Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015

Lord Patel Excerpts

Tuesday 24th February 2015 Lords Chamber

Is it too much to ask that we complete the tests, that we learn from the Chinese why the only time one of these two techniques has been used, they were so appalled by the results that they banned them—they had very clear evidence, which we can have—and that we have absolute assurance on the matter of the European law? We can then all do what is best, and if it goes wrong, we can say, honestly, that we took the best steps and did what was right at the time. That is the only thing human beings can ever do. If we are wrong then, that is due to the wrongness of human nature, and not the wrongness of avoiding what it is necessary to do to make us as safe as is humanly possible. I therefore hope that this House will accept that what could be the shortest of delays is a necessary part of making sure that none of us comes back and says, “We allowed something to happen that should never have happened”.

[Lord Patel (CB)]

My Lords—

[The Deputy Speaker (Lord Geddes)]

I assume the noble Lord would like to move his amendment.

[Lord Deben]

I beg to move.

[Lord Patel]

My Lords, I am sorry for rushing in, but the noble Lord, Lord Deben, excited me so much with the comments he made that I have to answer some of his points, particularly on safety. I hope that noble Lords will have patience, because I need to go through each of the points he has made on safety, as I have no doubt that they will come back again in subsequent debate.

It is important that I put down some ground work. What are we talking about? We are talking about a mitochondrial DNA disease that commonly affects multiple different organs. Symptoms include severe muscle weakness, diabetes, heart problems, cardiac failure and sudden cardiac death, as well as central nervous system problems, which include dementia, epilepsy, stroke and such other horrible conditions. It results in death, which can occur early in childhood or after a prolonged period of incapacity and pain that can last for years.

It is important to have some facts about mitochondrial DNA genetics and inheritance. Mitochondrial DNA is strictly inherited maternally, via the egg. The mitochondrial DNA copy number and the number of mitochondria vary between cell types, with more than 200,000 in the egg and early embryo down to perhaps as few as 10 to 20 in many cells of the two to three-week old embryo, and hundreds to thousands in most cell types in adults, where the number tends to correlate with energy demand. Cells can have a mixture of two or more types of mitochondrial DNA sequence, a condition referred to as heteroplasmy, in contrast to homoplasmy, where each copy has the same sequence. More than 300 distinct mutations of mitochondrial DNA have been found in patients with mitochondrial disease. Although some mutations are far more common than others, if an individual is heteroplasmic, with a mixture of mutant and normal mitochondrial DNA, the proportion of the former determines whether they show symptoms of mitochondrial disease. Some women at risk of transmitting mitochondrial disease to their children are heteroplasmic and may have levels considerably below the disease threshold, but their eggs can have very high levels of mutant mitochondrial DNA or even be homoplasmic. This can be explained by the so-called bottleneck, which I will not go into in detail, but, during the development of the egg, only a certain number of mitochondria go into fertilisation, and that causes a bottleneck that sometimes results in only the mutant mitochondria getting through.

It is estimated that at least one in 200 children in the UK is born with some faulty mitochondrial DNA—so quite a lot of them may well have some faulty mitochondrial DNA. It is estimated that one in 6,500 babies goes on to develop serious mitochondrial disorders. The severity varies from mild to extremely debilitating and may result in early childhood death. Almost 2,500 women of child-bearing age in the UK are at risk of transmitting mitochondrial disease to their children. Estimates based on this figure suggest that between 100 and 150 births a year in the UK risk passing on mitochondrial disease to the child. If today we were discussing cancer or dementia, and how we could modify those diseases with some form of genetic or mitochondrial manipulation so that people would not get it, everybody would be in favour of it; but as mitochondrial disease affects 100 to 150 people a year, we do not take it so seriously—or so it seems.

I will now go on to what the noble Lord, Lord Deben, said about the two techniques that we are likely to be discussing—the maternal spindle transfer, which the noble Lord prefers, and pronuclear transfer—and I will say why I believe it is necessary that currently the HFEA, as a regulator, is allowed to decide which method might be appropriate for a given patient in a given centre. We do not know which technique is the more efficient and safer, despite what some others may believe. In fact, they may not be equally efficacious in every woman.

