Tag Archives: genetics

TOP TEN STORIES IN GENETICS, 2016: An Adolescent Science Meets the Big World

Clinical genetics is a young science, not yet come of age – a new discipline. It’s early days, say the small group of clinicians and researchers who have watched over its formative years, dreaming like proud parents of a future where genetics and genomics are integral to clinical medicine. And as for many parents, it may sometimes have seemed that the all-consuming, semi-hermetic little laboratory of childhood would go on forever.

But guess what, people? I believe we have entered the teenage years.  I believe baby has borrowed the car keys and taken it out for a spin.  I see a field boasting a few real accomplishments, and on the cusp of so many changes, from therapies for genetic disease and cancer to a suddenly burgeoning DTC marketplace. And like all parents, geneticists are poised to discover the limits of our ability to control what we have nurtured. That’s exciting, more than a little bit scary, and the theme of this year’s top ten.

  1. FDA CANCELS PLANS TO REGULATE LDT’s

Over the past two decades, a single technological advancement has revolutionized the way we practice medicine.

I am talking, of course, about overnight delivery of packages.

Years ago, laboratory testing services were divided into large companies that sold test kits and devices nationwide, and the small labs in hospitals and other clinical settings providing services to their local providers. With limited resources, government regulators focused on the tests that affected more people, and agreed by convention that ‘laboratory-developed tests’ would not be subject to the same scrutiny. Today these distinctions are virtually meaningless, as giant companies like LabCorp and Quest perform tests ‘in-house’ on samples gathered worldwide, tossed in a box and sent overnight. Still laboratory-developed tests (or LDT’s) – a category that includes virtually all genetic tests – remain in regulatory limbo.

In 2010, the FDA announced its intention to address this loophole. In July 2014, they issued draft guidance detailing their plan for a regulatory structure that divided the LDT universe into high, low and medium risk tests. While some professional organizations disputed the FDA’s right to have a role in regulation of LDT’s and threatened legal action, others approved the framework in principle but disagreed on specifics, including how to handle the thorny new territory of exome and genome sequencing. A dialogue ensued with representatives of labs, clinicians and patients that has lasted two years and included multiple workshops and public meetings. That process, it was widely assumed, was nearing its end, with the resulting draft guidance expected to be sent to Congress for approval in the near term.

And then came November 8th and the election of Donald J. Trump, ushering in an executive opposed to regulation on principle, to join a similarly inclined House and Senate. Ten days later, the FDA ran up the white flag, announcing that the agency would not take steps to finalize its existing plan and would instead reopen the discussion with a new administration and a new Congress. What this means precisely is a matter of some interesting speculation, but in general it suggests that an industry that has been struggling for years to avoid too much regulation will have to consider the consequences of living with none at all.

 

  1. IS THIS THE FUTURE? CRISPR EXPERIMENT ADDS RARE PROTECTIVE VARIANTS TO HUMAN EMBRYOS

The second experimental use of CRISPR technology to alter human embryos was reported in May of 2016, again by a group out of China. Again, the embryos used were not viable, and no attempt was made to transfer them for reproductive purposes. While this experiment did not produce the same ethical firestorm as the first, it was in several ways a more significant indicator of both the potential and the peril of human germline engineering using CRISPR.

In the first experiment investigators attempted to alter a gene variant responsible for causing hemoglobinopathy, with limited success – proof in principle that it could be done, but nothing to assure worried observers that it could be done safely. In version 2.0 there were fewer off target effects, but researchers were not able to consistently control the content of changes introduced in place of the edited DNA. This is not inconsistent with what we know so far about CRISPR: if we envision it as a word processing search-and-replace function, it is good at the finding and erasing part, but hit or miss when it comes to  putting in a replacement.

What stands out about the second experiment is that the goal was not to eliminate a disease-causing gene, but to insert a rare and protective one – in this case, the CCR5Δ32 allele that offers the bearer reduced susceptibility to AIDS. Gene editing is often envisioned as a way that individuals whose children are at risk can avoid or change genes that cause disease, but in the vast majority of these cases there are simpler and better established tools such as PGD if the goal is to obtain embryos that do not carry a specific variant associated with some catastrophic risk. Why use technology to substitute out a pathogenic BRCA variant or a double dose of the sickle cell genes when the parents are perfectly capable of producing a healthy embryo themselves? What CRISPR and related technologies can do that is not available through other means is to introduce a gene that neither parent carries. That is a powerful new option, and it is both exciting and scary in the manner of all things powerful and new.

