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Gene editing can end disease and fight global famine

Engadget Engadget 28/06/2016 Andrew Tarantola

© Provided by Engadget

We're looking at the single greatest advancement in genetics since Mendelev started growing peas. CRISPR-Cas9 gene-modification technology is powerful enough to cure humanity's worst diseases, yet simple enough to be used by amateur biologists. You thought 3-D printers and the maker movement were going to change the world? Get ready for a new kind of tinkerer -- one that wields gene-snipping scissors.

CRISPR -- clustered regularly interspaced short palindromic repeats -- is a potent genetic-editing tool. It's called this because each CRISPR unit is made of repeated DNA base-pair sequences that can be read the same way forward or in reverse and are separated by "spacer" pairs. Think of it like an organic Morse code palindrome.

With CRISPR we can now edit any genetic code -- including our own. In the three years since its advent, researchers have used CRISPR to investigate everything from sickle-cell anemia and muscular dystrophy to cystic fibrosis and cataracts. One group has even used it to snip off the cellular receptors that HIV exploits in order to infect the human immune system. If the disease is caused by your genetics -- doesn't matter if it's due to a single malformed gene, as is the case with Huntington's or sickle cell, or if it's the byproduct of hundreds mutations like diabetes and Alzheimer's -- CRISPR can conceivably fix it.

Even complicated conditions like cancer and autism, which we've studied for years and still barely have a grasp on, can benefit from CRISPR technology. A big reason treatment advances for these marquee diseases come at such a glacial pace is that researchers have to develop them on animal models first. This trial-and-error technique takes forever. But with CRISPR, that process stands to accelerate exponentially by creating the precise desired genetic changes on the first try, every time.

These CRISPR units can easily slice through DNA and replace nucleotide bases with others, but they aren't accurate enough to consistently aim at specific locations. For that, each CRISPR needs an RNA-based "guide," called a Cas (CRISPR associated) gene. These guides search for a specific set of nucleotides, usually a 20-pair sequence, and bind to the site once they locate it. That's a pretty impressive feat, given that the human genome contains around 20,000 genes. Working in unison, a CRISPR/Cas system can target and silence the expression of single genes anywhere along a given strand of DNA about as easily as you can edit a Word document. It's basically "find-and-replace" for genetics.

This technology can be applied to any living organism, though its effects vary greatly depending on which genes are being targeted. The two primary versions of CRISPR-based edits are somatic cell engineering, which only modifies the genes of the individual, and germline engineering, wherein an individual's modified genes are passed onto their offspring.

The biological mechanism behind CRISPR is actually quite ancient. See, scientists used to think that bacteria were equipped only with innate immunity -- the lowest, most budget form of biological defense around. Since a microbe's restriction enzymes will blindly attack and destroy any unprotected DNA they come in contact with, scientists figured that it was just automatic, a simple reflex. Multicellular organisms, conversely, enjoy acquired immunity, which enables them to mount specific counters to different threats. It wasn't until they discovered CRISPR that researchers figured out bacteria and archaea have been leaning on acquired immunity for eons. They'd been using it as a rudimentary adaptive immune system against viruses. Here's a video from the McGovern Institute for Brain Research at MIT that explains the process in detail:

This system enables the bacteria to obtain immunity against that specific breed of virus and respond to future infections far more rapidly than it could otherwise. It's much in the same way the human immune system uses T-cells and antigens to keep us from repeatedly being sickened by the same diseases. This is why vaccinations work and why it's so important to vaccinate your kids. (Seriously, vaccinate your damn kids.)

Granted, there is a lot of hype surrounding both CRISPR's potential benefits and dangers. Not everything we do with the technology is going to be Earth-shattering advancements and cancer cures. We're probably going to do a lot of silly shit with it as well. "I would bet that within 20 years, somebody is going to make a unicorn," Hank Greely, director of Stanford University's Center for Law and the Biosciences, told me during a recent phone call. "Some Silicon Valley billionaire with a 12-year-old daughter will get her a unicorn for her birthday. It will involve taking genes that grow horns and moving them into a horse."

