Author Archives: laurahercher

Ancestry and the Long Distance Call

These are the days of miracles and wonder


I read the science news in 2016 and hear lyrics from that Paul Simon song echoing in my head.


These are the days of miracles and wonder

And better variant calls

The way that CRISPR works on everything

The way we sequence it all


Perhaps I paraphrase. But these are heady times, when the boy seems poised to burst out of his bubble, and fantasies of a baboon heart turn into dreams of a human heart instead, grown in a lab or in a pig, and we will have no more of slaughtering primates thank you very much.


These are the days of promises and phase one trials,

and medicine is magical and magical is art


When we cure your disease, I will feed you pancakes with maple syrup and put frosting on your birthday cake, I tell my beloved friend with type I diabetes. We will float Islets of Langerhans in a pouch beneath your skin. We will re-engineer your pancreatic stem cells to be invisible to your immune system.


Promises of miracles come with questions. Can we? Should we? How will we pay for it all?


We. We use the word freely, but what does it mean? This is a genetics question too, one that we (the purveyors and patrons of genetic technology, the readers of this blog) don’t ask ourselves often enough. Who will benefit from the miracles that are now only twinkles in the eye of brilliant minds?


Who is included when we talk about ‘we’? A family, a tribe, a nation, a species? It is one of the ironies of the genomic age that the technological revolution that makes it possible for us to think and act globally has also spawned a growing interest in atavistic concepts like bloodlines. Racism raises its ugly old head on new platforms like Twitter and Facebook. The through-the-roof popularity of ancestry testing both testifies to and nurtures an instinct to tribalism that is ancient beneath the glossy surface of its web-based, consumer-facing interface. A powerful thing, genealogy, beyond the fun and games, with the power to bring us together or tear us apart.


Research testifying to this was published earlier this year, in the form of an article called “Living in a Genetic World: How Learning About Interethnic Genetic Similarities and Differences Affects Peace and Conflict”. The authors conducted a series of studies observing how reading a single article about genetic relatedness or the lack thereof altered the response of a Jewish audience toward a hypothetical Arab population, and vice versa. Participants queried after being given a mock BBC article describing Jews and Arabs as genetic cousins expressed a less negative attitude toward individuals of the other ethnicity. Repeating their experiment with populations of Jews of different ages and from different parts of the United States, Sasha Kimel from Harvard and colleagues from the University of Michigan, Europe and Israel found that a suggestion of genetic kinship consistently increased support for peacemaking between Israel and the Palestinians.


Now don’t get me wrong, small studies and academic hypotheticals don’t represent a road map to peace in the Middle East. But the discussion points to something we as genetic counselors know from experience: genetic ideation is a powerful force in shaping notions of identity. It helps define ‘we’ for each of us.


This is something to think about every time we give out genetic information. For 23andMe and, it could mean writing a report that puts as much emphasis on what unites us as on what divides us. By convention, we talk about first cousins sharing 12.5% of their DNA.   But we share more of our DNA than that with a banana. Yes, I know that what we mean is that 12.5% of our DNA and our cousin’s DNA is identical by descent. Testing companies give FAQ’s explaining the numerics of relatedness; perhaps the 99.9% we all share ought to merit an asterisk at the very least.


It is a strange moment in which we live, full of hope and promise and fear and sadness. A new era builds at our back, with unprecedented tools to diagnose, treat and even prevent disease, while the landscape in front of us is one of increasing income inequality and fitful, angry isolationism. The routine injustice of bigotry and unequal access are far greater threats to the genomic era than the sci-fi horrors of Drs. Frankenstein and Moreau. CRISPR can’t change your zip code.


There is no simple solution to this, but the battle begins with how we define ‘we’. Genetics needs to remind us of what we share as often as it tells us how we are different. Many of you are out there every day fighting battles you may not recognize as part of a larger war: battling insurance companies for access, battling to bring diversity to our biobanks and clinical trials, supporting a new vision of family, in which our 99.9% shared DNA is enough, and we are not defined by the fraction that is identical by descent. We are educators in a field that is an agent of change, and so it falls to us to work for an ever more expansive and inclusive definition of ‘we’. Without that, we risk that the amazing technology of the genomic age will be perverted into a tool for doubling down on the things that divide us.


