Category Archives: Laura Hercher


On July 31st, the FDA announced its intention to regulate both laboratory developed tests (LDT”s) and in vitro diagnostic (IVD) companion devices, and it will soon be asking for public comment on the proposed regulations. Should genetic counselors be among the people commenting? Well yes, as the new rules are likely to affect genetics practice, since many of the tests that look at genetic susceptibility are LDT’s and could be subject to a premarket review by the FDA that will delay or deny the clinical availability of new tests, and a mandatory process of adverse result reporting. The impact will be felt most immediately in cancer settings, where genetic tests that look at tumor DNA for purposes of choosing targeted therapies or predicting prognosis are likely first candidates to draw FDA scrutiny, but eventually the new rules should affect a range of clinical specialties. At stake is finding the balance between too much regulation, wherein it becomes prohibitively difficult and expensive to introduce new tests that can help diagnose patients and personalize recommendations for screening and treatment, and too little regulation, wherein we suspect that our information on the accuracy and reliability of new tests is not adequately accurate or reliable (an ongoing issue, by the way, with non-invasive prenatal testing. See Katie Stoll’s post here and a study, new this week, suggesting that the dreaded false positive result may be more common than test makers have led us to believe).


A little background on the two closely related entities that are the focus of new regulations. LDT’s are what used to be called “home-brews”: tests that are used by a single lab and not marketed as a kit or a device. Somewhat by historical accident, LDT’s have come to exist in a regulatory grey area, effectively exempt from FDA oversight. The assumption behind this was that what went on in an individual lab affected only that lab’s patients and that no agency could track every one-off solution engineered by a mom-and-pop lab. As with everything else in 2014, the status quo has been disrupted by new technology – but in this instance the new technology isn’t the magic of Google or whole genome sequencing but overnight shipping. Yes, the world of genetic testing has been turned on its ear by the likes of UPS and Fed Ex.


In brief, now that the Pony Express has picked up its game, laboratories can test samples from all over the world in centralized locations with sophisticated and expensive testing capability that isn’t available back on the farm. At the same time, lab tests, including genetic tests and biomarkers like measures of gene expression, play an increasingly important role in making diagnoses and determining treatment. For this reason, the FDA has moved in its determined yet glacial manner to regulate a subset of tests that are considered high or medium risk – those tests which have the potential to alter medical care, and therefore have significant implications if the information they provide is incorrect. This risk-based approach is a measured step – it allows the FDA to continue to use discretion when tests are low risk or experimental or involve a rare disease for which there is no other test.


IVD companion diagnostics are tests developed to be used in conjunction with a drug or other therapy – tests that can be used to refine dosages or identify good candidates for a given therapy. Obviously pharmacogenetics is a subset of this broader category of companion testing. Again, the proposed regulatory framework would stratify the tests as high risk, moderate risk, low risk – requiring pre-market approval for higher risk tests, and allowing the agency to exercise “discretion” in low risk situations (discretion is FDA-speak for a wink and a nod). With regard to IVD diagnostics, the FDA intends not just that the tests on offer be confirmed as reliable, but is instituting the requirement that companion testing be included in the development of new therapies as a matter of course. In effect the government is mandating that all new therapies be individualized to the greatest extent possible: When an appropriate scientific rationale supports such an approach, FDA encourages the joint development of therapeutic products and diagnostic devices that are essential for the safe and effective use of those therapeutic products.” The age of personalized medicine is upon us, and the FDA is ON IT.


If all this sounds familiar, it only means that you have been paying attention. Since 2010, the FDA has been asserting publically that it has both the intention and the authority to regulate LDT’s and IVD’s. Going back even further, the Genomics and Personalized Medicine Act of 2006, introduced by then Senator Barack Obama, emphasized the development of companion diagnostics, calling on the National Academy of Sciences to recommend incentives and requiring the Institute of Medicine to improve “oversight and regulation of genetic tests.” While the bill was never passed, it is not surprising to see a similar emphasis under the current administration.


So, genetic counselors, are we for or against the proposed regulations? Probably the answer to that question is — yes. Like the FDA, most people seem to be in favor of some middle option – regulating everything is virtually impossible and regulating nothing is an appealing libertarian fantasy, but in fact it would put counselors in the uncomfortable position of having to rely on figures supplied by the companies who manufacture the tests. Careful observers like the Genetics and Public Policy Center have been calling for increased oversight for genetic testing for years. Their 2006 summary of a genetic testing quality initiative sums it up this way:


assessment of public attitudes shows that the public widely believes that the government regulates genetic tests to ensure their quality and, moreover, that the government should play this role. In fact, however, genetic tests are subject to very little governmental oversight when compared to other health care products. There is no formal approval procedure a laboratory has to go through before offering a new genetic test, and government requirements to ensure that genetic testing laboratories are getting the right answers to patients are minimal. Moreover, there is no government requirement that a test must be clinically valid – i.e., actually relate to a particular disease or risk of disease – in order to be sold.”


However, both the American Clinical Laboratory Association and the American Medical Association have reacted negatively to the proposed FDA regulatory strategy. The ACLA pushback comes as no surprise – few entities welcome idea of FDA regulation – and the organization has submitted a petition claiming that only CLIA and not the FDA had authority over LDT’s (the FDA rejects this). The more measured response of the AMA reflects the concerns of clinical care-givers, and may align with the attitude of many genetic counselors:


The draft FDA Framework for Oversight of Laboratory Developed Tests (LDTs) announced today, outlines a risk-based approach that raises a number of questions and concerns. 

The FDA proposal adds an additional layer of regulatory requirements which may result in patients losing access to timely life-saving diagnostic services and hinder advancements in the practice of medicine. 

The AMA is committed to ensuring that the proposal that is ultimately adopted by the FDA preserves rapid access to care and medical advancements. 

What makes it difficult to respond to the FDA is that there is a lot of wiggle room left in the regulations as written. High and moderate risk tests will be required to report adverse results and apply for pre-market review according to separate timetables – but the FDA will not define those terms for up to 2 years after the regulations are finalized (Policy and Medicine has a useful chart if you are looking for specifics on timelines). In other words, the FDA has designed a system that gives them room to maneuver – and is asking for respondents to give feedback on the plan without knowing where the agency plans to draw the line. For example, breast cancer susceptibility panels probably aren’t low risk; they are medically actionable and complicated to interpret. Are they high risk or moderate risk? The somewhat hyperbolic letter from the FDA to 23andMe last fall* suggested that the agency believes the fallout from breast cancer risk prediction done badly might be unnecessary mastectomies. That sounds pretty high risk – but is that the perceived reality of counselors who work with these tests?


The rare disease exemption in the FDA plan means that whole exome or whole genome sequencing would not be affected, in those cases where the patient presents with an apparently genetic condition that has eluded diagnosis. WES for those with no apparent disease, who wish to use the information prophylactically? I have literally no idea what risk the FDA would assign to clinical versions of genome scanning. What about the genetic testing done for children with autism? These supplement rather than point to a diagnosis and would rarely change treatment but may have a big impact on the parents reproductive choices – is that consequence enough to bump a test from low risk to high risk?


I might sound like I am criticizing the FDA, but in fact I am sympathetic to the difficulties inherent in a modulated approach and appreciate that they are attempting to tread that knife’s edge. I do think it makes it difficult to provide feedback, and I would suggest that their policy be reopened for public comment at critical junctures, such as the point at which high, low and moderate risk categories are more carefully defined. Useful commentary now, I would suggest, will need to be far more granular than the FDA regulatory language itself. What tests do you feel work well for you and your patients? Are there tests in use or in the pipeline that concern you? Which ones? Why? Share your concerns here, and I will write up a response incorporating reader response when the draft regulations are posted for public comment.


*Note: don’t bother telling the FDA that you are concerned about direct-to-consumer testing, because the agency has already noted that this applies only to testing in a clinical context. No DTC testing will be exempt from review – a footnote to the FDA’s announcement that had DTC advocates screaming foul – for details see Jennifer Wagner’s irritated response at the Genomics Law Report.


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The Bumpy Road From Bench to Bedside: Top 10 Genetics Stories of 2013

10. 23andMe and the Thanksgiving Week Massacre


You can get anything you want…except personal genome screening.

The Monday before Thanksgiving 2013 the FDA issued a letter to 23andMe directing them to cease and desist sales of their personal genome service (PGS) within 15 working days.  In shutting down 23andMe, the government agency was in effect shutting down an industry, since 23andMe was the last player standing of any significance in the fledging direct-to-consumer genetic health information services field.  This added some drama to the situation and some volume to the howls of outrage from libertarian-minded science geeks who not only liked but believed in 23andMe.  To be entirely fair, its hard to blame the FDA for taking down the last lonely cowboy, since 23andMe has helped a number of competitors out the door, dipping into their deep pockets and selling their test at a loss.

Of course this is 2013, and information never really goes away.  The FDA ban covers the PGS – the advice, not the SNP data.  There are no rules that prohibit giving back sequence data sans annotation.  Those willing to do their own digging can use promethease, a free online tool for SNP analysis.  And the FDA cannot regulate promethease because it is not for sale – impersonating a doctor for money is against the rules, but giving out crap advice for free is the god-given right of cranks and yoga enthusiasts and pretty much every neighbor I have ever had.

