Archive for the ‘Crispr’ Category

William Peranteau is the guy parents call when theyve received the kind of bad news that sinks stomachs and wrenches hearts. Sometimes its a shadow on an ultrasound or a few base pairs out of place on a prenatal genetic test, revealing that an unborn child has a life-threatening developmental defect. Pediatric surgeons like Peranteau, who works at Childrens Hospital of Philadelphia, usually cant try to fix these abnormalities until their patients leave their mothers bodies behind. And by then it might be too late.

Its with the memory of the families he couldnt help in the back of his mind that Peranteau has joined a small group of scientists trying to bring the fast-moving field of gene editing to the womb. Such editing in humans is a long way off, but a spate of recent advances in mouse studies highlight its potential advantages over other methods of using Crispr to snip away diseases. Parents confronted with an in utero diagnosis are often faced with only two options: terminate the pregnancy or prepare to care for a child who may require multiple invasive surgeries over the course of their lifetime just to survive. Prenatal gene editing may offer a third potential path. What we see as the future is a minimally invasive way of treating these abnormalities at their genetic origin instead, says Peranteau.

To prove out this vision, Peranteau and colleagues at the University of Pennsylvania injected Crispr editing components, encoded in a virus, into the placentas of pregnant mice whose unborn pups were afflicted with a lethal lung-disease-causing mutation. When the fetuses breathed in the amniotic fluid they also inhaled the Crispr bits, which went to work editing the DNA inside their rapidly dividing alveolar progenitor cells. These cells give rise to many types of cells that line the lungsincluding ones that secrete a sticky substance that keeps the lungs from collapsing every time you breathe. Mutations to proteins that make up this secretion are a major source of congenital respiratory conditions. All of the mice with the mutation died within a few hours of birth. Of those edited with Crispr, about a quarter survived. The results were published in todays issue of Science Translational Medicine.

Its the second proof of concept from the group of scientists in the past year. In October, they published a paper describing a slightly different procedure to edit mutations that lead to a lethal metabolic disorder. By changing a single base pair in the liver cells of prenatal mice, Peranteaus team was able to rescue nearly all of the mouse pups. Other recent successes include unborn mice cured of a blood disorder called beta-thalassemia following a prenatal injection of Crispr, carried out last year by a team at Yale and Carnegie Mellon.

Though the field is still in its infancy, its pioneers believe that many of the problems Crispr-based therapies have to contend withlike reaching enough of the right cells and evading the human immune systemcan be solved by treating patients while they are still in the womb.

If youre trying to edit cells in an adult organ, theyre not proliferating, so you have to reach a lot of them to have any impact, says Edward Morrisey, a cardiologist at the University of Pennsylvania, who coauthored the latest study. Fetuses, on the other hand, are still developing, which means their cells are in a state of rapid division as they grow into new tissues. The earlier in life you can edit, the more those genetic changes will multiply and propagate through developing organs. Morriseys mice might have only been born with the genetic edit in about 20 percent of their lung cells, but 13 weeks later, the correction had spread to the entire surface of the lung. Theyve actually outcompeted the nonedited cells, because those cells are very sick, says Morissey.

For lung diseases in particular, this represents a huge advantage. As soon as a baby leaves the watery world of the womb, its lung cells start secreting a barrier of mucus mixed with surfactant, to keep any dust or viruses or other foreign objects, including Crispr components, from reaching those tissues. A developing fetus also has a less aggressive immune system than a human whos been exposed to the outside world. So its less likely to mount an attack on Crispr components, which do, after all, originate in the bacterial kingdom.

Now, you might be thinking, if editing earlier is better, why not edit an embryo right after its been fertilized, when its only a cell or two old? But this technique, known as germline editing (you might remember it from last years Chinese Crispr baby scandal), is a much more complicated ethical endeavor. Editing at that stage would pass on any changes to every cell, including the ones that would go on to make sperm or eggs. This kind of editing is effectively banned in the United States, following a directive from Congress to the US Food and Drug Administration to not allow any clinical trials involving genetically modified human embryos. (The ban, which has to be renewed annually, was most recently reaffirmed in February of 2019). The other thing though, is that getting an accurate diagnosis when an embryo is only a few cells old can be tricky. Waiting long enough to get a visual on a fetus along with other vital signs can provide important clues as to the severity of the condition. It gets us right in that sweet spot to treat a disease at the very beginning, basically as soon as its diagnosed, says Peranteau.

But there are still safety issues to resolve. For one thing, in utero editing involves two patients, not just one. In the process of curing a child, this technique would potentially expose a healthy bystanderthe motherto a treatment that provides no potential benefit and only potential risks, including dangerous immune reactions. And because the editing is taking place inside her reproductive tract, some wayward Crispr components might wend their way up her fallopian tubes and into her ovaries, potentially making changes to other, unfertilized eggs. A lot more science will need to be done to better assess these risks. To give you an idea of how long these things can take, consider that in utero gene therapyan older approach that entails replacing a defective gene with a functioning one using a viruswas first proposed back in the mid-1990s following a series of positive proof of concept studies in mice. Today, only a single clinical trial is in progress.

This is not a panacea for curing every genetic disease thats out there, says Peranteau. But he believes that a Crispr approach will be able to piggyback on the work of the gene therapy field, and may offer a new way forward for at least some of his patients. At some point in the futurenot tomorrow or the next day, years from nowI think in utero editing would provide hope for families that today have none.

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Crispr Gene Editing Is Coming for the Womb | WIRED

CRISPR gene-editing technology allows scientists to make highly precise modifications to DNA. The technology is now starting to be used in human trials to treat several diseases in the U.S. Molekuul/Getty Images/Science Photo Library hide caption

CRISPR gene-editing technology allows scientists to make highly precise modifications to DNA. The technology is now starting to be used in human trials to treat several diseases in the U.S.

The powerful gene-editing technique called CRISPR has been in the news a lot. And not all the news has been good: A Chinese scientist stunned the world last year when he announced he had used CRISPR to create genetically modified babies.

But scientists have long hoped CRISPR a technology that allows scientists to make very precise modifications to DNA could eventually help cure many diseases. And now scientists are taking tangible first steps to make that dream a reality.

For example, NPR has learned that a U.S. CRISPR study that had been approved for cancer at the University of Pennsylvania in Philadelphia has finally started. A university spokesman on Monday confirmed for the first time that two patients had been treated using CRISPR.

One patient had multiple myeloma, and one had sarcoma. Both had relapsed after undergoing standard treatment.

The revelation comes as several other human trials of CRISPR are starting or are set to start in the U.S., Canada and Europe to test CRISPR's efficacy in treating various diseases.

"2019 is the year when the training wheels come off and the world gets to see what CRISPR can really do for the world in the most positive sense," says Fyodor Urnov, a gene-editing scientist at the Altius Institute for Biomedical Sciences in Seattle and the University of California, Berkeley.

Here are highlights of the year ahead in CRISPR research, and answers to common questions about the technology.

What is CRISPR exactly?

CRISPR is a new kind of genetic engineering that gives scientists the power to edit DNA much more easily than ever. Researchers think CRISPR could revolutionize how they prevent and treat many diseases. CRISPR could, for example, enable scientists to repair genetic defects or use genetically modified human cells as therapies.

Traditional gene therapy uses viruses to insert new genes into cells to try to treat diseases. CRISPR treatments largely avoid the use of viruses, which have caused some safety problems in the past. Instead they directly make changes in the DNA, using targeted molecular tools. The technique has been compared to the cut and paste function in a word processing program it allows scientists to remove or modify specific genes causing a problem.

Is this the same technique that caused a recent scandal when a scientist in China edited the genes of two human embryos?

There's an important difference between the medical studies under discussion here and what the Chinese scientist, He Jiankui, did. He used CRISPR to edit genes in human embryos. That means the changes he made would be passed down for generations to come. And he did it before most scientists think it was safe to try. In fact, there have been calls for a moratorium on gene-editing of heritable traits.

For medical treatments, modifications are only being made in the DNA of individual patients. So this gene-editing doesn't raise dystopian fears about re-engineering the human race. And there's been a lot of careful preparation for these studies to avoid unintended consequences.

So what's happening now with new or planned trials?

We've finally reached the moment when CRISPR is moving out of the lab and into the clinic around the world.

Until now, only a relatively small number of studies have tried to use CRISPR to treat disease. And almost all of those studies have been in China, and have been aimed at treating various forms of cancer.

There's now a clinical trial underway at the University of Pennsylvania using CRISPR for cancer treatment. It involves removing immune system cells from patients, genetically modifying them in the lab and infusing the modified cells back into the body.

The hope is the modified cells will target and destroy cancer cells. No other information has been released about how well it might be working. The study was approved to eventually treat 18 patients.

"Findings from this research study will be shared at an appropriate time via medical meeting presentation or peer-reviewed publication," a university spokesperson wrote in an email to NPR.

But beyond the cancer study, researchers in Europe, the United States and Canada are launching at least half a dozen carefully designed studies aimed at using CRISPR to treat a variety of diseases.

What other diseases are they testing treatments for?Two trials sponsored by CRISPR Therapeutics of Cambridge, Mass., and Vertex Pharmaceuticals of Boston are designed to treat genetic blood disorders. One is for sickle cell disease, and another is a similar genetic condition called beta thalassemia.

In fact, the first beta thalassemia patient was recently treated in Germany. More patients may soon get their blood cells edited using CRISPR at that hospital and a second clinic in Germany, followed by patients at medical centers in Toronto, London and possibly elsewhere.

The first sickle disease patients could soon start getting the DNA in their blood cells edited in this country in Nashville, Tenn., San Antonio and New York.

And yet another study, sponsored by Editas Medicine of Cambridge, Mass., will try to treat an inherited form of blindness known as Leber congenital amaurosis.

That study is noteworthy because it would be the first time scientists try using CRISPR to edit genes while they are inside the human body. The other studies involve removing cells from patients, editing the DNA in those cells in the lab and then infusing the modified cells back into patients' bodies.

Finally, several more U.S. cancer studies may also start this year in Texas, New York and elsewhere to try to treat tumors by genetically modifying immune system cells.

What can go wrong with CRISPR? Are there any concerns?

Whenever scientists try something new and powerful, it always raises fears that something could go wrong. The early days of gene therapy were scarred by major setbacks, such as the case of Jesse Gelsinger, who died after an adverse reaction to a treatment.

The big concern about CRISPR is that the editing could go awry, causing unintended changes in DNA that could cause health problems.

There's also some concern about this new wave of studies because they are the first to get approved without going through an extra layer of scrutiny by the National Institutes of Health. That occurred because the NIH and FDA changed their policy, saying only some studies would require that extra layer of review.

"Every human on the planet should hope that this technology works. But it might work. It might not. It's unknown," says Laurie Zoloth, a bioethicist at the University of Chicago. "This is an experiment. So you do need exquisite layers of care. And you need to really think in advance with a careful ethical review how you do this sort of work."

The researchers conducting the studies say they have conducted careful preliminary research, and their studies have gone through extensive scientific and ethical review.

When might we know whether any of these experimental CRISPR treatments are working?

All of these studies are very preliminary and are primarily aimed at first testing whether this is safe. That said, they are also looking for clues to whether they might be helping patients. So there could be at least a hint about that later this year. But it will be many years before any CRISPR treatment could become widely available.

Continued here:
CRISPR Research Moves Out Of Labs And Into Clinics Around The ...

It's not certain how effective the treatment has been, and you won't find out for a while when the trial has been cleared to treat a total of 18 patients. You won't hear more about it until there's been a presentation or a peer-reviewed paper, the university said. Other trials, such as ones for blood disorders in the Boston area, have yet to get underway.

No matter what, any practical uses could take a long time. There are widespread concerns that CRISPR editing could have unanticipated effects, and scientists have yet to try editing cells while they're still in the body (a blindness trial in Cambridge, MA may be the first instance). There's also the not-so-small matter of ethical questions. Chinese scientist He Jiankui raised alarm bells when he said he edited genes in human embryos -- politicians and the scientific community will likely want to address practices like that before you can simply assume that CRISPR is an option.

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CRISPR gene editing has been used on humans in the US

Like any self-respecting farmer, Zachary Lippman was grumbling about the weather. Stout, with close-cropped hair and beard, Lippman was standing in a greenhouse in the middle of Long Island, surrounded by a profusion of rambunctiously bushy plants. Dont get me started, he said, referring to the late and inclement spring. It was a Tuesday in mid-April, but a chance of snow had been in the forecast, and a chilly wind blew across the island. Not the sort of weather that conjures thoughts of summer tomatoes. But Lippman was thinking ahead to sometime around Memorial Day, when thousands of carefully nurtured tomato plants would make the move from the greenhouse to Long Island loam. He hoped the weather would finally turn.

Although he worked on a farm as a teenager and has a romantic attachment to the soil, Lippman isnt a farmer. Hes a plant biologist at Cold Spring Harbor Laboratory in New York with an expertise in genetics and development. And these greenhouse plants arent ordinary tomatoes.

After introducing me to his constant companion, Charlie (a slobberingly gregarious Labrador-Rottweiler mix), Lippman walked me through hundreds of plants, coddled by 80-degree daytime temperatures and 40 to 60 percent humidity, and goaded into 14 hours of daily photosynthetic labor by high-pressure sodium lights overhead. Some were seedlings that had barely unfurled their first embryonic leaves; others had just begun to flash their telltale yellow flowers, harbingers of the fruit to come; still others were just about ripe, beginning to sag with the weight of maturing red fruit.

What makes this greenhouse differentwhat makes it arguably an epicenter of a revolution in plant biology that may forever change not just the future of the tomato but the future of many cropsis that 90 percent of the tomato plants in the building had been genetically altered using the wizardly new gene-editing tool known as Crispr/Cas-9. Lippman and Joyce Van Eck, his longtime collaborator at the Boyce Thompson Institute in Ithaca, New York, are part of a small army of researchers using gene editing to turn the tomato into the laboratory mouse of plant science. In this greenhouse, Crispr is a verb, every plant is an experiment, and mutant isnt a dirty word.

Lippman walked to the rear of the building and pointed out a variety of tomato known as Large Fruited Fresh Marketone of the commercial varieties that turn up in supermarkets, not farmers markets. This particular plant, about two months old, bowed with big, nearly ripe fruit. It was, Lippman explained, a mutant called jointless. Most tomato varieties have a swollen knuckle of tissue (or joint) on the stem, just above where the fruit forms; when the tomato is ready, it tells itself, as Lippman put it, OK, Im ripetime to fall, and the cells in the joint receive a signal to die, letting go of the tomato. That is natures way of spreading tomato seeds, but the joint has been a thorny problem for agricultural production, because it leaves a residual stem that pokes holes in mechanically harvested fruit. Jointless tomatoes, whose stems can be plucked clean, have been bred and grown commercially, but often with unwanted side effects; these gene-edited versions avoid the unintended consequences of traditional breeding. We can now use Crispr to go in and directly target that gene for the molecular scissors to cut, which leads to a mutation, Lippman said. Voil: the jointless trait in any variety you want.

We moved on to several examples of Physalis pruinosa, a relative of the tomatillo that produces a small, succulent fruit called a ground cherry. The plant has never been domesticated, and Lippman referred to the wild version as a monstrosity: tall, unkempt, and stingy, bestowing a single measly fruit per shoot. Next to it stood a Physalis plant after scientists had induced a mutation called self-pruning. It was half as tall, much less bushy, and boasted half a dozen fruits per shoot. Lippman plucked a ground cherry off one of the mutated plants and offered it to me.

Smell it first, he entreated. Enjoy the smell. It was exotic and faintly tropical. I popped it in my mouth and bit into a complex burst of flavor. Like all its cousin tomatoes, the taste was a mystical, time-lapse blur of sugar and acidity, embellished by the whiff of volatile compounds that found my nose and rounded out the flavor.

You just ate an edited plant, Lippman said with a smile. But dont be too nervous.

Zach Lippman in a Cold Spring Harbor test field of tomato plants edited to produce more fruit.

Dolly Faibyshev

A gene-edited tomato plant.

Dolly Faibyshev

Like the majority of scientists, Lippman regards genetically modified plants as safe to eat. But his mischievous smile acknowledged that not everyone views the technology as innocuous. There is a lot of nervousness about genetic tinkering with food plants. Genetically modified (GM) transgenic crops such as corn and soybeans have infiltrated processed foods, animal feed, and biofuels for many years, and the battle over them has long divided the public in the US and overseas. The Crispr revolution is reinventing, if not reigniting, that debate. Most of the plants that have been gene-edited to date have been created by knocking out genes (that is, mutating them), not by introducing genes from unrelated species, as first-generation genetic modification generally didrousing cries of Frankenfoods and fears of environmental contamination. Precisely because its subtraction rather than addition, scientists argue that this form of gene editing mimics the process of agriculturally induced mutations that characterizes traditional plant breeding. This distinction may not assuage critics, but it has apparently persuaded federal regulators; gene-edited soybean and potato crops are already in the ground, and last March the US Department of Agriculture declared that crops developed with gene-edited mutations are indistinguishable from those produced by traditional breeding and do not require regulatory oversight.

Huge questions vex the future of foodhow to feed 9 billion mouths, how to farm in an era of unprecedented climate uncertainty, how to create more resilient and nutritious foods for a public wary of the new technology. Plant scientists are already using Crispr and related technologies to reshape food crops in dramatic waysediting wheat to reduce gluten, editing soybeans to produce a healthier oil, editing corn to produce higher yields, editing potatoes to store better (and not throw off a carcinogen when cooked). In both industrial and academic labs, new editing tools are being developed that will have a profound impact on the foods all of us eat. Yet this newfound power to transform food traits coincides with a moment when the agriculture business has consolidated into essentially three mega-conglomerates. Those companies have the money to put this new technology to use. The question is: What use will they put it toward?

Soybeans, potatoes, and corn melt invisibly into the food chain, but tomatoes add a big red exclamation point to the current debate. Perhaps no food crop is more emblematic of what is at stakeagriculturally, biologically, culturally, and perhaps even in homegrown foodie waysthan the tomato: queen of the farmers market, jewel of the backyard garden, alpha vegetable of locavores everywhere. Lippmans greenhouse reveals just some of the ways gene editing is already altering the tomatohe has plants that flower earlier, that are oblivious to daylight cues, that prune themselves into smaller footprints, that can be genetically programmed to space out the position of fruits on the stem like an accordion.

For people who love to eat or grow tomatoes (I do both), the arrival of Crispr provokes both cynicism and giddy hope about the future of our favorite vegetable. Cynicism because most of the practical scientific efforts would perpetuate the dreary taste of commercially produced tomatoes. In one sense, this is simply the latest in a century-long conquest of the produce aisles by the desires of food growers, who prize greater yield at lesser cost, over the desires of consumers, who cherish taste and nutrition. (Harry Klee, a tomato expert at the University of Florida, says that the perfect tomato for industry is one that exactly matches the size of a McDonalds hamburger.) Hope because there is something intriguing about using new technology to preserve the ravishing, sweet acidic burst of an heirloom tomato in a hardier, disease-resistant plantan heirloom-plus, if you will.

