Archive for the ‘Crispr’ Category

The findings of a recent study on the CRISPR gene editing technique have been called into question (Credit: vchalup2/Depositphotos)

Last month, a study was published claiming that the groundbreaking CRISPR-Cas9 gene-editing technique could potentially introduce hundreds of unintended mutations into an animal's genome. Unsurprisingly, this study sent shockwaves through the scientific community, with the stock prices from several gene-editing companies falling. Critics are now calling into question the veracity of the study, claiming it is filled with flawed assumptions.

Published in the journal Nature Methods, the research from a team of scientists from Stanford, the University of Iowa and Columbia University examined the entire genome of mice that had undergone CRISPR gene-editing. The study claimed to find over 100 unintended large deletions or insertions in each of the two mice examined, and attributed these alterations to the CRISPR gene-editing process.

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Within 24 hours of the research being published, stocks in several major biotech companies fell up to 14 percent. Two of these companies have since published open letters to the journal Nature Methods, criticizing the veracity of the study.

Editas Medicine, in a letter co-signed by 13 of the company's scientists, claimed the conclusions drawn from the study could not be ascribed to CRISPR and any observed mutations were likely present prior to the genome-editing procedure.

A letter from Intellia Therapeutics made similar claims, questioning the study's conclusions and pointing out flaws in the study design. Nessan Bermingham, CEO of Intellia, has even called for Nature Methods to retract the study.

While it is not unexpected to see these letters criticizing the study coming from companies with a financial interest in CRISPR, several independent scientists have also voiced concerns over the findings of the study.

Gaetan Burgio, a geneticist from Australia National University, has been working with CRISPR for several years and was vocal in his skeptical response to the study. He published a comprehensive essay detailing several misgivings around the study. He noted numerous factors as to why the mutations found in the research should not be necessarily attributed to CRISPR.

From an unusual delivery mechanism to a low sample size, Burgio explained the abnormal number of mutations are unlikely to be CRISPR related. He also wrote a scathing critique of the journal itself for publishing what he felt to be dubious research.

"I find absolutely astonishing this paper got published in Nature Methods," Burgio writes. "This is a terrible paper and as a reviewer I would have dissmiss (sic) it from the first round of review. This is a worrying trend from 'high impact' journals to promote the hype over good science. The publication of this paper is clearly a failure in the peer review process."

Other CRISPR specialists including Dr Lluis Montoliu, from the Spanish National Centre for Biotechnology, and Matthew Taliaferro, from MIT, backed up Burgio's concerns, tweeting doubts about the study's conclusions.

With such a public, and vociferous backlash, focus has now turned to the journal Nature Methods. If the original study's findings are so easily called into question then, as Gaetan Burgio noted, the question over how this article was published in the first place needs to be answered.

A spokesperson from the publishing company behind Nature Methods commented to MIT Technology Review, "We are carefully considering all concerns that have been raised with us and are discussing them with the authors."

With human trials involving CRISPR already underway, it is no surprise that a study like this has kicked up such a controversy. There has already been plenty of time and money invested in CRISPR, so it's not unexpected to see such vociferous criticisms of a study claiming flaws in the technology.

What is surprising is the broad spectrum of critics pointing out such a volume of flaws in the study. Only time will tell whether it is ultimately discredited or vindicated.

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The CRISPR controversy: Scientists skeptical over recent critical study - New Atlas

When people talk about the gene-editing technology CRISPR, its usually accompanied by adjectives like revolutionary or world-changing. For this reason, its no surprise that a study out last month questioning just how game-changing the technology really is caused quite a stir.

Its well-known that using CRISPR can sometimes also result in some unintended genomic changes, and scientists have long been working on ways to fine-tune it. But the researchers found that when they had used CRISPR to cure blindness in mice, it had resulted in not just a few but more than a thousand, unintendedoff-target effects.

This finding warns that CRISPR technology must be further tailored, particularly before it is used for human gene therapy, the researchers wrote. The technique has already been used in two human trials in China, and next year one is slated to kick off in the US.

Their finding kicked off a battle for CRISPRs honor, with some researchers speaking out to question the studys methods while others piped up to agree that CRISPR is not yet ready for people.

The first criticism came the day after the study was published, via a comment from a researcher on PubMed who argued careless mistakes and flaws in the methodology cast serious doubts about the results or interpretation, concluding that it was hard to imagine CRISPR-cas9 causes so many [unintended] homozygous deletions in two independent mice.

On social media, scientists raised red flags about basic mistakes, such as misidentifying genes, mislabeling genetic defects, and the small number of animals the researchers had included in their research.

I think the Nature Methods paper was a false alarm on CRISPR induced mutations, the geneticist Eric Topol told Gizmodo. Ironically, the methods used were flawed. While we remain aware of such concerns unintended genomic effects that might occur with editingthat report was off-base.

Scientists from the CRISPR-focused companies Intellia Therapeutics and Editas Medicine sent separate letters to the journal, Nature Methods, chiming in with their own critique.

Based on the information available on the mouse study, the more plausible conclusion is that the genetic differences reflect a normal level of variation between individuals in a colony.

We believe that the conclusions drawn from this study are unsubstantiated by the disclosed experiments as they were designed and carried out, the scientists from Editas wrote. Further, it is impossible to ascribe the observed differences in the subject mice to the effects of CRISPR per se. The genetic differences seen in this comparative analysis were likely present prior to editing with CRISPR.

The study sent the stocks of those two companiesand a third, CRISPR Therapeuticstumbling. Nearly two weeks later, those market prices had still not fully recovered. Some went so far as to call for a retraction.

All of our methods are described in our peer reviewed Correspondence and sopplemental materials in Nature Methods and the raw data have all been publicly deposited, so that others may further learn from our data, one of the authors, Alexander Bassuk, told Gizmodo via email.

Springer Nature, which owns Nature Methods, said that they have received a number of communications regarding the paper and said that it had undergone peer review as all papers in the journal do.

We are carefully considering all concerns that have been raised with us and are discussing them with the authors, a spokesperson said.

On his blog, UC Davis professor Paul Knoepfler asked several scientists about the study and got mixed results. One cited the same flaws in methodology others have brought us. Another posited that it was a good reminder to hunt thoroughly for off-target effects.

Overall, this study adds a bit to the knowledge base, but it has been over-interpreted in the media, Knoepfler concluded. It was unlikely, he wrote, that so many unintended edits were occurring in most research, but it still suggested more studies to investigate the problem are necessary.

This brings us to the one thing that is definitely true: Despite all our recent progress, there is still a lot we dont know about CRISPR. It does indeed allow us to make precise gene edits more easily than ever before, but this ability has limitations that could wind up being disastrous if used in humans, and disappointing when genetically engineering everything else. CRISPR is still a nascent technology, and whether one day it might really be used to cure diseases or create a unicorn, there are still a whole lot of things that need to happen first.

Update: This story has been updated to include comments from one of the study authors, Nature Methods and Eric Topol.

Read more:

A Controversial Study Is Tearing the CRISPR World Apart - Gizmodo - Gizmodo

I

f there was one misstep that doomed the long and bitter fight by the University of California to wrest key CRISPR patents from the Broad Institute, it was star UC Berkeley scientistJennifer Doudnas habit of being scientifically cautious, realistic, and averse to overpromising.

A biochemist who co-led a breakthrough 2012 study of CRISPR-Cas9, Doudna repeatedly emphasized in interviews the challenges of repurposing the molecular system, which bacteria use to fend off viruses, to edit human genomes. The U.S. patent office, in a February rulingthat let the Broad keep its CRISPR patents (for now), relied heavily on those statements We werent sure if CRISPR/Cas9 would work in animal cells, for example to conclude that when scientists at the Broad CRISPRd human cells in 2013, it was a non-obvious advance and therefore deserving of patents.

So its striking that the careful, measured Doudna who said CRISPRing human cells and thereby curing devastating diseases would be a challenge is hardly in evidence in A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, the new book she co-authored with her former student Samuel Sternberg. It goes on sale Tuesday.

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This Doudna doesnt hold back. We are on the cusp of a new age in genetic engineering and biological mastery, she and Sternberg write, dangling the prospect of life-changing treatments and lifesaving cures. She says she is not kidding that CRISPR could bring about woolly mammoths, winged lizards, and unicorns. It wont be long before CRISPR allows us to bend nature to our will.

University of California appeals CRISPR patent setback

The hyperbole contrasts with CRISPRs stumbles, including altering parts of genomes (in lab studies, not patients yet) it wasnt supposed to. I dont think well have a version of CRISPR thats 100 percent perfect, so it comes down to a risk-benefit analysis, Sternberg, a biochemist at Caribou Biosciences (which Doudna co-founded), said in an interview. There has been phenomenal progress in understanding off-target effects; I think its a solvable problem. We have every reason to be optimistic but I hope we avoided overhyping and didnt give the impression that there would be windfall of cures in the next couple of years.

This is not a tell-all. The farthest Doudna goes in addressing the patent fight a disheartening twist is to say that because of such rivalries she experienced the gamut of human relationships, from deep friendships to disturbing betrayals. She doesnt name the betrayers.

An early reviewchastised Doudna for presenting herself as so flawless the book seems more concealing than revealing, not insightful [and] candid.

So what she does choose to reveal is fascinating, especially about her collaboration with Emmanuelle Charpentier. The two are so closely linked that all the prizes theyve won for CRISPR, theyve won together; among CRISPR watchers DoudnaandCharpentier is virtually a macro.

But the books account of their breakthrough experiment showing that CRISPR could be programmed to edit a precise spot in a genomeleaves a different impression. We read that Martin [Jinek, Doudnas postdoctoral fellow] showed and Martin labored tirelessly, Martin and I brainstormed and designed an experiment, and when Martin walked me through the data, Doudnaknew wed done it.

That work was described in the 2012 paper, which is widely recognized by prize committees, the European Patent Office, and many scientists as the Bastille moment for the CRISPR revolution. It identified the three crucial molecules in the CRISPR system one to cut, one to guide the cutting enzyme to its target DNA, one to activate the cutting enzyme that produced a programmable DNA-cutting machine. We had built the means to rewrite the code of life, Doudnaand Sternberg write. Nothing after that would ever be the same.

Although Doudna and her collaborators didnt actually change genomes in cells their CRISPR molecules altered cell-free DNA in test tubes that was an obvious next step. How difficult a next step was the core dispute in the patent fight and one that she repeatedly cautioned was no slam dunk. But Crack in Creation says that doing so was immediately clear to us, and there were good reasons to expect success.

That contrasts with her cautious statements, cited by the patent office, at the time. When Feng Zhang of the Broad Institute and George Church of Harvard used CRISPR to edit genes, it was just as we had proposed in 2012, according to the book. She waselated that her 2012 work inspired others to pursue a line of experimentation similar to our own.

Doudna became a public scientist shes given aTED talkand will appear on Sunday Night with Megyn Kelly because of her research, but also because she was instrumental in getting the scientific community to focus on ethical issues it raises, especially about editing embryos in a way that would be inherited by future generations (germline editing). She writes that she had nightmares that a man asking her about this was Hitler and that she began to feel a bit like Dr. Frankenstein.

No red line against CRISPRing early embryos, experts rule

Her own moral journey is intriguing. She feels germline editing can be safe, and the its unnatural! argument doesnt carry much weight with me anymore, she writes. It seems to me that wed be justified in using CRISPR to eliminate genes that cause untold suffering, such as those for Huntingtons disease. When I think about the pain that genetic diseases cause families, the stakes are simply too high to exclude the possibility of eventually using germline editing, as an expert panel also concluded.

Doudnaacknowledges, however, that its difficult to see how wed do it equitably, especially when the line between therapy and enhancement is paper thin: Some families might purchase a genetic legacy that gives them less need for sleep, greater endurance, extra-strong bones, leaner or larger muscles, lower risk of diabetes and Alzheimers, even less armpit odor while other families muddle through with the genes nature gave them.

That threatens to transcribe our societies financial inequality into our genetic code, Doudna writes.

Her solution? Redoubl[ing] our commitment to building a society in which all humans are respected and treated equally, regardless of their genetic makeup.

