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11th May, 2018

Jeanette Radcliffe Secretary, Senate References Committee Parliament PO Box 6100, Canberra 2600

Dear Ms Radcliffe,

Re: Inquiry into the Science of mitochondrial donation and related matters Thank you for the invitation to provide a submission addressing the terms of reference. I have written this submission with the support and approval of Prof. Kathryn North, Director of the Murdoch Children's Research Institute (MCRI), and Prof. Martin Delatycki, Clinical Director of the Victorian Clinical Genetics Services (VCGS). To provide some personal context, I have been a close observer of in this area, with expertise based on: • leading the MCRI Mitochondrial Research Group and VCGS Mitochondrial Diagnostic Laboratory for over 25 years, with the latter long regarded as the Australasian referral laboratory for children suspected of mitochondrial disease; • being involved in diagnosis of over 600 children with mitochondrial disorders and over 150 relevant peer-reviewed publications; • publishing the first study on disease-causing mitochondrial DNA mutations in oocytes1; • defining approaches to predict the likelihood of having a with mitochondrial DNA disease and to predict outcomes of mitochondrial DNA mutations based on the amount of the mutation that a carries2-4; • writing one of the first comprehensive reviews on reproductive options for mitochondrial disease5, including defining circumstances where it was appropriate to offer prenatal diagnosis or pre- implantation genetic diagnosis; • professional involvement in human genetics and pathology via previous roles such as President of the Human Genetics Society of Australasia (HGSA), a member of the Royal College of Pathologists of Australasia (RCPA) Genetics Advisory Committee, Principal Examiner in Genetics for the RCPA Faculty of Science, and current roles including being a Director of the Australian Mitochondrial Disease Foundation (AMDF), Chair of the AMDF Scientific and Medical Advisory Committee and Co-Lead of the Australian Genomics Alliance Mitochondrial Diseases Flagship with Prof. John Christodoulou, who has put in a separate response. I should also acknowledge that I have collaborated for many years with the Newcastle, UK team who have pioneered the mitochondrial donation approach. This collaboration has focused on the genetics and prevention of mitochondrial disorders but I have not been directly involved in their research on mitochondrial donation. A brief summary of my Key Recommendations is provided below, followed by a detailed Response to the specific Terms of Reference. I have provided some background on the unique genetics of mitochondrial disease that are relevant to this inquiry in my responses but a useful 3-minute overview of mitochondrial disease and mitochondrial donation in lay language is provided as a video as part of a recent review I contributed to at www.nature.com/nrdp/animations/mito-dis-16.

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Key Recommendations • The devastating outcomes caused by mitochondrial DNA disease and the lack of effective treatments provide a compelling case to enable to access effective reproductive options to have healthy children. • Enormous progress has been made in the science of mitochondrial donation since previous reviews in 2010/2011 of relevant Australian legislation, namely the Prohibition of Human Cloning for Reproduction Act 2002 and Research Involving Human Act 2002. Research in Newcastle, UK and , USA suggests that mitochondrial donation is highly likely to be safe and effective. • The science and of mitochondrial donation have been reviewed extensively in the UK over the last 10 years. can incorporate most of the learnings and outcomes from that process rather than starting from scratch. • I recommend adopting the recommendations of the UK Human Fertilisation & Embryology Authority (HFEA), that: “The panel continues to see clinical value in maternal spindle transfer (MST) and pronuclear transfer (PNT) to mitigate or prevent the of mitochondrial disease. It recommends that, in specific circumstances, MST and PNT are cautiously adopted in clinical practice where inheritance of the disease is likely to cause or serious disease and where there are no acceptable alternatives.” • Extensive preclinical studies justify that the potential benefits now outweigh the potential risks if mitochondrial donation is offered in a cautious and targeted manner. As with the introduction of any new medical procedure or treatment, some uncertainties remain about safety and efficacy. • It is thus timely to amend Australian legislation to enable provision of mitochondrial donation in Australia to prevent severe mitochondrial diseases under appropriate regulatory oversight. • Australia should adopt the UK practice of issuing licenses to centres that wish to offer mitochondrial donation subject to “a requirement for appropriate levels of skill being demonstrated by named practitioners within a named clinic, and relevant key performance indicators being met”. The legislation should provide the capacity for centres seeking to offer mitochondrial donation to perform the preliminary experiments required to demonstrate competence in the licensing process, including that they can achieve carry-over of less than 2% of maternal mitochondrial DNA, as recommended by the HFEA panel. Licensing should also ensure that the proposed clinical pathway will ensure appropriate counselling and follow-up during and in childhood. • Australia should adopt the UK practice of issuing licenses only to couples “for whom preimplantation genetic diagnosis (PGD) or other methods would be inappropriate or unlikely to succeed”. • Regulation is potentially more complex in Australia and requires careful thought. In the UK, licensing is the responsibility of the HFEA. Given the level of expertise required and likely patient numbers, it would be desirable if there were no more than one or two Australian centres approved to offer mitochondrial donation. • To ensure community confidence in the licensing of centres and couples, a body independent of the IVF industry should oversee the licensing process. • It is imperative that prospective receive counselling about potential alternative approaches (both reproductive options and for concepts such as haplogroup matching), risks and benefits. • Appropriate legislative changes and a strong regulatory regime should ensure the community has confidence that this novel procedure will only be used for prevention of serious diseases caused by mitochondrial DNA disease and allay any concerns about slippery slope arguments.

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Response to Terms of Reference (a) the science of mitochondrial donation and its ability to prevent transmission of mitochondrial disease;

Mitochondrial diseases are basically problems in converting the energy in food into a small molecule called ATP, which all our cells and organs use to go about their normal business. The magnitude of this energy demand is shown by the estimate that we each have to make and degrade about 70 kilograms of ATP each day! Mitochondria are the powerplants in virtually all our cells that do this and are composed of more than 1200 different proteins that are encoded by an equivalent number of genes. The vast majority of these genes are among the roughly 20,000 regular (nuclear) genes in the 23 pairs of chromosomes, half of which are inherited from our mother and half from our .

