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
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.
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).
One response to “The List Returns: My Top 10 Stories in Genetics in 2019”
Thanks Laura! I always appreciate your end of year post. I think 1, 6 and 10 on your list could be connected through a common thread of the commercialization of genetics. If a commercial lab is behind a chatbot, these tools are likely more about *making the sale* rather than extending or elevating the role of genetic counselors. Guided by the chatbot, individuals may be encouraged to check the box to proceed with testing and accept the terms of service. Most will not review the TOS which may, among other things, give authorization for an open invitation for the lab to share your “de-identified” data, track your online behavior, and for their 3rd party partners to market back to you. From here, genetic testing may be ordered by a physician who will never care for you as a patient but is accepting payment from the lab to “approve” and sign test orders. Maybe you will pay a couple hundred bucks for the test as “self-pay”, or if you meet certain criteria, maybe the lab will suggest insurance be billed for the test for a much higher fee. Or maybe the testing will be done at no charge to you or the insurance, but rather paid for by your employer as part of an employee wellness program, or by a pharmaceutical company “partner” who will then have access to better enlist patients in the R&D of new drugs. And when these drugs eventually make it to market, the cost will be prohibitive to many of those who need them. In addition to luck we need better policies and regulations with a goal towards greater equity in genetics and medicine.