One week ago, MIT Technology Review reported that scientists at an Oregon-based lab had modified the DNA of human embryos using the gene-editing technique known as CRISPR. That was a first for the United States; until then, such a procedure had only ever been done in China.
The researchers, led by Shoukhrat Mitalipov from Oregon Health and Science University, had altered the gene behind an unspecified inherited disease in a number of one-cell embryos. These embryos weren’t allowed to develop for more than a few days, and there was never any intention to implant them into a womb. The story fueled another cycle of discussion about designer babies, and fears that a Gattaca-style world was just around the corner.
But the full details of the experiment, which are released today, show that the study is scientifically important but much less of a social inflection point than has been suggested. “This has been widely reported as the dawn of the era of the designer baby, making it probably the fifth or sixth time people have reported that dawn,” says Alta Charo, an expert on law and bioethics at the University of Wisconsin-Madison. “And it’s not.”
Given the persistent confusion around CRISPR and its implications, I've laid out exactly what the team did, and what it means.
Who did the experiments?
Shoukhrat Mitalipov is a Kazakhstani-born cell biologist with a history of breakthroughs—and controversy—in the stem cell field. He was the scientist to clone monkeys. He was the first to create human embryos by cloning adult cells—a move that could provide patients with an easy supply of personalized stem cells. He also pioneered a technique for creating embryos with genetic material from three biological parents, as a way of preventing a group of debilitating inherited diseases.
Although MIT Tech Review name-checked Mitalipov alone, the paper splits credit for the research between five collaborating teams—four based in the United States, and one in South Korea.
What did they actually do?
The project effectively began with an elevator conversation between Mitalipov and his colleague Sanjiv Kaul. Mitalipov explained that he wanted to use CRISPR to correct a disease-causing gene in human embryos, and was trying to figure out which disease to focus on. Kaul, a cardiologist, told him about hypertrophic cardiomyopathy (HCM)—an inherited heart disease that’s commonly caused by mutations in a gene called MYBPC3. HCM is surprisingly common, affecting 1 in 500 adults. Many of them lead normal lives, but in some, the walls of their hearts can thicken and suddenly fail. For that reason, HCM is the commonest cause of sudden death in athletes. “There really is no treatment,” says Kaul. “A number of drugs are being evaluated but they are all experimental,” and they merely treat the symptoms. The team wanted to prevent HCM entirely by removing the underlying mutation.
They collected sperm from a man with HCM and used CRISPR to change his mutant gene into its normal healthy version, while simultaneously using the sperm to fertilize eggs that had been donated by female volunteers. In this way, they created embryos that were completely free of the mutation. The procedure was effective, and avoided some of the critical problems that have plagued past attempts to use CRISPR in human embryos.
Wait, other human embryos have been edited before?
There have been three attempts in China. The first two—in 2015 and 2016—used non-viable embryos that could never have resulted in a live birth. The third—announced this March—was the first to use viable embryos that could theoretically have been implanted in a womb. All of these studies showed that CRISPR gene-editing, for all its hype, is still in its infancy.
The editing was imprecise. CRISPR is heralded for its precision, allowing scientists to edit particular genes of choice. But in practice, some of the Chinese researchers found worrying levels of off-target mutations, where CRISPR mistakenly cut other parts of the genome.
The editing was inefficient. The first Chinese team only managed to successfully edit a disease gene in 4 out of 86 embryos, and the second team fared even worse.
The editing was incomplete. Even in the successful cases, each embryo had a mix of modified and unmodified cells. This pattern, known as mosaicism, poses serious safety problems if gene-editing were ever to be used in practice. Doctors could end up implanting women with embryos that they thought were free of a disease-causing mutation, but were only partially free. The resulting person would still have many tissues and organs that carry those mutations, and might go on to develop symptoms.
What did the American team do differently?
The Chinese teams all used CRISPR to edit embryos at early stages of their development. By contrast, the Oregon researchers delivered the CRISPR components at the earliest possible point—minutes before fertilization. That neatly avoids the problem of mosaicism by ensuring that an embryo is edited from the very moment it is created. The team did this with 54 embryos and successfully edited the mutant MYBPC3 gene in 72 percent of them. In the other 28 percent, the editing didn’t work—a high failure rate, but far lower than in previous attempts. Better still, the team found no evidence of off-target mutations.
This is a big deal. Many scientists assumed that they’d have to do something more convoluted to avoid mosaicism. They’d have to collect a patient’s cells, which they’d revert into stem cells, which they’d use to make sperm or eggs, which they’d edit using CRISPR. “That’s a lot of extra steps, with more risks,” says Alta Charo. “If it’s possible to edit the embryo itself, that’s a real advance.” Perhaps for that reason, this is the first study to edit human embryos that was published in a top-tier scientific journal—Nature, which rejected some of the earlier Chinese papers.
Is this kind of research even legal?
Yes. In Western Europe, 15 countries out of 22 ban any attempts to change the human germ line—a term referring to sperm, eggs, and other cells that can transmit genetic information to future generations. No such stance exists in the United States but Congress has banned the Food and Drug Administration from considering research applications that make such modifications. Separately, federal agencies like the National Institutes of Health are banned from funding research that ultimately destroys human embryos. But the Oregon team used non-federal money from their institutions, and donations from several small non-profits. No taxpayer money went into their work.
Why would you want to edit embryos at all?