We currently know of more than 250 different nuclear genes in which mutations cause severe mitochondrial disease in children or . However, mitochondria are unique in that they also contain a tiny chromosome (the mitochondrial DNA) containing just 37 genes, which is often regarded as an evolutionary relic.

Mitochondrial DNA is absolutely essential to energy and thus to our health and survival but does not contribute to characteristics such as appearance or intelligence, other than via mutations causing ill health.

Mitochondrial DNA has unique genetics in that it is inherited only from our . This is largely because mature human have about 200,000 copies of mitochondrial DNA, which vastly outnumber the approximately 50 copies present in . Sperm mitochondria also degrade soon after fertilising the .

In thinking about patients with mitochondrial disease, in about half the patients the genetic problem is in a nuclear gene, while in the other half it is in a mitochondrial DNA gene. Mitochondrial donation is only relevant to families affected by mitochondrial DNA disease. It has no role in prevention of any genetic disorder caused by any nuclear gene problem. The aim of mitochondrial donation is to allow parents to have a healthy child by replacing the mother's mitochondrial DNA (some of which carries a disease-causing mutation) with healthy mitochondrial DNA from a donor. The results of international research into mitochondrial donation

The science of mitochondrial donation has been largely pioneered by one centre in Newcastle, UK and another in Oregon, USA. The Oregon group developed a method called Maternal Spindle Transfer that involved removing the nuclear genes from mature eggs of Macaque monkeys. They then transferred the nuclear genes from one egg into another egg from which the nucleus had been removed. This led to carry- over of less than 3% of the mitochondrial DNA from the original egg, meaning the new egg had the mother’s nuclear genes but that over 97% of the mitochondrial DNA came from the donor egg. Eggs with donor mitochondrial DNA, could be fertilized and developed normally under IVF conditions6. They could also be implanted into Macaque monkeys, leading to the birth of Macaques that were later reported to show normal growth and development7.

Subsequently, the Oregon group showed that the Maternal Spindle Transfer method could also be applied to human eggs successfully. Unlike in Macaques, about half the human eggs that underwent mitochondrial transfer showed abnormal fertilization with this method, but those that did fertilise successfully showed 4 normal embryonic development7. The authors concluded that normal blastocysts could be derived with sufficient efficacy for the procedure to be safe and effective. More recently, the Oregon group demonstrated that maternal spindle transfer worked comparably for eggs from women who carried disease-causing mitochondrial DNA mutations and those who did not. They also showed they could achieve less than 1% carry-over of the mother’s mitochondrial DNA8. The Newcastle group started with fertilized human eggs (also called or 1-cell embryos), and used Pronuclear Transfer to transfer the nuclear genes from both parents into another 1-cell from which the nuclear genes had been removed. The treated embryos develop into blastocysts (embryos with about 100 cells) at the same rate as embryos which had not undergone mitochondrial transfer9. For ethical reasons, the initial experiments were performed on abnormal embryos that were unsuitable for IVF use due to having chromosomal abnormalities. As part of four reviews performed by the UK HFEA, the group was then required to demonstrate the method worked efficiently on normal human embryos. After some modifications to the timing, they showed equivalent results10. Additional safety experiments were performed to determine whether there was any potential for mitochondrial DNA carry-over to result in the original mitochondrial DNA from the mother’s egg increasing back up to substantial levels. Their data showed that this did not happen so long as the procedure ensured no more than 2% of the mother’s mitochondrial DNA was present in the embryo after mitochondrial transfer10. Skilled operators using Maternal Spindle Transfer or Pronuclear Transfer can ensure that less than 2% of the mother’s mitochondrial DNA is carried over in the mitochondrial transfer procedure.

It is almost always impossible with medical advances to be able to offer absolute certainty that a new technology will completely prevent disease. However, I believe that so long as these methods are restricted to a limited number of expert centres, and appropriately regulated, then for parents who wish to have a child genetically related to both parents, these methods will provide a huge reduction in the risk of having a child with mitochondrial DNA disease.

Together with the other leading Australian researchers in mitochondrial research related to embryology, biochemistry, paediatric disease and disease (Professors John Carroll, Mike Ryan, John Christodoulou and Carolyn Sue, respectively), I was one of 40 international experts on mitochondrial disease who wrote an open letter to the UK government in 2015 (https://www.theguardian.com/science/2015/jan/30/parliament-should-approve-regulations-for- mitochondrial-donation). We encouraged them to legalise mitochondrial donation as we believed the method was appropriate to “offer some affected families the opportunity to have healthy children”. I am not aware of any of the 40 co-signatories changing their based on new data published since then.

(b) the safety and efficacy of these techniques, as well as ethical considerations;

As background to this section, it is worth noting that the introduction of any new medical procedure or treatment is accompanied by some degree of uncertainty about safety and efficacy, irrespective of the extent of preclinical studies.

It is unlikely that any IVF technique or most other medical advances could ever have been introduced if absolute certainty was a pre-condition of their application to human subjects. It is thus necessary to consider the balance of potential benefits and potential harms to decide whether application to human subjects is appropriate and what types and duration of monitoring should be in place to assess safety and efficacy if the benefits outweigh the harms. 5

Efficacy

The two key issues abut efficacy are firstly whether mitochondrial DNA donation procedures can allow efficient replacement of mitochondrial DNA in the egg or embryo and secondly, will the original amount of the donor’s mitochondrial DNA remain stable throughout pregnancy and childhood. As noted above, the Oregon and Newcastle groups have shown that both mitochondrial donation methods can generate human embryos with efficient replacement of maternal mitochondrial DNA by healthy donor mitochondrial DNA (over 98% efficiency). Furthermore, these embryos can develop comparably to eggs or embryos that have not been subject to mitochondrial donation. Thus, expert groups can achieve high efficacy in replacement of mitochondrial DNA. Stability of donor and maternal mitochondrial DNA during pregnancy

The Oregon and Newcastle groups both noted that when embryonic stem cells are generated from embryos that have undergone mitochondrial donation, a minority showed partial reversion to the maternal mitochondrial DNA type following prolonged cell culture8, 10. A third group from Columbia University, New York studied this phenomenon in human oocytes that underwent mitochondrial donation then parthenogenesis (the development of an oocyte without fertilisation) prior to generation of stem cells and also found that a minority underwent reversion to the maternal mitochondrial DNA.

