In a first, scientists edit DNA of human embryos
Using a powerful gene-editing technique, scientists have rid human embryos of a mutation that causes an inherited form of heart disease often deadly to healthy young athletes and adults in their prime.
The experiment marks the first time that scientists have altered the human genome to ensure a disease-causing mutation would disappear not only from the DNA of the subject on which it is performed but from the genes of his or her progeny as well.
The controversial procedure, known as “germ-line editing,” was conducted at Oregon Health and Science University using human embryos expressly created for the purpose. It was reported Wednesday in the journal Nature.
The new research comes less than six months after the National Academies of Science, Engineering and Medicine recommended that scientists limit their trials of human germ-line editing to diseases that could not be treated with “reasonable alternatives” — at least for now.
In a bid to make the experiment relevant to real-life problems faced by parents who carry genes for inherited diseases, the researchers focused their editing efforts on a mutation that causes inherited hypertrophic cardiomyopathy.
“No matter what anybody says, this is not the dawn of the era of the designer baby.”
Alta Charo, bioethicist at the University of Wisconsin and chairwoman of the National Academies committee looking at gene editing
In this genetic condition, a parent who carries one normal and one faulty copy of a the MYBPC3 gene has a 50-50 chance of passing that mutation on to his or her offspring. If the child inherits the mutation, his or her heart muscle is likely to grow prematurely weak and stiff, causing heart failure and often early death.
In diseases where one parent carries such an “autosomal dominant” mutation, a couple often will seek the assistance of fertility doctors to minimize the risk of passing such a mutation on to a child. A woman’s egg production is medically stimulated, and eggs and sperm meet in a lab — a process called in vitro fertilization. Then embryologists inspect the resulting embryos, cull the ones that have inherited an unwanted mutation, and transfer only unaffected embryos into a woman’s uterus to be carried to term.
In the new research, researchers set out to test whether germ-line gene editing could make the process of choosing healthy embryos more effective and efficient by creating more of them.
In the end, their experiment showed it could. The targeted correction of a disease-causing gene carried by a single parent “can potentially rescue a substantial portion of mutant human embryos, thus increasing the number of embryos available for transfer,” the authors wrote in Nature. Co-author Dr. Paula Amato, an Oregon Health and Science University professor of obstetrics and gynecology, said the technique “could potentially decrease the number of cycles needed for people trying to have children free of genetic disease” if it’s found safe for use in fertility clinics.
Along the way, though, many of the researchers’ findings were scientifically surprising. Long-feared effects of germ-line editing, including collateral damage to “off-target” genetic sequences, scarcely materialized. And “mosaicism,” a phenomenon in which edited DNA appears in some but not all cells, was found to be minimal.
The study’s lead author, biologist Shoukhrat Mitalipov, called these “exciting and surprising moments.” But he cautioned that “there is room to improve” the techniques demonstrated to produce mutation-free embryos. As for conducting human clinical trials of the germ-line correction, he said those would have to wait until results showed a near-perfect level of efficiency and accuracy and could be limited by state and federal regulations.
Eventually, Mitalipov said, such germ-line gene editing might also make it easier for parents who carry other gene mutations that follow a similar pattern of inheritance — including some that cause breast and ovarian cancers, cystic fibrosis and muscular dystrophy — to have healthy children who would not pass those genes to their own offspring.
“There is still a long road ahead,” predicted Mitalipov, who heads the Center for Embryonic Cell and Gene Therapy at the Portland university.
The research drew a mix of praise and concern from experts in genetic medicine.
Dr. Richard O. Hynes, who cochaired the National Academies’ report issued in February, called the new study “very good science” that advances understanding of genetic repair on many fronts.
University of California molecular and cell biologist Jennifer Doudna, one of the pioneers of the CRISPRCas9 technique, acknowledged the new research highlights a prospective use of gene editing for one inherited disease and offers some insights into the process.
But Doudna questioned how broadly the experiment’s promising results would apply to other inherited diseases. She said she does not believe the use of germ-line editing as a means to improve efficiency at infertility clinics meets the criteria laid out by the National Academies of Science, which urged that the techniques be explored as treatment only for diseases with “no reasonable alternative.”
Doudna said she worried that the new findings “will encourage people to proceed down this road” before the scientific and ethical implications of germ-line editing have been fully considered.
“A large group of experts concluded that clinical use should not proceed until and unless there’s broad societal consensus, and that just hasn’t happened,” Doudna said. “This study underscores the urgency of having those debates. Because it’s coming.”
Alta Charo, a bioethicist at the University of Wisconsin who is co-chairwoman of the National Academies committee looking at gene editing, said that concerns about the work are overblown.
“What this represents is a fascinating, important and rather impressive incremental step toward learning how to edit embryos safely and precisely,” she said. However, “no matter what anybody says, this is not the dawn of the era of the designer baby.”
Researchers who worked on the heart-condition experiment appear to have differing views on where their work is headed.
Paula Amato, a reproductive endocrinologist with Oregon Health, was excited about the idea of being able to edit out diseases before birth. She said that while pre-implantation genetic screening of embryos is now available, it isn’t perfect. She talked about how one of her patients went through three cycles of in vitro fertilization but all of the eggs that were harvested had the gene mutation that causes a diseases.
With gene correction technology, Amato said, “we could have rescued some of those embryos.”
But Izpisua Belmonte said he is focusing on using the findings to further research into gene modifications during a pregnancy or after birth into adulthood. “I feel that the practical thing to do is deal with the diseases people have, not with the disease they may have,” he said.
Mitalipov said he hopes regulators will provide more guidance on what should or should not be allowed.
Otherwise, he said, “this technology will be shifted to unregulated areas, which shouldn’t be happening.”