MRT and three-parent babies

In December, Britain became the first country in the world to officially give the green light for the controversial three-person in vitro fertilisation (IVF) technique. Although the British parliament had already voted for regulations on its use in early 2015, the power to give final approval was given to the Human Fertilisation and Embryology Authority (HFEA), the regulatory body in charge of the country’s fertility clinics and human embryonic research. Almost a decade in the making, with countless studies, reviews and public consultations to gauge both the scientific and ethical arguments around this issue, the technique was finally given the go-ahead.

Three-person IVF, also known as mitochondrial replacement therapy (MRT), was developed to give families suffering from or with a history of mitochondrial DNA disease the option to have children free of any related complications. Almost all human cells contain organelles called mitochondria that are largely responsible for producing energy, but they also house a small set of 37 genes – 0.1 per cent of the entire human genome, with the rest contained in the cell nucleus – that can cause severe complications if mutated.

Professor David Thorburn, who leads the mitochondrial research team at the Murdoch Childrens Research Institute, says HFEA approval would give fresh hope for families with a history of mitochondrial DNA disease. “It’s an experimental technique, so there’s issues around that, like introducing any new technique to medicine,” he says. “And this has been, I think, an exemplary process.”

Mitochondrial disease can sometimes be difficult to diagnose, but according to a study Thorburn was involved in, it affects about one in 5000 people. “About 60 births in Australia each year will result in a child who will develop mitochondrial disease at some stage during their life, and about half of those are mitochondrial DNA disease,” he says. Treatment options are limited, with an extensive review of literature in 2012 concluding there was no evidence to support that any of the available treatments were beneficial to patients, leaving some at the mercy of life-threatening conditions. For example, in a debilitating neurological disorder called Leigh syndrome, where about one in five cases are linked to mutations in mitochondrial DNA, the average life expectancy is about two to three years.

Sean Murray, chief executive of the Australian Mitochondrial Disease Foundation, says MRT provides genuine hope. “Patients or people who have family members with mitochondrial disease have seen firsthand the devastation that this disease can cause,” he says. “This is one of the first opportunities or therapies that will have a very high likelihood of preventing the transmission of mitochondrial disease.”

However, one of the main reasons MRT has been so controversial and the approval process so arduous is that the resulting embryo – and eventually child – will have not two but three genetic parents. The process works by taking the nucleus out of the egg that contains the faulty mitochondrial DNA and inserting it into a donor egg, which has no faulty mitochondrial DNA and has also had its nucleus removed. There are variations on this technique that involve the transfer taking place before fertilisation and after, but the resulting embryo essentially has 99.9 per cent of their DNA from the mother and father couple, with the remaining 0.1 per cent coming from the donor mother’s mitochondria. However small the donor’s DNA contribution, the recipient will have three biological parents.

Dr Ainsley Newson, associate professor of bioethics at the University of Sydney, says MRT “is not an ethically neutral technology” and that there will inevitably be disagreements about issues such as alternative routes to parenthood and whether it will cause changes in the human germline – the generational succession of descendants. That is, any defects inadvertently caused by the procedure would affect not just the resulting child but could be passed on to their children.

MRT may also raise such ethical considerations without addressing the disease. “We know that even with the best techniques, there can be no absolute guarantee that a child born of MRT will remain free of disease,” she says. “But then no reproductive technology is perfect. Who gets to make that call? And as to experience, what will life be like for those born of MRT?”

These questions are of particular importance when considering the case of the first baby to be born from MRT, who was five months old when the news broke in September last year. A team of United States researchers took the unprecedented step of travelling to Mexico, which has no regulations around the use of this technology, to help a Jordanian family in which the mother had a history of mitochondrial DNA disease and had already experienced four miscarriages and the deaths of two children.

However, the US doctors have faced fierce criticism for their brazen efforts to dodge the law at home and a lack of transparency. “This group has just gone and done it,” David Thorburn says. “They’ve not been subject to any peer review in their methods and in fact the American group have no real evidence of any expertise with mitochondrial DNA.” He also says the family wouldn’t have even been eligible for MRT if the case had been presented in Britain, as the mother had a relatively small amount of mitochondrial DNA mutations.

Thorburn further raises the issue of possible carryover of abnormal mitochondrial DNA – the MRT technique is incredibly precise but some mitochondria can end up being transported from the mother’s egg to the donor egg alongside the nucleus. Could it expand in the embryo and end up causing disease? Reports from the University of Newcastle in Britain, where researchers have been perfecting the technique, suggest this is unlikely to occur if there is a carryover of less than 2 per cent, but Thorburn says it remains a significant concern.

There are other complicating factors. Some scientists have questioned whether complications can arise from potential mismatching of nuclear and mitochondrial DNA. As generations of humans dispersed further around the world, their nuclear genomes have evolved alongside their mitochondrial genomes to ensure they work well together – some human populations are more closely related to each other than others. Theoretically, the closer the ancestral link between the genomes the better chance of developing well together to create a healthy specimen. Hence, to ensure a successful MRT, it’s better to get mitochondria from a donor more closely related in evolutionary terms to the recipient mother so that the mitochondrial and nuclear DNA are optimally matched. Professor Stefan Hiendleder, an expert in epigenetics from the University of Adelaide, says, “If there’s no matching here, you can create a condition that’s called heteroplasmy, and animal models have shown that heteroplasmy can be detrimental and affect various phenotypic aspects including behaviour and cognition.” However, studies in mice have shown that such a DNA mismatch might not be so detrimental and could in fact be beneficial to health and longevity, but further research is needed.

Hiendleder also notes that some have proposed to restrict MRT to having male children, as only females can pass on mitochondrial DNA.

Opponents of the technique have accused researchers of playing God, and fear that MRT will lead to the creation of designer babies. Dr Alexandra Harvey, a reproductive biology expert from the University of Melbourne, counters that we need to look at it from a risk-benefit perspective. “At the end of the day, any time we do any medical intervention, we’re basically playing God in a sense,” she says. “The main purpose behind this technique is so that ethically we can’t condemn children to be diseased and have a deteriorated life and potentially not live long enough to really have a life.”

It is currently illegal to offer MRT in Australia, thanks to both the Prohibition of Human Cloning for Reproduction Act and the Research Involving Human Embryos Act. The University of Sydney’s Ainsley Newson explains that these laws were developed in response to reproductive human cloning back in 2002. “Legislation can be cumbersome to create and expensive and slow to change,” she says. “The UK has responded by using specific regulations [for MRT] to complement legislation, as these are faster and simpler to change. Australia needs a regulatory regime that is forward-looking and more responsive to the science.”

Sean Murray says the Australian Mitochondrial Disease Foundation stepped up its lobbying efforts in the past 12 months in response to British developments, in an effort to bring about a review of the current legislation. “I think that it would only be fair and reasonable to the Australian people to progress and to make sure that that therapy is available to women at risk of passing on mitochondrial disease to their children,” he says.

“This therapy really is one that offers hope to a community – the mitochondrial disease community – that’s really been lacking hope up until this point. And for that reason we’re really encouraged that this is something that really offers us some hope.”