These observations raise some uncertainty about whether donor mitochondrial DNA could be partly or significantly replaced by the mother’s mitochondrial DNA in embryos during pregnancy. The Newcastle group found that this reversion phenomenon did not occur when less than 2% of the mother’s mitochondrial DNA was carried over.

All these studies have been based on embryonic stem cells following prolonged cell outside the embryo. In terms of ongoing efficacy of mitochondrial donation, the key issue is whether mitochondrial reversion may occur in the tissues and organs of the developing . It is not yet clear if this phenomenon will occur in human and impact on efficacy. It is relevant to note that Macaque monkeys born following mitochondrial donation had undetectable levels of the maternal mitochondrial DNA, so the phenomenon was not observed in the most relevant model.

A group led by Dr John Zhang of the New Hope Fertility Center in New York has also published data on mitochondrial transfer in human pregnancies. This group has attracted controversy by performing mitochondrial donation by maternal spindle transfer in Mexico to avoid regulatory scrutiny by US authorities. The inappropriateness of such practices will be commented on later. However, in the one with mitochondrial DNA disease for whom they reported outcomes, studies of multiple tissues collected within two days of birth found low levels of maternal DNA carry-over, ranging from undetectable to 9%, which were comparable to the levels of 5% – 6% maternal mitochondrial DNA measured in the blastocyst prior to implantation11. Thus the available data on Macaque and human pregnancies following mitochondrial transfer have not detected reversion to the maternal mitochondrial DNA type. The HFEA studied this issue carefully and did not regard it as warranting further delay in approval of mitochondrial donation. Safety

Some academics have expressed concerns that mitochondrial transfer could lead to incompatibility between the donor mitochondrial DNA and the nuclear genome of the parents. Most of the reasoning relates to what are known as mitochondrial DNA haplogroups, which represent the 6 ancestral of human populations. All modern are thought to be descended from a group of individuals present in some 100,000 to 200,000 years ago. As some groups migrated from Africa, their nuclear and mitochondrial genomes began to accumulate sequence changes that have allowed tracking of population movements around the world. These sequence changes can be called mutations as that term really means any change in the DNA and does not necessarily imply a harmful change. If we sequence the approximately 16,500 nucleotides that make up the mitochondrial DNA in any two unrelated humans we typically find from 5 to 40 locations where an individual nucleotide differs. The more distant the separation of two maternal lineages giving rise to individuals, the greater the expected number of sequence differences between mitochondrial haplogroups. The two major potential safety concerns that have been raised relate to potential problems that may occur due to (i) two different mitochondrial DNA haplogroups being present in one embryo or (ii) the human mitochondrial genome having “co-evolved” with the nuclear genome in , raising the possibility of a conflict with the paternal nuclear genome.

It is clear that on an evolutionary timeframe, mitochondrial DNAs in different species have evolved in parallel with variants in the nuclear genome, such that mitochondrial DNA and nuclear DNA from distantly related species (such as humans and chimpanzees) are now incompatible. There remains some uncertainty about the relevance of mitochondrial DNA variants within species to health outcomes.

Numerous studies in humans, mice and other species have suggested that mitochondrial DNA haplogroups may influence parameters related to a wide range of characteristics or outcomes, including sperm motility, infection resistance, susceptibility to neurodegenerative disease and . However, most human studies are based on association studies that have often not been replicated robustly.

Many animal studies have relied on using mitochondrial DNA from strains of mice12, flies13 or other species that are much more divergent than human populations or on measuring characteristics in inbred strains that enable detection of variations that may well be undetectable or within the normal range in outbred populations.

Such studies have led to suggestions that in mitochondrial donation the donor mitochondrial DNA should be a close genetic match to the maternal mitochondrial DNA. I agree with the conclusions of the HFEA review which noted that “At present, the panel any risks associated with a mtDNA-nuclear DNA mismatch remain theoretical; the recent studies examining embryonic cells and stem cells generated from MST- and PNT-derived human embryos reported no evidence of any complications or compromise of mitochondrial function arising from unmatched mtDNA haplogroups”. The HFEA panel concluded that “consideration is given to mtDNA haplogroup matching as a precautionary step in the process of selecting donors”. My personal opinion is that haplogroup matching is unlikely to be an issue of clinical significance in mitochondrial donation and I am concerned that requiring it will decrease the chance of at-risk families being able to access a suitable egg donor. However, I do acknowledge that this remains an area of uncertainty and support the concept that couples must be provided with balanced . Until there is more experience with mitochondrial donation, it seems reasonable to recommend haplogroup matching if practicable but to enable couples to choose to use an unmatched haplogroup donor.