Pronuclear transfer has been used successfully in animals for more than 30 years with no evidence of adverse effects. On the other hand, maternal spindle transfer is a newer technique, which is likely to result in less carryover of mitochondria but has a higher risk of chromosomal abnormalities. That is an important point: pronuclear transfer may have more carryover of mitochondria but maternal spindle transfer has a higher risk of chromosomal abnormality. Maternal spindle transfers are very sensitive to manipulation. The embryo is less sensitive in its early stage to such manipulation.

Furthermore, both techniques have been found to be variable for avoiding mitochondrial disease. Which technique will be used for each individual patient will be a decision for the patient, based on their informed consent, their clinicians, the evidence from research and the safety aspects. In my view, it would be inappropriate for Parliament to make a scientific judgment as to which technique should be able to be used. One thing is certain: the scientists and the clinicians will go with whichever method is the safest and most efficacious. If it turns out, through research that is currently going on, that we can make maternal spindle transfer safer and less likely to lead to chromosomal abnormalities, that is the method that the scientists and the clinicians will choose. Research is going on to make that process safer. There are many ways of doing this. I am not being flippant when I say that one of the methods that has been tried is to use a small amount of caffeine to make the maternal spindle transfer more stable. Eventually, we will get that research right and whatever method is safest will be used. However, it would be wrong to opt now for one method which is not as successful as others.

Issues have been raised about the health and safety risks of some of the techniques. I agree with the noble Lord, Lord Deben, that it is never possible to be certain that new medical procedures will be 100% safe or effective. That applies to the whole of medicine—drugs, devices or surgery. Risks have been assessed in detail. As the Minister said, there have been three separate reviews of the scientific evidence on the technique’s safety by a specially convened independent panel of experts. It would be wrong to suggest that these experts might be biased when none of them has any financial interest in mitochondrial research or treatment, or that they might not have understood the issues and that we in this Parliament are more likely to understand the science which underpins this research, which has led to the point where it is now possible to use this technique to help women to have normal babies.

Decisions on safety and efficacy should be taken by the statutory regulatory authority created to do this—the HFEA. Risks must be balanced. Evidence suggests that any risks of mitochondrial donation are proportionately less than the significant risk that children will continue to be born who will develop severe mitochondrial disease if these techniques are not used. Ultimately, it will be up to affected families to judge the balance of these risks. They are the ones who will take the risks.

I would like to explore some of the health risks that the noble Lord, Lord Deben, mentioned, although he did not mention that of the potential effects of the donated mitochondrial DNA on the rest of the cell. I turn first to traits attributed to mitochondrial DNA. On variations in the 37 well studied genes, a whole mitochondrial genome has been sequenced for all these genes and they have all been found to have one function in expressing the protein that produces energy. No other trait has been identified from the sequencing of the whole mitochondrial genome. Therefore, the variations have been well studied. Although this is still contentious among mitochondrial experts, theoretically—I admit—it is possible that a child born after mitochondrial donation might have a slightly different energy metabolism compared with his or her female ancestors. However, none of this has resulted in devastating mitochondrial disease.

Evidence has also been cited that a mismatch between the DNA in the donor’s mitochondria and the mother’s nuclear DNA might have a negative impact, namely sterility and impaired growth—the noble Lord mentioned sterility—in the resulting child, as well as slow metabolism. This issue was considered in great detail by the HFEA scientific panel. In normal human populations the mixing of nuclear DNA during sexual reproduction means that there can be a complete exchange of nuclear and mitochondrial DNA type over a few generations—I calculate it to be about six generations. Given that I married an English lady, the mitochondria of my children have changed dramatically. My ancestors’ mitochondria are no longer in my children—they have English mitochondria. However, I am glad to say that they have produced terrific children. Evidence of mismatch between nucleus and mitochondrial genomes has come mostly from research where new combinations have been made experimentally across animal species that have been separated for many hundreds of thousands of years or longer—for example, rats and mice. Within species, such as in some experiments involving mice or fruit flies, evidence of mismatch is seen only when particular sub-strains of a species have been reproductively isolated from each other and each inbred. The one species, the human race, is the most outbred species there is. Some of us are examples of that.

