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Thursday 15 April 2010

New research uncovers potential method to avoid passing mitochondrial myopathy onto future generations

Research funded by the Muscular Dystrophy Campaign at Newcastle University has shown that it might be possible to prevent mitochondrial diseases being passed from mother to child. The researchers led by Prof. Doug Turnbull (in collaboration with Dr Mary Herbert and Prof. Alison Murdoch) used a technique which involves removing the genetic material (chromosomes) from an embryo and transferring it into a donor egg. Embryos manipulated in this way had minimal amounts of mitochondria transferred to the donor egg and developed into later stage embryos in the laboratory. Further research is required to test the safety of this technique before it can be considered safe for clinical practice.

Diagram of a human egg with a nucleus and mitochondria (click here for a larger diagram).The majority of our genes are located in a compartment in the centre of our cells called the nucleus. However, a very small proportion of genes - approximately 0.01% of our DNA - are located in structures called mitochondria. Thousands of mitochondria exist in every cell (except red blood cells) and are responsible for producing energy.

The DNA of the mitochondria is inherited from the mother only. Errors in these genes cause mitochondrial disorders such as mitochondrial myopathy which, in the most severe cases, can cause debilitating and life threatening muscle weakness.

Previous studies in mice and monkeys have shown that it is possible to prevent the transmission of mitochondrial myopathy by transferring the nucleus (which carries the vast majority of genetic information) from an embryo that contains abnormal mitochondria to an egg that contains healthy mitochondria. This new research investigated if such a method has potential for use in humans.


What did the research show?

The researchers used embryos and eggs donated to research by couples undergoing in vitro fertilisation (IVF). These eggs had fertilised abnormally and could not be used for IVF so would have been discarded. The DNA contained within the nucleus of the embryos was transferred into eggs that had previously had their own nucleus removed. The embryos were allowed to develop in the laboratory for 6-8 days.Diagram of the process known as 'pronuclear transfer' to prevent the transmission of mitochondrial disease (click here for a larger diagram).











Embryos that fertilise abnormally do not normally develop in the laboratory as well as other embryos, with only 17% reaching the stage known as a 'blastocyst' which consists of around 70-100 cells. Of the manipulated embryos 8.3% successfully developed to the blastocyst stage.

The researchers then measured if any of the mitochondria from the embryos were transferred over to the donor eggs. On average less than 2% was carried over and often no transfer of mitochondria could be detected. Previous research has shown that levels of abnormal mitochondria this low would not be expected to cause mitochondrial disease.

"What we've done is like changing the battery on a laptop. The energy supply now works properly, but none of the information on the hard drive has been changed," explains Prof. Turnbull. "A child born using this method would have correctly functioning mitochondria, but in every other respect would get all their genetic information from their father and mother."

What does this mean for patients?

Considering there is no curative treatment available for mitochondrial disease, preventing it being passed from one generation to the next is important for families affected by these conditions. Prenatal testing is not possible for mitochondrial disease, so an alternative way of preventing its transmission needs to be found.

This research has shown that transferring nuclear DNA from embryos into donor eggs has the potential to achieve this. Recent research in the US has also given strength to this approach- it was shown that a similar technique tested on monkeys gave rise to apparently healthy offspring.

If this technique were to be brought into clinical practice, families would require IVF treatment and they would need a donor egg, which are often in short supply. The resulting children would have 99.9% of their parent's genes and the mitochondrial DNA from the woman that donated the egg.

Further research is required before this technique is considered for introduction into clinical practice. Only 8.3% of the embryos in this study developed successfully into blastocysts in the laboratory after manipulation. This is likely to be due to the fact that, due to their availability for research, abnormal embryos were used. The researchers hope to study the efficiency of this technique in normally fertilised eggs in the future to find out if the success rate of producing healthy embryos is high enough for it to be a feasible treatment option. It is also possible that manipulating embryos in this way could damage the DNA, so further experiments are needed to understand the safety of this approach.

Prof. Doug Turnbull, from Newcastle University said:

This study funded by the Muscular Dystrophy Campaign is a very exciting development with immense potential to help families at risk from mitochondrial myopathies. We have no way of curing these diseases at the moment, but this technique could allow us to prevent the diseases occurring in the first place. It is important that we do all we can to help these families and give them the chance to have healthy children, something most of us take for granted.

Philip Butcher, Chief Executive of the Muscular Dystrophy Campaign said:

These findings will be a ray of hope for people affected by mitochondrial diseases who can often be left with the heart-breaking decision of whether to have children who may be born with a serious illness.

In the future this technique may give parents the choice to have a healthy child and end the tragic cycle that some families go through, passing on these conditions from generation to generation.

I would urge the Human Fertility and Embryology Authority to permit fertility treatment using these techniques as soon as the method is proved to be effective and safe in humans.

Further information and links

Watch a video about this research on youtube.

More information about mitochondrial myopathy

Read about the research testing this technique in monkeys

More about Prof. Turnbull's project funded by the Muscular Dystrophy Campaign

The original paper is not freely available and is written in scientific language. You can find the paper on the website for the journal Nature.

Frequently asked questions

What are mitochondria?

They are microscopic energy-producing structures inside cells. They are sometimes referred to as the 'powerhouse' or 'batteries' of the cell. Since muscle cells require a large amount of energy to function, they tend to contain more mitochondria than other cells.

What is mitochondrial DNA?

More than 99% of a cell's DNA exists in the 46 chromosomes of the nucleus, half of which are inherited from the mother and half from the father. The DNA in the nucleus contains more than 20,000 genes. The mitochondria have a very small amount of DNA, including 37 genes. Mitochondrial DNA is inherited from the mother only.

What is mitochondrial disease?

Mitochondrial disease includes a wide range of disorders caused by changes to the DNA code in the mitochondria. Some are mild but many are serious, including types of epilepsy, cancer and diabetes, heart, muscle, kidney and liver conditions, deafness and blindness.

Mitochondrial myopathy is a collective term for a group of diseases that particularly affect muscle, but which may also affect every other part of the body including the brain, heart and the eye. Mitochondrial myopathies affect people in different ways. The most common problem is a combination of mild weakness of the arms and legs together with droopy eyelids and difficulty in moving the eyes. If the illness is severe, muscle weakness may be obvious in small babies, and they may have difficulties with swallowing and feeding.

Are there any treatments available?

There are no efficient treatments. Many of the symptoms associated with mitochondrial myopathies can, nevertheless, be treated effectively. For instance, pacemakers are very effective for the disturbances of heart rhythm. Some patients find that muscle fatigue and weakness can be improved with exercise- studies on which are also being funded by the Muscular Dystrophy Campaign. A few patients improve on treatment with specific vitamins, but most do not.

What barriers remain to the clinical use of this technique?

The safety and efficiency of this technique needs to be studied in normal human embryos. Approval for these studies is being sought from the Human Fertilisation and Embryology Authority. The clinical use of this technique depends on new legislation.

What is the difference between the Newcastle research and the previous research in the US on monkeys?

The Newcastle group are the first to show the potential benefit in human eggs. The techniques used are slightly different with the Newcastle group modifying fertilised eggs whereas the US team modified monkey's eggs before fertilisation.

How long before a child will be born using this technique?

It will be several years at least. Further safety tests are required and changes to the legislation governing embryo manipulation will be required.

Is this cloning?

No. Eggs would still be fertilised by sperm. Cloning involves transplanting the DNA from an adult cell into an empty egg.

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Tags: Mitochondrial myopathies, Research Panel, Research news

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