In addition to the apparently normal development of Macaque and human embryos following mitochondrial donation, several other observations on small numbers of Macaque and human pregnancies suggest that mitochondrial donation is expected to be safe, as follows: 7

(i) Macaque monkeys born after mitochondrial donation show normal growth and development as well as normal markers of mitochondrial function7. (ii) The one baby reported to be born after mitochondrial donation in a family with mitochondrial DNA disease was said to be healthy at 7 months of age11. (iii) Prior to experiments on mitochondrial donation, an IVF clinic led by Dr Jacques Cohen at Saint Barnabas Medical Center in New Jersey, USA reported the use of a procedure known as “ooplasmic transplantation”. This involved transfer of about a third of the cytoplasm (including mitochondria) from eggs of young donors to eggs of older women with a fertility problem known as recurrent implantation failure14. The study took place between 1996 and 2001 and was unrelated to mitochondrial disease. In total, 13 couples delivered 18 babies who appeared to be healthy at the time of delivery. As commented on at the time by myself15 and others, these studies were poorly designed science without appropriate controls or follow-up. A limited survey-based follow-up study on the children was recently reported in which 12 out of 13 parents completed a questionnaire on pregnancy, birth, health, academic performance and disclosure16. The report is subjective and open to biases given that no independent clinical assessments were performed. However, all parents who responded reported their children as being in good health, doing well in and having never repeated a grade. Despite the limitations of the report, it provides at least anecdotal support that children carrying a mixture of two mitochondrial DNA haplogroups do not appear to have suffered major problems related to growth and development.

Regarding safety and efficacy, I agree with the HFEA panel that potential parents should receive counselling about there being some uncertainty about these issues, which means the procedure should be described as risk reduction rather than prevention. The available data on humans and Macaques provide reassurance but the true efficacy of mitochondrial donation will only be resolved by monitoring of babies during childhood to confirm the stability of donor mitochondrial DNA levels.

(c) the status of these techniques elsewhere in the world and their relevance to Australian families

The United Kingdom

The UK was the first country to change their legislation and introduce a process to regulate mitochondrial donation. towards that outcome began well over 10 years ago with the Human Fertilisation and Embryology Act 1990 being amended in 2008 to allow experimental studies to be performed on human embryos. This led to HFEA reviews in 2011, 2013, 2014 and 2016, together with multiple forms of public consultation and a Nuffield Bioethics Council review. The HFEA (Mitochondrial Donation) Regulations were passed in February, 2015 in the House of Commons by a majority of 382 to 128 votes, while in the House of Lords, a Motion to block approval was rejected by 48 to 280 votes. Prior to the votes, Jeremy Farrar, the Director of the Wellcome was quoted as saying "I don't think there's been any more rigorous look at any scientific endeavour coming into humans". As noted in the 2015 Guardian letter referred to earlier, 40 international experts stated that “the UK has run an exemplary and internationally admired process for considering benefits, risks, ethical issues and public , which must properly precede a change in the ”. Further, the HFEA 2016 report stated “In deciding to change the law Parliament has always been clear that neither MST nor PNT should be introduced into clinical practice until they were judged sufficiently safe.” 8

Thus the UK Parliament recognized that developing detailed legislation to regulate all aspects of the mitochondrial donation process was impractical and they devolved much of this responsibility to the HFEA to determine exactly when and how mitochondrial donation would be delivered in the UK. The 2014 HFEA review required additional safety experiments to be performed on normal human embryos. Following publication of these experiments by the Newcastle group in June 2016, the final HFEA report in November 2016 enabled licensing of mitochondrial donation. The Newcastle centre was licensed to offer the procedure in March 2017 and the first two couples were licensed to access the procedure in February 2018. It is thus expected that the first births following mitochondrial donation in the UK will occur later this year or in early 2019. The of America

In the USA, mitochondrial donation is commonly referred to as Mitochondrial Replacement Therapy (MRT). The NIH commissioned the Institute of Medicine of the National Academies of Sciences, Engineering, and Medicine to assemble an expert committee who generated a final report entitled Mitochondrial Replacement Techniques: Ethical, Social, and Policy Considerations. The report was delivered to NIH in February 2016 and can be accessed at http://www.nationalacademies.org/hmd/~/media/Files/Report Files/2016/Mitochondrial Replacement Techniques/MitoEthics-RIB.pdf.

The report recommended initial investigations be considered by the Food & Drug Administration (FDA) after further conditions were met regarding safety and efficacy subject to specific conditions, namely:

• limiting its use to women who are at risk of transmitting a serious mtDNA disease • consideration of the mother’s health status and any impact of the pregnancy on her and the fetus • allowing only male embryos to be implanted in to prevent any potential adverse consequences from being passed on to future (until longer-term safety was proven) • investigations be limited to investigators and centers with demonstrated expertise in and skill with relevant techniques • further consideration of haplogroup matching as a means of mitigating the possible risk of mtDNA-nDNA incompatibilities

The panel specifically considered whether mitochondrial donation should be considered as germline genetic modification, which has been considered as inappropriate in almost all international jurisdictions. They noted an important distinction between modification of mitochondrial DNA versus nuclear DNA in terms of technology, traits and potential for enhancement and stated “These distinctions could allow justification of MRT independent of decisions about heritable genetic modification of nDNA”.

Mitochondrial donation in the USA is currently blocked by Congress. As noted on the FDA website, “The clinical use of MRT in the United States falls within FDA’s regulatory authority. Since December 2015, Congress has included provisions in annual federal appropriations that prohibit FDA from accepting applications for clinical research using MRT. Therefore, clinical research using MRT in humans cannot legally proceed in the United States.” www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ucm570185.htm Other international experience

I am not aware of other countries that have changed legislation or regulations related to mitochondrial donation or had a formal consideration of so doing. However, there are several examples of practitioners apparently trying to perform mitochondrial donation experiments in ways that bypass regulatory authorities. These raise significant concerns about Australian families with mitochondrial disease 9 potentially trying to access unregulated and potentially poor quality practitioners overseas. The most prominent examples are as follows: Mexico (and USA)

As mentioned earlier, there has been one example of an apparently successful attempt to prevent transmission of a mitochondrial DNA mutation by maternal spindle transfer, led by Dr John Zhang from New Hope Fertility Center in New York with a couple who lived in Jordan11. This group evaded US regulatory oversight by performing the embryo studies in the USA but implanting the embryo in Mexico, where Dr Zhang was quoted as saying “There are no rules”.

