I haven’t updated this blog for a while, the reason being the usual for many researchers working in the US: grant writing. Part of this grant writing involved producing diagrams to illustrate various processes occurring at different scales in prostate tissue. These diagrams describe rather sophisticated intra and extra cellular interactions in the simplest possible manner. Yet these diagrams can be complicated and selecting the right symbols and colours to describe these interactions in a visually appealing but consistent manner can be far from trivial.

As someone with a background in computer science I appreciate the advantage of having a standard notation to describe processes. Software engineers use tools such as UML to describe software modules and how they interact to form complex software systems. This allows other software engineers to understand complex systems with little ambiguity. Now systems biologist will be able to do the same thanks to SBGN, recently discussed in Seed magazine (article that came to my attention thanks to Simon Hayward).

Standarising on a formal graphical notation will allow computational, mathematical and system biologists to better communicate with biologists but only if both communities learn how to speak this language. This will be tricky but if funding bodies and journals start requesting diagrams in this notation, that could ease its introduction. I hope that this (or an alternative formal graphical notation) will eventually emerge successfully. Formal graph notations are easier to read by non experts than mathematical equations or software algorithms but being more precise than informal non-standard ones they represent a more solid foundation in which to build integrative work, combining theoretical and experimental research, and exchanging models between different groups.

Evolution of coperation is one of my main interests and I think it is a topic that could be very relevant to cancer researchers as I discussed a while ago.

Rand DG, Dreber A, Ellingsen T, Fudenberg D, & Nowak MA (2009). Positive interactions promote public cooperation. Science (New York, N.Y.), 325 (5945), 1272-5 PMID: 19729661

Cooperation in nature occurs mostly between individuals that are closely related from a genetic point of view. In most other instances cooperation happens when all the interacting individuals benefit to some extent from their cooperation. Still, in some situations altruism happens if the benefactor expects to get rewarded at some point in the future, potentially by another individual. This is problematic as it was thought that a mechanism of punishment would be necessary: those that cooperate should be rewarded but those that cheat should be punished. And punishing is not simple: cooperators should stick together to punish the cheaters as punishing itself is rarely cost free. That means that some individuals might be cooperators when it comes to the game but cheaters when it comes to punish. And that would require an extra layer of punishing, one that would deal with those that cheat at the punishing level. This, of course, has no end as one cooperator at one level might be a cheater at the next.

What Rand and colleagues have proven is that punishment might not be necessary for this type of cooperation, at least in the public goods game. Remarkably, in a population that is expected to interact together a number of times. Sometimes just the carrot (when other players reward the best cooperators) can be a better alternative than the stick (punishing the cheaters). Even when both options are available, those groups that leaned on rewarding more than on punishing were more likely to obtain higher payoffs.

Can biologists and mathematicians accomplish more together than working separately? My answer to that question has always been a resounding yes but today I am backing up that statement with a piece of research: the result of a collaboration involving mathematicians and biologists (and a pathologist) in Tampa, Nashville and Houston.

Basanta, D., Strand, D., Lukner, R., Franco, O., Cliffel, D., Ayala, G., Hayward, S., & Anderson, A. (2009). The Role of Transforming Growth Factor- -Mediated Tumor-Stroma Interactions in Prostate Cancer Progression: An Integrative Approach Cancer Research, 69 (17), 7111-7120 DOI: 10.1158/0008-5472.CAN-08-3957

The paper, of which I am one of the authors, studies the role of stromal-tumour interactions in prostate cancer progression. It introduces a computational model, developed as a result of extensive conversations with Vanderbilt’s Hayward Lab and the results have led to interesting biological experiments and observations of relevance in pathology. Hope you guys will find it an interesting read.

Spending so much time on planes and airports (as I am doing lately) means that I have more time to read books, some of which were in my reading list for way too long. The book I am reading now is Dawkins’s The Extended Phenotype. I am a big fan of Dawkins so there’s no easy explanation for why it took me so long to start reading the book that Dawkins himself consider’s his most important.

In one of the earlier chapters (chapter 3), Dawkins mentions some constraints that put limits to commonly held view that evolution optimises the phenotypes of individuals in a species. These are:

1. Time lags: your usual living being has a genetic material that makes him very well adapted to an environment that, in many cases, has changed. Given enough time there are good chances that the species will evolve to adapt to the current situation but by then there might be new changes to adapt to. An example from the book: the hedgehog strategy of rolling up into a ball to escape predators doesn’t work too well when crossing a motorway. The fact that cancer phenotypes represent an adaptation to an environment that might have changed significantly means that tumour cells are more vulnerable when there is sudden change but using this fact therapeutically is dangerous as this will select for those cancer cells more able to cope with change, making tumours more difficult to treat in the long term.

