Warburg's Lens: A pre-print discussion forum for the mathematical oncology community

As I posted about earlier, there is a growing movement in the biological sciences to post #preprints of manuscripts on openly accessible fora to circumvent the problems with standard academic publishing.  Most worrisome are the issues surrounding #openaccess and the length of time it takes to get information from one's brain to the literature - drastically slowing down the pace of science.  This is an issue in every field of science, but in Cancer Research it is unconscionable, as it literally slows down the pace of novel treatments coming to bear.

To this end, our group (Integrated Mathematical Oncology) and others, have begun to utilize the forum that the high energy physicists started quite some time ago: the arXiv.  This is an imperfect solution for a number of reasons, but one that I still think is worth utilizing.  The thing that I find most frustrating about it is the lack of specificity and the associated difficulty in finding the papers you are interested in while 'browsing'.  A secondary issue is that there is no way to publicly comment on the papers there, and you are restricted to emailing the authors (which is better than nothing).

The population and evolutionary biology community (a strongly quantitative community working in the biological sciences) has cleverly gotten around this by making a blog (Haldane's Sieve) which they use to post relevant preprints and serves as a discussion forum.

I approached them about creating a scion of their existing blog for use by our  community (theoretical/computational oncology), but they demurred, for good reason.  Their reasoning was that they wanted to keep the population small to encourage submission of preprints and proper discussion in a field (biology) that has been historically gunshy about preprints. So....

I and some of my colleagues, +Paul Macklin, +David Basanta, +Russ Rockne, +Philip Gerlee, Dominick Wodarz and +Alexander Anderson have decided to start a mathematical oncology preprint discussion forum, which we've named Warburg's Lens.

Our goals for this forum are to have a post every Monday/Wednesday/Friday that consists of the title and abstract of a recently posted #openaccess #preprint plus a short paragraph describing the salient points to get discussion going.  As we'll be using the #blogger software, all of the discussion will be visible on Google+. We hope that we can develop a community that is interested in open, objective discussion of the science and that is interested in contributing their preprints for posting as well.  We aim to be able to offer a wider dissemination and discussion and thereby help improve the quality of people's work presubmission.  In a perfect world, this would also speed up the acceptance process as the final product would have already had one round of review, in essence.

So - without further ado:

Go visit Warburg's Lens and check out the first preprint!

Also - feel free to follow along @WarburgsLens on twitter, and spread the word!

Update to 'My Sarcoma' project

A few weeks ago I posted about my friend and neighbor, Ray Paul's battle with Sarcoma and his amazing response to it - to create art using histologic images of his own tumor.  Ray finished the first painting in the series and entered it into a contest, and it won!  You can see the contest - and Ray's finished painting, at the ArtSlant Competition website,

and here it is as well:

Ray Paul, "SP12-6796 x 40 - 3," acrylic, latex, enamel on canvas printed with a photographic image of the metastatic myxofibrosarcoma to my left lung, 26" x 36"  2013

 

He tells me he plans a total of 6 in this series (all quite different) and then hopes to exhibit them all at Moffitt and possibly take them on a tour of several cancer center's throughout the US with strong Sarcoma programs.  If you know of anyone interested, please do contact me or Ray.

As an aside, the TEDMED blog also ran a piece about this project.  Great exposure for art and healing.

You can follow Ray on twitter at @raypaul4 or see more of his work at his website, www.RayPaulArt.com

Metastasis - an overview and network perspective

My collaborators, +Philip Gerlee +David Basanta and +Alexander Anderson and I have been working on the problem of metastasis for a few years now, using a physical sciences, network based perspective to try to uncover some truths about this enigmatic process.

Metastatic disease has always been an interest of mine clinically for a number of reasons.  First, metastatic disease causes 90% of cancer death, and the vast majority of morbidity.  Second, for the most part (with a FEW counter examples like testicular cancer and some subsets of limited metastatic disease) we can't cure these patients.  Finally, radiation therapy - my specialty - is extremely well suited to help palliate patients with metastatic disease, and it is very gratifying to help patients in this way.