These are the days of miracles and wonder

This is the long distance call

The way the camera follows us in slo-mo

The way we look to us all

The way we look to a distant constellation

That’s dying in a corner of the sky

These are the days of miracle and wonder

And don’t cry baby don’t cry

Don’t cry



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The GC Crucible: the pressures on modern genetic counselors open the doors to opportunity

A Guest Post By Brianne Kirkpatrick

In a chemistry lab, a ceramic crucible held over an open flame melds disparate materials into a single, new, cohesive thing. Indestructible, it stands up to the heat and pressure. When used in metaphor, it’s a severe test or tribulation that leads to transformation. What comes out of a metaphorical crucible is the true character brought about by the need to adapt and change in a new environment.


If there is one thing I can get behind, it’s a belief that our job as genetic counselors is getting

harder. We work in a cauldron of new pressures and new challenges, ones that are causing us to adapt and discover what is at the core of our profession and what make us strong and unique, as individuals and as a cohesive group. We’re in a crucible right now, and that Bunsen burner is cranked up high.


Our clinical challenge is that the more we learn about genetics, the more complexity we discover (see item two in Laura Hercher’s top ten stories list for 2015 ). More information makes our job harder, even as it provides new hope for our patients. Similarly, the challenges of discovery and complexity that complicate our lives also provide new opportunities for genetic counselors.


How do we capitalize on those opportunities? Here are three suggestions:


  1. Rally around the development of the Genetic Counseling Assistant vocation. The NSGC funded a grant to study this, and there have been discussions about this at recent meetings and on various listservs. GCAs job are available, and individuals are employed as GCAs around the country already, in laboratory and clinical settings. Like a para-legal to a lawyer, GCAs master administrative tasks and carry the burden of extra work that often sidelines the genetic counselor or reduces his or her efficiency – phone calls, paper work, records requests, insurance pre-certifications, initial intakes, and the like. The only way we are going to keep up with the demand for GC services is to increase efficiency for ourselves and free up genetic counselors from work that impedes their ability to serve all who need and are seeking their services.


  1. Evolve or die. We as a profession must figure out how the future of genomics will include us. To do this we must immerse ourselves in current issues – in the clinic, in the research world, in the spheres of business and government – and then speak up when the genetic counselor voice must be heard. Get involved in your state’s genetic counselors’ group (consider founding one if it doesn’t exist). Volunteer in groups and for projects of the National Society of Genetic Counselors. Develop a professional social media presence. I chose to involve myself in the NSGC Public Policy Committee, believing strongly that taking a stand on issues of policy that affect us as genetic counselors allows us to determine our profession’s destiny, not others. Every committee and special interest group and task force of the NSGC contributes important work to the genetic counseling profession, but none of that work happens unless individuals decide to take that step and get involved.


  1. Embrace the expansion of our professional opportunities, despite the shortage of genetic counselors to fill existing clinical and laboratory roles. GC’s are finding opportunities to do something new and different, which is fitting for a group who collectively are thinkers outside of boxes. For as long as the profession has existed, GCs have used creativity, ingenuity and chutzpah, trailblazing new roles out of necessity. In every city and in every specialty area, there was a “first” GC there. If you have been contemplating blazing your own trail, now might be a good time to test out the waters, to find your niche and try something you’ve been dreaming of.


There are role models for those looking for them, as GCs excel at identifying needs and making connections. We’re problem-solvers and sleuths, and we’re a resourceful bunch. From this, we have seen Bonnie Liebers develop Genetic Counseling Services, which creates specialized teams of genetic counselors for growing businesses who need them, utilizing a world-wide network of CGCs. A group of GCs recently published an article in the Journal of Genetic Counseling sharing their experiences working for startup companies. I recently launched my own solo venture, WatershedDNA, to provide consultations on ancestry and other home DNA tests, both privately and as a part of larger projects or for companies. The niche I found was filling a need for genetic genealogists, adult adoptees, the donor-conceived community and others, all of them looking for someone who understood the psycho-social dimensions and the science behind genetic testing for ancestry and ethnicity. A perfect role for a genetic counselor, and a match for my own natural interests and passion.


