It’s A Slippery Slope. Get Over It.

This week, the FDA is holding hearings to examine the use of a new IVF technique that could allow women with mitochondrial disease to have children who are genetically their own without the risk of passing along the condition.  The proposed treatment involves yanking out the nucleus of a donor egg and popping in a nucleus from the mom-to-be.  Studies of monkeys have demonstrated that this method can be used to produce healthy monkeys; studies of humans thus far have demonstrated the potential to create what appear to be viable embryos.  Shoukhrat Mitalipov, the Oregon-based researcher who has done both human and animal studies, is interested in moving to clinical trials – or as Dina Fine Maron puts it in Scientific American, “human clinical trials.”

 

The issue of oocyte modification was debated last year in the UK, where the government has opted to allow nuclear transfer to be used on an experimental basis.  The story got major play in the press there, as it has here, with catnip headlines about ‘3-parent babies.’  There are some serious questions to be answered about the risks – the first studies using human eggs showed an increased rate of abnormal fertilization, although zygotes with an appropriate number of pronucleii seemed to develop normally.  Minimizing the risk of harm to any child born of this technique is an important focus of the regulatory agencies and if we can’t do it safely, we shouldn’t do it at all – which brings me to the other question under debate: should we do it at all?

 

Marcy Darnovsky of the Center for Genetics and Society, a non-profit organization that leans precautionary on the use of reproductive technologies, has been waging a one-woman war against nuclear genome transfer, protesting the UK decision in Nature, circulating a petition to the FDA to decry human germline modification and penning an OpEd for the N.Y. Times entitled “Genetically Modified Babies.”  Darnovsky brings up safety issues but the heart of her objection is the slippery slope argument.  We have informally agreed not to make changes in the germline that will be passed down to subsequent generations – not to tinker with eggs and sperm.  This is a step over that line.  If we do this, what else will we do?  It could, she says, “open the door to further germline manipulations.”

 

Last winter, I attended a panel on the ethics of germline manipulation where participants debated a resolution to prohibit genetically engineered babies.  Lee Silver (Princeton) and Nina Farahany (Duke Law) represented the anti position (i.e., let’s NOT prohibit genetically engineered babies) and won the debate by focusing on – wait for it — nuclear transfer for mitochondrial disease!  Forbid genetic engineering, they argued, and you rule out this potentially game-changing therapy for afflicted families hoping to give their kids a life free from the burden of life-long, incurable disease.  In other words, another slippery slope argument, only the other way round – accept the concept of regulation in any form, let the bureaucrats in, and you cut yourself off from progress and doom families forever to suffering that could have been prevented.

 

The thing is, I am not at all convinced this example – like many other models we construct — represents anything other than itself.  I don’t mean to say it’s trivial.  But mitochondrial replacement therapy isn’t a reasonable stand-in for the complex issues associated with genetic engineering, like trait selection or eugenics.  You can make the case that mitochondria are more like the bacteria we harbor in our gut than they are like nuclear DNA , in terms of how they affect our health and well being.  Gut bacteria have DNA too.  If we gave the 3-parent child a fecal transplant, would we have a 4-parent child?  (Is that a bad thing?  Cool or creepy?) 

 

The problem with slippery slope arguments is that they don’t relieve the obligation to assess each and every situation on its own merits.  They don’t provide some easy moral clarity or regulatory guidelines.  Everything exists on some sort of continuum, whereby you can draw a straight line from the ludicrous to the patently unacceptable.  When does life begin?  It’s a tightrope, with one end tied around infanticide, and the other clasped in the hand of some guy out of a Monty Python sketch singing “every sperm is sacred.”  Every decision we make is about drawing a line.  And every ethical quandary worthy of the name is unique enough that it deserves its own weighing of the pros and cons.