Destroyed or not (and we shall see; I’m expecting a resurrection, minus a few of the more controversial tests like BRCA 1 and 2), the entire personal genomics industry isn’t much more than a blip (the company claimed to have scanned 500,000 people since 2006, but did not say how many were paying customers).  For a more thorough discussion of the issues involved in this case see here, but for the purposes of this column, I would make two general points about why this story was significant.  First, it indicates that the FDA is willing to play a more active role than the heretofore have in the regulation of genetic testing as a medical device.  Second, and with all deference to point one and the need for some regulatory power, the story demonstrates the essential futility of trying to control the flow of information in the internet age.

9. The Supreme Court delivers a verdict in the MYRIAD Lawsuit, bringing clarity and … myriad lawsuits.

Three years after District Court Judge Robert Sweet shocked the genetics world by declaring gene patents a “lawyers trick,” the Supreme Court weighed in, ruling unanimously that naturally occurring DNA sequences are laws of nature, and thereby striking down a number of the patents held by Myriad Genetics on BRCA 1 and 2.  In their opinion, the Court distinguishes between genes as they appear on the chromosome and cDNA, the edited form obtained by working backwards from a gene product – a transcript of the performance rather than a copy of the script, so all the notes and stage directions are missing.  The Court’s reasoning – that cDNA is not found in nature – is not entirely true, and future cases may challenge that notion, but for the moment the message is clear: DNA patents are out, and cDNA patents are in.  This splitting-the-baby approach may have been a judge’s version of a lawyer’s trick, because it invalidated gene patents, which the justices clearly felt were problematic, but did not in a single swipe eliminate all claims relating to DNA, thus wreaking havoc in biotech.

Did I say things were clear?  Well….  This was a result that satisfied the genetics community, which was never comfortable with the restrictions and costs imposed by Myriad’s decision not to license its BRCA patents.  There was celebration in the air as rival labs announced the availability of BRCA testing, or maybe that was gunfire, since Myriad immediately declared its intention to defend its remaining patents.  Here is what clarity looks like in December 2013:

Screen Shot 2013-12-20 at 11.53.24 AM

Okay.  So perhaps not entirely clear.  But the decision does resolve some theoretical issues going forward, as we put to rest whatever anxieties there might have been about negotiating a genome littered with patents in the age of next-generation sequencing.  And if not the final word, it is still an important moment in the BRCA saga, a story that has kept us entertained for years, a story that has had everything: Mary Claire King, dueling labs, Mormons, the ACLU, Clarence Thomas, even a cameo by Angelina Jolie.  It is the story of a test that single-handedly brought into being the field of clinical cancer genetics.  It is a story that defines its time, and somehow to me, this decision, this imperfect and welcome decision, feels like the end of an era.

8. North Dakota passes an anti-abortion law that is the first of it’s kind (but may not be the last).

Remember the law restricting abortion that North Dakota passed last March — no abortions after the fetal heartbeat can be detected, about the 6th week of gestation?

No, not that one.

It’s the other North Dakota law, the one that makes it illegal for a physician to provide abortion:

“with the knowledge that the pregnant woman is seeking the abortion solely: a) On account of the sex of the unborn child; or b) Because the unborn child has been diagnosed with either a genetic abnormality or a potential for a genetic abnormality.”

Sure, there are loopholes here you could drive a Mack truck through.  It requires doctors to know the woman’s state of mind.  Isn’t ambivalence the natural state of all mankind?  In practice, the law is of so little significance that North Dakota’s only abortion clinic dropped their legal challenge to ND 14-02.1-02.  The clinic, like the media, has chosen to focus on the fetal heartbeat law, which a judge has blocked pending a ruling.  But google the story, and you will see that groups like LifeNews and American United for Life are paying close attention.  “Dismissal of the portion of the lawsuit challenging the ban on sex-selection or genetic abnormality abortions should be seen as a victory, for now,” said the New American.

Take home: prenatal diagnosis is on the radar of the anti-abortion movement.  This law is not a burst of craziness or the brainchild of some random legislator in North Dakota.  It is a response to the increasing capabilities of genetic and prenatal testing, an informed, calculated, ideological response, not just to abortion but to the idea of selecting against certain fetuses.  The eugenic capabilities of prenatal screening concern large swaths of the population: push those buttons, and they will push back.

7. Sequencing, The Next Generation: Oxford Nanopore offers researchers a chance to beta test the adorable MinION.

After many years of development and a couple of false starts, Oxford Nanopore seems poised to usher in 3rd generation sequencing.  It’s nanopore technology offers longer read lengths (and thus fewer alignment and assembly issues), relatively low costs and real-time capabilities, with the potential to bringing sequencing of DNA, RNA and protein expression to the bedside.  The company did a much buzzed show-and-tell at ASHG in October, and has issued an invitation to researchers to apply for up to 50 free MinION sequencers, in a tone that veers from infomercial (“additional shipping charges” will apply) to vague (“at least two days notice will be given of closure of the registration period. This will be noted on our website and on Twitter”) to zen (“We are requesting little information about your intentions for MAP and no supplementary information is necessary”) to hard-nosed (“Competitors of Oxford Nanopore and their affiliates need not apply”).


The MinION is the smaller of two Oxford Nanopore products in development, and it’s so cute if they put a brushed aluminum bezel around it they could sell it at Apple (I hear the iphone 7 is going to have gene sequencing anyway).  For data reads, it plugs in to a computer via a USB port.  A larger-capacity product, GridION, is essentially lots of little minions in a bigger box (maybe they should have called it PlantatION).  To get a sense of how the technology works, check out the video on the Oxford Nanopore website.  “Oxford Nanopore designs and manufactures bespoke nanopore structures,” says the narrator in a lovely Downton Abbey accent strikingly at odds with a technology that has been called, in that most 2013 of phrases, “disruptive.”

6. “Anonymous” gets outed.

In January, Whitehead Institute fellow Yaniv Erlich and fellow MIT hacktivists announced that they had successfully identified participants in the 1000 Genomes Project whose DNA was published “anonymously” online, using only publicly accessible databases like genealogy websites, where DNA markers are linked to surnames.  Designed to test the limits of de-identification, the project was a wake-up call for any researcher, institution or biobank who offers donors hard and fast promises of anonymity.

With proof-in-principle established by the Cambridge crew, MTV tested clinical applications with its November premiere of Generation Cryo, a reality show following a young woman conceived by donor sperm who enlists a crew of half-sibs to find their collective donor dad.  “Perhaps he doesn’t want to be found,” suggests one adult to 18-year-old Breeanna Speicher, who pauses to think about that momentarily before ignoring it entirely and rededicating herself to her quest.

Will she find him?  Chances are she’ll be knocking on his door any day now.  Why?  Because DNA is THE BEST IDENTIFIER IN THE WORLD.  Anonymous DNA is an oxymoron.  And anonymous DNA donors are an endangered species.

5. Two-year-old girl gets a trachea manufactured from her own stem cells.


Fabricated organs were everywhere in 2013.  In April, a team of Japanese scientists led by Takanori Takebe announced in Nature that they had succeeded in creating tiny but functioning livers from human stem cells, able to perform basic liver functions when transplanted into mice.  In April, researchers in San Diego produced what Gizmodo called “itty-bitty livers” using a 3-D printer; later versions lasted as long as 40 days.  In August, Nature profiled researchers in Kyoto who had managed to turn murine induced pluripotent stem cells into sperm and eggs – and to prove that they were real by using them, creating viable and fertile mouse pups.

But the organogenesis story of the year concerns a real treatment for a real girl: 2-year-old Hannah Warren, born without a windpipe.  A trachea is not as complicated as a liver or as sexy as sperm and eggs, but you can’t survive without one.  So the little Korean-Canadian girl who had never lived a day outside the ICU flew to the United States to be operated on by Dr. Paolo Macchiarini, the Italian director of a Swedish Institute.  They used a windpipe grown with her own stem cells on a matrix of plastic shaped to resemble a trachea.  The parents could not afford the operation, so Children’s Hospital of Illinois donated its services. There’s a lot of messages in this story: the incredible potential of the technology, of course, and the global nature of it all.  The fact that it was possible but unaffordable says something important about the future as well.  And finally, unhappily, it must be reported that little Hannah Warren died of lung complications in July, three months after her surgery.

And that’s the final message: it may sound like magic, but this ain’t no fairy tale.

4. The Archon Prize is cancelled for lack of interest.

In 2003, proponent of gladiatorial science Craig Venter announced a contest: $500,000 for the development of technology that would bring down the cost of genome sequencing to $1000.  Subsequently re-branded as the Archon X Prize for genome sequencing, the challenge helped make ‘the $1000 genome’ a meme that represented the future of the field.  The Archon prize, after serving for a decade as goal and talking point for rival sequencing companies, was scheduled to be held as a month-long competition in September 2013, until it was abruptly cancelled in August for lack of interest.

An event that did not happen is an odd candidate for a top ten story of the year, but think about what this cancellation suggests.  First, it suggests our technological horizons have changed so rapidly that we became bored with the goal even before we reached it.  Peter Diamandis, X-Prize chief executive, acknowledged in the Huffington Post that the $1000 genome remains elusive – costs still linger closer to $5000 — but suggested that the field has moved on.  “Genome sequencing technology is plummeting in cost and increasing in speed independent of our competition.”  Second, it suggests that in 2013 our ability to produce sequence data has so outpaced our ability to process and understand sequence data that a competition to produce more of it, more cheaply, seemed suddenly like not such a good idea after all.