Currently, I work one-on-one with clients referred to me by the genetic genealogy community, mostly individuals who have already pursued a home DNA test or are considering it. Just as in a clinical setting, we begin with family history when available and identify a client’s goals and areas of concern. We review any results they already have and discuss additional testing options, and how they might affect them and family members, now and in the future. Working fee for service and owning my own business come with financial uncertainty and lots of unknowns, but it gives me other freedoms, including flexibility and the sense of adventure that comes with pursuing an entrepreneurial path (like my father and grandfather – genetics?). It isn’t easy; I’m a worrier by nature, and some days that Bunsen feels like it’s a-burnin’ hotter than usual. But like the genetic counseling profession as a whole, I’ve found myself in the midst of a crucible that isn’t trying to destroy me; it is providing me an opportunity. A chance to change and create, to extend the reach of genetic counselors. It will engender a future of great things, if I allow it.


Let’s be willing to face the uncertainty that the wild west of genetics brings, be daring, and embrace the shades of gray as we blaze new trails. None of us chose the profession of genetic counseling because we thought it would be easy.



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The Top Ten Stories in Genetics, 2015: A Bacterial Editing System Goes Viral

Genetic modification was not invented in 2015. DNA was edited before CRISPR/Cas 9, just as books were printed before the Gutenberg Bible. Is it crazy to compare CRISPR to the printing press? Perhaps, time will tell. But the comparison does illustrate the enormous transformative power of technology made cheaper, faster and more efficient. It is hard to overstate the likely impact of CRISPR on medicine; it is already revolutionizing the development of new therapeutics from gene therapy to stem cell therapy to customized cell lines for drug development. Improvements to the technology and new applications for use have come so thick and fast that at times it seems like #crisprfacts, the hashtag invented to mock the CRISPR hype, can hardly keep up.

crispr facts 2


crispr facts

Here’s mine…

Now is the winter of our discontent made glorious summer by CRISPR. #crisprfacts

Oh, yeah, and some other things happened too. Here’s the countdown:

  1. Roche Buys Billion Dollar Stake in Foundation Medicine

In January 2015, the Swiss pharmaceutical company Roche spent just over 1 billion dollars to obtain a majority stake in Foundation Medicine, a pioneer in cancer genomic testing. The deal not only symbolizes but may catalyze the mainstream role of genomics in cancer therapy, as tumor testing continues its rapid ascent from cameo performer to standard of care.

Foundation, which has yet to turn a profit, offers separate tests for solid tumors and blood-based malignancies. The tests offer sequencing of a large number of genes known to be implicated in cancer, but fall short of exome sequencing and examine only cancerous cells and not the germline comparison. Foundation reports are intended to help oncologists choose therapeutic options, including drugs and clinical trials. Roche’s involvement should increase marketing of the tests in the U.S. and abroad, and they likely hope that it will bolster research, such as identifying the markers of tumor DNA that could provide the basis for the highly anticipated ‘liquid biopsies’.


  1. Matchmaker Exchange Goes Live

Screen Shot 2015-12-29 at 9.15.23 PM

When you’re driving in traffic, other people are annoying. When you are in line at the supermarket, other people are annoying. But when you are trying to solve medical mysteries with a genetic test, other people are the answer.

Parenting a child with an undiagnosed genetic disease is a trip without guidebooks. Treatment is a series of guesses, prognosis is unknown. No one can warn you about what’s to come, or reassure you about what will pass. Genetic testing may reveal the apparent cause, but in cases where the variant has not been seen before it can only be confirmed by the second case. Patient networks built around genotype can improve treatment, clarify reproductive risk and provide emotional support.

Because clinically significant genetic changes are individually rare and collectively common, finding another person with the same gene variant or the same mutation in a tumor requires access to vast amounts of information and the means of searching it. Fortunately for us, we live in an age defined by the ability to access vast amounts of information and the means search it. But sharing genetic information on the internet has been complicated by rules designed to protect patient privacy and the hot mess that is our patient records system.

