3-parent babies: necessity or controversy?

Danny Daphnis, PhD
Senior Clinical Embryologist & Scientific Director

Donor Eggs, Failed IVF Cycles

3-parent babies: necessity or controversy? #IVFWEBINARS
From this video you will find out:
  • mitochondrial replacement therapy  (MRT) to prevent transmission of mitochondrial disease
  • types of MRT: Maternal Spindle Transfer (MST), Pronuclei Transfer (PNT), Polar Body Transfer (PBT) and Germinal Vesicle Transfer (GVT)
  • MST – the details of the procedure
  • the first 3-parent baby born in Greece
  • why MRT for poor oocyte quality
  • MRT controversy
  • MRT legislation




How does mitochondrial transfer work and when it can help?

Danny Daphnis, PhD, Scientific Director at Mediterranean Fertility Institute in Greece, is discussing the 3-parent baby technique (mitochondrial transfer) and the surrounding controversy.

Dr Daphnis started his talk by explaining that IVF is an assisted reproduction technique that aims in helping infertile couples achieve a pregnancy. Oocyte donation or egg donation is part of an IVF procedure and is usually performed in patients who either have an ovarian failure or have problems accessing the ovaries. It’s used when there are some chromosome abnormalities, and there is a need to use the donor’s oocytes. If a woman has attempted many IVF attempts before and as her biological age has increased, it can become a necessity for that patient to perform oocyte donation or if the ovaries have been removed because of cancer treatment.

One of the main disadvantages and one of the main concerns that couples have is that the woman will not give any part of her DNA to the resulting baby. This causes patients distress, and it might give rise to religious and ethical issues, etc.

In 2016, in New Mexico, Dr Ihang reported the birth of a healthy boy after mitochondrial replacement therapy (MRT) by the spindle to prevent the transmission of mitochondrial disease. In a US-based clinic, they flew the patients to Mexico and did the procedure because it wasn’t allowed in the US at that time, the patients were suffering from a mitochondrial disease. Mitochondria are energy sources for the egg and are located in the egg’s cytoplasm. MRT is based on the fact that the nucleus of the mother’s egg, the one that carries the DNA, is fused with a healthy donor cytoplasm.

Types of MRT (Mitochondrial Replacement Therapy)

There are 4 types of MRT, the first is maternal spindle transfer (MST), that’s what Dr Ihang used.
It uses own genetic material removed from the eggs and transferred into donor eggs, which have their nuclear genetic material removed. The resulting eggs are then fertilized with sperm to create the embryos.

In Ukraine, another option was used, called Pronuclei Transfer (PNT) They fertilized the mother’s eggs with the father’s sperm, but they removed the two pronuclei (the embryo on day 1 of development) and inserted it into embryos created from donor eggs.

There is also Polar Body Transfer (PBT), there are two ways of doing that. Either removing the first polar body from an unfertilized egg and transferring it to an unfertilized donor egg, which has had its nuclear DNA removed or removing the second polar body after fertilization and transferring it to a newly fertilized egg (a zygote), which has had its maternal nuclear DNA removed.

The last method is called Germinal Vesicle Transfer (GVT). Very immature eggs are called Germinal Vesicles (GV), and they are usually not utilized in an IVF cycle. The technique entails the removal of the GV from a patient egg (it still has the DNA) and transferring it to an unfertilized donor egg which again, in turn, had its GV removed.

Maternal Spindle Transfer (MST)

MST involves using DNA from three people to prevent serious inherited diseases. The nucleus is removed from the mother’s eggs, then the donor’s eggs are taken, and the nucleus is removed and destroyed, the donor ‘vehicle’ which has normal mitochondria is transferred and fused with the DNA from the mother, following that, the fertilization with the father’s sperm occurs. This is the most common technique that is used and will be possibly used, but the possible effects that the baby might have when it gets born are yet unknown.

