John Zhang three parent IVF

John Zhang, with the first baby born through mitochondrial donation

Open a news website (or even a newspaper – remember those?) these days, and you are likely to be confronted with a story about “three parent babies”. Mitochondrial donation, a controversial IVF technique, has leapt to media prominence over the past few years, particularly in the UK where there has been a concerted research and regulatory effort to develop the technique to treat inherited disease. The recent birth of the first “three parent baby” to a Jordanian couple in Mexico last year, and the birth of another child in Ukraine at the start of 2017, have reignited the discussion about the technique. How does mitochondrial donation work? Is it safe? Will this lead to the creation of designer babies? We’ve put together our handy crib sheet to get you up to speed on all things “three parent”.

What’s the deal here?

Each human cell contains mitochondria, tiny ‘organelles’ that generate energy to keep the cell (and by extension the human body) functioning and healthy. During reproduction, mitochondria are passed from mother to child. However, mutations in mitochondria can lead to fatal inherited diseases in the child that affect key organs such as the brain and muscles, organs which need the most energy to function. Currently no effective treatment or cure exists for these mitochondrial diseases. 

Mitochondrial replacement therapy, mitochondrial donation, or ‘three parent IVF’ is a technique for in vitro fertilisation where the future baby’s mitochondria come from a third party donor. In the UK the Human Fertilisation and Embryology Authority approved research into human embryos in 2001, and in 2005 Newcastle University was granted a license to develop the treatment for mitochondrial disease. 

In 2016, John Zhang and his team from New Hope Fertility Center in New York, USA, used mitochondrial donation to assist the reproduction of a Jordanian couple. Their baby was born in Mexico. In January 2017, the Nadiya clinic in Kiev, Ukraine, announced the birth of a baby conceived using mitochondrial donation, to a previously infertile couple. 

How does it work?

Broadly speaking, there are two different approaches to mitochondrial donation.

Pronuclear transfer

The first technique developed for mitochondrial replacement, pronuclear transfer was first conducted in mouse embryos in 1983. In this method the ‘pronuclei’ – nuclei from the egg and the sperm that has fertilised the egg that have not yet fused to form a single nucleus – are transplanted into an empty donor egg.

pronuclear transfer three parent ivf

Source: Third scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception, Human Fertilisation and Embryology Authority, June 2014

The problem with pronuclear transfer is the number of embryos involved. As both the mother’s egg and the donor egg are fertilised during the procedure, some argue that this is the unethical destruction of a human embryo.

While fertility clinics in the UK are permitted to use this technique, none have so far. 

Spindle transfer

John Zhang and his team in the US used spindle transfer in their procedure that lead to the birth of a healthy baby. When a cell divides, the chromosomes are attached to protein fibers called microtubules or spindles. During the transplant the spindle and its attached chromosomes are removed from the mother’s egg and transferred into an empty donor egg. Once this procedure is complete the new egg is fertilised. 

spindle transfer three parent ivf

Source: Third scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception, Human Fertilisation and Embryology Authority, June 2014

While spindle transfer removes some of the ethical worries associated with pronuclear transfer, there are still concerns. During the transplant, it is possible for chromosomes to detach from the spindle, resulting in an embryo that has too few chromosomes, resulting in abnormal development. During Zhang’s study, only one out of five embryos that had undergone spindle transfer developed normally and went on the become a baby.

Wait, doesn’t that mean a child will have three parents?

This is a tricky one. Mitochondria do have their own DNA, so technically a child conceived using mitochondrial donation will have DNA from three people. This has lead to the common term ‘three parent baby’, which while highly descriptive is pretty misleading.

As far as we know, mitochondrial DNA does not influence essential human characteristics. That is the job of nuclear DNA, which comes only from the mother and the father. So it has been argued that mitchondrial donation is equivalent to organ or blood donation, and does not automatically confer any additional parental rights on the donor. 

How safe is it?

A briefing document produced by the HFEA in 2015 states that “there is no evidence to show that mitochondrial donation is unsafe,” and adds that current research is expected to confirm this position. 

Animal tests, predominantly in mice and monkeys, have provided the majority of the safety evidence for mitochondrial donation. Pronuclear transfer has been conducted in mice in the 1980s, and spindle transfer has been tested in a wide range of animals. Animals born using donated mitochondria have now reached maturity and have shown no health issues. 

Is it even legal?

Since 2015 human mitochondrial donation has been legal in the UK. Currently the UK is the only country to have formally approved the technique.

However, not every country has laws specifically prohibiting mitochondrial donation, which is why John Zhang was able to conduct his work in Mexico, and why the clinic in the Ukraine was able to offer the technique as an option to an infertile couple. One of the key ethical concerns surrounding mitochondrial donation is how it should be regulated, and if indeed it can be regulated effectively.

What’s next? Designer babies?

Honestly? Probably not. At least not in the short term. Mitochondrial donation does not impact upon the germline, the portion of DNA that is inherited from a parent, and so could be considered a far cry from editing the genome of an embryo to create desired characteristics.

However, the use of mitochondrial donation does open up the discussion about what level of “interference” in reproduction is acceptable. Is it ethical to screen embryos for genetic disease? Across the world pregnant women are routinely offered screening for trisomy conditions such as Down’s syndrome. And if it is ethical to screen embryos, is it ethical to intervene, either in the form of prenatal screening, mitochondrial donation, or termination?

Many people are comfortable with the idea of screening, and even interventions for the treatment of disease. But what about other characteristics? While it is not currently possible to edit ‘desirable’ characteristics into embryos, it is possible to screen them for sex. In 2015 the Australian government, concerned at the number of its citizens heading overseas for sex selection IVF, opened a public consultation to determine whether the procedure should be legalised. At the moment sex selection IVF is legal only in cases of inherited genetic disease that affects one sex more than the other, such as fragile X syndrome, or haemophilia. 

Finally, we should mention the molecular elephant in the room: CRISPR. While ‘designer babies’ may be some way off, CRISPR will almost certainly be the technology that creates the first one. The gene-editing technique taking the world of genomics by storm and igniting its fair share of both commercial and ethical disputes across the world has already been used to edit human embryos, with mixed reactions from scientists and regulators. Using CRISPR to influence human reproduction is almost certain to occur somewhere in the world in the next decade or so.