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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Identifying therapy targets & evolutionary potentials in ovarian cancer

For those of us attending the 7th annual Integrated Mathematical Oncology workshop (IMO7) at the Moffitt Cancer Center in Tampa, this week was a gruelling yet exciting set of four near-all-nighters. Participants were grouped into five teams and were tasked with coming up with a new model to elucidate a facet of a particular type of cancer. With $50k on the line and enthusiasm for creating evolutionary models, Team Orange (the wonderful team I had the privilege of being a part of) set out to understand something new about ovarian cancer. In this post, I will outline my perspective on the initial model we came up with over the past week.

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Ontology of player & evolutionary game in reductive vs effective theory

In my views of game theory, I largely follow Ariel Rubinstein: game theory is a set of fables. A collection of heuristic models that helps us structure how we make sense of and communicate about the world. Evolutionary game theory was born of classic game theory theory through a series of analogies. These analogies are either generalizations or restrictions of the theory depending on if you’re thinking about the stories or the mathematics. Given this heuristic genealogy of the field — and my enjoyment of heuristic models — I usually do not worry too much about what exactly certain ontic terms like strategy, player, or game really mean or refer to. I am usually happy to leave these terms ambiguous so that they can motivate different readers to have different interpretations and subsequently push for different models of different experiments. I think it is essential for heuristic theories to foster this diverse creativity. Anything goes.

However, not everyone agrees with Ariel Rubinstein and me; some people think that EGT isn’t “just” heuristics. In fact, more recently, I have also shifted some of my uses of EGT from heuristics to abductions. When this happens, it is no longer acceptable for researchers to be willy-nilly with fundamental objects of the theory: strategies, players, and games.

The biggest culprit is the player. In particular, a lot of confusion stems from saying that “cells are players”. In this post, I’d like to explore two of the possible positions on what constitutes players and evolutionary games.

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Hackathons and a brief history of mathematical oncology

It was Friday — two in the morning. And I was busy fine-tuning a model in Mathematica and editing slides for our presentation. My team and I had been running on coffee and snacks all week. Most of us had met each other for the first time on Monday, got an inkling of the problem space we’d be working on, brainstormed, and hacked together a number of equations and a few chunks of code to prototype a solution. In seven hours, we would have to submit our presentation to the judges. Fifty thousand dollars in start-up funding was on the line.

A classic hackathon, except for one key difference: my team wasn’t just the usual mathematicians, programmers, computer & physical scientists. Some of the key members were biologists and clinicians specializing in blood cancers. And we weren’t prototyping a new app. We were trying to predict the risk of relapse for patients with chronic myeloid leukemia, who had stopped receiving imatinib. This was 2013 and I was at the 3rd annual integrated mathematical oncology workshop. It was one of my first exposures to using mathematical and computational tools to study cancer; the field of mathematical oncology.

As you can tell from other posts on TheEGG, I’ve continued thinking about and working on mathematical oncology. The workshops have also continued. The 7th annual IMO workshop — focused on stroma this year — is starting right now. If you’re not in Tampa then you can follow #MoffittIMO on twitter.

Since I’m not attending in person this year, I thought I’d provide a broad overview based on an article I wrote for Oxford Computer Science’s InSPIRED Research (see pg. 20-1 of this pdf for the original) and a paper by Helen Byrne (2010).

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Oxygen fueling dark selection in the bone marrow

While November 2016 might be remembered for the inauspicious political upset likely to leave future historians as confused as we are, a more positive event transpired in tandem – the 6th Integrated Mathematical Oncology (IMO) Workshop. I was honoured to take part as a member of Team Orange, where we were tasked with investigating the emergence of treatment resistance in chronic myelomonocytic leukemia (CMML).

Unlike many other cancers where the evolution of resistance to treatment is well understood, CMML is something of an enigma as the efficacy of treatment flounders even though the standard treatment doesn’t directly impinge upon tumour cells themselves.  This raises a whole host of questions, and Artem has already eloquently laid out both why this question captivated us, and the combined approach we took to probing it. In this blog post, I’ll focus on exploring one of our mechanistic hypotheses – the potential role of oxygen in treatment resistance.

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Poor reasons for preprints & post-publication peer-review

Last week, I revived the blog with some reflections on open science. In particular, I went into the case for pre-prints and the problem with the academic publishing system. This week, I want to continue this thread by examining three common arguments for preprints: speed, feedback, and public access. I think that these arguments are often motivated in the wrong way. In their standard presentation, they are bad arguments for a good idea. By pointing out these perceived shortcoming, I hope that we can develop more convincing arguments for preprints. Or maybe methods of publication that are even better than the current approach to preprints.

These thoughts are not completely formed, and I am eager to refine them in follow up posts. As it stand, this is more of a hastily written rant.

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Preprints and a problem with academic publishing

This is the 250th post on the Theory, Evolutionary, and Games Group Blog. And although my posting pace has slowed in recent months, I see this as a milestone along the continuing road of open science. And I want to take this post as an opportunity to make some comments on open science.

To get this far, I’ve relied on a lot of help and encouragement. Both directly from all the wonderful guest posts and comments, and indirectly from general recognition. Most recently, this has taken the form of the Canadian blogging and science outreach network Science Borealis recognized us as one of the top 12 science blogs in Canada.

