Author Archives: laurahercher

Ohio seeks to criminalize abortion based on a prenatal diagnosis of Down Syndrome. Can they do that? The answer may be more complicated than you think.

This fall, the Ohio State Legislature will vote on a bill that would make it illegal for a woman to get an abortion if she is terminating the pregnancy because her fetus has Down syndrome. If passed – and it is expected to pass – the bill must be signed by Governor John Kasich, who happens to be running for the Republican nomination for president. That should tell you everything you need to know about the chance of a veto.

Ohio is poised to join North Dakota as the second state to restrict abortion from being used to prevent the birth of a child based on a prenatal diagnosis. North Dakota’s law does not specify Down Syndrome, but makes it a crime to perform an abortion that is sought because of a “genetic anomaly.” You might think this restriction is unconstitutional under Roe v Wade — and you might be right about that – but as of today the North Dakota law remains on the books. Abortion rights advocates considered a challenge, but decided that the law was impossible to enforce, and therefore not worth the time and expense.

Beyond the Orwellian specter of a law that parses women’s motivation — and the perversity of allowing abortion only when a fetus is healthy – these laws demonstrate a deeper truth: anti-abortion activists have taken aim at prenatal diagnosis. Rick Santorum’s attack on amniocentesis in 2012 may have been badly articulated, but ideologically like-minded employers have embraced his call to cut off funds for prenatal testing. Genetic counselors may not feel that prenatal testing and abortion are two sides of the same coin, but it is important to understand that the rest of the world sees a clear and causative relationship between testing and termination.

Geneticists are not fortune tellers – a point we are forced to make frequently – and it is hard to predict what will happen in the courts BUT you have to assume these laws would not survive a legal challenge. If it stands it is hard to imagine a prosecution. How do you prove motivation?

Does that mean it doesn’t matter? A recent Bioethics Forum post noted that It seems odd to allow prenatal testing for Down syndrome – which the American College of Obstetricians and Gynecologists has recommended should be offered to all pregnant women – and then deny women the opportunity to decide what to do with the information.” This was meant as a criticism of the law, but there’s amore chilling implication. If you want to prevent abortions based on prenatal diagnosis, you can restrict the right to abortion OR you can restrict the right to prenatal diagnosis. One of these things is unconstitutional. What about the other?

There are objections you could raise. Free speech! Yes, but telling your patient about prenatal diagnosis isn’t going to help if her health plan refuses to pay for it. The sacred doctor-patient relationship! Yes, but remember that many states already have laws requiring doctors to read from a script to any woman seeking termination. In some states women seeking abortion are told, by law, that abortions are associated with breast cancer. Are you surprised to hear about this alarming association? That’s because it isn’t true.

If you believe that a fetus is exactly the same thing as a baby – and despite widespread uneasiness with abortion most people do not – then prenatal diagnosis is offensive. One typical and less confrontational approach to this attack is to talk about the value of prenatal diagnosis apart from termination. This feels like safer ground, but I would argue that it is short-sighted. Even if prenatal therapies improve, and there are some promising things in the works, testing will remain a vehicle for giving couples the option of termination, and when we deny that fact we look cagey and defensive. We open ourselves to the same charges of hypocrisy that we throw at anti-abortion advocates who cloak themselves in the language of the women’s rights movements. “We are just empowering women,” they say of mandated anti-abortion scripts. No, you are not. “We are fighting for women’s health,” they say, of regulations that put abortion providers out of business. No, you are not.

We need to be prepared to make the argument for what we do. Carefully and sensitively, but transparently, and without shame. We help families have healthy children and that’s a good thing and not a bad thing. We help people make the choices that are right for them. People in this field know that restrictions on prenatal diagnosis are not empowering. We know who they will end up hurting – the poor the young, the vulnerable – all the usual suspects. Prenatal diagnosis is not going away anytime soon. But keeping it available to everyone is going to take work and vigilance.

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For decades we have speculated about what it might mean to be able to change the genes of an embryo. Not to be able to treat disease, or to prevent disease, or even to generate extra embryos in order to pick the best of the litter, but to get in there, to insert ourselves into the process by adding variation that nature in its evolutionary wisdom, has not made available. Germline engineering, it is called by some. Tampering with humanity, by others. Playing God.

The language betrays an unease that is both non-specific and widespread. The stakes are enormous. If we can alter a child’s DNA to make the child smarter, stronger, less susceptible to cancer or heart disease, why would we not do it? There are a multitude of answers, but perhaps the most compelling one is this: we don’t know what we don’t know. A generation raised on nuclear fears does not trust the intentions of man; a generation facing the fallout of climate change has no faith in humanity’s ability to foresee long-term consequences.

Let’s spill a little ink on some of the other qualms as well. Expensive genetic technology will exacerbate inequality in a world where the haves and the have-nots are increasingly at odds. It will make life harder for those who are not helped, the ultimate children left behind. It will enshrine the prejudices of those who control the technology. “What do you see?” I ask my students. “Taller,” they say. “Smarter.” “Blond hair and blue eyes.”

