'Three-parent babies' prevent inherited genetic condition
James Tytko explores the science behind 'three-parent' embryos: the incredible medical procedure that prevents children from inheriting incurable mitochondrial diseases.
In this episode
What is mitochondrial disease?
Doug Turnbull
Deep inside almost all of our cells are microscopic powerhouses: the mitochondria. They’re responsible for turning food into a usable form of energy. But when these engines fail, the consequences can be devastating. Here’s Liz Curtis, founder of the Lily Foundation, speaking to Sky News…
Liz - We lost our third daughter Lily to a mitochondrial disease. She was eight months old when she passed away but was diagnosed at seven weeks following a number of seizures where she'd stopped breathing and which ended her in intensive care on life support. So we were told then when she was about seven weeks that she had this disease with no cure and no treatment and that she was going to die.
That was Liz Curtis. As she was just explaining, her daughter Lily was diagnosed with mitochondrial disease - which is an umbrella term for a group of disorders caused by defective mitochondria that can affect the brain, heart, muscles, and other energy-demanding organs. Currently, there’s no cure for these severely life-limiting conditions, but now, an amazing scientific breakthrough is allowing children who would have been at risk of disease to be born without inheriting the genetic defect in their mitochondrial DNA.
But what exactly do we mean by this? Sir Doug Turnbull is a clinical neurologist and a leading expert on these conditions…
Doug - Well, mitochondria are, in simplified terms, the powerhouse of the cell. They convert the food that we eat into a usable form of energy. So when mitochondria are defective, as they are in mitochondrial diseases, one of the things that happens is the cell runs out of energy. Mitochondria are inherited exclusively through the mother. They carry a small piece of DNA called mitochondrial DNA, and mitochondrial DNA diseases are transmitted purely maternally.
James - Usually we think of genetic material as residing in a cell's nucleus. That's where the DNA is. But you've just referred there to mitochondrial DNA, and we know that mitochondria sit in the main body of the cell outside the nucleus.
Doug - Yes, that's correct, James. It's an entirely separate piece of DNA. It's a tiny piece of DNA. It's only 13,500 bases compared to the 3 billion bases present in the nuclear DNA. It only encodes for 37 genes, all of which are essential for allowing the mitochondria to work properly.
James - And so when they don't work properly, mitochondria are involved with metabolising, turning food into energy. So one would assume it's going to affect a wide variety of organs in the body when they go wrong.
Doug - Yes, it tends to particularly involve those organs which require a lot of energy. Good examples of this are that the heart is frequently involved in mitochondrial disease, as are the muscles and the brain. So it does tend to be those organs which have a high energy use. And how might it present in those energy-hungry organs? For example, you can get cardiac disease, heart disease, where your heart doesn't pump properly. It can lead to muscle weakness. In the brain, it can have much more varied effects. If you get mitochondrial disease as a young child, it can cause neurodegeneration of the lower part of the brain called the brainstem. Later in life, it can induce epilepsy, incoordination, poor cognitive function, and a variety of different clinical phenotypes associated with mitochondrial disease.
James - What are the determinants of those phenotypes then? Are all mitochondria affected in a person with mutated mitochondrial DNA?
Doug - Mitochondrial DNA is present in multiple copies within an individual mitochondrion and therefore in literally thousands of copies within an individual cell. Mitochondrial genetics is a bit complicated in the sense that you can actually have all your mitochondrial DNA being normal, all of it having a mutation, or, in quite a large number of patients, a mixture of normal and abnormal mitochondrial DNA. This is termed heteroplasmy. That mixture between what we call normal and abnormal mitochondria is critical. The higher the level of abnormal mitochondrial DNA you have, the more likely you are to get disease. Some patients are completely asymptomatic, some are very severely affected by the mitochondrial DNA mutation, so it does vary. There are other factors which will influence this. We're not entirely sure what those factors are; some will be genetic, some will be environmental. Understanding what causes that difference in phenotype is an area of intense research at the moment, because if you understood the difference that was causing that phenotype, then potentially you might have a treatment that would actually help patients.
James - Where are we with treatments for mitochondrial diseases related to mutations in mitochondrial DNA?
