Fertility Docs Uncensored Today’s episode of Fertility Docs Uncensored is hosted by Dr. Carrie Bedient from the Fertility Center of Las Vegas, Dr. Susan Hudson from Texas Fertility Center, and Dr. Abby Eblen from Nashville Fertility Center. In this episode, we explore how targeted nutrition and genetics intersect to influence reproductive health, highlighting emerging science that may change how we approach fertility optimization for both men and women. Today, we welcome Steven Zeisel, PhD, founder of SNP Therapeutics and a leader in research on one-carbon metabolism and fertility. What is one-carbon metabolism and how does it affect egg and sperm quality? Which nutrients—such as folate, choline, and vitamin B12—are essential for reproductive success? How do genetic variants impact the body’s ability to produce or utilize these nutrients? We discuss the Genate test, designed to identify which genes related to nutrient metabolism are active or impaired. Why shouldn’t patients simply take all fertility supplements? Dr. Zeisel explains how excess supplementation may be unnecessary or even harmful without personalized insight. How does choline support fetal brain development and early childhood growth? What happens when men have genetic variants that impair ATP production in sperm, affecting motility and fertilization? Could targeted nutritional supplementation improve sperm function and reduce the need for IVF in some cases? We also review data showing that 9–10% of men may have these metabolic variants. This episode provides a personalized, science-based approach to fertility nutrition. This episode is sponsored by Shady Grove Fertility.

Episode Transcript:

Susan Hudson (00:01)

You’re listening to the Fertility Docs Uncensored podcast, featuring insight on all things fertility from some of the top rated doctors around America. Whether you’re struggling to conceive or just planning for your future family, we’re here to guide you every step of the way.

Susan Hudson MD (00:22)

Hello everyone, this is Dr. Susan Hudson from Texas Fertility Center with another episode of Fertility Docs Uncensored. I am here with my marvelous, magnificent, and motivating co-host, Dr. Abby Eblen from Nashville Fertility Center, and Dr. Carrie Bedient from Fertility Center of Las Vegas. And we are so, so excited today to have an amazing guest, Dr. Steven Zeisel, who is a professor emeritus of nutrition at Chapel Hill and co-founder of SNP Therapeutics. And he’s going to talk to us a little bit about nutrition and what you really need to know today going into fertility care and how not one pill is the solution for everyone. And so thank you so much for joining us today.

Steven Zeisel (01:13)

I’m so happy to be here.

Susan Hudson MD (01:15)

Absolutely, absolutely. So before our show, we were talking about as you were going to enter retirement from your kind of day job, you still have another day job, but you decided to dive into another passion and that’s bonsai trees. Is that correct?

Steven Zeisel (01:33)

That is right. I just decided one day I would have the time. So I had a start to have a collection of trees and now I have more than 100 trees to work on, which keeps me busy.

Susan Hudson MD (01:44)

Wow.

Abby Eblen MD (01:45)

When you say work on, what do you mean work on?

Steven Zeisel (01:47)

Well, a bonsai tree just doesn’t become a bonsai tree because you put it in a pot. It needs to be cared for so that it survives. It needs to be shaped and styled so that it has art. It’s like sculpture. So bonsai is sort of half sculpture, half gardening. And they constantly need attention and care. This time of year, early spring,

They’re budding out and you often change the pot they’re in to give them new soil. In a few weeks, they’re going to need to be cut back so that they don’t get so much overgrowth, et cetera. And so, it’s an interesting hobby. I chose it because I was a scientist running laboratory and I wanted something that used the other side of my brain.

This is more artistic and sculpture and I enjoy it. Now I can do it with much more time because I have retired.

Abby Eblen MD (02:43)

So I a question about bonsai trees. Can you take any plant and make it into a bonsai or? 

Steven Zeisel (02:49)

Yes, so there’s nothing genetically special about a bonsai tree. What you’d like is a plant that has relatively small leaves. Magnolia doesn’t make a great bonsai because the leaves are so big, but you can make a bonsai out of it. I have beautiful azalea bonsai ⁓ that will be blooming in the next few weeks. I have pine bonsai, juniper bonsai, Japanese maple bonsai, almost everything. And the thing that people don’t understand is that except for the tropical plants, like a fig, they all live outside all year long. They don’t like to be inside. They need the cold. They need to go through the same cycle as the trees in your yard. And if they can live in your community, they’ll live outside as bonsai.

Abby Eblen MD (03:23)

Really? Wow.

Abby Eblen MD (03:34)

Hey Steve, so how do you create a bonsai then?

Steven Zeisel (03:36)

You go to a nursery and you find a plant that has a nice base of its trunk because that takes time to grow. So a juniper or something like that. Don’t worry about what the branches look like. And then at the right time of year, usually the spring when the buds are just starting to push and turn green on a juniper or on a maple, you see the buds starting to come out, it’s the right time to put them in a pot, cut the roots back because they’re getting all kinds of signals to grow at that.

