Meditations of an oncology geek

23andMe, the FDA, and evolving science ethics

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27 November 2013

I’ve got a thesis to write, manuscript to edit, and a pesky microscope problem to work around, but I just cannot help but follow the current discussions surrounding the battle between 23andMe and the FDA. There’s a LOT of hype and charged discussions going on in social media at the moment, and I’ve had the pleasure of watching it all unfold. All in all, I have seen some very healthy ethical discussion on many fronts. I thought I’d share a few enlightened points I’ve come across.

First, came the announcement:

The actual letter from the FDA is a fantastic read:

Your company submitted 510(k)s for PGS on July 2, 2012 and September 4, 2012, for several of these indications for use. However, to date, your company has failed to address the issues described during previous interactions with the Agency or provide the additional information identified in our September 13, 2012 letter for (b)(4) and in our November 20, 2012 letter for (b)(4), as required under 21 CFR 807.87(1). Consequently, the 510(k)s are considered withdrawn, see 21 C.F.R. 807.87(1), as we explained in our letters to you on March 12, 2013 and May 21, 2013.  To date, 23andMe has failed to provide adequate information to support a determination that the PGS is substantially equivalent to a legally marketed predicate for any of the uses for which you are marketing it; no other submission for the PGS device that you are marketing has been provided under section 510(k) of the Act, 21 U.S.C. § 360(k).  {emphasis added}

Matthew Herper in Forbes gives a great introduction to what is a highly nuanced ethical debate quickly becoming a macrocosm of a battle between 23andMe and the FDA:

I’d like to be able to start here by railing against our medical system, which prevents patients from getting data about our own bodies because of a paternalistic idea that people can’t look at blood test results, no less genetic information, without a doctor being involved or the government approving the exact language of the test. I’d like to be able to argue that the Food and Drug Administration is wantonly standing in the way of entrepreneurism and innovation by cracking down on 23andMe, a company that is just trying to give patients the ability to know about their own DNA, to understand their own health risks, and to participate in science.

I wish that was the story I’m about to write, but it’s not, and it all really comes down to one fact in the FDA’s brutally scathing warning letter to 23andMe, the Google GOOG +0.36%-backed personal genetics startup. It’s this quote from the letter by Ileana Elder, in the agency’s diagnostics division: ‘FDA has not received any communication from 23andMe since May.’

more here:

The blog Genotopia makes some very important distinctions about what the FDA is trying to regulate:

We must be clear that the FDA letter does not prohibit 23andMe from selling their test. It demands they stop marketing it. The difference may not amount to much in practice—how much can you sell if you don’t market your product?—but the distinction does help clarify what is actually at stake here. FDA is not attempting to instigate a referendum on the public’s access to their own DNA information. They are challenging the promises 23andMe seems to make. This is, in short, not a dispute about access, but about hype.

The company seems to promise self-knowledge. The ad copy for 23andMe promises to tell you what your genome ‘says about you.’ ‘The more you know about your DNA,’ they trumpet, ‘the more you know about yourself.’ On one level, that’s perfectly, trivially true: your genome does have a lot to do with your metabolism, body structure, how you respond to disease agents, and so forth. The problem is, we as yet know very little about how it all works. The 23andMe marketing exploits a crucial slippage in the concept of ‘knowledge,’ which FDA correctly finds misleading. In short, the marketing implies a colloquial notion of knowledge as a fixed and true fact, while the science behind the test is anything but.

Genotopia continues:

…The 23andMe product, like every genome test, provides probabilities of risk, not mechanisms. Probabilities are messy and hard to understand. They carry an almost irresistible tendency to be converted into hard facts. If you flip a coin 9 times and it comes up heads every time, you expect the next flip to come up tails. And if you get heads 49 times in a row, the next one has got to be tails, right? Even if you know intellectually that the odds are still 50:50, just like on every previous flip. You can know you have a particular gene variant, but in most cases, neither you nor anyone else knows exactly what that means. Despite the language of probability that dots the 23andMe literature, their overall message—and the one clearly picked up by many of their clientele—is one of knowledge in the colloquial sense. And that is oversell.

…the 23andMe test is being sold directly to individuals who may not have any knowledge of genetics. The tendency to convert risks into certainty is higher than ever. The knowledge they sell is a set of probabilities, and further, those probabilities are not stable. The consumer may not—indeed probably doesn’t—appreciate how much we know, how much we don’t know, and how much we don’t even know we don’t know. The company claims to be selling knowledge but in fact they are selling uncertainty.

More here:

David Dobbs’s NEURON CULTURE has created a fantastic list of diverse, intelligent commentary on the ethics, regulations, and science surrounding the current story:

He also offers some of his own commentary, perhaps advocating that a little messiness in the system must be weighed against the potential for positive impacts:

But do those apparently rare errors inflict more harm than the sorts of errors our medical system makes every day? Do they inflict more harm than a lack of information about important risk genes inflict? Does any harm done outweigh the great good that people gain from having inexpensive access to lots of information about medical risk?