My scientific interest in metastasis started when I heard about the new technologies for measuring circulating tumor cells (CTCs). I realized that if we could have information about the concentration of these cells at different points in the vascular network at different times, we could infer quite a bit of information about what was happening to them in the organs: something that is currently really hard (impossible) to study in humans.  I drew a hand sketched drawing:

incomprehensible and ugly

and then worked with a medical illustrator in Peter Kuhn's lab named Katya Kadyshevskaya and we produced this: (moral of the story, work with a medical illustrator!)

beautiful and instructive

We published a version of this figure along with a short perspective piece in Nature Reviews Cancer - in which we posited that one could model the vascular system almost like an electrical circuit, considering the CTC flow like current, and the organs like resistors.  We then began working to use the formalism to learn something, other than to simply illustrate an idea (something that +Artem Kaznatcheev has recently talked about in his blog - see! we're learning from our models!)

What we first used this formalism to do was test the 'self-seeding' hypothesis of Larry Norton et al..  This is an hypothesis, first put into the literature in 2006 in Nature Medicine, which suggests that tumors can accelerate their growth by putting cells (CTCs) into the vasculature, letting them circulate around, and then come back to the primary.  This theoretical work was followed by a beautiful experimental paper in Cell, which showed that this phenomenon indeed was occurring, at least in mice. After lots of discussion, we couldn't agree about one of the conclusions of this work - that this mechanism (self-seeding from the primary directly back to itself) could truly drive primary tumor progression, so we built a model to test it.  You can see the full model in this pre-print on the arXiv, or, if you have access, in the Journal of the Royal Society Interface.  I also just presented a poster which summarizes both of the papers I just talked about, and put it on slideshare as an experiment:

Selfseedposter mss2013 from University of Oxford, Moffitt Cancer Center

In short, we find that it is far more likely that there is an intermediate step in between shedding and re-seeding where cells colonize a secondary tissue and subsequently shed their own progeny into the vasculature.  This adds a number of levels of complication and also opportunities for evolution in a foreign landscape - possibly speeding the 'search' for resistant phenotypes (a question I am eager to work on with +Steffen Schaper and +Daniel Nichol).

The next step we are working on (which should be on the arXiv soon) is to show that all metastatic patterns are able to be explained with this formalism, and further, that it represents a novel opportunity to personalized medicine - details to follow!

I've also just finished writing a short review of mathematical models of metastasis.  There has surprisingly little work done in this field and it represents a ripe area for theory.  This review should be available in a book published by Springer later this year, and you can read the pre-print on the arXiv here.  Springer is very open about the policy for pre-prints, which you can read here.  They basically say you can put up whatever you like, pre-acceptance/typesetting/copy editing, and they only reserve the rights to the version that they help with, which makes complete sense.  Seems this publisher is on board with #openaccess science.  Thank goodness.

I should also mention that my collaborator, +Philip Gerlee - wrote a nice post on metastasis a few days ago on his blog and he just promised me another post on it.  Keep your eyes peeled.

New on the arXiv: Modeling the Dichotomy of the Immune Response to Cancer: Cytotoxic Effects and Tumor-Promoting Inflammation

I was just trolling the q-bio submissions on the arXiv and came across this new article.  We've made several attempts to include the immune system in our models to date at #IMO, but it isn't easy!  I look forward to reading this one. 

Modeling the Dichotomy of the Immune Response to Cancer: Cytotoxic Effects and Tumor-Promoting Inflammation

Kathleen P. Wilkie, Philip Hahnfeldt

Comments: 24 pages, 2 tables, 5 figures, 2 appendices

Subjects: Cell Behavior (q-bio.CB); Tissues and Organs (q-bio.TO)

Although the immune response is often regarded as acting to suppress tumor growth, it is now clear that it can be both stimulatory and inhibitory. The interplay between these competing influences has complex implications for tumor development and cancer dormancy. To study this biological phenomenon theoretically we construct a minimally parameterized framework that incorporates all aspects of the immune response. We combine the effects of all immune cell types, general principles of self-limited logistic growth, and the physical process of inflammation into one quantitative setting. Simulations suggest that while there are pro-tumor or antitumor immunogenic responses characterized by larger or smaller final tumor volumes, respectively, each response involves an initial period where tumor growth is stimulated beyond that of growth without an immune response. The mathematical description is non-identifiable which allows us to capture inherent biological variability in tumor growth that can significantly alter tumor-immune dynamics and thus treatment success rates. The ability of this model to predict immunomodulation of tumor growth may offer a template for the design of novel treatment approaches that exploit immune response to improve tumor suppression, including the potential attainment of an immune-induced dormant state.

