Synopsis: Infertility is often due to poor egg quality, or chromosomal damage. Some of this damage may occur in the egg’s mitochondria, the cell’s powerhouse. A new procedure seeks to replace mitochondria in old eggs with fresher mitocohndria to improve egg quality. However, some doctors say there haven’t been enough studies to know if the procedure is either safe or effective. Experts discuss.

Host: Reed Pence. Guests: Dr. Owen Davis, Professor of Reproductive Medicine, Weill Cornell Medical College and President, American Society for Reproductive Medicine; Dr. Michelle Dipp, CEO and co-founder, Ovascience; Dr. Neal Mahutte, Medical Director, Montreal Fertility Center and President, Canadian Fertility and Andrology Society

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Recharging Old Eggs

Reed Pence: The holidays are made for kids… And it’s a time when many of our treasured family memories are made. But for millions of couples, this season may produce deep feelings of longing. According to the Centers For Disease Control and Prevention, about 12% of American couples are infertile. They want children, but haven’t been able to conceive or carry them. About a third of the time, doctors attribute infertility to male factors. Another third of the time, a combination of factors are to blame, or the cause is unexplained. And female factors are to blame in the final third of cases often as a result of poor egg quality.

Owen Davis: For women of more, quote, advanced reproductive age, classically women as they approach 40 or over the age of 40, then egg quality becomes probably the major problem for these women primarily because these eggs when they fertilize will often be chromosomally abnormal, which leads to a much lower pregnancy rate, a higher miscarriage rate.  

Pence: Dr. Owen Davis is Professor of Reproductive Medicine at the Weill Cornell Medical College and President of the American Society for Reproductive Medicine.

Davis: Age of the eggs will affect egg quality even if the eggs look good under a microscope and behave well in the lab, because a lot of them are intrinsically chromosome non-viable, so they may look good in the lab and they may look like normal eggs, but ultimately, if you genetically test them you’ll see that a lot of them are abnormal. So for example, if you pick a woman who is 45 years old and you have what look like healthy embryos in a dish so they look like normal oocytes just under the microscope, something like 90% of those embryos when you test them would be chromosomally non-viable.

Pence: One of the problems that can make older eggs nonviable is a deterioration of the part of the egg cell that provides energy. It’s called the mitochondria, and the energy they produce is called ATP.

Davis: In any cell, in most cells in the body, the powerhouse that sort of provides the energy, that drives most of the cells’ functions resides in these little what they call “organelles,” which are organs within each cell called the mitochondria. And the egg is certainly no exception. Eggs have mitochondria and mitochondria drive a lot of really important functions in the egg, particularly at the time of fertilization and in development of the early embryo up until the time the embryo actually implants in the lining of the womb or the uterus. The mitochondria are interesting because they are organelles within a cell that have their own DNA. This DNA in the mitochondria gets damaged over time, so as the woman ages there are more mutations and injuries within the mitochondrial DNA, which are not totally able to repair themselves. So the concept is poor mitochondrial quality may translate into poor egg fertilization and underdevelopment.

Pence: Some experts have likened mitochondria problems in the egg to its batteries running down. Dr. Michelle Dipp is CEO and co-founder of the biotech firm Ovascience.

Michelle Dipp: Essentially we need energy or AT in order for that egg to undergo cell division. When we are younger our eggs have a lot of very healthy functioning mitochondria or batteries, but as we get older the batteries get tired with age. What they’ve been able to show over the last 20 years is the better functioning your batteries or the better functioning your mitochondria, the higher your chance of success just in general with pregnancy or with in vitro fertilization, which is the mainstay of treatment for women who struggle with infertility.

Pence: In theory, if you replace the batteries, the rest of the egg should work fine and be much more likely to result in a pregnancy. Dipp’s firm has developed a technique called AUGMENTSM that more or less does exactly that through a surgical procedure and in vitro fertilization.

Davis: So the AUGMENTSM procedure, the concept as well, if you could take a mitochondria from a healthy young egg and transfer those microsurgically with a needle into the egg that is of poor quality that this could improve the egg’s function, and therefore, improve and overcome certain causes of infertility. Now, obviously you get mitochondria presumably from any other cell in the body so why not just inject mitochondria from the skin rather than going into an egg, which after all is inside the ovary, and the answer to that is that mitochondria are specific to different tissues. Mitochondria that are in your muscle will function somewhat differently than mitochondria that are in the heart or in theory mitochondria that are in the ovary.

Dipp: All we’re doing is adding the woman’s own batteries or mitochondria to her own eggs. We always thought that women are born with a set number of eggs that die over time. It turns out that’s absolutely the case in the middle part of the ovary. But what we didn’t know is that in the outer lining of the ovary there are immature egg cells and those are called egg precursor cells and those egg precursor cells have the ability to mature into fresh young healthy eggs. So the other thing that we could do is quite simply get the batteries out of those egg precursor cells and just use those batteries to essentially rejuvenate the woman’s own eggs.       

Pence: The AUGMENTSM procedure is not available in the United States, but it has been introduced in Canada. In the U.S., the FDA has refused to approve it, demanding more data than is now available on AUGMENT’s safety and effectiveness.