If you did that in the summer, they would die. And so you put them in a small pot and then you keep them in that pot and they can’t get big because the root mass of a tree is equal to its leaf mass. And that’s how you make a good bonsai.

Abby Eblen MD (04:13)

And so how, so how do know how much of the root ball to cut though? Cause I don’t think that’s kind of dangerous. You’re living on the edge there. You’re going to kill the plant if you cut too.

Steven Zeisel (04:19)

Yeah, well, it’s part of learning. When I knew I was going to go into bonsai, I joined ⁓ a local bonsai club and people taught me about the right amount. So in deciduous trees like a maple, I can take more than half the roots off. While on conifers like a juniper or pine, I can take maybe a third of the roots off and they’ll survive. And it’s got to be done only at the time of year when they’re just starting to grow, not after they’ve leafed out.

Abby Eblen MD (04:21)

All right, well next spring maybe I’ll try that. ⁓

Steven Zeisel (04:47)

Yes, join, look for a local club. In Nashville, there are number of good local bonsai societies.

Susan Hudson MD (04:54)

All right, well, let’s go ahead and do a question for today. And our question is, I’m a 37 year old with PCOS and possible arcuate uterus noted on HSG. AMH was 14, BMI 18, 35 to 45 day cycles. Menarche was delayed until 20s due to ballet training. After two years trying to conceive and three failed IUIs with Letrozole, we did IVF and got 10 euploid embryos.

My first medicated FET failed. Second, with two months of lupron suppression worked. Healthy girl, but had vasaprevia requiring preterm delivery. Now we’re trying for baby number two. How do we reduce these risks? Do we do a supported natural FET? They did that before and it failed. How would you proceed? At what point should we move on from natural FETs given history?

Abby Eblen MD (05:41)

I mean, I think either one is potentially a possibility just because she did not get pregnant the first time around with a natural FET. Sometimes you can do everything perfectly, have a beautiful embryo, have a great transfer, and you still just don’t have a good outcome. I always joke and say that IVF is one of the few times where the definition of stupidity is doing the same thing twice and expecting a different outcome, but we do that all the time. So I don’t think necessarily that was the reason because I think if you talk to different physicians, some people love to do modified natural FETs and some people like to do program cycle. It’s where you can control more of the hormones and when they’re given. But that tends to be a longer cycle and I’m finding more and more people don’t want to do that. They want to jump right in and do a natural cycle FET or modified natural cycle FET. So I think either one’s fine. I don’t think that really was the reason she did not get pregnant the first time around.

Carrie Bedient, MD (06:30)

And I don’t think there’s a whole lot that you can do for a vasaprevia prevention either. That’s to a degree, it’s just the luck of the draw. Whatever kind of protocol you use is independent of that. And I think that you don’t have to use that as one of the points of consideration when you’re deciding what kind of protocol to use next. I think if you want to go with the Lupron again, cause you feel better about it, cause that’s how you can see last time you can, but you can also combine things and do the Lupron and then do the Letrazole immediately after.

It’s just, you have to know that when you’re starting to combine things like that, there’s a little bit higher likelihood that lining won’t grow, you have to stop, restart, which none of that is a deal breaker at all, but you just have to kind of be mentally prepared that that might happen.

Susan Hudson MD (07:11)

Another thing, if you want to do suppression and then going into a modified natural cycle, considering something like Orilissa instead of Lupron, because it turns off within a few days of you stopping it, whereas the Lupron is lingering and it’s though you get that shot once a month at the end of one month, it’s not like it’s completely out of your system. And so just another thing to consider, but I completely agree.

Susan Hudson MD (07:36)

If IVF has been living in the I’ll deal with it later category, summer might be your window to change that. Schedules shift, things slow down just enough and suddenly you’ve got the space to actually figure out what comes next. At Fertility Docs Uncensored, we’ve spent years helping patients cut through the noise and understand IVF for what it really is. Not overwhelming, not mysterious, just a series of steps you can learn and navigate. That’s exactly why we created the IVF Blueprint. It’s a straightforward, no-nonsense guide to the entire IVF process. What happens, what decisions you’ll face and how to think through them without second-guessing every move. Whether you’ve just started to seriously consider IVF or you’re already in it and want to feel more control, the IVF Blueprint helps you move from, I think I should, to, I know what I’m doing. You can find it in print, ebook, and audiobook with a bonus conversation from us at the end, wherever books are sold, and at Fertilitydocsuncensored.com.

If you’ve been waiting for the right moment to get clarity, this might be it.

Susan Hudson MD (08:43)

All right, so Steve, tell us a little bit about how you started your research and how it led you to the creation of SMP Therapeutics.

