A picture of capsules, syringes and a stethoscope lying on dollar bills together with a note mitochondrial disease written on a pad.

May 17, 2023, by Brigitte Nerlich

Mitochondrial replacement and the pangenome

Recently two events caught my attention, which should at least be noted on this blog: the publication of the first human pangenome on 10 May 2023 and the birth of babies through a new human fertilisation technique variously known as mitochondrial donation, mitochondrial transfer, mitochondrial transplant or mitochondrial replacement on 12 May.

I’ll say a few words about the pangenome and then a few more about mitochondrial replacement. Both topics deserve much more in-depth analyses, particularly from a linguistic perspective, but that will have to wait.

The pangenome

Around twenty years ago, the human genome was sequenced – or rather a human genome was sequenced and there were a lot of gaps. Now a much bigger and much better human genome, the ‘pangenome’, has been sequenced, derived from a wide diversity of people. The results were announced on 10 May in an article published in Nature, followed by a series of publications in Nature and Nature Biotechnology on 11 May, 2023.

If you want to understand the achievements around the pangenome – the sequencing and the discoveries – you should read various Twitter threads by Ewan Birney. One thing that struck me here was Birney’s use of a metaphor or analogy – and I was, of course, not the only one who noticed that.

As Eric Topol said in a summary of the pangenome affair: “In sum, to use a metaphor, Ewan Birney (European Molecular Biology Laboratory, EMBL Deputy Director) via a twitter thread, aptly put it ‘the pangenome is like the complete works of Shakespeare including all the big variations in quattros and folios and anything else. And by having this we can better take any person’s DNA and analyse it appropriately.’” But, of course there is much more to it than that. Read the threads and get your brain cells knitting!

Mitochondrial therapy/donation/replacement…

Around a decade ago, there was much debate about the ethics of mitochondrial replacement, a possible way of dealing with rare diseases carried by a mother. This involved the use of a special form of in vitro fertilisation “in which some or all of the future baby’s mitochondrial DNA (mtDNA) comes from a third party” (another woman) (for more on mitochondrial replacement therapy or MRT, read this wiki article).

Now, in May 2023, actual babies have been born within the UK’s regulatory framework after using this technique. The Human Fertilisation and Embryology Authority (HFEA) “confirmed that ‘less than five’ UK children had been born using the procedure as of April 2023, in response to a freedom of information request by The Guardian newspaper. The HFEA provided no further information about the procedure or the children.” You can read the Guardian article here and, of course, there is a lot of other coverage too that would be worthy of attention, and a lot of uncertainty about what’s going on.

But to understand where we are now, we need to understand what happened over the last decade or so.

At the end of the 1990s, when cloning was debated, including human cloning, there were some references to how this could be used for the treatment of rare diseases. In 1998 Ruth Deech, then chairwoman of the HFEA, talked about a possible application for rare diseases in an interview with The Independent (and using a metaphor that I approve of): “A possible application, cited by Ruth Deech, is in the treatment of sufferers from a rare inherited disorder of the mitochondria – the “power-plant” of the cell – which surround the nuclei of cells. This problem can cause blindness and epilepsy. By removing the nucleus – minus the defective mitochondria – from an embryo created by in vitro fertilisation in the normal way and placing it in a donated egg stripped of its own nucleus, a cloned baby could be created that would be the genetic offspring of its parents, but without the disorder.”

In 2012, Shoukhrat Mitalipov and colleagues at Oregon Health and Science University published a paper in Nature in which they proposed, to use a wording from a review of MRT, “a new form of reproductive in vitro fertilization (IVF) which works on the principle of replacing a women’s abnormal mitochondrial DNA (mt-DNA) with the donor’s healthy one”. No mention of cloning, of course.

In June 2012 The Nuffield Council on Bioethics published an ethical review arguing that the technique “would be an ethical treatment option for affected families, provided research shows that treatment is likely to be safe and effective, and families are offered full information and support”. In September 2012 the HFEA launched a public consultation on the “ethics of new IVF-based techniques designed to prevent inherited forms of mitochondrial DNA disorders” and another one in 2014 on MRT regulation.

According to Britannica, “The first three-parent babies were born in the 1990s and early 2000s, the products of a then-novel IVF-based technique known as ooplasmic transfer (cytoplasmic transfer). The success of the technique was seen as miraculous, but its use was controversial.” Interest in this technique dwindled over time and other techniques came to the fore, namely “maternal spindle transfer and pronuclear transfer”.