“Heterosexual,” says one boy, with a sad shrug.

Anxieties about the personal and social costs of tampering with humanity are as old as Icarus, who flew too close to the sun on his homemade wings. Inchoate fears have accompanied every step forward in genetics. We want better children, “ said Leon Kass, in a Washington Post editorial in 2003, “but not by turning procreation into manufacture or by altering their brains to give them an edge over their peers. We want to perform better in the activities of life–but not by becoming mere creatures of our chemists or by turning ourselves into tools designed to win and achieve in inhuman ways.” Evidence from polls suggests that society agrees with him in theory, but does that mean individuals would be willing to forego perceived advantages for their own children? Does it mean that they should?

In response to threats real and perceived, genetics has lived for decades with germline engineering as our line in the sand. Gene therapy for the individual, but no changes to DNA that will be passed along to successive generations. Frankly, this was an easy point to concede, when no credible means of accomplishing the goal safely was in view. But out there, in the absence of regulation, in the unconstrained global marketplace, in the power of what might someday be possible, the question lurked, not answered, just deferred.

Last month, twin editorials in Nature and Science served notice that the time has come to make some hard decisions. Things long envisioned as a part of our future are suddenly edging into the present, thanks to the stunning success of the CRISPR/Cas9 system of DNA editing.   A recent article by Antonio Regalado in the MIT Technology Review posits that we are teetering on the cusp of successful human germline alteration, and that in fact we may already be there (the article says that papers claiming successful embryo modification have been submitted to journals, but no evidence is in print — yet). In response, a veritable who’s-who of the genetics world (including Jennifer Doudna, a co-inventor of CRISPR) have called for a time out – a moratorium on human germline research while the world considers whether or not the technology – and the technologists – are ready for prime time.

Although the array of voices joining in this chorus are impressive, don’t overestimate this show of unanimity. The arguments in favor of a pause are diverse, and don’t represent the same long-term goals. There are three major types of arguments made against proceeding with germline manipulation, often conflated, and it is important to sort them out. The first line of argument concerns safety alone. Some signatories, such as Harvard’s George Church, see the ‘pause’ as simply an acknowledgment that safety and efficacy data are not yet available. Others are anxious to avoid the threat of a public outcry that could complicate the use of CRISPR/Cas9 for less controversial uses.

Essentially everyone agrees that if it isn’t safe enough you can’t ethically proceed, although defining ‘safe enough’ could be contentious.

A second set of arguments reflects concerns that some practices, though perhaps not dangerous themselves, will lead us in the direction of something more fraught. These slippery slope arguments are consistently employed in appeals to a popular audience, in part because they help make complicated issues accessible, and in part because they allow those making the argument free rein to speculate on the most click-worthy of potential scenarios. “The technology could be used to create, say, a unicorn, or a pig with wings..” suggests a Daily Beast article entitled, New DNA Tech: Creating Unicorns and Curing Cancer For Real?

For realz. And you wonder why I don’t care for slippery slope arguments.

And then there are those who are concerned about the potential negative consequences of the technology itself. Those voices too are a part of the quorum calling for a moratorium.   One Science co-author, stem cell researcher George Q. Daley, told the New York Times that the ability to modify our germline “raises enormous peril for humanity.” The Times quotes lead author and Nobel Laureate David Baltimore as saying “I personally think we are just not smart enough — and won’t be for a very long time — to feel comfortable about the consequences of changing heredity, even in a single individual.”

So presuming the world agrees to a pause – and presuming what Baltimore calls our “moral authority” is a thing in science, because it sure as hell isn’t in other spheres of would-be influence – what are we to do with the downtime? Editorials across the board call for a public discussion, so let’s start right here. I’ll go first. Four points:

  1. The tide has come in and the line in the sand is gone.

I don’t say that flippantly, because I understand the allure of a line. A line means you don’t have to think everything through every time. It suggests someone has an answer. It says some things are right, and some things are wrong, and somebody has gone to the trouble of figuring out which are which. But sad to say, it isn’t so. We don’t know. There’s too much at stake to arbitrarily rule out whole fields of research based on the need to avoid existential distress.

All the slopes on which we practice are slippery. Subtleties matter. Details matter. We are going to have to figure these things out case by case. Accept this and move on.

  1. Change has its price, and the good comes along with the bad.

Articulating a risk, or describing a negative consequence, is not adequate evidence in and of itself that something is bad and we should not do it. Vaccinations and IVF do have negative consequences for some individuals. There are risks. Those risks are well outweighed by the benefits. This is inarguable (do you hear me, Internet? Inarguable). Conversely, the fact that a subset of humanity can be helped by some practice is not in itself an argument that it must be allowed to move forward. There are times when individual’s best interests have to take a back seat to the needs of society. In China, where sex selection is rampant, the number of women ‘missing’ in the past 25 years is equal to the entire female population of the United States. Ask them how that’s working out.

