Most of us learned in biology class that our nuclear DNA — 23 pairs of chromosomes shuffled from mom and dad — is responsible for assigning our genetic traits, from our eye color to our inherited disease risks. It is less commonly known that mitochondria, the energy factories in our cells, have their own genetic material (mitochondrial DNA, mtDNA) that is inherited only from mom. When mutations, or errors, occur in mtDNA that are transmitted from mother to child, they can pass on a diverse array of medical disorders associated with defects in energy production, energy balance, and other aspects of metabolism that often involve multiple organ systems.
Inherited mitochondrial diseases vary widely in presentation and severity, but frequently observed health consequences include metabolic strokes and seizures, muscle weakness and fatigue, problems with movement, heart problems, vision and hearing loss, and developmental delays. The most serious forms of mitochondrial disease can be debilitating, progressive, and even fatal at young ages. Estimates suggest that about 30,000 to 60,000 people in America have something wrong with the way their body generates energy, due to a primary mitochondrial problem originating at a genetic level in either the nuclear genes or mtDNA.
Couples who want to conceive a child, but who are at significant risk of their offspring manifesting serious mtDNA disease, may be interested in learning about sophisticated mitochondrial replacement techniques (MRT) that are under development but have not yet been conducted in humans in the U.S. These techniques involve modification of an egg (oocyte) or fertilized egg (zygote) by replacing the intended mother’s mitochondria that contains pathogenic mtDNA with mitochondria containing unaffected mtDNA from a female donor. The resulting child would have the nuclear DNA only of their intended mother and father, but due to the donor mtDNA contribution be genetically related to three individuals. Scientists do not expect MRTs will be 100 percent effective at depleting the abnormal mtDNA, but they anticipate only up to 1 or 2 percent of the original amount would remain, a level below that which is likely to cause disease.
While these novel techniques could one day offer families a new reproductive option, many medical and technical challenges and other safety and efficacy issues remain under question before clinical investigations of MRTs in patients could proceed under supervision of the Food and Drug Administration (FDA). Marni Falk, MD, an attending physician and director of the Mitochondrial-Genetic Disease Clinic at The Children’s Hospital of Philadelphia, participated in an expert committee convened by the Institute of Medicine (IOM), a division of the National Academies of Sciences, Engineering, and Medicine, at the request of the FDA to evaluate the ethical, social, and policy considerations of these techniques.
The IOM (recently renamed the National Academy of Medicine) is an independent, free-standing, objective body that evaluates the leading scientific dilemmas of the day to advance the nation’s health. Since it was established in 1970, some of the most seminal activities in medicine have been decided in IOM reports.
Over the past two years, Dr. Falk worked with the IOM committee, which included a diverse range of 12 experts from physicians, scientists, and ethicists to historians, lawyers, and patient advocates, to help them clarify the clinical and genetic implications of MRTs in the context of their ethical discussions. They came to a consensus and issued a report in February, “Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations,” that recommended that clinical research into MRTs should proceed with careful oversight.
“It was a great experience because of the unique opportunity to get to interact with such thoughtful people having deep expertise in policy and ethics and have them learn and carefully consider the broader implications of quite intricate aspects of science and medicine,” Dr. Falk said. “It was an intense process. To me, the most amazing part was that something about mitochondrial biology and disease had made it to this level of national interest and attention.”
The first mitochondrial DNA disease was recognized in 1988 by mitochondrial medicine pioneer Douglas Wallace, PhD, director of the Center for Mitochondrial and Epigenomic Medicine. It is a young field, and many people in clinical medicine are still learning about the subtleties and implications of mitochondria biology, genetics, and disease.
While mitochondrial dysfunction seems to be connected to many common diseases, Dr. Falk pointed out that the scope of her work on the IOM committee has the most implications for a specific subset of female patients who want to have their own genetic offspring and are at risk of transmitting a severe mitochondrial DNA-based genetic disease that could lead to a child’s early death or substantial impairment. For these prospective parents, the committee recommended that a “slow, cautious approach to MRT is justified” and that it is “ethically permissible to conduct clinical investigations of MRT subject to certain conditions and principles.”
Under this cautious approach, the committee recommended that MRTs initially should be studied only using male embryos, since males do not transmit mitochondrial DNA to their children. They also encouraged the FDA to pay special attention to communicating the novel aspects of this research to MRT research participants. For example, because MRTs require mixing mtDNA from a female donor with DNA from the nucleus of the mother and father, the researchers should investigate unanticipated health problems and possibly questions about identity, before regulatory approval or clinical use can occur for the techniques.
Three members of the committee, including Dr. Falk as the first author, wrote a Perspective article that appeared in the New England Journal of Medicine on MRTs’ implications for clinicians. The article begins, "Mitochondrial DNA (mtDNA) disease may be the poster child for highly targeted, 'personalized' medicine."
"Even though MRTs would not confer health benefits on patients who already have mitochondrial DNA diseases, many patients with a known risk for transmitting such a disease to their offspring are highly motivated to prevent that from occurring," Dr. Falk said. "That motivation is clear when we counsel patients and families affected by mtDNA disease, and recent patient surveys have reinforced that preventing disease transmission is a prevailing concern in this population."
Dr. Falk also is an assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.
For more information, see the CHOP press release.