Chemical games and the origin of life from prebiotic RNA

From bacteria to vertebrates, life — as we know it today — relies on complex molecular interactions, the intricacies of which science has not fully untangled. But for all its complexity, life always requires two essential abilities. Organisms need to preserve their genetic information and reproduce.

In our own cells, these tasks are assigned to specialized molecules. DNA, of course, is the memory store. The information it encodes is expressed into proteins via messenger RNAs.Transcription (the synthesis of mRNAs from DNA) and translation (the synthesis of proteins from mRNAs) are catalyzed by polymerases necessary to speed up the chemical reactions.

It is unlikely that life started that way, with such a refined division of labor. A popular theory for the origin of life, known as the RNA world, posits that life emerged from just one type of molecule: RNAs. Because RNA is made up of base-complementary nucleotides, it can be used as a template for its own reproduction, just like DNA. Since the 1980s, we also know that RNA can act as a self-catalyst. These two superpowers – information storage and self-catalysis – make it a good candidate for the title of the first spark of life on earth.

The RNA-world theory has yet to meet with empirical evidence, but laboratory experiments have shown that self-preserving and self-reproducing RNA systems can be created in vitro. Little is known, however, about the dynamics that governed pre- and early life. In a recent paper, Yeates et al. (2016) attempt to shed light on this problem by (1) examining how small sets of different RNA sequences can compete for survival and reproduction in the lab and (2) offering a game-theoretical interpretation of the results.

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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.


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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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.

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.
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Social algorithms and the Weapons of Math Destruction

Cathy O'Neil holding her new book: Weapons of Math Destruction at a Barnes & Noble in NYC.

Cathy O’Neil holding her new book: Weapons of Math Destruction at a Barnes & Noble in New York city.

In reference to intelligent robots taking over the world, Andrew Ng once said: “I don’t work on preventing AI from turning evil for the same reason that I don’t work on combating overpopulation on the planet Mars.” Sure, it will be an important issue to think about when the time comes. But for now, there is no productive way to think seriously about it. Today there are more concrete problems to worry about and more basic questions that need to be answered. More importantly, there are already problems to deal with. Problems that don’t involve super intelligent tin-men, killer robots, nor sentient machine overlords. Focusing on distant speculation obscures the fact that algorithms — and not necessarily very intelligent ones — already reign over our lives. And for many this reign is far from benevolent.

I owe much of my knowledge about the (negative) effects of algorithms on society to the writings of Cathy O’Neil. I highly recommend her blog A couple of months ago, she shared the proofs of her book Weapons of Math Destruction with me, and given that the book came out last week, I wanted to share some of my impressions. In this post, I want to summarize what makes a social algorithm into a weapon of math destruction, and share the example of predictive policing.

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Drug holidays and losing resistance with replicator dynamics

A couple of weeks ago, before we all left Tampa, Pranav Warman, David Basanta and I frantically worked on refinements of our model of prostate cancer in the bone. One of the things that David and Pranav hoped to see from the model was conditions under which adaptive therapy (or just treatment interrupted with non-treatment holidays) performs better than solid blocks of treatment. As we struggled to find parameters that might achieve this result, my frustration drove me to embrace the advice of George Pólya: “If you can’t solve a problem, then there is an easier problem you can solve: find it.”

IMO6 LogoIn this case, I opted to remove all mentions of the bone and cancer. Instead, I asked a simpler but more abstract question: what qualitative features must a minimal model of the evolution of resistance have in order for drug holidays to be superior to a single treatment block? In this post, I want to set up this question precisely, show why drug holidays are difficult in evolutionary models, and propose a feature that makes drug holidays viable. If you find this topic exciting then you should consider registering for the 6th annual Integrated Mathematical Oncology workshop at the Moffitt Cancer Center.[1] This year’s theme is drug resistance.
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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.
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Argument is the midwife of ideas (and other metaphors)

In their classic book Metaphors We Live By, George Lakoff and Mark Johnson argue — very convincingly, and as I’ve reviewed before — that “[m]etaphor is one of our most important tools for trying to comprehend partially what cannot be comprehended totally” and that these conceptual metaphors are central to shaping our understanding of and interaction with the world we are embedded in. Based on the authors’ grounding in linguistics, part of their case proceeds by offering examples of, by my count, over 58 different metaphors and metonymies in our everyday language; and given their book’s intentions, they chose a particularly pertinent first case: ARGUMENT is WAR.[1]

They show this metaphor in action through some example of common usage (pg. 4):

What do you want me to do? LEAVE? Then they'll keep being wrong!Your claims are indefensible.
He attacked every weak point in my argument.
His criticisms were right on target.
I demolished his argument.
I’ve never won an argument with him.
You disagree? Okay, shoot!
If you use that strategy, he’ll wipe you out.
He shot down all my arguments.

Notice that the even the xkcd I borrowed for visual reinforcement is titled ‘Duty Calls’, an expression usually associated with a departure for war. With our awareness drawn to this militaristic structure, Lakoff and Johnson encourage the reader to ask themselves: how would discussions look if instead of structuring arguments adversarially, we structured them after a cooperative activity like dance?[2]

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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.

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.

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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 all the current/recent Moffitteers that made their way to the meeting.

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.
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