After Lippman walked me through his garden of man-made mutations, I couldnt resist asking if the heirlooms I struggle to grow every year might also benefit from Crisprs scissors.

Were not doing any editing of heirlooms, Lippman said. Not yet. But its in the works. They could benefit from a little bit of tweaking.

Tomatoes are coddled and goaded into photosynthetic labor in a greenhouse at the Boyce Thompson Institute.

Dolly Faibyshev

This is a story about tomatoes, of course. But it is also, like all agricultural stories, about mutationsnatural mutations and man-made mutations, invisibly insidious mutations and overtly grotesque mutations, mutations that were created earlier this year at Cold Spring Harbor Laboratory and mutations that may have occurred 10,000 years ago, like the ones that transformed Solanum pimpinellifolium from a scraggly perennial weed producing pea-sized fruit along the Pacific coastal margins of Peru and Ecuador to those beautiful big-lobed heirlooms in your backyard. Our cultural thesaurus has reduced the word mutant to a term of derision, but if you think mutation is a dirty word, you should probably stop readingand probably stop eating plant-based food too. The foundational principle of plant breeding is to take advantage of genetic modification, whether the mutation is caused by sunlight or x-rays or Crispr. As Klee puts it, there isnt a single crop that I know of in your produce aisle that is not drastically modified from what is out there in the wild.

Every backyard gardener is a connoisseur, witting or otherwise, of mutation. The intense, thin-skinned freshness of Brandywines, the apricot glow of Jaune Flamme, the green standoffish shoulders of Black Krims, and my personal favorite, Rose de Berne, with its blush of color and amazing tasteall those heirlooms are the product of long-ago, hand-me-down mutations.

Every spring, almost inevitably during March Madness (this year, during Villanova-Michigan), I get down on the floor with a bunch of peat pots and starter soil and clumsily press seeds of all of the above varieties into virgin dirt. My wife wonders why I cant buy seedlings at the market like everyone else, but Ive never outgrown the childlike thrill of watching an itty-bitty snippet of plant DNA, encased in the stiff callus of a seed coat, unfurl into a 5-foot-tall plant that yields its sublime bounty. Gardenersthe original DIY biologistsall know this thrill. And so does Lippman. Thats how he got into gene-editing tomatoes in the first place.

If you think mutation is a dirty word, you should probably stop reading. And probably stop eating plant-based food too.

Lippman grew up in Milford, Connecticut; his father was an English teacher and his mother worked in health care. Among his earliest memories is visiting a nearby farm with his father when he was 6 or 7 years old and picking up leftover Halloween pumpkins and gourdswith their mind-blowing shapes and colorsthat littered the field.

That pumpkin field was part of Robert Treat Farm, and when he was 13, Lippman began working summers there, cultivating his fascination with plants. By the time he graduated from high school in 1996, he had decided to pursue plant breeding and genetics, first at Cornell University and then at Cold Spring Harbor, where he got his PhD and is now a Howard Hughes Medical Institute investigator.

Lippmans office is a shrine to the tomato: On his walls are old tomato-can labels and antique postcards of implausibly gigantic tomatoes, and thousands of little brown envelopes containing seeds, each marked by year and variety, are stacked on his desk, in old seed boxes, in wooden trays and plastic cabinets against the wall. The most telling relic is just behind the door: a large framed reproduction from a 16th-century book by Pietro Andrea Mattioli, believed to be the earliest color depiction of the tomato following the Spanish conquest of the Americas. To a geneticist like Lippman, the Mattioli print is especially significant because it is early evidence that pre-Columbian cultures knew a beneficial tomato mutation when they saw onethey had already converted the nubbin of wild fruit into a large, multiple-lobed golden beefsteak.

Up until the 1930s, agricultural scientists essentially relied on the same techniques as the original tomato farmers in Central America: Be patient enough to wait for nature to produce a useful mutation, be smart enough to recognize that desirable trait (bigger fruit, for example), and be clever enough to create a new variety with that trait by selecting the mutant strains and propagating them. Put another way, agriculture has always been about unnatural selectionhuman choice privileging certain mutations while discarding others. Biologists sped up this process around the time of World War II by deliberately inducing random mutations in seeds with the use of chemicals, x-rays, and other forms of radiation. But even so, the process was slow. Selective breeding of a desirable trait could easily take a decade.

This all began to change in 2012, an annus mirabilis for the tomato. In May of that year, plant geneticists completed the Tomato Genome Projectthe entire DNA sequence of the tomato plant, all 900 million base pairs on 12 chromosomes. Then, in June, a group led by Jennifer Doudna at UC Berkeley published the first report on the new gene-editing technique known as Crispr, followed soon after by a group at the Broad Institute of MIT and Harvard. The fruit of those two converging streams of researchand, yes, botanically speaking, tomato is a fruitwas a race among scientists to see if the new technique worked in plants.

As soon as word of Crispr broke, Lippman wondered, Can we do it in tomato? And if we can, lets move. Moving fast meant doing an experiment on a tomato gene that would prove the efficacy of Crispr without too much delay. Which gene did Lippman and Van Eck target? Not one that would improve the size or shape of the fruitthat would take too long, and Van Eck was impatient. I dont want to have to put it in the greenhouse and wait for it to grow, she told Lippman. I want to be able to see something in the petri plate. So they picked a gene that was of zero economic significance and less-than-zero consumer appeal. It was a weird gene that, when mutated, produced disfigured tomato leaves that looked like needles. The mutant version was called wiry.

A research field at Cold Spring Harbor with some 8,000 gene-edited plants.

Dolly Faibyshev

Seeds are stored in boxes, and then planted.

Dolly Faibyshev

The wiry mutation was so obscure that Van Eck had to dig up a paper from 1928 that described it for the first time to know what shed be looking for. Each Crispr-directed mutation requires a customized, genetically engineered tool called a constructa so-called guide RNA to target the right tomato gene and an enzyme riding shotgun to cut the plant DNA at precisely that spot. In this case, Lippman designed the construct to target the wiry gene and cut it; the mutation is not created by Crispr per se but by the plant when it attempts to repair the wound. Van Eck used a bacterium that is very good at infecting plants to carry the Crispr mutation tool inside tomato cells. Once mutated, these cells were spread onto petri plates where they began to develop into plants. Van Eck still had to wait about two months before the tomato cells developed into seedlings and sprouted leaves, but it was worth the wait.

I still remember when I saw the first leaves coming up, she recalls. The leaves were radializedcurled up into needlelike shapes. Omigod, it worked! she cried, and raced down the hallways of the institute to tell anyone who would listen. I was thrilled because, you know, when does something work the first time?

Not only had they demonstrated that Crispr could produce a heritable trait change in a fruit crop, they also had their answer in two months rather than a year. They knew that the same basic process could theoretically be used to edit, with exquisite precision and unprecedented speed, any gene in any food crop.

As soon as they knew it worked, Lippman and Van Eck began Crispring every trait theyd wanted to study for the past 15 years. One of them was jointless. For 60 years, researchers had been trying to solve the problem of the joint on the tomato plants stem. Large-scale farming of tomatoesCalifornia alone produces more than 10 million tons each yearrequires mechanical harvesting, and those stabbing stems of jointed tomatoes make the task harder and more wasteful. Lippman, who studies plant architecture, knew that many jointless tomato plants produce excessive branching and lower yields. He discovered that this unintended consequence was the result of traditional breeding: When breeders favored the jointless mutation, they unwittingly produced unwanted branching as well because of a complex interaction between jointless and another ancient mutation. Traditional breeding produced another side effectabnormally shaped tomatoesbecause the process of selecting the jointless trait dragged along a chunk of DNA with an unwanted mutation. (This phenomenon is known as linkage drag.)

If Lippman could Crispr his way to the jointless mutation without dragging along the deleterious effects related to traditional breeding, it would offer a significant advance for growers. He and Van Eck had to wait longer than they had for the needle-nosed leaves of wiry, but by March 2016, Lippman had jointless tomatoes growing in his greenhouse. They published the work in the journal Cell in the spring of 2017, and Lippman shared the gene-editing tool with Klee at the University of Florida. Last March, Klee and his team planted a plot of gene-edited jointless mutants, in a commercial variety called Florida 8059, in a test field north of Gainesville.

Joyce Van Eck saw curled leaves on a tiny tomato plant growing on a petri plate and knew that the Crispr experiment was a success.

Dolly Faibyshev

Quick reality check: Despite the hype about the gene-editing revolution, the past couple of years have revealed limitations as well as successes. Scientists will tell you Crispr is great at knocking out a gene. But using it to insert a new gene and, as many popular accounts suggest, rewrite the germline of man, beast, or plant? Not so easy. Crispr is not the be-all and end-all, says Dan Voytas of the University of Minnesota, one of the pioneers of agricultural gene editing. Moreover, genomes are complex, even in plants. Just as a dozen knobs on a stereo console can shape the overall sound of a single song, multiple genetic elements can control the effect of a single gene.

That daunting complexity inspired Lippmans lab to pursue a clever riff on gene editing. I remember having a sticky note here, Lippman says, pointing to his keyboard. The note simply read: Promoter CRISPR.

In plants as well as animals (and humans), there is part of the DNA that lies outside the protein-encoding segment of the gene and essentially regulates its output. This upstream patch of regulatory DNA is called the promoter, and it sets different levels of outputvolume, if you willfor specific genes, from a little to a lot. What if, Lippmans group asked, you could use Crispr to, in effect, adjust the volume of a particular gene, turning it up or down like a stereo knob, by mutating the promoter in different places?

The Long Island greenhouse is now full of examples of what happens. As they reported in Cell last October, Daniel Rodrguez-Leal and colleagues in Lippmans lab showed that, by mutating the promoter of the self-pruning gene in different places, they could adjust its output like a dimmer switch, producing subtle but important changes. By using Crispr to create varying doses of a gene, Lippman says, scientists can now find better versions of plants than nature ever provided.

But better for whom? One of Lippmans pet phrases is sweet spotthat point of genetic balance where desirable traits for agriculture can be improved without sacrificing essential features like flavor or shape. Now we can start to think about taking some of our best tomato varieties, and if they can flower faster, you can start to grow them in more northern latitudes, where the summers are shorter, he says. We can begin to imagine new crops, or new versions of existing crops, for urban agriculture, like tiered cropping that they have in these abandoned warehouses ... Adapt the plant so that its more compact, flowers faster, gives you a nice-sized fruit with a decent yield, in a very compressed growth setting, with the equivalent of protective agriculturegreenhouse conditionsbut with LED lights. Because every plant gene comes with its own promoter, this genetic tuning, as Lippman puts it, could apply to virtually any vegetable crop.

The sad reality is that industry is not really committed to making a better-tasting tomato.

Tuning is just one of many ways biologists are remaking the tomato. Last year, researchers at the Sainsbury Laboratory in England gene-edited a tomato variety called Moneymaker to be resistant to powdery mildew, and a Japanese research group recently created tomatoes without seeds. On the day in May that I set my first heirloom seedlings into the ground, I happened to have a Skype conversation with two plant biologists in Brazil who have taken the gene editing of tomatoes to a whole new level. In collaboration with the Voytas lab at the University of Minnesota, Agustin Zsgn of the University of Viosa and Lzaro Peres of the University of So Paulo claim to have, in essence, reverse-engineered the weedlike wild tomato believed to be the forerunner of all cultivated varieties. (They havent published this work to date, but have discussed it at meetings.) Rather than tweak a domesticated variety of tomato, they went back to square onethe wild plantand used Crispr to knock out a handful of genes all at once. The result? Where the wild plant was sprawling and weedy, the gene-edited tomato was compact and bushy; where the ancestral plant had pea-sized fruit, the gene-edited version had reasonably plump, cherry-sized tomatoes. The edited fruit also contained more lycopene, an important antioxidant, than any other known variety of tomato. The process is called de novo domestication.

We didnt go from pea-sized to beefsteak, but we went from pea-sized to cherry-sized, said Zsgn of this first attempt. And how did the tomatoes taste? They taste great! Peres insisted. In a similar vein, Lippman and Van Eck are domesticating the wild ground cherry in the hope that it can join blueberries and strawberries as one of the basic berry crops.

What makes the de novo approach so intriguing is that it takes advantage of all the accumulated botanical wisdom of a wild plant. Over tens of thousands of years of evolution, a wild species acquires traits of hardiness and resilience, such as resistance to disease and stress. Domestication eliminated some of those traits. Since those resistance traits typically involve a suite of genes, Peres says, they would be extremely difficult to introduce into domesticated tomatoes, via Crispr or any other technology. And the approach can exploit other extreme traits. Peres wants to domesticate a wild species from the Galapagos, which can tolerate extreme environmental conditions such as high salinity and droughttraits that might enhance food security in a future with enormous climate fluctuations.

Rising temperatures. Changing growing seasons. A rising global population. The environmental toll of herbicide overuse. What if gene editing, for example, could favor disease-resistance genes that would reduce pesticide use? Lippman asks. Thats not just feeding the world, thats protecting the planet.

Lippman, outside a tomato greenhouse: Ive eaten many gene-edited tomatoes, yeah.

Dolly Faibyshev

All this new plant scienceknocking out genes, fiddling with the volume knob of promoters, de novo domesticationis wonderfully creative and happening very fast. But sooner or later, the other shoe drops in the conversation. Will consumers want to eat these tomatoes? Are Crispr vegetables and grains simply new GMOs, as a number of environmental groups maintain, or are gene-edited plants intrinsically different? This is the beginning of the new conversation, Lippman says.

The old conversation was acrimonious and emotional. The initial GM foods that Monsanto introduced in the 1990s were transgenic, meaning that biologists used genetic engineering to introduce foreign DNA, from an unrelated species, into the plant. Gene editing is much more analogous to older forms of mutagenesis such as irradiation and chemicals, though much less scattershot. Rather than creating random mutations, Crispr targets specific genes. (Editing that misses its mark is possible, though Lippman hasnt detected any in his work.) That is why plant scientists have been so eager to use it, and why the USDA regards gene-edited knockouts as similar to earlier mutagens and thus not requiring special regulation. (In the case of knocking in, or adding, a gene to crop plants, the USDA has indicated it will assess on a case-by-case basis.) Some European countries have banned GMOs, and the European Union has yet to issue a final judgment on gene-edited plants.

Although multiple studies have failed to show that GMOs pose a threat to human health, public doubts persista Pew Research Center survey in 2016 indicated that 39 percent of Americans believe that genetically modified foods are less healthy than non-GMOs, and in his household, Lippman admits, his wife initially preferred not to eat his gene-edited tomatoes.

The domesticated tomato possesses thousands, perhaps millions, of spontaneous mutations that helped turn a forlorn, ground-hugging weed into the most popular American garden plant. Now scientists are using gene editing to create these mutations and optimize the plants.

self-pruningThis mutation affects the plants size, shape, and compactness and alone can change the wild, sprawling shrub into the orderly, compact crop familiar to gardeners.

self-pruning 5gThis affects the tomatos day-length sensitivity apparatus, allowing it to be grown during shorter summers at northern latitudes.

fasciatedThis mutation affects the plants size, shape, and compactness and alone can change the wild, sprawling shrub into the orderly, compact crop familiar to gardeners.

jointless-2This mutation eliminates a break point in the middle of the stem, just above the fruit, facilitating mechanical harvesting.

lycopene beta-cyclaseThis mutation increases the fruits lycopene, the chemical that gives the tomato its red color.

There are other reasons that genetically altered foods continue to arouse suspicion. Monsantos early GMO effort used a revolutionary technology not to make healthier or more environmentally sustainable foods but to confer resistance in soybean and corn to the companys proprietary herbicide, Roundup. The companys aggressive promotion of such a self-serving first product was considered a public relations disaster.

Big agribusinesses are now positioning themselves to take advantage of gene editing. A recent rash of mergers has created three giant multinationals in global agriculture: Bayer (which completed its acquisition of Monsanto this year), DowDuPont (following Duponts earlier merger with Dow Chemical), and Syngenta (which was acquired last year by the huge Chinese gene-editing company ChemChina). The intellectual property issues are possibly more complex than plant genetics. Both the Broad Institute and DuPont Pioneer hold basic Crispr patents that apply to agriculture, and the two entities teamed up last fall to jointly negotiate licenses for farming applications (all three giant agribusinesses have licensed the technology). According to agricultural sources, the right to use Crispr for commercial agriculture requires an upfront fee, annual royalty payments on sales, and other conditions. (The Broad Institute did not discuss licensing terms, except to say that it is not involved in product development.)

This is where gene editing bumps up against the harsh economics of agriculture. Academic scientists can conduct basic research with Crispr without paying a licensing fee. But thats as far as it goes. I cant develop products and start to sell them, Lippman says. Commercial development requires payment of a licensing feea cost more easily borne by deep-pocketed agricultural companies.

There are some smaller biotechs seeking to maneuver around the giant companies and the intellectual property obstacles. Calyxt, a Minnesota-based firm cofounded by Voytas, has already received USDA approval to grow several crops using an earlier and more-difficult-to-use gene-editing technology known as TALENs. Lippman consults for a Massachusetts startup called Inari. Benson Hill Biosystems, based in St. Louis, has been working on improving plant productivity using a patented set of new gene-editing scissors the company calls Crispr 3.0. But CEO Matthew Crisp (yes, thats his name) claims innovation is being stifled by an intellectual property landscape that is very murky. Benson Hills partners and prospective licensees, he says, have complained that commercial rights to Crispr gene-editing technology are too expensive, too cumbersome, or too uncertain. The discovery of new gene-editing enzymes and other innovations may complicate the patent landscape even more. As one source put it, Its a mess. And its only going to get worse.

Thats why theres a lot of attention focused on a new startup called Pairwise Plants, in which Monsanto has teamed up with several Crispr pioneers from the Broad Institute. Recent statements to Bloomberg by company CEO Tom Adams, a former vice president of Monsanto, stressing new crops that are really beneficial to people, raised some eyebrows. You know, its not Monsanto language, Voytas noted. And the Monsanto pedigree has some plant biologists concerned. The question will be: They have enormous baggage in terms of consumer acceptance, Lippman says. And if they botch it, theyre going to ruin it for everybody else. Everyone is sort of holding their breath.

Trays for germinating tomato seeds.

Dolly Faibyshev

Physalis pruinosa plants at the Boyce Thompson Institute in Ithaca.

