As more details regarding the first gene-edited humans are released, things continue to look worse. The researcher who claimed the advance, He Jiankui, has now given a public talk that includes many details on the changes made at the DNA level. The details make a couple of things clear: we don't know whether the editing will protect the two children from HIV infections, and we can't tell whether any areas of the genome have been damaged by the procedure.
All of that raises even further questions as to whether He followed ethical guidelines when performing the work and getting consent from the parents. And, more generally, nobody is sure why He chose to ignore a strong consensus that the procedure wasn't yet ready for use in humans. In response to the outcry, the Chinese government has shut down all further research by He, even as it was revealed that a third gene-edited baby may be on the way.
While the US already has rules in place that are intended to keep research like He's from happening, a legal scholar Ars spoke with suggested there may be a loophole that could allow something similar here. In light of that, it's important to understand the big picture He has potentially altered. What exactly happened in China and why does it concern so many in the scientific community?
Technical failures
Prior to this work, a strong consensus existed among the scientific community that, although technology for editing the human genome was available, we didn't know enough yet about how to check its safety and effectiveness to determine how to ethically use it. And, as it turns out, He's work appears to provide a demonstration of nearly everything that had the research community concerned.
(Researchers at the conference where He spoke provided a transcript of his talk and shared his slides; other details have come out via data he's shared with the AP.)
The goal of the editing was to damage the CCR5 gene, which encodes a protein that HIV uses to enter cells during infection. He and his colleagues used a gene-editing technique that is expected to generate small deletions. They targeted one of these deletions to a spot in the center of the gene that's the site of a mutation that blocks HIV infection. The data shared so far indicates they were successful in terms of generating deletions, but whether or not they inactivated the gene is far less clear.
When a gene is translated into a protein, its DNA is read using a code where three of the bases in DNA encode one of the amino acids in a protein. This makes a gene very sensitive to whether deletions eliminate a number of bases that's a multiple of three. If a deletion takes out six or nine bases, for example, the resulting protein will only be missing two or three amino acids, respectively. Thus, it may be able to function normally. If the deletion doesn't remove a multiple of three—if it takes out 11 or 16 bases, for example—then the rest of the gene after the deletion won't be read properly. You'd end up switching to the protein equivalent of random keyboard bashing, often stopping the protein very short.
In the case of one of the twins born, the deletion eliminates 15 base pairs, meaning the CCR5 protein will lack five amino acids but otherwise be normal. In the second twin, some of her cells will have a four base pair deletion, which will cause a short tail of 10 random amino acids. Other cells will actually have an extra base, which also results in a randomization of the amino acids that follow, although the tail is much longer in this case.
The key thing for the twins' health and safety is that we have no idea whether any of these proteins will be made and placed on the cell surface as normal and, if they are, whether HIV can interact with them. All of these things can be tested, but He has given no indication of whether those tests have been done. So we have no idea of whether the edited genes will accomplish the intended goal of blocking HIV infection, and, worse still, it's not clear whether He's team knows.
Quantifying risk (or not)
The fact that one of the two twins has different deletions also points to another worrisome aspect to this work: not every cell in the embryo was edited at the same time and in the same manner, even though the editing machinery was injected when the embryo was a single cell. The resulting embryos could be a mosaic of unedited cells and cells with different types of damage to the intended gene. In fact, we now know that one of the twins also has some cells where one copy of the gene wasn't edited at all, meaning this twin has thus taken on the risks of gene editing without the supposed benefit of HIV protection.
This also means we don't know which of these changes (if any) will be inherited by any kids the twins have.
The risk of gene editing is that the process sometimes leads to what are called "off target" effects: deletions elsewhere in the genome or more complex rearrangements of the DNA. Either of these could potentially damage or alter genes that are not the intended targets of the editing, which would have unpredictable effects on health. To check for these, He allowed the edited embryos to develop to the point where it was safe to remove several cells; the DNA from these cells was then sequenced and the sequence compared to that of the two parents.
Unfortunately, the techniques that allow sequencing from extremely small samples like this are relatively inefficient. As a result, He was only able to obtain 80-90 percent of the genomes of the edited embryos. If there was damage in the remaining percentage, He didn't know. And because of the mosaic nature of the embryos, it's not even clear whether the DNA sequences He obtained were representative of the remainder of the embryo.
In the information that was obtained, however, there was one indication of off-target damage. Yet because it wasn't in the immediate vicinity of a gene, He decided that it was acceptable to proceed, even though the damage could influence gene activity or chromosome structure.
In sum, the data available so far indicates that we do not know whether the editing will actually protect either of the twins from HIV infection, the ostensible goal of the work. And as we noted in our original coverage, there are other, less drastic ways of preventing HIV infections and treatments available if those fail. Even if gene editing were used, it could be used on the blood stem cells that reside in the bone marrow, rather than on an embryo.
At the same time, this procedure exposed the twins to risks that we can't fully catalog and don't currently understand. As University of Wisconsin bioethicist Alta Charo said, “Having listened to Dr. He, I can only conclude that this was misguided, premature, unnecessary, and largely useless.”
