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!


Friday, July 1, 2016

Courage

Last night +Alexander Anderson hosted a going away party for me. It was a lot sadder than I thought. I am going to dearly miss the people in the IMO, and Moffitt Cancer Center in Radiation Oncology and elsewhere that I've worked with over the past 7 years. While there was a lot of silly-ness, in particular some of the funny shots of me and others from IMO over the years displayed on the big-screen:



There were also some sad farewells


The whole evening reminded me how strongly I feel about the work we're doing in the IMO, and also of the courage it took to create such a place. Originally started by +Alexander Anderson and Bob Gatenby the IMO, when I joined was about 5 people: the two fearless leaders and +David Basanta , +Edward Flach  and +Kasia Rejniak. In the intervening (only 6) years, it has grown to nearly 25 people, with 5 faculty members. I say it took courage to start, because at the time it began, mathematical oncology was nearly an unknown phenomenon. Since, however, it has become much more accepted - supported by specific initiatives from the NCI like the Physical Sciences in Oncology Network (formerly PSOC, now PSON) as well as the Integrative Cancer Biology Program.

The work is meaningful to me on many levels. First, the fact that we're chasing down the fundamental principles of a disease which has proven largely impenetrable for most of human history is intellectually satisfying. But moreso, for me at least, it brings hope to my time in clinic, when times become difficult. The fact that I can take that energy back to the lab lifts me back up and drives me to work harder, and also let's me reassure my patients that we're doing everything we can, both for them and for the future.

Moffitt started a new campaign, called the community of courage, to allow researchers and clinicians to talk about what courage means to them. I was flattered to be asked to join this campaign, and through it talked both about the courage I see in +Alexander Anderson and his group to go outside the norm in mathematical onoclogy, but also the courage I see in my patients, who choose to get up and LIVE every day, even in the face of difficult odds.  They made a little video, which you can see below, and also wrote a nice article, which captures what I've said here quite a bit better than I have.



You can find the article here:  https://moffitt.org/media/5161/momentum_vol31_scott.pdf

Next post there will be a post-doc advertisement attached...  so if you know someone who is interested in a post-doc position in mathematical oncology, or in studying the evolution of resistance to antibiotics, let them know there's a new lab coming to the +Cleveland Clinic - mine!  Oh, and also that Cleveland Rocks...

Thursday, June 16, 2016

The end of one road, and the beginning of another.

One month ago I sat for my oral boards for final certification by the American Board of Radiology. This exam represents the final hurdle in what is (normally) a decade long road after college. It should be 4 years of medical school, then 5 years of residency and one final year of independent practice. During this time, you take innumerable exams: the USMLE Steps 1, 2CK, 2CS and 3 followed by the ABR radiation physics and biology exam, then written clinical exams, followed at last by the oral boards.

I found it interesting that during the time leading up to residency (during undergrad), we have been selected based on who performed the best. This includes striving for As in college (and high school...), the highest #MCAT score you can manage, and then doing as well as you can on 'the Steps' so as to assure the residency you desire. Once you make it to your speciality training however, this turns on its head. The desire to perform your best is replaced by the abject fear of failure. This fear basically ramps up higher and higher until by the week before the oral exams, everyone in your discipline is just standing at the edge of the abyss of self-doubt (at least I was).

The change is from filter to pump. At the beginning, the desire is to filter folks out, but once the desired level of rarification is reached, they don't want you to fail any more - they want to pump you through. It was a long road, and one which I am extremely happy to be done with.

I will resume this stream next week with an update on my research and what I think is a nice result about stem cells and phylogenetic trees...

A final thought. I was speaking with a friend and mentor of mine recently about the transition from resident to faculty. He said when you finish residency you feel like you've finally climbed to the top of the mountain. But, in academic medicine, you realize that the mountaintop that you just summited is actually the bottom of an even bigger one. Now you are no longer competing against your peers and co-trainees, but instead you are competing against those who trained you. In the ridiculous funding climate, this is a hard truth.  So, while I feel good to have gotten to where I am, the climb is just beginning.


Wednesday, January 6, 2016

Rotating student: Jeff Peacock - working on evolution of resistance in ALKmut NSCLC using CRISPR

+Andriy Marusyk and I have a medical student rotating through our collaborative lab for the next couple of months, here's an intro with a couple figures from a recent grant of mine.

