Daily Archives: August 1, 2017

Updated | Late last week, reports emerged that scientists in Oregon had used gene-editing technology, known as CRISPR-Cas9, to edit a human embryo. While research like this is already occurring in China and Great Britain, this is the first time scientists in the U.S. have edited an embryo.

The move raises thequestion of whether regulations are strict enough in the U.S. Both Congress and the National Institutes of Health have explicitly said they would not fund research that uses gene-editing to alter embryos. But laws and guidelines are not keeping pace with this fast-moving and controversial work.

CRISPR is an experimental biomedical technique in which scientists are able to alter DNA, such as change the misspellings of a gene that contributes to mutations. The technology has the potential to reverse and eradicate congenital diseases if it can be used successfully on a developing fetus.

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Here's how CRISPR gene editing works. REUTERS

The news frenzy that followed this announcement was based on a leak from unknown sources. Initial reports emerged from a number of less known sources, including MIT Technology Review, that Shoukhrat Mitalipov of Oregon Health and Science University used the technology to change the DNA of not just one, but a number of embryos. But the news stories about this research werent based on a published study, which means they dont provide the full picture. No one yet knows what the researchers did or what the results were.

Until now, most of the breakthrough research on CRISPRaside from the discovery itself, which is attributed to multiple research groups in the U.S. has occurred in China. InApril 2015, Chinese scientists reported that theyd edited the genome of human embryos, a world first, in an attempt to eliminate the underlying cause of a rare blood disorder.

Researchers there have also been experimenting with CRISPR technology to treat cancer. Last spring, a team of scientists at Sichuan Universitys West China Hospital used the approach to modify immune cells in a patient with an aggressive form of lung cancer. The researchers altered genes in a bid to empower the cells to combat the malignancy. Another group of Chinese scientists tried changing genes in blood that were then injected into a patient with a rare form of head and neck cancer to suppress tumor growth.

Despite potential of CRISPR to cure fatal diseases, the technology has fast become one of the most significant challenges for bioethicists. Some people view its power as potentially dangerous because it could allow scientists to cherry-pick genetic traits to create so-called designer babies.

Arthur Caplan, a professor of bioethics at New York University's Langone Medical Center and founding director of NYULMC's division of medical ethics thinks the fears are overblown. Gene-editing technology, says Caplan, is nowhere near this sci-fi fantasy.

If you would compare this to a trip to Mars, you're basically launching some satellites, says Caplan. He suggests that much of the media coverage on CRISPR is melodramatic, including last weeks coverage of researchers meddling with an embryo. We haven't shown that you can fix a disease or make someone smarter.

Lack of Guidelines

CRISPR technology isnt ready for clinical use, whether to stop serious genetic diseases or simply make brown eyes blue. But geneticists are working toward these goals, and the scientific community is ill-prepared to regulate this potentially powerful technology.

So far guidelines for using CRISPR are minimal. In 2015, the National Institutes of Health issued a firm statement. Advances in technology have given us an elegant new way of carrying out genome editing, but the strong arguments against engaging in this activity remain, the NIH said in its statement. These include the serious and unquantifiable safety issues, ethical issues presented by altering the germline in a way that affects the next generation without their consent, and a current lack of compelling medical applications justifying the use of CRISPR/Cas9 in embryos.

But although the NIH wont back CRISPR research for embryo editing, that doesnt mean such research is prohibited in the U.S. Private organizations and donors fund researchers. Caplan suspects this is how the team in Oregon managed to carry out their experiment.

In February 2017, the National Academy of Sciences and the National Academy of Medicinetwo leading medical authorities that propose medical and research guidelines for a wide range of research and medical topics issued sweeping recommendations for the use of CRISPR technology. In their joint Human Genome Editing: Science, Ethics, and Governance report, the panel of experts deemed the development of novel treatments and therapies an appropriate use of the technology. The recommendations also approve investigating CRISPR in clinical trials for preventing serious diseases and disabilities and basic laboratory research to further understand the impact of this technology.

The authors of the report caution against human genome editing for purposes other than treatment and prevention of diseases and disabilities. But the line between treatment and enhancement isnt always clear, says Caplan. And policing so-called ethical uses of CRISPR technology will be increasingly difficult because single genes are responsible for a myriad diseases and traits. You don't realize that you're changing DNA in places you don't want to, he says.

