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Everything You Need To Know About Crispr Gene Editing

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days of gene editing, biologists had a molecular tool kit that was somewhat akin to a printing press. Which is to say, altering DNA was a messy, labor-intensive process of loading genes onto viruses bound for target cells. It involved more than a fair amount of finger-crossing. Today, scientists have the genetic equivalent of Microsoft Word, and they are beginning to edit DNA almost as easily as software engineers modify code. The precipitating event? Call it the Great Crispr Quake of 2012.If you’re asking “What’s Crispr?” the short answer is that it’s a revolutionary new class of molecular tool that scientists can use to precisely target and cut any kind of genetic material. Crispr systems are the fastest, easiest, and cheapest methods scientists have ever had to manipulate the code of life in any organism on Earth, humans included. It is, simply, the first technology truly capable of changing the fundamental chemistry of who we are.The long answer is that Crispr stands for Clustered Regularly Interspaced Palindromic Repeats. A Crispr system consists of a . Such systems naturally evolved across the bacterial kingdom as a way to remember and defend against invading viruses. But researchers recently discovered they could repurpose that primordial immune system to precisely alter genomes, setting off a billion-dollar boom in DNA hacking.Every industry is throwing mad money at Crispr—pharma, agriculture, energy, materials manufacturing, you name it. . Companies are using it to make , , —and, yes, . Academic researchers have almost universally adopted Crispr to more deeply understand the biology of their model organisms. Supporting this biohacking bonanza is an increasingly crowded Crispr : businesses building gene-editor design tools and shipping synthetic guide RNAs or pre-Crispr’d cell lines to these companies’ doors. So far, though, very few Crispr-enhanced products have made it into the hands of actual consumers. In their place, hyperbolic headlines have bugled society’s greatest hopes and fears for the technology, from saving near-extinct species to igniting a superbaby arms race.In November 2018, a Chinese scientist named He Jiankui stunned the world with claims that he had in an experiment . The fast-unfolding scandal roused the world’s scientists and government officials to address the now-urgent need to figure out how to regulate such a powerful technology. Crispr may have delivered designer children faster than anyone thought possible. But it’s still a long way from ending disease or hunger or climate change. Maybe it never will. Crispr is, however, already beginning to reshape the physical world around us in much less radical ways, one base pair at a time.The History of CrisprIt all started with yogurt. To make it, dairy producers have long employed the help of Streptococcus thermophilus, bacteria that gobble up the lactose in milk and poop out lactic acid. It wasn’t until 2005, though, that a young microbiologist named Rodolphe Barrangou discovered that S. thermophilus contained odd chunks of repeating DNA sequences—Crisprs—and that those sequences were keeping it safe from the viruses that can attack it and result in spoilage. (If the thermophilus is gone, nastier bacteria can move in and feed off the lactose, ruining the product.)Before long, DuPont bought the Danish company that Barrangou worked for and began using strains carrying this naturally occurring Crispr to protect all of its yogurt and cheese cultures. Since DuPont owns about 50 percent of the global dairy culture market, you’ve probably already eaten Crispr-optimized cheese on your pizza.3 (Non–Gene Editing) Uses for CrisprDisease DiagnosisViruses work by turning your cells into little factories for their DNA. A Crispr-based test could pick out that foreign DNA from just a drop of blood, spit, or urine and tell you in minutes if you’ve got dengue, yellow fever, or the novel coronavirus circulating in your body.Spot RotEvery year, fungi wipe out a third of all crops. Crispr panels tuned to identify the worst offenders could help farmers save their harvests before the blight sets in.Smartbomb BugsThanks to overuse, the world’s antibiotic arsenal is losing its effectiveness. New Crispr-based drugs that only target bad bugs would leave your microbiome intact and help fight antibiotic resistance.All the while, gene sequencing costs were plummeting and research scientists around the world were assembling the genomes of bacteria. As they did, they found Crisprs everywhere—more than half of the bacterial kingdom turned out to have them. Oftentimes those sequences were flanked by a set of genes coding for a class of strand-cutting enzymes called endonucleases. Scientists suspected they were involved in this primitive immune system, but how, exactly?The key insight came from a particularly nasty bug—the one that causes strep throat. Its Crispr system made two RNA sequences that attached to a clam-shaped endonuclease called Cas9. Like a genetic GPS, those sequences directed the enzyme to a strand of DNA complementary to the RNA sequences. When it got there, Cas9 changed shape, grabbing the DNA and slicing it in two. The molecular biologists who made this discovery—Jennifer Doudna and Emmanuelle Charpentier—demonstrated Crispr’s programmable cutting on circular stretches of DNA floating in test tubes. They published their work , but not before patenting the technology as a tool for genetic engineering. If you just switch out the RNA guide, you can send Cas9 anywhere—to the gene that causes Huntington’s disease, say, and snip it out. Crispr, they realized, would be a molecular biologist’s warp drive.Six months later, a molecular biologist at the Broad Institute of MIT and Harvard named published showing that Crispr-Cas9 could edit human cells, too. In fact, with the right genetic guides, you can Crispr pretty much anything. That meant it might be put to work on next-generation medicines that could do things like erase genetic defects and supercharge the body’s natural defenses against cancer. And that meant big money.Most PopularPerhaps predictably, a