Mini workshop in Oxford

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

From the CMB I got to know the work of:

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

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

Mini workshop on cancer and cellular automata

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

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

Back from Scotland and Gatenby's talk

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

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

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

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

The cost of validation

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

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

Cooperation in a tumour and workshop in Scotland

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

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

Columbus workshop and interactions with life scientists

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

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

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

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

Workshop in Ohio

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

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

Recap from Lyon (II)

Philip Maini is one of the most entertaining speakers (entertaining in the good sense, of course) in the European biomathematical community. Prof. Maini is the director of the Centre of Mathematical Biology at Oxford University and gave in Lyon a talk entitled "Modeling aspects of cancerous tumour dynamics".

The modeling aspects he mentions are three different projects:

1) The first project, in which he collaborates with people like Gatenby (Arizona) and Gavaghan (Oxford) studies the acid mediated invasion hypothesis.
According to (my interpretation of) this hypothesis, when tumour cells lack oxygen and start to starve then a mutation might appear that would make some cancer cells switch to what is called glycolitic phenotype. This means that these cells have an alternative metabolism that works without oxygen and that is not as efficient as the regular one. The reason why this alternative phenotype has a chance of success is because the waste produced (galatic acid) can be used to degrade the extra cellular matrix and lead to invasion of other tissue. Gatenby, Gavaghan and Maini came with a model in which tumours contain cells with the glycolitic phenotype. The results is that tumours are not benign and that an possible explanation for the existence of necrotic cores (material generated when cells die disorderly because of starvation) can be the result of too much acidification of the environment, even for acid-resistant glycolitic-type tumour cells.

2) Metabolic changes during carcinogenesis. Also with Gavaghan and Gatenby and referring to research covered by a paper in Nature reviews cancer (vol 4, 891-889, 2004). They study somatic evolution in a system in which tumour cells can be of one of three different types: hyperplastic, glycolitic or acid-resistant. These cells inhabit the space of a 2D lattice in which there is oxygen, glucose and hydrogen that diffuse in a continuous manner. Altering the reach and concentration of these elements leads to different numbers of cells displaying one or the other phenotype.

For me this is a good place in which to see how game theory could be used to study the interactions of different players (cancer cells) using different strategies (the different phenotypes) to maximise their payoff from the environment (O,H,glucose).

3) Together with Benjamin Ribba (Lyon, organiser of the workshop and one guy I am working with as of lately) Maini works on a multiscale model on which to study the differences between the vasculature generated by the normal process of vasculogenesis and the ones generated by tumour cells capable of angiogenesis. One of the conclusions he mentioned: don't trust parameters.

Recap from Lyon (I)

As I mentioned in a previous post one of the nice talks in Lyon came from Vito Quaranta, from Vanderbilt University in Nashville, USA.

He is and MD collaborating with researchers in the States and Europe (eg Sandy Anderson from Dundee) to develop models on tumour invasion. That is the defining feature that separates tumours from benign to malign (eg cancer).

In order to know if a cancer is invasive MDs tend to look at the way the tumour grows. A tumour with a smooth margin is unlikely to be invasive whereas one with fingering is likely to be so.

Of course I am interested to know if there are alternative studies that could be used to predict the evolution of the cancer that are not based on how the tumour shape looks like. First because in many cases physicians don't have accurate images of the contour of tumours (or sometimes haven't got enough information about what is the result of tumour growth). Second, and maybe most important, because the current shape of a tumour doesn't say much about the potential evolution of it towards malignancy. Maybe a different measure (based on the phenotypic composition of tumour cells) could help not only to tell if a tumour is malignant or benign but if the chances of becoming invasive are high or not.

In any case his presentation showed some interesting results on how the microenvironment affects the evolution of the cancer. Homogeneous microenvironments, that is, those in which space can be created with the same ease everywhere, lead to smooth contours whereas inhomogeneous ones lead to fingering. Interestingly these inhomogeneous microenvironments tend to lead to tumours with little diversity in terms of phenotype: when it is difficult for a tumour cell to create space only invasive phenotypes tend to survive.

Reporting from Lyon

Still in Lyon after attending the cancer modeling workshop mentioned in my previous post.

From a couple of very brief escapades, Lyon seems to be quite a pleasant town but the workshop has been interesting enough that I didn't had a lot of time for tourism. Nice talks from the likes of Philip Maini from Oxford and Vito Quaranta from Nashville and chats with Benjamin Ribba from Lyon have kept me entertained. The word from modelers: multiscale modeling. Lots of researchers producing models studying cancer at all sorts of scales from molecular to tissue and from seconds to years and we still have not got the way to integrate them.

Tomorrow back to Dresden

off to France again

It seems that September is my French month: I am off to an interesting workshop in Lyon. The topic is Cancer Modelling and Therepeutic Innovation. Although I won't be presenting I hope to meet physicians and discuss one of my models.

The Workshop URL is : http://www.spc.univ-lyon1.fr/workshop-modcan

I am off!!

Only until next Wednesday. The Marie Curie Training Network that sponsors my research here in Dresden is organising a meeting of all the scientists involved in the different projects it manages. The meeting is this monday in Paris!!

It will not be my first time in Paris but I am still looking forward spending the weekend there and meeting some friends.