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TOP TEN STORIES IN GENETICS, 2016: An Adolescent Science Meets the Big World

Clinical genetics is a young science, not yet come of age – a new discipline. It’s early days, say the small group of clinicians and researchers who have watched over its formative years, dreaming like proud parents of a future where genetics and genomics are integral to clinical medicine. And as for many parents, it may sometimes have seemed that the all-consuming, semi-hermetic little laboratory of childhood would go on forever.

But guess what, people? I believe we have entered the teenage years.  I believe baby has borrowed the car keys and taken it out for a spin.  I see a field boasting a few real accomplishments, and on the cusp of so many changes, from therapies for genetic disease and cancer to a suddenly burgeoning DTC marketplace. And like all parents, geneticists are poised to discover the limits of our ability to control what we have nurtured. That’s exciting, more than a little bit scary, and the theme of this year’s top ten.

  1. FDA CANCELS PLANS TO REGULATE LDT’s

Over the past two decades, a single technological advancement has revolutionized the way we practice medicine.

I am talking, of course, about overnight delivery of packages.

Years ago, laboratory testing services were divided into large companies that sold test kits and devices nationwide, and the small labs in hospitals and other clinical settings providing services to their local providers. With limited resources, government regulators focused on the tests that affected more people, and agreed by convention that ‘laboratory-developed tests’ would not be subject to the same scrutiny. Today these distinctions are virtually meaningless, as giant companies like LabCorp and Quest perform tests ‘in-house’ on samples gathered worldwide, tossed in a box and sent overnight. Still laboratory-developed tests (or LDT’s) – a category that includes virtually all genetic tests – remain in regulatory limbo.

In 2010, the FDA announced its intention to address this loophole. In July 2014, they issued draft guidance detailing their plan for a regulatory structure that divided the LDT universe into high, low and medium risk tests. While some professional organizations disputed the FDA’s right to have a role in regulation of LDT’s and threatened legal action, others approved the framework in principle but disagreed on specifics, including how to handle the thorny new territory of exome and genome sequencing. A dialogue ensued with representatives of labs, clinicians and patients that has lasted two years and included multiple workshops and public meetings. That process, it was widely assumed, was nearing its end, with the resulting draft guidance expected to be sent to Congress for approval in the near term.

And then came November 8th and the election of Donald J. Trump, ushering in an executive opposed to regulation on principle, to join a similarly inclined House and Senate. Ten days later, the FDA ran up the white flag, announcing that the agency would not take steps to finalize its existing plan and would instead reopen the discussion with a new administration and a new Congress. What this means precisely is a matter of some interesting speculation, but in general it suggests that an industry that has been struggling for years to avoid too much regulation will have to consider the consequences of living with none at all.

 

  1. IS THIS THE FUTURE? CRISPR EXPERIMENT ADDS RARE PROTECTIVE VARIANTS TO HUMAN EMBRYOS

The second experimental use of CRISPR technology to alter human embryos was reported in May of 2016, again by a group out of China. Again, the embryos used were not viable, and no attempt was made to transfer them for reproductive purposes. While this experiment did not produce the same ethical firestorm as the first, it was in several ways a more significant indicator of both the potential and the peril of human germline engineering using CRISPR.

In the first experiment investigators attempted to alter a gene variant responsible for causing hemoglobinopathy, with limited success – proof in principle that it could be done, but nothing to assure worried observers that it could be done safely. In version 2.0 there were fewer off target effects, but researchers were not able to consistently control the content of changes introduced in place of the edited DNA. This is not inconsistent with what we know so far about CRISPR: if we envision it as a word processing search-and-replace function, it is good at the finding and erasing part, but hit or miss when it comes to  putting in a replacement.

