tag:blogger.com,1999:blog-59756314773066465692024-03-13T11:09:16.189-07:00Connecting the DotsA place for me to lay out all of my thoughts on my disparate projects, and to talk about recent research. Posts will cover theoretical biology, evolution, cancer therapy, medical education and science communication. Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.comBlogger66125tag:blogger.com,1999:blog-5975631477306646569.post-16690569841059473072020-12-31T11:12:00.002-08:002020-12-31T11:23:35.689-08:00Forming Voltron: bringing new and disparate skills together to study cancer evolution -- 4 new post-docs for Theory Division<p></p><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://lh3.googleusercontent.com/-3BsLo9s-4Xw/X-4e_B39cOI/AAAAAAAAF8I/Xfy5rqVxRd4yyx3sUKQ0vvVIm9MAcwCWgCLcBGAsYHQ/synergy.png" style="margin-left: auto; margin-right: auto;"><img alt="" data-original-height="1165" data-original-width="2048" height="364" src="https://lh3.googleusercontent.com/-3BsLo9s-4Xw/X-4e_B39cOI/AAAAAAAAF8I/Xfy5rqVxRd4yyx3sUKQ0vvVIm9MAcwCWgCLcBGAsYHQ/w640-h364/synergy.png" width="640" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">4 new post-docs have joined us in 2020 whose skills have a perfect amount of overlap to allow collaboration, but disparate enough so that we will constantly be learning from one another. Look out cancer and pathogens, we're coming for you.</td></tr></tbody></table><p></p><p><br /></p>I have been extremely lucky in the first few years of my time building a laboratory to have had three extremely kind, talented and passionate post-docs choose to work with us. Starting with <a href="https://www.adelphi.edu/faculty/profiles/profile.php?PID=0905">Nara Yoon</a>, who completed her <a href="https://mathstats.case.edu/">PhD in the math department at CWRU</a> and is now an <a href="https://www.adelphi.edu/faculty/profiles/profile.php?PID=0905">Assistant Professor at Adelphi University</a>; and then <a href="https://www.linkedin.com/in/inom-mirzaev-30920b80/">Inom Mirzaev</a>, who was a joint post-doc between Theory Division and the <a href="https://mbi.osu.edu/">MBI at Ohio State</a> University, who now works as a machine learning engineer; and then <a href="https://cse.msu.edu/~dolsonem/">Emily Dolson</a>, who came from (and went back to) Michigan State University, where she is now an Assistant Professor of computer science.<p></p><p>These three young scientists (along with some talented students who deserve their own post, but this one is about post-docs) really kick-started the work here in Theory Division, and helped spread the word about our work. When I finally got some <a href="http://cancerconnector.blogspot.com/2019/11/a-long-and-winding-r0ad1.html">real funding</a>, and was able to hire more than one post-doc at a time, I started looking to hire two, as I knew Dr. Dolson was leaving us for the greener pastures of a tenure track job. This funny thing seems to happen to me... once I realize a post-doc is leaving I start to get really nervous. I think: who in their right mind would come work with me? How can I possibly ever replace (post-doc X) who is leaving? </p><p>These two questions are both ill-posed, but for different reasons:</p><p>1 - you can't replace (post-doc X), they are wonderful and unique in their own way, and 'replacing them' would stifle the growth of the lab anyways -- one needs new ideas, new skills, new faces...</p><p>2 - 'who would ever work with me??' is an impostor syndrome laden question -- but impostor syndrome is real, I ask myself this question every time (and still don't know the answer!)</p><p>So, I was shocked when <a href="http://www.matterwithcuriosity.com/">Kyle Card</a>, finishing his Phd in the <a href="https://mmg.natsci.msu.edu/people/faculty/lenski-richard/">Lenski lab</a>, responded positively to my twitter DM asking if he was thinking about post-docs yet (as I had just read his excellent new paper: <a href="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000397&rev=2">Historical contingency in the evolution of antibiotic resistance after decades of relaxed selection</a>). </p><p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://lh3.googleusercontent.com/-lMqh9cKOzsU/X-4DMjh1iSI/AAAAAAAAF78/mFqaiJjkdt0t4tIXCKpnHwhQlpb47B_jwCLcBGAsYHQ/image.png" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="1794" data-original-width="650" height="640" src="https://lh3.googleusercontent.com/-lMqh9cKOzsU/X-4DMjh1iSI/AAAAAAAAF78/mFqaiJjkdt0t4tIXCKpnHwhQlpb47B_jwCLcBGAsYHQ/w232-h640/image.png" width="232" /></a></div><div class="separator" style="clear: both; text-align: center;"><br /></div><div class="separator" style="clear: both; text-align: left;">Kyle came to visit right before COVID, and we hit it off immediately, and before his visit ended, he took me up on an offer of a post-doc.</div><div class="separator" style="clear: both; text-align: center;"><br /></div><div class="separator" style="clear: both; text-align: left;">At the same time, I was chatting with <a href="https://twitter.com/lopasic1">Luka Opasic</a>, who was completing his PhD with <a href="https://www.evolbio.mpg.de/person/12087/15650">Arne Traulsen</a> at the <a href="https://www.mpg.de/153384/evolutionsbiologie">Max Planck Institute for Evolutionary Biology</a>. Luka had spent a summer with us during the middle of his PhD (some of his work can be read here: <a href="https://link.springer.com/article/10.1186/s12885-019-5597-1">How many samples are needed to infer truly clonal mutations from heterogenous tumours?</a>), and was a great fit. A varied background in medicine and maths, and interest in evolution, and all the right kinds of nerd :).</div><p>The summer before all this happened, I was in Cambridge lecturing to the PhD students in a unique program called <a href="https://itn-contra.org/">CONTRA: Computational ONcology TRaining Alliance Innovative Training Network</a>.</p><p></p>After my lecture, I was approached after my talk (<a href="https://www.youtube.com/watch?v=zrxERwqBiC0&ab_channel=ITNCONTRA-ComputationalCancerResearch">which you can watch here</a>) by <a href="https://twitter.com/doessteph">Steph Owen</a>, a talented PhD student working in cancer who was eager to get back to their roots in Physics. As a physicist myself was now doing cancer research, we hit if off immediately. The timing was such however, that Steph's PhD hadn't finished, and so we postponed the discussion of future work for a few months... which put our renewed conversation right at the beginning of COVID lock downs. Some of Steph's work can be read here: <a href="https://www.nature.com/articles/s41416-020-0822-x">Combining measures of immune infiltration shows additive effect on survival prediction in high-grade serous ovarian carcinoma</a>.<p></p><p>At this point there were three people interested when I imagined I wouldn't find any, and now I was nervous about how to make this happen (strictly from a funding perspective). Then, the universe spoke. <a href="https://twitter.com/nkrishnan_">Nikhil Krishnan</a>, a fourth year <a href="https://case.edu/medicine/">CWRU medical student </a>in our lab (to whom I had promised PhD funding), got a <a href="https://case.edu/medicine/about/newsroom/our-latest-news/fourth-year-medical-student-nikhil-krishnan-selected-2020-gates-cambridge-scholar">Gates Fellowship to study Physics at Cambridge with Diana Fusco</a> -- freeing up the funds to hire another person -- we'll call them the Nikhil Krishnan Post-doctoral fellow :)</p><p>The final piece of the puzzle I didn't know I was building was an unlooked for applicant. A friend and colleague, <a href="http://woodlab.biop.lsa.umich.edu/">Kevin Wood from UM Biophysics</a> visited us (actually the same weekend Kyle Card interviewed) to give a Biophysics colloquium, hosted by me and <a href="https://hinczlab.org/">Mike Hinczewski</a> (a friend and collaborator in <a href="https://physics.case.edu/">CWRU Physics</a>). A grad student in his lab (essentially Black Mirror version of our own lab), Jeff Maltas, was just finishing his PhD. It turns out that we had reviewed half of his thesis papers (anonymously) so I was quite familiar with his (excellent!) work (I take some credit for Figure 6 :) in: <a href="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000515">Pervasive and diverse collateral sensitivity profiles inform optimal strategies to limit antibiotic resistance</a>). I didn't think Jeff would want to work with us, but invited him for a visit anyways. and then, there were 4...</p><p>I couldn't have possibly decided between the 4, so I decided to go with them all, and sort the funding out later. Turns out, they did it for me -- between a <a href="https://case.edu/cancer/training-education/postdoctoral-training/computational-genomic-epidemiology-cancer-cogec">computational genomics T32</a> and a competitive <a href="https://grants.nih.gov/grants/guide/contacts/Diversity-Supp_contacts.html">NIH diversity supplement</a>, the universe (and my talented new young scientists) provided, and I am SO EXCITED to see what science we do together. There is just enough overlap between us all that we can speak freely and in our own scientific mother tongues, and enough separation that each is synergistic with the others. I feel incredibly honored to be able to host these young scientists and can't wait to see what science we're able to in <a href="https://www.lerner.ccf.org/thor/scott/lab/">Theory Division</a> in 2021.</p><p><br /><br /></p><p></p>Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com4tag:blogger.com,1999:blog-5975631477306646569.post-22988541728944947212020-12-16T12:12:00.004-08:002020-12-21T10:41:46.346-08:00The effect of genetic background on the evolution of antibiotic resistance.<p></p><div class="separator" style="clear: both; text-align: center;"><a href="https://1.bp.blogspot.com/-AComvrPSXRE/X9pqD3XaMyI/AAAAAAAAF7M/jaQYoQwBmbk7_Cs5LSTBPeiSFsUAy0HWQCLcBGAsYHQ/s1960/kyletalk.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1430" data-original-width="1960" height="466" src="https://1.bp.blogspot.com/-AComvrPSXRE/X9pqD3XaMyI/AAAAAAAAF7M/jaQYoQwBmbk7_Cs5LSTBPeiSFsUAy0HWQCLcBGAsYHQ/w640-h466/kyletalk.png" width="640" /></a></div><br /><p></p><p><span face="Slack-Lato, appleLogo, sans-serif" style="background-color: #f8f8f8; color: #1d1c1d; font-size: 15px; font-variant-ligatures: common-ligatures;">Our second video is a long form research talk from one of our awesome new post-docs, <a href="https://www.matterwithcuriosity.com/">Kyle Card</a>. Kyle came to us from <a href="http://myxo.css.msu.edu/">Richard Lenski's lab at Michigan State University</a>, and is working on disentangling population size, mutation rate and genetic background in the evolution of antibiotic resistance. Check out his talk here:</span></p><p><a href="https://www.youtube.com/channel/UCr_3HE-tUGu9mlSHQGZSYQA">https://www.youtube.com/channel/UCr_3HE-tUGu9mlSHQGZSYQA</a></p><p><span face="Slack-Lato, appleLogo, sans-serif" style="background-color: #f8f8f8; color: #1d1c1d; font-size: 15px; font-variant-ligatures: common-ligatures;">Short Abstract:</span></p><p><span face="Slack-Lato, appleLogo, sans-serif" style="background-color: #f8f8f8; color: #1d1c1d; font-size: 15px; font-variant-ligatures: common-ligatures;">Antibiotic resistance is a growing public-health concern. Efforts to control the emergence and spread of resistance would benefit from an improved ability to forecast when and how it will evolve. To predict the evolution of resistance with accuracy, we must understand and integrate information about many factors, including a bacterium’s evolutionary history. In this presentation, I discuss the effects of <a href="https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000397&rev=2">genetic background on the evolution of phenotypic resistance</a></span><span face="Slack-Lato, appleLogo, sans-serif" style="background-color: #f8f8f8; color: #1d1c1d; font-size: 15px; font-variant-ligatures: common-ligatures;">, its <a href="https://www.biorxiv.org/content/biorxiv/early/2020/08/20/2020.08.19.258384">genetic basis</a></span><span face="Slack-Lato, appleLogo, sans-serif" style="background-color: #f8f8f8; color: #1d1c1d; font-size: 15px; font-variant-ligatures: common-ligatures;">, and its <a href="https://www.biorxiv.org/content/biorxiv/early/2020/09/12/2020.09.12.294355">fitness costs</a></span><span face="Slack-Lato, appleLogo, sans-serif" style="background-color: #f8f8f8; color: #1d1c1d; font-size: 15px; font-variant-ligatures: common-ligatures;">.</span></p><span class="c-mrkdwn__br" data-stringify-type="paragraph-break" face="Slack-Lato, appleLogo, sans-serif" style="background-color: #f8f8f8; box-sizing: inherit; color: #1d1c1d; display: block; font-size: 15px; font-variant-ligatures: common-ligatures; height: 8px;"></span><span face="Slack-Lato, appleLogo, sans-serif" style="background-color: #f8f8f8; color: #1d1c1d; font-size: 15px; font-variant-ligatures: common-ligatures;">First, I ask how readily bacteria can overcome prior losses of intrinsic resistance through subsequent evolution when challenged with antibiotics. Second, I consider whether lineages founded from different genotypes take parallel or divergent mutational paths to achieve increased resistance. Third, I inquire whether fitness costs of resistance mutations are constant across different genetic backgrounds. In general, I focus attention on the interplay between repeatability and contingency in the evolutionary process. I demonstrate that genetic background can influence both the phenotypic and genotypic evolution of resistance and its associated fitness costs. I conclude this presentation by highlighting clinical and public-health implications of this work.</span>Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com4tag:blogger.com,1999:blog-5975631477306646569.post-69913368289488063362020-12-09T09:40:00.000-08:002020-12-09T09:40:26.923-08:00Introducing our new Theory Division YouTube channel!<p>It turns out managing a blog is really hard during the assistant professor years. As in, I've posted on average once a year since I started this job... </p><p>So -- in hopes of doing better, we're going to start something new!</p><p>Each week in Theory Division we have lab meeting (which in itself is worthy of a post -- turns out no one teaches you how to run these, and how to best do it changes a LOT depending on the size of your lab), and we also have a one hour slot separately for either journal club, or for a long form research talk. Given the pandemic, these have been done via Zoom, and so have been recorded. So, what we are going to do is, for each long form research talk we will post the recording to our <a href="https://www.youtube.com/channel/UCr_3HE-tUGu9mlSHQGZSYQA/featured"><b>new youtube channel</b></a>, along with a short textual abstract here on the blog with a link to the talk.</p><div class="separator" style="clear: both; text-align: center;"><a href="https://1.bp.blogspot.com/-Xa6N0dlPH7I/X9ELUfX_QMI/AAAAAAAAF6o/XwYpstCf8egcIZJZm6g7XNWofjKmJulawCLcBGAsYHQ/s2048/youtubechannel.