Helix Takes Clinical Genetic Testing Straight to Consumers

During a recent Uber ride, Madhuri Hegde’s driver asked her what she did for a living. The chief scientific officer for laboratory services at PerkinElmer, she prepared to bore him with a description of the tests her company had developed—most recently to flag serious genetic disorders. Instead, he was intrigued. “Where can I get one of those?” he asked.

For years, PerkinElmer has only offered that clinical test to doctors. It screens for all 59 genes that researchers are sure play a role in one of 34 conditions you can treat if you catch it early enough. Genes like PKP2, mutations in which can increase the risk of arrhythmogenic right ventricular cardiomyopathy, a leading cause of sudden heart failure in young people. Or ATP7B, which can point to Wilson disease, where copper accumulates dangerously in the liver. Usually physicians only prescribe the test when they think their patients might be at risk for one of those conditions. But soon, anyone curious about their health—Hegde’s Uber driver included—will be able to request it.

PerkinElmer announced Tuesday it will start selling its test this summer through the consumer genomics marketplace Helix, a spin-out of sequencing giant Illumina. Helix launched its platform last July, with 18 products meant to inspire customers to embark on a journey of discovery through DNA. Some boasted dubious science; some were just silly. Only one of them had a hardcore health bent—a test to see if hopeful parents carried any disruptive genes they could pass on to their kids.

Since then, though, Helix has built a number of partnerships to offer more medically relevant insights, PerkinElmer being one. Helix says it's just responding to demand; patients are into democratizing access to clinical tests. But as more people turn to their DNA to make decisions about their health, medical professionals who help make those decisions wisely worry about their ability to keep up.

“You may think DNA is DNA regardless of what you’re looking for, but context really matters here,” says Ana Morales, a certified genetic counselor at the Ohio State University Medical Center and president-elect of the American Board of Genetic Counseling. Normally, a doctor would order a test like PerkinElmer’s when a patient starts presenting symptoms, like an abnormal heart rhythm. Maybe they even have a brother or sister with similar complaints. Algorithms and experts would then comb through the patient’s DNA looking for places in their genome where specific mutations—called variants—might appear. All mutations aren’t created equal; they’re only looking for ones that geneticists have validated as playing a role in certain diseases. How big a role changes from variant to variant, and from patient to patient. Without symptoms, matching becomes a guessing game.

“We’re now moving away from interpreting a variant in someone who has a disease to someone who doesn’t,” says Morales. “That is possible, but the level of expertise required to do that is limited to within a few experts in the genetic community. There’s only a very select group of people in the US right now who would feel comfortable doing that on a routine basis.”

That’s one reason a doctor might not tell all their patients about the availability of tests like this one. The other is cost. Sequencing plus analysis can run into the thousands of dollars, which insurers won’t reimburse if the test-taker is healthy. Right now insurance companies are only required to cover such screens under certain criteria—like if a woman has a family history of breast cancer. Responsible physicians are reluctant to put their patients or their institutions on the hook for that bill.

Hegde says Helix’s infrastructure will allow them to offer the test at a greatly reduced rate when it actually launches on the platform a few months from now, though she couldn’t give an exact price tag. That includes whole exome sequencing on their Illumina machines (that’s the portion of the genome that codes for proteins), and the physician network that Helix has already built out to accommodate any products that might require a doctor’s signature. That’s right, to buy this test you’ll still need to talk to a doctor—just maybe not the one you’re used to seeing for your annual check-up.

Customers who want to buy PerkinElmer’s test have to fill out a brief questionnaire—some basic family history and reasons why you might want to take the test—which gets routed to a hire-a-doc third party. If there’s a chance they’re already presenting symptoms or have a family history suggesting a condition that would be covered by insurance, they’ll suggest that user go the traditional testing route through their primary physician. If they appear healthy, they get the all-clear to order the test.

Then Helix sequences all 22,000 coding regions of the customer’s genome and sends the file over to PerkinElmer for analysis, which takes about a week. If they find anything that requires further attention they’ll bring in some real humans to compare what they know about the customer with what they know about the variant—how it’s inherited, how it changes pathways in the body. It could take another week to spit out that report, which goes back to the physician network, which then contacts the customer with any variants that could require follow-up. Genetic counseling services also bundled through Helix’s platform will be available upon request.

“We’re really trying to focus on the 99 percent of people that have never had access to this kind of testing, but of course we want it to be responsible access,” says Helix co-founder James Lu. “It’s for people who are ostensibly healthy and want to stay that way for as long as possible.”

Access to those kinds of proactive customers are what drew Hegde to Helix. “Not a lot of people know about this kind of testing,” she says. “But for every one of the 59 genes on this list there are interventions, and earlier intervention translates to saving health care costs as well as lives.”

It’s true that on an individual level, knowing you have a bad BRCA mutation might lead you to more regular check-ups and an earlier diagnosis of breast or ovarian cancer. But on the question of whether or not widespread genetic testing will actually lead to better outcomes and cut costs? Researchers still aren’t so sure. And with only about 4,000 certified genetic counselors total in the US—or one for every 80,000 Americans—it’s hard for most medical professionals to justify widespread testing. But hey, if your doc won’t order up a test you want, we’re betting Helix can find you one who will.

More Consumer Genetics

Read more: https://www.wired.com/story/helix-takes-clinical-genetic-testing-straight-to-consumers/

Will Your Baby Like Cilantro? These Genetic Tests Say They Can Tell

You have instant communication, on-demand entertainment, and dial-up transportation—why should you have to wait nine months to see what kind of baby you’re going to have? Now there’s an app for that.

In a modern-day reboot of Lindsay Bluth’s “Mommy What Will I Look Like” business venture, Denver-based startup HumanCode has introduced BabyGlimpse. It’s a $259 test that uses DNA from each member of a couple to predict how their future child might look and act—from skin, hair, and eye color to preferred kinds of snacks. (With a variant of the SLC2A2 gene your kiddo might have more glucose receptors than average, and therefore a sweet tooth, so goes the scientific reasoning.) Fun, right?

“We’ve coined it sunshine science,” HumanCode co-founder Jennifer Lescallet told the Balitmore Sun last month. “You get to look at the fun part of your potential future baby versus some of the scary stuff.” The scary stuff being more traditional carrier screen genetic tests, which tell couples if they have any disease-related genes they could potentially pass on to their offspring. These are either ordered by a doctor based on family history, or are now increasingly available to buy directly, after an online or phone consultation with a physician.

BabyGlimpse is one of the latest examples of a growing direct-to-consumer genetic testing industry aimed at new, expecting, and aspiring parents. Some, like BabyGlimpse, rely on a combination of each partner’s DNA. Others, like Orig3n’s Child Development test, collect spit or cheek swabs from the new kiddos themselves, and then work with labs to sequence, analyze, and interpret that genetic information. The companies behind these tests say they’re mostly for entertainment, and for educating folks about how genetics work. But doctors and public health officials have concerns that they might, in fact, do the opposite.

“At this point in time, in 2018, consumers should approach these tests with caution,” says Muin Khoury, the director of the Office of Public Health Genomics at the Centers for Disease Control and Prevention. His five-person team tries to help people understand how to use genomics appropriately to improve public health. They currently designate direct-to-consumer tests with a “tier 3” classification, meaning that “there is no evidence for clinical validity or utility of such applications in healthy individuals.”

Khoury says personal genomic testing isn’t harming anyone, but it’s also not conferring any real health benefits. “And we still don’t understand very well the unintended consequences of labeling people,” he says. “Once you think you know certain information, it’ll affect how you think about your baby for life.”

