The wei wu wei of evolutionary oncology

The world was disordered, rains would come and the rivers would flood. No one knew when. When it rained, plants would grow, but no one knew which were fit to eat and which were poisonous. Sickness was rife. Life was precarious.

The philosopher-king Yu dredged the rivers, cleaned them so they would flow into the sea. Only then were the people of the Middle Kingdom able to grow the five grains to obtain food.

Generations later, Bai Gui — the prime minister of Wei — boasted to Mengzi: “my management of the water is superior to that of Yu.”

Mengzi responded: “You are wrong. Yu’s method was based on the way of the water. It is why Yu used the four seas as receptacles. But you are using the neighbouring states as receptacles. When water goes contrary to its course, we call if overflowing. Overflowing means flooding water, something that a humane man detests… As for Yu moving the waters, he moved them without interference.”

Although Yu made changes to the environment by digging channels, he did so after understanding how the water flowed and moved naturally. He did so with knowledge of the Way. Yu’s management of water was superior to Bai Gui’s because Yu’s approach was in accordance with the Way. This is what evolutionary oncology seeks to achieve with cancer treatment. By understanding how the dynamics of somatic evolution drive tumour growth, we hope to change the selective pressures in accordance with this knowledge to manage or cure the disease.

Mistake of equating Natural and Good

The hope is that by working in accordance with nature — with the way set by evolutionary dynamics — instead of opposed to it, we can provide better treatments. But this, like much of Chinese philosophy, can be easily misinterpreted. Since the 19th century or so, the West declared itself modern and painted the East as its dual. It saw Chinese thought as ‘traditional’. Often this caricature was used in the negative. But when this caricature was positive, it romanticized the Way as an ideal; a natural perfection that existed before the modern. It suggested that we need to return to harmony with this past Way. But this passive and backwards looking caricature misses much of the point.

We can see variants of this unreasonable idealization of the ‘natural’ with health-food trends like buying raw unfiltered ‘live water’. Closer to cancer, this passive idealization of nature has forms like chelation therapy and dangerous claims that “cannabis oil cures cancer”. And many other cancer myths that David Robert Grimes has chronicled, including the curative properties of: alkaline and ketogenic diets; homoeopathy; and avoiding deodorants, cell-phones, and artificial sweeteners. These ‘natural remedies’ are most dangerous when they lead patients to abandon, avoid, or delay standard therapies. The most notable examples of this might be Steve Job’s regrets over delaying surgery for his pancreatic cancer while he instead pursued acupuncture, drinking special fruit juices, and visiting spiritualists.

But overly idealizing the ‘natural’ can be dangerous even when modern treatments aren’t avoided, just supplemented. There is a common misconception that natural remedies don’t have serious side effects. But Dr Andrew Dhawan warns that “some “natural” therapies can have adverse effects.” The common culprits include remedies like “astralgus (which can have gastrointestinal side effects, and interacts with various immune-modulating drugs we use in cancer treatment), St John’s wort (for the depression associated with cancer, has a million drug-drug interactions as well), and cesium chloride therapy (which can cause heart problems).”

Similarly, the unperturbed natural way of somatic evolution of cancer will often lead to death.

Hence, it is not the passive cartoon of natural that the mathematical oncologist studying somatic evolution advocates. And of course, ancient Chinese philosophers also didn’t present or defend this cartoon sketched by western orientalists.

Restoring or creating Harmony through intervention

Ancient Chinese philosophers were more than aware that ‘natural’ doesn’t mean good. Xunzi looked at the story of the philosopher-king Yu as an example of human ingenuity. People understood that the events shaping their lives were not just random:

They came to realize when it would rain and when it would not… They began to realize which plants they could eat, and which were poison. … They would plant then according to changes in the weather, which they came to know as the seasons.
…
Eventually, what had once seemed like unpredictable chaos of natural phenomena … were turned into a harmonious system. … But this was not natural. Humans had domesticated the world. Humans had made it so that these disparate phenomena became a harmonious set of processes.

For Xunzi, humans and their social institutions and material technologies are not separate from the Way. In fact, without institutions and technology, nature can be random and destructive: just like an untreated tumour. But by studying the unpredictable ways of nature we can come to understand it and work with it. Similarly, the evolutionary oncology tries to understand the dynamics of somatic evolution. Just like the farmer plans according to the season, the evolutionary oncologists might aim to measure the games that cancers play, catalog them into an almanac and then apply different therapies based on which game couples the tumour population. The aim of an evolutionary therapy then becomes to redirect the power of evolution towards ends that are more harmonious for the patient. To domesticate the tumour.

In fact, when a patient is diagnosed with cancer, the natural path can become an adversary. And here we can turn back to Mengzi. Mengzi believed that world is fragmented, in perpetual disorder and in need of constant work. This is like adaptive therapy and managing cancer instead of curing it. In certain cases, the evolutionary oncologist will realize that there is no ‘solution’ to the disease. Rather, it is a state of perpetual disorder and in need of constant therapy. By observing and responding to the constantly changing tumour, we can manage it. Although sometimes, like with CML, we might find that good managing leads us to a cure.

In the world of people, Mengzi saw the right way to approach social conflicts as “directed at changing the underlying dynamic rather than responding heatedly to the immediate issue.” Evolutionary oncology approaches tumours in the same way: change the local environment and let evolution guide a tumour towards the more desired outcome. Sometimes this means not targetting the most common (i.e. direct) subclone, but altering selective pressures against an uncommon subtype first to prep the tumour for later intervention. We showed an example of this in the double goods model. And this is what I mean by statements like “don’t treat the player, treat the game”.

Of course, Laozi, Mengzi, and Xunzi have many aspects of the Way and how to live life that they would disagree on. Similarly, Joel Brown might view evolutionary games as an aspect of cellular decision making, and I might view it as a summary of interactions between types. Archetti et al. might see IGF-II as a locally diffused public good with nonlinear payoffs and Gerlee & Altrock might question that. Dhawan, Nichol et al. might see collateral sensitive as a potential mechanism for steering evolution, while others might see it as a mark of inter-patient heterogeneity. But the evolutionary perspective allows these debates to bring something new to oncology.

And of course, we can have all these debates without reference to ancient Chinese philosophy. But sometimes it is more fun to draw inspiration from the past and from the story of how Yu tamed the waters.