In Context
New IVF techniques put mitochondrial diseases in focus As laws are drafted to regulate a new form of IVF that could prevent some mitochondrial diseases, David Holmes looks at the scientific and ethical issues raised by these techniques. Published Online November 1, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70190-X
Louise Oligny/Bsip/Science Photo Library
For more on mitochondrial diseases see Review Lancet Neurol 2010; 9: 829–40
The recent decision by the UK Government to press ahead with plans to allow the tightly regulated use of pioneering in-vitro fertilisation (IVF) techniques to prevent the transmission of a group of rare and devastating mitochondrial diseases has brought a fascinating set of ethical questions into the public eye. But it has also focused attention on a group of often overlooked diseases that have been implicated in a wide range of neurological disorders, and which are finally starting to be better understood. Mitochondria are well known as the organelles that undertake many vital metabolic functions in the cell, the most important of which is the process of oxidative phosphorylation that provides essential chemical energy for cellular processes. The central role of mitochondria in cell metabolism means that when things go awry, the consequences for the tissues and organs that are most energy dependent can be catastrophic. Together with muscle (including the heart) and β cells in the pancreas, the nervous system is particularly susceptible; in about 60% of cases, mitochondrial dysfunction manifests as a range of often severely debilitating
New IVF methods use donated eggs to avoid mitochondrial disease transmission
28
neurological disorders. “Neurons are very dependent on oxidative phosphorylation”, explains Tony Schapira, Head of the Department of Clinical Neuroscience at the University College London Institute of Neurology and an expert in mitochondrial disorders. “They don’t multiply, they can’t regenerate, and they have the cell body and the synapse, both of which are energy dependent, and dysfunction at either end can cause defective neuronal function”.
“‘Neurons are very dependent on oxidative phosphorylation... dysfunction at either end can cause defective neuronal function.’” The range of neurological presentations of mitochondrial disorders is extremely broad. Among the most common signs and symptoms are eye muscle weakness causing eyelid ptosis and inability to move the eyes from side to side, or up and down; deafness; impaired vision leading to blindness due to retinal degeneration; seizures; ataxia; migraine headaches; muscle weakness and exercise intolerance; and spasticity. “Patients with mitochondrial diseases who develop neurological manifestations usually get just one or a few of these manifestations”, explains Albert La Spada, Professor of Pediatrics, Cellular and Molecular Medicine, and Neurosciences at the University of California in San Diego. But to make matters more complicated, patients with the same mutations can present with symptoms ranging in severity from full-blown encephalomyopathic disorder with strokes, epilepsy, and ataxia, to just a little deafness or, in some cases, no symptoms at all. “One of the unanswered questions is why there’s such a big clinical
spectrum with the same mutation”, says Schapira. At least part of the answer is thought to be mutational load. “Mitochondrial genetic diseases fall into two broad groups”, Schapira explains. Mitochondria contain their own small 16·6 kilobase genome encoding 37 genes, a legacy of their likely origin as endosymbiotic bacteria living inside eukaryotic host cells. The first group of mitochondrial genetic diseases are caused by mutations to this mitochondrial genome. In human beings only mitochondria from the egg survive after fertilisation (paternal mitochondria are destroyed in the embryo). As a result, mitochondrial diseases are maternally inherited, even though the mother herself may be asymptomatic. Because cells typically contain many mitochondria, the concentration of mitochondria that carry mutations, known as the degree of heteroplasmy, probably accounts for most of the variation in clinical phenotypes between patients with the same mutation. However, the mitochondrial genome is only semiautonomous; a second group of genetic disorders are caused by mutations in nuclearencoded mitochondrial proteins. These disorders are inherited along mendelian lines, and tend to have a more characteristic pattern. About 200 mutations of mitochondrial DNA have been identified so far. Although each individual mutation can be rare, taken together this group of mitochondrial diseases is more common than are childhood cancers, affecting around 9 in 100 000 adults under 65 according to estimates from prevalence studies. There are no cures, although some of the symptoms can be ameliorated in milder cases. However, many cases prove fatal, and although prenatal diagnosis can now www.thelancet.com/neurology Vol 13 January 2014
In Context
