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.
Showing posts with label comment. Show all posts
Showing posts with label comment. Show all posts
Sunday, June 03, 2007
Friday, May 18, 2007
What science is not
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"
"science is not truth; it is, instead, a method for diminishing ignorance"
Monday, May 07, 2007
Evolution and medicine
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.
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.
Friday, May 04, 2007
Cell article on science blogs
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.
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.
Friday, April 27, 2007
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.
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.
Monday, April 23, 2007
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.
Thursday, March 29, 2007
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.
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.
Wednesday, March 21, 2007
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.
Tuesday, March 13, 2007
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:
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.
Wednesday, March 07, 2007
Telomeres, cancer and aging
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.
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.
Monday, March 05, 2007
Bioinformatics and google
First of all, I am not a bioinformatician. I even thought I had an idea of what is the aim of bioinformatics but after a visit to the group of Nuria Lopez Bigas at the Biomedical Research Parc in Barcelona I realised that the scope of what I thought the field is about was too narrow (they do some nice machine learning and statistical work on disease related genes).
I have seen this video on Google video (only one of these sites that allows the user to download the video for offline use) some time this weekend. It is just a talk by David Vise, the author of a book about Google, to staff at Google Inc. Google is one company that fascinates (and in a sense, worries) me tremendously. As a side note, this blog is posted in one of their servers.
The thing is that at the end of the talk, David mentions the interests of one of Google founders (I think it is Larry Page) on biology. Then I thought (and I am sure that I will be the last of a long list of people) that, wow, that is really a good match: google and bioinformatics. Biology until know was mostly a science in which practitioners collected facts. There is loads of data and little idea of how to make sense of it, asides from evolution and a few other very general ideas. One of the aims of google is precisely to find patterns in the zitabytes of information stored in their servers. I have the feeling that we will see more of Google in that field.
I have seen this video on Google video (only one of these sites that allows the user to download the video for offline use) some time this weekend. It is just a talk by David Vise, the author of a book about Google, to staff at Google Inc. Google is one company that fascinates (and in a sense, worries) me tremendously. As a side note, this blog is posted in one of their servers.
The thing is that at the end of the talk, David mentions the interests of one of Google founders (I think it is Larry Page) on biology. Then I thought (and I am sure that I will be the last of a long list of people) that, wow, that is really a good match: google and bioinformatics. Biology until know was mostly a science in which practitioners collected facts. There is loads of data and little idea of how to make sense of it, asides from evolution and a few other very general ideas. One of the aims of google is precisely to find patterns in the zitabytes of information stored in their servers. I have the feeling that we will see more of Google in that field.
Friday, February 23, 2007
In Barcelona
I have finished my stay in Lyon and arrived to Barcelona to attend a round table for young researchers organised by the Universitat Autonoma de Barcelona. Interestingly enough the definition of young researcher seemed to include any researcher after the PhD but without a stable contract (that is, postdocs, non tenured group leaders and people in teaching positions).
I was a rather interesting discussion that dealt with things that I imagine are common worries for young researchers across Europe and elsewhere. Mainly the difficulty of living on short term research contracts, (for those of us postdocing somewhere else) the strain of keeping up with friends, relatives and former colleagues while living abroad, the gap between our real age (late twenties or early thirties) and how our status is perceived by the rest of the population (not like assistant professors or people with "real" jobs and more like students with a fancy "Dr." in front). Other issues that I found very relevant not only for young researchers are the link between research and teaching (in Spain, like many other countries, university lecturers are paid to teach but their progress on the career ladder depends exclusively on publications) and linked to that if the main duty of academic staff is to perform research or to teach (there seemed to be some consensus that universities should be free to chose wether to have a research profile or a teaching profile).
I was a rather interesting discussion that dealt with things that I imagine are common worries for young researchers across Europe and elsewhere. Mainly the difficulty of living on short term research contracts, (for those of us postdocing somewhere else) the strain of keeping up with friends, relatives and former colleagues while living abroad, the gap between our real age (late twenties or early thirties) and how our status is perceived by the rest of the population (not like assistant professors or people with "real" jobs and more like students with a fancy "Dr." in front). Other issues that I found very relevant not only for young researchers are the link between research and teaching (in Spain, like many other countries, university lecturers are paid to teach but their progress on the career ladder depends exclusively on publications) and linked to that if the main duty of academic staff is to perform research or to teach (there seemed to be some consensus that universities should be free to chose wether to have a research profile or a teaching profile).