A person learning the status of hundreds of genes of medical interest (along with information about their ancestry) with a simple spit-test may learn much actionable information — not to mention an education about genetics — that would otherwise depend on … what? Expensive access to doubtless heavily marked-up genetic tests prescribed by physicians and executed by companies happy to charges hundreds of dollars per gene? We need more such information; not less. I pray this will soon be reversed.

Lastly, there is the discussion about whether the FDA is hindering what could be a fantastic new dawn of public interest in science, not just for of un-health aversion, but just for the sake of inquiry, curiosity and education in itself. I have to admit, that this arena plucks a special chord in my heart. At the very least, I’m so glad to see these types of discussions continue, and move forward general public interest in science and genetics.


Written by Ryon

November 27th, 2013 at 1:44 pm

Posted in Science Blog

N of 1 Study Insightful to Prostate Cancer Evolution, Therapy?

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18 November 2013

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It’s tantalizing (and extremely important) to factor the fourth dimension in cancer: time. Cancer is a microcosm of evolution, the most lethal versions of which are bestowed with an immense reservoir of genetic heterogeneity, providing the raw resources to adapt to changing environments. The physical manifestations of this are the same that thwart treatment: chemotherapy resistance and metastasis (1).

Tumor heterogeneity over time is difficult to study, owing to a rarity in genomics-grade longitudinal samples in cancer patients. Last week I had the pleasure of presenting a curious N=1 study to our weekly journal club here at the Moores Cancer Center. Haffner and colleagues performed genomic and histological analyses on unusually well-preserved specimens collected over a man’s 17 year disease course with prostate cancer (2). (article available for free here)

The ensuing analyses revealed a few interesting pieces of information:

The region of the prostate surveyed that likely gave rise to a wave of lethal metastases 17 years after diagnosis (and radical prostatectomy) was of low histological grade compared to the rest of the prostate tumor region.

The lymph node metastasis removed the same time as the radical prostatectomy differed in molecular signature to the lethal metastases 17 years later, indicating a diverging evolution and suggesting, at least in this patient, that the palpable lymph node tumor did not act as a way station for the lethal, visceral metastases 17 years later in the lung, liver, and thoracic lymph nodes. This gives weight to the “embolization” theory of metastasis in prostate cancer, which posits that lymphatic and hematogenous dissemination are two separate paths, the lethal one being hematogenous. In breast cancer, this distinction was the subject of much debate until clinical trials very clearly demonstrated that aggressive removal of regional lymphatics does not reduce the risk of distant organ dissemination in breast cancer (3, 4). Perhaps the same could be true for prostate cancer? While not “essential” organs, aggressive surgical removal of regional lymphatics is far from innocuous. Even small hints at tumor evolution can glean valuable information for the most effective, least invasive means to treat prostate cancer.

Lastly, the metastatic clones that aggressively arose 17 years after diagnosis were all highly similar in both driver and passenger mutations, indicating a temporally recent progenitor. The questions that I would like to ask are:

Where were these metastatic clones hiding out for 17 years? The patient had multiple gaps without detectable disease. Also, what caused re-immergence from metastatic latency? Why then and not 10 years prior or 10 years in the future? Was there an undetected watershed moment mutation after decades of genomic Russian roulette and genomic instability that enabled the emergence of a lethal clone? Or, were there coordinated changes in many tissues at once that could have given rise to a more favorable environment for metastasis (i.e. perhaps some threshold related to aging)?

These questions cannot be answered with the current study, and I agree with Brannon and Sawyers (5) that N=1 studies could be immensely more powerful if we are able to better transpose genomics to the spatial and temporal disease course of many patients. At this point we have the technology; the real challenges in implementation are clinical and logistical, which can be overcome.


1. Klein CA. Selection and adaptation during metastatic cancer progression. Nature. 2013 09/19/print;501(7467):365-72.
2. Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, et al. Tracking the clonal origin of lethal prostate cancer. The Journal of clinical investigation. 2013 Nov 1;123(11):4918-22. PubMed PMID: 24135135. Pubmed Central PMCID: PMC3809798. Epub 2013/10/19. eng.
3. Donker M, Straver ME, van Tienhoven G, van de Velde CJ, Mansel RE, Litiere S, et al. Comparison of the sentinel node procedure between patients with multifocal and unifocal breast cancer in the EORTC 10981-22023 AMAROS Trial: Identification rate and nodal outcome. Eur J Cancer. 2013 Mar 19. PubMed PMID: 23522754. Epub 2013/03/26. Eng.
4. Fisher B, Redmond C, Fisher ER, Bauer M, Wolmark N, Wickerham DL, et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. The New England journal of medicine. 1985 Mar 14;312(11):674-81. PubMed PMID: 3883168. Epub 1985/03/14. eng.
5. Brannon AR, Sawyers CL. “N of 1″ case reports in the era of whole-genome sequencing. The Journal of clinical investigation. 2013 Nov 1;123(11):4568-70. PubMed PMID: 24135144. Pubmed Central PMCID: PMC3809802. Epub 2013/10/19. eng.

