Have infertility specialists pushed the genetic envelope too far this time?
Have infertility specialists pushed the genetic envelope too far this time?
No oversight for controversial technique
Following disclosure by a group of New Jersey infertility doctors that an assisted reproduction technique they pioneered led to the birth of babies with altered mitochondrial DNA, ethicists are calling for increased federal oversight of privately funded medical research that may result in inheritable germline modification (IGM).
Whether federal oversight is achieved or not, ethics committees will no doubt have to revisit policies regarding assisted reproductive technology.
"The United States, as far as I know, is the only developed country where there is no oversight over private-sector work with human subjects," says Audrey R. Chapman, PhD, director of the Program on Science and Human Rights and the Dialogue for Science, Ethics and Religion at the American Association for the Advancement of Science (AAAS) in Washington, DC. "In the area of genetic technologies, the distinction we currently have — where federal regulation only comes if there are federal funds involved — is anachronistic and completely inadequate. This work is going to have significant repercussions for this and future generations."
In the March 2001 issue of the journal Human Reproduction,1 researchers at the Institute for Repro-ductive Medicine and Science of St. Barnabas at St. Barnabas Medical Center in West Orange, NJ, acknowledged that a technique known has ooplasmic transfer led to the birth of approximately 30 children worldwide, with 18 babies conceived at the institute itself.
The technique, also known as cytoplasm transfer, involves the injection of a small amount of cytoplasm from a donor egg into a female patient’s egg. (Cytoplasm is the jellylike fluid surrounding the nucleus of a cell. It is called ooplasm if taken from an oocyte, the female human reproductive cell.) The procedure is used in women whose own eggs, due to mitochondrial abnormalities or unknown reasons, do not produce embryos that develop properly.
"Cytoplasmic transplantation has caused apprehension, since the mixing of human ooplasm from two different maternal sources may generate mitochondrial heteroplasmy [both recipient and donor mtDNA] in offspring," the authors wrote.
A follow-up study of blood samples from two 1-year-old children conceived using this procedure revealed that both children did indeed have mitochondrial DNA from both their mother and the cytoplasm donor in their cells. "This report is the first case of human germline genetic modification resulting in normal, healthy children," the authors concluded.
Going where no one else has gone
The report is also the first known case of scientists modifying the "germline" or group of human genes inherited from one generation to the next in human beings, say ethicists concerned about the development.
Several countries ban experiments or procedures that would result in altering the human germline in such a way that the alterations could be passed on to future generations — IGM. In the United States, the National Institutes of Health’s Recombinant DNA Advisory Committee (RAC), the body that oversees federally funded research into genetic technologies, states that it would not "entertain any proposals" that involve altering the germline because of the unknown risks to future generations and the ethical issues involved, says Chapman.
In addition, a special working group convened by the AAAS and made up of scientists, ethicists, and religious scholars from across the country recently completed two years of work examining the issue of inheritable genetic modifications and concluded that such experimentation, at this point, would be unethical.
"We concluded that you could not undertake generational genetic modification safely and responsibly because the techniques that we are currently using, and the vectors that we have, don’t meet the standard of assuring that the corrective genes are going to be delivered to the intended location within the cells, you can’t assure proper gene expression over time, and, if you were to do this and leave the mutation in place, you would have no idea what would happen in subsequent generations," Chapman explains.
Drifting across the germline
However, the AAAS working group and the RAC almost exclusively focused on the issue of IGM related to modification of nuclear DNA (which contains the genes that control almost all human characteristics, such as stature, eye color, hair color, and propensity to disease) and did not really consider modifications of mitochondrial DNA, admits Erik Parens, PhD, associate for philosophical studies at The Hastings Center for Bioethics in Garrison, NY.
"This is sort of backing across’ or drifting across the germline," he explains. "We always assumed that when this line was crossed people were going to be adding genes to the nuclear DNA — manipulating mitochondrial DNA was not a possibility that was even considered. It is a new technology." There is no small amount of scientific debate about the role of mitochondrial DNA in our genetic makeup, he adds.
Mitochondria are small, rodlike structures found in the cytoplasm outside the nucleus of a cell, which serve as "energy factories" for the cell. Because mitochondrial DNA is not known to affect the phenotype or physical characteristics of an organism, altering it would not have the same consequences as alterations of nuclear DNA, proponents of the transfer technique have argued. (See "Conception at any cost: Experts question procedure," in this issue.)