In 2019, in Greece, a woman gave birth to a boy using MRT. The difference was that this woman had no genetic disease, there was no life-threatening disease that had to be avoided to give birth to a healthy child. The woman had a history of multiple IVF failures and poor oocyte quality, therefore, it was done for other reasons. They used the same procedure as Dr Ihang, and they did it in collaboration with Spain and had a very good result.

Poor Oocyte Quality vs MRT

The quality of the egg is the most important aspect of an IVF to work. If you have poor-quality eggs, you won’t produce good-quality embryos or you won’t have a healthy pregnancy. We know that ovarian cytoplasmic function is very important as it reduces the chance of premature development, which is caused by deficiencies in the cytoplasm. Therefore, if you use the ‘vehicle’ donor egg, which does not have the nucleus but has everything else, in this case, the cytoplasm, it will help get a healthy baby. Improving mitochondrial function in the cytoplasm usually leads to the improvement of reproductive capacity. The idea of using MRT using the mother’s DNA is quite innovative, and hopefully, it will remove some ethical or religious stress. So far, this technique has been used either for patients who are suffering from mitochondrial genetic diseases or with a history of IVF failures due to poor oocyte quality.

MRT controversies

There is still little information about problems that can be caused because of MRT. There are some concerns regarding designer babies by allowing partners to select traits. Another thing is the presence of 3 genetic parent babies as there is the nuclear DNA from the mother, sperm from the father and the donor who provides the cytoplasm that contains mitochondrial DNA (mtDNA). It is still unknown what that effect might have on the baby, although there is a low mutant mtDNA carry over to the embryo. Other controversies include the rights of the child, the future adults and the next generation, the status of the embryo also needs to be included, donors’ roles and interests and the community considerations because we still don’t know what this could cause to the resulting baby.

MRT legislation

The HFEA in the UK was the first to regulate MRT and mitochondrial donation, and it is advisable to do MRT under specific circumstances, MST or PNT can be used cautiously in a specific situation where there is no other alternative because of inherited disease that is likely to cause the death of serious disease. It is not allowed to be used for women who have an ovarian failure or just want to do oocyte donation. The Australian Senate debate concluded that in special circumstances and when all aspects are controlled, MST can be applied, but the debate is not yet finished.

This method is still new, and it is still being researched. It’s very important to know where it can be done, who can do it, and if it’s safe.

- Questions and Answers

What is the age limit for this treatment? Is there AMH that one should have? Is it a good idea to combine it with PRP therapy?

At the moment, as I said different countries do it in different modes. For example, if you’re in the UK, they don’t consider it for oocyte donation. They only do it if you have a mitochondria genetic disease. In Greece, the clinic which does it considers only ladies below 40 years of age who have had multiple IVF attempts and they have eggs to be retrieved. You need to have eggs in order to do this. If you don’t have eggs, if you cannot produce eggs, there is no way they can find eggs for you. We need as many eggs as possible to take the nucleus out and put it back into the donor’s egg so at the moment in Greece, the clinic only looks at patients under forty years of age, specific multiple IVF failures but you have to have eggs. In Ukraine, I think that has broadened the horizon and you’re able to do it because they do the PNT (pronuclei transfer) but again I don’t know the exact guidelines. In Mexico, you can do almost anything but I think that they have a limit of 45 at the moment. PRP, if you’re not familiar with it, it’s the ovarian rejuvenation. There are two different techniques. PRP will, hopefully, help you achieve more follicles which means more eggs, which means, hopefully, you have a more broad broader section. However, I must stress this, in Greece for example, at the moment, they’re doing it as part of the research. They don’t do it when going into the program and I think you don’t even pay the amount of money that they’re thinking of charging if it goes into the public. Be aware that, at the moment, it’s done mostly research-wise and not so much in routine. It’s very new and it’s not something very easily performed.

Can a woman in her 50s do the 3-parents baby? My AMH is zero. I’ve been in menopause now for 10 months. I was told I was not a candidate when I approached a clinic in Kyiv that is doing the nuclear and spindle transfer currently.