Tuesday, February 13, 2007
Lenski et al: Balancing robustness and evolvability
R. Lensi, J. Barrick and C. Ofria. Balancing robustness and evolvability. PLoS Biology, Vol. 4, 12, pp 2190-2193
This paper has not much to do with cancer but I have been interested in evolvability issues for a while so I decided to take a look at it. Tumour evolution has many but not all the features of the evolution involving longer time scales but its evolvability is not a thoroughly investigated topic. That is a shame because it seems that, given enough time, one would expect that tumour cells will not evolve only towards phenotypes that can take better advantage of the environment but also to genotypes that allow evolution to adapt better to that changing environment.
This paper does not explore this but something also interesting: that robustness and evolvability might be desirable but incompatible aims. Robustness can be seen as he ability to counteract change while evolvability represents the capability to adapt. In general it is true that species must strike some sort of compromise between these two abilities since organisms need the robustness provided, for instance, by the DNA repair mechanism but species need mutations that actually allow these organisms to better adapt to the environment. This is not always true and there are cases in which robustness and evolvability can go happily hand by hand. One such case is genomic redundancy. Up to a point, genomic redundancy improves robustness since functionality is kept in more than one location making it less vulnerable but also it helps evolvability since it allows duplicated genes to evolve different functions.
The general rule though is that organisms cannot be entirely robust to change in the form of genetic mutations since such an organism would freeze from an evolutionary point of view and thus subject to become extinct when a fitter rival comes around. I guess that that is a good explanation to cancer, a perfect reproduction mechanism would have not led from simple organisms to humans.
This paper has not much to do with cancer but I have been interested in evolvability issues for a while so I decided to take a look at it. Tumour evolution has many but not all the features of the evolution involving longer time scales but its evolvability is not a thoroughly investigated topic. That is a shame because it seems that, given enough time, one would expect that tumour cells will not evolve only towards phenotypes that can take better advantage of the environment but also to genotypes that allow evolution to adapt better to that changing environment.
This paper does not explore this but something also interesting: that robustness and evolvability might be desirable but incompatible aims. Robustness can be seen as he ability to counteract change while evolvability represents the capability to adapt. In general it is true that species must strike some sort of compromise between these two abilities since organisms need the robustness provided, for instance, by the DNA repair mechanism but species need mutations that actually allow these organisms to better adapt to the environment. This is not always true and there are cases in which robustness and evolvability can go happily hand by hand. One such case is genomic redundancy. Up to a point, genomic redundancy improves robustness since functionality is kept in more than one location making it less vulnerable but also it helps evolvability since it allows duplicated genes to evolve different functions.
The general rule though is that organisms cannot be entirely robust to change in the form of genetic mutations since such an organism would freeze from an evolutionary point of view and thus subject to become extinct when a fitter rival comes around. I guess that that is a good explanation to cancer, a perfect reproduction mechanism would have not led from simple organisms to humans.
Friday, February 09, 2007
Axelrod et al: Evolution of cooperation among tumor cells
R. Axelrod, D. Axelrod and K. Pienta: Evolution of cooperation among tumor cells. PNAS vol 103, 36, pp. 13474-13479, 2006.
A few months ago a friend of mine from Vienna send me the link to this paper (thanks Peter!) and although I skimmed through it at the time only now did I have the chance to read it with a little bit more of care. Robert Axelrod is well known in the complex systems and game theory communities. The research he did almost a quarter of century ago (detailed in his book: The evolution of cooperation) explained how cooperation can be established between two agents (people, elephants or cells) even when the mechanisms of the cooperation have not been agreed beforehand and the agents could gain more in the short term by not cooperating.
Now Axelrod and coauthors speculate on how this approach could be used to study carcinogenesis. They present this in the framework of Hanahan and Weinberg and the six capabilities required to progress towards cancer (self sufficiency in growth signals, ignoring anti growth signals, evasion of apoptosis, angiogenesis, limitless replicative potential and invasion/metastasis).
