Increasing my mileage

In my younger years I was never particularly keen on running, and during my military service I was lucky enough to develop shin splints, which kept me away from running distances longer than hundred meters. During my time at university I made a couple of half hearted attempts at running regularly, but they all failed miserably. But during my PhD something happened. All of a sudden I didn't get fed up with being exhausted and feeling like shit both during and after a run. I kept on going for two weeks, three weeks, a full month!

Without me noticing it running had become a habit, and, believe it or not, I was starting to like it. After another couple of months running was turning into an addiction and, following advice from a friend who was into running, I was forcing myself into not increasing my weekly mileage excessively. Despite this I contracted my first injury after about 6 months, and for the first time experienced the feeling of desperately wanting to run, but not being able to. Lesson learned. I recovered from the injury and slowly, very slowly, increased my mileage. Of course this didn't stop me from getting injured again and I think I can count up to four different injuries that I have been struggling with since (stress fracture to the shin, strained calves, non-identifiable pain to the foot, and patellofemoral pain syndrome).

Since 2009 I have been keeping an online diary of my running at a Swedish site called jogg.se, and can therefore view my improvements in retrospect. The below figure shows my yearly mileage (monthly stats are a bit to variable and seasonal), where the blue circle for 2013 is what I've achieved so far this year, and the red circle is my projected mileage. It might seems like a massive increase, but if you instead view 2012 as an anomaly it makes a lot more sense. 3000 km over the course of one years makes roughly 8 km per day, every day of the year, which I must say I'm pretty pleased with.

Translation

The last couple of months I've been preoccupied with two things: translating and running. This post will cover the first topic, and other posts will follow on the second.

The object of my attention has been the translation of a book on scientific modelling that I wrote about two years ago in Swedish together with my colleague Torbjörn Lundh. From the very start we thought that this book would benefit a community larger than the Swedish speaking one, so we always had a translation in mind. The last couple of weeks I finally came around to it, and in the process I decided to keep track of my output. I've now finished a first draft and the below figure shows my progress. I was surprised to find how consistent I've been (the bumps in the curve actually correspond to section that were pre-translated in a previous effort). The average rate turned out to be 790 words/hour, which I'm pretty happy with. As I said this is only a first draft that will be polished further.

We already have deal with a publisher, but considering the copy-editing and pre-production work that needs to be done I don't expect the book to hit the shelves any time soon.

Thinking about complexity

I have in previous blog posts alluded to my interest in philosophy of science. Together with my friend and colleague Henrik Thorén I've previously written a short piece analysing 'weak emergence', the idea that certain systems display properties that cannot be predicted through theory, but only by simulating them. This inevitably lead us down the route of complexity and complex systems, and we have for some time struggled to make sense of, and understand the notions of emergence, complexity and chaos. We decided early on that the best way to achieve this is to get together and write a book about it. A book that tries to disentangle these concepts and also analyses the role of complexity in the sciences today. Or in the words of an abstract for a grant application:

The purpose of this project is to write a book that investigates the concept of complexity from a philosophy of science perspective. This work is motivated by the fact that the concept is used diligently in almost all scientific disciplines, often without a specific meaning or definition. The main question that we hope to answer relates to the basic meaning, or possibly multiple meanings, of the concept: what is complexity, and what consequences does it have? Are there many types, or kinds, of complexity? Is complexity something that can unify disciplines? When is somethingto be considered complex, and when does the concept aid in understanding a system? These questions will be answered by carrying out a thorough conceptual analysis, in close proximity to the disciplines in which it is used. In particular we will focus our study on physics, biology, economics, sociology and sustainability science. Further, we will explore the consequences of complexity on policy making, which is closely related to our ability to describe, regulate and control complex systems. Answering the above questions is of great importance if we are to discuss and handle changes in complex systems such as the climate and global economy in a factual and objective way.

As a matter of fact or application was successful with the Helge Ax:son Johnson Foundation, and we now have some funds to continue our collaboration and realise our idea of a book about complexity. I'll keep posting as the work progresses.

