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Monkeys, Mitochondria, and the Human Germline

by Jesse ReynoldsBioethics Forum
September 18th, 2009

Researchers at the Oregon National Primate Research Center recently announced the birth of four monkeys after a procedure that involved swapping the genetic material of one egg into another. An article in Nature and a conference call briefing with reporters resulted in dozens of news stories in outlets around the world. But few accurately captured the significance of the study or the way the researchers are promoting it.

Scientifically and ethically, the development breaks new ground and revisits well-worn terrain. The researchers insist they will move rapidly to test the method on humans - "maybe within two to three years" - even though that will still be too early for the monkeys to reproduce and thus reveal any inheritable adverse effects.

If the scientists follow through, they would raise serious questions about risks to the children born after such procedures, the difficulties and dangers of obtaining the large numbers of women's eggs that would be required, and the potentially dire social consequences of human genetic modification. The researchers' casual attitude toward these concerns is particularly alarming.

Understanding why scientists would swap genetic material between two eggs may require a brief biology lesson. While most of our genes are found on the well known 46 chromosomes in a cell's nucleus, a very small portion resides outside the nucleus in parts of cells called mitochondria. Mitochondria perform the critical but invisible task of energy production, but their DNA - which is passed solely from mother to child - is often overlooked. However, mutations in mitochondrial DNA accumulate rapidly and are distributed unequally among a woman's eggs, contributing to infertility and a range of diseases.

Using rhesus macaque monkeys, the research team led by Shoukhrat Mitalipov took the nuclear genetic material from one egg and placed it into an egg whose nuclear genetic material had been removed. After the egg was fertilized and implanted into a female monkey, four seemingly healthy babies were born. There was no trace of mitochondrial DNA from the egg that provided the nuclear genome. Thus, if the mother (that is, the monkey whose egg provided the nuclear DNA) had defective mitochondrial DNA, these offspring would likely not.

The researchers propose this procedure as a way to prevent the birth of children with mitochondrial disease. Various rare conditions that are caused entirely by defective mitochondrial DNA, some of them deadly, together affect about one in 5,000 people.

Recently, scientists have found evidence that a number of more common ailments may also be caused in part by mitochondrial mutations. Though the associations and the mechanisms at play are only tentatively understood - and likely involve complex interactions among nuclear DNA, mitochondrial DNA, and the environment - the very first paragraph of Mitalipov's Nature paper mentions that mitochondrial DNA mutations "are increasingly implicated in a range of prevalent public health conditions, including Alzheimer's Parkinson's and Huntington's diseases."

It's unusual, and many would say irresponsible, for a research paper to include such a blatantly promotional statement. Not surprisingly, some reporters and editors took the claim at face value; producing headlines such as "Genetically Modifying Human Eggs Could Wipe out Inherited Disease" and "Parkinson's disease 'could be eradicated' by new development."

The researchers' insistence that their novel technique be moved so hastily to human trials also raises eyebrows, especially considering alternative avenues to prevent the births of children with the conditions in question. Genetic screening and selection of embryos or eggs are already used to prevent the transmission of other genetic conditions. The application of such "preimplantation genetic diagnosis" to deleterious mitochondrial mutations is under development and holds significant potential.

Even limited clinical trials of the mitochondrial gene swapping procedure would pose serious ethical concerns. First and most obvious are the risks of deliberately creating children with a mismatch between their nuclear and mitochondrial DNA without knowing the consequences. These two sets of genes do not operate in isolation, but instead have significant interactions and have likely coevolved.

The monkeys are still infants; no one can yet know whether they will remain healthy, or whether their offspring will be healthy. Even if additional animal experiments are reassuring, differences between humans and other primates will make the first clinical trials risky.

Second, even preclinical research on this procedure would require large numbers of women's eggs. But egg extraction is invasive, and puts women at risk of both short-term and long-term health problems whose frequency and severity are unknown. When scientists wanted eggs for cloning-based research, some proposed to offer cash as an inducement. But this practice has been generally rejected at the state, national, and international levels as exploitative, as it induces young women who need money to expose themselves to risks about which they can't be properly informed.

Finally, the mitochondrial gene transfer technique is a form of inheritable genetic modification. It's not "designer-baby technology" because it involves swapping only a few genes rather than changing DNA sequences. Moreover, mitochondrial genes are generally understood to have little effect on appearance or other traits. But the procedure would affect the genome of every cell of a future person, and Mitalipov has made it clear that he considers it an inheritable intervention.

Thus, Mitalipov's research can and should be thought of as a significant step toward altering the human germline. This has long been considered the most controversial and objectionable of reproductive and genetic technologies.

In addition to the potential for compromising the health of future generations, it could all too easily exacerbate social inequities and divisions by encouraging those with access and resources to reproduce children with socially desirable genetically influenced traits - height, beauty, intelligence, etc. - while leaving everyone else to the uncertainly of the genetic roulette. Especially in a competitive market-based society like ours, inheritable genetic modification could lead to a world in which a genetically enhanced elite - termed the "GenRich" by a Lee Silver, a Princeton biologist who promotes such a prospect - rule over the majority population of "Naturals."

To be sure, Mitalipov and most genetic researchers intend their work to address diseases, not to produce genetically redesigned superbabies. But as bioethicist Art Caplan of the University of Pennsylvania told Bloomberg News, this is "the classic example of the road to hell is paved with good intentions." Although mitochondrial DNA does not control fundamental traits, it could, in fact, be modified for enhancement purposes.

Harvard University mitochondria expert Vamsi Mootha points out that because mitochondria are key to energy production, altering them could improve athletic performance. "Good mitochondrial DNA could facilitate athleticism, and reduce risk for obesity or diabetes," he said. "It's a theoretical possibility that some people might want to use or misuse this technology for that purpose. This is a slippery slope."

Some use the phrase "slippery slope" to dismiss concerns that a procedure such as mitochondrial gene transfer (which may or may not be medically justifiable) could open the door to practices that are fundamentally wrong, such as inheritable genetic enhancements. But both in terms of technical possibility and social acceptance, the slope is real, and slathered with grease. If we are going to stand on its precipice, or perhaps even intentionally slide down it just a bit, then we must ensure that the requisite barriers and brakes are in place to prevent a wholesale fall.

Unfortunately, the United States has no regulation of the fertility industry, much less laws to prevent human inheritable genetic modification. In contrast, every country that does have a binding policy on inheritable genetic modification - a group that includes 26 of the 30 industrialized nations of the Organization for Economic Cooperation and Development - has prohibited the practice. A national discussion of this issue and the adoption of clear and enforceable public policy are long overdue.

Treating disease and preventing avoidable suffering are clearly worthy endeavors. But reckless experiments with the health of future children are unacceptable, especially when there are safer medical interventions and when societal as well as individual well-being is at stake.

A majority of Americans, including many scientists, and dozens of nations around the world have deemed the human germline off limits. No researcher should be permitted to push us across a line that could have momentous social consequences.

Jesse Reynolds is the director for the project on Biotechnology in the Public Interest at the Center for Genetics and Society and a writer for Biopolitical Times, the Center's blog.


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