Sharon Begley can be reached at sharon.begley@statnews.com Follow Sharon on Twitter @sxbegle

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CRISPR pioneer Doudna envisions a world of woolly mammoths and unicorns - STAT

In brief

The first CRISPR gene-edited crops are coming. A new waxy corn variety from DuPont Pioneer will hit the market in about three years. And given the speed, ease, and wide use of CRISPR gene editing, many other crops are sure to follow. Compared with traditional breeding and older genetic engineering techniques, CRISPR is much more precise: A gene-edited plant with a target trait can be produced in one generation. In the pages that follow, C&EN explores how people are using CRISPR to develop new varieties of corn, tomatoes, and cotton. Yet despite the clear technological advantages of the strategy, proponents dont know how it will be regulated or if consumers will embrace it.

Sometime around 2020, a new corn variety will mark a huge leap in how humans design agricultural crops. It will be the first commercialized, gene-edited plant altered using CRISPR/Cas9 technology. But dont be surprised if the corn debuts without much hype. It is a starchy or waxy corn that is not much different from varieties already on the market. When the seed firm DuPont Pioneer first announced the new corn in early 2016, few people paid attention. Pharmaceutical companies using CRISPR for new drugs got the headlines instead.

But people should notice DuPonts waxy corn because using CRISPRan acronym for clustered regularly interspaced short palindromic repeatsto delete or alter traits in plants is changing the world of plant breeding, scientists say. Moreover, the techniques application in agriculture is likely to reach the public years before CRISPR-aided drugs hit the market.

Until CRISPR tools were developed, the process of finding useful traits and getting them into reliable, productive plants took many years. It involved a lot of steps and was plagued by randomness.

Now, because of basic research in the lab and in the field, we can go straight after the traits we want, says Zachary Lippman, professor of biological sciences at Cold Spring Harbor Laboratory. CRISPR has been transformative, Lippman says. Its basically a freight train thats not going to stop.

Using CRISPR to addor removea plant trait is faster, more precise, easier, and in most cases cheaper than either traditional breeding techniques or older genetic engineering methods. Although scientists can use CRISPR to add genes from other species to a plant, many labs are working to exploit the vast diversity of genes that exists within a plant species. In fact, enhancing many of the most valued traits in agriculture doesnt require adding DNA from other species.

Gene-edited crops have the potential to revive some of the early promise that genetic engineering has not fulfilled, such as making plants that are higher yielding, drought tolerant, disease resistant, more nutritious, or just better tasting. In addition, CRISPR can efficiently improve not just row crops such as corn but also fruits and vegetables, ornamentals, and staple crops such as cassava.

Proponents hope consumers will embrace gene-edited crops in a way that they did not accept genetically engineered ones, especially because they neednt involve the introduction of genes from other speciesa process that gave rise to the specter of Frankenfood.

But its not clear how consumers will react or if gene editing will result in traits that consumers value. And the potential commercial uses of CRISPR may narrow if agriculture agencies in the U.S. and Europe decide to regulate gene-edited crops in the same way they do genetically engineered crops.

DuPont Pioneer expects the U.S. to treat its gene-edited waxy corn like a conventional crop because it does not contain any foreign genes, according to Neal Gutterson, the companys vice president of R&D. In fact, the waxy trait already exists in some corn varieties. It gives the kernels a starch content of more than 97% amylopectin, compared with 75% amylopectin in regular feed corn. The rest of the kernel is amylose. Amylopectin is more soluble than amylose, making starch from waxy corn a better choice for paper adhesives and food thickeners.

Like most of todays crops, DuPonts current waxy corn varieties are the result of decades of effort by plant breeders using conventional breeding techniques.

CRISPR technology employs a guide RNA to direct the Cas9 enzyme (light blue) to a target DNA sequence. Once there, Cas9 will bind when it finds a protospacer-adjacent motif sequence (red) in the DNA and cut both strands, priming the gene sequence for editing.

Credit: Adapted from OriGene Technologies

Breeders identify new traits by examining unusual, or mutant, plants. Over many generations of breeding, they work to get a desired trait into high-performing (elite) varieties that lack the trait. They begin with a first-generation cross, or hybrid, of a mutant and an elite plant and then breed several generations of hybrids with the elite parent in a process called backcrossing. They aim to achieve a plant that best approximates the elite version with the new trait.

But its tough to grab only the desired trait from a mutant and make a clean getaway. DuPonts plant scientists found that the waxy trait came with some genetic baggage; even after backcrossing, the waxy corn plant did not offer the same yield as elite versions without the trait. The disappointing outcome is common enough that it has its own term: yield drag.

Because the waxy trait is native to certain corn plants, DuPont did not have to rely on the genetic engineering techniques that breeders have used to make herbicide-tolerant and insect-resistant corn plants. Those commonly planted crops contain DNA from other species.

In addition to giving some consumers pause, that process does not precisely place the DNA into the host plant. So researchers must raise hundreds or thousands of modified plants to find the best ones with the desired trait and work to get that trait into each elite variety. Finally, plants modified with traditional genetic engineering need regulatory approval in the U.S. and other countries before they can be marketed.

Instead, DuPont plant scientists used CRISPR to zero in on, and partially knock out, a gene for an enzyme that produces amylose. By editing the gene directly, they created a waxy version of the elite corn without yield drag or foreign DNA.

Plant scientists who adopt gene editing may still need to breed, measure, and observe because traits might not work well together or bring a meaningful benefit. Its not a panacea, Lippman says, but it is one of the most powerful tools to come around, ever.

The Lippman group uses CRISPR gene editing to alter the number and branching pattern of flowers that become tomato fruit.

Credit: Zachary Lippman

DuPont was an early adopter of CRISPR technologies, before Monsanto and other seed industry rivals. In 2015, the company signed technology license deals with Vilnius University and Caribou Biosciences. Caribou was founded by CRISPR research pioneer Jennifer Doudna of the University of California, Berkeley.

Gutterson says his team started work on the new waxy corn in early 2015. One observation or lesson we have with our first product is that the reduced time to market is significant, he says. It will take less than five years, compared with about eight for a hybrid, to get the new corn to farmers.

Waxy corn was an ideal variety on which to try CRISPR for a first commercial product, Gutterson says. It has a trait that has been long marketed and is familiar to farmers.

Another reason was that plant scientists understand the corn genome and the waxy trait in particular. You really have to understand the gene for the trait, the genome, and the effect of the edit, Gutterson says. Many versions of this gene exist in nature. It made it easy for us to get exactly the property we want.

According to plant scientists, better understanding of a species genome, including the identity of genes that code for desired traits, is the main hurdle to widespread use of gene editing. Researchers have had access to the full corn genome only since 2010, and they are still sequencing a number of important corn varieties.

Plantslike animalshave lots of genes, most of which we dont understand, notes Heike Sederoff, professor of systems and synthetic biology at North Carolina State University. We dont know what they do or why they are there or how they got there.

But here, too, CRISPR easily beats out competing techniques. To figure out the function of one of the 20,000 to 30,000 genes in a plant, scientists either knock out the gene or dial up its impact by adding copies. We used to use viruses or bacteria that insert DNA, but the targeting part is really difficult, Sederoff says.

Thats where CRISPR helps us. It allows us to very specifically target a gene and either take it out or modify it. We can study any gene, and we can do more than one at a time. And its not hard to do.

Sederoffs lab is studying ways to increase the amount of oil produced by oilseeds such as canola and the industrial crop camelina. Her team is looking for genes that control how a plant transports sugar or regulates the amount of sugar that goes out of its stem and into the seed, where it is converted into fatty acids. Can we make more seeds? Can we change the composition or size of the seeds? she asks.

In one set of experiments, Sederoff used CRISPR to place a gene that makes tomatoes sweet into an oilseed plant. Seed yield doubled. She reports it took less than two years, compared with the 10 years that older techniques would require. In the long run, researchers might find and use native oilseed genes that work like the one taken from the tomato to create a higher-yielding crop that isnt transgenic.

Cold Spring Harbors Lippman is also working with tomatoes. His team is looking for the genes that control how many, when, and where flowersand thus tomatoesare produced on plants. That means understanding what happens in the stem cells that produce flower branches, called inflorescences.

In the past, breeders had trouble fine-tuning the amount and pattern of inflorescences. The problem, Lippman discovered, is that two traits that arose during decades of domestication and crop improvement combined to thwart the altering of flower production via additional breeding. One of the traits helped the plant support heavier fruit; the other eliminated a joint on the fruit stem to prevent tomatoes from falling off before harvesting.

With CRISPR, Lippman notes, what was done can be undone. We have ways now to use gene editing to separately modify fruit size and weight, the branches that make flowers, and the amount of flowers, as well as the architecture of a plant from a compact bush to one that keeps growing.

A different breeding mistake may be to blame for modern tomato varieties lack of flavor and aroma. Research shows that as breeders sought traits for productivity, uniformity, and harvest-ability, the tastier traits were inadvertently lost. Wild tomatoes and heirloom varieties still carry those genes.

Now lets breed them in or edit them to bring back a better-flavored tomato, which is what everybody asks for all of the time, Lippman says.

Cotton growers are also excited about the quality improvement that CRISPR gene editing could bring. Cotton is a small-acreage crop compared with corn and soy, explains Kater D. Hake, vice president of agricultural and environmental research at Cotton Inc., a promotion organization supported by cotton farmers. With the regulatory cost associated with traditional biotechnology, cotton has been off the radar except for extremely high-value traits such as insect and weed control.

Researchers are probing the cotton genome, which was first sequenced in 2015, to find genes that control the shape, structure, length, and strength of cotton fibers. Its a sustainability story, Hake says. When you push cotton quality up, you can make stronger, finer yarns so garments require less total mass of cotton and are more durable.

Indeed, researchers have no shortage of ideas for how to use CRISPR to make higher-quality, more sustainable crops that consumers may desire. But to date, most of the work has been to prove the concept. Its not yet clear which innovations will actually reach the market.

One concern is that smaller seed firms and research organizations arent geared up to develop and commercialize crops with new traits; they ceded most of that ground to agriculture giants such as DuPont decades ago.

Benson Hill Biosystems, a St. Louis-based start-up, is working with small seed companies and academic researchers to help them pursue crop improvement projects using its data-driven genomics platform. For example, the firm is working with the family-owned seed firm Becks Hybrids and potato experts at J.R. Simplot Company to bring more R&D power in-house.

We believe DuPont and Monsanto will play a decreasing role relative to innovation across the industry, Benson Hill Chief Executive Officer Matthew Crisp asserts. It will be like the shift in big pharma 1015 years ago when early-stage discovery went to smaller players. Crisp says CRISPR gene editing and genomic data tools will level the playing field for new trait introductions.

Another constraint is that a few organizations control important patents for CRISPR, some of which have been the subject of lawsuits. So scientists at Benson Hill are working on a way to replace Cas9, the enzyme that cuts the DNA. Crisp calls the work CRISPR 2.0 and says he expects the tools to be even more efficientand easier to accessthan current ones. Researchers at the University of California, Berkeley, are also developing Cas9 alternatives.

But as CRISPR technology advances, questions persist about government regulation and consumer acceptance.

Today, companies that wish to market a gene-edited plant can ask the U.S. Department of Agriculture whether their product will require regulatory review. So far, for plants that do not contain foreign genes, USDA has responded that it does not have the authority to regulate. Transgenic plants, in contrast, are regulated because they contain genes from other species or from a vector organism that may introduce a plant pest into the environment.

That regulatory framework, which was set up in 1987, is undergoing a comprehensive review; USDA is accepting comments through June 19 about how it should assess risk in modified crops. In addition, other countries may write different, more onerous rules.

Many researchers share the view that regulators should focus on whether added or altered traits pose a foreseeable risk and not on the process used to get the trait into the plant.

I propose doing regulation based on the phenotypethe specific characteristics you put in, says Gregory Jaffe, director of the biotechnology project at the consumer advocacy group Center for Science in the Public Interest. Clearly, one aspect of doing risk assessment is that how you put the trait in could inform risk assessment. Using a Brazil nut gene to improve disease resistance, for example, could introduce a nonnative protein that may be allergenic, Jaffe points out.

Jaffe and others say regulatory changes and the new editing technologies could blur the line between what is and is not a genetically modified organism (GMO). Currently, food containing genetically modified ingredients must carry a label. Its not clear if CRISPR-edited products will also require a label.

Thats one reason why Jaffe has proposed a registry for both the public and the food industry to track what crops come from gene editing. Its important not to make the kinds of mistakes that were made with GMO crops, Jaffe says. We should start with more transparency in the food chain.

