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Embryonic Editing Therapies Still Seem Unlikely Despite CRISPR Progress

After it was revealed in a pre-publication scoop three weeks ago by the MIT Technology Review, the news media has extensively covered a story about an Oregon research team’s use of the CRISPR gene editing technique to correct a disease-causing mutation in human embryos. As one might expect, much of the coverage has revolved around the central ethical questions raised by such work. Does this open the door to the development of designer babies? And would that be such a bad thing? The fact that this was the first time human embryo editing has been done by an American team is also noteworthy, especially given the calls to ban or heavily regulate embryo editing by prominent American scientists and the National Institutes of Health.

But aside from all of the ethical and political implications, if the results are real, this a genuinely interesting scientific development. Though we already knew that embryos could be manipulated by CRISPR, this was only the second time it’s been done in viable human embryos, as previous reports have used genetically defective ones that would have never developed properly. The researchers also found a way to perfectly time the genome editing events so that they occurred right around the moment of conception, severely limiting the capacity of the resulting embryo to become a “mosaic” that contains a mixture of both healthy and diseased cells. But the biggest development was that the CRISPR editing appeared to preferentially induce precise, more therapeutically valuable gene correction events (as in, the conversion of a disease gene to a healthy one) instead of the imprecise gene knockout events that scientists have come to expect. For some, this undoubtedly marks the next step toward the inevitable adoption of embryo editing as a real-world procedure that will be used to prevent diseases before they happen.

I disagree.

Thanks to the prevalence of in vitro fertilization technology, couples who know they’re at risk for passing on defective genes to their children can use a process called pre-implantation genetic diagnosis (or PGD) to screen out embryos that contain harmful gene variants. And though this is somewhat routine (about 15,000 children were born using PGD between the years 1990 and 2006), it isn’t necessarily a pleasant procedure. The authors of the recent embryo study contend that CRISPR could make PGD more efficient by converting some embryos’ disease genes into healthy ones, giving PGD practitioners a larger pool of embryos to implant and therefore greater odds for success. By their own numbers, they’re able to boost the frequency of “healthy” embryos to about 73% – 23% higher than would be expected by Mendelian genetics.

The problem with this is that any embryo-editing gene therapy would require extensive – and expensive – clinical trials before being approved by regulatory agencies. CRISPR is great at genome editing, but it isn’t perfect and can cause unwanted mutations at other sites throughout the genome. Though scientists are working to improve specificity, and the delivery techniques used in the recent report minimize the genomic exposure to mutations, there’s a real risk that the people who would develop from CRISPR-edited embryos would carry new, unintended mutations that may end up doing more harm than good. Risky clinical experiments can sometimes be performed on consenting patients who have no other clinical options, but in this case the person being experimented on could in no way consent to the procedure, and since the person wouldn’t even exist beforehand, there wouldn’t be any harmful disease being treated to offset the risks. So aside from asking unborn, unconsenting people to fully bear the risks, the only real option for CRISPR embryo editing “trials” would be to exhaustively test the technique in non-human primates, a notoriously expensive model, before you could even think about moving into human trials, if they’re even allowed to happen. And since every CRISPR target site can behave differently, it’s possible that each gene target could be treated as its own drug that would require its own clinical trial.

All that uncertainty, and all that expense – that’s why I don’t think this is going to happen. Expensive clinical trials happen all the time, but only when a pharmaceutical company is willing to bet that the treatment will be deemed safe and will recoup the costs of the investment and then some. The current cost of PGD is about $5,000 dollars, so even if PGD demand increases in the near future to around 20,000 cases in the next decade, it would take the entire potential patient population to agree to pay double for the CRISPR treatment to yield about $100M in revenue over 10 years. For a product that could easily cost that much to develop, run clinical trials on, and then implement, that doesn’t really seem feasible.

And keep in mind, that’s a for a potentially dangerous procedure whose purpose is to modestly boost the number of embryos produced in one cycle of in vitro fertilization (by 23%, in the reported case). I personally can’t imagine that most people would elect to pay extra for a slightly more efficient but more dangerous flavor of PGD. And while it’s true that there are some cases where edit-free PGD simply wouldn’t be an option, like those in which two people who are both homozygous for a deleterious gene-variant decide to have children, those cases must be extremely rare. Even for a fairly common genetic disease like cystic fibrosis, the chances that a Caucasian couple (the ethnic group with the highest cystic fibrosis prevalence) are both homozygotic for the disease allele are about 2 in 10,000,000, which means there are roughly 15 such couples in the USA. And for those cases, there are already other promising, non-embryonic gene therapy clinical trials that may further reduce the need to stop diseases at the embryonic stage.

To be clear, I’m not saying that CRISPR therapies in general won’t be viable. There are plenty of ways to implement genome editing that don’t involve messing with embryos that I am certain will eventually become commonplace. But unless a benevolent government or a philanthropic billionaire decides that embryo editing is both ethical and worth pursuing, while realizing that the money they invest is probably never coming back, I can’t see CRISPR embryo editing becoming a therapeutic reality anytime soon.

Note from the author: While I hold the views of my colleagues in high regard, the opinions expressed in this blog are mine alone and not necessarily representative of those held by my laboratory or departmental affiliations.

Learn more about CRISPR and genome engineering tools at SynBioBeta SF 2017, October 3rd – 5th, San Francisco, CA


James Angstman

Graduate Student at Joung Lab, Massachusetts General Hospital and Harvard Medical School

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