Some things, like knowing about lactose intolerance and peanut allergies from an early age, could certainly make for happier and healthier outcomes. But what about traits like math ability, noise pattern and music learning, and bone strength, which Orig3n claims to be able to tell you something about? The fallout could be subtle, but insidious. Maybe you discourage your kid from playing sports because Orig3n told you she was among the 30 percent of the population with weaker than average bones. Or you don’t give them a hard time about their sub-par math scores. Instead of telling them they can be whatever they want to be, you tell them they can be whatever they want to be, within genetic constraints.

HumanCode

The company gives you percentages, which is as much certainty as the science will allow, but the reality of genetics in the wild is more complicated still. Humans are born with two copies of every gene; one from each parent. The two different versions of each gene combine and interact to make a totally unique genome. Some traits, like eye color, are controlled by only a handful of genes. Others, like height, are likely influenced by thousands. HumanCode and Orig3n use machine learning models trained on a mix of publicly available genomes and proprietary data to come up with what’s called polygenic risk scores for each trait. Basically, a predicted likelihood that your kid will be taller than six feet, say, or be bad at math.

But the thing about these kinds of genes is that they’re not deterministic. (Unlike genetic diseases such as cystic fibrosis, which are clearly linked to changes in a single gene.) What you eat, where you live, what kind of an education you get—all of these things have as much, if not more, of an impact than your DNA. That’s not to say there isn’t strong evidence that certain genetic variants are associated with specific traits. But genes alone can’t predict how tall you’ll grow or how good you’ll be at long division.

Non-geneticists tend not to think too hard about these distinctions. “I think consumers are going to have to learn to differentiate between products that are scientifically rigorous and truly health-related and products that are the genetic equivalent of skin cream for wrinkles, and that’s a big lift,” says Robert Green, who studies direct-to-consumer genetic testing at Brigham and Women’s Hospital. “Genetics is novel and poorly understood and we haven’t yet immunized ourselves against these exaggerated claims. These companies are using our respect for the science of genetics to do an end-run around common sense.”

There may be a day in the future where common sense (and science) dictate that every infant get their genes sequenced upon birth. But until then, maybe save your money and get to know your baby the old-fashioned way, with time.

Read more: https://www.wired.com/story/will-your-baby-like-cilantro-these-genetic-tests-say-they-can-tell/

Cancer Diagnosis from a Blood Draw? Liquid Biopsies Are Still a Dream

Nick Papadopoulos tracks down tumors for a living. Not with X-rays or CT scans, but with DNA. The oncologist and director of translational genetics at the Johns Hopkins Kimmel Cancer Center has spent decades uncovering the unique sets of mutations that define cancers—the kind of genetic signals that not only drive tumor formation and metastasis, but distinguish one cancer from another. And now, he’s working to develop a test that could sniff out those signals before a patient starts to get sick.

It’s the kind of test that Papadopoulos thinks could have saved his uncle’s life, had it been around a few years ago. “He had no symptoms until a cough showed up,” he says. But when it didn’t go away he went in for an X-ray, and there on the radiograph were the lesions. Dozens of them, filling his entire chest cavity. The doctors sequenced the tumors, and got him signed up for a clinical trial for a new, targeted drug. It worked for a few of them, shrinking them back to almost nothing. But the rest developed resistance.

“He was supposed to only live two months, and the drugs prolonged his life by a year. But that year wasn’t good.” says Papadopoulos. “I think it’s time to start thinking more about detecting cancers early and less about treating them when they are late.”

On Thursday, Papadopoulos’ research group at Hopkins revealed a novel blood test based on the combined analysis of DNA and proteins that correctly detected eight kinds of the most common cancers with a range of accuracies—from 98 percent for ovarian cancers to less than 40 percent for breast cancers. Published in Science, the test is just one among many so-called “liquid biopsies” in development; noninvasive tests that classify cancers by identifying the tiny bits of DNA that tumors shed into the bloodstream.

Most published studies, including this one, focus on measuring and monitoring advanced tumor stages. A few liquid biopsies have even been approved to help match tumors to targeted drugs. But the dream is to develop a simple blood test to actually diagnose solid tumors in healthy-looking people. The scarcity of circulating cancer biomarkers (both in quality and quantity; tumor DNA makes up less than 0.1 percent of blood) has held those aspirations back for decades. But now, sensitive assays and computational platforms are driving the discovery of biomarkers and better ways to measure them, luring a pack of well-financed startups into the field.

In 2016, for example, the world’s largest sequencing company, San Diego-based Illumina, spun out a new company called Grail. Its mission is described as “detecting cancer early, when it can be cured.” This ambitious aim is supported by $1.2 billion of venture capital Grail raised last year, which it intends to put toward financing massive, population-based clinical studies and optimizing its sensitive sequencing technologies.

Grail has yet to publish any actual data (its website does advertise a commentary published in Cell last year). And neither has its chief rival in the Valley, a machine learning startup called Freenome. That three-year old company snagged a $65 million Series A last March, led by Andreessen Horowitz. Freenome isn’t limiting itself to the genetic breadcrumbs left by tumor cells—it looks to capture other disease signatures in the blood, like how the immune system changes in response to tumor microenvironments.

Of course, Freenome has offered scant details on how exactly that kind of test would work. “You show your cards at the end, not while you’re playing poker,” says Andreessen partner Vijay Pande, who heads the investment firm’s biofunds. “Publications indicate that you’re not interested in building a company.” That said, he does expect Freenome to publish in a peer-reviewed journal ahead of its first foray into the market.

When that could be, though, is anyone’s guess. To evaluate any of these blood screens, thousands of patients will have to get tested—and then researchers will have to wait for some of them to actually get cancer. That’s the only way to determine not only their predictive power, but also whether they lead to improved patient outcomes. The noninvasive screening tests available today—mammography for breast cancer, a protein-measuring test for prostate cancer—are rife with their own issues. Incorrect diagnoses waste time and money on treatments and burden patients with unnecessary anxiety.

Liquid biopsy is likely to be beset by the same kinds of controversy, says Geoff Oxnard, a thoracic oncologist at the Dana-Farber Cancer Institute and a professor at Harvard Medical School. He routinely uses a single-gene liquid biopsy developed at Dana Farber to figure out which drugs represent the best options for his lung cancer patients. But will early detection versions one day be part of routine doctor’s visits? “No. I think these tests will help us better understand the risks for patients who already have a history of cancer in their family or who’ve already had something show up on a scan,” he says. “But I don’t think we have the kind of data we need to support liquid biopsy as a panacea for diagnosing cancer. At the end of the day, it’s still just a shortcut.”

Still, Oxnard pointed out that Papadopoulos’s test represents an important step forward. One, it starts to identify where a tumor might be located. That’s been a big limitation of liquid biopsies; OK, you’ve found cancer, but what do you do next? Where do you look for the tumor? Most mutations don’t tell you anything about location. But by layering in measurements for 31 additional proteins to their machine learning model, the Hopkins team was able, on the first try, to correctly identify the tissue of origin around 80 percent of the time colorectal cancers, pancreatic, and ovarian cancers.

The other advance is cost. Papadopoulos estimates the test could be commercialized for around $500, and cancer-spotting approaches that rely on ultra-deep sequencing could stretch costs for existing screening tests, which only look for a single gene. “This is great for the field and provides promise that these analyses will become a reality in the clinic,” says Victor Velculescu, an oncologist and colleague of Papadopoulos’ at Johns Hopkins, who has also developed liquid biopsy technologies, though he was not involved in the Science study.

The two have developed a sort of friendly turf war as they’ve turned Baltimore into its own little liquid biopsy hub. Both researchers have recently spun off diagnostics companies to further develop their own early detection technology platforms. Earlier this month, Velculescu’s venture, Personal Genome Diagnostics, hauled in a $75 million Series B led by pharma giant Bristol-Myers Squibb. That brings its total financing to $99 million, putting it on par with some of its better-known counterparts in the Valley, adding some bicoastal intrigue to the race to the market. Whatever the outcome, it’s patients who will ultimately be the winners.