The case for pre-prints in biology

So when I first met +Jonathan Eisen at TEDMED in 2012, in addition to the social media mandate he gave to me, he started to introduce me to the whole #openaccess debate (his brother founded PLoS and he is the chair of the advisory board at PLoS Biology).  As a physicist by training, I was an easy convert, but I've found that MANY of my biological colleagues (even the theoretical ones) have been more difficult to sway.

I just had a conversation today, in our awesome collaboration space - the collaboratorium (this panorama doesn't do it full justice, but there's +Philip Gerlee)

with a friend and colleague Jonathan Wojtkowiak (who doesn't seem to have a G+ account), where I faced the same arguments that I've heard so many times before:

Why should I post my papers on a pre-print server where anyone can see it before it is published!?  They could scoop me!

I honestly don't understand this argument, but I hear it all the time.  By nature of pre-print servers, like the arXiv, the idea is yours! Time and date stamped. And, better yet, it is completely #openaccess, free of charge, and helps move science along at a better pace.  Only a very few journals have problems with posting of pre-prints before they get their (greedy) hands on the results of all your hard work, but most are totally OK with it.

There is a nice movement starting in biology to get things posted.  And some communities, like the population and evolutionary biology one, have their own pre-print discussion site - Haldane's Sieve.  I am starting to consider trying to do something similar for quantitative cancer research as well, with the help of some friends and colleagues, but we'll see.

If you still aren't convinced, here is a nice article in PLoS Biology highlighting the issue.  Also, take a look at the some of the nice press that my mentor +Alexander Anderson and +David Basanta recently got on a pre-print about Game Theory and cancer they posted by MIT Technology Review - this is press this article likely wouldn't have gotten through the standard route... and we know that you don't get cited unless people read your paper...

If you are against it - please leave some comments about why, I'd love to try to convince you otherwise!  If you are a biologist (or know one) who DOES post pre-prints, weigh in and share your good experiences!

My Sarcoma

This is the story of a Cancer Connection I never hoped to make and also the one that has brought me the most joy.


About a month before my family and I left for Oxford, my dear friend and neighbour Ray came over and asked if I'd look at this side, where a orange sized mass was growing.  I took a feel and suggested he get the thing cut out by a cancer surgeon.  Like any good neighbour, he asked if I'd do it...  which I declined (I only do RADIO surgery).  Being a self-employed artist, Ray didn't have any insurance, so he ended up convincing a friend to resect it in return for a painting.

So, you know I'm a cancer doc... so you can probably guess how this story plays out.  But before I tell you (or let Ray tell you), I want to share a bit about Ray (you can also learn more about him on his website: http://raypaulart.com).  Ray's paintings have always struck me, and my scientist and physician friends in similar ways.  There is just something alive about them.  Something cellular.  Something moving.

This makes sense as Ray studied biology as an undergrad, but it is also something that is always moving in his mind: at the heart of this artist is a scientist.  Here is the one that first grabbed my eye when we first met (and that I immediately bought for my house): Lionfish.  (Sorry for the terrible image quality, the rest will be better).

Ray and his partner Missie have also always been a touchstone for me during my training - reconnecting me to art and beauty when my world became overrun with data and facts and death, and for that I can never repay them or thank them enough.

Anyways, I'll let Ray's words tell the rest of the story: here is his manifesto about his treatment, and the subsequent healing that he has found through this new project, My Sarcoma.


**

My name is Ray Paul. I am a 50 year old artist, musician, frustrated biologist and myxofibrosarcoma patient at Moffitt Cancer Center in Tampa, FL. I received a BS in Biology from Florida State University in 1986, and a MFA in Painting from the University of Cincinnati in 1991. As of my latest scans in February 2013, I am free of detectable cancer. My next round of scans are scheduled for June 2013.

