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.”

https://arstechnica.com/?p=1420385