3. First gene silencing drug approved by the FDA.

Gene therapy and gene silencing are mirror images – turning genes on, turning genes off – and for years they have shared the burden of great potential with not much to show.  But this may be starting to change.  And although the trickle remains a trickle, gene therapy continues to show progress in clinical trials, and in January a gene silencing drug was approved for the first time by the FDA.  Called Kynamro, the drug is intended for familial hypercholesterolemia homozygotes.  In preliminary tests, it reduced LDL levels by 25%.

Raising the stakes on gene silencing, Jeanne Lawrence of UMASS published an article in Nature in July, detailing how her team was able to use the XIST gene to silence a single copy of chromosome 21 in trisomic cell lines.  The authors expressed a hope that the technique will eventually lead to treatments for features of Down Syndrome.

2. The best thing since sliced bread?  Maybe better!  CRISPR slices genomes to order.

On December 12th, researchers operating out of an assortment of low-rent facilities in Cambridge, MA published a report in Science identifying genes involved in acquired resistance to chemotherapy, the first discoveries made by systematically testing human cell lines using the miraculous new technology, CRISPR.

This powerful gene editing technique hijacks a component of the bacterial immune system – a sort of programmable warrior armed with enzymatic, DNA-snipping scissors and a list of targets written in a DNA code — snippets from viruses that attack bacteria.  The system, elucidated by Jennifer Doudna of Berkeley and Emmanuelle Charpentier of Umea University in Sweden, was re-jiggered to use as a guide an RNA molecule that could be made to order.  The result: a mechanism for cutting DNA at will throughout the genome, effectively repressing or even altering genes in a very specific and targeted fashion.

The new technique has drawn raves for its versatility and ease of use (“A total novice in my lab got it to work,” marveled Nobel Laureate Craig Mello) and has been used successfully in all five food groups of the genetics lab: yeast, bacteria, fruit flies, zebrafish and mice.  In February, George Church announced that he had used CRISPR to alter human induced pluripotent stem cells, adding: “results establish an RNA-guided editing tool for facile, robust, and multiplexable human genome engineering.”

Potential uses for CRISPR beyond interrogation of cell lines include: development of model organisms, modeling the effects of specific genes and gene changes, somatic cell gene therapy, and new treatments for acquired diseases with genetic components such as cancer and AIDS.  And of course, as George Church points out – with an enthusiasm that may not be shared by all – as a platform for germline gene therapy and genetic enhancement of embryos.  But, I mean, besides that, it is hardly interesting at all.


1. ACMG produces guidelines for reporting of incidental findings in whole genome and whole exome sequencing.

The ACMG guidelines are the genetics story of the year because both their existence and the controversy surrounding them illustrate exactly where we are today:

1. Desperately in need of guidelines, because exome and genome sequencing are a clinical reality today,


2. So unready to deal with all the information that comes along with sequencing that we can’t even agree on what to call it: incidental findings; secondary findings; opportunistic findings; unanticipated news.

Here are some crib notes, without recapitulating the argument in its entirety (covered here and here, for starters).  Many people believe that access to genetic information is a right, and argue vehemently that doctors and other genetics professionals should not function as intermediaries, deciding what information is significant, what information is superfluous, and what information patients may be unable to handle or comprehend.  This is a sort of a power-to-the-people argument, wherein ‘power’ is defined as genomic information (which may be a bit of a stretch.  Jus’ saying).  The other side is concerned about the logistical and ethical complexities of giving out information which is not well enough understood – ‘well enough understood’ being one of those ill-defined metrics that, like Justice Potter Stewart’s description of obscenity, seems to come down in the end to “I know it when I see it.”

The ACMG came out somewhere in the middle, and has been soundly criticized by all sides, which I think means they must have done something right.


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On Monday, the FDA celebrated the start of the holiday season by sending a letter to 23andMe, informing the direct-to-consumer personal genomics service that they must cease and desist offering their signature test.  The proximal cause of this action, as described by the FDA and not disputed by the company, was that 23andMe had ceased to participate in a process of establishing their PGx test as “validated for its intended uses.”  They had, the FDA suggested, dropped the ball – well, not just dropped the ball, but kicked it out of bounds, an old soccer trick for delay of game, which Mya Thomae and Dylan Reinhardt suggest might have been exactly what the company had in mind, playing for time while they attempted to accumulate better data than what-all they have right now.

The FDA move prompted a vast twitterlanche of commentary, ranging from indignant outrage to smug satisfaction (Dietrich Stephan, founder of the erstwhile DTC competitor Navigenics, said, “Engaging the FDA as a partner to bring the most robust and safe new type of test to market is diagnostics 101”).  Genetic counselors might be suspected of indulging in a bit of schadenfreude, since the relationship between 23andMe and the GC community has inclined in the direction of mutually suspicious, if not downright frosty.   The company, which advocates for access to one’s DNA information with almost a religious fervor, sees GC’s as gatekeepers, as a self-anointed coterie of priestesses guarding the oracle at Delphi.  Genetic counselors, for their part, tend to perceive the very existence of 23andMe as an affront, as though the possibility that a subset of people might benefit from genetic testing without access to counseling was insult and injury — an existential threat.

To be fair, nobody reacts well to the suggestion that their chosen profession is a cabal that threatens the freedom and well-being of fellow citizens – not even investment bankers, and at least they get to soothe their wounded souls with lots of material goods.  But pettiness is unbecoming and unproductive, and we would all do well to remember that a groundbreaking organization like 23andme is a part of the energy and excitement of the field – an expression of an explorer’s mentality that draws people to the potential of genetics in 2013.  That’s not only fun and sort of cool but also incredibly powerful because it attracts the kind of intelligence and curiosity that makes big new ideas possible (David Dobbs does a thoughtful and balanced job making the case for 23andMe in this piece for the New Yorker).

So minus any animus toward 23andMe, was this a reasonable move by the FDA?  There are two main questions that have been raised: 1. can they regulate? and 2. should they regulate? (a third question, HOW DARE THEY?, has also gotten a lot of play but I am going to ignore that one because, c’mon guys get over yourselves this isn’t ONE STEP FROM TOTALITARIANISM).  The first one takes up the issue of whether or not a personal genomics test falls under the FDA jurisdiction.  I am going to say yes, but will not rehash those arguments here, since they have been more ably covered elsewhere – I particularly recommend this piece by Hank Greely at the Stanford Law School Center for Law and the Biosciences blog.

So, should they regulate?  The rationale for regulatory action in the letter to 23andMe is a risk of harm to customers, including the possibility that a customer might alter his medication without medical advice or misunderstand her risk for breast cancer and have an unnecessary prophylactic mastectomy.  While theoretically true, it seems wildly unlikely that very many people would insist on a mastectomy without getting more information than mail-order genetic results – and those cases might be more indicative of out-of-control anxiety issues and irresponsible medical practice than the power of a PGx report.  More commonly, misunderstanding the limits of the test in terms of risk reduction might empower a customer to skip out on appropriate preventative measures. Either way, this is nothing new — a rehash of concerns genetic counselors have had about DTC testing since its inception.  In practice, perhaps the best summary of the clinical impact to date comes from Anders Nordgren, who called it “Neither as harmful as feared by critics nor as empowering as promised by providers.”  Having spent hours poking through the generally well-written and thorough 23andMe reports, and spoken to some of their customers, I would suggest that misunderstanding the results that come from 23andMe could pose some risk — real risk, to be sure, but limited risk.

However, it is possible to envision a scenario where a genetic testing sold DTC did pose a significant danger to consumers, with inaccurate results, irresponsible advice, tests used to market scam treatments or preventatives.  None of this is farfetched, and some of it has already been documented.  For this reason alone, the possibility of FDA action is an important deterrent.  A company like 23andMe, which makes real efforts to be thoughtful and responsible, will ultimately benefit from the restraint on less scrupulous entities.  And of course, it is possible that 23andMe would have been less thoughtful and less responsible if they had not been motivated by the threat of FDA action.  So arguments against regulation in general based on the fact that 23andMe is well-intentioned are misguided.

But despite a bias in favor of showing some muscle, I have questions about how much time and energy the FDA should spend cracking down on the likes of 23andMe.  Is it, I wonder, the best use of resources?  For one thing, attempts to stop the free flow of information in 2013 are fingers in the dike. Razib Khan at Slate expands on this argument, suggesting that companies pushed by the FDA could simply move offshore, away from any regulation.

And more importantly from my point of view, the emphasis on negative action diverts us from the possibility of doing something positive.  Rather than keeping consumers away from tests we think are insufficiently documented, how about providing a resource to the general public that endorses tests that are ready for prime time?  After all, a few bold individuals may be excited at the prospect of downloading Promethease to query their own exome data but most people would rather not, thank you very much.  Most people would be happy to have some guidance.  They can get that guidance from the company, but even the classy companies have a vested interest in hyping the significance of their results – that’s what they’re selling, right?  There is an opportunity here for the government and the genetics community to create a trusted source of information that is neutral, unbiased and supports a best-case scenario use of genetic testing by those eager to take the plunge.  Hell, you could imagine tying in such a resource to something like ClinVar or GenVar, so that early adapters could contribute to publically accessible databases rather than giving it to 23andMe to sell.

After years of running up and down the pitch, the FDA has demonstrated that it knows how to blow the whistle – that’s good.  I’m pretty sure 23andMe will be back – and that’s good too.  But if we really want something great to come out of this discussion, let’s stop doing color commentary on the FDA action, and imagine what it could be like if we changed the game.

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Once, when out fishing for flounder, my mother caught a shark.

