No question that 2014 has been a year to celebrate for the field of genetics. Stem cell therapy, gene therapy, next-generation sequencing as a reliable clinical tool: we may not be there yet, but surely we are close. We have reached the suburbs of the Promised Land. Technical milestones have been met, technical challenges surmounted – palpably, we stand on the cusp of a new era, where we will have means to treat the untreatable and cure the incurable.
The many success stories of 2014 bring along with them reminders of an important corollary: that the cost of what we are capable of doing already exceeds our collective ability to pay. The idea that personalized medicine will pay for itself is a joke, and every $300,000 a year drug we produce is the punchline. As we recognize the many amazing ways in which genetics is poised to change medicine, there are other questions that must be raised, about who will benefit and who will be left behind.
10. $1000 GENOME? — YUP, GOT THAT.
In January 2014 Illumina announced the arrival of the HiSeq X, a sequencing platform that can produce 5+ genomes per day, and at capacity delivers the results for less than $1000 per genome. The new system is sold only in sets of ten or more, and a set of 10 costs around 10 million dollars. Congratulations, people! We have reached our arbitrary threshold and may now proceed with the genomic revolution.
9. IT’S SNOT JUST A DREAM ANYMORE: PARALYZED MAN WALKS AGAIN WITH THE HELP OF NASAL CELLS
In October, Surgeons from Poland announced in Cell Transplantation that a 40-year-old patient paralyzed following a 2010 stabbing had regained the ability to walk after a transplant of olfactory sheathing cells grown in culture. The treatment seeks to capitalize on the unique regenerative capacity of mucosal stem cells.
Okay, there are caveats and concerns. The extent of his recovery is limited. He’s using a walker. We await replication. A woman who underwent a similar but unsuccessful procedure more than eight years ago was recently reported to have required surgery for a cystic mass in her back at the site of transplantation producing “thick, copious mucus-like material.” But GUYS!!!! Paralyzed man walks again.
8. WE FIND THE GENES FOR INTELLIGENCE!!!! (OR NOT)
There’s controversy regarding how much genes contribute to IQ, but most people would agree that genetics is involved, and studies of the heritability of IQ (the measure of how much genes contribute to the variance in test scores) put it somewhere between 50 and 80%. A genome-wide association study of more than 100,000 people published this summer looked at educational performance as a proxy for intelligence, and then checked those findings on a sample of almost 25,000 people using cognitive performance tests as a proxy for, well, cognitive performance. Did they find something? Yes: they found 69 SNP’s associated with educational attainment, three of which were significantly associated with cognitive performance. Something! But not much: each of the three was associated with, on average, a difference of 1/3rd of a point on an IQ test.
To recap, this was a big study with a lot of statistical power and it provided nothing adequate to predict individual performance or cognition. It did provide some proof in principle that genes affecting intelligence exist and that more might be found – maybe. Daniel Benjamin, one of the co-principal investigators, told Ewen Callaway of Nature News that explaining 15% of the variance in IQ would require over a million participants.
Sadly, the most important thing this study was not what it told us about genetics as it relates to our intelligence, but what it told us about our intelligence as it relates to genetics. A lot of the media coverage of this story missed the point – or buried it beneath misleading headlines.
Here are two soberer takes on this story, from Nature and Ars Technica:
And by contrast, check out this headline from Business Insider:
Or these, from the Sydney Morning Herald, and Science 2.0:
Or this, from an editorial at RealClearEducation:
C’mon media people. You don’t need rocket scientist genes to do better than that.
7. SEQUENCING JOINS THE FIGHT AGAINST EBOLA
Genetic sequencing has been put to work in the fight against Ebola, providing a surer method of diagnosis – crucial for a disease where isolation of the sick is a key step in containing the epidemic – and a method of tracking the origin and the path of the rapidly evolving virus currently ravaging parts of western Africa.
In September, fifty authors, led by Pardis Sabeti of the Broad Institute in Massachusetts, published a paper in Science describing rapid evolution of the Ebola virus found in the blood of 78 patients from Sierra Leone. What could emblemize the strange contradictions of 2014 more than this: machines reading a language written in single molecules, interpreted by programs that cost billions of dollars to develop, in the service of a battle fought in blood-spattered tents where people die for the lack of IV fluids.
There were 58 authors listed on the Science publication in September. As of October 24th, five of these individuals had died from the disease.
6. CRISPR GENE EDITING SYSTEM CORRECTS GENE MUTATION IN MICE WITH LIVER DISEASE
Oh come on, just give them the Nobel Prize already.
CRISPR, a top genetics story in 2013, could have made this list again for any number of reasons in 2014. The ability of the CAS9 gene editing system to efficiently target specific sites in human stem cells was reported in this Nature Communications article, suggesting that unintentional effects may be less of a problem than people had feared. Other experiments have explored the potential of CRISPR to cure muscular dystrophy, fight cancer, and make cells immune to AIDS. And that – no, I mean this – is only the beginning.
