Tag Archives: CRISPR

by laurahercher | December 26, 2019 · 10:45 AM

The List Returns: My Top 10 Stories in Genetics in 2019

2019!! I’m going to declare it The Year of the Phoenix, with old promises rising from the dead (gene therapy) along with left-for-dead approaches (you came back with a vengeance, polygenic risk scores) and even older fears (remember when we were a post-racial civilization and genetic discrimination – whew! – didn’t happen?).

Writing about 2019 got me thinking about the end of a decade, and so this year I am offering an end-of-the-decade special: two lists in one. Here’s my take on the top ten stories in genetics for the 2000-teens (in no particular order):

Clinical use of exome sequencing

The rise of mega-databases

The ancestry-testing craze and the death of genetic privacy

Data sharing becomes the norm (kumbaya awards to gnomAD; ClinVar)

Nanopores! And other forms of heterogeneity in the F2 generation of DNA sequencing

Cell free DNA testing

Polygenic risk scores 2.0

NGS rewrites laws of economics by getting cheaper & better despite Illumina monopoly

Gene therapy rebounds

CRISPR

No surprise, many of these larger trends are reflected in the Top Ten for 2019:

DTC: THE TRAIN HAS LEFT THE STATION BUT NOBODY KNOWS WHERE WE ARE HEADED

Can’t talk about genetics in 2019 without a word about DTC testing, as we persist in calling it for lack of a better word (consumer-initiated testing? Not a better word, though possibly a better phrase…). The thing is – wait for the irony – you can’t generalize about DTC anymore. So what’s the biggest DTC story of the year? I’m going with Ancestry branching out into the health and trait testing business. This can hardly rate as a giant surprise, as they have hinted at it for years, but the big question was whether or not they would go with a 23andMe Fun Facts approach or something more medical. Would they try and compete with Invitae or Color and offer a more comprehensive and more expensive CONSUMER-INITIATED, DOCTOR-APPROVED testing? Seems like this choice would say something about where they see the field going…

And the answer was (drum roll): both. Take your pick. This actually does say something about the future, which is to say, we have no idea where the field is headed. Their two-tiered approach debuts in 2020 and I expect it is more beta testing than market strategy. I predict they are down to a single product by the time we (please God) inaugurate a new president in 2021.

MILASEN

There are so many stories about the success of new treatments in 2019, that it was hard to pick just one. Trikafta, the new CF combination therapy that will extend effective treatment to over 90% of the cystic fibrosis population? Studiessuggesting the PCSK9 inhibitor inclisiran may offer a new option for individuals with a genetic predisposition to high cholesterol?

But with all these big stories to talk about, I’m going small: the development of a drug to treat a single individual, reported in October by the New York Times. This n-of-1 drug was developed for Mila Makovec, a Colorado 8-year-old with an atypical form of Batten’s disease. The drug, named Milasen, has improved but not cured the little girl, who has gone from 30 seizures a day to something less than 6 on average. This example of highly personalized medicine was enabled by DNA testing, but also by the 3 million+ dollars Mila’s mother raised via a GoFundMe campaign. Additionally, as the article points out, the nature of a custom drug is a challenge for regulators, who cannot use data to establish effectiveness or risks associated with treatment. And without means to get FDA approval, these drugs will operate indefinitely in self-pay mode.

FLORIDA MAN AND ACCIDENTAL PHILOSOPHER SELLS BUSINESS AND RETIRES FROM UNPAID ROLE AS ARBITER OF FORENSIC DNA USE BY AMERICAN LAW ENFORCEMENT

In 2010, retired businessman Curtis Rogers and his friend John Olsen founded GEDmatch, a website providing a set of tools to help adoptees find biological relatives. “Premium members” paid $10 a month, most of which went to offset the cost of servers. More of a hobby than a business, GEDmatch was staffed by volunteers.