Our debates are filled with people talking at one another, one side telling us why we should be afraid, and the other pointing out that it is a terrible thing to stand in the way of progress when people are in pain. The thing is, they are both right. Don’t imagine that there is some secret formula that will allow us to have the benefits of new technology and not experience any negative consequences.

  1. Realistically, we don’t have the option to stop moving forward.

When the cave people discovered fire, do you think perhaps one of them pointed out the danger? I mean, this stuff burns. Our great-great grandchildren will live in a different century. We may have something to say about what that world looks like, but we will not have the option of handing them a world that looks like ours, and neither did our ancestors.

  1. Consensus, not government regulation, will govern practice.

 Sticking out your hand and saying no is not a useful response. Suggesting regulation without acknowledging who will be doing the regulating is not a useful response. In the end, in a world where all the players can vote with their feet, consensus and not regulation will dictate behavior once the whistle blows and the timeout is over.

What do you think? Please join the conversation.

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No question that 2014 has been a year to celebrate for the field of genetics. Stem cell therapy, gene therapy, next-generation sequencing as a reliable clinical tool: we may not be there yet, but surely we are close. We have reached the suburbs of the Promised Land. Technical milestones have been met, technical challenges surmounted – palpably, we stand on the cusp of a new era, where we will have means to treat the untreatable and cure the incurable.

The many success stories of 2014 bring along with them reminders of an important corollary:  that the cost of what we are capable of doing already exceeds our collective ability to pay. The idea that personalized medicine will pay for itself is a joke, and every $300,000 a year drug we produce is the punchline. As we recognize the many amazing ways in which genetics is poised to change medicine, there are other questions that must be raised, about who will benefit and who will be left behind.

10. $1000 GENOME? — YUP, GOT THAT.

In January 2014 Illumina announced the arrival of the HiSeq X, a sequencing platform that can produce 5+ genomes per day, and at capacity delivers the results for less than $1000 per genome. The new system is sold only in sets of ten or more, and a set of 10 costs around 10 million dollars. Congratulations, people! We have reached our arbitrary threshold and may now proceed with the genomic revolution.


In October, Surgeons from Poland announced in Cell Transplantation that a 40-year-old patient paralyzed following a 2010 stabbing had regained the ability to walk after a transplant of olfactory sheathing cells grown in culture. The treatment seeks to capitalize on the unique regenerative capacity of mucosal stem cells.

Okay, there are caveats and concerns. The extent of his recovery is limited. He’s using a walker. We await replication. A woman who underwent a similar but unsuccessful procedure more than eight years ago was recently reported to have required surgery for a cystic mass in her back at the site of transplantation producing “thick, copious mucus-like material.” But GUYS!!!! Paralyzed man walks again.


There’s controversy regarding how much genes contribute to IQ, but most people would agree that genetics is involved, and studies of the heritability of IQ (the measure of how much genes contribute to the variance in test scores) put it somewhere between 50 and 80%. A genome-wide association study of more than 100,000 people published this summer looked at educational performance as a proxy for intelligence, and then checked those findings on a sample of almost 25,000 people using cognitive performance tests as a proxy for, well, cognitive performance. Did they find something? Yes: they found 69 SNP’s associated with educational attainment, three of which were significantly associated with cognitive performance. Something! But not much: each of the three was associated with, on average, a difference of 1/3rd of a point on an IQ test.

To recap, this was a big study with a lot of statistical power and it provided nothing adequate to predict individual performance or cognition. It did provide some proof in principle that genes affecting intelligence exist and that more might be found – maybe. Daniel Benjamin, one of the co-principal investigators, told Ewen Callaway of Nature News that explaining 15% of the variance in IQ would require over a million participants.

Sadly, the most important thing this study was not what it told us about genetics as it relates to our intelligence, but what it told us about our intelligence as it relates to genetics. A lot of the media coverage of this story missed the point – or buried it beneath misleading headlines.

Here are two soberer takes on this story, from Nature and Ars Technica:

nature smart genes ara technica genes

And by contrast, check out this headline from Business Insider:

bunsiness insider

Or these, from the Sydney Morning Herald, and Science 2.0:

science 2.0 sydney morning herald

Or this, from an editorial at RealClearEducation:


C’mon media people. You don’t need rocket scientist genes to do better than that.


Genetic sequencing has been put to work in the fight against Ebola, providing a surer method of diagnosis – crucial for a disease where isolation of the sick is a key step in containing the epidemic – and a method of tracking the origin and the path of the rapidly evolving virus currently ravaging parts of western Africa.

In September, fifty authors, led by Pardis Sabeti of the Broad Institute in Massachusetts, published a paper in Science describing rapid evolution of the Ebola virus found in the blood of 78 patients from Sierra Leone. What could emblemize the strange contradictions of 2014 more than this: machines reading a language written in single molecules, interpreted by programs that cost billions of dollars to develop, in the service of a battle fought in blood-spattered tents where people die for the lack of IV fluids.