Dolly Faibyshev

Heres a simpler question: What about flavor? When I asked Harry Klee if he had tasted any of the jointless 8059 tomatoes hes growing, he laughed and said he hadnt bothered. We know that Florida 8059 by itself doesnt really have too much taste to begin with. A better-tasting tomato always plays second fiddle to market economics. The majority of tomatoes grown in Florida, for example, go to the food service industryto the McDonalds and Subways, Klee says. The sad reality, Klee says, is that industry is not really committed to making a better-tasting tomato. Klee loves to talk about tastehe heads a group that identified about two dozen genetic regions related to exceptional tomato flavor. We know exactly how to give you a sweeter tomato that will taste better, he says. But those tomatoes are not as economically attractive to producers. The growers wont accept it.

What about consumers? Would they accept a gene-edited tomato if it tasted better? Or, to put it in a slightly more idiosyncratic way, would it be botanical blasphemy to gene-edit an heirloom?

In his tour of the greenhouse, Lippman paused at one point to express good-natured scorn for heirlooms. They are terrific tomatoes, he admits, but pretty crappy producers. From personal experience, I can confirm that heirlooms are finicky plants and stingy producers, with lousy immune systemsmost of all, theyre heartbreakers, at least in the backyard. They start out like Usain Bolt in the 100 meters and end up looking spent, shriveled, hobbled by all manner of wilts and fungi and pests, leaves drooping like brown funereal crepe. It was tempting to think of using the new genetic tools to improve them. Klee is very anxious to introduce gene editing into the home garden. He thinks gardeners like me might be the place to make the argument that gene-edited tomatoes are not GMOs.

What if I could give you a Brandywine that had high lycopene, longer shelf life, and was a more compact plant? Klee asked me. I could do all of those today, with knocking out genes and genome editing. And I could give you something that was virtually identical to Brandywine that was half as tall and had fruit that didnt soften in less than a day, and were deep, deep red with high lycopene. I mean, would you grow that?

Absolutely! I told him.

I think most people would grow that, he replied. I think this could be a huge opportunity to educate home gardeners in what plant breeding is all about.

Not everyone would agree with Klee (or me). Voytas, a pioneer of gene editing in plants, chuckled when I asked him about a gene-edited heirloom. You know, part of it is, theyre heirloom, he said. The name inherently suggests this is something of value from the past. Not something new and techy. More to the point, he reminded me of the sort of outrageous licensing fees for the gene-editing technology. So your heirloom tomato idea would never be financially lucrative enough to pay the requisite licensing fees.

The bottom line: Gene-edited tomatoes are probably on their way to the market. But tomatoes with better flavor? Probably not going to happen anytime soon.

In early June, Zach Lippman went back to being a farmer. On what initially seemed like a sunny day, he and a dozen coworkers got their hands dirty transplanting some 8,000 gene-edited tomato plants into an outdoor field on the grounds of Cold Spring Harbor Laboratory. There were lots of the familiar mutantsjointless, self-pruning, daylight insensitivity. (The outdoor planting required prior approval from the USDA.) Plant em deep! he cried, as the crew raced to get the tomato seedlings in the ground under suddenly darkening skies.

The ultimate fate of the gene-edited tomato is as unpredictable as the weather, but the fate of these particular tomatoes is less of a mystery. Lippman often takes them home. Ive eaten many gene-edited tomatoes, yeah, he laughs. (Not surprisingly, he finds absolutely nothing different about them.) Theyre not GMO, he insists. Its just that youre left with what would be equivalent to a natural mutation. So why not eat it? Its one of just thousands or millions of mutations that may or may not affect the health of the plant and were still eating them!

Stephen S. Hall is the author of six books and teaches science writing at New York University.

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We are in the midst of a gene-editing revolution.

For four decades, scientists have tinkered with our genes. Since the 1970s, they've experimentally switched them on and off, uncovering their functions; mapped their location within our genome; and even inserted or deleted them in animals, plants and human beings.

And in November 2018, aChinese scientist claimedto have created the world's first genetically modified human beings.

Though scientists have made great inroads into understanding human genetics, editing our genes has remained a complex process requiring imprecise, expensive technology, years of expertise and just a little luck, too.

In 2012, a pair of scientists developed a new tool to modify genes, reshaping the entire field of gene-editing forever: CRISPR. Often described as "a pair of molecular scissors," CRISPR is widely considered the most precise, most cost-effective and quickest way to edit genes. Its potential applications are far-reaching, affecting conservation, agriculture, drug development and how we might fight genetic diseases. It could even alter the entire gene pool of a species.

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The field of CRISPR research is still remarkably young, yet we've already seen how it might be used to fight HIV infection, combat invasive species and destroy antibiotic-resistant bacteria. Many unknowns remain, however, including how CRISPR might damage DNA, leading to pathologies such as cancer.

Such a monumental leap in genetic engineering is full of complexities that ask big, often philosophical questions about science, ethics, how we conduct research and the future of humanity itself. With the confirmation that two human embryos were modified using CRISPR and carried to term, those questions have come sharply into focus. The future of gene-editing seemingly arrived overnight.

But what exactly is CRISPR and what are the outstanding concerns about such a powerful tool?

Let's break it all down.

CRISPR has the potential to be used in editing human embryos to create "designer babies."

Few predicted how important CRISPR would become for gene editing upon its discovery 30 years ago.

As early as 1987, researchers at Osaka University studying the function of Escherichia coli genes first noticed a set of short, repeated DNA sequences, but they didn't understand the significance.

Six years later, another microbiologist, Francisco Mojica, noted the sequences in a different single-celled organism, Haloferax mediterranei. The sequences kept appearing in other microbes and in 2002, the unusual DNA structures were given a name: Clustered regularly interspaced short palindromic repeats.

CRISPR.

Studying the sequences more intensely revealed that CRISPR forms an integral part of the "immune system" in bacteria, allowing them to fight off invading viruses. When a virus enters the bacteria, it fights back by cutting up the virus' DNA. This kills the virus and the bacteria stores some of the leftover DNA.

The leftover DNA is like a fingerprint, stored in the CRISPR database. If invaded again, the bacteria produce an enzyme called Cas9 that acts like a fingerprint scanner. Cas9 uses the CRISPR database to match the stored fingerprints with those of the new invader. If it can find a match, Cas9 is able to chop up the invading DNA.

Nature often provides great templates for technological advances. For instance, the nose of a Japanese bullet train is modeled on the kingfisher's beak because the latter is expertly "designed" by evolution to minimize noise as the bird dives into a stream to catch fish.

In a similar way, CRISPR/Cas9's ability to efficiently locate specific genetic sequences, and cut them, inspired a team of scientists to ask whether that ability could be mimicked for other purposes.

The answer would change gene editing forever.

In 2012, pioneering scientists Jennifer Doudna, from UC Berkeley, and Emmanuelle Charpentier, at Umea University Sweden, showed CRISPR could be hijacked and modified. Essentially, they'd turned CRISPR from a bacterial defense mechanism into a DNA-seeking missile strapped to a pair of molecular scissors. Their modified CRISPR system worked marvelously well, finding and cutting any gene they chose.

An illustration of the CRISPR-Cas9 gene editing complex. The Cas9 nuclease protein (white and green) uses a guide RNA (red) sequence to cut DNA (blue) at a complementary site.

Several research groups followed up on the original work, showing that the process was possible in yeast and cultured mouse and human cells.

The floodgates opened, and CRISPR research, which had long been the domain of molecular microbiologists, skyrocketed. The number of articles referencing CRISPR in preeminent research journal Nature has increased by over 6,000 percent between 2012 and 2018.

While other gene-editing tools are still in use, CRISPR provides a gigantic leap because of its precision and reliability. It's really good at finding genes and making accurate cuts. That allows genes to be cut out with ease, but it also provides an opportunity to paste new genes into the gap. Previous gene-editing tools could do this, too, but not with the ease that CRISPR can.

Another huge advantage CRISPR has over alternative gene-editing techniques is its expense. While previous techniques might cost a laboratory upward of $500 to edit a single gene, a CRISPR kit can do the same thing for under $100.

The CRISPR/Cas9 system has been adapted to enable gene editing in organisms including yeast, fungi, rice, tobacco, zebrafish, mice, dogs, rabbits, frogs, monkeys, mosquitoes and, of course, humans -- so its potential applications are enormous.

For research scientists, CRISPR is a tool that provides better, faster tinkering with genes, allowing them to create models of disease in human cell lines and mouse models with much higher proficiency. With better models of say, cancer, researchers are able to fully understand the pathology and how it develops, and that could lead to improved treatment options.

One particular leap in cancer therapy options is the genetic modification of T cells, a type of white blood cell that's critical for the human immune system. A Chinese clinical trial extracted T cells from patients, used CRISPR to delete a gene that usually acts as an immune system brake, and then reintroduced them into the patients in an effort to combat lung cancer. And that's just one of the many trials underway using CRISPR edited cells to fight particular types of cancer.

Beyond cancer, CRISPR has the potential to treat diseases caused by a mutation in a single gene, such as sickle cell anemia or Duchenne muscular dystrophy. Correcting a defective gene is known as gene therapy, and CRISPR is potentially the most powerful way to perform it. Using mouse models, researchers have demonstrated the efficacy of such treatments but human gene therapies using CRISPR remain untested.

Mosquitoes will be targeted using CRISPR gene drives, which could potentially drive malaria-carrying species to extinction.

Then there are CRISPR gene drives, which use CRISPR to guarantee a genetic trait will be passed from parent to offspring -- essentially rewriting the rules of inheritance. Guaranteeing certain genes will spread through a population provides an unprecedented opportunity to tackle mosquito-borne diseases such as malaria, enabling scientists to create infertile mosquitoes in the lab and release them in the wild to crash the population -- or even render a species extinct. CNET published an extensive report of their proposed use and the ethical concerns that surround them in February 2019.

And CRISPR's potential benefits don't end there. The tool opens up new ways of creating antimicrobials to combat rising levels of antibiotic resistance, targeted manipulation of agricultural crops such as wheat to make them hardier or more nutritious, and, potentially, the ability to design human beings, gene by gene.

CRISPR may be the most precise way to cut DNA we've yet discovered, but it's not always perfect.

One of the chief barriers to getting CRISPR effectively working in humans is the risk of "off-target effects." When CRISPR is tasked with hunting down a gene, it sometimes finds genes that look very similar to its target and cuts them, too.

An unintended cut may cause mutations in other genes, leading to pathologies such as cancer, or it may have no effect at all -- but with safety a major concern, scientists will need to ensure CRISPR acts only on the gene it's intended to impact. This work has already begun, and several teams of researchers have tinkered with CRISPR/Cas9 to increase its specificity.

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To date, CRISPR work in humans has been confined to cells that don't pass on their genome to the next generation. But gene editing can also be used to edit embryos and thus, change the human gene pool. In 2015, an expert panel of CRISPR scientists suggested that such editing -- known as germline editing -- would be irresponsible until consensus can be reached on safety, efficacy, regulation and social concerns.

Still, research into germline editing has been occurring for several years. In 2017, scientists in the UK edited human embryos for the first time, and researchers in the US used CRISPR to correct a defective gene that causes heart disease. The ability to edit embryos begins to raise ethical concerns about so-called designer babies, wherein scientists may select beneficial genes to increase physical fitness, intelligence or muscle strength, creeping into the controversial waters of eugenics.

That particular future is likely a long way off -- but the era of editing the human genome has already begun.

On Nov. 25, 2018, Chinese scientist Jiankui He said he had created the world's first CRISPR babies. By using CRISPR, He was able to delete a gene known as CCR5. The modified embryos resulted in the birth of twin girls, known by the pseudonyms Lulu and Nana.

The scientific community widely condemned the research, criticizing He's lack of transparency and asking whether there was an unmet medical need for the two girls to receive such a modification. In the wake of the research, several high-profile researchers involved with CRISPR's creation even suggested a global moratorium on using the tool for germline editing.

Few would argue that He's work highlights a need for stricter regulatory controls and effective oversight of clinical trials in which embryos are edited. While He maintains his own experiment was concerned with improving the health of the twin girls by making them HIV-resistant, the experiment was deemed reckless and ethically wrong and the potential consequences overlooked. Recent research suggests that the deletion He created in the CCR5 gene may affect brain activity, after a study in mice showed that blocking CC5 improves cognition and recovery from stroke.

In January 2019, the Chinese government said that He acted both unlawfully and unethicallyand would face charges. He was later dismissed by his university.

Jiankui He claimed to have created the world's first gene-edited babies.

The most recent International Summit for Human Genome Editing, in November 2018, concluded, as it did in 2015, "the scientific understanding and technical requirements for clinical practice remain too uncertain and the risks too great to permit clinical trials of germline editing at the time."

He's work, which remains unpublished, heralds the first clinical trial and birth of genetically modified human beings -- which means, whether it was the intention or not, a new era for CRISPR has begun.

As the revolution surges forward, the greatest challenges will continue to be effective oversight and regulation of the technology, the technical hurdles that science must overcome to ensure it is precise and safe, and managing the larger societal concerns of tinkering with the stuff that makes usus.

CRISPR continues to make headlines as scientists refine its specificity and turn it toward myriad genetic diseases. On Feb. 4, researchers at UC Berkeley, including CRISPR pioneer Jennifer Douda, revealed that another enzyme, CasX, could be used to edit genes in place of Cas9.

The scientists identified CasX in a ground-dwelling bacteria not normally present in humans, which means our immune systems are less likely to rebel against it. Because it's smaller and potentially more specific than Cas9, it can clip genes with greater success and less chance of any negative effects.

Then, on Feb. 18, scientists at UC San Francisco revealedthey had used CRISPR to make stem cells "invisible" to the immune system. Stem cells are able to mature into adult cells of any tissue, so they have been proposed as a way to repair damaged organs. However, the immune system typically tries to annihilate any foreign invader and stem cells are seen as such. CRISPR has enabled the stem cells to evade the immune system so they can get to work at healing.

Only a day later, researchers at the Salk Institute for Biological Sciencespublished in Nature Medicine their findings on a CRISPR therapy for Hutchinson-Gilford progeria, a disease associated with rapid aging. The disease is caused by a genetic mutation that results in a buildup of abnormal proteins, ultimately leading to premature cell death. A single dose of CRISPR/Cas9 was shown to suppress the disease in a mouse model, paving the way for further exploration of CRISPR's therapeutic potential.

And still more CRISPR success stories continue to roll in. On Feb. 25, CRISPR Therapeutics, a company co-founded by CRISPR visionary Emmanuelle Charpentier, announced thatthe first human patients had been infused with a CRISPR/Cas9 drug to treat the disease beta-thalassemia. The illness is caused by a genetic mutation that results in red blood cells being unable to create the oxygen-transport molecule haemoglobin. To combat this, the CRISPR Therapeutics team takes stem cells from a patient, edits them with CRISPR/Cas9 outside the body to increase haemoglobin production and then transfuses them back into the bloodstream. The company plans to use a similar approach to treating the blood disease known as sickle cell anemia.

CRISPR research is advancing at a rapid pace, and it can be hard to keep up. In only seven years, CRISPR went from an evolutionary adaptation in bacteria to a gene-editing tool that created the very first genetically modified human beings. We've already seen CRISPR transform the entire field of molecular biology and that effect has rippled across the biological and medical fields.

First published, Jan. 23, 2019.Update, on Feb. 28 5 a.m. PT: Adds recent advances section

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CRISPR gene editing explained: What is it and how does it ...

Alt-R CRISPR-Cas9 System

Simple delivery of ribonucleoprotein complexes (crRNA:tracrRNA:Cas9 or sgRNA:Cas9).

CRISPR-Cas9 genome editing methods use a Cas9 endonuclease to generate double-stranded breaks in DNA. Cas9 endonuclease requires a CRISPR RNA (crRNA) to specify the DNA target sequence, and the crRNA must be combined with the transactivating crRNA (tracrRNA) to activate the endonuclease and create a functional editing ribonucleoprotein complex (Figure 1A). In an alternative approach, the crRNA and tracrRNA can be delivered as a single RNA oligonucleotide (Figure 1B). After cleavage, DNA is then repaired by non-homologous end-joining (NHEJ) or homology-directed recombination (HDR), resulting in a modified sequence. Alt-R CRISPR-Cas9 reagents and kits provide essential, optimized tools needed to use this pathway for genome editing research.

Option 1: Alt-R CRISPR-Cas9 crRNA:tracrRNA

Alt-R CRISPR-Cas9 crRNA

Alt-R CRISPR-Cas9 tracrRNA

The Alt-R CRISPR-Cas9 System offers two options for generating synthetic guide RNAs. The two-part system pairs an optimized, shortened universal tracrRNA oligonucleotide (67 nt) with an optimized, shortened, target-specific crRNA oligonucleotide (36 nt) for improved targeting of Cas9 to dsDNA targets (Figure 2). The single guide RNA (sgRNA) option combines the crRNA and tracrRNA segments into one long RNA molecule, reducing the number of components and simplifying the CRISPR workflow.

While delivering Cas9 nuclease as part of an RNP is the preferred method, the Alt-R CRISPR-Cas9 System is also compatible with S. pyogenes Cas9 from any source, including cells that stably express S. pyogenes Cas9 endonuclease, or when Cas9 is introduced as a DNA or mRNA construct.

All Alt-R CRISPR-Cas9 crRNAs are 3536 nt RNA oligos containing the 19 or 20 nt target-specific protospacer region, along with the 16 nt tracrRNA fusion domain. We recommend 20 nt protospacers for most applications. crRNAs must be duplexed with Alt-R CRISPR-Cas9 tracrRNA before RNP complex formation.

Alt-R CRISPR-Cas9 crRNAs are synthesized with proprietary chemical modifications, which protect the crRNA from degradation by cellular RNases and further improve on-target editing performance. When using 2-part gRNAs under highly challenging conditions (e.g., high nuclease environments or with Cas9 mRNA), use Alt-R CRISPR-Cas9 crRNA XT, which have additional chemical modifications for the highest level of stability and performance.

We guarantee* our predesigned guide RNAs targeting human, mouse, rat, zebrafish, or nematode genes. For other species, you may use our proprietary algorithms to design custom guide RNAs. If you have protospacer designs of your own or from publications, use our design checker tool to assess their on- and off-targeting potential before ordering guide RNAs that are synthesized using our Alt-R guide RNA modifications.

The 67 nt Alt-R tracrRNA is much shorter than the classical 89 bases of the natural S. pyogenes tracrRNA. We find that shortening the tracrRNA increases on-target performance. Alt-R CRISPR tracrRNA also contains proprietary chemical modifications that confer increased nuclease resistance.

Alt-R CRISPR-Cas9 tracrRNA labeled with ATTO 550 (ATTO-TEC) provide the same function as their unlabeled counterparts. However, the fluorescent dye allows you to monitor transfection or electroporation efficiency during preliminary experiments to optimize transfection conditions in your cell types (Figure 3).

Labeled tracrRNAs can also help concentrate transfected cells via FACS (fluorescence-activated cell sorting) analysis, which can simplify your screening process for cells with CRISPR events. (For more information and tips on using Alt-R CRISPR-Cas9 tracrRNA ATTO 550, see the application note.)

