Scientists Find Gene Editing with CRISPR Hard to Resist

CRISPR, a new technique for editing DNA, is so cheap and easy to use, we may be genetically engineering human embryos before we have time to decide if we should. 

Hacking the human genome has long made for great science fiction theater because it has always seemed fantastically impossible and it lends itself so readily to sinister plotlines.

But since scientists succeeded in mapping the human genome in the 1990s, genetically engineering people seems less like fiction and more like the presumptive endpoint of medical research.

We still fear tinkering with the human genome in heritable ways, even as using genetic engineering to treat people who are sick begins to make real progress. It’s illegal to edit heritable DNA in many countries, though not in the United States. But we’ve left discussion of the ethical implications and the nuts and bolts of regulation to be worked out as the technology moves into reach.

But in 2012, what once seemed only a future possibility became an immediate dilemma.

That’s when University of California molecular biologist Jennifer Doudna, Ph.D., and some colleagues outlined a new genetic engineering technique called CRISPR-Cas9 in a paper in the journal Science. In short, the technology allows a scientist to snip out problematic pieces of DNA, a procedure with profound potential to cure devastating genetic diseases such as Huntington’s.

The technique is easy enough that any biologist who felt so inclined could “edit” the genetic makeup of a human embryo and implant it into a woman using in vitro fertilization (IVF). That change would enter the gene pool once and for all.

A number of groups have raised the alarm that it’s now time. It’s no longer science fiction.
Dr. George Daley, Harvard Medical Center

CRISPR-Cas9 could also potentially reprogram the genes that cause genetic diseases such as sickle-cell anemia and Huntington’s disease, promising an all-purpose cure.

Scientists and regulators have scrambled to catch up.

“Given that the issues of being able to modify a genome, especially an embryo, are now much more immediate and more concerning, that’s why a number of groups have raised the alarm that it’s now time. It’s no longer science fiction,” said Dr. George Daley, Ph.D., a stem-cell biologist at Harvard Medical Center.

But critics say the process guiding whether and how we will change our human genetic inheritance is slapdash, exclusionary, and tainted by the promise of profit for those who could profit from a cure for cancer or a genetic disease — or from a fix for some subjectively undesirable genetic trait.

Read More: Harvard, MIT Make CRISPR Gene Editing Tool More Powerful »

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A Eureka Moment

Technically, it has been possible to edit human DNA since the mid-1970s, when Paul Berg, Ph.D., cultured human DNA in E. coli bacteria in his Stanford lab. But those early methods were labor-intensive and unreliable.

Doudna (pronounced DOWD-na) entered the debate over human engineering by accident. An expert in RNA, she had been called in to help some colleagues investigate how bacteria fight off viruses.

It gradually became clear that bacteria identify and target bits of viral DNA using a process called CRISPR-Cas9. The first time a bacterium meets a virus, it stores a bit of its DNA. Later on, that DNA serves as a “most wanted” poster. If the bacterium runs into the same virus again, it attacks it by snipping out the familiar pattern of DNA.

Doudna and her colleagues quickly realized that scientists could piggyback on the bacterial process to edit DNA — whether it belonged to a virus, an agricultural plant, or a human being.

“I thought, wow, if this could work in animal or plant cells, this could be a very, very useful and very powerful tool. Honestly, I didn't even realize at the time how powerful,” Doudna told NPR in a 2014 interview. (She declined Healthline’s request for an interview, citing her professional travel schedule.)

The power of the new approach did not go unnoticed.

This spring, Chinese researchers who had used the CRISPR-Cas9 method on human embryos published their findings in an American journal.

The embryos were nonviable and the approach didn’t work as well as expected, but the report sent a wave of alarm through the scientific community, revealing just how strong the temptation was to use CRISPR to modify inheritable human DNA.

Within days of that publication, a team at the University of California, San Diego (UCSD) announced success using CRISPR on fruit flies. They made changes to the genes of a pair of mating fruit flies, ensuring that the trait they had inserted would be passed on to all of the offspring. This kind of genetic engineering is called “gene drive.”

The UCSD scientists imagined using the approach to make better mice and fruit flies for research, but the implications were clear: We could quickly change an entire species, including ourselves, using CRISPR.

Just last week, British scientists requested a license from the UK’s Human Fertilisation & Embryology Authority to edit the genomes of human embryos stored in fertility clinics. They plan to use viable embryos but promise not to implant them after they’ve been modified.

Read More: New Technology Allows Scientists to Target HIV, Cancer Cells »

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Looking to the Past to Handle Futuristic Technology

Meanwhile, Doudna and other scientists, ethicists, and lawyers have begun to wrestle with the ethical challenges of CRISPR.

In January, Doudna and a small group of U.S. thought leaders met in Napa, California, to discuss what to do about the genie that they’d let slip out of its bottle. Paul Berg, who pioneered genetic engineering with his 1975 discovery of recombinant DNA, was there.

The group was taking its cue from the conference Berg organized in 1975 at Asilomar Conference Grounds, just outside Monterey, California, to decide how science would proceed with genetic engineering. That meeting is widely heralded as proof that scientists can safely handle controversial and potentially destructive tools.

In the spring, several participants of the Napa meeting — including Doudna, Berg, and Harvard’s Daley — published a position piece arguing that CRISPR should not be used on reproductive DNA, or germline cells. But, they said, laboratory research should continue.

At the end of this year, an international scientific brain trust will converge on Washington, D.C., to start sketching out a plan for possible limits on CRISPR. The effort has hurtled ahead, reflecting the urgency of the matter.

