By: Bharat Kirthivasan

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The UK government might soon become the platform for an explosive debate on the utility and ethics of three-person in vitro fertilization (three-person IVF). According to the Human Fertilization & Embryology Authority, there is no evidence to suggest that any form of IVF is unsafe for the mother or the fetus. A public vote on whether three-person IVF should be considered for legalization showed “general support” for the idea.¹  Three-person IVF involves assembling an embryo containing nuclear DNA from the two original parents, using mitochondria obtained from a donor.¹ A potential hot-button issue, the implementation of three-person IVF may further polarize the debate concerning the ethics of IVF.

Nonetheless, the technology may be essential in aiding many who suffer. About 1 in 5000 children suffers from progressive and debilitating mitochondrial diseases, with the rate of incidence in adults being approximately 1 in 10,000.^2,3 The United Mitochondrial Disease Foundation lists 44 known mitochondrial diseases such as Barth syndrome, creatine deficiency syndrome, and Kearns-Sayre syndrome. Mitochondrial diseases have no cure—current treatments only manage symptoms and retard disease progression.⁴ While mutations in either nuclear DNA or mitochondrial DNA (mtDNA) can cause mitochondrial diseases, the latter is more likely, perhaps due to increased levels of mutagenic free radicals and reduced capacity for DNA-repair in mitochondria.⁵

While both sexes suffer from mitochondrial disease, only women transmit the disease to their children.⁶ Children get equal nuclear genetic information from both parents, but their mitochondrial DNA is purely maternal.⁶ Hence, children inherit their mothers’ mitochondrial defects.⁶ Prenatal and pre-implantation testing are used to inform women of underlying mitochondrial aberrations, so that couples with high risks for inherited mitochondrial disorders could decide to pursue adoption or IVF involving an egg-donor.⁶

However, if the nuclei from the mother’s ovum and the father’s sperm are taken along with mitochondria from a healthy donor (the third parent), the developing embryo will have the donor’s mitochondria. By using the original parents’ nuclear DNA and the cytoplasmic machinery of the third parent, crippling diseases with origins in mtDNA can be evaded.²

There are two basic approaches to three-person IVF. Either the mother’s nucleus is added to the cytoplasm (ovum depleted of nucleus) of the third parent and then fertilized with a sperm (maternal spindle transfer or MST), or the nucleus from a fertilized ovum is added to the cytoplasm of the third parent (pronuclear transfer or PNT).² Tachibana et al. successfully employed MST in Rhesus monkeys⁷, yielding offspring that were healthy and had developmental statistics in the normal range. The scientists found that the donated mtDNA did not affect the nuclear DNA and the impacts thereof. Craven et al. in the UK performed PNT on abnormally-fertilized human eggs and found under 2% carryover of defective mitochondria in the embryos.⁸

However, three-person IVF has unsettling moral implications. Allowing scientists to genetically manipulate embryos, even on a peripheral level, may be a point-of-no-return  in technological development—for the first time, human beings would have genetic material from more than two parents. Some might look askance at the possible phenotypic ramifications of such children growing into adulthood, and others might be wary of the slippery slope towards modifying nuclear DNA to produce ‘designer babies.’ The extent of permissible intervention in a natural, evolutionary step in human development—growing from a single cell to an organism—will soon be tested, as will the already tenuous relations between religion and science in some regions.

The Nuffield Council on Bioethics reviewed the ethics of the various IVF techniques that are in consideration for the prevention of mitochondrial disease.⁶ Among the various bioethical contemplations is the idea of limiting this technology to the conception of male embryos only, as males do not pass on their mtDNA to their offspring, thereby restricting any possible consequences from this procedure to that single generation. The council added that if the donor were a direct genetic relative of the original mother, the ramifications in future generations could be partially assuaged becausethe mitochondrial DNA would essentially be identical to the mother’s, but without the mutation that the mother may have acquired later in life. ⁶ Hugh Whittall, the Director of the Nuffield Council on Bioethics weighs in on the legal rights and responsibilities of the ‘third parent’:

“Given that only some elements of the donor egg are used, not including the cell nucleus, we do not believe that it is legally or biologically correct to refer to the mitochondrial donor as ‘third parent’ of the resulting child. We therefore argue that mitochondria donors should not be treated in the same way as egg donors for IVF, for example, they should not be required later to be identifiable to those born from their donation.”⁹

The experts on the council consider mitochondrial donation akin to tissue donation, and hence not subject to the scrupulous evaluation reserved for gamete donation.⁶ This logic is used to draw a distinction between mtDNA donors and sperm- or egg-donors, who might risk being found legally responsible for the welfare of the child.¹⁰

Amidst the overwhelming support among scientists, there exist voices of caution. Debates over the ethics of the procedure call for further evaluation of risk-to-benefit ratio.  Dr David King, the director of Human Genetics Alert, opines:

“Historians of the future will point to this as the moment when technocrats crossed the crucial line, the decision that led inexorably to the disaster of genetically engineered babies and consumer eugenics.”¹

While the U.S. government has softened its stance on federal funding for human embryonic research in recent years, it still seems likely that the first clinical data will come from the UK.¹¹ The legalization of three-person IVF in even one country, however, will bring permanent changes to the whole world, given the ubiquity of international travel and possibilities of immigration in today’s world. The ethical and moral implications notwithstanding, this technology would help women with mitochondrial defects whose currently available options preclude a genetic connection to their children.

SOURCES:

1. Gallagher J. Three-person IVF moves closer in UK. BBC News Health. http://www.bbc.co.uk/news/health-21806911. Accessed Apr 4, 2013
2. Callaway E. UK sets sights on gene therapy in eggs. Nature 2012 Jan 24;481(7832):419
3. Schaefer AM, McFarland R, Blakely EL, et al. Prevalence of mitochondrial disease in adults. Ann Neurol. 2008 Jan;63(1):35-9.
4. Type of mitochondrial disease. United Mitochondrial Disease Foundation. http://www.umdf.org/site/pp.aspx?c=8qKOJ0MvF7LUG&b=7934629. Accessed Apr 4, 2013.
5. Linnane AW, Marzuki S, Ozawa T, Tanaka M. Mitochondrial DNA mutations as an important contributor to ageing and degenerative diseases. Lancet 1989;1: 642.
6. Nuffield Council on Bioethics. Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review. http://www.nuffieldbioethics.org/sites/default/files/Novel_techniques_for_the_prevention_of_mitochondrial_DNA_disorders_compressed.pdf. Accessed Apr 4, 2013
7. Tachibana M, Sparman M, Sritanaudomchai H, et al. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 2009 Sep 17;461(7262):367-72
8. Craven L, Tuppen HA, Greggains GD, et al. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 2010 May 6;465(7294):82-5
9. Nuffield Council on Bioethics. Novel techniques to prevent mitochondrial DNA disorders would be an ethical treatment option. http://www.nuffieldbioethics.org/news/novel-techniques-prevent-mitochondrial-dna-disorders-would-be-ethical-treatment-option. Accessed Apr 4, 2013.
10. The New York Times. Kansas: Sperm donor is ordered to pay support. http://www.nytimes.com/2013/01/03/us/kansas-sperm-donor-is-ordered-to-pay-support.html?_r=0. Accessed Apr 4, 2013
11. CNN. Obama overturns Bush policy on stem cells. http://www.cnn.com/2009/POLITICS/03/09/obama.stem.cells/index.html. Accessed Apr 4, 2013.