The reason is simple. They need your eggs. Patients need to remember that if you’re doing it instead of oocyte donation, you must have your own eggs. If you don’t have eggs, where are they going to find the nucleus to transfer it to the donor’s eggs? It’s as simple as that they need your eggs. You need to have as many eggs as possible in order to get your nucleus and transfer it and fuse it into the donor’s eggs. That’s why in Kyiv they did not accept you. It’s not because they didn’t want you to do it; it’s because they needed your eggs. If your AMH is zero and you’re in menopause, you do not have eggs.

Can PRP bring back my periods if I’m in menopause?

PRP works for around 40-45% of the patients. It is patient specific. You cannot foresee if it’s going to work because it’s your own blood, your own platelets inside your own body and which are infused inside your own ovaries. If it’s going to work and if your AMH increases, if your antra follicular count increases and you hopefully get eggs, yes, it can take place. But, again, I’m stressing this whichever clinic does it, it requires eggs, your eggs which will have the nucleus removed in order to put it to the cytoplasm. I’m guessing, at the moment, you won’t get what you want because, at the moment, we don’t have the technology to take the nucleus from your skin cell, for example, and transfer it to the donor’s eggs. In Greece, for this research, they’re not allowing any patients over 40 years of age. Unfortunately, they want only ladies below 40 years of age who produce eggs.

Can I do the procedure in your clinic? If not, where?

No, we don’t do that. We don’t operate this at the moment. It still hasn’t passed in the Greek HFA if I could call it like that. The clinic which did it in Greece has created some problems in the law by doing it but they passed it as research. Again, it’s not very clear how it’s going to work. You can apply either to Kyiv in Ukraine if you want it with oocyte donation or to the clinic in Athens. This is, unfortunately, something that needs to be researched. At the moment, Mexico and Ukraine are the easiest to access places to do it.

Who is a good candidate for this treatment?

A good candidate for this treatment is, as I mentioned in my slides, the best candidate is a patient who has oocytes but they’re poor quality. They’re ladies who have done many IVFs before, who have some oocytes even if it’s 3-4 oocytes, we can get these oocytes, remove the nucleus, put it into donor eggs and hopefully get a nice embryo. Apart from if you have a mitochondrial genetic disease, of course, that’s that goes without saying, but it’s for patients who have the ability to produce at least some eggs and then going forward using those eggs infusing them with donor eggs.

What if you are over 40 but still have eggs?

You can do it. That is I think the main aspect. If you go to IVMED in Kyiv, they’re doing it and they don’t have an age restriction at the moment. They just want to see the AMH, they want to see that you have eggs so the age restriction up to 40 is only for the clinics in Greece. If you research Mexico or Kyiv, I’m sure they might be able to help you. For example, if you are 40 and have had 21 eggs retrieved I think that is spectacular. I think the clinic agrees to treat patients who produce eggs. Because the more eggs you produce the more chances of getting the embryo that they want. In your case, it is a possibility that you are creating eggs that are not of good quality either for cytoplasmic reasons or mitochondrial reasons. They’re not giving you your baby. I think you are probably the best candidate for an MRT procedure in these programs.

Is mitochondrial transfer more expensive than normal IVF/egg donation?

There is no price at the moment. I don’t know how much they charge in Mexico. But it’s definitely much more expensive. In Greece, you only pay for an egg donation cycle because it’s part of a research program but as I said they have quite a bit of limitation. The other clinics, in other countries which have the legislation a little bit broader I’m sure they will have more expensive prices in that.

If the nucleus of the mother is put in the donor’s cytoplasm, does the resulting child have the phenotype of the mother?

First of all, the most important thing that you care about is the genotype. The phenotype is what we look like, it’s our outside characteristics. The most important thing is that the resulting child has the genotype of the mother and subsequently the phenotype is regulated by the genotype of the mother, the genetic mother and the genetic father. I think you wanted to ask if the child has the genotype because that’s the most important thing. It is what I said in my slide which says “keep the genes” because the genotype is the one that regulates the phenotype, what we look like. If it has the genotype of the mother, then most likely it’s going to have the phenotype of the mother, the genetic mother and the genetic father.

