Thursday, June 26, 2014

Impact of vascular patterning on radiation response - contributed talk from ECMTB 2014

So - I meant to try to use +Camtasia Studio to record my voice during this talk, which would have made following along much easier, but somehow, the meeting was so chock-a-block with content and excellent social outings, that I failed to download and sort it out.  Next time...



For now, here is a short presentation that I gave as a contributed talk at #ECMTB2014 in Goteborg.  It represents the meat of the second chapter of my growing (fingers crossed) DPhil thesis. My hope is that by finding a metric (Ripley's K) that predicts radiation response in our CA model (based on a simplification of a CA I worked on previously with +David Basanta which we published here), that we (or someone!) could translate this into histopathologic sections from patient samples.

This is essentially an extension to a poster I presented at the #PSOC meeting in DC in early April which I blogged about previously.  Please feel free to ask questions or make comments. I'll let everyone know once there is a proper #preprint available, and in the mean time I'll try to learn to use camtasia.

'Till then, here's the presentation:



Monday, June 23, 2014

ECMTB 2014 in Goteborg, Sweden

I've just returned from nearly two weeks in the UK and Sweden, visiting friends and colleagues in both countries. The impetus for the trip was the once-every-three-years meeting of the European Society of Mathematical and Theoretical Biology called the European Conference of Mathematical and Theoretical Biology (ECMTB).  I first attended this meeting in Krakow, Poland (thanks to the futuristic vision of +Alexander Anderson ), before I even began my DPhil, and found a true intellectual home. This is an unbelievable group of people - intelligent, kind, fun loving and open minded.

The scientific content for this meeting was excellent (and can be found here) and included many parallel sessions of contributed talks, a poster session as well as member organized minisymposia (I hosted two, which I will blog about separately). There was a lot of activity in the +Twitter sphere recording both the scientific content as well as much of the social activity of the meeting - which are both, I firmly believe, are equally important to the success of a meeting.

I have storified the tweetcast of the meeting and social events, and will embed it below, but I also wanted to take a moment to thank +Torbj√∂rn Lundh and +Philip Gerlee and the rest of the organizers for a throughful and beautifully organized meeting. Everyone to whom I spoke had only nice things to say - the only complaint being that there wasn't enough time to see all the amazing content! Thank you so much for your hard work.

Take a moment to scan what's below - there is lots of linked content and interesting people. Also, keep your eyes out for a group (pro-con) post on tweetcasting on the WCMBlog in the coming days.




Sunday, May 25, 2014

A success story for Warburg's Lens

I've been travelling a lot of late, which I'll blog about on its own in a bit (including a 'best of the best' coffee machines post), but I heard a story from a friend, which triggered a memory which I want to share. It took a moment, but I realised that a whole chain of events that I was unaware of, yet intimately involved in) added up to a success story for Warburg's Lens, the theoretical oncology preprint discussion forum that some colleagues and I started to try to speed up the process of scientific discussion.

So the story goes like this:

I was trolling the qBio section of the arXiv, as you do on a Friday night, looking for interesting papers. For the record, I also always scan the +bioRxiv Preprints. On this night, I came across one from one of my favorite authors, +Arne Traulsen, who has an evolutionary theory group at the Max Planck Institute in Plon, Germany. The #preprint, entitled, Cancer initiation with epistatic interactions between driver and passenger mutations, seemed like a very interesting one, so I put it on Warburg's Lens for discussion. It generated some nice discussion on the site which even included the authors, who were able to defend some of the points, but also take on board some very relevant (non-anonymous) feedback.



Fast forward a bit, and I'm minding my own business trying to get a job, and I get a request from a journal to review an article.... lo and behold it is the same one we are talking about. For various reasons, I declined to review it, but I remembered that there were some very constructive criticisms from people on Warburg's Lens (people who have published significant works in this direct area), so I knew who I could suggest as a replacement reviewer, which I did. Readers won't have a problem guessing who any of the anonymous people are, but I will not divulge that here.

Fast forward again, and I'm visiting some colleagues in Boston (again, post to follow, there was wide #heterogeneity in coffee machines) and a friend mentioned that this great paper that he had reviewed just came out...  and on the same day, my colleague and supervisor, +Alex Fletcher sent me an email notifying me of the paper, which is now out, and you can find it online here, but of course, I can't get it at home without dropping $40. I am eager to read the paper and compare it to the #preprint.


Either way, congrats to +Arne Traulsen et al. on the nice paper and thanks to all who contribute to the discussion on Warburg's Lens - and it's inspiration website, Haldane's Sieve. Keep submitting your #preprints to repositories like the arXiv and +bioRxiv Preprints, keep doing good #openscience. This seems like a win for everyone.