 

8. GENETIC DISCRIMINATION MAKES A CAMEO

Many wise observers have noted that for all our deeply felt concerns about genetic discrimination, to date the examples are few, far between, and usually more clumsy than systemic (looking at you, Burlington Northern Santa Fe Railroad). These arguments, redux, were on display in 2016 as Canada debated and ultimately passed its own national genetic discrimination law. Yes, Globe and Mail Guy, there is little evidence of a big problem, and a look at law suits filed between 2010 and 2015 under GINA, America’s genetic discrimination law, proves the point. But one real unanswered question remains: is the absence of institutionalized discrimination a sign that it is destined to be a bit player in the big picture of genomics, or is it only too soon to tell? Big companies, whether they are offering insurance or providing employment, may not have had an incentive to weather a PR shitstorm in order to use genetic information to limit their exposure to risk when not that many people have been tested, and the reliability of the data is debatable – which it has been in these early days. Genetic discrimination, in other words, may be making an appearance in Act II.

Two stories got some attention in 2016; whether they are one off events or signs of the future – well, that’s crystal ball territory. Are they important? They are something to which we should be paying attention. Attention should be paid.

In January, Stephanie Lee at Buzzfeed published an account of a boy named Colman Chadam who was asked to leave his Palo Alto, CA school because he carried two mutations commonly associated with cystic fibrosis, although he did not have any signs or symptoms of the disease. The results of genetic testing, inappropriately revealed by a teacher at the school, were taken, also inappropriately, as diagnostic. The reason this got him thrown out of school was to avoid contact with another student who did have CF. The emphasis on keeping children with CF apart, which sounds weird if you don’t know much about the disease, was about the only appropriate thing that happened, because individuals with CF are at risk of passing one another dangerous and life-limiting infections.

Although Colman did not have to leave the school, and the Chadam’s lawsuit against the school district has settled, the case continues to raise issues about how genotype as distinct from phenotype can be used under the law. In addition, it may signal the need for measures to protect personal privacy (no such thing, I know, I know) in an age when genetic testing is commonplace.

Three weeks later, Christina Farr wrote an article for Fast Company about a woman who was turned down for life insurance because she had a risk-conferring BRCA1 variant. Unlike the Chadam case, this is not a result of genetic illiteracy, and it is not a violation of any law: GINA does not cover insurance for life or long-term care. It is, in fact, exactly the kind of genetic discrimination that ethicists and patients thinking about genetic testing have worried about over the years, and if systemic, would certainly be an important point for genetic counselors to raise in pretest counseling (if pretest counseling is still something we do, which is an issue unto itself…but related). According to the article, genetic testing for cancer susceptibility is not required by any insurance company, although nothing stops them from doing that, but companies are starting to request to see test results when they exist. Failure to answer questions honestly can invalidate policies if you are caught.

If this becomes the status quo, it may affect uptake of genetic testing. If it is curbed through regulation, genetic testing may change the way the insurance industry operates. Act II is going to be interesting! I am having a couple of stiff drinks and heading back to my seat.

 

7. TYPE II DIABETES: RESISTANT TO INSULIN AND EASY ANSWERS

Genome wide association studies (GWAS), a way of looking at common variants in the gene pool to identify genetic susceptibility to common diseases, have been unable to explain the degree to which liability to these common diseases is inherited, although it clearly is. If you are in genetics and this is news to you, you have not been paying attention.

Many reasons for this have been proposed, and many are likely a part of the answer. One thought was that individually rare variants might be collectively common enough to play a big role in generating risk, which would not be picked up by GWAS, as it traditionally looked only at variants carried by at least 5% of the population (“the population,” as though there was only one!). Looking at rare variants takes a village, but that is what a googleplex of Type II Diabetes researchers did to produce an epic July 2016 paper in Nature.

