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:

Screen Shot 2013-12-20 at 11.53.24 AM

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

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

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

No, not that one.

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

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

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

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

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

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

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

6. “Anonymous” gets outed.

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

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

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

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

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

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

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

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

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

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

3. First gene silencing drug approved by the FDA.

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

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

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

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

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

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

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

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

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

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

AND

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

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

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

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

  1. Pingback: I’ve Got Your Missing Links Right Here (4 January 2014) – Phenomena: Not Exactly Rocket Science

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