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W.H.O. Experts Seek Limits on Human Gene-Editing Experiments

The panel also called on countries to ensure that beneficial forms of genetic alteration be shared equitably.

By Gina Kolata

A committee of experts working with the World Health Organization on Monday called on the nations of the world to set stronger limits on powerful methods of human gene editing.

Their recommendations, made after two years of deliberation , aim to head off rogue science experiments with the human genome , and ensure that proper uses of gene-editing techniques are beneficial to the broader public, particularly people in developing countries, and not only the wealthy.

“I am very supportive,” said Dr. Leonard Zon, a gene therapy expert at Harvard University who was not a member of the committee, but called it a “thoughtful group.” Recent gene-editing results are “impressive,” he said, and the committee’s recommendations will be “very important for therapy in the future.”

The guidelines proposed by the W.H.O. committee were prompted in large part by the case of He Jiankui, a scientist in China who stunned the world in November 2018 when he announced he had altered the DNA of human embryos using CRISPR, a technique that allows precision editing of genes. Such alterations meant that any changes that occurred in the genes would be replicated in every cell of the embryo, including sperm and egg cells. And that meant that the alterations, even if they were deleterious instead of helpful, would arise not just in the babies born after gene editing but in every generation their DNA was passed on to.

Dr. He’s goal was to alter the DNA of babies in an attempt to make them genetically unable to contract H.I.V. from their parents. A court in China determined he had forged ethics documents and misled subjects in the experiments who had not realized what his gene-editing experiment consisted of. He was sentenced to three years in prison in December 2019.

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Science News

Crispr enters its first human clinical trials.

The gene editor targets cancer, blood disorders and blindness

CUTTING ROOM   Scientists will soon wield the molecular scissors CRISPR/Cas9 in the human body. Some people with a form of inherited blindness will have the gene editor injected into their eyes, where researchers hope it will snip out a mutation. Two other trials are CRISPR editing cells outside of the body to treat cancer or blood disorders.

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By Tina Hesman Saey

August 14, 2019 at 8:00 am

Since its debut in 2012, CRISPR gene editing has held the promise of curing most of the over 6,000 known genetic diseases. Now it’s being put to the test.

In the first spate of clinical trials, scientists are using CRISPR/Cas9 to combat cancer and blood disorders in people. In these tests, researchers remove some of a person’s cells, edit the DNA and then inject the cells back in, now hopefully armed to fight disease.

Researchers are also set to see how CRISPR/Cas9 works inside the human body. In an upcoming trial, people with an inherited blindness will have the molecular scissors injected into their eyes.

Those tests, if successful, could spur future trials for Duchenne muscular dystrophy, cystic fibrosis and a wide variety of other genetic diseases, affecting millions of people worldwide.

“CRISPR is so intriguing,” says Laurie Zoloth, a bioethicist at the University of Chicago Divinity School, “and so elegant.”

But big questions remain about whether CRISPR/Cas9 can live up to the hype.

Other previously promising technologies have fallen short. For instance, stem cell injections helped paralyzed rats walk again. But they didn’t work so well for people, Zoloth says.

Conventional gene therapies, which insert healthy copies of genes to replace or counteract disease-causing versions, also suffered severe setbacks, says Ronald Conlon, a geneticist at Case Western Reserve University in Cleveland. Some kids who had therapy for immune defects developed cancers ( SN: 1/1/11, p. 24 ); a blindness therapy worked temporarily , but couldn’t halt disease progression ( SN Online: 5/3/15 ); and, most devastatingly, participants died — including 18-year-old Jesse Gelsinger in 1999 — while taking part in gene therapy trials.

CRISPR’s reputation was tarnished last year after a researcher in China edited a gene in embryos that went on to develop into two baby girls in 2018 ( SN: 12/22/18 & 1/5/19, p. 20 ). The current CRISPR trials don’t have the same ethical challenges — the therapies are being tested in adults and children, and won’t lead to DNA changes that can be inherited, says Alan Regenberg, a bioethicist at Johns Hopkins Berman Institute of Bioethics. Still, he says, there’s reason for caution when working with humans.