be offered, in many cases it is not possible or not effective. For these reasons, two new closely related IVF techniques (pronuclear transfer and maternal spindle transfer, which were pioneered by Doug Turnbull and his Mitochondrial Research Group at Newcastle University in the northeast of England) have been hailed by many as a major breakthrough. “What we are proposing to do is to transfer the nuclear material from the egg or early embryo of a mother that carries mitochondrial DNA disease into the egg or early embryo of another woman who has normal mitochondria, so we can transfer the nuclear DNA into an egg with the healthy mitochondria from another woman”, explains Turnbull. This would mean that any child resulting from the procedure would derive 0·2% of its DNA (the mitochondrial portion) from what some of the press have referred to as a “third parent”. The process has not been attempted in human beings yet, and would require the UK Parliament to draw up new legislation to govern its use. The first draft of these regulations are due in the autumn and will be debated by Members of Parliament next year, after a consultation by the UK Human Fertilisation and Embryology Authority concluded in the spring that the UK public was largely happy for the technology to be used. However, Turnbull acknowledges that the ethics of the procedure are “complex”. “Three-person IVF is viewed by some geneticists as tantamount to germline modification”, says La Spada. This modification of the genetic instructions of a zygote to alter or enhance the characteristics of the future newborn is considered by some to be unethical, raising the spectre of so-called designer babies. But the Nuffield Council on Bioethics, based in the UK, concluded after a lengthy consultation that “due to the health and social benefits to individuals and families of living free from mitochondrial disorders”, in this instance, “if these novel www.thelancet.com/neurology Vol 13 January 2014
techniques are adequately proven to be acceptably safe and effective as treatments, it would be ethical for families to use them”. And the council further concluded that “mitochondrial donation does not indicate, either biologically or legally, any notion of the child having either a ‘third parent’, or ‘second mother’”.
“‘If these novel techniques are... proven to be acceptably safe...it would be ethical for families to use them.’” The new IVF techniques are only applicable in cases where mitochondrial DNA is defective. For mitochondrial disorders caused by mutations to nuclear-encoded mitochondrial proteins, there is no prospect of prevention at present. But an increasing understanding of mitochondrial biochemistry and behaviour is starting to point the way to a new generation of therapies. “For the past decade, we have come to appreciate that mitochondria are very dynamic organelles that constantly undergo a process of fission and fusion; splitting apart to give rise to two ‘daughter’ mitochondria, and joining together to create a new single mitochondrion”, explains La Spada. “This ongoing process of mitochondrial dynamics is one way that defective mitochondria can be restored to normal function, or if a mitochondrion is too dysfunctional, these processes enable the cell to target that mitochondrion for degradation”. Although how these processes are regulated and how they become dysregulated in disease is still not clear, changes to these processes have been implicated in an increasing number of neurological diseases, from neurodegenerative disorders (eg, Parkinson’s disease) to rare conditions such as the subacute necrotising encephalopathy Leigh’s syndrome. “I think Parkinson’s disease [PD] is probably the neurodegenerative disorder together with Huntington’s disease that’s most accepted as
having a significant mitochondrial component to pathogenesis”, explains Schapira. “In PD, mutations of mitochondrial proteins like PINK1, the parkin [PARK2] mutations, DJ1, et cetera, are associated with inherited familial PD, and a number of the other mutations tend to have some mitochondrial effects”. The past few years have yielded several important insights into mitochondrial dynamics, courtesy of these mutations. “When parkin and PINK1 were first identified as causes of recessive PD we didn’t really understand their function”, Schapira explains; “but it’s become clear over the past few years that they’re intimately involved in the identification of defective mitochondria and their removal by mitophagy [a selective form of autophagy]”. This feeds into the notion that a buildup of defective mitochondria in Parkinson’s disease could result in an increase in the production of free radicals, so if a way could be found to increase the removal of defective mitochondria, the damage from free radicals could be reduced. Alongside attempts to develop drugs that enhance mitochondrial function, there is now an increasing push to develop drugs that can improve the general health of the mitochondrial population by increasing the turnover of defective mitochondria through mitophagy. “If you can prevent mitochondria becoming defective that would be very good, but if they are going to be defective then let’s get rid of them”, says Schapira. That would probably mean finding a mechanism to target the lysosome for increased removal of mitochondria. “There are a number of pharmaceutical companies and biotechs looking in detail at that pathway”, Schapira notes. With new insights into mitochondrial biochemistry coming thick and fast, these tiny organelles look destined to have a role in the treatment of an ever-greater number of neurological disorders.