What stands out about the second experiment is that the goal was not to eliminate a disease-causing gene, but to insert a rare and protective one – in this case, the CCR5Δ32 allele that offers the bearer reduced susceptibility to AIDS. Gene editing is often envisioned as a way that individuals whose children are at risk can avoid or change genes that cause disease, but in the vast majority of these cases there are simpler and better established tools such as PGD if the goal is to obtain embryos that do not carry a specific variant associated with some catastrophic risk. Why use technology to substitute out a pathogenic BRCA variant or a double dose of the sickle cell genes when the parents are perfectly capable of producing a healthy embryo themselves? What CRISPR and related technologies can do that is not available through other means is to introduce a gene that neither parent carries. That is a powerful new option, and it is both exciting and scary in the manner of all things powerful and new.

 

8. GENETIC DISCRIMINATION MAKES A CAMEO

Many wise observers have noted that for all our deeply felt concerns about genetic discrimination, to date the examples are few, far between, and usually more clumsy than systemic (looking at you, Burlington Northern Santa Fe Railroad). These arguments, redux, were on display in 2016 as Canada debated and ultimately passed its own national genetic discrimination law. Yes, Globe and Mail Guy, there is little evidence of a big problem, and a look at law suits filed between 2010 and 2015 under GINA, America’s genetic discrimination law, proves the point. But one real unanswered question remains: is the absence of institutionalized discrimination a sign that it is destined to be a bit player in the big picture of genomics, or is it only too soon to tell? Big companies, whether they are offering insurance or providing employment, may not have had an incentive to weather a PR shitstorm in order to use genetic information to limit their exposure to risk when not that many people have been tested, and the reliability of the data is debatable – which it has been in these early days. Genetic discrimination, in other words, may be making an appearance in Act II.

Two stories got some attention in 2016; whether they are one off events or signs of the future – well, that’s crystal ball territory. Are they important? They are something to which we should be paying attention. Attention should be paid.

In January, Stephanie Lee at Buzzfeed published an account of a boy named Colman Chadam who was asked to leave his Palo Alto, CA school because he carried two mutations commonly associated with cystic fibrosis, although he did not have any signs or symptoms of the disease. The results of genetic testing, inappropriately revealed by a teacher at the school, were taken, also inappropriately, as diagnostic. The reason this got him thrown out of school was to avoid contact with another student who did have CF. The emphasis on keeping children with CF apart, which sounds weird if you don’t know much about the disease, was about the only appropriate thing that happened, because individuals with CF are at risk of passing one another dangerous and life-limiting infections.

Although Colman did not have to leave the school, and the Chadam’s lawsuit against the school district has settled, the case continues to raise issues about how genotype as distinct from phenotype can be used under the law. In addition, it may signal the need for measures to protect personal privacy (no such thing, I know, I know) in an age when genetic testing is commonplace.

Three weeks later, Christina Farr wrote an article for Fast Company about a woman who was turned down for life insurance because she had a risk-conferring BRCA1 variant. Unlike the Chadam case, this is not a result of genetic illiteracy, and it is not a violation of any law: GINA does not cover insurance for life or long-term care. It is, in fact, exactly the kind of genetic discrimination that ethicists and patients thinking about genetic testing have worried about over the years, and if systemic, would certainly be an important point for genetic counselors to raise in pretest counseling (if pretest counseling is still something we do, which is an issue unto itself…but related). According to the article, genetic testing for cancer susceptibility is not required by any insurance company, although nothing stops them from doing that, but companies are starting to request to see test results when they exist. Failure to answer questions honestly can invalidate policies if you are caught.

If this becomes the status quo, it may affect uptake of genetic testing. If it is curbed through regulation, genetic testing may change the way the insurance industry operates. Act II is going to be interesting! I am having a couple of stiff drinks and heading back to my seat.

 

7. TYPE II DIABETES: RESISTANT TO INSULIN AND EASY ANSWERS

Genome wide association studies (GWAS), a way of looking at common variants in the gene pool to identify genetic susceptibility to common diseases, have been unable to explain the degree to which liability to these common diseases is inherited, although it clearly is. If you are in genetics and this is news to you, you have not been paying attention.