Steven Zeisel (08:58)

Sure. I, for many years, have been interested in an area of nutrition involving the nutrients folate, choline, methionine, betaine, B12. It’s called one carbon metabolism. And it’s a wing of nutrition that is intriguing. I got into it because when I first started my PhD, unfortunately, 1970s, people didn’t think that one of those nutrients, choline, was needed by humans. And yet, I knew that dogs needed it. And I knew that many mammals needed it. And it didn’t make that much sense to me that people didn’t. And so my PhD was on choline and an interesting part of it that just during pregnancy, choline levels are delivered from the mother to the baby in very high concentrations. And the baby lives in about 15 times as much choline as is present in mother’s blood. So she’s concentrating it into the baby. And over the years, that drove my research team to ask, why is that? And we discovered that this set of nutrients is exceedingly important for the development of the fetus. And it turns out earlier than that for the development of the egg and sperm. And that this set of nutrients couldn’t totally substitute from one another. So giving a lot of folate didn’t make up for the need for choline, but it spared some of the need. In the same way, choline spared some of the need for folate, et cetera. So they interacted, but not to exclusion. And we took people and put them in the hospital, research hospital, and we took these nutrients down to as low as we could get them in the diet. We kept folate at the recommended intake and took choline way down 10 % of what you might eat in a normal diet. And we asked, do people get sick? And no surprise to me, but to the surprise to many of the textbook authors, 80 or 90 % of men and post-menopausal women became sick when deprived of this nutrients within 42 days. So our criteria for calling them sick was either they had an elevation in liver function tests that was above 125 % of the upper limit of normal in our clinical laboratory, or they had an elevation of creatine kinase.

Abby Eblen MD (11:07)

What do you mean, sick? In what way?

Steven Zeisel (11:34)

Again, above 150 % of the upper limit of normal.

We also did toxicity tests for all the other organs, but those were the two that triggered it off and that always caused us to stop the study. And we did MRIs for liver fat accumulation. And we also had an increase by more than 60 % in liver fat, but was also an endpoint to the study. So 90 % of men and post-menopausal women went this way about 90 % of them went with the liver problems, 10 % with muscle problems. But the surprising thing to me was that only about a little less than half of young women, premenopausal women, got sick in this way. And the other half did get sick just like men. So first we ask, why did half seem to need less choline than men and postmenopausal women and obviously something different is estrogen. So we went back and found that there’s a gene that can make a choline molecule called phosphatidylcholine, the thing used to make membrane.

There was a gene that could do that in the liver and it had eight switches on it that could be turned on by estrogen. So it was an estrogen responsive gene. And we knew that young women have more estrogen than postmenopausal women and men. We also knew that during pregnancy, estrogen rises so that by the second trimester, it’s pretty high. And so what we discovered is that this was a design mechanism in women to allow them to be a little less dependent on getting choline in their diet because they could turn it on with estrogen during the time it was most important and that’s when they wanted to make a baby. And you need to have a huge amount of choline and folate and B12, betaine, methionine when you’re making a baby because from the start of the egg precursor dividing into the many cells it has to divide into and the sperm maturing so that it can fertilize going on to making all the parts of the fetus, including the brain, you need these nutrients. And we went on to show that babies choline concentrations in their blood were 15 times higher than mothers concentrations. That stayed up for a year after birth. And it turned out it was as long as they were breastfeeding. And then we found that the mammary gland pumps these nutrients into the baby into milk and was designed to do that. And in fact, our work got the US government to realize that many infant formulas didn’t have all of these, as much of these nutrients as mature human milk did. And so, in 2007, they required any infant formula commercially sold to contain the amounts of choline, for example, that matched what’s in mature breast milk, which is pretty high.

Abby Eblen MD (14:24)

So wow.

Carrie Bedient, MD (14:24)

So where do you find choline in the natural diet? What does it show up in?

Steven Zeisel (14:28)

Sure. Choline is found in eggs. Well, obviously chickens have to make babies too. And so those same babies need a lot of choline. So it’s in the yellow part of the egg, the yolk. It’s in meats. And unfortunately, it’s in the things that contain cholesterol. And so starting in the 90s, 80s, nutrition people were telling people, away from cholesterol.

created a problem in America that people stayed away from these nutrients as well. And in fact, the US dietary national survey called the NHANES repeatedly in every survey done since 1990 have found that Americans aren’t getting the recommended intake of these nutrients. And that only, for instance, 7 % of women with exceptional potential are achieving the recommended intake. And 93 % fell well below this. And that was caused by recommendations that stay away from these foods. Over many studies, and I have more than 300 papers you can find in the literature to ask what are these nutrients doing? We found that these nutrients not only are needed to make the walls around cells called membranes, to make DNA, to make the energy producing parts of the cell called mitochondria, the batteries to make ATP. We found all of them were necessary, but in addition, they were important for placing marks on your DNA, on your genes, that tell genes when to turn on and when to turn off. These are called epigenetic marks, and they’re made from, many of them, from methyl groups derived from these nutrients. So the chemical marks are pieces of these nutrients attached to DNA that tell the gene to turn on and turn off.

