Posts Tagged ‘patient participation’

DTC Genomics: Opportunity Lost?

Monday, December 31st, 2012

Once I warmed up to the idea of startup companies offering to sequence the DNA of anyone capable of ordering from Amazon.com, I began to look forward to what might come of this nascent industry. Enabling individuals to have their DNA sequenced certainly seemed like an out-of-the-box idea at the time. I wondered if a so-called paradigm shift might arise from placing genetic information, unfiltered and unadvised, in the hands of those whose genes were being sequenced. Here were (and still are) two of my chief hopes for paradigm shifting that might come from throwing the genetics box wide open:

  • Will breaking the “chain of command” on health information change how we think about healthcare? The initial response from the medical world to the DTC genomics industry was less than enthusiastic, ostensibly because of the potential for harm when the uninformed masses got their hands on their gene sequences. This turns out not to be true—there is no evidence of harm from accessing one’s own DNA sequence information. Furthermore, there has been neither a flood of buyers nor a spate of lawsuits. The collective yawn over the availability of DNA sequencing (initial excitement not withstanding) suggests this might be more of a step along the way than a cannon shot.
  • Will putting this information in the hands of all who wish to know change how we think about genes? Over the last 60 years we have become quite genocentric in our view of biology. Genes are the “blueprints of life”, an identifiable “first cause” that drives everything else in the living world. For example, the term “oncogene” suggests that we have genes whose purpose is to cause cancer. That is possible, of course, but that suggests that there is some advantage to the organism to develop cancer, which doesn’t seem likely. As I think of it, genes are a part of a system we call an “organism” and they are no more or any less important than proteins, carbohydrates, etc that comprise that organism. It may be that not all of the diverse causes of cancer are genetic and we need to take a more holistic view of disease pathogenesis.

Essentially, what I am hoping for with the emergence of the DTC genomics industry is that the “hive mind” might provide new direction on genetics and its role in health and society. We might get really novel answers to thorny genetics questions like “what happens to missing heritability and is it important anyway?” Might it also be enough of a nudge to permanently put the paternalistic relationship between physicians and patients in the past? My hope for the DTC genomics industry is that it will help us reach a more balanced view of the role of DNA in living organisms.

However, for the moment at least, it appears that the wind is going out of the sails of the industry. As evidence, here are some recent developments:

  • Over the summer Navigenics was bought by Life Technologies, Inc. Gone was an industry pioneer.
  • This fall, deCODE was bought by Amgen. Not a surprising end to deCODE’s rocky road, but gone is another industry pioneer.
  • Recent developments announced by 23 and Me (patent received, grants funded, seeking FDA approval for products) sound suspiciously conventional. Has 23 and Me lost its will to break the mold?

Will there be a DTC genomics industry 2.0? The failure of pioneering companies in any new industry is not unusual. Yet, I am hopeful that these shifts will still happen. It seems likely, though, that it will be new companies that move the field forward and that (as usual) it will take longer than it initially seemed it would.

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Time to Rethink Cancer Therapy?

Wednesday, November 28th, 2012

In an earlier post, I wondered a bit about the ultimately causes of cancer.  For the last several decades cancer has been labeled as a genetic disease, an idea which we have chased with great fervor.  Yet, It feels to me sometimes as though the evolving story of the causes of cancer is like a hall of mirrors in an amusement park in that there seems to be an ever receding chain of causal genetic alterations fueling cancer’s inexorable progression.

The most visible of these alterations are in the growth modulating molecules of the cell.  Over expressed growth factor receptors or transcription factors, mutant signaling molecules, etc.  How did these components come to be broken?  Genetic insults of various kinds have been discovered, studied, and labeled as causes of cancer.  We are actually getting pretty good at intervening in some of these malfunctioning growth pathways that have been co-opted by cancer.  For example, antibodies that block the activity of HER2, the human epidermal growth factor receptor that seems in some cases to drive breast cancer proliferation are quite effective.

Yet, even when we do intervene with seeming effective tools, such as trastuzumab for HER2 over-expressing breast cancer, the cancer seems in most cases to rebound by activating still other pathways of growth.  It has come to be reminiscent of the proverbial leaky dike and us with not enough fingers to plug the leaks.

