Mini workshop on cancer and cellular automata

Today we are hosting in our group at TU Dresden a mini workshop on cellular automata in biology. Three talks (one in the morning and two in the afternoon) are actually about CAs and cancer. It will be a busy but interesting day.

The booklet for the afternoon part of the workshop (the longest part of it) is here.

evolution of multicellularity

A friend of mine has found this interesting essay in Nature entitled "Unity from conflict" that deals with the evolutionary mechanisms that allowed the emergence of multicellular organisms.
The problem of how multicellular organisms came about from single cells is quite intriguing. I heard from Lewis Wolpert that this is probably the most important of the seven transitions in evolution as described by Maynard Smith and Szathmáry in their book. In retrospect it is clear that such a transition is possible (since we are here) but, why did it happen?

Paul Rainey (whom I suspect might be a microbiologist) seems to be suggesting that with the right mutation rate (or right mutation bias) multi-cellularity should be possible. Organisms such as myxobacteria seem to be able to alter their mutation rate in response to stress in the environment so I guess that evolution fiddling with the right mutation rate is not unreasonable. In any case I'd rather see it from the point of view of my friend, that is, a harsh environment does enforce cooperation in a way that makes cheating very costly. In reality I would imagine that other factors such as the immune system (that in a way can be though of a police on the lookout for cheaters) or the fact that cells in a multicellular organism share the same DNA could also help explain why there is not that much cheating in our bodies.

This article is quite interesting for any one interested in cancer. At the end of the day a cancer cell is a normal cell that due to genetic or epigenetic reasons stops cooperating. Once they evolve the means to avoid the immune system and other mechanisms designed to maintain homeostasis I would imagine that the life expectancy of a tumour cell should be rather short (necrosis, running behind in the evolution game or due to a poor microenvironment) and thus crime might not pay, at least in the mid/long term (which still would leave room for a benefit in the short term that would be enough to kick-start somatic evolution).

It should be possible using a computational model to demonstrate that an aggressive microenvironment would favour cell cooperation. A mutlicellular organism in which individual cells suffer when exposed to the exterior would evolve a morphology that would minimise the interface with the outside world. it would be also quite likely that a niche of stem cells would evolve to be in charge of generating the cells in this interface that would be in need of constant repair and maintenance. That is what happens in places in which the environment is hostile to cells like the colon or the skin. If cells in the model are allowed to cheat (by means of mutations leading cells to try to avoid being part of the interface if that is their role) that would presumably affect negatively the overall fitness of the organism. However I am not sure that this would rule out other explanations for the evolution of multicellular organisms.

Acceptance of evolution around the world

National Geographic has published this chart that depicts the public acceptance of Darwinian evolution in 34 countries around the world. As a Spaniard I am happy to see that evolution is widely accepted in my country, with a higher acceptance rate than even in Germany where I currently live although not as high as in Scandinavian countries or in the UK (the birthplace of Darwin). In the U.S. less than half of the population (if the results of the poll can be extrapolated) have at least some reservations towards evolution although the country (of all those polled) that seems most hostile to it seems to be Turkey.

The laws of biology

The side effect of having spending so much time traveling these last months is that I have this stack of Nature and Science journals (I switched from the former to the latter a month ago to see the difference) which I am going through quite slowly.

In a Nature from the 7th of February there is an interesting essay about the clash of cultures between biologists and physicists working on biological topics written by a physicist from MIT (good to know where the bias will come from). Physicists have a long tradition of studying an (increasing) range of phenomena and producing theoretical models that characterise as many of those phenomena as possible. These are what are called the laws of physics. The question is if biology can have also models and laws that represent biological phenomena.

Although there are some (fairly generic and neat) biological laws (thing of Darwin's evolution and Mendel's genetics) most biologists seem to be more interested in fact collecting than in putting the available information in the form of theoretical models and universal laws of biology. The physicists (and mathematicians) coming to the field have not much knowledge in how the facts are collected (which it is easy to imagine as the source of many frustrations) but a deep interest in integrating those facts into models (especially when it involves using their favourite tools such as phase transitions, fractal analysis, power laws or networks). It remains to be seen if (in the view of the author) these general laws are possible at all and if (not my view but at least my question) the tools that were useful in physics will be that useful in biology (which does not mean they could at the very least, constitute a good starting point).

Back from Scotland and Gatenby's talk

I am back from sunny Scotland in sunny Saxony. Of the remaining speakers in Dundee, the one whose talk I was looking for the most was the one from Robert Gatenby, Arizona University (as with Vito Quaranta, a life scientist).

I know the work of Gatenby because he is one of the few researchers involved in using evolutionary game theory (although not of the most conventional, fitness-and-payoff-table kind) to study cancer evolution. Specifically he is working on how acidity due to glycolysis (the anaerobic metabolism that constitutes and advantage for tumour cells that lack oxygen due to the distance to a blood vessel) is a necessary step in the evolution towards cancer. The so called Warburg effect is the result of a well known biochemical mechanism but, what is the evolutionary advantage?