For the UK Human Fertilisation and Embryology Authority report see http://www.hfea.gov. uk/6896.html For the Nuffield Council on Bioethics report see http:// www.nuffieldbioethics.org/ mitochondrial-dna-disorders/ mitochondrial-dna-disordersconclusions-and-ethicalconsiderations
David Holmes 29
New IVF techniques put mitochondrial diseases in focus As laws are drafted to regulate a new form of IVF that could prevent some mitochondrial diseases, David Holmes looks at the scientific and ethical issues raised by these techniques. Published Online November 1, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70190-X
Louise Oligny/Bsip/Science Photo Library
For more on mitochondrial diseases see Review Lancet Neurol 2010; 9: 829–40
The recent decision by the UK Government to press ahead with plans to allow the tightly regulated use of pioneering in-vitro fertilisation (IVF) techniques to prevent the transmission of a group of rare and devastating mitochondrial diseases has brought a fascinating set of ethical questions into the public eye. But it has also focused attention on a group of often overlooked diseases that have been implicated in a wide range of neurological disorders, and which are finally starting to be better understood. Mitochondria are well known as the organelles that undertake many vital metabolic functions in the cell, the most important of which is the process of oxidative phosphorylation that provides essential chemical energy for cellular processes. The central role of mitochondria in cell metabolism means that when things go awry, the consequences for the tissues and organs that are most energy dependent can be catastrophic. Together with muscle (including the heart) and β cells in the pancreas, the nervous system is particularly susceptible; in about 60% of cases, mitochondrial dysfunction manifests as a range of often severely debilitating
New IVF methods use donated eggs to avoid mitochondrial disease transmission
28
neurological disorders. “Neurons are very dependent on oxidative phosphorylation”, explains Tony Schapira, Head of the Department of Clinical Neuroscience at the University College London Institute of Neurology and an expert in mitochondrial disorders. “They don’t multiply, they can’t regenerate, and they have the cell body and the synapse, both of which are energy dependent, and dysfunction at either end can cause defective neuronal function”.
“‘Neurons are very dependent on oxidative phosphorylation... dysfunction at either end can cause defective neuronal function.’” The range of neurological presentations of mitochondrial disorders is extremely broad. Among the most common signs and symptoms are eye muscle weakness causing eyelid ptosis and inability to move the eyes from side to side, or up and down; deafness; impaired vision leading to blindness due to retinal degeneration; seizures; ataxia; migraine headaches; muscle weakness and exercise intolerance; and spasticity. “Patients with mitochondrial diseases who develop neurological manifestations usually get just one or a few of these manifestations”, explains Albert La Spada, Professor of Pediatrics, Cellular and Molecular Medicine, and Neurosciences at the University of California in San Diego. But to make matters more complicated, patients with the same mutations can present with symptoms ranging in severity from full-blown encephalomyopathic disorder with strokes, epilepsy, and ataxia, to just a little deafness or, in some cases, no symptoms at all. “One of the unanswered questions is why there’s such a big clinical
spectrum with the same mutation”, says Schapira. At least part of the answer is thought to be mutational load. “Mitochondrial genetic diseases fall into two broad groups”, Schapira explains. Mitochondria contain their own small 16·6 kilobase genome encoding 37 genes, a legacy of their likely origin as endosymbiotic bacteria living inside eukaryotic host cells. The first group of mitochondrial genetic diseases are caused by mutations to this mitochondrial genome. In human beings only mitochondria from the egg survive after fertilisation (paternal mitochondria are destroyed in the embryo). As a result, mitochondrial diseases are maternally inherited, even though the mother herself may be asymptomatic. Because cells typically contain many mitochondria, the concentration of mitochondria that carry mutations, known as the degree of heteroplasmy, probably accounts for most of the variation in clinical phenotypes between patients with the same mutation. However, the mitochondrial genome is only semiautonomous; a second group of genetic disorders are caused by mutations in nuclearencoded mitochondrial proteins. These disorders are inherited along mendelian lines, and tend to have a more characteristic pattern. About 200 mutations of mitochondrial DNA have been identified so far. Although each individual mutation can be rare, taken together this group of mitochondrial diseases is more common than are childhood cancers, affecting around 9 in 100 000 adults under 65 according to estimates from prevalence studies. There are no cures, although some of the symptoms can be ameliorated in milder cases. However, many cases prove fatal, and although prenatal diagnosis can now www.thelancet.com/neurology Vol 13 January 2014
In Context