There were 58 authors listed on the Science publication in September. As of October 24th, five of these individuals had died from the disease.



Oh come on, just give them the Nobel Prize already.

CRISPR, a top genetics story in 2013, could have made this list again for any number of reasons in 2014. The ability of the CAS9 gene editing system to efficiently target specific sites in human stem cells was reported in this Nature Communications article, suggesting that unintentional effects may be less of a problem than people had feared. Other experiments have explored the potential of CRISPR to cure muscular dystrophy, fight cancer, and make cells immune to AIDS. And that – no, I mean this – is only the beginning.

In mice with a mutated FAH gene and congenital liver disease, researchers led by Daniel Anderson at MIT reported that CRISPR machinery along with a template for the normally-functioning gene were inserted by high pressure injection and resulted in the production of enzyme-producing liver cells. For the first time, a designed, controlled, human-mediated process of gene editing occurred inside the cells of living animals. And it worked! Measurable improvement occurred in the health of the affected mice.

Another sign of how big this could be: the hotly-contested battle for control of the intellectual property rights, with the Broad Institute’s Feng Zhang and Zhang-associated biotech Editas Medicine taking round one earlier this year in the form of a broad U.S. patent. Final disposition remains in the hands of the judges, with co-discoverers Jennifer Doudna from UC Berkeley and Emmanuelle Charpentier from the Helmholtz Centre for Infection Research each having established relationships with competing start-ups, all of them angling to bring the power of search-and-replace functionality into genomic medicine.

In November, Charpentier and Doudna accepted several million dollars apiece as their share of the Breakthrough Prizes, funded by an assortment of Silicon Valley multi-billionaires and handed out by a bevy of Hollywood bold-faced names. Here they are, looking glamorous next to Cameron Diaz:

Screen Shot 2014-11-10 at 8.26.51 AM

So what do you say, Sweden? Make it official. They already have the gowns.


Photo Credit: graphia via Compfight cc

Photo Credit: graphia via Compfight cc

If you know ONE SINGLE THING about genetics, you know this: every cell in your body has the same DNA. Every cell in your body has the same DNA, except… well, of course there are always exceptions. If genetics was easy, everybody would do it.

Some exceptions are so rare as to defy belief: Washington resident Linda Fairchild found herself in jeopardy of losing custody of her children when a routine test suggested that none of the three boys she had given birth to was her biological child. Fairchild turned out to be a chimera – a single individual with two distinct genomes, in her case the result of a twin pregnancy where one fetus stops developing early on, and is absorbed into the body of the surviving twin. In Fairchild’s case, a second test, on her cervical cells, revealed an alternate genome that was a match for her boys. In effect, Fairchild was the children’s mother – and also their aunt.

Events that incorporate a whole alternative genome are unusual, but other changes that occur early in embryonic life can result in distinct cell lines in the body with subtle but sometimes important differences. Depending on when and where these changes occur, they may affect one organ or tissue type, or groups of cells scattered throughout the body like the patchwork fur of a tortoiseshell cat. Effects visible to the naked eye, like the large, irregular hyper-pigmented spots seen in McCune-Albright syndrome or the inconsistent areas of overgrowth in Proteus syndrome, have been recognized for years as instances of somatic mosaicism.

Trending in 2014: evidence that somatic mosaicism may not be as rare as we had thought. Newly available sequencing techniques show that the closer we look, the more variation we find within individuals. A study published in the American Journal of Human Genetics in July looked at the parents of children with small deletions that appeared to be de novo – that is, blood tests didn’t find the change in either parent – and found that 1 in 25 are mosaic for the variant in other tissues. Similarly, causal mutations in one cohort of individuals with brain malformations were found to be mosaic 30% of the time. Something to keep in mind when searching for the underlying genetic cause of a condition, or in advising a family about recurrence risk! Another 2014 report described an unaffected mother who had a second child with nemaline myopathy, which conventional wisdom suggests should be virtually impossible. A closer look after the fact found low grade somatic mosaicism – only 1.1% in blood leukocytes, but 8.3% in her fingernails.

Okay, but seriously, almost all of the time, most of your cells have (virtually) the same DNA – that’s our story and we’re sticking to it. Probably.

No numbers 4 or 3!  A three-way tie for second biggest story of 2014 goes to these, highlighting staggering technical achievements with equally staggering price tags:


Never mind that the field started the year on a sour note: a paper describing a new method of generating stem cells using an ‘acid bath’ generated its own acid bath of critical response and was subsequently withdrawn. Consider that a head fake, because 2014 was a banner year for stem cell research, the year we moved beyond rodents into human trials.