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[Lord Gordon of Strathblane (Lab)]

Would the noble Lord comment on the HFEA’s recommendation that, as available data are limited, an extensive range of pre-clinical research should be carried out before proceeding?

[Lord Patel]

The data that the report suggested were not available were actually presented to the committee. They have not been published because, as any scientist would know, if you publish—

[Lord Winston (Lab)]

I wonder whether I can help my noble friend Lord Patel. Does he agree with me that there were very few available data for the first in vitro fertilisation babies, and that that was a step in the dark, as were pre-implantation diagnosis and sperm microinjection? Before he concludes his speech, would my noble friend be kind enough to answer an important question asked by the noble Lord, Lord Deben, about the possibility that we might be making infertile children? Was that not the accusation made when infertility was treated by in vitro fertilisation, and was there not a widespread fear at that time, too, that we would be making infertile children?

[Lord Patel]

I thank my noble friend for that interruption. It was worse than that: it was suggested not only that those children might be infertile, but that they might be half monsters of some kind. To answer the question raised earlier about the HFEA’s evidence—yes, it did ask, and the evidence was verbally produced. The reason why it is not published is that anything that is published, even in the form of an extract, cannot then be published in a reputable journal. I know that that evidence has now been sent for publication.

To go back to the subject of the evidence requested, if we were to go down that road and do those experiments, what would be required in the human population is the deliberate creation and destruction of many hundreds, if not thousands, of embryos—to prove a point that does not require proving. Hundreds and thousands of human embryos have already been tested and found to go to a blastocyst state, and I hope my noble friend Lord Winston will agree that if we see them in that state, the embryo will be satisfactory. He nods slightly.

The alternative would be human population genetic studies to fulfil that requirement for evidence. What that shows is that exchange of mitochondrial DNA haplotypes by normal reproduction should reveal combinations that are deleterious. Human population genetic studies will do that. Such studies include genome-wide association studies and whole genome sequencing projects looking at many specific diseases and syndromes. Those kinds of studies will be required. They do not require embryos to be created, nor is it necessary to do these studies before this treatment is available.

I know I am going on a bit, but other points were made. If there are points about epigenetics et cetera, those are also spurious and have no basis in science.

Let me go now to something that the noble Lord, Lord Deben, mentioned twice: the Chinese example. The technique that was used in the United States and in this Chinese example is called cytoplasmic injection. No doubt the noble Lord, Lord Winston, is more familiar with it from his work than I am. It is a technique that is not allowed in the United Kingdom. That is the first point. It is completely different in design and intent from what we are talking about in mitochondrial replacement; it is nothing to do with it.

What was done in China was a cytoplasmic injection not for replacing mitochondria, but for infertility treatment in older women. That was also the case in the United States; it was an extra cytoplasm with possible mitochondria in older women, where both are at risk of producing chromosomal abnormality. In China it was used in only one study, which was conducted by an American, Professor Grifo. They inserted five embryos. We do not allow that in the United Kingdom because of the risk of multiple pregnancy. It resulted in a multiple pregnancy. They then tried to reduce the number of foetuses by injecting one of them to reduce the number of foetuses from three to two. I do not know what kind of technique they used—

[Lord Winston]

Dangerous.

[Lord Patel]

“Dangerous”, my noble friend says. It killed the other two and resulted in a premature birth. They never published this, despite being asked if there was a publication. It is wrong to say that the HFEA did not ask them; the review panel did. Professor Grifo sent a letter saying that, in his view, all the foetuses were normal but they died of prematurity. What they died of was an obstetric botch-up. It had nothing to do with what we are talking about today. It was a completely different technique. We should dismiss it completely. It would be wrong to put any credence on it and say that it is a good reason why we should not do this.