We went on to show, for instance, that the development of the fetal brain depends on these nutrients being present in high amounts for a brief period of time. If they were given later, they weren’t any good. They had to be there during a critical window in time. And what they did is they turned on and off the genes needed for the stem cells, that will form the nerves in brain to multiply.

And we showed in mice that if these nutrients weren’t exactly right in very early pregnancy, then the progenitor cells didn’t divide and they ran out of these stem cells to make the brain and only formed the earlier layers of brain. And the later layers that formed later in development were inadequately populated. And these mice were dumb for the whole lives. They didn’t run mazes well.

And they became senile at a much earlier age than mice whose mothers had enough of these nutrients during pregnancy. So we published a series of showing how this happens but it all showed us that these nutrients were really important.

Abby Eblen MD (17:27)

So Steve, you had mentioned earlier that one size doesn’t fit all, that everybody that’s listening doesn’t need to go out and eat a bunch of eggs and buy a bunch of choline. How are women able to kind of figure out, or how would our listeners be able to figure out if is what they need or if they need something different?

Steven Zeisel (17:43)

Turns out that we have genetic differences, I’ll call them spelling errors in our genes, that are very common and we inherited them from ancient ancestors. And when we did our study in the hospital and found that half of young women didn’t need choline and the other half did, that’s approximately, that was in North Carolina, we asked ourselves, well, why did half of the young women need choline in their diets when they could make their own with this estrogen-induced gene? And we found they all had genetic variants. Half of women almost had genetic variants that made them unable to turn on the gene with estrogen. So these women were reduced to the sad state of men and they had to eat choline. They didn’t have this protective backup that young women normally have to be a little less sensitive to their diet during pregnancy. We then found that if you had genetic variants in folate metabolism, and many women interested in fertility know about folate because it’s part of preventing neural tube defects in babies and very important for development, it turns out that if you didn’t have enough folate, choline metabolites tried to make up for it and use more part made from choline called betaine as a methyl donor to try to spare some use of folate as a methyl donor. So that folate could be used only to make DNA and not to donate these small methyl groups that you need to make things. So there was an interaction. And if you were low in choline, you needed more folate. And if you had B12 problems, you needed more folate and choline.

And if you had problems with methionine and amino acid that makes protein, you also needed it. And we found that some genetic variants made your liver more sensitive to low choline and some genetic variants made you present with muscle breakdown. And every time you ate low choline, your muscles broke down. So we all found that out from those human studies. And we were able to develop a genetic test that could identify women who had these gene differences that created roadblocks in their metabolism that made them need more or less. Now, the first idea was, why not give every woman more choline, like we gave every woman more folate? The problem is folate you need in very small quantities. Choline you need about a half a gram a day. And so to get half a gram a day, you had to eat a bunch of eggs, maybe five or six eggs a day, not likely among women. Well, a good egg could contain a quarter of a gram, so maybe two eggs if you had a large egg, maybe three or four, to be sure. Many of the companies making prenatal pills came to me and said, well, we’ll put a little choline in, but it turned out…They didn’t want to make their pills bigger because women didn’t want to swallow a bigger pill. And half a gram, prenatal vitamin only weighs about half a gram. So to double its size ⁓ wouldn’t work. And yet it turns out, when people, eat these nutrients in various forms, phosphatidylcholine is the membrane part of your membranes about two thirds of your membrane are made out of that phospholipid. So we normally eat a lot of that. So if you want to give it to match what women would normally eat, you’d give it as a combination of various choline compounds and betaine and some B12, et cetera. But it turns out that these roadblocks occurred in different parts of this complicated pathway. It’s sort of like a highway. There are different exits. If there’s a roadblock and you’re GPS program tells you, you have to know which exit to get out of to get around the roadblock and just putting more gas in the car isn’t going to get you through the roadblock. So eating more choline, for instance, isn’t going to push your way through a block.

Susan Hudson MD (21:28)

Starting a family is one of life’s greatest adventures, but sometimes the path to parenthood isn’t as straightforward as expected. Shady Grove Fertility is there to guide hopeful parents every step of the way, offering compassionate care and advanced fertility treatments to help make parenthood possible. With their exclusive 100 % refund program for IVF and flexible monthly payment options, Shady Grove Fertility makes treatment more accessible.

Visit ShadyGroveFertility.com to schedule a consultation and take the first step, because the adventure of a lifetime starts with Shady Grove Fertility.

Steven Zeisel (22:06)

But if you knew you had a block between converting choline to betaine, you could eat more betaine and get around the block. And if you had a problem of using betaine to…make methyl groups, you could take more of the other methyl groups like folate methyl groups to get around that block, et cetera. So it’s much more complicated than just saying go to the health food store and eat more of everything because you need to know where your block is. Yes.