A source familiar with the controversial Oregon research reported last week told Newsweek that a major journal will publish a paper on the work by the end of this week. According to The Niche, a blog produced by the Knoepfler Lab at University of California Davis School of Medicine in Sacramento, California, the paper is slated to be published in Nature . Mitalipov did not respond to Newsweek s requests for comment or confirmation.

Caplan hopes that publication of the paper will initiate further discussion about the ethics of experimenting with CRISPR including practical measures such as a registry for scientists conducting studies through private funding. We need to have an international meeting about what are the penalties of doing this, he says. Will you go to jail or get a fine?

This story has been updated to note that the initial report of the CRISPR research in Oregon was based on a leak, but did not necessarily misconstrue the research.

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Gene Editing Is Revolutionizing Medicine but Causing a Government Ethics Nightmare - Newsweek

Xconomy Boston

One day after the release of a Nature Medicine paper warning of the potential hazards of testing CRISPR-Cas9 gene editing in humans, Homology Medicines, a startup advancing a different genetic surgery technique, has just grabbed a big round of funding to make its own clinical push.

Homology, of Bedford, MA, wrapped up an $83.5 million Series B round this morning. A wide group of investors led by Deerfield Management provided the funding, bringing the companys total amount raised to a whopping $127 million since it was formed last year.

Homology is making the bold claim that its underlying science, technology it calls AMEnDR, is a better version of existing gene editing methods, among them the CRISPR-Cas9 technology that has taken the scientific research world by storm and has led to the formation of three now publicly traded companies, Editas Medicine (NASDAQ: EDIT), Intellia Therapeutics (NASDAQ: NTLA), and CRISPR Therapeutics (NASDAQ: CRSP).

CRISPR gene editing is a two-part biological system that researchers can use to help irreversibly alter DNA. The three companies are involved in a high-stakes race to use the technology to develop human therapeutics, with the first clinical trials expected to begin next year. Yet one of the fears involved in bringing the technology to human trials is the possibility of off-target effectsa genetic surgery error that causes irreparable damage, like cancer. One of the fields pioneers, Feng Zhang of the Broad Institute of MIT and Harvard, just co-authored a paper in Nature Medicine urging caution about the rush to move forward. Zhang and colleague David Scott argued that researchers should analyze patients DNA before giving them CRISPR-based drugs, citing the myriad differences between each persons genetic makeup.

Homology isnt using CRISPR, like its publicly traded rivals. Instead, its recreating a natural biological process known as homologous recombination, which cells in humans and other species do to repair DNA damage or, in the case of bacteria, to improve their genetic diversity. In homologous recombination, one chromosome essentially swaps one short DNA sequence for another similar one. Homology aims to engineer a piece of healthy DNA, pack it into a type of adeno-associated virus, or AAVa delivery tool commonly used in gene therapy and gene editing technologiesand infuse it into the body. The virus carrying the DNA locks on to the cell that needs a genetic fix, enters it, and releases its DNA payload. The healthy DNA then swaps places with the faulty gene inside the patients cells. If and when the cells divide, the new cells would carry the fixed gene, not the faulty one. One potential benefit of this approach is there may be less likelihood of an off-target error, like mutations in the target DNA that cause cancer, than with CRISPR.

Thats the hope, but the technology hasnt been tested in humans as of yet. With the new cash, however, Homology is getting a shot to try. In a statement, Homology CEO Arthur Tzianabos said the funding will help Homology bring its first drug candidate toward the clinic, though he didnt specify how long that might take. The company is focusing on rare diseasesno surprise given Tzianabos, chief operating officer Sam Rasty, and chief scientific officer Albert Seymour all worked with one another at rare disease giant Shire (NASDAQ: SHPG). According to its website, the company will develop therapies for inborn errors of metabolism, and Duchenne muscular dystrophy and cystic fibrosis are among its potential targets as well. (Duchenne and cystic fibrosis are early targets of CRISPR-based medicines as well.)

Fidelity Management and Research, Novartis, Rock Springs Capital, HBM Healthcare Investments, Arch Venture Partners, Temasek, 5AM Ventures, Maverick Ventures, Vida Ventures, Vivo Capital, and Alexandria Venture Investments also took part in the funding. Heres more on Homology, and gene editing with CRISPR-Cas9.