Eight years later, Rogers described himself as shocked and surprised to discover via news reports that his site had been used by law enforcement to locate a suspected serial killer named Joseph DeAngelo, later convicted of a rape/homicide in 1977. “It took a couple of weeks for me to really wrap my head around what was happening,” said Rogers. GEDmatch, which was not a testing service like Ancestry or 23andMe, accepted DNA from a variety of sources, making it accessible to profiles derived from crime scene samples, and its DIY set of tools for finding relatives was tailor-made for the new field of forensic genealogy.

Did people who uploaded their DNA for genealogical purposes intend for it to be used by law enforcement? And did their intentions matter? Accidentally, this Florida man found himself the arbiters of forensic DNA use in the U.S. How did he do? Not bad, considering. In the wake of the initial Golden State Killer hubbub, Rogers informed law enforcement that they could use GEDmatch only for crimes that included murder or sexual assault.

Then in December 2018, Rogers bent the rules to allow a search for an assault he described as “as close to a homicide as you can get” (an elderly woman playing the organ in church was choked and beaten). This exception provoked a significant negative reaction from the GEDmatch user community, which in turn caused Rogers to rethink his approach, and in May he announced a new “opt-in” policy, restricting the police searches to those profiles whose users had provided consent. Overnight, the new policy shrunk law enforcement’s access to GEDmatch to a meaningless fraction of the total database. While responsive and thoughtful, this sudden about-face illustrated how much the forensic use of genealogical data rested entirely upon the decision-making of one many with no particular expertise and some conflict of interest (Rogers also mused allowed at one point that he might start charging law enforcement to use the site because, why not???).

This status quo held only briefly, with several latte-year events altering the forensic DNA landscape. In September, the U.S. Department of Justice released interim guidelines for law enforcement that permits them to use DNA databases only for violent crimes like rape and murder, or to identify human remains, and only when traditional investigatory efforts have come up empty. Two months later, a GEDmatch search occurred for the first time by court order, after a Florida court issued a subpoena. And in December, Rogers sold the company and his de facto control of forensic DNA use in the U.S. to Virogen, a sequencing company specializing in forensic use of DNA. Virogen claims it will maintain the opt-in standards set by Rogers even though those standards complicate its core business. Anyone who takes that promise at face value should contact me; I have a bridge you might be interested in buying.

ASCENSION HEALTH PATIENTS, MEET OUR NEW ASSOCIATE, DR. GOOGLE

Maybe they should have called it Project Canary in the Coal Mine.

Ascension Health’s Project Nightingale struck a nerve this November, when the Wall Street Journal reported that they had hired (or, in HIPPA-compliant terms, entered into partnership with..) Google to collect and analyze identifiable health data from the electronic medical records of their patients. HIPAA forbids the sharing of a patient’s medical information without express consent, but allows for access within a medical system if it is used to improve patient services. While Google denied any intention to use the data for other purposes or to link it with Google subsidiaries such as Calico (a partner with Ancestry, the largest of the consumer genealogy databases), many skeptical observers pointed out that health data is a valuable commodity in which Google has a previously expressed interest.

Sans accusation, it is fair to say that Project Nightingale raises legitimate concerns about the adequacy of existing privacy regulations in an age when the quantity and richness of data accessible through large health system EMR’s and genomic databases is unprecedented, and there are players like Google potentially capable of connecting the dots between genomic and health outcome data to draw conclusions about individuals and families. It is unlikely that the architects of HIPAA envisioned the size and scope of Ascension Health (78 hospitals and over 2600 ‘points of care’ according to… Google) and there is no way that HIPAA rules governing internal partnerships were designed with Google in mind. What could happen? I don’t know, and neither do you, and that is actually the point.

