glitch far less than humans do

CRISPR-Edited Cells Linked to Cancer Risk in 2 Studies

June 12, 2018 - Editing cells’ genomes with CRISPR-Cas9 might increase the risk that the altered cells, intended to treat disease, will trigger cancer, two studies published on Monday warn—a potential game-changer for the companies developing CRISPR-based therapies.

In the studies, published in Nature Medicine, scientists found that cells whose genomes are successfully edited by CRISPR-Cas9 have the potential to seed tumors inside a patient. That could make some CRISPR’d cells ticking time bombs, according to researchers from Sweden’s Karolinska Institute and, separately, Novartis.

CRISPR has already dodged two potentially fatal bullets—a 2017 claim that it causes sky-high numbers of off-target effects was retracted in March, and a report of human immunity to Cas9 was largely shrugged off as solvable. But experts are taking the cancer-risk finding seriously. On supporting science journalism

If you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today.

The CEO of CRISPR Therapeutics, Sam Kulkarni, told STAT the results are “plausible.” Although they likely apply to only one of the ways that CRISPR edits genomes (replacing disease-causing DNA with healthy versions) and not the other (just excising DNA), he said, “it’s something we need to pay attention to, especially as CRISPR expands to more diseases. We need to do the work and make sure edited cells returned to patients don’t become cancerous.”

Another leading CRISPR scientist, who asked not to be named because of involvement with genome-editing companies, called the new data “pretty striking,” and raised concerns that a potential fatal flaw in some uses of CRISPR had “been missed.”

On the other hand, the Novartis paper has been available in preliminary form since last summer, and CRISPR experts “haven’t freaked out,” said Erik Sontheimer of the University of Massachusetts Medical School, whose CRISPR research centers on novel enzymes and off-target effects. “This is something that bears paying attention to, but I don’t think it’s a deal-breaker” for CRISPR therapies.

The Karolinska and Novartis groups tested CRISPR on different kinds of human cells—retinal cells and pluripotent stem cells, respectively. But they found essentially the same phenomenon. Standard CRISPR-Cas9 works by cutting both strands of the DNA double helix. That injury causes a cell to activate a biochemical first-aid kit orchestrated by a gene called p53, which either mends the DNA break or makes the cell self-destruct.

Whichever action p53 takes, the consequence is the same: CRISPR doesn’t work, either because the genome edit is stitched up or the cell is dead. (The Novartis team calculated that p53 reduces CRISPR efficiency in pluripotent stem cells seventeenfold.) That might explain something found over and over: CRISPR is woefully inefficient, with only a small minority of cells into which CRISPR is introduced, usually by a virus, actually having their genomes edited as intended.

“We found that cutting the genome with CRISPR-Cas9 induced the activation of p53,” said Emma Haapaniemi, the lead author of the Karolinska study. That “makes editing much more difficult.”

The flip side of p53 repairing CRISPR edits, or killing cells that accept the edits, is that cells that survive with the edits do so precisely because they have a dysfunctional p53 and therefore lack this fix-it-or-kill-it mechanism.

CRISPR edits genomes in either of two ways. It slices out a chunk of disease-causing DNA, in a process called non-homologous end joining (NHEJ), or gene disruption. That’s how CRISPR Therapeutics is going after sickle cell disease. Alternatively, CRISPR both cuts out a disease-causing stretch of DNA and replaces it with healthy nucleotides, in homology-directed repair (HDR), or gene correction. Several university labs are investigating HDR to treat Duchenne muscular dystrophy, among many other diseases.

In the normal, mature cells she and her team studied, Haapaniemi said, gene disruption “can happen even when p53 is activated.”

Beta’s facility at the Plattsburgh International Airport will undergo a $41 million expansion with half of the money coming from Beta and the other half from New York state.

The airport’s master plan also highlights the ambitious goals Beta has for the future,

Eric Chase, the owner of Mansfield Heliflight, says his lease agreement with the airport is being redrawn to exclude the parking lot space so that it can be shared with Beta. He says he had big plans for the space and is frustrated.

Federal officials have granted a $169 million loan to Beta Technologies, the South Burlington electric aircraft manufacturer, aimed at bolstering the company’s capacity to build its planes for buyers throughout the Asia-Pacific region.

After hearing proposals about how Beta could get around the zoning restriction — including a plan to designate the area between the road and the parking lot as a public green space — the Development Review Board approved the campus’s master plan — but declined to offer an exemption on the parking issue.