Ben Fidler is Xconomy's Deputy Biotechnology Editor. You can e-mail him at bfidler@xconomy.com

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Homology Med Bags $83.5M More, Fueling Push For Gene Editing ... - Xconomy

Xconomy Boston

A leading genome-editing researcher is urging extra caution as drug companies race to turn the landmark technology he helped create into human medicine.

In a paper published today in Nature Medicine, Feng Zhang of the Broad Institute of MIT and Harvard and colleague David Scott argue that researchers should analyze the DNA of patients before giving them experimental medicines that alter their genes with the breakthrough technology CRISPR. The suggestion, among others in the paper, stems from a deeper look at the wide array of subtle differences in human DNA.

Zhang is a key inventor of CRISPR-Cas9, which describes a two-part biological system that slips into the nucleus of cells and irreversibly alters DNA. One part is an enzyme, natures molecular scissors, which cuts DNA. The second part is a string of ribonucleic acid (RNA) that guides the enzyme to the proper spot. In five years since its invention, CRISPR-Cas9 has become a mainstay of biological research, and researchers including Zhang (pictured above) have moved quickly to improve upon its components. His work is at the center of a long-running patent battle to determine ownership of the technology.

Zhang and Scotts recommendation taps into a long-running debate in the gene-editing field about off-target effectsthe fear of misplaced cuts causing unintended harm. Most recently, the FDA took up a similar issue at a meeting to assess a type of cell therapy, known as CAR-T, for kids with leukemia. The FDA highlighted the risk that the cells, which have certain genes edited to make them better cancer fighters, may cause secondary cancers long after a patients leukemia has been cured. (FDA advisors unanimously endorsed the therapys approval nonetheless.)

Some researchers say there should be near certainty that gene altering techniques wont go awry before testing in humans, caution that stems in part from gene therapy experiments in the U.S. and Europe nearly 20 years ago that killed an American teenager and triggered leukemia in several European boys.

While no medicine is risk-free, other researchers say the tools to gauge risk have improved.

Andy May, senior director of genome engineering at the Chan Zuckerberg Biohub in San Francisco, calls Zhang and Scotts recommendation for patient prescreening a good discussion point, but the danger is someone will pick up on this and say you cant push forward [with a CRISPR drug] until everyone is sequenced.

Its an extremely conservative path to take, says May, who until recently was the chief scientific officer at Caribou Biosciences, a Berkeley, CA-based firm in charge of turning the discoveries of UC Berkeleys Jennifer Doudna and her colleagues into commercial technology. (May was also a board member of Cambridge, MA-based Intellia Therapeutics (NASDAQ: NTLA), which has exclusive license to use Caribous technology in human therapeutics.)

Berkeley is leading the challenge to Zhangs CRISPR patents and last week filed the first details in its appeal of a recent court decision in favor of Zhang and the Broad Institute.

Zhang sees prescreening as a form of companion diagnostic, which drug companies frequently use to identify the right patients for a study. A whole genome sequencewhich costs about $1,000could filter out patients unlikely to benefit from a treatment or at higher risk of unintended consequences, such as cancer. In the long run, it could also encourage developers to create more variations of a treatment to make genome-editing based therapeutics as broadly available as possible, said Zhang.

Its well known that human genetic variation is a hurdle in the quest to treat genetic diseases either by knocking out disease-causing genes or replacing them with healthy versions. But Zhang and Scott use newly available genetic information to deepen that understanding. In one Broad Institute database with genetic information from more than 60,000 people, they find one genetic variation for every eight letters, or nucleotides, in the exomethat is, the sections of DNA that contain instructions to make proteins. (There are 6 billion nucleotides in each of our cells.) The wide menu of differences is, in effect, an open door to misplaced cuts that CRISPRs enzymes might be prone to.

Zhang and others are working on many kinds of enzymes, from variations on the workhorse Cas9, to new ones entirely. He and Scott found that the deep pool of genetic variation makes some forms of the Cas enzyme more likely than others to go awry, depending on the three-nucleotide sequence they lock onto in the targeted DNA.

