p53: The Gene that Cracked the Cancer Code

207 Pages·2015·1.18 MB·English

by  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
Contents
Preface
Chapter 1: Flesh of our Own Flesh
Chapter 2: The Enemy Within
Chapter 3: Discovery
Chapter 4: Unseeable Biology
Chapter 5: Cloning the Gene
Chapter 6: A Case of Mistaken Identity
Chapter 7: A New Angle on Cancer
Chapter 8: p53 Reveals its True Colours
Chapter 9: Master Switch
Chapter 10: ‘Guardian of the Genome’
Chapter 11: Of Autumn Leaves and Cell Death
Chapter 12: Of Mice and Men
Chapter 13: The Guardian’s Gatekeeper
Chapter 14: The Smoking Gun
Chapter 15: Following the Fingerprints
Chapter 16: Cancer in the Family
Chapter 17: The Tropeiro Connection?
Chapter 18: Jekyll and Hyde
Chapter 19: Cancer and Ageing: A Balancing Act?
Chapter 20: The Treatment Revolution
Dramatis Personae
Glossary
Notes on Sources
Acknowledgements
eCopyright
Preface
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.
‘Science without storytelling,’ wrote the American astrophysicist Janna Levin
in a commentary for New Scientist, ‘collapses to a set of equations or a ledger
full of data.’ My aim here is to stand clear of those ledgers full of data as far as
possible and tell the story of some of the curious, obsessive, competitive minds
that filled them, thereby helping to unravel the deepest mysteries of cancer.
A NOTE FROM THE AUTHOR
I have tried hard to avoid jargon as far as possible. But there is one expression I
am loath to replace with something more readily understood: that expression is
‘wild type’ in reference to the status of the p53 gene. Essentially, the ‘wild-type’
gene means the ‘normal’ gene that functions as nature intended, as opposed to
the ‘mutant’ gene whose behaviour is aberrant. ‘Wild type’ is a term so widely
used by the biology community, and by my interviewees – and so much more
vivid than ‘normal’ – that I have decided not to substitute it. I trust my readers
will forgive me.