p53
Authors: Sue Armstrong
For Struan, Isla, Louise and Fraser
who, I hope and trust, will reap the full rewards
of this mighty endeavour in cancer research
Chapter 1: Flesh of our Own Flesh
Chapter 6: A Case of Mistaken Identity
Chapter 7: A New Angle on Cancer
Chapter 8: p53 Reveals its True Colours
Chapter 10: ‘Guardian of the Genome’
Chapter 11: Of Autumn Leaves and Cell Death
Chapter 13: The Guardian’s Gatekeeper
Chapter 15: Following the Fingerprints
Chapter 16: Cancer in the Family
Chapter 17: The
Tropeiro
Connection?
Chapter 19: Cancer and Ageing: A Balancing Act?
Chapter 20: The Treatment Revolution
Where do we
[scientists]
get our ideas, our inspiration for solving problems? It’s the same place a composer gets an idea for a piece of music, or a
painter gets an idea for a painting. It comes out of somewhere that you don’t know. It’s the same flash of inspiration, and it’s associated with the same colour – and
the same glory, for want of a better word.
Gerard Evan
***
Luana Locke is a vivacious woman on the threshold of middle age, with a round pretty face, large hazel eyes and a tumble of wavy dark hair to her shoulders. There is such an
air of robust good health about her as she sits talking over a frothy cappuccino in a busy Toronto café that if I didn’t already know something of her story I would never suspect that
her life has been dogged by sickness, heartache and loss. A survivor of cancer, Luana already had long experience of the disease by the time of her own diagnosis at the age of 24. When she was just
three years old, her sister Manuela, aged nine, died of a brain tumour. Of that period, Luana can only really remember being left frequently with relatives as her parents visited the hospital, her
mother’s terrible grief when Manuela finally died and her own helpless desire to see her smile again.
‘I remember one time giving her a tissue and being upset because she blew her nose. I thought, “No! I gave it to you to wipe your tears.” I just remember her being really
really sad.’ The little girl did not know then that her mother Giulietta was also sick. She and Luana’s father Franco, a tile-setter by trade, had emigrated from Italy to Canada a few
years earlier for what they intended to be a short spell
taking advantage of the high demand for skilled craftsmen. They were planning to go home to Italy – drawn
partly by the fact that Luana’s Aunt Rina, her mother’s twin sister, had recently died of breast cancer at the age of 29, leaving four small children. But their plans were scuppered
when their own daughter was diagnosed with a brain tumour, and then Luana’s mother began her own treatment – chemotherapy and radiation for breast cancer.
‘She had a mastectomy, and I do have some very clear images of that time,’ says Locke. ‘I remember watching my mother as she was getting dressed, putting on her make-up, fixing
her hair and slipping her prosthesis under her shirt.’ All this seemed normal, just part of life, to the small girl, until her mother’s cancer, which had responded to the initial
treatment, returned and spread to her bones and killed her. Luana was six years old, and she speaks poignantly of the heartache and emptiness that filled their home, reduced now to her father, her
brother David and herself, and of the fear that gripped her in bed at night that this monster might strike again and take more of her loved ones.
In fact the next person to be diagnosed was Locke herself. She was 24 years old and eight months pregnant when she noticed a tiny scab on her nipple. It would slough off from time to time
leaving a small, weeping sore that would scab over again, but never seemed to heal. Keen to breast-feed her baby when it arrived and anxious therefore to clear up the spot, she eventually went to
her doctor, who gave her some ointment. No one she saw as part of her routine maternity care seemed concerned, but when the spot appeared to be getting bigger despite a variety of ointments, her
doctor referred her to a dermatologist, Donna McRitchie, who decided to take a biopsy.
‘Dr McRitchie said, “It will probably take about a week to get the results back, and we’ll call you,”’ says Locke, looking back across the years. ‘I remember
going and sitting in my car and starting to cry. Even though I didn’t feel anything
– she put a needle in to freeze the area – I remember hearing the
clipping of the scissors and I knew that she was cutting tissue, and it really affected me in a weird kind of way. So I got into the car and cried . . . But then I stopped and I was so angry with
myself. I thought: You baby! Think what your mother went through; she had her breast
removed
, for the love of God, and here you are weeping like a baby because they took a little piece of
skin off your breast. Like, grow up and get over it! I was just kind of scolding myself, right? Snap out of it, off you go.’
Luana was not ready to admit her fears even to herself. A naturally optimistic person, she hung on to the belief that lightning could not strike again in the same spot, and whenever a morbid
thought entered her mind she would squash it, telling herself, ‘That’s ridiculous; who’s ever heard of breast cancer manifesting itself that way? There’s no lump;
there’s nothing there; you’re 24 years old . . . Gosh, I scolded myself a lot in those days!’ she laughs. But the results came back unusually fast, and they were serious: Luana
had Paget’s disease, a type of breast cancer that is often mistaken for eczema until the tumour growing secretively below the sore is advanced. Given her family history, her oncologist
recommended the most radical treatment, mastectomy.
The diagnosis was a shock, but one of Luana’s first concerns was for her father. ‘Telling him was one of the hardest things I ever had to do,’ she comments quietly, looking
down and stirring the froth in her coffee cup. ‘He’d already been through so much and it was just a journey I didn’t want him to have to travel again.’ In the event, Franco
put on a brave face, urging his daughter and her distressed husband Paul not to look back to her mother’s and sister’s experience nearly 20 years earlier. ‘“Medical science
has come such a long way since then,” he said.’