Alt-R CRISPR tracrRNA orders include Nuclease-Free Duplex Buffer for forming the complex between crRNA and tracrRNA oligos. Alt-R tracrRNA can be ordered in larger scale and paired with all of your target specific crRNAs, allowing for an easy and a cost-effective means of studying many CRISPR sites.

Alt-R CRISPR-Cas sgRNA

Alt-R CRISPR-Cas9 sgRNAs are long RNA oligonucleotides (99100 bases) containing the target-specific crRNA region and the Cas9-interacting tracrRNA region within a single molecule (i.e., 1920 base protospacer region and 80-base universal sgRNA region). Like other Alt-R RNAs, it contains chemical modifications to stabilize the RNA, increasing resistance to nuclease activity. For challenging conditions (e.g., high nuclease environments or with Cas9 mRNA), sgRNAs may provide increased potency.

The Alt-R S.p. Cas9 Nuclease V3 enzyme is a high purity, recombinant S. pyogenes Cas9. The enzymes include nuclear localization sequences (NLSs) and C-terminal 6-His tags. The S. pyogenes Cas9 enzyme must be combined with a gRNA to produce a functional, target-specific editing complex. For the best editing, combine the Alt-R S.p. Cas9 Nuclease V3 enzyme with the optimized Alt-R CRISPR gRNA in equimolar amounts.

The Alt-R S.p. HiFi Cas9 Nuclease V3 offers improved specificity over wild-type Cas9, greatly reducing the risk of off-target cutting events. This Cas9 variant also preserves the high level of editing efficiency expected from a Cas9 nuclease, maintaining 90100% on-target editing activity at most sites. For applications that are sensitive to off-target events, combining the Alt-R S.p. HiFi Cas9 Nuclease V3 with optimized Alt-R CRISPR-Cas9 gRNA (crRNA:tracrRNA) is highly recommended.

Cas9 nickases allow specific cutting of only one strand at the DNA target site. Cuts to both strands of DNA are accomplished by using either Alt-R S.p. Cas9 D10A Nickase V3 or Alt-R S.p. Cas9 H840A Nickase V3, with 2 gRNAs that target two neighboring Cas9 sites, one on either strand of the target region. This functionally increases the length of the recognition sequence from 20 to 40 bases. For more information about using Cas9 nickases, see the application note.

Alt-R S.p. dCas9 Protein V3 has mutations that result in the loss of nuclease activity. This protein can form RNP complexes with Alt-R gRNAs and bind to the target region specified by the gRNA without cutting the DNA.

In some cases, transfection of RNP or the creation of stably transfected cells is not possible. In those applications, AltR S.p. Cas9 Expression Plasmid is designed to provide expression of Cas9 endonuclease under CMV promoter control. Note that the plasmid contains no eukaryotic selectable marker, making expression of S.p. Cas9 transient. The Alt-R CRISPR-Cas9 System Plasmid User Guide provides instructions for using this plasmid.

Optional controls for human, mouse, and rat are available for the 2-part Alt-R CRISPR-Cas9 System.

We recommend using the appropriate Alt-R CRISPR-Cas9 Control Kit for studies in human, mouse, or rat cells. The control kits include an Alt-R CRISPR HPRT Positive Control crRNA targeting the HPRT (hypoxanthine phosphoribosyltransferase) gene and a computationally validated Alt-R CRISPR-Cas9 Negative Control crRNA. The kit also includes the Alt-R CRISPR-Cas9 tracrRNA for complexing with the crRNA controls, Nuclease-Free Duplex Buffer, and validated PCR primers for amplifying the targeted HPRT region in the selected organism. The inclusion of the PCR assay makes the kits ideal for verification of HPRT modification using the Alt-R Genome Editing Detection Kit.

Alt-R control kit components can also be ordered individually.

For information about sgRNA controls, contact applicationsupport@idtdna.com.

If you are studying primary or hard-to-transfect cells, electroporation is often a viable alternative to lipid-based transfection in CRISPR experiments. The Alt-R Cas9 Electroporation Enhancer is a Cas9-specific carrier DNA that is optimized to work with the Amaxa Nucleofector device (Lonza) and Neon System (Thermo Fisher) to increase transfection efficiency and thereby increase genome editing efficiency (Figure 4).

Alt-R HDR Enhancer is a small molecule compound that increases homology-directed repair. Alt-R HDR Enhancer exhibits its activity in multiple cell lines, including both adherent and suspension cell lines. Its activity is independent of the enzyme employed; for example, it can be used either with Alt-R S.p. Cas9 Nuclease V3 or Alt-R A.s. Cas12a (Cpf1) Nuclease V3.This versatile reagent is also compatible with electroporation and lipofection methods.

Use this kit to detect on-target genome editing and estimate genome editing efficiency in CRISPR experiments. Learn more >>

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Start genome editing with CRISPR-Cas9 | idtdna.com

Bassik Human CRISPR Knockout Library 101926 101934 Knockout Human Bassik 3rd 10 Varies Bassik Mouse CRISPR Knockout Library 1000000121 1000000130 Knockout Mouse Bassik 3rd 10 Varies Activity-optimized genome-wide library Discontinued Knockout Human Sabatini and Lander 3rd 10 178,896 Activity-optimized genome-wide library 1000000100 Knockout Human Sabatini and Lander 3rd 10 187,535 Broad GPP genome-wide Brunello 73179 (1 plasmid)73178 (2 plasmid) Knockout Human Doench and Root 3rd 4 76,441 Broad GPP genome-wide Brie 73632 (1 plasmid)73633 (2 plasmid) Knockout Mouse Doench and Root 3rd 4 78,637 Broad GPP kinome Brunello 75314, 75315 (1 plasmid)75312, 75313(2 plasmid) Knockout Human Doench and Root 3rd 4 3,052 Broad GPP kinome Brie 75317 (1 plasmid)75316 (2 plasmid) Knockout Mouse Doench and Root 3rd 4 2,852 Broad GPP activation Calabrese p65-HSF 92379 (Set A)92380 (Set B) Activation Human Doench and Root 3rd 36 56,762 (Set A)56,476 (Set B) Broad GPP activation Caprano p65-HSF 92383 (Set A)92384 (Set B) Activation Mouse Doench and Root 3rd 36 67,187 (Set A)66,889 (Set B) Broad GPP inhibition Dolcetto 92385 (Set A)92386 (Set B) Inhibition Human Doench and Root 3rd 36 57,050 (Set A)57,011 (Set B) Broad GPP inhibition Dolomiti 104090 (Set A)104091 (Set B) Inhibition Mouse Doench and Root 3rd 36 67,366 (Set A)67,194 (Set B) Cas13a/C2c2 Protospacer flanking site (PFS) Library 79153 Knockout E. coli Zhang N/A N/A - The protospacers contained in the library represent all 4096 (46) combinations of 6 nucleotides. N/A CRiNCL - Human CRISPRi Non-coding Libraries 86538 86550 Inhibition Human Weissman 3rd 10 Varies CRISPR/Cas9-assisted Removal of Mitochondrial DNA (CARM) Library 82480 Knockout Mouse Xie N/A N/A 395 CRISPRa Discontinued Activation Human Weissman 3rd 10 198,810 CRISPRa-v2 839781000000091 Activation Human Weissman 3rd 510 104,540209,080 CRISPRa-v2 839961000000093 Activation Mouse Weissman 3rd 510 107,105214,210 CRISPRi Discontinued Inhibition Human Weissman 3rd 10 206,421 CRISPRi-v2 839691000000090 Inhibition Human Weissman 3rd 510 104,535209,070 CRISPRi-v2 839871000000092 Inhibition Mouse Weissman 3rd 510 107,415214,830 Enriched subpools (kinase, nuclear, ribosomal, cell cycle) 51043 51048 Knockout Human Sabatini and Lander 3rd 10 Varies Focused Ras Synthetic Lethal Human CRISPR Knockout Library 92352 Knockout Human Sabatini and Lander 3rd 50 6,661 hCRISPRa-v2 subpooled libraries 83980 83986 Activation Human Weissman 3rd 5 Varies hCRISPRi-v2 subpooled libraries 83971 83977 Inhibition Human Weissman 3rd 5 Varies mCRISPRa-v2 subpooled libraries 83998 84004 Activation Mouse Weissman 3rd 5 Varies mCRISPRi-v2 subpooled libraries 83989 83995 Inhibition Mouse Weissman 3rd 5 Varies Human CRISPR Knockout Library 1000000132 Knockout Human X.S. Liu 3rd 10 185,634 Human GeCKO v2 1000000048 (1 plasmid)1000000049 (2 plasmid) Knockout Human Zhang 3rd 6 123,411 Human genome-wide library v1 69763 Knockout Human Wu 3rd 4 77,406 Human improved genome-wide library v1 67989 Knockout Human Yusa 3rd 5 90,709 Human CRISPR lncRNA Activation Pooled Library 1000000106 Activation Human Zhang 3rd 10 96,458 Human CRISPR Metabolic Gene Knockout Library 110066 Knockout Human Sabatini 3rd 10 30,290 Human miRNA CRISPR Knockout Library 112200 Knockout Human Lin 3rd 4-5 8,382 Human Paired-guide RNA (pgRNA) Library for Long Non-coding RNAs (lncRNAs) 89640 Knockout Human Wei 3rd Varies 12,472 pairs Mouse GeCKO v2 1000000052 (1 plasmid)1000000053(2 plasmid) Knockout Mouse Zhang 3rd 6 130,209 Mouse genome-wide library v1 Discontinued Knockout Mouse Yusa 3rd 5 87,897 Mouse improved genome-wide library v2 67988 Knockout Mouse Yusa 3rd 5 90,230 Oxford Fly 64750 Knockout D. melanogaster Liu N/A 3 40,279 Perturb-seq Guide Barcodes (GBC) 85968 Barcode Human Weissman 3rd N/A N/A SAM v1 - 3 plasmid system 1000000057 (Zeocin)1000000074 (Puromycin) Activation Human Zhang 3rd 3 70,290 SAM v1 - 3 plasmid system 1000000075 (Puromycin) Activation Mouse Zhang 3rd 3 69,716 SAM v2 - 2 plasmid system 1000000078 (Blasticidin) Activation Human Zhang 3rd 3 70,290 Toronto KnockOut - Version 1 1000000069 Knockout Human Moffat 3rd 12 176,500 Toronto KnockOut - Version 3 90294 Knockout Human Moffat 3rd 4 70,948 Toxoplasma Knockout 80636 Knockout T. gondii Lourido N/A 10 8,158 Two plasmid human activity-optimized genome-wide library 1000000095 Knockout Human Sabatini and Lander 3rd 10 187,536 Two plasmid mouse activity-optimized genome-wide library 1000000096 Knockout Mouse Sabatini and Lander 3rd 10 188,509

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Addgene: CRISPR Pooled gRNA Libraries

The past year hasn't been easy for Sangamo Therapeutics (NASDAQ:SGMO), CRISPR Therapeutics (NASDAQ:CRSP), and their respective shareholders. The market has cleaved billions from their market values even though they hardly did anything.

Both are going to have some important clinical trial readouts in 2019 that could send their share prices screaming toward the moon again. Let's stack these biotechs side by side to see which has a better chance of coming out on top.

Image source: Getty Images.

There's no disputing the value of CRISPR-based gene editing in the world of academia, but the jury's still out on whether CRISPR is a useful drug discovery tool. Although investors are ready to leap to broad conclusions, we're going to receive the verdict in tiny baby steps.

In partnership with Vertex Pharmaceuticals (NASDAQ:VRTX), CRISPR Therapeutics treated its first patient with CTX001 in late February. This experimental gene therapy involves editing a patient's stem cells outside their body with CRISPR/cas9 technology before reintroducing the cells to patients who need help producing functional hemoglobin.

CTX001 edits stem cells in a way that allows production of fetal hemoglobin to begin again. That should help patients with transfusion-dependent thalassemia and severe sickle-cell disease to reduce their reliance on frequent blood transfusions. Frequent transfusions are inconvenient, painful, and so expensive that a one-time cure could be a big hit for patients and insurers.

The plan is to treat two thalassemia patients first, then wait for safety data before putting anyone else at risk. If CTX001 can get these patients to safely produce enough fetal hemoglobin to make transfusions unnecessary, CRISPR's stock will soar and trigger milestone payments from Vertex.

CRISPR Therapeutics also plans to begin clinical studies with two cellular cancer therapies that it still owns outright. Once the ball gets rolling with more clinical trials, the bills could start piling up.

By the time patients begin showing meaningful data, CRISPR will probably be ready for a cash injection. The company finished 2018 with $456 million in cash after losing $165 million last year. CRISPR is codeveloping the drug with Vertex, which could get expensive. CRISPR spent $114 million last year on research and development before a single patient had been dosed.

Image source: Getty Images.

Year after year, Sangamo publishes a study that proves its zinc-finger nuclease (ZFN) technology is superior to all other gene editing methods in one way or another. Before you get carried away by the possibilities, it's important to remember that this biotech has been going at it since the mid-1990s and it still hasn't sent a single new drug application to the FDA.

Sadly, the company's recent attempts with ZFN-based candidates haven't been too successful. Sangamo was able to show us that SB-913 successfully inserted a gene that should help patients with mucopolysaccharidosis type II (MPS II) produce iduronate-2-sulfatase (IDS), an important digestive enzyme they can't make on their own.

Sangamo detected a small amount of IDS production from just one patient who received the highest dose during a dose-determination study. Investigators noticed signs of possible liver damage from this patient, which means Sangamo probably won't be able to use a higher, possibly effective dosage in a larger study.

After a couple of fruitless decades with earlier versions, Sangamo plans on releasing next-generation ZFN treatments before the end of the year. Until we see data that says they work, you probably shouldn't pin any significant value to this company's ZFN-based pipeline.

The only reason to buy Sangamo is its proprietary synthetic liver-specific gene promoter that's also a part of SB-525, a candidate for the treatment of hemophilia A. Pfizer (NYSE:PFE) has agreed to take the reins for SB-525 if an ongoing trial hits the right mark.

It turns out that the hard part about gene editing isn't the editing, it's getting the target cells to do something with the new gene once it's been pasted into place. Pfizer's interested in Sangamo's synthetic liver-specific promoter because it looks like it did the trick for hemophilia A patients.

Hemophilia patients need regular infusions of blood-clotting factors that they can't produce themselves or they risk an uncontrolled bleeding event. During the first dose-ranging study with SB-525, patients produced more of the clotting factor than anyone imagined possible.

Sangamo promised to give us an interim look at the follow-up Alta study with SB-525 last December but decided at the last moment to hold these cards close to the vest. Instead, the complete results will be released sometime in 2019.

Image source: Getty Images.

At recent prices, Sangamo's market cap is just $935 million, so another success for SB-525 could send its stock price through the roof. Pfizer's already on the hook for development expenses, and Sangamo is entitled to milestones and royalty payments that the big pharma could avoid by simply acquiring Sangamo.

Right now CRISPR Therapeutics' market cap is at $1.8 billion, which is a lot for a company without any human proof-of-concept data yet. If the first two patients don't report amazing results, the stock will receive an awful beating.It's probably best to cheer for CRISPR from the sidelines, and put the better buy, Sangamo, in a diverse portfolio.

See the article here:
Better Buy: CRISPR Therapeutics vs. Sangamo Therapeutics

In the early 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 youre asking, whats Crispr? the short answer is that its a revolutionary new class of molecular tools 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.

The long answer is that Crispr stands for Clustered Regularly Interspaced Palindromic Repeats. Crispr systems consist of a protein with sequence-snipping capabilities and a genetic GPS guide. 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 Crisprpharma, agriculture, energy, materials manufacturing, you name it. Even the weed guys want in. Companies are using it to make cancer-curing medicines, climate-change-fighting crops, biofuel-oozing algae, and self-terminating mosquitoes. 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 backend supply chain; businesses building gene-editor design tools and shipping synthetic guide RNAs or pre-Crisprd 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 societys greatest hopes and fears for the technology, from saving near-extinct species to igniting a superbaby arms race.

Crispr isnt going to end disease or hunger or climate change any time soon. Maybe it never will. Nor is it about to deliver designer children or commit genetic genocide. (Though its never too early to start talking about the ethical dilemmas such a powerful technology could pose.) Crispr is, however, already beginning to reshape the physical world around us in much less radical ways, one base pair at a time.

It all started with yogurt. To make it, dairy producers have long employed the help of Streptococcus thermophilus, a bacteria that gobbles up the lactose in milk and poops out lactic acid. It wasnt until 2005, though, that a young microbiologist named Rodolphe Barrangou discovered that S. thermophilus contained odd chunks of repeating DNA sequencesCrisprsand that those sequences were keeping it safe from the viruses that 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 Crispr to protect all of its yogurt and cheese cultures. Since DuPont owns about 50 percent of the global dairy culture market, that means youve probably already eaten Crispr-optimized cheese on your pizza.

Viruses 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 youve got the Zika virus, dengue, or yellow fever circulating in your body.

Every 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.

Thanks to overuse, the worlds 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 everywheremore 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 bugthe 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 discoveryJennifer Doudna and Emmanuelle Charpentierpublished their work on bacteria in Science in 2012. But not before patenting the technology as a tool for genetic engineering. If you just switch out the RNA guide, you can send Cas9 anywhereto the gene that causes Huntingtons disease, say, and snip it out. Crispr, they realized, would be a molecular biologists warp drive.

Six months later, a molecular biologist at the Broad Institute of MIT and Harvard named Feng Zhang published a paper in Science showing how 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 bodys natural defenses against cancer. And that meant big money.

Perhaps predictably, a patent battle ensuedone that is still going on today. Crisprs early pioneers founded three companies with exclusive licenses to exploit Crispr/Cas9 to cure human diseases; the first clinical trials are expected to begin in the US in 2018. Uncertainty over who will ultimately own the technology has done little to slow the appetite for all things Crispr. If anything, it has unleashed a flood of interest in developing competing and adjacent tools that promise to further refine and expand Crisprs already ample potential.

For now, Crispr is still 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 weave seamlessly into the fabric of our physical reality. It will simply be the way to solve a problem, if that problem is remotely biological 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 brewers yeast into factories that can make everything from insulin to ethanol. Crispr will rapidly enlarge the catalog of designer chemicals, molecules, and materials 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.

But we wont get there with the tools weve currently got. Which is why researchers are now racing to chart the full expanses of the Crispr universe. At this moment theyre scouring the globe for obscure bacteria to sequence, and theyre tinkering with the systems that have already been discovered. Theyre 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 advance Crisprs gene editing powers, but extend its capabilities far beyond DNA manipulation. You see, slicing and dicing isnt the only interesting thing to do to DNA. Tricked out new Crispr systems could temporarily toggle genes on and off or surveil the genome to fix mutations as they happen in real time, no snipping required. The first would let scientists treat human diseases where theres too much or too little of a certain substancesay insulinwithout permanently altering a patients 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 cant yet imagine.