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1126" data-original-width="2048" height="352" src="https://1.bp.blogspot.com/-Xa6N0dlPH7I/X9ELUfX_QMI/AAAAAAAAF6o/XwYpstCf8egcIZJZm6g7XNWofjKmJulawCLcBGAsYHQ/w640-h352/youtubechannel.png" width="640" /></a></div><br /><p><br /></p><p>I'll start things off!</p><p>Just yesterday, my colleagues and I had a paper come out in the Journal of Thoracic Oncology: </p><p><a href="https://www.sciencedirect.com/science/article/abs/pii/S1556086420310467" target="_blank">Personalizing Radiotherapy Prescription Dose Using Genomic Markers of Radiosensitivity and Normal Tissue Toxicity in Non-Small Cell Lung Cancer</a></p><p>This paper was the subject of my <a href="https://www.test.schulich.uwo.ca/biophysics/about_us/news/2020/peter_canham_annual_fall_lecture.html">Peter Canham lecture in biophysics</a> at Western University this year -- and we have ported this talk to be our first in the channel -- head over to the channel to watch/subscribe!</p><p><a href="https://www.youtube.com/watch?v=DiCwPKKlpV0&ab_channel=TheoryDivision">Click here to watch this talk on our new channel.</a></p><p>In this talk I discuss some of the frustration I feel as a radiation oncologist that our field has not yet entered the era of personalized medicine -- that is, each cancer patient doesn't have their radiation therapy (DOSE!) tailored to their tumor's genomic profile. Certainly, each prescription is physically personalized (geometrically), but biologically personalized dosing is not yet standard of care. Starting with the beautiful opening (to use a chess analogy) starting with a <a href="https://www.sciencedirect.com/science/article/abs/pii/S0360301609009195">breakthrough creation of a Radiation Sensitivity Index (RSI)</a> which linked canonical ideas of SF2 in radiation biology to genomics, by my friend and mentor <a href="https://moffitt.org/providers/javier-torres-roca/">Javier Torres-Roca</a>, he and I and our colleagues have slowly and methodically moved through the middle game, setting the stage for a relationship to dose, which we outlined in our article: <a href="https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30648-9/fulltext">A genome-based model for adjusting radiotherapy dose (GARD): a retrospective, cohort-based study</a>. </p><p>We then (I hope) end the middle game with this paper from yesterday (see above), where we use information about what dose is needed to optimize a given patient's tumor control to then make inferences about OVER and UNDER treatment -- and using a novel combined model of TCP and NTCP, determine how much we could make radiation therapy better right now.</p><p>So - head on over to our youtube channel, watch the video, let me know what you think! And subscribe to see future talks in our lab!</p>Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com3tag:blogger.com,1999:blog-5975631477306646569.post-9076865344911903792019-11-17T08:09:00.000-08:002019-11-17T08:09:29.754-08:00A long and winding R0(ad)1It's an unbelievable relief that, two weeks ago, I got an official email from my (very supportive) program officer at the NCI letting me know that my first R01 was going forward for funding. In celebration of this, I want to do convey three things.<br />
<br />
1 - The science we are going to do!<br />
2 - The long road of rejections (and necessary improvements) leading up to this (persistence pays off)<br />
3 - How grateful I am to the many, many people who were involved along the way.<br />
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I'm going to convey these in opposite order...<br />
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3 - Gratitude:<br />
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It wasn't just me working on my own... on the contrary, this was a process that began during my scientific training where my mentors let me read/edit their grants, read/edit manuscripts, and yes, write my own. It was gracious colleagues reading my drafts, editing my aims, discussing the science with me. It was people betting on me by giving me a job and startup... joining our lab team before we were funded. It was family and friends listening to me rant after rejections. And of course, scientific collaborators working as hard and long as I did (looking at you Andriy). So, first order of business: thanks!<br />
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2 - Long and winding (painful) road.<br />
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This particular grant, which I will describe in the next section, was not, by any means, funded on the first try. In fact, it took about 4 years... and 6 submissions. <br />
Three R21s: one scored (*8*, 4, 3), a resubmission not discussed, and a new submission after that not discussed.<br />
Then three submissions of R01s: 21% (3, 4, 5), 17% (3, 4, 4) and finally the awarded grant (which was 10% (2, 2, 4)).<br />
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Some takeaway thoughts about this.<br />
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Many of the ideas were the same (not all) -- those which the study section liked, I kept -- those they didn't, I rethought. For the most part, while I was frustrated and sometimes even angry at my rejections, but upon further reflection I usually found that their opinions were pretty well founded.<br />
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In hindsight, I'm also sort of amazed how immature the ideas I originally submitted were. While the ideas were sound (for the most part), the data wasn't there to support any of my claims. Here is an example from the first R21 submission in 2016, side by side with one from the funded R01 in 2019 (almost 2020). You can see on the left some 'background' where I suggest the experiment I WANT to do... then, we did it, and analyzed it, and <a href="https://www.nature.com/articles/s41598-017-00791-8" target="_blank">published it (1.5 years later), and it became a subpanel of 'previous work'</a> in the funded proposal (right).<br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://1.bp.blogspot.com/-47zdEMm3TUw/XdFSnyMCkRI/AAAAAAAAFiw/OPABm0fnaFkEAHHvDMgS9x0jWRqQTQHdACLcBGAsYHQ/s1600/before_after.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="301" data-original-width="663" src="https://1.bp.blogspot.com/-47zdEMm3TUw/XdFSnyMCkRI/AAAAAAAAFiw/OPABm0fnaFkEAHHvDMgS9x0jWRqQTQHdACLcBGAsYHQ/s1600/before_after.png" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Left: an idea of what a collateraa sensitivity matrix MIGHT look like after the experiments I posed (yes, i made that with powerpoint). Right (panel A), what it looks like now as preliminary data... and B-F some more interesting observations from those (now published) experiments -- see <a href="https://www.nature.com/articles/s41598-017-00791-8" target="_blank">Dhawan et al.</a></td></tr>
</tbody></table>
<br />
Another interesting tidbit. After getting back my first R01 score (21%), I was able to take advantage of the 'quick turnaround resubmit' for ESIs (now defunct), so only had a few weeks to get it back in. This meant that I could only really address small issues the reviewers had. In this case, I was able to add a co-authored <a href="https://www.nature.com/articles/s41698-018-0060-3" target="_blank">publication with a new method for comparing in vivo growth curves</a>, but not much else except a small in vivo experiment Andriy has performed (which has since been expanded into a <a href="https://www.biorxiv.org/content/10.1101/504837v1" target="_blank">whole paper on its own showing the graduality of the evolution of resistance</a> -- which in turned has spawned a new grant -- this one still in the infant stages of development). Changing out the aim that was the big sticking point wasn't possible though on the short timescale. I was frustrated by the result (but maybe shouldn't have been surprised), and got a 17% on the A1.<br />
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17% is pretty far outside the funding range, but the PO was very supportive, and presented it for exception. At the end, it wasn't funded, but I was very encouraged by the support. TALK TO YOUR PROGRAM OFFICERS!<br />
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So, with more time, and the new summary statement, I was able to thoughtfully rewrite a new A0, which included two new publications (the EGT one from above, and our <a href="https://www.nature.com/articles/s41467-018-08098-6" target="_blank">collateral sensitivity/experimental evolution work in E. coli</a>, both of which I've blogged about here before (<a href="http://cancerconnector.blogspot.com/2019/02/the-road-to-measuring-evolutionary.html" target="_blank">road to measuring evolutionary game in cancer</a> and <a href="http://cancerconnector.blogspot.com/2019/01/antibiotic-collateral-sensitivity-is.html" target="_blank">Antibiotic collateral sensitivity is contingent on the repeatability of evolution</a>). Cynically, one could say it was the two 'shiny' journals we published in that put us over the edge, which is likely in part true, but I think it was much more the honing of the science and grantspersonship that we managed.<br />
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Anyways, happy to share any/all of the grants/summary statements if you want to learn from my mistakes, just shoot me an email.<br />
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Right. Now the science (in blog/tweetorial format - which I will cross-post on <a href="http://blog.mathematical-oncology.org/" target="_blank">the mathoncoblog</a>):<br />
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my third attempt at this R01 submission that went to MABS - scores went A0: 21%, A1: 17%, rewritten new A0: 10% (funded through magic of ESI thank you @NIHFunding) #persistence<br />
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we are excited to study the evolution of TKI resistance in lungcancer - through three specific aims:<br />
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Together with @AndriyMarusyk our first aim will be to see if we can use <a href="https://www.nature.com/articles/s41559-018-0768-z" target="_blank">@kaznatcheev‘s evolutionary game assay</a> in a pair wise fashion to predict three strategy dynamics in vitro. (n.b. I didn't manage to get a fundable score until after that paper was published... even with the whole paper on <a href="https://www.biorxiv.org/" target="_blank">biorxiv</a> for over a year...)<br />
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<a href="https://1.bp.blogspot.com/-0TqEalLRj9k/XdFeBthqoRI/AAAAAAAAFi8/AWWADYslyCYTSRkOiomdmW8Rc7IEzS0xwCLcBGAsYHQ/s1600/game%2Bassay.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="448" data-original-width="777" height="368" src="https://1.bp.blogspot.com/-0TqEalLRj9k/XdFeBthqoRI/AAAAAAAAFi8/AWWADYslyCYTSRkOiomdmW8Rc7IEzS0xwCLcBGAsYHQ/s640/game%2Bassay.png" width="640" /></a></div>
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2nd aim will be to study commonalities in drug sensitivity/resistance - over a long (well - longish, not @RELenski long) term evolution experiment - how do sensitivities change and can we ID them? This will support super ⭐️ @CWRUSOM MSTP @ScarboroughJess -w/ help from @n8pennell. (this aim supported by <a href="https://www.nature.com/articles/s41467-018-08098-6" target="_blank">our own work in E. coli</a>).<br />
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<img alt="Image" height="529" src="https://pbs.twimg.com/media/EIx4_jwXkAAprB9?format=jpg&name=medium" width="640" /><br />
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3rd aim will probe the evolutionary stability (in space (<a href="https://royalsocietypublishing.org/doi/full/10.1098/rsif.2015.0154" target="_blank">as we've done before on graphs</a>) and time) of the ecological dynamics we measure in our game assays. Implementing <a href="https://journals.aps.org/pre/abstract/10.1103/PhysRevE.91.052907" target="_blank">replicator-mutator dynamics in collab w/ @stevenstrogatz</a><br />
- we’ll see how these games change through time. (h/t to <a href="https://egtheory.wordpress.com/" target="_blank">@kaznatcheev</a> for the idea!)<br />
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This also means that we are looking for someone to join the team... specifically a postdoc with an interest in ecology and evolution and a desire to do some modeling and in vitro experiments. Cancer experience is NOT required, kindness and inclusivity are. Please spread the word or <a href="https://www.lerner.ccf.org/thor/scott/lab/software/" target="_blank">check out lab website</a> and get in touch if interested by email.Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com63tag:blogger.com,1999:blog-5975631477306646569.post-76281023858740466172019-10-15T10:24:00.003-07:002019-10-15T10:31:25.299-07:00Range expansion shifts clonal interference patterns in evolving populations<span style="font-size: large;"><span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;">While <a href="https://twitter.com/nkrishnan94" target="_blank">Nikhil</a></span><span style="background-color: white; color: #14171a; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; white-space: pre-wrap;"> </span><span style="background-color: white; color: #14171a; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; white-space: pre-wrap;">was trying to sort out a simulation of <a href="https://science.sciencemag.org/content/353/6304/1147" target="_blank">Michael Baym'</a></span><span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;"><a href="https://science.sciencemag.org/content/353/6304/1147" target="_blank">s beautiful megaplate</a></span><span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;"><a href="https://science.sciencemag.org/content/353/6304/1147" target="_blank"> experiment</a>, we started wondering about the comparison of effective population size and agents in his (Nikhil’s) individual based model. The struggle was that to 'realistically' simulate this in a <a href="https://www.sciencedirect.com/science/article/pii/S0092824098900428" target="_blank">CA model</a> would require order 10^10 agents, something that is not feasible. We were looking at something more like order 10^4... so what did that mean? Each CA element was something like 10^6 bugs? If that was the case -- what does 'mutation' mean in terms of our CA model? </span></span><br />
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<tr><td style="text-align: center;"><a href="https://1.bp.blogspot.com/-kXDb7QKOA54/XaHbB_TxnCI/AAAAAAAAFdo/izILdDoZ4ZYQaAj90JhjC8ph6Jq2MpILgCLcBGAsYHQ/s1600/megaplate.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><span style="font-size: large;"><img border="0" data-original-height="602" data-original-width="1142" height="336" src="https://1.bp.blogspot.com/-kXDb7QKOA54/XaHbB_TxnCI/AAAAAAAAFdo/izILdDoZ4ZYQaAj90JhjC8ph6Jq2MpILgCLcBGAsYHQ/s640/megaplate.png" width="640" /></span></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-size: large;">Figure 1B from Baym's science paper (link above). The real size is on the order of feet... that is a LOT of bugs.</span></td></tr>