Written by Ryon

November 18th, 2013 at 10:11 am

Posted in Science Blog

An Amazing Weekend with Pedal the Cause

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30 October 2013

Pedal the Cause is many things. It’s a cancer research fundraiser. It’s a bike ride. It’s a celebration of trial, tribulation, and growth. It’s a metaphorical and physical act honoring the stamina of cancer patients. It’s a community.

For one weekend a group of cancer patients, friends of cancer patients, researchers, caretakers, doctors, and kindred spirits made their way from the UCSD Moores Cancer Center to the mountain town of Julian and back. Via bicycles. The entire experience was simply amazing. There are too many things I could say about it, so instead I will guide my story with photographs.

Image: I’m up there, I promise!

My Saturday started pretty early. I refused to drive to the start and had a nice warmup hauling my 30lb backpack up Gilman Drive. I dropped it off, said hello to many familiar faces, and quickly found my way to the starting chute.

The course profile to Julian is pretty much up, up, and up. A long bike ride in San Diego County can take one through many microclimates. Saturday did not disappoint. Gray skies at the start transitioned to mist and fog as we ascended up to Poway, then as we hit Scripps Poway Parkway we ascended above that as well, finding clear skies.

Image: My buddy Andrew Ulvestad shot this (while moving, yes he’s talented!) as we ascended above the clouds and up to the desert air of Ramona.

Within a matter of miles mist and fog gave way to Ramona and desert air. I managed to find company with those that just love to ride hard and fast, so I tagged along. Before I knew it we were at the Santa Ysabel aid station snacking on orange slices, which at that moment in time was quite possibly the most pleasant thing in the world.

Our extraordinarily ambitious friends headed north from there to circle around Julian and ascend from the east side. My friend Andrew Ulvestad and I felt that lunch sounded like a better idea, and ascended the final 7 miles straight up to Julian.

Image: I had the honor of being the first cyclist into the riders’ village

Throughout the afternoon and evening I met so many amazing people at the riders’ village. It was inspiring to hear the stories of those that not only survived, but were made stronger by their experiences with cancer. Everyone there had no facade. Any metaphorical mask was magically discarded somewhere on the road to Julian.

Image: It’s hard to find better company. Here I am with Bill Koman, Diane Hyat, Robert Kaplan, and Mike McHale

Hundreds of people present were completely open and exchanging their incredible, extremely personal life experiences and stories. I was somewhat apprehensive that perhaps a depressed or sad mood might underly an event associated with something (cancer) that causes grief to so many people. What I found instead was an honesty, openness, and kinship with almost complete “strangers” that became the theme of my Pedal the Cause. It’s taken a few days, but it’s still registering how uplifting, enlightening, and rich that was. The spice of life was served up all night.

Image: The evening’s ceremonies flawlessly transitioned the vibe, with cancer survivor Bill Koman laying down some extremely ambitious goals for the coming years, including 1000 riders for next year’s event.

As expected, the night was pretty cold up on the mountain. And also as expected, this coast-loving weakling didn’t pack warmly enough. Lesson learned! The next morning saw clear skies, and a FAST descent down the mountain to Santa Ysabel. We also descended the stunning Highway 78 down to Escondido. Again, those microclimates… we went from clear and cold, to clear and warm-ish, to borderline hot in Ramona, all the way down to the fog bank that met us at the base of the 78.

Up Torrey Pines and on to UCSD, we were greeted by a finishing chute lined with cheering people and cowbells! I wanted to thank everyone there at the same time, but realizing the absurdity of that wish rolling by at 15mph I simply sat up and pointed and smiled at everyone that came to cheer.

Image: well, no image yet. I’m hoping the photographer at the end got this. He might still be editing and getting them online. I’ve got my fingers crossed!

I want to thank all of my friends and family that supported me in this cycling and fundraising journey, even if it was in the smallest way. Thanks for reading, and I am already looking forward to next year’s event!


KFMB Channel 8 coverage of Pedal the Cause

Written by Ryon

October 30th, 2013 at 3:06 pm

Posted in Science Blog

Could the liquid biopsy circumvent tumor heterogeneous hurdles?

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24 October 2013

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Nature magazine recently had a special Insight on tumor heterogeneity, complete with no less than six fantastic review articles on the topic.

