The Noble Eightfold Path to Mathematical Biology

Twitter is not a place for nuance. It is a place for short, pithy statements. But if you follow the right people, those short statements can be very insightful. In these rare case, a tweet can be like a kōan: a starting place for thought and meditation. Today I want to reflect on such a thoughtful tweet from Rob Noble outlining his template for doing good work in mathematical biology. This reflection is inspired by the discussions we have on my recent post on mathtimidation by analytic solution vs curse of computing by simulation.

So, with slight modification and expansion from Rob’s original — and in keeping with the opening theme — let me present The Noble Eightfold Path to Mathematical Bilogy:

  1. Right Intention: Identify a problem or mysterious effect in biology;
  2. Right View: Study the existing mathematical and mental models for this or similar problems;
  3. Right Effort: Create model based on the biology;
  4. Right Conduct: Check that the output of the model matches data;
  5. Right Speech: Humbly write up;
  6. Right Mindfulness: Analyse why model works;
  7. Right Livelihood: Based on 6, create simplest, most general useful model;
  8. Right Samadhi: Rewrite focussing on 6 & 7.

The hardest, most valuable work begins at step 6.

The only problem is that people often stop at step 5, and sometimes skip step 2 and even step 3.

This suggests that the model is more prescriptive than descriptive. And aspiration for good scholarship in mathematical biology.

In the rest of the post, I want to reflect on if it is the right aspiration. And also add some detail to the steps.

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Minimal models for explaining unbounded increase in fitness

On a prior version of my paper on computational complexity as an ultimate constraint, Hemachander Subramanian made a good comment and question:

Nice analysis Artem! If we think of the fitness as a function of genes, interactions between two genes, and interactions between three genes and so on, your analysis using epistasis takes into account only the interactions (second order and more). The presence or absence of the genes themselves (first order) can change the landscape itself, though. Evolution might be able to play the game of standing still as the landscape around it changes until a species is “stabilized” by finding itself in a peak. The question is would traversing these time-dependent landscapes for optima is still uncomputable?

And although I responded to his comment in the bioRxiv Disqus thread, it seems that comments are version locked and so you cannot see Hema’s comment anymore on the newest version. As such, I wanted to share my response on the blog and expand a bit on it.

Mostly this will be an incomplete argument for why biologists should care about worst-case analysis. I’ll have to expand on it more in the future.

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Mathtimidation by analytic solution vs curse of computing by simulation

Recently, I was chatting with Patrick Ellsworth about the merits of simulation vs analytic solutions in evolutionary game theory. As you might expect from my old posts on the curse of computing, and my enjoyment of classifying games into dynamic regimes, I started with my typical argument against simulations. However, as I searched for a positive argument for analytic solutions of games, I realized that I didn’t have a good one. Instead, I arrived at another negative argument — this time against analytic solutions of heuristic models.

Hopefully this curmudgeoning comes as no surprise by now.

But it did leave me in a rather confused state.

Given that TheEGG is meant as a place to share such confusions, I want to use this post to set the stage for the simulation vs analytic debate in EGT and then rehearse my arguments. I hope that, dear reader, you will then help resolve the confusion.

First, for context, I’ll share my own journey from simulations to analytic approaches. You can see a visual sketch of it above. Second, I’ll present an argument against simulations — at least as I framed that argument around the time I arrived at Moffitt. Third, I’ll present the new argument against analytic approaches. At the end — as is often the case — there will be no resolution.

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Separating theory from nonsense via communication norms, not Truth

Earlier this week on twitter, Brian Skinner wrote an interesting thread on how to distinguish good theory from crackpottery. He started with a trait that both theorists and crackpots share: we have an “irrational self-confidence” — a belief that just by thinking we “can arrive at previously-unrealized truths about the world”. From this starting point, the two diverge in their use of evidence. A crackpot relies primarily on positive evidence: he thinks hard about a problem, arrives at a theory that feels right, and then publicizes the result.

A theorist, on the other prong, incorporates negative evidence: she ponders hard about a problem, arrives at a theory that feels right and then proceeds to try to disprove that theory. She reads the existing literature and looks at the competing theories, takes time to understand them and compare them against her own. If any disagree with hers then she figures out why those theories are wrong. She pushes her theory to the extremes, looks at its limiting cases and checks them for agreement with existing knowledge. Only after her theory comes out unscathed from all these challenges does she publicize it.