Many reasons for this have been proposed, and many are likely a part of the answer. One thought was that individually rare variants might be collectively common enough to play a big role in generating risk, which would not be picked up by GWAS, as it traditionally looked only at variants carried by at least 5% of the population (“the population,” as though there was only one!). Looking at rare variants takes a village, but that is what a googleplex of Type II Diabetes researchers did to produce an epic July 2016 paper in Nature.

Okay 300 authors on the paper so close enough.

The report by first author Christian Fuchsberger showed that MEGA*GWAS produced the most GWAS-y result possible: intellectually interesting, informative and ultimately inadequate. Using exome and whole genome data to capture a broader range of variation, the study found significant association to a handful of previously unknown common variants, and then failed to replicate a good chunk of what we thought we knew. Uncommon variation? The researchers found 23 loci that appeared significant, which was meaningful, but nowhere near enough to validate the rare variant hypothesis as the smoking gun in the Mystery of the Missing Heritability. “A comprehensive and extremely well written paper,” said Dan Koboldt at MassGenomics, and you can almost hear him sigh.

 

6. DATABASES: IT’S NOT JUST FOR WHITE PEOPLE ANYMORE

We don’t have enough diversity in our databases. It’s not exactly news, and yet publication of an article called “Genetic Misdiagnoses and the Potential for Health Disparities” in the August issue of the New England Journal of Medicine felt like a slap in the face.

The methodology was not complex. For hypertrophic cardiomyopathy patients, doctors use genotyping to identify individuals and family members at risk for sudden and catastrophic cardiac events. Identification as ‘at risk’ is a traumatic and often life changing event, requiring ongoing medical screening and behavioral modifications. For these families, a lot rides on whether or not a variant is considered pathogenic. One bioinformatics tool is to look at databases, because there are limits on how bad a variant can be if it shows up regularly in healthy individuals. The study checked variants labeled pathogenic against an increasing wealth of exome data available in public databases and found that a number were common in the African-American population. Result: reclassification from pathogenic to benign of multiple variants affecting primarily African-American families.

“Simulations,” said the authors, “showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications.

 

5. IMMUNOTHERAPY: A NEW STAR BURNS BRIGHT AND HOT

Earlier this week, my sister-in-law was telling me about a friend with a cancer deemed treatable but not curable. “But if they get it in remission,” she said, “and he has more time, maybe there will be something new.” There it was – the cancer prayer. May There Be Something New. And I thought, has there ever been a moment when those words felt more hopeful than right now?

Hopes have been raised before, by promises that money would bring answers, and we wandered down blind alleys and into mazes waving cash as though the scent of it would draw the answers to us, but this time, progress is lighting the way like street lamps, and money follows hope instead of the other way round. Immunotherapy – engineered cells meant to light the bodies own defenses into a controlled burn that destroys cancer cells and leaves the rest untouched – has burst onto the scene since 2015. Cancer researchers report on progress in Hemingway stories, terse narratives of a few more days, an extra month or two, and that’s a win, but suddenly we are getting Gabriel Garcia-Marquez fables of magic beans and people rising from their deathbed.

So which story is more 2016: Sean Parker’s 250 million dollar cancer institute, connecting Silicon Valley money with Car-T cells that he describes as “little computers,” and presenting to the NIH in comic sans? Or the unexpected lethal immune response that shut down a Car-T trial by Juno Therapeutics in November, after four people died of cerebral edema?

It’s the two in conjunction that tell the tale. Immunotherapy is truly a candle in the wilderness, but it’s a candle that burns rocket fuel. Or perhaps I should say, in the spirit of the season: catch a falling star and put it in your pocket – bet it burns a hole in your ass.

 

4. A NEW DTC GENETICS EMERGES WITH HELIX

In October, Helix announced the first fruit of its partnership with DNA-lifestyle start-up Exploragen and it’s grapes: Vinome, a company that promises to sell you wine tailored to your genetic profile for something like fifty bucks a bottle. I’m not a wine drinker and that sounds like a lot of money but, hey, you do you.