The pre-metastatic niche is only half of the story of metastasis (it's the biological one)

Recently, Cancer Research UK posted an article on their blog in which they explain, in layman's terms, recent trends and ideas in research into metastatic spread. The focus of that article is on the concept of a 'pre-metastatic niche', the idea that the primary tumour emits signalling molecules that prime certain organs for the arrival of metastatic cells. We find this line of thought very interesting, as it could, at least in part, explain patterns of metastatic spread, but have strong opinions about how the ideas were presented and the lack of acknowledgment of the other factors that could be at play.  

First, the reader is given a condensed historical background, in which the surgeon Stephen Paget is given credit for having solved the riddle of metastatic patterns 150 years ago. His method of studying metastatic spread in breast cancer is briefly mentioned, however, as is often the case when the seed-soil hypothesis is mentioned, these old 'truths' do not seem to be carefully checked. For example, a much more recent study from by Dr. J Pickren (reported in The Principles of Metastasis by L. Weiss, p. 231, recently reviewed here), which reports a 4:1 ratio between splenic and hepatic metastases (compared to the 14:1 ratio that Paget observed). Another fact not accounted for by Paget in his analysis, is that the liver not only receives arterial blood, but also blood from the gut organs via the portal vein, thereby increasing the chance of it receiving circulating tumour cells (CTCs). If micro-metasases are present in the gut, then these secondary CTCs will most likely lodge in the liver increasing the risk of developing liver metastases. Lastly, Paget only studied a single location of primary tumours, making general conclusions difficult to draw - especially as the connectivity differs greatly between organs. These simple observations should make it clear that Paget's hypothesis is nothing more than an indication of what might be the case in certain circumstances, rather than a settled fact.

From reading the article one also gets the impression that CTCs are drawn to certain organs in the body (e.g. the caption of the 2nd figure reading "Tumour cells are selective about where they end up." or later in text "...which wandering tumour cells find irresistible."). This is not in agreement with what we know today (and have known for the last 30 years) about the dynamics of metastasis formation.

Figure 1: Human vascular system network topology schematic. It is evident by inspection of the network diagram that tumors originating in the gut and lung experience significantly different flow patterns and order in which they experience filtration at capillary beds than tumors originating in other parts of the ‘body’. The alternate pathways (purple) define the fraction of cells which evade arrest (filtration) at a given capillary bed. There are scant measurements of this in the literature, and none for clinical studies.

On the contrary CTCs have little influence over where they end up, instead the correct picture is that of a primary tumour releasing astronomical numbers of CTCs into the blood stream (roughly 100 million cells per day, of which most die in the blood stream), and that these cells are distributed according to physiology of the circulatory system. 

This means that each organ (except the lung and liver) receive a fraction of CTCs in direct relation to their relative blood supply, and only at this point, at which the cancer cells flow through the capillary bed of the organ, can organ specific mechanisms influence the fate of the cancer cell. This means that any explanation of why patterns of metastatic spread look as they do needs to first take into account the characteristics of the circulatory system, and only then the organ specific mechanisms such as the formation of a pre-metastatic niche.

These facts suggest (at least to us) that one should view the formation of the pre metastatic niche from a more passive point of view. The signals secreted by the primary tumour induce a systemic inflammatory response - which may or may not effect all organs. The evidence suggests that some distant sites respond in a way that makes them more hospitable to the CTCs that happen to pass though them and hence these cells are more likely to form overt metastases - but to present this as an active process is to stretch the data and to anthropomorphize to a dangerous extent.

When attempting to synthesize and communicate difficult scientific information to the public, it is always tempting to present a small slice of the story - and indeed, this is good practice as only so much can be communicated effectively at one time.  But when doing this, it is essential to point out where the limits of our understanding are, and not oversell current hypotheses as the 'truth'.  Science is, and always has been, a steady progression toward understanding, paved by models that are (we hope) less and less wrong.  The way we think today is not likely to be the same as the way we think in 10 years time.