My journey begins in the spring of 2011, when I noticed a rapidly enlarging lump protruding from my left flank. Unfortunately, I fell into the category of the uninsured who wait and hope for their medical issues to resolve magically. Finally, as the mass grew to the size of an Idaho baking potato, I felt compelled to go into the local Emergency Walk-In Clinic. I was told it was likely a lipoma and I needed to find someone to remove it. After weeks of worry and several inquiries, I approached a surgeon friend who agreed, with some trepidation, to perform a tabletop resection, using local anesthesia. It soon became clear that the mass was more than a lipoma.

I was sewn up and a sample was sent to his pathologist who forwarded it to the pathology team at Moffitt Cancer Center. Soon thereafter, I received "The Call." Shock and confusion rushed in, but curiously, was followed by a sense of calm resolve and numb determination. Fear was thankfully suppressed. By pure, sublime serendipity, my next door neighbor, and friend, happened to be a resident in the Radiation Department at Moffitt. Through him, I have enjoyed a deep well of knowledge, compassion, honesty and inspiration. For that I am eternally grateful.

I was admitted as a patient to Moffitt Cancer Center in August of 2011. I began neoadjuvant radiation therapy in September 2011. Whilst undergoing treatment, I enthusiastically and gratefully took part in a clinical trial: "A Phase II Study Evaluating Neoadjuvant Administration of High Dose Radiation Therapy and Intratumoral Dendritic Cells in Patients with High-Risk Soft Tissue Sarcomas." I am also a part of a research study: "Total Cancer Care Protocol: A Partnership with High Risk and/or Diagnosed Cancer Patients for Life." In October 2011, I underwent a radical resection of the 12 x 12 cm ulcerated high-grade left flank myxofibrosarcoma, along with a right-sided DIEP flap closure of acquired 20 x 17 cm soft tissue defect. In April 2012, I had liposuction and debulking surgery of the flap area (30 x 10 cm). In July 2012 I was diagnosed with a left lung mass. I underwent a lung subsegmentectomy to remove a 0.8 x 0.6 x 0.6 cm metastatic myxofibrosarcoma. During a followup visit, a large mass was detected in my right posterior thigh. In August 2012 I started chemotherapy with pazopanib. In October 2012 I underwent a radical resection of a 13.5 x 10 x 3.5 cm metastatic myxofibrosarcoma. In November 2012 I began adjuvant radiation therapy.

During this life-consuming ordeal I have managed to keep a calm and positive attitude, never becoming too emotionally low or too ecstatically high. I have remained otherwise healthy and have maintained my body weight. I have placed my complete faith and trust in my team at Moffitt, and in my physical and spiritual ability to heal. I am surrounded and supported by friends, family and my steadfast partner, Missie. I made the decision to go public with my battle, posting my progress on Facebook. The outpouring of love and support has been overwhelming and has provided me with a warm blanket of peace and strength. Between surgeries and treatments, I have enjoyed long walks with my beloved Boston Terrier, Blue. He went blind concurrently with my cancer diagnosis. Watching him bravely attack life has been an inspiration and has helped prevent me from descending into self-pity. Music has remained vitally important, and I have managed to write and record. In fact, this whole experience has been strangely life-affirming and fascinating. Never have I dreaded going into Moffitt. The strength and determination of my fellow patients has been humbling and has greatly increased my sense of compassion. It is a great honor to have had the opportunity to interact with my medical team, all members of a profession I so deeply admire. I am proud to have contributed, in my own small way, to the field of medicine and cancer research. I have been inspired to create a painting for the Radiation Department, which hangs in the waiting room

Porpoise Song:

and have donated a piece to the Integrated Mathematical Oncology Department.

Sweet Jane:

My SAE Fraternity brothers, both past and present, at FSU have joined the cause, and are currently involved in fundraising for the Sarcoma Department. A "SAE Slams Sarcoma" sand volleyball tournament benefitting the Moffitt Cancer Center is planned for April 14 in Tallahassee.