Also, here's Jeff:



Hello,
As an aspiring radiation oncologist, what originally drew me to the field is its investment in scientific research. My name is Jeffrey Peacock, and I am a visiting 4th year student from UCF who is working in Jake’s lab for the first 2 months of 2016. I am excited to work on some really cool projects that Jake has started. I have spent a few years in a wetlab, both during undergrad and before and during medical school, performing genetic engineering on bacteria and yeast to produce commodity chemicals. One experiment that I designed was a directed evolution study to increase turnover of a bottlenecked enzyme in a metabolic pathway. I have always been fascinated with using mother nature to our advantage in the laboratory, especially when curing cancer is the goal.  When I heard a talk given by Jake at Moffitt during an away rotation for radiation oncology in mid-2015, I knew he was doing some really exciting work that I was interested in doing and that was tangentially similar to work I had done in the past. We spoke briefly after his talk and threw around the idea of me returning during January and February to work in his lab. After meeting with Jake a few times, everything fell into place, and I am on board to start doing research with Jake for the next 2 months.




Although 2 months is not a long time to spend in a wetlab, I am excited to begin a handful of projects that will hopefully produce impactful data. Jake was the first to introduce me to the concept of mapping evolutionary landscapes. A paper published in Science in 2006 showed that there exist certain pathways that populations take in order to evolve to handle a selective pressure (see http://www.ncbi.nlm.nih.gov/pubmed/16601193). Once these landscapes are mapped, they can be used to steer populations along certains paths, such as a path that leads cancer cells to be sensitive to a drug (see Figure 1). In order to begin creating these maps, cancer cell lines need to be evolved to gain resistance to various drugs. My active role in this project will be performing radiation sensitivity and genetic assays on these cancer cell lines at different time points during their evolution against various chemotherapy drugs (see Figure 4). The idea is to gain insight into temporal changes cancer cells experience when exposed to chemotherapy drugs and to determine if there are key time points when synergism between chemo and radiation are at its best and its worst.



The next project involves engineering non small cell lung cancer strains with common mutations that confer resistance to chemotherapy drugs to measure evolutionary landscape. Rather than relying on mother nature to create these mutations, I will be utilizing CRISPR/cas9 to perform common genomic edits on non small cell lung cancer strains to create resistance. These cell lines will then be used to infer evolutionary landscapes developed in prior evolutionary experiments and to create mathematical models to predict chemotherapy regimens that minimize resistance.
I remember being asked during my interviews for medical school the question of where I see myself in 5 years. I would answer that I imagined myself as a clinician who is actively involved in research. At the time, I did not know what type of clinician I wanted to be or what role I would play in research, but I knew that both aspects of medicine were necessary to satisfy my insatiable curiosity and my desire to help people directly. I can honestly say as I approach that 5 year mark that I am beginning to see my vision become a reality, and this beautiful marriage between scientist and clinician is more perfect than I could have ever hoped.

Jeff can be found on twitter at: @ggcancer898





Saturday, October 31, 2015

bioRxiv vs. arXiv

If you've been reading along since the beginning, you'll know that I'm a huge #openaccess fan, and, really, am something of an oversharer. When I began my scientific career, I was posting all of my work on the qBio section of the arXiv. Me and some colleagues responded to the increase in utilisation of #preprint servers by making Warburg's Lens, a blog inspired by Haldane's Sieve to help aggregate mathematical oncology pre-prints, and allow for discussion. We've had a ton of success with Warburg's Lens, and it has been helpful for many folks. One of the nice aspects of it, that the arXiv didn't have, was the ability to comment, and to link in to social media in general.

A couple years ago, Richard Sever contacted me about an upcoming project, the bioRxiv, and asked me to be an affiliate - which I eagerly accepted. It seemed the perfect way to help convince my more open minded biological colleagues - something to which there are still quite a few (unsubstantiated) barriers.