 

Are you concerned about doing PGD for later-onset conditions?  This is a line some people have suggested, between what is a good and a bad use of preimplantation technology.  What if that condition is Huntington’s?  Okay, what if it is a BRCA 1 mutation?  Or what if it is a subtly increased risk of Parkinson’s disease?  Each of these is a very different scenario.  Every family is going to experience those risks differently.  The fact that you can draw a line from here to there does not automatically absolve you of considering the facts at hand in each case, the good that can be done, what stands to be gained, what may be lost.  It’s very hard to take away happiness for one person based on what might (someday, somewhere, possibly, in a related case) happen to somebody else. 

 

The thing is, it would be so much easier if we could find that certainty.  Slippery slope arguments are a plea to make things stand still for a moment, so a person can get their bearings.  Anyone who works in genetics can relate to that sentiment.  But history is itself a slippery slope from a turbulent past to an uncertain future, and we don’t have the luxury of stepping off.  So what should we do about nuclear transfer for mitochondrial disease?  Well, let’s make a decision based on mitochondrial disease and the very sensitive nature of the human embryo, which may not take kindly to this manipulation.  Let’s not make it the last word on anything.  Let’s not pretend we are now for all time choosing to abandon sufferers to their fate, or opting for GATTACCA.  It’s hard enough and scary enough without conjuring up the ghosts of battles to come.

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A Mixed Verdict

A recent $50 million dollar jury verdict in a “wrongful birth” lawsuit in the Seattle area* has caught the attention of genetic counselors, hospitals, patient advocates, and legal experts. The ruling in this case may have both positive and negative implications for the genetic counseling profession. Let me be clear up front – I am not passing judgement on the verdict, the medical providers, the parents, the quality of care, or the laboratory. This case is very complicated and no doubt many details were not publicly reported. Although I know some of the parties involved, I was not directly connected to the case and I have no insider knowledge. Indeed, I did not know about the case until it hit the news.

In 2007 a woman underwent chorionic villus sampling (CVS) because her husband was a known carrier of a very subtle 2;9 translocation. The institution where the procedure had been performed had no genetic counselor working on the day the CVS was performed, contrary to departmental guidelines for complex cases. Somehow the details of the translocation were not clearly communicated to the cytogenetics laboratory. The fetus had an unbalanced translocation that was erroneously reported out as a normal karyotype. The couple continued the pregnancy to term and the misdiagnosis was detected after the child was born. In 2010 the couple sued the hospital, the laboratory, and the physician who performed the CVS. The physician and the plaintiffs entered into a “High/Low” agreement  in which the defendant agrees to pay a minimum recovery in return for the plaintiff’s agreement to accept a maximum amount regardless of the outcome of the trial. The medical center and the laboratory  were held equally responsible for the $50 million payout, with half the money going to a Guardian ad Litem for the child to pay for his medical care and other expenses and half going to the parents.

The core argument of the plaintiff’s lawyer was that the error would likely have been prevented if a genetic counselor had overseen the patient’s prenatal testing to assure that the critical information about the translocation was clearly communicated to the laboratory. The medical center had reduced the genetic counseling staff despite pleas from the maternal fetal medicine specialists and in the face of growing patient volumes and increasing net revenue. Lawyers for the plaintiff further claimed that the medical center and laboratory did not follow Error Prevention and Quality Management Policies and that the misdiagnosis was the result of a systemic failure. These arguments were important to the extraordinarily large size of the award; the missed diagnosis was attributed to “true negligence” rather than a one-time human error.

The outcome of this case can be beneficial in several ways for the genetic counseling profession. The jury acknowledged the critical role that genetic counselors serve in the delivery of medical care. For genetic counselors trying to justify their positions and salaries can now also argue that their institution’s legal vulnerability can be dramatically reduced by having an adequately staffed genetic counseling service. After all, genetic counselors’ salaries are a pittance in the overall hospital budget and pale in the face of multi-million dollar legal damages. Genetic counselors served as expert witnesses for both the plaintiffs and the defendants, further enhancing the profession’s status.