Okay 300 authors on the paper so close enough.

The report by first author Christian Fuchsberger showed that MEGA*GWAS produced the most GWAS-y result possible: intellectually interesting, informative and ultimately inadequate. Using exome and whole genome data to capture a broader range of variation, the study found significant association to a handful of previously unknown common variants, and then failed to replicate a good chunk of what we thought we knew. Uncommon variation? The researchers found 23 loci that appeared significant, which was meaningful, but nowhere near enough to validate the rare variant hypothesis as the smoking gun in the Mystery of the Missing Heritability. “A comprehensive and extremely well written paper,” said Dan Koboldt at MassGenomics, and you can almost hear him sigh.

 

6. DATABASES: IT’S NOT JUST FOR WHITE PEOPLE ANYMORE

We don’t have enough diversity in our databases. It’s not exactly news, and yet publication of an article called “Genetic Misdiagnoses and the Potential for Health Disparities” in the August issue of the New England Journal of Medicine felt like a slap in the face.

The methodology was not complex. For hypertrophic cardiomyopathy patients, doctors use genotyping to identify individuals and family members at risk for sudden and catastrophic cardiac events. Identification as ‘at risk’ is a traumatic and often life changing event, requiring ongoing medical screening and behavioral modifications. For these families, a lot rides on whether or not a variant is considered pathogenic. One bioinformatics tool is to look at databases, because there are limits on how bad a variant can be if it shows up regularly in healthy individuals. The study checked variants labeled pathogenic against an increasing wealth of exome data available in public databases and found that a number were common in the African-American population. Result: reclassification from pathogenic to benign of multiple variants affecting primarily African-American families.

“Simulations,” said the authors, “showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications.

 

5. IMMUNOTHERAPY: A NEW STAR BURNS BRIGHT AND HOT

Earlier this week, my sister-in-law was telling me about a friend with a cancer deemed treatable but not curable. “But if they get it in remission,” she said, “and he has more time, maybe there will be something new.” There it was – the cancer prayer. May There Be Something New. And I thought, has there ever been a moment when those words felt more hopeful than right now?

Hopes have been raised before, by promises that money would bring answers, and we wandered down blind alleys and into mazes waving cash as though the scent of it would draw the answers to us, but this time, progress is lighting the way like street lamps, and money follows hope instead of the other way round. Immunotherapy – engineered cells meant to light the bodies own defenses into a controlled burn that destroys cancer cells and leaves the rest untouched – has burst onto the scene since 2015. Cancer researchers report on progress in Hemingway stories, terse narratives of a few more days, an extra month or two, and that’s a win, but suddenly we are getting Gabriel Garcia-Marquez fables of magic beans and people rising from their deathbed.

So which story is more 2016: Sean Parker’s 250 million dollar cancer institute, connecting Silicon Valley money with Car-T cells that he describes as “little computers,” and presenting to the NIH in comic sans? Or the unexpected lethal immune response that shut down a Car-T trial by Juno Therapeutics in November, after four people died of cerebral edema?

It’s the two in conjunction that tell the tale. Immunotherapy is truly a candle in the wilderness, but it’s a candle that burns rocket fuel. Or perhaps I should say, in the spirit of the season: catch a falling star and put it in your pocket – bet it burns a hole in your ass.

 

4. A NEW DTC GENETICS EMERGES WITH HELIX

In October, Helix announced the first fruit of its partnership with DNA-lifestyle start-up Exploragen and it’s grapes: Vinome, a company that promises to sell you wine tailored to your genetic profile for something like fifty bucks a bottle. I’m not a wine drinker and that sounds like a lot of money but, hey, you do you.

For Helix, the Illumina spinoff that debuted in 2015, this was one of a series of 2016 announcements giving us a more concrete vision of their plans for a sequence-once-access-often platform for DTC genomics. The structure of it is like Apple, if your IPhone didn’t even pretend to be a phone, and existed entirely as a vehicle for apps. With your first purchase, Helix will underwrite the cost of sequencing and storing your entire exome, and then sell it back to you bit by bit in the guise of applications created by partners.