There are multiple contenders for stem cell story of the year. In France, a team led by Philippe Menasche announced plans to introduce cardiac progenitor cells using a patch in heart failure patients undergoing surgery, with hopes to improve heart function. In England, according to a fingers-crossed, early report in Stem Cell Translational Medicine, autologous stem cell therapy for stroke victims appears to be going well. Researchers testing stem cell therapy for blindness caused by macular degeneration or Stargardt’s macular dystrophy reported in the Lancet that over half of their participants have improved vision – an unexpectedly good result for a phase I trial of severely affected patients that was designed only to show safety.

Blind people seeing! It’s hard to beat that for drama. Still, my stem cell story of the year comes from California, where the stem cell therapeutics firm ViaCyte has announced that the first of forty patients in an FDA-approved trial has been implanted with pancreatic progenitor cells that are designed to mature into insulin-producing cells in situ. The cells sit in a sort of pouch made of a thin, porous membrane intended to allow insulin to pass into the bloodstream as needed, but insulate the cells from the destructive immune response that causes Type I diabetes. Here’s my reasoning: the work was supported by the California Institute for Regenerative Medicine, which has a lot to talk about right now after a slow start and a lot of snickering about government-run programs, and it involves a unique, creative delivery method and a common disease that starts in childhood and causes lifelong morbidity and expense. This might not turn out to be the solution that sticks (a group at Harvard recently announced a new method for reprogramming fibroblasts into pancreatic-like progenitor cells, so maybe we will have an East Coast-West Coast battle. Perhaps they can rap it out). But there are a lot of type-1 diabetics out there who should be feeling upbeat about their chances for a breakthrough in the near future.

And given the cost associated with the disease, this might even be a stem cell therapy insurers pay for without a fight. Or – well, maybe not.


Two years ago, the introduction of Kalydeco from Vertex Pharmaceuticals made this list as the first ever pharmaceutical treatment designed to correct an underlying genetic defect. Although it is effective for only a single mutation, which means it helps only 4-5% of those affected with the disease, Kalydeco represents proof in principle that targeted therapies can provide a virtual cure for CF, and by extension, a sign that understanding the genetic underpinnings of disease can improve the lives of that big universe of affected people.

Now Kalydeco is back in the news for less happy reasons. This summer, three women sued the state of Arkansas, claiming that Medicaid violated their federal rights by refusing to pay for Kalydeco, although they met eligibility criteria established by the FDA. Arkansas’s Medicaid program claims it does not categorically refuse to pay for Kalydeco, which costs more than $300,000 per year, but requires applicants to prove that conventional therapy is inadequate. That’s a catch: the older therapies are less successful, more arduous and leave patients liable to repeated infection and lung damage that may permanently compromise their health, but they may be adequate to attain ‘acceptable’ lung function. Joseph Walker, writing in the Wall Street Journal, describes the rigors of one litigant’s “traditional” regimen, including hours a day in percussive therapy, where pounding on the chest loosens hardened mucus in the lungs. Vertex, which has a compassionate care program for those with zero coverage, which is another catch: they refuse to provide the drug unless the individual has no grounds on which to appeal – in other words, if they need it, they can’t get it. Otherwise, Vertex argues, all Medicaid programs would be incentivized not to pay.

So what is with the Catch-22’s? Medicaid and the drug companies are worried about setting policy, knowing that Kalydeco is the tip of an iceberg, with a slew of extraordinary and extraordinarily expensive targeted therapies on the way. This year, Genzyme has introduced a new pill for people affected with Gaucher disease that will cost $310,250 per annum, and researchers released data showing that the drug asfotase alfa could help form bone, rescuing infants with a rare and lethal condition called hypophosphatasia – at $200,000 per year, which suddenly seems like a bargain. This list is by no means complete, and it’s not getting any shorter. And limiting compensation, as the pharmaceutical companies constantly remind us, will make them less interested in finding treatments for rare diseases.


Most people want to be one in a million, but if you ask someone with lipoprotein lipase deficiency, you might get a less positive response. This rare disease leads to sky-high triglycerides, eruptive fat-filled lesions, frequent abdominal pain and bouts of pancreatitis. Glybera, a cure for LPLD and the first commercially available gene therapy in the western world, will be introduced by UniQure in Germany in 2015. It is estimated that 150-200 people in Europe could benefit from treatment, which will cost, on average, 1.4 million dollars per patient.

The most stunning thing about that number is that it might be considered a bargain. With targeted therapies clocking in at $200,000+ per year, the one-time fee represents a substantial savings if amortized over a decade or more. To get your money’s worth, just keep living.



Photo Credit: Rikot via Compfight cc

Photo Credit: Rikot via Compfight cc


The Exome Aggregation Consortium (ExAC) released debuted its massive database of exomes at the American Society of Human Genetics meeting in October, and the response crashed the server on day one. Way to break the internet, guys. According to a post from the head of the ExAC production team Monkol Lek, the exome browser garnered 120,000 page view from over 17,000 unique users in the first month.

