Life's lethal quality control

A US businessman's claims to have found the unseen architect of evolution fell on deaf ears. But after a string of coincidences, some scientists are starting to listen. Geoff Watts reports

One day in 1995, biologist Armand Leroi walked into Manhattan's Strand Bookshop and made a remarkable discovery. He came across a rather plain-looking remaindered volume bearing the title Cancer Selection . The postdoc student had not heard of the book or its author, James Graham. But, Leroi recalls: "I'm a sucker for odd theories of evolution, so I bought it." It was an impulse decision that was to have profound implications. For buried in the book was a bold new idea that has become a muse to the young scientist.

The book was lying on a table in front of him when I visited his South London flat. Leroi, a reader in evolutionary developmental biology at London's Imperial College, is an articulate and rather intense man with a hint of an accent betraying his Dutch origins. He says he knew the book was not a work by a professional scientist: "In fact, Graham's very frank about this. His whole thing is he's an outsider." At this point Leroi reads aloud from the book's cover blurb. "James Graham began work on his theory in 1977 while working as a senior executive in a large multinational corporation.

He now devotes his full time to writing. He is a member of MensaI" He pauses. "Well, these are obviously not standard scientific credentials. And scientists who are members of Mensa don't usually advertise it."

In 1995, Leroi read Graham's book but then put it aside. He now credits it as having spurred him and two colleagues at Imperial to reconsider a piece of received wisdom in the field of evolutionary biology. Like the book, Leroi's paper in last month's Nature Reviews Cancer is titled "Cancer Selection". In it, he asks whether cancer may have played a hitherto overlooked role in the evolution of complex animal life.

Biologists view events that are both common and life-threatening as among the driving forces of evolutionary change. The occasional creature born genetically endowed to cope more successfully with such an event has a greater chance of surviving to reproduce and pass on whatever useful genes underpinned its good fortune. Thus is evolution guided by the adaptive hand of natural selection.

Cancer is a common occurrence, and certainly a life-threatening one. But biologists generally regard it as having no effect on evolutionary change because it mostly afflicts people beyond their child-bearing years. As a result, cancer cannot affect their chances of passing on any protective genes they may possess to the next generation.

But not all malignancies are confined to the elderly: a minority of children also develop lethal cancers. Leroi and his co-authors suggest that perhaps childhood cancer mostly affects organs that have undergone recent and rapid evolution. It is a radical proposal. In the first page of their paper is an acknowledgement: "The idea that changes in morphology and life-history can expose animals to an increased risk of cancer has been argued forcefully by James Graham in his 1992 book Cancer Selection ."

Graham - now in his early 70s and living in Lexington, Virginia - started to think about cancer after reading The Selfish Gene by Richard Dawkins. He had no particular knowledge of the disease. What Graham knew about was manufacturing. He had spent much of his working life in multinational corporations, and had become the chief financial officer of a leading cosmetics company. From his industrial background he was well aware that design improvements in a product often lead to an initial fall-off in the quality of the manufactured goods. To retain the advantages of the improvement while restoring the lost quality, adjustments have to be made to the production process. Among living things, Graham reasoned, death caused by cancer might play a similar role. It could serve to eliminate those individuals who inherited a genetic programme unable to cope with any damaging side-effects associated with change. Cancer, in other words, is evolution's method of quality control.

Having received what he laughingly calls this "gift from the unconscious" he began garnering the evidence. "I guess I went about it backwards," Graham says. "The typical scientist studies for years before he even attempts to deal with evolutionary theory. I knew nothing when I had this idea."

In a determined attempt to persuade others, Graham started writing to learned journals, initially with some modesty. "I was looking for someone to come back with intelligent comments about my inept efforts, and to advise me. That didn't happen. The reception I got was more like swatting a fly."

He also wrote to evolutionary biologists. "I knocked on so many doors my knuckles were bleeding. My dream was that someone would say to me, 'Mr Graham, you've got a good idea here. Why don't we collaborate?' I would have jumped at the opportunity." This didn't happen either. Graham's modesty began to evaporate. One journal, Evolution , did take a more sympathetic view but an attempt to set up a collaboration fell through.

Eventually, he managed to get two severely pruned letters published in the Journal of Theoretical Biology . "I then put on my PR hat," Graham says. "I wrote a press release, and even hand-delivered it to media people in Manhattan." But there was still no serious consideration from the scientific community.