CRISPR's benefits aren't limited to animals. In 2014, a team of geneticists in China managed to give wheat full immunity against powdery mildew -- one of the most common and widespread plant pathogens on the planet -- by cutting just three genes out of its DNA. Similarly, researchers at the King Abdullah University of Science and Technology's Center for Desert Agriculture have used CRISPR technology to "immunize" tomatoes against the yellow leaf curl virus while a team from the National Institute for Biotechnology and Genetic Engineering (NIBGE) in Pakistan has done the same for cotton leaf curl. And just last year a Japanese team drastically increased the shelf life of tomatoes by editing the gene that controls the rate of their ripening.

Examples of yellow leaf curl virus in cotton plants. credit: the NIBGE

This technology stands to revolutionize nearly every aspect of modern agriculture. We can create stronger, more robust crops with higher yields and increased tolerance to drought, pests and blight. We can do this without waiting multiple generations, as is the case with traditional breeding methods, and without introducing foreign DNA into the plant's genome, as we would with conventional genetic modification (GMO) techniques.

"CRISPR is just a more efficient way of doing what's been done for millennia of looking for genetic variance within a population that would make it better," Greely said. "With CRISPR instead of waiting for them to arise naturally, you make them. Heck, for the last 50 years we've used radiation to increase the rates of mutation. With CRISPR we're instead causing mutations where we know what mutations we are causing. It's a much smarter way to do the kind of crop and livestock improvement we've done since the agricultural revolution."

Of course, this new technology is not without potential danger. We're at the point now where we understand the technology just well enough to hurt ourselves but haven't used it long enough to fully comprehend the long-term implications.

Take the recent controversy surrounding the creation of the world's first modified human embryo, for example. This technology theoretically will allow doctors to cure any human disease or defect before a person is born, but were something to go awry during the operation, the results could be devastating. That said, those sorts of procedures will be exceedingly rare for the foreseeable future, contends Greely. "Ninety-nine-point-nine percent of the population won't need gene editing to have a baby that won't get the disease that they're carrying," he told me. And even if someone is born with a genetic disease, Greely extrapolated, somatic cell editing should still be able to treat them.

"Most people are more concerned with doing it for enhancement reasons but right now we don't know squat about enhancements," he continued. "We know all sorts of intelligence genes that, when mutated a certain way, you end up with very low intelligence. But we know basically nothing about gene editing to make you smarter. Or taller. Or more athletic. We can't even do a particularly good job with eye, hair or skin color." So don't expect to see Gattaca-style designer babies coming to your local fertility clinic anytime soon.

What you will see is an explosion of novel uses for the technology. Gene editing is quickly moving from the realm of pure academia and into the hands of the general public and private enterprise. This transition resembles that of another transformative technology: personal computers. Computers went from being, essentially, toys for adults to a keystone of the modern era. CRISPR has the potential to do the same but for biology.

Take Ethan Perlstein for example. "I initially wanted to be a professor," he explains. "Like a lot of people who get trained in graduate school, especially in biomedical sciences, are thinking we're going to be professors ... that's how you can be a scientist professionally." However, the nation's glut of postgraduates has long outpaced the supply of available professorships. "My goal was academia; reality suggested that I take another path. And actually through my explorations on Twitter, I learned about rare diseases." His subsequent interactions with the social media communities that spring up around these rare diseases led him to found Perlstein Lab.

Ethan Perlstein, CEO Perlstein Lab. credit: Engadget / Benito Gonzalez

This San Francisco-based biotech startup is using CRISPR technology to drastically accelerate research into some of humanity's least-studied diseases. "There are about 4,000 inherited diseases that are caused by a single broken gene," Perlstein said, with roughly 5 percent of those manifesting during childhood and nearly all of which have no known pharmaceutical treatment. Specifically, Perlstein's team is working on drugs that can treat Niemann-Pick Type C, a lysosomal storage disorder that causes a buildup of toxic material within cells; and N-glycanase 1 Deficiency, a congenital glycosylation disorder that causes a whole host of issues, from cognitive impairment to joint deformities. Both of these devastating illnesses are caused by a single recessive gene, potentially by just one incorrect base pairing.