The genomic instability that is so characteristic of most cancers seems to be the driver of genetic diversity that provides resistant variants.  It appears that cancers “evolve” to a state of significant heterogeneity and the genomic instability seems to be a player in that process.  But, where does the genomic instability come from?  We can then propose a change in cells that causes genetic instability.  But, where then does that come from?  See what I mean?

This genetic, linear causation idea is the foundation on which our cancer therapy strategy is built.  Naturally, our combat strategy is direct.  Cut it out.  If you can’t cut it out, hammer it with chemicals or radiation.  If a little doesn’t work, then try a lot.  Too much cell division and DNA replication? Inhibit DNA replication.  Too much RAF signaling? Inhibit RAF signaling.  Battle this problem where it occurs: inside the cancer cell itself.  This strategy has produced some remarkable results; however, for most cancers, the fact remains that some cells inevitably escape destruction to arise as an even more fulminant tumor later.

The feeling of frustration in chasing cancer up the path only to have it resurrect out of seemingly nowhere still further upstream is a signal to me.  I have sensed in this frustration a signal to think about cancer pathogenesis and treatment in new ways, like I’m sure others have.  Recently I have been gratified to hear a number of researchers propose new views of what cancer is and new strategies for treating it.

I have been a member of a tumor microenvironment interest group for a while, mostly to keep an ear to the ground in that area.  Having spent many years trying to grow cancer cells in various ways, it is clear to me that they depend heavily on their microenvironment to survive.

Over the summer I noticed a few publications (see this news story in Nature Medicine for more details) suggesting that resistance to chemical therapy may be mediated by more than just the response of the tumor cells.  These studies suggest that the tumor microenvironment may provide protection from anti-cancer agents by secreting of growth factors from stromal cells intermingled with the tumor cells.  In one study, WNT16B growth factor secretion was induced in stromal fibroblasts, which in turn protected the cancer cells from programmed cell death.  In another pair of studies (here and here), stimulated secretion of hepatocyte growth factor from stromal cells attenuated the sensitivity of melanoma cells to BRAF inhibitors, one of our newest targeted therapeutic classes.  It seems that the effects of treatment are more complicated than we had thought.  Our cell-autonomous approach to drug development is probably too simplistic.  In retrospect, it seems obvious that we should account for the effects of other cells that, with the tumor cells, create the environment in which the cancer develops.

Rethinking cancer therapy has been proposed by Robert Gatenby and colleagues for some time now (see, for example, their article in Cancer Research in 2009).  Over the summer, Gillies, Gatenby, and colleagues published another paper describing how these concepts impact targeted therapy as progress in cancer therapy.  These folks have brought concepts from evolutionary biology and the control of invasive species to bear on cancer therapy.

Gatenby and colleagues describe a model for how evolutionary dynamics operate in the tumor microenvironment: phenotypic diversity, courtesy of genetic instability, provides the substrate for selective forces, provided by cytotoxic drugs, resulting in selection of tumor cells that can survive almost any insult.  Under this scenario, toxic drugs will select for some variant that will then proliferate to fill the niche vacated by the cells killed by the therapy.  Adaptive therapy is described as a potential solution to this problem.  In essence, adaptive therapy uses interventions that strategically impose a substantial evolutionary cost on cancer, thereby reducing its fitness to survive and ability to adapt to its new environment.

A high evolutionary cost means that interventions are difficult to evolve around.  To illustrate what these might be like, they draw examples from control of invasive species.  Might cancer be better handled as if it were an invasive species?  Two points that they make are 1) that eradication is often not possible and control of population size is the goal; and 2) the high-evolutionary cost interventions are often biological.

Although the cancer genome is an important component of the disease, it is becoming clear that there are additional facets of the disease, such as the interaction of the cancer genome with genomes in its environment.  Consideration of the role of tumor microenvironment modulation of therapy is a welcome expansion of how we think about cancer and our response.  Likewise, radically new strategies for cancer therapy, possibly like adaptive therapy, are welcome, as well.  Incorporating these new concepts into our view of cancer helps put us on the path to effective new treatments.