CRISPR/Cas9 is a re-engineered virus-hunter, originally developed by bacteria. In 2012 and 2013, scientists described how the system could be tweaked to cut DNA in precise locations, and then demonstrated how it could be deployed in human and animal cells. A piece of RNA — a single-stranded genetic molecule similar to DNA — is the CRISPR part and guides an enzyme called Cas9 to particular spots in the genetic instruction book, or genome. The enzyme slices through both strands of the DNA double helix. Cuts can be used to disable certain genes, snip out troublesome DNA or even repair a problem.

But CRISPR sometimes goes to the wrong spot, resulting in unwanted edits, or “off-target effects ” ( SN: 9/3/16, p. 22 ). Even with intended cuts, unwanted errors can arise. “We don’t always fully understand the changes we’re making,” Regenberg says. “Even if we do make the changes we want to make, there’s still question about whether it will do what we want and not do things we don’t want.” 

Still, CRISPR is more precise than conventional gene therapy and therefore may have the power to treat some diseases for which gene therapy hasn’t worked well, says Conlon, who discussed challenges to gene editing for cystic fibrosis in the June Genes & Diseases . But another big hurdle, he says, is getting CRISPR into the cells where it is needed.

Dishing up data

Delivery is less of a problem for the gene-editing therapies in trials to treat cancer and blood disorders, Conlon says. That’s because, for those trials, researchers don’t have to set CRISPR/Cas9 loose in the body. Instead, they take blood-forming stem cells out of participants and edit those cells in lab dishes, where the scientists can check for problems.

University of Pennsylvania researchers have given two people with recurring cancers a CRISPR/Cas9 therapy, a university spokesperson said. One person has multiple myeloma; the other, sarcoma. As part of an ongoing trial , both received T cells, a type of immune cell, programmed with CRISPR to go after cancer cells. Similar trials are under way in China .

Trials are also under way for two blood disorders: sickle-cell disease and beta-thalassemia. Both result from defects in the gene for hemoglobin, the oxygen-carrying protein in red blood cells. The therapy is designed to mimic a fix that nature has already devised, says David Altshuler, chief scientist at Vertex Pharmaceuticals. Usually, a form of hemoglobin that helps fetuses in the womb grab more oxygen from their mother’s blood stops being produced after birth. But some people have a harmless genetic variant that causes fetal hemoglobin to be produced throughout life. “People like that who also inherited a sickle-cell mutation or a beta-thalassemia mutation weren’t sick,” Altshuler says.

The fetal hemoglobin compensates for the disease-causing defect, something Vertex, a cystic fibrosis drugmaker headquartered in Boston and London, hopes to use to sickle-cell sufferers’ advantage. Vertex and CRISPR Therapeutics, a company in Cambridge, Mass., are testing whether CRISPR/Cas9 cuts can mimic the genetic variant that keeps fetal hemoglobin turned on for life and ease symptoms in people with the blood disorders. “We’re very confident that the edits that are being made in the cells are translating into clear and reproducible increases in fetal hemoglobin,” Altshuler says.

Researchers check for both off-target cuts and mutations at the desired cutting site before giving cells back to the study volunteers via a bone marrow transplant, Altshuler says.

The companies announced in February that they had treated one person for beta-thalassemia . Another person has undergone the same type of therapy for sickle-cell disease , researchers said in July. The scientists have not yet announced results from these trials.

Into the eye

Still, many genetic diseases affect the whole body or organs that can’t be removed and edited in a lab. No one knows whether CRISPR can work well in the human body. But a clinical trial using the gene editor to treat an inherited type of blindness called Leber congenital amaurosis 10 may help answer the question. The disorder is caused by a mutation in the CEP290 gene that leads to a nonfunctional protein. When the protein doesn’t work, rod cells in the retina die and light-gathering photoreceptors can’t renew themselves, resulting in blindness.

