genome editing CRISPR Crystal structure of the Cas9 gene-editing enzyme (light blue) in complex with an RNA guide (red) and its target DNA (yellow). Credit: Bang Wong, Broad Institute of Harvard and MIT, via NIH Director’s Blog.
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CRISPR Genome Editing is Here to Stay, Regardless of Pending Regulations

Not long ago, only two groups of people were using the phrase “genome editing”: science fiction writers, and a small group of scientists collectively banging their heads against their benchtops, hoping that they would one day be able to tweak and tune genomes just as easily as science fiction writers could edit their stories. For those scientists, the name of the game was programmable DNA binding. We’d known for a long time that cutting a strand of DNA could cause it to mutate, so it followed that the ability to make cuts at specific DNA sequences would allow us to make specific mutations. And while cutting DNA had been routine for decades – enzymes that do so sparked the molecular biology revolution of the 1970’s – doing it at specific and user-dictated sequences within the genome was not. The value of the technique was clear – the prospects of being able to genetically re-design crops and livestock, to conduct extremely precise studies on genes of interest, or even to engineer human cells to cure disease were all strong motivators. But the execution wasn’t there to match. However, in just the last three years, an extraordinary and elegant breakthrough has simplified genome editing and made it a nearly ubiquitous technique across all biotechnological research.

This expansion was sparked by a realization in 2012 that an enzyme called CRISPR-associated protein 9 (or Cas9) could be programmed to both bind and cut (and therefore mutate) specific DNA sequences. Conceptually, this was no different from earlier generation genome-editing platforms, namely zinc-finger nucleases (ZFNs) and transcription-activator-like-effector nucleases (TALENs), except for a small but critical detail. The DNA binding interfaces of ZFNs and TALENs are made up of protein sub-domains, so re-targeting them to a new site always required a protein engineering step that could be both complicated and resource intensive. Doing so was so costly, in fact, that only a handful of labs in the world were willing to do it. Cas9, on the other hand, uses a small RNA molecule to find its genomic targets, and unlike proteins, RNA-DNA binding interfaces are extremely simple to design. As a result, anyone equipped with standard laboratory equipment and a basic understanding of molecular biology can now do genome editing using Cas9.

Applications of CRISPR Genome Editing. Adapted from “Development and Applications of CRISPR-Cas9 for Genome Engineering“, Cell, 2014.

Applications of CRISPR Genome Editing. Adapted from “Development and Applications of CRISPR-Cas9 for Genome Engineering“, Cell, 2014.

For the most part, this “democratization” of genome editing has been nothing short of a revolution in biology and biotechnology. It means that scientists can now conduct large-scale genetic experiments in weeks when it would have taken them months or even years in the not-too-distant past. And it also means that clinical and translational researchers now have access to powerful genome editing techniques without necessarily needing an expertise in protein engineering. This has spurred a growing number of studies to develop clever therapeutic applications for Cas9, such as a case in which scientists re-engineered the inner ear cells of genetically deaf mice to potentially restore their sense of hearing.

But because Cas9 is so remarkably easy to use and technologically powerful, there have been the inevitable instances where its use has produced legitimate cause for concern. In one case, a research group showed that Cas9 could be used to create a hyper-functional “gene-drive,” or a self-perpetuating genetic device that can transmit itself throughout a population at rates that defy standard Mendelian inheritance. While such an approach may prove useful for controlling the populations of invasive species or disease vectors, it also gives the ability to irreversibly alter natural genetic diversity to anyone who can obtain just a few simple reagents. And in a much closer-to-home and more widely reported instance, a Chinese laboratory used Cas9 to produce the first genome-edited human embryos. While the embryos in question were never viable and the experiment was conducted under the auspices of correcting an inborn genetic disorder, this study brought to the fore an obvious but dauntingly uncomfortable question:

Are designer babies just around the corner?

The answer is probably not. Accompanying the embryo editing paper was a slew of opinion pieces calling into question the ethics of engineering humans and urging caution before heading down that path. The authors of these articles were some of the top scientists and respected bioethicists in the field, and even Edward Lanphier, CEO of one of the first and most respected genome-editing companies, Sangamo Biosciences, co-authored an editorial in Nature entitled “Don’t Edit the Human Germline.” Their main concerns are the obvious ethical issues surrounding the idea of altering the genomes of future people who can in no way consent to the procedure, but there are also lingering safety issues to be addressed. Cas9 isn’t perfect – it can and does cause mutations at sites other than its intended target (a topic I will expand upon in future posts). Even if we thought genome editing with Cas9 was perfectly safe in human embryos, there would be no way to actually test that hypothesis without developing engineered embryos into fully realized humans, which is an unambiguous ethical dead-end. In the aftermath, the US Congress has responded by considering legislation to regulate embryo editing and the NIH has vowed not to fund research into the area.

To some, this possible regulation might seem like enough to dampen excitement over Cas9 and genome editing. For instance, an article at Bloomberg – one that non-ironically uses the word “frankenbabies” – suggests that such regulations might hinder the development of Cas9 technologies (and therefore diminish its future value). But that line of thinking belies just how expansively disruptive genome editing with Cas9 is. The proposed regulations have nothing to do with the vast majority of therapeutically or commercially valuable applications for which Cas9 is being considered. Strategies such as the inner-ear approach mentioned above rely on modifying a very small subset of adult tissues made up of differentiated somatic cells that no longer have the capacity to develop into a person. For these, there’s no need to risk editing at the delicate (and potentially illegal) embryo stage to accomplish the therapeutic goals. Instead, the modifications are made directly to the cells that are impacted by the disease. Add that to the dozens of other similar therapeutic strategies, the potential applications in industrial bioengineering, and the ability to engineer livestock and crops, and it’s clear that Cas9 is, in all likelihood, soon going to be affecting a great number of things in everyday life, regardless of the legality of some of its more dubious uses.

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.

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James Angstman

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

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