Monday, July 29, 2013

A visitor, the resulting hackathon, and a nice result.

So, I was sitting in a pub in Oxford (the head of the River - gorgeous place and one that Lewis frequents), and I met this guy +Artem Kaznatcheev. No, he wasn't having a pint at the table next to me. No, he wasn't there for an academic visit.  I met him on twitter, because of a tweet from +Steven Strogatz about mathematics in biology.  Here's how it all began:

In there, we can also see the first thoughts about making this blog - about 6 months before I actually did it. Better late than never?

Anyways, +Artem Kaznatcheev and +David Basanta and I (and some others) started what is now a 10 month long conversation, mostly on Google+, in a community Artem started and we co-moderate, called Evolutionary Game Theory.  This conversation has covered topics (subsequently blogged about) ranging from understanding vs. predicting (followed up nicely by +Philip Gerlee in his blog here), games bacteria play (and a recent +Jeff Gore paper in PLoS Biology), connectors in science and, more recently, the topic of our original connection: the use of game theory in cancer.

The conversations have been lots of fun, we all think a bit differently, but have many of the same ideals about science, understanding and the uses of mathematics.  Further, we are all hopeless nerds and *cough* workaholics.  So, when Artem noticed that the conference he was going to (Swarmfest 2013) was near us, he jumped at the chance to come meet us and get some work done.  On his way down, he gave a couple of David's papers a detailed read through to get the lay of the land (and blogged about it - clever way to annotate things for yourself as well as manage a post).

So, here's the hackathon part.  Artem arrived Wednesday night and he and David worked into the wee hours.  He then came in to #IMO and they spent the day doing a full analytic treatment of a game David and I published in the British Journal of Cancer.  They then worked again into the wee hours at David's house.  I arrived from an out of town trip the next day (Friday).  Artem came in to IMO and gave a talk (which we managed to broadcast on G+, something we hope to continue, but with better sound quality, any ideas on a bluetooth mic?).

Here's me and Chandler looking interested.  Also, you can see we had 4 or 5 others from all over, Germany, Oxford and I don't know where else... 
After his talk, we spent the afternoon identifying a tight question: in a growing tomour, what would change in a simple game or proliferative vs. motile cells between the middle and the edge, if anything?

One of the difficulties in EGT is that neighborhoods and population structure is not considered, indeed, it is assumed that the population is inviscid (well mixed).  A great paper from Martin Nowak at Harvard gave us a way to think about effective neighborhood sizes (formally, how to understand changing game dynamics on graphs of differing, but regular, degree).  This has some obvious applications to growing tumours - when they hit a basement membrane or an organ capsule they go from growing in 'free 3-d space' (neighbors on all sides) to growing almost in 2-d, against a wall (with neighbors only on one 'side').

So, we spent the rest of friday afternoon doing some analysis

Then, on Friday night, we celebrated by buying a bunch of redbulls and working 'till 2am at my house.  I dropped him off at his hotel, then picked him up for a late breakfast and we worked, using this great new on-line app we found +writeLaTeX (which is AWESOME) and started a manuscript.  At dinner time, we broke company...  Then, Saturday night, we really blew off some steam - and made the figures for the paper.  Dropped off at his hotel around 2am, he was picked up by David the next morning and they worked until his plane left.

So, that was the hackathon.  The result, we are proud to announce, is a paper, done and dusted, beginning to end, in 15 days, with the lion's share of the work done in the first 4 days (about 48 hours of which saw the three of us working full on).  To be fair, we thought hard about the question in conversations for several months, and the groundwork had been laid by previous papers, but really, this felt like doing theory the way you're meant to.  It felt inspired.  And, I think, this is the best paper I've been a part of so far.  But, don't take my word for it, check out the preprint, just released on the arXiv today:

We also have submitted it, and it is now under consideration at the Proceedings of the Royal Society, Series B.  While we were motivated by a cancer scenario, we feel the result applies more broadly to biology than many of our previous papers, and so have targeted a broader biological journal.  And, PRS B does publish theory, and has recently published some interesting work from +Arne Traulsen's group at Max Planck on evolution in structured populations, so it seemed like we have a chance...  we'll see.

After this experience, we hope to weave hackathons like this into our schedule more often.  It certainly isn't something I (or my family) could tolerate every week, but it was fun and highly productive and we'll try to do it again soon.

