## Fusion and sex in protocells & the start of evolution

In 1864, five years after reading Darwin’s On the Origin of Species, Pyotr Kropotkin — the anarchist prince of mutual aid — was leading a geographic survey expedition aboard a dog-sleigh — a distinctly Siberian variant of the HMS Beagle. In the harsh Manchurian climate, Kropotkin did not see competition ‘red in tooth and claw’, but a flourishing of cooperation as animals banded together to survive their environment. From this, he built a theory of mutual aid as a driving factor of evolution. Among his countless observations, he noted that no matter how selfish an animal was, it still had to come together with others of its species, at least to reproduce. In this, he saw both sex and cooperation as primary evolutionary forces.

Now, Martin A. Nowak has taken up the challenge of putting cooperation as a central driver of evolution. With his colleagues, he has tracked the problem from myriad angles, and it is not surprising that recently he has turned to sex. In a paper released at the start of this month, Sam Sinai, Jason Olejarz, Iulia A. Neagu, & Nowak (2016) argue that sex is primary. We need sex just to kick start the evolution of a primordial cell.

In this post, I want to sketch Sinai et al.’s (2016) main argument, discuss prior work on the primacy of sex, a similar model by Wilf & Ewens, the puzzle over emergence of higher levels of organization, and the difference between the protocell fusion studied by Sinai et al. (2016) and sex as it is normally understood. My goal is to introduce this fascinating new field that Sinai et al. (2016) are opening to you, dear reader; to provide them with some feedback on their preprint; and, to sketch some preliminary ideas for future extensions of their work.

## Three mechanisms of dark selection for ruxolitinib resistance

Last week I returned from the 6th annual IMO Workshop at the Moffitt Cancer Center in Tampa, Florida. As I’ve sketched in an earlier post, my team worked on understanding ruxolitinib resistance in chronic myelomonocytic leukemia (CMML). We developed a suite of integrated multi-scale models for uncovering how resistance arises in CMML with no apparent strong selective pressures, no changes in tumour burden, and no genetic changes in the clonal architecture of the tumour. On the morning of Friday, November 11th, we were the final group of five to present. Eric Padron shared the clinical background, Andriy Marusyk set up our paradox of resistance, and I sketched six of our mathematical models, the experiments they define, and how we plan to go forward with the \$50k pilot grant that was the prize of this competition.

You can look through our whole slide deck. But in this post, I will concentrate on the four models that make up the core of our approach. Three models at the level of cells corresponding to different mechanisms of dark selection, and a model at the level of receptors to justify them. The goal is to show that these models lead to qualitatively different dynamics that are sufficiently different that the models could be distinguished between by experiments with realistic levels of noise.

## Dark selection and ruxolitinib resistance in myeloid neoplasms

I am weathering the US election in Tampa, Florida. For this week, I am back at the Moffitt Cancer Center to participate in the 6th annual IMO Workshop. The 2016 theme is one of the biggest challenges to current cancer treatment: therapy resistance. All five teams participating this year are comfortable with the evolutionary view of cancer as a highly heterogeneous disease. And up to four of the teams are ready to embrace and refine a classic model of resistance. The classic model that supposes that:

• treatment changes the selective pressure on the treatment-naive tumour.
• This shifting pressure creates a proliferative or survival difference between sensitive cancer cells and either an existing or de novo mutant.
• The resistant cells then outcompete the sensitive cells and — if further interventions (like drug holidays or new drugs or dosage changes) are not pursued — take over the tumour: returning it to a state dangerous to the patient.

Clinically this process of response and relapse is usually characterised by a (usually rapid) decrease in tumour burden, a transient period of low tumour burden, and finally a quick return of the disease.

But what if your cancer isn’t very heterogeneous? What if there is no proliferative or survival differences introduced by therapy among the tumour cells? And what if you don’t see the U curve of tumour burden? But resistance still emerges. This year, that is the paradox facing team orange as we look at chronic myelomonocytic leukemia (CMML) and other myeloid neoplasms.

CMML is a leukemia that usually occurs in the elderly and is the most frequent myeloproliferative neoplasm (Vardiman et al., 2009). It has a median survival of 30 months, with death coming from progression to AML in 1/3rd of cases and cytopenias in the others. In 2011, the dual JAK1/JAK2 inhibitor ruxolitinib was approved for treatment of the related cancer of myelofibrosis based on its ability to releave the symptoms of the disease. Recently, it has also started to see use for CMML.