"These rare diseases, especially the ones that are caused by a single broken gene, tend to involve pathways and networks within the cell that are very ancient," Perlstein explained. What's more, those primal genes are disproportionately more likely to "break" than, say, the relatively new genes that control your autoimmune system. Their ancient nature enables the lab to effectively model them in simple animals -- specifically, fruit flies, zebrafish and yeasts.

"In the past, there have been technologies available with which to make disease models but that would essentially require taking a sledgehammer to the genome," Perlstein said. "CRISPR changes the situation as it allows for very elegant and precise changes to happen -- down to a single letter change." So once researchers identify the genetic source of the disease, they're able to "program" that same fault into their animal models and measure the effect of the disease in them.

By using CRISPR to break a test animal's genes in the exact same place and the exact same way as in the patient, Perlstein's researchers are able to create a perfectly customized model. Plus they can do so far more quickly than traditional methods would allow. "Depending on the kind of mutation you're trying to create [using CRISPR], it can be quite fast," Perlstein said. "You're only really limited by the breeding time of the animal."

Since the diseases that Perlstein's team research are recessive, the lab can't introduce these gene breaks directly into the models and then immediately study them. Instead, the team introduces these breaks into an organism and then breeds a second generation. Those organisms are then screened those that possess both copies of the recessive gene. Once a sufficient population of models that carry the gene defect has been bred, the lab leverages an automated system to expose them to thousands of chemicals and compounds to see if they have any positive effect -- reversing, or at least reducing the disease's symptoms.

Josiah Zayner, bio-hacker with The Odin. credit: Engadget / Benito Gonzalez

Not all of the emerging uses for CRISPR technology are quite as severe as the diseases Perlstein Lab is combating. Josiah Zayner, founder and biohacker of The Odin, wants to turn the everyman into a citizen scientist -- specifically, an amateur synthetic biologist. "I worked for Motorola in the early 2000s before the dot-com bubble burst. ... I controlled the systems that allowed those old walkie-talkie cellphones to work." Zayner told me during a recent interview at his home/headquarters in Castro Valley, California. After going back to school to earn his Ph.D. at the University of Chicago, Zaynor worked at NASA's synthetic biology lab at Ames Research Center.

"One scientist can only accomplish so much," Zayner reasoned. So, he asked himself, "How can I get more people involved? What happens if I go out get five people ... train them, pay them a decent wage and have them help me with these science projects?"

This was impetus for The Odin's DIY CRISPR kits. "I thought something like the CRISPR kits is something the public could grasp and be able to use," Zayner said. It would provide people who have no previous experience with not only a new and unique experience but also stimulate their curiosity in biology and science in general. "I'm showing them how cool science can be and, in the process, they're learning to do science, which, I think, strengthens the world."

Zayner wants to use harmless (as in nonvirulent) E. coli and yeast cultures to help teach the basics of genetic engineering. The kits are designed to act as introductions to the technology by providing simplified sample experiments for people to follow. "You get to change the genome of an organism and see the results visually," Zayner exclaimed. That could be a change in the organism's color or its response to light simply by adjusting the expression of genes that code for fluorescent protein production. And with more advanced and involved experiments available on the Odin website, neophyte biohackers can expand their technical repertoire as they see fit.

"We're trying to take genetic engineering, which the public has really only experienced in an abstract way," Zayner concluded, "and move it into their everyday lives through things like brewing [with a DNA-customized yeast culture] or making yogurt ... something that people can experience on a personal level."

Of course, genomic editing isn't going to remain an abstract technology for very long. We've already seen how quickly it's moved out of the confines of academia, and the positive effects that it has had on humanity. The pace of its adoption is only going to accelerate. Just as with personal computers that preceded it, CRISPR is going to radically advance our civilization in ways that we can't even fathom. Whether it involves beating back the scourge of congenital disease or improving crop and livestock yields, CRISPR technology is here to stay. But like all transformative technologies (looking at you, nuclear energy), it's up to us to apply it responsibly. Now then, who want's to make some unicorns?

A unicorn, as seen in its natural habitat. credit: Engadget / Andrew Tarantola

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