Friday, June 29, 2018

Thinking, working, racing and sweating -- Velosano 5: 100% for the cure.

I owe a lot of updates from the lab, but first let me advertise a bit for a charity bike ride I'm doing in next month.

Like last year, I am riding in the Velosano cancer charity bike ride. I will be riding 200 miles over two days in support of important, innovative research done here in Cleveland under the auspices of the Cleveland Clinic and the Case Comprehensive Cancer Center.  Last year was my first year riding, and thanks to you, I raised over $4,000 (over $4 MILLION was raised overall). I started alone (this is a LONG ride to do alone), but eventually was adopted by a 'wolf pack' of riders who I had never met. This group of riders became like a little family over the next two days, and included founding members of the ride.

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What I didn't know at the time was the my lab would end up being directly supported, to the tune of $100,000 by this ride. This is particularly important, as we are a young lab, and do thing quite differently than many, and this seed grant has allowed us to think completely outside the box -- and to pursue a project that would have little chance at standard funding methods.  I'd like to tell you a little about it.

First off, I think it's important to realize that I see cancer research almost entirely differently than most do.  I am not interested in new drug development (this takes decades, and BILLIONS of dollars) because we already have excellent drugs... we just don't know how to use them in the face of a changing, evolving foe.  Cancer, like all living entities, responds dynamically to external stresses... by EVOLVING. Therefore, the focus of our lab (which you can find out more about here) is the purposeful, direct study of the evolutionary process.  We are not interested in any one of the uncountable ways cancer evolves resistance to drugs (mutations) but instead on the process by which these solutions are chosen. We study this in a number of ways, typically with mathematics.

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Example results of ODEs describing the growth of a well-mixed population limited by nutrients and killed by drugs.


Recently, however, we have begun to start thinking about how to design experimental systems that give us the ability to constantly monitor the genomic changes in evolving populations of cancer cells -- the idea being if we can monitor these changes in real time (not just after months of treatment), we can learn the patterns in more detail. We are seeking to know our enemy's ways, not just stop any individual plan. To do this, we have had to rethink how experimental systems work, and to design one of our own, which we call EVE (the EVolutionary biorEactor). EVE will be a robotic system consisting of state of the art sensors, computer programs we had to write ourselves, microcontrollers, pumps, and an interface between the biology itself, and this robotic system. This requires many scientists, from many disciplines to come together -- making funding from tradition, focused, funding boards almost impossible. We are basing this system on a 'morbidostat' that was published previously, and also are using some open source parts from the eVOLVER project - but the application to cancer is brand new, and making the jump from bugs/yeast to cancer carries a lot of difficult bits.

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Schematic of the board connecting the micro-controller to sensors and pumps.

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A basic schematic of the morbidostat system to be extended
   


With flexible funding like that raised in this event, however, the funding board can take a risk... and while I'm not suggesting that this device will sort out all our problems, history tells us that breakthroughs come from the fiery interface between disciplines, which is where my lab sits.  There are some cool schematics and diagrams you can see describing this project (and others) in our lab on our research in progress page here.

We have also just recently gotten the baseline device working, and can now proudly show off a gorgeous logistic growth curve ...  next steps are to start killing the bugs.  

holy moly - it's logistic growth!!!  (optical density vs. time E. coli growth in media, no antibiotics, well done Nikhil and team)

While we're still behind the groups that pioneered these systems, we are learning fast, and will soon start evolving cancer cells, and testing drug combinations in earnest to see if we can steer evolution, optimize the timing of therapy, and test how repeatable evolution really is, and how this maps to secondary drug sensitivities.

If you gave to my ride last year, THANK YOU, and please consider continuing your support of this important process.  If you are a first time donor, THANK YOU for considering, and know that every dollar counts.

These grants help support the equipment and salaries of the hard working folks who make this research happen. Many folks in the lab have touched this project, but Nikhil, Julia and Erin have been the driving forces of late - and so we went to a Velosano launch party last night to show off the research. Nikhil even brought along some props to show off to interested passers-by, in this case Kara - part of my wolf pack!




tl;dr: I'm hoping to get to $5,000 for my ride this year - please consider helping me.  If you can't donate, please consider sharing this post, or the donation link (below), with your social network to help expand the reach.  The fight against cancer is one we are all touched by. 

If you are in the Cleveland area, you could also consider joining our team, or volunteering - every rider, every dollar and every volunteer help the cause.

To donate to my ride, and to support cutting edge research like this, please follow this link, and press the green DONATE button.

Monday, April 2, 2018

Endogenous miRNA sponges mediate the generation of oscillatory dynamics for a non-coding RNA network

Hello all!  It's been a grant-writing heavy early spring without much new science coming out.  Stay tuned for some news on revisions we've submitted... hopefully good.