Partly to learn more about ourselves. By using CRISPR to manipulate the genes of embryos, scientists can learn more about the earliest stages of human development, and about problems like infertility and miscarriages. That’s why biologist Kathy Niakan from the Crick Institute in London recently secured a license from a British regulator to use CRISPR on human embryos.
The Oregon team has more immediate goals in mind. Through their work, they hope to eventually give people with HCM the certainty that they would not pass on their condition to their children. “If we had the freedom to do this, we could theoretically remove HCM in a generation,” says Kaul. “That’s the potential and we have to let the potential and reality meet someday.”
In February, an expert committee convened by the U.S. National Academy of Sciences (and co-chaired by Charo) offered qualified support for germ-line editing. In a report, they said that such editing shouldn’t be used to enhance healthy people, but could be permitted to treat or prevent disease and disability, provided certain criteria were met. The technique would need to become much safer and more efficient, and a “stringent oversight system” should be set in place. It should be an option of last resort for couples who have a serious genetic disease and have no other way of producing a healthy child. But remember that the Oregon team haven’t done anything even close to this yet. They just edited embryos for basic research purposes—a use that the NAS report wholeheartedly endorsed.
How do people with HCM feel about this?
I reached out to an advocacy organization that raises awareness of HCM, but haven’t heard back. But John Jefferies, a cardiologist at Cincinnati Children's Hospital Medical Center, says, “I think those caring for these patients would greatly welcome this move. The medical therapies we have for this disease are limited and do not reverse the cardiac [problems]. This offers a potential ‘cure’ for the disease by avoiding it.”
Aren’t there already other ways of doing that?
Yes, and therein lies the debate. A couple could opt for preimplantation genetic diagnosis (PGD), where their sperm and eggs are introduced in a lab, and the resulting embryos are genetically screened to find those that are free of disease genes. This technique already works well, so why bother with gene-editing at all? If one of the wannabe parents has a copy of an HCM-causing mutation, then half of the resulting embryos will carry that mutation—and be discarded. But if Oregon team gets their technique working perfectly, then every embryo could be potentially implanted. They’re not trying to supplant PGD. They’re trying to bolster it.
But “these days with IVF, the tendency is to put in one embryo at a time to avoid having twins or triplets,” says Charo. “If it doesn’t work after a few times, you’re less likely to succeed. So it’s not clear to me how relevant this is for preventing genetic disease.” Mitalipov disagrees. “IVF is not efficient and with this procedure, we hope patients will be able to become pregnant on just one cycle,” he says. He also he sees this as a moral issue. “You have no right to throw away 50 percent of these embryos when you can correct them. It’s very 19th-century. Some people say that our work is ethically wrong but I think it is ethically right.”
Does the editing approach have limitations?
Yes, and they are important ones. CRISPR works by cutting DNA at a precise point. A cell then uses a matching piece of DNA as a template for repairing the cut. It’s like tearing a misprinted page from a book and using a pristine edition to fill out the missing text. Mitalipov’s team offered the embryos a pristine copy of the MYBPC3 gene to be used in the repair process. But to their surprise, the embryos largely ignored this gift. Instead, they used the healthy copy of the gene from the egg to repair the CRISPR-sliced mutant version from the sperm. That means that this technique would not work if both parents have HCM. If both pass a mutant version of MYBPC3 to an embryo, there’s no healthy copy to use as a template. “We still need to figure out how to correct those,” says Mitalipov.
When can we expect such editing to be commonplace?
Not for a while. The technique would need to be refined, tested on non-human primates, and shown to be safe. “The safety studies would likely take 10 to 15 years before FDA or other regulators would even consider allowing clinical trials,” wrote bioethicist Hank Greely in a piece for Scientific American. “The Mitalipov research could mean that moment is 9 years and 10 months away instead of 10 years, but it is not close.” In the meantime, Kaul says, “We’ll get the method to perfection so that when it’s possible to use it in a clinical trial, we can.”
Isn’t this a slippery slope toward making designer babies?
In terms of avoiding genetic diseases, it’s not conceptually different from PGD, which is already widely used. The bigger worry is that gene-editing could be used to make people stronger, smarter, or taller, paving the way for a new eugenics, and widening the already substantial gaps between the wealthy and poor. But many geneticists believe that such a future is fundamentally unlikely because complex traits like height and intelligence are the work of hundreds or thousands of genes, each of which have a tiny effect. The prospect of editing them all is implausible. And since genes are so thoroughly interconnected, it may be impossible to edit one particular trait without also affecting many others.
“There’s the worry that this could be used for enhancement, so society has to draw a line,” says Mitalipov. “But this is pretty complex technology and it wouldn’t be hard to regulate it.”
Wait, haven’t I read about DIY gene-editors, who are using CRISPR in their basement labs?
Yes, but none of those people are using the technique to edit human embryos. Mitalipov’s work is essentially a form of IVF. “It’s not simple IVF either,” he says. “Everything needs to be done exactly the way we did it. You’d need to do a biopsy with every embryo to screen for off-target mutations. You can’t do it at home.”
So, this isn’t the start of Gattaca?
I doubt it.
Brave New World?
Does this discovery have any social importance at all?
“It’s not so much about designer babies as it is about geographical location,” says Charo. “It’s happening in the United States, and everything here around embryo research has high sensitivity.” She and others worry that the early report about the study, before the actual details were available for scrutiny, could lead to unnecessary panic. “Panic reactions often lead to panic-driven policy ... which is usually bad policy,” wrote Greely.