I am currently embarking on a collaborative endeavor entitled "The My Sarcoma Project." I plan on combining painting, photographic images of my tumor cells, printmaking, video and music to create an exhibit that illuminates my experiences as an artist and cancer patient. My pathologist at Moffitt, Dr. Marilyn M. Bui, has graciously provided me with the images. She has stepped out of the shadows of the lab and made me realize that pathologists are an integral part of the team and are vital to patient care. We are also collaborating on a book proposal. She is helping me begin my journey from cancer patient back to artist. All my experiences as a biology student, artist and cancer patient seem to be coalescing in this project. Hazy memories of undergraduate experiments involving plasmid mobilization and bacterial resistance, forms and shapes that have evolved in my paintings over the past 10 years, and the inspiration I have gleaned from my time at Moffitt have all come into focus and have given my work direction and resolution. This revelation has led me to a deep understanding and appreciation of my work. I envision my art to be a prescient, visual manifestation of the battle raging within, and a powerful testament to the beauty of Hope.

Ray Paul

**

As a teaser, here is a prototypical 'My Sarcoma' piece.  You can see his signature style of abstract forms detailed into cellular figures, and beneath, an H&E pathology image of his own tumor.

I can't be prouder to be part of Ray's healing journey, but I can also take no credit at all.  I delivered no radiation, removed no tissue, prescribed no medications.  I have been just a friend and guide.

I'll be sure to tweet about My Sarcoma as Ray continues his project, but you could also follow him on Twitter at @raypaul4 for details and music.

Update:

This post and Ray's project were highlighted on the TEDMED blog.

New on the arXiv from IMO. Evolution of intratumoral phenotypic heterogeneity: the role of trait inheritance

A new paper from +Jill Gallaher and +Alexander Anderson is out on the arXiv.  I asked Jill for a PLoS style 'author summary' in non-technical language, and here it is:

Author Summary:

A tumor can be thought of as an ecosystem, which critically means that we cannot just consider it as a collection of mutated cells. A tumor is more of a complex system of many interacting cellular and microenvironmental elements. There is variation among cells within the tumor, and with an increased proliferation capacity, there is competition for space, so evolution and selection occurs.  Because our current understanding at the genetic scale gives little information on translating to actual changes in cell behavior, we bypass the translation of genetics to behavior by focussing on the functional end result of the cell’s traits (phenotype) combined with the environmental influence of limited space, which will ultimately dictate tumor aggressiveness and treatability. 

The evolution of the population depends on the way in which traits are passed on as cells divide. We investigate trait inheritance by building a cell based simulation in which individual cells with varied trait combinations compete for space over time. Specifically, we characterize cell behavior in terms of two traits: proliferation rate and migration speed. The mode in which these traits are inherited significantly affects the evolution, composition, and fitness of a tumor population. To investigate competition for space, we initiate the population as a tight cluster, representing a growing tumor mass, and as a dispersed population, representing a cell culture experiment. We find that the dispersed population has more space, less competition, and reduced selection.  With a growing cluster of cells, there is more competition and selection. But constraining the allowable trait combinations so that several phenotypes are equally fit reduces competition and leads to the coexistence of several phenotypes. In this case, local heterogeneity may be advantageous to maximize growth.

As before, any comments on the paper will be passed directly to the authors!  Here is the link and abstract:

http://arxiv.org/abs/1305.0524

Evolution of intratumoral phenotypic heterogeneity: the role of trait inheritance

Jill Gallaher, Alexander R. A. Anderson

(Submitted on 2 May 2013)

A tumor can be thought of as an ecosystem, which critically means that we cannot just consider it as a collection of mutated cells but more as a complex system of many interacting cellular and microenvironmental elements. At its simplest, a growing tumor with increased proliferation capacity must compete for space as a limited resource. Hypercellularity leads to a contact-inhibited core with a competitive proliferating rim. Evolution and selection occurs, and an individual cell's capacity to survive and propagate is determined by its combination of traits and interaction with the environment. With heterogeneity in phenotypes, the clone that will dominate is not always obvious as there are both local interactions and global pressures. Several combinations of phenotypes can coexist, changing the fitness of the whole.
To understand some aspects of heterogeneity in a growing tumor we build an off-lattice agent based model consisting of individual cells with assigned trait values for proliferation and migration rates. We represent heterogeneity in these traits with frequency distributions and combinations of traits with density maps. How the distributions change over time is dependent on how traits are passed on to progeny cells, which is our main inquiry. We bypass the translation of genetics to behavior by focussing on the functional end result of inheritance of the phenotype combined with the environmental influence of limited space.

