Evolution and Cancer

Moving to Nature Networks

2007-06-19T21:59:00.000+02:00

Dear everybody.

From now on this blog is moving to Nature Networks. Find it following this link.

See you there!

Mini workshop in Oxford

2007-06-12T13:51:00.000+02:00

Today Marcus Tindall has organised a mini symposium (for lack of a better name) for me and the guys here working on mathematical models of cancer to get to know each other. I have given a very small presentation [PDF] (<30m) that covers stuff I presented before.

From the CMB I got to know the work of:

Philip Murray, who has created a CA model to study the role of the cell cycle in tumours and that is now trying to obtain a continuous model that displays the same behaviour.
Alex Fletcher who studies hypoxia in tumour development at the sub-cellular scale.
Matt Johnston who works with W. Bodmer (whose game theory models have inspired my own work) to study the dynamics of cell populations in a colon crypt in colorectal cancer. His model shows how a homeostatic population could explode by slightly altering some of the paramers.
Natasha Li who collaborates with Gatenby to study, using Cellular Automaton and continuous models, the role of glycolysis in tumour invasion and the influence of the stromal environment. This is specially relevant to me since it is one of my two main lines of work at the moment. She mention in her talk that glycolytic cells are especially sensitive to glucose deprivation.
Rebecca Carter works on multiscale models of fluid and drug transportation in tumours.
Marcus Tindall gave a brief introduction to his multiscale model of interaction between the cell cycle and cell density.

The presentations were all quite short but I hope to hear more from these people in the coming days.

Queerer than we can suppose

2007-06-05T11:37:00.000+02:00

I found this video from a Richard Dawkins's talk in which he talks about the strangeness of science.

He talks that science is about truth but that our brain is evolved to cope with every day's reality, within the scope of the reality we have to live with. He cites the example that matter is mostly composed of space but we do not perceive it like that since it is more useful for us to perceive it as solid and opaque. He argues that a living being of the size of a neutrino and capable of vision would see matter as mostly empty space only by the nature of the space it inhabits. Similarly, things that look entirely unlikely to us (the existence of life) become inevitable when considering the vast amounts of time and space the universe has been going on compared to the space and time of our human lifetimes.

More shockingly to me he claims that humans are more akin to automata than to agents seeking what they consider positive things and avoiding negative things. The reason being that evolutionarily we rather model fellow humans as people with a purpose than as systems made of components whose design and integration we ignore.

In any case this is an important issue for scientists and philosophers of science: our brains have evolved for certain purposes and with certain biases and that should impose some limitations and constraints in what things we can understand and how we chose to interpret natural phenomena.

Oxford

2007-06-03T20:15:00.000+02:00

I will be staying one month at the Centre for Mathematical Biology directed by Philip Maini at the University of Oxford. With a little of luck I will be able to meet people interested in mathematical discrete models of cancer evolution and angiogenesis.

In the Centre they have some interesting (and relevant) research lines like "individual and collective behaviour in ecology" and of course "cancer modelling". The Centre is pioneering (with Arizona's Gatenby and Oxford's Comlab Gavaghan) the idea that glycolytic acidity promotes invasion. Maybe this could be an opportunity to test my hypothesis that this invasion comes in waves.

Talk in Girona

2007-06-01T17:18:00.000+02:00

I have been invited by Josep Vehi to give a talk about my research at the institute he directs at the University of Girona.

In this talk I have introduced for the first time the game theory model in which I have worked with people in Dresden (Andreas Deutsch, Haralambos Hatzikirou) and Bonn (Matthias Simon) in which I study Gatenby's hypothesis of acid mediated tumour invasion. I have also talked about the Cellular Automata model I have developed with Benjamin Ribba (Lyon) to study the microenvironmental influence in cancer evolution which I have previously presented in Lyon, Dundee and Dresden.

The presentation can be found here in PDF format.

cancer and the cell cycle

2007-05-29T11:16:00.000+02:00

Last Friday I came to the Max Planck Instute for Cell Biology, at the other side of Dresden, to attend a series of seminars including one from a colleague and friend of mine, Babis Hatzikirou, about the cell cycle.

The classical view on the cell cycle can be seen in this picture that I took from Babis's presentation (and which I suspect he took from somewhere else :)):
This is quite interesting although not precisely research news. Most of the cell cycle is of course devoted to interphase and only a minority of the time (assuming that the cell is not in arrest mode) is devoted to create a copy of itself (through mitosis and cytokinesis). The cell cycle is controlled by a finely tuned balance of proteins cdc2-cdc13 and a number of checkpoints make sure that before changing the phase of the cell cycle everything is in order. These checkpoints and their associated proteins (such as the famous TP53) are quite critical to prevent tumour formation as they impede the growth of cells that need DNA repair.

What science is not

2007-05-18T12:32:00.000+02:00

From an extract of the book The invisible sex: Uncovering the true roles of Woman in Prehistory (review in Nature 3rd of May issue).

"science is not truth; it is, instead, a method for diminishing ignorance"

A 3D model of human breast cancer

2007-05-16T18:01:00.000+02:00

This has been covered in a few places like the BBC and ScienceDaily. It seems that some researchers at Queen Mary College in London have recently come with a non animal 3D human breast cancer model.