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<span style="font-size: large;"><span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;"><br /></span><span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;">What it would mean is that instantly, all 10^6 or so bugs would change their genotype... well, this was clearly crazy wrong :)</span></span><br />
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<a href="https://1.bp.blogspot.com/-6IZazuLz3-s/XaHZqdOWxmI/AAAAAAAAFdc/D0wtc1p4PiorzDawjDYKf_FWiMwaYWEjwCLcBGAsYHQ/s1600/MegaPLate_CA_tree.gif" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><span style="font-size: large;"><img border="0" data-original-height="1200" data-original-width="1200" height="640" src="https://1.bp.blogspot.com/-6IZazuLz3-s/XaHZqdOWxmI/AAAAAAAAFdc/D0wtc1p4PiorzDawjDYKf_FWiMwaYWEjwCLcBGAsYHQ/s640/MegaPLate_CA_tree.gif" width="640" /></span></a></div>
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<span style="font-size: large;"><span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;">So, we started thinking about how populations spread in space (Fisher-like waves), and we found the wonderful body of work from </span><span style="background-color: white; color: #14171a; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; text-align: center; white-space: pre-wrap;">the </span><a href="http://www.gorelab.org/" style="background-color: white; text-align: center; white-space: pre-wrap;" target="_blank">Gore</a><span style="background-color: white; color: #14171a; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; text-align: center; white-space: pre-wrap;">, </span><a href="http://hallatscheklab.berkeley.edu/" style="background-color: white; text-align: center; white-space: pre-wrap;" target="_blank">Hallatschek</a><span style="background-color: white; color: #14171a; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; text-align: center; white-space: pre-wrap;"> and </span><a href="http://physics.bu.edu/people/show/korolev" style="background-color: white; text-align: center; white-space: pre-wrap;" target="_blank">Korolev</a><span style="background-color: white; color: #14171a; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; text-align: center; white-space: pre-wrap;"> labs thinking about mutational surfing (essentially at the wave tip there is a changed effective population size so the balance between drift and selection can change) </span></span></div>
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<span style="background-color: white; color: #14171a; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-size: large; white-space: pre-wrap;">Formulating a model of (stochastic) mutation dynamics in a Fisher-like wave like those before us yielded known results. For a range of parameters, fixation of mutants can be promoted near the wave front - often called "<a href="https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1002447" target="_blank">mutations surfing on a wave</a>".</span></div>
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<span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-size: large; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;"><br /></span>
<span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-size: large; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;">So far, all this is known. Let's also recall from standard (well mixed) popgen (think Kimura) that depending on the relationship between the average time to establishment of a mutant, and the time to fixation, we can have qualitatively different evolutionary dynamics (e.g. strong selection weak mutation (SSWM) when the time to establishment is far larger than time to fixation; and weak selection strong mutation (WSSM) or strong selection strong mutation (SSSM) when the opposite is true, of if they are comparable). This is where we started to wonder... </span><br />
<span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-size: large; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;"><br /></span>
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<a href="https://1.bp.blogspot.com/-bk2TnWNGgFo/XaX87NU9gTI/AAAAAAAAFeE/dWhr4M4APvUs_IzKt4Kb-Xxq4-PTjc_KQCLcBGAsYHQ/s1600/box2.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><span style="font-size: large;"><img border="0" data-original-height="732" data-original-width="1300" height="360" src="https://1.bp.blogspot.com/-bk2TnWNGgFo/XaX87NU9gTI/AAAAAAAAFeE/dWhr4M4APvUs_IzKt4Kb-Xxq4-PTjc_KQCLcBGAsYHQ/s640/box2.png" width="640" /></span></a></div>
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<span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-size: large; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;">we think a lot about strong selection (like in the form of <a href="https://www.nature.com/articles/s41467-018-08098-6" target="_blank">experimental evolution in antibiotics</a> or associated <a href="https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004493" target="_blank">mathematical models of similar systems</a>) and often make the assumption that our dynamics are in the SSWM regime -- but this need not always be the case (in fact, it likely isn't).</span><br />
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<span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-size: large; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;"><br /></span></div>
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<span class="css-901oao css-16my406 r-1qd0xha r-ad9z0x r-bcqeeo r-qvutc0" style="background-color: white; border: 0px solid black; box-sizing: border-box; color: #14171a; display: inline; font-family: , , , "segoe ui" , "roboto" , "ubuntu" , "helvetica neue" , sans-serif; font-size: large; font-stretch: inherit; line-height: 1.3125; margin: 0px; min-width: 0px; overflow-wrap: break-word; padding: 0px; white-space: pre-wrap;">So, to really get at this, Nikhil defined a 'clonal interference index' as the log of the ratio of the fixation and establishment time, and calculated this all along the wavefront. What popped out is a pretty fun result: <b>depending where are you on the wave front, you experience qualitatively different evolutionary dynamics.</b></span></div>
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<a href="https://1.bp.blogspot.com/-Gd-NNL08nVw/XaX87GZz3aI/AAAAAAAAFeI/4o9hMMTSMV07YvGwixlmXYklT2MVO2OGwCLcBGAsYHQ/s1600/fig2.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><span style="font-size: large;"><img border="0" data-original-height="1020" data-original-width="1382" height="472" src="https://1.bp.blogspot.com/-Gd-NNL08nVw/XaX87GZz3aI/AAAAAAAAFeI/4o9hMMTSMV07YvGwixlmXYklT2MVO2OGwCLcBGAsYHQ/s640/fig2.png" width="640" /></span></a></div>
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<span style="font-size: large;">This is our first real effort working in the range expansion space -- so we are very eager for any feedback (in particular if we've missed key references or if this is already a solved problem!).</span><br />
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<span style="font-size: large;">Please <a href="https://www.biorxiv.org/content/10.1101/794867v2" target="_blank">check out the full preprint on bioRxiv</a> for more details, and drop us a line if you have comments/questions.</span><br />
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<span style="font-size: large;"><br /></span>Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com29tag:blogger.com,1999:blog-5975631477306646569.post-36169623956515021062019-02-27T11:35:00.001-08:002019-02-27T11:35:45.075-08:00The road to measuring evolutionary games in cancerAfter I finished residency I actually wasn't able to negotiate for a full faculty job that had the parameters I was looking for (read: protected time, lab startup). But, I had worked for so long to get to the physician-scientist track that I wasn't willing to accept less than what I thought I needed to succeed. This is something we can revisit in another post, but it sets the scene for this story, because what I did was take a sort of combination fellow/post-doc position where I trained. My two chairs, <a href="https://twitter.com/ara_anderson?lang=en" target="_blank">Sandy Anderson</a> (<a href="http://labpages.moffitt.org/imo/?_ga=2.134544117.581587135.1551019981-922079749.1546525618" target="_blank">Integrated Mathematical Oncology</a>) and <a href="https://moffitt.org/providers/louis-harrison/" target="_blank">Lou Harrison</a> (<a href="https://moffitt.org/for-healthcare-providers/clinical-programs-and-services/radiation-oncology-program/" target="_blank">Radiation Oncology</a>) were open minded and generous enough to create a position for me, so that I could get started on research that might lead me to be more competitive the next cycle.<br />
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This ended up being a super productive year, and led me to the job I now have (many thanks!). Also, during that year I met <a href="https://scholar.google.com/citations?user=APi9dQkAAAAJ&hl=en" target="_blank">Andriy Marusyk</a>, who is now my principle collaborator, and a close friend (sadly, not close in distance, but that's ok). Also during that year, <a href="https://twitter.com/kaznatcheev?lang=en" target="_blank">Artem Kaznatcheev</a> was working in Tampa with <a href="https://cancerevo.org/" target="_blank">David Basanta</a>, another friend and collaborator (and game theorist) of mine. At the time, <a href="https://cancerconnector.blogspot.com/2016/01/rotating-student-jeff-peacock-working.html" target="_blank">Jeff Peacock was a 4th year medical student at UCF, and was rotating in my lab</a> before starting his radiation oncology residency at Moffitt where I was (pseudo)faculty. During the course of that year, we had weekly discussion and brainstorming sessions, which were low stress, exciting times (Figure 0).<br />
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<tr><td style="text-align: center;"><a href="https://3.bp.blogspot.com/-8NfKndEEw80/XHbjiVxTTjI/AAAAAAAAFL0/qPw54lqSl0Et0L_WD9rAJiUSgg8BsvQDgCLcBGAs/s1600/artem_longago.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="1200" data-original-width="1600" height="300" src="https://3.bp.blogspot.com/-8NfKndEEw80/XHbjiVxTTjI/AAAAAAAAFL0/qPw54lqSl0Et0L_WD9rAJiUSgg8BsvQDgCLcBGAs/s400/artem_longago.png" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><b>Figure 0</b>. <a href="https://twitter.com/kaznatcheev?lang=en" target="_blank">Artem</a>, <a href="https://twitter.com/robertvanderve1" target="_blank">Robert</a> and <a href="https://twitter.com/andrewdhawan?lang=en" target="_blank">Andrew</a>. Three awesome PhD students, discussing this project in what was likely the best office I will ever have.</td></tr>
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<br />David and Artem and I had been working for some time on evolutionary game theory (EGT) -- in the form of theoretical models. As a matter of fact, the <a href="https://cancerconnector.blogspot.com/2013/07/a-visitor-resulting-hackathon-and-nice.html" target="_blank">first time we interacted with Artem produced a 96 hour hackathon</a> and one of our most influential papers to date which I (and Artem) have previously blogged about -- an <a href="https://royalsocietypublishing.org/doi/full/10.1098/rsif.2015.0154" target="_blank">exploration of the effect of interaction neighborhood size on EGT dynamics</a> (See Figure 1) - where we applied an algebraic transform on the game matrix to account for local interactions, derived from evolutionary graph theory, called the Ohtsuki-Nowak transform (more <a href="https://egtheory.wordpress.com/2017/06/30/spatializing-the-go-vs-grow-game-with-the-ohtsuki-nowak-transform/" target="_blank">here on Artem's blog</a>, or <a href="https://www.sciencedirect.com/science/article/pii/S0022519306002426?via%3Dihub" target="_blank">the original paper</a>).<br />
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<tr><td style="text-align: center;"><a href="https://4.bp.blogspot.com/-q3Jxz-dQVbA/XHKuLaXOW8I/AAAAAAAAFJ0/s9R_WB_W8iQ4oFHZX8DkcXQV_P53jY7KwCEwYBhgL/s1600/edge_effects.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="572" data-original-width="742" height="307" src="https://4.bp.blogspot.com/-q3Jxz-dQVbA/XHKuLaXOW8I/AAAAAAAAFJ0/s9R_WB_W8iQ4oFHZX8DkcXQV_P53jY7KwCEwYBhgL/s400/edge_effects.jpg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><b>Figure 1.</b> Taking a cartoon version of a tumor (upper left) and a prescribed (invented) evolutionary game to go with it (just below, left-most equation), we can transform the game to take into consideration the relative opportunities to interact with different types based not just on frequency, but also on location. This yields a somewhat messier game matrix (right-most equation), but also lets you explore how the dynamics will change with changing neighborhood size (lower left).</td></tr>
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Andriy had just come off an exciting paper where he and colleagues explored an experimental model of breast cancer dynamics and showed that <a href="https://www.nature.com/articles/nature13556" target="_blank">'non-cell autonomous effects' (i.e. interactions) could change the overall composition of a tumor</a>. In this paper, they used different fluorescent labels to track proportions of different types over time. This led our discussions to how we might be able to directly measure a game over time (there is a nice series of more technical blog posts by Artem which you can find referenced in the most recent in the series: <a href="https://egtheory.wordpress.com/2019/02/16/python-game-assay/" target="_blank">here</a>).<br />
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In addition to being ABLE to measure a game, we wanted to start with a situation which we thought would have a decent chance of also being interesting. We had just come off a project studying the <a href="https://www.nature.com/articles/s41598-017-00791-8" target="_blank">changes in drug sensitivity over time of ALK mutated non-small cell lung cancer</a>, and so had evolved TKI-resistant lung cancer cells lying around. We hypothesized (as most were at the time) that there would be a *cost* to the resistance, which we might be able to take advantage of in the form of a measurable *trade-off*. A quick and dirty first experiment that Jeff ran gave us some hope that this might be true (Figure 2).<br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://2.bp.blogspot.com/-_sBIF91coUA/XHK3md1TgbI/AAAAAAAAFKA/mkJVnaJvp70rNdtkzzVAZyhS2Tdl7Mj8gCLcBGAs/s1600/the_cross.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="768" data-original-width="1024" height="480" src="https://2.bp.blogspot.com/-_sBIF91coUA/XHK3md1TgbI/AAAAAAAAFKA/mkJVnaJvp70rNdtkzzVAZyhS2Tdl7Mj8gCLcBGAs/s640/the_cross.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><b>Figure 2.</b> We plot drug (Alectinib) dose on the x-axis, and optical density on the y-axis for three cell types, evolved Alectinib resistant H3122 (blue), drug sensitive H3122 (red) and Cancer Associated Fibroblasts (grey). We see that the higher fitness of naive cells at low drug dose switches to a lower fitness (relative to the resistant) at high dose.</td></tr>