Good at cutting DNA, great for knockouts. Already being replaced by newer base pair editors with more fine-tuned control.

Like Cas9 but not as sloppy. It leaves sticky DNA ends, which are easier to work with when making edits.

Cuts RNA not DNA. Could knock down protein levels without permanently changing your genome. Pair it with a reporter signal and youve got a diagnostic.

Cas3 gives zero f***. It offers no repair mechanismonce it finds that target DNA sequence it just starts cutting till there aint no DNA left.

Just discovered in an abandoned silver mine, we dont know yet what these tiny enzymes superpowers will be.

Meanwhile, consumers can expect to see their first Crisprd products lining grocery store shelves very soon. Because Crispr doesnt use plant pathogens to manipulate DNA (the old GMO-generating method), the USDA has given a free regulatory pass to gene-edited crops, allowing drought-tolerant soybeans and extra-starchy corn to ease into your favorite processed foods. Specialty fruits and vegetables will likely follow the commodity crops; the reduced regulatory burden and the cheapness of Crispr will allow companies appealing to 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, make today a great time to be a molecular biologist. Want to make antibiotics that only target bad bugs without wiping out the entire microbiome? There are companies doing that. Want to make paper-based diagnostics that doctors can take into the field to test for diseases like dengue and Zika? There are research labs and startups doing that too. And as more tools come online, the backend Crispr ecosystem will continually expand to support, supply, and optimize them.

Crispr applications are only going to become more powerful, and when they do they will rightly invite more scrutiny, and probably more regulation. Were going to have to figure out if its OK to wipe out an entire species in the name of conservation and bring other ones back from extinction. Well have to wrestle with the possibility that gene editing tools might be used to produce biological weapons of unfathomable destruction. And yes, well eventually have to talk about designer babies; when is it acceptable to fix a genetic mutation? Would we ever start adding features? Where do we draw the line? Crispr, and all the tools that will one day make up the Crispr universe will undoubtedly force societiesnot just scientiststo confront these questions and ponder the oldest one of all; what does it mean to be human?

Everything You Need To Know About Crispr Gene EditingOkay, you get it, Crisprs a big deal. But now, arent you curious to know exactly how it works? You dont have to be a microbiologist to understand this step-by-step look inside the molecular multitool of the century.

What Good Is Crispr If It Cant Get Where It Needs To Go?It doesnt matter how good Crispr gets, in order to actually snip away humanitys worst diseases, it first has to get to the right cells. And thats way harder said than done. Its time to talk about Crisprs delivery problem.

First Human-Pig Chimera Is a Step Toward Custom OrgansScientists have long been dreaming of xenotransplantationputting animal organs into peopleas a possible solution to the current human organ shortage. But almost all attempts to do so have failed. Heres how Crispr is bringing new hope to the dream of animal organ farms.

Read This Before You Freak Out Over Gene-Edited SuperbabiesIn the last few years, scientists in the US and China have used Crispr to fix genetic mutations in human embryos, prompting concerns over the imminent takeover of genetically superior designer children. Breathe, people: You dont need to worry about that for a long, long, long time.

America Needs To Figure Out the Ethics of Gene Editing NowStill. All that successful human embryo modification has scientists around the world calling for varying levels of caution against it. And while pretty much everyone agrees on avoiding a Gattaca-type situation, thats where the consensus ends.

Process of EliminationFor decades conservationists have used medieval methods for eradicating invasive island predators like rats. And all those traps and guns and poisons still havent gotten the job done. Local species are still under threat of extinction. Now some scientists are turning to Crispr gene drives, a particularly potent genetic tool that could forever transform our power over nature. Emma Marris went to the Galapagos to see how they might work in the wild.

The FDA Wants to Regulate Gene-Edited Animals as DrugsWe get it. Its hard to contort the USs 1938 patchwork of laws around 21st century technology. But companies making hornless cows and tailless pigs and all-male beef cattle are pissed at the FDAs new interpretation of the rules, and talking about taking their tech elsewhere.

Easy DNA Editing Will Remake the World. Buckle Up.Still havent had enough Crispr? Amy Maxmens 2015 cover story is the definitive survey of this gene-editing technology; from its humble bacterial beginnings, to the trenches of its ferocious patent battle, to inside the companies already churning toward our Crispr-created future.

Plus! Crispr uploads a galloping horse GIF into a living bacteria and more WIRED gene editing coverage.

This guide was last updated on April 26, 2018.

Enjoyed this deep dive? Check out more WIRED Guides.

Continued here:
What is Crispr Gene Editing? The Complete WIRED Guide | WIRED

We are in the midst of a gene-editing revolution.

For four decades, scientists have tinkered with our genes. Since the 1970s, they've experimentally switched them on and off, uncovering their functions; mapped their location within our genome; and even inserted or deleted them in animals, plants and human beings.

And in November 2018, aChinese scientist claimedto have created the world's first genetically modified human beings.

Though scientists have made great inroads into understanding human genetics, editing our genes has remained a complex process requiring imprecise, expensive technology, years of expertise and just a little luck, too.

In 2012, a pair of scientists developed a new tool to modify genes, reshaping the entire field of gene-editing forever: CRISPR. Often described as "a pair of molecular scissors," CRISPR is widely considered the most precise, most cost-effective and quickest way to edit genes. Its potential applications are far-reaching, affecting conservation, agriculture, drug development and how we might fight genetic diseases. It could even alter the entire gene pool of a species.

The field of CRISPR research is still remarkably young, yet we've already seen how it might be used to fight HIV infection, combat invasive species and destroy antibiotic-resistant bacteria. Many unknowns remain, however, including how CRISPR might damage DNA, leading to pathologies such as cancer.

Such a monumental leap in genetic engineering is full of complexities that ask big, often philosophical questions about science, ethics, how we conduct research and the future of humanity itself. With the confirmation that two human embryos were modified using CRISPR and carried to term, those questions have come sharply into focus. The future of gene-editing seemingly arrived overnight.

But what exactly is CRISPR and what are the outstanding concerns about such a powerful tool?

Let's break it all down.

CRISPR has the potential to be used in editing human embryos to create "designer babies."

Few predicted how important CRISPR would become for gene editing upon its discovery 30 years ago.

As early as 1987, researchers at Osaka University studying the function of Escherichia coli genes first noticed a set of short, repeated DNA sequences, but they didn't understand the significance.

Six years later, another microbiologist, Francisco Mojica, noted the sequences in a different single-celled organism, Haloferax mediterranei. The sequences kept appearing in other microbes and in 2002, the unusual DNA structures were given a name: Clustered regularly interspaced short palindromic repeats.

CRISPR.

Studying the sequences more intensely revealed that CRISPR forms an integral part of the "immune system" in bacteria, allowing them to fight off invading viruses. When a virus enters the bacteria, it fights back by cutting up the virus' DNA. This kills the virus and the bacteria stores some of the leftover DNA.

The leftover DNA is like a fingerprint, stored in the CRISPR database. If invaded again, the bacteria produce an enzyme called Cas9 that acts like a fingerprint scanner. Cas9 uses the CRISPR database to match the stored fingerprints with those of the new invader. If it can find a match, Cas9 is able to chop up the invading DNA.

Nature often provides great templates for technological advances. For instance, the nose of a Japanese bullet train is modeled on the kingfisher's beak because the latter is expertly "designed" by evolution to minimize noise as the bird dives into a stream to catch fish.

In a similar way, CRISPR/Cas9's ability to efficiently locate specific genetic sequences, and cut them, inspired a team of scientists to ask whether that ability could be mimicked for other purposes.

The answer would change gene editing forever.

In 2012, pioneering scientists Jennifer Doudna, from UC Berkeley, and Emmanuelle Charpentier, at Umea University Sweden, showed CRISPR could be hijacked and modified. Essentially, they'd turned CRISPR from a bacterial defense mechanism into a DNA-seeking missile strapped to a pair of molecular scissors. Their modified CRISPR system worked marvelously well, finding and cutting any gene they chose.

An illustration of the CRISPR-Cas9 gene editing complex. The Cas9 nuclease protein (white and green) uses a guide RNA (red) sequence to cut DNA (blue) at a complementary site.

Several research groups followed up on the original work, showing that the process was possible in yeast and cultured mouse and human cells.

The floodgates opened, and CRISPR research, which had long been the domain of molecular microbiologists, skyrocketed. The number of articles referencing CRISPR in preeminent research journal Nature has increased by over 6,000 percent between 2012 and 2018.

While other gene-editing tools are still in use, CRISPR provides a gigantic leap because of its precision and reliability. It's really good at finding genes and making accurate cuts. That allows genes to be cut out with ease, but it also provides an opportunity to paste new genes into the gap. Previous gene-editing tools could do this, too, but not with the ease that CRISPR can.

Another huge advantage CRISPR has over alternative gene-editing techniques is its expense. While previous techniques might cost a laboratory upward of $500 to edit a single gene, a CRISPR kit can do the same thing for under $100.

The CRISPR/Cas9 system has been adapted to enable gene editing in organisms including yeast, fungi, rice, tobacco, zebrafish, mice, dogs, rabbits, frogs, monkeys, mosquitoes and, of course, humans -- so its potential applications are enormous.

For research scientists, CRISPR is a tool that provides better, faster tinkering with genes, allowing them to create models of disease in human cell lines and mouse models with much higher proficiency. With better models of say, cancer, researchers are able to fully understand the pathology and how it develops, and that could lead to improved treatment options.

One particular leap in cancer therapy options is the genetic modification of T cells, a type of white blood cell that's critical for the human immune system. A Chinese clinical trial extracted T cells from patients, used CRISPR to delete a gene that usually acts as an immune system brake, and then reintroduced them into the patients in an effort to combat lung cancer. And that's just one of the many trials underway using CRISPR edited cells to fight particular types of cancer.

Beyond cancer, CRISPR has the potential to treat diseases caused by a mutation in a single gene, such as sickle cell anemia or Duchenne muscular dystrophy. Correcting a defective gene is known as gene therapy, and CRISPR is potentially the most powerful way to perform it. Using mouse models, researchers have demonstrated the efficacy of such treatments but human gene therapies using CRISPR remain untested.

Mosquitoes will be targeted using CRISPR gene drives, which could potentially drive malaria-carrying species to extinction.

Then there are CRISPR gene drives, which use CRISPR to guarantee a genetic trait will be passed from parent to offspring -- essentially rewriting the rules of inheritance. Guaranteeing certain genes will spread through a population provides an unprecedented opportunity to tackle mosquito-borne diseases such as malaria, enabling scientists to create infertile mosquitoes in the lab and release them in the wild to crash the population -- or even render a species extinct.

And CRISPR's potential benefits don't end there. The tool opens up new ways of creating antimicrobials to combat rising levels of antibiotic resistance, targeted manipulation of agricultural crops such as wheat to make them hardier or more nutritious, and, potentially, the ability to design human beings, gene by gene.

CRISPR may be the most precise way to cut DNA we've yet discovered, but it's not always perfect.

One of the chief barriers to getting CRISPR effectively working in humans is the risk of "off-target effects." When CRISPR is tasked with hunting down a gene, it sometimes finds genes that look very similar to its target and cuts them, too.

An unintended cut may cause mutations in other genes, leading to pathologies such as cancer, or it may have no effect at all -- but with safety a major concern, scientists will need to ensure CRISPR acts only on the gene it's intended to impact. This work has already begun, and several teams of researchers have tinkered with CRISPR/Cas9 to increase its specificity.

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To date, CRISPR work in humans has been confined to cells that don't pass on their genome to the next generation. But gene editing can also be used to edit embryos and thus, change the human gene pool. In 2015, an expert panel of CRISPR scientists suggested that such editing -- known as germline editing -- would be irresponsible until consensus can be reached on safety, efficacy, regulation and social concerns.

Still, research into germline editing has been occurring for several years. In 2017, scientists in the UK edited human embryos for the first time, and researchers in the US used CRISPR to correct a defective gene that causes heart disease. The ability to edit embryos begins to raise ethical concerns about so-called designer babies, wherein scientists may select beneficial genes to increase physical fitness, intelligence or muscle strength, creeping into the controversial waters of eugenics.

That particular future is likely a long way off -- but the era of editing the human genome has already begun.

On Nov. 25, 2018, Chinese scientist Jiankui He said he had created the world's first CRISPR babies. By using CRISPR, He was able to delete a gene known as CCR5. The modified embryos resulted in the birth of twin girls, known by the pseudonyms Lulu and Nana.

The scientific community widely condemned the research, criticizing He's lack of transparency and asking whether there was an unmet medical need for the two girls to receive such a modification. In the wake of the research, several high-profile researchers involved with CRISPR's creation even suggested a global moratorium on using the tool for germline editing.

Few would argue that He's work highlights a need for stricter regulatory controls and effective oversight of clinical trials in which embryos are edited. While He maintains his own experiment was concerned with improving the health of the twin girls by making them HIV-resistant, the experiment was deemed reckless and ethically wrong and the potential consequences overlooked. In January 2019, the Chinese government said that He acted both unlawfully and unethicallyand would face charges. He was later dismissed by his university.

Jiankui He claimed to have created the world's first gene-edited babies.

The most recent International Summit for Human Genome Editing, in November 2018, concluded, as it did in 2015, "the scientific understanding and technical requirements for clinical practice remain too uncertain and the risks too great to permit clinical trials of germline editing at the time."

He's work, which remains unpublished, heralds the first clinical trial and birth of genetically modified human beings -- which means, whether it was the intention or not, a new era for CRISPR has begun.

We've already seen CRISPR transform the entire field of molecular biology -- and that effect has rippled across the biological and medical fields at lightning speed. In only six years, CRISPR went from an evolutionary adaptation in bacteria to a gene-editing tool that, potentially, created the very first genetically modified human beings.

As the revolution surges forward, the greatest challenges will lie in oversight and regulation of the technology, the technical hurdles that science must overcome to ensure it is precise and safe, and the larger societal concerns of tinkering with the stuff that makes us us.

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CRISPR explained: The revolutionary tool that's transforming ...

A team that includes the scientist who first harnessed the revolutionary CRISPR-Cas9 and other systems for genome editing of eukaryotic organisms, including animals and plants, has engineered another CRISPR system, called Cas12b. The new system offers improved capabilities and options when compared to CRISPR-Cas9 systems.

In a study published today in Nature Communications, Feng Zhang and colleagues at the Broad Institute of MIT and Harvard and the McGovern Institute for Brain Research at MIT, with co-author Eugene Koonin at the National Institutes of Health, demonstrate that the new enzyme can be engineered to target and precisely nick or edit the genomes of human cells. The high target specificity and small size of Cas12b from Bacillus hisashii (BhCas12b) as compared to Cas9 (SpCas9), makes this new system suitable for in vivo applications. The team is now making CRISPR-Cas12b widely available for research.

The team previously identified Cas12b (then known as C2c1) as one of three promising new CRISPR enzymes in 2015, but faced a hurdle: Because Cas12b comes from thermophilic bacteria which live in hot environments such as geysers, hot springs, volcanoes, and deep sea hydrothermal vents the enzyme naturally only works at temperatures higher than human body temperature.

We searched for inspirations from nature, Zhang says. We wanted to create a version of Cas12b that could operate at lower temperatures, so we scanned thousands of bacterial genetic sequences, looking in bacteria that could thrive in the lower temperatures of mammalian environments.

Through a combination of exploration of natural diversity and rational engineering of promising candidate enzymes, they generated a version of Cas12b capable of efficiently editing genomes in primary human T cells, an important initial step for therapeutics that target or leverage the immune system.

This is further evidence that there are many useful CRISPR systems waiting to be discovered, said Jonathan Strecker, a postdoc in the Zhang Lab, a Human Frontiers Science program fellow, and the studys first author.

The field is moving quickly: Since the Cas12b family of enzymes was first described in 2015 and demonstrated to be RNA-guided DNA endonucleases, several groups have been exploring this family of enzymes. In 2017 a team from Jennifer Doudnas lab at the University of California at Berkeley reported that Cas12b from Alicyclobacillus acidoterrestris can mediate nonspecific collateral cleavage of DNA in vitro. More recently, a team from the Chinese Academy of Sciences in Beijing reported that another Cas12b, from Alicyclobacillus acidiphilus, was used to edit mammalian cells.

The Broad Institute and MIT are sharing the Cas12b system widely. As with earlier genome editing tools, these groups will make the technology freely available for academic research via the Zhang labs page on the plasmid-sharing website Addgene, through which the Zhang lab has already shared reagents more than 52,000 times with researchers at nearly 2,400 labs in 62 countries to accelerate research.

Zhang is a core institute member of the Broad Institute of MIT and Harvard, as well as an investigator at the McGovern Institute for Brain Research at MIT, the James and Patricia Poitras Professor of Neuroscience at MIT, and an associate professor at MIT, with joint appointments in the departments of Brain and Cognitive Sciences and Biological Engineering.

Support for this study was provided by the National Human Genome Research Institute, the National Institute of Mental Health, the National Heart, Lung, and Blood Institute, the Poitras Center for Psychiatric Disorders Research, and the Hock E. Tan and K. Lisa Yang Center for Autism Research. Feng Zhang is an investigator with the Howard Hughes Medical Institute.

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CRISPR | MIT News

Last month, Chinese national He Jiankui flouted a vigorous scientific debate when he told a room full of scientists that he had manipulated the embryos of Chinese twins, using Crispr, and made one resistant to their fathers HIV. He announced to the group that the twins of the experiment had already been born.

The big reveal was ethically dubious at best. He never went through proper channels to get his experiment approved. The scientist is being condemned by his contemporaries for ignoring universally respected protocol and forgoing peer research. In The Washington Post, Eileen Hunt Botting wrote that Hes experiment had no moral or scientific justification, given that the medical profession can successfully prevent fathers from transmitting HIV without genetic engineering. Botting went on to compare Hes experiment to popular science fiction: However extreme their scenarios, both Gattaca and Frankenstein remind us that all children are vulnerable to discrimination based on factors beyond their controlincluding circumstances shaped by artificial reproductive technology.

Collier Meyerson is an Ideas contributor at WIRED. She was awarded an Emmy for her work on MSNBC's All In with Chris Hayes and two awards for her reporting from the National Association of Black Journalists. She is a contributing editor at New York Magazine, and maintains the Nobler Fellowship at The Nation Institute.

It's easy to fear this kind of procedure: follow embryonic gene editing to its logical conclusion and well end up with a society dramatically altered through eugenics, with generations of people engineered to fit a single vision of perfection. Its an unequivocally scary prospect. (Also, those people would be boring in their uniformity, and no sane person wants a world full of cogs.)