That story arose in my mind yesterday, as I was reading an article published in FastCompany by a science writer working under a pseudonym.  The writer (who calls herself Elizabeth, so let’s go with that) has a five-year-old daughter adopted from Ethiopia.  Her editor suggests that she do a piece 23andMe from the point of view of a mother considering testing her own little girl.  As for the decision about whether or not to test – that was up to her.

But it’s a better story if you do the test, right?  An even better story if you find out something interesting.  Which is not so likely, since the experts you contact are telling you that most of what 23andMe has to offer is not clinically significant.  A few things that are meaningful, a few things you might not want to know… but Anne Wojcicki, founder of 23andMe, says it is a parent’s duty to arm herself with her child’s genetic blueprint.  Ultimately, Elizabeth says, she finds the ‘knowledge is power’ argument persuasive.

So, anyway the kid turns out to be a ApoE 4 homozygote.  23andMe quotes a 55% chance of ApoE 4 homozygotes being diagnosed with Alzheimers between the ages of 65 and 79.

I spoke with Elizabeth while she was writing the article, but before the test results came back.  “Do you judge me for having my daughter tested,” she asked?  I said no at the time – and for the record, I stick with that.  We were talking then about privacy and confidentiality issues, and in that context I have concerns about the DTC industry in general and 23andMe in particular, but I can completely understand the desire of a mother raising her child without access to any medical or family history to get whatever information she can.  We talked about the limitations of SNP data on common disease.  This wasn’t a genetic counseling session, but I am a genetic counselor, and I am extremely regretful that I didn’t think to discuss ApoE, and perhaps urge her not to unlock that box.

Elizabeth spends the last third of the article grappling with the downstream issues that follow from that significant result.  She acknowledges difficult decisions they will face around when and if to tell the child.  “Never!” suggests a psychologist friend of mine with whom I share this story.  But in my experience information finds it’s way out, no matter how deeply buried, as if knowledge were a seed searching for the sun.  And in this case it is only shallowly interred – after all, she has shared her story in print.  The pseudonym makes it more private, but won’t the ruse – and the reason — be an open secret among her close friends and family?

Interesting to me that 23andMe publicized this story, tweeting about it yesterday morning:


I would have thought this particular personal journey represented something of a worst-case scenario for them.  Judging by reactions among my friends (not very scientific, I know) it was not a great advertisement for their product.  But then, I do them a disservice to suggest that they are simply marketers.  No question, the folks at 23andMe are true believers.  Emily Drabant, a neuroscientist at 23andMe, tells Elizabeth that their database will help pharma locate people with her daughter’s geneotype who don’t get sick, so they can uncover the reasons why some people stay healthy despite their genetic predisposition.

Wherever you stand on DTC, it is easy to see Elizabeth’s story as a parable.  For enthusiasts like Wojcicki, it is a tale about embracing the power of information as a call to action and an opportunity for intervention.  For haters, it is a harbinger of exactly the type of harm they picture when they think about DTC: inappropriate testing of minors, lack of pre-test counseling (that one makes my stomach hurt), post-test distress.   For me, having planted my standard awkwardly in the muddy soil of ambivalence, I see it as further evidence that DTC is a decent option only for a select few, and should not be mistaken for a new world order.

Here is the model set forth in this article: mother tests child, discovers disturbing information, goes on a mission to find out what it means and – hopefully – how to use what she has learned to her kid’s advantage.  This makes for a lovely read (it’s actually a very good article: balanced, well-written, funny at times).  But it’s important to note that to the extent something good comes out of this, it is because Elizabeth has access to resources and information beyond the factually accurate but necessarily limited and impersonal explanation on the 23andMe website.  “Our daughter is going to get Alzheimers,” she wails to her husband, after ‘blundering past the notes of caution’ to unlock her results.  Next steps for a science writer doing a feature on 23andMe?  First, a personal conversation with Anne Wojcicki, who cancels her next appointment when she hears about the ApoE finding.  Discussions with Drabant, the neuroscientist.  Discussions with geneticist Ricki Lewis, and with Bob Green up at Harvard, who spearheaded the REVEAL study that investigated the impact of receiving ApoE results on individuals and family members.  A conversation with Jennifer Wagner, a lawyer specializing in issues related to genetics and genetic discrimination.  We cannot hypothesize that this is the experience of the average consumer.  Wojcicki and the legion of science bloggers who can’t understand why everyone doesn’t want to test their children should consider the likely experience of a parent receiving this result with no more resources than Google and a distant memory of high school biology.

Ultimately, we are informed, Elizabeth comes to terms with the good and bad of genetic testing for her child.  “I choose to think of this as a potentially beautiful new world opening up for her–but one that requires an extraordinarily thoughtful bravery from all of us.”  Even so, she notes that the “best advice” she got was to “burn that damn report and never think of it again.”  Despite the positive rhetoric, her enthusiasm for that advice suggests she learned something she would in retrospect choose not to know.  Elizabeth went fishing for flounder, and caught a shark.  At least my mother could throw her fish back.



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When Numbers Do Not Tell The Tale: A Tribute To My Friend


Holly Osman 1959-2013

There is an emotional toughness one must have, working with cancer patients.  Oncologists tend to be pretty well-armored.  You don’t, for example, expect the head of Clinical Genetic Services at Memorial Sloan-Kettering Cancer Center to get emotional when a student asks a question about surveillance after prophylactic mastectomy.  So it was a surprise when Dr. Robson paused, and raised his eyes, with a blank expression that might have been masking tears.  “I used to say no more surveillance was necessary,” he said.  “But then I had a patient who rocked my world.”

Sitting in the audience, a chill ran down my spine.  You see, I knew her too.  Not as a counselor but as a friend.  A BRCA 1 mutation ran in her family.  She had tested positive for it years earlier, so after she had her beloved Sarah and Eric she did the surgery – smiled her way through it, no problems, no complaints, no second guesses.  “No big deal,” she said, with a smile that dared you to doubt her.  She was going to get the gift her own mother was denied: a little more time.  Time to watch her kids grow up, get married, have children of their own.

It’s never an easy business telling women to cut off their healthy breasts and put themselves into an early menopause.  No matter how deeply you believe in what you are offering, these are hard conversations to have.  But it wouldn’t have been hard with Holly.  She would have smiled from ear to ear and waved away all the negatives with a flutter of her left hand.  She was brave like that, and certain.

If your prior risk of breast cancer is 85%, and a mastectomy removes 98% of the breast tissue, your posterior risk should be approximately 3%.  That’s a risk reduction of 96.5%.  Wonderful numbers — but only numbers.  Numbers didn’t matter when Holly was diagnosed with breast cancer in 2004.  Or when it came back in 2006 (stage four, incurable).  I spoke to Dr. Robson and one of the genetic counselors from MSKCC after the lecture.  “I know Holly too,” I said.  There was pain in their faces.  “She did everything right.  It’s so unfair.”

“It’s not just that,” said the counselor.  “She is the nicest person.  Whenever someone really needs support we have them talk to Holly.  She never says no.”

What can I tell you about Holly Osman?  She would not forgive me if I did not describe her as happy and successful.  A great family.  A husband who adores her.  Two wonderful kids – almost adults now.  Her daughter looks just like her, but with a hell of a lot more attitude, and Holly loved that.  She loved it when her kids were independent and she loved it when they needed her.  Her son is ridiculous: handsome, smart, poised and kind.  ‘Screw up a little,’ you want to say.  Stop making the rest of us look bad.

If I had to pick one word for Holly it would be effortless.  Some of us clean up nicely, but Holly looked great all the time, in a classic way that required no adornment. Roll her out of bed at 3 AM, and she would still be beautiful.  And effortless wasn’t just her style, it was her way of being – ask her how things were going and she said “great!”  You could try and empower her to complain a bit — good luck with that.  Holly wasn’t very interested in complaining — which was annoying for me.  I myself would have whined.  Not Holly.  Her life was SO fabulous.  Her doctors were SO great.  If you asked her about how treatment was going she would look blank for a moment, as though she didn’t remember what you were talking about.  She had this look that seemed to say, ‘Oh yes, chemo – I had forgotten.’  Did she need anything?  Could I drive carpool for her this week?  “Why?” Holly said.

She was the luckiest person in the world.  She insisted on that right until the last moment, until last Friday, the day she died, in Holly-fashion, quietly and without drama, nestled in the heart of the family she had nurtured on every level imaginable.  I don’t know; maybe she was the luckiest person in the world.  I can tell you that the rest of us left behind feel a little bit less lucky now.

She did have a lot of luck, it’s just that some of it was bad.  As a friend who happened to be a genetic counselor, I always felt a little guilty, as though we had let her down.  We counselors love the safety of numbers, of facts, of things we know.  We told her the truth, it just wasn’t her truth.  As predictive testing goes, BRCA analysis is one of the best.  It has, as we say, clinical validity and clinical utility.  Holly understood that too; even after her own diagnosis she counseled a much-adored younger sister to have the same surgery, the one that had failed to save her.  Holly’s story is not a repudiation of what we have to offer.  It is a reminder of the limitations of the fortune-teller’s art.  Percentages are true only for epidemiologists, while people live out their lives as a series of n=1 experiments.  There is an arrogance in the certainty of numbers that will always be undone by the stochastic process that is life.

Here’s how I know: I had a friend who rocked my world.

Rest in peace, Holls.  Rest in peace.


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Bye-Bye Bi-Polar: A New Nosology for Psychiatric Disease — What Does It Mean for Genetic Counseling?

