Genes and Genomes at the Start of Life.

Credit: Science Photo Library.

​John writes …
 
Newcastle scores eight!
 
Just over ten years ago, in March 2015, the Human Fertilisation and Embryology Authority (HFEA) authorised the use in clinical practice of a modified version of IVF (The Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015). This involves not just an egg and sperm from the prospective parents but also a small – very small – number of genes from a second female. The new regulations came into force in October 2015 and in March 2017, the Newcastle Fertility Centre was the first (and so far, only) fertility clinic authorised to provide treatment based on these regulations.

Figure 1. Newcastle Fertility Centre. Credit: University of Newcastle.

Let me explain: nearly all our genes reside in a part of the cell called the nucleus but a small number (about 0.18% of the total) are in a cell compartment called the mitochondrion (plural: mitochondria). The mitochondria are the organelles which carry out ‘energy metabolism’, providing the chemical energy to perform cellular – and hence bodily – functions. Because of the absolutely essential function of mitochondria, mutations in mitochondrial genes have very serious consequences for a baby, ranging from death in infancy to a range of significant impairments. Thus, one of my undergraduate tutees, who had intended to do his final-year project in my lab, became almost completely blind towards the end of his second year. This was because of a mutation in one of his mitochondrial genes. (We were able to provide him with special IT facilities that enabled him to carry out a computer-based bioinformatics project).

A key feature of mitochondria is that they are only inherited from the mother and it was this fact that led to the development of the modified form of IVF. In a very clever procedure, a woman has a mitochondrial mutation provides her eggs as in normal IVF but those are manipulated so that they receive healthy mitochondria from an egg donor, as shown in Figure 2 (if you want to know more, please see pp. 51-53 of Introduction to Bioethics, Bryant and la Velle, Wiley, 2019).

Figure 2. Diagrammatic representation of mitochondrial donation. An egg of the prospective mother with faulty mitochondria and the egg of a donor with healthy mitochondria are fertilised to produce zygotes. The egg and sperm nuclei are removed from the donor zygote, leaving in place the healthy mitochondria. The egg and sperm nuclei from the zygote of the prospective mother are transferred into the donated zygote. This constructs a zygote (fertilised egg) containing the nuclear DNA from the prospective parents and the mitochondrial DNA from the donor. Credit: ResearchGate.com via Creative Commons.

As a scientist, I can look at the technique and acknowledge that it is brilliant. However, I also need to acknowledge that some commentators raised ethical concerns (see Introduction to Bioethics, mentioned earlier). The first of these concerns came from the tendency of many journalists to call the process ‘Three-parent IVF.’, the implication being that the baby to be born will have a complex genetic inheritance with unclear family boundaries and may therefore be confused about their identity. In fact, this is very far-fetched. The mitochondrial genes transferred from the ‘third person’ control a small number of metabolic processes. They do not contribute genetic information about growth and development, even though mitochondrial processes are essential for growth and development. I think it is best to think of the process as a ‘transplant’ of mitochondria, albeit a transplant that is inherited.

This brings us to the second ethical issue. In all the countries where the technology is possible, it is not permitted to change the genetic makeup of a human, whether by genetic modification or by genome editing, in such a way that the genetic change is inherited. Readers will remember the case of the Chinese medical scientist who was sacked because he carried out genome editing on two human embryos which came into the world as babies with a genome-manipulated resistance to HIV. Now, there is absolutely no doubt that mitochondrial donation is a form of genetic modification, albeit a very specialised one, and that the modification is heritable. In 2012-2103 the HFEA carried out a public consultation (to which I responded) on the process and also invited contributions from organisations such as the Wellcome Trust and the Nuffield Council on Bioethics. The general view was that mitochondrial donation was a therapeutic process, leading to an avoidance of serious genetic disease and that an exception to the general rules about heritable genetic change was therefore acceptable. According to this majority view (which I share) there was no danger of starting down a ‘slippery slope’ to heritable genetic enhancement.