Doug - I think it's very important to say that as a clinician who's looked after patients for many, many years, for certain aspects of mitochondrial DNA diseases, we do have treatments. For example, at one stage, a lot of our patients were dying from cardiac disease, but some of the advances in cardiac drugs have meant that we can manage the cardiac disease, at least in some patients. For example, some patients might develop a heart block and you can have a pacemaker put in. Some patients, as I've mentioned before, with central nervous system involvement will develop epilepsy, and we can try to treat the epilepsy with drugs. It's successful in most patients to a degree, so those are treatments for current symptoms. However, trying to cure mitochondrial DNA disease is a much more difficult problem, and as yet, there are no curative therapies for patients with mitochondrial DNA diseases. This is why we must look for curative therapies, but it also highlights why prevention is so critical for families who have mitochondrial DNA disease running through many generations.
07:43 - How can IVF help prevent inherited diseases?
How can IVF help prevent inherited diseases?
Robert Winston
Shortly, we’ll hear about a new breakthrough that can reduce the risk of mitochondrial disease entirely by completely replacing the defective mitochondria with healthy ones. This is achieved by using a form of IVF - in vitro fertilisation - and a healthy “donor” egg - replete with working mitochondria but devoid of its own genetic material - to fix the problem. The resulting embryo is implanted back into the mother’s womb, and - if all goes according to plan - a normal pregnancy follows. Before diving into the new breakthrough, we called an IVF pioneer to ask how this approach can help prevent inherited conditions…
Robert - I'm Robert Winston. I'm Professor of Science and Society at Imperial College London and, of course, I've been involved with in vitro fertilisation since the very first IVF treatments. We've been able to deal with genetic diseases for some time since pre-implantation genetic diagnosis was undertaken in my own laboratory. What we were able to do was to take a human embryo and remove a single cell or several cells and then look at the DNA which was in the nucleus. And we had a pretty reliable method of making sure that that baby would be free of the inherited disease which was running in that family because, of course, not all the embryos would be affected.
Selective embryo transfer like this has already helped stop life-limiting conditions like cystic fibrosis from being passed down. But these conditions are carried by the main “genomic” DNA in the cell. So the approach couldn’t help women with faulty mitochondrial DNA - because their eggs, and hence all of the cells in their ensuing embryos, are affected. For these parents, scientists needed a new approach - one that could ensure their embryos are powered by healthy mitochondria. And because the affected woman’s own eggs are all potentially affected, this is where a donor egg, from an unaffected individual - the third person in a three parent embryo - comes in. Robert Winston again…
A woman who is going to be giving birth to a baby with mitochondrial disease has in her egg some of the mitochondria that will cause the disease potentially later on. So what you can do is what's called a nuclear transfer. So what we do actually is to take a single pipette and remove the egg's nucleus, the cell's nucleus, and that then is transferred into another egg from a normal woman who has had no problems genetically. Her egg has been enucleated and you can then put the nucleus straight into that cell and with luck, of course, you'll get a normal embryo developing.
Officially, you're using, if you like, the so-called three-parent family. It's really not, of course, because actually the amount of DNA you're transferring is less than 0.02% of the DNA. As far as we know, you don't change the normal characteristics of the person.
You don't make them more intelligent or super strong or more pleasant to be with. You might, of course, reduce their disease risk and once that's done, once you've done the nuclear transfer, then you actually will want to look at the resulting embryo that you're producing and decide whether it actually is an oral embryo to do the technique that we first started with, which is pre-implantation genetic diagnosis and sample one or two of the embryo's cells to see, in fact, if that embryo really is, in fact, free of any serious mitochondrial disease.
11:24 - How 'three-parent babies' can prevent mitochondrial diseases
How 'three-parent babies' can prevent mitochondrial diseases
Mary Herbert, Newcastle University and Monash University
Scientists have long searched for a way to help mothers with faulty mitochondria have healthy children, without passing on the risk of disease. That search led to a groundbreaking technique known as mitochondrial donation IVF, standing on the shoulders of fertility science up to this point, and applying it to mitochondrial research. So far, eight babies have been born in the UK using this technique. One of the researchers behind this work is Mary Herbert, a reproductive biologist at Newcastle University and Monash University…
Mary - The patient, once they have approval, will undergo ovarian stimulation and egg collection. We will freeze those eggs, and then once a suitable donor has an egg collection, we thaw the patient’s eggs, fertilise both sets of eggs with the partner’s sperm, and then perform pronuclear transfer six to eight hours after fertilisation. What you get after that is a reconstructed fertilised egg, which contains the nuclear DNA from the parents and predominantly the mitochondrial DNA from the egg donor.
James - In this way, the doctors have effectively decoupled the inheritance of the nuclear genome from the mitochondrial genome. But despite how simple Mary makes it sound, this is a very tricky procedure to pull off.