Carrie Bedient, MD (22:29)

So that begs the question of how does a normal average woman know which one of these blocks she might have and how to best work around them?

Steven Zeisel (22:43)

Right. So what happened was, I was working in the laboratory for decades and wondering why people weren’t listening when we showed how critical these nutrients were for developing a normal embryo. And other scientists were showing that the ovum doesn’t divide properly without betaine, that the sperm didn’t work properly. We were showing that. And it turned out that it was hard to find out if you had a problem.

There wasn’t an easy genetic test to do it. So one of the things I did when I realized I was going to have a little more time as I got near retirement was help to start a company called SNP Therapeutics, SNP being the name for these genetic variants, single nucleotide polymorphism. That’s not a good company name. So SNP Therapeutics. And they came out, yeah, SNP.

Susan Hudson MD (23:29)

I like SNP.

Abby Eblen MD (23:31)

I wondered how you got SNP and now that makes perfect sense. ⁓

Steven Zeisel (23:33)

And we developed a product called Genate, which is a genetic test in which you do a cheek swab with a big Q-tip and send it in and your genetic variants are looked at. And we put together a special chip with all of the variants that we found in these women who we studied in the hospital as increasing their needs. And then others that we read new from the literature were important and did an analysis, not of one gene at a time, but in this complicated web of pathways where your blockages were, and came up with a rating score that told you how many of the blockages you have and how important they were. And from knowing them, you could then devise an intervention. Which nutrients do you need to get? Which exit from the highway do you have to get off or get in, so to get betaine or choline or methyl groups or folate. And that test is now commercially available. Really for the first time, it’s easy to get this test and know whether you need it. Yes.

Abby Eblen MD (24:36)

So do patients get, can they get that online? Get they through their doctor’s office? How would somebody get that?

Steven Zeisel (24:39)

Yes. So either way, it can be ordered through your doctor’s office or it can be ordered online. And the website, as I understand it, is HIPAA compatible. Your information is only available to your doctor if you give permission for the doctor to see it.

A report is given to you of what the findings are in more straightforward language, and your physician can get a report that lists each of the genetic variants you have in detail so that more complicated report they can work with if they want it. But in the end, that report also gives you the bottom line. You have a block between A and B, and it shows you the highway map where your block is and what the nutrients or interventions you’d need to get around. And it then gives you how to get it out of your diet, or if not out of the diet, which supplement mixture would be the best for you. It’s online, it’s fairly simple. The overwhelming question I get is why bother with a genetic test? Just eat those nutrients. And the problem really is, just like in medicine, you wouldn’t treat somebody with a medicine without knowing they needed it because all the negative effects of that medicine aren’t balanced off by having a positive advantage, a need for it. And the same thing here, if we give too much of these nutrients, the gut bacteria can convert them to a molecule that may be associated with increased heart disease. And so we want to know that you really need more because you have a metabolic inefficiency, a roadblock that you need to step around and your benefit from getting more outweighs the small risk of increased heart disease, which I’m not that worried about in young women anyway right now.

Susan Hudson MD (26:33)

Is that specifically related to choline or which of the pathways?

Steven Zeisel (26:36)

So choline and betaine, phosphatidylcholine can all be converted to this metabolite. Folate, again, we give everybody extra folate, but we know that a portion of the population is having a problem with too much folate. They accumulate unmetabolized folic acid, and that interferes, competes with their uptake of the active vitamin. And so for all nutrients, this idea that you can go to a supplement store load up and 10 times what you might need and it’ll be okay isn’t true. Just like a medicine, these have good effects and bad effects and you want to take them when you have a problem that will benefit from the effect and not when you don’t. And simple genetic tests can tell you that. And physicians use tests like this all the time. For instance, the blood thinner warfarin you can be a fast metabolizer or a slow metabolizer. And how much I have to give to you depends. If you’re a fast metabolizer, I have to give you a bigger dose. And if you’re a slow metabolizer, a lower dose. If I skip the test and just give you a dose, two thirds of the time, have given you the wrong dose. And you either bleed too much or you don’t, it doesn’t work well enough. So I think the same thing is true in nutrition. And that’s why I’ve been one of the founders of the area of precision nutrition that the NIH for the last 10 years has been investing heavily into develop this data set like the data set we developed when we took women and men and took these nutrients away from them and ask who got sick and who didn’t, but to do this for many other nutrients, vitamin D, et cetera, so that we’ll have a much bigger data set to develop precision nutrition. And SNP Therapeutics has focused on this area because we knew the most about it.

It might as well start with something you know about.

Abby Eblen MD (28:21)

Steve? So to be clear, you had mentioned earlier, and I think it was before we went on air, you had mentioned that this test is not just for women, but also for men. It can also impact men and their ATP. And so if you’d expand upon that, and also mention the name of the test. I don’t think we heard the name of the test at the beginning.