And so, back to my headline. In its annual report, the key points of which were published by Newcastle University on July 16th this year (Mitochondrial Donation treatment - Press Office - Newcastle University), the Newcastle Fertility Centre states that since 2017, eight babies have been born after IVF involving mitochondrial donation. The report goes on to tell the stories of some of those babies and also presents the reactions of some of the parents – altogether it is a very ‘good news’ account.

Credit: University of Newcastle.

Embryos and their genes.
 
Readers of this blog and/or of the books mentioned earlier will be aware that it is possible to carry out specific genetic tests on embryos created by IVF, prior to implanting them into the uterus of a prospective mother. The process is called pre-implantation genetic testing (PGT) and it is used when there is a high chance that the embryo has a genetic variant that will, in life, cause a serious or even fatal condition. Currently, in the UK about 1100 babies are born each year after IVF involving PGT.

Figure 4. Removal of a single cell from an early-stage embryo in order to carry out Pre-implantation Genetic Testing. Credit: Science Photo Library.

Many of you reading this will also be aware of the huge advances in whole genome sequencing that have occurred since the Human Genome Project. In that project it took about 12 years to obtain a genome sequence of the ‘average’ human whereas it is now possible to obtain this information for an individual human within a day or even faster if need be. Further, extraction and amplification techniques are now so reliable that genome sequences can be obtained from a very low number of cells. Thus, over the past three years, several genetic/fertility research groups have been able to obtain complete genome sequences from pre-implantation embryos. It is said that in some circumstances in which more than one genetic test needs to be carried out in PGT, it is easier to obtain a complete genome sequence than to do the individual tests – a statement which I still find amazing. Watch this space for further developments.

New-born babies and their genes.
 
The previous section, immediately above, indicates how whole genome sequencing has become a routine analytical tool, a situation which has been further exemplified by the announcement by the NHS in June that all new-born babies will have their genomes completely sequenced (NHS plans to DNA test all babies in England to assess disease risk - BBC News).  Currently, babies are tested for nine genetic conditions following a ‘heel-prick’ to extract some blood when they are a day or two old. However, in trials initiated last year which involved 100,000 babies and a focus on 200 genetic conditions, the feasibility of whole-genome sequencing  for new-borns was put to the test, leading to the recent announcement. Wes Streeting, the current Health Minister, was very positive about the move, stating that it will enable us to ‘leapfrog disease, so we're in front of it rather than reacting to it’ while others have spoken of the ability to ‘revolutionise prevention.’

All this sounds very good but it seems to many us to be over-optimistic. For genes with high levels of penetrance and expressivity (see note below), it is hard to see how the development of the condition can be prevented. The best that can be done is to provide treatments which mitigate the symptoms. At the other end of the scale, for genes with low penetrance and low expressivity, people may go through their lives worrying about something that may not happen. As Professor Frances Flinter (Figure 5) wrote in her blog (Whole Genome Sequencing in newborns: benefits and risks – Nuffield Council on Bioethics)  “For a significant number of conditions, … there may be many years of uncertainty and worry until symptoms begin to appear, if at all.” (See also the discussion by Rachel Horton and Anneke Lucassen: Ethical issues raised by new genomic technologies: the case study of newborn genome screening | Cambridge Prisms: Precision Medicine | Cambridge Core).

Figure 5. Professor Frances Flinter. Credit: Nuffield Council on Bioethics.

​I have asked before, in a different context, whether there is too much emphasis on genetics in medicine (albeit that I am very enthusiastic about DNA and genes). As one GP put it: he can get a better picture of a person’s general health from the post-code of where they live than from their DNA sequence, the implication being that factors such as poor housing and social deprivation are major factors in poor overall health. And thus we wait and watch to see if the optimism expressed by the NHS and Department of Health about the new genome sequencing programme is justified.
 
Note: Penetrance means the percentage of individuals who carry a particular gene (genotype) actually show the effects of the gene (phenotype). Expressivity means the level at which a gene, if it is switched on, actually works. Both penetrance and expressivity, and especially the latter, can be affected by other genes – which contributes to the uncertainty that I mentioned above.
 
John Bryant
 
Topsham, Devon
July 2025