“If it can even catch 50 percent of cancers that right now we have no way of screening for, that’s still 50 percent of patients who can now be treated in Stage 1, when they still have a chance,” says Papadopoulos. “It doesn’t have to be perfect to still save a lot of lives.”

Read more: https://www.wired.com/story/cancer-diagnosis-from-a-blood-draw-liquid-biopsies-are-still-a-dream/

How Americas Diet Culture Hinders Those With Eating Disorders

The inevitable January advertising of New Year, New You has arrived, and with it, the societal pressure to drop weight.

For some, this can be motivating, even goodafter all, Americas obesity rate is at a record high, according to research from the Centers for Disease Control and Prevention. But for many, the pressure to lose weight can be quite triggering, especially for those predisposed to developing eating disorders.

Longstanding research has shown that eating disorders can be hereditary, meaning some people are simply more likely to develop them than others. But new research from the Eating Recovery Center shows there might be a more specific genetic link than previously thought.

The risk of developing an eating disorder is largely inherited, meaning that people with a family history of eating disorders are more likely to have one, but the identity of which genetic variation increases that risk is unknown, Michael Lutter, who works as an attending psychiatrist for the Eating Recovery Center, told The Daily Beast.

Lutter researches the genetic and neurobiologic basis of eating disorders; his goal is to find a very specific genomic mutation that could cause eating disorders. While the genomic mutation hes looking for most likely affects a very small amount of people, it could be a game changer for treating eating disorders.

Lutter compared his search for this gene to that of breast cancers BRCA1 and 2 mutations.

Individuals with those mutations have a much higher risk of breast cancer, but only three percent of breast cancers are caused by these mutations, according to the CDC.

Similarly, we are trying to find something similar in the eating disorder population. If we can find the rare mutation, then it gives a better understanding of the underlying neurobiology of eating disorders, he said.

Lutters latest research sequenced the genes of 93 unrelated people with eating disorders, some who restrict their food and some who binge eat. Its pretty uncommon for an eating disorder patient to struggle exclusively with anorexia, bulimia or binge eating disorder, as people will cross over disordered eating behaviors in their lifetime, Lutter said, so the two groups of patients that were tested was a fair sample for this study.

He found specific links in two different genetic variations. For restrictive eaters, the variant is called neurotensin, which works in the brain to regulate appetite and tells your body it needs more food. For binge eaters, its called glucagon-like peptide 1, a hormone released by the gastrointestinal system after meals to tell you when youre full.

These results dont surprise Lutterhe says the fact that people with eating disorders would have genetic mutations for genes involved in appetite and fullness makes sensebut they had never been seen before. Still, the findings are in their preliminary stages; they cant be applied in a clinical setting yet.

Right now theres no way to use genetics to guide treatment but it does offer a better understanding of the pathophysiology of the illness that we can do these studies and measure levels of these hormones, Lutter said. He thinks that were close to developing treatment for eating disorders based on genetics in the next 10 or 20 years.

Lutter said that whats exciting is that there are drugs on the market that could target the hormones in the genetic variations his research found. For example, some diabetes medications might be able to restrict ones urge to binge eat. There are good drug targets so there are a lot of new potential leads for researchers to develop new treatments, he noted.

Until then, however, the New Years resolution madness can be quite challenging.

Lauren Muhlheim, Psy.D., a clinical psychologist for Eating Disorder Therapy LA, says that while this genetic research is important, its also relevant to know that there is no one single cause of someones eating disorder.

They are very complicated illnesses that dont stem from a single cause but from a complex interaction of biological, psychological and environmental factors. And I dont think you can ever tease it apart, she said.

Those environmental factors? The huge focus around losing weight or becoming a better version of yourself for the New Year.

Even though research shows that 80 percent of New Years resolutions (the top two being exercising more and eating healthier) fail, its easy to buy in to the idea that you need to lose weight, specifically at a time when were bombarded with messages that target body insecurities.

I cant remember who said it, but someone once said that the diet industry is brilliant because its the one product that repeatedly fails and makes you believe that its your fault, Muhlheim said. People are very susceptible to the newest fad diet, so I think its a very challenging time of year to people who are susceptible to eating disorders, especially with social media. Were getting more bombarded than we have in the past.

How do you know if youre susceptible to eating disorders? As its a very complex disease, its impossible to pinpoint this, but Tom Hildebrandt, Chief of the Division of Eating & Weight Disorders at Mount Sinai Health System, told The Daily Beast that some things to take note of are whether or not youre in an environment where restriction and dieting is valued in a critical way, are extremely stressed or are going through a big transition in your lifewhether thats high school to college, college to adulthood, becoming a parent, or even going through menopause.

The thing about this time of year is really not to get caught up in the swarm of information that comes from peers, social media and advertisers trying to sell you fixes to it, Hildebrandt said. Try to insulate yourself against that stuff.

This, of course, is easier said than done. Muhlheim suggested curating a healthy, body-positive feed on your social media channels and consuming culture that steers away from harmful messaging. Muhlheim recommended following the hashtag #haes, or healthy at every size, and #intuitiveeatinga quick search yields registered dietitians like Claudia T. Felty and Alissa Rumsey, whose feeds are all about having a healthy relationship foodor downloading podcasts like Love, Food.

That said, eating disorders are dangerous. If you or someone you know is struggling, its important to get an evaluation by a physician or a therapist, Muhlheim said, referring those who may be binging or purging, is preoccupied by obsessive thoughts about food, is having trouble functioning normally, or is skipping social events to contact the National Eating Disorders Association Helpline or the Eating Recovery Center.

Read more: https://www.thedailybeast.com/how-americas-diet-culture-hinders-those-with-eating-disorders

Warnings over shock dementia revelations from ancestry DNA tests

Companies have been told to accept moral responsibility and provide counselling for people who inadvertently discover health risks

People who use genetic tests to trace their ancestry only to discover that they are at risk of succumbing to an incurable illness are being left to suffer serious psychological problems. Dementia researchers say the problem is particularly acute for those found to be at risk of Alzheimers disease, which has no cure or effective treatment. Yet these people are stumbling upon their status inadvertently after trying to find their Viking, Asian or ancient Greek roots.

These tests have the potential to cause great distress, said Anna Middleton, head of society and ethics research at the Wellcome Genome Campus in Cambridge. Companies should make counselling available, before and after people take tests. The issue is raised in a paper by Middleton and others in the journal Future Medicine.

A similar warning was sounded by Louise Walker, research officer at the Alzheimers Society. Everyone has a right to know about their risk if they want to, but these companies have a moral responsibility to make sure people understand the meaning and consequences of this information. Anyone considering getting genetic test results should do so with their eyes open.

Alzheimers is linked to the build-up in the brain of clumps of a protein called amyloid. This triggers severe memory loss, confusion and disorientation. One gene, known as ApoE, affects this process and exists in three variants: E2, E3 and E4. Those possessing the last of these face an increased chance of getting the disease in late life.

About 3% of the population has two copies of the E4 variant one inherited from each parent, Professor John Hardy, of University College London, said. They have about an 80% chance of getting Alzheimers by the age of 80. The average person has a 10% risk.

The link with ApoE was made in 1996 and Hardy recalled the reaction in his laboratory. We went around testing ourselves to see which variant we possessed. I found I have two low-risk E3 versions on my genome. But if I had found two E4 versions? By now, having reached my 60s, I would be facing the prospect that I had a serious chance of getting Alzheimers disease in 10 years. I would be pretty fed up.

