July 15, 2020

The Niche

Knoepfler lab stem cell blog

Heads up on Hui Yang, another potential aspiring CRISPR baby researcher

Making a CRISPR baby is a controversial idea to even propose now for many reasons, yet even after He Jiankui’s train wreck some people have seemed eager to try it including apparently a scientist whose name perhaps many readers here are not so familiar with in this context: Professor Hui Yang.

‘CRISPR baby guys’

Is it really a good time to be pushing CRISPR babies? The original “CRISPR baby guy” He Jiankui was recently sentenced to three years in prison for a variety of actions he took while making three gene-edited human babies, at least two of which had the CCR5 gene mutated. We don’t know what the future holds for these three children (and their children and so on), but illnesses or other negative repercussions for them related to the gene editing cannot be ruled out.

When I think about people seemingly eager to try making CRISPR babies, the Russian researcher Denis Rebrikov comes to mind too for what he says he wants to do. We’ll see how Rebrikov’s efforts go, but I don’t see him bucking Russian authorities who don’t seem in a hurry to allow such work given what happened with He Jiankui.

Most people are familiar now with both He and Rebrikov in the CRISPR baby context, but perhaps less so for Hui Yang.

Yang was one of He’s strongest critics in an excellent piece on what went wrong with these efforts. It’s quite a takedown of He. Still, it seems that Yang himself wants to make some kind of CRISPR babies too, but perhaps “do it right” so to speak, meaning legally and apparently with a much more robust scientific foundation.

Hui Yang background and work

Professor Yui Hang (杨辉 ) who apparently wants to make a CRISPR baby.
Professor Yui Hang (杨辉 ).

Hui Yang runs a lab at the University of China Academy of Sciences. Before his current faculty appointment, he was a postdoc in the Jaenisch lab at MIT. He has an impressive record of publications.

Yang’s research is focused on the newer area of gene editing called “base editing“, which doesn’t rely on double-strand breaks induced by nucleases but still can lead to off-target mutations. For instance, there’s this STAT News article mentioning Hui Yang in the context of studies trying to better define the off-target activities of base editing in mouse embryos.

Also, check out this 2019 Science pub reporting on the abundant base-editor off-target effects in some cases. The targeting there in mouse embryos was focused on a reporter gene tdTomato already in the cells.

In addition last year Yang led a team that published a paper on base-editing of human embryos, perhaps reflecting a transition toward an emphasis on more human embryo work.

This human embryo worked targeted the β-globin (HBB) gene for editing.

News article has some striking words from Hui Yang on CRISPR babies

So why does it seem that Yang wants to take that extra big leap to heritably use CRISPR in humans?

An article on making CRISPR babies published last summer in The South China Morning Post by Stephen Chen has some striking quotes from Yang including this one:

“The investment in the US on gene-editing technology is now more than 10 times [the investment] in China,” Yang said, but he insisted that Chinese researchers were not giving up on the fight.

“We are working with the same spirit as building the first nuclear bomb,” he said. But he warned that, like thermonuclear weapons, gene-editing technology could also bring destruction to human society if it was left to run out of control.”

How about that comparison of gene editing to the race to build nuclear weapons? And “the fight”?

I’m a little puzzled because the text of the article suggests that Yang is going to try to make gene-edited babies as soon as in the next year or two (cast in the article at least subtly as a good thing), but the article’s subtitle also implies that he’s warning the field about the possibility of more CRISPR babies soon. So which is it? Both? Maybe the warning part is meant to be focused on others who might do this kind of thing very irresponsibly?

Within one or two years?

From that same article on Yang’s research:

“Base-editing technology with a high safety standard should be ready for clinical use in one or two years…we are ahead of the competition in the United States,” he said.”

Chen clarifies that gene-edited babies are indeed the ultimate goal here for Yang (emphasis mine):

“Yang, a researcher with the Shanghai Institute for Biological Sciences, part of the Chinese Academy of Sciences, said the tool would soon be ready for clinical use, paving the way for legal production of gene-edited babies in a year or two.”

It’s also notable that Yang is again apparently placing this planned human heritable gene editing research in the context of a fierce competition between China and the U.S. I guess we shouldn’t put too much weight on this rhetoric and the nuclear weapons race reference above? Also, for sure some other researchers including here in the U.S. who are also interested in human CRISPR view this all as a race too. There are many risks to this “gene editing race” mentality.

It’s not clear what mutations and in what genes Yang is perhaps planning to try to target for heritable modification in humans with base editing. Since his paper last year on base editing of human embryos targeted HBB, could he be planning to target mutations in that gene since they are associated with Beta-Thalassemia and Sickle Cell Anemia? There’s a lot more we need to know about all of this.

How fast could this actually happen?

One-to-two years is probably way too optimistic. Given that Chen’s article on Yang was posted 7 months ago, one might wonder whether perhaps Yang could try to get a trial approved as early as this year, a possibility more directly suggested by the caption of a photo in Chen’s article, “A breakthrough by Chinese scientists in gene-editing technology has raised the prospect of approved human clinical trials in just one or two years’ time.”

However, realistically, Chinese authorities are highly unlikely to approve any such trials that soon. I’m not an expert in searching the Chinese clinical trial database, but so far I also don’t see any such trials listed for Yang by searching for his name or “CRISPR”, “base editing”, or “gene editing.” Further, another 2019 new article by Chen mentioning Yang a bit and focused on cancer gene editing notes that new oversight rules may slow down trial gene editing approvals.

But then again there’s that sense of international competition which could creature pressure for regulators.

Note that Yang is a co-founder of a biotech working this area called Hui-Gene Therapeutics, which raised millions from investors in December. Commercial interests could also come into play.

Some reflections

In part based on Yang’s own work showing the abundance of off-targets (although he reports that his team has more recently greatly reduced that frequency), I’m not convinced this kind of gene editing will soon or ever be accurate enough for safe heritable use in humans. Just to be 100% clear, I’m not talking about somatic gene therapy uses.

Then, of course, there are other technical issues on the heritable human gene editing front such as mosaicism, perhaps reduced, but not eliminated by some of Yang’s newer methods. Mosaicism in human embryos can never be entirely ruled out since you’d have to use up all the cells in the embryo to be sure of the status, leaving no embryo to move forward with if you have reproductive intent.

Also, what about societal and ethical issues especially given the safe, less controversial alternatives out there like PGD embryo screening? Are we actually done discussing those? Chen’s article isn’t reassuring to me on that front either (emphasis mine):

“Yang said the secret of their success was in the timing of the injections. He also said the team was close to solving ethical issues and other problems relating to the procedure, such as off-targeting and unintended gene modification.”

How do you solve the ethical issues?

Whatever gene(s) he’s planning to target for production of babies, how would that effort be better than PGD or even necessary at all?

To try to clear up these kinds of questions, I politely emailed Yang last week. I just wanted to briefly ask a few questions about his plans and clarify if indeed he’s aiming to make human gene-edited babies soon. I also sent him a link to the Chen news article to see if perhaps there were some mistaken impressions from it. 

Perhaps since the publication of Stephen Chen’s article, Yang’s plans have changed? Mainly now focused on somatic use?

I also reached out to journalist Chen on FB to try to clarify things as I couldn’t find him on Twitter or find his email, but no luck so far.

We’ll see how this and other potential ‘CRISPR baby’ research programs develop, and whether the “need for speed” competition mindset across the globe persists or gets even more intense.

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