There is a gene therapy, approved in 2017 by the U.S. Food and Drug Administration, for a type of Leber congenital amaurosis caused by a mutation in the RPE65 gene. But CEP290 is too big to pack into a virus to do conventional gene therapy, says Charles Albright, chief scientist of Editas Medicine, a company based in Cambridge, Mass., that develops CRISPR gene editing for various genetic diseases.

In July, Editas and global pharmaceutical company Allergan opened recruitment for a blindness gene-editing trial . In the trial, two guide RNAs will lead Cas9 to make two cuts that will snip out the troublesome piece of DNA.

The first people to get the experimental therapy will be adults who are nearly blind, Albright says. Small amounts of the CRISPR editor will be injected under the retina to test for safety. It’s uncertain whether the low doses will improve vision. If the doses prove safe, later volunteers will get higher doses. The researchers may also test the therapy in children.

“We’re going into arguably the most difficult patients to start with and we’re going to improve from there,” Albright says.

Editing as few as 10 percent of retinal cells may help restore some sight, he says. In animal tests, CRISPR edited up to about 60 percent of cells in mice and almost 28 percent in monkeys , scientists reported in the February Nature Medicine .

Sticking with it

Even if these first trials don’t pan out as hoped, CRISPR won’t be shelved, Albright thinks. “This is a technology that’s here to stay,” he says. “If this doesn’t work, it’s going to be more about the underlying biology or our ability to deliver the editing machinery.”

There’s precedence that perseverance — and choosing the right disease to target — can eventually pay off. After setbacks, conventional gene therapy has recently had a big success.

In May, the FDA approved a gene therapy for children with spinal muscular atrophy, a debilitating and deadly genetic disease caused by a mutation that disables the SMN1 gene. That gene is needed for specialized nerve cells called motor neurons to survive and function properly. Children with the genetic disease often die because the muscles that control breathing fail. The FDA said August 6 that it had been alerted to problems with data manipulation from animal testing of the therapy. But the agency says that the therapy is working well in humans and should stay on the market.

“These kids with SMA who otherwise would have died are up and running and talking and learning and progressing,” Conlon says. “It is just mind-blowing.”

When it comes to gene editing, researchers are banking on similar happy endings. “People are so optimistic and so hopeful again,” Zoloth says. “I want it to work. Everyone who thinks seriously about human suffering should really be wanting this to happen and should be optimistic … about medicine’s capacity and its power.”

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The CRISPR Revolution

New u.s. experiments aim to create gene-edited human embryos.

Dieter Egli, a developmental biologist at Columbia University, and Katherine Palmerola examine a newly fertilized egg injected with a CRISPR editing tool. Rob Stein/NPR hide caption

Dieter Egli, a developmental biologist at Columbia University, and Katherine Palmerola examine a newly fertilized egg injected with a CRISPR editing tool.

A scientist in New York is conducting experiments designed to modify DNA in human embryos as a step toward someday preventing inherited diseases, NPR has learned.

For now, the work is confined to a laboratory. But the research, if successful, would mark another step toward turning CRISPR, a powerful form of gene editing, into a tool for medical treatment.

A Chinese scientist sparked international outrage in November when he announced that he had used the same technique to create the world's first gene-edited human babies. He said his goal was to protect them from infection with HIV, a claim that was criticized because there are safe, effective and far less controversial ways of achieving that goal.

In contrast, Dieter Egli , a developmental biologist at Columbia University, says he is conducting his experiments "for research purposes." He wants to determine whether CRISPR can safely repair mutations in human embryos to prevent genetic diseases from being passed down for generations.

So far, Egli has stopped any modified embryos from developing beyond one day so he can study them.

"Right now we are not trying to make babies. None of these cells will go into the womb of a person," he says.