The ability to find a persons ApoE status has become even easier as a result of the development of genetic tests that provide information about a persons ancestry, health risks and general traits. Dozens of companies offer such services and adverts portray happy individuals learning about their roots 43% African or 51% Middle Eastern often to the sound of Julie Andrews singing Getting to Know You or a similarly happy-sounding track. All you have to do is provide a sample of spittle.

The resulting information about predilections to disease is not stressed but it is given. Kelly Boughtflower, from London, took a gene test with the company 23andMe because she wanted to prove her mothers family came from Spain. The results provided no evidence of her Iberian roots but revealed she carried one E4 version of the ApoE gene, which increases her chances of getting Alzheimers, though not as drastically as a double dose.

I didnt think about it at the time, said Boughtflower. Then, when I took up work as an Alzheimers Society support worker, I learned about ApoE4 and the information has come to sit very heavily with me. Did I inherit the ApoE4 from my mother? Is she going to get Alzheimers very soon? Have I passed it on to my daughter? I have tried to get counselling on the NHS but that is not available for a person in my particular predicament, I was told.

Other examples appear on the ApoE4 Info site, a forum for those whose gene tests show an Alzheimers susceptibility. Have stumbled upon my 4/4 ApoE status. Im still in shock, writes one. Another states: I got paid a $50 Amazon gift-card to take part in a genetic study. I was naive and unprepared.

There is no drug or treatment for Alzheimers and although doctors advise that having a healthy lifestyle will help, the baseline risk for E4 carriers remains high. That is a real problem, said Middleton. Genetic test companies say they offer advice about counselling but that usually turns out to be a YouTube video outlining your risks. Affected people needed one-to-one counselling.

For their part, gene test companies say results about Alzheimers and other such as breast cancer and Parkinsons are often hidden behind electronic locks. A person has to answer several questions to show they really want to open these and is informed of potential risks. But Middleton dismissed these precautions. You know there is medical information about you online and so you will go and find it. It is human nature.

Margaret McCartney, a GP and author of The Patient Paradox, agreed. What worries me is the aggressive way these tests are marketed. People are told all the benefits but there is no mention of the downsides. The NHS is expected to mop these up.

Meanwhile, the gene test company has made its profit and walks away from the mess they have created. I think that is immoral. They should be made to pay for counselling for their customers.

Read more: https://www.theguardian.com/science/2017/aug/26/alzheimers-disease-shock-for-genetic-ancestry-hunters

Deadly gene mutations removed from human embryos in landmark study

Groundbreaking project corrects faulty DNA linked to fatal heart condition and raises hopes for parents who risk passing on genetic diseases

Scientists have modified human embryos to remove genetic mutations that cause heart failure in otherwise healthy young people in a landmark demonstration of the controversial procedure.

It is the first time that human embryos have had their genomes edited outside China, where researchers have performed a handful of small studies to see whether the approach could prevent inherited diseases from being passed on from one generation to the next.

Crispr atom

While none of the research so far has created babies from modified embryos, a move that would be illegal in many countries, the work represents a milestone in scientists efforts to master the technique and brings the prospect of human clinical trials one step closer.

The work focused on an inherited form of heart disease, but scientists believe the same approach could work for other conditions caused by single gene mutations, such as cystic fibrosis and certain kinds of breast cancer.

This embryo gene correction method, if proven safe, can potentially be used to prevent transmission of genetic disease to future generations, said Paula Amato, a fertility specialist involved in the US-Korean study at Oregon Health and Science University.

The scientists used a powerful gene editing tool called Crispr-Cas9 to fix mutations in embryos made with the sperm of a man who inherited a heart condition known as hypertrophic cardiomyopathy, or HCM. The disease, which leads to a thickening of the hearts muscular wall, affects one in 500 people and is a common cause of sudden cardiac arrest in young people.

Humans have two copies of every gene, but some diseases are caused by a mutation in only one of the copies. For the study, the scientists recruited a man who carried a single mutant copy of a gene called MYBPC3 which causes HCM.

This
This sequence of images shows the development of embryos after injection of a gene-correcting enzyme and sperm from a donor with a genetic mutation known to cause hypertrophic cardiomyopathy. Photograph: (OHSU)/OHSY

When the scientists made embryos with the mans sperm and healthy eggs from donors, they found that, as expected, about half of the embryos carried the mutant gene. If the affected embryos were implanted into women and carried to term, the resulting children would inherit the heart condition.

Writing in the journal Nature, the researchers describe how gene editing dramatically reduced the number of embryos that carried the dangerous mutation. When performed early enough, at the same time as fertilisation, 42 out of 58 embryos, or 72%, were found to be free of the disease-causing mutation.

The work has impressed other scientists in the field because in previous experiments, gene editing has worked only partially, mending harmful mutations in some cells, but not others. Another problem happens when the wrong genes are modified by mistake, but in the latest work the scientists found no evidence of these so-called off target effects

Theyve got remarkably good results, its a big advance. said Richard Hynes, a geneticist at MIT who this year co-chaired a major report on human genome editing for the US National Academy of Sciences (NAS). This brings it closer to clinic, but theres still a lot of work to do.

Today, people who carry certain genetic diseases can opt for IVF and have their embryos screened for harmful mutations. The procedure can only help if there is a chance that some embryos will be healthy. According to Shoukhrat Mitalipov, who led the latest research, gene editing could bolster the number of healthy embryos available for doctors to implant.

More work is needed to prove that gene editing would be safe to do in people, but even if it seems safe, scientists face major regulatory hurdles before clinical trials could start. In the US, Congress has barred the Food and Drug Administration from even considering human trials with edited embryos, while in the UK it is illegal to implant genetically modified embryos in women. The procedure is controversial because genetic modifications made to an embryo affect not only the child it becomes but future generations too. Its still a long road ahead, said Mitalipov. Its unclear when wed be allowed to move on.

In the latest study, the mutation was corrected by a route that scientists have not seen before, with the cell copying healthy DNA from the mothers egg instead of the template. One question scientists need to explore now is whether mutations carried by eggs can be corrected as easily as those carried by sperm.

If all of this holds up for different genes and is also true when the mutation is inherited from the mother, it will be a major step forward, said Janet Rossant, senior scientist and chief of research emeritus at the Hospital for Sick Children in Toronto.

Asked about the potential for gene editing to produce designer babies, Rossant, a co-author of the NAS report on gene editing, said it was a distant prospect. We are still a long way from serious consideration of using gene editing to enhance traits in babies, she said. We dont understand the genetic basis of many of the human traits that might be targets for enhancement. Even if we did, a genetic alteration that enhanced one trait could have unexpected negative consequences on other traits, and this would be an inherited feature for the next generation.

The NAS report came out strongly against any form of gene editing designed to simply enhance human potential, she added.

Read more: https://www.theguardian.com/science/2017/aug/02/deadly-gene-mutations-removed-from-human-embryos-in-landmark-study

We are all mutants now: the trouble with genetic testing

The long read: With so many unknowns in our DNA, using genetics in medical testing doesnt always bring the answers sometimes it brings only doubt

AnneMarie Ciccarella, a fast-talking 57-year-old brunette with more than a hint of a New York accent, thought she knew a lot about breast cancer. Her mother was diagnosed with the disease in 1987, and several other female relatives also developed it. When doctors found a suspicious lump in one of her breasts that turned out to be cancer, she immediately sought out testing to look for mutations in the two BRCA genes, which between them account for around 20% of families with a strong history of breast cancer.

Ciccarella assumed her results would be positive. They werent. Instead, they identified only whats known as a variant of unknown or uncertain significance (VUS) in both BRCA1 and BRCA2. Unlike pathogenic mutations that are known to cause disease, or benign ones that dont, these genetic variations just arent understood enough to know if they are involved or not.