patent battle ensued—. Crispr’s early pioneers founded three companies with exclusive licenses to exploit Crispr/Cas9 to cure human diseases; one of them began its first human trials in early 2019. Uncertainty over who will ultimately own the technology has done little to slow the appetite for all things Crispr. If anything, it in developing competing and adjacent tools that promise to further refine and expand Crispr’s already ample potential.Many of the field’s founding luminaries have also formed, or are currently advising, companies working to lower the cost and labor associated with gene editing, to make it accessible to everyone. But in November 2018, at least some of them got a lesson in what democratization of Crispr really looks like.On the eve of the Second International Summit on Human Gene Editing, that a Chinese scientist named He Jiankui, who was scheduled to speak at the meeting, had been recruiting couples in an effort to create the first Crispr’d babies. Hours later, He Jiankui himself posted five slickly produced to YouTube claiming to have already done so: “Two beautiful little Chinese girls, Lulu and Nana, came crying into the world as healthy as any other babies a few weeks ago.” The only difference was that the twins had been injected with Crispr when they were still embryos, in an effort to eliminate and make them resistant to HIV. In a presentation to the summit a few days later, He provided further evidence of his experiment, which he appears to have conducted largely in secret, and revealed that Buried in the pages of his clinical paperwork were notes that indicated He had ordered his Crispr components , in violation of their “research use only” policies.These firms joined the scientific community’s chorus of disgust, outrage, and of He’s work. Jennifer Doudna said she was Feng Zhang called for an on the implantation of gene-edited embryos, and more than 100 Chinese scientists decrying the study as “crazy.” Within days, He had been fired from his university post and all his research activities were suspended. A by government authorities found that He violated Chinese law, and he is now serving a .And as new revelations keep trickling in, policymakers are scrambling to lay down some ground rules for this new Crispr-baby world. In the aftermath of the He debacle, China formed a new national ethics committee with broad authority over all high-risk medical biotechnologies. It will be tasked with enforcing the country’s new clinical research guidelines, released in February. The World Health Organization has assembled a panel to develop global standards for governments to follow. Late last year, the Russian government cited the advice of this panel when it barred a Russian scientist from creating Crispr babies.Most PopularUnder current US regulations, the Food and Drug Administration is banned from considering any studies that would start a pregnancy with embryos that have been genetically modified. But that language has to be renewed every year by Congress—and, last year, the language was . Given the implausibility of a global consensus on how to move the technology forward responsibly, the task will likely fall to individual nations, and it seems unlikely that every country will institute equally strict regulations.But scientists who hope to move forward with modifying future generations of humans may have more to worry about than just politics. have just demonstrated that Crispr can have catastrophic, unintended effects—like deleting huge chunks of DNA—when used to genetically modify human embryos. While these results have not yet been peer reviewed, they suggest that scientists have a long way to go before they can edit human embryos safely, not to mention ethically.The Future of CrisprDespite the arrival of Lulu and Nana, Crispr is still mostly a biologist's buzzword. But just as computers evolved from a nerdy, niche tool for math geeks to a ubiquitous, invisible extension of our own bodies, so Crispr will one day into the fabric of our physical reality. It will simply be the way to solve a problem, if that problem is remotely genetic in nature.Take industrial fermentation, for example. With the help of old-school genetic engineering techniques, scientists have already reprogrammed microbes like E. Coli and brewer’s yeast into factories that can make everything from insulin to ethanol. Crispr will rapidly enlarge the catalog of that biorefineries can produce. Self-healing concrete? Fire-resistant, plant-based building materials lighter than aluminum? Fully biodegradable plastics? Crispr not only makes all these possible—it makes it possible to produce them at scale.Most PopularBut we won’t get there with the tools we’ve currently got, which is why researchers are now racing to chart the full expanses of the Crispr universe. At this moment, they’re scouring the globe for obscure bacteria to sequence, and they’re that have already been discovered. They’re filing patents on every promising new nuclease they come across, adding to a list that is sure to expand in the coming decade. Each new enzyme will not only but also extend its capabilities far beyond DNA manipulation. You see, slicing and dicing isn’t the only interesting thing to do to DNA. Tricked-out new Crispr systems . The first would let scientists treat human diseases where there’s too much or too little of a certain substance—say, insulin—without permanently altering a patient’s DNA. The second could one day prevent diseases like cancer from occurring altogether. The specificity of Crispr, perhaps more than its actual cutting mechanism, will inspire applications we can’t yet imagine.The Amazing Crispr Enzyme ClanCas9 | The OGGood at cutting DNA, great for knockouts. Already being replaced by newer base pair editors with more fine-tuned control.Cas12 | The SticklerLike Cas9 but not as sloppy. It leaves “sticky” DNA ends, which are easier to work with when making edits.Cas13 | The CowboyCuts RNA, not DNA. Could knock down protein levels without permanently changing your genome. Pair it with a reporter signal and you’ve got a diagnostic.Cas3 | The GobblerCas3 gives zero f***. It offers no repair mechanism—once it finds that target DNA sequence it just starts cutting till there