2. Historical constraints: What you do today will limit and bias what you will do in the future. Same goes in evolution. Flatfish share a lot of their developmental programme with other fish but given their lifestyle (laying flat on the surface of the ocean) they are better off having both eyes on the same side of their head. Evolution has to work around the fact that both eyes are developed in different sides of the head by adding an extra step in which one of the eyes slowly shifts in the direction of the other. With the right knowledge of how a cell genotype maps into a phenotype, we could select for phenotypes that require genetic or molecular mutations that would make difficult or impossible to acquire, later on, more aggressive features. Although initially these phenotypes would be more fit than other tumour cells, in the long term their genotypes would make them evolutionary dead ends.

3. Available genetic variation: That one is pretty straightforward, evolution requires that individuals are different in a manner that can be passed on from parents to offspring. A population with little genetic diversity will always take longer to adapt (sometimes for all practical purposes will never succesfully adapt) to changes in the environment. We know that very selective microenvironments (those that exact a high toll on phenotypes that are not well adapted) will reduce the phenotypic (and hopefully the genotypic) diversity of the tumour. This could slow down the pace of tumour evolution but the selection should be such that does not select for more malignant phenotypes.

4. Costs: Even if time was not a constraint, some adaptations are more costly than others. An individual that devotes its time and resources doing something might not have enough to do something else even if that turned out to be beneficial. Like in engineering, evolution has to deal with costs and tradeoffs in which perfection is the enemy of good. We know that some adaptations are more costly than others. Gatenby and colleagues idea of double bind therapies, by which a treatment selects for phenotypes that have to pay a high fitness cost to survive, could be considered a tool based on the cost of adaptation evolutionary constraint.

5. Mistakes due to environmental unpredictability or malevolence: The environment of any given individual is extremely complex and dynamic. It would be rather difficult (and costly!) for evolution to produce individuals capable of coping optimally with every conceivable situation. What evolution does then is to evolve individuals that are good at coping with most situations, especially if they happen often enough and the consequence of mismanaging them would be too high. Providing a tumour with a stable microenvironment will select for phenotypes that could overadapt to this environment (and select against more generalistic tumour phenotypes as this generality comes at a fitness cost and provides little advantage in a stable environment). Such tumour would then be more sensitive to small (and big) alterations to the microenvironment.

While Dawkins places all these constraints in terms of classical ecological species (ants, wasps, fish…) there’s no reason to believe that this same constraints apply to the evolution in tissues where cancer has been initiated. Here I just put a few examples off the top of my head (very likely not very good ones) of ways in which these constraints could be exploited therapeutically but the point is that evolution, which makes cancer such a difficult disease, can also be used to fight it. Knowledge of these constraints could be a powerful tool to hinder tumour progression towards malignancy if we could have some degree of control over the selection pressure.

Some time ago I learnt that a significant proportion of cancers are started as a result of virus activity (I believe that the figure was something around 20% of them). That left me thinking how neat (intellectually, that is) would be if viruses and tumour cells became mutualistic cooperators. A virus that alters the behaviour of a cell making it proliferate when in other circumstances wouldn’t (as tumour cells do) does provide a fitness benefit to tumour cells. The payback that would make this interaction mutualistic would be something that increases the reproductive rate of the virus.

Virus (even those associated with tumourigenesis) are not normally too concerned about boosting the replicative capabilities of the cells they infect. If they do initiate a tumour that is more likely than not a side effect of the virus taking over the replicative machinery of the host cell. As soon as enough copies of the virus have been produced, the host cell will burst making the virus free to infect new cells.

I am currently reading One renegade cell, a pop science book by the well known cancer biologist Robert Weinberg. The book is not exactly new (first published more than 10 years ago) and, despite mentioning somatic evolution, it is (unsurprisingly) heavily biased towards a genetic interpretation of cancer. Still, Weinberg does a superb job of explaining a complex disease to a non specialist readership without dumbing the topic down and while keeping the book readable and entertaining.

In chapter 3 (The elusive quarry), Weinberg shows that I was not the first one to think that viruses and tumour cells could interact cooperatively (although I doubt that a lot of people framed this idea in terms of cooperation). Apparently a now forgotten school of thought about tumour initiation a few decades ago thought that virus were the prime cause of tumourigenesis. Those viruses would trigger uncontrolled cellular growth as that would allow the viruses to grow a large population without having to expose themselves (as they are particularly vulnerable out of a host cell). This way the virus drives tumour growth and the tumour growth translates into more viruses. A perfect example of mutualism. Still no evidence for this though, but a neat idea.