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We termed this result 'the cross' as our proxy for fitness (in this case optical density) *crossed* at a specific drug dose. That is, after a specific dose, the most fit cell type changed from the wild type to the resistant, but critically, at low doses, we saw that the wild type was higher fitness than the resistant -- confirming our hypothesis (and bias) that at low drug concentration, being resistant *carried a cost* of lower growth rate. Interestingly, when we played this out in a different experimental system (measuring growth rate in a time lapse microscope), this fitness cost disappeared (see right-most two sub-figures in Figure 3). I sometimes wonder if we would have continued with the experiment if we hadn't see this cost up front... <br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://1.bp.blogspot.com/-SF6BDIa72jE/XHbgH-CezAI/AAAAAAAAFLo/1Cje5OcY11YvtBOF_s88KTXswpfPXU_uQCLcBGAs/s1600/fig1NEEALKEGT.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="539" data-original-width="1539" height="224" src="https://1.bp.blogspot.com/-SF6BDIa72jE/XHbgH-CezAI/AAAAAAAAFLo/1Cje5OcY11YvtBOF_s88KTXswpfPXU_uQCLcBGAs/s640/fig1NEEALKEGT.jpg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><b>Figure 3.</b> Naive H3122 and evolved resistant to Alectinib (erAlec) cells grown in monoculture compared across four experimental conditions.</td></tr>
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Anyways, by the time we measured the growth rates in Figure 3, Artem had already come up with a clever way to directly measure a game (which we assume to be a linear matrix game). By plating sensitive and resistant cells in a variety of proportions (ranging from 0:100 to 100:0) and measuring growth rate (proxy for fitness), then fitting a line, the intercepts would be the entries to the payoff matrix! Figure 4 is the <a href="https://www.nature.com/articles/s41559-018-0768-z" target="_blank">figure from the paper</a> showing 4 different experimental conditions (with/without Alectinib and with/without Cancer Associated Fibroblasts (CAFs)). It is a little busy, but it has ALL the info. The inset plots are example shots of how we measured growth rate, by figuring out the total area of each (minor y-axis) red and green (sensitive and resistant) frequently over time (minor x-axis). Each of the individual proportion conditions are then plotted on the major axes with the opacity of the point telling what plated proportion were parental.<br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://3.bp.blogspot.com/-j7T5nNwxvIY/XHK-lUpI2KI/AAAAAAAAFKU/JelUasY1RG8mIH-p27LHXa-DCGj_3I7ewCLcBGAs/s1600/isemph2018.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="768" data-original-width="1024" height="480" src="https://3.bp.blogspot.com/-j7T5nNwxvIY/XHK-lUpI2KI/AAAAAAAAFKU/JelUasY1RG8mIH-p27LHXa-DCGj_3I7ewCLcBGAs/s640/isemph2018.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><b>Figure 4</b>. ALL THE DATA. Each experimental condition is a different color/shape as represented by the labelled convex hulls. Opacity is plating proportion of parental (1-resistant). The inset show how we obtained the growth rates, with example data points shown (green and red lines).</td></tr>
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<br />To explain how we get from here to a familiar appearing game notation, I'll 'blow up' one of the datasets (the Alectinib treated one - blue squares - in the far left convex hull).<br />
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<tr><td style="text-align: center;"><a href="https://3.bp.blogspot.com/-gQS8gI2KckU/XHXY1lKB_PI/AAAAAAAAFK4/u-undhj0lHwt5cSIUhljmXNpseH7Ijp2gCLcBGAs/s1600/blog_EGT.001.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="768" data-original-width="1024" height="480" src="https://3.bp.blogspot.com/-gQS8gI2KckU/XHXY1lKB_PI/AAAAAAAAFK4/u-undhj0lHwt5cSIUhljmXNpseH7Ijp2gCLcBGAs/s640/blog_EGT.001.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><b>Figure 5.</b> Blowing up just the Alectinib treated cells, we can see how each data point in Figure 4 corresponds to a pair of points in the left sub-figure here (and the x/y axis in Figure 4). </td></tr>
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All the data points here are paired (80:20 etc), and the pairs (vertically aligned) match up to a single point in the previous figure. You can see here that we then perform a linear fit, which we can now use the intercepts to derive the payoff matrix elements, like this:</div>
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<tr><td style="text-align: center;"><a href="https://4.bp.blogspot.com/-feuHKiy1tj0/XHXY1lsHphI/AAAAAAAAFLI/WQgjNJH8CGoMF0IigMShbiqQiSCx403QQCEwYBhgL/s1600/blog_EGT.002.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="768" data-original-width="1024" height="480" src="https://4.bp.blogspot.com/-feuHKiy1tj0/XHXY1lsHphI/AAAAAAAAFLI/WQgjNJH8CGoMF0IigMShbiqQiSCx403QQCEwYBhgL/s640/blog_EGT.002.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><b>Figure 6. </b> We can now see how the intercepts of these lines forms the entries into the familiar payoff matrix.</td></tr>
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Now we have a familiar payoff matrix!! We can then plot the payoff matrix in a game space (which <a href="https://egtheory.wordpress.com/2012/03/14/uv-space/" target="_blank">Artem nicely explains on his blog here</a>), and compare the experimental conditions -- and we see that the DMSO+CAF game is qualitatively different than the others (Figure 7). A cool result on its own. The canonical games represented are 'Leader' and 'Deadlock' - games which have not received much (any) attention to date in the oncology-EGT literature.</div>
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<tr><td style="text-align: center;"><a href="https://1.bp.blogspot.com/-g29e9Dl9g5g/XHXY2d20eUI/AAAAAAAAFLE/7PJFe8AS9LYfNN7fBVAI9rsH7yja60_NACEwYBhgL/s1600/blog_EGT.004.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="768" data-original-width="1024" height="480" src="https://1.bp.blogspot.com/-g29e9Dl9g5g/XHXY2d20eUI/AAAAAAAAFLE/7PJFe8AS9LYfNN7fBVAI9rsH7yja60_NACEwYBhgL/s640/blog_EGT.004.jpeg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><b>Figure 7</b> - some future directions/food for thought...</td></tr>
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Another fun thing we noticed is that it appears that each perturbation (drug/CAF) shift the game in a particular way (see cartoon versions of vectors representing these changes in the game in red and blue). We haven't fully explored this yet, but it is thought provoking...</div>
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Taken together, we have a new assay, which we hope more folks use to measure a catalogue of games played by other cancer types, and a new way to perturb evolution -- by treating the game instead of the player. The central focus of our lab is exactly this: to get control of/take advantage of the evolutionary process on the way to resistance. While this assay, and the resulting measured game, takes place over a short time-scale (5 days), it does give some insight into some new ways to pick/bias the winner in a low complexity game. We are hoping to extend the assay to more strategies to better represent more complex tumors, and also to think about longer timescales -- this will require not just new experimental technique, but some new theory as well. Further, this theory fits in well with the work on collateral sensitivity which we <a href="http://cancerconnector.blogspot.com/2019/01/antibiotic-collateral-sensitivity-is.html" target="_blank">recently reported in E. coli</a> with <a href="https://twitter.com/d4n__?lang=en" target="_blank">Dan Nichol</a> as lead author... though that work is the opposite end of the time-scale spectrum (relatively very long time scales - actually <a href="https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004493" target="_blank">infinite time in the theoretical work</a>, but <a href="https://www.nature.com/articles/s41467-018-08098-6" target="_blank">ten-days in the experimental work</a>, which for bacteria is MUCH longer than the 5 days in cancer cells here).</div>
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Anyways, the work continues! For more information on measuring games, check out the full paper: </div>
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<a href="https://www.nature.com/articles/s41559-018-0768-z" target="_blank">Fibroblasts and alectinib switch the evolutionary games played by non-small cell lung cancer</a> </div>
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published last week in the journal <a href="https://www.nature.com/natecolevol/" target="_blank">Nature Ecology and Evolution</a>, along with an associated editorial which describes a bit more about <a href="https://www.nature.com/articles/s41559-018-0785-y" target="_blank">evolutionary therapy</a>.</div>
Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com103tag:blogger.com,1999:blog-5975631477306646569.post-72938963387568625292019-01-30T12:21:00.004-08:002019-01-30T12:21:40.342-08:00Antibiotic collateral sensitivity is contingent on the repeatability of evolutionYou know those moments when you read a paper and your head just explodes? It's happened a few times to me in my life, and when it does the whole moment gets seared into my head. One of those moments happened on a spring day in Oxford. I was eating a bap I had bought at the Taylor's expansion (1) by the old <a href="https://www.maths.ox.ac.uk/groups/mathematical-biology" target="_blank">math's institute</a> on Little Clarendon, sitting by a war monument (2). Here:<br />
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<a href="https://3.bp.blogspot.com/-uu8bbEE6sSM/XFG6_5wT3AI/AAAAAAAAFEw/tRNbwqe6sWs-XASOgDTvZAltr8vbcahqwCLcBGAs/s1600/Bap.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1461" data-original-width="1600" height="365" src="https://3.bp.blogspot.com/-uu8bbEE6sSM/XFG6_5wT3AI/AAAAAAAAFEw/tRNbwqe6sWs-XASOgDTvZAltr8vbcahqwCLcBGAs/s400/Bap.png" width="400" /></a></div>
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<span id="goog_483215355"></span><span id="goog_483215356"></span>What I read was a paper from Dan Weinreich called <a href="http://science.sciencemag.org/content/312/5770/111.long" target="_blank">Darwinian Evolution Can Follow Only Very Few Mutational Paths to Fitter Proteins</a>. In this paper they engineering 2^5 = 32 strains of E. coli with 5 different basepair substitutions in a gene that encodes resistance to a certain kind of antibiotics. Then they simply measured the fitness of each of the strains, and constructed a hypercube, like <a href="https://en.wikipedia.org/wiki/Sewall_Wright" target="_blank">Sewall Wright</a> suggested first in 1932 (before anyone knew anything about genes! he just called them allelomorphs). If you make a 5-cube, like Wright sketched:<br />
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<a href="https://3.bp.blogspot.com/-e0tOZ5Lq5Tc/XFG8_fTmEQI/AAAAAAAAFE8/2OQbnwMIiGQXV8TIq1UQcLJBU33eMovAwCLcBGAs/s1600/5cube.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="183" data-original-width="347" height="210" src="https://3.bp.blogspot.com/-e0tOZ5Lq5Tc/XFG8_fTmEQI/AAAAAAAAFE8/2OQbnwMIiGQXV8TIq1UQcLJBU33eMovAwCLcBGAs/s400/5cube.png" width="400" /></a></div>
If every mutation gives you a fitness boost (as the literature showed they individually do) you should be able to get from wildtype (far left) to 'fully mutated' (far right) in 120 different ways. This would be something called a Mt. Fuji landscape, with one peak. All paths go 'up' - which is essentially the null hypothesis that this paper was testing. At the time, I hadn't thought much about any other possible concepts -- being taught from the clinical oncology more-mutations-is-bad canon -- the more mutations a cancer has, the worse (more fit) it is. (n.b. we can talk a lot about different 'kinds' of mutations - like <a href="http://cancerres.aacrjournals.org/content/early/2017/08/23/0008-5472.CAN-15-3283-T.short" target="_blank">passengers vs drivers</a>, some other time, and also there's the whole fact that mutational effects are likely context dependent -- but we'll get to that later). Anyways, this is where the hair on fire part came for me. After they measure all the corner's fitnesses, they found that <b>only 18 paths </b>existed to get from left to right - and showed this figure:<br />
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<a href="https://4.bp.blogspot.com/-d_sBhH_CqoM/XFG_3MVb0-I/AAAAAAAAFFI/0SWKHSZiXcQKVppPo8lJ_qGNn7ic2RB8wCLcBGAs/s1600/mindblow.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="332" data-original-width="483" height="436" src="https://4.bp.blogspot.com/-d_sBhH_CqoM/XFG_3MVb0-I/AAAAAAAAFFI/0SWKHSZiXcQKVppPo8lJ_qGNn7ic2RB8wCLcBGAs/s640/mindblow.png" width="640" /></a></div>
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There I sat, with my hair on fire, and a bap dangling out of my mouth. My world had changed forever. What they showed here was empirical proof that the theoretical possibility that some combinations of mutations (even if they are individually beneficial) can be deleterious! That means to two beneficial mutations could add up to a fitness penalty. This is something called epistasis (actually it's a special type called reciprocal sign epistasis, <a href="https://en.wikipedia.org/wiki/Epistasis" target="_blank">which you can read more about here</a>). While this was known to other members of the scientific community, it was not to me, and this set of a bunch of thinking that led to the idea that <a href="https://twitter.com/d4n__?lang=en" target="_blank">Dan Nichol</a> and I (and friends) explored in our 2015 paper <a href="https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004493" target="_blank">Steering Evolution with Sequential Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance</a>. Here, we used a set of <a href="https://en.wikipedia.org/wiki/Fitness_landscape" target="_blank">fitness landscapes</a> that were measured in a similar way to the above description, but for a lot of drugs, that were published by <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122283" target="_blank">Mira et al.</a> together with a mathematical model that Dan came up with.<br />
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This model is a time homogeneous absorbing Markov chain model of evolution that requires assumptions about the population all being on a single corner of the hypercube at any given time (often referred to as Strong Selection Weak Mutation (SSWM)). Dan then calculated the probability of any given mutation from corner <i>i</i> to corner <i>j</i> ($P_{ij}$) based on changes in fitness from one corner to the next, like this:<br />
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<a href="https://1.bp.blogspot.com/-cD_sSFc3QQo/XFHeIReK7EI/AAAAAAAAFFU/kYdcli17y4kLXhtceNlGr9NZrdoeN6nmQCLcBGAs/s1600/markov.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="592" data-original-width="1600" height="235" src="https://1.bp.blogspot.com/-cD_sSFc3QQo/XFHeIReK7EI/AAAAAAAAFFU/kYdcli17y4kLXhtceNlGr9NZrdoeN6nmQCLcBGAs/s640/markov.png" width="640" /></a></div>