On the other hand, the verdict did little to improve the rocky and complicated relationship between genetic counselors and people with disabilities, their families, and their advocates. From the perspective of many in this group, prenatal diagnosis and selective termination are bright shining examples of society’s intolerance of people with disabilities. Because genetic counselors are integral to the delivery of prenatal diagnosis services, we are criticized for being part of a larger social and systemic bias.

Genetic counselors counter that they do not direct patient’s decisions, only support them. Genetic counselors are all too familiar with the gut-wrenching, emotionally draining process that patients go through when they decide to terminate or continue a pregnancy in which the fetus has a chromosomal imbalance. And in many situations, genetic counselors serve as advocates for people with disabilities and their families. But this defense does not hold water with those who argue that the very existence of prenatal screening is an insult to people with disabilities who, after all, do not see much in direct benefit from NIPS, amniocentesis, CVS, etc. What positive message can someone with disabilities find when half of the fifty million dollar award was for pain and suffering of the parents, and the very justification of the life of someone with disabilities is called into question when he or she is labeled “a wrongful birth?”

For now, we live in a society where women have the hard-earned right to terminate a pregnancy for whatever reason they choose (although the ability to act on that right can be severely hampered by socio-economic status and governmental policies). Genetic counselors line up behind the defense that they nondirectively help women to act on this reproductive freedom. Disability advocates are often avid supporters of reproductive rights too but do not feel that prenatal testing is necessary to the expression of reproductive freedom and point out that society’s negative view of disabilities and unwillingness to allocate appropriate resources further worsens the effects of disabilities. The two sides seem to be at an impasse and the fact that genetic counselors might applaud this court’s decision may only further contribute to this impasse.

We cannot ignore the voice of our critics.  I am not sure what the solution is. Prenatal diagnosis is unlikely to go away unless abortion becomes illegal again. If genetic counselors suddenly decided to pull out of prenatal diagnosis services, I suspect that informed patient decision-making would deteriorate and people with disabilities would lose one of their few potential advocates in the prenatal system.

As a profession and as individuals we need to reach out to our critics and find some common ground, such as the recently developed Open Lines forum where disability scholars, genetic counselors, parents, and people with disabilities can openly and safely discuss their perspectives. Surely the two sides are not as dysfunctional as the US Congress. It will be painful and difficult, but great achievements often require great suffering.

* – King County (Washington) Superior Court Case # 10-2-43289-2, Judgment Record # 13-9-35173-6 & 13-9-33521-8

Note: Some of the information in this posting is based on an article written by the plaintiffs’ lawyer (Gardner T, “Significant verdict in wrongful birth suit” Trial News, January 2014, pp. 9-11).

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Guest Post: NIPS: A Call to Embrace and Educate!

By Lisa Demers

Lisa Demers is a certified genetic counselor working in a prenatal diagnosis program at Dartmouth-Hitchcock in Nashua, NH.  She graduated from the Arcadia Genetic Counseling Program in 2003.  Lisa has been president of the New England Regional Genetics Group, is a member of the New Hampshire Perinatal Loss Taskforce, and is the proud mother of two little boys who teach her more and more about Star Wars every day. 

I feel like it’s time to show some appreciation for the amazing screening test that has truly enhanced the prenatal screening world.  Non-invasive prenatal screening (NIPS) has taken our prenatal world by storm and is rapidly infiltrating university hospitals and private practices alike.  This is a change (who really likes change?) and it’s fast.   Testing has jumped out of the controlled hands of research laboratory scientists and into the lucrative playing field of investor-backed industry.  But is this a bad thing?

NIPS has taken traditional screening and made it better.  There is no denying that NIPS is a superior screening test.  The benefit of NIPS over traditional screening is acknowledged by the rapid approval of coverage by major insurance plans. I applaud Katie Stoll in her eloquent summary of the discrepant positive predictive value (PPV), but I do not think this area of ambiguity should overshadow the benefits of testing.  The PPV for a “high risk” (or whatever language the report contains) sample, even if it is 11% (using the data in Katie’s initial post), is about the same as a 1 in 9 risk for trisomy 18 using traditional methods.   So is the counseling really very different?   “This screening test suggests a very high risk for trisomy 18, diagnostic testing will tell us for sure”.