This is interesting at more than one level. Their research was funded by a research charity (Dr Hadwen Trust) that supports the development of methods that avoid animal experiments. Working with rats is not that satisfactory for ethical reasons and also because there are many cases in which the results of rat experiments cannot be extrapolated to humans (seems we are not so similar in some respects after all). It is also much more realistic than just taking some human cancer cells and studying them on a petri dish.

Being capable of performing experiments using realistic 3D models quickly and efficiently is one of the holy grails of theoreticians since it would make experimental validation of our models much easier (confusingly enough what theoreticians call model, eg, equations or computer rules, is not what experimentalists understand as a model, eg. rat, arabidopsis or drosophila). This validation is quite complicated as I have already mentioned in another post. Making this validation easier and more convenient will go a long way in terms of making our work more reliable and quantitative.

Somatic and non somatic evolution

2007-05-14T10:16:00.000+02:00

Many ecologists study evolution of the non somatic kind. That is, evolution that happens as a consequence of mutations in the germ line of multicellular organisms during reproduction. The evolution of cancer is of the somatic kind. This means that it affects cells of the soma, the ones that are not transmitted to the offspring.

Some time ago I got this paper from Crespi and Summers (nicely enough, publicly available). I will probably talk about this paper, entitled Evolutionary biology of cancer (and presented to a readership of ecologists) some other time but I liked a table in which they compare somatic and non somatic evolution.

Phenotypic variation. In most ecosystems of multicellular organisms variation is attained through genetic recombination (sexual reproduction) and mutation. In a tumour we also have to consider also genomic instability (a hypothesis by which some individuals have a higher probability of mutation) and epigenetic alteration (the environment also affects the behaviour of cells in ways that could make tumour progression to cancer more or less likely).
Selection. In most ecosystems it means dealing better with competitors, avoiding predators, parasites and producing many fit successors. In a tumour means being good at competing for resources with other cells (tumour or otherwise), avoiding the immune system and coping with environmental signals designed to maintain homeostasis.
Drift. That is similar in both types of evolution.
Inheritance. In many cases that involves the transmission of genes from parents to offspring through sexual recombination. In tumours there is no sexual reproduction.
Result. In most ecosystems the result is adaptation across generations. In a tumour the end results is in many cases the death of the individual and thus of all the cells in the body, including the cancer cells.

I think that this is a quite interesting and useful comparison of evolution although I am not sure I agree with all the differences suggested. In my view the evolution in a tumour does not differ much from other types of evolution. For instance, epigenetic changes do play a role in other ecosystems asides from cancer. Genetic instability is not a source of variation, genetic mutations are (genetic instability just makes genetic mutations more likely). Also the fact that tumour cells reproduce asexually is not a big difference with more conventional ecosystems. At the end of the day most of the biomass of the planet is made of bacteria that reproduces asexually. What it is true is that as far as we know, the end result of cancer evolution is either the end of the cancer itself or the end of the individual that hosts the cancer and thus the end of the cancer cells. Thus the only way tumour cells have to be successful is to evolve in such a way that the life of the host is not threatened (you can call that tumour sustainable growth).

Autophagy and cancer

2007-05-09T10:02:00.000+02:00

This is a new cellular mechanism I did not know about: autophagy. Nature's issue of April 12th (I am bit behind I know) has an interesting article in the section Q&A on autophagy and its role in cancer.

Autophagy is the process by which cells degrade faulty or redundant components. It is used by cells when they need to reuse molecules for other uses and also it plays an important role in complementing apoptosis. Both apoptosis and autophagy are connected to cell death but in the case of autophagy cell death is not always the outcome although it can be a substitute when the apoptotic mechanism is crippled. In that case the cell literally eats itself to death.

The image bellow comes from the article. Autophagy has the potential of being useful for cancer supression but also for cancer promotion. The balance is important, too little and you get cell death when the cell cannot produce things it needs by reusing parts of itself. Too much of it and you also get cell death since the cell can eat itself. Altering this balance in a tumour cell could be the source of a new therapy although as usual it is important to remember that cells might evolve mechanisms to avoid the trouble of autophagy, maybe by inactivating the atophagy mechanism all together. Even in that case the tumour cell would be less capable of surviving in situations of stress since it would not be able to recycle material.

Autophagy seems to be a mechanism whose precise role in cancer has not been fully studied yet but could be a promising extra target for a multi target therapy that could hinder cancer evolution and growth.

Evolution and medicine

2007-05-07T10:49:00.000+02:00

Catriona MacCallum, an editor at PLoS Biology has posted the following essay (being PLoS, it is available to everybody) about medicine and evolution.

According to the article, physicians do not get much of a training in evolution as a method to study the origin of diseases. That is because most of the training of physicists is not to make them good scientists but to make them good at treating patients. Quoting the article: "does a mechanic need to understand the origins, history and technological advances that have gone into the modern motor vehicle in order to fix it?".