Now, this paper is no regular paper. Most research papers I read describe a particular piece of clinical research (we have investigated this gene in this context...), mathematical or computational model (in this paper we introduce a model that explains the influence of acidity in...) or are review papers. This one does not describe new clinical research nor does propose a formal way to describe any aspect of oncology nor represents a review of carcinogenesis research from the cooperation point of view. This is not meant to be a criticism. The paper represents for me a new category of papers, one whose aim is not as much as telling finished research as to suggest to the reader new venues of research under a particular perspective.
If that was indeed the aim then this is a good paper. According to the authors, the conventional view on tumor progression using the Hanahan and Weinberg framework is that cells have to acquire all the six capabilities but under the new cooperation based view this is no longer necessary. It could be possible that, at least some of this capabilities are provided by some cells to others and thus cancer could occur when groups of cells displaying a mixed set of capabilities collaborate to create the same effect of a single cell acquiring all the capabilities and reaching fixation (taking over the tumour population) by clonal expansion. One of the things that I was not very comfortable with is that the authors state that cancers are the result of genetic (or epigenetic) instability. Readers of this site probably know that this is currently a hotly debated topic (something as fundamental such as: what starts carcinogenesis) and that in front of the Weinberg school (cancer starts from genetic instability) is the , say, Tomlison school (a bigger number of cells and selection suffices to explain the start of cancer). My view is that if tumour cells can cooperate in order to share capabilities and progress down the path of carcinogenesis then having a higher mutation rate might not be so relevant and thus a cooperation based view on cancer would favour the view that cancer does not really need genetic instability to get started. If this view of mine turns out to be a stupidity remember that you read it here first.
The paper provides a number of examples of capabilities in which cooperation can happen. In angiogenesis (where cells can produce growth factors that benefit not only the producing cell but others in the neighbourhood), self sufficiency from (certain) growth signals (there is a certain amount of growth signals which can be produced in paracrine or autocrine fashion) and in invasion/metastasis (collaboration to degrade the ExtraCellular Matrix).
The authors point out that this view of carcinogenesis arises a number of new research questions such as what are the resources that can be shared among cooperating tumour cells, what mechanisms are used to share these resources, how does this affect the order in which mutations appear (since mutations can appear in parallel)? Interesting questions but it might take some for someone to come with the answers...if it is that answers can be found using evolutionary cooperation.
A few months ago a friend of mine from Vienna send me the link to this paper (thanks Peter!) and although I skimmed through it at the time only now did I have the chance to read it with a little bit more of care. Robert Axelrod is well known in the complex systems and game theory communities. The research he did almost a quarter of century ago (detailed in his book: The evolution of cooperation) explained how cooperation can be established between two agents (people, elephants or cells) even when the mechanisms of the cooperation have not been agreed beforehand and the agents could gain more in the short term by not cooperating.
Now Axelrod and coauthors speculate on how this approach could be used to study carcinogenesis. They present this in the framework of Hanahan and Weinberg and the six capabilities required to progress towards cancer (self sufficiency in growth signals, ignoring anti growth signals, evasion of apoptosis, angiogenesis, limitless replicative potential and invasion/metastasis).
Now, this paper is no regular paper. Most research papers I read describe a particular piece of clinical research (we have investigated this gene in this context...), mathematical or computational model (in this paper we introduce a model that explains the influence of acidity in...) or are review papers. This one does not describe new clinical research nor does propose a formal way to describe any aspect of oncology nor represents a review of carcinogenesis research from the cooperation point of view. This is not meant to be a criticism. The paper represents for me a new category of papers, one whose aim is not as much as telling finished research as to suggest to the reader new venues of research under a particular perspective.
If that was indeed the aim then this is a good paper. According to the authors, the conventional view on tumor progression using the Hanahan and Weinberg framework is that cells have to acquire all the six capabilities but under the new cooperation based view this is no longer necessary. It could be possible that, at least some of this capabilities are provided by some cells to others and thus cancer could occur when groups of cells displaying a mixed set of capabilities collaborate to create the same effect of a single cell acquiring all the capabilities and reaching fixation (taking over the tumour population) by clonal expansion. One of the things that I was not very comfortable with is that the authors state that cancers are the result of genetic (or epigenetic) instability. Readers of this site probably know that this is currently a hotly debated topic (something as fundamental such as: what starts carcinogenesis) and that in front of the Weinberg school (cancer starts from genetic instability) is the , say, Tomlison school (a bigger number of cells and selection suffices to explain the start of cancer). My view is that if tumour cells can cooperate in order to share capabilities and progress down the path of carcinogenesis then having a higher mutation rate might not be so relevant and thus a cooperation based view on cancer would favour the view that cancer does not really need genetic instability to get started. If this view of mine turns out to be a stupidity remember that you read it here first.
