I’m honored to be here guest-blogging for the week. Thanks, Alex, for the warm welcome.
In April, Chinese scientists announced that they’d used the CRISPR gene editing technique to modify non-viable human embryos. The experiment focused on modifying the gene that causes the quite serious hereditary blood disease Beta-thalassemia.
Marginal Revolution aside, the response to this experiment has been largely negative. Science and Nature, the two most prestigious scientific journals in the world, reportedly rejected the paper on ethical grounds. Francis Collins, director of the NIH, announced that NIH will not fund any CRISPR experiments that involve human embryos.
NIH will not fund any use of gene-editing technologies in human embryos. The concept of altering the human germline in embryos for clinical purposes has been debated over many years from many different perspectives, and has been viewed almost universally as a line that should not be crossed.
This is a mistake, for several reasons.
- The technology isn’t as mature as reported. Most responses to it are over-reactions.
- Parents are likely to use genetic technologies in the best interests of their children.
- Using gene editing to create ‘superhumans’ will be tremendously harder, riskier, and less likely to be embraced by parents than using it to prevent disease.
- A ban on research funding or clinical application will only worsen safety, inequality, and other concerns expressed about the research.
Today I’ll talk about the maturity of the technology. Tomorrow I’ll be back to discuss the other points. (You can read that now in Part 2: Don’t Fear Genetically Engineered Babies.)
CRISPR Babies Aren’t Near
Despite the public reaction (and the very real progress with CRISPR in other domains) we are not near a world of CRISPR gene-edited children.
First, the technique was focused on very early stage embryos made up of just a few cells. Genetically engineering an embryo at that very early stage is the only realistic way to ensure that the genetic changes reach all or most cells in the body. That limits the possible parents to those willing to go through in-vitro fertilization (IVF). It takes an average of roughly 3 IVF cycles, with numerous hormone injections and a painful egg extraction at each cycle, to produce a live birth. In some cases, it takes as many as 6 cycles. Even after 6 cycles, perhaps a third of women going through IVF will not have become pregnant (see table 3, here). IVF itself is a non-trivial deterrent to genetically engineering children.
Second, the Chinese experiment resulted in more dead embryos than successfully gene edited embryos. Of 86 original embryos, only 71 survived the process. 54 of those were tested to see if the gene had successfully inserted. Press reports have mentioned that 28 of those 54 tested embryos showed signs of CRISPR/Cas9 activity.
Yet only 4 embryos showed the intended genetic change. And even those 4 showed the new gene in only some of their cells, becoming ‘mosaics’ of multiple different genomes.
From the paper:
~80% of the embryos remained viable 48 h after injection (Fig. 2A), in agreement with low toxicity of Cas9 injection in mouse embryos […]
ssDNA-mediated editing occurred only in 4 embryos… and the edited embryos were mosaic, similar to findings in other model systems.
So the risk of destroying an embryo (~20%) was substantially higher than the likelihood of successfully inserting a gene into the embryo (~5%) and much higher than the chance of inserting the gene into all of the embryo’s cells (0%).
There were also off-target mutations. Doug Mortlock believes the off-target mutation rate was actually much lower than the scientists believed, but in general CRISPR has a significantly non-zero chance of inducing an unintended genetic change.
CRISPR is a remarkable breakthrough in gene editing, with applications to agriculture, gene therapy, pharmaceutical production, basic science, and more. But in many of those scenarios, error can be tolerated. Cells with off-target mutations can be weeded out to find the few perfectly edited ones. Getting one complete success out of tens, hundreds, or even thousands of modified cells can suffice, when that one cell can then be replicated to create a new cell line or seed line.
In human fertility, where embryos are created in single digit quantities rather than hundreds or thousands – and where we hope at least one of those embryos comes to term as a child – our tolerance for error is dramatically lower. The efficiency, survivability, and precision of CRISPR all need to rise substantially before many parents are likely to consider using it for an unborn embryo, even to prevent disease.
That is, indeed, the conclusion of the Chinese researchers, who wrote, “Our study underscores the challenges facing clinical applications of CRISPR/Cas9.”
More in part two of this post on the ethics of allowing genetic editing of the unborn, and why a ban in this area is counterproductive.