Archive for July, 2013
26 July 2013
The current culture surrounding clinical trials hinders our ability to learn from our failures. Currently available technology and a slightly different mindset can fix this.
One of the biggest problems that exists today with anti-cancer clinical trials general is publication bias. And by that, I mean the non-publication of trial failures. For instance, groups A, B, C and D could all be testing drug X on breast cancer, but if only group B gets a positive result, all researchers like Yours Truly would see in the literature would be results from group B. And all the results would be positive. Yours Truly would have no knowledge of the failed trials from groups A, C, and D, and if he did, he might think twice about pursuing further trials with drug X.
In the last six months the All Trials campaign has been gaining momentum to get all clinical trials published, regardless of their outcome.
Publication of negative results could prevent other research groups from wasting their time, or learning from the failures of previous trials… and that’s where a “big data” approach could revolutionize cancer treatment.
I recently read “Big Data: A Revolution That Will Transform How We Live, Work, and Think” by Viktor Mayer-Schonberger and Kenneth Cukier
Schonberger and Cukier define “Big Data” as “the ability of society to harness information in novel ways to produce useful insights or goods and services of significant value.” In particular, this is driven by two things things:
1) The cost of storing data has plummeted, making it feasible to keep data around that might not yet have a clearly defined use.
2) An altered mindset, where more emphasis is placed on “what” and less on “why.” Less emphasis on causation and more on correlation. For instance, Wal Mart did not care why pop-tarts became an especially popular item right before hurricanes. In fact, it was irrelevant to them. They went ahead and ordered extra pop-tarts before impending natural disasters at their stores and boosted their sales. They were able to do this because data storage is so cheap these days, and they were able to keep a record of what every customer bought, when, and that else was in their basket at checkout. From this macro view of buying trends they discovered something that they did not expect or could not anticipate based on their common knowledge.
In terms of cancer, there something else that has plummetted: sequencing costs. Sequencing of entire exomes can be done for about $500 these days! That was almost unthinkable just a few years ago. Pretty soon sequencing of entire genomes might be available for comparable cost.
So, here’s a vision I have: A center that runs many cancer clinical trials is partnered with a center that can do exome or genome sequencing for every patient enrolled in a cancer clinical trial, and this data would be published* regardless of the success or failure of the trial. Sequencing would be done on primary tumor mass from surgery or before treatment. If possible, sequencing would be done on tumor(s) post-clinical trial or even post-mortem.
Regardless of success or failure, the results from clinical trials in cancer would be published, and this data would be available (though to whom exactly and in what capacity, what security, and other ethical concerns considered) for future analysis to find trends not otherwise comprehensible without such a macro view. Items that could be investigated could include:
1) What genetic profiles predict response to therapy or non-response?
2) Are there similarities between cancer types?
3) Do mechanisms of resistance correlate between types of cancer and types of drugs?
4) Do these insights correlate with other defined risk factors?
5) Questions or correlations that have yet to be considered(!)
In summary, recent plummeting costs of both sequencing and data storage can allow us to learn much more from our failures (as well as our successes) by enabling a macro view of the changing genes correlating with cancer therapy response or non-response.
15 July 2013
This October I will ride my bike from the ocean to the mountains and back to promote cancer research and healthier living. It’s a two-day, 180 mile trek that pays tribute to the stamina of current, past, and future cancer patients. Concurrently, it has the very literal purpose of raising critical funds for cancer research here in San Diego, benefitting the C3 Initiative of the UCSD Moores Cancer Center, the Sanford-Burnham Medical Research Institute, and the Salk Institute.
My fundraising page can be found here.
ETHOS AND RATIONALE
Everyone should have a chance to live a happy, productive life. We can do a lot to promote healthier, happier living regardless of life circumstances. We all have different ways we promote this, but a few ways I’ve personally chosen are through cancer research, cancer education, and cycling.
In this blog I’ve written a lot about the established and emerging science surrounding the disease, but I want to make it clear that the scientific side of things is just one aspect of the battle against cancer, which is just one initiative toward more healthy, productive lives for everyone. Even the complete absence of disease is not health.
I’m a big fan of bikes and of cycling. I commute to work almost every day via bicycle. Most errands I run (groceries, bank, visiting nearby research institutions) are also conducted using myself as the motor. There is much I could write about the extra hours per week in the fresh air and rarely finding myself in traffic or without parking, or the extra exercise, or the money I save on gasoline, wear and tear on my truck, and on auto insurance. But for now, I will suffice to say that I love incorporating the bicycle to wherever I can in my life, and I enjoy a healthier, happier lifestyle because of it. These experiences and positive life benefits are things I wish I could share with more people. And if you’re reading this and I could be ANY assistance with getting you on a bike, please contact me. I would love to be of help to you, dear reader.
I’ve also written a bit about the anti-cancer effects of exercise and I see inactivity as a problem. I also see metabolic disease (and its other manifestations of obesity and diabetes) reaching far beyond the cancer problem as well; collectively they put a severe burden on individuals, families, and society.
Perhaps it is not surprising that when I found out about the inaugural Pedal the Cause I could not help but immediately sign up.
I often joke that I am a bit of a bastard child between two of the institutions. I am in the last year of my doctoral research as part of the Sanford-Burnham School of Biomedical Sciences and I currently spend most of my time in the lab of my co-advisor at the UCSD Moores Cancer Center. I can attest to the world-class research conducted at both institutions, and I will save you (for now) the lauded praise for the amazing scientists and physicians I’ve gotten to know and work with. The collaborative research community we have here in San Diego is phenomenal on so many levels, and I am confident that donations will go to very good use.
