by Kirk, Edwin;
As you’d expect, this is more likely to happen if the problem is something that allows an affected person to have children of their own. One such condition is called Leber hereditary optic neuropathy (LHON). People with LHON are generally well and healthy, until, one day in their teens or 20s, they notice their vision is cloudy in one eye. Quickly, the symptoms worsen, until, at best, the sight on that side is barely enough to be able to count fingers held up before the eye. Then, a couple of months later, the same thing happens to the other eye.5 Most affected people never have any improvement in their vision; most become legally blind. Occasionally, there can be neurological problems that go along with the eye condition, but, usually, vision loss is the only thing that happens.
[5 About a quarter of the time, both eyes go at once.]
There are some mysteries about LHON. One is that many people, despite having no normal copies of the mitochondrial genome, go their whole lives without losing their sight. Another is that men are far more likely to lose their vision: about half of men but only about 10 per cent of women with an LHON variant have vision loss. And lastly, when we can track the change through the family, we often see that the proportion of abnormal mitochondrial DNA — the ‘mutant load’ — rapidly increases to 100 per cent, usually within a generation or two. For this condition, the bottleneck seems to be eliminating normal rather than abnormal mitochondrial DNA. We have no idea why.
All of this makes discussions with families about the implications of the condition very different for LHON than for other genetic conditions. A woman who has LHON has a one hundred per cent chance of passing this on to each of her children (an affected man has effectively zero chance of passing it on, because our mitochondria are inherited only from our mothers6). This means that all of her children will inherit the genetic change, but only half the boys and 10 per cent of the girls will lose their vision because of it. We can’t tell in advance which ones, we can’t predict exactly when they will have problems, and there is nothing that we know that can prevent it.7
[6 This is a general rule — as for so many things, there have been a couple of exceptions reported, in which paternal mitochondrial DNA somehow ran the gauntlet of conception and survived to contribute to the resulting child’s genetic makeup.]
[7 There is some general advice for at-risk people, such as not smoking and avoiding excessive alcohol, that might help a bit.]
For other mitochondrial mutations, it can be a different story.
By the time we made the diagnosis of Leigh disease in Joseph, his younger sister, Kylie, had already been born. In his first year, their mother, Pauline, had taken Joseph to see several doctors, who had reassured her that his slow weight gain and low muscle tone were nothing to be too concerned about. He was gaining skills normally, and otherwise seemed fine. Gradually, though, things got worse. Around the time of his first birthday, Joseph had a bout of gastroenteritis, with vomiting and diarrhoea that lasted for a week. He had finally started crawling just a few weeks before, and now he stopped. He would never crawl again. Over the next few weeks, he developed some unusual movements of his hands and his breathing took on a strange pattern, with bouts of hyperventilation. Heavily pregnant, Pauline took Joseph to a paediatrician, who was deeply worried by Pauline’s story, and by what he found when he examined the child. Referral to a neurologist followed quickly; she ordered scans and blood tests. Finally, a biopsy of muscle and liver was done, to measure the function of the mitochondria. This test result was abnormal, telling us that the mitochondria were not functioning as they should.
By now, Kylie was two months old. She was there in the room when we discussed the results with Pauline and her husband, Mark. We knew that Joseph had a mitochondrial condition, but didn’t yet know the genetic basis for this. Almost any type of inheritance was possible, since the mitochondria rely so heavily on input from the nuclear genome. But the testing showed that nearly all of his mitochondria carried a genetic change, a single alteration that changed a T to a G. This was a change that had been seen in many other people with Leigh disease, and confirmed everything that the neurologist had feared. The diagnosis of Leigh disease meant that Joseph had a degenerative condition that would relentlessly worsen, taking away the skills he had learned and stopping him from gaining new ones, affecting his breathing and his ability to swallow. Like many children affected by this terrible condition, Joseph would not live to see his third birthday.
Often, this type of problem is a one-off in a family. Often — but not this time. Over the next few months, Kylie, too, showed signs that she might be affected. We went straight to the DNA test this time. This showed that almost every copy of Kylie’s mitochondrial genome had a G at position 8,993 instead of a T. The news could not have been worse.
We tested Pauline next, and found that 35 per cent of her mitochondrial DNA had the change. An adult neurologist examined her and found no trace of any ill effect on her own health from this.
It took nearly a year of grieving and learning to live with the truth that her two children were dying of a condition we were powerless to treat before Pauline and Mark could start to think about the future. Finally, though, they came back to clinic and asked what they could do to have a healthy child.