I thought you could have a mutated gene or not, and with all the cancer in my family, I believed I would carry a mutation. I didnt know there was this huge third category, she says. I got no information it felt like a huge waste of blood to get a giant question mark.

Thousands of people have had their BRCA genes tested for increased genetic susceptibility to breast, ovarian, prostate and other cancers. About 5% have learned that they carry a VUS. That number is even higher for other genes: in one study, almost 20% of genetic tests returned a VUS result.

Thats a lot of uncertainty, says Robert Klitzman, a bioethicist at Columbia University in New York. People want genetic tests to be like pregnancy tests, he explains: Youre either pregnant or youre not. Instead, theyre more like a weather report. And most people arent prepared to cope with the probabilities and uncertainties that entails.

When scientists surveyed a group of women one year after they received BRCA gene test results, the women whose results were uncertain or uninformative were feeling much more stress and anxiety than those whose results were clearly either pathogenic or benign. A follow-up study showed that the higher the risk an individual thought her result indicated, and the less tolerant she was of uncertainty, the more likely she was to experience serious long-term distress.

Even before her sequencing results came in, Ciccarella had decided on a bilateral mastectomy, based on her family history. For her, the question of whether she would one day develop breast cancer had been answered, and in the worst possible way. But she still wanted information for her son and daughter so they could know if they had inherited a genetic risk of cancer. Like a number of families, they are learning that genetic sequencing wont deliver answers for everyone.

We are all mutants. The 3bn pieces of DNA that make us who we are were long thought to be constant, chiselled in granite like a classical monument, with only tiny changes made here and there. Scientists used to believe that DNA mutations were largely harmful.

By the late 1990s and early 2000s, as the first sequences of the human genome came rolling in, researchers realised that their view of mutations was completely backwards. Instead of being rarities that almost inevitably harm health, mutations litter the human genome. The average human carries around 400 unique mutations, and most of us are none the worse because of them.

This challenged some basic tenets of genetics, as well as they ways that scientists and physicians interpreted genetic tests.


When Robert Resta, a genetic counsellorat the Swedish Medical Center in Seattle, first began examining genetic test results in the late 1980s, he could identify only chromosomal abnormalities or alterations of massive amounts of DNA. When other types of genetic tests were introduced, such as those for detecting the mutations in the CFTR gene that cause cystic fibrosis, interpretation was still reasonably straightforward. Because most of the people who had their CFTR gene sequenced showed clinical signs of cystic fibrosis, Resta could be reasonably confident that an observed mutation in that gene was the one that had led to the disease. In the past few years, however, the price of genetic sequencing has fallen dramatically, and doctors are increasingly requesting DNA testing earlier in the diagnostic process. As more data is gathered, the sheer number of mutations we all carry becomes more significant.

It turns out mutations are the norm. You expect to find mutations in a gene. Its a very different way of thinking about the human genome. If you dont find a mutation, your machine is probably having technical difficulty, Resta says.

When scientists test for mutations in large numbers of genes with a single test, known as a gene panel, they are virtually guaranteed to find at least one VUS, says Colleen Caleshu, a genetic counsellor at Stanford Universitys Center for Inherited Cardiovascular Disease. The more genes you look at, the more variation youll find, she adds. We all have tons of variations in our genes, most of which are extremely rare and, by the very nature of rarity, uninterpretable. In short, there isnt enough data to know what you are seeing.

Photograph
Photograph by Catherine Losing/Hattie Newman

This grey area has only expanded as next-generation DNA sequencing has led to the growing use of gene panels to look for mutations in a range of genes that may be related to a patients symptoms. Of the three possible results pathogenic, benign or unknown pathogenic is the least common, says Resta. Youre much more likely to get uncertainty.

If interpreting genetic testing results is difficult for clinicians, its also tremendously hard for patients. Yvonne Bombard has spent the last several years of her career as a genomics health services researcher at St Michaels hospital in Toronto, working to understand how families make sense of genetic testing results.

Theres very little research on the impact of uncertain results on families yet the technology is just too new, Bombard says.

A small study in Psycho-Oncology surveyed 24 women with breast or ovarian cancer who had received VUS results for their genetic testing. Many of them had a distorted perception of what those results meant. Although two-thirds correctly remembered three years later that the variants detected by the test were unclassified, 79% interpreted the results as a higher genetic risk for developing cancer. One-third had also made significant medical changes in their lives based only on their test results, which Resta and Caleshu do not recommend.

Families of children with suspected genetic diseases have similar difficulties. Parents tend to interpret any variant not classified benign as being the cause of their childs disease, explains Caleshu. But she appreciates that its hard not to do that, especially when families have been looking for answers for so long.

Families can feel let down by the medical establishment, who often seem to throw up their hands when a patient defies diagnosis, and in the absence of definitive answers it is all too easy to believe that the genetic variants identified on the test must be whats wrong. One of Caleshus main jobs is providing pre-test counselling so that patients understand the risks and the limitations of testing. She says her team have changed the way they present results, so that patients and doctors dont read too much into a VUS. Even with the right genetic counselling, however, uncertainty can be agonising.


Ciccarella had watched her motherendure chemotherapy, and had undergone a similar gruelling regimen herself. If she could get genetic information that might help her children and any future generations to avoid that agony by using improved screening, reproductive planning and prophylactic mastectomies, then she was determined to make that happen.

She decided to get another lab to review the results of her genetic tests, and requested the data from the sequencing company, Myriad Genetics. They refused. Since they owned patents on the two BRCA genes, no one else could have their proprietary genetic data.

So she followed with interest a lawsuit by the American Civil Liberties Union (ACLU) against Myriads genetic patent, hoping that if the ACLU won, she could get a second opinion on her unclassified variants after all. In 2013, the US supreme court found in favour of the ACLU, invalidating Myriads patents. Myriad still refused to release raw sequencing data, however, saying that doing so would violate the 1996 Health Insurance Portability and Accountability Act (Hipaa).

Ciccarella teamed up with the ACLU and three other people who wanted access to their full sequencing data and prepared to file a suit against Myriad in 2016, arguing that Hipaa actually guarantees patients the right to their own data. On 18 May, one day before the suit was due to be filed, Myriad reversed their stance and released the sequencing data to Ciccarella and the others. She found that Myriad had reclassified one of her VUSs as benign, but when she checked this against public databases of genetic variants, she found that no one else had changed this classification.

So whos right? There are two different opinions thats exactly the problem. One place says one thing, one place says another, and Im stuck in the middle with a daughter who just found a suspicious lump, Ciccarella says.

Ciccarellas case was settled out of court, but another case is showing that the battles over genetic testing uncertainty are just beginning. In February 2016, Amy Williams filed a lawsuit against Athena Diagnostics, ADI Holdings and Quest Diagnostics (Athenas parent company) relating to the death of her son, Christian.

Christian was born a seemingly healthy blond-haired, blue-eyed cherub on 23 August 2005. Just before Christmas that year, he had his first massive seizure. Many more followed. Despite countless medications and tests, no one could figure out what was causing his unrelenting seizures. He had a massive battery of tests in early 2007, including the sequencing of a gene called SCN1A. Athena, which performed the genetic tests, reported that he had a VUS. With no clear genetic answers, his doctors treated him for an undiagnosed mitochondrial disorder, although his treatments had minimal effects on his continuing seizures.

On 5 January 2008, Christian went to bed after celebrating a belated Christmas holiday with his family. Videos taken that day gave no hint that he would be dead by morning. The official cause of death was listed as a seizure.

