Last week, the House of Commons voted to allow in vitro fertilisation (IVF) to be carried out with eggs from two different women and sperm from one man, a technique which has been dubbed the “three-person baby”. The vote opened a novel avenue for treating mitochondrial diseases because the actual nuclear mother, whose family would have a history of mitochondrial (MT) diseases, does not pass on her mitochondria, with the baby receiving the female donor’s healthy mitochondria instead.
Dr Burga Kalz Fuller, product manager at HypOxygen, presents an interesting outline of the scientific implications and explains why the media’s term “three-person baby” is a misnomer:
The method is based on nuclear genome transfer which has been practiced experimentally for years. It essentially goes back to a 2010 Nature paper and relies on removing either the nucleus of an unfertilised egg and placing it in an enucleated “healthy” egg with its intact mitochondria (egg repair), or removing the pro-nuclei of a fertilised egg and transferring these into a healthy, nucleus-free egg from a second woman (embryo repair). The schematics below, from the Human Fertilisation Embryology Authority, show the process:
Why are mitochondria so important?
Mitochondrial DNA carries only 37 genes, but along with at least 1500 nuclear genes, the encoded functions of the mitochondrion extend far beyond the “power plant” activity of synthesizing ATP (adenosine triphosphate) classically associated with the mitochondria. There are hundreds to thousands of mitochondria in every cell, replicating independently of the nuclear genome. Mitochondria are subjected to rigorous quality control procedures through fission, fusion, and mitophagy processes. One of their eminent functions is sensing the oxygen tension in the cell, and responding to hypoxia beyond the very low levels that are considered physiological by the cell by increasing the production of reactive oxygen species (ROS), which in turn induces HIF-1α pathways. Both excessively high and extremely low oxygen represent forms of oxidative stress to the cells and impact metabolic pathways and energy homeostasis, in large part through the mediation of the mitochondria.
Over the course of a body’s lifetime, the mitochondria suffer through the activities of both endogenous and exogenous mutagens, epigenetic modifications take place, and replications are perturbed such that mutations accumulate in the mitochondrial DNA, to varying degrees in the many mitochondria present in each cell. An estimated 1 in 200 people are carriers of grievous, maternally-inherited mitochondrial mutations and approximately 1 in 5000 newborns will develop some form of MT disease in their lifetime.
What are mitochondrial diseases?
The term “mitochondrial disease” actually describes hundreds of different diseases which may result from different gene mutations manifesting as the same disease (phenocopies) or one mutation resulting in very different disorders (genocopies). In addition, developmental and tissue-specific factors determine the onset and severity of the various diseases’ manifestation. As the proportion of these grievously mutated mitochondrial-genomes increases, damage to the high-energy tissues and organs accumulates and MT diseases become evident. These impact primarily the muscles, brain, heart, liver, eyes and ears. A mitochondrial disease component is implicated in diseases such as Alzheimer’s, Parkinson’s, prostate cancer, various epilepsies, forms of blindness and deafness, diabetes, and ageing itself.
When could the first baby be born?
The House of Lords is yet to vote on the topic, but if permission is granted, the first such baby could be born in 2016. The current study being carried out to examine the ethical and medical aspects of this technique in the UK and USA respectively, reverberates emotionally with the public in part because of the misnomer “three-person baby”, when in fact such babies would carry more than 99.999% of the genome of their parents. Dr. Samuel Pang of the Reproductive Science Center (RSC) of New England states that the donated mitochondrial DNA contributes only approximately 0.001% of the baby’s genome. The designation “nuclear genome transfer”, which more accurately describes the process, would perhaps contribute to a more rational attitude towards this new therapy method.
How many people would this affect?
Only a very few couples would receive the treatment, resulting in maybe 150 births each year in the UK by this method. In comparison, approximately 17,000 babies were born in 2011 in the United Kingdom after IVF [1.http://www.hfea.gov.uk/ivf-figures-2006.html#1279] It is possible that this type of therapy for MT disease may evolve into a more widely applicable therapy for mitochondria-mediated aspects of ageing, for example, as energy homeostasis deteriorates.
There are some concerns, however, that the UK’s decision to allow nuclear genome transfer does not mandate accompanying the therapy by the requirement for clinical trials in humans or follow-up of the children. Moreover, some evidence exists to suggest that epigenetic perturbations can occur through nuclear transfer, that mitochondria affect epigenetic nuclear conformation, and that mito-nuclear mismatch can alter metabolism and development. [2. Wolff JN, Ladoukakis ED, Enrı́quez JA, Dowling DK. 2014 Mitonuclear interactions: evolutionary consequences over multiple biological scales. Phil. Trans. R. Soc. B369 : 20130443] [3. Gershoni et al. 2014 Disrupting Mitochondrial–Nuclear Coevolution Affects OXPHOS Complex I Integrity and Impacts Human Health. Genome Biology and Evolution, Volume 6, Issue 10, Pp 2665-2680]
Introducing the Hypoxystation
Use of theHypoxystationto create low oxygen conditions for cell culture has been proven to increase cell survival, enhance growth, increase cell yield, accelerate generation and self-renewal of stem cells, and improve maintenance and longevity of stem cell pools. In the lab setting, culturing cells under hypoxia has manifold benefits. Research on IVF carried out at hypoxia to the blastocyst stage has demonstrated improved rates of implantation, pregnancy and delivery.