I could go on about other safety aspects that were brought up, but let me close by saying that hitherto the science has gone as far as it can in thousands of animal experiments that have resulted in normal pups. In human embryos it has gone as far as it can to produce normal embryos, which, if implanted, there is no reason to believe would not develop into normal, healthy babies who would not carry the defective mitochondria. All we are doing today is allowing the regulator henceforth to decide, on a case-by-case basis, to issue a licence to those clinics for those mothers who request this treatment, and which are allowed to use both techniques that we currently know are safe while further research goes on. None of us stops researching: the noble Lord, Lord Winston, still carries on researching; the noble Lord, Lord Kakkar, still carries on researching. If a chance was given, the noble Lord, Lord Walton, would still carry on researching. We do not stop researching; that is the nature of medicine and of academic medical science. I hope that we will pass these regulations.

[Lord Turnberg (Lab)]

My Lords, I am extremely grateful to be able to follow the noble Lord, Lord Patel. I am also grateful to the noble Earl for setting out the issues so carefully at the beginning. I listened with great attention to the eloquent and persuasive speech from the noble Lord, Lord Deben, but I am afraid I was not persuaded. I cannot go along with the idea that we should put this regulation on hold for the time being. My reason is the awful position parents find themselves in when they have a child severely affected by one of these dreadful mitochondrial diseases. They are desperate to avoid having more children with the same disease. The noble Lord, Lord Deben, started from the same position but I believe that we are now in a position to move forward.

We have all been bombarded with information about mitochondria to the extent that few of us can be entirely ignorant of what they are and what they do. Yet there is still considerable room for confusion, at least according to some of the correspondence I have received. References to GM crops and cloned animals are way out of line. Suggestions that mitochondrial transfer techniques are a form of cloning when they are nothing of the sort, or that they are on the slippery slope to genetic manipulation and designer babies when there is no conceivable link between them, are very unhelpful and not part of any reasoned discussion about the issues. I could elaborate on that but will leave it for the moment to concentrate on what I think are the more rational arguments that have been and will be made today.

The noble Earl discussed the safety issues, as did the noble Lord, Lord Patel. The suggestion has been made that the techniques may not yet be safe enough. Let me take this a little further. The basic animal experiments have been going on since the 1980s and the specifics of maternal spindle and pronuclear transfer have been very fully researched for the last seven years. We have heard about the three thorough scientific reviews by expert panels set up by the HFEA. In each, further research that needed doing was suggested and each time the research has been actively and successfully pursued. On the last occasion, in 2014, they clearly stated that there were no major safety issues remaining. It is true that they suggested some further tests—and they are all under way, as we have heard—but they pointed to the fact that at the end of the day there will be no substitute for trying it in humans who carry the abnormal mitochondria.

In vitro studies in the test tube with human embryos after mitochondrial replacement have revealed no problems, and experiments with macaque monkeys—yes, they have been done—and maternal spindle transfer are all reassuring. It is interesting that monkeys are not suitable models for pronuclear transfer techniques because research shows that pronuclear transfer in vitro fails in monkeys but works perfectly well in human studies. The only way in which safety can be finally tested is in humans since no procedure or drug can be certainly safe without that. We have gone almost as far as we possibly can before that step is taken. We have heard some issues about the China syndrome, which I believe the noble Lord, Lord Patel, has dealt with perfectly well. Clearly, that was quite something else and not relevant to our discussions today.

Equally important is that these regulations do not simply allow human trials to start now—they do not; they allow the HFEA only to examine applications made to it for full assessment. It will then decide if the science is persuasive enough, that those proposing to do it have sufficient experience and capacity, and that the patients being put forward are clearly those likely to benefit. Remember that the HFEA is no pushover. It has in its membership not just three scientists and a clinical geneticist but three patients who have gone through IVF, a barrister, a professor of philosophy, a bishop and a national security adviser. That is quite an interesting mix but not one likely to be easily moved by faulty argument. It is they and their scientific advisory panel who will be assessing applications when these regulations come into force in October.