I don’t watch telly so although I imagine that this programme was meant to be watched in the comfort of your living room I only found about it on the PBS website. The programme I am referring to is called Animals behaving worse: America’s least wanted and shows some species that have (relatively) recently arrived to America and, in many cases, displaced the local populations.

People have already found parallelisms between species invading new ecosystems and tumour cells metastasing to different sites so this show will appeal to those of us that see tumour cells as constituents of a tissue ecosystem. For instance, the africanised honeybee has displaced the european kind from the south of the USA as they outcompete other pollinators. Other invading species might not have clear local competitors to displace but by consuming resources more aggressively they alter the ecosystem in significant ways, thus affecting the viability of other species. The reasons by which the invaders reach the new ecosystem are varied (and oftentimes due to us, careless humans) but all cases presented in the programme show them as quite capable to take advantage of the resources of their new home as well as free from predators (although in some cases, humans have introduced predators to gain control on their growth, sometimes successfully).

I mentioned a few times how in my view (and in that of other people I have the luck of meeting and working with) tumours are not just colllections of cells behaving nasty but are part of a grander ecosystem (including my last post). The image taken from Anderson and Quaranta, Nature Reviews Cancer 8, 227-234 shows this in a simplified manner.

One aspect of the tumour-as-ecosystem view that might not be easy to reconcile is that of stem cells. Stem cells can self-renew or differentiate into a number of different specialised types. Their role in cancer is still not fully understood but it is likely to be significant. Is the role they fulfil something specific of developing organisms or are there equivalent roles in traditional ecosystems?

It is known that in certain species of fishes, individuals can be female one season and male the following one meaning that they have keep their potential to differentiate and perform different functions. In some ant colonies, all the females (the vast majority of the colony) are genetically capable of becoming the queen (a mophologically and functionally distinct individual) if provided with the right environmental cues.

There are certainly some similarities between stem cells and certain individuals in certain species. I am not sure about how this affects ecosystems in the way that stem cells are thought to affect cancer (to say nothing of development) but goes to say that the capacity of some individuals to reprogramme their phenotypes to perform different functions is something that evolution will favour.

I have been neglecting this blog for the last few weeks due to work (why do I have the feeling that this might be one of the most common excuses in the blogsphere??). Part of that work involved hypothethising whether cells in a tumour cooperate, and if they do, how does that happen and what are the implications (from the therapeutical point of view and otherwise).

Although discussed in this blog before (here, here,here, here and here), I know that cooperation is not an entirely uncontroversial topic. The idea of cells competing or cooperating is, admittedly, a problematic one if it results in anthropomorphism. What is the meaning of cells in a tumour cooperating? Does it mean that they sit down and discuss possible alliances? do they sign contracts to make sure that the cooperation can be legally enforced? Obviously we are not talking about that type of cooperation: cells (tumorous or not) have no will or mind, they do not decide to cooperate.

We can also try to think differently about cooperation and competition. Tumours are made of various types of cells, some of them normal (in a healthy tissue) some of them not. This diversity is dynamic and new types appear and disappear as the tumour progresses. In this context, each new cell type interacts with the remaining ones in ways that can contribute or be detrimental to the fitness of each of them. Fitness being, as usual, the capability of having a large progeny in the long term. For instance, if two cells are after the same nutrient we can say that they compete for it, which has a detrimental effect on both of them. On the other hand if during progression a mutation appears that allows a cell to produce a growth factor that could be shared with other neighbouring cells, then that cell is cooperating. In general (and this is, unashamedly taken from wikipedia), depending on the fitness that each of cells (with phenotypes A and B in the example) obtain, the types of interactions are:

It seems reasonable to think that when two cellular species compete for a resource they will evolve to become more efficient at either competing for the resource or finding it through different means. It seems equally reasonable that when two cellular species cooperate (basically mutualistic but to certain extent, comensalistic interactions) there is an evolutionary pressure to make this cooperation more effective (e.g., trait specialisation).

In a recent article in Science (perspective and the article itself) shows that the fact that cells in a tumour can cooperate (the cooperation being not necessarily among tumour cells but includes stromal cells like fibroblasts) could be used against cancer. Olive and colleagues studied, using animal models, how fibroblasts in pancreatic tissues are responsible for poor vasculature. This could seem to be bad news for the tumour as that would limit the amount of oxygen and other resources but it also means that drug delivery becomes less efficient. Furthermore, not all tumour phenotypes suffer equally from poor oxygenation. Cells with a glycolytic metabolism fare better in hypoxic environments which means that these cancer associated fibroblasts in effect cooperate with the more aggressive tumour phenotypes. This cooperation can be (crudely) formulated as “Fibroblast, if you make sure that us, aggressive cancer cells, are sheltered from drugs and allowed to have an upper hand on our competition with other tumour cells, then we will produce Hedgehog factors which you relay on”. What Olive and his colleagues did was to target the Hedgehog, thus reducing the population of fibroblasts, helping to renormalise the vasculature and help drug (gemcitabine) delivery.