Our knowledge about how to best utilize this test and interpret the results is an ongoing process.  This is completely on par with other technologies. At one point, supernumary rings were identified on karyotype with little way to identify the origin.  The argument that we shouldn’t use a technology until we completely understand it is unreasonable.  We need large testing numbers to give us these uncertain results so that we can learn from them.  Ambiguity with test results is hardly a new concept for us.  Genetic counselors deal with this all the time!  Our counseling isn’t really changing; it’s just the same uncertainty coming from a different test.

I argue that this test provides much LESS ambiguity since most women are getting reassuring results.  The number of women who are screen positive is dramatically decreased.   Fewer women being anxious, fewer amnios being considered and performed, and fewer losses of otherwise normal babies.    And why wouldn’t an informed patient want the BEST screening test?   And why wouldn’t providers want to offer it?

I absolutely acknowledge that not all patients are fully informed about NIPS prior to testing, and I hate to think about the ignorance that providers may pass along to patients.  But what genetic counselor hasn’t had a patient arrive at their office with an abnormal screening result thinking that their baby is, in fact, affected?  We hear this endlessly.  And how long has traditional screening been around?  And those results even have a risk estimate listed!  Sometimes I like being the hero in these situations “You mean my pregnancy is at a one percent risk for Down syndrome?  What a relief!”  The misinterpretation of testing results is inevitable.  We should not back away from better testing simply because some people do not understand.

While I agree that I would prefer that the commercial labs present their results with some more obvious notation of the limitations of the testing, no report can eliminate ignorance.  So perhaps our focus can be a shift to better education.  After all, isn’t that we do?  We need to talk with providers in our area and help them understand the test more clearly.  Review with the nursing staff when a referral is sent to us that the results are screening and not diagnostic.  I can tell you that in my own experience, education isn’t always successful because I still have providers who offer universal SMA and Fragile X testing without being able to interpret the results. *Sigh*  But these patients are ultimately referred for counseling, and I consider that a success.

Education at the patient level is important too.  Group counseling sessions can be an effective way to inform the pregnant population, especially about universal topics like screening.  The overwhelming task of education is not unique to prenatal genetic counselors, but to the profession as a whole.  Rather than hold back on a test that is truly superior because providers misunderstand it, why don’t we try to tackle the larger issue of provider education?

What I hope is that the consumers of NIPS can work closely with the industry providers to further study the performance of this technology to better understand cell free fetal DNA and its utility in pregnancy screening.  Let’s work together in educating providers about the testing and the importance of pre-test counseling.  Patients deserve it.  Without the cooperation and participation from genetic counselors we risk delaying universal acceptance of NIPS.  Let’s all jump aboard and steer this train.

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TMI?

Genetic testing for single disorders is rapidly going the way of yogh (Ȝ), eth (ð), and thorn *(Þ), those Old English fossil letters of the alphabet. With the advent of massively parallel sequencing and other new testing technologies, multi-gene panels are the wave of the immediate future. Some labs offer testing for 1700 genetic diseases on a single saliva sample. Single gene tests will soon seem as quaintly ancient as The Canterbury Tales.

The eye-blink rapidity of the evolution of genetic testing has made this an exciting time to be a genetic counselor. There is much to be said about multi-gene panels and the technological, scientific, clinical, ethical, and social issues that they raise. Here I want to share a recent experience with a hereditary cancer risk gene panel that made me think about some less discussed issues stemming from gene panels – Will patients  be able to understand this Midas-like wealth of genetic information, integrate it into their health care, and share it with their families? How adequate are current counseling strategies to deal with this complexity? 