A dialogue about evolution

I wrote this dialogue a few years ago in the wake of reading Gödel Escher Bach by Douglas Hofstadter, but I didn't know quite what to do with it. It was originally written in Swedish and when I stumbled across it the other day I realised that I could try to translate it into English and publish it here. So here goes, a dialogue about problem solving, evolution and grass:

In a leafy clearing facing a newly plowed field the Hare and the Fox meet on a fine spring day. The Hare chews away on the light green grass while the Fox bask in the rays of the newly risen sun. He looks over the field, squints and slowly faces the Hare who continues to enjoy his herbaceous snack.

The Fox: Did you know that the grass you're eating might be one of the most intelligent life forms on earth?

The Hare: Well, that's just nonsense. It's only grass, right? Just as simple and stupid as any other plant. Or are you trying to say that all plants are intelligent?

The Fox: I think you are being a bit narrow-minded when it comes to intelligence. Just because the grass is unable to talk, and converse as we do, does not mean that it's unintelligent.

The Hare: Well, then I think you have to explain what you mean by intelligence.

The Fox: Ok. To me it's the ability to solve problems. And by that I mean unexpected and novel situations that present obstacles in ones way to achieve a certain objective.

The Hare: And how on earth do you expect the grass I'm eating to achieve anything close to that? When really all it's capable of is converting carbon dioxide and sunlight into oxygen and water. 

The Fox: Now you're being too simple-minded again. You need to widen you perspectives slightly, let some more light in. Plants have simply chosen another strategy compared to us animals when it comes to staying alive and procreating. Instead of running about looking for food, they simply stay put and let it fall down on them. And in the end it might be a clever move, considering how much energy we spend on moving, you looking for fresh grass and me chasing after you.

The Hare: You might have a point.

The Fox: Of course I have, not to talk about all the energy spent on finding the right mate. The plants instead enter the great lottery and find their mate purely through chance. Actually quite convenient when you think about it.

The Hare: This is starting to make sense. So you saying that plants have chosen a completely different strategy when it comes to surviving?

The Fox: Exactly. And therefore I find it a bit unjust to judge them by our standards.

The Hare: I agree that it's a different strategy, but still a pretty stupid one. It's not like they're fighting back, like I do when you're trying to catch me. But then again, maybe it's you being stupid for not eating the defenceless plants.

The Fox: I think you're being a bit presumptuous my dear friend. You forgot to take into account the fact that I only need to spend roughly one quarter of my time looking for food and eating compared to herbivores as yourself. But we're loosing our focus now. My point was that we need to wait longer for plants to solve their problems compared animals. The problem solving instead occurs on evolutionary time scales.

The Hare: Now you've lost me again. Or rather, I've lost myself in your complicated reasoning.

The Fox: Ok. Let me explain. What I'm saying is that if a species of grass is faced with a change in its natural environment, be it a higher temperature or an invading species that competes for light and nutrients, then those plants that can stand the heat or somehow outcompete the invader will succeed while those that don't will perish. If these plants produce offspring that resemble their parents then the beneficial trait will become more common and spread in the plant population. Without too much exaggeration one could claim that the species has adapted and learnt how to handle the change, and therefore solved the problem it was faced with. Right?

The Hare: Wow, that's mouthful, or maybe I should say mindful. But are you saying that your hypothetical species of grass is making a conscious change in response to the external environment?

The Fox: No no, not at all. The only things that are required for this to happen is that there is random variation within the grass population, plants with certain properties are better at producing offspring, and lastly that the property in question is heritable.

The Hare: Now I see.

The Fox: All the life forms on planet earth have solved a whole bunch of problems throughout their history, otherwise they would never be what they are today. Giraffes have long necks because the best food on the savannah was (and still is) high up in the trees, and sharks are streamlined because it makes swimming in water a lot more efficient.