Mary - It is indeed tricky. It requires a high level of skill, all the more so because we do it about eight hours after fertilisation, usually between midnight and 2 a.m., so it’s a pretty tough calling. The reason we do it at that time is because, initially in our preclinical research, we came in the next morning to do the pronuclear transfer, but the eggs didn’t survive that very well. We realised this was because it was too close to the time of division to the two-cell stage. So we decided to radically change the protocol so that we removed the pronuclei as soon as they appeared. That makes it a small-hours-of-the-morning job.
James - Putting the all-nighter to one side for a moment, the key technical challenge of the pronuclear transfer is presented by the natural rigidity of human egg cells.
Mary - You have to inhibit that rigidity before you can take out the pronuclei. You use fine pipettes to do this to exactly the right diameter. Once you have placed your egg into these inhibitors, the cytoplasm becomes a bit more fluid, and you pinch off the pronuclei so they are surrounded by a little bit of cytoplasm and bounded by a fragment of the egg’s plasma membrane. That’s what we call the karyoplast. Like a little cell in itself, it contains the pronuclei surrounded by a small piece of cytoplasm from the egg and bounded by the plasma membrane. We take one pronucleus out at a time. There are therefore two of these karyoplasts per patient egg enucleated. We then give them a very brief exposure to a fusogen, an agent that enables them to fuse back with the enucleated donor egg, and they fuse very nicely. It’s really nice to see this in a movie, actually.
James - But as precise as these highly skilled surgeons may be, removing the patient’s nucleogenetic material carries some risk.
Mary - Human eggs are really packed full of mitochondria. So when we transplant the patient’s nuclear DNA, it’s almost inevitable that it will also contain some patient mitochondrial DNA. Of course, you have to consider what happens to that. If it’s preferentially amplified, then you may not be preventing the disease. In the research phase, we found that when we did this procedure, the embryos had very low levels once we optimised the process. But when we made embryonic stem cells, 20% of them reverted to the maternal mitochondrial genome. That told us that pronuclear transfer can reduce risk, but we cannot guarantee prevention.
James - All patients are rightly informed of the limitations of mitochondrial transfer, that it’s a risk-reduction strategy rather than a guarantee of prevention. But without letting the perfect be the enemy of the good, Mary and the team have been able to give families who thought they might never safely have children a wonderful opportunity.
Mary - We got the go-ahead to start treatment in 2018. In the paper we published in the middle of July, we reported on 19 patients who had the pronuclear transfer procedure. Of those, seven became pregnant, and so far there are eight babies with another one on the way.
James - But as to the crucial information: what levels of mutated mitochondrial DNA were found in these babies in follow-up testing?
Mary - Crucially indeed. Six of the eight have undetectable levels; five of the eight had undetectable levels at birth, and one had 5%. When they went back and looked at three months, that case was undetectable. That level dropped. The other two cases had 12% and 16%, but the important point is that these levels are far below the threshold for disease. In general, you don’t get severe symptoms until over 60%. The eggs that would have given rise to these babies, had we not done pronuclear transfer, had levels of mutated mitochondrial DNA ranging from 67% to 100%.
James - Bearing down on exactly why these mutated mitochondria are still present will therefore be the next step in the development of this hugely promising technique.
Mary - This resurgence of the maternal mitochondrial DNA has been a focus of research, and we’re still trying to understand what the drivers are and whether we can prevent it so that we bridge the gap between risk reduction and prevention.
17:31 - Changing the law to allow 'three-parent babies'
Changing the law to allow 'three-parent babies'
Emily Jackson, London School of Economics
In 2015, the UK became the first country in the world to approve legislation allowing the use of mitochondrial donation in tightly controlled clinical settings. So how did they navigate the regulations? And how did they address ethical concerns about bringing in genetic material from a third person to new babies? Emily Jackson is a professor of law at the London School of Economics and one of the country’s leading voices on medical ethics and fertility law. Emily told me why she doesn't believe this is a step towards ‘designer’ babies…
Emily - I think what the arguments were for why this is maybe not so concerning as, for example, gene editing of embryos, is that there's no change to the nuclear DNA of the embryo. The embryo will continue to be a mixture of the genetic mother and the genetic father's DNA. The mitochondria, in a sense, provides the battery or the energy for the cells. So I think because it was a change to this very small number of cells that are to do with the mitochondria, it wasn't seen as making the substantial changes that could be made, for example, by gene editing.