Benson Hills Crisp agrees that the industry must be more transparent and do a better job at outreach. We need to ensure that consumers are informed about the benefits and not inundated with misinformation or a lack of information.

Food shoppers will likely be won over with gene-edited products that directly benefit them, Jaffe predicts. And hes already got something in mind: I would like a better-tasting tomato.

Read the rest here:

CRISPR: A new toolbox for better crops - The Biological SCENE

Researchers say they discovered hundreds of mutations during a gene editing experiment, casting doubt on CRISPR's safety and precision.

CRISPR gene editing technology has tantalized the public with its potential to cure disease.

However, new research suggests it could be more dangerous and less precise than previously believed.

CRISPR-Cas9 was discovered in 2012 by University of California molecular biologist Jennifer Doudna and her colleagues. It allows for genetic editing by snipping out small bits of defective or harmful DNA and replacing it.

Gene editing has existed since the 1970s, but CRISPR-Cas9 has reinvented it as a precise, accessible technology.

The potential applications seem almost limitless.

This year, Dr. Edze Westra of the University of Exeter, told the Independent that he expects the technology to be used to cure all inherited diseases, to cure cancers, to restore sight to people by transplanting genes.

Read more: Scientists find gene editing with CRISPR hard to resist

Still in its infancy, CRISPR-Cas9 has yet to deliver on these promises, in humans anyway.

One of the key talking points of CRISPR-Cas9 has been its precision its ability to accurately edit small sections of DNA without affecting nearby sections.

However, a new study from Columbia University says that CRISPR-Cas9 can introduce hundreds of unexpected mutations into the genome beyond what was intended.

We feel its critical that the scientific community consider the potential hazards of all off-target mutations caused by CRISPR, said co-author Dr. Stephen Tsang, a professor at Columbia University Medical Center, in a press release.

Tsang and his team discovered the mutations while conducting research on mice, using CRISPR-Cas9 to correct a gene that caused blindness.

The technology worked effectively in curing the blindness, but when the researchers later looked at the genome of the mice, they said they found additional, unintended mutations.

Despite this, the mice appeared to be in fine health.

We did not see any observable complications in the mice, despite having all these extra CRISPR-related mutations, Tsang told Healthline.

Sheila Jasanoff, professor of science and technology studies at Harvard University, told Healthline that precision can have a slippery definition in biotechnology.

Genetic engineering was also sold some 40 years ago as a highly precise technique. Now, CRISPR is being heralded as even more precise, she said.

Undoubtedly, there is some truth in that claim ... But we also know from older genetic engineering techniques that very precise interventions into one part of a genome can produce unexpected side effects or off-target impacts that scientists were not expecting, Jasanoff added.

Read more: CRISPR gene editing and cancer treatment

Tsang frames the message of his research in two ways.

First, he hopes that his work will bring a newfound awareness to the potential side effects caused by CRISPR.

Although the mutations he and his team observed did not appear to have any malignant effects, they should be a wake-up call for researchers.

Secondly, Tsang says that no matter what kind of medicine or treatment is being used, there is the potential for side effects.

If we apply CRISPR, its just like any other intervention medicine. There is always off-targeting and risks and benefits, he says.

Jasanoff is more tempered in her assessment of the risk vs. reward of CRISPR.

The assumption that there are untold benefits in store long before the work has been done to establish how a new technology actually will have an impact on any disease is a typical example of the hype that surrounds new and emerging technologies, she said.

Tsangs research offers no hard answers to the larger questions of efficacy, risk, and benefit of using CRISPR on humans.

Lets not go overboard, said Pete Shanks, a consultant who is an expert on genetics. Three blind mice dont prove much.

Tsangs research does provide some cautionary insight into how research must be conducted in order to make the technology safer.

Currently most studies of off-target mutations depend on computer algorithms to locate and examine affected areas. Tsang and his team say that this isnt sufficient when using live specimens.

These predictive algorithms seem to do a good job when CRISPR is performed in cells or tissues in a dish, but whole genome sequencing has not been employed to look for all off-target effects in living animals, Alexander Bassuk, professor of pediatrics at the University of Iowa, and co-author of the study, said in a press release.

Researchers who arent using whole genome sequencing to find off-target effects may be missing potentially important mutations, Tsang said.

Read more: Gene editing could be used to battle mosquito-borne disease

This study comes at an important time.

China has begun its first round of human testing using CRISPR-Cas9.

The United States is due to start its own tests next year.

The research field is moving quickly perhaps too quickly.

We hope our findings will encourage others to use whole genome sequencing as a method to determine all the off-target effects of their CRISPR techniques and study different versions for the safest, most accurate editing, Tsang said.

Jasanoff is much blunter.

We should put aside the notion the benefits of CRISPR are already proven, and all we need to worry about is risks, she said.

Continued here:

Is CRISPR Gene Editing Moving Ahead Too Quickly? - Healthline

Download PDF Sequence search: A DNA-editing tool helps scientists find functions for the more than 98 percent of the genome that doesn't include genes.

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Tweaks to the CRISPR gene-editing system allow researchers to identify stretches of DNA that regulate gene expression1. Researchers could use the method to find sequences that control genes tied to autism.

The CRISPR system uses RNA guides to direct the DNA-cleaving enzyme CAS9 to specific spots in the genome. Scientists have used the system to edit, activate and disable genes. But regions that control these genes are hidden in the vast expanse of poorly understood DNA dubbed the dark genome.

The new method, described in the April issue of Nature Biotechnology, involves the use of chemical tags for DNA that activate or deactivate certain sections of the genome. Researchers engineered one version of CAS9 to add an activating tag, and another to add a deactivating tag.

They created two libraries that each contain thousands of guide RNAs. Each of the RNAs targets a DNA segment thought to regulate the expression of a gene or group of related genes. One library is specific for the beta-globin region, which contains genes involved in the production of hemoglobin. The other targets the breast cancer gene HER2.

The researchers loaded each of the guide RNAs into a virus and injected the virus into cultured human cells.

After 14 days in culture, the researchers gauged the expression of HER2 and beta-globin genes in the cells using fluorescent markers on the genes. They used a specialized instrument to sort out the brightest 10 percent and the darkest 10 percent of cells.

The researchers then identified where in the genome the guides had attached, revealing the sequences that regulate the expression of HER2 or beta-globin genes.

The study confirmed known regulatory segments for beta-globin genes and revealed new ones for HER2.

The regulatory segments generally produce subtle changes in gene expression, those that differ from baseline by less than twofold. But several of them working together might produce more dramatic changes, the researchers say.

They also say the method can be scaled up to enable screening of the entire genome, rather than just selected regions.

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CRISPR hack unearths gems buried in 'dark genome' - Spectrum

2 : a gene editing technique in which CRISPR and the RNA segments and enzymes it produces are used to identify and modify specific DNA sequences in the genome of other organisms Just a few years after its invention, CRISPR gene editing is already having a major impact on biomedical research. It makes it easy to turn off genes one at a time, to see what they do. It can introduce specific mutations, to find out why they make cells cancerous or predispose people to diseases. And it can be used to tinker with the genes of plants and animals Michael Le Page Using CRISPR, they have now disabled four rice genes, suggesting that the technique could be used to engineer this crucial food crop. Elizabeth Pennisi Scientists hope Crispr might also be used for genomic surgery, as it were, to correct errant genes that cause disease. Andrew Pollack The technique is sometimes called CRISPRCas9, which includes the name of the enzyme that cleaves DNA. an incredibly fast-paced field in which laboratories around the world have used CRISPR-Cas9 to edit genomes of a wide range of cell types and organisms. Jennifer A. Doudna and Emmanuelle Charpentier

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Crispr | Definition of Crispr by Merriam-Webster

CRISPR pioneer Feng Zhang's lab spawns a new Cambridge biotech Boston Business Journal They include Zhang, a co-inventor of CRISPR/Cas9, the experimental and potentially revolutionary technology for cutting out and replacing parts of genes. Two graduate students who work in Zhang's lab and have conducted research related to CRISPR, ...

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CRISPR pioneer Feng Zhang's lab spawns a new Cambridge biotech - Boston Business Journal

The gene-editing tool CRISPR is everywhere these days. Scientists are using it to try and fight cancer and treat muscular dystrophy, companies are using it in agriculture, and TV executives are even writing it into shows.

And it's ubiquity isn't surprising because CRISPR is one of the biggest scientific discoveries of our time. It tremendously improves upon earlier gene-editing techniques because it's fast, cheap, and accurate. Or so we thought. A new study published last week in Nature Methods found that CRISPR might not be as precise as researchers believed it to be. But not everyone agrees.

In the study, researchers were using a strain of mice that had mutations causing early onset retinal degenerationa disorder that blinded the mice. Using CRISPR, the researchers were able to snip out and correct a mutation in a particular gene to restore the mice's vision.

But the scientists were curious about what are known as "off-target" effects, or secondary mutations caused by CRISPR that occur away from the intended genetic target. So, they compared the DNA from two CRISPR-treated mice to that of a mouse which hadn't received the gene editing. They found a surprisingly large number of differences. Namely, the CRISPR-treated mice had around 1400 small off-target mutations and over 100 more considerable genetic alterations.

"When you read about CRISPR, the focus is on the amazing ability of this system to go in and fix a single nucleotide out of the three billion in a genome. People have been looking at off-targeting, but generally you get the sense that it's not that bad, or it's not consequential. So this definitely came as a surprise," Vinit Mahajan, a Stanford University ophthalmology professor and researcher on the project, told Seeker.

According to the paper, the researchers didn't observe any physical effects of the off-target mutations at the time. But they warned that such effects could show up later in the CRISPR-treated mice or even in their offspring.

Off-target mutations are definitely something researchers need to pay attention to. Particularly those involved in clinical studies and the ongoing human trials. But not everyone thinks the study's findings are as valid as the authors present.

"CRISPR isn't ready to be used in human gene editing."

Cara Moravec is a postdoctoral researcher at the University of Wisconsin - Madison and she uses CRISPR in her research all the time. She found a few anomalies in the study that raised some concerns for her in regards to the interpretations of the findings. She says off-target effects are a known issue with CRISPR but that this study isn't the best representation of those problems.

"I think this paper does bring to light that CRISPR isn't ready to be used in human gene editing," Moravec told Motherboard, "And there are concerns about off-target effects, but in this study they're overestimating those off-target effects because of some of the choices they made in their methods."

Moravec points to a comment left on Pubmed's listing of the article, which claims that a number of the off-targets listed in the paper are actually on-target, meaning the mutations happened on the gene the researchers were shooting for, not elsewhere. And other concerns, many shared by Moravec, are raised on UC Davis professor Paul Knoepfler's blog.

While this study brings some CRISPR limitations to the forefront, all of its claims may not stand up under scrutiny. We're definitely going to need more research to really figure out the extent of off-target mutations, when they happen, and why.

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CRISPR Is Not Accurate Enough to Save Us Yet - Motherboard - Motherboard

The End of Genetic Disease CRISPR-Cas9,the worlds best gene editing tool, has lent itself toa plethora of research and experiments. Scientists owea great deal to the person considered to be its founder if we could really credit one person specifically with its advent. Certainly, University of California Berkeley biologist Jennifer Doudna deserves consideration for thetitle as one of the worlds leading figure in whats being called the CRISPR Revolution. It was Doudnas work in 2012 that first suggested the possibility of using CRISPR-Cas9 for genome editing. Since then, it has certainly been put into good use human clinical trials of the technologys capabilities areexpected to begin soon in the United States.

On Thursday,speaking at WIREDs 2017 Business Conference in New York, Doudna made a bold claim about the future of CRISPR. I think its really likely that in the not-too-distant future it will cure genetic disease, she saidat the conference.However, Doudna remains aware thatthe use of such a powerful tool needs to be carefully considered especially since studies have shownit can haveunintended repercussions.

But globally we need to come up with a consensus on moving forward in a responsible way, Doudna added. This wasnt the first time she emphasized need for ethical responsibility in using CRISPR.

Doudna herself has certainly been careful to practice what she preaches: In 2015, she became part of a broad coalition of leading biologists that put parameters in place for the use of CRISPR. They agreed to a worldwide moratorium on gene editing to whats called the germ line. In other words, putting a prohibition onedits that would bepassed down to subsequent generations. However, because it isnt legally binding, it wasnt able tostop such experiments from taking place. In China, for instance, theres already work involving CRISPR to edit the genome of human embryos.

