He Jiankui didn’t really gene edit those girls; he mutated them

Did Chinese researcher He Jiankui really CRISPR gene edit the CCR5 gene in two embryos producing twin baby girls? In my opinion the answer is “no”, but probably not for the reason you might think at first.

He proclaims gene edits

He claimed he had made twin baby girls with “gene edits”, which I feel is unethical overall and risky to those babies. He’s announcement also may have been intentionally timed to occur right before an international meeting on human gene (or genome) editing last week too. Glossy YouTube videos from He accompanied all of this as well, raising further suspicions of a PR angle for himself. For these and other reasons, I believe we need a temporary 3-year pause on implantation of CRISPR’d human embryos.

Could He have been stopped and when?

CRISPR gene edit vs mutation
CRISPR gene edit vs mutation. Analogy of what He did to trying to edit a book with a thrown scalpel. Photo Paul Knoepfler

Given the timing and He’s actions, the organizers of the human genome editing meeting could have yanked He’s invitation to speak, but they didn’t. On the whole, that was probably a wise decision so we could all learn more about what supposedly happened.

Others argued He shouldn’t have been allowed to retain that meeting platform since what he did appeared to most likely be unethical on a number of levels. Beyond the questionable science of He’s work, there are still unresolved ethics and transparency questions. As my colleague here at UC Davis Mark Yarborough wrote, in a sense ideally the life sciences community should have hoped to have stopped He much earlier in a different kind of way including via better bioethics training and a different kind of research culture.

Did He really “gene edit” them?

Some people have wondered if the whole thing might be a fraud in which He didn’t actually make CRISPR’d babies. Based on what we do know, I think most likely He isn’t lying at a core level about having made babies with CRISPR, although we may never know for sure. However, at a common sense level I would still say that He did not gene edit these babies.

What do I mean?

As someone who has been doing genetics for a long time, mostly in mice, I remember that in the pre-CRISPR era we called various interventions in genes by other terms: mutations, genetic modifications, gene targeting, etc. Some of us still often use those terms. “Gene editing” sounds more precise and deliberate and benign. Maybe that’s the appeal of this term to some.

In my view as a scientist who uses CRISPR, not all uses of it actually qualify as gene editing and it’s not just semantics. I would argue the term “gene editing” should be reserved only for precise, deliberate changes that justify using versions of the key word “edit”. There’s been far too much loose use of the phrase ‘gene editing” and others like “gene surgery.” This kind of language can be harmful by misinforming people, exaggerating precision, and underestimating risks.

How we write and talk about science is very important (see more on CRISPR metaphors here, work also led by Mark Yarborough). If you think about the “edit” analogy more broadly, would you want your editor to just throw a scalpel or scissors at a specific section of your writing (even if for some weird reason this editor is a very accurate although not perfect thrower) and hope for the best outcome? I’d hardly call that editing.

Gene editing versus mutating

To qualify as a gene edit, He would have had to have been deliberately trying to make one and only one precise change, and have achieved that edit alone. That’s not at all what happened. Instead, it seems He deleted fairly random chunks of a certain region of CCR5 in the human embryos who supposedly became twin girls. None of the He mutations were the same as those occurring naturally in humans who then have substantial resistance to HIV infection.

Even in basic science research using CRISPR, if we make random mutations (what are collectively termed indels, which is short for “Insertions” and “deletions”) should we be calling that “gene editing”? No, we really shouldn’t, even if sometimes those indels are useful and powerful tools. In my lab we have used CRISPR to both make precise gene edits and separately to make indel mutations.

A gene edit is still a type of mutation, but a uniquely precise, deliberate one, while conversely not all mutations are gene edits. Further, not everything done by CRISPR should be called “gene editing.”

Frankly, what He did really was to mutate those twin girls, particularly since he was changing a normal wildtype gene to a mutant form. We should call it what it is so as to be as accurate as possible and think about the reality of the situation.

10 thoughts on “He Jiankui didn’t really gene edit those girls; he mutated them”

  1. It’s not a matter of if Human germline modding will provide consistent efficacy in the future.. The question is which country is going to lead the way in offering this service to the public.. You can carry on whining ‘but but Its unethical..’ the same could be said about abortions, factory animal farming, drug trade, and prostitution. Goodluck policing the globe.. meanwhile my wife and I will be making plans to go on an ‘exotic vacation” where she may or may not return home pregnant.. ✌️

  2. Too impatient to wait for an answer about the delta32 mutation in CCR5, I looked it up in OMIM. Here’s an excerpt; “…[in homozygous mutants]..the severely truncated protein could not be detected at the surface of cells that normally express the protein… coexpression of the deletion mutant with wildtype CCR5 reduced the fusion efficiency of 2 different viral envelope proteins in 3 independent experiments.” So in heterozygotes, the delta32 mutation interferes with the normal protein and reduces the ability of cells to bind HIV, and in homozygotes HIV can’t bind to cells at all. With some caveats, of course.

  3. The CCR5 delta32 mutation truncates the open reading frame of CCR5. This does not result in a loss of CCR5, it results in a functionally altered protein and you require the presence of this stable deleted CCR5 delta32 protein for the anti-HIV effect. This suggests that He’s team didn’t understand the biology they were trying to alter. They didn’t manage to replicate the CCD5 delta32 mutation in the twins and we have no idea whether the alterations they did manage in the twin with the two frameshift mutations resulted in the required stable truncated CCR5 protein.

    1. @Martin- a lot of us need catchup on CCR5. I thought it was a null mutation in the German patient, but then I never looked at the scientific literature about it. What do you recommend that we read?

  4. @Paul
    I watched the Hong Kong meeting- the talks before He’s were especially interesting.
    Someone asked a question about the talk from Shoukhrat Mitalipov’s lab. In that work, sperm was injected with CRISPR Cas9 AND a template to correct a mutation in the sperm. But instead of using the template, the sperm gene was allegedly repaired by copying the normal sequence from the egg’s DNA. I say allegedly, because when this repair was supposedly going on, the male and female pronuclei were still separate, so the egg’s and sperm’s DNA were worlds apart in cellular space. There’s still a lot of mystery to this.
    There was also a talk showing that CRISPR targeting the POU5F1 (OCT4) gene in human embryos caused some serious DNA damage. We should do more science before we put people at risk.

  5. Back in the old days, we used to knock out genes in mice to discover their function.
    He’s experiment was a gene knockout, not an edit.
    That’s why He chose CCR5. Anyone who does gene editing knows that it’s easy to just cut the DNA and have it repair itself by non-homologous end joining (NHEJ).
    He chose CCR5 because it’s one of the only genes that has any arguable clinical benefit when it’s completely missing, not when it changed to another version. Knocking out most genes has dire consequences. For example, mutations in hemoglobin cause sickle cell anemia, but you wouldn’t want to knock out the hemoglobin genes – hemoglobin is essential to life. You’d want to replace the mutated gene with a non-mutated functioning gene. Gene editing is much more difficult than knock out, requiring an additional component- a DNA sequence that can be copied to introduce the desired changes.

    1. @Jeanne,
      He’s choice of targeting CCR5 has come under a lot of criticism on many levels. Instead of trying to make a precise gene editing, he just was hoping for some disruptive indel. Using a carefully designed HDR template he could have had a much better chance of making the naturally occurring Delta32 CCR5 mutation. At least so far I didn’t see it mentioned that he even used an HDR template, which seems reckless. It really isn’t gene editing, but just mutating. More broadly I would have thought the 1st person to do this would have chosen a disease-associated mutation and changed that back to WT, but he changed a WT, non-disease causing gene to mutant.

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