Other anxieties have been expressed that we will be disrupting the relationship between the nuclear and mitochondrial genes: the nuclear genes carry the information that determines all the characteristics that make us human, and the mitochondrial genes provide the energy supply for cells. This argument was discussed at great length in the HFEA’s scientific report in 2014 and was found wanting, not least because half the genes in a fertilised egg are derived from the father and are therefore already foreign to the mitochondria, yet they do not interfere with each other. Furthermore, mitochondrial genes are pretty well conserved between different individuals because they perform a limited number of functions, while there are large differences between the nuclear genes of different people, each of whom is made up of a mixture of DNA from a mother and a father.

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[Baroness O'Loan]

I thank the noble Lord for that intervention. However, the research shows that there is a shortage of women donors.

Eggs used have to be extracted from women’s ovaries by a process known as controlled ovarian hyperstimulation, which can lead to complications for women. According to the Royal College of Obstetricians and Gynaecologists, it affects up to one in three women to some degree. It says that between 3% and 8% of IVF cycles are complicated by either moderate or severe OHSS, which can cause a variety of painful and upsetting symptoms such as abdominal pain, nausea, diarrhoea, haemoconcentration, thrombosis, pleural effusion and respiratory distress. It can be further complicated by ovarian rupture and renal insufficiency. In some cases, it can be life-threatening.

The Newcastle Centre for Life conducted research on the prevalence of OHSS and published the results. It found that the risk of hospitalisation increased massively if more than 20 eggs were collected. We do not know whether the pattern that it established is repeated at other research centres because the data have not been compiled. There is a gap in the evidence base. The really important point is that, as I understand it, the collection of 20 or more eggs is very common in the UK. Tens of thousands of women have been through the process, so there is a substantially increased risk of a serious medical condition.

Mitochondrial donation is impossible without a supply of donor eggs. The procedures rely on the willingness of women to undergo a process which may bear serious health risks and about whose safety there are not extensive data. Two Answers were given in Parliament last summer which suggested that the monitoring of the incidence of ovarian hyperstimulation syndrome is inadequate. On 9 July, the Health Minister in another place said:

“The HFEA does not, therefore, hold definitive data on the number of women admitted to hospital with OHSS, including non-patient egg donors and egg-share donors”.—[Official Report, Commons, 9/7/14; col. 313W.]

On another occasion, it was said that,

“licensed fertility clinics are only required to report instances of OHSS to the authority that require a hospital admission with a severe grading”.—[Official Report, Commons, 24/6/14; col. 157W.]

It was stated that other cases were reported as well. I do not think that the Government have given enough consideration to the effects of the legalisation of mitochondrial donation on the donor’s health. There is a possibility that it will lead to further problems.

This concern is underlined very effectively by the fact that the Newcastle scientists pressed Parliament very hard to sanction legislation to permit the creation of animal hybrid embryos. Parliamentarians who recall that debate will remember that the principal justification for changing the law was to allow the creation of admixed human embryos in order for research to be conducted without it being dependent on human eggs because of their limited availability. The legislation was passed; the research is dead.

[Lord Patel]

I thank the noble Baroness for giving way. It is important to clarify that point, particularly as it was crucial in the debate on that amendment. Admixed embryos were required for the research to be carried out then in order to study the diseases in embryonic stem cell lines without using human eggs. She is correct in saying that. On why that research has been abandoned, as the noble Lord, Lord Alton, may well remember, I made the comment in closing that the utopian dream of the scientist would be that, one day, we might reach a point where we were able to take a skin fibroblast and down-regulate it so that it behaved like a pluripotent cell. That dream came true two weeks after that legislation was passed, when Yamanaka in Japan published an article saying how it could be done. That is why the research stopped; it was not because it could not be done.

[Baroness O'Loan]

I thank the noble Lord for his intervention. It remains the case that there is a shortage of donated eggs. My concern is for the women who are asked to donate eggs.