As we’ll see in chapter 7, there’s more than one way to make a baby. We talked about using donor eggs; they considered this, but asked about having IVF and testing the mitochondria in the embryos, then implanting only an embryo that was predicted to be healthy. This process is called pre-implantation genetic testing (PGT). PGT is commonly used in situations where there is a known genetic condition in a family — for example, if both parents are carriers for a recessive condition — and can also be used for checking embryos’ chromosomes. At the time of these events, PGT for mitochondrial conditions had only been technically possible for a few years. Early on, there had been concern that the cells of an embryo that had only gone through a few cell divisions might have varying levels of abnormal DNA, so that the few cells that were biopsied for the PGT procedure may not have given an accurate picture of the whole embryo. Fortunately, this turned out not to be the case, and, by the early 2000s, there were even statistics for this specific variant that gave a guide to what might happen for any given mutation load, allowing us to turn a percentage into useful information. From around 60 per cent load, the likelihood of severe problems affecting the child rises steeply.
At Pauline’s first cycle of IVF, all four embryos had a load of more than 95 per cent. We thought it might never be possible for Pauline to have a healthy child of her own, but she tried again. This time there were six embryos. Two had a load of more than 95 per cent; three had similar loads to Pauline herself — but one had less than 5 per cent. A successful pregnancy followed, with the birth — against considerable odds — of a healthy girl.
It’s obvious, though, that things could easily have gone differently. Pauline might never have had an embryo with a low risk of disease; there have been others who found themselves in that boat. In the early 2000s, when this story happened (Pauline’s daughter is a teenager now), if that had been the case, there would have been no option for Pauline to have a healthy child who was biologically hers. Today, a new option is becoming available for families like this. It’s yet another way to make a baby.
The idea has been kicking around for at least 20 years. Every five years or so, it pops up in the press as a startling new idea, with much fulminating about the ethical issues it supposedly raises, but in the last few years it has become a practical option. It’s a simple enough concept: if a woman’s eggs contain faulty mitochondria (let’s call her ‘woman A’), why not get healthy mitochondria from another woman (‘woman B’)? In practice, because our cells are not just bags of fluid but have a complex internal structure, it turns out to be much easier to do it the other way round and transfer the cell nucleus from woman A into an egg from woman B — removing the nucleus from woman B’s egg first, of course
— and then fertilising the resulting egg. Alternatively, the egg from woman A can be fertilised and then the pronucleus — the combined egg + sperm nucleus — can be transferred into the donor egg from woman B. Either way, what you wind up with is nuclear DNA from the couple who are trying to have a healthy baby, and mitochondria from another woman. A few abnormal mitochondria are likely to tag along with the nucleus, but, as long as they make up a tiny proportion of all the mitochondria in the resulting child, it shouldn’t be a problem.
We know this can be done, because there have been animal experiments over a number of years, as well as increasingly ambitious experiments with human embryos. Reportedly, there was an attempt in China in 2003 in which a woman conceived twins. They were born prematurely and died, although their mitochondria were said to be normal. In 2016, a group from New York announced that they had performed the first successful procedure, in a woman from Jordan who gave birth to a healthy baby. The work was done in Mexico, not in New York — because all such procedures are banned in the United States, as they are in many countries. One of the few places mitochondrial transfer is permitted is the United Kingdom. The Human Fertilisation and Embryology Authority (an Orwellian name if ever there was one) conducted reviews and public consultation in 2011, 2013, 2014, and 2016 and finally, in December 2016, gave approval for ‘cautious’ use in ‘specific circumstances where inheritance of the disease is likely to cause death or serious disease and where there are no acceptable alternatives’.
There are some real concerns about the use of the technology, and also some rather silly ones. The main real concern is the same as for genetic editing of an embryo’s DNA: safety. On the face of it, the risks seem lower for mitochondrial transfer, because nothing is being altered — it is a transfer of something we know is functioning normally, from one cell to another (the term ‘mitochondrial transfer’ is a bit misleading because it’s the nucleus that’s transferred, but in concept that’s what happens). Yet there are still ways that things might go wrong, with consequences for the resulting baby.
Less sensibly, there has been a lot of arm-waving about ‘babies with three parents’. Some people are concerned that this medical procedure might be ‘playing God’, although it’s hard to see that it’s more God-like than any other form of artificial conception. Others worry that this could put us on a slippery slope to designer babies. In this case, the babies are ‘designed’ to have mitochondria that aren’t faulty, making them essentially indistinguishable from almost everyone who wasn’t designed. It’s a bit hard to take that one seriously. And some suggest that a person born with genetic material from three parents might have a conflicted sense of self.
That last one is perhaps best answered by bringing our ultimate genealogist back. This time, we’re not going to restrict the UG’s activities to just the female line — we’re going to look at everyone. How many ancestors do you think you have? Well, let’s be conservative this time and assume a 30-year generation time. Say, three generations per century. Go back 100 years and we’re only up to eight ancestors. By 200 years, it’s 64. But as we go further into the past, the numbers ramp up quite quickly. At 500 years, we’re up to 32,768 ancestors: a good-sized country town.
Why not have a guess at how many there are by the time you have gone back 1,000 years?
