Hobbes on knowledge & computer simulations of evolution

Earlier this week, I was at the Second Joint Congress on Evolutionary Biology (Evol2018). It was overwhelming, but very educational.

Many of the talks were about very specific evolutionary mechanisms in very specific model organisms. This diversity of questions and approaches to answers reminded me of the importance of bouquets of heuristic models in biology. But what made this particularly overwhelming for me as a non-biologist was the lack of unifying formal framework to make sense of what was happening. Without the encyclopedic knowledge of a good naturalist, I had a very difficult time linking topics to each other. I was experiencing the pluralistic nature of biology. This was stressed by Laura Nuño De La Rosa‘s slide that contrasts the pluralism of biology with the theory reduction of physics:

That’s right, to highlight the pluralism, there were great talks from philosophers of biology along side all the experimental and theoretical biology at Evol2018.

As I’ve discussed before, I think that theoretical computer science can provide the unifying formal framework that biology needs. In particular, the cstheory approach to reductions is the more robust (compared to physics) notion of ‘theory reduction’ that a pluralistic discipline like evolutionary biology could benefit from. However, I still don’t have any idea of how such a formal framework would look in practice. Hence, throughout Evol2018 I needed refuge from the overwhelming overstimulation of organisms and mechanisms that were foreign to me.

One of the places I sought refuge was in talks on computational studies. There, I heard speakers emphasize several times that they weren’t “just simulating evolution” but that their programs were evolution (or evolving) in a computer. Not only were they looking at evolution in a computer, but this model organism gave them an advantage over other systems because of its transparency: they could track every lineage, every offspring, every mutation, and every random event. Plus, computation is cheaper and easier than culturing E.coli, brewing yeast, or raising fruit flies. And just like those model organisms, computational models could test evolutionary hypotheses and generate new ones.

This defensive emphasis surprised me. It suggested that these researchers have often been questioned on the usefulness of their simulations for the study of evolution.

In this post, I want to reflect on some reasons for such questioning.

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Labyrinth: Fitness landscapes as mazes, not mountains

Tonight, I am passing through Toulouse on my way to Montpellier for the 2nd Joint Congress on Evolutionary Biology. If you are also attending then find me on 21 August at poster P-0861 on level 2 to learn about computational complexity as an ultimate constraint on evolution.

During the flight over, I was thinking about fitness landscapes. Unsurprising — I know. A particular point that I try to make about fitness landscapes in my work is that we should imagine them as mazes, not as mountain ranges. Recently, Raoul Wadham reminded me that I haven’t written about the maze metaphor on the blog. So now is a good time to write on labyrinths.

On page 356 of The roles of mutation, inbreeding, crossbreeding, and selection in evolution, Sewall Wright tells us that evolution proceeds on a fitness landscape. We are to imagine these landscapes as mountain ranges, and natural selection as a walk uphill. What follows — signed by Dr. Jorge Lednem Beagle, former navigator of the fitness maze — throws unexpected light on this perspective. The first two pages of the record are missing.

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QBIOX: Distinguishing mathematical from verbal models in biology

There is a network at Oxford know as QBIOX that aims to connect researchers in the quantitative biosciences. They try to foster collaborations across the university and organize symposia where people from various departments can share their quantitative approaches to biology. Yesterday was my second or third time attending, and I wanted to share a brief overview of the three talks by Philip Maini, Edward Morrissey, and Heather Harrington. In the process, we’ll get to look at slime molds, colon crypts, neural crests, and glycolysis. And see modeling approaches ranging from ODEs to hybrid automata to STAN to algebraic systems biology. All of this will be in contrast to verbal theories.

Philip Maini started the evening off — and set the theme for my post — with a direct question as the title of his talk.

Does mathematics have anything to do with biology?

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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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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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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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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.

imo2016_participants

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.
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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.

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