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.
Thursday, March 08, 2007
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.
Thursday, March 01, 2007
Old Dawkins video on cooperation
I have found this video on google video. It is an old Richard Dawkins BBC TV programme in which he goes through some topics of which I am quite fond and which I personally think have some yet-to-be-explored relevance to cancer research.
The documentary was produced a few years after Dawkins wrote The selfish gene and not long after Robert Axelrod had written The evolution of cooperation. It takes from Axelrod's research on cooperation (whose own take on how this can be observed in cancer has been mentioned in this blog before) to illustrate how cooperation might evolve in an place in which agents (say humans, bacteria or buffaloes) are selfish. The topics are the usual ones in game theory such as prisoners dilemma (how playing if for an undetermined number of times changes what is the best strategy), tragedy of the commons (if everybody is overusing a resource why shouldn't you, and if few people overuse, why shouldn't you since it will make no difference whatsoever?).
The tragedy of the commons seems to me a suitable game to model global warming (why should your country cut on carbon emissions if nobody else does or why should you if everybody does? this seems to apply to most countries but the likes of U.S. and China whose weight is to big to be considered just another player) or cancer (at the end, tumour cells do kill the host and thus themselves).
The documentary was produced a few years after Dawkins wrote The selfish gene and not long after Robert Axelrod had written The evolution of cooperation. It takes from Axelrod's research on cooperation (whose own take on how this can be observed in cancer has been mentioned in this blog before) to illustrate how cooperation might evolve in an place in which agents (say humans, bacteria or buffaloes) are selfish. The topics are the usual ones in game theory such as prisoners dilemma (how playing if for an undetermined number of times changes what is the best strategy), tragedy of the commons (if everybody is overusing a resource why shouldn't you, and if few people overuse, why shouldn't you since it will make no difference whatsoever?).
The tragedy of the commons seems to me a suitable game to model global warming (why should your country cut on carbon emissions if nobody else does or why should you if everybody does? this seems to apply to most countries but the likes of U.S. and China whose weight is to big to be considered just another player) or cancer (at the end, tumour cells do kill the host and thus themselves).
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.
Monday, February 12, 2007
Cancer and biofuels
I have recently commented how (in my particular view, especially at the theoretical level) research in some area can be used in a different one but I guess I did not expect this: Cancer research may help biofuels.
It seems that, inspired by research done at the Fred Hutchinson Cancer Research Center in Seattle, a company called Targeted Growth is doing to corn the opposite of what oncologists do to human cancer cells taking advantage of the fact that some pathways in these two different cells are similar. The idea is to promote plant growth by overriding the genetic clock that tells the cell when to stop growing. The advantage is that plants thus modified are not transgenic (whith the load that this label carries to many consumers) and that it can lower the price of growing them as biofuels and thus promoting them as a good value alternative to oil.
It seems that, inspired by research done at the Fred Hutchinson Cancer Research Center in Seattle, a company called Targeted Growth is doing to corn the opposite of what oncologists do to human cancer cells taking advantage of the fact that some pathways in these two different cells are similar. The idea is to promote plant growth by overriding the genetic clock that tells the cell when to stop growing. The advantage is that plants thus modified are not transgenic (whith the load that this label carries to many consumers) and that it can lower the price of growing them as biofuels and thus promoting them as a good value alternative to oil.
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.
Tuesday, February 06, 2007
Mitochondria and apoptosis
A couple of posts ago I mentioned this research in which RNAi was used to restore the functionality of the mitochondria, especially its role in apoptosis. Now I read that the same results are being obtained by Dr. Michelakis and colleagues at the University of Alberta in Canada using a well known drug, dichloroacetate (DCA).
DCA is an affordable drug that has been previously used to treat metabolic disorders so it is known to be safe and has no patent. What should have been a blessing could also be a curse since there is little incentive to large pharmaceutical companies to finance the clinical trials. The news has been reported in all sorts of news outlets from Cancer Cell to Slashdot and including The Economist. In this website you will be able to find the latest results as well as information on how to donate money so Dr. Michelakis and his group can finance the clinical trials.
Incidentally, in the link pointing to these news in the online version of The New Scientist, a researchers from Dundee mentions something I did not think of at that time. It could be that the metabolism and not genetic mutations spark cancer. Of course for the metabolic switch to take place you will still need hypoxia (low oxygen due to distance to vasculature) which means, if I am not wrong, a neoplasm.
DCA is an affordable drug that has been previously used to treat metabolic disorders so it is known to be safe and has no patent. What should have been a blessing could also be a curse since there is little incentive to large pharmaceutical companies to finance the clinical trials. The news has been reported in all sorts of news outlets from Cancer Cell to Slashdot and including The Economist. In this website you will be able to find the latest results as well as information on how to donate money so Dr. Michelakis and his group can finance the clinical trials.
Incidentally, in the link pointing to these news in the online version of The New Scientist, a researchers from Dundee mentions something I did not think of at that time. It could be that the metabolism and not genetic mutations spark cancer. Of course for the metabolic switch to take place you will still need hypoxia (low oxygen due to distance to vasculature) which means, if I am not wrong, a neoplasm.
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.
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