Since the cloning of the sheep ‘Dolly’, the first mammal resulting from somatic cell nuclear transfer (SCNT), the world has been waiting for the technology to be used therapeutically and in biomedical applications related to humans. Nuclear transfer (NT) involves the fusion of either an embryonic or adult donor cell with an enucleated recipient oocyte (egg). The thus reconstructed oocyte is activated electrically or biochemically and appropriately developed in culture in the in vitro fertilization (IVF) laboratory. Viable embryos, at various stages of development, are then transferred into surrogates. In 1997, Dolly was the one viable offspring out of the generation of 283 embryos. So far, about 12 animal species have been cloned by NT; the efficiency of the process has significantly increased but is still not optimal.
This year brought a breakthrough, not only in the progress of a technique, but also in proof of principle that the transmission from mother to child of mitochondrial DNA diseases can be abrogated, leading to a healthy child. Scientists from Newcastle University in Britain, led by Mary Herbert and Doug Turnbull, used abnormally fertilized and otherwise discardable human embryos from an IVF program to study the achievability of nuclear transfer to prevent mitochondrial DNA (mtDNA) disease transmission from mother to child. There is no available treatment for these patients and their families, making the prevention of mtDNA disease transmission a priority.
Mitochondria are often referred to as the cell’s “batteries” or “powerhouses.” Mitochondria are found in almost all eukaryotic cells, and their essential function is to convert the biochemical energy from food into energy the cells can use to fuel metabolic reactions necessary for life. Dissimilar to other subcellular compartments or organelles, mitochondria contain their own circular genome (mtDNA), which together with nuclear DNA encodes the proteins required for mitochondrial metabolism and maintenance. The cell’s nuclear genome is composed of DNA from both the mother and the father at fertilization; however, mtDNA in the embryo is passed nearly exclusively from the mother.
When a gene is damaged or changed in such a way as to alter the protein or product encoded by that gene, namely a mutation, disease can result. Genetic errors affecting the mitochondria are known to cause about 150 diseases. Roughly, one person in 8,500 adults and one in 6,500 children has a mitochondrial disease, conditions that manifest as liver failure, stroke-like episodes, blindness, some forms of epilepsy, muscular dystrophy, diabetes, deafness, and even death in childhood. As such the clinical syndromes involving mtDNA mutations extend over a wide range, and their effects may be seen at any stage in life.
The Newcastle University team took a fertilized egg from a recipient mother, removed the DNA (pronuclei of the zygote), leaving behind a “shell” containing healthy mitochondrial “batteries.” Nuclear DNA extracted from a fertilized egg of a woman carrying a mtDNA mutation was then transferred into the recipient zygotic shell. The scientists demonstrated that pronuclear transfer between zygotes can give rise to a healthy reconstituted embryo with little or no detectable donor (carrier of damaged mtDNA) mitochondrial DNA present. The success rate of embryo development to the blastocyst stage was 8.3%. The researchers expect the success rates will be higher with normal embryos, but further research is needed.
The procedure of pronuclear transfer in humans has been specifically designed with mitochondrial diseases in mind and is not intended for other types of genetic malfunctions. Questions will probably be raised concerning safety, effectiveness, and ethics, including the potential consequences of a reconstituted embryo with ‘three genetic parents.’ However, the argument of designer babies is not applicable because the technique does not alter the chromosomal genes. What the technology does offer is choice to those wondering whether to risk birthing a child with an incurable disease and hope that the inheritance chain within a family line can be broken.
References and Read-more-about-it:
1. Craven L, Tuppen HA, Greggains GD, Harbottle SJ, Murphy JL, Cree LM, Murdoch AP, Chinnery PF, Taylor RW, Lightowlers RN, Herbert M, Turnbull DM. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature. 2010 May 6;465(7294):82-5.
2. Cree LM, Samuels DC, Chinnery PF. The inheritance of pathogenic mitochondrial DNA mutations. Biochim Biophys Acta. 2009 Dec;1792(12):1097-102.
3. Bredenoord AL, Pennings G, de Wert G. Ooplasmic and nuclear transfer to prevent mitochondrial DNA disorders: conceptual and normative issues. Hum Reprod Update. 2008 Nov-Dec;14(6):669-78.
4. Niemann H, Tian XC, King WA, Lee RS. Epigenetic reprogramming in embryonic and foetal development upon somatic cell nuclear transfer cloning. Reproduction. 2008 Feb;135(2):151-63.
5. ScienceDaily. Retrieved May 18, 2010, from http://www.sciencedaily.com¬ /releases/2010/04/100416121800.htm