Recognizing the legal and ethical hurdles CRISPR still needs toovercome, Doudna went on tospeak about a much more plausible area for this gene editing tool to demonstratemore immediate success: its application for farming. When I think about where we are likely to see the biggest impacts in the shortest amount of time, I really think its going to be in agriculture, Doudna told the audience in New York.

Indeed, CRISPR has already been already been successfully used to grow and eat! one crop in particular. The first wasthat cabbage in Sweden, and now, agricultural giant Monsanto has even been given license by the Broad Institute to use CRISPR-Cas9 in seed development. Doudna also mentioned research by scientists from the Cold Spring Harbor Laboratory in New York that could make harvesting tomatoes easier.

For me, that really illustrates the potential for this, Doudna said who is herself a tomato farmer. [CRISPR] allows plant breeders to do things that would have been very difficult, sometimes impossible in the past.

With the science, the ethics, and the legal ramifications of CRISPR still being ironed out, farming seems to a reasonable compromise for continue to experiment with the tech, and many experts are already working on its continued refinement.Given that dedication, itmight not be that long before the end of genetic diseases which is what Doudna hopes could be ultimately realized would be accomplished with the help of CRISPR.

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Berkeley Biologist: CRISPR Gene Editing Will Cure Genetic Disease - Futurism

There has been speculation over whether a patent pool for CRISPR licensing might be created, making it easier for commercial parties to get involved with the technology, according to Larry Coury, senior director of dispute resolution at Regeneron.

Courys comments were made at the Life Sciences Patent Network North America, a conference hosted by Life Sciences IP Review in Boston on Thursday, June 1.

The longer you wait [to get involved in CRISPR], the more certainty you will have. But at the same time, you will also be further behind compared to the others who did some evaluation and took a risk, said Coury, when offering his advice to commercial parties.

He added: It will depend on how important this technology is to your company, and youll have to make a decision about the most appropriate time to get in. But no matter when you decide to get in, you will have to sit down and do some negotiation.

Coury explained in the panel discussion that from a commercial point of view, he thinks it is the life sciences industrys belief that firstly, no party is going to get an exclusive licence, and secondly, every party will have the opportunity to obtain a licence.

He added: I dont think there will be lawsuits with people seeking injunctions trying to prevent other parties from using CRISPR.

As was noted in the discussion, the IP landscape for CRISPR technology remains unclear and can create confusion for companies that are looking to commercialise this technology.

The moderator of the panel, Frits Gerritzen, partner at Allen & Overy, said that the CRISPR landscape was unclear.

Jared Cohen, senior director at Alexion Pharmaceuticals, said that companies that are looking to license the technology look for certainty.

He added: There is anything but certainty right now. All you can do is look at the merits of each portfolio and come up with different conclusions.

Cohen said that, depending on how important the CRISPR technology is to a company, there are other technologies which can be considered as well.

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LSPN North America: CRISPR patent pool may emerge, says Regeneron - Life Sciences Intellectual Property Review (subscription)

The Scientist

Was a Drop in CRISPR Firms' Stock Warranted? The Scientist ISTOCK, VCHALLast week, a study made headlines worldwide with its claim that the CRISPR-Cas9 genome-editing technique is more error prone than expected. In response, some investors chose to sell their shares in CRISPR-based biotech firms and stock ... CRISPR Therapeutics Appoints James R. Kasinger as General ...Nasdaq Insider Selling: Crispr Therapeutics AG (CRSP) CEO Sells 49384 Shares of StockSports Perspectives Could Crispr Therapeutics AG (NASDAQ:CRSP) Skyrocket? The Stock Has Too Many SellersFinance News Daily all 5 news articles »

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Was a Drop in CRISPR Firms' Stock Warranted? - The Scientist

Jennifer Doudna was sitting in her UC Berkeley office when she got the first call from a reporter asking what she thought about scientists using Crispr to modify embryos. At the time, the embryos in question were monkeys. It was late 2014, and Doudna was just beginning to become the face of Crispr/Cas9the bacterial enzyme behind todays gene editing revolution. Since then she has fielded an ongoing avalanche of questions about the implications of her discovery. How its going to change the future of everything from medicine to agriculture to energy production. But inevitably the questions always get around to super-babies.

Today, at WIREDs 2017 Business Conference in New York, it took just a few minutes. Doudna said it was exactly this possibilityCrispr custom-designed human offspringthat made her take a step back from her own research and get involved in public discussions around the technology. For the last few years shes been speaking to scientists, politicians, and federal regulators around the world about the potential risks and rewards of Crispr. I think its really likely that in the not-too-distant future it will cure genetic disease, she said. But globally we need to come up with a consensus on moving forward in a responsible way.

In 2015, Doudna was part of a broad coalition of leading biologists who agreed to a worldwide moratorium on gene editing to the germ line, which is to say, edits that get passed along to subsequent generations. But its legally non-binding, and scientists in China have already begun experiments that involve editing the genome of human embryos. Using Crispr to cure inheritable genetic diseases is still a long way off, and fraught with ethical potholes. Which is why Doudna said people who are excited about the possibilities of Crispr shouldnt look to the clinic for its first big successes, but rather to the farm field.

When I think about where we are likely to see the biggest impacts in the shortest amount of time, I really think its going to be in agriculture, she said. Plant breeders have always been geneticists at heart. And with the precision and ease of Crispr, identifying and separating out desirable traits has the potential to speed up new crop development by several orders of magnitude. Agro-giants DuPont and Monsanto have invested in Crispr licenses to accelerate their R&D efforts toward creating crops that can withstand changing climates and new disease and pest burdens. In test plots around the world gene edited crops are already growingfrom longer-lasting potatoes and flood-resistant rice to drought-hardy corn and mildew-proof wheat, to name just a few.

As a tomato farmer, Doudna was most excited about a paper that came out just last month. In it, scientists from Cold Spring Harbor Laboratory in New York tackled some of the crops trickiest modern traits. While wild plants benefit from dropping fruitit helps seed dispersalfarmers want plants where the fruit stays on, so mechanical pickers have an easier time harvesting them. When breeders found a trait called jointless that did keep the fruit on the vine, they rushed to incorporate it into their domesticated tomato varieties. But when they crossed jointless into existing tomato breeds, the resulting plants put out all these extra branches, actually diminishing the number of fruits they produced.

Using genetics to trace back 10,000 years of tomato domestication, Cold Spring Harbor researchers discovered which genes led to that weird branching. Then they used Crispr to edit their activity. The resulttomato plants with great yields that dont drop their fruits.

For me, that really illustrates the potential for this, Doudna said. Crispr allows plant breeders to do things that would have been very difficult, sometimes impossible in the past.

The first season of Westworld wasted no time in going from hey cool, robots! to well, that was bleak. Death, destruction, android tortureits all been there from the pilot onward. Then again, on a show about a theme park staffed with sentient robotssorry, hoststhose outcomes are exactly what audiences have come to expect. If science fiction has taught folks anything, its that the machines will always rise up against humankind. But why does sci-fi always veer dystopian? Westworlds creators have a theory.

Storytelling, according to show co-creator Jonathan Nolan, serves an evolutionary purpose, allowing us to try out different realities. With sci-fi, because its so often forward-looking, were inventing cautionary tales for ourselves, Nolan said today at WIREDs 2017 Business Conference in New York. In other words, when your creations would hurt a fly, its time to start worrying.

It's not going to be a beautiful lady or a beautiful man who is going to come and be your overlord.

So does that mean Nolan and his co-creator (and wife) Lisa Joy think Westworld is a foreseeable future? Not entirely. For Nolan, the robots on his show represent more of an allegory for human behavior than a cautionary tale. And Joy sees Westworld, and sci-fi in general, as an opportunity to talk about what humanity could or should do if things start to go wrong, especially now that advancements in artificial intelligence technologies are making things like androids seem far more plausible than before. Were leaping into the age of the unfathomable, the time when machines [can do things we cant], Joy said.

Even though their show loosely taps into the dystopian trope of the AI uprising, Westworlds co-creators dont think the actual AI being developed right now will lead to total apocalypse. Instead, Joy said, little bits of AIlike Amazon predicting your purchasing needs or cars helping you drive homewill take over peoples lives piecemeal. Right now, however, these technologies dont have a moral compass yet, Nolan said, adding that thanks to the algorithms telling people what news they might want to read and what opinions they might want to hear, were in a time of artificial ignorance.

If and when true androids do arrive, though, dont expect them to look like the passing-for-human hosts of Westworld, though. We anthropomorphized what the AI will look like, Joy says. Thats not going to happen. Its not going to be a beautiful lady or a beautiful man who is going to come and be your overlord.

Ask Norman Foster what if anything hed like to change about Apples recently constructed headquarters in Cupertino, California, and hell need a moment to think. The famed architect, whose firm spent the last eight years perfecting plans for Apples glassy Campus 2, is mostly pleased with the results. But there is one thing: The only hesitation I have is in terms of the changing patterns of transportation, Foster said today at the WIRED Business Conference.

Apples headquarters feature a massive underground garage built to hold 11,000 vehicles. Today, thats an amenity. But not too far in the future, its entirely possible that cars (and garages) will be far less important. Maybe the conventional garage needs to be rethought and rethought now, Foster continued. Maybe if I had a second time around Id be putting a lot of persuasive pressure to say, Make the floor-to-floor of a car park that much bigger, so if youre not going to be filling it with cars in the future you could more easily retrofit it for more habitable space.

For Foster, the future of workplace design is dependent on this kind of flexibility. It might sound counterintuitive given Steve Jobs unrelenting attention to detail. Foster recalls when Jobs first approached him in 2009 to talk about building a new campus. He had a very clear vision in terms of what the project was, Foster said on stage. Jobs wanted the building to lie low to the ground to blend into the surrounding landscape. The late Apple CEO dictated everything from door handles to materials to the ultra-tight tolerances required throughout the building. Jobs was obsessed with glass and wanted to encourage the connection between indoors and outdoors, going as far as to build a door in the campus restaurant that could completely open in 12 seconds, eliminating the barrier to the outside world.

Its easy to assume a strict adherence to vision would stifle flexibility. The reverse is actually true, Foster said. The best buildings, he contends, require a strong point of view. They must be thoughtfully designed to adapt to the ways humans and society will inevitably change, and that requires more than just building open-plan layouts.

Ultimately, the most enduring workplaces will take into account the deep-rooted desires of the people who spend time there. Theyll prioritize smart paths of circulation to help people connect with one another. Instead of sequestering employees into glass boxes, theyll encourage them to connect with nature. To be truly competitive, architects and companies have to think beyond productivity. From the very beginning, Ive protested the idea that an office headquarters, whether its mega or micro, is only about work, Foster said. Its about lifestyle.

Andy Rubin is an excellent sharer. The longtime inventor, founder of Android, and current CEO of two companiestech incubator Playground and gadget maker Essentialbelieves strongly that the best way to invent the future is to do it together. Thats why he encourages the companies he funds and advises at Playground to share technology, he said today at WIREDs 2017 Business Conference in New York. A lot of those building blocks are pretty repetitive, Rubin said. So a lot of the work this team does is repeatable. For the same reason, Rubins already sharing details of how Essential plans to organize and orchestrate the smart home, and then help others do the same.

Essential only launched publicly at the end of May, introducing two products: a phone and a smart-home hub. The phone, Rubin told the Business Conference crowd, is a necessary first step for the company. Your phone is your main screen, he said. You probably sleep with your phone two feet away from you on your nightstand. (Guilty.) The screen in your pocket is your primary point of access for all the communication, work, and time-wasting you do in a day. Rubin wanted to make a great phone, earn space in your pocket, and then start to build new tech atop that platform.

The long-term vision for Essential, Rubin said, is more closely aligned with the Essential Home, which Rubin hopes youll put in your kitchen or living room and use to control all the connected devices where you live. Just dont call it a smart speaker, or compare it to an Amazon Echo. Its beginning to explore the relationships of the mixed-mode interface, Rubin said. You have a touchscreen and an LCD combined with speech, combined with the other sensors you have in your home like cameras and doorbells and locks.