Zhang and Scott write that CRISPR drug developers should avoid trying to edit DNA strings that are likely to have high variation. In their paper, they examine 12 disease-causing genes. While more common diseases, such as those related to high cholesterol, will contain higher genetic variation because of the broader affected population, every gene, common or not, contains regions of high and low variation. Zhang and Scott say developers can build strategies around the gene regions they are targeting.

For example, going after a more common disease might require a wider variety of product candidates, akin to a plumber bringing an extra-large set of wrenches, with finer gradations between each wrench, to a job site with an unpredictable range of pipe sizes.

CRISPR companies say they are doing just that. We have always made specificity a fundamental part of our program, says Editas Medicine CEO Katrine Bosley. Zhang is a founder of Editas (NASDAQ: EDIT), which has exclusive license to the Broads Next Page

Alex Lash is Xconomy's National Biotech Editor. He is based in San Francisco.

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CRISPR Pioneer Zhang Preaches Extra Caution In Human Gene Editing - Xconomy

For the first time in the United States, scientists have edited the genes of human embryos, a controversial step toward someday helping babies avoid inherited diseases.

The experiment was just an exercise in science the embryos were not allowed to develop for more than a few days and were never intended to be implanted into a womb, according to MIT Technology Review, which first reported the news.

Officials at Oregon Health & Science University confirmed Thursday that the work took place there and said results would be published in a journal soon. It is thought to be the first such work in the U.S.; previous experiments like this have been reported from China. How many embryos were created and edited in the experiments has not been revealed.

The Oregon scientists reportedly used a technique called CRISPR, which allows specific sections of DNA to be altered or replaced. It's like using a molecular scissors to cut and paste DNA, and is much more precise than some types of gene therapy that cannot ensure that desired changes will take place exactly where and as intended. With gene editing, these so-called "germline" changes are permanent and would be passed down to any offspring.

The approach holds great potential to avoid many genetic diseases, but has raised fears of "designer babies" if done for less lofty reasons, such as producing desirable traits.

Last year, Britain said some of its scientists could edit embryo genes to better understand human development.

And earlier this year in the U.S., the National Academy of Sciences and National Academy of Medicine said in a report that altering the genes of embryos might be OK if done under strict criteria and aimed at preventing serious disease.

"This is the kind of research that the report discussed," University of Wisconsin-Madison bioethicist R. Alta Charo said of the news of Oregon's work. She co-led the National Academies panel but was not commenting on its behalf Thursday.

"This was purely laboratory-based work that is incredibly valuable for helping us understand how one might make these germline changes in a way that is precise and safe. But it's only a first step," she said.

"We still have regulatory barriers in the United States to ever trying this to achieve a pregnancy. The public has plenty of time" to weigh in on whether that should occur, she said. "Any such experiment aimed at a pregnancy would need FDA approval, and the agency is currently not allowed to even consider such a request" because of limits set by Congress.

One prominent genetics expert, Dr. Eric Topol, director of the Scripps Translational Science Institute in La Jolla, Calif., said gene editing of embryos is "an unstoppable, inevitable science, and this is more proof it can be done."

Experiments are in the works now in the U.S. using gene-edited cells to try to treat people with various diseases, but "in order to really have a cure, you want to get this at the embryo stage," he said. "If it isn't done in this country, it will be done elsewhere."

There are other ways that some parents who know they carry a problem gene can avoid passing it to their children, he added. They can create embryos through in vitro fertilization, screen them in the lab and implant only ones free of the defect.

Dr. Robert C. Green, a medical geneticist at Harvard Medical School, said the prospect of editing embryos to avoid disease "is inevitable and exciting," and that "with proper controls in place, it's going to lead to huge advances in human health."

The need for it is clear, he added: "Our research has suggested that there are far more disease-associated mutations in the general public than was previously suspected."

Hank Greely, director of Stanford University's Center for Law and the Biosciences, called CRISPR "the most exciting thing I've seen in biology in the 25 years I've been watching it," with tremendous possibilities to aid human health.

"Everybody should calm down" because this is just one of many steps advancing the science, and there are regulatory safeguards already in place. "We've got time to do it carefully," he said.

Michael Watson, executive director of the American College of Medical Genetics and Genomics, said the college thinks that any work aimed at pregnancy is premature, but the lab work is a necessary first step.

"That's the only way we're going to learn" if it's safe or feasible, he said.

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In US first, scientists edit genes of human embryos - Indiana Gazette