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AS THE US faces up to its 鈥渇iscal cliff鈥� of massive spending cuts, a major issue is burgeoning health costs. High on the list of those costs is cancer therapy, with the clamour for hugely expensive drugs 鈥� many of which have little or no clinical benefit 鈥� set to grow as baby boomers age.

Cancer research swallows billions of dollars a year, but the life expectancy for someone diagnosed with cancer that has spread to other parts of the body has changed little over several decades. Therapy is often a haphazard rearguard action against the inevitable. And the search for a general cure remains as elusive as ever.

Recognising this depressing impasse, the US National Cancer Institute (NCI) took a bold step in 2008 by deciding that the field might benefit from the input of mathematicians and physical scientists, whose methods and insights differ markedly from those of cancer biologists.

After all, the history of science teaches us that major advances come when a subject鈥檚 conceptual foundations are revised. Maybe progress is slow because we are looking at the problem in the wrong way? So the NCI created 12 centres for physical science and oncology. Four years on, they are starting to bear fruit, for example, by showing how the elastic properties of cells change as cancer progresses.

In the 19th century, living organisms were widely regarded as machines infused by vital forces. Biologists eventually came to realise that cells are not some sort of magic matter, but complex networks of chemical reaction pathways. Then came the genetics revolution, which describes life in the informational language of instructions, codes and signalling. Mainstream research today focuses almost exclusively on chemical pathways or genetic sequencing. For example, drugs are designed to block reaction pathways implicated in cancer. The cancer genome atlas is amassing terabytes of data in which people hope to spot some sort of mutational pattern. But while of great scientific interest, such projects have not led to the much-anticipated breakthrough.

Why? There are fundamental obstacles: living cells, including cancer cells, are a bottomless pit of complexity, and cancer cells are notoriously heterogeneous. A reductionist approach that seeks to unravel the details of every pathway of every cancer cell type might employ researchers for decades and consume billions of dollars, with little impact clinically. Linear chains of cause and effect rarely work in biology, which is dominated by elaborate networks of interactions such as feedback and control loops.

There is, however, another way of looking at cells. In addition to being bags of chemicals and information processing systems, they are also physical objects, with properties such as size, mass, shape, elasticity, free energy, surface stickiness and electrical potential. Cancer cells contain pumps, levers, pulleys and other paraphernalia familiar to physicists and engineers. Furthermore, many of these properties are known to change systematically as cancer progresses in malignancy.

First, though, we need to get away from the notion of a cure, and think of controlling or managing cancer. Like ageing, cancer is not so much a disease as a process. And just as the effects of ageing can be mitigated without a full understanding of the process, the same could be true of cancer.

鈥淟ike ageing, cancer is not so much a disease as a process鈥�

Many accounts misleadingly describe cancer as rogue cells running amok. In fact, once cancer is triggered, it is usually very deterministic in its behaviour. Primary tumours are rarely the cause of death. It is when cancer spreads around the body and colonises other organs that the patient鈥檚 prospects deteriorate sharply.

This so-called metastasis is a well characterised, if poorly understood, physical process. Cells migrate from the primary tumour to blood vessels, which they enter through spaces in the vessel walls. Then, swept along in the torrent, they circulate in the blood system, sometimes individually, sometimes 鈥渞afting鈥� in gangs like Lilliputian raiders, stuck together by blood platelets. A fraction of these migrants get jammed in tiny blood vessels called venules or, more spectacularly, roll along the vessel wall and fling out little molecular grappling hooks called cadherins. Thus anchored against the blood flow, they inveigle their way into the nearest organ.

During this process, the physical properties and shape of the cells can change dramatically. Generally, cancer cells are soft and misshapen compared with healthy cells of the same type, a transformation that may affect their motility and increase their invasive potential. Cancer cells are adept at building nests in foreign tissue, by altering the structure and physical properties of the host organ鈥檚 supporting extracellular matrix, and recruiting local healthy cells. There are also hints that a primary tumour may send out chemical signals ahead of time to prepare the physical and chemical ground for the colonists.

Although metastasis seems fiendishly efficient, most disseminated cancer cells never go on to cause trouble. The vast majority die, and the survivors may lie dormant for years or even decades, either as individual, quiescent, cells in the bone marrow, or as micro-metastases in tissues, before erupting into proliferating secondary tumours. Hence the many cases of 鈥渃ancer survivors鈥� who die when the same cancer returns with enhanced malignancy years or even decades after a primary tumour has been removed.

The spread of cancer presents many possibilities for clinical intervention once the dream of a cure has been abandoned. For example, if the period of dormancy can be extended by, say, a factor of five, many breast, colon and prostate cancers would cease to be a health issue. How could this be achieved?

Evolutionary roots

We do not need to know the intricate details of the cancer cells鈥� innards to figure out how their overall behaviour might be controlled. It is well known that cells regulate the action of genes not just as a result of chemical signals, but because of the physical properties of their micro-environment. They can sense forces such as shear stresses and the elasticity of nearby tissue. They are also responsive to temperature, electric fields, pH, pressure and oxygen concentration. All these variables offer opportunities for intervening and stabilising widespread cancer cells. For example, a few doctors are attempting to treat cancer using hyperbaric oxygen therapy, where the patient is placed in a chamber of high-pressure pure oxygen, which affects cancer cell metabolism.

We also need to involve other kinds of biologists in cancer research 鈥� after all, cancer is widespread among mammals, fish, reptiles, even plants. Clearly it is an integral part of the evolutionary story of multicellular life over the last billion years.

Most normal cells seem to come pre-loaded with a 鈥渃ancer subroutine鈥� that can be triggered by a variety of insults, and we need to understand the evolutionary origin of this just as much as the triggering mechanisms. In addition, it has long been recognised that there are many similarities between cancer and embryo development, and evidence is mounting that some genes expressed during embryogenesis get re-awakened in cancer.

Right now, the huge cancer research programme is long on technical data, but short on understanding. By reshaping the conceptual landscape, we may at last see how to make serious inroads into tackling a much- feared disease that touches every family on the planet.