Also, lest I forget, cheers to the Journal of Theoretical Biology for being cool with preprints. Let's keep adding to the list.  This is a tangible example of how preprint servers help EVERYONE, even the journals. We got faster, more on target review, because of the preprint. A list of journals and their preprint policies can be found here:

http://en.wikipedia.org/wiki/List_of_academic_journals_by_preprint_policy

Wednesday, April 30, 2014

My visit to the Mathematical Neuro-Oncology group at NorthWestern and the talk I gave about glioblastoma evolutionary dynamics and metastasis

I recently was honored by an invitation to visit Chicago and present some of my recent research to my friends and collaborators in a new group formed there by +Kristin Swanson called Mathematical Neuro-Oncology. I spent my time visiting their new, beautiful lab;



celebrating +Russ Rockne's transition;



having some coffee;







visiting my roots;



finding out that a paper long in the works, based on an opinion piece I wrote a few years ago about the effects of the #IDH1 mutation in secondary #glioblastoma, is finally in press at Neuro-Oncology (aside: Somehow there is an editorial written about it that is available (if you PAY, which I haven't yet), but the article is not yet itself available); listening to +Kristin Swanson practice for her +TEDx talk, which I've heard went well, but haven't seen yet (more info here: http://www.tedxuchicago.com/kristin-swanson); and actually giving a talk.



I couldn't decide what to talk about, and since the audience was going to be half computational neuro-oncologists (casual dress) and half general scientific/medical folks (white coast, ties, scrubs), I decided to give a talk in two parts - about a half an hour each.

I spent the first half hour talking about an exciting (to me at least) extension to previous work I've done here at IMO with +Alexander Anderson and +David Basanta and others on glioblastoma stem cells. I've blogged on this topic before, from posts about our recent paper in PLoS Comp Biology to a recent grant we submitted - which, frustratingly didn't get scored due to a very prototypical reviewer #3 (reviewers 1 and 2 gave us 1's 2's and 3's and reviewer #3 gave us 7's, 8's and 9's).

The second half I talked about the work I've done with +Philip Gerlee and +Alexander Anderson and others to understand how a filter-flow paradigm of metastatic spread can help us understand (and intervene) in the process of #metastasis itself. We've published most of this work as a perspective piece in Nature Reviews Cancer, a test of the self-seeding hypothesis in J. Roy. Soc. Interface, a review in a Springer textbook (pre-print here) and recently, a more clinically oriented piece under review at Clinical and Experimental Metastasis (you can see a pre-print here on the +bioRxiv Preprints site). Both I and Philip Gerlee have blogged about it (including a shared post here in response to a Cancer Research UK blog post which we took exception to (at least to parts of it)) in the past as well.

So - anyways, here are the slides. The first half is work in progress, and we're pretty excited about it. I'd love to know if anyone has any feedback.


Sunday, April 6, 2014

5th Annual (final?) Physical Sciences in Oncology Centers meeting at the NCI

I just got back from 3 days at the National Cancer Institute for the (final?) meeting of the Physical Science in Oncology Centers. It hopefully isn't the REAL final meeting, but it is the final one as we know the PSOCs, as they are changing drastically in the way that they fund folks - in ways that haven't been entirely decided yet.  Either way, I've been attending these meetings since the beginning, and they have been quite important as formative experiences for me: showing me that outside the box thinking is OK (even encouraged) in cancer research, and that being a non-standard cancer biologists can be a way forward.

Anyways, it was a great meeting, with interesting talks ranging from origin of life, to mouse modeling to evolutionary game theory. There was a young investigator session (which I missed, but heard was really good) and a poster session, where I gave this poster -
As always, there were lots of great opportunities for networking, catching up with old friends, and making new ones. I storified the tweetcasting under the hashtag #PhysOnc (it was lively) to give you a flavor of the meeting. So, here that is:

Saturday, March 8, 2014

The role of mathematics in oncology - a discussion

A few weeks ago, my friend and colleague +Philip Gerlee wrote a post on his blog with about the role of mathematics in oncology in which he generally suggested that our role, to date, as mathematical/theoretical oncologists has been to help see old data in new ways.  In the post he said further that there has yet to be a 'seminal paper' in the field that has changed the way that biologists (or clinicians) think about a problem or disease. In an addition to the post, at the suggestion of another friend and colleague, +Heiko Enderling, Philip added an errata, which suggested that maybe he was wrong, and that maybe an early paper on chronic myelogenous leukemia (which you can find our more about here) represented the 'seminal paper' that we needed.




I commented that, while I thought that paper added valuable insight to the field, that it hadn't really changed the way we think of (or treat) the disease. This comment kick-started a much more cogent, and thorough, blog post from +Artem Kaznatcheev



which was re-blogged and further discussed by +David Basanta on his blog, cancerevo.



I think that this debate is an important one.  As our field, mathematical oncology, is still young, defining our role is extremely important, especially for the new generation, as only by understanding our role can we measure our success and plan for the future. While I'm working as hard as I can to finish my DPhil at the Wolfson Centre for Mathematical Biology, I'm excited to think about trying to build a group centered around meeting these goals. Other fields of mathematical biology have better established roles (take for example, developmental biology in which many important advances have been made by theorists, like our own +Ruth Baker and her mathematical model of the clock and wavefront model, for instance), and I fear we'll lose promising theorists to this field (I'm talking to you +Alex Fletcher) if we don't better define our role.