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DTC Genomic Testing—What’s it good for anyways?

Friday, December 30th, 2011

What is the fuss over DTC genomic/genetic testing all about anyways?  DNA is just a sequence of letters, isn’t it?  Lots of people are experiencing angst over the fact that these upstart companies would have the nerve to sequence part of people’s DNA for them.  I mean, it’s just a bunch of letters, isn’t it?

Seriously, I have to admit, I, as a molecular biologist, have experienced a degree of self-righteous indignation that these so called entrepreneurs would debase the field of genomics and medical genetics by offering to sequence anybody’s DNA for a price.  It seems beneath all of the effort and concern that has been invested in developing the field.  All of that hard-earned knowledge being sold off the shelf like a cheap tabloid.  That was the feeling, anyway, and I imagine some amount of that type of sentiment contributes to the resistance to the development of the DTC genomics field.

However, the reality is that those letters are attached to a lot of other information that may have health implications.  There are several serious genetic diseases (ironically, most discovered prior to the genomic era) whose sufferers (or carriers) traditionally receive genetic counseling to learn how to cope with the situation.

Beyond these known disease situations, the hype of the genomic age has led to lofty expectations for genomics.  Those letters are our shorthand for the substance (DNA) that gives us our individuality and which when altered is may give rise to disease, tell us who our relatives are, and potentially make us weller-than-well (if only we can change it a little bit).  We’ve bought pretty heavily into the idea that we are our DNA and therefore, revealing it is, in a sense, giving ourselves away.  There is an ever-growing body of genomic information that pins many hopes and dreams and futures to those four letters.  So, it’s not surprise that feelings run high when it comes to genomic information.

So, DNA/genes/genomics is loaded with expectation, but what’s DNA sequence information really good for when one takes a hard look at it?  How is it being used now?  We can start with a partial list of uses that have been found for DNA sequence information:

  • Disease risk assessment
  • Disease diagnosis
  • Preconception screening
  • Forensics
  • Genealogy
  • Recreation

The fuss that these upstart companies have created has revolved around health information for the most part.  That would be the first three items on the above list.  These companies are seeking to sell their customers their own DNA sequence information, along with an assortment of linked information regarding the health implications of the DNA sequence in question.  It’s the health information being sold along with the sequence information that has caused the kerfuffle with the FDA and the medical profession.  And, for some understandable reasons…

Long before we even knew what DNA was, enterprising companies and individuals were taking advantage of our sensitivity around health issues, selling remedies and other noxious (or inert) substances to solve health problems.  This profitable, but unethical, behavior was addressed through creation of the FDA, whose job it is to keep the nation’s healthcare resources safe.  So, here we have what might be called the modern day version of the snake oil salesmen (at least in the estimation of some): the DTC Genomics companies.  Not surprising, then, that the FDA might feel compelled to step in, as it appears they are likely do.  Similarly, many in the medical community have allowed as to how they would prefer that their patients not have access to their DNA information.  Also not surprising, since for known genetic diseases the medical profession has heretofore controlled this information  However, as it currently stands, the genomic profiles being sold by DTC genomic companies are pretty innocuous, so it doesn’t stand to reason to restrict the type of genomic information the DTC companies are selling.

My view is that we stand at a crossroads of sorts.  Down one road we regulate human DNA sequencing as a medical procedure, bequeathing control of the resulting information to specialists licensed to dispense that information in carefully predetermined ways.  This is a suitable model when the dispensing requires extensive training to avoid injury to the receiving party, as in the case of prescription drugs or cardiac catheters.  For genetics in the current information-rich environment and age of patient empowerment, I believe that there are a limited number of situations in which harm would come to a person who knew their own DNA sequence.  And, even those cases (e.g. Tay Sachs disease) it is questionable if the actual harm is sufficient to bar access except under carefully controlled conditions.