"The fact is, we really don’t understand what the phenotypic effects of mitochondria are," he says. "We know they are involved in energy production, surely this is important for all sorts of basic physiologic functions, presumably how well a muscle is going to perform, for example."
A variety of illnesses and syndromes in humans have been linked to mitochondrial abnormalities, including schizophrenia, cerebral palsy, autism, nerve deafness, and developmental delays. "The relationship between mitochondrial DNA and nuclear DNA is quite complicated and not well-understood," he says, adding that it is much more disturbing that these reproductive techniques were pursued, resulting in genetic modifications in humans, even if the modifications were inadvertent.
"They stated that the purpose was to transfer cytoplasm as opposed to transferring mitochondria, but we all know that with cytoplasm goes mitochondria," he says. "They might not have set out to insert mitochondrial DNA into the egg, but that is what happened."
Whether mitochondrial or nuclear DNA was affected this time, or whether the result was intended, are beside the point in terms of the need for a new approach to allowing this sort of practice to continue, says Chapman. "They intentionally injected these fertilized eggs with cytoplasm; it was not accidental," she says. "They did it in a completely experimental environment, and I think it shows that people who come to fertility clinics are often desperate enough that even if they provide informed consent, they do so under great duress."
There needs to be widespread public discussion of the risks vs. the benefits of genetic technology and genetic engineering before such experimentation becomes commonplace, she says. "This industry is not regulated and I predict that we will see someone try enhancement techniques [altering the nuclear DNA] to get favorable physical characteristics, such as height, eye color, etc., in the not-so-distant future," she says.
Industry decries reckless image
The researchers at St. Barnabas refused to grant interviews about the procedure, but released a statement saying the procedure had been performed since 1996, was safe, and that all participants were informed of the potential risks. "All research into cytoplasmic transfer complies with stringent medical guidelines and the rigorous restrictions set forth by the St. Barnabas internal review board (IRB), a committee comprised of physicians, religious representatives, patients, ethicists, and others to oversee all medical procedures," the statement adds.
Reproductive specialists are not scientific "loose cannons" attempting to improve birth rates at every turn, regardless of the consequences, adds James Grifo, MD, a professor of obstetrics and gynecology specializing in reproductive medicine at New York University Medical Center in New York City.
"We are the most heavily regulated specialty in the country," he notes. They answer not only to their respective IRBs, but to state medical boards, as well as SART — the Society for Assisted Reproductive Technology, a subgroup of the American Society of Reproductive Medicine. "We have come together voluntarily for the last several years to develop standards of practice, ethical guidelines, and policies to improve the specialty and improve the practice of the specialty," he says.
Specialists in assisted reproduction are focused on helping their patients in the safest and best way possible, not on breaking scientific taboos or gaining money or notoriety, he emphasizes. "The effect of this increased coverage and increased focus on what we do, by people who are not scientists and not researchers and not involved in patient care, most will have the effect of preventing us from helping patients."
Despite the good intentions of the specialty, a wider public examination of the possible consequences of inheritable genetic modification and other genetic technologies is essential, argue Chapman and Parens. In addition to safety concerns, modifying the human germline raises significant ethical concerns, Chapman says. "Human germline modification might change attitudes in society toward the human person, toward the nature of human reproduction, and parent-child relationships. In addition, it could exacerbate prejudices against persons with disabilities."
In a society without universal access to health care, this technology could raise significant justice issues that need to be examined on a societal basis, not just among medical professionals or the scientific community, she adds.
"Insofar as the new germline techniques can raise the same ethical issues as the old germline techniques, then the new techniques ought to be thought about in the same ethical context and evaluated in the same fashion," adds Parens. He and others have argued that federal legislation should increase RAC’s oversight to include privately funded gene research or a separate body be formed to do so.
"We have been happy for the most part to leave reproductive technologies to the private sector with professional regulation," he adds. "On the other hand, we have this really robust public conversation about genetics. For a long time, it’s worked pretty well. But, at the moment, we are seeing these two technologies converging — it no longer makes sense to think about reproductive technology vs. genetic technology. We should really be speaking about reproductive genetic technologies. This example really illustrates why we need to rethink how we are going to regulate this."
Reference
1. Baritt JA, Brenner CA, Malter HE, et al. Mitochondria in human offspring derived from ooplasmic transplantation: Brief communication. Human Reprod 2001; 16:513-516.
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