The paper provides a number of examples of capabilities in which cooperation can happen. In angiogenesis (where cells can produce growth factors that benefit not only the producing cell but others in the neighbourhood), self sufficiency from (certain) growth signals (there is a certain amount of growth signals which can be produced in paracrine or autocrine fashion) and in invasion/metastasis (collaboration to degrade the ExtraCellular Matrix).
The authors point out that this view of carcinogenesis arises a number of new research questions such as what are the resources that can be shared among cooperating tumour cells, what mechanisms are used to share these resources, how does this affect the order in which mutations appear (since mutations can appear in parallel)? Interesting questions but it might take some for someone to come with the answers...if it is that answers can be found using evolutionary cooperation.
Monday, February 05, 2007
World cancer day
I guess I missed it. It seems that yesterday, 4th of February, was the world day of cancer. As many other "World day of...", this WOC was one of these events designed to raise awareness of the problem of cancer in the world, although given that cancer is in the top two of the diseases that are responsible for more deaths in the developed world I guess that many people are more than aware of it.
The headlines I am reading sound actually quite optimistic. Death rates are decreasing due to early detection and improved therapies. Of course nobody is suggesting that cancer will be eradicated but that it will become a chronic disease. I am not sure of how much impact has mathematical oncology had on all these successes but I suspect that it has been limited. For one, mathematical oncology is a fairly relative newcomer in the world of oncology and oncology is a discipline in which cutting edge discoveries take many years (or decades) to reach the public. For another one, I think it is highly unlikely that there will ever be headlines of the kind "theoretician cures cancer". Theoreticians deduce rules or laws that try to describe things like, for instance, cancer growth. These can be used by experimentalists to focus on the more promising areas of research and design the therapies with more likelihood of success faster.
Another added advantage of theoreticians is that they can connect research in different areas. Things that apply to cancer evolution can also be used to study the evolutionary dynamics of other diseases. Many diseases are dangerous due to their capability of evolving and being able to tell what (phenotypes) to expect in the near future from what is there now (genome) would be crucial to deal with them. This week's issue of science carries a paper (http://www.sciencemag.org/cgi/content/abstract/315/5812/655) about how the H5N1 virus (infamous for the avian flu) suggest that only two mutations stand between the current problem and one in which the virus could affect and spread in humans causing a global pandemic. Is there anything that we know about how a tumour evolves that could be used here? I would not be surprised if the answer turns to be positive.
The headlines I am reading sound actually quite optimistic. Death rates are decreasing due to early detection and improved therapies. Of course nobody is suggesting that cancer will be eradicated but that it will become a chronic disease. I am not sure of how much impact has mathematical oncology had on all these successes but I suspect that it has been limited. For one, mathematical oncology is a fairly relative newcomer in the world of oncology and oncology is a discipline in which cutting edge discoveries take many years (or decades) to reach the public. For another one, I think it is highly unlikely that there will ever be headlines of the kind "theoretician cures cancer". Theoreticians deduce rules or laws that try to describe things like, for instance, cancer growth. These can be used by experimentalists to focus on the more promising areas of research and design the therapies with more likelihood of success faster.
Another added advantage of theoreticians is that they can connect research in different areas. Things that apply to cancer evolution can also be used to study the evolutionary dynamics of other diseases. Many diseases are dangerous due to their capability of evolving and being able to tell what (phenotypes) to expect in the near future from what is there now (genome) would be crucial to deal with them. This week's issue of science carries a paper (http://www.sciencemag.org/cgi/content/abstract/315/5812/655) about how the H5N1 virus (infamous for the avian flu) suggest that only two mutations stand between the current problem and one in which the virus could affect and spread in humans causing a global pandemic. Is there anything that we know about how a tumour evolves that could be used here? I would not be surprised if the answer turns to be positive.
Saturday, January 20, 2007
The Darwinian perspective, the mutator phenotype and response to stress
Although today I will be writing about a paper recently published in the international journal of Epidemiology and authored by Paolo Vineis and Marianne Berwick, this is not going to be a review in the usual sense. This time I would like to write about the ideas and make no reference to the methodology.
