Principles of biological computation: from circadian clock to evolution

For the final — third — day of the Santa Fe Institute workshop on “What is Biological Computation?” (11 – 13 September) organized by Albert Kao, Jessica Flack, and David Wolpert, we opened the floor to short impormptu talks from all the participants. The result was 21 presentations organized in 4 sessions. As with my posts on the previous two days of this workshop (Day 1: Elements of biological computation & stochastic thermodynamics of life; Day 2: The science and engineering of biological computation: from process to software to DNA-based neural networks), I want to briefly touch on all the presentations from the closing day in this post and the following. But this time I won’t follow the chronological order, and instead regroup slightly. In this post I’ll cover about half the talks, and save the discussion of collective computation for next week.

If you prefer my completely raw, unedited impressions in a series of chronological tweets, then you can look at the threads for the three days: Wednesday (14 tweets), Thursday (15 tweets), and Friday (31 tweets).

As before, it is important to note that this is the workshop through my eyes. So this retelling is subject to the limits of my understanding, notes, and recollection. This is especially distorting for this final day given the large number of 10 minute talks.

The science and engineering of biological computation: from process to software to DNA-based neural networks

In the earlier days of TheEGG, I used to write extensively about the themes of some of the smaller conferences and workshops that I attended. One of the first such workshops I blogged about in detail was the 2nd workshop on Natural Algorithms and the Sciences in May 2013. That spawned an eight post series that I closed with a vision for a path toward an algorithmic theory of biology. In the six years since, I’ve been following that path. But I have fallen out of the habit of writing summary posts about the workshops that I attend.

Since my recent trip to the Santa Fe Institute for the “What is biological computation?” workshop (11 – 13 September 2019) brought me full circle in thinking about algorithmic biology, I thought I’d rekindle the habit of post-workshop blogging. During this SFI workshop — unlike the 2013 workshop in Princeton — I was live tweeting. So if you prefer my completely raw, unedited impressions in tweet form then you can take a look at those threads for Wednesday (14 tweets), Thursday (15 tweets), and Friday (31 tweets). Last week, I wrote about the first day (Wednesday): Elements of biological computation & stochastic thermodynamics of life.

This week, I want to go through the shorter second day and the presentations by Luca Cardelli, Stephanie Forrest, and Lulu Qian.

As before, it is also important to note that this is the workshop through my eyes. So this retelling is subject to the limits of my understanding, notes, and recollection. And as I procrastinate more and more on writing up the story, that recollection becomes less and less accurate.

Elements of biological computation & stochastic thermodynamics of life

This week, I was visiting the Santa Fe Institute for a workshop organized by Albert Kao, Jessica Flack, and David Wolpert on “What is biological computation?” (11 – 13 September 2019). It was an ambitious question and I don’t think that we were able to answer it in just three days of discussion, but I think that we all certainly learnt a lot.

At least, I know that I learned a lot of new things.

The workshop had around 34 attendees from across the world, but from the reaction on twitter it seems like many more would have been eager to attend also. Hence, both to help synchronize the memory networks of all the participants and to share with those who couldn’t attend, I want to use this series of blog post to jot down some of the topics that were discussed at the meeting.

During the conference, I was live tweeting. So if you prefer my completely raw, unedited impressions in tweet form then you can take a look at those threads for Wednesday (14 tweets), Thursday (15 tweets), and Friday (31 tweets). The workshop itself was organized around discussion, and the presentations were only seeds. Unfortunately, my live tweeting and this post are primarily limited to just the presentations. But I will follow up with some synthesis and reflection in the future.

Due to the vast amount discussed during the workshop, I will focus this post on just the first day. I’ll follow with posts on the other days later.

It is also important to note that this is the workshop through my eyes. And thus this retelling is subject to the limits of my understanding, notes, and recollection. In particular, I wasn’t able to follow the stochastic thermodynamics that dominated the afternoon of the first day. And although I do provide some retelling, I hope that I can convince one of the experts to provide a more careful blog post on the topic.

Effective games from spatial structure

For the last week, I’ve been at the Institute Mittag-Leffler of the Royal Swedish Academy of Sciences for their program on mathematical biology. The institute is a series of apartments and a grand mathematical library located in the suburbs of Stockholm. And the program is a mostly unstructured atmosphere — with only about 4 hours of seminars over the whole week — aimed to bring like-minded researchers together. It has been a great opportunity to reconnect with old colleagues and meet some new ones.

During my time here, I’ve been thinking a lot about effective games and the effects of spatial structure. Discussions with Philip Gerlee were particularly helpful to reinvigorate my interest in this. As part of my reflection, I revisited the Ohtsuki-Nowak (2006) transform and wanted to use this post to share a cute observation about how space can create an effective game where there is no reductive game.

Suppose you were using our recent game assay to measure an effective game, and you got the above left graph for the fitness functions of your two types. On the x-axis, you have seeding proportion of type C and on the y-axis you have fitness. In cyan you have the measured fitness function for type C and in magenta, you have the fitness function for type D. The particular fitnesses scale of the y-axis is not super important, not even the x-intercept — I’ve chosen them purely for convenience. The only important aspect is that the cyan and magenta lines are parallel, with a positive slope, and the magenta above the cyan.

This is not a crazy result to get, compare it to the fitness functions for the Alectinib + CAF condition measured in Kaznatcheev et al. (2018) which is shown at right. There, cyan is parental and magenta is resistant. The two lines of best fit aren’t parallel, but they aren’t that far off.

How would you interpret this sort of graph? Is there a game-like interaction happening there?

Of course, this is a trick question that I give away by the title and set-up. The answer will depend on if you’re asking about effective or reductive games, and what you know about the population structure. And this is the cute observation that I want to highlight.

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.

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 Wadhwa 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.

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?

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.

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.

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.