Steven Zeisel (28:33)

Yes. Okay, so the test that’s being marketed is called Genate, G-E-N-A-T-E, and you can find it online at genate.com. and there’s a package of it. It looks real nice. In there is a special tube with a preservative in it and a cheek swab that you swab and your cheek is sent in there and then you send it in and within a short time the genetic test is done and reported to you online. So for men, the story is as follows.

When we did those human studies and put people in the hospital, took nutrients away from them, asked who got sick, and we spent a fortune, $50,000 a patient to do 150 patients and discover all these needs. But I also said, there are a lot of things I can’t look at in people. So I took mice and every genetic misspelling variant that we discovered was important to people, we made a mouse.

And we asked, what do we see in the mouse that we might not have looked at? And in the male mice, we found that with some of these genetic variants, the mice had sperm that couldn’t swim. And they had batteries in these sperm called mitochondria that looked very abnormal. They were empty when we did them under electron microscopy. And we measured what those mitochondria, those batteries make, the energy molecule called ATP. And we found that people with a very common version of this variant, men who had both copies of their genes, you have two copies of every gene, both copies of their genes with the spelling variant had ATP levels that were 60 % lower than men who didn’t have any of the variants. And the men who had only one of the two genes with this copy fell right in the middle. So, either 30%, 60%, or 100 % ATP in the three groups. And we found that in these mice, because they had no energy, the sperm didn’t wiggle and didn’t swim, and we could see it. So then we said, does this happen in people? So we went on, collected a bunch of men, and looked for variants in the same gene that we found in the mice did this. And we found that in North Carolina, about 9 % of young men had this variant. And when we looked at their ATP, we found the exact same thing. Their ATP in their sperm, if they had two copies, was way reduced. One copy was partially reduced. Now, in those men, they were all young men not trying to get pregnant or have a baby. Their history was helpful. The ones who were trying to get pregnant, the ones who had both copies had a lower success rate than the ones who weren’t. But that brings me back to the mouse. So then we ask, what can we do for these mice? They have this gene variant. Are they permanently not going to be fertile? And they mice were not fertile. They could not have babies, these male mice.

So we looked and they had a roadblock in converting the nutrient choline to betaine. And we found, we said, hell, that’s the roadblock. Let’s get them on the bypass and give them betaine and see that they get better. And indeed the ATP returned to near normal.

So those men with that genetic variant needed those male mice, not men, needed that treatment. And so we went to the US Patent Office, got a patent for the genetic test and the treatment, and now that’s available. And the same Genate test will tell you whether you have that variant. Shortly, the company will come out with a male-specific test, but the Genate test just tests a lot more, but it has that variant in there.

Two or three variants in this gene. And we found that about 40 % of men have at least one copy of a gene with one of these variants. And about 10%, 15 % have both copies of their genes affected. So these men might not be having babies, even though they have normal numbers of sperm. And their sperm look pretty normal unless you look under an electron microscope, which we rarely do.

And you wouldn’t know. And you’d say, well, why can’t we just look at motility? Well, in the mouse…It was obvious the sperm just sat there and didn’t wiggle no matter what. In men, the sperm wiggled and we had to use computer assisted sperm analysis to see that they weren’t swimming straight. They were swimming in circles. So their linear progress, what you need to do to get from the bottom of the fallopian tube up to the egg, wasn’t happening.

It’s hard to see just under a microscope, but if you had computer-assisted sperm analysis, you would see that these men with low ATP were not swimming straight. And we never looked, but with low ATP, you run out of it pretty quickly. You need to swim for days as a sperm. And we only looked at an hour. So at an hour, they could still wiggle a little bit. But the point is, is now there is a group of men who have been going to IVF because they couldn’t have babies unless their sperm were injected into the ovum, who may be able to go through a course of therapy. And the sperm production cycle in a man is about 90 days. So the therapy we’re recommending is 120 days to bracket that sperm production, spermatogenesis with extra betaine.

And what we believe is that these men will have higher ATP and therefore it may be something worthwhile checking out before going fully to IVF. And even with IVF, the thing with ATP is it’s the universal energy source in the sperm. And it isn’t only for moving.

Sperm penetrates the egg, a series of ATP dependent reactions have to occur to activate the egg and make it start dividing and the penetration to occur, as you all well know. And having low ATP in the sperm creates a problem with that activation of the sperm so that it can penetrate and do its job. So it may not just be movement. It’s likely also the other functions of ATP. So even in IVF, it may be useful to pre-treat the male with, if they have this genetic variant with this thing. And as I said, at least 10 to 15 percent of men have ⁓ a severe problem, both genes affected, and probably 40-something percent of men will have at least one gene. So it might be worthwhile thinking about that.