This led to a mixed response of excitement that the procedure appeared to have been successful but strong criticism, including from myself, about deliberate evasion of regulation and the contrast with the exemplary preliminary studies and public by the Newcastle and Oregon teams. Specific concerns about this related to:

(i) performing the technique in Mexico to avoid US regulations;

(ii) publicising the research via a conference abstract that lacked many of the relevant details;

(iii) lacking a track record of transparency, having previously publicised controversial data at a conference, followed by a 13-year delay in subjecting it to peer review, as described in the section below;

(iv) reporting an efficacy that was inferior to the expert Newcastle and Oregon groups, achieving only 95% removal of maternal mitochondrial DNA (compared to levels of over 98% achieved and recommended by the Newcastle and Oregon groups) and noting that 3 of the 4 blastocysts they generated had chromosomal abnormalities;

(v) stating that their regulatory advice was from Dr Jacques Cohen, who led the ooplasmic transfer experiments described previously that were subsequently banned by the FDA;

(vi) lack of clarity about counselling, consent and planned follow up, including whether the couple were offered advice about other reproductive options. Indeed, the couple who underwent the procedure would not have been eligible for mitochondrial donation in the UK system, at least initially, given the specific mutation and the amount the mother carried. They may have been eligible after first attempting pre- implantation genetic diagnosis (PGD). I advised Melbourne IVF in provision of PGD to a couple where the mother carried an equivalent amount of the same mutation, which enabled the couple to have a healthy child.

As noted, the group announced the results in the press rather than publishing a peer-reviewed journal article to enable appropriate expert scrutiny. The latter was not published until some months later11 and was accompanied by an editorial noting that “the scientific community must be informed of the details of the work in full in order to evaluate it critically and discuss it openly. We decided this despite the fact that the work has weaknesses and limitations in a number of areas. Moreover, although we were able to encourage the authors to include more details of their work in the submission, some uncertainties concerning and results still remain”17. There was also speculation that the group was leading with mitochondrial disease but really wanted to use the procedure for the unproven purpose of addressing age-related infertility in the general population. This seemed to be confirmed when they founded a start-up company “Darwin Life”, and began marketing the approach as Human Egg In Vitro Fertilization or “HER IVF”, as described elsewhere (www.geneticsandsociety.org/biopolitical- 10 times/fda-reprimands-fertility-doctor-marketing-genetic-modification-human-embryos).

Appropriately, the FDA sent Dr Zhang a Cease and Desist letter (www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Compliance Activities/Enforcement/UntitledLetters/UCM570225.pdf) and it seems unlikely they are now able to proceed with any aspects of these studies in the USA. It was subsequently pointed out that if the embryo studies had been done in Mexico, it appeared they would have also broken Mexican federal health regulations (https://www.bionews.org.uk/page_96153). Given Dr Zhang is now barred from performing the embryo studies in the USA, it seems unlikely that further studies could proceed in Mexico. China

Prior to his work in New York, at a conference in 2003, Dr John Zhang reported a study performed in Guangzhou in which Pronuclear Transfer was used in an attempt to treat unexplained infertility. This attracted much criticism and the details were not subjected to peer review and published until some 13 years later18. They attained a triplet pregnancy in an infertile patient, but the pregnancy resulted in no live births.

Shortly after, in 2003, the Chinese Ministry of Health published Principles that appear to ban clinical use of mitochondrial donation techniques. More recently, a group from Shandong province have published two studies of the efficacy of mitochondrial donation techniques in human embryos19, 20. A Nature news article in late 2016 commented on a baby supposedly having been born in China following mitochondrial donation (www.nature.com/news/reports-of-three-parent-babies-multiply-1.20849), but I am not aware of any evidence substantiating this.

Ukraine

There have been media reports about doctors in the Ukraine using Pronuclear Transfer to establish a pregnancy that resulted in a baby being born to an infertile couple (www.sciencealert.com/world-first-in- ukraine-as-three-parent-baby-born-to-an-infertile-couple).

This provoked controversy because of the lack of details, lack of a peer reviewed publication, and ambiguity around the rigour of the approval process given the lead researcher, Dr Valeriy Zukin, is Vice- President of the Ukraine Association for Reproductive Medicine, which oversaw the approval process. As with the Zhang studies marketing these technologies to infertile couples, there is a lack of evidence to substantiate that mitochondrial donation improves IVF outcomes.

Cambodia

The AMDF will likely have explained in more detail that in early 2018, a branch of the First Fertility IVF group in Phnom Penh attempted to join the AMDF Facebook page, which would have enabled them to families affected by mitochondrial disease. When questioned why, they stated that Phnom Penh is the only city where they can legally offer mitochondrial replacement therapy.

They stated that “Next month on Feb 18 and 19, we will have the world renowned MRT scientist to perform in our lab, due to confidentiality agreement I am unable to disclose his but he is always on CNN n Times. I thought it would be helpful to patients with this disease that's why I made a move to contact.” This raises clear concerns about medical tourism and seeking to attract Australian couples to access a procedure in an environment where standards of expertise, safety, efficacy and consent are unclear. 11

In summary, the UK has clearly led the world in developing an exemplary process to introduce mitochondrial donation. The USA has invested considerable time in considering the relevant issues but is currently blocked by Congress and appears to lack a path to move forward. A recent review of regulations in 16 countries noted that clinical use of mitochondrial donation methods were either largely prohibited (in USA and China), not regulated (in Northern Cyprus and Ukraine), or insufficiently regulated (in the remaining 12 countries, including Mexico)21. Australia can show international leadership in this area by being only the second country to adopt the targeted and cautious use of mitochondrial donation to enable families affected by mitochondrial disease to have healthy children.

