Adam Smith: They say it takes a village to raise a child. But how many people does it take to make one? Two has been the answer for a very long time, even with the dawns of IVF and single-sex couples, families have only ever needed an egg from a woman and sperm from a man.

But that may not be good enough for some couples affected by a certain debilitating disease. To save parents passing the disease on to their child through their genes, researchers at Newcastle University have developed a daring new technique. The only catch is: it produces embryos that contain DNA from three people.

Professor Mary Herbert: Very slowly we began to build up a picture that actually we could perform this pronuclear transfer on these embryos. That was very encouraging and we published it in Nature and it gave us a proof of concept, that it’s technically feasible in humans.

Professor Mary Herbert is part of the research team at Newcastle University. The therapy she’s working on is not yet proven in humans or available for patients. Because it raises so many ethical questions, the research  is undergoing a public consultation process right now to help the health secretary decide whether to allow a change in the law so that the researchers can begin testing it in humans. The consultation asks us questions about the limits of scientific research and the interaction between science and family life.

Professor Martin Richards, who studies families and how reproductive technologies have shaped them, explains…

Professor Martin Richards: there are clearly a set of issues I think that the standards if we look at other kinds of assisted reproduction, that are problematic.

AS: I spent some time with both Mary and Martin, to hear about how the Newcastle technique was developed and what the history of the family tells us about whether we’ll adopt it.

First, let’s look at the disease that, it is hoped, could be stamped out by the science.

Inside almost every cell in your body are tiny little things that generate your energy. They’re called mitochondria and are often referred to as the batteries of the cells. Mitochondria hold a little bit of DNA, just a handful of genes – 37 in fact. The vast majority of your DNA, up to 30,000 genes, is held elsewhere in the cell – in the nucleus. Each cell nucleus contains 99.9% of your DNA, half of it comes from your father and half from your mother. This nuclear DNA contains the genes that determine everything about you: from whether you’re tall or short to whether you’re likely to develop breast cancer.

Your mitochondria contain only 0.1% of your overall genetic material, and all it does is help them to make the proteins they need so your cells always have enough energy. While the vast majority of your cell’s DNA comes from both your parents, the DNA in mitochondria comes only from your mother. For some people, the DNA in their mitochondria is damaged, which can lead to disorders. They can cause miscarriage or stillbirth. Some babies born with mitochondrial disease live only a few days; others struggle on for months or maybe even years. Symptoms, and the age at which they become apparent, vary widely between patients. They can affect single organs – for example, causing blindness or heart failure – or the whole body.

But because mitochondria are not part of the all-important cell nucleus, researchers at Newcastle have been making human embryos with mitochondria from a third party (but not implanting these into mothers yet). They’ve developed two techniques where they make an embryo with the DNA from the mum and dad that will make a nucleus and the mitochondria from another female. This means that faulty mitochondria from the mum wouldn’t be passed on to the offspring. The embryo could develop normally into a foetus and still inherit 99.9% of its DNA from its mum and dad – everything it needs to determine its eye colour and all the usual things we inherit from our parents – but its mitochondria contain a little bit of genetic material from another person.

Here’s Mary on a very long, drawn-out experiment.

MH: I was rather surprised it work because the pro-nuclei in the human are enormous structures, 30 microns, so you’re working with big pipettes and so on. But we worked with it, it took quite a bit of doing and our early results were not that promising.

AS: Those of us who are grappling with the ethics are weighing up the fact that, if the treatment were given the green light, the mitochondrial DNA from the second woman would be passed on by the resulting child into the next generation – if the child was female, because remember that mitochondria are only passed on through the mother. It is very hard to guess what the consequences of this would be generations and generations down the line. It’s that where the law stands: you cannot alter the ‘genetic structure’ of a cell while it is part of an embryo. This meant that the HFEA originally did not even approve of the basic research Mary and her colleague Professor Doug Turnbull wanted to do.

MH: every research project using embryos has to be licensed by the HFEA. When we put in the application they turned it down, we appealed, they turned it down again and then we appealed to the authority and Doug Turnbull and I were about to make a trip to London ith a bundle sent by the HFEA when we realised the HFEA now had two barristers there, so we sort of said, maybe we can postpone this.

AS: You didn’t have any lawyers.

MH: No.

AS: You were just going to argue your case?

MH: We were just going to argue our case. You know, what does ‘genetic structure’ mean, because ‘genetic structure’ has no meaning in biology.

AS: That’s the term in the legislation.

MH: Yeah. After that appeal tot h authority they allowed us to do it and my understanding was that it really came down to measly words. They agree that the genetic structure was changed, in that it contained DNA it didn’t have before, but that we didn’t alter it.

AS: So that gave the initial go-ahead to the first stage in the research. Now, a few years on, Mary and her colleagues are keen to move the project on and see whether the embryos they produce can be implanted into mothers and lead to pregnancies. But first they have to win the support of the public through this consultation process, then the secretary of state for health – currently Jeremy Hunt – who will have to decide whether to make the required change in the law.