My bright and educated patient had been diagnosed with young onset breast cancer, as had several of her first degree relatives.** One of these relatives previously had normal BRCA analysis. No other relatives had been diagnosed with cancer. A multi-gene panel indicated that my patient carried two pathogenic mutations, one in BRCA1 and the other in MUTYH. On the surface, this is not too complicated – a dominant mutation (BRCA) and a recessive condition (MUTYH polyposis) within one sibship, something that a first year genetic counseling student would be able to think through without much difficulty.

Simple. Or so it seemed until the discussion quickly became complex when I started switching back and forth between dominant and recessive inheritance and the different risks to siblings, nieces, and nephews; the need to test the patient’s spouse and potentially her siblings’ spouses for MUTYH mutations; and what further hereditary breast cancer genetic testing might be worth considering for the affected sibling who previously had normal BRCA analysis. It was like trying to focus on two different radio stations that were playing different songs simultaneously.

When a test result indicates a pathogenic mutation, I provide a detailed letter to the patient that serves as a guide to clinical management and to review the implications for the patient’s family. My first go-round with writing the letter for this double mutation patient was a 7 page affair that left my head aching. I eventually settled for two 3+ pages letters, one for each condition, but it still felt unsatisfactory to me. The follow-up took several sessions, a large chunk of administrative time, and multiple phone calls. Because some relatives do not live in the immediate area, it will be difficult to know how well this information will be communicated to the rest of the family.

Think of those female family members who may wind up testing positive for the BRCA1 mutation and carrying two MUTYH mutations. Will they have the drive to undergo annual colonoscopy, annual mammography, annual MRI, monthly self-breast exams, semi-annual physical breast exams, and whatever other screening we might suggest? Or elect to have risk-reducing salpingo-oophorectomy, prophylactic mastectomy, and, if they have a high polyp burden, prophylactic colectomy? That is asking a lot of someone, to say the least. Many patients will follow screening recommendations initially but after five or so years may begin to fall off in their compliance if the demands are too great.

And that is just for a small gene panel. No doubt we will encounter multiplex mutation patients who carry more than just two high risk genetic markers as routine whole genome/exome sequencing comes closer to reality. We cannot expect patients to regularly consult their genomes on a daily or weekly basis, like a genetic I Ching, to guide their life choices.  I suspect what may happen is that patients will focus on a few aspects of one or two diseases depending on their particular circumstances and experiences, and let the rest fall by the wayside. I not uncommonly encounter BRCA positive patients who say “Well I don’t have to worry about ovarian cancer because there is only breast cancer in my family, so there is no need for me to have my ovaries removed.” Even for the most medically sophisticated, highly motivated, and well-educated patients, there is a limit to how much information they can process and act on.

Then there are the possible psychosocial implications and narcissistic threats engendered by carrying not just one but multiple gene mutations, and the familial issues as increasingly complicated information is transmitted across the kinship network. With no family history of colon cancer, the MUTYH results came out of the blue and added another level of psychological complexity by raising concerns about a cancer that had not been part of the family’s prior medical landscape.

Some labs provide excellent educational materials, far better than what most counselors can put together with their limited time and resources. However, these pamphlets and online materials are geared toward explaining a single disorder within a family, not with providing a comprehensive narrative that interweaves the implications of multiple hereditary conditions. We need to develop  better counseling and education techniques to allow patients to effectively utilize complex genetic information and to help patients adhere to a screening strategy with as few financial, practical, scheduling, and emotional barriers as possible. Genetic testing may become relatively inexpensive and widely available, but the social and ancillary medical costs may be where the real expense lies . And that is not even considering the massive problem of maintaining properly curated databases to track, study, and communicate information about variants of uncertain significance.

To some extent, the situation may be analogous to PKU. As thoughtfully discussed in The PKU Paradox by Diane Paul and Jeffrey Brosco, PKU is typically described as a straight-forward mendelian recessive disease that has a remarkably effective simple intervention. PKU has had its share of astonishing success that has provided moral capital for justifying all kinds of genetic testing. Hundreds of millions of babies have been screened for PKU.  However the clinical, ethical, resource utilization, and social issues engendered by PKU screening are anything but simple, far from being resolved, and we are still uncomfortable acknowledging them. And that is for just one relatively uncommon genetic disease. Those problems will be magnified as we test for many conditions, some of which are not so rare.