Barbara Marte gave an introduction on the matter:

Cancer is not one but many diseases. It is different in each patient and continuously evolves into a progressively complex interplay of diverse tumour cells with their changing environment.
In an insightful and prescient 1976 paper, Peter Nowell proposed the now prevailing view of cancer as a process of clonal evolution, in which successive rounds of clonal selection give rise to tumours with diverse genetic and other molecular alterations that may necessitate ‘personalized’ therapies.

There is great variability between cancers, but it is the variability within tumors that I see as the biggest hurdle for diagnosis, treatment, and resistance even with the multi-faceted revolution in sequencing and targeted therapies.

If every cancer, and perhaps every cancer cell, is unique, and some cancer cell populations are more ‘unique’ than others, this needs to be taken into consideration for the improvement of cancer diagnoses and prognoses, for the treatment and monitoring of each patient and for the design of clinical trials to evaluate new therapies.

I could not agree more. A caveat to every molecular analysis on tumor tissue is that it offers only a spatial and temporal snapshot of the disease. This caveat is seldom acknowledged in oncology literature, almost never directly addressed in discussions, and sometimes completely ignored in experimental methodology that would be greatly affected by the heterogeneous snapshot caveat. What was present at that moment in time might be no more in weeks’ or months’ time. While there is a potential for a malignant tumor to continue to evolve, tremendous spatial heterogeneity already exists in many tumors. (1-4)

Any targeted therapy might not hit every tumor cell even with perfect pharmacodynamics, because a particular target might not be present in every tumor, and it’s difficult to know what other targets exist in other regions of a tumor without a comprehensive survey of tumor heterogeneity. Genetic testing requires biopsies for genomic surveys, and even the most advanced sequencing technologies cannot get past a particular caveat: it is impossible to survey an entire tumor’s genetic heterogeneity. Repeat biopsies are highly invasive to cancer patients and pose logistical and ethical problems. Besides, and if a particular tumor was easily accessible, it would likely be removed surgically anyway.

So, what part of a tumor could or should be biopsied? How much weight should be put on the driver mutations detected in a particular biopsy? What essential molecular targets might evade our notice?

While there is a growing appreciation (apprehension?) at the immense heterogeneity within tumors and the associated hurdles to more effective therapy, there is also a growing interest in cell free DNA (cfDNA). It was recently reported that advanced cancer patients have an order of magnitude higher amount of DNA floating around in their blood plasma than healthy volunteers (5). Furthermore, the amount of cfDNA was shown to correlate with disease progression (6), and to carry tumor-specific mutations that can be used to track genomic evolution of metastatic cancer in response to targeted therapy (7).

The origin of this cfDNA is likely the same cells that will cause the most harm to cancer patients: the ones that escape tumor(s) and seed the bloodstream. Studies from circulating tumor cells (CTC) indicate that the vast majority of CTC’s do not form tumors (8, 9), and the detection of shards of tumor cells along with long strands of genomic DNA is consistent with many of these cells being torn apart by sheer forces in the vasculature. The genomic interrogation of this cfDNA might not be too far away with the current trends in sequencing technology, giving rise to the non-invasive “liquid biopsy” of solid tumor heterogeneity surveyed with a blood draw (7, 10).

Such analyses are amendable to serial biopsies and might give light to the kinetics of tumor heterogeneity over time, portraying patterns of tumor evolution that could be exploited therapeutically, and perhaps even prophylactically.


1. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England journal of medicine. 2012 Mar 8;366(10):883-92. PubMed PMID: 22397650. Epub 2012/03/09. eng.
2. Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature. 2010 Oct 28;467(7319):1114-7. PubMed PMID: 20981102. Pubmed Central PMCID: PMC3148940. Epub 2010/10/29. eng.
3. De Mattos-Arruda L, Cortes J, Santarpia L, Vivancos A, Tabernero J, Reis-Filho JS, et al. Circulating tumour cells and cell-free DNA as tools for managing breast cancer. Nature reviews Clinical oncology. 2013 Jul;10(7):377-89. PubMed PMID: 23712187. Epub 2013/05/29. eng.
4. Park SY, Gonen M, Kim HJ, Michor F, Polyak K. Cellular and genetic diversity in the progression of in situ human breast carcinomas to an invasive phenotype. The Journal of clinical investigation. 2010 Feb;120(2):636-44. PubMed PMID: 20101094. Pubmed Central PMCID: PMC2810089. Epub 2010/01/27. eng.
5. Perkins G, Yap TA, Pope L, Cassidy AM, Dukes JP, Riisnaes R, et al. Multi-purpose utility of circulating plasma DNA testing in patients with advanced cancers. PloS one. 2012;7(11):e47020. PubMed PMID: 23144797. Pubmed Central PMCID: PMC3492590. Epub 2012/11/13. eng.
6. Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. The New England journal of medicine. 2013 Mar 28;368(13):1199-209. PubMed PMID: 23484797. Epub 2013/03/15. eng.
7. Murtaza M, Dawson SJ, Tsui DW, Gale D, Forshew T, Piskorz AM, et al. Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature. 2013 May 2;497(7447):108-12. PubMed PMID: 23563269. Epub 2013/04/09. eng.
8. Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 Oct 15;10(20):6897-904. PubMed PMID: 15501967. Epub 2004/10/27. eng.
9. Meng S, Tripathy D, Frenkel EP, Shete S, Naftalis EZ, Huth JF, et al. Circulating tumor cells in patients with breast cancer dormancy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 Dec 15;10(24):8152-62. PubMed PMID: 15623589. Epub 2004/12/30. eng.
10. Lianidou ES, Mavroudis D, Georgoulias V. Clinical challenges in the molecular characterization of circulating tumour cells in breast cancer. British journal of cancer. 2013 Jun 25;108(12):2426-32. PubMed PMID: 23756869. Pubmed Central PMCID: PMC3694246. Epub 2013/06/13. eng.