In September, a team led by Heidi Rehm announced the launch of the Matchmaker Exchange, a collaboration with multiple partners that provides secure sharing of patient information linking phenotype and genotype. Rehm described the new venture as “a reliable, scalable way to find matching cases and identify their genetic causes.” Congratulations to the field of genomics, and welcome to the Internet Age.


  1. Illumina Launches Helix, a Consumer Genomics Platform


In 2015, the consumer genomics industry is not so much an industry as it is a high tech field of dreams, a plowed-under cornfield in the cloud, waiting for the crowds to arrive. “They will come,” says the prophet in the James Earl Jones voiceover voice, “not even knowing for sure why they’re doing it. They’ll arrive at your door as innocent as children, longing for the future. They will pass over the money without even thinking about it; for it is money they have and peace they lack.”

But while back in Iowa poor Ray had to fight the bankers to keep his dream of a self-sustaining ghost baseball industry alive, capitalists are lining up to host the field of genomes. Both Google and Apple have cloud-based storage systems for DNA sequence data; Illumina’s proposal is unique in that you pay not for storage but for use. The company is betting that multiple third parties will develop consumer applications that require genomic information, smartphone apps that personalize your risk for side effects from pharmaceuticals or calculate the degree of relationship between you and your Tinder match. Helix holds onto your genomic digits the way Amazon holds onto your credit card information, making it easier for each new purchase to flow through them.

Illumina, the undisputed heavyweight champion of second generation sequencing, makes a forward-looking move here, tilling the soil in a hypothetical ecosystem. Two years ago, the ‘consumer genomics industry’ was a fancy synonym for 23andMe, one single tree that dominated the landscape. Ironically, the FDA pruning of 23andMe in 2013 that cut back their health and wellness business provided a little sunshine for smaller farmers, and in 2015 the first green leaves of a thousand consumer genomics products popped up out of the dirt, offering gene-based advice on the treatment of mental illness, on diets to suit your metabolic type, on the probability of cardiac events. These new shoots are individually weak – in many cases not rooted in the science, in others likely to be mown down by regulatory mechanisms not yet in place – but collectively they represent a widespread belief that there is money to be made in these fields.


  1. In Memento Moratorium

 “It is easier to stay out than to get out.”

                                                –Mark Twain

On April 18th, a group of Chinese scientists led by Junjio Huang published a paper in Protein and Cell describing their attempt to edit (but not implant) human embryos using the CRISPR/Cas 9 system. The goal was to alter the hemoglobin-B gene, which happened in 4 out of 54 embryos, although all 4 were mosaic – some cells were altered and others were not. This, the authors concluded, was not a success. Improving “fidelity and specificity,” they wrote, is a “prerequisite for any clinical applications of CRISPR/Cas 9-mediated editing.”

But failure or no, the publication ignited a firestorm of debate. On one thing the scientific community agreed: the experiment was evidence that the question of to edit or not to edit is in the offing. Improvements in the efficiency of gene editing are occurring so fast that the technology used in the study was itself a generation or so out of date before it made it into print. Can we do this? Not yet, say the authors of this paper. Should we do this? That is a much harder question, a question that launched a thousand editorials in 2015.

Early debates about what should or should not be allowed in DNA engineering did not focus on the human germline, but the consensus that evolved drew a line between somatic human uses for gene therapy, and changes that would affect eggs, sperm or embryos. Avoiding changes that would be passed down through generations confined any unintended effects to the individual, and sidestepped all the societal issues wrapped up in the concept of ‘designer babies.’ The moratorium that some scientists called for after word spread of the beta thal experiment is not new, and if heeded would reinstate a tacit agreement that had been in place since the 1970’s.

Oh, but it is easy to say you wouldn’t do something when you can’t. The Chinese paper resulted in an international summit on human gene editing in December, hosted by the National Academy of Sciences. The statement produced after 3 days of meetings endorsed somatic uses and germline research, but labeled any clinical use (i.e., use that could result in a baby with edited genes) irresponsible – for now. The note of caution may have obscured what is effectively a rejection of any hard and fast limitations. “As scientific knowledge advances and societal views evolve,” the organizers wrote, “the clinical use of germline editing should be revisited on a regular basis.”