Six years later, thinking of starting a family again, Williams wanted to get her own DNA sequenced in order to learn whether the disease that had affected her son could affect any future children. Again, she turned to Athena, but as well as her own results, she also requested Christians 2007 lab report. She saw from the revised report they provided that Athena had reclassified Christians VUS as a disease-associated mutation, which suggested he had a form of childhood epilepsy called Dravet syndrome (also known as severe myoclonic epilepsy in infancy). Several of the medications used to treat seizures in young children, including Christian, are toxic to children with Dravet and can increase the risk of death.

Williams believes this means the treatment Christian received was only making things worse. What she now wanted to know from Athena was when and why they reclassified the variant. As Williams, a former special education teacher, taught herself the nuances of scientific literature, she found out that the same SCN1A mutation Christian carried had been identified in an Australian family in 2006, before Christians DNA was tested. Even more concerning was a patent document on the SCN1A gene that listed this mutation (a change in a single amino acid in the gene) as pathogenic. When Athena refused to answer, Williams sued.

Her allegations include that Athena had had enough information to reclassify Christians mutation before he was tested, and that if they had done so, it would have changed his diagnosis and treatment such that his death from a seizure related to Dravet syndrome could have been avoided.

Athena and the other two companies reject these allegations, and argue that the case should be dismissed. They say that the 2007 lab report emphasised the inconclusiveness of the test results, that Dravet could have been the cause of Christians seizures without his medication being implicated, that further testing was strongly recommended (in particular, testing of his parents, which was offered at no additional charge but not taken up), and that a conclusive diagnosis could be reached only by additional testing. Quest, the parent company, declined to comment on this ongoing legal action, but the case has caused many in the genetic sequencing community to consider what changes may be required in the future.

This case reflects the uncertainties of modern genetic testing, and the tension that it can cause for patients and their families, and illustrates the increasing scrutiny of clinical genetic sequencing labs, how they share data on variants, and how this data is interpreted. Regulators, researchers, patients and the sequencing labs themselves will have to work together to find ways to improve these processes.


Tess Bigelow is a bubbly seven-year-old with light brown hair that curls forward into her face, framing a pair of bright pink glasses. A few months after Tess was born, in November 2009, her parents, Bo and Kate, noticed that something was wrong. She wasnt rolling over or meeting other developmental milestones. By June 2010, her parents realised that something was very wrong.

She was not interacting with other people. It was just like she was checked out. We knew she was in there, we just couldnt get to her, her father says.

As she got older, Tess didnt start to speak or communicate, and she continued to have problems walking and standing. A full diagnostic examination revealed nothing, so genetics experts in Boston, and in the Bigelows hometown of Portland, Maine, recommended sequencing all of her genes. The team were hopeful that this would turn up results, but they cautioned the Bigelows not to get their hopes up. Tesss sequencing revealed a mutation in a gene called USP7, but no one could say whether or not this was the cause of her illness.

No matter how much they tell you, you believe youre going to get an answer. Its hard to hear that this is where it ends, Bo Bigelow says.

He began learning everything he could about USP7. There wasnt much. Researchers were just starting to learn what the gene did, and he couldnt find any other families with a USP7 mutation. So he decided to see if he could make those other families come to him. In a public Facebook post he drafted late at night in August 2015, Bigelow described his daughters symptoms, along with her sequencing results. He crossed his fingers and clicked share.

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Photograph by Catherine Losing/Hattie Newman

The post went viral. One person shared it to Reddit, from where a graduate student brought it to the attention of Christian Schaaf, a geneticist at Baylor College of Medicine in Houston, Texas. He was working on USP7 and other genes that had been linked to genetic conditions such as Prader-Willi syndrome.

USP7 is part of our cells protein-recycling machinery, making sure that cells dump their garbage quickly enough to prevent the buildup of proteins that are damaged or no longer needed, but not so quickly that it removes healthy proteins. Suspecting that faults in USP7 could lead to disease, Schaaf had searched through Baylors own genetic sequencing databases and other genome data depositories, and found seven clinical cases of children who had mutations in USP7.

By the end of the day on which his post was shared on Facebook, Bigelow had received an email from Mike Fountain, one of Schaafs co-authors on the research paper about the USP7 mutations and their links to disease. On the phone the next morning, Fountain outlined the array of symptoms experienced by the seven other children, and they all sounded remarkably like Tess. It looked as if they had found the smoking gun, but only the results of more laboratory studies will show for sure whether or not this was the cause of Tesss condition.

Like many parents of children with rare diseases and special needs, Bigelow has come to live with the uncertainty. But he and other parents and patients have begun sharing their genetic data through portals such as MyGene2 to help others. Created by Michael Bamshad and Jessica Chong, MyGene2 lets people share their own sequencing results in the hope of facilitating research and finding other families with similar medical problems. Other initiatives are springing up, too, and researchers hope they will reduce the uncertainty that continues to plague genetic sequencing.

Heidi Rehm is a clinical medical geneticist at the Broad Institute in Cambridge, Massachusetts. She led teams at the US National Institutes for Health that created two databases helping to improve sharing and curation of genetic data. ClinVar, launched in 2012, links genetic variants with symptoms. ClinGen, introduced the following year, is described as building an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. Using these two resources, commercial and academic sequencing labs can combine their expertise to offer people the most accurate description of what their genetic variants mean.

The depositing of results from large sequencing studies, such as the Exome Aggregation Consortium at the Broad Institute, also promises to help reduce genetic uncertainty. Some of the earliest results of this initiative provided some of the largest reclassifications of VUS results yet, according to Rehm. Nearly all of those reclassifications were shifting a VUS to benign an indication of the sheer volume of normal variation and mutation inherent in all of our genetic blueprints.

At the Institute of Cancer Research in London, Nazneen Rahman is leading the Transforming Genetic Medicine Initiative to address many issues involved in bringing genetics into medicine. When it comes to managing uncertainty in genetic testing, she says we need to change the way we think about VUS and rare variants in general.

Although disease-causing variants are rare, most rare variants do not cause disease, she explains, in the same way that bananas are yellow but most yellow objects are not bananas. Instead of considering a genetic variant guilty unless proven innocent, we should consider all genetic variants innocent unless proven guilty. For example, women with a BRCA VUS should be managed in the same way as women with variants that are known to be innocent.

To get a better handle on all the variation in humans, scientists are going to need to sequence tens of millions of people. And the only way to ever get these kinds of large numbers is by sharing data. But regardless of how good the databases get, and how many people have their genomes sequenced, uncertainty will never completely go away.

Every time our cells divide and copy their DNA, mutations can arise. This uncertainty may be maddening for patients looking for answers, but its as much stamped into our genetic blueprint as the double helix itself.

Main photograph by Catherine Losing/Hattie Newman

This is an edited version of an article first published by Wellcome on mosaicscience.com. It is republished here under a Creative Commons licence

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Read more: https://www.theguardian.com/science/2017/jul/18/we-are-all-mutants-now-the-trouble-with-genetic-testing

A Patent Decision on Crispr Gene Editing Favors MIT

The fight over who owns the most promising technique for editing genes—cutting and pasting the stuff of life to cure disease and advance scientific knowledge—has been a rough one. A team on the West Coast, at UC Berkeley, filed patents on the method, Crispr-Cas9; a team on the East Coast, based at MIT and the Broad Institute, filed their own patents in 2014 after Berkeley’s, but got them granted first. The Berkeley group contended that this constituted “interference,” and that Berkeley deserved the patent.

At stake: millions, maybe billions of dollars in biotech money and licensing fees, the future of medicine, the future of bioscience. Not nothing. Who will benefit depends on who owns the patents.

On Wednesday, the US Patent Trial and Appeal Board kind of, sort of, almost began to answer that question. Berkeley will get the patent for using the system called Crispr-Cas9 in any living cell, from bacteria to blue whales. Broad/MIT gets the patent in eukaryotic cells, which is to say, plants and animals.

