The following is a transcript of an interview by Oriana Kraft with Dr. Lynae Brayboy, Chief Medical Officer at Clue. 

 

What sparked your interest in studying oocytes?

I started off my career as a reproductive toxicologist. When I started off that was my goal. Science pushed me in this direction away from a pure toxicology perspective and more to molecular biology. I started out with one simple question: how can oocytes protect themselves?

I became interested in oocytes because of the kinds of patients I would see. It would just break my heart: I would see a patient that just got married and they were trying to start a family – but then they’d find out they had breast cancer and they hadn’t even finished their honeymoon. All of a sudden they had to think about how they were going to preserve their fertility.

 

The medications we give to treat breast cancer are toxic to the ovary. For a select few we can do IVF beforehand to preserve some oocytes. But they have to have money. It’s not free just because you have cancer.

When I was a fellow, it became standard of care to cryopreserve oocytes. To me that felt very primitive. Oh, we can freeze your eggs. Yay. And then what happens if they’re not high enough quality? You don’t have that many chances.

 

I particularly felt for single women who were going through this. Because they had even less in terms of resources. Fertilized eggs are already one step ahead further ahead. You’ve been freezing embryos for a long time, and then they’ve already been fertilized.

So what I wanted to know is: is there anything we can do for these patients instead of IVF? They don’t talk about it enough, but IVF is just a band-aid.

It essentially just covers up a problem, but it doesn’t treat the underlying cause. People are so invested in IVF because it pays the bills. It’s very lucrative. So no one has really looked at anything else since 1978 when the first IVF birth occurred. I thought there must be a better way. There must be some way that the oocyte, the ovary can protect itself? I had a mentor at the time who told me to look into ABC transporters in starfish.They’re cellular pumps that help starfish get rid of their toxins and allow their eggs to survive in the ocean. What people may not know is that when IVF began it was modeled off sea urchins and starfish. They spawn their eggs into the ocean and for the sperm to survive they have to beat each other away and make an embryo. And that’s how they keep the species alive. It’s extra corporal fertilization. So the initial focus of the project became looking into these transporters which pump out toxins. And as we did more experiments, we found that the transport was linked to oocyte mitochondria. We would look at knockouts of multidrug-resistant transporters and they would have mitochondrial differences. Basically the genes that were differentially expressed tended to be genes and metabolism, genes associated mitochondria.

And then I was like, what does this mean? I had a panel of metabolites that didn’t make any sense that were different between the mutants and the wild type.

So I Googled all these metabolites and they were all a part of the TCA cycle of Krebs. So at this point all roads were leading into mitochondria. I looked at the mitochondria in mutant versus the wild type. These are mice I’m talking about – to clarify. ‘Mutant’ mice versus ‘wild type mice’.

The mitochondira of these mice were abnormal. There was much more ROS (Reactive Oxygen Species) with more inflammation at the germinal vesicle stage, which is the most immature stage of the post gonadotrope influenced follicle.

 

Could you explain what a post gonadotrope influenced follicle is for our readers?
Of course, so the metaphor I like to use is – our eggs go through these various life stages. When our eggs are in the form of primordial follicles (which is when they’re really, really tiny) that’s kind of like the bank account(the reserve). But then say you take your bank account and invest it in some stocks that you start to get other things – much more developed follicles which are when they transition to primary follicles. Then they transition to the periantral stage.

Anyway, that’s where we started noticing differences. We saw that the mutant females were producing twice as many eggs to make the same number of pups as the wild-type. That’s an expensive thing, right? It’s like, you’re buying a Mercedes, and you and your sister bought same Mercedes, but you have to pay twice as muchto get the same Mercedes.

 

It’s an investment. An egg is a very expensive thing to make. It takes almost 300 days for a human female to make an egg, a mature egg from start to finish. And it’s a very inefficient process in that you have about the potential for 500 ovulations, but you recruit, you have millions of eggs.

 

When you’re born, you have about 600,000 eggs. By the time you hit menopause, you have about 1000. You don’t ovulate all of those eggs. You lose a lot of them. And if you’re recruiting many more eggs in the process (the way the mutant type was) you’re depleting, your ovarian reserve (your ovarian bank account) a lot faster.

 

That’s one of the fundamental flaws with IVF: we do the same thing for everybody, more cycles, more cycles – depleting your ovarian reserve.

 

And what do we offer as an answer if it doesn’t work? If you’re not able to get pregnant we tell people to use a donor egg. Often in the US people will recruit, you know, talented, good looking women to be egg donors, and they’ll pay them.

 

And they think great – I have a baby all is well – but remember what I said about IVF just being a band-aid? Well, when we looked closer into the mutant mice what we found is that they made less eggs, even though their wild type counterparts still had a steady number of eggs. When we looked into it closer we saw that they had some metabolic disturbance. The mutants were heavier, even though they were eating the same food and living in the same conditions. So we start to look into metabolism and sent some mice to Munich. (There’s actually something called a German mouse clinic – it’s a tiny little clinic).

