People, populations and body systems

PROFILE: Battling mitochondrial diseases

Doug Turnbull
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At the University of Newcastle, Professor Doug Turnbull and his colleagues have pioneered a technique to transfer DNA between two human eggs, which could ultimately be used to stop mitochondrial diseases in their tracks.

Doug is a busy man. He is Professor of Neurology at the University of Newcastle, running a clinic for patients with mitochondrial disease from all over the country. For the past two years he has also been director of the Lifelong Health and Wellbeing Centre for Brain Ageing and Vitality, which is co-funded by a group of research councils, including the MRC.

“The people in my lab either work on understanding mitochondrial diseases, trying to find new ways of treating or preventing them, or looking at mitochondria in other diseases such as neurodegeneration and the basic mechanisms of ageing,” says Doug.

“For me, the motivation of our work is that there’s not a lot we can do for patients with these diseases at the moment – we can help them, but we can’t cure them – and prevention’s going to be better than cure.”

Mitochondria are tiny structures inside our cells which are essential for generating energy. When they are faulty, mitochondrial diseases occur. The more complicated the cell is, or the more energy it needs, the more likely it is to be affected when mitochondria don’t work properly. Cells which need the most energy include those of the brain, muscle, heart and ears – so faulty mitochondria in these cells can cause conditions like severe muscle weakness, heart problems and deafness. Very severe defects mean that a baby born with the disease will not survive beyond the first few hours of life, but milder defects produce symptoms which only appear in childhood or later life.

“Mitochondria are unique because they have their own DNA, which is inherited only from the maternal side of a person’s family and which is entirely separate from DNA in the cell’s nucleus,” explains Doug. “Unlike the DNA in the nucleus, which contains the 23,000 genes needed to make up a person, mitochondrial DNA is a tiny piece of DNA comprising 37 genes, 13 of which are involved in actually making the mitochondria.”

With MRC funding, one area of the team’s research is concentrating on ways of preventing diseases caused by these 13 genes, and in 2010 they made a major breakthrough.

The reason why these diseases can’t presently be cured, explains Doug, is that trying to alter the genetic make-up of the cell is very difficult, and getting inside the mitochondria is even more tricky. But there is a way around this. He describes mitochondria as being like the batteries in a laptop computer. Without them, the computer (or cell) won’t work, but the batteries can be removed and swapped for new ones without having any detrimental effect.

Doug explains: “What we have been working on, with our colleagues Mary Herbert and Alison Murdoch at the Newcastle Fertility Centre, is using very early stage human embryos which are not suitable for IVF treatments which have been abnormally fertilised.

“In normal fertilisation, you get a female pronucleus from the mother’s egg cell and a male pronucleus from the father’s sperm cell. We’ve been using abnormal embryos with one or three pronuclei, so they can’t be used for IVF, and we’ve been able to successfully transfer pronuclei from one embryo to another without taking any mitochondria with them.”

The technique is a major leap forward for preventing mitochondrial diseases, because it means that the pronuclei from an embryo with faulty mitochondrial DNA can be removed and put into an ‘empty’ donor embryo which has had its pronuclei removed. The embryo would then have the donor cell’s normal mitochondrial DNA and grow up to be completely free of the disease.

In practice, the technique could be used to help women going through IVF treatment who have a known risk of passing on mutations which cause mitochondrial disease.

“The technique is for women who have high levels of mutations and have really limited reproductive options. For example, I’ve seen one lady who has had ten pregnancies and she’s lost five children in the first 24 hours of life. Her only surviving child recently died aged 21 from a severe type of degenerative brain disease called Leigh’s syndrome. These are the sort of people we want to be able to help. And of course if you take the disease out at this stage then the child won’t pass it on to her children either.”

More research is needed and ethical, legal and practical issues associated with the research need to be addressed before it can go forward. The next steps will be to assess the safety and effectiveness of the technique in normal human embryos, and scientists in this field of research are working with the government to try to change regulations in this area to bring it closer to benefiting patients.

Achievements

Grip strength could predict longevity

Grip strength, the speed at which we walk or rise from a chair and our ability to balance could be indicators of how long we may live. These are the findings of a study by scientists at the MRC Unit for Lifelong Health and Ageing in London, co-funded by a cross-research-council initiative called New Dynamics of Ageing.

The team looked at the findings of 33 studies across the world, which included over 50,000 men and women who had been followed for up to 43 years. Study volunteers with a stronger hand-grip and better performance in other physical tests lived longer than their weaker counterparts. Researchers believe these simple measures could be used in health assessments and guide decisions on healthcare.