Nevertheless, Graham persevered. "I was convinced I was correct, and if an idea is correct it's important." As simple as that. And his conviction drove him to the only remaining option: to publish himself. He did so under the imprint Aculeus Press. Aculeus is Latin for needle or sting. The book received several reviews, not least in Nature , whose critic wrote: "I, at least, like the idea." But then silence.

Frustrated at years of being ignored by the scientific establishment, Graham's tone had, by this time, grown belligerent. Many biologists reading his book would balk at the first chapter. Provocatively titled "Biology's dirty little secret" it dismisses conventional thinking about Darwinian evolution as "utter nonsense" and an "intellectual error of the rankest sort". Although the prose is clear and readable it is also assertive, didactic and sometimes patronising. The reader is constantly warned that all contrary views are foolish, absurd or self-evidently wrong: "Unlike the old theory, mine is correct."

Graham goes on to compare himself to Darwin (neither had been educated as a scientist) and Friedrich Wegener of continental drift fame (as a meteorologist not a geologist, Wegener too was an outsider). Thomas Kuhn's classic The Nature of Scientific Revolutions is wheeled out to remind us that people responsible for the "fundamental inventions of a new paradigm have been either very young or very new to the field whose paradigm they change". (The italics are Graham's.) He even compares his method of work to Albert Einstein's.

At this point it is difficult not to lose patience. "Its whole tenor as it rails against the biological establishment is that scientists are just too thick," Leroi says. "They've missed it all. They're stuck in their paradigms of conventional Darwinian evolution. But James Graham is going to set them right."

Happily for Graham, Leroi had the forebearance to judge the work on its merits. "When I'd originally read Graham's book, I thought there was something in it. But I forgot it," he admits. Then he moved to the UK and started working with another evolutionary biologist, Austin Burt. "I can't remember whether he was in my office or I was in his, but we looked on each other's bookshelves and said, 'Gosh, Cancer Selection , you've got it too'."

It turned out that Burt had also picked up a remaindered copy of the volume in Moe's Bookshop, Berkeley, while in California as a postdoc.

An extraordinary chain of coincidences that began with two postdoc biologists buying the same rare book on opposite sides of America has now brought them together in London with a third colleague, Vassiliki Koufopanou, to pen their own thoughts on cancer.

They accept Graham's premise that the disease is ancient and ubiquitous and can be a force in natural selection. "That idea is the central one," Leroi admits. Needless to say, Graham doesn't stop there. He reinterprets the diversity of animals in the light of his discovery, opining, for example, that snails evolved shells to protect themselves not from birds but from ultraviolet light and hence cancer. "You can apply this approach to any feature of the biological world," Leroi says, "and Graham does so, willy-nilly."

Graham claims that cancer selection is not a but the driving force in the emergence of complex animal life. "He believes that with good, clear thinking one can arrive at an answer," Leroi says. "But this isn't enough.

Because something could be a certain way doesn't mean that it actually is that way. All those biologists who spend their time trying to test evolutionary theory - well, he thinks they're just number-crunchers who can't see the big picture."

Nevertheless, spurred on by Graham's reasoning, Leroi began to consider cancer in children. It turns out that only a few of the body's organs are particularly susceptible to childhood cancer, such as the bones and the brain. Both incorporate recent evolutionary novelties. "As Homo sapiens , we are famous for our big brains that have evolved so enormously over the past few million years," Leroi says. And then there's our pubertal growth spurt.

"Chimpanzees don't have it. It's possible that the osteosarcomas that kids get in the bones undergoing the growth spurt are a consequence of this being an evolutionary novelty." Although admitting that the evidence is circumstantial, Leroi also thinks it is persuasive.

Childhood cancer kills before the age of reproduction, and is therefore amenable to selection. Yet it continues to exist. Why? Because natural selection has not yet had the time to deal with it.

The possibilities for speculation are limitless. For example, one outcome of evolution can be an increase in size. But bigger animals have more dividing cells, and therefore more cells to turn cancerous. So why don't elephants suffer cancer more than mice? Maybe they do; maybe it's the success of large animals in developing better anti-cancer mechanisms that has allowed them to become large.

As diseases go, cancer is seldom far from our attention. The thought that this much-feared disease might have played a major role in shaping our evolution is tantalising. But it took an outsider to see this possibility, and the chance interest of an insider to draw it to our attention.