Several factors make this the top story of 2014. First, the remarkable technical achievement of turning over 15 data sets into a single, searchable entity, and the equally remarkable feat of getting all those research entities to turn over their hard-won libraries for universal access. “Here are a bunch of data sets that individually cost millions of dollars to generate, and you have people willing to make that data available to a shared resource, which is amazing” marvels ExAC principal investigator Daniel MacArthur, speaking to Nature’s Erika Check Hayden in October.

ExAC isn’t the first genomic database to be made available to researchers, and it won’t be the last. The Haplotype Reference Consortium, a resource for genotype imputation and phasing, will begin releasing data in early 2015. And the new resources aren’t sufficient – HRC organizers note that their current data set is European-centric, and getting a more even distribution of ethnicities represented is an important challenge going forward.

But the fact that these open access resources exist represents an acknowledgement by all concerned that clinically significant progress will require genotypic and phenotypic information on more individuals than any single research entity can assemble on its own. By implication, it acknowledges the significance of rare variants in human health and disease and the need to look beyond simple deterministic models of gene effect and give sufficient power to studies that encompass a subtler, more complicated vision of how phenotype emerges from genotype.

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The Downside of the Downside of Resilience: A New York Times Oped Ventures Into Dangerous Territory

Although we take seriously the threat of genetic discrimination, there aren’t a lot of examples you can offer. In my ethics class, I discuss the Burlington Northern Santa Fe Railroad case — everyone discusses the Burlington Northern Santa Fe Railroad case, not because it is such an interesting precedent but because it is all we’ve got. BNSF secretly tested their employees for genetic liability to carpal tunnel syndrome. The fact that it was genetic testing was almost beside the point. Can ever you secretly test your employees? No, you cannot. But the genetic testing angle made it extra creepy. Why? Because we are primed to worry about genetics. It is too new and too powerful not to carry with it the seeds of some unspecified disaster. We just don’t know what it is yet. We are heading out into the wilderness here, the wilderness within. How can we set about to tinker with the machinery of life without wondering if we run the risk of turning our tears acid and drowning our good intentions in our own rising tide?

Sometimes I wonder if genetic discrimination is a Yeti, a word we whisper around the campfire to give shape to our fears of the great unknown. After all, formlessness does not diminish fear, it makes it worse. If you don’t know what you are looking for it could be anything. It leads us into a state of vigilance that is both laudable and incredibly annoying, since every step forward is met by cheers and then, at the back of the crowd, a sideways glance and a muttered, “what could possibly go wrong?”

This is why I was so struck by Jay Belsky’s article, the Downside of Resilience, published in the New York Times Sunday Review this past week. Belsky points to work, his own included, that suggests some genes that may predispose children to do badly under stressful conditions – abuse, trauma, etc – are not so much “bad” genes as “responsive” genes – and that the same genetic inheritance makes them equally responsive to good parenting or helpful interventions. It is called the orchid and the dandelion theory, with the idea being that some kids do fine in all circumstances – the dandelions, growing like proverbial weeds – while others are hothouse flowers, dying in adverse conditions and blooming in the right hands. If this interests you, read more in this article from the Atlantic by the inimitable David Dobbs (and really just read anything the man writes; you can’t go wrong).

Belsky goes on to propose that we identify children with this genetic predisposition to responsiveness and target them – a good use for our “scarce intervention and service dollars.” We’re not ready to do that, he concedes. But, he asks, “if we get to the point where we can identify those more and less likely to benefit from a costly intervention with reasonable confidence, why shouldn’t we do this?”

Well, okay. A few reasons. First of all, the proposal implies a level of genetic determinism that is unsupported by the facts and fundamentally misleading when it shows up in a place like the NY Times. These are population-based observations, very interesting as to the nature of the genes and how they work, but not valid predictors of individual performance. There are too many confounding variables in the lives and the genetic makeup of individuals. As genetic counselors could tell him, even when you have the same variant in the same gene in the same family, outcomes may vary wildly.

However*, as I said in a response to the Belsky editorial, arguing the science suggests that if we could get that right it would be a good idea. History, on the other hand, suggests that creating classes of people based on what genes they carry is a dangerous proposition and not something to which scientists should lend credibility. The Belsky proposal is obviously well intended. He talks about benefitting the children who have the genes to respond, not disadvantaging the others. But, as he says himself, intervention dollars are scarce. Scarce resource are a zero-sum game. To give to one, you take away from others. You designate certain people as more worthy based on their genes. You incorporate genetics into social policy in a way that is ripe for abuse and prejudice masquerading as scientific facts. We have been down this road before. We know where it leads. It’s not a pretty place.

What does genetic discrimination look like? It looks like this.

*This is what I wrote but not what they published, because the NY Times doesn’t like sentences that start with ‘however’ and changed it to ‘but’. Whatever, NY Times.