This approach is not entirely wrong and once can treat things that are the result of an evolutionary process without having to spend too much time studying evolution. A different thing is when the disease is not a result of evolution but they are evolution itself. They never mention cancer in the article but cancer and infectious diseases are clear cases of diseases in which evolution should be dealt with if the disease is to be cured or even contained. Without an understanding of evolution a physician will be unable to understand how the bacteria or cancer cells will react and evolve when a treatment is used or what phenotypical traits are more likely to be evolved and thus cause problems to or be exploited by the medical community.

Cell article on science blogs

2007-05-04T16:54:00.000+02:00

Blogs as a way to communicate science. This is quite an unusual topic for Cell that, as opposed to Science and Nature journals, devotes less space to the non-technical side of science. For those of you that are subscribed, the article is here.

According to the article there are approximately 20000 blogs with the label 'science'. That is quite an impressive number since most of my colleagues seem to be doing lots of things but not blogging. It seems that most of these science blogs are actually about pseudo science which would be the number of more conventional science blogs to around 1200 (always according to sources cited in the article). These are generally blogs like mine (of course in many cases better written and updated more often) which deal with fairly specific issues in a specific field of science.

These science blogs can be just about anything. Many do like I do and comment (what we personally find) interesting stuff in our own field of research that we find reading, mostly, papers and journals. Some do also include bits about their own lifes and produce some sort of hybrid between the conventional blog (understood as a personal diary) and the scientific blog. Some take the idea of science blog a step further and every day record their latest results online (although in some fields, like biology, this behaviour seems to be quite rare due to the extreme levels of competition between experimental biologists).

Why would any one start a science blog? On top of the conventional reasons why people start a blog (and weighted down by the fact that most of us do not carry sizable audiences) is the thought that when you write something with the expectation (as unlikely as it might be) that someone will read it that surely helps to clarify that something in your mind.

Mini workshop on cancer and cellular automata

2007-05-02T10:08:00.000+02:00

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

2007-04-27T12:20:00.000+02:00

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

2007-04-23T10:08:00.000+02:00

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

2007-04-17T11:58:00.000+02:00

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

2007-04-03T17:22:00.000+02:00

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

2007-03-29T16:29:00.000+02:00

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

2007-03-26T18:29:00.000+02:00

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

2007-03-21T11:52:00.000+01:00

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

2007-03-18T15:47:00.000+01:00

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

2007-03-13T12:54:00.000+01:00

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.

Workshop in Ohio

2007-03-09T13:12:00.000+01:00

I will not probably have much time for posts next week since I plan to attend a workshop in Columbus, Ohio. The workshop is organised by the Mathematical Biosciences Institute of the Ohio State University and is entitled Workshop for young researchers in mathematical biology (remember what the meaning of young researcher is from my previous post from my visit to Barcelona :().

At any rate there will be some interesting people both in the category of keynote speakers and "young" researchers. Some of them doing bio mathematics of cancer so expect a report on that when I come back.

cancer genes

2007-03-08T18:14:00.000+01:00

The information can be found tailored for all types of users. For those who want an easy take here is the BBC version. Nature has a nice overview and the article proper.

Here is my take: a (fairly large) group of researchers mainly at the Sanger, in UK have studied hundreds of genes that are mutated in about 200 types of cancers. The trick here is to find what genes DO drive cancer as opposed to 'just happen to be mutated' in a cancer. At the end of the day your average tumour cell in an advanced stage tumour is likely to contain several mutations and many of them will probably be hitchhikers not necessarily contributing to the overall fitness of the cell. Unfortunately the result of the research is that the number of genes mutated in many cancers is higher than expected and telling apart driving genes from others will be a challenging task. One thing of working with so many types of cancers (200) is that genes that might not play any significant role in one type of cancer might turn to be important in the next.

Telomeres, cancer and aging

2007-03-07T17:22:00.000+01:00

One quite fascinating thing in animal biology is the question of immortality or, to be more precise, the lack of it. While most unicellular organisms can divide for as long as they have the luck to find resources and space to do so, human cells can divide only a limited amount of times (approximately around 50 times, although this does not apply to stem cells that can divide an unlimited amount of times). In principle the limitation in divisions for most human cells is due to a mechanism that has been evolved and is not an intrinsic limitation. The cancer hypothesis is that the limitation makes the appearance of cancer more unlikely. If a cell is limited to just a few divisions, if it acquires a mutation that mutation is unlikely to spread to far.

The reason for this limitation are the telomeres, situated at the end of the chromosomes, that get shorter each time the cell divides. Once these telomores reach a critical size and become to small the cell will enter a state called senescence by which they will not divide again.

This is an interesting link in which they talk about this and how in the next few decades we might know enough about the effects of limited cell replication in human life expectancy, how to increase it (maybe for ever) and how to do that avoiding nasty side effects (like increased probability of dying from cancer). The website in which this is hosted is covering all sorts of news, many of them of dubious scientific interest, but the information in the link looks sound.

On the other hand in a more reliable source (PNAS) there is a nice study on how telomere dysfunction can cause genetic instability. They work on a disease known as Werner syndrome but it is quite useful stuff for cancer research. This Werner syndrome results in people aging prematurely and researchers at the Salk institute have found how extra short telomeres can be the source of the problem.