Tom Insel, director of the National Institute of Mental Health (NIMH), roiled the world of psychiatry in a blog post (how very 21st Century of him!).  The post concerned the revised Diagnostic and Statistical Manual of Mental Disorders – the DSM V, due out in a matter of weeks – and it was not a good review for the ‘bible of psychiatry’: “Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure.  In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever. Indeed, symptom-based diagnosis, once common in other areas of medicine, has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best choice of treatment.”

“It’s weakness, “ said Insel, “is its lack of validity.”

Wow.  That is a pretty bad weakness.

Insel’s statement is not news to anyone who studies the genetics of psychiatric disease.  Although many psychiatric illnesses have high heritability, it is increasingly obvious that current list of diseases as defined do not line up neatly with genetic risk factors, whether those risks are established through family history or molecular testing.  A first degree relative with obsessive compulsive disease is a risk factor for Tourette’s as well as OCD; a deletion in 22q11.2 is almost equally likely to lead to a diagnosis of schizophrenia or bipolar disease.  We might think of this as overlapping genetic inheritance, but in fact it illustrates how badly our current labels function when it comes to identifying etiology.

What was news was Insel’s plan to re-orient research funding away from the diagnoses defined by the DSM and towards a new system based on biomarkers like genetic findings, gene expression and brain imaging along with categories of phenotypic information like anhedonia or psychosis without regard to diagnosis.  To this end, the NIMH has launched a campaign to establish research domain criteria (NIMH being an arm of government, it has an acronym: LDT EGAP IVDMIA RDoC).  Researchers are encouraged to base their inquires on RDoC that cut may across, or subdivide, traditional diagnostic categories.

NIMH, as virtually every article, blog or twitter post on this subject pointed out, is ‘the world’s largest funder of research on mental illness.’  That makes this a high-stakes announcement, and change of this magnitude is complicated – after all, valid or not, all the existing literature is based on these diagnostic categories.  Ongoing research is based on DSM diagnoses, as is clinical practice, billing and reimbursement.  So to some extent we are stuck with what we have, warts and all, for the time being.  Insel knows this, just as the authors of the revised DSM know that their system is flawed.  The take-home story here is not a fight between two sides, but a demarcation of a significant moment in time, as the ocean liner that is psychiatry begins a slow turn away from labels based on symptoms and towards a alternate world where diagnosis is based on biological causes, markers and measures of disease.

Someday, designations like schizophrenia or major depressive disorder may sound as quaint as rheumatism or dropsy.  For genetic counselors, it presents a dilemma in the near term.  What goes into the pedigree?  We don’t want to make it more difficult, since we know that genetic counselors are already disinclined to tackle psychiatric illness as a part of the family history.  But possibly this too is a symptom and not a cause: perhaps one reason genetic counselors are hesitant to ask about mental illness is that the associations between disease and recurrence risk are too complicated.  Because anything you can say is squishy and vague and threatening and non-specific.  Who likes that?  Not science people.

Would it be an improvement, if we recorded information about phenotype and test results as defined by RDoC?  Do we need to think about that?  Is this simply a research designation, or is it going to bleed into clinical care sooner rather than later?  I don’t have answers for these questions, but I am directing them to the wonderful and small but highly motivated cadre of genetic counselors who work primarily in psychiatric genetics (I know who you are!  No hiding).  Can you weigh in for us on what all this means for genetic counseling?

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Morality and Reality: Two Arguments in Favor of the Recommendations for Return of Incidental Findings Released by the ACMG

Recently, the ACMG released recommendations for return of incidental findings  following genome or exome sequencing, garnering a great deal of attention in the science media and some in the popular media as well – most of it stressing two points: the fact that the guidelines call for certain results to be returned regardless of patient preferences, and that they call for the same results to be returned regardless of patient age.  These are big departures from current practice, and they have drawn a lot of fire for going too far (or for not going far enough).

The reasons for the paradigm change were explained at length in the ACMG report, which is well written and worth reading in it’s entirety.  I am going to discuss a few of those reasons here, but first let me emphasize one thing I believe was often obscured in the first-reaction coverage: the report does not suggest that all incidental findings should be reported.  Not even close.  The list of conditions is relatively short (about 35, although the authors acknowledge that it will inevitably get longer) and strictly curated.  In each case the result in question has a well-established risk of likely and serious harm, at least potentially amenable to intervention.  Likely, serious, preventable: the criteria echo the language of duty to warn, stemming from the famous Tarasoff case in the 1970’s.  In duty to warn cases, the danger is such that it demands action even when that action violates a patient’s right of confidentiality – a serious breach, and as such the bar is set high.  In this case, the competing right, as it were, is the right not to know – or to state one’s preferences – and the danger is to oneself and one’s family rather than to a stranger.  But the model is the same, as is the commitment to reserving this option for circumstances where the risk is compelling.

One difference between a duty to warn scenario and incidental findings is that with IF’s, you have the option, theoretically, of asking the individual for his or her preferences in advance, and then using that as a guide.  That has always been our default recommendation, and the ACMG report explains several reasons why they deviated from this standard:

1. The information is THAT important.

 Driving the issue of incidental findings is a better understanding of what certain gene changes mean – not perfect, but better.  Mutations of significant prognostic value used to be the exception and not the rule – okay, they still are.  A lot of the information we have about genetic variation is suggestive rather than diagnostic.  Only a limited number of known gene changes produce risks in the manner of, say, BRCA 1/2 mutations.  But some things do.  Hypertrophic cardiomyopathy.  MEN2.  Familial hypercholesterolemia.  Remember, the right not to know – the acknowledgement that someone might reasonably assume they were better off not knowing – is predicated on the inherent uncertainty of genetic information, and our inability to change the outcome.  And while I would be the last person to suggest that is no longer the case as a rule, we have made some progress on both of those fronts.

We still have a way to go to understand the relationship between genotype and phenotype, especially where medical or family history are uninformative.  For some if not most of genetic variation, I personally doubt we will ever reach the point of acceptable or compelling certainty.  But we have come to the point where BRCA 1/2 is not the ONLY example of a relatively common genetic variant with real predictive utility.  The list assembled by ACMG is going to get added to – and perhaps subtracted from – over time.  But there are a limited number of circumstances where the risk of harm is so great and so well substantiated that in the event of a bad outcome, our justification after the fact for not identifying and disclosing those results would ring hollow in our own ears.

2. Setting a standard that relies on pre-test counseling is unrealistic as the use of genome-based testing expands beyond the genetics clinic.

 The best thing about the ACMG recommendations is that they are what I like to call reality-based.  First, genetic testing is increasingly used in all sorts of subspecialties (cardiology, pediatrics, audiology, oncology, etc).  We can’t dictate to them how to do pre-test counseling, and even if we could, they are not necessarily prepared to explain genetic concepts.  We imagine a world where sequence-based testing is a first-line alternative in all sorts of medical situations, from emergencies to routine medicine.  If you assume that an expert and careful process of informed consent does not occur, as it absolutely will not in many circumstances, then you need to establish what happens by default, when the clinician does not have any information on patient preferences.  This set of recommendations doesn’t close the book on that process, but it does provide a really well thought out starting place.  It gives you a baseline: if nothing else don’t miss these.  That’s tremendously valuable.

Additionally, standards that rely on pre-test counseling may sound ideal, but often prescribe procedures for the informed consent that are problematic in their own right.  Informed consent is not a junk drawer where you cram everything that does not fit somewhere else.  Beyond a certain point, pre-test counseling becomes a process of wearing down rather than educating a patient – in writing or in person, the moral equivalent of ten pages of fine print is a bludgeon and not a tool.

3. Inconsistent reporting from laboratories is dangerous.

 No question but that the thrust of the ACMG recommendations is to suggest that this is information that should be delivered to the patients and their families.  But in fact, the guidelines don’t dictate what a clinician should tell a patient; they spell out what a lab should give to a clinician.  They set standards for what a lab should be obligated to look for and report in all uses of exome and genome sequencing.  And even if you take issue with the list, there is still a benefit to establishing uniformity.  Currently, the labs that do commercial exome sequencing vary widely in reporting procedures – some give back a great range of results, others only those relevant to the diagnostic question, and others provide a choice.  For the clinician, this means that advising a patient for what to expect from testing must be tailored to each lab’s protocol.  And it leaves a lot of room for confusion.  For instance, a physician accustomed to getting incidental information on – say cardiomyopathies – might see the absence of that information as a clean bill of health, when it might merely represent the typical practice of a certain lab.

Clinicians, the ACMG report acknowledges, will put the results in context for patients and families.  Therefore, the recommendations as written provide more room for clinical judgment than the headline suggest.  It is at the clinical level that family history, medical history and immediate context are integrated into how, what and when information is given out.  Patient preferences can be taken into account, as can the priorities of a patient or a family in times of stress.

Furthermore, since most incidental findings (including carrier status, pharmacogenetic information, etc) are not included in this list, there is a lot of room for a clinician who design a process based largely on patient preferences.  The recommended list is a floor and not a ceiling; it begins but does not end the dialogue between the provider and the patient.