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Mary-Claire King (winner of the 2014 Lasker Prize!) proposes a plan for universal BRCA 1/2 testing that is both TOO MUCH and TOO LITTLE

First things first: congratulations to Mary-Claire King, who this week won the Lasker Prize in Medicine for “bold, imaginative, and diverse contributions to medical science and human rights”. The award acknowledges King’s work in the 1980’s, reuniting families with the biological children taken from them during Argentina’s “Dirty War”, and it highlights her role in the pursuit and identification of genes implicated in familial breast cancer. Myriad’s Mormon database may have won them the patent race, but their Rosie Ruiz victory belied the long history of the chase, which King pursued for more than 20 years, stubbornly refusing to believe that pedigrees strewn with cancer were simply bad luck. What seems like common sense now was iconoclasm at the time, and it begs the conclusion that it took a woman in science to take these women’s stories seriously. King’s role in the discovery of BRCA1 was a triumph of independent thinking, as well as brilliance and persistence. You go, girl scientist!!!


King used the occasion of the Lasker Foundation’s announcement to publish a call for BRCA 1 and 2 testing for all women at age 30. The manifesto, published in JAMA, decries the current state of affairs, where women are frequently tested only after they get cancer. “To identify a woman as a carrier only after she develops cancer is a failure of cancer prevention.” This is a bold challenge, and given the source, one that demands some careful consideration.


There are some negatives to universal screening, many of which King discusses. A diminished but enduring problem with BRCA testing is the tendency to produce variants of uncertain significance (the dreaded VUS!). King suggests that for this purpose, we report only unambiguous loss-of-function mutations. Another concern is that our empiric data about the risk of cancer associated with these genetic findings comes primarily from families with a history of cancer – suggesting a possible ascertainment bias. For that reason, the US Preventative Services Task Force recommends testing only in at-risk populations. In response King cites a new study out of Israel documenting increased cancer risk in women with one of three Ashkenazi Jewish founder mutations even among women with no family history of cancer (and amazingly, 50% of all women identified with a mutation had no history of breast or ovarian cancer that would have brought them to clinical attention).


But, as King herself recognizes, “major questions arise in generalizing from the results of the study in Israel to population-based screening in the United States or any other country.” That study reviewed only 3 very well-characterized mutations in a single ethnic group with an equally well-characterized risk for breast cancer. It is a leap to assume the results are valid for all variants and all populations. Still the likelihood is high that mutations that disable BRCA 1 or 2 will cause at least some significant increase in cancer risk. Should we be advocating for universal screening?


Well, there are a couple of negatives to consider. First, King rightly notes that we can’t hand out results on a huge scale when we aren’t certain what they mean. So that means we are only looking at a subset of BRCA results with the potential to increase cancer risk. Furthermore, her plan reduces the complexities involved in cancer counseling in that it looks only at BRCA 1 and 2, and not at any of the other genes that contribute to overall cancer risk. While this makes universal screening much simpler, it also limits the effectiveness. So while you might make a ‘something is better than nothing’ argument for screening, you have to wonder if this quick and dirty approach will end up replacing a more thorough risk analysis for many women in the higher risk categories. It’s not easy getting women in for cancer counseling now – are they not less likely to seek out genetic counseling if they have already been ‘screened”? Similarly, will physicians be less likely to refer and insurance companies less likely to pay for a more thorough breast cancer risk assessment and panel testing? Not an issue, perhaps, for families with a striking, definitive cancer history– and never an issue for those with their own resources — but beyond this we run the risk of cannibalizing the cancer counseling programs that we have built, which provide a fuller and deeper approach to of risk assessment.


Second, the program King describes will not generate the data we need to improve our ability to interpret results of genetic testing for breast cancer predisposition. One of the goals if universal testing ought to be that an investment now would get us out of the too-much-data-too-little-interpretation hole we are stuck in today. On Twitter, response to King’s essay buzzed about the prospect of a massive database of variants:

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But returning only information on variants we have already characterized will not enable us to make any headway on classifying the rest.


Universal BRCA 1 and 2 screening is an enticing idea, and there is no doubt that it will identify tens of thousands of women at increased risk for breast and ovarian cancer, for which we have preventative measures with proven efficacy. But a program at this scale will not provide assessment or counseling at anything like our current standard of care, and the potential harm that could cause for families with mutations in BRCA 1 and 2 as well as the other cancer-related genes that will not be reported must be weighed against what we can accomplish; to that end, a pilot study would put some numbers on the scale. Furthermore, as a project universal screening represents a significant investment in public health. It makes sense for us to consider whether or not such an investment moves the ball forward in terms of improving genomic interpretation, and King’s plan, as envisioned, does not.



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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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Hobby Lobby Sounds Like Fun But It’s Really Yucky Sucky for Genetic Counseling


Hobby Lobby sure sounds like something that would never harm you. As Ray the Ghostbuster said in Ghostbusters, “Something I loved from childhood…something that could never ever possibly destroy us…”   But sadly, it is true: a threat wrapped in adorableness, Hobby Lobby v Sibelius is the 100’ tall Stay Puff Marshmallow Man of legal cases.