Cool "snake" I saw the other night and convergent evolution

So around 7pm the other night I was taking a walk with my wife and baby boy (we live in Tampa, FL) and we saw this cool snake:

It was quite docile and never struck at the stick I poked it with.  It didn't move very efficiently, not much of a slither, more of a thrashing around kind of movement.  It's belly was yellow and smooth, and it had a funny tip to its tail.

Now, I quite like snakes.  My mom signed me up for NOAH (the northern Ohio association of herpitologists) when I was 10, and she and I went to all the meetings and I got to visit some labs of herpitologists at the local universities.  After about a year, she let me get a red-tailed boa (who I named Rocky, as in Rocky BalBOA).  This snake was awesome - my mom used to vacuum with it around her neck, and it cuddled with our golden retriever, Casey.  No Joke.  We eventually got a California kingsnake (Damian) as well, but it wasn't as friendly.  Anyways, I digress.  The point is, I like snakes, so I was curious about this one, that I didn't recognize, in my own neighborhood.

So I looked at this nice website called Florida Backyard Snakes.  And, I got bupkis.

So I crowd-sourced the ID to twitter, and within 20 minutes, was told by two users (thank you @LinkLayer and @GaryBurness) that it wasn't a snake at all, but a legless lizard! (The Eastern Glass Lizard, Ophisaurus ventralis to be precise) So, there's the nature lesson for the weekend.  Not a cancer related one, but fun nonetheless.  But, if I stretch, I could say this post is really about convergent evolution, something which many cancer cells experience as they "find" the invasive/metastatic/glycolytic phenotype.  There, cancer connection.  Done!

Also, how awesome is my mom?  

Happy Mother's Day Momma, thanks for instilling a life long curiosity into this boy - I'll pay you back by doing the same for my kiddos.

World Oncology Forum

One of the benefits to being in my group at Moffitt Cancer Center is that we have three really smart, world renowned thought leaders: +Alexander Anderson, Robert Gatenby and +Robert Gillies.  These three gentlemen are so busy, in fact, that they can't even go to all the amazing events that they are invited to.  Sometimes, when this happens, they are able to suggest a replacement.   I was lucky enough to be in the right place at the right time when Bob Gillies (Bob G_i) was unable to go to Lugano, Switzerland, to attend the World Oncology Forum, and further, lucky enough to be accepted as his replacement.  This is an event that would not have qualified to attend for another 20 years, assuming that I did well for those coming 20 years.  It was hosted by the European School of Oncology (ESO), an organization less well known in America than it should be, but quite influential in Europe and the rest of the world.


The mission of ESO is to contribute to the reduction of death from cancer due to late diagnosis or inadequate treatment, with a focus on education.  On the occasion of their 30th anniversary, they held a conference, the World Oncology Forum, to bring 100 cancer experts and cancer specific journalists (including Clifton Leaf, Science editor at the NYT whose face is just above) together to answer one question: Are we winning the war on cancer?

I was lucky enough to be the pinch hitter for Bob Gillies, and represent Moffitt as one of only 4 partipants from the USA.  Most of the people with whom I was speaking were knights of the realm (one even had his own paradox!), cancer center directors and even ministers of health for entire countries. I was, in a word, outclassed.  That being said, my patron, Bob G_i, made sure I felt emboldened to speak out for our agenda - the use of rigorous theory and evolutionary thinking in cancer research.  And, as luck had it, I ended up at the table next to Marge Foti, the head of the AACR (who, it turns out, is a super nice lady), so I got to talk a bunch (when she finished saying what she wanted, I just grabbed the microphone and kept going!).