(d) the current impact of mitochondrial disease on Australian families and the healthcare sector;

MCRI published the largest international study on the incidence of mitochondrial disease in childhood in 2003 and, combined with adult data, documented that at least 1 in 5,000 births will result in a child who will develop severe mitochondrial disease during their lifetime22. This corresponds to approximately 60 children being born in Australia each year, and makes mitochondrial disorders the most common group of inherited metabolic disorders.

The real impact, however, may be much higher since studies by Prof. Carolyn Sue (in the Australian population) and others have shown that at least 1 in 250 individuals carry a mutation in their mitochondrial DNA that could cause disease23, 24. Mitochondrial diseases most often affect organs with the highest energy requirements such as brain and heart, but can affect any organ system either individually or in combination. Common clinical features include impaired physical or , cardiomyopathy, myopathy, diabetes mellitus, deafness, blindness, renal disease, strokes and dementia25.

Some patients show prolonged periods of clinical stability, but these disorders are generally progressive with episodes of decline, often triggered by acute infection or other stresses. Onset of symptoms can be at any age and this clinical variability combines with the complicated genetics of these disorders to mean that many patients have suffered a diagnostic odyssey of many years, seeing multiple doctors, and undergoing tests including muscle biopsies before they receive a diagnosis.

Fortunately, the advent of new genomic sequencing technologies is transforming our ability to obtain genetic diagnoses in a much higher proportion of patients without the need for muscle biopsy. Our 2012 Cochrane review of over 1300 publications related to treatment of mitochondrial disease concluded that “there is currently no clear evidence supporting use of any intervention in mitochondrial disorders26”. Some symptomatic treatments do help patients and a number of preclinical studies are showing promise for new pharmacological approaches that should improve outcomes for some patients. If affected individuals had survival that was comparable to the general population, there would be at least 5000 Australian patients with severe mitochondrial disease. However, survival is markedly compromised.

Nearly half of all patients with mitochondrial disease have onset in childhood and a number of studies on different subgroups and in different countries have found that median age of survival in affected children ranges from less than 3 to less than 12 years of age27-29. It is difficult to provide an accurate estimate of median survival for all forms of these highly diverse diseases but it would seem reasonable to assume that the median lifespan of affected individuals would be less than half that of the general population, meaning that the point prevalence of mitochondrial 12 disease corresponds to about 2000 people in Australia living with severe mitochondrial disease, due to the early death of most affected individuals. Of course, the impact of mitochondrial diseases goes well beyond just the patient. Issues such as delayed diagnosis, uncertain prognosis and lack of effective treatments weigh heavily on the emotional and financial resources of all family members, frequently resulting in time off work or out of the workforce. An American study estimated that each child with an inherited rare disease has a lifetime cost to the healthcare system of US$5M30. While no comparable Australian estimates are available, it is clear that diseases like mitochondrial diseases have a major impact on health care costs for families and society. Disorders caused by mitochondrial DNA mutations have additional impacts on families, one of which is that it is often not practical to predict the likelihood of parents and female maternal relatives having an affected child.

It is important to note that some individuals with a family history of mitochondrial DNA disease can use conventional reproductive options such as donor egg IVF, prenatal diagnosis or preimplantation genetic diagnosis (PGD) to reduce their risk of having an affected child. However, all these methods have limitations. Egg Donation

Egg donation can prevent inheritance of mitochondrial DNA disease, with the resulting child genetically related to the father and egg donor but not the mother. Many parents have a strong wish to have a child who is genetically related to both parents and are unwilling to use egg donation, the waiting list for which can also be several years long due to a shortage of donors. Prenatal Diagnosis

Prenatal diagnosis for mitochondrial DNA disease is complicated by the potential difficulty in predicting outcomes for babies where the amount of mutant DNA is neither very high nor very low. Parents are also in the position of having to make a decision on potentially ambiguous results 12-16 weeks into the pregnancy, making the decision to terminate or continue the pregnancy particularly fraught.

Preimplantation Genetic Diagnosis (PGD)

PGD has the advantage of decisions being made prior to a pregnancy being established since the testing is typically done on 8-cell embryos generated by IVF. The only embryos that would be regarded as suitable for implantation would be those containing very low amounts of a mitochondrial DNA mutation, or none at all. However, if most of the mother’s embryos are found to contain significant amounts of a mitochondrial DNA mutation, then PGD is highly unlikely to achieve a successful pregnancy. These limitations mean that, in practice, prenatal diagnosis and PGD are only suitable for women who carry low levels of mutant mitochondrial DNA in blood and other tissues and who are thought to have a low chance of having an affected child. They are thus unsuitable for the majority of women at risk of having a child with mtDNA disease. These issues have been the driver for developing mitochondrial donation approaches.

(e) consideration of changes to legal and ethical frameworks that would be required if mitochondrial donation was to be introduced in Australia;

Enormous progress has been made in the science of mitochondrial donation since previous reviews of relevant Australian legislation, namely the Prohibition of Human Cloning for Reproduction Act 2002 and 13

Research Involving Human Embryos Act 2002. Regulatory and legal issues

The devastating outcomes caused by mitochondrial DNA disease and the lack of effective treatments provide a compelling argument to enable cautious and regulated use of mitochondrial donation given most international mitochondrial disease experts believe the preclinical data now justify the likely safety and efficacy if performed in an expert centre. It is timely to amend Australian legislation to enable provision of mitochondrial donation in Australia to prevent severe mitochondrial diseases under appropriate regulatory oversight. As a practical issue, it is relevant to note the existence of -based legislation around Assisted Reproduction Technology, which exists in Victoria, NSW, South Australia and Western Australia. I believe these are essentially mirror legislation and State legislatures could potentially adopt equivalent changes to the federal legislation.

At least some of those States have regulatory bodies, such as the Victorian Assisted Reproductive Treatment Authority, which could be an appropriate regulatory body if responsibility was delegated to the States. However, the lack of such bodies in all States and desire for a uniform national approach complicate this.