MH: The research and the regulatory process is moving in parallel so I hope that these discussions and the public consultation will encourage the secretary of state to have this debated in parliament and allow this in principle to be permitted as a clinical treatment, and then it’s up to the regulator I believe to look at the evidence that we produce.

AS: You can see how this one piece of research shines a light on the layers on layers of interests, regulations, legislation – which are all up for discussion at the moment. Of course, there are researchers who study these sorts of conversations and the way that public attitudes to reproductive techniques change over time. One such person is Martin Richards, emeritus professor of family research at the University of Cambridge.

Martin has spent decades looking at family relationships and how they change, so I asked him how he expects the public to view the new techniques to thwart mitochondrial disease.

MR: WE need to understand what this would all mean to the various people concerned. In terms of the same kinds of things we ask abut if this straight egg donation. There are questions about how we should treat these donors, should we say, this woman has given an egg for this kind of treatment, should we treat her as if that egg had been used directly in IVF which would mean that the donation cannot be anonymous, that when the child is grown up, it will have access to the information, name. Or the fact that the whole egg is not being used, not the nucleus, which some people say that’s where the genes that in one way make us who we are, although other things are needed for that too, should that make a difference? Should we say, she’s not really a reproductive donor.

AS: Before the research can continue into humans, now the government wants to know how you feel about this. On 14 September, the Department of Health launched a consultation through the Human Fertilisation and Embryology Authority, the HFEA, to collect public opinion on this technique.

Gene watchdog opens door to fertility technique that gives children THREE parents

… screamed the Daily Mail headline.

‘Three people, one baby’ public consultation begins

… said the BBC. The Guardian called it genetic modification, before changing its story when it was pointed out to editors that the technique did not amount to fiddling with the actual genes inside a cell. These headlines show just how controversial – and political – this scientific research is.

I asked Mary how it feels to be subject to such public scrutiny.

MH: I think the public consultation’s really interesting, actually, because these are very difficult concepts. And I think the media coverage has been very good and people in generally, I think they can grasp it. It’s been a good exercise in public engagement, because obviously you can explain it in a way that people can get their heads around. And then form a view. My dealing with the public on this, is I Was involved in another sounding board organized by the HFEA and it was very heartening and very encouraging that people wanted to understand, and were able then once they had sufficient information to form a view, so I don’t think it’s sensationalist. I know we’ve had all the complaints about the headlines, which are confusing. I mean, the ‘three-parent baby’ thing is very confusing even to people who know some science, but overall I think the coverage has been excellent. People are getting a grasp.

AS: No doubt Martin and colleagues will be pouring over the HFEA consultation response once it is published early next year – it will be, after all, the latest public attitude work on the cutting edge of assisted reproductive technology. But there has already been plenty of research done on technologies available today, such as IVF and donor insemination.

MR: In fact, one of the things that came out of that research pretty early on is that most children are not told that they’re born through donor gametes.

AS: Did that surprise you?

MR: It didn’t surprise me because it used to be the practice. Now in fact, not so long back, the practice has actually removed anonymity, so now when the children reach adulthood they’re allowed to ask for details of their donor. I had assumed and I think other people had assumed that there were reasons in the past, particularly when the legal situation wasn’t clear, that the child would technically be illegitimate. Those were removed. Another issue which was raised about secrecy was that men wouldn’t wish for their infertility to be sort of publicised, so that needed to be a secret.

AS: I wondered whether you could tell us a bit about the nuts and bolts of when you are doing research in this area.

MR: Depends what the issue is. Let me perhaps give you an example of one of the projects some of my colleagues have been engaged in. In the USA there’s a website were donor children, donor parents and donors can sign up because they’re interested in making contact with each other. There’s a lot of interst in why are people doing that, what do they want to gt out of it, what happens when they meet their donors and so on. And that was done by collaboration by with the people who run the website for matching, and they posted something on the website asking people if they would b interested in being interviewed or answering questionnaires. Most of the people who sign up to that website aren’t successful in any of their searches. They may be in the future but they haven’t yet been. So the number of people who’ve made contact is actually quite small. Some of the main data there is what one might call straightforward description, asking people, why were they searching, did they want information, did they want to meet, and that was done through questionnaires which basically set out a set of possibilities. What is interesting about the results is that most of the searching is done by donor parents, who have donor children but they are typically quite young. And many of them were as if not more interested in finding donor siblings than they were in finding the donor. I think it was a surprise that that was so important. People did know, I mean, people in research knew that there were cases where people have been very interested in trying to find the other children from the same donor.

AS: Presumably there are sometimes hundreds, or maybe not hundreds, but lots and lots of siblings. More than we might think of in a very conventional family at least.