In mice with a mutated FAH gene and congenital liver disease, researchers led by Daniel Anderson at MIT reported that CRISPR machinery along with a template for the normally-functioning gene were inserted by high pressure injection and resulted in the production of enzyme-producing liver cells. For the first time, a designed, controlled, human-mediated process of gene editing occurred inside the cells of living animals. And it worked! Measurable improvement occurred in the health of the affected mice.
Another sign of how big this could be: the hotly-contested battle for control of the intellectual property rights, with the Broad Institute’s Feng Zhang and Zhang-associated biotech Editas Medicine taking round one earlier this year in the form of a broad U.S. patent. Final disposition remains in the hands of the judges, with co-discoverers Jennifer Doudna from UC Berkeley and Emmanuelle Charpentier from the Helmholtz Centre for Infection Research each having established relationships with competing start-ups, all of them angling to bring the power of search-and-replace functionality into genomic medicine.
In November, Charpentier and Doudna accepted several million dollars apiece as their share of the Breakthrough Prizes, funded by an assortment of Silicon Valley multi-billionaires and handed out by a bevy of Hollywood bold-faced names. Here they are, looking glamorous next to Cameron Diaz:
So what do you say, Sweden? Make it official. They already have the gowns.
If you know ONE SINGLE THING about genetics, you know this: every cell in your body has the same DNA. Every cell in your body has the same DNA, except… well, of course there are always exceptions. If genetics was easy, everybody would do it.
Some exceptions are so rare as to defy belief: Washington resident Linda Fairchild found herself in jeopardy of losing custody of her children when a routine test suggested that none of the three boys she had given birth to was her biological child. Fairchild turned out to be a chimera – a single individual with two distinct genomes, in her case the result of a twin pregnancy where one fetus stops developing early on, and is absorbed into the body of the surviving twin. In Fairchild’s case, a second test, on her cervical cells, revealed an alternate genome that was a match for her boys. In effect, Fairchild was the children’s mother – and also their aunt.
Events that incorporate a whole alternative genome are unusual, but other changes that occur early in embryonic life can result in distinct cell lines in the body with subtle but sometimes important differences. Depending on when and where these changes occur, they may affect one organ or tissue type, or groups of cells scattered throughout the body like the patchwork fur of a tortoiseshell cat. Effects visible to the naked eye, like the large, irregular hyper-pigmented spots seen in McCune-Albright syndrome or the inconsistent areas of overgrowth in Proteus syndrome, have been recognized for years as instances of somatic mosaicism.
Trending in 2014: evidence that somatic mosaicism may not be as rare as we had thought. Newly available sequencing techniques show that the closer we look, the more variation we find within individuals. A study published in the American Journal of Human Genetics in July looked at the parents of children with small deletions that appeared to be de novo – that is, blood tests didn’t find the change in either parent – and found that 1 in 25 are mosaic for the variant in other tissues. Similarly, causal mutations in one cohort of individuals with brain malformations were found to be mosaic 30% of the time. Something to keep in mind when searching for the underlying genetic cause of a condition, or in advising a family about recurrence risk! Another 2014 report described an unaffected mother who had a second child with nemaline myopathy, which conventional wisdom suggests should be virtually impossible. A closer look after the fact found low grade somatic mosaicism – only 1.1% in blood leukocytes, but 8.3% in her fingernails.
Okay, but seriously, almost all of the time, most of your cells have (virtually) the same DNA – that’s our story and we’re sticking to it. Probably.
No numbers 4 or 3! A three-way tie for second biggest story of 2014 goes to these, highlighting staggering technical achievements with equally staggering price tags:
2. STEM CELLS
Never mind that the field started the year on a sour note: a paper describing a new method of generating stem cells using an ‘acid bath’ generated its own acid bath of critical response and was subsequently withdrawn. Consider that a head fake, because 2014 was a banner year for stem cell research, the year we moved beyond rodents into human trials.
There are multiple contenders for stem cell story of the year. In France, a team led by Philippe Menasche announced plans to introduce cardiac progenitor cells using a patch in heart failure patients undergoing surgery, with hopes to improve heart function. In England, according to a fingers-crossed, early report in Stem Cell Translational Medicine, autologous stem cell therapy for stroke victims appears to be going well. Researchers testing stem cell therapy for blindness caused by macular degeneration or Stargardt’s macular dystrophy reported in the Lancet that over half of their participants have improved vision – an unexpectedly good result for a phase I trial of severely affected patients that was designed only to show safety.
Blind people seeing! It’s hard to beat that for drama. Still, my stem cell story of the year comes from California, where the stem cell therapeutics firm ViaCyte has announced that the first of forty patients in an FDA-approved trial has been implanted with pancreatic progenitor cells that are designed to mature into insulin-producing cells in situ. The cells sit in a sort of pouch made of a thin, porous membrane intended to allow insulin to pass into the bloodstream as needed, but insulate the cells from the destructive immune response that causes Type I diabetes. Here’s my reasoning: the work was supported by the California Institute for Regenerative Medicine, which has a lot to talk about right now after a slow start and a lot of snickering about government-run programs, and it involves a unique, creative delivery method and a common disease that starts in childhood and causes lifelong morbidity and expense. This might not turn out to be the solution that sticks (a group at Harvard recently announced a new method for reprogramming fibroblasts into pancreatic-like progenitor cells, so maybe we will have an East Coast-West Coast battle. Perhaps they can rap it out). But there are a lot of type-1 diabetics out there who should be feeling upbeat about their chances for a breakthrough in the near future.