The Homes job is to take your August Smart Lock, your Nest thermostat, your Philips Hue lights, and that Samsung fridge you bought with a huge touchscreen, and make them all work together. Right now, they dont; theyre all built on different ecosystems and platforms that refuse to talk together. Everybodys building islands, Rubin said. And theyre expecting people to plug into them. When really what has to happen isand this happened with Androidthese islands need bridges.

Rubin admitted this is hard work, and a long road. But hes even starting to think about Essentials next product. Theres Home, Phoneand maybe soon, Car. Rubin specifically mentioned the potential power of a really smart dashcam anyone can put in their car. Before he gets there, Rubin has a phone and a smart-home hub to ship. And a whole lot of bridges to build.

Google is poised to begin a grand experiment in using machine learning to widen access to healthcare. If it is successful, it could see the company help protect millions of people with diabetes from an eye disease that leads to blindness.

Last year researchers at the search and ads company announced that they had trained image recognition algorithms to detect signs of diabetes-related eye disease roughly as well as human experts. The software examines photos of a patients retina to spot tiny aneurisms indicating the early stages of a condition called diabetic retinopathy, which causes blindness if untreated.

At the 2017 WIRED Business Conference in New York City today, a leader of Googles project said that work has begun on integrating the technology into a chain of eye hospitals in India. The country is one of the many places around the world where a lack of ophthalmologists means many diabetics dont get the recommended annual screening for diabetic retinopathy, said Lily Peng, a product manager with the Google Brain AI research group.

This kind of blindness is completely preventable, but because people cant get screened, half suffer vision loss before theyre detected, she said, describing the current situation in India. One of the promises of this technology is being able to make healthcare more accessible. There are more than 400 million people worldwide with diabetes, including 70 million in India.

Peng, who is an MD, was featured on WIREDs Next List of 20 tech visionaries creating the future earlier this year.

In India, Google is working with the Aravind Eye Care System, a network of eye hospitals established in the late 1970s and credited with helping reduce the incidence of blindness caused by cataracts in the country. Aravind helped Google develop its retinal screening system by contributing some of the images needed to train its image parsing algorithms. The system uses the same deep learning technique that allows Googles image search and photo storage service do things like differentiate between dogs, cats, and people.

Googles paper last year just described the accuracy of that technology when applied to retinal images, not its use in the clinic. Peng said today that Google has just finished a clinical study in Indiameaning the technology was used in real patient carewith Aravind. Work is now under way on getting the technology into routine use with patients, she said.

Peng dismissed suggestions that while this technology might be good for patients, it could mean fewer jobs for doctors. She said Googles algorithms would instead do screening work not being done today due to skills shortages while freeing physicians for more important tasks. Theres not enough expertise to go, we need to have our specialists working on treating people who are sick, said Peng.

Visa is one of the most recognized brands in the world. Its logo is synonymous with the plastic forms of payment for which the company is still best known.

The ability to pay for things with a debit card or your smartphone instead of having to carry around cash (or something to barter) is sort of miraculous. For nearly the whole of human history, and in many parts of the world still, economies have been built on the premise of physical mediums of exchange. If Visas innovation chief Jim McCarthy has his way, Visa itself may soon become invisible.

The magic of Uber and Amazon, they made payment kind of disappear, McCarthy said at the 2017 Wired Business Conference in New York today. (Visa is the conferences main corporate sponsor.)

Naturally, McCarthy wants Visa to stay at the center of the payments ecosystem, even as the consumer-side of paying for stuff becomes less visible. And to do that, he says, Visa has focused on making it easier for tech companies like Apple and Samsung to tap into Visas services.

As an example, when you use something like Apple Pay or Samsung Pay, the software actually creates a unique card number for each of your devices. So if you have an iPhone, a Samsung Gear watch, and a debit card, each one of those has a unique card number tied back to your bank account. If one of your accounts is compromised, new numbers can be created for the devices in the background without you ever having to know about it

Eventually, that that could mean the end of having to manually change your credit card number with every different service every time you get a new card.

To make all that work, the payment apps actually have to communicate with Visas servers to generate and process card numbers. Its not hard to imagine more radical scenarios, like the ability to simply walk into a store, take what you want, and leave without having to worry about the entire payment process. When that finally happens, Visa wants to be there, making all the hard parts of sending and receiving money around the world look easy.

When David Limp thinks about the future of Alexa, the AI assistant he oversees at Amazon, he imagines a world not unlike Star Treka future in which you could be anywhere, asking anything, and an ambient computer would be there to fulfill your every need.

Imagine a world in the not-so-distant future where you could have infinite computing power and infinite storage, Limp said today at WIREDs 2017 Business Conference in New York. If you take off the constrains of servers and building up infrastructure, what could you do?

Limp, who has worked at Amazon since 2010 as the senior vice president for devices, sees Alexa as a critical part of this future. Already, you can shout Hey, Alexa, and get the assistant to tell you the weather forecast, turn off the lights, hail an Uber, or thousands of other things that Amazon and developers have trained it to do. But Limp says theres still plenty more work to be done before we live in the AI-assisted future he thinks about every day, and much of that effort has to do with training machines to better understand humans.

Since Alexa made its debut in 2014, the virtual assistant has taken lease in dedicated devices like the Echo, Tap, Echo Dot, Echo Look, Echo Show, as well as dozens of other supported devices. All that interaction with humans has given Alexa plenty of voice data to parse throughdata thats helped train the assistant to understand preferences, recognize different accents, even figure out the intent of a request without specific keywords. A year ago, if youd told Alexa to order a car, it wouldnt have understood what you meant. (What, like, order one from the Amazon Marketplace?) Now, through improved machine learning, Alexa knows what you mean and will prompt you to enable an Uber or Lyft skill so that it can summon your ride.

Of course, Alexa is far from perfect. Limp says one near-future goal would be improving Alexas understanding of anaphoraso if you ask, Whos the president of the United States? and then follow up by asking, How old is he? Alexa knows youre still talking about Donald Trump. Amazon is also tinkering with Alexas short-term and long-term memory, so that the bot can recall context from yesterdays conversation as well as the thing you asked it five seconds ago.

Those changes involve a shift toward making devices that arent personal but can work for everyone. Think more like a wall clock in the kitchen, which everyone in a household can glance at to get the time, rather than a smartphone, which is designed for one person to use.

As we design the interfaces for Alexa, whether voice or graphical, its about making it ambient and so that anybody can use it, Limp said on stage. If you ask for a timer and I ask for a timer, theyre both going to work.

In a world where devices will surround people all the time, those gadgets will have to understand what humans mean, however they choose to say it. For anyone who uses Alexa, that education is already under way: Every time someone talks to their Echo, the world inches a little bit closer to that Starship Enterprise future Limp imagines.

Urs Hlzle has a big job. As senior vice president of technical infrastructure at Google, hes in charge of the hundreds of thousands of servers in data centers spread across the planet to power the companys ever widening range of services.

Hes also the person that the companys engineers turn to when all that computing power turns out not to be enough.

Today at the 2017 Wired Business Conference in New York, Hlze explained that even with its enormous resources, Google has had to find ways to economize its operations in order to meet its ambitious goals. Most recently, he said, the company was forced to start building its own artificial intelligence chips because the companys existing infrastructure just wouldnt cut it.

Around five years ago, Jeff Dean, who ran Googles artificial intelligence group, realized that his teams technique for speech recognition was getting really good. So good in fact, that he thought it was ready to move from the lab to the real world by powering Androids voice-control system.

But when Dean and Hlzle ran the numbers, they realized that if every Android user in the world used about three minutes of voice recognition time per day, Google would need twice as much computing power to handle it all. The worlds largest computing infrastructure, in other words, would have to double in size.

Even for Google that is not something you can afford, because Android is free, Android speech recognition is free, and you want to keep it free, and you cant double your infrastructure to do that, Hlzle says.

What Google decided to do instead, Hlzle said, is create a whole new type of chip specialized exclusively for machine learning. He likens traditional CPU chips to everyday carsthey have to do a lot of things relatively well to make sure you get where your going. An AI chip, on the other hand, has to do just one thing exceptionally well.

What we built was the equivalent of a drag race car, it can only do one thing, go straight as fast as it can, he says. Everything else it is really, really bad at, but this one thing it is super good at.

Googles custom chips could handle AI tasks far more efficiently than traditional chips, which meant the company could support not just voice recognition, but a broad range of other tasks as well without breaking the bank.

This pattern has repeated itself again and again during Hlzles time at Google. He says that when he started at the company in 1999 (he was somewhere between the seventh and 11th employee hired by Google, depending on how you count), Google only had around 50 servers and was straining to support the number of search queries it received each day. But even with $25 million in venture funding, the company couldnt afford to buy enough ready-made servers to meet its growing demand.

If we had done it with the machines, the servers, that people were using, professional servers, real servers, that would have blown our $25 million in an instant, he says. It really was not an option, so we were forced to look for other ways to do the same thing more cheaply.

So Hlzle and company built their own servers out of cheap parts. Each individual server was less powerful and reliable than a professional-grade machine, but together the clusters of computers they assembled was more powerful and reliable than what they could purchased otherwise. Google didnt invent the idea of using big clusters of cheap machines in lieu of more expensive hardwarethat honor might go to the nearly forgotten search engine Inktomibut it did popularize the model by proving that it could work on a massive scale.

Hlzle and his team had to do something similar years later when it found that off-the-shelf networking gear no longer met its needs. So few companies needed switches that could support the number machines Google had that no established networking company was interested in producing them. So, once again, Hlzle and his team had to build their own gearsomething that other companies, like Facebook, now do as well.

These decisions become a lot easier if all the other alternatives are non-viable, Hlzle says. Its not necessarily that were somehow bolder or more insightful, but its actually that for many of these things in our history, it was almost a forced choice, you didnt really have a viable alternative that you could buy.

But Hlzle probably isnt giving himself enough credit. Most people, after exhausting all the viable options, would conclude that their task is impossible. When Hlzle ran out of options, he created new ones.

Yasmin Green leads a team at Googles parent company with an audacious goal: solving the thorniest geopolitical problems that emerge online. Jigsaw, where she is the head of research and development, is a think tank within Alphabet tasked with fighting the unintended unsavory consequences of technological progress. Greens radical strategy for tackling the dark side of the web? Talk directly to the humans behind it.

That means listening to fake news creators, jihadis, and cyber bullies so that she and her team can understand their motivations, processes, and goals. We look at censorship, cybersecurity, cyberattacks, ISISeverything the creators of the internet did not imagine the internet would be used for, Green said today at WIREDs 2017 Business Conference in New York.

Last week, Green traveled to Macedonia to meet with peddlers of fake news, those click-hungry opportunists who had such a sway over the 2016 presidential election in the US. Her goal was to understand the business model of fake news dissemination so that she and her team can create algorithms to identify the process and disrupt it. She learned that these content farms utilize social media and online advertisingthe same tools used by legit online publishers. [The problem of fake news] starts off in a way that algorithms should be able to detect, she said. Her team is now working on a tool that could be shared across Google as well as competing platforms like Facebook and Twitter to thwart that system.

Its mostly good people making bad decisions who join violent extremist groups.

Along with fake news, Jigsaw is intensely focused on combatting online pro-terror propaganda. Last year, Green and her team travelled to Iraq to speak directly to ex-ISIS recruits. The conversations led to a tool called the Redirect Method, which uses machine learning detect extremist sympathies based on search patterns. Once detected, the Redirect Method serves these users videos that show the ugly side of ISISa counternarrative to the allure of the ideology. At the point that they are buying a ticket to join the caliphate, she said, it was too late.

Its mostly good people making bad decisions who join violent extremist groups, Green says. So the job was: lets respect that these people are not evil and they are buying into something and lets use the power of targeted advertising to reach them, the people who are sympathetic but not sold.

Since its launch last year, 300,000 people have watched videos served up by the Redirect Methoda total of more than half a million minutes, Green said.

Beyond fake news and extremism, Greens team has also created a tool to target toxic speech in comment sections on news organizations sites. They created Perspective, a machine-learning algorithm that uses context and sentiment training to detect potential online harassment and alert moderators to the problem. The beta version is being used by the likes of the New York Times. But as Green explained, its a constantly evolving tool. One potential worry is that it could be itself biased against certain words, ideas, even tones of speech. To counteract that risk, Jigsaw decided not to open up the API to allow others to set the parameters themselves, fearing that an authoritarian regime might use the tool for full-on censorship.