Effectively, the Helix model lowers the barrier of entry for any product based on DNA testing, by spreading out the cost over a myriad of marketing opportunities. Some current players in the DTC universe have signaled their interest in playing in Helix’s playground; Geno 2.0, National Geographic’s version of ancestry testing, is already available on the Helix website. Others may take their toys and stay at home. Daniel MacArthur of the Broad Institute once penned an April Fool’s Day account of a company named Helix Health’s plans for a hostile takeover of 23andMe using Somali pirates, but for real the entry of an Illumina-backed company into the DTC space must have some Mountain View observers concerned that the current industry thought leader might end up the Blockbuster Video of the genomics world.

The uncorking of Vinome raises a few questions that existing partnerships with, say, the Mayo Clinic or the Icahn School of Medicine at Mt Sinai do not. One role that Helix could potentially play is to provide the vetting service much needed in the consumer genomics world, with its mishmash of pharmacogenetics and Warrior Gene testing and supplements designed just for your DNA.

As for Vinome, the eminently quotable Jim Evans called it “silly” in an article by Rebecca Robbins in STAT. “Their motto of ‘A little science and a lot of fun’ would be more accurately put as ‘No science and a lot of fun,’” said Evans — which I guess is true, if paying fifty dollars for a bottle of wine is your idea of fun. But like Apple, Helix is going to have to make some hard decisions about how much it takes responsibility for the quality of the partners it allows to come play in its sandbox.

 

3. GENOMES OF MASS DESTRUCTION

In February, for the first time but probably not the last, the U.S. Director of National Intelligence’s assessment of worldwide threats included genome editing as a weapon of mass destruction. Congratulations, genetics: we’ve made the big time.

The report pointed to the widespread use of new genetic technologies like CRISPR in countries with different regulatory and ethical standards, its low cost and the rapid pace of change as pre-conditions that might lead to intentional or unintentional misuse, though it was vague as to what form they thought the threat might take. More specific concerns were articulated later in the year by the Pentagon’s Defense Advanced Research Projects Agency (called DARPA of course, because…government) in announcing a program called Safe Genes intended to establish a military response to of dangerous uses engineered genes. DARPA, which Scientific American reports has been a major funder of synthetic biology, will support projects that look at ways to remove engineered genes from a variety of habitats and in a variety of circumstances, including those spread through gene drive.

 

2. A BREAKTHROUGH DEFIES CONVENTION AND GEOGRAPHY

On April 6, 2016, a baby was born after the transfer of his mother’s nuclear DNA into an enucleated donor egg in an effort to avoid the mitochondrial disease that killed the couple’s two previous children. The success of mitochondrial transfer therapy itself was not a shock, since earlier experiments had demonstrated good outcomes in animal models and in in vitro human embryos. The circumstances, however, were startling: the procedure was done in Mexico, for Jordanian parents, with the help of a New York-based fertility doctor with no known expertise in mitochondrial disease.

Some have argued that mitochondrial transfer therapy represents a violation of international norms forbidding any germline genetic change, which were meant to provide a clear dividing line between somatic changes associated with gene therapy and genetic engineering with the potential to impact future generations. Pretty clear in theory, but all of these divisions are less clear in reality – there are no guarantees that gene therapy doesn’t affect eggs or sperm, and mitochondrial DNA itself challenges any simple equivalence between the molecular structure of DNA and the intellectual concept of our ‘germline’.

Mitochondrial transfer is illegal in the United States but permitted in Great Britain under a 2015 law, and applications for clinical use have been approved for 2017. Its apparent success – independent sources confirm that the baby appears to have traces of maternal mt DNA associated with Leigh syndrome but no sign of disease – is a cause for celebration for the families whose children are at risk. The step forward is a milestone, but so is the way in which it occurred, which demonstrates the extent to which geography and national laws are no match for money and access in determining what is possible.

Personal note: on my wish list for 2017, can we PLEASE stop cheapening the concept of parenthood by using the term ‘3-parent babies’? If I donated a kidney, that person would have some of my DNA, but it wouldn’t make me their momma.