In reviewing the current debate over the return of incidental findings, the ACMG report categorizes the two sides thusly: there are genetic libertarians and the genetic empiricists.  Libertarians wish to give individuals unfettered access to their genomic information – all the hits, Google-style – and trust the algorithmic magic of search engines and accumulated wiki-wisdom to bring test-takers closer to the truth than physicians can by doling out information according to their own judgment (in support of which, the libertarians are likely to cite the lack of genetics expertise among physicians, and you can’t argue with that).  Empiricists – and I am a little less certain about how well that word applies – are more concerned with the dangers of over-sharing, and they typically point to the potentially misleading nature of results with a small or unsubstantiated effect size and the loss of autonomy that occurs when information is thrust unrequested upon patients or given out to parents and caretakers on behalf of minors.  The good news for ACMG is that their recommendations have come under attack from both sides, so they can reasonably assume that they are doing something right. 

This libertarian-empiricist divide can reflect many prisms: age; personal experience; East Coast establishment values versus a West Coast ethos of let-the–information-run-free.  In any event, it is the more protective point of view that emphasizes the value of genetics expertise and counseling, and the genetic counseling community tends to identify strongly with norms that stress caution in terms of what, when and how information is shared with patients.  But we should be carefully not to become reflexively protective of our own practices so that we cannot reexamine them to reflect changes in what we know, or the best interests of our patients and their families.


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What New Laws in North Dakota Tell Us About the Anti-Abortion Movement in 2013

Follow abortion law long enough, and you will begin to appreciate its Talmudic qualities.  Figuring out what the literal meaning is only the beginning.  For a deeper understanding, you must decode the text.  Consider these recent examples:

Earlier this month, Arkansas passed a law banning abortions after 12 weeks gestation.  Then, on March 15th, the North Dakota legislature passed a law banning non-emergency abortions after 6 weeks gestation.  So you ask yourself: are the North Dakotans really that competitive?  Quite possibly.  But that’s not what’s at issue here.  Actually, both bans are tied to the idea of fetal heartbeat, which can be detected by vaginal ultrasound at 6 weeks and abdominal ultrasound at 12 weeks.  Arkansas changed the terms of its law from 6 weeks to 12 weeks to avoid the whole ‘politicians want to stick a wand up your vagina’ brouhaha, while the North Dakota legislators hedged by sidestepping specifics on gestational age and declaring it a felony to do an abortion procedure after the heartbeat could be found, which means that any procedure after 6 weeks – or possibly even 5 – puts the doctor at significant legal risk.

Textual analysis requires a little context: these two laws are not without detractors within the anti-abortion community. Blatantly unconstitutional, they will not go into effect unless the Supreme Court chooses to overturn Roe v Wade altogether – or to redefine its standard of viability.  Since this law puts the state on the line for substantial legal costs if the challenge fails, it is entirely possible that North Dakota’s Governor Dalrymple will veto the law as fiscally irresponsible.

Deeper truth: in recent years the organized anti-abortion movement has eschewed direct challenges to Roe in favor of enacting an all-you-can-eat buffet of restrictions and regulatory hurdles that make the process of getting an abortion more difficult, humiliating, expensive and time-consuming – all of which serves to reduce access without making abortion illegal, and presumably to avoid triggering a popular outcry, a likely outcome if Roe v Wade was in obvious jeopardy.  What’s more, this smorgasbord approach (waiting periods, mandatory counseling, special requirements for abortion facilities, parental notification, etc) affects mainly the poor, the young and other vulnerable populations – leaving the empowered classes free to find abortion distasteful without giving up any of their reproductive rights.  The stealth approach, orchestrated by a sophisticated and media-savvy crew, has been largely successful at limiting abortion regionally, while chipping away nationally at popular support for abortion rights.

The new laws then, as a departure, represent a throw of the dice on the part of the anti-abortion movement’s country cousin, looking to win big on a game-changing Supreme Court decision – a long shot, though hardly impossible.  And not unlike the Tea Party with its candidates that win in the primary and lose in the general election, the constituency that launched these laws is a tail-wagging-the-dog phenomenon that illustrates hardening fissures within the conservative movement – a quasi-rebellious move on the part of ideologically motivated individuals who are not prepared to compromise or prioritize strategy over gospel.

While the prohibitions on first trimester abortion is sucking up most of the media oxygen, a second legislative initiative out of North Dakota presents an alternate window into anti-abortion sentiment in 2013 – and one of particular importance to genetic counselors.  The second bill prohibits any abortion for purposes of “sex selection” or “genetic abnormalities.”  Of course, intent is a tricky thing to prove and for the moment abortion is available for no reason, making these provisions hard to enforce, but it could vastly complicate a counselor’s ability to discuss options in the event of a fetal anomaly.  Would it be illegal to even suggest that abortion was an option, in the context of a prenatal diagnosis?  Could you raise the subject?  What if the patient brought it up?  How would you handle the informed consent for prenatal testing, if you could not mention termination?  Why even test?

Why indeed.  Was that not exactly ex-presidential candidate Rick Santorum’s point one year ago, when he criticized the system for forcing employers to provide insurance coverage that included prenatal testing?  Sure, he got some details wrong – but to point out what he does not understand is to miss what he does understand.  There was nothing random about his comments — or this law — and the heart of the problem is not an absence of science literacy.  This is a revolt aimed at what we do, based on a reasonably accurate understanding of what we do.  It reflects the hard truth that, for people who genuinely believe that a fetus is morally indistinguishable from a child, prenatal diagnosis amounts to a war on handicapped persons.  It suggests that we think that some people are more valuable than other people, and that some lives are more worth living than other lives, and that therefore parents deserve a choice about whether or not to have a child whose health or abilities or prospects are compromised.

Improvements in prenatal diagnosis – the innovations we celebrate because they allow us to do what we do more safely and effectively – are threatening developments for a significant minority.  The better we get at our jobs, the more blowback we can expect to experience.  The North Dakota statute may not survive a challenge – it may not even get signed into law – but the rallying cry of anti-abortion forces against the use of genetic testing for eugenic purposes is a sound we will hear again, and louder.


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James Watson is many things – geneticist, Nobel laureate, agent provocateur – but in the realm of psychiatry he is first and foremost the parent of a son with schizophrenia.  So when he spoke in 2007 at the World Congress of Psychiatric Genetics, it was as a family member, albeit a family member with an unusually good grasp of the science.  And it was as a family member that he exhorted the scientists in the audience to keep up the good work, so that “someday we could identify those individuals destined to suffer from mental illness in utero, and weed them out.”

How often do you hear an audible gasp in the midst of a plenary talk?  The dismay and the indignation were palpable.  Researchers throughout the day interrupted their talks on GWAS to express in the strongest possible language that the goal of their work was to understand the pathophysiology of the disease and perhaps to aid in diagnosis – not to provide pre-symptomatic risk  assessment and not – no, never – not to be used prenatally.

“But if this is what families want,” I asked one speaker later that day.  “How do you propose to restrict testing, once the means to test is available?”

“They can’t,” he replied.  “They must not.”

Ah.  Of course.  They must not – I will pass that along.

Five years later, it is not GWAS but whole exome sequencing and whole genome sequencing providing all the buzz at conferences.  Solving the diagnostic odyssey!  Revolutionizing cancer treatment!  Ushering in an era of personalized medicine!  It’s very exciting.  Prenatal testing is rarely mentioned, and then only in passing – while prognosticators sing happy songs of a not-so-far-off day when every baby will be sequenced at birth.

Sequenced at birth?  Will it even be necessary?  Maybe Mom and Dad have baby’s DNA already, on a hard drive or a memory stick or downloaded onto their cell phones along with the ultrasound pics.

This is not the genome sequencing story you are seeing in the papers or the blogs.  It’s not what researchers are excited about.  The ones we hear are all about science journalists getting their DNA decoded and setting off on odysseys of self-discovery that involve hours of consultation with clinical and academic superstars who donate their time. We hear about kids with strange constellations of symptoms finding answers after years of disappointment.  Those are heartwarming tales: anecdotal and difficult to imagine at scale, but hopeful and exciting nonetheless.  But there is another theme playing, in a minor key, and I hear it faintly, hidden beneath the violins and the trumpets.

I hear it, an unspoken question, when we debate the utility of genomic information.  What does to mean to say that information is actionable? (Prevention? Treatment? Cure?  Prenatally, there is only Yes or No.)  Can patients handle uncertainty?  (And what will we lose, when pregnancies are terminated just to be on the safe side?)  Doesn’t everyone have the right to know what is in their own DNA? (The information is available – why not use it?  What could possibly go wrong?)

Whatever tests are available postnatally will find their way into prenatal use.  The gateway technologies – PGD, cell-free fetal DNA testing – are in place. And there is no use saying, “they can’t, they won’t, they shouldn’t” because they can and they will – and sometimes they should.  There will be good uses too: success stories and disasters averted.  A blanket “no” is not an option, and granting anyone authority to pick and choose which uses are worthwhile vests altogether too much power in the hands of any one person, or profession, or bureaucratic entity.

The same tests can be done before or after birth, but the experience is entirely different.  Uncertainty after birth is an opportunity.  The least useful information is that which will absolutely come true, no matter what you do.  Uncertainty before birth is a crisis.  Anyone who has ever discussed a variant of uncertain significance with a pregnant mother can tell you that.  But what are the chances there will be developmental delay?  Are you certain that the heart will be affected? How sure are you that this means anything?  Not nearly sure enough.  Please understand that.

In general, notions of genetic determinism increase the likelihood that genomic testing will have negative consequences.  Fatalistic attitudes about the power of genes could lead people to overestimate the meaning of elevated risks and underestimate the meaning of reduced risks.  Anxiety, stress, missed mammograms – you have heard this before.  Shrug.  People are grown ups.  They will figure this out.  Information is power.