Written by Ryon

October 24th, 2013 at 9:50 am

Posted in Science Blog

Does the end of gene patents mean rising demand for diagnostic sequencing?

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1 October 2013

Image source:

Last week I attended a fantastic panel debate on gene patents hosted by the San Diego chapter of Oxbridge Biotech Roundtable at The Scripps Research Institute. Rachel Tsui moderated a panel of four:

Pro gene Patents:
Lisa Haile
Anthony Kuhlman

Against Gene Patents:
Lisa Madlensky (Genetic Counselor at UCSD Moores Cancer Center)
Lana Feng (Founder, Personalized Diagnostics)

The debate itself was more of a discussion, with minimal rhetorical tactics used by either side. However, the debate could have been improved with a better overview of patent law in general; the nature of audience questions indicated inadequate fundamental knowledge about what was being debated.

That said, the questions and discussions were very good. A few ideas / questions that stuck out to me:

1) Along the lines of patenting a technique for detecting something “natural”: Is the Reference Genome actually “natural” or a best-fit amalgamation of the genetic heterogeneity of mankind? If so, perhaps this is not actually natural and could be patented in itself?

2) Companies holding gene patents usually do not sue academic institutions, though they can. It is in their best interests most of the time to let academic labs do research and publish, purportedly adding value to their patents. (Lisa Haile)

3) Currently, diagnostic sequencing of patented genes (in her experience as a genetic counselor) are not dramatically more expensive than non-patented genes. (Lisa Madlensky)

After the panel discussions and audience questions concluded, I had a chance to catch up with Dr. Madlensky on the topic of diagnostic testing. As a genetic counselor with decades of experience, she has literally witnessed the birth of the genomic age through the eyes of medicine. I always see a sense of irony about the incredible multitude of what we “know” about genetics and how little is used in the clinic. The reasons for this are multifaceted, but are quickly rising from esoteric to painfully relevant with the growing tide of the genomic age.

In particular, I was interested in the impact of platforms like Understand Your Genome from Illumina that aim to put personal genomic data directly into the hands of the consumer. The Understand Your Genome conference will take place next month here in San Diego, and for a $5000 ticket and a DNA sample, Illumina will provide participants with an iPad with their genome browser application containing participant’s entire genome! I could wax poetic about the dawn of personalized genomics and science fiction becoming science fact, but for I am most immediately concerned with the way this will affect the physician-patient relationship. I wrote recently about the harms of overdiagnosis in otherwise healthy patients and many of these concerns could be carried over for considerations relating to personal genomics and genetic curation.

I relayed some of these concerns to Dr. Madlensky, and she had a few perspectives to add to the mix. Although the FDA guidelines are evolving, there is regulation in place for diagnostic-grade sequencing information, and before making any recommendations in genetic counseling it is necessary to have gene(s) in question re-sequenced, usually via the Sanger method. Critically, diagnosis today is mostly phenotype driven, not genotype driven: physicians and genetic counselors do not usually go looking for things that could be “wrong” when no obvious malady is present. Even then, they do not usually do genetic interrogation without having other reasons for doing so, like presence of disease symptoms in the patient or a family history of such.

That said, there is a changing trend, and the rising genomic tide might entice more patients and physicians to use the emerging genetic tools for screening purposes. However, there is still one major gatekeeper for any medical intervention: the physician (as it should be, in my opinion. More on that some other time). The physicians’ recommendations and prescriptions, in turn, are regulated by follow-up medical grade sequencing diagnostics of individual genes. Given this scenario, it would not be too much of a stretch to imagine a hugely increased demand for diagnostic-grade sequencing tests and centers (private or public) and for qualified genetic counselors, as most primary care physicians are are not adequately trained in the nuances of molecular diagnostics to make use of the rising tide of personal genomics.

