There is a well-known quote (apparently often falsely attributed to Albert Einstein) that "everything should be made as simple as possible, but no simpler." That idea seems apt as one considers the task facing Sue Armstrong in her book p53: The Gene that Cracked the Cancer Code. After all, the gene, discovered in 1979 and named based upon its molecular weight of 53 Daltons, has already spawned over 70,000 research papers, with an uninterrupted stream likely for the foreseeable future.
We know that p53, appropriately described as the "guardian of the genome," is the most frequently mutated gene in human cancer. It also regulates a vast array of critical functions necessary for healthy growth and development.
How it was discovered and found to play a central role in cancer as well as aging is adeptly explored in this book by Armstrong, an accomplished science writer for New Science magazine and the World Health Organization, and a frequent contributor to the BBC on scientific topics.
As she says about the topic: "It is not a straightforward story because nothing in science ever is."
She sets out her goals very clearly in the preface. "My aim here is to stand clear of those legers full of data and tell the story of some of the curious, obsessive, competitive minds that filled them, thereby helping to unravel the mysteries of cancer."
It All Began with Peyton Rous
The narrative really begins with the work of Peyton Rous in 1911 and the subsequent studies of the Rous Sarcoma Virus that in the '70s led to the Nobel Prize-winning work of Bishop and Varmus on the src gene and its function as an oncogene. Researchers en masse coalesced around the accelerator model of cancer. It was rogue oncogenes that caused uncontrolled proliferation. This seemed to be the unifying hypothesis that explained much of the cancer problem.
p53 was discovered independently in four separate laboratories in 1979 working with the monkey virus SV40. Because some of the labs were focused on virology and others immunology, it took over a year for the groups to realize they were describing characteristics of the same molecule.
Tumor Suppressor, Not Oncogene
The initial assumption by most investigators was that p53 was an oncogene. After all, it was capable of immortalizing cells. p53 produced abundant protein product when overexpressed in cells, and when partnered with other oncogenes like ras, seemed to function like an oncogene, albeit a less efficient one. This work suggested that p53 was just another oncogene-and one of minor importance at that.
Many senior laboratory directors advised younger colleagues against working on p53. As the book relates, comments like "p53 has no future" or even "don't work on that bullshit protein, change your topic" were not rare. Although this mindset likely delayed progress during the next decade, a handful of scientists soldiered on, convinced that p53 held unrecognized promise.
Several labs sought to clone the gene and discover how it and its protein product functioned. Although gene cloning is a relatively simple procedure now, in the early 1980s it took one experienced lab two and a half years to accomplish the task. In a testament to the cold war's impact on science, p53 cloning had actually been completed in the Soviet Union a year earlier but published in a Russian language journal largely unread in the West.
Tumor-suppressor genes had been proposed in the late 1960s by Knudson, based on his analysis of the differences in behavior and frequency of retinoblastoma in familial and sporadic settings. Although it was not possible then to isolate genes or identify them individually, he reasoned that some kind of a cellular brake on proliferation must have been lost. One gene copy was lost at birth in the familial cases and the second through injury during life.
Unfortunately in 1971 when he published his two-hit hypothesis, the scientific community was not receptive. Al Knudson, a personal colleague and friend, told me that the publication initially received little attention. It was an observation felt to be relevant only to a rare eye tumor in children.
Finally in the late 1980s, p53 research began to coalesce around some of the unusual characteristics of p53. Three labs-Bert Vogelstein's, Arnie Levine's, and Moshe Oren's-all had p53 clones. But Levine's worked differently than the others. It turned out that he had the only wild type p53. The others had mutants. These investigators were subsequently able to piece together the story of how p53 worked as a tumor suppressor, and some of the mutants actually did function like oncogenes.
Voluminous research has subsequently established that mutant forms of p53 contribute to tumor proliferation, uncontrolled replication, genomic instability, inflammation, migration, invasion, angiogenesis, and metastasis. Wild type p53 functions in cellular stability, senescence, and apoptosis.
Deft Quotes
This complex functional polyglot is explored deftly in the book. While Armstrong delves deeply into details of the science, she begins each chapter with an introductory lead followed by a quote to nicely highlight the science to be covered.
For example, in the chapter "p53 Reveals its Colors," she opens with: "In which we hear of the brilliant work and strokes of luck that showed p53 to be a tumor suppressor not an oncogene." This is followed by a Francis Crick quote: "People don't realize that not only can data be wrong in science, it can be misleading. There is no such thing as a hard fact. It's only afterwards that the facts are hard."
This book is fundamentally about how science is actually done-not the retelling of the story after the work is complete and the narrative scrubbed of imperfections, but rather about scientific progress in fits and starts. Progress delayed by the "herd mentality" seen in even the most astute scientists. Progress that must pause until new technology develops capable of exploring transformational hypotheses. Progress delayed by the disciplinary "silos" so common in science. Sue Armstrong does an admirable job of exploring the real rough roads and blind alleys that always mark scientific progress.
On the other hand, the chapter on "The Treatment Revolution," is less successful, which examines the promise of therapeutically targeting p53. She sees "p53 at the cutting edge of gene therapy and personalized medicine which are revolutionizing the treatment of cancer." Unfortunately, while research is ongoing and intense, the clinical trials she describes are preliminary, the number of patients studied is small, and the clinical benefits highlighted are unconvincing. Whether it will ever be possible to successfully modulate the delicate balance accomplished by this remarkable "guardian of the genome" is as yet unknown.
What does seem clear, though, is that the multiple critical functions of p53 will continue to fascinate scientists and lure creative and tenacious minds to explore its secrets for many years to come.
2015, BLOOMSBURY, ISBN 1472910516, AVAILABLE IN HARDCOVER, PAPERBACK, AND AUDIO EDITIONS
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