Pronuclear transfer was pioneered in a groundbreaking study by a team at Newcastle University in 2010. The announcement of the breakthrough used the metaphor of changing a battery – see here. We’ll come back to that.

In 2015 the UK became the first country in the world to allow mitochondrial replacement within a regulatory environment and in 2017 the first licence for MRT was issued. In 2016 MRT (maternal spindle transfer) was used in unregulated ways by a US team in Mexico to provide a Jordanian couple with a healthy child. “In 2017, the year following the birth of the first baby born using MRT, medical scientists in Ukraine reported the birth of two babies from MRT.” (Britannica)

All this inspired various social science and bioethics investigations into the matter, interestingly at a time when gene editing also emerged and was also being discussed. I won’t do a literature review, but you can gain some insights into the debate in the UK from this article by Ilke Turkmendag (a former alumna of our very own Institute for Science and Society) entitled “It Is Just a ‘Battery’…” (and also in this 2016 special issue).

The children born in 2023 were also born using pronuclear transfer.

Batteries, three parent babies, GM babies and designer babies (and more)

For me, as somebody interested in language, it was rewarding to see at least two articles on language being published in this context back in 2015, one by linguists at the University of Lancaster and one by bioethicists in Montreal.

The Lancaster research was actually a blog post by Baker and Semino based on analysing 119 news articles published in the UK press between April 2010 and September 2014. They found “the words used to express the case for or against approval frame the issue in opposite and irreconcilable ways. This, we suggest, reduces the chances of a reasoned debate, and makes it difficult to see the merits of the case.”

The case in favour used a vivid metaphor namely ‘changing a faulty battery’, as mitochondria are often depicted as batteries that produce more than 90% of the energy in a body’s cells – although it might be better to call them power stations!

The case against used the phrase that became almost ubiquitous, namely that of ‘three parent babies’. Sometimes phrases like ‘GM babies’ or ‘designer babies’ were used. “More specifically, the corpus contains 40 instances of three-parent baby/babies, 33 instances of designer baby/babies and 12 instances of GM babies”. One online magazine, Quarz, said in fact that “2015 was the year it became OK to genetically engineer babies”!

There was also an article that briefly discussed the ethics of the notion of ‘the other woman’ involved in mitochondrial ‘donation’.

Another bioethics article delved more deeply into the language around MRT. This was an article by Ravitsky, Birko and Dupras-Leduc published in The American Journal of Bioethics, based on an analysis of academic literature around MRT as well as media articles.

They link their work directly to an article dealing with the language of gene editing by O’Keefe and colleagues that I have briefly summarised in this blog post.

Ravitsky et al. found similar phrases used around MRT that had also intrigued Baker and Semino, including GM babies and designer babies. And with ‘designer babies’ we come to, as they found, the use of clichés (in academic literature!), such as ““opening a Pandora’s box” (Nuffield 2012), “letting the genie out of the bottle” (Dyer 2015), and “leading us down a slippery slope”’ (Darnovsky 2013).”

As we found previously, when surveying the ‘designer baby’ debate of the year 2000 these phrases are always ready to use in any debate about such issues. In the year 2000 Adam Nash had been born as a donor or saviour sibling for his sister who suffered with Fanconi Anaemia using preimplantation genetic diagnosis – the ‘first designer baby’. (On the issue with this label, see my post here)

Ravitsky et al. conclude their study by saying: “We … join O’Keefe and colleagues in a call for sensitivity and awareness when choosing terminology. We share the concerns they express regarding the use of terms that ‘trigger gut reaction rather than thoughtful deliberation’ and support their call toward ‘a vocabulary and tone that will facilitate engagements that are both scientifically sound and ethically productive.’ We also join them in calling for additional interdisciplinary research on how terms are currently used, how their use evolves over time, and what impact language actually has on public debate, on social acceptance or rejection of new technologies, and on public policy”

I totally agree. What is needed now is a new study of the language used in discussions of the child or children just born and to see whether the language has shifted or has stayed the same. Some such reflections have already begun, for example in these reactions to the May 2023 announcement by scientific experts, collected by the Science Media Centre.

Image: Mitochondrial Disease Mitochondrial disease by Nick Youngson CC BY-SA 3.0 Pix4free






Posted in Language