PKU Cover

Am I sounding an alarm over a non-issue? What are the thoughts  and ideas of our DNA Ex readers?

* – A little bit of language trivia for the curious reader: The letter thorn (Þ), which represents the phoneme “th” (/θ/) as in “there,” survives in modern English in a peculiar role in the names of certain businesses like Ye Olde Clothing Shoppe or Ye Dragon’s Den. The Y in “Ye” is derived from the Early Modern English version of thorn, which was indistinguishable from the letter Y. “Ye” in these names is a modern cutesy way of spelling “The” and “Ye” should be properly pronounced “the” rather than “yee.”

**- Clinical details have been changed to maintain confidentiality.

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Metaphorically Speaking

With more than 30 years of experience, my tenure as a genetic counselor is roughly equal to the age of  the average practicing genetic counselor. It is no exaggeration to say that I entered the field when many of today’s genetic counselors were still zygotes. A few years ago I ran into a patient whom I had counseled during her pregnancy 27 years ago who proudly informed me that the daughter she was pregnant with back then is now a genetic counselor.

Truth be told, I have reached  a point in my career where I question my relevance to the genetic counseling profession. I worry that the issues that concern and stimulate me are irrelevant to the current and future practice of genetic counseling, that I am stuck in a professional time warp where I am fighting yesterday’s battles and fretting about irrelevant ethical and clinical dilemmas. Maybe my work here is done.

Even more concerning is the possibility that younger patients may think that I cannot possibly understand their problems. They are at vastly different points in their life cycles than I. There is little overlap between our cultural reference points and we likely have distinctly different comfort levels with the technological advances of the last 3 decades. Who wants to be counseled by their father?

Photo courtesy of Lizzie Resta

Phone

VHS Tapes For VCR

When I first started out as a counselor, I fretted that I was so much younger than my patients that they would not take me seriously. Now I struggle with how to relate to a 30-year-old female BRCA mutation carrier trying to decide whether she should tell her fiancé about her carrier status, and if should she have a prophylactic mastectomy, which in her mind might render her an “unfit” mother because she would not be able to breast feed. My insecurity has come full circle. Sure, good counseling skills should make those differences irrelevant, but still…..

The potential generation gap between me and my younger patients surfaced recently when I met with a woman whom I had initially met with in the 1990s when she was pregnant and amniocentesis had revealed an apparently balanced de novo translocation.* Because of our past experience together she requested to meet with me again because of her subsequent personal and family history of cancer.

Before we started addressing her current situation she told me that she wanted to let me know how much she had appreciated the counseling I had provided during her pregnancy nearly two decades ago. What she had found particularly helpful was a metaphor I had used to help her grasp the concept of translocations. “Bob, you described chromosomes as essentially being a set of encyclopedias, genes were the words in the encyclopedias, and DNA was the alphabet used to spell the words. A balanced translocation was like a few chapters from Volume 10 had broken off and joined Volume 4, and vice versa. You couldn’t say for sure if a few words or letters were lost as a result of the translocation, but as far as the lab could tell, the encyclopedia had all of the necessary information, just rearranged. The light bulb went on in my head, and I was able to make a decision to continue that pregnancy.” I am not claiming that I broke new counseling ground with this explanation; I suspect that many genetic counselors use some version of it.

She continued “My husband and I liked that imagery so much that we used it when we finally decided to tell our teenage son about his translocation.” After they broke the news to their son about his genomic constitution, the patient said that her son silently contemplated what he had just been told. The parents held their collective breath, anticipating a complicated genetics question or a deep emotional response. Finally, he looked up and asked “An encyclopedia – is that anything like Wikipedia?”