Using this, and some matrix multiplication, we came up with the cute idea that <b>evolution doesn't (necessarily) commute</b> - that is, the evolutionary outcome could be quite different if you applied drug A and then B, as opposed to drug B and then A.<br />
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Given that many of the landscapes have more than one peak, there are also a number of situations in which evolution has to make a choice... it can go uphill in more than one direction. You can visualize this like a series of hills in which the population is 'walking up' them. Given that the population can't 'see ahead' but can only make decisions about going 'up' instead of 'down', you can imagine that a population could easily evolve to an optima that is not globally optimal. You can see an example below (in panel (a)) where a strain starting at the yellow circle would move uphill to the blue triangle and then have to choose 'left' or 'right'. (obviously the geometry of this is wrong, but it is the best we can do as humans to visualize)<br />
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<a href="https://2.bp.blogspot.com/-WwnMxk_d2ao/XFHhl1mBrkI/AAAAAAAAFFs/OuBYvz3vZhsRMcLxql7tiPqm84qJZUWLwCLcBGAs/s1600/hills.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="928" data-original-width="1600" height="369" src="https://2.bp.blogspot.com/-WwnMxk_d2ao/XFHhl1mBrkI/AAAAAAAAFFs/OuBYvz3vZhsRMcLxql7tiPqm84qJZUWLwCLcBGAs/s640/hills.png" width="640" /></a></div>
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A few things become clear - one is that the fitness through time would be different (as you travel different trajectories even going 'up', it could be different along the way), and the other is that the end fitnesses will also differ (if you believe that evolution will EVER find a peak, which <a href="https://twitter.com/kaznatcheev?lang=en" target="_blank">Artem</a> doesn't -- more here in his <a href="https://www.biorxiv.org/content/10.1101/187682v3" target="_blank">bioRxiv preprint</a> or on his <a href="https://egtheory.wordpress.com/" target="_blank">blog</a>). AND if you then consider the end position, and how it relates to fitness IN ANOTHER LANDSCAPE (see panel (b), above for a visual representation), you have a situation where the outcome of drug sequencing can change with the evolutionary 'decision' - or in our jargon <b>collateral sensitivity changing depending on evolutionary contingencies</b>.<br />
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This led us to want to <b>do the experiments</b>. So, we continued our collaboration with <a href="http://case.edu/med/id/faculty/bonomo_robert.html" target="_blank">Robert Bonomo </a>at the Cleveland VA hospital, and performed 60 replicates of the same experiment - 60 what we now term <b>evolutionary replicates</b>. Just showing the first 12, we see evidence for the different trajectories encoding different fitnesses through time, here:<br />
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<a href="https://1.bp.blogspot.com/-Z-sIq6oMqyA/XFHjvxDpURI/AAAAAAAAFF4/clPtAtavS-UeYrSws4pduy3N7Mj8je6TQCLcBGAs/s1600/tracjectories.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="918" data-original-width="1318" height="443" src="https://1.bp.blogspot.com/-Z-sIq6oMqyA/XFHjvxDpURI/AAAAAAAAFF4/clPtAtavS-UeYrSws4pduy3N7Mj8je6TQCLcBGAs/s640/tracjectories.png" width="640" /></a></div>
Out of curiosity, we wondered how common it would be to get a different answer to the question: If I give one drug (drug A) and then another (drug B), how much variation could I see in collateral response. To answer this, we used another version of the mathematical model from our first paper (which you can <a href="https://github.com/Daniel-Nichol/CollateralSensitivityRepeatability" target="_blank">download here</a>, along with the data needed to redo our analysis). It turns out that there is <b>wide</b> variability in collateral sensitivity (according to our mathematical model), so much that any one repeat of an evolution experiment could give you an opposite answer (could reveal collateral sensitivity) when the very next one could reveal cross-resistance.<br />
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<a href="https://4.bp.blogspot.com/-ps6cIDjUuF0/XFHmd8TZImI/AAAAAAAAFGE/KLExKte4kloiLG9iWXxVkn4JIhqg3IP8wCLcBGAs/s1600/modelresults.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1600" data-original-width="1556" height="640" src="https://4.bp.blogspot.com/-ps6cIDjUuF0/XFHmd8TZImI/AAAAAAAAFGE/KLExKte4kloiLG9iWXxVkn4JIhqg3IP8wCLcBGAs/s640/modelresults.png" width="620" /></a></div>
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This is sorta bad news... but to try to find the bright side, we propose using a new metric, which we call Collateral Sensitivity Likelihood (CSL), which is a measure of a sequence of drugs providing <b>any</b> collateral sensitivity at all. This would make for safer recommendations -- where what you want is some method for clinicians to rationally choose a drug ordering that has a high probability of being better (or the opposite, a low probability of the drugs inducing resistance to one another).<br />
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So - from hair on fire to 5 years of research later, we finally were able to get this story out there. We published it last week, and you can read the whole paper, which is open access, here: <a href="https://www.nature.com/articles/s41467-018-08098-6" target="_blank">Antibiotic collateral sensitivity is contingent on the repeatability of evolution</a>. Lots more details and figures are available there...<br />
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In addition to making the code and phenotype data available (in the embedded github repo link), we also performed whole genome sequencing on 12 of the evolutionary replicates, and we uploaded those data to the NCBI Sequence Read Archive (SRA), and they are freely available through accession code PRJNA515080, or <a href="https://www.ncbi.nlm.nih.gov/bioproject/PRJNA515080/" target="_blank">through this link</a>. So, hurray for #openscience - we'd love any secondary analyses or ideas for future projects. Lots to think about.<br />
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If this research interests you, please check out our <a href="https://www.lerner.ccf.org/thor/scott/lab/" target="_blank">lab page</a> to see what else we're up to. We're trying to apply evolutionary thinking, mathematical models and experimental evolution to cancer and pathogens to ease suffering.Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com38tag:blogger.com,1999:blog-5975631477306646569.post-4723167100690105982018-06-29T11:02:00.002-07:002018-06-29T17:53:00.353-07:00Thinking, working, racing and sweating -- Velosano 5: 100% for the cure.<div style="background-color: white; color: #222222; font-family: sans-serif; font-size: 13px;">
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.</div>
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Like last year, I am riding in the <a data-saferedirecturl="https://www.google.com/url?q=http://ccf.convio.net/goto/JakeScottVelosano&source=gmail&ust=1530292788691000&usg=AFQjCNG2kQmkr9xfkG9EKkkyCyAlj7awpg" href="http://ccf.convio.net/goto/JakeScottVelosano" style="color: #1155cc;" target="_blank">Velosano cancer charity bike ride</a>. I will be riding 200 miles over two days in support of important, innovative research done here in Cleveland under the auspices of the <a data-saferedirecturl="https://www.google.com/url?q=http://www.ccf.org&source=gmail&ust=1530292788691000&usg=AFQjCNE2VKJYON9UC_qI-N7akRThKR_Tug" href="http://www.ccf.org/" style="color: #1155cc;" target="_blank">Cleveland Clinic</a> and the <a data-saferedirecturl="https://www.google.com/url?q=https://case.edu/cancer/&source=gmail&ust=1530292788691000&usg=AFQjCNE8iOtn9H_px2StvTL_QY7ibanH5Q" href="https://case.edu/cancer/" style="color: #1155cc;" target="_blank">Case Comprehensive Cancer Center</a>. 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.</div>
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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.</div>
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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, <a href="https://www.sciencedirect.com/science/article/pii/S0304419X1730029X" target="_blank">responds dynamically to external stresses... by EVOLVING</a>. Therefore, the focus of our lab (<a data-saferedirecturl="https://www.google.com/url?q=https://www.lerner.ccf.org/thor/scott/lab/&source=gmail&ust=1530292788691000&usg=AFQjCNGyhlJk4XicFHZxyE69qig6FcwWoA" href="https://www.lerner.ccf.org/thor/scott/lab/" style="color: #1155cc;" target="_blank">which you can find out more about here</a>) 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.</div>
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<tr><td class="tr-caption" style="text-align: center;">Example results of ODEs describing the growth of a well-mixed population limited by nutrients and killed by drugs.</td></tr>
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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 <a href="https://www.nature.com/articles/nprot.2013.021" target="_blank">'morbidostat' that was published previously</a>, and also are using some open source parts from the <a href="https://www.nature.com/articles/nbt.4151" target="_blank">eVOLVER project</a> - but the application to cancer is brand new, and making the jump from bugs/yeast to cancer carries a lot of difficult bits.</div>
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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 <a data-saferedirecturl="https://www.google.com/url?q=https://www.lerner.ccf.org/thor/scott/lab/research/&source=gmail&ust=1530292788691000&usg=AFQjCNH9gCOBZcDu9qWkkKQkTftsmjWFGw" href="https://www.lerner.ccf.org/thor/scott/lab/research/" style="color: #1155cc;" target="_blank">research in progress page here</a>.</div>
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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. </div>
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<tr><td class="tr-caption" style="text-align: center;">holy moly - it's logistic growth!!! (optical density vs. time E. coli growth in media, no antibiotics, well done Nikhil and team)</td></tr>
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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 <a href="http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004493" target="_blank">steer evolution</a>, <a href="https://link.springer.com/article/10.1007%2Fs11538-018-0434-2" target="_blank">optimize the timing of therapy</a>, and test <a href="https://www.biorxiv.org/content/early/2017/10/11/185892" target="_blank">how repeatable evolution really is, and how this maps to secondary drug sensitivities</a>.</div>
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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.</div>
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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!</div>
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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. </div>
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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.</div>
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To donate to my ride, and to support cutting edge research like this, <a href="http://ccf.convio.net/site/TR?px=3413355&fr_id=1722&pg=personal" target="_blank">please follow this link, and press the green DONATE button</a>.</div>
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Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com288tag:blogger.com,1999:blog-5975631477306646569.post-2691463708404680522018-04-02T06:24:00.004-07:002018-04-02T06:30:54.272-07:00Endogenous miRNA sponges mediate the generation of oscillatory dynamics for a non-coding RNA networkHello 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.<br />
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Just a quick note, as <a class="g-profile" href="https://plus.google.com/109354365673315960743" target="_blank">+Andrew Dhawan</a> has covered most of it. Just wanted to share some excitement about a new preprint from our group which you can find here:<br />
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<a href="https://www.biorxiv.org/content/early/2018/03/31/292029">https://www.biorxiv.org/content/early/2018/03/31/292029</a><br />
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A full 'Story behind the preprint' to be found on Andrew's blog: <a href="https://andrewdhawan.wordpress.com/2018/04/01/the-story-behind-the-preprint-circrna-leading-to-oscillations/" target="_blank">Tabula Rasa</a><br />
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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!<br />
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<iframe allowtransparency="true" frameborder="no" height="750" src="//storify.com/CancerConnector/endogenous/embed?border=false" width="100%"></iframe><script src="//storify.com/CancerConnector/endogenous.js?border=false"></script><noscript>[<a href="//storify.com/CancerConnector/endogenous" target="_blank">View the story "Endogenous miRNA sponges mediate the generation of oscillatory dynamics for a non-coding RNA network" on Storify</a>]</noscript></div>
Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com20tag:blogger.com,1999:blog-5975631477306646569.post-64607638541591033132018-01-15T16:37:00.001-08:002018-01-15T16:37:55.968-08:00New 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.<br />
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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 <a href="http://www.lerner.ccf.org/thor/scott/lab/" target="_blank">see it here</a> - I'd love feedback... just leave in comments or email me...</div>
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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 <a href="https://api.altmetric.com/embeds.html" target="_blank">how to do it here</a> (I don't speak html, and it was really easy), and you get this nice effect:</div>
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Which is the article I wrote the <a href="https://cancerconnector.blogspot.com/2017/12/new-publication-just-in-time-for-new.html" target="_blank">'story behind the paper' for the last post</a>. 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. </div>
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On Monday, Jan 15, <a href="https://twitter.com/stevenstrogatz?ref_src=twsrc%5Etfw">@stevenstrogatz</a> will answer your questions on his recent eLife paper, and the applications of mathematics more broadly, in a <a href="https://twitter.com/hashtag/RedditAMA?src=hash&ref_src=twsrc%5Etfw">#RedditAMA</a> <a href="https://t.co/aTnNGpj3Yi">https://t.co/aTnNGpj3Yi</a> <a href="https://t.co/zbz5S2PJcy">pic.twitter.com/zbz5S2PJcy</a></div>
— eLife - the journal (@eLife) <a href="https://twitter.com/eLife/status/951838891203538944?ref_src=twsrc%5Etfw">January 12, 2018</a></blockquote>