The other road might be one in which one can obtain the sequence of their genome, if they are so motivated and can afford it.  It is likely that reasonable quality services will be available to provide this information soon (currently there are concerns about quality with many of the providers; note to DTC genomics companies: you would do well to pay attention to the quality of your sequencing if you want to survive).  The latter three items on the list above would be supported by relatively simple, low hurdle access to sequencing services.  In fact, my guess is that FDA regulations or no, in the near future a motivated person will be able to get their genome sequenced.  Somewhere.

My concern  is what we might lose if we over-regulate DTC genomic testing.   The latter three items on the list have emerged in recent years.  What else might be added to the list in the future?  What uses for DNA sequence data are not on that list?

What is DTC genomic testing good for anyways?  I don’t think we know the answer to that question yet.  Should we follow the Silicon Valley paradigm, let go of the information, and see what millions of “users” out there do with it?  Should we “crowd source” genomics?  Maybe there is someone out there with a marketing degree, a penchant for spreadsheets, and the interest in genetics who can offer a creative solution for the problem of missing heritability of SNPs.  Maybe a user group will surprise us by producing a creative solution to one or another vexing biology or health problem that has stumped the collective brain power of us professionals?  We may not know what DTC genomics is good for unless we give it a chance.

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DTC Genomic Testing: a Window on Society?

Tuesday, April 19th, 2011

I continue to believe that the discussion surrounding the Direct to Consumer (i.e. DTC) genomic testing is basically a healthy thing (pardon the pun).  It seems to me to be a window into the larger conversation about the role of health care in society and evidence that we do pretty well in letting information flow freely.  I think that’s a good sign of a free society.

The DTC genomics testing debate seems to have looped in a group of people that are: a) health conscious, b) sophisticated, and c) medical non-professionals.  These folks are interested in taking advantage of the health empowerment that information technology and genomic technology have provided.  In this endeavor, they are bumping up against the health care system, which is fairly conservative and has its own status quo.  This latter element is certainly something those sophisticates who have been empowered by genomic technology (via DTC genomics companies) are not necessarily interested in minding.  The good news is that the debate around genomics and health care empowerment has been civil so far.  The court in which the debate is being conducted is the halls of the US Food and Drug Administration.

The FDA had a meeting…

In between the summer of 2010 and the US FDA’s meeting in March 2011 to hear feedback regarding DTC testing, Amy McGuire and colleagues published an article in Science proposing a mechanism for regulating these new genetic tests.  Essentially, McGuire et al proposed a “risk-based stratification” of regulation of these tests.  This means that tests thought to carry higher risks of harm will faced tighter regulation.  For example, testing for breast cancer predisposition might be subject to significant oversight because women face the risk of surgery or other significant and potentially harmful healthcare consequences based on the outcome of the test.

On March 8-9, the FDA’s Molecular and Clinical Genetics Panel heard testimony from a variety of stakeholders of DTC testing.  On one side, as one would expect, were the DTC genomics testing providers arguing that these tests should not be regulated out of hand.  In fact, the representatives of these companies seem to be willing to accept the risk-based stratification approach that the FDA appears to be leaning toward.  Their backers further argue that individuals should have access to their own genetic information and that the FDA should not come down hard on a promising new industry.

On the other side were some significant groups, such as the American College of Pathologists, who argued that lax regulation could be harmful to consumers.  The significant risks of DTC genomic testing were pointed out, including privacy concerns and inadequate support for the inevitable health-related questions from the recipients.  These folks also raised other interesting new concerns that need to be vetted.  For example, inappropriate dissemination of genetic information could be harmful, both to the tested individual (through inappropriate use by employers and insurance companies) and to their relatives who share some of their genotype.

Others brought recent information to the FDA panel.  Subsequent to the initial actions by the FDA last summer, a number of studies have been performed to examine the behavioral consequences of DTC testing among consumers.  So far the results have not suggested any systematic negative consequences, such as anxiety, for those who undergo testing.

All told, my sense of the reports from the meetings was that it was a pretty fair exchange of information, which raised legitimate concerns both for and against DTC genomic testing.  Yet, there are a lot of questions still to answer about how these technologies will serve society.