  1. Sequenom Introduces a Non-Invasive Scan of the Genome

 Facts are stubborn, but statistics are more pliable.”

                                                            –Mark Twain

 In September 2015, Sequenom launched MaterniT Genome, an expanded version of its non-invasive prenatal screen designed to catch all microdeletions or duplications greater than or equal to 7 MB. This is simultaneously not that important at all and an illustration of everything we are dealing with now and a window into the future.

The new Sequenom test joins its stablemates VisiblitiT (tests for trisomies 21 and 18) and MaterniT Plus (tests for all the trisomies plus select, well-characterized microdeletion syndromes like Wolf-Hirschorn or Cri-du-chat).   All the tests report on fetal sex. Everybody reports on sex, and the most common form of informed consent for testing consists of an obstetrician asking the patient “do you want to do the test for gender?” (I can’t prove this but it’s true. Ask around.).

Of the three other U.S. purveyors of non-invasive testing, only Natera includes the option of a microdeletion panel. Although NIPT is the hottest selling thing in the universe, reaction to the microdeletion panels have been lukewarm, and here’s why: math. The Achilles heel of NIPT is positive predictive value, or the percent of the time that the test flags a pregnancy and is wrong. Even when a test is very accurate, the rarer the condition, the higher the percentage of false positives. Doctors and genetic counselors don’t like false positives because in real life a ‘false positive’ is a very frightened and very upset patient, and in real life some of these patients have ignored advice for follow up and terminated pregnancies that turned out to be unaffected (this sounds very extreme but remember that they are looking at a test labeled 99+% accurate, and under intense time pressure at just around the point when most people go public with a pregnancy).

Microdeletion syndromes are rarer than trisomies, so even as accuracy remains high, positive predictive value drops precipitously. Sequenom offers no estimates of PPV, and Natera’s own numbers suggest a PPV of just 5.3% for 22q11 deletion syndrome. In this context, the Sequenom genome-wide test seems like a curious step. Not only does it raise serious questions about PPV, but most of the deletions and duplications would be uncharacterized, meaning that counseling patients on the predicted effect of the change would be complex. None of this is exactly obvious in the Sequenom promotional material, which highlights 99.9% specificity and 92.9% sensitivity.

Why is a test likely to be used sparingly a top story for 2015? Because it has a ‘more information/less clarity’ aspect that is very 2015. Because it shows the quandaries into which we wander, when we take our limited 2015 knowledge into the realm of prenatal testing. And… because limited use may grow over time, as Sequenom no doubt knows, so that this may well be a first look at the prenatal testing of the future.


  1. Gene Expression? There’s a CRISPR for that.


When exactly did the reports on CRISPR start to sound like an infomercial? Maybe it was March of 2015, when scientists from Duke University led by Timothy Reddy and Charles Gersbach published an article describing their success using an adapted CRISPR/Cas 9 system to create a targeted increase in gene production.

CRISPR! It slices, it dices… No wait, there’s more…

In this case, the modified CRISPR program links a guide RNA that searches out the target DNA with a protein that catalyzes acetylation – so instead of gripping and snipping, your bonus CRISPR tool finds the appointed enhancer region and flips a switch, turning gene production on. And voila: “A programmable, CRISPR-Cas9-based acetyltransferase…leading to robust transcriptional activation of target genes from promoters and both proximal and distal enhancers.”

Clap on, clap off… the Clapper!ld0oalpb8u8le

Debates may yet rage about the nature of epigenetics and its intergenerational significance (hell, spellcheck still refuses to recognize it as a word) but no one argues about the importance of gene expression. Changes in gene expression are central to both development and stasis; altering gene expression provides a possible avenue of control of every process from learning to aging.

Amazing! And for far less than you might think! Does it come in red?