Anyways, we'd love feedback on the paper.  Artem has a more technical post today about the work and some future directions which you can read here.

Friday, July 19, 2013

Visit to Summer Science Program in Socorro, NM

About a year and a half ago, after my talk at TEDMED 2012, I got a call from a medical oncologist asking if I would come to visit a summer camp in the desert of New Mexico that featured a bunch of really smart kids and astrophysics. This sounded right up my alley (I love nerds, and I love stars), but the trip from Oxford to New Mexico seemed a little bit...  far.  So, I said I was interested, but maybe we could talk next year, when I was back in Tampa in IMO - which I promptly forgot about.  Thankfully, they didn't forget, and a year later, I got the call again.  So I packed up and headed for the Summer Science Program's, Socorro, New Mexico campus (on the campus of New Mexico tech, home of the Miners and well known for excellent work on explosives!).

As I left the rental car place in the Albuquerque airport, I asked the attendant how to get to 25 South and he said:

"You mean 25 North, there isn't anything to the south"

Which is how I knew it was the right direction...

After arriving, I was met at my hotel by the site director, Barb, and I asked to go up to the telescope to see the kids doing their observations.  This camp is set up in a really cool way, they spend 6 hours a day in the classroom doing intensive math/physics and computer science (Python) coursework.  They are split into teams of three, and at the very beginning they choose a near earth asteroid (the way they choose the asteroids is kind of a funny story, but maybe one of the students will comment with how that works...).  The teams then get a certain amount of telescope time, during which they take measurements of their asteroid's position.  They are then expected to do the math and write up some code to predict the orbit - which they then share with some astrophysicists at Harvard.  Really cool - not just taking courses and playing with telescopes, but DOING MEANINGFUL SCIENCE. Needless to say, I didn't fly all the way to NM to just give a talk, so at around midnight, I wandered up to the observatory.  It was DARK (perfect) and Barb got out a flashlight, which I asked her to extinguish so I could enjoy the darkness...  she demurred suggesting that we needed it to see any snakes in the path.

Me:  Snakes, pshaw...  wait, you mean like that one?

She ran away, and I snapped this pic - can anyone ID it?  Not the best pic - iPhone flash sucks...  its head was narrow, like a non-venomous snake, but I don't know my high desert fauna...  little help?

We finally got to the telescope and found the group observing.

They weren't able to see their asteroid this night, but they showed me a beautiful globular cluster (pictured) and a spiral galaxy that they found.  How cool. 

The TA who was there gave me a short tour and I found out that he is starting his DPhil in Oxford next year, at Summerville college (right next to the CMB, my home!) doing condensed matter physics.  Small world.

I finally crashed and awoke to take a short run and saw this really cool 'M' in the hills.  This delighted my daughter (Maren - of course the 'M' was for Maren!) who thought of the Thomas the tank engine episode about the Man in the hills.  It turns out it is for the NM tech Miners, but I like the M in the hills better.

Anyways, after my run, I went up to the campus and set up to give my talk,.which you can see here:

 Beyond an introduction into the uses of mathematics in cancer research (and theoretical biology in general) I focused on the need for taking risks in science, and how we ought not shy away from creative thinking.  Further, I talked a bit about my tortuous career path and how having done a ton of different things, and not just following a straight arrow course, had informed my science and my life in general. After the talk, they gave me a sweet green SSP engraved laser pointer (THANKS!) and I had lunch with the students and a chat afterwards...  it was at this point that I started ranting about open access science (I was overtired) and tried to convince them to put the findings from their summer research onto the arXiv (might need an endorsement for astrophysics...anyone willing to help?) and their asteroid tracking code onto github.  Why not!?

Here's the pic.  I was overjoyed to see a large cadre of girls at the camp - a good sign for our future!  I am certainly going to keep this place, a well-kept secret, in mind for when my kiddos are in high school.  I just wish I had had an opportunity like this - and I'm amazed that I had never heard of it.  My high school teacher - Bob Shurtz (LEGEND) - is the coach of the US Physics Olympiad team and is well plugged in in these matters, but had never heard of this camp.  Considering it has been around since Sputnik, this surprised me.  Further, there were kids from all over the world - India, Hungary and China in addition to the US.  Oh well.  In my next lifetime...