In an unusual move, however, the board voted to reopen Beta’s application on Tuesday. It is now scheduled to hold another hearing on April 25 to hear more testimony from company officials on why they should get an exemption.

Beta’s expansion in the southeast corner of the airport — known as “the Valley” — stirred pushback from some nearby aviation companies, which expressed concern that the airport’s embrace of Beta came at the expense of their businesses.

If South Burlington does not let Beta through, Scott said, he would ask the Legislature to step in. "This is too important for Vermont,” Scott said. “This is not just about jobs for Chittenden County. This is going to have a ripple effect across the entire state.

Beta founder Kyle Clark said the close connection to Scott and other leaders is a key reason he located the company in his home state of Vermont.”

"The company was founded in 2017 and successfully partnered with United Therapeutics, a biotechnology company, to develop a prototype for transplant organs and tissues. The prototype led to a $48 million deal with United Therapeutics, and Beta signed a “similarly sized contract” with the U.S. Air Force, Clark said."

Starting in the 1980s, SEK Studio began subcontracting for media companies from Italy, France, and Spain. This represented a win-win scenario for both sides. North Korea would have a relatively wholesome (compared to drug smuggling, for example) way to earn much-needed foreign cash, while Western corporations could enjoy massive cost savings due to the DPRK’s low wages. Dealing with European studios also gave SEK an opportunity to learn best practices, and even send young employees to France and Italy to study advanced animation technologies.

By the early 2000s, SEK had dealings with over 70 different European companies across hundreds of projects. Among these projects was the 1997 series Simba: The Lion King, commissioned by Italy-based Mondo TV. This series’ name may have helped spark an oft-circulated (but unverified) rumor that SEK helped animate Disney’s 1994 blockbuster The Lion King.

North Korea didn’t just collaborate with Europeans though. When liberal Kim Dae-jung ascended to South Korea’s presidency in 1998, he initiated the Sunshine Policy, calling for rapprochement and economic collaboration with the North.

As a result of the Sunshine Policy, South Korean animators began working with their Northern brethren. A prominent example of this cooperation was the children’s show Pororo the Little Penguin, which remains a cultural icon in South Korea to this day.

Subcontracted through South Korean production company Iconix, SEK animated part of Pororo’s first and second seasons between 2003 and 2005. Iconix sent technicians northwards to train SEK’s staff, though, once the technicians left, the lack of efficient communications methods eventually made collaboration too difficult to continue.

Born 1939 in North Korea’s Pyongsan County, Shin moved to South Korea at age 13 during the Korean War. After immigrating to the US and working for American animators (including on Star Wars’ lightsaber) during the 1970s, Shin returned to South Korea and founded AKOM Production—best known for animating The Simpsons.

Wanting to tell his own stories instead of animating others’, Shin decided to make Empress Chung, a feature film based on a famous Korean folk tale about a daughter who sacrifices herself to restore her father’s eyesight. While trying to get Empress Chung off the ground, Shin unexpectedly bumped into representatives of SEK Studio at an international film market. Since he was largely self-financing the project, Shin decided to work with SEK in order to save costs; it was also a poetic move for a man who’d been born in the North.

Thus, Empress Chung became the first feature-length film co-production between North and South Korea. Around 500 staff from SEK Studio handled main production, while Shin’s South Korean animators performed pre and post-production; Shin personally visited Pyongyang 18 times to supervise production.

Empress Chung opened simultaneously in North and South Korea on August 12, 2005, the 60th anniversary of the end of Japanese rule on the peninsula. Though it wasn’t a box office hit, the film represented a milestone in inter-Korean relations, and inspired Shin to further collaborate with SEK Studio. After Empress Chung, Shin and SEK went on to make an animated TV series called Warriors of the Goguryeo, inspired by the history of an ancient Korean kingdom.

At the same time, Shin’s company AKOM was still animating American projects. This is where things get interesting: drawing upon the existing relationship, one of AKOM’s interlocutors apparently subcontracted work on US films to SEK Studio.

According to DVD commentary and IMDB, 2007’s The Simpsons Movie was the most prominent US project that SEK helped with. Other projects include Futurama: Bender’s Big Score and even an episode of Avatar: The Last Airbender. Therefore, it’s highly possible that millions in America and beyond have unknowingly experienced the handiwork of North Korean animators.

https://www.cinemaescapist.com...