The Hare: And I have such strong legs because of dodgy characters like yourself.

The Fox: Precisely. One could say that each species on earth constitutes the solution to one and the same problem. The problem of staying alive, and to that problem it seems like there are quite a few distinct solutions. Algae and deer are very different life forms, but they both manage to stay alive.

The Hare: But my long and strong legs have hardly solved the problem. Not that I have had any difficulties escaping myself, but I know, or rather used to know, quite a few hares who ended up in a fox's belly. 

The Fox: You're absolutely right, but that's because we foxes are trying to solve the opposite problem. That of trying to catch up with you. So it all turns into an arms race where you have to keep moving just to stay in the same place.

The Hare: That sounds an awful lot like the Red Queen in Alice in Wonderland. She says that it takes all the running you can do, to keep in the same place, and if you want to get somewhere else, you must run at least twice as fast as that!

The Fox: That might be so. I never really cared for that book.

The Hare: Why? I find them really clever and hilarious.

The Fox: Well, you actually get to play a part in the story, but nowhere to be found is a character in the shape of a fox.

The Hare: Now then, I think you are being a bit egotistic. In any case, let's return to the case of problems and solutions. Maybe it's just me, but you're making it sound like every property of every animal or plant had a purpose. The neck of the giraffe, the shape of the shark. How can you be so sure about the problems they correspond to? Is there a problem for each solution? For example take the fact that your nose is black, what problem does that solve?

The Fox: An acute observation my dear friend. Of course you're right, some things just appear by pure chance, or as a by-product of some other solution. Like the lungs that both you and me carry, they developed a long time ago from the esophagus of a poor choking fish that tried to make a living on land. If the lungs had developed from another structure they might have looked completely different today. What I mean is that the solution depends both on the problem and on the solutions that are already in place. Evolution is a tinkerer who works with whatever material is at hand.

The Hare: Finally I think I understand what you're getting at. But we started talking about the grass, let's return to that. What's so special about it?

The Fox: Well, there are several things, but for one it has managed to turn a weakness into an advantage.

The Hare: That sounds exciting. Do continue!

The Fox: Grass has the peculiar property of growing from beneath instead of, as most other plants do, with shoots from the top of the plant. This means that if the grass is chewed by characters as yourself it doesn't really hurt the grass, since it's the oldest bits that are being eaten. But that's only half the story.

The Hare: Yes…

The Fox: Now, if the grass is eaten by a herbivore, then there's an obvious chance that the neighbouring plant, that might not be a grass, is also eaten. The other plant, in contrast to the grass, might suffer from the grazing and die, which in the end means more space and nutrients for the grass. And here's the punch line: the better the grass tastes to grazing animals the more it and its neighbouring plants will be eaten. The grass doesn't mind since it's growing from beneath, while the other plants take a beating from the grazing. So in the end it pays off for the grass to be eaten! Talk about a clever solution.

The Hare: Not bad. But you said that there were even more reasons to admire the grass, right?

The Fox: Yes, you're right. There exists even more sophisticated ways of getting rid of competing plants. The smartest thing you can do is actually to get someone else to do the job for you. Most species of grass make use of grazing animals, but some have gone into partnership with a more efficient player.

The Hare: Now you've lost me again. You have to keep in mind that I'm not as clever as you are.

The Fox: Look at this field. What is usually grown here?

The Hare: I believe it's wheat. To me a pretty useless crop, doesn't really taste anything. I prefer old fashioned grass.

The Fox: That's your view, but someone else is obviously of a different opinion.

The Hare:  Ah, the humans!

The Fox: Exactly. But let's start from the beginning of the story. Not so long ago, roughly ten thousand years ago, when foxes already were foxes, and hares already hares, but humans definitely not what they are today, there was a species of grass growing in the middle east whose seeds were large, tasteful and nutritious. The humans who lived in that region really enjoyed them and realised that they could be used for cooking. At this point someone came up with a brilliant idea: let's collect the seeds, plant and grow them at one spot, instead of walking about all day looking for them.