INVITAE INVESTS IN CHATBOTS

If you attended a genetic counseling conference this year, you likely heard a great deal about chatbots, even before reports in November of Invitae’s plans to purchase chatbot pioneer Clear Genomics for $50 million dollars (drinks on you, Shivani Nazareth!!!). The move represents a clear (no pun intended) double down on Invitae’s other significant 2019 initiative: expanding into the world of consumer-initiated testing. Chatbots, in this story, play the role of support staff, allowing us to triage questions and concerns that require genetic counseling from those that do not, a crucial step in expanding the use of genetic testing or screening without sacrificing our commitment to informed decision-making and responsible return of results. In fact, relieved of menial question-answering, the GC staff are able to take more time with those who need it, and practice the sort of personalized and therapeutic relationship-building that characterizes genetic counseling at its best.

Do you sense a *but* coming? I sense a *but* coming.

But… I have to say that while I buy the potential of chatbots for this purpose, my own view of the future is a bit of a choose-your-adventure story with alternate endings. In the darker version, institutions and insurers decide, once the automated information-givers are in place, that this system is not intended to enable genetic counseling but to replace it. So, yes, let’s embrace GC-Siri, but at the same time, let’s double down on producing data to support the value of the (human to human) genetic counseling experience.

DATA SHARING HITS A MILESTONE

The clinical value of genomics is based not just on our power to sequence, but on our ability to interpret the variant calls, and for improving interpretation, there is no resource more powerful than past experience – an early-days problem for the nascent field of genomics. ClinVar, the government-funded repository of variant calls, was developed to provide a way to maximize the value of our collective experience of the relationship between genotype and phenotype. A real-life exercise in game theory, ClinVar represented an act of trust: hand over your work for the common good and, if enough people participate, everyone will benefit.

The result? In December 2019, ClinVar announced that the number of shared records has passed one million. Routinely consulted by clinicians and researchers, ClinVar has become an invaluable resource to the world. Congrats and thanks to the thousands of volunteers who have organized data, searched records, curated variant calls and worked to promote the gospel of data sharing.

And by the way an example of government doing what private industry cannot, in the service of the public good.

CRISPR PRIME PROMISES TO A CURE FOR YOUR GENETIC DISEASE DELIVERED IN TWO DAYS OR LESS

A novel CRISPR technique, reported in an October article in Nature, uses reverse transcriptase to introduce a desired transcript into a DNA strand, without the messiness and unpredictability of CRISPR’s double-stranded breaks. The technique was widely hailed as a way of improving reliability of the ‘replace’ aspect of CRISPR as a ‘search and replace’ function for DNA. And called CRISPR prime, so I guess they will give me my money back if it isn’t delivered to the right chromosome in two business days (this joke has fallen flat multiple times but I believe in it and I have the courage of my convictions).

Will CRISPR prime be transformational? Despite the excitement it is too soon to tell, but here’s what the story represents to me: the incredible pace of technological advancement in the CRISPR era continues unabated. Prior to 2012 – LESS THAN 8 YEARS AGO – most people excited about CRISPR probably thought of it as an intriguing way to improve yogurt. In less time than it typically takes to bring a single drug to market, CRISPR has launched a multi-billion dollar industry, with the first CRISPR-mediated therapies approved for human trials (and, less positively, the first CRISPR gene-edited babies already past their first birthday in China). If CRISPR prime doesn’t deliver, something else will; I’d put an Amazon-sized bet on that.

THE UK BIOBANK FUELS A NEW ERA OF POLYGENIC RISK SCORES FOR… EVERYTHING.

Move over, Iceland. Your collection of genomic and health history information was good but how can a small island nation with a genetically homogenous population compare with the vast genomic richness of… England?

Okay, so 94% of the half million participants in the UK Biobank are white. But, as papers appear almost daily, it is hard to deny the fundamental impact of the UKB as a research resource. Funded in 2002, the dataset combines the results of genomic testing with phenotypic measures of more than 2400 traits, and survey data covering everything from sexual history to political preferences. And with only a handful of restrictions and a $2500 fee for use, UKB data is available to almost everyone, and it has been used to link common genetic variants with everything from depression to obesity to income.