ain’t no DNA left.Casɸ | The DavidMuch smaller than its cousins, Casɸ still packs a mighty punch. And its diminutive size means it’s easier to package and send to cells.As of now, scientists working on the medical applications of Crispr have already achieved some impressive results with real human impact: Victoria Gray, a 34-year-old woman who has struggled with sickle cell anemia for most of her life, . To treat her debilitating illness, researchers extracted some of her stem cells, used Crispr to reprogram them to produce healthy blood cells, and returned them to her body. Scientists are working to treat and with a similar approach and have been able to establish its safety—but not, as of yet, its effectiveness.But none of these trials involved inserting Crispr directly into the patient’s body, because it can be difficult to deliver Crispr to a specific organ or tissue where needles and syringes can’t reach. Though scientists have devised some methods for doing so, these approaches can have potentially harmful consequences: Crispr, when administered in this way, can wreak havoc on portions of the genome where it should never have been in the first place. These unintended modifications, called off-target effects, could theoretically prevent tissues from functioning properly or could jump-start cancers. Figuring out how to limit these off-target effects is a major goal of current Crispr research. And scientists have made some material progress. A team at Johns Hopkins University recently created a , which can be deactivated to limit its off-target effects. And scientists are experimenting with other approaches for delivering Crispr to particular locations in the body: One individual has even had Crispr in an effort to cure their blindness.Crispr for the Covid EraIt’s no surprise that a biological tool as powerful as Crispr is being leveraged in the fight against Covid-19. The FDA has already issued an emergency-use authorization for a , which takes under an hour; its designers are also working to create a version that could be administered at home.What’s more, a group at Stanford has developed a Crispr-based treatment that . But like all other potential Covid-19 treatments, this Crispr tool has many regulatory steps to go through before it can see use in patients.Meanwhile, consumers can expect to see the first Crispr-designed foods lining grocery store shelves very soon. Because Crispr doesn’t use plant pathogens to manipulate DNA (the old GMO-generating method), the , which may allow drought-tolerant soybeans and extra-starchy corn to ease into your favorite processed foods without any additional labeling. will likely follow the commodity crops; the reduced regulatory burden and the cheapness of Crispr will allow companies that prioritize consumers’ senses rather than farmers’ bottom lines to enter the market. Already a dozen or so startups have popped up to challenge the Bayer/Monsanto, DowDupont/Pioneers of the world.This democratizing aspect of Crispr-based tech, combined with its nearly limitless commercial possibilities, makes today a great time to be a molecular biologist. Want to make antibiotics that only target bad bugs without wiping out the entire microbiome? . Want to make paper-based diagnostics that doctors can take into the field to test for diseases like dengue, Zika, and even the novel coronavirus? R are . And as more tools come online, the backend Crispr ecosystem will continually expand to support, supply, and optimize them.As some scientists work to apply Crispr to new and surprising biological problems, others are working to generate more powerful, more precise tools for gene editing. Some of these inventions are improvements on the Crispr we know and love: , for example, pair Cas9 with reverse transcriptase to make for a tool that can precisely modify bits of DNA. But others leave Crispr aside entirely. This year, researchers designed an to edit mitochondrial DNA, which lives apart from the rest of our DNA in our cells and can transmit a number of diseases from mother to child. Like Crispr, this new system takes advantage of bacteria’s natural defense machinery—in this case, a toxin that bacteria can use to kill competing strains. And a startup has into the genome, something that is currently beyond Crispr’s capabilities.Crispr and other editing tools are only going to become more powerful, and, when they do, they will rightly invite more scrutiny and probably more regulation. Scientists and regulators are going to have to figure out if it’s OK to wipe out an entire species and . They’ll have to wrestle with the possibility that gene editing tools might be used to . Lulu and Nana have already kindled difficult conversations around the real possibility—or, perhaps, inevitability—of designer babies; when is it acceptable to fix a genetic mutation? What about adding features? Where do you draw the line? Crispr, and all the tools that will one day make up the Crispr universe will undoubtedly force societies—not just scientists—to confront these questions and ponder the oldest one of all; what does it mean to be human?Most PopularLearn More:Plus! Crispr uploads a and more .This guide was last updated on July 30, 2020.Enjoyed this deep dive? Check out more . is a science writer at STAT News. Previously, she was a staff writer at WIRED, covering , , and . She studied biology and ultimate frisbee at Carleton College and has a graduate degree in journalism from the University of California, Berkeley.

days of gene editing, biologists had a molecular tool kit that was somewhat akin to a printing press. Which is to say, altering DNA was a messy, labor-intensive process of loading genes onto viruses bound for target cells. It involved more than a fair amount of finger-crossing. Today, scientists have the genetic equivalent of Microsoft Word, and they are beginning to edit DNA almost as easily as software engineers modify code. The precipitating event? Call it the Great Crispr Quake of 2012.If you’re asking “What’s Crispr?” the short answer is that it’s a revolutionary new class of molecular...

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Everything You Need To Know About Crispr Gene Editing

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