Abby Eblen MD (34:50)

We were talking earlier, there’s a test called a SpermQT test, and it’s really interesting, it’d be really interesting to see if they look at the genes that you’re talking about, because we have the test available and we can look at, and there’s a certain, a small percentage of men, but a certain percentage of men who appear to have normally moving sperm, and yet the sperm can’t fertilize the egg. And so we can do that. Okay, okay, well.

Steven Zeisel (35:25)

Right. I don’t think they’re looking at this gene, I’m sure of that.

Abby Eblen MD (35:31)

We can look at that and we can know that that percentage of guys are not gonna do well with, timed intercourse at home or with doing intrauterine insemination in the office. But I just wonder if there is not some, even though it may not be the same gene, maybe there’s something that could be reversible because…

Steven Zeisel (35:44)

It be, it might be the same, it could well be. And that’s why I think it’s just as important that this is a two person ⁓ plan to have a baby and that the male should have optimal cellular function for his sperm and the female has to have optimal cellular function, not only for ovum, but for all the other things required for making a pregnancy. And knowing you have a metabolic roadblock, does a few things for you. One, it identifies specific interventions that might help you. Two, it provides the motivation to go to the trouble of eating differently or choosing a different set of prenatals and supplements. It motivates the physician to think about how you might have to change IVF, for instance.

The genetic test is worth the trouble for that reason, because you could, and if it saves you 10 or $20,000 in an IVF cycle by doing something that you do for 120 days and see if you didn’t need it, it would be well worth the effort. And it’s part of the due diligence that I think everybody would like to do before going the whole route to IVF.

Coming back, for the male, we know there’s a very specific problem that’s important. There may be other things that would like you to not have these other variants because they all add up. I can increase your requirement for B-TAIN by, for instance, if you have bad folate metabolism, and there are multiple common variants in folate that everybody’s aware of. The methyl tetrahydrofolate reductase is a common difference, 15 % of population. We found there’s a gene just before that that directs folate either to making DNA or to making methyl groups. And if that gene has a common variant, it makes it much more likely that men and women will run into troubles if they don’t get enough of these nutrients.

That gene seems to be very important in that direction. And it also says to you that folic acid, which is in prenatals, isn’t always enough. You may need methyl tetrahydrofolate, which is after that gene vectors it to make methyl out of it. If that gene is not working properly, it’s all being vectored to making DNA. You don’t make much methyl folate, and then you need that specifically. And that’s another intervention that’s very possible to do if you knew you had that roadblock.

Susan Hudson MD (38:14)

For our listeners who might be interested in doing this test, how much does this test cost? Is it something that’s ever covered under insurance or is it really cash pay at this point? What’s that type of

Steven Zeisel (38:27)

I’m not on the financial end of the company, but I believe it’s retailing for $299 as a test. So it’s not as expensive as some of the rare genetic tests, but it’s there.

Whether it’s insurance pay, right now the company is working to get insurance coverage, but it’s right now cash pay until there’s enough usage of it that the benefit for an insurance company of, let’s say, paying for an intervention as opposed to an IVF makes commercial sense to them and they decide we should cover it. So right now it’s early and that’s there. I think the sperm test is going to be more rapid in coverage because it’s so easily apparent that you either can or cannot have a baby with it. Getting back to the story, the same is true for the production of the ovum.

The precursor cells that will end up becoming the egg divide more or less depending on the same things that the precursor cells that make the brain up. They all seem to require these nutrients to be present in the right concentrations at the time that they are

switching between being able to make every kind of cell in the body they want to make to being more specialized and making either egg cells or brain cells or kidney cells or liver cells. And at that point, they all undergo a series of cell divisions to make a pool of specialized, what we call progenitor cells. They are committed to become some kind of tissue. They’re making different tissues because they’ve been marked especially by these epigenetic marks on DNA that come from these nutrients we’re talking about. And what we found is that their division is heavily regulated. And it’s a little complicated. They’re regulated by a kind of RNA that we thought was junk RNA until 15 years ago. We knew the body made a lot of RNA.

The cell made a lot of RNA.

And we thought that a lot of it was junk. It turned out it wasn’t junk. It’s used to regulate how DNA is made. And these small RNAs called microRNAs, we found that a number of them are regulated by these nutrients and that they are turned on or inhibited by these nutrients being present.