Dr Rachel Cooper, who led the analysis, said: “Simple non-invasive assessment measures like these, which are linked to current and future health, could help doctors identify those most vulnerable to poor health in later life, and those who may benefit from early intervention to keep them active for longer. “Research that helps people to enjoy a long and healthy life is a crucial part of the MRC’s work and evermore important to help cater for the health needs of an ageing population.”

Heavy mothers store up problems for their children

MRC Scientists have shown that piling on too many pounds in pregnancy may lead to future heart problems for the child. The team found that when a woman gained more than the recommended amount of weight during pregnancy, her child was on average 2.2lb heavier, had a larger waist, more body fat and lower levels of ‘good’ cholesterol which reduce the risk of heart disease.

Based at the MRC Centre for Causal Analyses in Translational Epidemiology (CAiTE) in Bristol, the scientists collected detailed information about mothers’ weight gain from antenatal records. Around 5,000 children were then assessed at age nine for heart disease risk factors.

All of these data were made available through the Avon Longitudinal Study of Parents and Children (ALSPAC), a long-term population study part-funded by the MRC. More than 14,000 pregnant mothers enrolled in 1991 and 1992, and the health and development of their children has been followed ever since. ALSPAC is a unique resource for studying the effects of weight gain in pregnancy; during the early 1990s it was routine to check expectant mothers’ weight at every antenatal clinic they attended. This practice was discontinued in the mid-90s.

Dr Abigail Fraser, an MRC Research Fellow at CAiTE, explained the importance of the team’s findings: “Our research suggests that those who put on most weight during the nine months of pregnancy risk health problems in their children several years later. Further research carried out at CAiTE also shows that gaining more than the recommended pregnancy weight is associated with increased body fat and higher blood pressure in mothers in the long term. These studies highlight the importance of healthy weight gain in pregnancy to both mothers and children.”

Genes link female sexual maturity to body fat

An international group of scientists including researchers from the MRC Epidemiology Unit in Cambridge have discovered 30 genes that control the age at which girls reach sexual maturity. Many of these genes also play a strong role in how the body metabolises fat, so this study suggests biological links between those who reach puberty at a younger age and increased risk of obesity.

The research helps to explain why girls in some families are more likely to go through puberty at an early age, and may eventually help to prevent chronic health problems associated with excessive weight gain. Early puberty not only puts women at an increased risk of obesity, but is also associated with several illnesses, including breast cancer, and poorer health in later life.

Senior author Dr Ken Ong said: “We know that girls who are overweight are more likely to go through puberty at younger ages. Our findings tell us that being overweight and having early puberty have intricate biological links. However, these common genetic factors may be modified by changes in lifestyle.”

Heart attack risk unravelled

The risk factors for heart attack are widely reported, but Professor Frank Kee from Queen’s University Belfast says that for many people current risk prediction is too imprecise. While treatment decisions are relatively straightforward for those at high risk of disease, it is more difficult for the many more people at intermediate risk, who form a large segment of the population. These people might otherwise benefit from early treatment.

With funding from the MRC, Professor Kee and his colleagues are assessing the value of measuring newly-discovered chemicals (markers) in the bloodstream, and whether they can help pin down an individual’s levels of risk before they shown signs of disease.

“We have assessed the usefulness of 30 measurable markers in huge population samples of around 10,000 people from across Europe. We show that three factors – levels of specific proteins called C-reactive protein, B-type natriuretic peptide and sensitive troponin I – could be used to score risk more accurately,” he explained.

“We can always measure blood pressure, cholesterol, obesity and history of diabetes to make a reasonable estimation, but using our new marker ‘score’ consistently leads to improved risk estimation. The next phase of research is to see if giving doctors and patients these scores can change management in the clinic and improve the outcomes for patients.”

B vitamins could halve brain shrinkage in elderly

A major neurological study funded by the MRC has shown that daily tablets of B vitamins can significantly reduce the rate of brain shrinkage in elderly people who suffer from Mild Cognitive Impairment (MCI). Around half of people with MCI develop dementia, mainly Alzheimer’s disease, within five years of diagnosis and it is hoped these findings could lead to a treatment to delay the onset of Alzheimer’s.

The researchers, who form part of the Oxford Project to Investigate Memory and Ageing, found that the brains of those taking B vitamins, such as folic acid (vitamin B9) and vitamins B6 and B12, shrank at a rate of 0.76 per cent per year, while brains of those in the placebo group shrank at a rate of 1.08 per cent per year.

Scientists have known for a while that certain B vitamins control levels of the amino acid homocysteine in the blood, high levels of which are associated with an increased risk of Alzheimer’s. In this study, people with the highest levels of homocysteine benefited most from the treatment, showing half the amount of brain shrinkage compared to those on placebo.