Its confusing. The patent that the Broad received is for the use of Crispr gene-editing technology in eukaryotic cells. The patent for the University of California is for all cells, saysJennifer Doudna, the UC geneticist and co-founder of Caribou Biosciences who co-invented Crispr, on a conference call. Her metaphor: They have a patent on green tennis balls; we have a patent for all tennis balls.

Observers didn’t quite buy that topspin. If Caribou is playing tennis, its looking like Broad/MIT is Serena Williams.

UC does not necessarily lose everything, but they’re no doubt spinning the story, saysRobert Cook-Deegan, an expert in genetic policy at Arizona State Universitys School for the Future of Innovation in Society. UC’s claims to eukaryotic uses of Crispr-Cas9 will not be granted in the form they sought. That’s a big deal, and UC was the big loser.

They have a patent on green tennis balls; we have a patent for all tennis balls.Jennifer Doudna, UC Berkeley

UC officials said Wednesday that they are studying the 51-page decision and considering whether to appeal. That leaves members of the biotechnology sector wondering who they will have to pay to use Crispr as part of a business—and scientists hoping the outcome wont somehow keep them from continuing their research.

Why It Matters Who Wins

Someone is going to make a lot of money licensing Crispr. And someone is going to make lot of money on therapies based on Crispr. Thats why, the day before the decision, the National Academy of Sciences released a long document laying out what kind of Crispr-based human therapies were kosher—so no one goes the full Gattaca.

In fact, the moneymaking part has already begun. Startups are getting funding based on Crispr-based business plans. Editas Medicine, which licenses the Broad patents to work on treatments for genetic disorders in human beings, had a 30 percent stock bump on word of the patent decision. It certainly caused some concerns, because depending on how the courts were going to rule on the two claims, if you went with one, you could lose, right? says Edison Liu, CEO of the Jackson Laboratory, a major source of genetically modified mice used in research. Jackson Labs has licenses from both sides, and since it aims at academic uses, gets better terms than a Silicon Valley biotech startup might.

But not everyone can make multiple deals. Its a bit frustrating that the patent office has done it this way, says Eric Rhodes, CEO of ERS Genomics, which licenses UCs Crispr technology to other companies for non-human therapeutic uses. A lot of people were hoping they would make a decision to go with one group or another.

Commercial outfits hoping to make new therapies will, for now, have to pay both institutions big fees. ERS Genomics, for example, charges from $10,000 to small start-ups to $1 million to large pharmaceutical firms. And an attenuated patent dispute could mean more red tape and lawyers on retainer for biotech scientists.

On the plus side, the patent fight doesnt look likely to slow basic research, or even research with an eye toward commercialization. Neither UC nor Broad will charge academic scientists who want to use Crispr just to better understand plant diseases, lets say. I dont think it’s going to slow down therapeutic development, says Rhodes.

The same goes for people trying to use animal models like mice. Thats good, because the models and the technique are ubiquitous. If youre creating a mouse model, you just have to use this. Its a little bit like, once internal combustion with a carbon source came out, nobody was spending a lot of money on the steam engine, you know? says Liu.

Two Biotech Institutions Enter; One Biotech Institution Leaves

The final outcome of this patent fight may be years away—especially if Berkeley appeals the decision. Its one battle in a larger war, says Jason Sherkow, a bioscience patent law expert at New York Law School. But its a very big, important battle.

There will be paperwork and cross-licensing that will have to be worked out before drugs are commercialized. Hopefully some of this patent situation will work itself out before then.Eric Rhodes, CEO, ERS Genomics

Thats because if a biotech company develops a megahit drug or treatment using Crispr, itmight now have to pay the Broad megabucks in fees. “There will be paperwork and cross-licensing that will have to be worked out before drugs are commercialized,” says Rhodes. “Hopefully some of this patent situation will work itself out before then.” Broad/MIT might even go Hollywood here, taking a small upfront fee in return for points off the gross revenue down the road. It does paint a dark and foggy picture for any of the companies that received licenses that originally came from Berkeley, says Sherkow.

Here’s where things get a little sketchy even for the most basic of basic researchers—because you never know, exactly, what youre going to come up with. If you are contemplating creating something that would be marketed in any way, Liu says, then it is actually the commercial end of it, the sale of the product, that will probably require a license.

This isn’t the first time universities and companies have fought over a lucrative invention that could further scientific research. Harvard fought for years for rights to the cancer-prone, genetically engineered oncomouse. Until the US Supreme Court took them away in 2013, Myriad Genetics held the rights to genes for breast cancer. In 1980, researchers at UC San Francisco and Stanford figured out how to make recombinant DNA in bacteria, and patented it. In that last case, university licensing offices negotiated ways to let people use the technology to do science and create businesses. But the time for that kind of sensible negotiation seems to have passed with Crispr. Its the only thing all parties really agree on: Too much is at stake.

Read more: https://www.wired.com/2017/02/patent-decision-crispr-gene-editing-favors-mit/

Genos Will Sequence Your GenesAnd Help You Sell Them to Science

Personal genetics is having a bit of a 1983 moment. Back then, the majority of Americans had never used a computer or heard the word internet. A year later, Apple launched the Mac and the rest, as they say, is history. Purveyors of personal genetics platforms—products that tell you exactly whats in your DNA—say they are at a similar tipping point. The only question is: Who will be the Apple of individualized genomics?

The latest contender is Genos, a genetic sequencing startup that is unveiling its whole exome-sequencing service today. The hot, shiny object of the industry, this type of next-generation sequencing offers a complete profile of all the expressed genes (the ones that code for proteins) in your genome. While a growing number of targeted genetic testing kits are currently on the market (Color, Myriad, and 23andMe, to name a few), whole exome sequencing produces 50 to 100 times more data.

Those extra nucleotides cost more, but at $499, Genos is still a steal over sequencing ordered up by physicians, which can run up to $2,000, and may or may not be covered by insurance. A Genos competitor, Helix, offers an ancestry discovery kit that sequences the whole exome for just $149 but doesn’t yet delve into health-related variants. Veritas will do your whole genome for the higher fee of $999. The idea is that all this extra information will land consumers deeper personal insights. Bigger net, more fish.

That all sounds great, in theory. But some doctors and geneticists caution that biologists’ ability to sequence DNA has far outpaced their ability to understand how those genes interact with each other and the environment to cause diseases like cancer, Alzheimers, and autism. Most of the 180,000 protein-coding bits of DNAin your body? Scientists dont know enough about them to be useful.

Most people ordering this testing are going to be underwhelmed by the results they get back, says Geoffrey Beek, a genetic counselor at Childrens Hospital of Minnesota. Its so unlikely to find something that changes the way we treat somebody. Doctors already say eat well, sleep well, and get regular exercise. Do you really need a genetic test to push you over the edge to do those things?

Probably not. But Genos is telling its customers to ask not what your data can do for you, but what your data can do for science. In a first for the personal genomics movement, the company is creating a research pipeline with academic and commercial partners, and paying customers to donate their data. The incentives range between $50 and $200 per project; the first four include a vaccine for breast cancer, a clinical trial for treating lymphoma, and research into prion diseases and common neurological disorders.

At some point people are going to develop a disease in some way, shape or form,” says Genos co-founder and CEO Mark Blumling. This is a way to feel directly empowered to contribute to research and make a change.

Crowdsourced Cures

Erik Vallabh Minikel is in a race against time. Five years ago, his wife Sonia Vallabh discovered that she carries a rare genetic mutation for a fatal prion disease, a gene she inherited from her mother who passed away from the affliction in 2010. Together, they dropped out of their careers and became full-time prion research scientists at the Broad Institute of MIT and Harvard, where they are working to find a cure before her prion proteins start folding up the wrong way, killing off the neurons in her brain in the process.