 

1. WHITE SUPREMACISTS LOVE GENETICS, BUT GENETICS DOES NOT LOVE THEM BACK

Nothing about the year 2016 was more disturbing than the empowerment of the alt right, an all-purpose term for the angry souls that crept out from under rocks to preach hate and division. Here at home and all around the world, narratives of race and ancestry emerged as powerful drivers in political and social movements based on appeals to base and tribal instincts – fear mongering about immigrants, Islamaphobia, white supremacy. In October, Elspeth Reeve at Vice ran a story about white supremacists posting their 23andMe results to prove their whiteness.

This embrace of a science that does not love them back is evident even without a deep dive into the world of Stormfront and 4chan.  Twitter trolls talk about ‘founder effects’ and ‘genetic drift’. A Breitbart tech editor, now barred from twitter, writes gleefully about associations between race, behavior and intelligence, mocking disbelievers as prisoners of an “all-consuming cult of equality.”  The L.A. Times describes the alt-right as “young, web-savvy racists who are trying to intellectualize and mainstream bigotry.”   These viewpoints aren’t mainstream, but their proponents can no longer be dismissed as fringe, with Breitbart’s founder about to be ensconced in the White House as chief strategist, and reports suggesting that the presumptive next National Security Advisor Michael Flynn taking meetings with the head of an Austrian political party founded by former Nazis.

The connection between white nationalism and population genetics is proof once again that genetics as a field is uniquely susceptible to misuse by agenda-driven movements intent on the subjugation of others. Donald Trump ran against political correctness, but his rise has proven the importance of language. As Michelle Obama says, “words matter.” Push back against the misuse of genetics to fuel ‘racialist’ theory. Ancestry sites should think very hard about the manner in which they present their findings, which stress differences without acknowledging the greater than 99% of DNA that we all share. Scientists need to address and refute the ways in which their work can be misconstrued to reinforce prejudice and unsubstantiated visions of racial differences. We all have to be careful not to promote explanations of genetic effects that oversell the determinative power of genes.

Genetics is a science of the future. Let’s not let it be used to drag us back into a tribal past. Peace out, Genetics, and here’s to a better year in 2017.

 

 

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

10. 23andMe and the Thanksgiving Week Massacre

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

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

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

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

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

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

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

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

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

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

No, not that one.

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

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

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

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

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

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

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

6. “Anonymous” gets outed.

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

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

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

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

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

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

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

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

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

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

3. First gene silencing drug approved by the FDA.

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

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

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

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

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

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

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

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

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

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

AND

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

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

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

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A SCIENCE WRITER USES HER CHILD’S 23ANDME TESTING EXPERIENCE AS A HOOK, AND CATCHES MORE THAN SHE BARGAINED FOR

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

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

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

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

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

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

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

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

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

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

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

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

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

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

10.  IT CAN’T GET MORE PERSONAL THAN THIS: A GENETICIST ANALYZES HIMSELF AND SHOWS US SOMETHING ABOUT THE POTENTIAL OF PERSONALIZED MEDICINE – AND EVEN MORE ABOUT IT’S COST

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

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

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

9. RICK SANTORUM BRINGS THE CULTURE WAR TO AMNIOCENTESIS

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

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

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

Photo credit: People.com

Photo credit: People.com

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

8. CLARITY CHALLENGE: BIG DATA GETS COMPETITIVE

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

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

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

7. EU APPROVES A STEM CELL THERAPY FOR CLINICAL USE

glybera

Photo credit: Pharmafile.com

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

6. TARGETED THERAPY: FDA APPROVES KALYDECO

vinylmation

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

Photo credit: Drugs.com

Photo credit: Drugs.com

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

5. TRANSLATIONAL MEDICINE MAKES GREAT STRIDES (IN ANIMAL STUDIES)

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

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

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

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

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

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

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

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

Photo credit: Wired.com

Photo credit: Wired.com

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

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

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

 4. FETAL GENOME SEQUENCED THROUGH NON-INVASIVE PRENATAL TESTING

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

3. BEHAVIOR ‘OMICS:  IN SEARCH OF A GENE FOR EVIL

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

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

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

 2. WHOLE EXOME SEQUENCING: AN INTERIM TECHNOLOGY GETS ITS MOMENT (BARELY)

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

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

1. ENCODE: IDENTIFYING THE UNKNOWN UNKNOWNS

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

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

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

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

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

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

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

[Follow me on twitter: @laurahercher]

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There’s a Gene for Everything, Right?