When treating these cancers with ruxolitinib, Eric Padron — our clinical leader alongside David Basanta and Andriy Marusyk — sees the drastic reduction and then relapse in symptoms (most notably fatigue and spleen size) but none of the microdynamical signs of the classic model of resistance. We see the global properties of resistance, but not the evidence of selection. To make sense of this, our team has to illuminate the mechanism of an undetected — dark — selection. Once we classify this microdynamical mechanism, we can hope to refine existing therapies or design new therapies to adapt to it.

## Don’t take Pokemon Go for dead: a model of product growth

In the last month, some people wrote about the decay in active users for Pokemon Go after its first month, in a tone that presents the game as likely a mere fad – with article on 538, cinemablend and Bloomberg, for example. “Have you deleted Pokémon Go yet?” was even trending on Twitter. Although it is of course certainly possible that this ends up being an accurate description for the game, I posit that such conclusions are rushed. To do so, I examine some systemic reasons that would make the Pokemon Go numbers for August be inevitably lower than those for July, without necessarily implying that the game is doomed to dwindle into irrelevance.

Students in Waterloo playing Pokemon Go. Photo courtesy of Maylin Cui.

Others have made similar points before – see this article and the end of this one for example. However, in the spirit of TheEGG, and unlike what most of the press articles can afford to do, we’ll bring some mathematical modeling into our arguments.

## Multiplicative versus additive fitness and the limit of weak selection

Previously, I have discussed the importance of understanding how fitness is defined in a given model. So far, I’ve focused on how mathematically equivalent formulations can have different ontological commitments. In this post, I want to touch briefly on another concern: two different types of mathematical definitions of fitness. In particular, I will discuss additive fitness versus multiplicative fitness.[1] You often see the former in continuous time replicator dynamics and the latter in discrete time models.

In some ways, these versions are equivalent: there is a natural bijection between them through the exponential map or by taking the limit of infinitesimally small time-steps. A special case of more general Lie theory. But in practice, they are used differently in models. Implicitly changing which definition one uses throughout a model — without running back and forth through the isomorphism — can lead to silly mistakes. Thankfully, there is usually a quick fix for this in the limit of weak selection.

I suspect that this post is common knowledge. However, I didn’t have a quick reference to give to Pranav Warman, so I am writing this.

## Evolutionary dynamics of acid and VEGF production in tumours

Today was my presentation day at ECMTB/SMB 2016. I spoke in David Basanta’s mini-symposium on the games that cancer cells play and postered during the poster session. The mini-symposium started with a brief intro from David, and had 25 minute talks from Jacob Scott, myself, Alexander Anderson, and John Nagy. David, Jake, Sandy, and John are some of the top mathematical oncologists and really drew a crowd, so I felt privileged at the opportunity to address that crowd. It was also just fun to see lots of familiar faces in the same place.

A crowded room by the end of Sandy’s presentation.

My talk was focused on two projects. The first part was the advertised “Evolutionary dynamics of acid and VEGF production in tumours” that I’ve been working on with Robert Vander Velde, Jake, and David. The second part — and my poster later in the day — was the additional “(+ measuring games in non-small cell lung cancer)” based on work with Jeffrey Peacock, Andriy Marusyk, and Jake. You can download my slides here (also the poster), but they are probably hard to make sense of without a presentation. I had intended to have a preprint out on this prior to today, but it will follow next week instead. Since there are already many blog posts about the double goods project on TheEGG, in this post I will organize them into a single annotated linkdex.

## Modeling influenza at ECMTB/SMB 2016

This week, I am at the University of Nottingham for the joint meeting of the Society of Mathematical Biology and the European Conference on Mathematical and Theoretical Biology — ECMTB/SMB 2016. It is a huge meeting, with over 800 delegates in attendance, 308 half-hour mini-symposium talks, 264 twenty-minute contributed talks, 190 posters, 7 prize talks, 7 plenary talks, and 1 public lecture. With seventeen to eighteen sessions running in parallel, it is impossible to see more than a tiny fraction of the content. And impossible for me to give you a comprehensive account of the event. However, I did want to share some moments from this week. If you are at ECMTB and want to share some of your highlights for TheEGG then let me know, and we can have you guest post.