Large sets of genetic data have provided one promising approach. Last year, Minikel and Vallabh analyzed an exome database maintained by the Broad; out of 60,000 people, they found three with an interesting mutation. Compared to the one that Vallabh has, which will cause her prion protein to misfold, their mutation essentially deletes one copy of the gene. That makes them, at least theoretically, much less likely to develop a prion disease than the average person youd pluck off the street. Minikel and Vallabh want to find more people like this, and see if theyre healthy or not. If they confirm that the mutation has a protective effect, it could lead to drug and gene therapy strategies. Theres just one problem: The Broads database isnt designed to get health information on individuals.

But Genos is.

The genotype were interested in occurs in one in 20,000 people, so its already really hard to find, says Minikel. We need to also be able to go back and look at peoples health and ask questions. Genos is building a platform to allow people like us to do that. Genos customers who consent to sharing their data with Minikel and Vallabh will fill out health surveys that the pair can access whenever they need. Then, as the data rolls in, theyll be able to go back and line up phenotypes with genotypes to figure out which mutations have protective effects, and maybe, the key to a cure. While this treasure trove of data is only currently available to researchers in the four pilot projects, Genos plans to expand the platform in the next few years to create a robust research pipeline that customers can contribute to directly.

Sequence Now, Discover Forever

For Vallabh, the potential impact of the Genos platform is clear. But for the average user, the immediate benefits of whole exome sequencing are a bit murkier. While consumers will be able to see the full results of their exome sequencing—all the As, Ts, Gs and Cs—the interpretation of those results has a ways to go. Robert Green, who has been studying direct-to-consumer genetic testing for close to 15 years at Brigham and Womens Hospital, is an expert in how access to genetic data changes consumers behaviors and interactions with the healthcare system. And his studies show that genetic information isnt as provocative as some have hoped (or feared).

The fear is that patients will misunderstand or misuse genetic information in these early days, with so much uncertainty about how to interpret results. Remember that time the FDA ordered 23andMe to stop offering health reports with its genetic analysis kits?1 The company was marketing its tests as a way to test your risk for conditions like breast cancer and heart disease but couldn’t prove the tests worked. The feds deemed it an unapproved medical device and stepped in on behalf of patients. But Green’s data suggests that people aren’t as quick to freak out as you might think. The notion that people would have either catastrophic emotional reactions or misunderstand to the degree they would do dramatic things to harm their health, most of those have not been borne out by the research, says Green. But theres a real lag time between making discoveries and using those discoveries for a clear-cut clinical benefit.

One recent study showed that only 20 to 30 percent of direct-to-consumer genetic test takers thought enough of their results to share them with a physician. But he says its also important to remember that early adopters arent necessarily representative of the larger population. Theyre the information seekers, people curious about their health and technology. The reactions of the rest of society are hard to predict. When everyone has access to genetic information, will it send people off on wild goose chases, or will it really benefit peoples health? he asks. We dont know that yet.

Genos hopes to avoid any wild goose chases by providing customers with access to genetic counseling (for an additional fee of $150 per hour). Blumling says theyre not getting any compensation from the service, which is provided by an independent third party, and are doing it out of a responsibility to provide the necessary context for users. He stressed that they are not a diagnostic company, and more of a personal exploration tool. This is an important distinction from a regulatory standpoint; the FDA recently expanded its oversight of laboratory testing, specifically in regards to direct-to-consumer diagnostic tools.

And the company isnt bothered that the results may indeed be underwhelming now. Those results are set to change drastically, as more and better information connecting variants to genetic conditions comes online. Genos is betting that a one-time investment will yield more valuable insights down the road for its customers, beginning a lifetime of engagement and increasing returns.

But the biggest dividend, says George Church, decorated Harvard geneticist and Genos advisory board member, will come when it comes time to start a family. There are thousands of diseases for which were all at risk of being a carrier—thats a high stakes thing were not handling right now, he says. More limited panels catch the big ones, like Tay-Sachs, but leave out more rare but equally devastating disorders. If you do the whole exome you can eliminate almost all those diseases overnight.

But if you can afford to wait, you should. While the results of exome sequencing are static, the price tag isnt. And its only going down.

1UPDATE 6:45 pm Eastern 12/15/16: This story has been updated to correct the fact that in 2013 the FDA ordered 23andMe to stop marketing its genetic analysis kits. A previous version of the story stated that the FDA shut down 23andMe.

Read more: https://www.wired.com/2016/12/genos-will-sequence-genes-help-sell-science/

‘Angelina Jolie effect’ boosted genetic testing rates, study suggests

Actors call for women to seek testing for breast and ovarian cancer mutations raised screening rates but may not have reached those most at risk

Angelina Jolies revelation that she underwent a double mastectomy to reduce her chances of developing breast cancer boosted rates of genetic testing among women, but might have failed to reach those most at risk, new research suggests.

In a 2013 article for the New York Times, Jolie explained her decision to undergo a double mastectomy after finding that she had a mutation in a gene known as BRCA1 that greatly increased her risk of breast and ovarian cancers.

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I am writing about it now because I hope that other women can benefit from my experience, she wrote. Cancer is still a word that strikes fear into peoples hearts, producing a deep sense of powerlessness. But today it is possible to find out through a blood test whether you are highly susceptible to breast and ovarian cancer, and then take action. After surgery her risk of developing breast cancer in later life fell from 87% to 5%.

The actors decision to tell her story was welcomed by medical experts and campaigners worldwide. But did women heed Jolies call?

Writing in the British Medical Journal, Sunita Desai and Anupam Jena of Harvard Medical School describe how they sought to answer the question by scrutinising data on US health insurance claims from more than nine million women aged between 18 and 64 .

These revealed that in the 15 working days following Jolies article, daily rates of testing for harmful mutations in BRCA1 and BRCA2 genes rose by 64%, compared with the 15 working days before. After six months, average monthly testing rates were still 37% higher than in the four months before the articles publication.

But the study also reveals that while genetic testing rates increased, there was no change in average, overall mastectomy rates in the six months following the articles publication and showed a slight drop in mastectomy rates among those who had BRCA tests.

The fact that mastectomy rates dropped after Angelina Jolies editorial suggests that that denominator of women who started getting the BRCA test became less appropriate for the BRCA test because they had a lower pre-test probability of having the mutation in the first place, said Desai.

However, Douglas Easton, professor of genetic epidemiology at the University of Cambridge, noted that the study did not offer insights into the BRCA test results meaning it was not possible to say whether women taking the test received negative results, or whether they had tested positive, but decided not to undergo surgery.

But Jennifer Litton, associate professor in the department of breast medical oncology at the University of Texas, said the results reflected what had been seen in clinics.

The Jolie effect was real, and we did have many more breast cancer patients ask about the test, she said. As only a small proportion of breast cancer patients harbour an abnormal gene, those that met national guidelines for testing had already had testing, so it did not change that group with the highest risk of a positive test.

The research is not the first to explore the impact of Angelina Jolies declarations, although previous UK-based studies found that both testing among women at risk, and subsequent preventative surgery, increased.

A co-author of the UK-based research, Tony Howell, professor of medical oncology and director of scientific research at Prevent Breast Cancer, says the new US study looked at too short a period after publication of Jolies article to truly reflect its impact. It takes weeks or months to get through the testing process in proper centres, he said. Same applies to risk-reducing breast surgery. This takes one to three years to filter through to surgery if all the checks and counselling are performed properly.

Overall, says Howell, the 2013 article was valuable in raising awareness. Jolie did a terrific job, he said.


Read more: https://www.theguardian.com/science/2016/dec/14/angelina-jolie-effect-boosted-genetic-testing-rates-study-finds-breast-ovarian-cancer