By Melissa Healy Los Angeles Times (TNS)
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 its 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 & 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 dilemmas faced by parents who carry genes for inherited diseases, the researchers focused their editing efforts on a mutation that causes inherited hypertrophic cardiomyopathy.
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 will often seek the assistance of fertility doctors to minimize the risk of passing such a mutation on to a child. A womans 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 womans 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 & Science University (OHSU) 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 its 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 studys lead author, OHSU 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 co-chaired the National Academies report issued in February, called the new study very good science that advances understanding of genetic repair on many fronts. Hynes, who was not involved with the latest research effort, said he was pleasantly surprised by researchers clever modifications and their outcomes.
Its likely to become feasible, technically not tomorrow, not next year, but in some foreseeable time. Less than a decade, Id say, said Haynes, a biologist and cancer researcher at MIT and the Howard Hughes Medical Institute.
University of California, Berkeley molecular and cell biologist Jennifer Doudna, one of pioneers of the CRISPR-Cas9 gene-editing 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 experiments 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 only be explored as treatment for diseases with no reasonable alternative.
Already, 50 percent of embryos would be normal, said Doudna. Why not just implant those?
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 theres broad societal consensus, and that just hasnt happened, Doudna said. This study underscores the urgency of having those debates. Because its coming.
What is clear is that the researchers a multinational team of geneticists, cardiologists, fertility experts and embryologists from OHSU and from labs in South Korea and China tried a number of innovations in an effort to improve the safety, efficiency and fidelity of gene editing. And most yielded promising results.
After retrieving eggs from 12 healthy female volunteers, researchers simultaneously performed two steps that had never been combined in a lab: At the same moment that they fertilized the eggs with the sperm of a man who carried a single copy of the mutated gene, they introduced the CRISPR-Cas9 repair machinery.
The resulting embryos took up the genetic-editing program so efficiently and uniformly that, after five days of incubation, 72.4 percent of the embryos (42 of 58) created and tested were free of the MYBPC3 mutation. By comparison, when sperm carrying the single mutation was used to fertilize eggs without any genetic manipulation, just 47.4 percent of embryos were free of the mutation linked to the deadly heart condition.
The researchers believe the timing and the techniques they used prompted the embryos to rely on the healthy maternal copy of the gene as a model for fixing the MYBPC3 mutation, and not a repair template they introduced alongside the editing machinery when the eggs were fertilized. Only one of the 42 embryos used the introduced template for repair. The scientists contrasted this process to the DNA-repair mechanism operating in stem cells, which do use repair templates.
As the embryos cells divided and they matured to the blastocyst stage the point at which they would usually be ready for transfer to a womans uterus they did so normally. After extensive testing, the embryos were used to make embryonic stem-cell lines, which are stored in liquid nitrogen and can be used in future research.
Researchers also noted that genetic mosaicism a concern raised by earlier experimental efforts at gene editing was virtually absent from the 42 embryos that were free of the disease-causing mutation. Only one of the 42 embryos exhibited mosaicism, a condition in which cells did not all carry the same mutation-free genetic code.
MITs Hynes said such findings offer important insights into how human embryos grow, develop and respond to anomalies, and will help families facing infertility and inherited illnesses.
Human embryogenesis is clearly different from that of a mouse, which we know a lot about, said Hynes. That needs to be studied in human embryos, and theres no other way to do it.
The results of the current study are not low enough yet for most applications certainly not for clinical applications, but its a big step forward, he added.
While calling the new research very nice science, Hynes downplayed fears that germ-line editing would soon lead to tinkering with such attributes as looks, personality traits and intelligence in human children. Were not looking at designed babies around the corner not for a long time, he said.
But we need to take advantage of the time and space we now have, he said, to make decisions about which uses of the technique are legitimate and which are not.
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