The Vineis and Berwick emphasize the role of population dynamics on cancer progression. The usual view on cancer is that cancer cells grow at a faster rate than normal cells and that is the reason why they end up (if successful) killing the host. Growing populations can be due to this but they can also be the result of other factors (think of longer lifespan). The authors hint that the success of most cancers (with respect to taking over a tissue) lays on the fact that cancer cells have a greater proportion of replicating daughter cells. That makes sense to me. For instance, in a tumour whose cells that are capable of dividing near the tumour growth front (let's call them motile tumour cells) will have an advantage over other non motile but faster proliferating tumour cells in terms of how many of its daughter cells will be in position to proliferative (regardless to the speed at which they can divide).
The authors have also something to say about the highly controversial topic of the mutator phenotype. Quick reminder: the amount of time to pick up all the mutations necessary for a neoplastic cell to become a cancer cell is, according to some researchers, big enough as to be unlikely to happen in our life time. Thus cancer is the consequence of a single mutation that makes the cell more likely to produced mutated offspring. To prove their point they compare tumour cells to the behaviour of E.coli under stress. Under normal circumstances the mutation rate of the E.coli is low but when the going gets tough the mutation rates increases significantly. The speculation is that this is no accident but a feature of the bacterial DNA that in such a way can explore a genetic solution out of the problem. Could tumour cells be attempting something similar?
I find this hypothesis quite interesting and from my limited experience it seems quite novel. It should be interesting to do some experimental work (maybe more than theoretical) to see if there are any molecular mechanisms that might have an effect on the probability of mutation (say, the DNA repair mechanism) that could be held down when there are 'stress' signals in the environment. It could even be that the mechanism is similar to that of the E.coli although since bacteria are far simpler cells than human cells that could be unlikely (not having any experience with molecular biology should make any one be skeptic about statements like this).
The Vineis and Berwick emphasize the role of population dynamics on cancer progression. The usual view on cancer is that cancer cells grow at a faster rate than normal cells and that is the reason why they end up (if successful) killing the host. Growing populations can be due to this but they can also be the result of other factors (think of longer lifespan). The authors hint that the success of most cancers (with respect to taking over a tissue) lays on the fact that cancer cells have a greater proportion of replicating daughter cells. That makes sense to me. For instance, in a tumour whose cells that are capable of dividing near the tumour growth front (let's call them motile tumour cells) will have an advantage over other non motile but faster proliferating tumour cells in terms of how many of its daughter cells will be in position to proliferative (regardless to the speed at which they can divide).
The authors have also something to say about the highly controversial topic of the mutator phenotype. Quick reminder: the amount of time to pick up all the mutations necessary for a neoplastic cell to become a cancer cell is, according to some researchers, big enough as to be unlikely to happen in our life time. Thus cancer is the consequence of a single mutation that makes the cell more likely to produced mutated offspring. To prove their point they compare tumour cells to the behaviour of E.coli under stress. Under normal circumstances the mutation rate of the E.coli is low but when the going gets tough the mutation rates increases significantly. The speculation is that this is no accident but a feature of the bacterial DNA that in such a way can explore a genetic solution out of the problem. Could tumour cells be attempting something similar?
I find this hypothesis quite interesting and from my limited experience it seems quite novel. It should be interesting to do some experimental work (maybe more than theoretical) to see if there are any molecular mechanisms that might have an effect on the probability of mutation (say, the DNA repair mechanism) that could be held down when there are 'stress' signals in the environment. It could even be that the mechanism is similar to that of the E.coli although since bacteria are far simpler cells than human cells that could be unlikely (not having any experience with molecular biology should make any one be skeptic about statements like this).
Wednesday, January 17, 2007
Edge of existance
Researchers of the Zoological Society of London have started a new campaign (called EDGE) to promote the protection of certain species that might not be so close to extinction as some other more famous ones (say, whales?) but whose impact on the survival of other species might be significant. The news can be found in BBC or for those of you that can read Spanish in El Pais.
Now, this is probably not something that many people might find relevant to cancer research but I think that there might be a connection. In ecological systems (and here I assume that a tumour is one of those) species depend on other species for their survival. This dependency does not need to come in terms of food webs (a species needs other to prey on) but also in the way that one species can change the environment for the benefit (or not) of the other ones. The idea then would be to identify 'agents' in a tumour whose role in principle might not look so relevant but that might provide support to other more important but less vulnerable targets. Given the current emphasis on the role of the microenvironment in cancer research I would be surprised if there was not already some work pointing in this direction.