MR: Indeed. In theory there is regulation of the number. In the States the regulation is really, it’s a kind of professional recommendation. In Britain we have a rather tighter regulation, but in the study we found some pretty big collections, I mean 50 plus. There’d already been a press story about the man who got called the God of Sperm who claims to have 500 children.

AS: Through donation?

MR: Through donation.

AS: And is there any merit in his claim?

MR: It’s very hard to say. One man, his story is he thought he was donating for medical research and his sperm wasn’t being used reproductively. It’s very hard to verify.

AS: The God of Sperm may have gone to the press with his story, and we all may be being consulted on our thoughts on the potential mitochondrial disease therapy, but reproductive technologies were not always talked about so openly. Martin’s historical research has spotted cases from over a century ago, when these treatments were still very much behind closed doors…

MR: In fact the earliest use of insemination was using husbands sperm. There was a wide belief that a certain amount of female infertility was because the sperm couldn’t reach the uterus, so that became, I’m talking now early nineteenth century and a bit earlier, that was quite a widely used treatment, to get sperm from the husband. And to inseminate it when the wife was having problems conceiving. It didn’t’ happen to be very successful but it didn’t’ stop people trying, and it’s a reasonable thing to do. but as early as the 1880s, the pope condemned it on the grounds that it was unnatural. And there was a concern then, and that continues, that the sperm by masturbation, and that was regarded as a sin.

In Britain the practice of assisted reproduction grew up in the late 1930s when infertility clinics opened and offered these kinds of treatment. But they were not popular, even in the medical profession…

MR: There was for example the first paper in the British Medical Journal describing the practice, which was 1940s, got a huge correspondence in the medical journal from other doctors saying in varying degrees of politeness, that this was outrageous and should be stopped. Not quite all of them  but broadly hostile.

AS: So was it very difficult if you wanted to have this treatment to find a doctor who would help you?

MR: Yes, I mean there were very few people at least doing it in clinics. It’s quite possible there was other doctors offering it as it were privately. There were other people: Marie Stopes, the sex guru as it were. She had a large correspondence with people who weren’t, she was a kind of agony aunt for people with sexual problems. She was writing letters to people, she claims form the early 1920s if not a little earlier, suggesting that if they were having problems conceiving, as she put it they should avoid expensive doctors. And she gave them clear instructions about how the husband should get hold of a friend, collect the sperm and how you can inseminate yourself.

AS: Have you found any primary source material, any accounts, from the people who did this

MR: Not quite that, I mean there are some letters to Marie Stopes about people who’ve used it successfully. WE have the accounts of the clinicians who were using it. but the whole thing was shrouded in secrecy.

Brits may be famous for their rather Victorian reserve when it comes to talking about these things – no assisted reproduction please, we’re British. But one thing we’re not prudish about is research. As this consultation into mitochondrial disease treatments shows, we’re keen to have research and the ethical implications of it discussed very openly. It’s a way for us all to get to decide the course of science and medicine. Most people I’ve spoken to about this consultation expect the public to be broadly supportive of the techniques, so I asked Mary Herbert what the next stage in her work would be, if she got the go-ahead from the health secretary next year. She told me that the research would inch forward, starting with the blastocysts they produced – blastocysts are very early embryos.

MH: The next stage of the research will be for us to satisfy ourselves that this is worth going for, in terms of the number of blastocysts we can produce. Obviously the blastocysts is an important development milestone because if they can’t become blastocysts then they can’t implant. That would be my first question: is it likely to be effective, is it likely to give us pregnancies. And then the enxt question would be: are these blastocycts normal, and we will look at a range of parameters. Part of the problem is we don’t know what normal is for a human blastocyst, but we do have unmanipulated blastocysts to look at and I think in the course of this research we will also uncover a great of knowledge about early embryonic development.

AS: SO there would still be a lot of research to be done even if it were given the green light for development?

MH: It depends on timing. We aspire to have the answer within five years, but you’re dealing with a biological system here, and with the donation of eggs. There are always unforeseen challenges.

AS: Remember the government needs YOU to say how you feel about this research, via www.hfea.gov.uk.

LINKS

Human Fertilisation and Embryology Authority (HFEA) homepage

Mitochondria disease consultation

Professor Mary Herbert

Newcastle University Institute for Ageing and Health

Professor Martin Richards

Centre for Family Research, University of Cambridge

The United Mitochondria Disease Foundation

What is Mitochondria Disease?

The Lily Foundation

MEDIA

The Daily Mail: Gene watchdog opens door to fertility technique that gives children THREE parents

BBC: ‘Three people, one baby’ public consultation begins

The Daily Beast: Mapping the god of sperm

BioNews: HFEA launches public consultation on mitochondrial replacement techniques

The Guardian: Regulator to consult public over plans for new fertility treatments

Comment is free: Misleading talk of ‘three-parent babies’ helps no one

CREDITS

• Baby sound courtesy of reinsamba at Freesound.
• Baby photo courtesy of storyvillegirl at Flickr.