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
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
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
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.
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!).
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]