Just a quick note, as +Andrew Dhawan has covered most of it. Just wanted to share some excitement about a new preprint from our group which you can find here:

https://www.biorxiv.org/content/early/2018/03/31/292029

 A full 'Story behind the preprint' to be found on Andrew's blog: Tabula Rasa

But to whet you interest, here is a little tweet thread I made, and you can see some of the conversation - even pointing us to some good references we missed, thanks Marc!


Monday, January 15, 2018

New lab website, a Reddit experience and the Strogatz effect...

Now that things are starting to settle down after my move, writing up thesis, doing oral boards, setting up new practice: most of the BIG things are done. The nice part about this is that I have been able to start thinking about the LITTLE things - little things which often matter a lot, but necessarily fall lower on the hierarchy of needs than the BIG things.

On this list has always been to set up a lab web site, which is finally done.  Thanks in no small part to a post-doc who's working with me, Inom Mirzaev, and Mike Baym (a twitter buddy who's html code I stole to use as boilerplate). Anywho, it's live and you can see it here - I'd love feedback... just leave in comments or email me...

We did a bunch of (what I think are) cool things, one of which was to embed an altmetric badge on the site next to each publication. This was SUPER easy, and looks pretty nice, I think.  You can find info on how to do it here (I don't speak html, and it was really easy), and you get this nice effect:


Which is the article I wrote the 'story behind the paper' for the last post.  And, holy crap that is by far my highest Altmetric score (the Strogatz effect - in addition to it being a lasting piece of high quality work)... and it brings me to the final part of the title, my first Reddit experience.  eLife (great journal, great publishing experience... more on that later) has a running relationship with Reddit, and they asked Steve to do an AMA (an 'Ask Me Anything') about this paper. 

Murray (the dog) didn't show up, but we did have a spirited discussion with a bunch of folks asking questions about the paper, and about life in general. It was my first time on Reddit in any capacity, so I just chimed in when I thought it was appropriate, and I think a good time was had by all. Not sure how it works, but I might try to host an AMA about #mathonco or #mathevo next time we have a paper out. Let's see if +Artem Kaznatcheev or +Dan Nichol 's papers are first (ooh - or actually I'd bet Nara's is...)


Friday, December 29, 2017

New publication, just in time for the new year: A tale of two papers and two new friends.

About a month before I left Moffitt, in June of 2016, I got a twitter direct message from Steven Strogatz that said he had read one of my earlier posts on evolutionary graph theory and he mentioned there might be some fun to be had with the more 'math-y' aspects of the problem.

This led to a long series of fun phone calls and discussions about how network connected structures related to the biology of cancer (and even infections within hosts). One of Steven's students at Cornell, Bertrand, grabbed ahold of the idea and ran some initial simulations of a few of our ideas and found a striking result: that the fixation time for a simple Moran process on a large number of known graph structures followed, almost perfectly, a simple log-normal distribution.

An except from a much more complete, and fun to read document from Bertrand....

This finding struck us as something worth chasing down a bit more. What we found ended up opening up several really fun cans of worms, and began an interesting and fruitful collaboration.
I ended up making the move to Cleveland Clinic, and in the mean time Bertrand and Steven continued to chew on this problem and we published the first paper of the collaboration Takeover times for a simple model of network infection, in Physical Review E. It was in this paper where we first realized that the distributions we were observing were not, in fact, log normal, but instead were a kind of extreme value distribution called a Gumbel distribution, which has been known to masquerade as log-normal.



We kept chewing on the problem, and I went to visit Cornell and took a long walk with Bertrand and Steven and Murray (the Strogatz family dog) and even more lightbulbs went off concerning a quite technical, but important detail of the models of evolutionary dynamics - in particular, the choice of the order of update (Birth or Death first) and how fitness biases are implemented (whether you choose which node to replace based on fitness, or how probable it is for a given node to divide).


I gave a short talk the next day, which was live streamed and can be seen here on Cornell's Applied Math colloquium page.  Overall it was a super nice visit, and we were able, I think, to solidify some of our thinking on this issue, which we dutifully scribbled on a napkin:



This led to some further thinking, and then Bertrand opened another kettle of fish when he found a series of papers that discussed 'Sartwell's Law' - which was a phenomenological law describing the 'log-normal' distribution of incubations times (within host) for a long list of diseases, including cancers. While this has been observed for over 100 years, there had yet to be any real work done describing WHY, and it seemed that our model formulation, and results to date, could help explain this. In fact, replotting some old data made for a nice figure one...



and if you want to know WHY??  you'll have to go read the paper that just came out: Evolutionary dynamics of incubation periods in eLife (aside: the review and publication experience was really stellar - 5 stars).