In the UK, the HFEA has responsibility for issuing licenses to centres that wish to offer mitochondrial donation. I support their recommendation of “a requirement for appropriate levels of skill being demonstrated by named practitioners within a named clinic, and relevant key performance indicators being met, parameters that will be assessed by the HFEA”.

Regulation is potentially more complex in Australia and requires careful thought. My understanding is that, as with any other IVF technique, any clinical application of mitochondrial donation will need to be accredited by the Reproductive Technology Accreditation Committee (RTAC), which is a subcommittee of the Board of the Fertility Society of Australia. Australian experience with related issues

Australian IVF providers have clearly been international leaders in developing and improving IVF techniques and in engaging with academia, government and the public. In the area of mitochondrial disease, I have had strong collaborations with Melbourne IVF (now Virtus), originally with Dr Debra Gook and more recently Dr Sharyn Stock-Myer, in relation to couples at risk of having a child with mitochondrial DNA disease. These have led to important basic knowledge about reproductive options and enabled some couples to have a healthy child via pre-implantation genetic diagnosis. Monash IVF and Sydney IVF (now Genea) have also been involved in important mitochondrial research at various times.

I am concerned, however, that publicity around some overseas IVF providers seeking to market and profit from using mitochondrial donation techniques as an unproven way to boost IVF fertilisation rates has the potential to imperil public confidence in mitochondrial donation in the event that Australia does not take a strong lead on this issue. I believe that most Australians provided with the relevant information would support the use of mitochondrial donation to prevent the devastating outcomes of mitochondrial disease.

Despite strong community support for IVF, I am not certain that would be the case for research on mitochondrial donation related to infertility. Perhaps that may be appropriate in the future when there is more experience confirming the effectiveness of using mitochondrial donation to prevent mitochondrial 14 diseases. I therefore regard it as important that legislative change ring-fences mitochondrial donation so that it can only be used for development and application of techniques for the prevention of severe mitochondrial diseases. A way forward

My personal view is that public confidence in regulatory requirements will also be much stronger if oversight of regulation is provided by a body that is seen to be independent of the IVF industry. Given the novel and technically demanding nature of the procedures, the need for interaction with mitochondrial disease experts and the anticipated patient numbers, it would be desirable if there were no more than one or two Australian centres approved to offer mitochondrial donation. Any such centres would need to invest in research and training, potentially by engagement with centres such as Newcastle in the UK, to ensure they can achieve satisfactory outcomes.

Together with the desirability of ensuring collection of data on medium- to long-term outcomes, I recommend that a body independent of the IVF industry should have oversight over licensing of centres seeking to offer mitochondrial donation. One potential body would be the NHMRC Embryo Research Licensing Committee. If this was unsuitable then it may require an independent body to be up, perhaps with input from the Australian Academy of Health and Medical Sciences.

Provision of counselling

In the context of mitochondrial donation, it is imperative that prospective parents receive counselling about potential alternative approaches (both in terms of reproductive options and for concepts such as haplogroup matching), risks and benefits. Equally it should be ensured that the procedure is only offered in appropriate cases for prevention of serious mitochondrial diseases.

In the UK, the HFEA has responsibility for issuing licenses only to couples “for whom preimplantation genetic diagnosis (PGD) or other methods would be inappropriate or unlikely to succeed”. Pre-treatment assessment must take into account a range of factors and I also believe this should be overseen by a body independent of the IVF industry, which could presumably be the same body overseeing licensing of centres, with input from experts in multiple disciplines.

Appropriate legislative changes and a strong regulatory regime should ensure the community has confidence that this novel procedure will only be used for prevention of serious diseases caused by mitochondrial disease and allay any concerns about slippery slope arguments. Ethical issues

I will not comment in detail on ethical issues since the Inquiry will receive input from at least two senior Australian biomedical ethicists with detailed knowledge of the UK process and an ongoing interest in mitochondrial donation who have published on this topic in peer-reviewed journals, namely A/Prof. Ainsley Newson31, 32 and Prof. Julian Savulescu33. It is worth reiterating that the UK process went to great efforts around ethics (via the Nuffield Council on Bioethics) and public engagement. The latter particularly involved the Lily Foundation, who engaged with politicians, provided accessible information (e.g., the video “What’s mitochondrial disease” narrated by Bill Nighy, https://www.thelilyfoundation.org.uk/get-informed/mitochondrial-disease) and encouraged patients and parents to tell their stories in the media so people understood the true human impact of mitochondrial diseases. It does not seem necessary to repeat this process in its entirety here but it does seem important to engage 15 the Australian community in an open way about the impacts of mitochondrial disease and the justification for legislative change. The AMDF have been attempting to do this by political engagement; through public symposia; by supporting communication of real-life stories of affected families (as in the ABC 730 report http://www.abc.net.au/news/2017-11-20/three-parent-babies-and-mitochondrial-donation/9100228); and by ensuring expert commentary is available whenever relevant developments have attracted media attention.

(f) the value and impact of introducing mitochondrial donation in Australia;

At the present time, most couples who are at risk of having a child with mitochondrial DNA disease are unable to access a reliable method to have children who are genetically related to them. In the absence of effective treatments, prevention is the key to minimizing the emotional and financial impact on individuals, on their extended families and on the Australian health system.

Mitochondrial donation has the potential to allow such couples to have a healthy child free of mitochondrial disease. In the absence of such options, some couples will choose to not have children while others will take their chances, which may result in them having another child affected by mitochondrial disease.

A key issue in planning for mitochondrial donation is to predict the likely number of women who may choose to access the procedure. This is difficult due to the clinical and genetic heterogeneity of these disorders meaning that substantial numbers of affected individuals may not currently be being diagnosed.

However, two types of calculations suggest that approximately 60 women each year in Australia are at substantial risk of having a child with mitochondrial disease and many of these may choose to access mitochondrial donation if it were available.