But if the approach is successful, Egli would likely allow edited embryos to develop further to continue his research.

Egli hopes doctors will someday be able edit embryonic human DNA to prevent many congenital illnesses, such as Tay-Sachs disease , cystic fibrosis and Huntington's disease .

In the lab, Egli is trying to fix one of the genetic defects that cause retinitis pigmentosa , an inherited form of blindness. If it works, the hope is that the approach could help blind people carrying the mutation have genetically related children whose vision is normal.

Egli is attempting to fix one of the genetic defects that cause retinitis pigmentosa, an inherited form of blindness. Rob Stein/NPR hide caption

Egli is attempting to fix one of the genetic defects that cause retinitis pigmentosa, an inherited form of blindness.

"Preventing inherited forms of blindness would be wonderful — very important for affected families," Egli says.

But that is likely to take years of additional research to demonstrate that the technique is both effective and safe.

Nevertheless, even this kind of basic research is controversial.

"This is really disturbing," says Fyodor Urnov, associate director of the Altius Institute for Biomedical Sciences in Seattle. He worries such experiments could encourage more irresponsible scientists to misuse gene-editing technologies.

"As we've learned from the events in China, it is no longer a hypothetical that somebody will just go ahead and go rogue and do something dangerous, reckless, unethical," Urnov says.

Egli's research is reviewed in advance and overseen by a panel of other scientists and bioethicists at Columbia.

While the debate over research like Egli's continues, the U.S. National Academies of Science, Engineering and Medicine, the World Health Organization and others are trying to develop detailed standards for how scientists should safely and ethically edit human embryos.

Some bioethicists and scientists are calling for an explicit global moratorium on creating any more gene-edited babies. Others, like Urnov, would like to see a hiatus in even basic research.

The U.S. government prohibits the use of federal funding for research involving human embryos. But gene editing of human embryos can be done using private funding. The Food and Drug Administration is barred from considering any studies that would involve using genetically modified human embryos to create a pregnancy. But laws that govern the creation of genetically modified babies vary widely internationally.

Egli is well aware that his work may be controversial to some people. To try to be completely transparent about his experiments, Egli recently invited NPR to his laboratory for an exclusive look at his research.

"We can't just do the editing and then hope everything goes right and implant that into a womb. That's not responsible," Egli says. "We have to first do the basic research studies to see what happens. That's what we're doing here."

To show NPR what he is doing, early one morning Egli pushes open the door of a tiny windowless room on the sixth floor of one of Columbia's research towers in Upper Manhattan. The lab is jammed with scientific equipment, including two microscopes.

Egli snaps on blue rubber gloves and opens a frosty metal cylinder holding frozen human eggs.

"I'm going to wear gloves because we want to keep things clean," he tells me.

To begin his experiment, Egli starts the long, slow process of thawing the frozen human eggs that were donated for research. After several hours of careful work and waiting, Egli has readied 15 eggs for his experiment.

After setting up a large microscope, Egli slides a round glass dish under the lens. The dish contains sperm from a blind man who carries the mutation that Egli is trying to fix. It also holds the CRISPR gene-editing tool.

"I'm starting with just one egg," he says as he gently places the first thawed egg into the dish.

"It's a beautiful cell," Egli says, pointing to a magnified image of the egg on a computer monitor. "I would say it's one of the most beautiful cells."

Egli maneuvers a tiny glass needle protruding into the side of the microscope dish toward one of the sperm. "So you can see a moving sperm over here," he says. "Now I'm picking it up. The sperm is in the needle. Now I'm dipping it in the CRISPR tool."

Once the sperm is inside the needle with the CRISPR gene-editing tool, Egli points the needle's tip at the egg. "Oh no!" he exclaims with a sigh. "The sperm is swimming away."

He searches the dish for the errant sperm.

"Oh, here it is," he says as he pulls the sperm back into the needle.