For Skinner, this second prong is the definition of scholarship. In practice, coming up with a correct theory is mostly a painful process of discarding many of your own wrong attempts. A good theorist is a thorough, methodical and skeptical of their own ideas.

The terminology of crackpottery vs scholarship is probably overly harsh, as Skinner acknowledges. And in practice, somebody might be a good theorist in one domain but a crackpot elsewhere. As Malkym Lesdrae points out, there are many accomplished accademics who are also crackpot theorists: “Most often it’s about things outside their field of specialty”. Thus, this ideal self-skepticism might be domain specific.

It is also a destructive ideal.

In other words, I disagreed with Skinner on the best way to separate good theory from nonsense. Mostly on the framing. Skinner crystalized our disagreement in a tweet: whereas he views self-skepticism as I an obligation to the Truth, I view a similar sort of self-reflective behavior as a social obligation. I am committed to this latter view because I want to make sense of things like heuristic models, where truth is secondary to other modelling concerns. Where truth is not the most useful yardstick for checking the usefulness of model. Where you hear Box’s slogan: “all models are wrong, but some are useful.

Given the brief summary of Skinner’s view above — and please, Brian, correct me in the comments if I misrepresented your position — I want to use the rest of this post to sketch what I mean by self-reflective behavior as a social obligation.
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John Maynard Smith on reductive vs effective thinking about evolution

“The logic of animal conflict” — a 1973 paper by Maynard Smith and Price — is usually taken as the starting for evolutionary game theory. And as far as I am an evolutionary game theorists, it influences my thinking. Most recently, this thinking has led me to the conclusion that there are two difference conceptions of evolutionary games possible: reductive vs. effective. However, I don’t think that this would have come as much of a surprise to Maynard Smith and Price. In fact, the two men embodied the two different ways of thinking that underlay my two interpretations.

I was recently reminded of this when Aakash Pandey shared a Web of Stories interview with John Maynard Smith. This is a 4 minute snippet of a long interview with Maynard Smith. In the snippet, he starts with a discussion of the Price equation (or Price’s theorem, if you want to have that debate) but quickly digresses to a discussion of the two kinds of mathematical theories that can be made in science. He identifies himself with the reductive view and Price with the effective. I recommend watching the whole video, although I’ll quote relavent passages below.

In this post, I’ll present Maynard Smith’s distinction on the two types of thinking in evolutionary models. But I will do this in my own terminology to stress the connections to my recent work on evolutionary games. However, I don’t think this distinction is limited to evolutionary game theory. As Maynard Smith suggests in the video, it extends to all of evolutionary biology and maybe scientific modelling more generally.

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Personal case study on the usefulness of philosophy to biology

At the start of this month, one of my favourite blogs — Dynamic Ecology — pointed me to a great interview with Michela Massimi. She has recently won the Royal Society’s Wilkins-Bernal-Medawar Medal for the philosophy of science, and to celebrate Philip Ball interviewed her for Quanta. I recommend reading the whole interview, but for this post, I will focus on just one aspect.

Ball asked Massimi how she defends philosophy of science against dismissive comments by scientists like Feynman or Hawking. In response, she made the very important point that for the philosophy of science to be useful, it doesn’t need to be useful to science:

Dismissive claims by famous physicists that philosophy is either a useless intellectual exercise, or not on a par with physics because of being incapable of progress, seem to start from the false assumption that philosophy has to be of use for scientists or is of no use at all.

But all that matters is that it be of some use. We would not assess the intellectual value of Roman history in terms of how useful it might be to the Romans themselves. The same for archaeology and anthropology. Why should philosophy of science be any different?

Instead, philosophy is useful for humankind more generally. This is certainly true.

But even for a scientist who is only worrying about getting that next grant, or publishing that next flashy paper. For a scientist who is completely detached from the interests of humanity. Even for this scientist, I don’t think we have to concede the point on the usefulness of philosophy of science. Because philosophy, and philosophy of science in particular, doesn’t need to be useful to science. But it often is.

Here I want to give a personal example that I first shared in the comments on Dynamic Ecology.
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Abstract is not the opposite of empirical: case of the game assay

Last week, Jacob Scott was at a meeting to celebrate the establishment of the Center for Evolutionary Therapy at Moffitt, and he presented our work on measuring the effective games that non-small cell lung cancer plays (see this preprint for the latest draft). From the audience, David Basanta summarized it in a tweet as “trying to make our game theory models less abstract”. But I actually saw our work as doing the opposite (and so quickly disagreed).

