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.

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.

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.

Evolutionary dynamics of cancer in the bone

I don’t know about you, dear reader, but when I was a senior in highschool, I was busy skipping class to play CounterStrike. And I wasn’t even any good at it. Pranav Warman, however, is busy spending his senior year curing cancer. Or at least modeling it. On Friday, David Basanta, Pranav, and I spent much of the evening trying to understand prostate cancer after it has metastasized to the bone. Below, you can see us trying to make sense of some Mathematica calculations.^[1]

In this post, I want to sketch some of the ideas that we fooled around with. First is a model of healthy bone. Second is an introduction of the tumour into the system. Third, we will consider a model of a simple chemotherapy as treatment. You might notice some similarities to Warman et al. (2015) and my old discussions of the Basanta et al. (2012) model of tumour-stroma interaction. This is not accidental.

Short history of iterated prisoner’s dilemma tournaments

Nineteen Eighty — if I had to pick the year that computational modeling invaded evolutionary game theory then that would be it. In March, 1980 — exactly thirty-five years ago — was when Robert Axelrod, a professor of political science at University of Michigan, published the results of his first tournament for iterated prisoner’s dilemma in the Journal of Conflict Resolution. Game theory experts, especially those specializing in Prisoner’s dilemma, from the disciplines of psychology, political science, economics, sociology, and mathematics submitted 14 FORTRAN programs to compete in a round-robin tournament coded by Axelrod and his research assistant Jeff Pynnonen. If you want to relive these early days of evolutionary game theory but have forgotten FORTRAN and only speak Python then I recommend submitting a strategy to an analogous tournament by Vincent Knight on GitHub. But before I tell you more about submitting, dear reader, I want to celebrate the anniversary of Axelrod’s paper by sharing more about the original tournament.

Maybe it will give you some ideas for strategies.

Helicobacter pylori and stem cells in the gastric crypt

Last Friday, the 4th Integrated Mathematical Oncology Workshop finished here at Moffitt. The event drew a variety of internal and external participants — you can see a blurry photo of many of them above — and was structured as a competition between four teams specializing in four different domains: Microbiome, Hepatitis C, Human papillomavirus, and Helicobacter pylori. The goal of each team was to build mathematical models of a specific problem in their domain that were well integrated with existing clinical and biological resources, the reward was a start-up grant to the project that seemed most promising to the team of judges. As I mentioned earlier in the week, I was on team H. Pylori — lead by Heiko Enderling with clinical insights from Domenico Coppola and Jose M. Pimiento. To get a feeling for the atmosphere of this workshop, I recommend a video summary of 2013’s workshop made by Parmvir Bahia, David Basanta, and Arturo Araujo:

I want to use this post to summarize some of the modeling that we did for the interaction of H. Pylori and gastric cancer. This is a brief outline — a reminder of sorts — and concentrates only on the parts that I was closely involved in. Unfortunately, this means that I won’t cover all the perspectives that our team offered, nor all the great work that they did. I apologize for the content I omitted. Hopefully, I can convince some other team members to blog about their experience to give a more balanced perspective.

This post also won’t cover all that you might want to know about bacteria and gastric cancer. As we saw earlier, fun questions about H. Pylori span many length and temporal scales and it was difficult to pick one to focus on. Domenico pointed us toward Houghton et al.’s (2004) work on the effect of H. Pylori on stem cell recruitment (for a recent survey, see Bessede et al., 2014), and suggested we aim our modeling at a level where we can discuss stem cells quantitatively. The hope is to use the abundance of stem cells as a new marker for disease progression. In the few days of the workshop, we ended up building and partially integrating two complimentary models; one agent-based and one based purely on ODEs. In the future, we hope to refine and parametrize these models based on patient data from Moffitt for the non-H. Pylori related gastric cancers, and from our partners in Cali, Colombia for H. Pylori related disease.

Predicting the risk of relapse after stopping imatinib in chronic myeloid leukemia

To escape the Montreal cold, I am visiting the Sunshine State this week. I’m in Tampa for Moffitt’s 3rd annual integrated mathematical oncology workshop. The goal of the workshop is to lock clinicians, biologists, and mathematicians in the same room for a week to develop and implement mathematical models focussed on personalizing treatment for a range of different cancers. The event is structured as a competition between four teams of ten to twelve people focused on specific cancer types. I am on Javier Pinilla-Ibarz, Kendra Sweet, and David Basanta‘s team working on chronic myeloid leukemia. We have a nice mix of three clinicians, one theoretical biologist, one machine learning scientist, and five mathematical modelers from different backgrounds. The first day was focused on getting modelers up to speed on the relevant biology and defining a question to tackle over the next three days.

Liquidity hoarding and systemic failure in the ecology of banks

As you might have guessed from my recent posts, I am cautious in trying to use mathematics to build insilications for predicting, profiting from, or controlling financial markets. However, I realize the wealth of data available on financial networks and interactions (compared to similar resources in ecology, for example) and the myriad of interesting questions about both economics and humans (and their institutions) more generally that understanding finance can answer. As such, I am more than happy to look at heuristics and other toy models in order to learn about financial systems. I am particularly interested in understanding the interplay between individual versus systemic risk because of analogies to social dilemmas in evolutionary game theory (and the related discussions of individual vs. inclusive vs. group fitness) and recently developed connections with modeling in ecology.