When we think about genetic engineering, we tend to think in absolute termsa black-and-white stance with a barrier that, once crossed, leads to the downfall of civilization as we know it. In reality, we make genetic decisions all the time, in ways that are already subtly altering the people who make up society. It might seem strange to group Hes experiment alongside the more common genetic procedures parents use to ensure their offspring don't inherit diseases. Yet both exist within a system in whichgenerallyonly the economically privileged are able to pay for treatment to alter the traits that their offspring will and wont inherit. The danger isn't in the procedure itself, but who has access to this type of medicineand right now that group is limited to those who can pay.

Suspend your belief in moral absolutism for just a moment. There is a universe in which the eugenics He practiced are actually a good idea. When we think of scientific eugenics, like in the movies, its generally of the nonessential sort, the kind that will work to maintain western European standards of beauty or universal standards of good healthwhite babies with blue eyes, blond hair, and an ability to run 12 marathons a year. But what if the technology were used, in earnest, to create better outcomes for those with a proverbial leg down on the ladder of white supremacy?

In the United States, where black women disproportionately contract HIV, or in eastern and southern Africa, where according to UNICEF half the worlds population with HIV live, breeding immunity into the population could be a good thing. The same thing goes for other possibly deadly diseases like sickle cell anemia, which most severely affects black children.

In practice, use of these techniques is a lot grimmer. The idea that [gene editing] could be rolled out in subsaharan Africa is a fantasy, Hank Greely, a professor who specializes in the ethics of genetics at Stanford, told me. The place where HIV is most prevalent is the place where people have the least access to medical care, he said, explaining that for the foreseeable future the technology will cost a lot of money.

In other places in the world, these kinds of genetic enhancements are already a readily used option. Last year my friend Allison tested positive for the BRCA gene, a mutation that dramatically increases her risk of developing ovarian cancer, breast cancer, or both. When Allison got the test results, it was a hard time, but ultimately she was thankful for the information. Recently Allison and I were discussing whether she would consider using in vitro fertilization to prevent passing the gene onto her children (should she choose to have them).

As far as Allison knows, she doesnt face fertility challenges, so there is no medical need for her to do in vitro. She would be electing to do something called preimplantation genetic diagnosis, a process that allows in vitro specialists to identify which embryos have BRCA and which dont, and then only implant the ones that dont.

My friend told me she doesnt expect to determine the fate of her future child using in vitro. I feel confident that, by the time I have kids who might be dealing with this, there will be other solutions, she said over text. But if her insurance were to cover it, she said shell reconsider.

Skewed access to the kind of treatment Allison considered is already creating a tiered genetic system, according to Judith Daar, a law professor at UC Irvine and author of The New Eugenics. Aside from preimplantation genetic diagnosis, Daar told me that lack of access to IVF has revived early-20th-century eugenics ideas that some are better fit to reproduce than others. Current law and policy surrounding IVFwhere some are given access to expensive treatments while, for others, they remain out of reachare tantamount to a new eugenics, she says, because they enable demographic features likes socioeconomic status, race, ethnicity, marital status, sexual orientation, and disability to suppress access to reproductive technology.

Though it doesnt involve manipulating embryos, weve already got a version of Hes vision right under our nose. Gene technology is, for the most part, geared toward those who have. Its different, for surethere is no editing, just eliminating embryos deemed undesirable. But traces of the same issue remain: Only some babies will benefit. How to universalize access is the real ethical pursuit.

Correction appended, 12/17/18, 9:35 PM EDT: This story has been updated to correct the spelling of Hank Greely's name.

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Crispr Babies, IVF, and the Ethics of Genetic Class Warfare ...

11. There is no way to tell whether Hes work did any good.

Both Nana and Lulu will be monitored at least until they turn 18. But the children were already at virtually no risk of contracting HIV, said Alta Charo, a bioethicist from the University of Wisconsin at Madison, in a statement. This means that there is no way to evaluate if this indeed conferred any benefit. If they remain HIV-negative, there is no way to show it has anything to do with the editing.

At the Hong Kong summit, He was asked whether the two children would be treated differently by their parents, who will know that they have been edited. I dont know how to answer this question, He said.

12. He has doubled down.

If He shows any contrition about how these events have unfolded, it has not been obvious. Speaking at the Hong Kong summit, he apologized, but only because news about his work leaked unexpectedly before he could present it in a scientific venue. That, He said, took away from the community. Regarding the experiment itself, he said: I feel proud.

13. Scientific academies have prevaricated.

In the wake of Hes bombshell, several scientists, including the CRISPR pioneer Feng Zhang and the stem-cell biologist Paul Knoepfler, have called for a temporary moratorium on similar experiments. By contrast, after the news first broke, the organizing committee of the Hong Kong summit, which includes representatives from scientific academies in Hong Kong, the United Kingdom, and the United States, released a bland statement in which it simply restated the conclusions from its earlier report. A second statement, released after the summit, was stronger, calling Hes claims deeply disturbing and his work irresponsible.

Read: A reckless and needless use of gene editing on human embryos

But the second statement still discusses the creation of more gene-edited babies as a goal that should be worked toward. The risks are too great to permit clinical trials of germ-line editing at this time, it says, but it is time to define a rigorous, responsible translational pathway toward such trials. George Daley from Harvard Medical School, who was one of the meetings co-organizers, made similar points during the event itself. Given that the world is still grappling with the implications of what has happened, no, its not time yet and its tone-deaf to say so, says Hank Greely.

Although the chair opened the summit by invoking Huxleys Brave New World, few of the discussions at the meeting, and nothing in the concluding statement, suggest a meaningful engagement with social consequences, says the Center for Genetics in Society, a watchdog group.

14. A leading geneticist came to Hes defense.

In an interview with Science, George Church, a respected figure from Harvard and a CRISPR pioneer, said that he felt an obligation to be balanced about the He affair. Church suggested that the man was being bullied and that the most serious thing about his experiment was that he didnt do the paperwork right. [Churchs] comments are incredibly irresponsible, says Alexis Carere, who is president-elect of the Canadian Association of Genetic Counsellors. If someone contravenes the rules that we have laid down, we are very justified in speaking out about it. The unfortunate effect of this is that it makes it seem like there is some kind of balance, and George is just in the middle. There is not.

Continued here:
15 Worrying Things About the CRISPR Babies Scandal - The Atlantic

From Popular Mechanics

When He Jiankui shocked the world last week by declaring he had successfully altered the genetic code of two babies, he was met with overwhelming skepticism and condemnation from the scientific community. Now, his case has gotten weirder. The South China Morning Post reports that the infamous scientist has gone missing.

Officials at He's now-former university, the Shenzhen-based Southern University of Science and Technology, denied claims that He had been detained by the Chinese government. Right now nobodys information is accurate, only the official channels are, the official tells the SCMP.

On November 26, He Jiankui released a series of YouTube videos announcing that he had made science fiction real-using the genetic editing tool CRISPR, he had successfully edited the genetic code of two twin baby girls to make them more resistant to the HIV virus. He had not allowed any independent scientific inspection of his work, choosing to announce his breakthrough through mainstream journalism and social media.

After the highly unconventional announcement, He's work has come under intense criticism in the realms of both ethics and pure science. Speaking at the International Human Genome Editing Summit, He falsely claimed that his results had "leaked," although their release had been part of a carefully coordinated media release.

During a 20-minute talk with a question and answer period, He attempted to justify his study to his peers. Presenting himself as a champion working against discrimination of those with HIV, He said that he feels "proud" of his work which targeted CCR5, a known pathway for the virus.

The scientific community disagreed on both purely scientific and as well as moral grounds. Several scientists who observed He's speech began challenging his work with the two girls, known as Lulu and Nana. One of the most thorough breakdowns of He's work comes from Gaetan Burgio of Australia National University.

"If you look into details," Burgio tells PopMech over the phone, "what they meant to target, they havent targeted. They targeted CCR5, which is correct, but they havent targeted the region known to show resistance to HIV." Burgio says that its "likely" that at least one of the children has no additional resistance to HIV at all.

A particular failure of He's, according to Burgio, was not recognizing what's known as the "allele mosaic." In genetics, a mosaic refers to two or more cell populations with differing genotypes (pieces of genetic material) in one individual. Alleles are crucial parts of our genetic code, variations on DNA that allow for unique traits like eye color. Like eye color, CCR5 has a wide variety of potential variations. Ignoring this mosaic while working on genes could end up in any number of results, ranging from the neutral to the deeply harmful.

He's lack of transparency means that "we dont know what has been done to the genes" of the two infants, Burgio says.

There also appear to have been significant problems with an important part of any study this risky-informed consent of the parents. The consent form that patients signed has come under stern criticism from other scientists, comparing it to a "business form, of the kind that a company might use when subcontracting" while downplaying any risks of the procedure.

"If this was a mouse," Burgio says, "I would not be concerned. But were talking about kids." When asked about He's motivations, Burgio felt sure that He wanted "to be first" in making the discovery. When asked about the possibility that He was genuine in his concern for HIV patients, Burgio laughed, noting that there are far safer ways to treat the disease.

Since He's appearance at the summit, he has not been seen. His university, where He has apparently been on leave since February, has disavowed knowledge of his work. A graduate of Rice University in Texas, He found a collaborator in a professor from the school, Michael Deem. Rice has released a statement declaring that the work "violates scientific conduct guidelines and is inconsistent with ethical norms of the scientific community and Rice University.

Source: SCMP

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The Infamous Scientist Behind the CRISPR Baby Gene Editing Is ...

For now, theyre known as Lulu and Nana, pseudonyms that are meant to give them some amount of anonymity amid the international uproar over their birth. As the first babies born after their genomes were edited (while they were embryos, by the genetics tool CRISPR) the twin girls, born in Shenzhen, China, are the subject of scientific and public scrutiny that will only escalate as they get older.

He Jiankui, a professor at the Southern University of Science and Technology, stunned the world when he claimed, both in a video posted by his lab and in an interview with a journalist, that he used CRISPR to disable a gene involved in helping HIV to enter healthy cells. By doing so, he gave the resulting edited embryos, including the twin girls, resistance to the virus. Doing so means He violated current guidelines prohibiting using CRISPR on human embryos for pregnancy. For now, Hes claims are only claims, since he has not published his work in a scientific journal for others to review and validate. While he did present his findings at a conference a few days after his YouTube announcement, researchers can only take the data at face value. He says he plans to publish the data, but now that the report has been released to the public, its difficult to predict which journals would accept the manuscript.

The Chinese researchers university denied knowledge of his experiment and said that He has been on leave since last February. Chinese authorities have now suspended Hes work, and Xu Nanping, vice minister of Chinas Ministry of Science and Technology, said Hes study was abominable in nature and violated Chinese laws and regulations, according to the governments Xinhua news.

The reason for the scientific censure boils down to the fact that He preempted a continuing debate over how and when CRISPR should be used in people. The technology, discovered in 2012, provides unprecedented precision and power to edit any genome, including the DNA of people, by snipping out portions of mutated genes and either allowing the genome to repair itself or by providing healthy versions of the gene. But because the approach is relatively new, scientists are still learning about exactly how precise their edits can be, and what some of the potential negative and long term consequences of altering human DNA could be.

Chinese geneticist He Jiankui of the Southern University of Science and Technology in Shenzhen, China, speaking during the Second International Summit on Human Genome Editing at the University of Hong Kong.

SOPA ImagesLightRocket/Getty Images

Nearly all international genetics groups have guidelines prohibiting using CRISPR to edit human embryos and implanting them for pregnancy, as the Chinese researcher did. Experts fully support using CRISPR in cells that cant be passed down from generation to generation, like skin cells or blood cells.

But what He did will forever change the twins DNA. Because he altered their genomes when they were embryos, those changes were picked up by every new cell that the embryos made as they continued to divide and develop, eventually forming the twins. So when the girls are ready to have children, their eggs may contain the CRISPR edits that He gave them, and they could pass on their altered genes to their children and all future generations of children in their lineage.

Having the gene itself is not necessarily a bad thing the edit He made is meant to protect people from getting infected with HIV but the problem is that scientists arent convinced yet that the HIV protection will be the only thing the CRISPR edit did to the twins genomes.

Its not clear, for example, that CRISPR is as precise as researchers would like it to be. It makes mistakes. In some cases, CRISPR may make unintended changes in random parts of the genome, like an autocorrect feature that mistakenly corrects typos to produce an entirely different word. In other cases, it may not make the edits as consistently as needed, so some cells may be edited while others are not, and some cells may even be partially edited, leaving a patchwork result scientists call mosaicism.

According to experts who reviewed some of the data He presented at a conference days after his stunning announcement, they say there is evidence that both girls born with the CRISPR edits showed such signs of mosaicism when they were embryos, meaning they are now likely to have the same mishmash of CRISPRd and unCRISPRd cells in their bodies. That means that they may not even benefit from the resistance to HIV that Hes grand experiment was meant to provide.

Theres also evidence that compromising the HIV gene may have other consequences for example, making people more susceptible to West Nile Virus and possibly the flu.

Its because of these unanswered questions and potential risks that scientists have favored a moratorium on using CRISPR in human embryos meant for pregnancy, at least until they have a better grasp on how CRISPR works and what some of the long term effects of editing might be. While the U.S. National Academy of Sciences in 2017 allowed for the eventual possibility of human babies whose genomes have been edited by CRISPR, it provided strict criteria for how that should happen: under strict monitoring and only in cases where there is no other medical option.

Neither of those criteria were met in the controversial CRISPR study. The university and the hospital where the births took place denied knowledge of Hes work, and the scientific community was blindsided that he had been proceeding with transferring human embryos for pregnancy. The gene he altered also does not represent an unmet medical need among the couples he worked with, only the fathers were HIV positive, meaning they were unlikely to pass on their infection to their children. Whats more, the fathers were on anti-HIV medications, which controlled their infection and make it even less likely they would infect their partners or their children.

In the twins case, what happens when they want to have children? Will they be allowed to have children naturally, and pass on their edited genes and whatever potential side effects might arise from their altered DNA? Or will regulatory or scientific authorities step in and attempt to control whether their genes continue into future generations by requiring the twins to have IVF and only implanting the embryos that do not show signs of the edited gene? Would those regulatory and scientific bodies even have the right to make such a request?

The implications go beyond just these twins, says Dr. Kiran Musunuru, professor of cardiovascular medicine and genetics at University of Pennsylvania Perelman School of Medicine. If we talk about the sanctity of human life, and the inherent dignity of human life, not much has been gained here. These babies were treated as subjects in a grand medical experiment, and we have to believe that they will be studied for the rest of their lives; its sad actually.

In his presentation and in his video, He justified his unorthodox actions by focusing on the personal. He said the father of the twins now feels motivated to find work and care for his family, and that altering the gene will protect future generations from HIV. But HIV experts say that judicious use and distribution of currently available drugs can effectively stop transmission of the virus, without taking such drastic steps of trying an proven genetic procedure and exposing people to its unknown risks.

While their identities are still protected for now, its unlikely the twins will remain anonymous for long. In bypassing ethical guidelines prohibiting the experiment that he conducted, He not only violated basic tenets of responsible scientific inquiry, he also forever changed how the girls will be viewed by society, and ultimately the decisions they make as a result of their involuntary status as the worlds first CRISPR babies.

Contact us at editors@time.com.

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What Happens to the CRISPR Twins? Their Lives Will ... - time.com

On the second day of the Second International Summit on Human Genome Editing, the last session before lunch was already running long. But the crowd crammed into the Lee Shau Kee Lecture Centre at the University of Hong Kong wasnt budging. Neither were the 5,500 people around the world glued to their live video feeds. Everyone was waiting to hear from the the final speaker, the man who says he helped make the worlds first gene-edited babies.

That man is He Jiankui, the Chinese-born, American-trained biophysicist who claims to have Crisprd a pair of twin baby girls.

Robin Lovell-Badge, a biologist at the Francis Crick Institute in the UK, took to the podium to introduce the controversial speaker. Lovell-Badge reminded everyone that the National Academy of the Sciences, the global non-governmental science panel that helped convene this summit, did not know in advance about Hes work. He sent me the slides he was going to show in this session and they did not include any of the work he was going to talk about, said Lovell-Badge. Nothing involving human embryos that were implanted.

But after MIT Technology Review broke the news of Hes covert trials two days ago, Hes session at this event became the object of intense fascination. Folks following along on Twitter wondered if He would show at all. And for one long, agonizing minute after Lovell-Badge welcomed He to the stage, it looked like he might not. When He at last appeared, he began to deliver a different talk, packed with details about what hed been up to.

For the last two years, He has been working in secret, skirting ethical and scientific codes of conduct, and possibly even some laws, to make biological history. On Wednesday morning, Hong Kong time, he revealed to the world just how he did it. It will take scientists days to parse the 59 data-dense slides that describe Hes methods and results. Only then will a fuller picture begin to emerge about just how safe and effective the experiment was. But in the meantime, He still gave the rest of us plenty to think about.

Like the fact that Lulu and Nana, the twin girls, arent the only children Hes group has Crisprd. When pressed on the number of implantations that have taken place so far, the scientist disclosed that there is another potential pregnancy involving a gene-edited embryo. He hesitated to answer the question because the pregnancy is in an early stage. His research team has so far injected Crispr systems into 31 embryos that have developed to the blastocyst stage. He said 70 percent of them were successfully edited and await further screening and implantation in five remaining couples. But now thats all on hold. The trial is paused due to the current situation, said He.

He is now under investigation by his own university, and other legal bodies in China.

After Hes presentation, he took questions from the audience and the moderators, including Lovell-Badge and Matthew Porteus, a Stanford researcher and the scientific founder of Crispr Therapeutics, a company developing Crispr-based drugs to treat genetic diseases. Throughout, He remained calm and thoughtful, if not always fully forthcoming.

At one point, Harvard biochemist David Liu questioned the unmet medical need that He said his experiments were addressing. He recruited couples where the mother is HIV-negative and the father HIV-positive, editing their embryos to bestow them with a rare but natural traitthe ability to resist HIV infections. Given that there are ways to make sure HIV-positive parents dont transmit their disease to their babies without altering their DNA, Liu asked He to describe the unmet medical need, not of HIV in general, but of these patients in particular.

He responded that his trial was not just for these few patients, but for the millions of children suffering from HIV all over the world. He described personal experience with a village in China where 30 percent of the residents are infected and children have to live with their relatives for fear of contracting the virus. I feel proud, actually, said He.

Not everyone agreed with Hes take. Between question and answer sessions, Nobel laureate and summit chair David Baltimore interjected to announce that the organizing committee would issue a formal statement regarding Hes work on Thursday. Baltimore then shared a few personal thoughts, including that the experiments as described do not meet the criteria of the National Academy of Sciences for a responsible application of human germline editing. Personally I dont think it was medically necessary, said Baltimore. I think there has been a failure of self-regulation by the scientific community because of a lack of transparency, he added.