The Hare: So the humans started to grow and harvest the grass.

The Fox: Indeed. But what does that really mean? Well, the grass was kept under strict surveillance. Weeds were removed by the humans, water was supplied regularly, and even though the seeds were eaten by the humans some were planted. The humans were given a steady supply of food, while the grass was properly cared for.

The Hare: That's an interesting view of things.

The Fox: But the history doesn't end there, it's more like the beginning. The fruitful symbiosis that humans and grass entered into on the plains of the middle east has been refined beyond recognition. The grass has been bred into oats, wheat, rye and barley, and has spread with the help of humans to almost every hospitable corner of the earth. With the aid of airplanes and pesticides the competing plants are held at a safe distance, and the grass thrives as never before.

The Hare:  But who's really benefiting from this whole scheme, the humans or the grass?

The Fox: In one way the humans are using the grass for their own purposes, but at the same time they have helped this particular species of grass to become the most common plant on earth. But let's return to my original question. It seems as if this species of grass has solved the problem of staying alive in a formidable way, so do you agree that it is intelligent?

The Hare: Well actually I think you've convinced me, and won the debate as so many times before. But at least I can still run faster than you!

The Fox: I'm not so sure about that. It must have been two weeks since I tried to chase you down the last time. I have definitely improved my running since then.

The Hare: Ok then, let's give it a go then. Just make sure you give me 10 seconds head start. My life is on the line here, but only a dinner for you.

The Fox: Alright. Don't worry, you can trust me.

The Hare: (starts running across the field)

The Fox: 10…9…8…7…6…5…4…3…2…1

Searching for synergies: matrix algebraic approaches for efficient pair screening

I have together with Sven Nelander and Rebecka Jörnsten been working on the problem of experimental design for the screening of pairs of perturbations to biological systems, be it gene knock-outs or drugs or a combination thereof. The problem that arises is that the number of possible pairs grows quadratically with the number of perturbations, and this makes it impractical to test all possible combinations. In answer to this we have developed an algorithm that searches the space of combinations in an adaptive fashion making use of information found during the screen to direct the search.

The results of this work were recently accepted for publication in PLoS ONE. Below is the abstract and here's a link to the paper (not yet available on the PLoS-site).

Abstract
Functionally interacting perturbations, such as synergistic drugs pairs or synthetic lethal gene pairs, are of key interest in both pharmacology and functional genomics. However, to find such pairs by traditional screening methods is both time consuming and costly. We present a novel computational-experimental framework for efficient identification of synergistic target pairs, applicable for screening of systems with sizes on the order of current drug, small RNA or SGA (Synthetic Genetic Array) libraries (>1000 targets). This framework exploits the fact that the response of a drug pair in a given system, or a pair of genes’ propensity to interact functionally, can be partly predicted by computational means from (i) a small set of experimentally determined target pairs, and (ii) pre-existing data (e.g. gene ontology, PPI) on the similarities between targets. Predictions are obtained by a novel matrix algebraic technique, based on cyclical projections onto convex sets. We demonstrate the efficiency of the proposed method using drug-drug interaction data from seven cancer cell lines and gene-gene interaction data from yeast SGA screens. Our protocol increases the rate of synergism discovery significantly over traditional screening, by up to 7-fold. Our method is easy to implement and could be applied to accelerate pair screening for both animal and microbial systems.

Warburg's Lens: a new preprint initiative in Mathematical Oncology

Recently there has been a lot of discussion on preprints in biology, and a call for a faster dissemination of unpublished research. In response to this I have joined a couple of colleagues in creating a blog that posts and discusses new preprints in mathematical oncology. Our site is inspired by Haldane's Sieve, that serves a similar purpose in the field of population genetics.

The blog was launched only a couple of days ago, but we already have our second preprint posted, which is a paper of mine that I have already mentioned on this blog.

Without further ado I give you Warburg's Lens.