Three-month Libor-overnight Interest Swap based on data from Bloomberg and figure 1 of Domanski & Turner (2011). The vertical line marks 15 September 2008 — the day Lehman Brothers filed for bankruptcy.

A particular interesting phenomenon to understand is the sudden liquidity freeze during the recent financial crisis — interbank lending beyond very short maturities virtually disappeared, three-month Libor (a key benchmarks for interest rates on interbank loans) skyrocketed, and the world banking system ground to a halt. The proximate cause for this phase transition was the bankruptcy of Lehman Brothers — the fourth largest investment bank in the US — at 1:45 am on 15 September 2008, but the real culprit lay in build up of unchecked systemic risk (Ivashina & Scharfstein, 2010; Domanski & Turner, 2011; Gorton & Metrick, 2012). Since I am no economist, banker, or trader, the connections and simple mathematical models that Robert May has been advocating (e.g. May, Levin, & Sugihara (2008)) serve as my window into this foreign land. The idea of a good heuristic model is to cut away all non-essential features and try to capture the essence of the complicated phenomena needed for our insight. In this case, we need to keep around an idealized version of banks, their loan network, some external assets with which to trigger an initial failure, and a way to represent confidence. The question then becomes: under what conditions is the initial failure contained to one or a few banks, and when does it paralyze or — without intervention — destroy the whole financial system?

Cooperation through useful delusions: quasi-magical thinking and subjective utility

Economists that take bounded rationality seriously treat their research like a chess game and follow the reductive approach: start with all the pieces — a fully rational agent — and kill/capture/remove pieces until the game ends, i.e. see what sort of restrictions can be placed on the agents to deviate from rationality and better reflect human behavior. Sometimes these restrictions can be linked to evolution, but usually the models are independent of evolutionary arguments. In contrast, evolutionary game theory has traditionally played Go and concerned itself with the simplest agents that are only capable of behaving according to a fixed strategy specified by their genes — no learning, no reasoning, no built in rationality. If egtheorists want to approximate human behavior then they have to play new stones and take a constructuve approach: start with genetically predetermined agents and build them up to better reflect the richness and variety of human (or even other animal) behaviors (McNamara, 2013). I’ve always preferred Go over chess, and so I am partial to the constructive approach toward rationality. I like to start with replicator dynamics and work my way up, add agency, perception and deception, ethnocentrism, or emotional profiles and general condition behavior.

Most recently, my colleagues and I have been interested in the relationship between evolution and learning, both individual and social. A key realization has been that evolution takes cues from an external reality, while learning is guided by a subjective utility, and there is no a priori reason for those two incentives to align. As such, we can have agents acting rationally on their genetically specified subjective perception of the objective game. To avoid making assumptions about how agents might deal with risk, we want them to know a probability that others will cooperate with them. However, this depends on the agent’s history and local environment, so each agent should learn these probabilities for itself. In our previous presentation of results we concentrated on the case where the agents were rational Bayesian learners, but we know that this is an assumption not justified by evolutionary models or observations of human behavior. Hence, in this post we will explore the possibility that agents can have learning peculiarities like quasi-magical thinking, and how these peculiarities can co-evolve with subjective utilities.

Hunger Games themed semi-iterated prisoner’s dilemma tournament

With all the talk surrounding it, crowdsourcing science might seem like a new concept and it might be true for citizen science efforts, but it is definitely an old trick to source your research to other researchers. In fact, evolutionary game theory was born (or at least popularized) by one such crowdsourcing exercise; in 1980, Robert Axelrod wanted to find out the best strategy for iterated prisoner’s dilemma and reached out to prominent researchers for strategy submissions to a round-robin tournmanet. Tit-for-tat was the winning strategy, but the real victor was Axelrod. His 1981 paper with Hamilton analyzing the result went on to become a standard reference in applications of game theory to social questions (at least outside of economics), agent-based modeling, and — of course — evolutionary game theory. Of Axelrod’s sizeable 47,222 (at time of writing) citations, almost half (23,370) come from this single paper. The tradition of tournaments continues among researchers, I’ve even discussed an imitation tournament on imitation previously.

The cynical moral of the tale: if you want to be noticed then run a game theory tournament. The folks at Brilliant.org — a website offering weekly olympiad-style challange problems in math and physics — took this message to heart, coupled it to the tried-and-true marketing technique of linking to a popular movie/book franchise, and decided to run a Hunger Games themed semi-iterated Prisoner’s dillema tournament. Submit a quick explanation of your strategy and Python script to play the game, and you could be one of the 5 winners of the $1,000 grand prize. Hooray! The submission deadline is August 18th, 2013 and all you need is a Brilliant account and it seems that these are free. If you are a reader of TheEGG blog then I recommend submitting a strategy, and discussing it in the comments (either before or after the deadline); I am interested to see what you come up with.