Yeah, that says 104F
Oh yeah... it was HOT.

Also worth checking out - the students at SSP have a blog.  Good stuff.  Watch these kids - they are a bright crew.  And, with any luck, I interested one of two of them in theoretical biology!

Great experience as a lecturer, looks amazing as a student.  Spread the word.

Wednesday, July 3, 2013

The pre-metastatic niche is only half of the story of metastasis (it's the biological one)

Recently, Cancer Research UK posted an article on their blog in which they explain, in layman's terms, recent trends and ideas in research into metastatic spread. The focus of that article is on the concept of a 'pre-metastatic niche', the idea that the primary tumour emits signalling molecules that prime certain organs for the arrival of metastatic cells. We find this line of thought very interesting, as it could, at least in part, explain patterns of metastatic spread, but have strong opinions about how the ideas were presented and the lack of acknowledgment of the other factors that could be at play.  

First, the reader is given a condensed historical background, in which the surgeon Stephen Paget is given credit for having solved the riddle of metastatic patterns 150 years ago. His method of studying metastatic spread in breast cancer is briefly mentioned, however, as is often the case when the seed-soil hypothesis is mentioned, these old 'truths' do not seem to be carefully checked. For example, a much more recent study from by Dr. J Pickren (reported in The Principles of Metastasis by L. Weiss, p. 231, recently reviewed here), which reports a 4:1 ratio between splenic and hepatic metastases (compared to the 14:1 ratio that Paget observed). Another fact not accounted for by Paget in his analysis, is that the liver not only receives arterial blood, but also blood from the gut organs via the portal vein, thereby increasing the chance of it receiving circulating tumour cells (CTCs). If micro-metasases are present in the gut, then these secondary CTCs will most likely lodge in the liver increasing the risk of developing liver metastases. Lastly, Paget only studied a single location of primary tumours, making general conclusions difficult to draw - especially as the connectivity differs greatly between organs. These simple observations should make it clear that Paget's hypothesis is nothing more than an indication of what might be the case in certain circumstances, rather than a settled fact.

From reading the article one also gets the impression that CTCs are drawn to certain organs in the body (e.g. the caption of the 2nd figure reading "Tumour cells are selective about where they end up." or later in text "...which wandering tumour cells find irresistible."). This is not in agreement with what we know today (and have known for the last 30 years) about the dynamics of metastasis formation.

Figure 1: Human vascular system network topology schematic. It is evident by inspection of the network diagram that tumors originating in the gut and lung experience significantly different flow patterns and order in which they experience filtration at capillary beds than tumors originating in other parts of the ‘body’. The alternate pathways (purple) define the fraction of cells which evade arrest (filtration) at a given capillary bed. There are scant measurements of this in the literature, and none for clinical studies.

On the contrary CTCs have little influence over where they end up, instead the correct picture is that of a primary tumour releasing astronomical numbers of CTCs into the blood stream (roughly 100 million cells per day, of which most die in the blood stream), and that these cells are distributed according to physiology of the circulatory system. 

This means that each organ (except the lung and liver) receive a fraction of CTCs in direct relation to their relative blood supply, and only at this point, at which the cancer cells flow through the capillary bed of the organ, can organ specific mechanisms influence the fate of the cancer cell. This means that any explanation of why patterns of metastatic spread look as they do needs to first take into account the characteristics of the circulatory system, and only then the organ specific mechanisms such as the formation of a pre-metastatic niche.

These facts suggest (at least to us) that one should view the formation of the pre metastatic niche from a more passive point of view. The signals secreted by the primary tumour induce a systemic inflammatory response - which may or may not effect all organs. The evidence suggests that some distant sites respond in a way that makes them more hospitable to the CTCs that happen to pass though them and hence these cells are more likely to form overt metastases - but to present this as an active process is to stretch the data and to anthropomorphize to a dangerous extent.

When attempting to synthesize and communicate difficult scientific information to the public, it is always tempting to present a small slice of the story - and indeed, this is good practice as only so much can be communicated effectively at one time.  But when doing this, it is essential to point out where the limits of our understanding are, and not oversell current hypotheses as the 'truth'.  Science is, and always has been, a steady progression toward understanding, paved by models that are (we hope) less and less wrong.  The way we think today is not likely to be the same as the way we think in 10 years time.