What about prenatal sequencing and other ethical questions

Although I don’t have the answer to this question, the recent paper from Lo et al in which the genome of a fetus was sequenced, raises questions about the appropriateness of massive prenatal testing.  Prenatal testing for even a single gene faces tough scrutiny, so what do we do when we can test for thousands of gene variants?  In this example the testing was for a single gene mutation (beta thalessemia), but the result showed that an entire fetal genome can be sequenced using a blood sample from the mother.  One positive here: this testing approach is non-invasive.  However, one can imagine the potential demand for prenatal sequencing to determine not only disease susceptibility, but also “soft” traits, like presumed intelligence.

Another question that I think may be under appreciated by people in favor of DTC testing (as pointed out by CAP) is the impact of the results on those genetically related to the tested individual.  What if those people, brother and sisters, are not interested in their genotype or would rather not know?  Does one have the right to post their genotype on the internet?

An extension of that idea came to life with the West family, in which each of the four members of the family underwent whole genome sequencing.  Although the genomic sequences of the kids are not public, one of the parents did submit their genome sequence to the NCBI database of genome sequences, thus releasing half of the genetic info of the kids.  Is that a privacy breach?

Another twist to that theme revolves around research on parental choice with respect to DTC testing of their kids.  A report from Tercyak et al in the journal, Pediatrics, suggests that parents who themselves undergo DTC testing are more likely to have their kids tested.  Parents were also more likely to favor testing if they thought their child was at risk or if they had a positive risk-benefit view of DTC testing (duh!).  Given the variability in quality of follow-up with these tests, it seems fair to question the use of DTC genomic tests in children.

Social liberty?

Not to overdo it, but what I find interesting in the DTC genomics debate is the renegotiation of power between health care consumers and health care providers.  It’s a bigger trend than just DTC testing, as evidenced by broader trends in consumerism in medicine.

One of the key arguments heard from those in favor of DTC testing is that they have the right to know information about themselves.  It’s hard to deny the truth in that.  But, there is definitely a balance that must be struck between individual liberties and the welfare of society.  The discussion of what to do with DTC testing is an interesting place to listen to that discussion in a very personal way.

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A Couple of Glimpses at the Genomic Future

Thursday, January 27th, 2011

There were a couple of stories in the news in the last few days regarding genomic/genetic testing that hit on recent controversies surround said testing.

In earlier posts, such as this one, I commented on the now world-wide discussion about the balance between regulation of DTC genetic testing and innovation.  A new browser plugin for viewing genomic data for data from Direct to Consumer testing company, 23andMe, was released by 5AM Solutions.  This plugin does some add-on processing of web pages as they are loading, such that single nucleotide polymorphisms (SNPs) mentioned by their common abbreviations are highlighted.  In addition, if one mouses over the highlighted SNP a balloon appears showing your genotype at that SNP, as well as links to SNP analysis resources.  This development is reminiscent of other internet technologies, such as Facebook and Linked In, where third party companies develop an overlay to platform software or datasets.  Only this time, it is personal genomics.  This little program represents the next step in mapping your genotype onto the mass of information available out there about genes, health, and life.  One can imagine where creativity may take personal genomics if it is not over regulated.

The second story could raise the specter of universal genomic testing in some people’s minds.  It certainly did touch that nerve for me.  The Department of Defense advisory group, Jason, produced a report that was released last week advising the DoD to move toward “’take a leading role’ in using personal genomics data”.  Among the goals that the report suggests is “eventual collection of complete human genome sequence data from all military personnel”, based on the notion that $100 complete genomic sequence will be available in the near future.  The supposition is that this information will give an advantage to the military in its missions.  If that is the thinking of the DoD advisory scientists with respect to genomic sequence data, then it is hard to imagine that the trend will go any other way than towards consideration of complete sequence data on individuals under other circumstances, too.  Given recent discussions on genome hacking we might want to keep an ear to the ground with respect to routine genome sequencing and its uses.

