Cancer is one of the most intensively studied phenomena in biology, with over a million published papers, yet a proper understanding remains elusive, writes Professor Paul Davies, the keynote speaker at this year’s Adelaide Festival of ideas.
Standard cancer therapy – a mix of surgery, radiation and chemical toxins – has changed little in decades. Survival rates overall have improved only modestly or not at all. Life extension through therapy is mostly a rearguard action against the inevitable, measured in weeks or months rather than years, confounding the incessant media hype about ‘cancer breakthroughs’. This dismal state of affairs can’t be blamed on lack of funding. The US government alone has spent 100 billion dollars on cancer research, while charities and drug companies have poured in billions more. Perhaps the lack of progress is because scientists are looking at the problem the wrong way? The conventional explanation for cancer is the somatic mutation theory, according to which genetic damage accumulates in cells as a result of aging, radiation or carcinogenic chemicals, causing the cells to misbehave and embark on their own agenda. This ‘neoplasm’, or population of new cells, rapidly develops several distinctive hallmarks, including uncontrolled proliferation and a tendency to spread round the body and colonise remote organs. The theory assumes that the same hallmarks of cancer are reinvented de novo in each host by a sort of fast-paced Darwinian process of natural selection. Though entrenched, the somatic mutation theory has almost no predictive power, its explanations amounting to little more than just- so stories on a case-by-case basis. Crucially, it fails to explain how random mutations confer so many fitness-improving gains of function together. It seems paradoxical that increasingly damaged and defective genomes should enable a neoplasm to acquire such powerfully functional and predictable hallmarks. Over the past two years, Charles Lineweaver of the Australian National University and I have developed a radically alternative account of cancer. We started by noting that cancer is not confined to humans, but is widespread among mammals, birds, reptiles and fish, suggesting it has deep evolutionary roots, probably stretching back to the dawn of multicellular life. We were also struck by the fact that cancer almost never invents anything new. Instead, it merely appropriates already existing properties of the host organism, many of them very basic and ancient. Limitless proliferation, for example, has been a fundamental feature of unicellular life for 3.5 billion years. Metastasis – the process whereby normally sedentary cells become mobile, leave a tumour and spread around the body – mimics what happens during embryogenesis, when immature cells surge in organized patterns to designated locations. And the propensity of circulating cancer cells to invade other organs closely parallels what the immune system does to heal wounds. These facts, which cancer biologists know well, combined with the predictable and efficient way that the cancer progresses through its various stages of malignancy, convinced us that cancer is not a case of damaged rogue cells running amok, but a well-organised and efficient survival response to a threatening cellular micro-environment. To use a computer analogy, we think all cells come pre-loaded with a powerful ancient ‘cancer subroutine’. It is normally quiescent, but it can be triggered in many ways – by faulty tissue architecture, lack of oxygen, or chemicals. Crucially, the various distinctive hallmarks of cancer are not stumbled across by accident – as the orthodox theory maintains – but are systematically deployed as part of the neoplasm’s survival response. An analogy is a genie in a bottle. Many assaults can smash the bottle, but once released, the genie executes its function with ruthless efficiency. The mainstream cancer community, in a massive effort to sequence any cancer cells they can get their hands on for signs of tell- tale mutations, is fixated with scrutinising the shards of glass from the shattered bottle, believing the answer lies in enigmatic patterns of change. But this is to conflate trigger with cause. The true villain is the (undamaged) genie, not the damaged confinement. In practice, the subroutine driving the cancer genie is unlikely to be a simple set of genes, but more likely a sophisticated regulatory network with complex pathways. In biology, an efficient complex process usually implies an extended period of evolution. Lineweaver and I believe that most of the cancer subroutine evolved gradually over a period between 1.5 billion and 600 million years ago, when primitive multicellular life first emerged. If we are right, then cancer is a sort of throwback or default to such an ancestral form; in technical jargon, it is an atavistic phenotype. Do we have any evidence for this? We do. It has been known since the work of the German Nobel prizewinner Otto Warburg in the 1920s that cancer flips to an ancient mode of metabolism called fermentation, adapted to very low oxygen conditions. Intriguingly, early multi-celled organisms evolved at a time when oxygen levels on the Earth were still very low. Why did evolution not eliminate the scourge of cancer over the many millions of years since it emerged? The answer is clear. Parts of the ‘cancer subroutine’ play a critical role in embryo development, wound healing and the immune system. It has been known for decades that cancer-associated ‘oncogenes’ are active during embryo development, but are normally switched off thereafter. If these ancient genes that guide the organism’s basic body plan (also in low-oxygen conditions) are re-awakened and re-expressed in the adult form, cancer results. Our theory incorporates many known facts and ideas from mainstream cancer biology, but we have connected the dots in a novel way. The theory makes several testable predictions, and it also has sweeping implications for therapy. We think the search for a general-purpose ‘cure’ for cancer is an expensive diversion, and that cancer, being so deeply embedded in the nature of multicellular life itself, is best managed and controlled (not eliminated) by challenging the cancer with physical conditions inimical to its ancient atavistic lifestyle. Only by fully understanding the place of cancer in the great sweep of evolutionary history will a serious impact be made on mortality rates. Professor Paul Davies is Principal investigator in the center for convergence of Physical Science and cancer biology at Arizona State University. The center is supported by a substantial grant from the US National cancer Institute. Paul Davies is the Adelaide Festival of Ideas (Thursday, October 17 to Sunday, October 20) keynote speaker. adelaidefestivalofideas.com.au