Are there any known side effects of having DNA from three parents in one person?

Aat the moment no but that’s why we’re very cautious. As I said there are very few children being born reported. I doubt there more than five children. However, they have not found a specific problem that can be linked. The number is too small. They have noted that some variations, however, these numbers are so small and cannot be attributed to the actual procedure or two, maybe, IVF. That is the biggest question at the moment, but it cannot be answered because of the very low numbers.

What is the improvement in success rates compared to using own eggs?

It’s like a donor cycle so you get a 50-60% and whatever number each clinic gives you as a success rate.

I spoke to one of the first women that did mitochondrial transfer in the USA before they banned it. Her daughter is now 17 and she said she hasn’t noticed anything about her daughter other than she’s very bright.

Again, as I said, there are very small numbers and when they did this back in the USA, you’re talking about quite many years back. It has changed quite a bit. The actual procedure is not the same as it was 17 years ago. Thank you for the comment. I can see you’re quite read on the subject. But we have to be very careful as you all know it’s something quite new. We don’t know the effects if we don’t have the correct numbers. Hopefully, my belief is it’s going to help people rather than hinder people. I’m more for the necessity rather than the controversy. I am pro the technique. However, I have to be cautious because we don’t have so much information at the moment.

Do the mother and the donor have to be matched? What about obesity?

No, actually they don’t. First of all, I don’t know about obesity. Again, it can be one of the variations. However, there’s no specific match. It’s like a donor cycle so you don’t have to be matched. You can’t match mitochondria from one person to another. They’re completely different. As I said before, mitochondria carry their own DNA that’s why we call it empty DNA so there’s no match as such. What we do want to match if you want is that you have the egg donor and the mother matched in the way that we don’t have any problems, e.g. matching blood groups, Rhesus, stuff like that which again do not have an effect but that’s what they’re trying to do. What I urge patients is to be careful. I know you want to have your dream which is a baby but it is something which is still experimental. As an embryologist, as a scientist, I was actually able to witness and then be part of the technique in a couple of patients and I saw that it’s something which is doable. I was very happy. I thought this is what we want to do, this is our future. But, on the other hand, my first thought was when we transfer the embryos back to the patient was what did we just do? Do we know what we just did? What I’m saying is that as I said before I’m very pro this technique and I think it’s going to help us. We just have to be sure that it doesn’t have a negative effect on all of us at the end of the day because we are, excuse my language, messing with our DNA.

Do you think cloning will be a thing in the future?

In one way or another, it’s going to help us and, hopefully, we’re going to use it to clone organs rather than people, rather than humans, hopefully, we’re going to learn how to clone and parts of our body in order to be able to do the transplants to help us. If cloning is going to be performed on humans and that’s going to be quite controversial. I don’t know what’s the positive effect of having a second Danny, for example. I think cloning in some extent will help us and not necessarily cloning humans.

I know they are doing cloning with horses in Brazil?

Yes, they’re doing it on many animals but people don’t know about it because it’s easier. It doesn’t work, it’s not an easy procedure, it’s quite expensive still but, yes, I’m sure they are doing it on many animals.
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Danny Daphnis, PhD

Danny Daphnis, PhD

Danny Daphnis, PhD has been a clinical embryologist for more than 15 years. He studied Biology and Biochemistry at the Metropolitan University of London and Masters in Prenatal Genetics and Fetal Medicine at UCL, London. He continued his postgraduate studies and completed his PhD at UCL studying chromosomal abnormalities and genetic diseases in human embryos. He entered the field of embryology and completed his certification acquiring the ACE diploma of embryology. He began his career in London Fertility Centre under Ian Craft and has worked in various fertility centers since, marking a rising course. He helped found the British-Syrian IVF center and especially the organization of the laboratory. Recently he established the Aegean IVF center in Tirana. Since 2010 he has been working in the Mediterranean Fertility Center in Chania as a scientific director actively helping the center acquire certifications and the prestige it deserves. Danny Daphnis has published scientific studies in reputable journals and participates regularly in conferences as a speaker. 
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Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.
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