Next, Egli gently pierces the egg with the needle. "The membrane is broken — breached. There we go," Egli says as he injects the sperm and CRISPR tool into the egg. He breathes a sigh of relief.

Egli injects a human egg with a sperm carrying a genetic mutation that causes blindness and a CRISPR tool he hopes will fix the mutation. Rob Stein/NPR hide caption

Egli injects a human egg with a sperm carrying a genetic mutation that causes blindness and a CRISPR tool he hopes will fix the mutation.

The idea is that CRISPR will slice out the mutation in the sperm, and the healthy DNA in the egg will serve as a template to repair the genetic mutation.

"Hopefully the CRISPR tool will cut the mutation and then the egg will replace that with a version that no longer causes disease," Egli says. "The genome from the mother would be rescuing the mutant genome from the father."

The approach was developed by scientists led by Shoukhrat Mitalipov of the Oregon Health & Science University in Portland.

Egli was initially skeptical of the Oregon group's claims that they had used CRISPR for the first time to repair a mutation in human embryos this way. Egli's research is aimed at trying to confirm that it works and how.

Mitalipov's group is also continuing to study the technique to see whether it can safely fix several genetic mutations in human embryos, including one of the breast cancer genes.

For the next two hours, Egli painstakingly fertilizes and edits one egg after another. He has to overcome a variety of technical complications. At one point, the tip of the fragile needle unexpectedly breaks off at a crucial moment.

"There we go," he says later, after the needle is replaced. "That one definitely worked. Beautiful."

This work may be beautiful to Egli, but it makes critics very nervous.

"Anyone with a connection to the Internet will be able to download the recipe to make a designer baby," Urnov says. "And then the question becomes: 'What's to prevent them from using it?' As we learned in the past year: apparently nothing."

So Urnov worries about any such research proceeding.

"We need to hit the pause button and keep it pressed until we understand how do we proceed in a way that minimizes the risk of people going rogue," Urnov says.

Urnov and others argue society needs a much broader debate about whether there is a truly a compelling reason to ever try to make any more gene-edited babies. There are many other ways to prevent genetic diseases, they note.

"If we've learned anything from what's happened in China, it's that the urge to race ahead pushes science to shoot first and ask questions later," says J. Benjamin Hurlbut , an associate professor of biology and society at Arizona State University. "But this is a domain where we should be asking questions first. And maybe never shooting. What's the rush?"

That's especially true when the prospect of creating gene-edited babies raises so many fraught ethical questions, including fears that it could eventually lead to the creation of "designer babies," critics say.

"We don't need to be mucking around with the genes of future children," says Marcy Darnovsky , director of the Center for Genetics and Society, a watchdog group. "This could open the door to a world where people who were born genetically modified are thought to be superior to others, and we would have a society of people who are considered to be genetic haves and genetic have-nots."

But many other scientists and bioethicists disagree.

"This is valid research, and I think it's important research," says R. Alta Charo , a bioethicist at the University of Wisconsin, Madison. "It has value not only for the possible use in the future for some number of conditions that would involve a live birth, but it has value for basic understanding of embryology, basic understanding of development," Charo says. "Of course I think we should be doing that research. Why wouldn't you be doing that research?"

Many leading scientists agree.

"Is there value in doing that kind of research? I think there is," agrees Jennifer Doudna , a biochemist at the University of California, Berkeley, who helped invent CRISPR. "Does it have to be carried out carefully and under the right regulatory guidelines? Of course. But I think there's value in doing research like that."

"I'd like to see the U.S. be involved and show leadership on how to do that responsibly rather than say we're not going to have a seat at the table," Doudna says.

Back in Egli's lab, it's now nearly 3 p.m., and he is wrapping up the day's experiments.

"OK, that's it. That's the last one," he says as he places back into storage the last of 14 eggs he managed to fertilize and hopefully edit. He will stop their development the next morning to see whether it worked.

• genetic disorders
• gene editing
• human embryos