For Helix, the Illumina spinoff that debuted in 2015, this was one of a series of 2016 announcements giving us a more concrete vision of their plans for a sequence-once-access-often platform for DTC genomics. The structure of it is like Apple, if your IPhone didn’t even pretend to be a phone, and existed entirely as a vehicle for apps. With your first purchase, Helix will underwrite the cost of sequencing and storing your entire exome, and then sell it back to you bit by bit in the guise of applications created by partners.

Effectively, the Helix model lowers the barrier of entry for any product based on DNA testing, by spreading out the cost over a myriad of marketing opportunities. Some current players in the DTC universe have signaled their interest in playing in Helix’s playground; Geno 2.0, National Geographic’s version of ancestry testing, is already available on the Helix website. Others may take their toys and stay at home. Daniel MacArthur of the Broad Institute once penned an April Fool’s Day account of a company named Helix Health’s plans for a hostile takeover of 23andMe using Somali pirates, but for real the entry of an Illumina-backed company into the DTC space must have some Mountain View observers concerned that the current industry thought leader might end up the Blockbuster Video of the genomics world.

The uncorking of Vinome raises a few questions that existing partnerships with, say, the Mayo Clinic or the Icahn School of Medicine at Mt Sinai do not. One role that Helix could potentially play is to provide the vetting service much needed in the consumer genomics world, with its mishmash of pharmacogenetics and Warrior Gene testing and supplements designed just for your DNA.

As for Vinome, the eminently quotable Jim Evans called it “silly” in an article by Rebecca Robbins in STAT. “Their motto of ‘A little science and a lot of fun’ would be more accurately put as ‘No science and a lot of fun,’” said Evans — which I guess is true, if paying fifty dollars for a bottle of wine is your idea of fun. But like Apple, Helix is going to have to make some hard decisions about how much it takes responsibility for the quality of the partners it allows to come play in its sandbox.

 

3. GENOMES OF MASS DESTRUCTION

In February, for the first time but probably not the last, the U.S. Director of National Intelligence’s assessment of worldwide threats included genome editing as a weapon of mass destruction. Congratulations, genetics: we’ve made the big time.

The report pointed to the widespread use of new genetic technologies like CRISPR in countries with different regulatory and ethical standards, its low cost and the rapid pace of change as pre-conditions that might lead to intentional or unintentional misuse, though it was vague as to what form they thought the threat might take. More specific concerns were articulated later in the year by the Pentagon’s Defense Advanced Research Projects Agency (called DARPA of course, because…government) in announcing a program called Safe Genes intended to establish a military response to of dangerous uses engineered genes. DARPA, which Scientific American reports has been a major funder of synthetic biology, will support projects that look at ways to remove engineered genes from a variety of habitats and in a variety of circumstances, including those spread through gene drive.

 

2. A BREAKTHROUGH DEFIES CONVENTION AND GEOGRAPHY

On April 6, 2016, a baby was born after the transfer of his mother’s nuclear DNA into an enucleated donor egg in an effort to avoid the mitochondrial disease that killed the couple’s two previous children. The success of mitochondrial transfer therapy itself was not a shock, since earlier experiments had demonstrated good outcomes in animal models and in in vitro human embryos. The circumstances, however, were startling: the procedure was done in Mexico, for Jordanian parents, with the help of a New York-based fertility doctor with no known expertise in mitochondrial disease.

Some have argued that mitochondrial transfer therapy represents a violation of international norms forbidding any germline genetic change, which were meant to provide a clear dividing line between somatic changes associated with gene therapy and genetic engineering with the potential to impact future generations. Pretty clear in theory, but all of these divisions are less clear in reality – there are no guarantees that gene therapy doesn’t affect eggs or sperm, and mitochondrial DNA itself challenges any simple equivalence between the molecular structure of DNA and the intellectual concept of our ‘germline’.

