MEDICAL researchers, like most of the rest of us, tend to be reductionists. They try to explain complex phenomena by breaking them down to their constituent parts. If we understand these basic building blocks, the theory goes, then we can understand the larger picture. But over the past century or so, physicists, chemists and other scientists have cast doubt over whether complex systems can be explained away like this.

Chaos theory, emergence theory, the study of dynamic systems and myriad other disciplines have shown how complex phenomena have nonlinear structures without neat causal chains. Properties emerge that cannot be predicted from constituent parts; feedback loops can reverse the causal direction; and macroscopic properties can be described without making any assumption about a system’s microscopic nature.

Such ideas have transformed physics, chemistry, sociology, psychology, economics, information technology, quantum mechanics and countless other areas of investigation. Medical research, however, has largely ignored the work that has been done on complex systems.

That might be about to change, says Dr Elizabeth Sigston, a head and neck surgeon at Monash Health who has codeveloped a new “emergence framework” for understanding cancer.

“The whole way science research has developed – and I started off doing the same thing – is that you have something you’re interested in, maybe a protein or a gene, and you become an expert in that and know everything about it. And you want your one thing to be the one thing, the magic bullet that solves whatever issue you’re dealing with. But the problem is that nature isn’t like that.”

The prevailing theory of carcinogenesis for the past half century has been the somatic mutation theory, which considers cancer as a genetic disease, caused by a mutation at cell level which leads to unfettered cell proliferation. More recently, another theory, the tissue organisation field theory, locates the problem at the tissue level: disorganised tissue leads to a pathological environment for cells, which then proliferate to form a tumour. Although these two theories appear to be contradictory, Dr Sigston thinks that they can be dissolved into an approach that sees cancer as an “emergent system”, where there is no ultimate causative level. Focusing solely on the microscopic level is not going to enable an understanding of cancer as an emergent complex phenomenon, she says.

“Of course genetics play a role but we’ve been unduly fixated on genes in cancer research,” she says. “It goes right back to the 1920s. Then in the 1970s, we had Richard Dawkins and his selfish gene and then later the Human Genome Project. We’ve poured billions of dollars into genomics and, yes, we’ve made some progress. But not a huge amount when you look at the sums of money involved. It hasn’t been a great return on investment.”

When we diagnose cancer, we find it occurring at the tissue level, and that’s where we need to focus on, she says, rather than the gene level.

“Once you define your functional tissue unit and look at it in the sense of a system, then we can look at how it’s different in cancer. We can look at risk factors, how the disease progresses, what things impact environmentally, and of course also genetics that may create change in the components at the tissue level. The trouble is that there aren’t enough people looking across the whole range of things, and pulling these disparate things together.”

She says that we need to shift our focus from causal relationships that are fundamentally difficult to predict towards interpreting the patterns of cancer as an emergent system.

Dr Sigston points to her own recent research on oral cancers. Leveraging insights from her work looking at cancer as an emergent system, she has identified a subset of patients whose cancers are very likely to recur regardless of whether they have radiotherapy or chemotherapy.

“There’s the potential to put them in immunotherapy to see if they get a better result. But at the moment they have to wait until they fail everything else. Immunotherapy is making advances, but it still only benefits 10–30% of patients. We’ve developed this new therapy but we still have to work out who’s going to benefit.”

But change is hard. Emergent systems can be counterintuitive, and reductionism so hard-wired that it’s hard to accept phenomena in a system that can’t be predicted at a lower level.

“And yet that’s how nature works,” says Dr Sigston. “Even in something as simple as baking a cake, you can’t infer it from the initial ingredients alone. If you mix them in the wrong order, it will be different. If the oven’s not hot enough, the cake won’t rise. We’ve got to get people looking at things in a totally different way, and not just focusing on the minutiae.”

 

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