Murray (the dog) didn't show up, but we did have a <a href="https://www.reddit.com/r/science/comments/7qj95q/science_ama_series_im_steven_strogatz_a_professor/" target="_blank">spirited discussion with a bunch of folks</a> 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 <a class="g-profile" href="https://plus.google.com/101780559173703781847" target="_blank">+Artem Kaznatcheev</a> or <a class="g-profile" href="https://plus.google.com/117744729500153177832" target="_blank">+Dan Nichol</a> 's papers are first (ooh - or actually I'd bet Nara's is...)<br />
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Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com45tag:blogger.com,1999:blog-5975631477306646569.post-26672044683072764272017-12-29T17:34:00.000-08:002017-12-29T17:34:39.198-08:00New 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 <a href="http://cancerconnector.blogspot.com/2015/10/some-fun-with-evolutionary-graph-theory.html">earlier posts on evolutionary graph theory</a> and he mentioned there might be some fun to be had with the more 'math-y' aspects of the problem.<br />
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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.<br />
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<tr><td class="tr-caption" style="text-align: center;">An except from a much more complete, and fun to read document from Bertrand....</td></tr>
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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.<br />
I ended up <a href="http://cancerconnector.blogspot.com/2016/07/new-post-and-looking-for-postdoc.html">making the move to Cleveland Clinic</a>, and in the mean time Bertrand and Steven continued to chew on this problem and we published the first paper of the collaboration <a href="https://journals.aps.org/pre/abstract/10.1103/PhysRevE.96.012313">Takeover times for a simple model of network infection, in Physical Review E</a>. 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 <a href="https://en.wikipedia.org/wiki/Gumbel_distribution">Gumbel distribution</a>, which has been known to masquerade as log-normal.<br />
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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).<br />
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I gave a short talk the next day, which was <a href="http://events.cornell.edu/event/cam_colloquium_jacob_scott_md_cleveland_clinic_-_understanding_the_evolution_of_resistance_a_comprehensive_and_integrated_mathematical_and_experimental_research_program">live streamed and can be seen here</a> 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:<br />
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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...<br />
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and if you want to know WHY?? you'll have to go read the paper that just came out: <a href="https://elifesciences.org/articles/30212">Evolutionary dynamics of incubation periods</a> in eLife (aside: the review and publication experience was really stellar - 5 stars).<br />
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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.<br />
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</style>Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com6tag:blogger.com,1999:blog-5975631477306646569.post-82596834677531671882017-08-27T05:29:00.001-07:002017-08-27T05:30:54.596-07:00A return to blogging and two new papers: Experimental measurement of evolutionary games and Evolutionary instability in collateral sensitivity networksWell, 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.<br />
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Before then however, I'm excited to highlight that the <a href="http://cancerconnector.blogspot.com/2016/07/new-post-and-looking-for-postdoc.html">two posters that I highlighted on this blog</a> just as I moved, are now full manuscripts. The first, led by <a class="g-profile" href="https://plus.google.com/109354365673315960743" target="_blank">+Andrew Dhawan</a> studies how drug sensitivities change over the course of treatment, and even during drug holidays.<br />
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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.<br />
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<a href="http://journals.lww.com/oncology-times/Citation/2017/08100/Evading_Therapeutic_Resistance_Through_Collateral.6.aspx">http://journals.lww.com/oncology-times/Citation/2017/08100/Evading_Therapeutic_Resistance_Through_Collateral.6.aspx</a><br />
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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:<br />
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<a href="https://www.nature.com/articles/s41598-017-00791-8">https://www.nature.com/articles/s41598-017-00791-8</a><br />
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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.<br />
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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 <a class="g-profile" href="https://plus.google.com/101780559173703781847" target="_blank">+Artem Kaznatcheev</a> . 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 <a class="g-profile" href="https://plus.google.com/108880714002171992138" target="_blank">+David Basanta</a>. David and <a class="g-profile" href="https://plus.google.com/109422830104234532994" target="_blank">+Alexander Anderson</a> and <a class="g-profile" href="https://plus.google.com/101780559173703781847" target="_blank">+Artem Kaznatcheev</a> and I have now published something like 10 total papers between us on cancer and game theory ranging from studying how <a href="http://www.nature.com/bjc/journal/v106/n1/full/bjc2011517a.html">hormone therapy timing should work in prostate cancer</a> to how we should think about how our <a href="http://www.nature.com/bjc/journal/v116/n6/full/bjc20175a.html">drug scheduling affects tumor composition </a> and even more abstract ideas like how <a href="http://rsif.royalsocietypublishing.org/content/12/108/20150154.full">local cell topology affects evolutionary stable states and dynamics</a>.<br />
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<tr><td class="tr-caption" style="text-align: center;">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)</td></tr>
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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, <a class="g-profile" href="https://plus.google.com/101780559173703781847" target="_blank">+Artem Kaznatcheev</a> 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!<br />
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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.<br />
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Here you can find "Cancer associated fibroblasts and alectinib switch the evolutionary games that non-small cell lung cancer plays"<br />
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<a href="http://www.biorxiv.org/content/early/2017/08/21/179259">http://www.biorxiv.org/content/early/2017/08/21/179259</a><br />
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OK, see you soon! Happy reading.Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com110tag:blogger.com,1999:blog-5975631477306646569.post-4038257179079893312017-01-25T17:31:00.001-08:002017-01-25T17:31:19.807-08:00Society for experimental biology meeting, Oxford, September 2016Having 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.<br />
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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.<br />
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For nitty gritty details of the meeting, you can still see the speaker list and abstracts that were presented here: <a href="http://www.sebiology.org/events/event/the-tissue-issue">http://www.sebiology.org/events/event/the-tissue-issue</a>.<br />
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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.<br />
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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.<br />
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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.<br />
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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.<br />
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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!<br />
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We also had some great tweeting going on, which you can see in this storify: <a href="https://storify.com/SEBiology/seb-2016-cell-symposium">https://storify.com/SEBiology/seb-2016-cell-symposium</a>Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com4tag:blogger.com,1999:blog-5975631477306646569.post-62328445079344240172016-07-10T15:00:00.001-07:002016-07-10T15:00:50.404-07:00A big move and a new research group. Join us!My decision to leave the <a href="http://labpages.moffitt.org/imo/">IMO</a> and <a href="https://moffitt.org/tests-treatments/treatments/radiation-therapy/?utm_source=Socius&utm_medium=CPC&utm_campaign=Socius&gclid=Cj0KEQjw5Ie8BRCJ9fHlr_bH24cBEiQAkoDQcZulBGmBIZRYFH09EwKpuDNg0gkrHhEEPhARlFABk1caAlkZ8P8HAQ">Moffitt Radiation Oncology</a> 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 <a href="http://my.clevelandclinic.org/services/cancer/departments-centers/radiation-oncology-department">Cleveland Clinic</a> doing exactly what I want to do. They have hired me be a physician-scientist, to start a research group in the department of <a href="http://my.clevelandclinic.org/services/cancer/departments-centers/thor">Translational Hematology and Oncology Research</a> (yes, they call it THOR - how awesome) studying the evolution of resistance, and to continue my work as a <a href="https://moffitt.org/cancers/sarcoma/">sarcoma radiation oncologist</a>.<br />
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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. <a class="g-profile" href="https://plus.google.com/101780559173703781847" target="_blank">+Artem Kaznatcheev</a> , a theoretical computer scientists and mathematician (who is also a prolific academic blogger - see <a href="https://egtheory.wordpress.com/">his blog TheEgg here</a>) will begin in the <a href="http://www.cs.ox.ac.uk/">department of Computer Science</a> this Michelmas with <a href="http://www.cs.ox.ac.uk/peter.jeavons/">Peter Jeavons</a>, <a href="https://cancerevo.wordpress.com/author/dbasanta/">David Basanta</a> 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 <a href="http://www.ncbi.nlm.nih.gov/pubmed/26040596">spatial structure into evolutionary game theory</a> 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.<br />
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and more recently using <a href="https://egtheory.wordpress.com/2016/05/07/population-dynamics-tlm/">time lapse microscopy to quantify competition dynamics in vitro</a> - something I'm presenting a poster on at <a href="http://www.ecmtb2016.org/">ECMTB2016</a> later this week.<br />
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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 <a class="g-profile" href="https://plus.google.com/117744729500153177832" target="_blank">+Dan Nichol</a> doing his DPhil with Pete Jeavons and <a class="g-profile" href="https://plus.google.com/109422830104234532994" target="_blank">+Alexander Anderson</a> - which we kicked off with <a href="http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1004493">Dan's evolutionary steering paper</a>.<br />
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I'm also very luck to have <a class="g-profile" href="https://plus.google.com/109354365673315960743" target="_blank">+Andrew Dhawan</a> joining, who will begin his DPhil in Oncology with <a href="http://www.oncology.ox.ac.uk/research/francesca-buffa">Francesca Buffa</a> and <a href="http://www.oncology.ox.ac.uk/research/adrian-harris">Adrian Harris</a>. Andrew's DPhil will be slightly more prescribed, it being under a <a href="http://www.cancercentre.ox.ac.uk/graduate-studies/dphil-studentships/">CRUK studentship</a>. 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.<br />
<br />
Andrew has spent this summer, since he finished medical school in Ontario, Canada at <a href="https://meds.queensu.ca/">Queen's University School of Medicine</a>, working with me and <a class="g-profile" href="https://plus.google.com/111336656050519689469" target="_blank">+Andriy Marusyk</a> on collateral sensitivity in non-small cell lung cancer. He is attending a summer school (sponsore by the <a href="http://www.cancerresearchuk.org/">Cancer Research UK</a> coincidentally) on <a href="https://registration.hinxton.wellcome.ac.uk/events/item.aspx?e=597">ecology and evolution in cancer</a> - annoying scheduled the same week as ECMTB. He'll be presenting the following poster there:<br />
<br />
<iframe frameborder="0" height="716" src="https://widgets.figshare.com/articles/3472421/embed?show_title=1" width="568"></iframe>
<br />
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.<br />
<br />
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.<br />
<br />
If you're coming to ECMTB, look me up!<br />
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<br />Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com5tag:blogger.com,1999:blog-5975631477306646569.post-32050862714979909982016-07-01T11:27:00.001-07:002016-07-01T11:45:23.665-07:00CourageLast night <a class="g-profile" href="https://plus.google.com/109422830104234532994" target="_blank">+Alexander Anderson</a> 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 <a href="http://labpages.moffitt.org/andersona/">IMO</a>, and <a href="http://www.moffitt.org/">Moffitt Cancer Center</a> in <a href="https://moffitt.org/tests-treatments/treatments/radiation-therapy/">Radiation Oncology</a> 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:<br />
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<a href="https://3.bp.blogspot.com/-5B6IpA27kqs/V3a6NKGZN3I/AAAAAAAADwA/pXwMUedmw1o8xiWx_g9NZ7zOUqayAt0XQCLcB/s1600/IMO_retro.001.jpeg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="480" src="https://3.bp.blogspot.com/-5B6IpA27kqs/V3a6NKGZN3I/AAAAAAAADwA/pXwMUedmw1o8xiWx_g9NZ7zOUqayAt0XQCLcB/s640/IMO_retro.001.jpeg" width="640" /></a></div>
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<br />
There were also some sad farewells<br />
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<blockquote class="twitter-tweet" data-partner="tweetdeck">
<div dir="ltr" lang="en">
Farwell my old friend, your passion for science, honesty & collaboration will be missed more than you can comprehend <a href="https://t.co/IgNDjrGr1y">pic.twitter.com/IgNDjrGr1y</a></div>
— Sandy Anderson (@ara_anderson) <a href="https://twitter.com/ara_anderson/status/748643652763852800">June 30, 2016</a></blockquote>