And the inhibition of some of them is very important because that’s what ends up, when they’re inhibited, these stem cells can divide. When these are not inhibited, the stem cells stop dividing. So that’s the signal to tell you to stop making daughters or cells, whatever you call them. And then you’re stuck with that population for the rest of your life of precursor cells that can populate your brain or populate your ovary. The basic structure is set up relatively early in life. And you’re given a certain endowment of progenitor cells. For the brain, this is important because throughout your life, you can replace neurons until late middle age when you stop having so many of these progenitor cells left. And it turned out in mice that for their brains, when we gave the mothers less of these nutrients during pregnancy, the babies were born with many fewer of these progenitor cells in their brain. And then when they had to grow a brain, they ran out of these cells early and didn’t form the higher levels of brain. And so their memories were terrible. They made 30 or 40 % more errors running mazes than mice whose mothers had this. And even more interesting is, mice live about three years, and then about two years, some of them become senile and make a lot of errors on maze running. And the mothers, the babies born of mothers who had the lower new choline related nutrients during pregnancy, they became senile much more rapidly. And the ones whose mothers had extra didn’t bother. And then researchers at Cornell have recently asked if they gave more of these nutrients specifically choline during pregnancy, did the babies come out better? And they’ve reported that in information processing speed and a test like that, they could see a significant difference between the babies and mothers who got twice as much as the babies who got only the recommended intake. 

Carrie Bedient, MD (42:58)

That it makes such a difference between both mom and babies. That’s the best take-home message of all.

Steven Zeisel (43:00)

Even more interesting is that that work was done at two, four, eight, 10 months of age. And now they recall many of those children at seven years of age, and they still can see a difference in things that have to do with attention at seven years. So they just published that recently. It’s out of a group out of Cornell. So for fertility, why this is important because that’s when you’re setting up the first initial structure, all of those stem cells and progenitor cells that will later have to form the entire fetus and then go on to form the baby and the young child and the older child. You want to buff yourself up and be in great shape as early as possible, not wait.

These studies done in Cornell and whatever starting in the second half of pregnancy to start treating, they’re getting some of the organs that form at that time like brain, which forms in the human at 25 weeks gestation. We know the spinal cord forms at 11 weeks, maybe 22 days in the mouse. And so you have to go earlier.

I think you have to go as early as possible. And if you want to have optimal fertility and outcome from the fertility, you’d like to know you have these problems and start addressing them in the time you’re setting yourself up to become optimally fertile and to have a baby. And if you’re going to go through normal pregnancy it helps, but if you’re going to even have to go through IVF, it’d be nice to set up the cells so they’re optimally functional, have the best potential when put through these expensive procedures. I’d also ask you as experts, you take the ova, that if you collect them and put them into culture essentially in a medium, and I bet you you’ve never thought about how much choline is in that medium.

Susan Hudson MD (44:55)

Now usually that’s, by that point it’s in the embryologist’s hands.

Steven Zeisel (44:55)

But I bet you sure. I understand, but the point is most of them never knew it was important, so never thought about it. And it turns out that when we do neurons in culture, they used to have a medium very low in choline and didn’t do very well. And when we increased that, they did much better. So I think we need to understand that this one set of nutrients is critically important. They’re not the only nutrients important, but since we know how important they are, might. We have a lot of evidence, we might as well make sure that we address them. One day, I think you’ll be able to do a genetic test to find all of your variations, because I’m sure people who have vitamin D transporter differences or vitamin D receptor differences need different amounts of vitamin D, and the same with vitamin C and everything. But right now, right, but right now, we know enough about this area to come up with a test to have somebody take it, to design a rational intervention, and in fact, to do clinical studies to ask, do we have better outcomes? And we’re trying to do that. Well, again, I would thank you if we could reach more people to actually hear the science, because it’s a shame to know this for 10 years and not see people benefiting from it yet. So this is the first attempt to reach out.

Carrie Bedient, MD (46:01)

Thank you so much, Steve.

It’s incredible, I think, the amount of research.

Susan Hudson MD (46:19)

We definitely appreciate you coming on today and for any of our listeners who are interested in the Genate test by SMP therapeutics, their website is www.genate-kit.com. And to our audience, thank you so much for listening and subscribe to Apple podcast to have next Tuesday’s episode pop up automatically for you. Also be sure to subscribe to YouTube that really helps us spread as much reliable information as possible.

Abby Eblen MD (46:49)

You can also visit fertilitydocsuncensored.com to ask a question for our Ask the Doc segment. Also check out our book, the IVF Blueprint, to help better understand IVF in detail. You can find it on Amazon, Barnes & Noble, and bookshop.org. We’d love for you to subscribe and leave a review for us on Apple Podcast, and we’d really love to hear from you.

Carrie Bedient, MD (47:08)

And as always, this podcast is intended for entertainment and is not a substitute for medical advice from your own physician. Subscribe, sign up for emails, and we will talk to you soon. Thank you so much, Steve. We appreciate you coming on today. This was a fascinating dive into the basic science that we don’t often get and is a beautifully compact, ⁓ actionable thing for our patients to work forward, to know what they can do and to act on. So thank you very much. We appreciate it.

Steven Zeisel (47:36)

I enjoyed it and I hope it does some good. You take care.

Carrie Bedient, MD (47:39)

Thank you.

Susan Hudson MD (47:39)

Thank you.

Abby Eblen MD (47:40)

Thank you.