So, take a look at the discussions and posts I've linked above, have a read and think, and chime in.

Tuesday, January 14, 2014

An Evolutionary Game to study the cancer stem cell hierarchy

So, I'm going to take a page out of my friend and colleague +Artem Kaznatcheev 's playbook and write a blog post about a project that I'm nearing the start of.  My DPhil thesis is centered around the study of the 'cancer stem cell' hypothesis, and how it affects tumour progression. You might remember a post earlier about an agent based model we've built to study this, and they'll be more in the future, covering other aspects such as radiobiologic response and niche evolution.  The first paper should be out soon in PLoS Computational Biology, and in the mean time there is a #preprint on the #bioRxiv here.

I've been slamming my head against the wall for the past several weeks working to write up the model in the form of a thesis chapter, which I'm finding is VERY different than writing a paper (at least for Oxford's Centre for Mathematical Biology).  So, as I can't stand it any more, I'm going to write this post about what I'm planning to be the final research chapter in my thesis - an exploration of plasticity in the cancer stem-cell phenotype using Evolutionary Game Theory (EGT).  EGT is a technique that has been used for half a century or so to study the evolutionary dynamics of populations containing species (or players) with different life-strategies (called payoffs).  It differs from standard Game Theory in that players can't change strategies, but instead, their frequency in the population will change based on the relative fitness as governed by the replicator equation.

We have used this technique in the past to study a few scenarios in cancer - specifically: +David Basanta and +Alexander Anderson and some collaborators from Vanderbilt studied the effect of therapy on prostate cancers made up of populations of cells independent and dependent on the stroma, which you can read here; and then we studied the role of IDH1 mutated glioma cells in glioblastoma with +Russ Rockne and +Kristin Swanson.  More recently, +David Basanta and +Artem Kaznatcheev and I studied what happens at the edge of a tumour using a method developed by Ohtsuki and Nowak which Artem has blogged about a fair bit to try to get around the limiting assumption that is typical of evolutionary games of the population being well-mixed (recently updated preprint).



Phew - that was a long introduction. Anyways, I'm eager to do some EGT in my thesis, and no one has tried to make sense of cancer stem-cell plasticity with this technique, so I figure I'll give it a go. We're interested in what sort of conditions would result in promotion of the stem phenotype, why the stem fraction would be heterogeneous and how different sorts of stem-cell niches would affect this fraction. These are good kinds of questions to ask using EGT as the end result is (typically) ranges in parameter space that map to certain population proportions in the long run (called the Evolutionary Stable State which you can read about here).

So - what's the game then?  Well, we've thought long and hard about how to structure this sort of game. We've gone back and forth thinking about pitting one stem cell against another, different types of tumours (with different stem parameters) against one another, but have recently settled on trying to pit the stem cells vs. plastic daughters vs. non-plastic daughters.  We're going to consider some intriguing data from our collaborator +Anita Hjelmeland about the role of IL-6 in promoting the stem phenotype and try to make some sense of all of this!  We begin by thinking about the allowable phenotypic transitions and population changes as stem cells either self-renew (probability s) or divide asymmetrically to form a non-stem daughter and maintain their population number.  The plastic progenitors can also self-renew (probability a) or differentiate (d) or dedifferentiate back into stem cells (1-a-d). You can see a schematic of this in the figure below:



We decided to move away from the standard formulations of EGT in this respect, and we consider these sorts of divisions (ones that increase or decrease a population) as being fitness payoffs. And, as I said we'd try to consider the effects of IL-6 which +Anita Hjelmeland and crew wrote about, we've added in an asymmetric cost (c) and benefit (b). In their paper, they found that both stem and non-stem cells produced IL-6, but that only stem cells benefitted from its presence.  So, our final payoff table looks something like this:


hmm... you can't really read that - but I can't NOT include a picture of the chalk board, so there it is. Here's the payoff table we think we're going to go with.  Now listen, if you are an EGT nerd (I'm talking AT LEAST to you +Artem Kaznatcheev - PLEASE DO NOT ANALYZE THIS GAME, or if you do, keep it to yourself, I need a DPhil!).

Yes, I know there's a -c in every block and that I can simplify the game a bunch more.  No one is sure if the cost of producing IL-6 (c) is the same across cell types, so we're still thinking on it.

So - that's where I'm going to start.  With any luck we can learn something.  Worst case, I'll be able to make some pretty pictures and do some proper analysis.  Next post will be an analysis of the three 2x2 subgames, a la Artem's method (analyze, blog, analyze, blog, PAPER!).

More soon.  If you have feedback on the payoff table, I'd LOVE to hear it (BEFORE I start analyzing it).

ciao for now