We have to take measures to keep these tools from being misused, she said. Just like the internet itself, which has been used in destructive ways its creators could never have imagined, Green is aware that the solutions her team creates could also be abused. That risk is always on her mind, she says. But its not a reason to stop trying.

Continued here:

Crispr May Cure All Genetic DiseaseOne Day - WIRED

June 06, 2017 08:30 ET | Source: CRISPR Therapeutics AG

BASEL, Switzerland and CAMBRIDGE, Mass. and GOSSELIES, Belgium, June 06, 2017 (GLOBE NEWSWIRE) -- CRISPR Therapeutics AG (NASDAQ:CRSP), a leader in gene-editing based therapeutics, and MaSTherCell SA, a full service contract development and manufacturing organization (CDMO), wholly-owned subsidiary of Orgenesis Inc. (OTCQB:ORGS), today announced the signing of an agreement to develop and manufacture allogeneic CAR-T therapies.

MaSTherCell will be responsible for the development and cGMP manufacturing of CTX101 for use in clinical studies. CTX101 is an allogeneic CAR T-cell therapy currently in development by CRISPR Therapeutics for the treatment of CD19 positive malignancies. The program utilizes CRISPRs proprietary gene-editing technology to make targeted modifications to the T-cell, thereby enabling an allogeneic, or off-the-shelf, product that is applicable to a broader patient population and addresses the challenges of the current generation of autologous therapies.

The signing of this agreement represents an important milestone for CRISPR Therapeutics as it not only demonstrates our progress with CTX101, but also lays the foundation for our broader activities and emerging pipeline in the allogeneic cell therapy field, said Jon Terrett, Head of Immuno-Oncology Research and Translation at CRISPR Therapeutics.

Were really excited to have initiated work with MaSTherCell. Their market-leading capabilities and deeply relevant experience stood out as we looked for a partner to help accelerate our pre-clinical programs towards the clinic in both the US and Europe, added Samarth Kulkarni, President and Chief Business Officer at CRISPR Therapeutics.

MaSTherCell provides process optimization and manufacturing services to cell therapy organizations. It has quickly built the most extensive experience in the field and is focused on developing solutions to the industrialization challenges facing the cell therapy sector.

We are looking forward to working with CRISPR Therapeutics. They have made significant progress to date with multiplexed gene editing and this provides a solid platform upon which we can bring to bear MaSTherCells significant experience in the manufacturing of allogeneic cell therapies, said Denis Bedoret, General Manager at MaSTherCell.

About CRISPR Therapeutics

CRISPR Therapeutics is a leading gene-editing company focused on developing transformative gene-based medicines for serious diseases using its proprietary CRISPR / Cas9 gene-editing platform. CRISPR / Cas9 is a revolutionary technology that allows for precise, directed changes to genomic DNA. The company's multi-disciplinary team of world-class researchers and drug developers is working to translate this technology into breakthrough human therapeutics in a number of serious diseases. Additionally, CRISPR Therapeutics has established strategic collaborations with Bayer AG and Vertex Pharmaceuticals to develop CRISPR-based therapeutics in diseases with high unmet need. The foundational CRISPR / Cas9 patent estate for human therapeutic use was licensed from the company's scientific founder Emmanuelle Charpentier, Ph.D. CRISPR Therapeutics AG is headquartered in Basel, Switzerland, with its wholly-owned U.S. subsidiary, CRISPR Therapeutics, Inc., and R&D operations based in Cambridge, Massachusetts. For more information, please visit http://www.crisprtx.com.

About MaSTherCell

MaSTherCell is a dynamic and global Contract Development and Manufacturing Organization (CDMO) on a mission to deliver optimized process industrialization capacities to cell therapy organizations, and speed up the arrival of their therapies onto the market. The company is the subsidiary of Orgenesis Inc. (OTCQB:ORGS), a cell therapy and regenerative medicine company that is committed to developing a cure for Type 1 diabetes. The heart of MaSTherCell is a team of more than 80 highly dedicated experts combining strong experience in cGMP cell therapy manufacturing with a technology-focused approach and a substantial knowledge of the industry. From technology selection to business modeling, GMP manufacturing, process development, quality management and assay development, MaSTherCells teams are fully committed to helping their clients fulfill their objective of providing sustainable and affordable therapies to their patients. The company operates in a validated and flexible facility located in the strategic center of Europe within the Walloon healthcare cluster, Biowin. For more information, please visit http://www.masthercell.com.

About Orgenesis

Orgenesis is a vertically-integrated biopharmaceutical company. The Companys MaSTherCell subsidiary is a global Contract Development and Manufacturing Organization (CDMO) delivering optimized process industrialization capacities to cell therapy companies, and speeding up the arrival of these therapies onto the market. Orgenesis is also developing its own proprietary cell therapies through its subsidiary Orgenesis Ltd., utilizing its proprietary process of Transdifferentiation (or cell reprogramming), whereby an adult cell is converted into another type of cell, such as reprogramming human liver cells into glucose-responsive, fully functional, insulin producing cells, which have the potential to provide a practical cure for insulin dependent diabetes. For more information, visit http://www.orgenesis.com.

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CRISPR Therapeutics and MaSTherCell SA sign service agreement ... - GlobeNewswire (press release)

Intellia Therapeutics is teaming up with Italys San Raffaele University and Research Hospital to develop engineered T-cell therapies for hard-to-treat cancers. The 3-year research collaboration, option, and license agreement will aim to leverage Intellias CRISPR/Cas9 genome-editing platform to generate improved T-cell therapies for both hematologic and solid tumors. The agreement includes options and licenses to key technologies developed at San Raffaele for producing engineered cell therapies.

The collaboration represents the first external partnership for Intellias eXtellia division, which it set up in January 2016 to focus on applying the CRISPR/Cas9 genome-editing platform for applications in immuno-oncology and autoimmune and inflammatory disease indications.

Chiara Bonini, M.D., head of San Raffaeles Experimental Hematology Unit and deputy director of the Division of Immunology, Transplantation, and Infectious Diseases, will lead the scientific work at San Raffaele. Through this collaboration, eXtellia aims to apply CRISPR/Cas9 genome editing in a multifaceted way to modulate the fundamental properties of engineered immune cells and amplify their anticancer properties far beyond current applications, said Andrew Schiermeier, Ph.D., svp at eXtellia. San Raffaele and Dr. Bonini are recognized globally as leaders in cell therapy and immuno-oncology, with excellent track records in translating innovative research into approved therapies."

Intellia is developing a series of ex vivo and in vivo genome-editing programs in-house and in partnership with industry. The firms preclinical in vivo pipeline is focused on using lipid nanoparticles to target the liver and is headed by a Regeneron-partnered program against transthyretin amyloidosis (ATTR). The in vivo pipeline also includes programs targeting alpha-1 antitrypsin deficiency (AATD), hepatitis B virus (HBV), and inborn errors of metabolism (IEMs). Regeneron and Intellia inked their licensing and collaboration agreement to develop CRISPR-based products for up to 10 targetsin 2016.

During late 2014, Intellia and Novartis inked a strategic collaboration and licensing agreement focused on developing ex vivo CRISPR/Cas9-based chimeric antigen receptor (CAR) T cells and hematopoietic stem cells (HSCs). Under the terms of the agreement, Novartis has exclusive rights to develop all programs focused on engineered CAR T cells. Novartis and Intellia are jointly developing multiple HSC programs, and Intellia will in addition develop its own proprietary internal HSC pipeline.

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Intellia, San Raffaele Partner on CRISPR/Cas9-Edited Anticancer T ... - Genetic Engineering & Biotechnology News

CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, is the basis for a revolutionary genome-editing technology that allows researchers to make very precise modifications to DNA.

The implications are enormous not only for the treatment of disease, but also for genetic engineering and scientific research more broadly.

It's no surprise, then, that CRISPR has been making the news, especially over the last few years, as its applications have become increasingly appreciated and developed. In 2015, the journal Science named CRISPR the breakthrough of the year; earlier this year, Emmanuelle Charpentier and Jennifer Doudna received the 2017 Japan Prize for their role in inventing the technology just one of the latest in a string of honors. CRISPR seems to be everywhere, from headlines to classrooms.

So surely everyone understands exactly what CRISPR is and how it works?

Or not. That's one reason a new video, produced by Wired magazine, is worth a look. The video features Dr. Neville Sanjana, an assistant professor at New York University and a member of the New York Genome Center, explaining CRISPR five ways: to a child of 7; a high school student; a college student; a graduate student; and an expert in the field. The conversation ranges from genomes to allergies, from ethics to the value of basic research.

Besides offering a valuable introduction to CRISPR, the video illustrates how understanding can evolve from a relatively short description to a dialogue with more nuance. Research finds that we indeed explain science differently to children than to adults, and Sanjana's explanations showcase some of that range.

The video won't transform your genome, but it might make a helpful edit to your understanding.

Tania Lombrozo is a psychology professor at the University of California, Berkeley. She writes about psychology, cognitive science and philosophy, with occasional forays into parenting and veganism. You can keep up with more of what she is thinking on Twitter: @TaniaLombrozo

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Five Different Ways To Explain CRISPR : 13.7: Cosmos And Culture ... - NPR

CRISPR may introduce hundreds of unwanted mutations into the genome, a small study finds.

Until now, 'off-target effects' of the CRISPR/Cas9 system were thought to be minimal, with improvements to the technique reducing errors to nearly undetectable levels. However, now a new study suggests previous methods for detecting off-target mutations may have underestimated the true scale of unwanted effects.

'We feel it's critical that the scientific community consider the potential hazards of all off-target mutations caused by CRISPR,' said co-author Dr Stephen Tsang, from Columbia University Medical Centre, New York. 'Researchers who aren't using whole genome sequencing to find off-target effects may be missing potentially important mutations. Even a single nucleotide change can have a huge impact.'

The precise nature of CRISPR has contributed to its growing popularity in recent years. Yet until now, researchers have been using computer algorithms to check the accuracy of the technique,by identifying and scanning regions of the genome most likely to be affected by genome editing.

'These predictive algorithms seem to do a good job when CRISPR is performed in cells or tissues in a dish, but whole genome sequencing has not been employed to look for all off-target effects in living animals,' said co-author Dr Alexander Bassuk at the University of Iowa.

In a previous study, the team had used CRISPR in two mice to correct a faulty gene that causes blindness. In their new study, published in Nature Methods, the researchers compared the genomes of the edited mice to a single non-edited control mouse.

They found over 1500 single-nucleotide mutations and over 100 larger deletions or insertions in the two CRISPR mice. In spite of this, the mice appeared healthy and did not show any obvious side effects due to the off-target mutations.

Some experts in the field are sceptical of the findings, raising concerns over the experimental design of the study. Dr Gatan Burgio from the Australian National University, Canberra, whose research group has a keen interest in CRISPR genome-editing technologies, stated to Medium:'I would predict very few if not close to none of these variants are CRISPR related.' Instead he believes a number of issues with the methodology, as well as the small sample size, can explain the 'abnormal number of mutations'. Further investigation by other research groups will be needed to validate these results and determine the future implications for CRISPR methods.

The first CRISPR clinical trial in patients already underway in China and another is expected to start in the US in the next year.

The researchers say they hope other groups will use their methods to assess off-target mutations and improve the accuracy of CRISPR.

'We're still upbeat about CRISPR,' said co-author Dr Vinit Mahajan at Stanford University. 'We're physicians, and we know that every new therapy has some potential side effects - but we need to be aware of what they are.'

Originally posted here:

CRISPR genome editing may cause unintended mutations - BioNews

In case you havent already heard of CRISPR-Cas9, it is the revolutionary gene-editing technology, discovered just a few years ago, that allows scientists to edit the DNA of any species with an unprecedented precision and efficiency. Today, thousands of researchers around the world are doing experiments with CRISPR, in the hope to cure us from genetic diseases and even deliver us designer babies. The first clinical trial to employ CRISPR-Cas9 is now underway in China, hoping to fight targeted cancers with modified immune cells.

The gene-editing method is based on the protective mechanism of bacteria against viruses. An RNA molecule carries segments of DNA from a previously encountered virus together with an enzyme (Cas9). Once the molecule encounters that same sequence of DNA, the enzyme gets activated and cuts it out. Researchers discovered that they can use this system to cut any DNA sequence at a precisely chosen location.