However, I could understand the way David was using ‘abstract’. I think I’ve often used it in this colloquial sense as well. And in that sense it is often the opposite of empirical, which is seen as colloquially ‘concrete’. Given my arrogance, I — of course — assume that my current conception of ‘abstract’ is the correct one, and the colloquial sense is wrong. To test myself: in this post, I will attempt to define both what ‘abstract’ means and how it is used colloquially. As a case study, I will use the game assay that David and I disagreed about.

This is a particularly useful exercise for me because it lets me make better sense of how two very different-seeming aspects of my work — the theoretical versus the empirical — are both abstractions. It also lets me think about when simple models are abstract and when they’re ‘just’ toys.

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Deadlock & Leader as deformations of Prisoner’s dilemma & Hawk-Dove games

Recently, I’ve been working on revisions for our paper on measuring the games that cancer plays. One of the concerns raised by the editor is that we don’t spend enough time introducing game theory and in particular the Deadlock and Leader games that we observed. This is in large part due to the fact that these are not the most exciting games and not much theoretic efforts have been spent on them in the past. In fact, none that I know of in mathematical oncology.

With that said, I think it is possible to relate the Deadlock and Leader games to more famous games like Prisoner’s dilemma and the Hawk-Dove games; both that I’ve discussed at length on TheEGG. Given that I am currently at the Lorentz Center in Leiden for a workshop on Understanding Cancer Through Evolutionary Game Theory (follow along on twitter via #cancerEGT), I thought it’d be a good time to give this description here. Maybe it’ll inspire some mathematical oncologists to play with these games.

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Dark selection from spatial cytokine signaling networks

Greetings, Theory, Evolution, and Games Group! It’s a pleasure to be on the other side of the keyboard today. Many thanks to Artem for the invite to write about some of our recent work and the opportunity to introduce myself via this post. I do a bit of blogging of my own over at vcannataro.com — mostly about neat science I stumble over while figuring out my way.

I’m a biologist. I study the evolutionary dynamics within somatic tissue, or, how mutations occur, compete, accumulate, and persist in our tissues, and how these dynamics manifest as aging and cancer (Cannataro et al., 2017a). I also study the evolutionary dynamics within tumors, and the evolution of resistance to targeted therapy (Cannataro et al., 2017b).

In November 2016 I attended the Integrated Mathematical Oncology Workshop on resistance, a workweek-long intensive competitive workshop where winners receive hard-earned $$ for research, and found myself placed in #teamOrange along with Artem. In my experience at said workshop (attended 2015 and 2016), things usually pan out like this: teams of a dozen or so members are assembled by the workshop organizers, insuring a healthy mix of background-education heterogeneity among groups, and then after the groups decide on a project they devise distinct but intersecting approaches to tackle the problem at hand. I bounced around a bit early on within #teamOrange contributing to our project where I could, and when the need for a spatially explicit model of cytokine diffusion and cell response came up I jumped at the opportunity to lead that endeavor. I had created spatially explicit cellular models before — such as a model of cell replacement in the intestinal crypt (Cannataro et al., 2016) — but never one that incorporated the diffusion or spread of some agent through the space. That seemed like a pretty nifty tool to add to my research kit. Fortunately, computational modeler extraordinaire David Basanta was on our team to teach me about modeling diffusion (thanks David!).

Below is a short overview of the model we devised.

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Ratcheting and the Gillespie algorithm for dark selection

In Artem’s previous post about the IMO workshop he suggests that “[s]ince we are forced to move from the genetic to the epigenetic level of description, it becomes important to suggest a plausible mechanism for heritable epigenetic effects. We need to find a stochastic ratcheted phenotypic switch among the pathways of the CMML cells.” Here I’ll go into more detail about modeling this ratcheting and how to go about identifying the mechanism. We can think of this as a potential implementation of the TYK bypass in the JAK-STAT pathway described experimentally by Koppikar et al. (2012). However, I won’t go into the specifics of exact molecules, keeping to the abstract essence.

After David Robert Grime’s post on oxygen use, this is the third entry in our series on dark selection in chronic myelomonocytic leukemia (CMML). We have posted a preprint (Kaznatcheev et al., 2017) on our project to BioRxiv and section 3.1 therein follows this post closely.

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