Now, this is probably not something that many people might find relevant to cancer research but I think that there might be a connection. In ecological systems (and here I assume that a tumour is one of those) species depend on other species for their survival. This dependency does not need to come in terms of food webs (a species needs other to prey on) but also in the way that one species can change the environment for the benefit (or not) of the other ones. The idea then would be to identify 'agents' in a tumour whose role in principle might not look so relevant but that might provide support to other more important but less vulnerable targets. Given the current emphasis on the role of the microenvironment in cancer research I would be surprised if there was not already some work pointing in this direction.
Tuesday, November 28, 2006
Speakers in Step conference
It has been a while since I came back from the Step conference in Brussels and I guess it is time to say something about some of the speakers I had the chance of listening to. Probably the most interesting ones from my highly subjective point of view were James Bassingthwaighte (University of Washington), Brian Goodwin (former Santa Fe Institute Faculty, now at Schumacher College) and Denis Noble (Oxford).
This Step conference was not meant to be about science per se so the talks were definitely not of a technical nature. James introduced the Physiome project which, as you might know, is about putting together all the current and future knowledge about the human phisiology with
the aim of improving health care. The ideal result would be a giant simulation of the human phisiology that could behave like a real whole organism. Such system would allow physicians and other researchers to test therapies quickly and without nasty side effects
and study 'what if' scenarios.What James thinks we need are:
* Training (No use of sophisticated systems if physicians don't use them)
* Databasing
* Standards (Too many groups out there and no way to compare or integrate their work)
* Modelling archives (I got a nice model, where do I put it for other people to play with?)
* Modelling tools
All in all a nice and light introductory talk. Everything he mentioned is quite reasonable although I am not sure if it is realistic to expect any of these things happening in the short term. People so far seem to be happy happy to come with their own models and not much effort is done to see if the results of one model are consistent with the results of the model of a different group.
Next talk came from Brian Goodwin who, although use to be in the Santa Fe Institute is know a professor of 'holistic science' (which looks quite a scary name for a professorship). The theme of his talk? Computational biology: a clash of cultures. The part of the talk which I found more interesting was when he dealt with the ambiguity of languages. Human languages are ambiguous and the meaning of a sentence gets shaped as we speak. This seems to be a good analogy to understand the language of genes which is also ambiguous (which is nice if you want to evolve it). In his view both human and gene languages have the property that are the best compromise between the effort that the speaker has to make to convey a message and the
effort of the listener. This is an interesting idea although I guess that proving it might be quite complicated (note to my self, should take a look at what has been published about this).
The talk from Denis Noble was also interesting despite the fact that his major point was: I have a new book ("The music of life") go and buy it (which I might do). He made a number of points:
1. There is no gene for function (no objections to that)
2. Transmission of information is not just one way (same here)
3. DNA is not the only transmitter of inheritance (heard that before)
4. Law of relativity in biology: there is no privileged level of causality. Message to Dawkins: the gene is not that important.
5. There is no genetic programme (message to Monod this time).
6. Actually there are no programmes at any level
7. ...and that means not even at the brain level
Thursday, November 09, 2006
The Step conference
I have just returned from my trip to Brussels for the Step conference in which a Physiome project was discussed. We had talks from some very nice speakers about which I will write in another post.
The Physiome project (or at least what I understood about it after being exposed to the idea for the very first time during this conference) is a highly ambitious project (and that is probably an understatement) whose aim is to integrate all the current and future knowledge about the human physiology. The idea is thus a multiscale modular framework in which all the models about the different parts of the human physiology could be integrated. Such a model would have a tremendous impact on our understanding of physiology, let alone the potential benefits for pharmaceutical companies. For all of you who have any experience doing modeling of biological processes I guess I don't need to tell you how (let's understate it once again) challenging this could be. In any case I am fine with any (extremly) difficult project as long as the intermediate steps are worth something.
In my opinion, the guys in the Step project should aim at something quite modest such as some system by which modelers can integrate just a few models together so different groups can check the consistency of their models and their assumptions. This process will probably take a long while but eventually most modellers will be used to think of their models not in isolation but as something that has to make sense in the context of all the models being developed elsewhere. There should be some infrastructure so the models can be shared between researchers and some protocols and interfaces between models at different scales or across the same scale (say molecular, cellular or tissue) so there can be integration.