While the tool is touted for its precision, it is far from error free. Mutations do occur around the areas where the DNA has been cut and needs to be repaired. And sometimes CRISPR may hit unintended parts of the genome. Computer algorithms identify the most likely areas for these off-target mutations, which are later examined by researchers for deletions and insertions. However, whole-genome sequencing (WGS) - examining the entire DNA of living animals that had undergone gene editing - hadn't been done.

In a recently published study in the journal Nature Methods, titled Unexpected mutations after CRISPRCas9 editing in vivo scientists used whole-genome sequencing to study the mutations that had occurred in the DNA of mice that had undergone CRISPR gene editing.

Genetic Engineering and Biotechnology News reports that the investigators were able to determine that CRISPR had successfully corrected a gene that causes blindness, but found that the genomes of two independent gene therapy recipients had sustained more than 1500 single-nucleotide mutations and more than 100 larger deletions and insertions. None of these DNA mutations were predicted by computer algorithms that are widely used by researchers to look for off-target effects.

Co-author of the study Vinit Mahajan, M.D., Ph.D. said:

"We're still upbeat about CRISPR, we're physicians, and we know that every new therapy has some potential side effectsbut we need to be aware of what they are."

The authors are encouraging scientists to use the WGS method to determine all off-target effects of their CRISPR experiments.

In the last few days, however, some scientists have raised concerns about the validity of the study, questioning its methodology. Dr Gaetan Burgio, Group leader and head of the transgenesis facility at the Australian National University said in a Journal club review of the paper:

The claims over this paper are unsurprising as Cas9 enzyme could remain in the cells for days and create random indels in the genome. However, the main issues for me resides in the overestimation of the number of off target effects due to the lack of rigor in the experimental design to detect these unexpected mutations. In short my main point is these unintended mutation are likely to have preexisted prior to the injection of CRISPR system.

One thing is sure there is a lot more work to be done to ensure the safety of the CRISPR/Cas9 technology.

Photo Credit:Pixabay

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CRISPR May Cause Hundreds of Unintended Mutations Into the ... - Big Think

For the past few years, CRISPR has constantly been in the spotlight for a myriad of reasons. In addition to the rapid advancements in the technology and its expanding applications, umpteen number of news stories have covered the battle for the patent between competing groups. Whether we talk about benignmosquitoes that do not transmit malaria or extraordinarily muscular beaglesormini pigs, CRISPR is everywhere and everyone is using it.

CRISPR is a natural adaptation found in bacteria which allows it to defend itself from invading bacteriophages. The host bacteria creates a memory of the invading bacteriophage DNA sequence in its own genome. This serves as a memory that can be used to cleave specific DNA sequences of invading organisms by the cleavage enzyme Cas9 in the event of an infection. Scientists have been able to use this ability of the Cas9 enzyme to undertake targeted gene editing inin vitroas wellasin vivomodel systems.

Last year backed by the venture capitalist Sean Parker, The National Institute of Health approved a proposal for human clinical trials of CRISPR. Taking it one step ahead, Chinese oncologists at Sichuan University injected CRISPR-Cas9 modified cells in a patient suffering from an aggressive form of lung cancer in October last year.Despite the ease of use offered by CRISPR to completely ablate gene expression, there have been concerns regarding the specificity and efficiency in practice.

A recent study revealing several unexpected mutationsafter CRISPR-Cas9 editing in vivohas set alarm bells ringing.

A team of researchers in the US set out to repair a genetic mutation known to cause blindness in mice. Using CRISPR gene editing, they were able to successfully correct the targeted mutation in each of the two mice they treated. In a later study, the team sequenced the entire genome of two mice that had undergone CRISPR gene editing, and one healthy control. They observed an alarming number of additional DNA changes more than 1,600 per mouse in areas of the genome they did not intend to modify. Researchers in the past used computer algorithms to identify and examine areas most likely to be affected by off-target mutations.

These predictive algorithms seem to do a good job when CRISPR is performed in cells or tissues in a dish, but whole genome sequencing has not been employed to look for all off-target effects in living animals Alexander Bassuk, team member, University of Iowa.

Researchers who arent using whole genome sequencing to find off-target effects may be missing potentially important mutations, even a single nucleotide change can have a huge impact.- Dr. Tsang

This new piece of information from Schaefer et alcomes at a crucial moment in time as regulatory bodies across the world are getting ready to approve CRISPR-based therapies. Whole genome sequencing could be an important emerging benchmark for approved CRISPR therapies.

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How many is one too many? Off target mutations in CRISPR reported by whole genome sequencing - Biotechin.Asia

Slide: 1 / of 1. Caption: Getty Images

When it comes toCrispr, the bacterial wnderenzyme that allows scientists to precisely edit DNA, no news is too small to stir up some drama. On Tuesday morning, doctors from Columbia, Stanford, and the University of Iowa published a one-page letterto the editor of Nature Methodsan obscure but high-profile journaldescribing something downright peculiar. About a year ago, they used Crispr to edit out a blindness-causing genetic defect in mice, curing two of their cohort. Later, they decided to go back and sequence their genomes, just to see what else Crispr did while it was in there.

A lot, it turned out. With their method, the researchers observed close to 2,000 unintended mutations throughout each mouses genome, a rate more than 10 times higher than anyone had previously reported. If that holds up, Crispr-based therapies are in for some serious trouble. No one wants to go in for a vision-restoring treatment, only to wind up with cancer because of it.

The ensuing headlines were gleefully apocalyptic: Crispr May Not Be Nearly as Precise as We Thought, Crack in Crispr Facade after Unanticipated In Vivo Mutations Arise, and my personal favorite, Small Study Finds Fatal Flaw in Gene Editing Tool Crispr. And then the biotech stocks went into a tailspin. The big three Crispr-based tech companies got hit the hardest. By the close of trading Tuesday, Editas Medicine was down nearly 12 percent, Crispr Therapeutics fell more than 5 percent, and Intellia Therapeutics had plunged to just over 14 percent.

This was far from just a blip in the nerdy news cycle. A reaction to a single scientific publication on this scale raises important questions about sciences incentive structure, its processes for publicly evaluating evidence, and what happens when those butt up against the prevailing philosophies of other professionsnamely, medicine.

A decade ago, most of the conversations about this letter would have happened in laboratory hallways. But this week, geneticists, microbiologists, and molecular bioengineers took to Twitter to digest the paper in public. While some experts decried the paper as unnewsworthy (everyones known about Crispr off-target mutations forever!) the majority of threads ticked off the experiments flaws: Tiny sample size! Insufficient controls! Weird Crispr delivery! Out of date/inefficient version of Crispr! The list goes on. Many doubted if it had been peer-reviewed. (It had.) The hashtag #fakenews even made a few appearances.

To be sure, the results do not match up well with whats already in the literature on this subject. And, as the paper itself says, The unpredictable generation of these variants is of concern. Which is to say, the authors have no idea why or how these mutations are happening. Derek Lowe, a longtime pharmaceutical industry researcher who writes a blog on the subject for Science, had enough doubt in the results that he bought up some Editas and Crispr Therapeutics stocks while they were down.

But most scientists, while skeptical of the results, were more disappointed in the way the paper was blown out of proportion. Its critically important to look closely at genomes being edited with the Crispr system, ideally with a method sensitive enough to detect even rare off-target events, says Stephen Floor, a biophysicist who worked in Crispr creator Jennifer Doudnas lab at UC Berkeley before beginning his own gene editing cancer research at UCSF. Saying Crispr is 100 percent accurate or grossly inaccurate isnt helpful. What scientists need to understand is which sites are being cut, what rules govern which sites get cut, and how to emphasize only cutting at sites you want. It will be interesting to watch subsequent validation that gets to the bottom of why this report found such a surprisingly high rate of mutation, he says.

The key word there, if you didnt catch it, is validation. Its pretty much the foundational tenet of science. You have an idea, you test it, you test it again, you eliminate confounding factors as best as you can and then you validate your results. All the critiques of the Nature Methods paper assumed the authors were operating with that same premise.

But in this case, the authors werent scientists: They were doctors. And in medicine, theres a different guiding principle that places a premium on sharing significant results at face value.

The history of the case study is long and celebrated in medicine. The first recorded report of what would one day be known as HIV/AIDS was published by the CDC as five strange cases of pneumonia in gay men in Los Angeles. Vinit Majahan, an opthamologist at Stanford and co-author of Tuesdays Crispr paper, says it was in that spirit that he and his collaborators submitted their results to the journal. I dont have any money in Crispr, I only have patients, he says. The culture and pressures of science right now push people to not share results that arent a splashy cure. But in medicine you cant do that. If you make an observation thats important enough to share with your community, youre obligated to do that right away.

Since Majahans team is working on turning its previous work into a human treatment, they saw it as irresponsible to take their results, small as they were, and sweep them under the rug. Crispr is most often described as molecular scissors, but doctors like Majahan tend to think of it more like a drug. And the more successes Crispr haslike curing mouse blindnessthe more doctors start asking the next logical questions about things like dosing and formulations and side effects. How long can you have the enzyme floating around your cells before it cuts somewhere it shouldnt? Whats the right enzyme for the job?

Matthew Taliaferro, who studies gene expression and gene editing at MIT, thinks the paper will get more scientists thinking about those kinds of questions. Crispr definitely has off-targets. But a lot of people use it assuming no other mutations get introduced during the process, he says. So getting people to talk about the need for controls is a good outcome of this whole thing. And while he was surprised by the lack of some straightforward controls, Taliaferro is awarethat his initial reactions were colored by some of the Twitter threads hed already absorbed before tracking down the paper himself. I think the data is perfectly fine, he says. Its just the interpretation of it that to me seems odd. Namely, that every Crispr application is deeply flawed.

Which was never Majahans intention in the first place. We didnt write the headlines, he says. We dont think Crispr is bad, we think its great. But he didnt get the opportunity to tell people that, because for one thing, hes not on Twitter. When asked how he was responding to the criticisms from the scientific community, he laughed and said, Can you read some to me? Ive heard theres some nasty stuff out there.

The amplifications (and denigrations) of those interpretations around Science Twitter may not have been as knee-jerk as all the Crispr Is Terrible and Broken Forever headlines. But still, they were an overreactionbecause after all, this was just a single paper. No one should presume a standalone study can predict the future of an entire technique. At most, it indicates that Crispr is entering its inevitable adolescence, when shiny silver bullet technologies get banged up and battle worn by new data. That doesnt mean it isnt the real deal. Just that it should be looked at real hard every step of the way.

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Crispr's Next Big Debate: How Messy Is Too Messy? - WIRED

A new research paper is stirring up controversy among scientists interested in using DNA editing to treat disease.

In a two-page article published in the journal Nature Methods on May 30, a group of six scientists report an alarming number of so-called off-target mutations in mice that underwent an experimental gene repair therapy.

CRISPR, the hot new gene-editing technique thats taken biology by storm, is no stranger to headlines. What is unusual, however, is a scientific article so clearly describing a potentially fatal shortcoming of this promising technology.

The research community is digesting this news with many experts suggesting flaws with the experiment, not the revolutionary technique.

Unwanted DNA changes

The research team sought to repair a genetic mutation known to cause a form of blindness in mice. This could be accomplished, they showed, by changing just one DNA letter in the mouse genome.

They were able to successfully correct the targeted mutation in each of the two mice they treated. But they also observed an alarming number of additional DNA changes more than 1,600 per mouse in areas of the genome they did not intend to modify.

The authors attribute these unintended mutations to the experimental CRISPR-based gene editing therapy they used.

A central promise of CRISPR-based gene editing is its ability to pinpoint particular genes. But if this technology produces dangerous side effects by creating unexpected and unwanted mutations across the genome, that could hamper or even derail many of its applications.

Several previous research articles have reported off-target effects of CRISPR, but far fewer than this group found.

Reaction is skeptical

The publicly traded biotech companies seeking to commercialize CRISPR-based gene therapies Editas Medicine, Intellia Therapeutics and Crispr Therapeuticsall took immediate stock market hits based on the news.

Experts in the field quickly responded.