Again, my fundraising page can be found here and I would be both grateful and honored if you could help me in this initiative.
12 July 2013
Today I’m writing in a slightly less formal style as I share a few thoughts floating through my head, dear reader. I have opted to write them down in hopes that a soul or two might find them
As a young scientist I have had the privilege of learning the fine art of banging my head against a wall in more ways than I could have possibly imagined, all the while not getting smarter, per se, but usually just a little less ignorant of my own ignorance.
In my quest to become less unaware of what I am unaware about, I’ve become fascinated by biases and logical fallacies. After all, we are a group of animals that evolved to hunt, farm, run, or otherwise outfox aging, disease, and each other to reproduce in time to see our genes survive the next generation or two. We did not evolve to intuitively understand permutations compounded by time, like evolution, statistics, or the cosmos. Such things were little use to our ancestors that were more likely to be preoccupied with their next meal and securing mating rights.
When it comes to understanding things in a fourth dimension (time) we are not always so bright. While a dingy might a boat be well-suited for fishing on a small lake, it would be hopefully difficult to cross an ocean in one. That’s not to say it couldn’t be done, but the tool was not developed for the job. Similarly, our minds contain many evolutionary vestiges that helped us get to where we are, but might not help get us where we want to be.
An example of this is Survivorship Bias, or “…concentrating on the people or things that ‘survived’ some process and inadvertently overlooking those that didn’t because of their lack of visibility.” (source)
This morning I came across a fun read by David McRaney in his blog You Are Not So Smart
“Survivorship bias also flash-freezes your brain into a state of ignorance from which you believe success is more common than it truly is and therefore you leap to the conclusion that it also must be easier to obtain. You develop a completely inaccurate assessment of reality thanks to a prejudice that grants the tiny number of survivors the privilege of representing the much larger group to which they originally belonged.”
I could easily draw analogies to the number of graduate students and postdoctoral fellows that truly believe that they will make it to the level of professor. Rarely do we focus on the postdocs that don’t make it and meekly fade away. Or better yet, for the reasons they don’t make it. Perhaps by recognizing our real chances of success, we can change our goals, or change our definition of “success” and avoid more years of grad students pounding their heads into oblivion? But I digress…
McRaney also touched upon an alternate idea of “luck.”
“Wiseman speculated that what we call luck is actually a pattern of behaviors that coincide with a style of understanding and interacting with the events and people you encounter throughout life. Unlucky people are narrowly focused, he observed. They crave security and tend to be more anxious, and instead of wading into the sea of random chance open to what may come, they remain fixated on controlling the situation, on seeking a specific goal. As a result, they miss out on the thousands of opportunities that may float by. Lucky people tend to constantly change routines and seek out new experiences. Wiseman saw that the people who considered themselves lucky, and who then did actually demonstrate luck was on their side over the course of a decade, tended to place themselves into situations where anything could happen more often and thus exposed themselves to more random chance than did unlucky people. The lucky try more things, and fail more often, but when they fail they shrug it off and try something else. Occasionally, things work out.”
In contrast to M.D., Pharm.D., R.N., and *shudder* N.M.D. students, a Ph.D. student does not have the degree of certainty in a defined career path, or security offered by it. But perhaps one could see this as an opportunity for creativity and maneuver oneself into a position to become lucky… To be open to other career paths and other directions… again, I digress…
Something that IS very important to science today is a subset of survival bias known as “publication bias” also touched upon by McRaney:
“The people who use the diet, or the product, or the pill, and fail to lose weight don’t get trotted out for photo shoots – only the successes do. That same phenomenon has become a problem in science publications, especially among the younger sciences like psychology, but it is now under repair. For far too long, studies that fizzled out or showed insignificant results have not been submitted for publication at the same level as studies that end up with positive results, or even worse, they’ve been rejected by prominent journals. Left unchecked, over time you end up with science journals that only present the survivors of the journal process – studies showing significance. Psychologists are calling it the File Drawer Effect. The studies that disprove or weaken the hypotheses of high-profile studies seem to get stuffed in the file drawer, so to speak. Many scientists are pushing for the widespread publication of replication, failure, and insignificance. Only then, they argue, will the science journals and the journalism that reports on them accurately describe the world being explored.”
When I stop to think about the publication process and the biases and innate conflict of interest to produce positive and not negative results, I have to wonder about all of the science that I’ve missed. Or rather, all of the science that was never published because it didn’t work. What else are we missing or not seeing? It’s nearly impossible to know, and for this Homo Sapien it’s not always easy to embrace uncertainty, to consider an idea without accepting it, or to realize that the best lab or study or data might be an illusion casting a disproportionate shadow on our visions or reality, buoyed in our own minds by our survivorship bias.
Ok, time for a second cup of coffee and back to things that don’t make my head hurt as much, like peering down a microscope or finding optimal conditions for frozen tissue antibody conjugation.
5 July 2013
More good news today. I just received notification that my second primary author paper (my first review article) has successfully gone through the peer-review process and has been accepted to the journal Current Molecular Medicine.
Graf R, Keller N, Barbero S, Stupack DG. Caspase-8 as a Regulator of Tumor Cell Motility. Current Molecular Medicine. (In Press)
“Caspase-8 as a Regulator of Tumor Cell Motility” is a review article on the molecular mechanisms of how caspase-8 can promote cellular migration, a process central to tumor metastasis, independent of its better-defined role as a cell death protein. A review article usually has minimal or no primary data, but instead is a narration of the work of dozens of research groups and hundreds of scientists encompassing a single topic. It’s currently in press, and it’s likely to be a few months before it’s available online. Still, this is some very good news, and is a critical step toward a final thesis.
I have also updated my CV to reflect the paper in press.