I'm looking forward to what comes next. I think this work has opened up a few doors for folks to go through in probability and network theory for maths folks, possibly in condensed matter/percolation theory for the more physics-y crowd and maybe even in biology and epidemiology. Only time will tell.

Sunday, August 27, 2017

A return to blogging and two new papers: Experimental measurement of evolutionary games and Evolutionary instability in collateral sensitivity networks

Well, the last year has been hectic. I moved my clinical practice to Cleveland Clinic, wrote and defended my thesis (corrections pending...) and have started to grow a research group here in the department of Translational Hematology and Oncology Research. I will begin asking each of the new group members to introduce themselves with short posts here soon, and hope to have at least bi-weekly update posts starting next month.

Before then however, I'm excited to highlight that the two posters that I highlighted on this blog just as I moved, are now full manuscripts. The first, led by +Andrew Dhawan studies how drug sensitivities change over the course of treatment, and even during drug holidays.



This work, which appeared in Scientific Reports, has gotten some attention and we were asked to write a more clinical follow on for Oncology Times called "Evading therapeutic resistance through collateral sensitivities: a paradigm shift?", which you can read here.

http://journals.lww.com/oncology-times/Citation/2017/08100/Evading_Therapeutic_Resistance_Through_Collateral.6.aspx

The most exciting result from this work was the idea that we need to think about collateral sensitivities a bit harder before we translate them directly to the clinic as they are dynamic even on very short timescales. The full paper, "Collateral sensitivity networks reveal evolutionary instability and novel treatment strategies in ALK mutated non-small cell lung cancer" can be read here:

https://www.nature.com/articles/s41598-017-00791-8

A tantalizing piece of info here too was the not only did drug sensitivity change over the course of treatment, but so did radiation sensitivity...  More on this later.

The second project, an experimental method to directly measure the evolutionary games cancer cells play during the evolution of resistance has just yielded a new pre-print from the group, led by +Artem Kaznatcheev . Readers of this blog and #mathonco work in general will know that we've been working on evolutionary game theory and cancer for some time - really work started by +David Basanta. David and +Alexander Anderson and +Artem Kaznatcheev and I have now published something like 10 total papers between us on cancer and game theory ranging from studying how hormone therapy timing should work in prostate cancer to how we should think about how our drug scheduling affects tumor composition  and even more abstract ideas like how local cell topology affects evolutionary stable states and dynamics.

Transforming the payoff matrix using the Ohtsuki-Nowak transform allows an understanding of how spatial organization (locally) might change the game... (See Intercace paper linked above)

At issue is that the payoff matrix, the heart of evolutionary games, is usually invented rather than parameterized in any meaningful way. And even when it is it is done indirectly (from literature, or disparate measurements...).  To address this, +Artem Kaznatcheev came up with a clever experimental method to directly measure these games, and we found that the qualitative nature of the game itself can be changed!


So, if this piques your interest, wander over to the bioRxiv and check out the pre-print. With any luck it will be appearing soon in the pages of your favorite journal.

Here you can find "Cancer associated fibroblasts and alectinib switch the evolutionary games that non-small cell lung cancer plays"

http://www.biorxiv.org/content/early/2017/08/21/179259

OK, see you soon!  Happy reading.

Wednesday, January 25, 2017

Society for experimental biology meeting, Oxford, September 2016

Having just handed in my thesis, after many travails, I am eager to get back to blogging regularly, and to keeping a record of my thoughts.

To begin, I'm going to start by addressing some back-log. So, here, I'd like to briefly describe a great meeting I was able to attend this past September in Oxford. Specifically, 12-15 September, at Lady Margaret Hall in Jericho, I attended a meeting hosted by the Society of Experimental Biology, and organized by my two friends, Ruth Baker and Alex Fletcher - both of whom I know from my own time in Oxford.

For nitty gritty details of the meeting, you can still see the speaker list and abstracts that were presented here: http://www.sebiology.org/events/event/the-tissue-issue.

I'd like to take a moment, instead of the nitty gritty, to describe what were some really nice points (outside the science itself - which was also great) about the meeting that I'd like to carry forward to any meeting I'm lucky enough to organize.

First, the size and scope of the meeting. I often find when I go to meetings like ASCO or ASTRO or even the larger mathematical biology meetings like ECMTB+SMB joint meetings, that I'm overwhelmed by parallel sessions and too many people to possibly wrap my head around.  There is often so much going on that I almost would rather isolate myself and speak only to my closest collaborators - which sort of defeats the purpose of the meeting itself. This meeting, called 'The Tisuee Issue', struck a very nice balance on this point. The size of the full attendance, which I would estimate around 50, was just right. It was large enough that there were people I didn't know, and single voices couldn't take over conversations, but small enough that it wasn't overwhelming, and I felt I could branch outside of my normal circle of friends.