And given the cost associated with the disease, this might even be a stem cell therapy insurers pay for without a fight. Or – well, maybe not.
2. IN ARKANSAS, 3 YOUNG WOMEN SUE MEDICAID FOR ACCESS TO CYSTIC FIBROSIS MIRACLE DRUG KALYDECO
Two years ago, the introduction of Kalydeco from Vertex Pharmaceuticals made this list as the first ever pharmaceutical treatment designed to correct an underlying genetic defect. Although it is effective for only a single mutation, which means it helps only 4-5% of those affected with the disease, Kalydeco represents proof in principle that targeted therapies can provide a virtual cure for CF, and by extension, a sign that understanding the genetic underpinnings of disease can improve the lives of that big universe of affected people.
Now Kalydeco is back in the news for less happy reasons. This summer, three women sued the state of Arkansas, claiming that Medicaid violated their federal rights by refusing to pay for Kalydeco, although they met eligibility criteria established by the FDA. Arkansas’s Medicaid program claims it does not categorically refuse to pay for Kalydeco, which costs more than $300,000 per year, but requires applicants to prove that conventional therapy is inadequate. That’s a catch: the older therapies are less successful, more arduous and leave patients liable to repeated infection and lung damage that may permanently compromise their health, but they may be adequate to attain ‘acceptable’ lung function. Joseph Walker, writing in the Wall Street Journal, describes the rigors of one litigant’s “traditional” regimen, including hours a day in percussive therapy, where pounding on the chest loosens hardened mucus in the lungs. Vertex, which has a compassionate care program for those with zero coverage, which is another catch: they refuse to provide the drug unless the individual has no grounds on which to appeal – in other words, if they need it, they can’t get it. Otherwise, Vertex argues, all Medicaid programs would be incentivized not to pay.
So what is with the Catch-22’s? Medicaid and the drug companies are worried about setting policy, knowing that Kalydeco is the tip of an iceberg, with a slew of extraordinary and extraordinarily expensive targeted therapies on the way. This year, Genzyme has introduced a new pill for people affected with Gaucher disease that will cost $310,250 per annum, and researchers released data showing that the drug asfotase alfa could help form bone, rescuing infants with a rare and lethal condition called hypophosphatasia – at $200,000 per year, which suddenly seems like a bargain. This list is by no means complete, and it’s not getting any shorter. And limiting compensation, as the pharmaceutical companies constantly remind us, will make them less interested in finding treatments for rare diseases.
2. GENE THERAPY DRUG GOES ON SALE IN GERMANY AT 1.4 MILLION PER PATIENT
Most people want to be one in a million, but if you ask someone with lipoprotein lipase deficiency, you might get a less positive response. This rare disease leads to sky-high triglycerides, eruptive fat-filled lesions, frequent abdominal pain and bouts of pancreatitis. Glybera, a cure for LPLD and the first commercially available gene therapy in the western world, will be introduced by UniQure in Germany in 2015. It is estimated that 150-200 people in Europe could benefit from treatment, which will cost, on average, 1.4 million dollars per patient.
The most stunning thing about that number is that it might be considered a bargain. With targeted therapies clocking in at $200,000+ per year, the one-time fee represents a substantial savings if amortized over a decade or more. To get your money’s worth, just keep living.
1. COALITION OF RESEARCHERS SHARES DATA!
WHOLE EXOME DATABASE OF 60,000+ INDIVIDUALS GOES ONLINE
The Exome Aggregation Consortium (ExAC) released debuted its massive database of exomes at the American Society of Human Genetics meeting in October, and the response crashed the server on day one. Way to break the internet, guys. According to a post from the head of the ExAC production team Monkol Lek, the exome browser garnered 120,000 page view from over 17,000 unique users in the first month.
Several factors make this the top story of 2014. First, the remarkable technical achievement of turning over 15 data sets into a single, searchable entity, and the equally remarkable feat of getting all those research entities to turn over their hard-won libraries for universal access. “Here are a bunch of data sets that individually cost millions of dollars to generate, and you have people willing to make that data available to a shared resource, which is amazing” marvels ExAC principal investigator Daniel MacArthur, speaking to Nature’s Erika Check Hayden in October.
ExAC isn’t the first genomic database to be made available to researchers, and it won’t be the last. The Haplotype Reference Consortium, a resource for genotype imputation and phasing, will begin releasing data in early 2015. And the new resources aren’t sufficient – HRC organizers note that their current data set is European-centric, and getting a more even distribution of ethnicities represented is an important challenge going forward.
But the fact that these open access resources exist represents an acknowledgement by all concerned that clinically significant progress will require genotypic and phenotypic information on more individuals than any single research entity can assemble on its own. By implication, it acknowledges the significance of rare variants in human health and disease and the need to look beyond simple deterministic models of gene effect and give sufficient power to studies that encompass a subtler, more complicated vision of how phenotype emerges from genotype.
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Thank you for summarizing, so eloquently, these incredible achievements!