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ESHG Chimes in on DTC Genetic Testing

Friday, September 3rd, 2010

The European Society of Human Genetics (ESHG) published a policy statement in the European Journal of Human Genetics on the Society’s position with respect to Direct to Consumer Genetic Testing services .  In this position paper the ESHG discusses its position with respect to DTC advertising, quality, supervision, counseling, consent, privacy, and more.

Overall, the authors present cogent arguments for their views about how to handle DTC genetic testing.  The authors open by affirming that individuals have the right to know information about their genetic makeup, a point that I have not seen argued yet.  Then the authors tackle advertising of DTC services and quality of DTC services.  In both cases I, like the ESHG, think the DTC companies leave much to be desired.

The following paragraphs of the position paper from the ESHG espouse supervision of all genetic testing by medical professionals, mandatory counseling, and a significantly more involved informed consent process.  These views from the ESHG seem pretty conservative to me, to the point of being paternalistic.  In fact, the authors state that the “right to know” needs to be balanced against “the need to protect the same individuals from inappropriate genetic information”.  Keep in mind that the ESHG has an interest in enhancing the public perception of genetic testing.

While their viewpoints are valid ones, they seem to me to reflect the current status quo and to lose the potential for discovering new uses for genetic information in healthcare that may result from “open horizon” creativity.  To be sure, the entrepreneurial attitude that characterizes the DTC genomics/genetics companies now comes with risks, but its exploratory character can result in quantum leaps in understanding.  The diminished quality and partial truthfulness of these young companies struggling in a new industry can be hazardous to society, but at some level we need to take risks like those in order to advance.  The secret, I believe, is to balance the liberty with restrictions in order to control the risk to society and its individuals as best as we can.

The good news is that this is exactly the kind of public conversation we should be having about how to handle this new area of medicine.

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Genomic-level Testing: the Debate Continues

Friday, August 20th, 2010

This is an interesting debate unfolding here: what to do about Direct To Consumer (DTC) genetic/genomic testing.  The two sides seem to be

  • It’s my DNA and I want to know what’s there
  • You may not get correct information on your DNA and what will you do with it anyways?

I don’t think there is substantial objection to an individual knowing what the sequence of bases is in their DNA, however, the technical adequacy of DTC tests is an issue.  Will you receive the correct information about the sequence of your genes?  At this time, that is not assured.

The second big issue, and the one that has the greatest implications for health care delivery in the future, is how genomic information will be used.  I’m fine with people sequencing their own DNA, but what happens next has implications for those beyond the individual who had their DNA sequenced.  As pointed out by Annes and colleagues in NEJM (Risks of Presymptomatic Direct-to-Consumer Genetic Testing, 18AUG2010), there could be liability and other issues for the physician to consider when a patient brings in their DNA sequence information for consideration.  If the utility of that information is uncertain, then many unanswered questions will linger.  In their example, what if the 30-year old man presents sequence data with a “prostate cancer risk allele”?  The clinical utility of such information is currently unknown.  Does the physician order additional testing (and thus incur additional health care costs) or does the physician take no action.  What if the physician takes no action and some years later the patient is diagnosed with prostate cancer?  Is the physician liable?  If the decision to sequence one’s own DNA affected only the individual I think there would be little objection to the expenditure.  But it doesn’t affect just that individual.

The implications for our healthcare delivery system of the shifting of health care information access, as exemplified by DTC genomic testing, are also interesting.  In a certain sense this debate is the most visible current example of the ongoing negotiation between healthcare consumers and providers regarding ownership and cost.

As pointed out by Evans and colleagues, (Preparing for a Consumer-Driven Genomic Age, also in NEJM on 18AUG2010), patients increasingly know more than their physician about specific genetic topics.  This shift has been enabled by widespread internet access.  This empowerment of consumers by transfer of knowledge ownership from doctors/healthcare professionals/industry to patients should rebalance the value equation in favor of patients/consumers.  This in turn will reduce the cost of health care in the long run.

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More on the Future of Medicine

Thursday, March 11th, 2010

Support for Participation as a key component of the improvement of health care going forward is found in this article from the Harvard Business Review.  Important developments cited include behavioral economics, patient portals,  and checklists (for physicians, but why not patients, too?).

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