But we are in a whole new universe trying to reconcile underpowered and often misunderstood predictive testing in the context of prenatal use.  So please, in telling tales of all the wonderful things that genome sequencing will do, save space for a mention of what it cannot do.  Make sure they understand that there are great wide cracks in our crystal ball.  Do not oversell the value of genotype in the absence of phenotype.  Remember that in the end neither researchers nor physicians nor genetic counselors will dictate how this new technology will be used.  Others will make that call, and we will be in the choir, singing songs of praise laced with sorrow.

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GENETICS and The Year in Review: My Top Ten Stories of 2012

In casual conversation, the phrase “it’s genetic” can mean any number of things.  It can serve as an excuse (‘don’t blame me, blame my parents!’) or a humblebrag (‘it’s a gift; I take no credit.’).   But most often, when people say “it’s genetic,” what they imply is: ‘that’s the way it is and there is nothing to be done about it.’

One promise of the Human Genome Project was to give us the means to fight back against this inevitability of genes, through prevention, mitigation and cure.  The first ten years post-HGP were full of revelation and technical achievement, and yet fell far short of that goal: for all that we learned, the lives of patients with genetic disease were essentially unchanged.  Now, news on a multitude of fronts brings the tantalizing prospect of progress.  Will we remember 2012 as the year when genetics fundamentally changed clinical medicine?  Probably not.  But the signs are there: treatments popping up like crocuses in the snow, new tests making their way from research only into the clinical realm, beta versions of technology that can — and will — do better.  And the other signs too: a growing intransigence from those who fear where these changes will take us, and a popular interest in testing that often takes the form of overestimating the scope and specificity of what genetics can tell us.  Progress – and pushback – is the story of 2012.


In Cell, Stanford Professor Michael Snyder published a study with an n of 1 that, despite its limitations, effectively captured the yin and the yang of personalized medicine.  The ”n” in this case was Dr. Snyder himself, who followed himself over a 14-month period using “genomic, transcriptomic, proteomic, metabolomic, and autoantibody profiles” – a staggering array of tests, with an equally staggering price tag. Long story short, Dr. Snyder’s genomic information suggested an increased risk for type II diabetes, so despite the absence of any family history or other risk factors, the medical profile was expanded to include a state of the art glucose test.  And in fact, following a viral infection,  Dr. Snyder’s blood sugar did rise.  Diagnosed with IDDM, the doctor’s blood sugar levels normalized after several months with changes in diet and exercise.  What didn’t normalize?  His life insurance premiums, which rose precipitously after the diagnosis was made.

What is wonderful about this story?  Dr. Snyder – who, it should be said, is a co-founder of company producing interpretive tools for genome studies – says the study saved him from months of damage, and may have saved his life.  Of course, you don’t really know, which is the thing about anecdotal reports.  Consider that, in a sense, all of medicine up until now could be viewed as one giant study with a massive ascertainment bias – after all, most of what we know about treatment comes from sick people.  Does it make sense that early and focused intervention worked?  Yes, it does.  Do we know that cutting out desserts and doubling down on his bike riding actually “cured” him?  No, we don’t.  Because this sort of testing is unprecedented, I’m not sure we know if transient changes in glucose levels are so abnormal following a virus.  Is this what risk means in the context of skinny guys with no family history?  Because in the context of obesity and family history, I am not convinced that cutting out pie is a game-changer.

But despite all the questions that remain, the Snyder study demonstrated proof in principle that the combined power of clinical measures and genomics – genes and gene expression – creates more value than either of these two alone.  And unfortunately it also demonstrates proof in principle that personalized medicine approaches are, at present, prohibitively expensive.  Bringing down the cost of sequencing is only a first step – it will take across the board reductions in the cost of testing, analysis and follow-up medical care if personalized medicine is not to be a niche service for the fabulously wealthy (and a few lucky academics with funding from NIH!).


In February of 2012, former Pennsylvania senator Rick Santorum went on the CBS News show Face the Nation and argued that employers who disapproved of prenatal diagnosis should not be compelled to pay for insurance policies that cover, say, amniocentesis.  An incremental extension of the argument against mandating insurance coverage for birth control which had become a hot button issue on the campaign trail, Santorum explained his opposition thusly: “Amniocentesis does, in fact, result more often than not in this country in abortion.”  Santorum, undeterred by the (modest) firestorm that greeted his results, doubled down on this position in a speech to the Christian Alliance: “One of the mandates is they require free prenatal testing in every insurance policy in America.  Why? Because it saves money in health care. Why? Because free prenatal testing ends up in more abortions and therefore less care that has to be done, because we cull the ranks of the disabled in our society.”

Okay, sure – it was silly season (aka, the Republican presidential primaries.  Remember Herman Cain?  Newt Gingrich and Ellis the Elephant?).  You might be inclined to dismiss this attack on prenatal diagnosis as nonsense.  Santorum certainly encourages us in our spirit of dismissiveness by getting his facts wrong – obviously MOST amnios don’t result in abortion.  Most amnios result in a reassuringly normal result.

But you know and I know that wasn’t what he meant.  Santorum is the father of a 4-year old with trisomy 18 (note to all

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genetic counselors: yes, I agree with you; she probably is mosaic.  But I don’t know and neither do you.  So please stop asking).  He is a hero to a not inconsiderable segment of the population.  And his sentiments are not an anomaly.  And I am willing to bet that Santorum’s stand is not some last vestige of an outdated and ill-informed resistance to genetic medicine, but an early sign of the sort of intransigent hostility that advances in prenatal testing will engender.  The Obamacare requirement that insurance plans pay for amniocentesis is, Santorum said, “another hidden message as to what President Obama thinks of those who are less able.” Many people – real people, not caricatures, not Republican primary candidates – are worried about how genetic technology will be used, and what those choices say about how the world sees them.  Their fears will grow as our capabilities improve.  In focusing only on what Santorum got wrong, we risk ignoring the more significant subtext.  There are questions here that deserve a real response, minus the snark.  Genetics professionals need to be prepared to define themselves, or risk being defined by someone else.


For years, discussion of the Archon X Prize for DNA sequencing has dominated sports-radio coverage of competitive genetics.  But this year, the annual handicapping of the Archon race (to sequence 100 genomes in 30 days or less, at a per-genome recurring cost of $1000 or less, to be decided once and for all in September 2013 and I don’t know about you but I am SO OVER IT) had to share the geek sports fan base with a new event: the Clarity Challenge.  In January 2012, Boston Children’s Hospital invited researchers around the world to analyze the DNA sequence data from 3 children with unknown genetic disorders.  Entrants were judged for their success in identifying genes or candidate genes for each child, and their ability to present their findings in a clear and accessible fashion.

The winner (Brigham and Women’s Hospital Division of Genetics – always nice for the crowd when the hometown team wins) was announced November 7 – PERHAPS YOU MISSED IT, as the press was inexplicably preoccupied with the U.S. presidential election, which occurred on November 6th.  Brigham’s team was praised for the clarity of its reports – a deciding factor, despite the fact that one of the runner-ups was actually the only team to identify putative deleterious mutations for all three kids.  More importantly, the competition highlighted the growing need for sophisticated and high quality analysis to complement the increasing quantity of sequence data.  The take-home from the Clarity Challenge is this: generating strings of A’s, C’s, T’s and G’s may be a technical tour de force, but only analysis will turn data into information, and provide clinical relevance.  For one child, the competition did result in a diagnosis after a 10-year medical odyssey – a success, but a qualified success, since the mutation for a muscle-wasting disease was identified by only 8 of 23 qualified groups participating.  Hailed as proof in principle of the power of DNA whole genome sequencing, the Clarity Challenge also illustrated the lack of universal standards for analysis (not to mention for handling tricky details like non-diagnostic findings unrelated to the presenting medical issue).

Mo’ data, mo’ problems, kids.  Having identified a serious issue that isn’t going away anytime soon, the Clarity Challenge is rumored to be gearing up for competition #2: the cancer genome analysis.  Great idea!  And guys — using a combination of computer simulations and a careful reading of the literature – in this case, the U.S. Constitution – I predict that the next presidential election will be held on November 8th, 2016.  PR protip: you might want to pick a different week to make any major announcements.



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European Commission approval of Glybera, a stem cell therapy for familial lipoprotein lipase deficiency, marks a big step forward for the field, which had a tough year in 2011 when the first US trial of a stem cell therapy was shut down early as stem cell pioneer Geron withdrew to focus on experimental cancer therapies.  Poor stem cells!  It’s hard to be dumped for more lucrative therapeutics.  But researchers in stem cell therapy headed back to the gym – I mean the lab – and came back looking strong in 2012.  Reports suggest that a number of therapies have shown promise in clinical trials, including a publication in The Lancet describing a human embryonic stem cell therapy from Advanced Cell Technology that has showed early success treating retinal damage from macular degeneration.



Lots of reasons NOT to get excited about Kalydeco, the Vertex pharmaceuticals drug approved by the FDA in January 2012.  Sure the drug improves outcome measures for patients with cystic fibrosis (CF) – but only for those carrying the G551D mutation, a paltry 4% of individuals with CF in the United States today.  And what’s with the name?  It sounds like the Disney mascot for Epcot’s Visual Hallucinations Pavilion.