I think my role there was really to be an uninhibited, undogmatized voice unafraid to say 'We don't know'.  Because of my role as a student, and not as someone that entire nations look up to, I am able to say that without breaking trust...  and in cancer, this is a very important thing to say.  We really, honestly, don't. know. &*!@.  Cancer is a disease that keeps outpacing us and our results aren't much better than they were 50 years ago.  We have learned a LOT, but it is not obvious how what we've learned is useful.  Where we have done well is in patient care and in maximizing the effectiveness of the therapies that we do have, but we have a long way to go before we can hope to end this disease (if we can at all...)

My major contention (and one that I managed to get squeeeeezed into the consensus statement) is that there is a MASSIVE theory gap in cancer research.  I would argue that we still don't have a deep understanding of the data generated 30 years ago!  Do we REALLY know the meaning of aneuploidy in cancer (feel free to weight in +Arturo Araujo)?  What about chromosomal aberrations?  How can we possibly hope to make sense of (and utilize) the information coming out of The Cancer Genome Atlas, if we don't understand the first principles?

I honestly fear sometimes that we've been blinded by the promise of easy answers in the genome, and because of this, we have abandoned almost all other forms of research in cancer.  If you don't have genetic analysis of some sort in your project, good luck getting it funded.  But what if the answer isn't in the genome?  Well, that is a topic for a future post...  back to the WOF.

So - what was the answer we came up with?  It was: No.  We aren't winning the war on cancer.

We published a call to arms in a number of newspapers throughout the world on World cancer day, February 4th. (International Herald Tribune, Le Monde, La Repubblica, El País, and Neue Zürcher Zeitung) that looked like this:

and a piece in the Lancet (which I don't have access to, ARGH why isn't THE LANCET #openaccess??).  And finally, a piece in Cancer World magazine, the ESO's own journal, in which I they put this paragraph, largely about our contention (yes, it was me who wasn't convinced), right after Professor Hanahan's hopeful talk that suggests that all we need to do is target the hallmarks of cancer, and we'll be OK.

Not everyone at the Forum was convinced. Doesn’t hitting targets harder (with all that implies for accompanying toxicity), and hitting multiple targets, sound a bit like a return to the chemotherapy carpet bombing approach? Given the way tumour cells mutate, shouldn’t we expect that if we target and shut down one mutation the cancer will simply find other mutations to exploit to keep going? Before investing billions on drugs targeted at one mutation after another, shouldn’t we start by trying to understand basic principles of cell behaviour, so we can anticipate the cancer cells’ evasive strategies, and devise rational counterstrategies, based on rigorous mathematical models, to cut off their options?

So I managed to at least get the words 'mathematical modeling' and 'rigorous theory' into the minds of the world's cancer leaders...

I also came away with a deeper understanding about the worldwide cancer situation: that really, my theories on metastasis, cancer stem cells, or the evolution of resistance to targeted therapy, while exciting to me, mean very little to the tens of thousands of people without access to a properly trained surgeon, ANY radiation therapy or even pain medication.  Humbling.  But, we do what we can.

Thanks to Anna Wagstaff for listening to me when she had MANY more influential people eager to get their two cents in.  Also, thanks for featuring me in their magazine, where I think I managed to piss of a few old teachers and maybe even some prospective bosses with my final answer in their 'My World' feature.

It was an amazing meeting run by passionate people.  If you ever have a chance to interact with the ESO, take the opportunity.  The USA could do with an organization like it.

A nice paper from our group (not me) recently posted on the arxiv.  Any comments are most welcome and will be passed directly to the authors.

Here is the link to the pre-print of:

Senescent fibroblasts can drive melanoma initiation and progression

By Eunjung Kim et al.

This is a collaboration between a theory group (Integrated mathematical oncology) and a wet lab (Smalley PI) and a great example of how a collaboration should work between theorists and experimentalists.

