'Three-parent babies' prevent inherited genetic condition

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0:34James Tytko:all engine running absolute genius get this welcome welcome this is the show where we bring you science what that essentially means is discovery advances research technology unbelievable without further ado this is the naked scientists hello and welcome to the naked scientists the show where we bring you the biggest breakthroughs and talk to the major movers and shakers in the worlds of science, technology and medicine. I'm James Titko. This week, three-person embryos, the incredible medical procedure that prevents children from inheriting incurable mitochondrial diseases.

1:18James Tytko: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 Lilly Foundation, speaking to Sky News. We lost our third daughter, Lilly, 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, 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.

2:05James Tytko: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? Well Sir Doug Turnbull is a clinical neurologist and a leading expert on these conditions.

2:44Well mitochondria are in simplified terms are the powerhouse of the cell. They convert their 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.

3:03James Tytko:Where do we get our mitochondria from? Well mitochondria are inherited exclusively through the mother. They carry a small piece of DNA called mitochondrial DNA. Mitochondrial DNA diseases are transmitted purely maternally. 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. Yes, that's correct, James. It's an entirely separate piece of DNA. It's a tiny piece of DNA. It's only 30 ,500 bases compared to the 3 billion bases that's present in the nuclear DNA.

3:50It only encodes for 37 genes. All those genes are essential for allowing the mitochondria to work properly.

3:59James Tytko:And so when they don't work properly, mitochondria they're involved with metabolizing 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 yes it tends to particularly involve those organs which require a lot of energy i mean good examples of this are that you know the hearts involve frequently in mitochondrial disease the muscles and the brain is involved frequently in mitochondrial disease. 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, your heart disease where your heart doesn't pump properly, it can lead to muscle weakness.

4:47In the brain it can have much more varied effects. If you get mitochondrial disease as a young child it can cause neurodegeneration of particularly the lower part of the brain called the brain stem later on in life it can induce epilepsy in coordination a variety of poor cognitive function a variety of different what we call clinical phenotypes which are

5:12James Tytko:associated with mitochondrial disease what are the determinants of those phenotypes then are all mitochondria affected in a person with mutated mitochondrial DNA? So mitochondrial DNA is present in multiple copies within an individual mitochondria and therefore present in literally thousands of copies within an individual cell. So mitochondrial genetics is a bit complicated in the sense that you can actually have all your mitochondrial DNA being normal. You can have all your mitochondrial DNA having a mutation in, or in some patients, and quite a large number of patients, you have a mixture of normal and abnormal mitochondrial DNA.

5:59This is termed heteroplasmy. That mixture between what we call normal and abnormal mitochondria is critical. So the higher the level of abnormal mitochondrial DNA you have, the more likely you are to get disease. So 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 of them will be genetic, some will be environmental. Understanding what causes that difference in phenotype is an area of intense research at the moment to try and understand, because clearly if you understood the difference that was causing that phenotype, then potentially you might have a treatment that would actually help patients.

6:50James Tytko:Where are we with treatments for mitochondrial diseases related to mutations in mitochondrial DNA? Well, I think it's very important to say that as a clinician that'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 well some of the advances in cardiac drugs have meant that we can manage the cardiac disease at least in some of the patients so for example some patients might develop a heart block and you could have a pacemaker put in some patients as I've mentioned before with the central nervous system involvement will develop epilepsy and of course we can try and treat the epilepsy with drugs.

7:38It's successful in most patients to a degree. So those are treating the 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, which is why we've got to be looking for curative therapies, but also highlights why prevention is so critical for these families who've clearly got mitochondrial DNA disease often running through many generations.

8:13James Tytko:Sir Doug Turnbull. Shortly we'll hear about the 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 though, we called an IVF pioneer to ask how this approach can help prevent inherited conditions.

8:53I'm Robert Winston. I'm Professor of Science and Society at Imperial College London and of course I've been involved with in vitro fertilization 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.

9:35James Tytko:Selective embryo transfer has thus already helped stop life-limiting conditions like cystic fibrosis from being passed down through generations. 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 all of 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. Because the affected women'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.

10:19James Tytko: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 egg 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.

11:05It'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.

11:54James Tytko:Robert Winston 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 the work is Mary Herbert, a reproductive biologist at Newcastle and Monash universities. The patient, once they have approval, will undergo ovarian stimulation and egg collection.

12:34We will freeze those eggs and then once a suitable donor has an egg collection, we thaw those patient eggs, we fertilise both sets of eggs with a partner sperm and then we perform phonuclear transfer six to eight hours after fertilisation. So what you get after that is this sort of reconstructed fertilised egg which contains the nuclear DNA from the parents and then it contains predominantly the mitochondrial DNA from the egg donor.