In summary:

The recent Supreme Court rulings will not directly, dramatically change the current medical genomic landscape for patients. However, it makes a smoother landscape for sequencing enterprises.

In the near future (less than a few years) we may all have our genomes on iPads.

Given this scenario, the rate limiting steps for medical action will still remain with physicians (I hope), and their actions are in turn limited by the availability of diagnostic-grade medical sequencing tests.

There might be vastly increased demand for FDA-approved medical diagnostic sequencing tests and centers.


Written by Ryon

October 1st, 2013 at 4:06 pm

Posted in Science Blog

On riding and ridding disease, motivations of medical researchers

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27 September 2013

I’ve made another guest appearance in the award-winning science blog Beaker, offering meditations on medical research, health ethos, cycling, and Pedal the Cause.

Image: Jamie Lynch (left) and I recently rode from UCSD to Julian and back, following the inaugural Pedal the Cause route. Not pictured are the copious amounts of Julian Pie consumed shortly thereafter.

There’s a certain duality to medical researchers. On one hand, there’s the immense dedication and time devoted (years, wrinkled skin, and gray hairs) toward the enormously engrossing practice of science. It’s a curious compulsion sharpened by a hunger to discover what has never been known before. I wrote briefly before about this on Beaker a few weeks ago. On the other hand is the deep motivation drawn from compassionate empathy for those crippled by disease. It’s a very human connection, and medical researchers need to allow both forces to guide their inquiry and labor.

Central to this ethos is the assertion that everyone should have the chance to live a happy, productive life. Of course, this ethos extends much further than medical research, and everyone can do a lot to promote healthier, happier living for themselves and those around them, regardless of profession and life circumstances. Medical research marches on and continues to improve lives and grant more birthdays, but the mere absence of disease is not health; medical research is critically important, but it is far from the only initiative toward that end.

Continued here:

Written by Ryon

September 27th, 2013 at 1:06 pm

Posted in Science Blog

Quantifying the Harms of Overdiagnosis?

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17 September 2013

A central tenant of the Hippocratic Oath is “Do No Harm” and a recent article brought to my attention how few clinical trials aimed at early cancer detection measure the harms to patients in the screening process (1). (downloaded for free here:

There is a huge push for early detection in cancer. Groups like the Canary Foundation and the American Cancer Society have early detection squarely in their mission ethos and have aggressively emphasized self-detection and funded research for early detection trials and technologies.

A late 20th century view of cancer progression is that of a long road with distant metastasis (the life-threatening threshold in disease progression) at the end (2), offering a hypothetical window of intervention… if that window was opened by screening. These views are still dominant in many circles, but (at least in the instance of breast cancer) have recently been challenged by a rising tide of clinical trials, epidemiological data, and experimental models of metastasis. Late metastasis is far from universal in solid tumor progression.

Nonetheless, the hypothesis that early detection might lead to a decrease in cancer-associated deaths was rigorously pursued in the last decade, and has resulted in some major changes in screening policy. The culmination of these data resulted in the UK Panel on Breast Cancer Screening recommending a decrease in screening (3). While early stage diagnosis of breast cancer increased with increased early detection measures, the overall reduction in cancer related deaths were so low that it was judged as unethical to screen so many women.

Yesterday, a paper came out in the British Journal of Medicine that took this a step further: the authors attempted to quantify the harms to patients from screening. Harms can come in a variety of forms, and they include (but are not limited to):

-Invasive procedures for early detection (body fluid sampling, biopsies, etc).
-Overdiagnosis (and unnecessary chemical or surgical procedures).
-Unnecessary psychological harm from misdiagnosis of a condition that is not physically harmful.

Results Out of 4590 articles assessed, 198 (57 trials, 10 screening technologies) matched the inclusion criteria. False positive findings were quantified in two of 57 trials (4%, 95% confidence interval 0% to 12%), overdiagnosis in four (7%, 2% to 18%), negative psychosocial consequences in five (9%, 3% to 20%), somatic complications in 11 (19%, 10% to 32%), use of invasive follow-up procedures in 27 (47%, 34% to 61%), all cause mortality in 34 (60%, 46% to 72%), and withdrawals because of adverse effects in one trial (2%, 0% to 11%). The median percentage of space in the results section that reported harms was 12% (interquartile range 2-19%).

Conclusions Cancer screening trials seldom quantify the harms of screening. Of the 57 cancer screening trials examined, the most important harms of screening—overdiagnosis and false positive findings—were quantified in only 7% and 4%, respectively.