http://arxiv.org/abs/1304.1054

Melanoma is the most devastating form of skin cancer arising from the melanocytes, the pigment producing cells of the skin. Its initiation and progression is known to involve genetic changes in melanocytes as well as the disruption of both cell-cell and cell-microenvironment interactions. However, the mechanisms by which the deregulated interactions lead to melanoma development have been less understood. It is our view, that we must first model normal skin form and the regulatory mechanisms that maintain skin homeostasis before we can model cancer initiation. To this end, we developed a hybrid multiscale mathematical model of normal skin (virtual skin). The model focuses on key cellular and microenvironmental variables that regulate normal skin homeostasis. The model recapitulates normal skin structure, and is robust enough to withstand physical as well as biochemical perturbations. Furthermore, the model revealed the important role of the skin microenvironment in melanoma initiation and progression. Experimentally, we found that as fibroblasts, an importance source of growth factors in the skin, become senescent their behavior changes significantly, leading to the expression of multiple growth factors, matrix proteins and proteases. We incorporated senescent fibroblasts into model to examine how microenvironmental changes affect skin structure. Our simulations showed that senescent fibroblasts transform the skin microenvironment and subsequently change the skin architecture by enhancing the growth and invasion of normal melanocytes as well as early stage melanoma cells. These predictions are consistent with our experimental results as well as clinical observations. Our co-culture experiments showed that the senescent fibroblasts promote the growth and invasion of non-tumorigenic melanoma cells. We also observed increased proteolytic activity in stromal fields adjacent to melanoma lesions in human histology. Based on our simulations combined with clinical data, we speculate that senescent fibroblasts may create a pro-oncogenic environment that cooperates with mutations to drive melanoma initiation and progression.

http://arxiv.org/trackback/{1304.1054}

Not all modeling is mathematical!

I found a nice blog from an entomologist at 'a teaching institution' through a post on twitter that raised my hackles a bit. The tweet, and title of the blog post was:

Ant science - how avoiding modeling led to a cool discovery

By this, he meant *mathematical* modeling. In the wake of the whole EO Wilson good scientist=\Good at math post on WSJ (yes, I'll post about that later in detail), I thought this deserved a reply. So, I responded with a comment on his blog, which I will append here. The comment is basically a short summary of a previous post, but it bears repeating, I think.

His post describes how he made a discovery about an species of ant by looking for big picture patterns, and not paying so much attention to the details... Being a Kepler, not a Newton if you will... It is worth a read, as it is well written and interesting, especially if you like ants.  Anyways, here's what I said in return, referencing an earlier post of mine:

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Hello, and a pleasure to find your blog. I enjoyed this post, and it is fitting as I literally JUST put down EOWs new book 'letters to a young scientist'. Anyways, I'd like to respectfully disagree a bit, and mostly semantically. This is NOT avoidance of modeling. It is just doing a modeling of a different sort. I recently (started and) wrote a blog post about just this issue, specifically in communication between mathematical and experimental biologists - which can be read here:

Whose model is it anyways?

Where I talk about how we are really ALL modelers! Our models just look different. Where the data collecting scientist (think Tycho Brahe) spends his/her time dreaming about where to look and what to look for, the pattern former (your role here - think Johannes Kepler) seeks the big picture patterns and the 'modeler' in your terminology (Isaac Newton in the analogy I've been using) puts together the more rigorous connections. There is no rigorous theory without patterns to connect, and there are no patterns without data. We are all on the same team. And, it's a lot of fun whichever role you play.

Anyways, great post, just wanted to argue the semantics :)

\end{rant}

For full disclosure, I'm a phd student in mathematical biology.
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For even more full disclosure, I stole the 'we are all modelers' from my mentor +Alexander Anderson - cheers Sandy.  And it turns out that I stole the whole Brahe->Kepler->Newton thing from Lord Robert May's lovely article on mathematical modeling in biology, though I didn't mean to.

Review of Whole Brain Radiotherapy for Brain Metastases

Just a quick post to let you know about a review I published with two collaborators today in Surgical Neurology International.  The heavy lifting for this was done by +Emory McTyre, a very bright and motivated medical student who has recently matched into radiation oncology at Wake Forest.  This is a comprehensive review of the use of whole brain radiotherapy in the treatment of brain metastases.  It is written for a clinical audience, but since it is #openaccess anyone can read it and use the information therein.  The corresponding author is a friend and radiation oncologist at Moffitt Cancer Center, Prakash Chinnaiyan.

Here is a link, enjoy and feel free to share.

http://www.surgicalneurologyint.com/text.asp?2013/4/5/236/111301