This is a very interesting piece of research that, in my opinion, highlights that if cooperation can explain certain aspects of tumour progression, then therapies that target the weaker elements of that cooperation could be very helpful.

Olive, K., Jacobetz, M., Davidson, C., Gopinathan, A., McIntyre, D., Honess, D., Madhu, B., Goldgraben, M., Caldwell, M., Allard, D., Frese, K., DeNicola, G., Feig, C., Combs, C., Winter, S., Ireland-Zecchini, H., Reichelt, S., Howat, W., Chang, A., Dhara, M., Wang, L., Ruckert, F., Grutzmann, R., Pilarsky, C., Izeradjene, K., Hingorani, S., Huang, P., Davies, S., Plunkett, W., Egorin, M., Hruban, R., Whitebread, N., McGovern, K., Adams, J., Iacobuzio-Donahue, C., Griffiths, J., & Tuveson, D. (2009). Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic Cancer Science, 324 (5933), 1457-1461 DOI: 10.1126/science.1171362

I am currently in Trento, Italy, visiting CoSBI, the Microsoft/University of Trento Centre for Computational and Systems Biology and while preparing my own talk I decided to look for inspiration watching a couple of TED talks talks. I got more than what I bargained for. One that caught my attention was a rather brief one by a very young scientist, Eva Vertes. Her talk was entitled My dreams about the future of medicine but more than a view on the future of medicine the talk was about something quite relevant to me. Her question was why does cancer arise in tissues like the prostate, the breast, the brain, etc but not in the heart or the skeleton muscle?.

She makes other interesting points like assuming that all cancers are the results of stem cells (which would surprise me if it were true) that go rogue as they are reactivated as a result of environmental insult (can’t help liking the word insult as is used by biologists!). She also makes the point that indiscriminate killing of tumour cells is unlikely to be a wise way of curing cancer (which is based on the assumption that stem cells are behind a growing tumour, but this is a statement that also makes sense if you consider that for most therapies, some cancer cells will be more susceptible than others so indiscriminate killing is in effect a selection for resistance).

But back to her interesting question of why is it that we get skin and lung cancer, but not muscle tissue cancer. This is quite relevant as muscle tissues are highly dynamic with a lot of turnover (as muscle tissue is destroyed and repaired during even mild exercise) and are highly vascularised. Her hypothesis (and that was a few years ago) is that evolution might have something to do with that. Precisely because muscle tissue is so highly dynamic and thus, at least theoretically, so good a soil in which to grow a tumour, evolution has made these tissues better able to cope with cancer. Under that assumption, muscles could have plenty of neoplasms, incapable of growing as they are not allowed to co opt the muscle vasculature. Also, due to the dynamism of the tissue, these neoplasms do not last too long. This sounds to me like a reasonable explanation but I am no expert. I wonder if there are other potential answers.

The (medical) news in the last few days has been, without doubt, the H1N1 strain commonly found in pigs (aka Swine/Mexican) flu. The journalistic news of the week was probably the treatment of the outbreak with different outlets either downplaying the importance of the virus [Guardian] or preparing their readership for imminent doom [El Pais, ES]

For those that are skeptic about the role of science in society (beyond that of fostering knowledge for cross words and collecting random facts) look no further than the specials put together by the likes of Science or Nature. The knowledge we now have will be crucial in understanding and containing this (and future) pandemics. It is not the fruit of a few days of work but has been distelled through many years of work when the political and social pressure was not there (at least not to this extent).

One of the most interesting facts about the strain of the H1N1 virus making the headlines during the last few (or maybe not so few anymore) days is its the way it evolved. Starting from a virus affecting only pigs, it learned (in the evolutionary sense, that is, by recombination, mutation and selection) how to infect humans from pigs and, unsurprisingly, from humans to humans.

Now that the first wave might have started to level and that the effects seem to be similar to those of other flus it might be the right time to consider that, as it reaches more people in more places (as a result of both globalisation and increase in the world’s population), the room the virus has to mutate and acquire new capabilities (potentially by mixing with other viruses in the same host) increases dangerously. One of the most infamous pandemics in human history, the Spanish flu (also a H1N1 virus) became famous on the second wave (see figure extracted from here).