Other members of the organizing committee were similarly skeptical. Having listened to Dr. He, I can only conclude that this was misguided, premature, unnecessary and largely useless, Alta Charo, a bioethicist at the University of Wisconsin-Madison wrote in an email to WIRED. Charo co-chaired the 2017 National Academies consensus study that laid out the criteria for an ethical path to human germline editing. Her greatest concern, she said, is that the consent forms that Hes patients signed created the impression that his project was an AIDS vaccine trial, and may have conflated research with therapy by claiming participants were likely to benefit.

As to the other embryos hes edited, which are on ice while the trial is itself frozen? What will happen to those embryos, or even who decides what happens, Charo says, is unknown.

Link:
Rogue Scientist Says Another Crispr Pregnancy Is Underway

In China, many people have already ventured into that terrain. Even before Crispr, it has been possible to create so-called designer babies using in vitro fertilization and selecting egg donors with desirable genetic enhancements, such as looks and intelligence. Thats what many wealthy Chinese have been doing for years. The practice is fairly standard among rich consumers of any nationality, but I was told by fertility clinics and doctors in California that Chinese customers were frequently the most upfront and demanding, driving up prices of East Asian donor eggs to twice and even triple market rates.

Wendie Wilson-Miller, who runs an egg donor agency in Southern California, told me that her Chinese clients almost always want taller, at least 5 foot 5. And they have questions about eyelids; they want to see baby pictures to see if the donors had eyelid surgery.

For years, B.G.I. Shenzhen, one of the worlds largest gene-sequencing facilities, has been running a project to explore the genetic basis for human intelligence, with the goal of eventually enabling parents to boost their offsprings I.Q. before birth. While it may not be possible to isolate human intelligence to a purely genetic component, the company clearly believes theres huge potential demand for such a service. One of its co-founders, Wang Jiang, recently caused a furor when he said in a speech that employees would not be allowed to have children with birth defects because they would be a disgrace.

No society is uniform, and news of the Crispr babies has generated much condemnation and outrage within China, particularly by Dr. Hes peers, who consider him an irresponsible rogue scientist. A top Chinese bioethicist, Qiu Renzong, compared his actions to using a cannon to shoot a bird.

But at the same time, a recent poll indicated wide support in China for gene editing to treat disease, with 24 percent in favor of legalizing gene editing for enhancing intelligence. By contrast, 68 percent of Americans say they are worried about gene editing and its effects, according to Pew Research.

Much is still unknown about the so-called Crispr babies. But it is almost certain that more will follow; Dr. He has already said his experiments have generated another pregnancy. It is also almost certain someone will attempt gene editing to make stronger, smarter, more attractive babies. Pandoras box is wide open in China.

Mei Fong, a Pulitzer Prize-winning journalist, is the author of One Child: The Story of Chinas Most Radical Experiment.

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Before the Claims of Crispr Babies, There Was Chinas One ...

We said dont freak out, when scientists first used Crispr to edit DNA in non-viable human embryos. When they tried it in embryos that could theoretically produce babies, we said dont panic. Many years and years of boring bench science remain before anyone could even think about putting it near a womans uterus. Well, we might have been wrong. Permission to push the panic button granted.

Late Sunday night, a Chinese researcher stunned the world by claiming to have created the first human babies, a set of twins, with Crispr-edited DNA. Two beautiful little Chinese girls, Lulu and Nana, came crying into the world as healthy as any other babies a few weeks ago, the scientist, He Jiankui, said in the first of five promotional videos posted to YouTube hours after MIT Technology Review broke the news.

Lulu and Nana are reported to have a genetic mutation, courtesy of Crispr, that makes it harder for HIV to invade and infect their white blood cells. The claim, which has yet to be independently verified or backed up by published data, has ignited furious criticism, international outrage, and multiple investigations. The scientific outcry has been so swift because Hes purported work, conducted in secret, bulldozes past existing ethical guidance on so-called germline editing, in which alterations to an embryos DNA will be passed down to subsequent generations.

Whats perhaps most strange is not that He ignored global recommendations on conducting responsible Crispr research in humans. He also ignored his own advice to the worldguidelines that were published within hours of his transgression becoming public.

On Monday, He and his colleagues at Southern University of Science and Technology, in Shenzhen, published a set of draft ethical principles to frame, guide, and restrict clinical applications that communities around the world can share and localize based on religious beliefs, culture, and public-health challenges. Those principles included transparency and only performing the procedure when the risks are outweighed by serious medical need.

The piece appeared in the The Crispr Journal, a young publication dedicated to Crispr research, commentary, and debate. Rodolphe Barrangou, the journals editor in chief, where the peer-reviewed perspective appeared, says that the article was one of two that it had published recently addressing the ethical concerns of human germline editing, the other by a bioethicist at the University of North Carolina. Both papers authors had requested that their writing come out ahead of a major gene editing summit taking place this week in Hong Kong. When half-rumors of Hes covert work reached Barrangou over the weekend, his team discussed pulling the paper, but ultimately decided that there was nothing too solid to discredit it, based on the information available at the time.

Now Barrangou and his team are rethinking that decision. For one thing, He did not disclose any conflicts of interest, which is standard practice among respectable journals. Its since become clear that not only is He at the helm of several genetics companies in China, He was actively pursuing controversial human research long before writing up a scientific and moral code to guide it.Were currently assessing whether the omission was a matter of ill-management or ill-intent, says Barrangou, who added that the journal is now conducting an audit to see if a retraction might be warranted. Its perplexing to see authors submit an ethical framework under which work should be done on the one hand, and then concurrently do something that directly contravenes at least two of five of their stated principles.

One is transparency. Reporting by Tech Review and The Associated Press has raised questions about whether He misled trial participants and Chinese regulators in his ambitions to make the first Crisprd baby. Two is medical necessity.

Take the gene Hes group chose to edit: CCR5. It codes for a receptor that HIV uses to infiltrate white blood cells, like a key to a locked door. No key, no access. Other controversial Crispr firsts have attempted to correct faulty versions of genes responsible for inherited, often incurable disorders, reverting them back to the healthy version. In contrast, Hes group crippled normal copies of CCR5 to lower the risk of future possible infection with HIVa disease that is easily prevented, treated, and controlled by means that dont involve forever changing someones DNA. Drugs, condoms, needle-exchange programs are all reasonable alternatives.

There are all sorts of questions these issues raise, but the most fundamental is the risk-benefit ratio for the babies who are going to be born, says Hank Greely, an ethicist at Stanford University. And the risk-benefit ratio on this stinks. Any institutional review board that approved it should be disbanded if not jailed.

Reporting by Stat indicates that He may have just gotten in over his head and tried to cram a self-guided ethics education into a few short months. The young scientistrecords indicate He is just 34has a background in biophysics, with stints studying in the US at Rice University and in bioengineer Stephen Quakes lab at Stanford. His resume doesnt read like someone steeped deeply in the nuances and ethics of human research. Barrangou says that came across in the many rounds of edits Hes framework went through. The editorial team did spend a significant amount of time improving both the language and the content, he says.

Its too soon to say whether Hes stunt will bring him fame or just infamy. Hes still scheduled to speak at the human genome editing summit on Wednesday and Thursday. And Chinas central government in Beijing has yet to come down one way or another. Condemnation would make He a rogue and a scientific outcast. Anything else opens the door for a Crispr IVF cottage industry to emerge in China and potentially elsewhere. Its hard to imagine this was the only group in the world doing this, says Paul Knoepfler, a stem cell researcher at UC Davis who wrote a book on the future of designer babies called GMO Sapiens. Some might say this broke the ice. Will others forge ahead and go public with their results or stop what theyre doing and see how this plays out?

What happens next makes all the difference. The fact that two babies now exist with one gene changed by Crispr to a less common form doesnt change the world overnight. What changes the world is how society reacts, and whether it decides to let such DNA-altering procedures become common.

See more here:
Scientist Who Crisprd Babies Bucked His Own Ethics Policy

Ever since scientists created the powerful gene editing technique Crispr, they have braced apprehensively for the day when it would be used to create a genetically altered human being. Many nations banned such work, fearing it could be misused to alter everything from eye color to I.Q.

Now, the moment they feared may have come. On Monday, a scientist in China announced that he had created the worlds first genetically edited babies, twin girls who were born this month.

The researcher, He Jiankui, said that he had altered a gene in the embryos, before having them implanted in the mothers womb, with the goal of making the babies resistant to infection with H.I.V. He has not published the research in any journal and did not share any evidence or data that definitively proved he had done it.

But his previous work is known to many experts in the field, who said many with alarm that it was entirely possible he had.

Its scary, said Dr. Alexander Marson, a gene editing expert at the University of California in San Francisco.

While the United States and many other countries have made it illegal to deliberately alter the genes of human embryos, it is not against the law to do so in China, but the practice is opposed by many researchers there. A group of 122 Chinese scientists issued a statement calling Dr. Hes actions crazy and his claims a huge blow to the global reputation and development of Chinese science.

If human embryos can be routinely edited, many scientists, ethicists and policymakers fear a slippery slope to a future in which babies are genetically engineered for traits like athletic or intellectual prowess that have nothing to do with preventing devastating medical conditions.

While those possibilities might seem far in the future, a different concern is urgent and immediate: safety. The methods used for gene editing can inadvertently alter other genes in unpredictable ways. Dr. He said that did not happen in this case, but it is a worry that looms over the field.

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Dr. He made his announcement on the eve of the Second International Summit on Human Genome Editing in Hong Kong, saying that he had recruited several couples in which the man had H.I.V. and then used in vitro fertilization to create human embryos that were resistant to the virus that causes AIDS. He said he did it by directing Crispr-Cas9 to deliberately disable a gene, known as CCR, that is used to make a protein H.I.V. needs to enter cells.

Dr. He said the experiment worked for a couple whose twin girls were born in November. He said there were no adverse effects on other genes.

In a video that he posted, Dr. He said the father of the twins has a reason to live now that he has children, and that people with H.I.V. face severe discrimination in China.

Dr. Hes announcement was reported earlier by the MIT Technology Review and The Associated Press.

In an interview with the A.P. he indicated that he hoped to set an example to use genetic editing for valid reasons. I feel a strong responsibility that its not just to make a first, but also make it an example, he told the A.P. He added: Society will decide what to do next.

It is highly unusual for a scientist to announce a groundbreaking development without at least providing data that academic peers can review. Dr. He said he had gotten permission to do the work from the ethics board of the hospital Shenzhen Harmonicare, but the hospital, in interviews with Chinese media, denied being involved. Cheng Zhen, the general manager of Shenzhen Harmonicare, has asked the police to investigate what they suspect are fraudulent ethical review materials, according to the Beijing News.

The university that Dr. He is attached to, the Southern University of Science and Technology, said Dr. He has been on no-pay leave since February and that the school of biology believed that his project is a serious violation of academic ethics and academic norms, according to the state-run Beijing News.

In a statement late on Monday, Chinas national health commission said it has asked the health commission in southern Guangdong province to investigate Mr. Hes claims.

Many scientists in the United States were appalled by the developments.

I think thats completely insane, said Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon Health and Science University. Dr. Mitalipov broke new ground last year by using gene editing to successfully remove a dangerous mutation from human embryos in a laboratory dish.

Dr. Mitalipov said that unlike his own work, which focuses on editing out mutations that cause serious diseases that cannot be prevented any other way, Dr. He did not do anything medically necessary. There are other ways to prevent H.I.V. infection in newborns.

Just three months ago, at a conference in late August on genome engineering at Cold Spring Harbor Laboratory in New York, Dr. He presented work on editing the CCR gene in the embryos of nine couples.

At the conference, whose organizers included Jennifer Doudna, one of the inventors of Crispr technology, Dr. He gave a careful talk about something that fellow attendees considered squarely within the realm of ethically approved research. But he did not mention that some of those embryos had been implanted in a woman and could result in genetically engineered babies.

What we now know is that as he was talking, there was a woman in China carrying twins, said Fyodor Urnov, deputy director of the Altius Institute for Biomedical Sciences and a visiting researcher at the Innovative Genomics Institute at the University of California. He had the opportunity to say Oh and by the way, Im just going to come out and say it, people, theres a woman carrying twins.

I would never play poker against Dr. He, Dr. Urnov quipped.

Richard Hynes, a cancer researcher at the Massachusetts Institute of Technology, who co-led an advisory group on human gene editing for the National Academy of Sciences and the National Academy of Medicine, said that group and a similar organization in Britain had determined that if human genes were to be edited, the procedure should only be done to address serious unmet needs in medical treatment, it had to be well monitored, it had to be well followed up, full consent has to be in place.

It is not clear why altering genes to make people resistant to H.I.V. is a serious unmet need. Men with H.I.V. do not infect embryos. Their semen contains the virus that causes AIDS, which can infect women, but the virus can be washed off their sperm before insemination. Or a doctor can inject a single sperm into an egg. In either case, the woman will not be infected and neither will the babies.

Dr. He got his Ph.D., from Rice University, in physics and his postdoctoral training, at Stanford, was with Stephen Quake, a professor of bioengineering and applied physics who works on sequencing DNA, not editing it.

Experts said that using Crispr would actually be quite easy for someone like Dr. He.

After coming to Shenzhen in 2012, Dr. He, at age 28, established a DNA sequencing company, Direct Genomics, and listed Dr. Quake on its advisory board. But, in a telephone interview on Monday, Dr. Quake said he was never associated with the company.

-

Austin Ramzy contributed reporting from Hong Kong and Elsie Chen contributed research from Beijing.

Continued here:
Chinese Scientist Claims to Use Crispr to Make First ...

He Jiankui at the Human Genome Editing Conference in Hong Kong

Kin Cheung/AP/REX/Shutterstock

By Michael Le Page

On Monday, the world was stunned by an Associated Press story claiming that the first gene-edited babies had been born in China. On Wednesday, the scientist responsible revealed far more details during a talk at a gene-editing summit in Hong Kong, including that there is another pregnancy.

There hasnt yet been any independent verification that two gene-edited girls really have been born. But the technical details revealed by He Jiankui today may have been enough to convince many of the scientists in attendance. However, questions still remain over the ethicsand safety of the experiment.

The stated aim of theproject was to make individuals immune to HIV by disabling the gene for a protein called CCR5, which is exploited by the virus. However, disabling this gene does not provide complete protection against HIV and the broader consequences of knocking out this gene which is involved in immune function are unclear.

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The team began by using the CRISPR gene editing method to disable CCR5 in mice and monkeys, He said, and found no health or behavioural issues. But one of the organisers of the summit, Robin Lovell-Badge of the Francis Crick Institute in London, pointed out that immune genes affect the entire body, and that a different mouse study found that deleting CCR5improved their cognitive abilities.

Have you inadvertently caused an enhancement? Lovell-Badge asked He after the talk. The mouse study needed verification, He replied. I am against using genome editing for enhancement.

Another big safety issue is off-target effects the risk that CRISPRcausesunintended, harmful mutations elsewhere in the genome. To try to prevent this, Hes team sequenced the entire genomes of both parents. They then removed 3 to 5 cells from each of the edited embryos before implantation in the mother and fully sequenced them, too, to check for unwanted mutations.

Comparing the genomes revealed several new mutations in the two edited embryos for which resultshave been released. Only one of these mutations found in the embryo of the girl nicknamed Lulu might be due to CRISPR, He concluded. Its possible that this may be the case, because every individual has up to 100 new mutations by chance anyway.

The possible off-target mutation was judged by the team to be harmless because itisin a region of DNA that is far from any genes. According to the slides He presented, the parents were told about it and decided to proceed.

But CRISPR expert Gaetan Burgio of the Australian National University tweeted thatthe checks for off-target mutations were not good enough. For instance, they would not have detected any very large deletions of DNA, he said.

The final big safety issue with using CRISPR on embryos is something called mosaicism. If the eggs started dividing before the gene editing took place, the twin girls might have a mixture of cells with and without the edit. Whether they do or not was unclear from Hes talk.

Tests on the placenta and umbilical cord blood and tissue found exactly the same mutations in each sample for both twins, the slides reveal. But the potential off-target mutation was found only in the cells taken from the embryo and not in later samples, which does imply mosaicism. And Burgio told New Scientist that the results suggest both twins are mosaics. I cant believe they went ahead and implanted the embryos, he says.

Mosaicism is an issue for two reasons. Firstly, if an embryo is a mosaic then removing a few cells for testing is not enough to check the health and status of an embryo. Secondly, if Lulus immune cells developed from non-edited cells, they would still be completely vulnerable to HIV.

We know the other twin, Nana, is definitely still completely vulnerable to HIV. She has a 15-DNA-letter long deletion in one of the two copies of the CCR5 gene that probably will not be enough to disable the protein. And the other copy was not edited at all.

Questions had been raised over why Nanas embryo was implanted at all, but He said the parents were informed and decided to implant it.

More on these topics:

See the rest here:
CRISPR babies: new details on the experiment that shocked ...

When Chinese researchers first edited the genes of a human embryo in a lab dish in 2015, it sparked global outcry and pleas from scientists not to make a baby using the technology, at least for the present.

It was the invention of a powerful gene-editing tool, CRISPR, which is cheap and easy to deploy,that made the birth of humans genetically modified in an in vitro fertilization (IVF) center a theoretical possibility.

Now, it appears it may already be happening.

According to Chinese medical documents posted online this month (hereand here), a team at the Southern University of Science and Technology, in Shenzhen, has been recruiting couples in an effort to create the first gene-edited babies. They planned to eliminate a gene called CCR5 inhopes of rendering the offspring resistant to HIV, smallpox, and cholera.

Southern University of Science and Technology

The clinical trial documents describe a studyin which CRISPR is employed to modify human embryosbefore they are transferred into womens uteruses.

The scientist behind the effort, He Jiankui, did not reply to a list of questions about whether the undertaking had produced a live birth. Reached by telephone, he declined to comment.

However, data submitted as part of the trial listing shows that genetic tests have been carried out on fetuses as late as 24 weeks, or six months. Its not known if those pregnancies were terminated, carried to term, or are ongoing.

[After this story was published, the Associated Press reported that according to He, onecouple in the trialgave birth to twingirls this month,though the agency wasn't able to confirm his claim independently. He also released a promotional video about his project.]

The birth of the first genetically tailored humans would be a stunning medical achievement, for both He and China. But it will prove controversial, too. Where some see anew form of medicinethat eliminates genetic disease, others see a slippery slope to enhancements, designer babies, and a new form of eugenics.

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The step toward genetically tailored humans was undertaken in secrecy and with the clear ambition of a stunning medical first.

In this ever more competitive global pursuit of applications for gene editing, we hope to be a stand-out, He and his team wrote in an ethics statement they submitted last year. They predicted their innovation will surpass the invention of in vitro fertilization, whose developer was awarded a Nobel Prize in 2010.

Gene-editing summit

Theclaim that China has already made genetically altered humans comes just as the worlds leading experts are jetting into Hong Kong for the Second International Summit on Human Genome Editing.

