Conception at any cost: Experts question procedure
Cytoplasm injection at the center of controversy
Is the assisted reproduction technique of cytoplasmic transfer safe? Pioneering infertility specialists say yes, but some scientists say it’s too soon to tell and using this technique in humans is questionable. In March, researchers at the Institute for Reproductive Medicine and Science at St. Barnabas Medical Center in West Orange, NJ, revealed that they had used cytoplasmic transfer — the practice of injecting cytoplasm from a donor egg into the egg of a female patient with defective cytoplasm — to produce 18 pregnancies in women previously unable to conceive.
In follow-up testing on two babies born using this technique, it was discovered that the children had mitochondrial DNA "heteroplasmy" — meaning their mitochondrial DNA was a mixture of their mothers’ and the egg donor’s. Researchers acknowledge that the experiment has modified the genetic makeup of these children, but say that the impact is minimal.
"The injected cytoplasm [which includes mitochondrial structures that are the cell’s energy producers] replaces missing and/or abnormally functioning components of the recipient egg," says a statement from St. Barnabas about the procedure. "The genetic blueprints of the mother and father are retained."
A list of frequently asked questions about the procedure, found on the institute’s web site (www.sbivf.com) even states that the procedure should not be considered "gene manipulation."
"The primary purpose of this technique is to correct the problems within the egg without changing the genetic blueprint in the nucleus," the document reads. "The fuel, or cytoplasm, is altered to allow it to further the development of the nucleus. This procedure is not gene therapy or any form of genetic engineering. Cytoplasmic DNA does not determine the individual’s genetic code."1
Mitochondria are the same in one human being as the next, adds James Grifo, MD, professor of obstetrics and gynecology at New York University Medical School in New York City and president-elect of the Society for Reproductive Technology. "The impact [of changing mitochondrial DNA] is nothing measurable at all," he says.
But experts in mitochondrial-related diseases fear otherwise. Scientists are just beginning to determine the true impact that mitochondria have on human development and functioning, says Robert Naviaux, MD, co-director of the Mitochondrial and Metabolic Disease Center at the University of California at San Diego in an interview with the web publication BioMedNet News in May.2
Gene manipulation
It has been known for years that mitochondrial deficiencies have been linked to a variety of illnesses in humans, including mild muscle weakness, epilepsy, autism, cerebral palsy, deafness, diabetes, amyotrophic lateral sclerosis, developmental disabilities, and dementia. Researchers have found that even a small degree of heteroplasmy can lead to one mitochondrial genome completely replacing another in some tissues, as well as in subsequent generations, Naviaux says. "You can have a mom who has only 5% heteroplasmy and seems normal," he notes, "and she may have two or three kids with severe mitochondrial disorders."
Cytoplasmic transfer should not continue to be performed in humans until more animal studies are done, he told the web magazine. And, the children already born should be followed closely over time. Fundamentally, the practice is gene manipulation, he added. "Subtle variations in mitochondrial gene function can alter nuclear gene expression. That’s what we’re seeing in animals when only 10% of the cytoplasm comes from a donor oocyte."
There have been some indications already that the procedure may carry an increased risk of disorders in offspring. An article in the May 18, 2001 Washington Post alleges the St. Barnabas researchers failed to report two instances of Turner’s syndrome among the 18 fetuses conceived using cytoplasmic transfer, an incidence of seven or eight times what experts consider normal, the newspaper reported. Turner’s syndrome is a rare genetic disorder in which one X chromosome is present, but a Y chromosome is mysteriously missing. People with this syndrome are infertile, and often have incomplete reproductive organs.
One of the pregnancies involving an affected fetus ended in a miscarriage and the other fetus was aborted after physicians detected the abnormality during prenatal screening.
In a statement, St. Barnabas officials acknowledged that it is too soon to tell whether the incidence of Turner’s syndrome was related to the medical procedure. "Turner’s syndrome is not a mitochondrial disease, but rather, an anomaly that occurs, along with other congenital defects, after natural as well as assisted reproduction," the statement reads. "The rate of first trimester spontaneous miscarriage following assisted reproduction is between 10%-15%. As much as 70% of such pregnancy losses are associated with chromosomal abnormalities. The most common single abnormality in this group is Turner’s syndrome, with an incidence of between 20%-25%."
The two incidents of Turner’s Syndrome were disclosed at several scientific conferences and had been reported in a previous issue of Human Reproduction,4 the statement added. The abnormalities also were reported to the St. Barnabas institutional review board and explained in the patient consent form given to all patients considering the experimental procedure.
References
1. The Institute for Reproductive Medicine and Science of Saint Barnabas. Cytoplasmic transfer procedure Q&A. www.sbivf.com/cytpqa.htm. Accessed: June 1, 2001.
2. Austin K. New germline-changing IVF procedure could easily have transferred severe disease. BioMedNet News and Comment. May 18, 2001. news.bmn.com.
3. Weiss R. Team failed to disclose genetic disorder in science report. Washington Post 2001; May 18:A3.
4. Barritt JA, Conner CA, Willadsen S, et al. Spontaneous and artificial changes in human ooplasmic mitochondria. Human Reprod 2000; 15:207-217.
Recommended Reading
• Parens E, Juengst E. Inadvertently crossing the germline. Science 2001; 292:397-398.
• Frankel MS, Chapman AR. Genetic Technologies: Facing inheritable genetic modifications. Science 2001; 292:1,303.
Sources
• Erik Parens, The Hastings Center for Bioethics, The Hastings Center, 21 Malcolm Gordon Road, Garrison, NY 105245555.
• Audrey R. Chapman, American Association for the Advancement of Science (AAAS), Science and Human Rights Program, Directorate for Science and Policy Programs, 1200 New York Ave. N.W., Washington, DC 20005. Web: www.aaas.org.
• James Grifo, New York University, School of Medicine, 660 First Ave., New York, NY 10016.
• Institute for Reproductive Medicine, St. Barnabas Medical Center, East Wing, 4th Floor, 94 Old Short Hills Road, Livingston, NJ 07039.
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