In turn, this mass outpouring of genetic association studies has spawned a sub-genre of “genetics is not deterministic” PSA’s, like this one from Kevin Mitchell, and I’d like to collectively thank you all for your efforts.

Because volume is the message, it is hard to single out a single UKB-themed story, but in the spirit of reductive end-of-year list-making, let me focus on an article on the genetic basis of same sex sexual behavior published in Science in August. The authors of this study, which reported on a GWAS of data drawn from the UKB and the 23andMe consumer customer database, identified results indicating genetic associations that accounted for 8-25% of the variation between individuals who had participated in same-sex sexual behavior and those who had not. The authors were extremely careful to explain that a single same-sex experience was not the same thing as homosexual orientation, and in fact further analyses indicated that there were genetic differences between the two. Additionally, the article made clear that while patterns emerged in a population, individual results were insufficient to indicate likelihood of homosexual behavior on an individual level. The authors even constructed a website putting this into more user-friendly language, in case anyone found the Science article inaccessible.

So it could come as a surprise to no one that, 6 weeks later, an app called “How Gay Are You?” went up for sale through the DTC gene-testing marketplace Gene Plaza. Under intense public pressure from the authors of the study among others, this app was removed in November. Was it only a bit of harmless fun, like the app that claims to identify your inner superhero? Maybe not says science journalist Emily Mullin, who pointed out on twitter that the person responsible for the app is based in Uganda, where homosexual behavior can get you the death penalty. Ha ha adorable.

Sure, this example fails to illustrate the medical value and legitimacy of many UKB-based gene tests reported in 2019. But it says something profound about how quickly the marketplace moves to commercialize genomic associations, and the difficulty of controlling how the information is used – but also (a bit more optimistically) that a response and clear communication from scientists can mitigate misuse.

POPULATION SCREENING

The steep fall of the cost of DNA sequencing has transformed genetic research and made exome sequencing a staple of medical management. It has also opened up the possibility of population-level screening programs, including research programs like the UK Biobank and the U.S. All of Us project and clinical programs like Geisinger Health System’s MyCode. Is genetic screening of healthy individuals a good idea? That depends on the circumstances. How about by government decree, without consent, for purposes of tracking a vulnerable and restive minority population? Hmmm… pretty sure even George Church and David Ledbetter are a hard no on that one.

But a report by the NY Times in February documented that involuntary “free health checks” of a Muslin minority population by Chinese authorities included facial scanning, fingerprinting and a DNA test. This perversion of health care is even more nefarious in the context of Chinese repression of the Uighars, over a million of whom are rumored to be in ‘re-education camps’ serving indefinite sentences for the crime of belonging to the wrong ethnic group. Thermo Fisher, the Massachusetts-based company that provided the equipment used for population sequencing, announced that it has ceased sales to China as information on the genetic testing program began to surface in the news.

How do they plan to use DNA sequence data? Will individuals be tracked using DNA profiles or groups of individuals sorted by genotype? I doubt even the Chinese know. But genetics has always had a dark side, and even the most ambitious of early eugenicists could hardly have imagined the power of population-level sequencing programs, and the toxic potential of new-fangled technology and ancient prejudice.

ZOLGENSMA AND THE COMPLICATED MORAL MATH OF MIRACLES

There is no bigger story in genetics in 2019 than the success stories in gene therapy, which have brought help to a handful, and hope to many. Two years removed from the first FDA approvals in 2017 (two immunotherapy drugs and Luxturna, for a rare inherited retinal disease), the 2019 update includes a handful of new market entries and a robust pipeline, with some tantalizing year-end hints about promising results in gene therapy trials for sickle cell disease and beta thalassemia. Nowhere is the optimism felt more keenly than the SMA community, where parents now have competing options to treat what was until recently a death sentence for their affected children.