Either the enzyme is acting at near optimal efficiency or something fishy is going on here, tweeted Matthew Taliaferro, a postdoctoral fellow at MIT who studies gene expression and genetic disease. The Cas9 enzyme in the CRISPR system is what actually cuts DNA, leading to genetic changes. Unusually high levels of enzyme activity could account for the observed off-target mutations more cutting equals more chances for the cell to mutate its DNA. Different labs use slightly different methods to try to ensure the right amount of cuts happen only where intended.

Unusual methods were used, tweeted Lluis Montoliu, who runs a lab at the Spanish National Centre for Biotechnology that specializes in editing mice genes using CRISPR. He believes the authors used suboptimal molecular components in their injected CRISPR therapies specifically a plasmid that causes cells to produce too much Cas9 enzyme likely leading to the off-target effects they observed.

Gatan Burgio, whose laboratory at the Australian National University is working to understand the role that cellular context plays on CRISPR efficiency, believes the papers central claim that CRISPR caused such an alarming number of off-target mutations is not substantiated.

Burgio says there could be a range of reasons for seeing so many unexpected changes in the mice, including problems with accurately detecting DNA variation, the extremely small number of mice used, random events happening after Cas9 acted or, he concedes, problems with CRISPR itself.

Burgio has been editing the DNA of mice using CRISPR since 2014 and has never seen a comparable level of off-target mutation. He says hes confident that additional research will refute these recent findings.

Continuing CRISPR work

Although the news of this two-mouse experiment fired up the science-focused parts of the Twittersphere, the issue it raises is not new to the field.

Researchers have known for a few years now that off-target mutations are likely given certain CRISPR protocols. More precise variants of the Cas9 enzyme have been shown to improve targeting in human tissue the lab.

Researchers have also focused on developing methods to more efficiently locate off-target mutations in the animals they study.

As scientists continue to hone the gene-editing technique, we recognize theres still a way to go before CRISPR will be ready for safe and effective gene therapy in humans.

Ian Haydon, Doctoral Student in Biochemistry, University of Washington

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CRISPR controversy raises questions about gene-editing technique ... - Salon

All pipelines showed that F03 harbored 164 indels and 1,736 SNVs (63 and 885 of these, respectively, associated with known genes). F05 harbored 128 indels and 1,696 SNVs (51 and 865 of these, respectively, associated with known genes). . .The same 117 indels and 1,397 SNVs were detected in both of the CRISPR-treated mice, which indicated nonrandom targeting. . .The mutation rate detected in CRISPR- treated mice was substantially higher than that generated by spontaneous germline mutations (3 to 4 indels and 90 to 100 SNVs, de novo, per generation).

Oh dear. If that holds up, thats clearly going to be a major difficulty in bringing CRISPR-based therapeutics forward, at least with the current state of the art. Just as worrisome, if not more, is that fact that software predictions of the fifty most likely off-target sites of action did not match any of the variants that were actually seen. So it would appear that we have no idea of whats going on here. As the paper says, with great restraint, The unpredictable generation of these variants is of concern.

Now we get to the arguing, though, because the big question is whether these results are correct. They do not match up well with whats already in the literature on the subject, thats for sure. On Twitter, Nicolas Bray brought up one of the concerns. His question is a simple one, but it needs to be answered: The two treated mice were siblings, while the control was (apparently) more distantly related. How many of these variations, then, can be ascribed to what the mice started out with?

The control animal was from the same inbred strain, but still the number of variations seen in this paper is way off what others have reported. Sam Sternberg noted that the paper (and its supplementary information) is not very clear about the relationship between the mice, and also suspects that many of these mutations are from the founders and not the CRISPR treatment per se. Meanwhile, Gaetan Burgio pointed out that the experimental details say:

Briefly, an sgRNA-expressing plasmid had been co-injected, into FVB/NJ zygotes, with the single-stranded oligodeoxynucleotide (ssODN) donor template and Cas9 protein to generate mosaic F0 founders.

Plasmids themselves, he notes, are known to cause mutations, since they have much longer half-lives than RNA or protein, and he says his own labs work with direct injection of sgRNA and Cas9 protein showed far fewer mutations, in keeping with the rest of the literature. Another potential problem has been brought up by many observers: This study has an n of 2, with one control animal. Thats a pretty thin platform on which to build the CRISPR Is Doomed! monument.

So there are a number of reasons to wonder if these results are real. If they are, other questions arise about the newer Cas9 variant enzymes and various sgRNA designs, but Im not even going to think about those, to be honest, until this result has been replicated and given a thorough going over. The implications are too big to start running around in circles just yet. There will be time for that, if needed...

Update, in the interests of full disclosure: After publishing this post and looking at the moves in the stock prices of both EDIT and CRSP yesterday and today, I found my own doubts convincing enough to have bought some of both as a short-term trade. I have no idea what their long-term prospects are, but their sudden drops due to this news may not be justified. On the rare occasions that Ive taken a position in any sort of individual biopharma stock, Ive noted it on the blog, and will continue to do so. Now you all can watch me lose money in real time...

Disclosure: I am long EDIT and CRSP.

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Trouble With CRISPR? Maybe - But Maybe Not - Seeking Alpha

Skip to content On November 4 2016, the Eiffel Tower was illuminated in green to celebrate the entry into the Paris Agreement. Credit: U.S. Department of State

This week, President Trump pulled the U.S. from the Paris Climate Agreement, which 195 countries had signed in 2015, pledging to reduce greenhouse emissions. Trump said that the agreement imposed draconian financial burdens on the U.S. and that he would negotiate for a deal that is fair. Maggie Koerth-Baker, senior science reporter at Fivethirtyeight.com, fills us in on the announcement. Plus, she talks about new CRISPR clinical trials, and NASAs Parker Probe Plus, a mission to explore the sun.

[What happens if the U.S. leaves the Paris climate deal?]

Maggie Koerth-Baker

Maggie Koerth-Baker is a senior science reporter with FiveThirtyEight.com.Shes based inMinneapolis, Minnesota.

Alexa Lim is a producer for Science Friday. Her favorite stories involve space, sound, and strange animal discoveries.

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Trump Pulls US From Climate Agreement, CRISPR Human Trials, And A NASA Sun Orbiter - Science Friday

Michael J. Wade. Credit: James Brosher, IU Communications

Researchers are exploring the use of the revolutionary gene-editing tool CRISPR-Cas9 to fight human disease and agricultural blight. But a study from Indiana University has found several challenges to the method's use in saving lives and crops.

The research, reported today in the journal Science Advances, combines advanced genetic and statistical analyses to show how certain genetic and behavioral qualities in disease-carrying insects, like mosquitoes, make these species resistant to genetic manipulation.

This resistance could complicate attempts to use CRISPR-Cas9 in the fight against malaria -- a deadly mosquito-borne disease that threatens over 3 billion people worldwide -- or crop blights such as the western corn rootworm, an invasive species that costs the U.S. about $1 billion in lost crops each year.

The discovery of the CRISPR-Cas9 system -- or simply "CRISPR" -- in the early 2010s introduced an unprecedented level of accuracy in genetic editing. Scientists can use the method to design highly precise genetic "scissors" that snip out and replace specific parts of the genome with sequences of their choosing. Two English scientists were the first to show the method could spread infertility in disease-carrying mosquitoes in late 2015.

"We found that small genetic variation within species -- as well as many insects' tendency to inbreed -- can seriously impact the effectiveness of attempts to reduce their numbers using CRISPR technology," said Michael J. Wade, Distinguished Professor of Biology at IU Bloomington. "Although rare, these naturally occurring genetic variants resistant to CRISPR are enough to halt attempts at population control using genetic technology, quickly returning wild populations to their earlier, 'pre-CRISPR' numbers."

This means costly and time-consuming efforts to introduce genes that could control insect populations -- such as a trait that causes female mosquitoes to lay fewer eggs -- would disappear in a few months. This is because male mosquitoes -- used to transmit new genes since they don't bite -- only live about 10 days.

The protective effect of naturally occurring genetic variation is strong enough to overcome the use of "gene drives" based on CRISPR-based technology -- unless a gene drive is matched to the genetic background of a specific target population, Wade added. Gene drives refer to genes that spread at a rate of nearly 90 percent -- significantly higher than the normal 50 percent chance of inherence that occurs in sexually reproducing organisms.

Wade, an expert in "selfish genes" that function similarly to gene drives due to their "super-Darwinian" ability to rapidly spread throughout a population, teamed up with colleagues at IU -- including Gabriel E. Zentner, an expert in CRISPR-based genetic tools and assistant professor in the Department of Biology -- to explore the effectiveness of CRISPR-based population control in flour beetles, a species estimated to destroy 20 percent of the world's grain after harvest.

The team designed CRISPR-based interventions that targeted three segments in the genome of the flour beetle from four parts of the world: India, Spain, Peru and Indiana. They then analyzed the DNA of all four varieties of beetle and found naturally occurring variants in the targeted gene sequence, the presence of which would impact the effectiveness of the CRISPR-based technology.

The analysis revealed genetic variation in all four species at nearly every analyzed DNA segment, including a variance rate as high as 28 percent in the Peruvian beetles. Significantly, Wade's statistical analysis found that a genetic variation rate as low as 1 percent -- combined with a rate of inbreeding typical to mosquitos in the wild -- was enough to eliminate any CRISPR-based population-control methods in six generations.

The results suggest that a careful analysis of genetic variation in the target population must precede efforts to control disease-carrying insects using CRISPR technology. They also suggest that the unintended spread of modified genes across the globe is highly unlikely since typical levels of genetic variation place a natural roadblock on spread between regions or species.

"Based on this study, anyone trying to reduce insect populations through this method should conduct a thorough genetic analysis of the target gene region to assess variation rates," Wade said. "This will help predict the effectiveness of the method, as well as provide insight into ways to circumvent natural genetic variation through the use of Cas9 variants with an altered sequence specificity."

This article has been republished frommaterialsprovided by Indiana University. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference

Drury, D. W., Dapper, A. L., Siniard, D. J., Zentner, G. E., & Wade, M. J. (2017). CRISPR/Cas9 gene drives in genetically variable and nonrandomly mating wild populations. Science Advances, 3(5), e1601910.

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CRISPR Gene Drives May Not Be As Effective As Once Hoped - Technology Networks

In Brief The CRISPR process will be used inside the human body for the first time on July 15th to combat HPV, which impacts millions of people worldwide. And this is just one of a huge amount of proposed CRISPR studies occurring soon. Uninvasive CRISPR

A new CRISPR trial, which hopes to eliminate thehuman papillomavirus (HPV), is set to be the first to attempt to use thetechnique inside the human body. In the non-invasive treatment, scientists will apply a gel that carries the necessary DNA coding for the CRISPR machinery to the cervixes of 60 women between the ages of 18 and 50. The team aims to disable the tumor growth mechanism in HPV cells.

The trial stands in contradistinction to the usual CRISPR method of extracting cells and re-injecting them into the affected area; although it will still use the Cas9 enzyme (which acts as a pair of molecular scissors) and guiding RNA that is typical of the process.

20 trials are set to begin in the rest of 2017 and early 2018. Most of the research will occur in China, and will focus on disabling cancers PD-1 gene that fools the human immune system into not attacking the cells. Different trials are focusing on different types of cancer including breast, bladder, esophageal, kidney, and prostate cancers.

The study, if it succeeds, will be promising for sufferers of HPV and act as a milestone in the CRISPR process. Although HPV is not necessarily cancerous, it cancause cervical cancer. In the U.S. alone, there are more than 3 million new infections every year.Although there is a vaccine for the virus, currently, once you have it you can never get rid of it.

More generally, the CRISPR process could be nothing short of a miracle: if it passes all medical tests it wouldnt just make medicine a whole new kettle of fish, it would reinvent the kettleand the fish, for almost any field. It is cheaper than other gene editing therapies, and could potentially save millions of lives by curing diseases we can only deal with therapeutically like cancer, diabetes and cystic-fibrosis. Crops could be altered more effectively using the process. Drugs and materials that were never possible before could be pioneered.

However, it is still extremely nascent technology, and many fear that there could also be a host of unexpected consequences. Recently, it has been found that it causes hundreds of unexpected mutations in DNA. While these concerns are valid, more research is necessary. Which is why the upcoming studies over the next few years are so vital to the future of our health.

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A World First CRISPR Trial Will Edit Genes Inside the Human Body - Futurism