  1. A Prenatal Genetic Test Reveals Cancer in the Mom-to-Be

In the four years since non-invasive prenatal testing was introduced it has grown into a market worth over half a billion dollars annually in the US alone, with double digit growth projected for years to come. The number of invasive procedures has fallen off a cliff, with many women opting not to do amniocentesis or CVS after reassuring results on a non-invasive prenatal screen. But not everyone has been reassured. In March of this year, Virginia Hughes at Buzzfeed reported on the case of Eunice Lee, who learned she had cancer after the lab reported unusual results on her non-invasive screen.

This rare event – Sequenom suggested that one in 100,000 of their tests results pointed at a malignancy, with just over half of those subsequently confirmed – affects only the (thankfully) limited universe of pregnant women with cancer, but the story is more universally significant for at least two reasons.

The first is how it reflects the challenges surrounding non-invasive testing, the first major testing modality to roll out as an industry unto itself. Since it’s inception, this technology has developed in a highly competitive and market-oriented environment (one Sequenom executive lied about early test results and would have gone to jail if she hadn’t died first) and many people have suggested that their pre-market studies were inadequate and self-serving. The FDA has pointed to non-invasive testing as an example of why laboratory-developed tests need more regulation. All of this criticism has continued despite the fact that the tests are extremely popular and largely successful, and have decreased the need for more expensive and more dangerous invasive testing. Because it is so new and because the early studies were limited, these funky results are an anomaly that put the testing company into an awkward spot. Although they look like cancer, they can’t be officially reported as cancer, because there are no studies to validate that claim. Ignoring them, on the other hand, seems like an ethical breach to me, given that there is some evidence that suspicions are correct. Sequenom chose to call the test non-informative, but alert the physician to their hunch. Other companies have chosen to say nothing in similar circumstances.

The second take home point of this story is how close we are to a new type of cancer diagnostic, one that will be used both as a screen and a test for recurrence or the effectiveness of chemotherapy. If prenatal testing is any model (and it is) it will appear soon, all the companies involved will sue one another frequently, and we will all work out the bumps as we go along. One of these days we will all be surprised to read about someone concerned about cancer who discovered she was pregnant.

Eunice Lee and Benjamin

Eunice and Benjamin  Lee

Ms. Lee, by the way, was successfully treated for colon cancer with surgery alone, and gave birth to Benjamin, a healthy baby boy.







  1. Baby With Cancer Responds to Treatment Using Genetically Modified Cells

The headline for this segment should have been, First Clinical Use of CRISPR Technology Saves Baby With Cancer, except no part of that sentence is true. The gene modification technology used wasn’t CRISPR but Talens, an older approach that is more expensive, less flexible and more technically demanding. It wasn’t the first use of gene modification as a therapy, just the first that presents a promising path to widespread use. And let’s not jinx the baby, five months into remission, with an overconfident use of the word cured.

And yet, 18-month-old Layla Richards is home with her dad and mom (probably mum; they say mum in Britain) 6 months after doctors counseled the family to consider palliative care for acute lymphoblastic anemia. If there was a miracle involved, it was simply the miracle of being in the right time and the right place – Great Ormond Street Hospital in London, which had on hand modified T cells intended for use in a clinical trial for the French biotech company Cellectis, slated to begin in 2016. The Cellectis process involves knocking out a gene in donor T cells so that they cannot attack host tissues – a step that eliminates the need to use the patient’s own cells, a personalized approach that makes it slower and more expensive. Several companies that have been developing autologous approaches saw their stock prices fall in the wake of this announcement. In the case of baby Layla, doctors say they were unable to find enough T cells to extract for treatment.

Who did what first is a subject best left to the historians (and the patent lawyers). This story represents where we stand in 2015, on the cusp of therapeutic innovation built not on serendipity, the great innovative engine of the past, but on knowledge and engineering. We are entering an age of miracles that are not miracles at all, because we can both explain and reproduce them. And we are entering it fast, with technology out of date before the gun goes off, like thoroughbreds groomed and trained who show up at the starting gate to find themselves racing unicorns.


  1. First Analysis of Large Data Sets Suggests: When It Comes to Variant Classification, It’s Clinician Beware, At Least For Now

 “The trouble with the world is not that people know too little; it’s that they know so many things that just aren’t so.”