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Okay, how did you go? It turns out the answer is 1,073,741,824. More than a billion ancestors. But since the entire population of the world only passed a billion people sometime in the early 19th century, and your ancestors are unlikely to have been evenly distributed across the world, it’s apparent that there must be a LOT of people who crop up in your family tree more than once. Yes, many of your ancestors were undoubtedly related to one another. Moreover, you are related to pretty much everyone who hails from the same part of the world that you do (and to everyone else in the world as well, although the link may be as far back as tens of thousands of years ago).
So … what possible difference could it make that you (sort of) have one extra relative in the most recent generation? It’s of no consequence at all when we consider your truly enormous family tree. And it really is only ‘sort of’; the tiny genetic contribution of the mitochondrial genome pales into insignificance beside the mighty nuclear genome.
People in Pauline’s unfortunate situation are rare, so there are no floodgates to open. Nonetheless, there is undoubtedly a demand for the procedure, and it is likely that people will calm down about it once it’s been going for a few years. It’s easy to forget how controversial in-vitro fertilisation was when it was first introduced. There were protests at conferences and outside IVF clinics — including, oddly, by ‘right to life’ groups. Now, IVF is routine. There’s a good chance you know someone who has used IVF in an attempt to conceive. Given the rarity of the problem that it treats, this may never be the case for mitochondrial transfer — but it is likely to similarly become routine, a non-issue.
You might reasonably think that since we know so much about the biology of mitochondrial diseases, we might have some treatments that work. Disappointingly, we mostly don’t. There is some evidence that supplements with a substance called creatine — beloved of bodybuilders, with the helpful side effect that it’s possible to buy the stuff at reasonable prices — are useful for people with muscle weakness due to mitochondrial disease. Many people still treat people with mitochondrial disease by giving them a ‘cocktail’ of vitamins, chosen as antioxidants and in the hope of giving a boost to parts of the mitochondria that are failing. Occasionally, you hear of someone who seems to respond very well to this — but the problem is that there is no way of knowing what would have happened had that person not been treated.
This point was brought home to me in a startling way in 2012, when I was contacted by Professor David Thorburn about a patient called Brandon who had been seen at Sydney Children’s Hospital more than 20 years previously, before I worked there. David is a luminary in the field of mitochondrial disease, esteemed for many reasons but particularly because he never, ever gives up on the possibility of making a diagnosis. A neurologist, since retired, had sent David samples for testing in the early 1990s, and now, at last, there was a likely genetic diagnosis. Could I provide more clinical information, and see if I could contact the family to let them know the news?
I dug out the old notes from deep storage. Brandon had started having trouble breathing in the first days after he was born. The levels of lactic acid in his blood and in his spinal fluid were very high, which can be a sign of sick mitochondria. He was floppy, and although eventually he started breathing well enough that he no longer needed artificial support of his breathing, he did not suck or swallow, so he had to be fed by tube. The levels of lactic acid in his blood remained sky-high throughout the time he was in hospital. The second-last entry in our notes said that he was being transferred back to his local hospital to be close to his family. The very last entry in our notes concerned the results of muscle and liver biopsies, which showed that his mitochondria were not functioning properly, confirming the general nature of the problem (but not telling us the exact genetic cause). The story reminded me of other newborn babies I had seen with severe mitochondrial problems, and I was sure that Brandon could not have lived much longer.
After 20 years, it took a bit of detective work, but I finally managed to get hold of Brandon’s mother. I wasn’t sure how she would take this call out of the blue, and was worried about the grief I might be causing her, reminding her of this long-lost baby. I need not have been concerned: her disposition was sunny, and she seemed pleased to hear from me. Then … she offered to give me her son’s phone number! He had made a full recovery from his early problems, had grown up and gone to school, and was now working in the family business. Soon, to my amazement, I found myself talking to the man himself.
Soon after, I heard of another bab
y who had exactly the same genetic change as Brandon, with similar early problems — but who had indeed survived only a few short months. You may well ask how all of this was possible. I certainly did. Why did one baby die while another, seemingly just as sick in the first few weeks of life, go on to not just survive, but thrive?
It turned out that Brandon had inherited a faulty copy of a gene called LYRM4 from both parents. The role of this gene has to do with the metabolism of sulphur in the body, which in turn is important for the function of the mitochondria. Newborn babies do not handle sulphur very well, but, over the first few months of life, the relevant systems mature rapidly. Make it past those first few months and it seems like you can cope pretty well despite a faulty LYRM4 gene.8
[8 This particular cause of mitochondrial disease appears to be very rare, and recoveries like Brandon’s are truly exceptional. Still, as David Thorburn and his team suggested in the paper reporting this discovery, it might be possible to treat babies in this rare situation by giving them specific sulphur-containing supplements. This doesn’t seem to have been tested yet, which isn’t surprising — only three people have ever been reported with problems due to LYRM4 variants.]
If we had treated him from soon after birth with a mitochondrial cocktail and seen stabilisation, then improvement of his condition, it would be awfully tempting to think that it was our treatment that had made the difference. Tempting, but completely wrong. This doesn’t mean that mitochondrial cocktails couldn’t sometimes help people … but mostly, it seems like they just don’t work.