If the numbers were not poignant enough, the authors offered a few comments on the matter:

While we acknowledge that collecting data on harms will complicate cancer screening trials, this is not a sound argument against the strong ethical obligation to collect such data. If trialists do not report certain outcomes because they consider that the harms will be either rare or irrelevant when compared with the potential decrease in mortality, such information will not be available for people who judge these outcomes differently. We think that future screening trials should collect and report the expected harms of screening (false positives, overdiagnosis and overtreatment, psychosocial consequences, somatic complications, and all cause mortality). Adequate reporting of harm requires data from the control group as these provide a reference level and help to interpret harms data from the screened group.

Not addressed by the authors is the argument that perhaps increased screening could offer a peace of mind for the concerned. Another recent review article (4) examined the psychological outcomes of patients in response to screening for rare diseases in otherwise healthy patients and found that:

Diagnostic tests for symptoms with a low risk of serious illness do little to reassure patients, decrease their anxiety, or resolve their symptoms…

The take-home message that I get out of this is that we must not assume that any intervention will not be harmful, and that we need to design trials to both quantify this effect and ethically weigh this against data obtained from the results of trials of early detection and beyond. Without such reporting there is no way to know if we are doing more harm than good.


1. Heleno B, Thomsen MF, Rodrigues DS, Jørgensen KJ, Brodersen J. Quantification of harms in cancer screening trials: literature review. BMJ. 2013 2013-09-16 11:34:45;347.
2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70. PubMed PMID: 10647931. Epub 2000/01/27. eng.
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4. Rolfe A, Burton C. Reassurance after diagnostic testing with a low pretest probability of serious disease: systematic review and meta-analysis. JAMA internal medicine. 2013 Mar 25;173(6):407-16. PubMed PMID: 23440131. Epub 2013/02/27. eng.

Written by Ryon

September 17th, 2013 at 11:16 am

Posted in Science Blog

Med Into Grad begins!

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16 September 2013

I’m proud to announce that I’m taking part in the 2013-2014 Med Into Grad Initiative hosted by the UCSD School of Medicine and the Howard Hughes Medical Institute (HHMI).

“Big Data” and “Personalized Medicine” are buzzwords that, to my astonishment and delight, have been born and are currently in their infancy right in front of my own eyes here at the Moores Cancer Center! I’ve spent a fair bit of time studying and applying my knowledge of cancer biology for the sake of cancer biology, but I am very interested in cancer diagnosis and clinical trials. The pace at which new target therapies are entering the clinic is staggering, and it’s truly amazing to see knowledge of signaling pathways and phenomena being utilized that a decade ago might have been regarded as esoteric to the point of banality for lack of tools of clinical intervention.

This week my 12 classmates and I began our coursework in anticipation of spending January through March 2014 away from the lab bench and in the clinic. And for me, “clinic” entails inpatient and outpatient oncology clinics, med school classes, tumor boards, and grand rounds. I’ll be shadowing oncologists and observing the nuts and bolts of current cancer therapy.

Although I’ve been attending tumor boards here at the Moores Cancer Center for some time now, Med Into Grad will allow me a new level of access to the broader knowledge (perspective) base that I seek to participate in this emerging age of oncology and medicine.


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Written by Ryon

September 14th, 2013 at 7:37 pm

Posted in Science Blog

The Future was Yesterday at the 25th Usha Mahajani Symposium on Cancer Genomics at the Salk Institute

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10 September 2013

Yesterday I had the pleasure of attending the 25th Usha Mahajani Symposium at the Salk Institute. This year’s theme was Cancer Genomics, an extremely hot area of research right now. It attracted an all-star cast of international bioinformaticians with “TED-quality” presentations, as referred to by a colleague.

Kenna Shaw is the (now-former) director of The Cancer Genome Atlas project (I’ve often wondered if the acronym TCGA was not perhaps a tad too perfect) and gave a great talk on the progress of the database and some of the fundamental insights into cancer biology already discovered in the process. They are approaching their goal of 500 cancer genomes per cancer type* with matching mRNA, copy number variation, survival data and more for both tumor tissue and matching normal tissue (usually blood). My favorite browser for this data is the cBioPortal from Sloan-Kettering.

*I find it somewhat ironic that TCGA data is organized by gross histological subtype – using a system of organization that it is simultaneously making obsolete.

It was not originally clear to me that only malignant tumor cases are represented. None of the patients had carcinomas in situ. Also, all of the patients were treatment-naiive. The data has not been affected by selection pressures of chemotherapy.

One of the best messages put forth by Shaw in her dense, frenetic paced talk was the need to look not just at genomic data, but all of the -omics, and the lengths her groups went through to get complete data on many fronts for these cancer patient samples.