As he has shown in other papers, the advantage for glycolytic cells is that the poison the environment of other cells so they face less competition. They also degrade the connective tissue and thus increase the motility of cells, which is a required step for a tumour to become invasive. From my point of view it is interesting that he seemed to imply that this acidification of the microenvironment is not only a facilitator for cancer but a necessary step. I guess that Hanahan and Weinberg could include this in the section for mechanisms for invasion and metastasis.

From the therapeutic point of view, his research suggests that either alkalising the microenvironment (to counteract the progressive acidification resulting from the glycolytic metabolism) or making it even more acidic by reducing the pH in the blood (and thus contributing to self poisoning of glycolytic cells) would be something worth trying.

The cost of validation

Many interesting speakers in this workshop in Dundee but most of them fall in the mathematics part of biomathematics. Among the few who do not is the biologist Vito Quaranta (Vanderbilt University). Although I have been told many times that things are changing for the better in that respect, the scarcity of life scientists and medical doctors in these type of conferences tells me that there is still a lot of work to do to convince them that computational and mathematical biology is not only relevant but necessary.

The talk from Vito Quaranta was not so much about science as about doing science at the interface between theory and experiments. He is lucky to count with the resources of the Vanderbilt Integrative Cancer Biology Center. Otherwise the problem of validating the mathematical and computational models with theoreticians come with would be next to impossible. This theoretical models make a number of assumptions about the properties of tumour cells, tissues and micro environments and predict outcomes that in many cases have to be contrasted with in vivo and in vitro experimental results. This experimental work is really challenging given the level of fragmentation of knowledge and expertise in biology and medicine. Different labs with different experimental techniques, machinery, cell lines and the necessary permissions to perform animal experiments and access human clinical data are required to validate one single theoretical model. That means that unless centres like the one in Vanderbilt become much more common most theoretical models will remain experimentally untested unless they proof to come out as the result of the consensus of the theoretical biology community.

Cooperation in a tumour and workshop in Scotland

I find myself in Dundee, in Scotland, attending a workshop entitled Mathematical modelling and analysis of cancer invasion of tissues. It promises to be an interesting event and some of the attendees are working on topics that are very close to mines so it is good to know what is their contribution to the state of the art.

When I arrived this morning I was expecting good stuff from people like Philip Maini (Oxford), Bob Gatenby (Arizona), Vito Quaranta (Vanderbilt) and Sandy Anderson. Still today's most relevant talk for me was given by Anna Marciniak-Czochra (Heidelberg) who presented work based on the research presented very recently by Robert Axelrod (and reviewed in this blog here). Axelrod's work is about how the collaboration between tumour cells could mean that cells do not have to acquire all the necessary capabilities (mentioned in Hanahan and Weinberg's 2000 work) in order for the tumour to become agressive. This is a word model but in Marciniak-Czochra's presentation a mathematical description was shown in which the characteristics of the growth factors (eg. diffusion strength) can determine how useful this collaboration is. It looks like an interesting model and hope a paper will come out soon so I can take a look. Still it seems that a paper that covers Axelrod's work more comprehensively is still work to be done.

The links between scientific disciplines

I have just found this amusing article about how some guys took more than a million and a half scientific papers from 776 different branches of science and came with the graph included in this post. You can find a larger version (5Mb) of it at this site. It shows how often papers from different disciples are cited by the same paper so it can give a measure of what fields are more likely to inspire interdisciplinary work.

Most of the research seems to be in Medicine and biochemistry (including all the -omics stuff). Math seems to be more unconnected to many other branches of science that I thought but to be honest I am not very sure about the methodology. More about it can be found in Mapofscience.com.

World Community Grid and Cancer

Since the guys at SETI came with the idea of using the CPU time of internet users when they are not using their computers, several other projects draw inspiration from this idea to obtain some sort of highly distributed high performance computing when the funding is not there.

One of these projects is called the world community grid which involves many research centres and universities and tries to tackle several problems that should be of general concern. One of the projects is about Cancer. One of the ways to go about cancer research is by using tissue microarrays in which samples of tumour cells are treated differently and the results of the different treatments can be obtained and compared in a comparatively efficient way. I am writing this from Columbus airport but when I get the chance of getting back to Dresden I should install this client on my Linux workstation. They do have versions for Linux, Mac and Windows.

Of course one thought is that if I know that I will not use the computer in a while the right thing to do (assuming one cares about the world) is to switch the computer off but I guess that those times in which the screen saver kicks in I would be happier thinking that my computer is doing something interesting instead of just displaying pointless and CPU intensive openGL pictures.

Columbus workshop and interactions with life scientists

Being a workshop on mathematical biology one of the issues we all face here is how to work with life scientists and thus one of the panel session yesterdays was precisely about that.

It seems that there are different kind of problems theoreticians might find when dealing with clinicians and experimentalists depending on a number of factors:

• What kind of people are they? Are they 'math-skeptic'? do they have affinity towards theory?
• Do you want them to share their expertise with you or do you want to influence the experiments they perform so they can be used in your theoretical model? The latter is significantly more difficult.
• Do you work with biologists or with physicians? There is a real difference between the average PhD and the average MD that does some research on the side when it comes to understand the usefulness of theory.

Some tips where also offered by some participants on how to make finding and establishing collaborations. Mainly it helps to attend seminars from the life sciences departments, get yourself familiar with their stuff and get your face known to them so you don't come as a complete stranger.