This past summer, at the annual Society for Mathematical Biology Meeting, I gave a talk on pre-print servers and social media in science. While I was preparing for the talk, I ran across a great infographic about the arXiv and was blown away how LITTLE qBio there actually is... (something like 1.6% - TONS MORE info here)



Anyways, I recently asked Richard if there were any stats on publications/utilization of the bioRxiv. At the time, there were no stats done, but today I saw on this twitter:


Within just a year, more than half have been published!  Good news. I'm hoping that my newest preprint (which is also on Warburgs Lens here) joins the majority ASAP :)

Anyways, I'm heartened to see the increase in utilisation.  I have to say, having submitted I think 6 manuscripts to the bioRxiv, and around the same number to the arXiv, the process at the bioRxiv is MUCH easier. It can be done in minutes, rather than fighting with the LaTeX compiler on the arXiv istelf. My current practice is to send everything to the bioRxiv, though I still read and monitor the qBio section of the arXiv... what are your practices?


Thursday, October 22, 2015

Some fun with evolutionary graph theory - and application to cancer?



For a few years now I've been interested in evolutionary graph theory - a branch of mathematics at the nexus of evolutionary dynamics and graph theory. To my knowledge this was all kicked off by Martin Nowak and colleagues with the 2005 Nature paper:  Evolutionary Dynamics on Graphs. One of the coolest results was that certain graph topologies exhibit striking changes in probabilities of fixation (assuming a Moran process) - particularly symmetric graphs called 'stars'.


A beautiful follow on paper by our friends at the Max Planck for evolutionary biology, led by +Arne Traulsen showed that this amplification of probability of selection led to a dramatic increase in time to fixation - sort of balancing out the advantage. You can read more about this in this terse paper in the Royal Society B entitled: The effect of population structure on the rate of evolution.

Since reading these two papers, I have given a fair amount of thought to this problem, but have not come to any sensible conclusions. +Alex Fletcher and +David Basanta and I spent a week or so once coming up with some code to think about how a cancer cell might invade an epithelial sheet (a biological structure that is topologically lattice-like). We never really figured out where to go from there (still working on it!!!), but in the mean time, conversations with Laura Hindersin and Benedikt Bauer at Max Planck about Laura's Phd work (example paper here: Almost all random graphs are amplifiers of selection for birth-death processes, but suppressors of selection for death-birth processes) has sparked a lot of interesting thought and conversation.

Further, at the recent conference: Cancer Evolution Through Space and Time the conversation continued and we started talking more about 'mixed' topology structures. The conversation has continued on twitter, culminating with a new student in my lab +Sudhir Manickavel starting some work simulating evolution. Here's where our thinking is going:







When he first started considering this project +Sudhir Manickavel , a medical student asked of the Royal Society paper mentioned above:

"I read the paper and I found it interesting, especially the idea that even though star structured populations have a greater fixation probability it actually takes them longer to fix.

I do have one question about the paper, in reference to a tumor how would you define a tumor population as well mixed or star structured?" 

A great question...  to which I responded:

"What is the topology of an epithelial sheet? What is the topology of a colonic crypt?  Does the topology of the stem cell niche within the crypt differ from that of the walls of the crypt?  How would you characterize the topology of bone marrow? Or - in infectious diasese: Of a blood borne pathogen? Of a biofilm?"

And included a link to a Gatenby classic which opens with:

"The human body plays with evolutionary fire" and discusses the unique (changing) topology of the colonic crypt and how this may influece evolutionary dynamics...

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744108/

Which seemed to sell him on the topic as just this morning, I looked in my dropbox, and it looks like +Sudhir Manickavel is making some progress (though there seems to be a missing node...  :) ):

initial condition plotted with networkx to study the moran process evolving on a 'mixed' topology structure... is it a ring or is it a star?
Anyways, the start of a fun project either way.

Sunday, September 27, 2015

Full storification of Cancer Evolution Through Space and Time: #CEST15

My friend, supervisor and department Chair +Alexander Anderson compiled a full storification of the recent Cancer Evolution Through Space and Time meeting with the hashtag #CEST15.

You can find it on his storify page here:

https://storify.com/ara_anderson/cancer-evolution-through-space-time

but I've also embedded it below.  It was an AMAZING week bringing together folks from the bacterial evolution community, game theorists and the cancer evolution world (theory, experiment and genomics). I've already heard calls to repeat the meeting next year. Personally, I can't wait to follow up on the relationships I made, which are myriad!

Thanks to Sandy and +Arne Traulsen and all the crew at The Max Planck for Evolutionary Biology who made the visit so nice.  Enjoy the storification that Sandy compiled.