But as this story by the Washington Post indicates, access to those options poses a world of new challenges. Zolgensma, a gene therapy for SMA, made headlines as the world’s most expensive drug at 2.1 million dollars per patient, and that fact means that insurance companies are going to take a long hard look at who qualifies for the treatment. This article concerns a toddler turned down for the drug because as a type-III SMA patient she is not severely affected enough to qualify – although she has difficulty walking and can anticipate lifelong disabilities. Since the use of the medication is only approved for children under two, there’s no room for a wait-and-see attitude.

The economics of gene therapy are built on a model of one-and-done treatment that replaces lifelong care, a promise that in these early days is aspirational at best. But even if it goes according to plan, the model doesn’t account for children like the adorable, moon-faced Daryn Sullivan, whose lifetime medical costs might not be so outrageous as to make 2.1 million up front sound like a bargain. With other diseases, off label use might include genotypes that are not the best case scenario for use, where we anticipate improvement not cure. If it’s the best medicine can do, can we pay 2.1 million for anything short of a miracle?

For all these substantial challenges, the biggest translational obstacle may be something more subtle, captured not in the article but in the comments. Daryn’s parents, it turned out, knew during pregnancy that the child would be born with SMA and chose not to end the pregnancy. Will our increasing ability to identify and prevent genetic disease make us less willing to fight the hard fight for access to treatment? “I had the deepest sympathy for the Sullivans,” one reader wrote, “until I read the part where they KNEW their baby was doomed to a terrible wasting disease, but continued the pregnancy anyway.” A quick review showed about 10% of the 320 comments said something similar: “people create children with disorders and then demand that everybody else pay for their treatment no matter what the cost. Shameful.”

In the past 10 years, we have addressed many of the technical challenges to gene therapy. In the next decade, we will have to confront the potentially even more challenging issues of access and empathy.

THAT’S IT FOR ME IN 2019! HAPPY NEW YEAR, EVERYBODY!!!! GOOD LUCK TO US ALL IN 2020 (WE’LL NEED IT).

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Filed under Laura Hercher

Tagged as 2019 top ten, Ancestry, Ascension Health, chatbots, ClinVar, CRISPR, DTC Genetic testing, GEDmatch, Google, Invitae, Milasen, Project Nightingale, UK Biobank, Zolgensma

by Robert Resta | June 24, 2018 · 5:25 PM

When Perfection Causes Imperfection: A Potential Non-Genomic Complication Of Germline Editing

There is wide consensus that we should not only treat but also try to cure genetic conditions that cause profound suffering. CRISPR and related technologies have descended on us like a deus ex machina from the heavens and made it possible to “cure” genetic diseases through germline editing. Precision molecular microsurgery has stimulated provocative discussions about which diseases are serious, where we draw the line, the acceptance of people who are different in appearance and abilities, increasing the disparities between wealthy and poor, religious concerns, etc. I don’t have any helpful insights into these issues but I hope that vigorous debate continues and that if germline editing becomes a reality, we proceed veeerrrrrryyyyy slowly, cautiously, and incrementally.

The more ardent “germline utopians” envision a world where all fertilized embryos undergo germline editing to prevent the resulting offspring from developing genetic disorders. Of course, this will never happen universally. Even in a fantasy world of full acceptance of, and unrestricted access to, germline editing, pregnancies have a habit of, well, happening on their own. But for argument’s sake, let’s make the unlikely assumption that many parents will utilize germline editing to prevent their children from developing genetic conditions. Given that Western societies place great value on individual autonomy and considering the conditions that are currently screened for through prenatal diagnosis and carrier screening, it is likely that prospective parents would choose to “correct” traits ranging in severity from hearing loss to profound physical and developmental disorders, and all points in between. And to twist the complexity we might see the reverse scenario where deaf parents choose to “correct” a hearing-abled embryo. Should genetic enhancement – adding a few IQ points, tacking on centimeters of height, a slimmer habitus, Faye Dunaway zygomatics – become a reality then a goodly number of parents will take advantage of that as well (please I hope never because it will bring out the worst in us).