Ten years after the completion of the Human Genome Project, our field is still debating genotype-phenotype correlations in single gene diseases, while the media is still searching for – and finding! – Gattacca.

This week, the Washington Post ran an article that asked “Is There a Gene For Liberals?”  Actually, only the headline and the first sentence asked that question.  The article itself dismissed the idea in line two: “Is there a gene for liberals?  Well, not quite, but scientists say they have found the first evidence that a gene can play a role in shaping an individual’s political leanings.” The piece goes on to detail a joint UC San Diego and Harvard longitudinal study showing that a single gene variant in combination with an active social life in high school (not junior high, not college, only high school) is associated with a modest increase in liberal political beliefs.  No relationship is seen except when the two are taken in tandem.

As Cher says in Clueless, the wounds of adolescence can take years to heal.

The writer calls this finding provocative, which I assume is a reference to the idea that this could be seen as genes dictating behavior, which hints at the scary thought shadowing all suggestions of biological determinism – the idea that we don’t have free will.  Perhaps liberal university professors and right wing radio Svengalis only channel us into the deeper ideological slavery into which we all are born.  Or not.

The rest of the article reports faithfully on the authors insistence that this “doesn’t mean a gene was found for anything,” and the relationship between the gene and the behavior cannot be seen as causal, but merely a window into how genes and experience interact to influence behavior.  This is explained in four careful paragraphs, at the end of which the writer says, of the authors’ call for further research, “Who knows, that could eventually lead to the discovery of a gene that plays a role in creating conservatives.”  So, lesson learned.

Here are two things the article does not define or question:

  1. What constitutes being “liberal.”
  2. What constitutes having “an active social life.”

In fact, going to the article Friendships Moderate an Association between a Dopamine Gene Variant and Political  Ideology in the Journal of Politics, the answers are as follows:

  • A person is liberal if they describe themselves as liberal, having been given a choice of liberal, moderate or conservative.  (This seems straightforward enough, although almost all my friends would, given this choice, describe themselves as liberal but there is enough difference of opinion between them to set a barn on fire.)
  • Having an active social life is defined by the number of people the respondents describe as friends, when allowed to pick any number between none and ten.  (I always thought that in high school the phrase “active social life” was code for who did and who did not get drunk on weekends.  I am discouraged to discover this new standard, which seems to suggest that I did not have as much fun in high school as I thought I did.)

Based on this irrefutable data (by which I mean bullsh*t), the results are calculated using a nifty looking formula of which I will reproduce only the first line:

gij = b0 + bbbi + bwwij + bEEij + bwEEijwij

I haven’t defined the parameters for you or completed the equation but perhaps this gives you the idea that while the data may be soft, the math is very very hard, especially for those of us who spent most of high school calculus sleeping off an active social life.

And of course, as always, the real educational effect of the article is to be found in the comments section, the essence of which is summarized in these two pithy remarks:

So now we can truthfully say that liberals are mutants? I suspected as much.

and

I think we already know the gene that makes conservatives…the poop gene.

Sigh.  I grow weary.  Everything we have learned in the past ten years suggests that genetics are far less deterministic than we had anticipated, and that both physiologically and psychologically we reflect a wondrously complex mix of genetics, epigenetics, environment, dumb luck and who knows whatever other factors – I myself am waiting to find out that astrology has a grain of truth after all, and that all these years I should have been reading my horoscope regularly, and not just when I got stuck on the tarmac with a two hour delay and nothing to read but an abandoned copy of Star magazine.

In the meantime, I beg you, journalists of the world, stop writing headlines that say, “Did Scientists Discover a Gene For X?” if the answer is NO.  You don’t write headlines that say, “Did Police Discover a Plot to Put Rat Poison in School Lunches?” if the answer is NO, just to get more people to read your article on improving the quality of meat.  I know you are busy and underpaid and everyone keeps threatening to take your job away and replace you with a blogger, but try to remember this: people only read the headline.  And this: genetics is complicated.

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