For the first time, the revolutionary gene-editing technology called CRISPR-Cas9 was used to repair a disease-causing genetic flaw in viable human embryos and prevent the mutation from being passed to future generations.
Of the many genetic engineering breakthroughs of 2017, it’s difficult to single one out as the most significant. But there’s a strong favorite for the year’s most polarizing achievement. For the first time, the revolutionary gene-editing technology called CRISPR-Cas9 was used to repair a disease-causing genetic flaw in viable human embryos and prevent the mutation from being passed to future generations. The breakthrough, ranked by Science News as the second most important of 2017, is a source of new hope for millions of families with a history of genetic disease. But it also pushes the envelope in the ethical debate over treatments that permanently alter the human genome.
At this early stage, however, the advance is neither a miracle cure nor a harbinger of widespread genetic manipulation. But by apparently demonstrating new techniques that address some of the central safety concerns about embryonic gene editing, the work could eventually influence new policies permitting human clinical trials of the technique in some circumstances and with close regulatory oversight.
Regulatory Grey Area
A year ago, a report by the National Academies of Science, Engineering and Medicine cautiously recommended that gene editing in human embryos should be allowed for research purposes and could, in time, be deemed acceptable for use in embryos intended for implantation when used to treat diseases without other reasonable alternatives. But the regulatory environment for germline gene editing research is still prohibitive. In the United States, no federal dollars can be spent on research that results in the destruction of embryos. The Food & Drug Administration (FDA) is also barred from engaging in clinical trials of embryonic editing. Some public universities involved with this type of work take pains to point out that its research is funded by private donations and carried out in laboratory facilities not built with public dollars.
Fixing the Flaw
Shoukhrat Mitalipov, Ph.D., and director of the Center for Embryonic Cell and Gene Therapy at Oregon Health & Science University in Portland is the man behind this recent breakthrough. As reported in the August 2 issue of Nature, Mitalipov used CRISPR-Cas9 in conjunction with in vitro fertilization (IVF) to target and fix the genetic mutation that causes hypertrophic cardiomyopathy, a cardiovascular ailment found in about one in 500 people. The disease can cause heart muscle to thicken, triggering complications ranging from rhythm disorders to heart failure. It’s particularly known as a common cause of sudden cardiac death in young athletes. The mutation is dominant, meaning it needs to be present in only one parent to be passed to offspring.
“Every generation on would carry this repair because we’ve removed the disease-causing gene variant from that family’s lineage,” Mitalipov says. “By using this technique, it’s possible to reduce the burden of this heritable disease on the family and eventually the human population.”
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CRISPR-Ca9 is a fast, simple and inexpensive way to chemically cut out a targeted genetic sequence on a mutant gene and then add or delete genetic material to achieve a desired result. It has shown promise against a wide range of conditions like cystic fibrosis, muscular dystrophy and sickle cell disease. Most CRISPR research to date has focused on editing mutations in non-reproductive somatic cells, which would not cause genetic changes to be passed to offspring. Mitalipov’s team, however, used reproductive cells – donated human eggs and sperm – to identify a safe way to permanently remove a germline mutation from a family’s lineage. Using donated eggs from 12 women and sperm from a man with hypertrophic cardiomyopathy (he tested positive for the disease-causing MYBPC3 gene) to produce 58 clinically viable embryos – albeit not intended for implantation – Mitalipov’s team has taken CRISPR to a new level.
In the Nature study, the researchers altered the standard CRISPR procedure to avoid two of the key safety hazards in gene editing: “off-target” mutations caused by cutting errors that introduce unwanted changes in the gene, and “mosaicism,” the creation of embryos in which some cells have the repaired gene and others don’t. Their method minimized these risks by injecting the CRISPR-Cas9 materials into each egg at the same time as the sperm cells, rather than the standard practice of waiting several hours after fertilization.
The study showed that the embryos effectively repaired the CRISPR-induced cuts with off-target mutations and mosaicism found in only a handful of embryos. Of 58 embryos, 42 carried two mutation-free copies of the gene in every cell, with no unwanted mutations – a 72% success rate which Mitalipov predicts to reach 90% after fine-tuning to his methods. The researchers were surprised to learn that the embryos repaired themselves not by copying the synthetic DNA sequence introduced as part of the CRISPR experiment but rather by using the healthy copy of the gene from the other parent as a template. Why this happened is one of the key questions to be answered in future work, the scientists say.
The method’s effectiveness is attributed to the injection of CRISPR-Cas9 material from the outset of fertilization. Because the enzymes used to edit genes degrade rapidly, the technique provided less time to create unwanted changes to the cell. And by triggering the intended gene repair process at the same time as fertilization, they ensured that 100% of the embryonic cells produced carried the repaired gene. As an added benefit, the advance also increases the number of healthy embryos produced through IVF, meaning fewer IVF treatment cycles for prospective parents and fewer defective embryos that would ultimately be discarded.
Hypertrophic cardiomyopathy is only of perhaps 10,000 known specific gene disorders that could in principle be permanently removed from a family’s genetic heritage through germline gene editing. One key target, the BRCA mutation, is linked to some of the most common forms of lethal forms of breast and ovarian cancers. Techniques like Mitalipov’s could be developed for these and other more widespread diseases. If, that is, policymakers allow them to be developed and tested in human clinical trials. Dan Dorsa, OHSU’s senior vice president of research, is taking the long view.
“The ethical considerations of moving this technology to clinical trials are complex and deserve significant public engagement before we can answer the broader question of whether it’s in humanity’s interest to alter human genes for future generations,” he says.
Michael MacRae is a technical writer based in Portland, OR.