 

They started to do some metabolic testing there and the preliminary data looks like there’s some differencethat’s sex specific = sexual dimorphism. So the mutant females tend to have some metabolic dysfunction. So there’s a theory that as you have chronic inflammation, you age faster. Inflammation can come from the electron transport chain not being efficient. And that happens in the mitochondria. You get increased ROS, which that leads to DNA damage, which depletes your ability to repair DNA, which is another hallmark of aging.

 

So that’s where we are right now: we’re trying to figure out how one multi-drug resistance transporter is involved with the mitochondria and what implications that might have for ageing.

 

If I had a magic wand and there were no conflict of interest and no limitations, I would really want to know what does the general population look like when they have a mutation in that Multidrug resistant transporter inreproductive age women. There was a paper in France where they sequenced the gene profiles of 33 women who had primary ovarian insufficiency – which is where you go into like a menopause like state, even though you’re not menopause age. So usually you have premature menopause before the age of 40. That’s not normal. And when that happens and we have seen some anecdotal literature for DLR, you have increased risk of heart disease. You have increase risk of diabetes, high cholesterol and all the things that are the chronic diseases that will make you age quicker. And that eventually would just kill you prematurely. And also there’s something that you have a decreased bone density. And one of the mutations of unknown clinical significance from that paper was in ABCD1 (the same transporter we’re looking into). And so we’re trying to follow up on that. But we just don’t know. We don’t know what the average profile of a young person’s gene expression for that transporter is, versus someone who was unable to have children. Right now we have no idea. We just tell people to go and get a donor egg – when they’re infertile. We don’t counsel them on what their long-term risks could be of metabolic disease. It could be premature death. And that the ovary ageing prematurely is actually the Canary in the coal mine. The ovary is the first organ to age in the woman. So once you go through puberty, you’ve already started the clock.

When you’re a 20 week old fetus – you already start losing follicles and that clock accelerates after 35. And so by the time you hit your late thirties, you’re at risk for having issues in fertility. And a lot of people don’t know that. So now moving onto fem tech, I think Femtech can actually help educate people about reproduction.

Most people don’t know what the ovary really does or where it is anatomically located. It’s this abstract thing. So they don’t know its role that it, yes, it makes eggs, which is great if you want to have children, but the ovary also makes hormones and those hormones impact your metabolism, bone health, your heart health.

So that’s why it’s important to make sure your ovaries are protected. If you’re going to have radiation or chemo or be an astronaut, or you’re exposed to high levels of radiation, or work in a lab or exposed to chemicals, that’s why it’s important to know about that in general.

And so the importance of FemTech I think here is that it can help educate people about reproductive health and reproductive physiology, which isn’t part of comprehensive sexual health education. You might learn about the ovary. You might learn about eggs in a very general sense, but you may not know how it impacts your overall health.

And fertility really is a marker of global health. That’s how FemTech can help and it can help recruit people. If I had a magic wand and there were no conflicts of interest I’d want to know what the gene expression profiles are of people who have normal menstrual cycles versus those who already had one or two kids and had no issues conceiving versus someone who had trouble. And look at that and compare those things.

Right now with the way clinical trials are you can’t do that on a large scale. I only had 33 women in the Primary ovarian Insufficiency study. I mean, that’s another thing, people clap for you at a meeting when you’re able toget 65 patients to enroll. But how can you really draw any generalizable conclusions off 65 people? Who knows maybe they all live near like some toxic plant and that’s turned on the expression of some genes that shouldn’t be turned on.

So the point is – Femech can be a great connector between basic science and clinical research. I think we’ve done that at Clue and that’s been part of my mission.

Because there’s no real way to collect or to enroll 10,000 people in a study. There’s no way. It took me two years to enroll, 50 girls for a study and 39 actually went through the entire study.

So, people who subscribe to Clue are a great audience. They’re people who are already. interested in their reproductive health. They then recruit their friends and their family and so on and so forth. So that’s how I think FemTech and clinical research connects, and then talking about personalized medicine, we can’t offer personalized medicine until we do the basic science first.

Everything we take right now, whether it’s aspirin in a birth control pills, it’s an aid for the masses, but we won’t ever know what we can do for people unless we know what the subpopulations are, then we get to the point where we can do profiling on one person.

Now there’s some companies that do that for nutrition or skin care. And that’s great, but it’s not really something you can walk into CVS or Target to do yet.

The best I’ve seen so far is a company called Modern Fertility: it’s a synergy of FemTech and clinical research. You can essentially test yourself on the same hormones that any reproductive endocrinologist would do.

And that’s great, but it doesn’t tell you about the future. It doesn’t tap into the fact that an ovary is sort of a crystal ball where you can sort of look in and say, ‘this is not normal’. The ovary is telling you ahead of time what’s going to happen.

 

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