13:05James Tytko: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. It is indeed tricky. It requires a high level of skill and all the more so because we do it about eight hours after fertilisation and that's usually after midnight to 2am. So it's a pretty tough calling. And the reason we do it at that time, initially in our preclinical research, we come in the next morning to do the pronuclear transfer, but the eggs didn't survive that very well. And so we figured it was because that was too close to the time of division to the two-cell stage.

13:46So we decided then to just radically change the protocol so that we were removing the pronuclei as soon as they appeared. So that's small hours of the morning job.

13:56James Tytko: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. And you've got to inhibit that before you can take out the pronuclei. So you use little gas pipettes to do this, exactly to the right diameter. Once you've put your egg into these inhibitors, it becomes a bit fluid, the cytoplasm, and you just pinch off the pronuclei so that they are surrounded by a little bit of cytoplasm and bounded by a fragment of the egg's plasma membrane. So that's what we call the karyoplast. Like a little cell in itself, it's just got the pronuclei surrounded by a little piece of cytoplasm in the egg and bounded by the plasma membrane.

14:38And we take one pronucleus out at a time. So there would be two of these karyoplasts per patient egg enucleated. And then you take those and you give them a very brief, very brief exposure to a fusogen, an agent that will enable them to fuse back with the enucleated donor egg. And they just fuse very nicely. It's really nice to see this in a movie, actually.

14:59James Tytko:But as precise as these highly skilled surgeons may be, removing the patient's nucleogenetic material carries some risk. Human eggs are just really jam-packed full of mitochondria. So when we're transplanting the patient nuclear DNA, it's almost inevitable that it will also contain some patient mitochondrial DNA. And of course, you've got to worry about what happens to that. If it's preferentially amplified, then you may not be preventing the disease. And so in the research phase, we found that when we did this procedure, there was very low levels in the embryos once we optimized the procedures.

15:36But then we made embryonic stem cells and 20 % of them actually reverted to the maternal mitochondrial genome. So that told us that productive transfer can reduce risk, but we cannot guarantee prevention.

15:50James Tytko: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. We got a go-ahead-to-start treatment in 2018, and then in the paper we published in the middle of July, we reported on 19 who had a pronocleotransfer procedure. Of those, seven became pregnant, and there are so far eight babies and another one on the way. But as to the crucial information, what levels of mutated mitochondrial DNA were found in these babies in follow-up testing?

16:39Crucially indeed. So six of the eight have undetectable levels. Five of the eight had undetectable at birth. One had 5%. And when they went back and looked at three months, that was undetectable. So that dropped. Then the other two, one has 12 % and another has 16%. But the important part to say is that these levels are way, way below the threshold for disease. In general, you don't get severe symptoms up to over 60%. The eggs that would have given rise to these babies had we not done pronuclear transfer, the levels of mutated mitochondrial DNA range from 67 % to 100%.

17:15James Tytko:Bearing down on exactly why these mutated mitochondria are still prevalent will therefore be the next step in the development of this hugely promising technique. 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, you know, we bridge that gap between risk reduction and prevention. Mary Herbert at Newcastle and Monash Universities. Summer's supposed to be the easy season. So why are so many people quietly googling a therapist between summer Fridays. Because more daylight doesn't fix the hard stuff.

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18:53James Tytko:This is the Naked Scientist podcast with me, James Titko. Today, the science of three-parent embryos and how this technique is enabling us to tackle formerly life-threatening mitochondrial diseases. 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.

19:34James Tytko:Emily told me why she doesn't believe this is a step towards designer babies. 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. It wasn't seen as making the substantial changes that could be made, for example, by gene editing. Drawing the distinction then between preventing an incurable inherited disease versus making designer babies, so to speak.

20:21There's pretty much a worldwide consensus that gene editing in embryos is not safe enough to be done in humans. And 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.

20:46James Tytko:So scientists clearly involved with every step in drawing up this new regulation. How were the public policymakers contributing to this process? Absolutely. So when the HFVA 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.

21:32James Tytko: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. 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.

22:16So I think what's really important is that safety is rigorously monitored after these children's birth.

22:23James Tytko:Emily Jackson, Professor of Law at the London School of Economics. Back now to Sir Doug Turnbull, whom we heard from earlier. A pioneer in mitochondrial research, Sir Doug 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. it's been a long time coming it you know 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 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.

23:26Trying 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.

24:04James Tytko: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? the clinical trial was funded by welcome with the nhs picking up the excess treatment costs it's very important to appreciate that for mitochondrial disease there is an nhs highly specialized service which was designated as specialized service back in 2007 and it transformed the care of patients with mitochondrial disease it means that there are three highly specialized centres around the UK and it allows us to provide what I believe is a world-class service for patients with mitochondrial disease and 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.