                                                                                                -Mark Twain

Anyone arrogant enough to believe we were equipped to interpret the human genome must have found the last few years humbling, poor foolish person. But most of us, veterans of the diagnostic odyssey and the variant of uncertain significance, were prepared to admit that it was early days. The collective need for more information has in recent years overcome proprietary and competitive instincts, and convinced many researchers and commercial laboratories to share their data. The top story for 2014 was ExAC, a Broad Institute initiative that has aggregated exome data from over 60,000 healthy adults.

Preliminary analysis of that data is in, with a couple of headlines. One – no surprise – there’s a lot we don’t know. As expected, mutations that result in a loss of function are constrained in genes associated with severe disease – in healthy individuals, you should see limited loss of function in genes where disruption causes a severe phenotype. We saw this purifying effect in many genes, and 79% of them are not yet associated with human disease. That’s the knowledge gap that we need to fill.

Headline number two: lots of things we thought we knew are wrong. The extent of this may qualify as a surprise, although careful observers will not be shocked. Plenty of evidence existed that existing databases and analyses were larded with inaccuracies. The database ClinGen reported in June that among the 12,895 unique variants with clinical interpretation from more than one source, 17% were interpreted differently by the submitters. The ACMG guidelines for variant interpretations published in March stressed that variant “analysis is, at present, imperfect, and the variant category reported does not imply 100% certainty.” Analysis of ExAC, a preliminary report suggests, shows that most individuals carry a rare and presumably deleterious variant in a gene associated with dominant disease. Beyond inaccurate classification, this may be evidence of incomplete penetrance, subclinical presentations, or simply the resilience of the genome. Take home point, as stated by Dan MacArthur et al, “The abundance of rare functional variation in many disease genes in ExAC is a reminder that such variants should not be assumed to be causal or highly penetrant with careful segregation or case-control analysis.


  1. The Power of Gene Drive

“The only difference between reality and fiction, is that fiction needs to be credible.”                                                                                                 –Mark Twain

Do you know that moment in the movie when the hero has to decide whether or not to commit some morally ambiguous act in order to save thousands of lives? Remember that? Well, forget about it. That make-believe drama cannot compare with the real life dilemma facing scientists, regulators — all of us, actually – in light of this year’s signature story, a CRISPR-mediated system that can rewrite the laws of evolution to propagate traits devised in the laboratory.

Gene drive is a term for a biological process that increases the probability that a given gene will be passed along to the next generation. In 2014, Kevin Esvelt and George Church at Harvard (et al) wrote a paper describing how CRISPR could be used to insert a tricked-out version of an edited gene that included the machinery to hack out the corresponding gene from the other parent and replace it with a copy of itself, complete with the gene drive complex. Introduce this zombie gene into any fast-replicating population and the allele frequency doubles with each new generation until there aren’t so many wildtype alleles left to convert.

Welcome to 2015, when a hypothetical is always just one grad student project away from reality. In November, Sharon Begley at STAT reported that success with fruit flies in the UC San Diego lab of Ethan Bier had led to a collaboration with UC Irvine’s Anthony James, who has developed an edited mosquito gene that destroys the parasite that causes malaria. Success could mean the most effective means of malarial control ever devised, and one that effectively spreads itself.

Herein lies the dilemma: this intervention is not so much introduced as unleashed. Although Church and Esvelt recently published a paper detailing strategies for containment and reversal of gene drives, concerns remain over the specter of unintended consequences. The Pentagon and the United Nations are reported to be concerned about the potential for weaponized insects. Scientists and ethicists have expressed alarm about the unknowns associated with any disruption of an evolved ecosystem. But the WHO reports that in 2015 there were 214 million cases of malaria and almost half a million deaths. So here’s the movie pitch: the mosquito is a terrorist killing 1500 children every day. You, the scientist, can reprogram the mosquito, with unknown impact on the entire planet. The developing and developed world can’t overcome their mutual distrust to make a plan. Do you release the zombie mosquito?

Buy it as a movie? No one would. It’s just too out there.

Screen Shot 2015-12-29 at 9.19.28 PM


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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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