But as the invitation-only summit, sponsored by The National Academies of Sciences, Engineering, and Medicine and its UK and Chinese counterparts, comes together, critics argue that it is doomed to fail because it excludes key questions and the opportunity for public comment.

The National Academies says there will be limited seating for members of the public.

If CRISPR represents “a tidal shift in terms of the way we think of ourselves as beings,” as Daley puts it, then what is the best way to decide such an important issue?

Sheila Jasanoff, Ph.D., a science and technology studies professor at Harvard’s Kennedy School, thinks the December meeting is already echoing some of the failures of the Asilomar conference.

The scientists at Asilomar looked at the products of early genetic engineering for their potential to be used for bioweapons and worried mainly about the risks of them escaping from the laboratory.

They did not anticipate what has proven to be a heated and long-standing debate over genetically modified (GM) organisms, which has had major consequences for farmers, environmentalists, and agribusiness heavyweights such as Monsanto.

“In retrospect, one can see the long, at times tragic, controversy over GM crops … as a reopening by global citizens of all the dimensions of genetic engineering that Asilomar had excluded,” Jasanoff wrote in an op-ed objecting to the next generation’s summit on genetic engineering.

Read More: Get the Facts on Genomics vs. Genetics »

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Cloning Money?

The scientists who gathered at Asilomar had little to do with the commercial applications of their research. But with the Bayh-Dole Act of 1980, professors and universities gained financial interest in how their discoveries were commercialized.

Their commercial interests may have influenced their choice not to consider the question of using CRISPR in agricultural plants and animals at the international meeting, even when the debate about them continues to simmer.

Doudna is involved with three of the dozen or so companies that have already formed in hopes of commercializing CRISPR gene editing. One company, Caribou Bio, is explicitly interested in agricultural applications.

According to Pete Shanks, M.A., of the Center for Genetics and Society, agriculture will likely be one of the first profitable businesses for CRISPR, because seed modification doesn’t require as much precision as human medicine.

“As long as you end up getting one seed that works, you’re OK,” Shanks said.

It would be hard to find someone in the biotech world who doesn’t have an interest because all the principals in this conversation do have what look like conflicts of interest.
Marcy Darnovsky, Center for Genetics and Society

But Doudna’s financial interests in her discovery are more the rule than the exception.

“It would be hard to find someone in the biotech world who doesn’t have an interest because all the principals in this conversation do have what look like conflicts of interest,” said Marcy Darnovsky, Ph.D., the executive director of the Center for Genetics and Society. Darnovsky, who will attend the Washington conference, wants to see genetic engineering limited to medical procedures on individuals, not heritable changes that will enter the gene pool.

Michael Kalichman directs the Center for Ethics and Society at UCSD. He describes Doudna’s involvement with the business side of her work simply as part of her job as the head of a research lab in a post-Bayh-Dole world.

“Your job is to try to sell it,” he said. “Doudna isn’t hiding her interests in that.”

In a roomful of scientists, doctors, and university lawyers, all of the opinions are colored by money.

“We only have people who have financial interests who are making not just decisions that are going to be applied, but they’re coming up with the questions that are going to be asked,” Darnovsky said.

Kalichman, whose career has “bracketed” the Bayh-Dole Act, says the law has resulted in a faster shift from pure research to clinical applications. But it also makes room for bias.

“The question is, ‘Does the system of financial interest create a bias toward seeing certain things?’ and the answer appears to be yes,” he said.

Read More: DNA Synthetic Vaccine May Protect Against MERS Virus »

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Pitting Heartstrings Against Hard Science

In their editorial on CRISPR — titled “A prudent path forward for genomic engineering and germline gene modification” — Doudna, Daley, Berg, and others say that researchers ought to explore how CRISPR works on human embryos — so long as no one implants the modified embryos.

“They're arguing that editing human germline cells (gametes and early embryos) for research purposes should move forward immediately while a dialogue about the social and ethical implications of using modified germ cells to initiate a pregnancy is underway,” Darnovsky said of the editorial.

Further research, the piece argues, will give us more information about how germ-line modifications work — or, as in the Chinese study, don’t.

“They call this ‘a prudent path forward,’” Darnovsky said. “But it would be easy to read it as ‘If our research demonstrates that we can modify the germline safely and accurately, that will be an argument for proceeding to create GM humans.’”

It has been only about a decade since we first read the human genome. We should exercise great caution before we begin to rewrite it.
Eric Lander, Broad Institute

Doudna has described CRISPR as a method for editing the typos we are given in nature’s hard-copy text. Her metaphor is intended to make an incredibly complicated process understandable to nonscientists. But it also glosses over the risks of gene editing: The reality is, the book of human genetics is written in a language we barely understand.

“It has been only about a decade since we first read the human genome. We should exercise great caution before we begin to rewrite it,” Eric Lander, Ph.D., head the Broad Institute, wrote in his op-ed on CRISPR.

The Broad Institute has competed with Doudna’s West Coast lab for advances in CRISPR and is engaged in a lawsuit over who holds the patents.

Lander agrees that we shouldn’t touch inheritable DNA, but he makes room for a “possible exception of correcting severe monogenic disease genes, in the few cases in which there is no alternative.”

What if the research Doudna advocates and UK scientists are already asking to do promises a cure for a devastating genetic disease such as Huntington’s not on a case-by-case basis but by eliminating the gene mutation altogether? The public would likely demand access to that cure.

But what if what seemed like a cure turned out to have major unintended genetic side effects that weren’t apparent until the next generation?

 “To get from a brilliant observation to something that helps the masses is complicated,” Jasanoff said.