Professor David Smith from Oxford University and co-leader of the trial, said: “It is our hope that this simple and safe treatment will delay the development of Alzheimer’s disease in many people who suffer from mild memory problems. These are immensely promising results but we need to do more trials to conclude whether these particular B vitamins can slow or prevent development of Alzheimer’s.”

Deprived Scotsmen 30 times more likely to die violently

Research has shown that Scotsmen under the age of 65 who are living in deprived neighbourhoods are 32 times more likely to die from assault compared with their richer counterparts.

Dr Alastair Leyland from the MRC Social and Public Health Sciences Unit in Glasgow led a study, part-funded by the MRC, which analysed over 25 years’ data collected from 1980 to 2005. The social patterning of deaths due to assault in Scotland was examined with particular focus on the involvement of individual socioeconomic status and local deprivation.

Analysis of death records from the General Register Office for Scotland showed that compared with affluent areas, in deprived neighbourhoods the male mortality rate due to assault, including stabbings with knives or sharp objects, increased by 75 per cent from 20 to 35 per million, whilst the rate involving just stabbings doubled to 20 per million.

This pattern was most pronounced for those aged 15 to 44, with a rise in death by assault from 27 to 57 per million, with death by stabbing increasing from 16 to 40 per million.

Dr Leyland commented: “The differences we see now in death rates due to assault between affluent and deprived groups are much greater than those that have been reported before. Understanding why Scottish society has become so polarised is key to reducing health inequalities and consequently improving the health of the population.”

Mental health benefits for ethnic minorities living side by side

MRC Training Fellow Dr Jayati Das-Munshi, of King’s College London, has shown that some people are less likely to suffer from common mental disorders when they are living in neighbourhoods with a higher proportion of people from their own ethnic background.

Compared to white British people, the prevalence of common mental disorders in ethnic minority populations varies considerably, with some ethnic minorities showing a lower prevalence and some a higher prevalence. However there has been very little research into what factors might account for these variations.

The study surveyed over 4,000 people from five ethnic minority backgrounds to measure the prevalence of mental disorders, experiences of discrimination, and the extent of their social support.

Dr Das-Munshi explained the results: “We were able to show that for some minority groups, in particular Irish and Bangladeshi people, there is a ‘protective effect’ of living in an area with a high concentration of people from one’s own ethnic background. For most ethnic groups, living in areas with a higher proportion of people from the same background is associated with improved social support and fewer reported experiences of discrimination. However, these effects did not fully account for the ‘protective’ effects on mental health.”

Fetal growth patterns linked to childhood allergies

Fetuses which develop quickly in early pregnancy but whose growth then falters at a later stage in pregnancy are likely to develop allergies and asthma as children, MRC and British Lung Foundation-funded research suggests.

Scientists at the MRC Lifecourse Epidemiology Unit and the University of Southampton studied 1,548 three-year-old children who were taking part in the Southampton Women’s Survey, a major study of women and their children. The team discovered that 27 per cent of children who had shown this pattern of growth in the womb went on to develop atopy – allergic reactions to common allergens in the environment – compared with 4 per cent of children who had grown at a normal rate in the womb.

The research also showed that fetuses who grow too slowly in the womb are more likely to go on to develop wheezing with common colds in infancy, possibly as a result of having narrower airways in the lungs.

Lead author of the study, the University of Southampton’s Professor Keith Godfrey, explains: “This research provides some of the most direct evidence yet that changes in how the baby’s immune system and lungs develop before birth can predispose them to some of the commonest childhood illnesses. The Southampton Women’s Survey has detailed information on maternal nutrition before and during pregnancy and we are now examining modifiable maternal factors that could reduce a baby’s risk of developing allergy and wheezing illnesses in infancy and childhood.”

Stay active to beat your genes

Genetic predisposition to obesity can be offset by around 40 per cent with regular physical activity, according to researchers from the MRC Epidemiology Unit in Cambridge. The findings challenge the popular myth that obesity is unavoidable if it runs in the family and could guide future treatments to combat obesity.

The study involved over 20,000 men and women aged 39 to 79, who had taken part in the EPIC-Norfolk study and given DNA samples and completed questionnaires about their physical activity levels at work and during leisure time. The researchers calculated each participant’s overall genetic susceptibility based on 12 genetic markers known to increase body mass index (BMI) and risk of obesity. They subsequently compared the genetic susceptibility of physically active and inactive volunteers.

Lead scientist Dr Ruth Loos explained: “Even those people with the highest genetic susceptibility to obesity can improve their health by taking some form of daily physical activity. Changing our behaviour can avoid us being slaves to our genetic make-up. We are now a step closer to targeting therapies for people who are genetically prone to becoming obese, and may be more effective than current approaches that target the whole population.”