Guest post day - The Tree of Life

A post from me is featured on the Tree of Life today trying to answer the question:

How do we build trust in the biological sciences to promote the use of preprints?

So head over and check it out.

http://phylogenomics.blogspot.com/2013/06/guest-post-from-jake-scott-building.html

There's also a new post up at Warburg's Lens discussing some work by +Benjamin Werner  and Arne Traulsen at Max Planck.

Next up I'll post about the NIH Extramural Loan Repayment program.

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.