Of course, this model of genetic disease prevention depends on whether the technique actually works and that it is safe. There is reason to believe that germline editing and “correction” of genetic conditions are technically achievable. Safety, however, is more open to question. Off-target genetic effects, among other safety issues, could relegate germline editing to the What If category of debate.

But let’s posit a world where efficacy is proven and off-target effects are negligible. There would still be another safety issue, unrelated to genomics. Germline microsurgery requires in vitro fertilization/intracyoplasmic sperm injection (IVF/ICSI) in order to gain access to the gamete or the fertilized egg and to achieve a pregnancy. And therein lies the rub – IVF/ICSI is associated with a higher risk of complications in singleton and multiple gestations, such as prematurity, low birthweight, small for gestational age, perinatal mortality, and congenital anomalies. It reminds me of the introduction of a phenylalanine-restricted diet to reduce the impact of PKU that eventually created the phenomenon of maternal PKU, in which maternal hyperphenylalaninemia produced babies with microcephaly, heart defects, and intellectual disabilities. The attempt to cure one problem can create a whole new set of problems.

Now maybe the complications of IVF/ICSI are in part due to the underlying causes of the parental infertility, and thus fertile couples may have lower complication rates. Maybe. Perhaps IVF/ICSI will become safer. Perhaps. Still, it is likely that some parents will be willing to accept the risks of pregnancy complications in return for not having a child with Tay-Sachs disease or severe ichthyosis. But are the pregnancy risks worth it to prevent genetic hearing loss, increase a child’s IQ, or create a child with movie star beauty?

You might understandably say “My God, we finally have the chance to prevent serious genetic problems and improve people’s lives. How can we not take advantage of it? We are just trying to do good in a world full of suffering.” Indeed, the goal of reducing suffering is as old as the field of Medical Genetics. But when we march beneath the banners of Cure, Good Intentions, and Highly Ethical Motivations, and throw in an unhealthy dose of hubris, our enthusiasm may blind us to the harm that we might do. Perfection comes with a price.

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Filed under Robert Resta

Tagged as CRISPR, germline editing, preventing genetic disease

by laurahercher | December 29, 2017 · 10:17 PM

Human Germline Editing: our crazy, scary, wonderful future is coming, but not quite yet

Publication this week of a paper by reproductive biologist Shoukrat Mitalipov and others put the subject of editing little baby humans front and center – above the fold news in the NY Times. Universally, the Mitalipov study was recognized as a milestone, and so it appears to be – a milestone on our journey to…wherever it is we are headed.

What did they do, and why is it important? Mitalipov improved greatly on previous efforts at germline editing, targeting embryos created using donor eggs and sperm carrying a pathogenic variant in the MYBPC3 gene associated with hypertrophic cardiomyopathy. Modification was successful over 70% percentage of the time, no off-target effects were detected, and only one of the 58 embryos was found to be a mosaic of altered and unaltered cells. While significant safety and efficacy concerns remain to be addressed, this work goes a long way toward validating the idea that, sooner rather than later, clinical use of this technology will be a realistic possibility.

The experiment raised hopes, but also some questions. CRISPR is often described as a DNA version of a search-and-replace function in a word processing program, but CRISPR itself only does search-and-remove. The ‘replace’ part leverages the cell’s own machinery for fixing breaks in DNA, and its innate penchant for tidying up any loose ends. Quick to the breach, cells can often be coaxed into using a template for the repair if one is provided along with enzymatic scissors and a guide RNA, allowing us to insert a custom DNA sequence. This bespoke DNA can be anything, but in this case it was meant to be a benign version of the MYBPC3 gene. In a surprising development, the cells preferentially ignored the synthetic template and used the unaffected version on the sister chromosome as a guide instead.