Well, I thought, I wasn’t just being paranoid about my relevance to genetic counseling. Even my Genetics-To-English Dictionary is obsolete. I really do need to think about packing it in as a counselor and taking an administrative position with no patient contact.

Rare First Edition of the Genetics To English Dictionary

After I recovered from that shock, I got to thinking more clearly about their son’s statement. Hey, I thought, maybe I could update my Genetics-To-English Dictionary and appropriate the Wikipedia metaphor to my current work in hereditary cancer. Wikipedia is essentially the genome. It contains a lot of information, but some of that information is inaccurate and needs to be corrected and updated, much as DNA can acquire mutations and needs to be repaired. Mismatch repair proteins, the culprits in Lynch syndrome, are like the anonymous editors who vigilantly proofread Wikipedia, reporting and correcting typos to restore the integrity of the information. When the mismatch repair protein genes are mutated, the proofreaders are less accurate, DNA damage accumulates in the cell and eventually leads to cancer. In Lynch syndrome, the proofreader has a hereditary dyslexia.

Perhaps there still is some hope for me as a genetic counselor. But first I have to figure out how to stop my stupidphone from making that awful chirping sound. At precisely 3:12. AM. Every morning.

* – Some clinical details of this scenario have been changed to maintain confidentiality.

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

10. 23andMe and the Thanksgiving Week Massacre

Image

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”).

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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.

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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.

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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,

AND

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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Guest Post: Adrienne Asch – Reflections from a Genetic Counselor

by Katie Stoll

Katie Stoll is a genetic counselor in Washington State. She graduated from the Brandeis University training program in 2003 and since that time has held positions in the areas of prenatal, pediatric and cancer genetic counseling.

We recently said good-bye to Adrienne Asch, a thoughtful and powerful voice in bioethics, disability, and reproductive rights. Adrienne passed away at her home in New York on November 19, 2013, surrounded by the love of many friends and family.

Adrienne touched my life deeply in the brief time I knew her and I am grateful to have had a connection with her. Her perspective has significantly shaped the way I view the genetic counseling profession and my role within it.

Adrienne was an accomplished scholar and an incredible person. Several beautiful tributes speak of character and her accomplishments, and these only give us a glimpse of her impressive body of work. See the The New York Times, as well as blogs related to philosophy, feminism, and bioethics for more about Adrienne.

Many genetic counselors are aware of Adrienne’s focus on the intersection of disability rights with reproductive technologies.   She was supportive of abortion rights, but questioned the implications of prenatal diagnosis and selection for disability rights, for individual parent expectations, and for humanity. She asked the question, if individuals with disabilities are not welcomed into family life, how can we expect inclusion in schools, in the work place, in society?

In her scholarly work, Adrienne spoke frequently about the parent-child relationship, and I had often wondered about her personal experiences as a child in this relationship. I came across the transcript of a fantastic interview with Adrienne conducted by Anna Kirkland at the University of Michigan, in 2006. I was delighted to find these insights into Adrienne’s own family life and it is heartening to realize that Adrienne’s views on this topic were in part shaped by her own childhood experiences of being supported to be true to herself:

“My parents taught me to think for myself and to be comfortable with who I was, even if people around me weren’t entirely comfortable with who I was either as a leftwing type or somebody who loved classical music, or someone who was Jewish, or someone who was blind. So they just taught me to be myself.” 

At one point the interviewer asking Adrienne if she had ever had the opportunity to address genetic counseling students. Adrienne has been an outspoken critic of prenatal diagnosis and this has made her quite a controversial figure among genetic counselors.

Anna: I’d be interested to know, have you ever had the opportunity to address a group of genetic counseling students or…or… 

Adrienne:  Yes. I have. 

Anna: Yeah. How did that go? 

Adrienne:  Not well. 

Anna: [laughs] What [laughs]…what did you say to them? 