I must admit, that there were also a number of my friends/collaborators gave me some confidence to branch out somewhat. Further, the organizers did a clever thing, which was to break us into discussion groups to discuss aspects of multi-scale (and multi-disciplinary) modelling ranging from education of multi-disciplinary scientists to mathematical limitations of these models. The small group discussions were then brought to the larger forum for a full group session. These sessions were great to break the ice between folks that didn't know eachother, and also allowed more junior members opportunities to present to the larger group.

I think the nicest thing about the meeting, however, was that there were two groups there who don't usually come together.  Namely, developmental biologists and oncologists. There are many commonalities between the disciplines, but there is little cross-over. This meeting allowed us to get to know one another, to see how we were using similar techniques for different problems and to learn some new techniques as well.  While I didn't understand all of what the DevBio crowd was talking about, I was able to appreciate the methods and see new ways to apply them to my own work.

On the whole it was a great experience, and we owe Alex and Ruth, and the Society for Experimental Biology a lot for a great meeting.  Hoping to have a repeat in a couple years time!

We also had some great tweeting going on, which you can see in this storify: https://storify.com/SEBiology/seb-2016-cell-symposium

Sunday, July 10, 2016

A big move and a new research group. Join us!

My decision to leave the IMO and Moffitt Radiation Oncology was one of the hardest professional (and personal) choices I've ever made. I've made friends I won't ever be able to replace, and learned lessons I'll never forget. However, for many reasons, including family and professional and personal growth, it is time for me to move on. I'm very lucky to have found a post in my home town at the Cleveland Clinic doing exactly what I want to do. They have hired me be a physician-scientist, to start a research group in the department of Translational Hematology and Oncology Research (yes, they call it THOR - how awesome) studying the evolution of resistance, and to continue my work as a sarcoma radiation oncologist.

I'm lucky to be joined by two brave souls who will begin their DPhils under my co-supervision between Oxford and my lab at the Cleveland Clinic. +Artem Kaznatcheev , a theoretical computer scientists and mathematician (who is also a prolific academic blogger - see his blog TheEgg here) will begin in the department of Computer Science this Michelmas with Peter Jeavons, David Basanta and myself supervising. Artem's thesis project will focus on the evolutionary process, but beyond that we're not sure - we'll find something that piques all of our interests I'm sure. Artem's work with David and I to date has included attempts to bring spatial structure into evolutionary game theory using the Ohtsuki-Nowak transformation. We found, broadly, that game dynamics can change significantly based on local neighborhood size. This finding has, I think, broad implications for understanding spatially heterogeneous tumors using game theoretic methods.





and more recently using time lapse microscopy to quantify competition dynamics in vitro - something I'm presenting a poster on at ECMTB2016 later this week.



There are more ideas than time, in general, when working with Artem, so I'm quite keen to begin this new journey and strengthen the connection between computer science that we began with +Dan Nichol doing his DPhil with Pete Jeavons and +Alexander Anderson - which we kicked off with Dan's evolutionary steering paper.

I'm also very luck to have +Andrew Dhawan joining, who will begin his DPhil in Oncology with Francesca Buffa and Adrian Harris. Andrew's DPhil will be slightly more prescribed, it being under a CRUK studentship. He will be focussing on building a comprehensive map of the transcriptional response to hypoxia in (breast) cancer. Many of you will note that this is reasonably far from my expertise, but I think it will be a great opportunity for me to hone my Next Gen Sequencing chops, and also to inject some theoretical thinking into Oxford Oncology.

Andrew has spent this summer, since he finished medical school in Ontario, Canada at Queen's University School of Medicine, working with me and +Andriy Marusyk on collateral sensitivity in non-small cell lung cancer. He is attending a summer school (sponsore by the Cancer Research UK coincidentally) on ecology and evolution in cancer - annoying scheduled the same week as ECMTB. He'll be presenting the following poster there:


On another random note: it turns out, unbeknownst to any of us, Andrew and Artem did their undergrad at the same institution, in the same department! They both went to the 'MIT of Canada' in Waterloo. Small world.

Anyways, I am immensely looking forward to this move - the next few weeks will see me at ECMTB, then home to Tampa for one day, and then the move Cleveland, where I start August 1st. I am also looking for someone interested in joining the team as a post-doc who wants to work with us to make a difference in patient's lives through the study of evolution in cancer (or bacteria) with primarily mathematical methods.

If you're coming to ECMTB, look me up!