Rene Bernards gave a fantastic talk outlining a resistance mechanism to vemurafenib, a BRAF V600E inhibitor that became available for melanoma a few years ago. In what seemed very odd at first, the upstream kinase EGFR was upregulated to escape BRAF / MEF / ERK blockade, which lead to PI3K pathway activation. The takeaway messages from his talk were twofold for me:

1) Cellular circuitry is much more redundant than we intuitively think and we’ve likely just begun to uncover many of the resistance pathways to targeted chemotherapy.
2) Understanding these most common resistance pathways might allow complementary blockade through combinational therapy (a PI3K or mTOR inhibitor paired with vemurafenib, for instance).

Atul Butte produced a vision of what computational biological labs (and garage biotech startups) might look like in the future. He stressed the point that it’s becoming more and more possible to “outsource everything but the questions.” He then told a story of his own research projects that was more about the process than the result, namely the use of several powerful pharmaceutical research experiment vendors like Assay Depot combined with (shockingly free) resources like the massive genome array database Gene Expression Omnibus and Chem Pub, and when topped off with the (yes, free) central clinical trials database IMMPort. Butte produces a vision (business model?) for someone with the appropriate computational skillset to create an academic research lab (or garage biotech company) with minimal overhead.

Razelle Kurzrock‘s presentation is worthy of its own follow-up article and commentary. She stressed that we absolutely need to change the way we conduct early stage clinical trials for targeted therapies. Toward that end, a few main messages from her talk:

1) We are shooting ourselves in the foot trying out new targeted therapies in patients that are already refractory for disease. She made many parallels to the CML / Imatinib revolution that resulted from treating early-stage patients with BCR-ABL blockade.

2) We need to organize clinical trials around “molecular hubs” (i.e. the EGFR / RAF / MEK / ERK / PI3K / mTOR axis) not necessarily tumor-tissue-of-origin type, and validate molecular hub targeting strategies, not specific drugs.

3) We need to determine rules of thumb for safe drug combinations, since the specific tailored combinations received by patients in her vision might might be rare and not vetted by thousands of patients getting the same tailored combinations.

Overall I had a great time at the symposium and look forward to attending next year.


Written by Ryon

September 10th, 2013 at 1:39 pm

Posted in Science Blog

All the kids are above average…

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6 September 2013

Didactic cognitive bias education could be very useful for medical researchers (and would have saved me a lot of head-banging!)

Image: Colloquially referred to as the “Lake Wobegon Effect” the experimentally derived Dunning-Krueger Effect explains why humans frequently believe they are more proficient at things than they actually are.

This morning I read a brilliant essay on the neuroscience of perception to discuss how internal biases develop by Robert Burton in Nautilus Magazine, Issue 5

Asking a juror to be ‘objective,’ recognize and control innate biases and understand his or her lines of reasoning, flies in the face of the evolving science of decision-making. The harsh and scary reality is the scales of justice aren’t tipped in the open courtroom; the real action occurs out of sight.

A few years back I started to understand the power that ubiquitous cognitive biases have in perception and decision-making. Likewise, I began to actively seek consciousness of innate biases, much like one would take up a workout routine or a new hobby. It’s an ongoing process, but as time goes on I’ve gotten much better recognizing my own biases of logic and reasoning, but also those of friends, colleagues, collaborators, and those published in the scientific literature.

Recognition is one thing, but countering intuition takes practice and persistence. Why do I “know” it’s not going to rain today? How and why do we overlook the obvious? Does a fish know it’s in water? What if this model of cancer metastasis is an association fallacy of a celebrity scientist bolstered by the momentum of hundreds of non-questioning researchers over time?

With my graduation less than a year away I’m frequently asked things like “what are you going to do with your PhD?” or “what will it allow you to do?” I’ll be the doctor that can’t help anyone! But really, one of the most valuable skills I’ve gained is how to recognize how cognitive biases affect my work (and every day life). From how I design my experimental controls, why I chose certain thresholds, what statistics would be most appropriate, to what I eat for breakfast and why I insist on riding my bike instead of driving when there’s a 50% chance of rain (that weatherman’s just a talking head, right?) I’ve come to recognize how pervasively influential innate cognitive biases are in everything I do, and how invaluable understanding these processes are for young scientists.

Toward that end, I’d like to think out loud that perhaps didactic training (i.e. classes) in cognitive biases would be very beneficial for PhD students. After all, the PhD is not about learning what to think, but how to think.

Admittedly I’m not very well versed in the coursework of many PhD programs, but I’ve never heard of formal training to recognize cognitive biases as a means to produce better scientists. Perhaps this is commonplace in some circles? Or maybe my circle is the odd exclusion? Maybe this is something the better scientists learn on their own without realizing it? These mind-twisters burn like 50-pound single arm curls for my brain, but I’m always glad I did the workout!


(back to for more ramblings)

Written by Ryon

September 6th, 2013 at 4:40 pm

Posted in Science Blog