On March 25th, the Supreme Court of the United States heard arguments for and against the claim that Hobby Lobby, a privately-held company run by a family with conservative Christian beliefs, should not be compelled to purchase insurance for its employees that includes coverage for contraceptives, as is mandated under Obamacare. Actually the company does not object to all contraceptives, only to those that they consider abortifacients, including IUD’s and the morning after pill. Because this case concerns their right to act in accordance with religious ideology, the question of whether or not these methods actually produce an abortion is moot – it only matters that the owners of Hobby Lobby believe them to be wrong. So while the particulars of their faith mean that some contraceptives would still be available to Hobby Lobby employees, the principle under review, untethered to any burden of proof or objective standard, is far more sweeping.


Although the contraceptives issue itself is important, people on both sides have emphasized that this decision will have broader consequences. For instance, advocates for gay rights have seen this as a foot in the door for state-sanctioned discrimination, giving companies the right to refuse service or employment based on prejudice dressed up as religious beliefs. Adam Winkler, UCLA law professor writing in the Huffington Post, describes a number of ways that anti-discrimination laws could be undermined if any employer could claim a “religion-based objection to the law.”


This case is something that genetic counselors and the NSGC should be watching with concern, as it is likely to impact our field as well. Employers who object to paying for coverage that includes contraceptives may take a similarly skeptical view of paying for insurance that covers prenatal testing, with the reasoning that prenatal testing is done only to provide the opportunity for abortion. You can (and we will) argue that prenatal testing can lead to therapy or better case management or simple reassurance, but others will assert that the point of prenatal testing is to open the door for termination and, right or wrong, this is an argument that is likely to be taken seriously by conservative justices. If that seems crazy to you, do this thought experiment: imagine that termination is not an option under any circumstances, and then picture trying to get insurance companies to pay for amniocentesis.


Why do I think that anti-abortion advocates will target prenatal testing? it’s simple: they’ve been talking about it for years. Remember Rick Santorum, who was for a time one of the frontrunners to be the Republican presidential nominee in 2012? He made a speech during the campaign where he talked about the fact that prenatal testing is included as a fundamental and required part of healthcare coverage under Obamacare rules. “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.” This speech shocked a lot of people in the field when it hit the presses, but it didn’t shock his Christian Alliance audience at all. This doesn’t come from nowhere. Prenatal diagnosis is on the radar of the anti-abortion movement in the United States, which is why Hobby Lobby should be on ours.


Want more proof? How about the law passed in North Dakota last year, which prohibits abortion for sex selection or genetic defect? This statute has gone unchallenged in large part because it is almost impossible to enforce, as opposed to — say — the law restricting all abortions past six weeks gestation, which was passed at the same time and (understandably) got the lion’s share of the press. But the genetic abortion law, first of its kind, is a clear manifesto expressing the intention of those who oppose abortion to limit the ability of women to terminate for cause. And t that end, eliminating coverage for prenatal testing is a far more effective tool than trying to pass laws that require prosecutors to prove something about a woman’s state of mind.


This is an issue that isn’t going away. In fact, I predict it’s going to get worse. Why? Because we are getting better at what we do. Keep in mind that all our steps forward (better sensitivity, better specificity, earlier results, less invasive testing) are threatening to a mindset that sees prenatal diagnosis as an ever more efficient way to identify and eliminate vulnerable individuals. When ACOG revised its practice guidelines in 2007 to increase the number of women eligible for prenatal testing, columnist George Will wrote, “what is antiseptically called “screening” for Down syndrome is, much more often than not, a search-and-destroy mission…” Will, the father of a son with Down syndrome, bemoaned the change in practice precisely because it would be more effective.


I know, not because I am psychic, but because I have had this conversation before, what genetic counselors will say when this line of attack is launched. First, they will talk about their own commitment to be supportive of all choices for their patients, including the choice not to terminate, which is incredibly important to your patients but doesn’t matter at all to anti-abortion activists.  They don’t care if you are a good counselor, or a good person, since it doesn’t change the fact that a large percentage (how large; under dispute) of all those who receive a diagnosis of Down syndrome, for example, will choose to abort. Second, they will argue that prenatal testing has a value beyond the opportunity to terminate, which is true but a bit disingenuous for the same reason as above. Prenatal testing puts termination on the table as an option.


What I don’t like about this defensive posture is that it implies that giving families the option to terminate is not a good enough reason to do testing, or that we are unwilling to champion it as such. I don’t think this is how most counselors feel, but it is natural to try and tiptoe around the sensitivities of others, especially when those sensitivities are emotionally charged and involve a lot of judging – judging of us, and of our patients, whose feelings as well as medical options we would like to protect. But ultimately I think it is a better and stronger position to argue on behalf of what we do without defensiveness. We shouldn’t base our case for prenatal testing on the need to provide reassurance or how it improves prenatal care because those are not our best arguments and it makes us sound ashamed.


And meanwhile, stayed tuned on Hobby Lobby, where a decision is expected in early June.





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