The first estimate is based on the epidemiological data mentioned previously that suggest at least 60 babies born in Australia each year will develop severe mitochondrial disease during their lifetime22. About half these individuals will have disease caused by mutations in a nuclear gene and mitochondrial donation is not relevant to their parents since they can access regular reproductive options.

However, for those families where the disease is caused by a mitochondrial DNA mutation, it is often not only the mother who is at risk of having an affected child. If she has or maternal or other maternal relatives of child-bearing age they are also at risk of having an affected child and mitochondrial donation may well be an appropriate method for them to access. It therefore seems reasonable to think that doubling the number of births with mitochondrial DNA disease could give a ball- estimate, and hence that mitochondrial donation could be relevant to up to 60 pregnancies per annum in Australia. The second way to estimate likely numbers is to start from the estimated numbers of mothers and maternal relatives rather than the number of patients. The Newcastle group estimated how many women were present in the UK between the ages of 15 and 44 years who carried potentially inheritable mitochondrial DNA mutations. The starting point was their registry of patients and family members in North-East who were known to be carrying a mitochondrial DNA mutation. They combined these numbers with estimates of fertility rates in the general population and among affected and unaffected female carriers of mitochondrial DNA mutations. This led to an estimate of the average number of births per year among women at risk for transmitting mitochondrial DNA disease of 152 (95% Confidence Interval of 125 to 200) in the United Kingdom34. Based on the respective populations of 66M and 25M, this predicts a figure of 58 births in Australia each year among women at risk for transmitting mitochondrial DNA disease. 16

Given the number of women at risk of having a child with mitochondrial DNA disease, and being conservative about the likely uptake, it would seem reasonable to predict that mitochondrial donation may lead to the birth of say 5 to 10 healthy children in Australia each year instead of 5 to 10 with mitochondrial disease. Factoring in the estimated lifetime cost to the healthcare system for children with an inherited rare disease of US$5M (mentioned previously), this would equate to an estimate of about A$33M to A$66M in future health care costs saved each year by such couples to access mitochondrial donation.

While this is a somewhat facile calculation with a number of assumptions, it does suggest there would be a strong health economic case underpinning provision of mitochondrial donation. Of course, the broader impact will be on the emotional, social and financial benefits to the family and society.

(g) other related matters.

Australian capability

A significant practical consideration is whether any Australian IVF centre will have the skills and desire to commit to developing a mitochondrial donation IVF program.

Given the strong academic history of Australian IVF groups, I think this will be achievable and know of at least one centre (Monash IVF) that has been engaging with AMDF and mitochondrial researchers on this topic. As demonstrated by submissions to this Inquiry, I believe there would be strong buy-in from expert Australian researchers and clinicians to one or two IVF centres seeking to introduce mitochondrial donation.

Relevant medical researchers such as myself and Profs Carolyn Sue, John Christodoulou, Aleks Filipovska, Mike Ryan and John Carroll have existing connections to the Newcastle, UK group that have pioneered mitochondrial donation. With support from the AMDF, we have sponsored lead researchers from Newcastle to present at AMDF Symposia and the biennial AussieMit meetings that bring the Australian mitochondrial research community together.

In 2018, two such researchers will visit Australia. Prof. Robert MacFarland, co-lead of the Newcastle mitochondrial donation clinical team, will speak at AMDF Public Symposia in Sydney on August 18 and in Melbourne on August 20. Prof. Sir Doug Turnbull, Director of the Wellcome Trust Centre for Mitochondrial Research, who has been the driving force behind the Newcastle research, will be a keynote speaker at the AussieMIt 2018 conference in Melbourne from November 29th to December 1st (www.aussiemit.com.au). As convenor of that conference, I have also arranged for him to give a public lecture in Melbourne on the evening of November 28th. I mention this to emphasise both our commitment to public engagement and our close interactions with the Newcastle group, who have indicated a willingness to train Australian embryologists and other team members to facilitate introduction of mitochondrial donation into Australia. Funding

Another significant practical consideration is funding the development of a mitochondrial donation service. Initially, much of this would need to come substantially from research funding and a number of sources have potential to support the translation of mitochondrial donation research into clinical practice.

There is already a national collaborative effort in mitochondrial disease diagnosis supported by the NHMRC-funded Australian Genomics Health Alliance, which forms the basis for a broader national collaboration going forward. The field also ties in to priorities of the Medical Research Future Fund such as Rare Diseases and Genomics. Potential also exists for applications for NHMRC Research grants including 17

Partnership grants between AMDF, clinical, genetics, neurology, embryology and ethics researchers together with an IVF provider or providers. Other philanthropic sources in addition to AMDF may be interested, so it is realistic to assume that if legislation is changed, there is strong likelihood of being able to deliver the benefits of mitochondrial donation. Potential for medical tourism

As a final point on the Australian context, I will point out the potential that if mitochondrial donation is not legalised in Australia, then Australian couples at risk of mtDNA disease will likely try to access overseas operators who may be acting under no regulatory oversight. As noted earlier, this has already been attempted by a Cambodian IVF clinic. A pathway to accessing mitochondrial donation in a regulated manner in Australia will ensure that Australian couples are not tempted to access “cowboy” IVF groups operating in unregulated environments.

I thank the Senate Community Affairs References Committee for their interest and engagement and hope that submissions provide the information and encouragement needed for the Committee to support and recommend the legislation of mitochondrial donation in Australia.

Yours sincerely,

Professor David Thorburn PhD FHGSA FFSc(RCPA) Head, Mitochondrial Research, Murdoch Children's Research Institute Head, VCGS Mitochondrial Diagnostic Laboratory Honorary Professorial , Department of Paediatrics, the University of Melbourne Chair, AMDF Scientific & Medical Advisory Panel Phone 03 8341 6235 Email: [email protected]

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