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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 <a class="g-profile" href="https://plus.google.com/109422830104234532994" target="_blank">+Alexander Anderson</a> and <a href="https://www.moffitt.org/research-science/researchers/robert-gatenby/">Bob Gatenby</a> the IMO, when I joined was about 5 people: the two fearless leaders and <a class="g-profile" href="https://plus.google.com/108880714002171992138" target="_blank">+David Basanta</a> , <a class="g-profile" href="https://plus.google.com/107991167434968510515" target="_blank">+Edward Flach</a> and <a class="g-profile" href="https://plus.google.com/118350635665840072616" target="_blank">+Kasia Rejniak</a>. 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 (<a href="http://physics.cancer.gov/">formerly PSOC, now PSON</a>) as well as the <a href="http://icbp.nci.nih.gov/">Integrative Cancer Biology Program</a>.<br />
<br />
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.<br />
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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 <a class="g-profile" href="https://plus.google.com/109422830104234532994" target="_blank">+Alexander Anderson</a> 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.<br />
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You can find the article here: https://moffitt.org/media/5161/momentum_vol31_scott.pdf<br />
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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 <a class="g-profile" href="https://plus.google.com/114088528681513501969" target="_blank">+Cleveland Clinic</a> - mine! Oh, and also that Cleveland Rocks...<br />
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Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com4tag:blogger.com,1999:blog-5975631477306646569.post-53442840138674176672016-06-16T06:33:00.001-07:002016-06-16T06:33:42.248-07:00The end of one road, and the beginning of another.One month ago I sat for my oral boards for final certification by the <a href="http://www.theabr.org/">American Board of Radiology</a>. 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.<br />
<br />
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).<br />
<br />
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.<br />
<br />
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...<br />
<br />
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.<br />
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<br />Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com6tag:blogger.com,1999:blog-5975631477306646569.post-23315475081402476552016-01-06T08:02:00.001-08:002016-01-06T08:02:56.229-08:00Rotating student: Jeff Peacock - working on evolution of resistance in ALKmut NSCLC using CRISPR<a class="g-profile" href="https://plus.google.com/111336656050519689469" target="_blank">+Andriy Marusyk</a> 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.<br />
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Also, here's Jeff:<br />
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<span style="mso-no-proof: yes;">Hello,<o:p></o:p></span></div>
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<span style="mso-no-proof: yes;">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 4<sup>th</sup>
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.<span style="mso-spacerun: yes;"> </span>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. <o:p></o:p></span></div>
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<span style="mso-no-proof: yes;">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 <i style="mso-bidi-font-style: normal;">Science </i>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. <o:p></o:p></span></div>
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<span style="mso-no-proof: yes;">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.<o:p></o:p></span></div>
<div class="MsoNormal">
<span style="mso-no-proof: yes;">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. <o:p></o:p></span></div>
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Jeff can be found on twitter at: <complete id="goog_25248983">@ggcancer898</complete></div>
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Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com6tag:blogger.com,1999:blog-5975631477306646569.post-14597081135105627312015-10-31T12:30:00.000-07:002015-10-31T12:39:26.301-07:00bioRxiv vs. arXivIf 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 <a href="http://arxiv.org/archive/q-bio">qBio section of the arXiv</a>. Me and some colleagues responded to the increase in utilisation of #preprint servers by <a href="http://cancerconnector.blogspot.com/2013/05/warburgs-lens-pre-print-discussion.html">making Warburg's Lens</a>, a blog inspired by <a href="http://haldanessieve.org/">Haldane's Sieve</a> to help aggregate mathematical oncology pre-prints, and allow for discussion. We've had a ton of success with <a href="http://mathematicaloncology.blogspot.com/">Warburg's Lens</a>, and it has <a href="http://cancerconnector.blogspot.com/2014/05/a-success-story-for-warburgs-lens.html">been helpful for many folks</a>. 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.<br />
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A couple years ago, Richard Sever contacted me about an upcoming project, the <a href="http://biorxiv.org/">bioRxiv</a>, and asked me to be an affiliate - which I eagerly accepted. It seemed the perfect way to <a href="http://cancerconnector.blogspot.com/2013/10/a-new-pre-print-server-for-biology.html">help convince my more open minded biological colleagues</a> - something to which there are <a href="http://cancerconnector.blogspot.com/2013/06/barrier-to-use-of-preprint-servers.html">still quite a few (unsubstantiated) barriers</a>.<br />
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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% - <a href="https://arxiv.org/help/stats/2014_by_area/index">TONS MORE info here</a>)<br />
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<a href="https://arxiv.org/help/stats/2014_by_area/newsubs.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="294" src="https://arxiv.org/help/stats/2014_by_area/newsubs.png" width="640" /></a></div>
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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:<br />
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<a href="https://pbs.twimg.com/media/CSk1XNzWoAEf-Hj.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="460" src="https://pbs.twimg.com/media/CSk1XNzWoAEf-Hj.png" width="640" /></a></div>
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Within just a year, more than half have been published! Good news. I'm hoping that my <a href="http://biorxiv.org/content/early/2015/10/26/029595">newest preprint</a> (which is also on <a href="http://mathematicaloncology.blogspot.com/2015/10/spatial-metrics-of-tumour-vascular.html">Warburgs Lens here</a>) joins the majority ASAP :)</div>
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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?</div>
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<br />Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com6tag:blogger.com,1999:blog-5975631477306646569.post-78152909731980968282015-10-22T19:47:00.000-07:002015-10-22T19:48:18.437-07:00Some fun with evolutionary graph theory - and application to cancer?<br />
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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: <a href="http://www.nature.com/nature/journal/v433/n7023/abs/nature03204.html">Evolutionary Dynamics on Graphs</a>. 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'.<br />
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<a href="http://www.nature.com/nature/journal/v433/n7023/images/nature03204-f3.2.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://www.nature.com/nature/journal/v433/n7023/images/nature03204-f3.2.jpg" height="320" width="301" /></a></div>
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A beautiful follow on paper by our friends at the Max Planck for evolutionary biology, led by <a class="g-profile" href="https://plus.google.com/108823374134411848421" target="_blank">+Arne Traulsen</a> 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: <a href="http://rspb.royalsocietypublishing.org/content/280/1762/20130211">The effect of population structure on the rate of evolution</a>.<br />
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Since reading these two papers, I have given a fair amount of thought to this problem, but have not come to any sensible conclusions. <a class="g-profile" href="https://plus.google.com/109477082719618458142" target="_blank">+Alex Fletcher</a> and <a class="g-profile" href="https://www.blogger.com/null" target="_blank">+David Basanta</a> 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: <a href="http://arxiv.org/abs/1504.03832">Almost all random graphs are amplifiers of selection for birth-death processes, but suppressors of selection for death-birth processes</a>) has sparked a lot of interesting thought and conversation.<br />
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Further, at the recent conference: <a href="http://cancerconnector.blogspot.com/2015/09/full-storification-of-cest15.html">Cancer Evolution Through Space and Time</a> 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 <a class="g-profile" href="https://plus.google.com/103095797184894290771" target="_blank">+Sudhir Manickavel</a> starting some work simulating evolution. Here's where our thinking is going:<br />
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Twitter crowdsource <a href="https://twitter.com/hashtag/graphtheory?src=hash">#graphtheory</a> problem. [assuming a Moran process] <a href="http://t.co/h5e6LLDasU">pic.twitter.com/h5e6LLDasU</a></div>
— Jacob G Scott (@CancerConnector) <a href="https://twitter.com/CancerConnector/status/649359539641450496">September 30, 2015</a></blockquote>
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<a href="https://twitter.com/CancerConnector">@CancerConnector</a> <a href="https://twitter.com/EvolTheoArne">@EvolTheoArne</a> <a href="https://twitter.com/dbasanta">@dbasanta</a> <a href="https://twitter.com/ara_anderson">@ara_anderson</a> The "ring" can't decide where it belongs... ;) <a href="http://t.co/dZn9dSjDNv">pic.twitter.com/dZn9dSjDNv</a></div>
— Benedikt Bauer (@EvolTheoBene) <a href="https://twitter.com/EvolTheoBene/status/656086310638231553">October 19, 2015</a></blockquote>
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<a href="https://twitter.com/EvolTheoBene">@EvolTheoBene</a> why not proper mixed topology? (Plus/minus green edges-pardon white board <a href="https://twitter.com/hashtag/clinicday?src=hash">#clinicday</a> <a href="https://twitter.com/LauraHindersin">@LauraHindersin</a> <a href="http://t.co/1V1diJkzC7">pic.twitter.com/1V1diJkzC7</a></div>
— Jacob G Scott (@CancerConnector) <a href="https://twitter.com/CancerConnector/status/656102773415682052">October 19, 2015</a></blockquote>
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<a href="https://twitter.com/CancerConnector">@CancerConnector</a> <a href="https://twitter.com/EvolTheoArne">@EvolTheoArne</a> <a href="https://twitter.com/ara_anderson">@ara_anderson</a> <a href="https://twitter.com/dbasanta">@dbasanta</a> Nice idea, this is what the rank in fix prob looks like <a href="https://t.co/pEW7rC4s5o">pic.twitter.com/pEW7rC4s5o</a></div>
— Benedikt Bauer (@EvolTheoBene) <a href="https://twitter.com/EvolTheoBene/status/657204453490212865">October 22, 2015</a></blockquote>
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Building his first adjacency matrix - new volunteer to Theory Division! <a href="https://twitter.com/hashtag/mathonco?src=hash">#mathonco</a> <a href="http://t.co/CRlYuQSIet">pic.twitter.com/CRlYuQSIet</a></div>
— Jacob G Scott (@CancerConnector) <a href="https://twitter.com/CancerConnector/status/655118538043211776">October 16, 2015</a></blockquote>
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When he first started considering this project <a class="g-profile" href="https://plus.google.com/103095797184894290771" target="_blank">+Sudhir Manickavel</a> , a medical student asked of the Royal Society paper mentioned above:<br />
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"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.</div>
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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?" </div>
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A great question... to which I responded:<br />
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<span style="background-color: white; color: #222222; font-family: arial, sans-serif; font-size: 12.8px;">"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?"</span><br />
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And included a link to a Gatenby classic which opens with:<br />
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"The human body plays with evolutionary fire" and discusses the unique (changing) topology of the colonic crypt and how this may influece evolutionary dynamics...<br />
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744108/<br />
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Which seemed to sell him on the topic as just this morning, I looked in my dropbox, and it looks like <a class="g-profile" href="https://plus.google.com/103095797184894290771" target="_blank">+Sudhir Manickavel</a> is making some progress (though there seems to be a missing node... :) ):<br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-sQi7y7Jm1ZA/Vij-s1VY8jI/AAAAAAAAC28/wt4IXULHAUI/s1600/image9.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="240" src="http://3.bp.blogspot.com/-sQi7y7Jm1ZA/Vij-s1VY8jI/AAAAAAAAC28/wt4IXULHAUI/s320/image9.png" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">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?</td></tr>
</tbody></table>
Anyways, the start of a fun project either way.<br />
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<script async="" charset="utf-8" src="//platform.twitter.com/widgets.js"></script>Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com3tag:blogger.com,1999:blog-5975631477306646569.post-60486370910982534972015-09-27T18:36:00.000-07:002015-09-27T18:38:57.044-07:00Full storification of Cancer Evolution Through Space and Time: #CEST15My friend, supervisor and department Chair <a class="g-profile" href="https://plus.google.com/109422830104234532994" target="_blank">+Alexander Anderson</a> compiled a full storification of the recent Cancer Evolution Through Space and Time meeting with the hashtag #CEST15.<br />
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You can find it on his storify page here:<br />
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https://storify.com/ara_anderson/cancer-evolution-through-space-time<br />
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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!<br />
<br />
Thanks to Sandy and <a class="g-profile" href="https://plus.google.com/108823374134411848421" target="_blank">+Arne Traulsen</a> and all the crew at The Max Planck for Evolutionary Biology who made the visit so nice. Enjoy the storification that Sandy compiled.<br />
<br />
