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.

About Artem Kaznatcheev
From the Department of Computer Science at Oxford University and Department of Translational Hematology & Oncology Research at Cleveland Clinic, I marvel at the world through algorithmic lenses. My mind is drawn to evolutionary dynamics, theoretical computer science, mathematical oncology, computational learning theory, and philosophy of science. Previously I was at the Department of Integrated Mathematical Oncology at Moffitt Cancer Center, and the School of Computer Science and Department of Psychology at McGill University. In a past life, I worried about quantum queries at the Institute for Quantum Computing and Department of Combinatorics & Optimization at University of Waterloo and as a visitor to the Centre for Quantum Technologies at National University of Singapore. Meander with me on Google+ and Twitter.

7 Responses to The wei wu wei of evolutionary oncology

  1. Andriy Marusyk says:

    Great Piece!

  2. Pingback: Cataloging a year of blogging: cancer and fitness landscapes | Theory, Evolution, and Games Group

  3. April says:

    We discussed this blog post in a journal club at my graduate school. For a long time there have been discussions internally how to define the concept of “evolutionary medicine”, so I proposed this blog post as a mean to discuss. There were a concensus that this approach to cancer research makes sense and so does the point of applying the terminology of evolutionary medicine. The reason is that there seem to be a general view of human physiology, and medicine, as something rather static. This Newtonian view of the human physiology does not fit as a body (human or another animal) is a dynamic entity which may be better approached as an ecosystem than a static clockwork. However, this is rather hard to communicate or formulate. This the approach of ‘story telling’, with the Chinese philosophy & water flow, was therefore appreciated and rather praized. We also discussed the blog post of whether or not a species concept for cancer is plausible: if you view the body as a dynamic ecosystem, what species definition would you then apply for the cancer residing within? Even though this was a curious reformulation, we could not land on a proper entity definition for cancer. Rather ending up debating what initial purpose and reality lies within a species concept than can transend as functional to cancer, etc. But it was good fun discussing! So, both are great posts!

    • Thank you April!

      I am glad that you considered the post interesting enough for a reading group. Have you guys come across particular good papers for the evolutionary medicine and evolutionary oncology theme? I’d be interested to hear about them. Katerina Stankova’s short piece on resistance games might also be of interest.

      I definitely think it is good to explore the ecology of cancer as an alternative to the static Newtonian view. And it is nice to see that as a field we are starting to leave mostly theoretical or descriptive work and moving towards direct measurement and even clinical trials.

      As for the species concept, I assume you are referring to this post: Looking for species in cancer but finding strategies and players. It might be worthwhile to take the conversation over to that comments section, to avoid splintering discussion, but overall I agree with you.

      I don’t necessarily think it is useful to define a species concept for cancer (and hence why I prefer thinking about strategies and players). But a lot of the philosophy of biology around the species concept can be useful for not hitting similar pitfalls with newer definitions. I think that the best approach is to not be dogmatic about ideas like ‘species’ and try to learn from the history of the term. After all, in the history of biology, species also had to undergo a transition from an Aristotelian static view to a fuzzy dynamic view.

      • April Kleppe says:

        Hi Artem,

        Indeed we enjoyed the blog post as a neat starting point for a discussion on evolutionary medicine. None of us actually deal with oncology, but rather evolutionary biology as a common denominator between our research. We discussed the blog post in the light of a talk at the graduate school, by visiting Prof. Frank Thuijsman (Maastricht Uni, Belgium). He spoke of the treating tumour cells (specifically prostate cancer) as agents in a game similar to paper-scissor-rock. Roughly speaking, medicine can take out one of the cell types, but not the others, and high consistent dosage of medication can yield a selection for tolerance against the medication. Awaiting for the internal fight/regulation between the cells (“paper” taking out “rock”), leaving the cell-type that is vulnerable to the human yielded medicine as the dominant one (eg “paper”), makes it possible to reduce the overall tumour population. I tried locate the exact paper where this is described, but it seems this work is mostly described in the research & workshops they organise at the Maastricht Univ., as well as publications that are under construction and not yet in print. A closely, related study is described here from same university group (https://www.sciencedaily.com/releases/2018/08/180809112526.htm, containing ref to original paper). They apparently applied this game theory model in real life, and not only theoretically, and with quite some success to patients suffering from late stage prostate cancer. The goal is to make it a chronic disease (eg HIV), treatable with regulated medication that keeps the cancer cells in check. All of this is evidently quite fascinating and a tad mindblowing for someone who is not in the field itself.

        So to answer your question, no we did not discuss any specific papers, but rather how oncology (and other fields, eg HIV) medical research seems to overall go into a direction of treating the game, rather than the player – thus, the concept of evolutionary medicine.

        I did not see the connection between his talk&research and your blog post – with respect to treating cancer as a game theory and as an evolving/ecological “biome” until we sat down to discuss. It should have been quite obvious, but sometimes you need to say things loudly and then the connections appear. Thank you for the tip of Katerina Stankova’s paper, I will pass it on to the group and maybe we can develop the discussion further.

        I will add the specifc comments to the “Looking for species in cancer..” post. To define a biological entity – consistently – is a tricky topic!

        And again thank you, I think the entire blog is brilliant also for people outside of game theory and oncology, as it is so tightly linked to how we think of dynamic, evolving systems.

  4. Pingback: British agricultural revolution gave us evolution by natural selection | Theory, Evolution, and Games Group

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