Mitochondrial transfer is illegal in the United States but permitted in Great Britain under a 2015 law, and applications for clinical use have been approved for 2017. Its apparent success – independent sources confirm that the baby appears to have traces of maternal mt DNA associated with Leigh syndrome but no sign of disease – is a cause for celebration for the families whose children are at risk. The step forward is a milestone, but so is the way in which it occurred, which demonstrates the extent to which geography and national laws are no match for money and access in determining what is possible.

Personal note: on my wish list for 2017, can we PLEASE stop cheapening the concept of parenthood by using the term ‘3-parent babies’? If I donated a kidney, that person would have some of my DNA, but it wouldn’t make me their momma.

 

1. WHITE SUPREMACISTS LOVE GENETICS, BUT GENETICS DOES NOT LOVE THEM BACK

Nothing about the year 2016 was more disturbing than the empowerment of the alt right, an all-purpose term for the angry souls that crept out from under rocks to preach hate and division. Here at home and all around the world, narratives of race and ancestry emerged as powerful drivers in political and social movements based on appeals to base and tribal instincts – fear mongering about immigrants, Islamaphobia, white supremacy. In October, Elspeth Reeve at Vice ran a story about white supremacists posting their 23andMe results to prove their whiteness.

This embrace of a science that does not love them back is evident even without a deep dive into the world of Stormfront and 4chan.  Twitter trolls talk about ‘founder effects’ and ‘genetic drift’. A Breitbart tech editor, now barred from twitter, writes gleefully about associations between race, behavior and intelligence, mocking disbelievers as prisoners of an “all-consuming cult of equality.”  The L.A. Times describes the alt-right as “young, web-savvy racists who are trying to intellectualize and mainstream bigotry.”   These viewpoints aren’t mainstream, but their proponents can no longer be dismissed as fringe, with Breitbart’s founder about to be ensconced in the White House as chief strategist, and reports suggesting that the presumptive next National Security Advisor Michael Flynn taking meetings with the head of an Austrian political party founded by former Nazis.

The connection between white nationalism and population genetics is proof once again that genetics as a field is uniquely susceptible to misuse by agenda-driven movements intent on the subjugation of others. Donald Trump ran against political correctness, but his rise has proven the importance of language. As Michelle Obama says, “words matter.” Push back against the misuse of genetics to fuel ‘racialist’ theory. Ancestry sites should think very hard about the manner in which they present their findings, which stress differences without acknowledging the greater than 99% of DNA that we all share. Scientists need to address and refute the ways in which their work can be misconstrued to reinforce prejudice and unsubstantiated visions of racial differences. We all have to be careful not to promote explanations of genetic effects that oversell the determinative power of genes.

Genetics is a science of the future. Let’s not let it be used to drag us back into a tribal past. Peace out, Genetics, and here’s to a better year in 2017.

 

 

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

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

crispr facts 2

crisprfacts

crispr facts

Here’s mine…

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

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

  1. Roche Buys Billion Dollar Stake in Foundation Medicine

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

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

 

  1. Matchmaker Exchange Goes Live

Screen Shot 2015-12-29 at 9.15.23 PM

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

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

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

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

 

  1. Illumina Launches Helix, a Consumer Genomics Platform

Helix

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

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

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

 

  1. In Memento Moratorium

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

                                                –Mark Twain

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

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

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

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

 

  1. Sequenom Introduces a Non-Invasive Scan of the Genome

 Facts are stubborn, but statistics are more pliable.”

                                                            –Mark Twain

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

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

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

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

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

 

  1. Gene Expression? There’s a CRISPR for that.

crisperizer

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

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

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

Clap on, clap off… the Clapper!ld0oalpb8u8le

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

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

 

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

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

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

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

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

Eunice Lee and Benjamin

Eunice and Benjamin  Lee

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

 

 

 

 

 

 

  1. Baby With Cancer Responds to Treatment Using Genetically Modified Cells

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

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

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

 

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

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

                                                                                                -Mark Twain

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

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

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

 

  1. The Power of Gene Drive

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

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

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

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

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

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

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