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But Kalydeco, despite these limitations, is a leading indicator of growth for a whole category of targeted pharmaceuticals.  The Vertex product is the first approved drug to act by correcting the underlying genetic defect rather than ameliorating symptoms.
The strengths and the limitations of Kalydeco are its specificity; it restores the ability of the mutated CFTR protein produced by G551D to unlock the ion channel that is lost in CF.  Kalydeco, which represents the sort of therapeutic breakthrough everyone hoped would follow organically from a better understanding of disease pathophysiology, is a hopeful sign for all CF patients – a version aimed at the more common DeltaF508 mutation is reportedly in the works – and a hopeful sign for anyone who ever dreamed that we might someday talk about a “cure” for genetic disease.


The new Francis Collins Initiative for Translational Medicine in Rodents got off to a flying start in 2012:

In Italy, researchers grew kidney-like “organoids” that performed many of the same functions as kidneys when transplanted – in rats.

A new drug tested by researchers at Washington State showed promise in treating Alzheimers Disease – in rats.

Scientists at the University of Michigan used gene therapy to develop a sense of smell to successfully treat congenital anosmia – in mice.

Researchers at UCSD debuted an RNA interference drug that reduced the severity of symptoms for Huntington’s disease – in mice …

And two groups (one in California; the other in Spain) demonstrated success using engineered zinc finger proteins to block production of the mutant huntingtin gene product – in mice.

A molecular embryologist in Brussels reestablished absent thyroid function through transplant of thyroid tissue engineered in the lab – in mice.

Blind mice see!  Vision restored after transplant of rod-cell precursors – mice (blind mice!).

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Deaf gerbils hear!  Hearing restored using human embryonic stem cells to replace damaged auditory cells – in gerbils.

Diabetic mice cured!  Insulin dependency ended with transplant of pancreatic stem cells – in mice.

Truly, has there ever been a better time to be a rodent? 


In an article published in Nature in July, 2012, researchers from Stanford announced  full genome sequencing done on fetal DNA drawn from the maternal blood stream – DNA, in other words, that could be obtained without invasive testing.  Several tests using non-invasive prenatal testing are already on the market, notably Sequenom’s MaterniT21 PLUS, the success of which drove a 68% increase in corporate revenue in the 3rd quarter of 2012 as compared to 2011 numbers.  Despite their commercial appeal, these beta versions of targeted non-invasive testing are still working out their kinks – amniocentesis or CVS are still needed as a follow-up to any positive MaterniT21 result – but the Stanford University researchers’ accomplishment drives home the potential of this technology to transform prenatal testing in the not-so-distant future.  Earlier, safer and more inclusive, this testing modality is likely to be a game changer that radically increases both the number of pregnant couples opting for testing, and the range of conditions included in a prenatal assessment.


On Friday, December 14th, Adam Lanza, a 20-year old loner described by former teachers as “intelligent, but nervous and fidgety,” took guns belonging to his mother and shot her four times in the head.  Then, for reasons we will never know, he took her car to the Sandy Hook Elementary School, shot his way through a locked door, and massacred 20 children and 6 adults and then himself with a systematic efficiency and precision that belied the random nature of the attack.  Sixteen of the children killed that day were 6 years old; the other four had already turned 7.

“Who would do this to our poor little babies?” asked Mrs. Feinstein, a Newtown teacher of 11 years.  For that question, no satisfactory answer would – or could – emerge.  Anecdotal reports of mental illness filtered out from people who had known Adam Lanza – he had a developmental disorder; he had autism; he was diagnosed with Aspergers.  Ten days after the attack, the Connecticut Medical Examiner sent a request to University of Connecticut scientists for help investigating Adam Lanza’s DNA.  “Geneticists Studying Connecticut Shooter’s DNA” ran the CNN headline on December 28th.  The article reported the consensus of the genetics community – no single genes existed that would be diagnostic for mental illness, and no single DNA sample could begin to establish variants or markers associated with violence – or any other behavior of a complex creature in a complex world.

DNA sequencing will shed no light on the painful question of why, but the use of sequencing in this context will color the public perception of genetics, with potentially dangerous consequences.  Ultimately, it is the headline that endures – the headline that suggests that some genetic quirk, some error in his code, some defect we can use to identify and root out the monsters among us — was the cause of this most horrific act.  It is far from the first headline of 2012 to imply genetic determinism (“Binge drinking gene’ discovered” proclaims the BBC; “As GOP convention begins, a look at how genes influence politics” trumpets the LA Times) but the Newtown tragedy illustrates most fully the potential for stigma and discrimination that accompany a reductive view of the relationship between genes and behavior.


 This was supposed to be about whole exome sequencing (WES) announcing its presence with authority in the clinical setting in 2012.  In May, David Goldstein et al published an article in the Journal of Medical Genetics documenting a high rate of success using WES to find diagnoses for patients with unexplained, apparently genetic conditions. Their exploratory studied considered a number of important, difficult issues: filtering of variants, variants of uncertain significance, communication of results to families, detection of carrier status and other non-diagnostic findings, obligations for re-contact.  Results were lauded as not only explanatory but in some cases “interesting” – the holy grail of academic research.

This story was supposed to be about WES, having its moment as the field transitions from targeted gene testing to whole genome analysis.  But everywhere I looked there it was, whole genome sequencing (WGS), hanging around the gym, saying “ooh, ooh coach – put me in!  put me in!”  Was 2012 the year of WES?  Well, yes! … but it was also the year when WGS with a 50-hour turn-around time was introduced for use in neonatal emergencies – and immediately declared standard of care for the neonatal intensive care unit at Children’s Mercy Hospital in Kansas City MO, where the pilot study was done.  And it was the year when the 1000 Genomes Project published data drawn from the WGS of over 1000 participants (thus the name), giving us what Genome Web Daily described as data that “made it possible to identify almost all of the variants found in as few as 1 percent of the population.”  Congratulations, WES!  Your moment has come.  Just don’t blink.


Remember “junk DNA”?  Me neither.  I am almost certain that none of us ever believed in the preposterous idea that the 98% of the human genome not coding for genes is a vast trash heap of discarded genes and chromo-babble.  A giant sea of artifacts and nonsense, meticulously copied by each dividing cell – surely this model defies everything we understand about the parsimony of the natural world?  For this reason alone biologists as a group instinctively knew the notion to be false.  At least, that is how I recall it.  As Lizzie Bennett says in Pride and Prejudice, “in cases such as these, a good memory is unpardonable.”

In September 2012, an international consortium of researchers organized by the NHGRI and wrangled by “cat-herder-in-chief” Ewan Birney of the European Bioinformatics Institute produced the first edition of the Encyclopedia of DNA Elements (ENCODE), in the unprecedented form of 30 articles published simultaneously in 3 cooperating journals: Nature, Genome Biology and Genome Research.  The combined publications constituted a first peek into the mysteries of the 98%, examining the expression and modification of non-coding DNA on a cell- and tissue-specific basis, identifying sequences receptive to chemical modification,  promoters of gene transcription, and all manner of transcriptionally active DNA signatures whose significance – if they have a significance – remains entirely speculative.  All together, it is an ambitious cataloguing of what Eric Green at NHGRI described as elements “involved in the complex molecular choreography required for converting genetic information into living cells and organisms.”

What is the take-home message of ENCODE?  That “not translated into protein” is not the same as “unused.”  In fact, the combined studies suggested that 80% of those shadowy untranslated regions were in fact transcribed into RNA – with a quarter of those RNA elements having known functional relevance.  As for the rest — well, some of it is regulatory – for instance, ENCODE documented a vast number of switches, used to turn genes on or off.  But for much of the genomic activity documented by ENCODE, all that one can say is that it exists.  Does it have functional implications for individuals?  The jury is out (and bickering).

The are so many reasons why ENCODE is the top genetics story of 2012.  It is on-trend as a BIG DATA story, producing raw DNA sequence data that required more than 300 total years of computer time to analyze – an illustration of the increased need for analytic skills that will follow as the celebrated technical achievements of the past decade become, in a flash, merely the norm.  The searchable ENCODE database is a model of open access – another 2012 hot topic.  And the project demonstrates that, despite a certain amount of clamor to the contrary, the most significant work in genetics today is a giant research project and several steps removed from clinical application.

In the dark years before the Human Genome Project, inebriated geneticists offered up back-of-the-cocktail-napkin approximations about the number of genes we carry, and every one of them was wrong.  Eighty thousand?  One hundred thousand?  Nope.  The final tally was more like 22,000 genes – and so unless we are prepared to declare ourselves less complicated than a water flea (31,000 genes), this can only mean one thing: that the architecture of human complexity is not derived solely from the blueprint laid out in our genes.  ENCODE, as a search for answers beyond the coding regions of our genomes, is a natural extension of the HGP, a first attempt to move beyond answers that lie solely in the exome.

For me, here is what makes ENCODE the genetics story of the year: it is both a beginning and an end.  The publication of ENCODE is a commencement ceremony for the HGP age – a moment in time when you come to the end of something and realize it is only the beginning of a greater journey.  The information it contains, while vast, is a mere sprinkling of breadcrumbs for others to follow.  But the trail it leaves shows us what we do not know.  Unknown unknowns are true ignorance – the sort of ignorance that leads us into a belief like “junk DNA.”  ENCODE is a great next step – the elucidation of what we do not know.  To a geneticist with exome data, like a man with a hammer, everything looks like a gene.  For ten years we have been hitting those nails hard.  ENCODE is a look beyond, to a wider array of targets, a wonderful acknowledgement of how much we do not know.

And that, ladies and gentlemen, is genetics in 2012!  Let me know what I’ve missed….

[Follow me on twitter: @laurahercher]


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