I did not come to Nottingham alone. Above is a photo of current/recent Moffitteers that made their way to the meeting this year.

On the train ride to Nottingham, I needed to hear some success stories of mathematical biology. One of the ones that Dan Nichol volunteered was the SIR-model for controlling the spread of infectious disease. This is a simple system of ODEs with three compartments corresponding to the infection status of individuals in the population: susceptible (S), infectious (I), recovered (R). It is given by the following equations

\begin{aligned} \dot{S} & = - \beta I S \\ \dot{I} & = \beta I S - \gamma I \\ \dot{R} & = \gamma I, \end{aligned}

where $\beta$ and $\gamma$ are usually taken to be constants dependent on the pathogen, and the total number of individuals $N = S + I + R$ is an invariant of the dynamics.

As the replicator dynamics are to evolutionary game theory, the SIR-model is to epidemiology. And it was where Julia Gog opened the conference with her plenary on the challenges of modeling infectious disease. In this post, I will briefly touch on her extensions of the SIR-model and how she used it to look at the 2009 swine flu outbreak in the US.

## Hamiltonian systems and closed orbits in replicator dynamics of cancer

Last month, I classified the possible dynamic regimes of our model of acidity and vasculature as linear goods in cancer. In one of those dynamic regimes, there is an internal fixed point and I claimed closed orbits around that point. However, I did not justify or illustrate this claim. In this post, I will sketch how to prove that those orbits are indeed closed, and show some examples. In the process, we’ll see how to transform our replicator dynamics into a Hamiltonian system and use standard tricks from classical mechanics to our advantage. As before, my tricks will draw heavily from Hauert et al. (2002) analysis of the optional public good game. Studying this classic paper closely is useful for us because of an analogy that Robert Vander Velde found between the linear version of our double goods model for the Warburg effect and the optional public good game.

The post will mostly be about the mathematics. However, at the end, I will consider an example of how these sort of cyclic dynamics can matter for treatment. In particular, I will consider what happens if we target aerobic glycolysis with a drug like lonidamine but stop the treatment too early.

## Acidity and vascularization as linear goods in cancer

Last month, Robert Vander Velde discussed a striking similarity between the linear version of our model of two anti-correlated goods and the Hauert et al. (2002) optional public good game. Robert didn’t get a chance to go into the detailed math behind the scenes, so I wanted to do that today. The derivations here will be in the context of mathematical oncology, but will follow the earlier ecological work closely. There is only a small (and generally inconsequential) difference in the mathematics of the double anti-correlated goods and the optional public goods games. Keep your eye out for it, dear reader, and mention it in the comments if you catch it.[1]

In this post, I will remind you of the double goods game for acidity and vascularization, show you how to simplify the resulting fitness functions in the linear case — without using the approximations of the general case — and then classify the possible dynamics. From the classification of dynamics, I will speculate on how to treat the game to take us from one regime to another. In particular, we will see the importance of treating anemia, that buffer therapy can be effective, and not so much for bevacizumab.

## Cancer metabolism and voluntary public goods games

When I first came to Tampa to do my Masters[1], my focus turned to explanations of the Warburg effect — especially a recent paper by Archetti (2014) — and the acid-mediated tumor invasion hypothesis (Gatenby, 1995; Basanta et al., 2008). In the course of our discussions about Archetti (2013,2014), Artem proposed the idea of combining two public goods, such as acid and growth factors. In an earlier post, Artem described the model that came out of these discussions. This model uses two “anti-correlated” public goods in tumors: oxygen (from vasculature) and acid (from glycolytic metabolism).

The dynamics of our model has some interesting properties such as an internal equilibrium and (as we showed later) cycles. When I saw these cycles I started to think about “games” with similar dynamics to see if they held any insights. One such model was Hauert et al.’s (2002) voluntary public goods game.[2] As I looked closer at our model and their model I realized that the properties and logic of these two models are much more similar than we initially thought. In this post, I will briefly explain Hauert et al.’s (2002) model and then discuss its potential application to cancer, and to our model.