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[Lord Patel]

May I comment on that, since the noble Lord refers to me?

[Lord Alton of Liverpool]

I did actually ask the noble Lord, Lord Winston.

[Lord Patel]

I think that the noble Lord was asking him to reply to my comment. He is quite right that China has used pronuclear transfer techniques, but the disaster was upsetting to me.

[Lord Winston]

I am very concerned that the noble Lord, Lord Patel, might get into trouble with the Whip sitting on the Front Bench. I am always in her bad books, and I would not want to allow him to be in her bad books as well.

Let me answer the noble Lord, Lord Alton. It is true that, two years ago, I said that it was unpredictable; of course, these things are unpredictable. In the context in which I was speaking, that was correct. To be fair, however, the noble Lord, Lord Alton, knows that, with the case of Jacques Cohen in New Jersey, 17 babies were born after mitochondrial transfer. Therefore, there has been some other evidence—other than that evidence from China—that suggests that this is not quite as daft as proposed. Added to which, of course, in two years, a huge amount of research has been done by our colleagues in Newcastle. They have been working flat out on a whole range of tests which, I think, have made a very big difference. Since the statement that I made in the House, three different committees have looked at the safety.

Science does not have the truth; we have a version of the truth. We have to interpret what we can as best we can.

I deeply respect the noble Lord, Lord Alton, as he knows very well. We both come from a very strong view about what is the right thing to try to do wherever possible. However, I feel here that, apart from the issue of preserving healthy life, if we decide not to vote for the amendment of the noble Lord, Lord Deben, we are doing something really important. We are expressing our concern—our compassion—as a House for people who are faced with an invidious and horrendous choice.

Under those circumstances, given that this will be a limited procedure affecting very few people, it would be utterly wrong for this House to turn down the democratically elected Chamber and not to support what the Government propose.

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[Baroness Hollins (CB)]

My Lords, I take a rather different view from some of my eminent medical colleagues. I have worked for over 30 years with families of severely disabled children. As a psychiatrist—and as the mother myself of a child born with a severe developmental disability—my heart goes out to those parents facing the prospect of inherited mitochondrial disorders. As a mother, I understand what is called the moral imperative to try to help. However, our first responsibility must be to the children who may be created through these proposed interventions: the most important moral imperative must be to do no harm.

A new technology of such potential importance must take as long as is needed to be as sure as possible of its safety. Being first is not always best. I have carefully read the HFEA 2014 review of scientific methods. It has been implied that the scientific reviews have not raised any concerns, but in paragraph 3.7.25 the review states,

“although the results with the two techniques continue to be promising, further experiments need to be carried out before introducing either into clinical practice to provide further reassurance about efficiency and safety”.

I asked a Written Question in December asking whether clinical trials were being planned and I am grateful for the helpful reply from the Minister and the mention he made of it in his opening remarks—although I disagree with his interpretation of medicine, which is defined much more broadly in the European directive. The Minister also explained that,

“for any new IVF technique there will need to be careful monitoring of the procedure and, subsequently, any pregnancies”.

But we are not talking about pregnancies primarily; this is me as the psychiatrist talking now. As the noble Lord, Lord Deben, pointed out, we are talking about children—children who will, we hope, grow up to be healthy human beings, and who will themselves be able to have healthy children. But what if they do not?

In paragraph 3.7.29 the HFEA expert panel said:

“Until knowledge has built up that suggests otherwise, the panel recommends that any female born following MST or PNT”—

maternal spindle transfer or pronuclear transfer—

“should be advised, when old enough, that she may herself be at risk of having a child with a significant level of mutant mtDNA, putting her child, and if female, subsequent generations at risk of mitochondrial disease”.

The science is complicated, but there is apparently a real possibility that resulting embryos from a woman born after MST or PNT could be heteroplasmic—

[Lord Patel]

May I ask the noble Baroness what experiments she would propose to determine that the children born through this procedure will be healthy in every way, including reproduction-wise?