James - Drawing the distinction then between preventing an incurable inherited disease versus making designer babies, so to speak.
Emily - There's pretty much a worldwide consensus that gene editing in embryos is not safe enough to be done in humans. The Chinese doctor who reported that he'd done gene editing in embryos actually went to prison in China for doing so. So I think there is pretty much a consensus on gene editing that it isn't safe enough yet. But there was a lot of research done into mitochondrial replacement which established that this would be safe.
James - So scientists were clearly involved with every step in drawing up this new regulation. How were the public policy makers contributing to this process?
Emily - Absolutely. So when the HFEA engaged in its really rigorous series of processes, preceding making a recommendation to ministers, obviously scientists were heavily involved in that. But I think what's important to remember is that scientists are involved in order to explore what this involves. Is it safe? How would it be provided? But there are other people involved in the decision about whether or not this should go ahead, including public engagement, but also engagement with people who are concerned about ethics and the patient voice and a whole range of different stakeholders.
James - And then to complicate the picture somewhat, we heard from Mary Herbert a little earlier that some of the babies still have some mutated mitochondrial DNA in their bodies and we don't really know why yet. So it's important, isn't it, that these are monitored going into the future?
Emily - With any new technique, in a sense, somebody has to go first. Louise Brown was the first baby born from IVF in 1978 and before her birth, people were really concerned about IVF and whether that was safe. And of course, 10 million babies worldwide later, we now know that IVF is a safe, effective technique which has led to lots and lots of incredibly wanted children and families that wouldn't exist without it. So I think what's really important is that safety is rigorously monitored after these children's birth.
20:52 - What is the future of mitochondrial disease treatment?
What is the future of mitochondrial disease treatment?
Doug Turnbull
A pioneer in mitochondrial research, Sir Doug Turnbull has spent decades with families affected by these rare but devastating disorders. Now, with the UK leading the way in mitochondrial donation, he joins us to explain why this moment matters - not just for parents hoping for healthy children, but for the future of mitochondrial science…
Doug - It's been a long time coming. It started 25 years ago. And to get to this stage and to have eight healthy babies is truly wonderful and great news for the families.
James - It's fantastic that there were undetectable levels of mutated mitochondrial DNA in the vast majority of the babies in this latest trial, but two babies have been born with some small amounts of mutated mitochondrial DNA. I presume what's next is keeping an eye on that and working out why and working out whether this could be passed on to future generations.
Doug - Trying to limit that is going to be important. It's also important to realise that the level of carryover of mitochondrial DNA is well below the level that we would expect to cause disease. So I think it is important to try and limit that transmission, but also to be aware that the risks of disease in those children is very, very low indeed if non-existent. About transmission to the next generation, clearly if they're a male it won't be transmitted. For females, yes, we have to be concerned about that and thinking about that in the future.
James - This particular research was funded by the Wellcome Trust and the NHS, the National Health Service in this country, was involved in offering it to eligible parents. How do you anticipate this procedure might be offered in the future in the healthcare system?
Doug - The clinical trial was funded by Wellcome with the NHS picking up the excess treatment costs. It's very important to appreciate that for mitochondrial disease there is an NHS highly specialised service which was designated a specialised service back in 2007 and it transformed the care of patients with mitochondrial disease. It means that there are three highly specialised centres around the UK and it allows us to provide what I believe is a world-class service for patients with mitochondrial disease. One would hope that if the success of the trial continues that this will be something that we will be able to offer on the NHS, hopefully as part of our NHS highly specialised service. The publicity that's come along with this trial will make patients more aware, make physicians more aware and I would expect that we'll see a greater number of referrals. It is absolutely fundamental to the way in which I think medicine should be practised that this is available to all that suffer from the disease and I hope that that will be able to be continued.
James - Such an exciting development. What else is it in the field of mitochondrial research that you're particularly excited about? Where do you see us going next?
Doug - Mitochondrial research has come a long way, a very long way. It's gone through different phases. There was a phase where we were looking very much at the clinical aspects and then the diagnostic aspects and that's obviously been transformed with the next generation sequencing. Then hopefully we're at the stage where we can say we're preventing transmission of mitochondrial disease. We've made major steps in that way. We still have patients and we will still get patients who've got mitochondrial DNA mutations. It is critical I think that we look to try and get better treatment for those patients and I think that a great deal of effort has gone into preventing the transmission. A lot more effort is going ahead with trying to cure these diseases and I think that should be a major goal of those of us working within mitochondrial DNA diseases.
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