cells, which are a vital component of the immune system (see also lymphoma).
Loss of function: An expression used in reference to a mutation that renders a gene useless – the mutant gene is either unable to make any protein or the protein it makes has no function. In most, if not all, tumour-suppressor genes other than p53, mutation leads to ‘loss of function’.
Lymphoma: Cancer originating in lymphoid tissue, a key component of the body’s immune system. Cancers of lymphocytes (lymphomas) and other white cells in the blood (leukaemia) together account for about 6.5 per cent of all cancers.
Malignant: In medical usage malignant means cancerous; able to spread to other parts of the body.
Metastasis: The spread of cancer cells from the original site to other parts of the body (hence metastases: secondary cancers).
Mutagen: A substance capable of causing mutation.
Mutant: Something that has undergone mutation (see below).
Mutation: A change of the DNA sequence within a gene or chromosome of an organism resulting in a new character or trait not found in the parental type; or the process by which such a change occurs.
Nucleotide: Nucleotides are the basic building blocks of DNA, which stack one on top of the other like nano-sized blocks of Lego to form the long ribbons of the double helix.
Oncogene: A gene that has the potential to cause cancer. Very often these are genes that have a normal role to play in the growth of cells, but that have sustained a mutation and lost the ability to respond to control signals.
Oncogenic: Causing development of a tumour or tumours.
Oncology: The study of cancer (hence oncologist, a doctor or scientist specialising in cancer).
‘Postdoc’: A postdoctoral scholar; an individual with a doctoral degree who is 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.
Recombinant DNA: DNA that has been formed artificially by combining genetic material from different organisms.
Sarcoma: A type of cancer that forms in the connective or supportive tissues of the body such as muscle, bone and fatty tissue. Sarcomas account for less than 1 per cent of cancers.
Senescence: In this book the term is used to describe a state in which cell is no longer able to divide but remains alive and functioning.
Somatic mutation: A mutation in a mature cell that has occurred spontaneously during the course of life, as opposed to one that is inherited and will be present in all the cells, both normal and cancerous.
Tissue culture: The growth of tissues or cells removed from an organism. The living material is placed in a lab dish such as a test tube or Petri dish with a growth medium, typically a broth or agar gel, that contains special nutrients.
Transcription factor: A protein that binds to DNA at a specific site and controls the expression of a gene or genes in the vicinity, switching them on and off as appropriate.
Transformation: In this book, this term is used to describe the process by which a cell acquires the properties of cancer (commonly described also as ‘malignant transformation’).
Tumour suppressor: A gene whose function is to prevent cells from becoming malignant.
Wild type: Used in reference to a gene, this means the ‘normal’ gene that functions as nature intended, as opposed to the ‘mutant’ gene whose behaviour is aberrant.
Notes on Sources
Besides my personal interviews with many of the key players in the p53 story, I have tapped into a rich repository of information contained in a great number of books, journals and multimedia websites in my research for this book. I often used multiple sources for a single discussion point, and list here those I found particularly useful and that deserve special mention in each chapter. Some sources, however, have provided information, insights and ideas of relevance throughout the book. They include:
Hainaut, Pierre, & Wiman, Klas (eds), 25 Years of p53 Research (Dordrecht, Netherlands: Springer, 2005)
Judson, Horace Freeland, The Eighth Day of Creation: Makers of the Revolution in Biology, (Woodbury, NY: Cold Spring Harbor Laboratory Press, 1996)
Lane, David, & Levine, Arnold, p53 Research: The Past Thirty Years and the Next Thirty Years (Woodbury, NY: Cold Spring Harbor ‘Perspectives in Biology’, May 2010). This is one among many excellent papers I drew upon from Cold Spring Harbor’s ‘Perspectives in Biology’ collection, available at cshperspectives.cshlp.org/cgi/collection/ (see: The p53 Family).
Mukherjee, Siddhartha, The Emperor of All Maladies: A Biography of Cancer (London: Fourth Estate, 2011)
Varmus, Harold, The Art and Politics of Science (New York: W W Norton & Co., 2009)
A Conversation with Robert Weinberg (from the ‘Conversations with Scientists’ series sponsored by the MIT Department of Biology and the Howard Hughes Medical Institute). Available at video.mit.edu/watch/a-conversation-with-robert-weinberg-4508/
Milestones in Cancer, a series of authoritative articles provided by the science journal Nature, available at www.nature.com/milestones/milecancer/index.html
The p53 Website. A resource for scientists working on p53 and cancer research set up by Thierry Soussi in 1994, available at: http://p53.free.fr/
Preface
The epigraph from Gerard Evan comes from my interview with him in Cambridge, England, in June 2012.
Chapter 1: Flesh of our Own Flesh
The epigraph from Peyton Rous comes from his lecture to the Nobel Committee on winning the prize, ‘The Challenge to Man of the Neoplastic Cell’, available at www.nobelprize.org/nobel_prizes/medicine/laureates/1966/rous-lecture.html
Besides the Conversation recorded at MIT and cited above, Robert Weinberg spoke of his work with Doug Hanahan on the Hallmarks of Cancer at a conference of the National Cancer Research Institute in 2010. Available at www.youtube.com/watch?v=RP4js-yYK2U)
Chapter 2: The Enemy Within
The epigraph from Michael Bishop comes from his book, How to Win the Nobel Prize: An Unexpected Life in Science (Harvard University Press, 2003), page 161.
For information on Peyton Rous, I relied on the excellent archives of the Nobel Foundation, see: http://www.nobelprize.org/nobel_prizes/medicine/laureates/1966/rous-bio.html
Besides their autobiographical books already cited, the Nobel archive also was a rich source of information on Varmus and Bishop, who won the prize in 1989. See www.nobelprize.org/nobel_prizes/medicine/laureates/1989
For the Asilomar debate see M. J. Peterson,
2010, Asilomar Conference on Laboratory Precautions. International Dimensions of Ethics Education in Science and Technology. Available at www.umass.edu/sts/ethics
Chapter 3: Discovery
The epigraph comes from Judson’s book, The Eighth Day of Creation, cited above, page 10. The footnote quote is from Jeffrey Taubenberger; see www.pathsoc.org/conversations
Chapter 4: Unseeable Biology
The epigraph comes from A Short History of Nearly Everything by Bill Bryson (London: Transworld Publishers, 2003), page 451.
For this chapter I relied substantially on the information provided by the National Human Genome Research Institute of the National Institutes of Health, available at www.genome.gov.
Chapter 6: A Case of Mistaken Identity
The epigraph from Judson comes from The Eighth Day of Creation cited above, page 594.
Besides the conversation recorded at MIT cited above, see Robert Weinberg’s description of his discovery of oncogenes in human tumours, available at http://www.bioinfo.org.cn/book/Great%20Experments/great25.htm
See also Nature Milestone 17 and 18 on the discovery of the first human oncogene and on oncogene co-operation www.nature.com/milestones/milecancer/timeline.html
Chapter 7: A New Angle on Cancer
The epigraph from the 19th-century French novelist Jules Verne comes from A Journey to the Centre of the Earth.
For information on Henry Harris, I relied on the rich archive of the Genetics and Medicine Historical Network set up by Cardiff University with support from the Wellcome Trust. See http://www.genmedhist.info/interviews/. See also ‘How Tumour Suppressor Genes were Discovered’ by Henry Harris in Journal of the Federation of American Societies for Experimental Biology (FASEB), Volume 7, pages 978-79.
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