<div class="storify">
<iframe allowtransparency="true" frameborder="no" height="750" src="//storify.com/ara_anderson/cancer-evolution-through-space-time/embed?border=false" width="100%"></iframe><script src="//storify.com/ara_anderson/cancer-evolution-through-space-time.js?border=false"></script><noscript>[<a href="//storify.com/ara_anderson/cancer-evolution-through-space-time" target="_blank">View the story "Cancer Evolution Through Space And Time" on Storify</a>]</noscript></div>
<br />Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com5tag:blogger.com,1999:blog-5975631477306646569.post-83866932936302095382015-09-22T01:20:00.003-07:002015-09-22T01:20:43.470-07:00First day of Cancer Evolution through Space and Time at Max Planck<div class="storify">
<iframe allowtransparency="true" frameborder="no" height="750" src="//storify.com/CancerConnector/cancer-evolution-through-space-and-time-day-1/embed?border=false" width="100%"></iframe><script src="//storify.com/CancerConnector/cancer-evolution-through-space-and-time-day-1.js?border=false"></script><noscript>[<a href="//storify.com/CancerConnector/cancer-evolution-through-space-and-time-day-1" target="_blank">View the story "Cancer Evolution through Space and Time Day 1" on Storify</a>]</noscript></div>
Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com4tag:blogger.com,1999:blog-5975631477306646569.post-31660319911182188572015-09-14T04:51:00.001-07:002015-09-14T05:01:26.170-07:00The first ever mathematical model to capture cancer growth dynamics, published 2015...Last week saw one of the most striking oversells of a paper I've seen in the recent past, and it frustrated a lot of people in my field.<br />
<br />
The paper -<br />
<br />
<h1 class="article-heading" style="background-color: white; color: #222222; font-family: arial, helvetica, 'MS Pゴシック', 'MS ゴシック', Osaka, 'MS PGothic', sans-serif; font-weight: normal; letter-spacing: -0.5px; line-height: 1.173; margin: 0px 0px 20px; padding: 0px;">
<span style="font-size: small;">
A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity</span></h1>
can be found here: <a href="http://www.nature.com/nature/journal/v525/n7568/full/nature14971.html">http://www.nature.com/nature/journal/v525/n7568/full/nature14971.html</a><br />
<br />
It is a spatial cellular automaton model (beautifully visualized) that looks at cancer growth and migration in a 3-d spatial context. The authors did a good job citing appopriate work (>100 citations) and never made any claims that were over the top. The press release, however... well... I'll let the twitter backlash speak.<br />
<br />
I think the most striking thing about all of this was the the senior author, <a href="https://scholar.google.com/citations?user=aNFzP50AAAAJ&hl=en&oi=ao">Martin Nowak</a>, one of the fathers of evolutionary dynamics and most successful mathematical biologists in the world, came on to twitter to apologize for the Press Release (see final tweet). Class move.<br />
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At the end of the day, we have little control of the press releases for our papers. And, while we certainly all want to see our work publicized (how else can people find out about it?), seeing good work cheapened in some way by an oversold press release doesn't help anyone.<br />
<br />
Anyways, here is a tour of spatial models of cancer, twitter style. #notthe1sttime<br />
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<br />
<div class="storify">
<iframe allowtransparency="true" frameborder="no" height="750" src="//storify.com/CancerConnector/oversold-paper/embed?header=false&border=false" width="100%"></iframe><script src="//storify.com/CancerConnector/oversold-paper.js?header=false&border=false"></script><noscript>[<a href="//storify.com/CancerConnector/oversold-paper" target="_blank">View the story "how to oversell a paper..." on Storify</a>]</noscript></div>
Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com3tag:blogger.com,1999:blog-5975631477306646569.post-3800851618011257062015-04-13T09:12:00.000-07:002015-04-13T09:12:48.804-07:00Author Manuscripts - clarification of PLoS Comp Biol's policyJust a quick post. I and some colleagues recently submitted one of our papers <span style="font-family: Times, Times New Roman, serif;">"<span style="background-color: white; color: #000033; line-height: 14px;"><a href="http://biorxiv.org/content/early/2015/02/10/007542">Steering Evolution with Combination Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance</a>" (which you can<a href="https://egtheory.wordpress.com/2015/02/14/evolutionary-non-commutativity/"> read a nice post</a> on <a class="g-profile" href="https://plus.google.com/101780559173703781847" target="_blank">+Artem Kaznatcheev</a>'s blog here) to PLoS Computational Biology, and I was surprised that an option to submit a full 'author manuscript' wasn't present, but instead that we had to upload images separately, reformat and the like. This surprised me, because the first time I submitted there, in a <a href="http://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1003433">paper I wrote</a> with <a class="g-profile" href="https://plus.google.com/108880714002171992138" target="_blank">+David Basanta</a> and <a class="g-profile" href="https://plus.google.com/109422830104234532994" target="_blank">+Alexander Anderson</a> I didn't remember having to do this. It might be that I just misread, but at the time I was confused.</span></span><br />
<span style="font-family: Times, Times New Roman, serif;"><span style="background-color: white; color: #000033; line-height: 14px;"><br /></span></span>
<span style="font-family: Times, Times New Roman, serif;"><span style="background-color: white; color: #000033; line-height: 14px;">So, I tweeted to them a quick question and it turns out they DO accept author manuscripts, but that their instructions are on the fritz right now! </span></span><br />
<blockquote class="twitter-tweet" lang="en">
<a href="https://twitter.com/CancerConnector">@CancerConnector</a> A single PDF at 1st submission is ok but needs to be changed at revisions. Will contact you by e-mail.<br />
— PLOS Comp Biol (@PLOSCompBiol) <a href="https://twitter.com/PLOSCompBiol/status/587548447575642113">April 13, 2015</a></blockquote>
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Anyways, they replied quickly with an email as well stating:<br />
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<div class="MsoNormal" style="background-color: white; color: #222222; font-family: Calibri, sans-serif; font-size: 11pt; margin: 0cm 0cm 0.0001pt;">
<span style="font-family: Arial, sans-serif;">We allow a single PDF to be submitted at initial submission, although as the paper is subsequently revised, we require the manuscript to be submitted in separate parts to begin to prepare the manuscript for production. This is to avoid asking authors to do everything at once at acceptance, a process that can, in some instances, be a substantial task.<u></u><u></u></span></div>
<div class="MsoNormal" style="background-color: white; color: #222222; font-family: Calibri, sans-serif; font-size: 11pt; margin: 0cm 0cm 0.0001pt;">
<span style="font-family: Arial, sans-serif;">I understand that this is not clear on the author instructions and we are looking at ways of improving our instructions.</span></div>
<div class="MsoNormal" style="background-color: white; color: #222222; font-family: Calibri, sans-serif; font-size: 11pt; margin: 0cm 0cm 0.0001pt;">
<span style="font-family: Arial, sans-serif;"><br /></span></div>
<div class="MsoNormal" style="background-color: white; color: #222222; font-family: Calibri, sans-serif; font-size: 11pt; margin: 0cm 0cm 0.0001pt;">
<span style="font-family: Arial, sans-serif;">So - submit away. And, thank for the quick reply to PLoS CB... now it's just fingers crossed for our submission.</span></div>
<script async="" charset="utf-8" src="//platform.twitter.com/widgets.js"></script>Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com4tag:blogger.com,1999:blog-5975631477306646569.post-90731209278841379262015-04-01T12:12:00.001-07:002015-04-01T12:26:52.561-07:00Healing Art of PathologyMany apologies for the long delay in writing, residency training has been weighing heavily on my creative time - but this is coming to an end! In the realm of more good news, on July 1st I will assume the post of Clinical Instructor here at the Moffitt Cancer Center, concentrating my efforts on taking care of patients with sarcoma using radiation for one day per week. The balance of my time will be spent finishing my DPhil and pursuing the clinician-scientist track - a balance I hope to maintain for the rest of my career (life?).<br />
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="http://2.bp.blogspot.com/-7bivYrApa9U/VRw-qPzevKI/AAAAAAAACIg/U5DIi4G_B8I/s1600/SP11-10678%2BX%2B40-2.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://2.bp.blogspot.com/-7bivYrApa9U/VRw-qPzevKI/AAAAAAAACIg/U5DIi4G_B8I/s1600/SP11-10678%2BX%2B40-2.jpeg" height="457" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Dendritic Swarm.</td></tr>
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My relationship with the <a href="http://moffitt.org/cancer-types--treatment/cancers-we-treat/sarcoma">Sarcoma department here</a> has been a very good one, and one that has transcended simply training and patient care. Immediately before I left for Oxford, my neighbor and friend <a class="g-profile" href="https://plus.google.com/106807408092862021920" target="_blank">+Ray Paul</a> came to my house and asked me to feel a lump on his side...<br />
<br />
It turned out that Ray had a <a href="https://en.wikipedia.org/wiki/Histiocytoma">myxofibrosarcoma</a>, and a nasty one at that. Honestly, things looked pretty bleak for a while, but now, after 4 surgeries (flank, thigh, and two in the lung), two bouts of radiation therapy (flank and thigh), two clinical trials (immunotherapy and a novel tyrosine kinase inhibitor) he is NED - nearly 4 years later. Incredible, and wonderful.<br />
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Much of Ray's story can be read on a <a href="http://blog.tedmed.com/examined-lives-my-sarcoma-the-story-of-a-tumor-told-with-art/">previous post of mine</a> on the <a class="g-profile" href="https://plus.google.com/101965276929158390601" target="_blank">+TEDMED</a> blog that discusses the healing power that Ray's own art had for him (<a href="http://cancerconnector.blogspot.com/2013/05/update-to-my-sarcoma-project.html">updated here</a>). A project he began, called My Sarcoma, during which Ray painted over the top of his OWN histology images, transformed Ray from a sick and dying patient back into a living and vibrant artist. Watching and participating was a real honor. This culminated in a <a href="http://moffitt.org/home/moffitt-in-the-news/press-releases/2014/ray-paul">beautiful opening of his art at Moffitt</a> which received both <a href="http://www.baynews9.com/content/news/baynews9/news/article.html/content/news/articles/bn9/2014/9/10/cancer_art_shows_rag.html">local</a> news attention and a national story shared with another Moffitt patient <a href="http://www.onmarch14.com/about-michelle.html">Michelle Boyd DeJong</a> on the <a href="http://www.wfmz.com/lifestyle/Health-Beat/health-beat-creative-coping-improves-cancer-recovery/30062404">healing power of creativity</a>.<br />
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<tr><td style="text-align: center;"><a href="http://3.bp.blogspot.com/-bJ4mULK5txE/VRw-qiJRuBI/AAAAAAAACIo/EJWCYfez0Jw/s1600/SP12-6796%2Bx%2B40.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="http://3.bp.blogspot.com/-bJ4mULK5txE/VRw-qiJRuBI/AAAAAAAACIo/EJWCYfez0Jw/s1600/SP12-6796%2Bx%2B40.jpeg" height="460" width="640" /></a></td></tr>
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<br />
Each of the paintings that Ray has made during this journey has had more than just Ray's hands involved. Indeed, to make the paintings as you see them, a surgeon had to cut out his tumor, a pathologist had to stain and mount the tissue and a screen printer had to prepare the canvas. As an offshoot of this collaboration, our Sarcoma pathologist, <a href="http://moffitt.org/research--clinical-trials/individual-researchers/marilyn-m--bui-md-phd">Marilyn Bui</a>, and Ray continued to talk and brainstorm, and a new project was born, a book entitled <i>Healing Art of Pathology</i>.<br />
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<br />
Sponsored by the College of American Pathologists, this book will be a compilation of art derived from, or inspired by, pathology - the study of disease. They are seeking submissions now, with a deadline of September 1st from the art and medical world (including patients) the world over. More details can be found in the attached letter.<br />
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"Please send all submissions and/or address any questions to Caryn Tursky, CAP Press Acquisitions and Development Editor, at ctursky@cap.org by September 1, 2015. Please make the subject of the email “Healing Art Submission.”"<br />
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<div class="separator" style="clear: both; text-align: center;">
Ray's project, My Sarcoma, featured here can be seen as well on his <a href="http://raypaulart.com/">website raypaulart.com</a></div>
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<br />Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com4tag:blogger.com,1999:blog-5975631477306646569.post-58336098873853457002014-11-14T03:48:00.000-08:002014-11-14T03:48:41.073-08:00Mathematical Oncology: an introduction given at a Moffitt Cancer Center Radiation Oncology CME conferenceToday at Moffitt Cancer Center I'm giving a short talk about Mathematical Oncology for a continuing medical education aimed at medical physicists and dosimetrists - though I think the talk is available to most folks with an interest in science and maths. It's a short talk (30 minutes) in which I hope to introduce the field, show some of the tools we use, and give a short example or two. I feel that this audience, in particular, is important to address because they have the skills needed to think like modellers, and work in cancer EVERY DAY.<br />
<br />
My hope is to spread awareness of mathematical oncology, but also to lure some clever folks across the street from the clinic to the laboratory!<br />
<br />
There are a host of great talks going on, many of which have their slides on line (I've been told) on topics as broad as #proton therapy, #StereotacticBodyRadiation, #cyberknife, #radiation toxicity, #HIV and cancer and more.<br />
<br />
A full agenda can be seen here:<br />
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http://www.cvent.com/events/radiation-oncology-conference/agenda-e3a4aaf164cd41929f01194fa077be14.aspx<br />
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And here's my talk.<br />
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<iframe frameborder="0" height="443" src="http://wl.figshare.com/articles/1241429/embed?show_title=1" width="568"></iframe>Jacob Scotthttp://www.blogger.com/profile/12788368243256158841noreply@blogger.com3