Within weeks of Luana’s diagnosis, her baby, a boy they named Lucas, was delivered by Caesarean section; her mastectomy was performed a few days later. Examination
of the tissue removed at surgery revealed a highly aggressive tumour, and Luana subsequently had her other breast removed as a precautionary measure. Her surgeons found a pre-cancerous
lesion here too. During all this, Luana coped with her own disease, with the painful memories it inevitably stirred and with the dreadful uncertainties of the future by focusing on her new baby.
‘It was all about, okay, I know I have to survive, so I’ll do whatever it takes . . . I really just poured myself into
nesting
,’ she says. ‘The worst thing that I
allowed myself to contemplate was not my death – that was too large, too big an issue for me to face, too big a fear, I guess . . . the farthest I allowed myself to go in terms of my biggest
fear was losing my hair. I’ve always had long hair, and so I allowed myself to go there, but I didn’t allow myself to think of death . . . Or not being here for my child, no, not at
all.’ She shakes her head.
Luana is now 41, and she has not had a recurrence of her cancer, though in the intervening years four other members of her immediate family in Italy and America have had tumours removed, and her
brother David’s little boy Marco died of cancer, aged five. Though no one knew it until relatively recently, the root of the family’s problem is a mutation in a gene that goes by the
prosaic name of p53 – bestowed on it simply because it makes a protein with a molecular weight of 53 kilodaltons.
When it was discovered in 1979, the scientists involved had little idea of the huge significance of their finding: p53 has gradually revealed itself to be one of the most important players in
the drama that is cancer – a master switch in our cells whose main function is to prevent tumours arising when their DNA is damaged. It has become the most studied single gene in the history
of molecular biology, generating over 70,000 research papers to date and spawning a community of researchers that, notwithstanding the customary competition between scientists, is unusually
collaborative. Every two years they come together from around the world
for a scientific meeting, a few days of bracing, esoteric debate which adds new bits to the mighty
jigsaw and fits some old ones into the existing picture.
p53 is the most commonly mutated gene in human cancer. This means that the gene is damaged and the information it carries is altered, in much the same way as a CD or computer file can be
corrupted and its information scrambled. In those cases where the gene is not mutated, typically some other abnormal event in the cell is preventing it from functioning as it should. ‘There
are lots of other genes you see mutant in the various tumour types,’ comments Bert Vogelstein of Johns Hopkins University in Baltimore, Maryland, ‘but p53 is one of the few that goes
across the board. It’s unique in that it’s a common denominator of cancers.’
Vogelstein, who was born and brought up in the shadow of Johns Hopkins in the 1940s and went to medical school there, has been involved with p53 since its earliest days. His lab, housed today in
a tall modern building of glass and light which looks out over Baltimore and down onto the warm red bricks of the old hospital, has provided some of the most important insights into the workings of
the gene. ‘I think you could safely say that it’s impossible – or very difficult – to get a malignant tumour without the activity of p53 being disrupted.’
***
I first heard of p53 in 1996 when I was newly returned to Scotland from seven years in South Africa, where I had been reporting for
New Scientist
magazine and BBC
Radio, and chronicling the ravages of AIDS across the continent for the World Health Organization. Now I was looking around for interesting science stories in Scotland, and I found myself in the
lab of David Lane, one of the four discoverers of p53. Intrigued by what I learnt, I got a commission from the BBC to make a radio documentary and flew off to Crete to join the p53 community at one
of their biannual workshops.
The setting was a conference centre perched on the lip of a sweeping bay with views out over private white sands and the sparkling ocean. At the
end of the first session I sat stunned – the scientists could have been speaking Greek for all I had understood.
Sitting next to me at the noisy dinner table later that evening was Peter Hall, small, bright, mischievous and a very good teacher, a scientist from Dundee with whom I’d worked before on
p53 stories. Leaning towards me, he whispered, ‘Don’t panic. This is what you need to know to get a handle on the debate . . .’ He pointed me towards the most interesting
presentations in p53 research and the people I must corner with my microphone. I began to relax and returned from Crete four days later with enough material and a good enough story for not just one
but two radio documentaries that looked at the basic science of this gene and at the promise it held for new kinds of cancer therapy.
That was 1998, and over the following years I have revisited the story of p53 whenever new bits of the jigsaw puzzle have piqued my interest, such as the chance discovery, when a genetically
engineered mouse experiment went dramatically wrong, of an intimate connection between cancer and ageing; and of the role of p53 in nailing the tobacco industry by furnishing unequivocal proof that
smoking is a direct cause of cancer. I have watched as morale among p53 researchers has waxed and waned in the light of new information that carries them forward on a wave of discovery and
enlightenment one moment, then mires them once more in the fog of complexity.
Over the years I began to realise that this was too good a story to leave to the passionless pages of academic journals, where it’s hard for the layperson to grasp the significance of even
some of the most momentous discoveries; the idea of writing a book about the gene took root. It’s not a straightforward story, because nothing in science ever is. Knowledge advances as much
through negative results and thwarted
hypotheses as it does by theories that prove to be correct. It takes open minds and intellectual courage to recognise the absence of
proof – or the totally counterintuitive outcome of an experiment – as offering important insights in their own right. In their quest to understand the workings of cancer, p53
researchers have been as much influenced by dogma and the power of paradigms as have scientists in any other field.