Three-parent IVF is a chance to create a generation free from mitochondrial diseases
The 'third-parent’ IVF technique is a potential clinical triumph but researchers must tread carefully
Seeds of doubt: a human egg is fertilised in vitro - The chance to create a disease-free generation
By Michael Hanlon
17 Sep 2012
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Science has taken human reproduction some way from its natural roots. Since the birth of the first “test tube” baby, Louise Brown, in 1978, we have seen babies created from donated eggs or donated sperm, and babies gestated in donated wombs.
But one constant has not been overturned to date, the one which says children must be the genetic offspring of just two adults. For all the recent advances in Assisted Reproduction Technology (ART), the notion that a child could be born containing DNA from three people seems to move the game on to a whole new level of complexity and controversy. For this marks a profound, philosophical step change from what has come before, raising questions not only of safety but deeper issues of identity and parenthood.
As The Daily Telegraph reported yesterday, Professor Lisa Jardine, the head of the Human Fertilisation and Embryology Authority, has announced a public consultation on “three-parent IVF”. If the findings are positive (and polls suggest support), the currently banned technology, pioneered by scientists at Newcastle University, could be legalised within five years, making Britain the first country to allow this technique.
Horrified opponents say this move is a lurch into the dark, an unethical attempt to meddle with the precious human germline. To supporters, it is simply a practical and ethical way to end the misery of what are known as mitochondrial diseases (including muscular dystrophy and ataxia, which causes problems with speech and co-ordination) that affect 0.5 per cent of births in the UK.
There is certainly a good argument to be made for “three-parent babies”. The new technique does not involve nuclear DNA, the genes that are responsible for our biological identity, but the DNA in mitochondria. These are the tiny “organelles” that sit in the cytoplasm outside the nucleus, and which power our cells.
Some heritable diseases are caused by faulty mitochondria – that can result in cells malfunctioning or failing completely. The new research aims to eradicate these conditions, so that women who carry defective mitochondria can give birth safe in the knowledge that the disease will not be passed on. One profound effect of the technique would be to eliminate these diseases completely – and forever – in a single generation. Few medical advances have the power to reach into the future so directly in this way.
What does three-parent IVF actually entail? During normal reproduction, DNA from sperm is fused with the DNA contained in the egg. The egg also contains mitochondria (the sperm’s mitochondria are destroyed by the egg and play no further role). Thus mitochondrial DNA is passed on exclusively down the female line and it is from mothers (who may or may not have symptoms) that mitochondrial diseases are inherited. Break that link and the problem vanishes.
There are two variations of the technique now in the spotlight, and both have been extensively studied at Newcastle University, one of the world’s leading centres in reproductive medicine that regularly generates headlines for pioneering work in stem cell research, human cloning and advances in ART.
One method, called spindle transfer, involves the removal of the nuclear material from the mother’s egg, which is then placed into a donor egg “shell” containing healthy mitochondria but no nuclear DNA. This egg is then fertilised, in vitro, by the father’s sperm. The second technique, called pronuclear transfer, involves the creation of two embryos in vitro, one using sperm and an egg from the parents, the other from donors. The donor egg is then ennucleated – it has its central genetic material removed and replaced by the genetic material taken from the parental egg.
Although it sounds more complex – scientists would need to perform two in vitro fertilisations rather than one – the researchers involved say there are distinct advantages to the pronuclear transfer technique, because an unfertilised egg is more susceptible to damage during the spindle transfer procedure. It is likely that pronuclear will be the preferred technique.
Either way the result is the same – a new embryo containing genes from father, mother and mitochondrial DNA from a female egg donor who does not need to be related to either parent. The resulting baby will, the scientists say, be genetically the child of its parents and not the egg donor. The technique has been likened to changing the batteries in a laptop computer; the hard drive, which contains all the important data, is unchanged.
In fact, in a profound way it can be argued that mitochondria are not really part of us at all, but a form of modified bacteria. The prevalent theory is that around two billion years ago, the ancestors of today’s mitochondria – bacteria – invaded a primitive cell and somehow managed to avoid being consumed, instead setting up home in the cytoplasm. The presence of the mitochondria hugely increased the amount of energy available to the host cell, synthesising the chemical adenosine triphosphate – “the fuel of life” – which is essential for all cellular activity. A successful symbiotic relationship was thus established. This in turn allowed evolution of complex life – plants and animals. Indeed, if it had not been for that chance encounter a couple of billion years ago, life on Earth may never have passed the microbial stage.
Many people are, predictably, horrified by the new research and the prospect of a third, or “mitiochondrial”, parent. The Catholic Church opposes IVF on ethical and religious grounds. First, IVF separates the process of procreation from marriage, and worse, in the Church’s eyes, many IVF techniques involve the creation of embryos which are then discarded. Other religions have varying objections, too. Sunni Islam generally permits ART, provided there are no third-party elements to the procedure, whereas Shia followers are told that this is permitted.
Then there is the identity problem. Children born of donated sperm or eggs already have to reconcile the fact that their social identity (their upbringing) does not correspond to their genetic identity. Add in a “third parent” and the issue of “Who am I?” becomes still more acute. Your mitochondria may not be as important as your cell nuclei, but they are still very much a part of who you are. Would a woman who donated her mitochondrial DNA have any rights – or, indeed, responsibilities – towards a child (as sperm donors do today)?
What about safety concerns? A serious objection is that anything which involves tampering with the human germline takes us into uncharted waters. Current gene therapies only last as long as the individual patient treated – any changes you make to your DNA in your lifetime cannot be passed on. But changes made to the germline will be inherited as long as (in this case) the female line continues.
However, concerns expressed by some critics, that the baby resulting from this new technology will contain “foreign” genes, are misplaced. According to Professor Mary Herbert, one of the researchers taking part in the Wellcome Trust funded project, the basis of reproduction in nature always involves “alien” genomes. “The male genome is a foreign genome and it gets stuck in and talks to the mitochondria and gets down to business,” she says. Mice have been bred using the three-parent technique since 1983 and after many generations, no problems have emerged.
Furthermore, this technology does not entail the creation of “designer babies”, the term used to refer to theoretical future attempts to tweak the nuclear germline to produce gifted or super-fit progeny. What is being proposed is simply the replacement of faulty cellular material, not the enhancement of the core genome. While it is likely that a small number of the “faulty” mitochondria will be carried over into the new egg, perhaps 1 to 2 per cent, according to Prof Herbert, this is “highly unlikely to cause disease, which normally needs a threshold of 60 per cent of damaged mitochondria”.
Nevertheless the possibility that the “new” mitochondria (from the donor egg) could fuse and swap genes with those carried over from the biological mother raises possible concerns, which will only be addressed when the embryos are allowed to develop beyond the earliest stages (14 days), the point at which the law currently says experimentation must stop.
Finally there is the issue of how much we understand the complex interplay of genes, proteins and non-coding DNA in both mitochondria and cell nucleii. Just last week research was published showing that our DNA is less a recipe book than a complex library, with an indexing system as important as the books.
Animal studies so far show that this three-parent technology is safe but, until the first babies are born, we will never know for certain. “It’s all about the balance of risk,” says Professor Herbert. “There are always elements of the unknown in any new treatment. But we have no evidence of anything cataclysmic that will happen.”
http://www.telegraph.co.uk/sci.....ndrial-diseases.html
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