Davis: With any new technology, especially when you’re dealing with pre-pregnancy events and early pregnancy, there is a potential that there could be some untoward and unanticipated effects. In theory you would say, well this is the woman’s own DNA, after all, it’s coming from her ovary you’re not putting in mitochondria that have DNA from another person. This is something that had been tried back in the early 2000’s and late 1990’s. So in theory that sounds like it should be pretty safe and one would think and hope that it would be, but we really don’t know. Injecting mitochondria from a precursor stem cell that’s not a mature egg into an egg so that you now have two populations of mitochondria in that egg you — have the mitochondria from the mature woman’s egg, you also have these stem cell mitochondria — we just don’t really know until there are more children born and followed on whether it’s going to turn out to be safe.

Mahutte: It may turn out in the future that it works and it’s safe. I think we’re far from having enough data points to say that.

Pence: That’s Dr. Neal Mahutte, Medical Director of the Montreal Fertility Center and President of the Canadian Fertility and Andrology Society.

Mahutte: It’s all speculative when you talk about safety, right? Because there is the concern when you start to increase the energy of a cell and that cell happens to be the cell from which all the other cells will be derived — you’re talking about the cell that gives rise to every subsequent cell after it — start to increase the energy in that cell, what could go wrong? Here is pure speculation. Maybe you’re increasing the metabolic performance of those cells and maybe that’s going to invite metabolic problems for the future, like diabetes, things like that. Maybe by increasing the energy of that cell you could be predisposing to other things. Who knows? Maybe cancer, maybe other abnormalities. You would never get those data points in the short term; you’d see them more in the long term, but it absolutely is speculation. It may be completely benign, but we just don’t know.

Pence: Dipp says fewer than two dozen babies have been born worldwide using AUGMENTSM, but they’ve all been healthy. And she says the procedure appears to have helped women who couldn’t get pregnant before.

Dipp: We have published the clinical experience of the doctors who are using AUGMENTSM and on average what you’re seeing is about an increase in success rates of approximately 20%. A woman who has, let’s say, a 10% chance of getting pregnant with IVS has about a 30% chance of getting pregnant with AUGMENTSM .

Davis: Certainly some preliminary reports suggest that women average age I think about 36 in the data that I’ve seen — they’re not women over 40, necessarily — that women who’ve had anywhere from one failed IVS cycle previously to several failed cycles have had what looks like a good success rate with this technique. Indeed, it could be true and indeed this could be very, very promising.

Pence: But Mahutte isn’t sure that such small numbers of births produced using AUGMENTSM really mean anything.

Neal Mahutte: Every time you do a cycle there is a chance that the cycle may work even if previous attempts have failed. We have very good data in the United States showing that between IVS cycle number one, IVS cycle number two, IVS cycle number three, IVS cycle number four success rates are the same. So they are not declining with each attempt, but rather they are staying pretty constant almost as they would if you were flipping a coin. So if your method of evaluation of a new technology is to say well a patient failed a previous IVS attempt or she failed two previous IVS attempts and then we did this and now she got pregnant you cannot assume that it was the intervention that you did that helped her get pregnant. It may simply be because she tried again.

Pence: Both Davis and Mahutte say doctors would have preferred that AUGMENTSM be introduced with a large randomized controlled trial to be sure that it works. Mahutte also would have liked more safeguards for patient safety.

Mahutte: You’d like to see that when a novel technique is being introduced that the way it’s introduced is to go about it doing everything possible to ensure safety and efficacy in the non-human models. And then assuming that you’re seeing that, when you introduce it into the humans, say, ok, do we have a very sound study protocol? Have we gone to an independent ethics review board and asked this exact question? Do we have a data safety monitoring board that’s going to monitor what happens to these patients in their long term follow-up, not just short term? And put every possible safeguard in place. That’s really I think what’s missing in the way that AUGMENTSM has been introduced.

Pence: But especially among would-be parents longing for a child, those steps may be much less important than the glimmer of hope that a new procedure may provide.

Mahutte: Patients are struggling with infertility and particularly those patients who have had several failed attempts are quite desperate to try to find something, to try to find some answer to their predicament, and they will often go to extreme ends to do that. I just think that if you introduce something into clinical practice, and remember this is quite expensive treatment, your talking about — an extra $25,000 – $30,000 on top of the IVS cycle itself. So it’s a substantial sum of money. If you’re going to do something where you’re going to charge patients that sum of money, you’d like to know that you have a very good likelihood of improving their chances of succeeding.

Pence: However, Davis says somebody has to be first. Somebody has to be willing to take a chance and be one of the first patients to try. The payoff could be life changing. Davis, and even Mahutte, say AUGMENTSM could end up being very important to infertile couples.

Davis: I think for some of these women, if these turn out to be helpful, it could be a very significant breakthrough and the procedures used, you know, the ICSI [intracytoplasmic sperm injection] where you inject the sperm into the egg, the concept of retrieving eggs, you know laparoscopy — these are the things that have been used in GYN virtually for many many years and have a fairly good track record, so it could be a major innovation.

Mahutte: We have so little that we can offer patients who have diminished or very reserve, we have so little that we can offer patients who have poor egg quality, so other than donor eggs most of them are just told well try again and hope for the best. Hopefully we have a good egg in the next group. So if the AUGMENTSM technique is actually able to improve egg quality, it would be a fantastic benefit to patients and it would be a breakthrough for the field.

Pence: However, both experts say there’s still a lot we don’t know… And given the way AUGMENTSM was introduced, it may take a little longer than they’d like to find out. You can find out about AUGMENTSM and all of our guests through links on our website…, where you can also find archives of our programs. You’ll also find them on iTunes and Stitcher. I’m Reed Pence.  


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