Welcome to the Age of Genomes, where just around the corner is the ability to cure genetic diseases using the powerful gene-editing tool called CRISPR. Described as a microscopic pair of scissors, CRISPR has been gaining traction in the news thanks to recent successful studies. Just as recently as last month, the first proposed testing of CRISPR on humans passed initial safety review. Cancers, neurological disorders, and other hereditary maladies could become a thing of the past sooner than we think. But how exactly does CRISPR work? In this passage from their book The Age of Genomes: Tales from the Front Lines of Genetic Medicine, geneticist Steven Lipkin, MD, PhD and science journalist Jon Luoma explain the ins and outs of what promises to be one of the most transformative advances in health and medicine in history.
In the next decade, we are likely to see a new generation of pre-implantation genetic diagnosis, which could lead to the possibility of actually repairing genes in ART [advanced reproductive technologies] embryos affected by genetic disorders. Recent powerful basic science advances using a technique called CRISPR (pronounced “crisper,” and the acronym for the tongue twister “clustered regularly interspaced short palindromic repeats”) have offered robust evidence that it’s possible to repair gene defects in embryos of several mammalian model organisms, including nonhuman primates. This is an inexpensive, remarkably effective gene-editing technique easy enough to be performed in literally thousands of laboratories around the world. The technique enables editing of DNA sequence changes that can be curative for both recessive and dominant genetic diseases. It can also be used in patient-derived embryonic stem cells, which can then be expanded in the lab to help ameliorate genetic diseases for such hard-to-treat areas as brain and heart tissue in patients living now, as well as to alter an individual patient’s sperm and egg to reduce the burden of genetic disease in future generations.
CRISPR is a bacterial immune system gene that protects a bacterium against invading viruses. Also called Cas9, it was originally discovered in 1987. Because its purpose was not well understood, Cas9 was initially thought to be unimportant bacterial DNA without any function. Now we know that these genes can be deployed in a way that makes it possible to actually “edit” genes in humans and other species. CRISPR can cut both strands of DNA and can be co-injected into fertilized embryos with a guide RNA that can be modified to alter most of the changes possible in the genome. It has been used to cure mice with genetic diseases involving the liver. Chinese scientists have created monkeys with artificial mutations by using CRISPR to modify otherwise normal embryos, including mutations in three different genes involving the immune system and diabetes. Once the monkeys were born, the CRISPR-introduced changes were present in most, although usually not all of the monkeys’ cells, because the CRISPR protein typically doesn’t actually perform its surgery until after the one-cell embryo has divided more than once. Genome sequencing of the monkeys after their birth did not yet reveal any “off-target” unintended mutations.
Subsequently, Chinese geneticists in Guangzhou published the first study of CRISPR gene editing on human embryos to correct beta-globin mutations that cause the disease beta-thalassemia. In this case, however, they worked only with embryos that would never have been able to be brought to term and born after pregnancy in a surrogate mother and would otherwise have been destroyed. Regardless, their work showed that the present CRISPR technology did not work as well in human embryos as expected. For many embryos, CRISPR did not correct the beta-globin mutation. More concerning, by using whole-genome sequencing, they discovered “off-target” new mutations introduced at other sites, including the delta-hemoglobin gene, which has DNA sequences similar to those of beta-hemoglobin. All in all, the effects of these off-target mutations if the embryos had been brought to term are difficult to predict.
Because of the technique’s potential for powerful gene editing, many scientists, including its inventors, have pleaded for a global moratorium on its use until physicians, scientists, governments, and the public understand more fully any accompanying risks.
While clearly a great deal more work needs to be done, this technology is quite well developed already. I anticipate that (likely initially from outside the United States) in the next decade we will hear about gene-edited children born with mutations successfully corrected by CRISPR. As discussed above, as with ART and PGD, longer-term safety issues and effects of the CRISPR gene-editing process will hang over us, likely for decades.
About the Authors
Steven Monroe Lipkin, MD, PhD, FACMG, has been a practicing clinical geneticist for almost twenty years. He directs the Adult and Cancer Genetics Clinic and is the vice chair for Translational Research at the Sanford I. and Joan Weill Department of Medicine at Weill Cornell in New York City.
Jon R. Luoma’s writing about science and the environment has appeared in National Geographic, GQ, the New York Times Sunday Magazine, and Audubon, where he was a longtime contributing editor. He is the author of three previous nonfiction books: The Hidden Forest, A Crowded Ark, and Troubled Skies, Troubled Waters.