Given this connection, it is natural to also view me as an ally of other movements associated with open science; like, (1) preprints and (2) post-publication peer-review (PPPR). To some extent, I do support both of these activities. First, I regularly post my papers to ArXiv & BioRxiv. Just in the two preceeding months, I’ve put out a paper on the complexity of evolutionary equilibria and joint work on how fibroblasts and alectinib switch the games that cancers play. Another will follow later this month based on our project during the 2016 IMO Workshop. And I’ve been doing this for a while: the first draft of my evolutionary equilibria paper, for example, is older than BioRxiv — which only launched in November 2013. More than 20 years after physicists, mathematicians, and computer scientists started using ArXiv.

Second, some might think of my blog posts as PPPRs. For example. occasionally I try to write detailed comments on preprints and published papers. For example, my post on fusion and sex in proto-cells commenting on a preprint by Sam Sinai, Jason Olejarz and their colleagues. Finally, I am impressed and made happy by the now iconic graphic on the growth of preprints in biology.

But that doesn’t mean I find these ideas to be beyond criticism, and — more importantly — it doesn’t mean that there aren’t poor reasons for supporting preprints and PPPR.

Recently, I’ve seen a number of articles and tweets written on this topic both for and against (or neutral toward) pre-prints and for PPPR. Even Nature is telling us to embrace preprints. In the coming series of posts, I want to share some of my reflections on the case for preprints, and also argue that there isn’t anything all that revolutionary or transformative in them. If we want progress then we should instead think in terms of working papers. And as for post-publications peer review — instead, we should promote a culture of commentaries, glosses, and literature review/synthesis.

Currently, we do not publish papers to share ideas. We have ideas just to publish papers. And we need to change this aspect academic culture.

In this post, I will sketch some of the problems with academic publishing. Problems that I think any model of sharing results will have to address.

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Spatializing the Go-vs-Grow game with the Ohtsuki-Nowak transform

Recently, I’ve been thinking a lot about small projects to get students started with evolutionary game theory. One idea that came to mind is to look at games that have been analyzed in the inviscid regime then ‘spatialize’ them and reanalyze them. This is usually not difficult to do and provides some motivation to solving for and making sense of the dynamic regimes of a game. And it is not always pointless, for example, our edge effects paper (Kaznatcheev et al, 2015) is mostly just a spatialization of Basanta et al.’s (2008a) Go-vs-Grow game together with some discussion.

Technically, TheEGG together with that paper have everything that one would need to learn this spatializing technique. However, I realized that my earlier posts on spatializing with the Ohtsuki-Nowak transform might a bit too abstract and the paper a bit too terse for a student who just started with EGT. As such, in this post, I want to go more slowly through a concrete example of spatializing an evolutionary game. Hopefully, it will be useful to students. If you are a beginner to EGT that is reading this post, and something doesn’t make sense then please ask for clarification in the comments.

I’ll use the Go-vs-Grow game as the example. I will focus on the mathematics, and if you want to read about the biological or oncological significance then I encourage you to read Kaznatcheev et al. (2015) in full.
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Cataloging a year of blogging: complexity in evolution, general models, and philosophy

Last month, with just hours to spare in January, I shared a linkdex of the 14 cancer-related posts from TheEGG in 2016. Now, as February runs out, it’s time to reflect on the 15 non cancer-specific posts from last year. Although, as we’ll see, some of them are still related to mathematical oncology. With a nice number like 15, I feel that I am obliged to divide them into three categories of five articles each. Which does make for a stretch in narrowing down themes.

The three themes were: (1) complexity, supply driven evolution, and abiogenesis, (2) general models and their features, (3) algorithmic philosophy and the social good.

And yes, two months have passed and all I’ve posted to the blog are two 2016-in-review posts. Even those were rushed and misshapen. But I promise there is more and better coming; hopefully with a regular schedule.

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Cataloging a year of cancer blogging: double goods, measuring games & resistance

Happy year of the Rooster and 2017,

This month marks the start of the 7th calendar year of updates on TheEGG. Time to celebrate and summarize the posts of the year past. In 2016 there was the same number of posts as 2015, but instead of being clustered in a period of <7 months, they were more uniformly distributed across the calendar. Every month had at least one new post, although not necessarily written by me (in the case of the single post by Abel Molina in October). There were 29 entries, one linkdex cataloging 2015, and two updates on EGT reading group 51 – 55 & 56 – 60.

In September, as part of my relocation from Tampa to Oxford, I attended the 4th Heidelberg Laureate Forum. I wrote two pieces for their blog: Alan Turing and science through the algorithmic lens and a spotlight on Jan Poleszczuk: from HLF2013 to mathematical oncology. You can read those (and more posts coming this year) on their blog. I won’t go into more detail here.

As before, this post is meant to serve as an organizing reference and a way to uncover common themes on TheEGG. A list of TL;DRs from 2016. The year was split up into four major categories: cancer, complexity & evolution, other models, and philosophy. The cancer posts make up almost half the articles from last year, and are further subdivided into three subsections: double goods game, experimental game theory, and therapy resistance. I want to focus on these cancer posts for this linkdex, and the other three categories in the next installment.

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