Pilar Ossorio, a bioethics scholar at the University of Wisconsin's Morgridge Institute, echoed her concerns. "He created the risk that these children will suffer from something that they need not have ever suffered from," she told Ars. "And we will not get good scientific information out of that."
International ethics
All of the safety and efficacy issues described above were already widely understood by the biomedical research community, and they've been enough to keep anyone from trying what He's done up until now. This hesitation has existed despite the fact that the individual steps involved in human gene editing have all been worked out.
"There's been very broad consensus that we shouldn't be doing CRISPR on embryos yet," Ossorio said. "There are many people who think never, but there's a growing scientific consensus that there could be good reasons for doing it at some point." Those reasons could include genetic diseases for which there's no treatment available.
But Ossorio told Ars there was also a recognition that the technique was easy enough that it would be possible for the work to be performed in a huge range of countries. Even if it was prohibited in some, there's a chance that the scientists who wanted to pursue this would simply move to a country with permissive regulations, something that happened at the start of human stem cell research. With that reality, there has been an international effort to try to figure out whether there could be common norms about when genome editing in embryos was appropriate.
The meeting at which He presented his results was (ironically) part of that effort. Ossorio said the effort has been far-ranging, looking into which disorders could justify the use of this sort of editing, what safety tests would have to be available to make sure its use minimized the risk of harm, and how thorough our validation in animal models should be before going forward.
The Chinese were frequent participants in previous meetings. The first genome editing done on human embryos (non-viable ones) was done in China, and Ossorio said that the Chinese Academy of Science wasn't ready for the response. "They were completely unprepared for the backlash from around the world and realized they were way out of step with the rest of the world," she told Ars. "And they didn't want to be. The president of their national academy was beyond horrified at the reaction to what had happened."
Many of the scientists there have spent time working in the West, and they wanted to continue collaborations. This made China's scientific community anxious to bring the country in line with international perspectives on this work.
This makes He's decision to go ahead that much more difficult to fathom. But how he went ahead is difficult to understand, as well.
Uninformed consent?
A key principle guiding experiments involving humans is the idea of informed consent: potential participants can only agree after it's clear they understand the risks of the research. And there have been substantial questions about whether the participants here were fully informed. For starters, He himself was part of the informed consent process, something that's generally avoided because someone who's anxious to do research can end up persuading, rather than informing.
He supposedly put the informed consent information shared with participants online on his server, but the server has been down for the last 48 hours. People who have seen it indicated that it described the gene editing as providing a "vaccine" against HIV in some locations, although it was described accurately elsewhere.
Regardless of the document's content, many researchers have been incredulous that the parents of the twins could be fully informed of the risks and move forward even after it became clear that one of the embryos would not be protected from HIV infection. There's also the issue of using this for a viral disease that we already know how to prevent and treat. "When there are less risky and much better understood alternatives that have a reasonable chance of working, why would anyone choose this?" Ossorio asked. "That's not rational." This raises questions about whether the parents were informed enough to make rational decisions.
But to some extent, Ossorio argued that informed consent is already a step beyond where this should have been stopped. "Informed consent is not the big issue, in the sense that it just should never have gotten that far," she told Ars. "You only offer an opportunity to participate in research after there's been some oversight where there's a consensus that the research meets some standards that help ensure that the balance of risks and benefits is reasonable. We don't just let scientists do research on people just because people would say yes to having it done."
Because we don't currently have a clear picture of what the edited versions of the gene do or the scope of off-target edits, the benefits to society as a whole may end up limited. "You put people at risk for no advance of knowledge, or a much smaller advance of knowledge than you could have gotten? That's been considered unethical since the Nuremberg Reports," Ossorio said.
Closer to home
In ordering that He's work be shut down, Chinese authorities indicate that these standards are operative there. The BBC quotes China's National Health Commission as saying the work "seriously violates China's laws, regulations, and ethical standards." Does the same apply in the US?
Currently, the federal government is prohibited from funding any research that involves the editing of genomes in human embryos. Even though a private source could potentially fund the work, any researchers would likely be forgoing any future federal funding—and any institutions involved in the work could face consequences as well. On the commercial side, Ossorio said that the FDA is required to treat any applications that include gene-edited embryos as legally invalid, meaning that no products can be licensed that involve this.
But there is a potential loophole amidst these limits, Ossorio told Ars. The FDA's ability to regulate medical procedures is derived from the federal government's ability to regulate interstate commerce. If gene editing were developed as a service that is offered within a single state and wasn't dependent upon materials shipped in from out of state, it's unclear how much authority the FDA would have. She pointed to the proliferation of clinics offering "stem cell treatments" of dubious value as a case where the FDA's authority is uncertain.
Complicating matters further, the conservative majority on the present Supreme Court has tended to take a narrow view of the interstate commerce clause and has been prone to limit its scope in terms of enabling federal regulations. All of which seems to open a gray area similar to the one that He operated in—he operated without the knowledge of his institution, likely using funds from the biotechnology startups he had founded.
And there are undoubtedly people in the US who would share He's desire to push the technology out regardless of potential consequences. "I believe families need this technology," He defiantly said in his announcement. "And I'm willing to take the criticism for them." Hopefully, He and anyone who might consider following in his footsteps will pay attention to the details of the scientific and ethical criticism that have greeted this news.