be offered, in many cases it is not possible or not effective. For these reasons, two new closely related IVF techniques (pronuclear transfer and maternal spindle transfer, which were pioneered by Doug Turnbull and his Mitochondrial Research Group at Newcastle University in the northeast of England) have been hailed by many as a major breakthrough. “What we are proposing to do is to transfer the nuclear material from the egg or early embryo of a mother that carries mitochondrial DNA disease into the egg or early embryo of another woman who has normal mitochondria, so we can transfer the nuclear DNA into an egg with the healthy mitochondria from another woman”, explains Turnbull. This would mean that any child resulting from the procedure would derive 0·2% of its DNA (the mitochondrial portion) from what some of the press have referred to as a “third parent”. The process has not been attempted in human beings yet, and would require the UK Parliament to draw up new legislation to govern its use. The first draft of these regulations are due in the autumn and will be debated by Members of Parliament next year, after a consultation by the UK Human Fertilisation and Embryology Authority concluded in the spring that the UK public was largely happy for the technology to be used. However, Turnbull acknowledges that the ethics of the procedure are “complex”. “Three-person IVF is viewed by some geneticists as tantamount to germline modification”, says La Spada. This modification of the genetic instructions of a zygote to alter or enhance the characteristics of the future newborn is considered by some to be unethical, raising the spectre of so-called designer babies. But the Nuffield Council on Bioethics, based in the UK, concluded after a lengthy consultation that “due to the health and social benefits to individuals and families of living free from mitochondrial disorders”, in this instance, “if these novel www.thelancet.com/neurology Vol 13 January 2014
techniques are adequately proven to be acceptably safe and effective as treatments, it would be ethical for families to use them”. And the council further concluded that “mitochondrial donation does not indicate, either biologically or legally, any notion of the child having either a ‘third parent’, or ‘second mother’”.
“‘If these novel techniques are... proven to be acceptably safe...it would be ethical for families to use them.’” The new IVF techniques are only applicable in cases where mitochondrial DNA is defective. For mitochondrial disorders caused by mutations to nuclear-encoded mitochondrial proteins, there is no prospect of prevention at present. But an increasing understanding of mitochondrial biochemistry and behaviour is starting to point the way to a new generation of therapies. “For the past decade, we have come to appreciate that mitochondria are very dynamic organelles that constantly undergo a process of fission and fusion; splitting apart to give rise to two ‘daughter’ mitochondria, and joining together to create a new single mitochondrion”, explains La Spada. “This ongoing process of mitochondrial dynamics is one way that defective mitochondria can be restored to normal function, or if a mitochondrion is too dysfunctional, these processes enable the cell to target that mitochondrion for degradation”. Although how these processes are regulated and how they become dysregulated in disease is still not clear, changes to these processes have been implicated in an increasing number of neurological diseases, from neurodegenerative disorders (eg, Parkinson’s disease) to rare conditions such as the subacute necrotising encephalopathy Leigh’s syndrome. “I think Parkinson’s disease [PD] is probably the neurodegenerative disorder together with Huntington’s disease that’s most accepted as
having a significant mitochondrial component to pathogenesis”, explains Schapira. “In PD, mutations of mitochondrial proteins like PINK1, the parkin [PARK2] mutations, DJ1, et cetera, are associated with inherited familial PD, and a number of the other mutations tend to have some mitochondrial effects”. The past few years have yielded several important insights into mitochondrial dynamics, courtesy of these mutations. “When parkin and PINK1 were first identified as causes of recessive PD we didn’t really understand their function”, Schapira explains; “but it’s become clear over the past few years that they’re intimately involved in the identification of defective mitochondria and their removal by mitophagy [a selective form of autophagy]”. This feeds into the notion that a buildup of defective mitochondria in Parkinson’s disease could result in an increase in the production of free radicals, so if a way could be found to increase the removal of defective mitochondria, the damage from free radicals could be reduced. Alongside attempts to develop drugs that enhance mitochondrial function, there is now an increasing push to develop drugs that can improve the general health of the mitochondrial population by increasing the turnover of defective mitochondria through mitophagy. “If you can prevent mitochondria becoming defective that would be very good, but if they are going to be defective then let’s get rid of them”, says Schapira. That would probably mean finding a mechanism to target the lysosome for increased removal of mitochondria. “There are a number of pharmaceutical companies and biotechs looking in detail at that pathway”, Schapira notes. With new insights into mitochondrial biochemistry coming thick and fast, these tiny organelles look destined to have a role in the treatment of an ever-greater number of neurological disorders.
For the UK Human Fertilisation and Embryology Authority report see http://www.hfea.gov. uk/6896.html For the Nuffield Council on Bioethics report see http:// www.nuffieldbioethics.org/ mitochondrial-dna-disorders/ mitochondrial-dna-disordersconclusions-and-ethicalconsiderations
David Holmes 29