This had the desired effect of introducing a functioning wildtype gene, but if it is not overcome as a technical issue, will limit the range of what can be achieved via gene editing. This model doesn’t work at all with recessive disease, where there are two copies of the pathogenic variant. Additionally, it would not allow for the introduction of DNA sequences other than what is carried by a parental allele – a capability which is, I would argue, the truly unique feature of gene editing.

Articles about CRISPR may (and usually do) talk about its potential to prevent Mendelian diseases like Huntington’s or sickle cell, but we are already capable of preventing transmission of these diseases using IVF with PGD to identify embryos that are unaffected. Yes, as has been pointed out, this is not foolproof. A round of IVF may produce no unaffected embryos. In rare circumstances, one parent may be homozygous for an autosomal dominant disease. These are non-trivial events when they occur but they are rare and limited circumstances. For the rest, replacing one expensive and complicated technology with another is incremental progress at best, and not the reason why this story was A-1 on the NY Times website. Media interest, let no one be confused, was about the potential of CRISPR to produce what they referred to (inevitably) as designer babies.

Antonio Regalado of the MIT Tech Review decodes media coverage of human genome editing

Can the technology produce designer babies? This would be an easier question to answer if designer babies were actually a thing that you could define, but they’re not. Generally, what people mean by ‘designer baby’ is one created through any use of reproductive technology to ensure specific traits, as opposed to using identical technology to avoid diseases. The problem with this is that drawing the distinction is a bit of Impressionistic painting – clear from a distance, but blurring together when you get close. A number of articles this week suggested that designer babies can’t happen because traits are not something that can be manipulated by tweaking a gene or two (here and here). This is comforting but may not hold up. It’s fair to say that you can’t tweak general intelligence – but what about, for example, executive function? And while we’re on it, would that be increasing intelligence (bad) or avoiding ADHD and other mental health problems (good)?

But this is leading me into rabbit holes, where we debate what is or might be or could be possible, when just now I want only to say that the potential of gene editing to add an entirely new dimension to what we can currently offer is bound tightly to its ability to introduce DNA sequences that are different from what either parent can contribute. When we are able do that, we can expand the concept of what it means to ‘choose’ a child’s genotype. We can add rare variants that confer some protection or competitive edge. We can even contemplate adding synthetic variants designed in a lab and not borrowed from natural experiments. When move past embryo selection to embryo improvement, we will have our little Gucci baby whose possible existence causes so much consternation.

So does this week’s blockbuster paper put us closer to that day? Yes, because the technology has moved forward a giant step. Not that technology ever moves backwards, but the speed with which it has improved is staggering, and while momentum is not going to carry it over the remaining hurdles like a hot wheels car going loop the loop, it does make it easier to assume that all technological barriers will eventually fall. But at the same time, the template surprise reminds us that every step forward reveals another twist in the road.

Are we almost there? Who knows. If 2016 taught me anything, it was to stay out of the prediction game.

So what would a wise republic do? Coincidentally, a workgroup under the auspices of the American Society of Human Genetics published a paper yesterday in the AJHG laying out recommendations for public policy on human germline editing. The position statement was approved by ASHG, NSGC and 9 other organizations from six continents (full disclosure: I am one of the co-authors). The take home point is that modification of the human genome (egg, sperm or embryo) would be premature at this time but may be justified in the future, providing that there is a compelling medical rationale, an evidence base to support its use, ethical justification and a transparent public process to solicit and incorporate stakeholder input. In the interim, the organizations encourage governments to permit and to fund work like Mitalipov’s that investigates the potential of human germline engineering.

Having been a part of this group, I can attest that we thought long and hard about this aspect of the statement, and that we made it despite our concerns that this technology holds risks for both individuals and society, including the potential to increase existing inequities in health and quality of life. We may try and regulate use and norms such that we get the upside and not the downside, but we must acknowledge that to a large extent the two are inextricable.