Adrienne:  The same kind of thing I’m saying to you. But it challenges…I mean, maybe that I haven’t said it gently and kindly enough and I’m trying to do that. I have sympathy for how difficult it is to do this work. But I have no sympathy for people telling me that parents aren’t interested in this information or it’s not appropriate to give them the kinds of information that I’m describing. I think in fact that’s what genuine information is.

Recently, I had a chance to work closely with Adrienne when she helped to conceptualize a symposium for the National Society of Genetic Counselors Annual Education Conference, Reaching for Common Ground: Prenatal Genetic Counseling and Disability Equality. Although  Adrienne’s health prevented her from traveling to Los Angeles for the meeting, she was determined to hear all of the presentations live and to participate in the conversation. We achieved this through the technological miracles of cell phones, speakers and microphones for the entire 6 hour conference and this allowed her to both listen and contribute to the conversation.

In early October, she recorded a video for this conference and the National Society of Genetic Counselors has kindly allowed me to share it here. I encourage you all to take the time to listen to Adrienne’s final address to genetic counselors. I think she finds the balance she was striving for in being sympathetic to the difficulties inherent in the work of genetic counseling and remaining strong in her challenge to our profession to be more than genetic educators.

In genetic counseling, you have an enormously important role to play in helping prospective parents’ to think about the meaning for themselves of the genetic impairments or prenatally diagnosable impairments that they might discover in a fetus or an embryo.   And the role that you have to play is not genetics education alone.  It is genuine counseling.  It is counseling with a genetic component.  But it is dialogic counseling.  It is not merely reciting facts about laws and services and family support for people with Down syndrome.  It’s not reciting how wonderful it is and how loving the children are…It’s not reciting how terrible it is and how bad group homes might be.  It’s asking parents to think about the goals they have for their family life and how a child with characteristics that they can know in advanced will affect the achievement of those goals… The other reason you have a big job is that you are not given much time in which to do it. And all of the institutional forces work against that kind of conversation.  But I am urging that genetic counselors take their respective places as counselors to really help prospective parents think through what they want for their family life.  How a particular characteristic or impairment will affect that…

…Just as life is made up of many experiences that are shareable, you don’t need to have particular characteristics in common to share a life and to share experiences.  And you as a genetic counselor have an opportunity to communicate that to prospective parents. And ask prospective parents to think about what they want in their family’s lives.  And whether a child with a particular characteristic you can name in advanced will make the achievement of those goals any harder or any less possible. 

That’s a job of real counseling.  It’s not a job of imposing your values.  It can be as nondirective as you like but it is a job of asking questions maybe questions parents don’t want to be asked but that’s often true of any counseling.  No therapist worth his or her salt merely smiles and nods and says, “Ahah!”, and says, “I see what you mean”.  Therapy and counseling are about asking people to reflect and think twice or three times about the views and the values they are bringing to their lives.  You don’t have three years or 3 months or sometimes even 3 weeks to do that with the people in front of you.  But in the 45 minutes to an hour that you have, or if you’re lucky, more than that, you have a chance to communicate the joys of parenthood, the problems of parenthood, and the ways in which a child with any set of characteristics may or may not fulfill the goals that a parent has.”

Part of our fundamental core professional values as genetic counselors is to be non-directive in our counseling – not to decide the morally ‘right’ path for pour patients. We strive to support individuals to choose the path that they decide is right for them. Our responsibility as genetic counselors is to do our best to make certain that the decisions people make are as informed as possible.

What Adrienne helped to crystallize for me is that part of ensuring informed decisions requires inquiry into of the prospective parent’s expectations, hopes and dreams. It may also call for us to challenge misconceptions about how life with a disability is imagined and this may need to begin first with examining our own misconceptions and biases.

Adrienne certainly dismantled my preconceptions about life and limitations for someone who has been blind since shortly after birth. Although too short, her life was undeniably rich and full and her contributions were many. I imagine there are many DNA Exchange readers who have some interesting reflections about Adrienne of their own. I hope you will share them here.

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