The purpose of the international meetingis to help determine whether humans should begin to genetically modify themselves, and if so, how. That purpose now appears to have been preempted by the actions of He, an elite biologist recruited back to China from the US as part of its Thousand Talents Plan.

The technology is ethically charged because changes to an embryo would be inherited by future generations and could eventually affect the entire gene pool.We have never done anything that will change the genes of the human race, and we have never done anything that will have effects that will go on through the generations, David Baltimore, a biologist and former president of the California Institute of Technology, who chairs the international summit proceedings, said in a pre-recorded message ahead of the event, which begins Tuesday, November 27.

It appears the organizers of the summit were also kept in the dark about Hes plans.

Regret and concern

The genetic editing of a speck-size human embryo carries significant risks, including the risks of introducing unwanted mutationsor yielding a baby whose body is composed of some edited and some unedited cells. Data on the Chinese trial site indicate that one of the fetuses is a mosaic of cells that had been edited in different ways.

A gene-editing scientist, Fyodor Urnov, associate director of the Altius Institute for Biomedical Sciences, a nonprofit in Seattle, reviewed the Chinese documents and said that, while incomplete, they do show that this effort aims to produce a human with altered genes.

Urnov called the undertaking cause for regret and concern over the fact that gene editinga powerful and useful techniquewas put to use in a setting where it was unnecessary. Indeed, studies are already under way to edit the same gene in the bodies of adults with HIV. It is a hard-to-explain foray into human germ-line genetic engineering that may overshadow in the mind of the public a decade of progress in gene editing of adults and children to treat existing disease, he says.

Big project

In a scientific presentation in 2017 at Cold Spring Harbor Laboratory, which is posted to YouTube, He described a very large series of preliminary experiments on mice, monkeys, and more than 300 human embryos. One risk of CRISPR is that it can introduce accidental or off target mutations. But He claimed he found few or no unwanted changes in the test embryos.

He is also the chairman and founder of a DNA sequencing company called Direct Genomics. A new breed of biotech companies could ultimately reap a windfall should the new methodsof conferring health benefits on children be widely employed.

The National Academies of Science, Engineering and Medicine

According to the clinical trial plan, genetic measurements would be carried out on embryos and would continue during pregnancy to check on the status of the fetuses. During his 2017 presentation, He acknowledged that if the first CRISPR baby were unhealthy, it could prove a disaster.

We should do this slow and cautious, since a single case of failure could kill the whole field, he said.

A listing describing the study was posted in November, but other trial documents are dated as early as March of 2017. That was only a month after the National Academy of Sciences in the US gave guarded support for gene-edited babies, although only if they could be created safely and under strict oversight.

Currently, using a genetically engineered embryo to establish a pregnancy would be illegal in much of Europe and prohibited in the United States. It is also prohibited in China under a 2003 ministerial guidance to IVF clinics. It is not clear if He got special permission or disregarded the guidance, which may not have the force of law.

Public opinion

In recent weeks, He has begun an active outreach campaign, speaking to ethics advisors, commissioning an opinion poll in China, and hiring an American public-relations professional, Ryan Ferrell.

My sense is that the groundwork for future self-justification is getting laid, says Benjamin Hurlbut, a bioethicist from Arizona State University who will attend the Hong Kong summit.

The new opinion poll, which was carried out by Sun Yat-Sen University, found wide support for gene editing among the sampled 4,700 Chinese, including a group of respondentswho were HIV positive. More than 60% favored legalizing edited children if the objective was to treat or prevent disease. (Polls by the Pew Research Center have found similar levels support in the US for gene editing.)

Hes choice to edit the gene called CCR5 could prove controversial as well. People without working copies of the gene are believed to be immune or highly resistant to infection by HIV. In order to mimic the same result in embryos, however, Hes team has been using CRISPR to mutate otherwise normal embryos to damage the CCR5 gene.

The attempt to create children protected from HIV also falls into an ethical gray zone between treatment and enhancement. That is because the procedure does not appear to cure any disease or disorder in the embryo, but instead attempts to create a health advantage, much as a vaccine protects against chicken pox.

For the HIV study, doctors and AIDS groups recruited Chinese couples in which the man was HIV positive. The infection has been a growing problem in China.

So far, experts have mostly agreed that gene editing shouldnt be used to make designer babies whose physical looks or personality has been changed.

He appeared to anticipate the concerns his study could provoke. I support gene editing for the treatment and prevention of disease, He posted in November to the social media site WeChat, but not for enhancement or improving I.Q., which is not beneficial to society.

Still, removing the CCR5 gene to create HIV resistance may not present a particularly strong reason to alter a babys heredity. There are easier, less expensive ways to prevent HIV infection. Also,editing embryos during an IVF procedure would be costly, high-tech, and likely to remain inaccessible in many poor regions of the world where HIV is rampant.

A person who knows He said his scientific ambitions appear to be in line with prevailing social attitudes in China, including the idea that the larger communal good transcends individual ethics and even international guidelines.

Behind the Chinese trial also lies some bold thinking about how evolution can be shaped by science. While the natural mutation that disables CCR5 is relatively common in parts of Northern Europe, it is not found in China. The distribution of the genetic trait around the worldin some populations but not in othershighlights how genetic engineering might be used to pick the most useful inventions discovered by evolution over the eons in different locations and bring them together in tomorrows children.

Such thinking could, in the future, yield people who have only the luckiest genes and never suffer Alzheimers, heart disease, or certain infections.

The text of an academic website that He maintains shows that he sees the technology in the same historic, and transformative, terms. For billions of years, life progressed according to Darwins theory of evolution, it states. More recently, industrialization has changed the environment in radical ways posing a great challenge that humanity can meet with powerful tools to control evolution.

It concludes: By correcting the disease genes we human[s] can better live in the fast-changing environment.

Note: This story was updated after publication to include claims by He Jiankui thatthe trial had produced live births.

Read more:
EXCLUSIVE: Chinese scientists are creating CRISPR babies ...

Its not the usual way that reputable scientists announce their breakthroughs to the world, but on Monday, Jiankui He released a video proclaiming that he had produced the worlds first human babies whose genomes were edited using the powerful technique called CRISPR. He had also previously spoken with the Associated Press about his study, which he says resulted in twin girls born with the first genomes edited by man.

The report was met with instant concern and skepticism by the scientific community. Hes experiment altered the genomes of embryos produced through IVF; their genetic changes will therefore be passed on to any future generations. Whats more, most experts in CRISPR are not convinced that the technology is ready or safe for treating humans.

Given the current early state of genome editing technology, Im in favor of a moratorium on implantation of edited embryos until we have come up with a thoughtful set of safety requirements first, Feng Zhang, one of the co-discoverers of CRISPR and from the Broad Institute of MIT and Harvard, said in a statement responding to the report. Not only do I see this as risky, but I am also deeply concerned about the lack of transparency surrounding this trial.

In 2015, prominent members of the scientific community familiar with the technology, including Zhang and another co-discoverer, Jennifer Doudna from University of California, Berkeley, agreed to voluntarily stop research on using CRISPR in human embryos because the safety and long term consequences of the technology were too uncertain. The researchers support studies in which CRISPR is used to develop treatments that would affect cells that arent passed on to the next generation i.e. anything except egg and sperm but say that more research is needed before CRISPR is used to make changes in genomes that can be carried by generation after generation.

While editing the DNA of a human embryo is not currently allowed in the U.S., in 2017, an international committee of the National Academy of Sciences called for loosening the moratorium and allowing trials of CRISPR in human embryos, under strict oversight, to treat rare genetic diseases that cant be addressed in any other way. In the U.K., officials approved studies of CRISPR in human embryos in 2016, but those embryos will not be transplanted to create a pregnancy. Those trials call for destroying the embryos after a week, since the technologys safety remains unclear.

He, on the other hand, has apparently jumped ahead to producing the first human babies born with CRISPR editing. He is on the faculty of Southern University of Science and Technology in Shenzhen China, but in a statement released in response to Hes videos, the university said he is on unpaid leave from February 2018 to January 2021; officials did not provide a reason for the leave.

The University was deeply shocked by this event and has taken immediate action to reach Dr. Jiankui He for clarification, the officials said in the statement. The research was conducted outside of the campus and was not reported to the University nor the Department [to which He belongs]. The statement went on to note that the university believes that Dr. Jiankui Hes conduct in utilizing CRISPR/Cas9 to edit human embryos has seriously violated academic ethics and codes of conduct The University will call for international experts to form an independent committee to investigate this incident, and to release the results to the public.

CRISPR, first described in 2012, gives scientists the most precise and effective way to edit the human genome by snipping out offending mutations or genes and either allowing the genome to repair itself or providing researchers with the ability to insert new genetic material to correct disease genes. But studies suggest that controlling CRISPR in human cells remains a challenge; in some cases CRISPR may cut unintended parts of the genome.

In his promotional video, He describes targeting the CCR5 gene, which helps the HIV virus enter healthy human cells. He worked with seven heterosexual couples in which the male partner was HIV positive and the women were HIV negative. After the couples produced embryos through IVF, he used CRISPR to cut the CCR5 gene, disabling it in the hopes of making the embryos less vulnerable to HIV infection. He claims that of 22 embryos, 16 showed signs of successful CRISPR editing, and 11 were implanted, resulting in a single pregnancy with twin girls who were born in November. One twin, according to Hes tests, showed signs that both copies of the CCR5 gene it inherited (one from its mother and one from its father) were successfully altered, while the other twin showed that one version of the gene it inherited was altered.

That so-called mosaicism, in which some but not all of the embryos cells are altered, is troubling since in this case, it would mean that girl may not be entirely protected from HIV infection like her sister. Thats one of the reasons why researchers are concerned about the report. Normally such scientific milestones are reported in scientific journals complete with detailed descriptions of how the researcher accomplished the feat along with data supporting their claims. Without such documentation, its impossible to verify whether the girls indeed showed successful CRISPR editing or not.

He, who created two companies based on his studies, is scheduled to present his findings at the Second International Summit on Human Genome Editing, and will certainly be the target of numerous questions from the leading gene-editing scientists in attendance.

Contact us at editors@time.com.

Read this article:
Chinese University 'Shocked' By News of First CRISPR ...

CRISPR is a term used in microbiology. It stands for Clustered Regularly-Interspaced Short Palindromic Repeats. These are a natural segment of the genetic code found in prokaryotes: most bacteria and archaea have it.[1]

CRISPR has a lot of short repeated sequences. These sequences are part of an adaptive immune system for prokaryotes. It allows them to remember and counter other organisms that prey on them, such as bacteriophages.

They have the potential to modify the genes of almost any organism. They are part of a tool that allows precisely targeted cutting and insertion of genes in genetic modification (GM). Work is under way to find how they can be used to attack virus diseases in humans.[2]

Each repetition is followed by short segments of "spacer DNA" from previous exposures to a bacterial virus or plasmid.[2] CRISPR spacers recognize and cut up the foreign genetic elements in a manner like RNA interference in eukaryotic organisms.

In effect, the spacers are fragments of DNA from viruses that have previously tried to attack the cell line. The foreign source of the spacers was a sign to researchers that the CRISPR/cas system could have a role in adaptive immunity in bacteria.[3]

The actual cutting is done by a nuclease called Cas9. Cas9 has two active cutting sites, one for each strand of the DNA's double helix. Cas9 does this by unwinding foreign DNA and checking whether it is complementary to the 20 basepair spacer region of the guide RNA (the spacer region RNA). If it is, the foreign DNA gets chopped up.

The technology has been used to switch off genes in human cell lines and cells, to study Candida albicans, to modify yeasts used to make biofuel and to genetically modify crop strains.[4]

See original here:
CRISPR - Simple English Wikipedia, the free encyclopedia

Posted on September 11th, 2018 by Dr. Francis Collins

Caption: A CRISPR/cas9 gene editing-based treatment restored production of dystrophin proteins (green) in the diaphragm muscles of dogs with Duchenne muscular dystrophy.Credit: UT Southwestern

CRISPR and other gene editing tools hold great promise for curing a wide range of devastating conditions caused by misspellings in DNA. Among the many looking to gene editing with hope are kids with Duchenne muscular dystrophy (DMD), an uncommon and tragically fatal genetic disease in which their musclesincluding skeletal muscles, the heart, and the main muscle used for breathinggradually become too weak to function. Such hopes were recently buoyed by a new study that showed infusion of the CRISPR/Cas9 gene editing system could halt disease progression in a dog model of DMD.

As seen in the micrographs above, NIH-funded researchers were able to use the CRISPR/Cas9 editing system to restore production of a critical protein, called dystrophin, by up to 92 percent in the muscle tissue of affected dogs. While more study is needed before clinical trials could begin in humans, this is very exciting news, especially when one considers that boosting dystrophin levels by as little as 15 percent may be enough to provide significant benefit for kids with DMD.

Posted In: News

Tags: animal models, beagles, Cavalier King Charles Spaniel, CRISPR, CRISPR/Cas9, diaphragm muscle, DMD, dogs, Duchenne muscular dystrophy, dystrophin, gene editing, genetic diseases, heart, muscle, muscular dystrophy, rare diseases, Somatic Cell Genome Editing

Posted on October 10th, 2017 by Dr. Francis Collins

About a month ago, I had the pleasure of welcoming the Juip (pronounced Yipe) family from Michigan to NIH. Although youd never guess it from this photo, two of the Juips five children9-year-old Claire and 11-year-old Jake (both to my left)have a rare genetic disease called Friedreichs ataxia (FA). This inherited condition causes progressive damage to their nervous systems and their hearts. No treatment currently exists for kids like Claire and Jake, yet this remarkable family has turned this serious health challenge into an opportunity to raise awareness about the need for biomedical research.

One thing that helps keep the Juips optimistic is the therapeutic potential of CRISPR/Cas9, an innovative gene editing systemthat may someday make it possible to correct the genetic mutations responsible for FA and many other conditions. So, Im sure the Juips were among those encouraged by the recent news that NIH-funded researchers have developed a highly versatile approach to CRISPR/Cas9-based therapies. Instead of relying on viruses to carry the gene-editing system into cells, the new approach uses tiny particles of gold as the delivery system!

Posted In: Health, Science, technology, Uncategorized

Tags: CRISPR, CRISPR-Gold, CRISPR/Cas9, DMD, Duchenne muscular dystrophy, dystrophin, FA, Friedreichs ataxia, gene editing, Juip, rare diseases, stem cells

Posted on July 18th, 2017 by Dr. Francis Collins

Credit: Seth Shipman, Harvard Medical School, Boston

Theres a reason why our cells store all of their genetic information as DNA. This remarkable molecule is unsurpassed for storing lots of data in an exceedingly small space. In fact, some have speculated that, if encoded in DNA, all of the data ever generated by humans could fit in a room about the size of a two-car garage and, if that room happens to be climate controlled, the data would remain intact for hundreds of thousands of years! [1]

Scientists have already explored whether synthetic DNA molecules on a chip might prove useful for archiving vast amounts of digital information. Now, an NIH-funded team of researchers is taking DNAs information storage capabilities in another intriguing direction. Theyve devised their own code to record information not on a DNA chip, but in the DNA of living cells. Already, the team has used bacterial cells to store the data needed to outline the shape of a human hand, as well the data necessary to reproduce five frames from a famous vintage film of a horse galloping (see above).

But the researchers ultimate goal isnt to make drawings or movies. They envision one day using DNA as a type of molecular recorder that will continuously monitor events taking place within a cell, providing potentially unprecedented looks at how cells function in both health and disease.

Posted In: Health, Science, Video

Tags: biosensor, biotechnology, Cas1, Cas2, CRISPR, CRISPR-Cas, DNA, DNA movie, DNA storage, E. coli, film, gene editing, genomics, Human and Animal Locomotion, imaging, information storage, molecular recorder, movie, spacers

Posted on May 4th, 2017 by Dr. Francis Collins

Jesse Dixon

As a kid, Jesse Dixon often listened to his parents at the dinner table discussing how to run experiments and their own research laboratories. His father Jack is an internationally renowned biochemist and the former vice president and chief scientific officer of the Howard Hughes Medical Institute. His mother Claudia Kent Dixon, now retired, did groundbreaking work in the study of lipid molecules that serve as the building blocks of cell membranes.

So, when Jesse Dixon set out to pursue a career, he followed in his parents footsteps and chose science. But Dixon, a researcher at the Salk Institute, La Jolla, CA, has charted a different research path by studying genomics, with a focus on understanding chromosomal structure. Dixon has now received a 2016 NIH Directors Early Independence Award to study the three-dimensional organization of the genome, and how changes in its structure might contribute to diseases such as cancer or even to physical differences among people.

Posted In: Health, Science

Tags: 2016 NIH Directors Early Independence Award, 3D genome structure, chromatin, chromatin structure, CRISPR, CRISPR/Cas9, DNA, DNA packaging, ENCODE, Encyclopedia of DNA Elements, enhancer, gene editing, genome, genomics, histones, TAD, topologically associated domains

Posted on January 24th, 2017 by Dr. Francis Collins

Caption: This image represents an infection-fighting cell called a neutrophil. In this artists rendering, the cells DNA is being edited to help restore its ability to fight bacterial invaders.Credit: NIAID, NIH

For gene therapy research, the perennial challenge has been devising a reliable way to insert safely a working copy of a gene into relevant cells that can take over for a faulty one. But with the recent discovery of powerful gene editing tools, the landscape of opportunity is starting to change. Instead of threading the needle through the cell membrane with a bulky gene, researchers are starting to design ways to apply these tools in the nucleusto edit out the disease-causing error in a gene and allow it to work correctly.

While the research is just getting under way, progress is already being made for a rare inherited immunodeficiency called chronic granulomatous disease (CGD). As published recently in Science Translational Medicine, a team of NIH researchers has shown with the help of the latest CRISPR/Cas9 gene-editing tools, they can correct a mutation in human blood-forming adult stem cells that triggers a common form of CGD. Whats more, they can do it without introducing any new and potentially disease-causing errors to the surrounding DNA sequence [1].

When those edited human cells were transplanted into mice, the cells correctly took up residence in the bone marrow and began producing fully functional white blood cells. The corrected cells persisted in the animals bone marrow and bloodstream for up to five months, providing proof of principle that this lifelong genetic condition and others like it could one day be cured without the risks and limitations of our current treatments.

Posted In: Health, Science

Tags: adult stem cells, bacteria, CGD, chronic granulomatous disease, clinical trials, CRISPR, CRISPR-Cas, CRISPR/Cas9, DNA editing, fungi, gene therapy, genetics, hematopoietic stem cells, immunodeficiency, immunology, infectious disease, inherited immuodeficiency, neutrophil, rare disease, translational medicine, X chromosome, X-linked chronic granulomatous disease

Originally posted here:
CRISPR NIH Director's Blog