One of the speakers mentioned that the keywords in this project are multiscale and modularity. I suggest taking a look at the field of software engineering in which different groups and companies work in different modules and at different levels of abstraction. The software produced is expected to work with other software modules. Of course the complexity to manage is different in the Physiome project but I still think it would be a good starting point.
The Physiome project (or at least what I understood about it after being exposed to the idea for the very first time during this conference) is a highly ambitious project (and that is probably an understatement) whose aim is to integrate all the current and future knowledge about the human physiology. The idea is thus a multiscale modular framework in which all the models about the different parts of the human physiology could be integrated. Such a model would have a tremendous impact on our understanding of physiology, let alone the potential benefits for pharmaceutical companies. For all of you who have any experience doing modeling of biological processes I guess I don't need to tell you how (let's understate it once again) challenging this could be. In any case I am fine with any (extremly) difficult project as long as the intermediate steps are worth something.
In my opinion, the guys in the Step project should aim at something quite modest such as some system by which modelers can integrate just a few models together so different groups can check the consistency of their models and their assumptions. This process will probably take a long while but eventually most modellers will be used to think of their models not in isolation but as something that has to make sense in the context of all the models being developed elsewhere. There should be some infrastructure so the models can be shared between researchers and some protocols and interfaces between models at different scales or across the same scale (say molecular, cellular or tissue) so there can be integration.
One of the speakers mentioned that the keywords in this project are multiscale and modularity. I suggest taking a look at the field of software engineering in which different groups and companies work in different modules and at different levels of abstraction. The software produced is expected to work with other software modules. Of course the complexity to manage is different in the Physiome project but I still think it would be a good starting point.
Thursday, October 12, 2006
Article in Nature: Driven to Market
Nature has a reputation for publishing academic articles of high-impact (that is, loads of people read nature so articules in nature are widely read and are more likely to be cited by other people which means that Nature becomes better ranked which means that more people buy it which means...), but also they have some nice articles that are more accessible to non specialists and that are written by freelance writers.
Yesterday I was reading one in last week's (I am always late with my issue) entitled "Driven to Market" by Jonah Lehre. The article is about a relatively new field called neuroeconomics which combines both psychology and economics. That does not seem related to the topic of this blog but what it is interesting (to me) is that one of the assumptions that is prevalent in economics and that the practitioners of neuroeconomics bring to question is that humans act guided by reason in order to maximise their own benefit. This is also one of the main assumptions in Game Theory (which is a common tool in Economics). Ironically one of the criticisms that opponents of evolutionary game theory have is that animals are not rational but it seems that reason is an even weaker predictor of the behaviour of humans. One nice example to illustrate that is the game called ultimatum. In this game one player is given, say, 10 euros and told that it has to share it with someone else in such a way that if any of the players is unhappy with the way the money has been split then no one gets anything. If people were rational the first player will always offer 1 euro to the second one knowing that the second one would take whatever he or she is offered since the alternative is to get nothing at all. It seems though that when this game is played by people, deals that seem to be too unfair are always rejected even if that rejection means that the money is lost.
Yesterday I was reading one in last week's (I am always late with my issue) entitled "Driven to Market" by Jonah Lehre. The article is about a relatively new field called neuroeconomics which combines both psychology and economics. That does not seem related to the topic of this blog but what it is interesting (to me) is that one of the assumptions that is prevalent in economics and that the practitioners of neuroeconomics bring to question is that humans act guided by reason in order to maximise their own benefit. This is also one of the main assumptions in Game Theory (which is a common tool in Economics). Ironically one of the criticisms that opponents of evolutionary game theory have is that animals are not rational but it seems that reason is an even weaker predictor of the behaviour of humans. One nice example to illustrate that is the game called ultimatum. In this game one player is given, say, 10 euros and told that it has to share it with someone else in such a way that if any of the players is unhappy with the way the money has been split then no one gets anything. If people were rational the first player will always offer 1 euro to the second one knowing that the second one would take whatever he or she is offered since the alternative is to get nothing at all. It seems though that when this game is played by people, deals that seem to be too unfair are always rejected even if that rejection means that the money is lost.
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