Speaking only for myself, I can say that I see the allure of a form of intervention that might prevent rather than merely treat sickness and suffering, even as I sympathize with those who worry about the impact of the technology on future generations. If the choice were mine, it would be a difficult choice. But in the end, what I recognize is that we are not given a choice between going backwards and going forwards. The truth is that gene engineering is going to happen. No one government or individual is going to stop it — the world is too big and the stakes are too large. The questions that sit in front of us are not yes or no, but where, how and under what circumstances. I believe that a thoughtful society should engage with the technology, providing capital and oversight, resources and regulation. To turn our back is to sacrifice whatever leverage we could bring to bear as we establish norms for use, and to cede our leadership role in the scientific community at the dawn of an era, the start of a journey to…wherever.

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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.

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 8^th 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.

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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Tagged as BRCA, Car-T, christina farr, CRISPR, Daniel MacArthur, databases, ELSI, elspeth reeve, FDA, genetic discrimination, genetics, genomics, Helix, Illumina, immunotherapy, LDT's, mitochondrial disease, mitochondrial transfer, sean parker, stephanie lee, top ten, Type II diabetes, Vinome

by laurahercher | June 8, 2016 · 12:49 PM

Ancestry and the Long Distance Call

These are the days of miracles and wonder

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

These are the days of miracles and wonder

And better variant calls

The way that CRISPR works on everything

The way we sequence it all

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

These are the days of promises and phase one trials,

and medicine is magical and magical is art

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

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

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

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

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

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

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

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

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

These are the days of miracles and wonder

This is the long distance call

The way the camera follows us in slo-mo

The way we look to us all

The way we look to a distant constellation

That’s dying in a corner of the sky

These are the days of miracle and wonder

And don’t cry baby don’t cry

Don’t cry

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Tagged as ancestry testing, CRISPR, paul simon, Sasha Kimel

by laurahercher | December 30, 2015 · 8:52 AM

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

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

crispr facts 2

crisprfacts

crispr facts

Here’s mine…

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

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

Roche Buys Billion Dollar Stake in Foundation Medicine

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

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

Matchmaker Exchange Goes Live

Screen Shot 2015-12-29 at 9.15.23 PM

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

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

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

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

Illumina Launches Helix, a Consumer Genomics Platform

Helix

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

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

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

In Memento Moratorium

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

–Mark Twain

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

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

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

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

Sequenom Introduces a Non-Invasive Scan of the Genome

“Facts are stubborn, but statistics are more pliable.”

–Mark Twain

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

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

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

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

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

Gene Expression? There’s a CRISPR for that.

crisperizer

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

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

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

Clap on, clap off… the Clapper! ld0oalpb8u8le

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

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

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

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

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

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

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

Eunice and Benjamin Lee

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

Baby With Cancer Responds to Treatment Using Genetically Modified Cells

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

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

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

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

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

-Mark Twain

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

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

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

The Power of Gene Drive

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

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

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

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

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

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

Screen Shot 2015-12-29 at 9.19.28 PM

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Tagged as 2015, Cellectis, Charles Gersbach, CRISPR, Daniel MacArthur, ExAC, Foundation Medicine, gene drive, genetic modification, George Church, Heidi Rehm, Helix, Illumina, Kevin Esvelt, Matchmaker Exchange, NIPT, Roche, Sequenom, Talens, Timothy Reddy, top ten, Virginia Hughes

by laurahercher | December 20, 2013 · 10:20 AM

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

10. 23andMe and the Thanksgiving Week Massacre

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:

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 6^th 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 3^rd 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”).

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.

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 12^th, 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.

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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Filed under Laura Hercher

Tagged as $1000 genome, 2013, 23andMe, bench to bedside, CRISPR, Generation Cryo, genetics, incidental findings, Kynamro, MinION, Myriad Genetics, organogenesis, Oxford Nanopore, top ten, Yaniv Erlich

Tag Archives: CRISPR

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