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We are a team of scientists, researchers, and medical professionals using epigenetics to improve pregnancy success rates for men dealing with infertility.

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Measuring a man’s fertility has relied on the semen analysis for half a century. Is this enough, or do advances in epigenomic medicine offer us a better way to predict fertility potential?

In this webinar, Drs. Alan Horsager and Paul Turek discuss personalized innovations in male infertility diagnosis, which promise more relevant and personalized information about fertility. You will learn how epigenetic mechanisms can be used to understand and help predict fertility potential, and how analysis of the sperm epigenome can be used to help guide treatment decisions and counsel patients.


Session Recording

 



Session Transcript

Dr. Alan Horsager: AH

Dr. Paul Turek: PT

PT: I want to welcome everybody to National Infertility Awareness Week. I’m a fertility clinician. Alan is the CEO of a company that is working on the genetics of sperm, specifically the epigenetics of sperm. I’m a clinician; I used to be a professor, now I’m in private practice. I have a very deep scientific interest in furthering the field...

Dr. Alan Horsager: AH

Dr. Paul Turek: PT

PT: I want to welcome everybody to National Infertility Awareness Week. I’m a fertility clinician. Alan is the CEO of a company that is working on the genetics of sperm, specifically the epigenetics of sperm. I’m a clinician; I used to be a professor, now I’m in private practice. I have a very deep scientific interest in furthering the field. Alan came up to me once and said, “I think we can figure out a lot about sperm health and fertility by looking at epigenetics.” What the hell is epigenetics, is the question. I’m just a clinician, but I’ve written a blog on this. It’s called “The Real Reason We Are Who We Are.” I just want to explain it quickly. There’s genetics, which is, let’s say, for example, Alan and I are about 99.5% identical genetically. Men and women are about 98.5% identical genetically.

                                    In fact, we're about 50% identical genetically to bananas. We are not bananas, and I am not Alan, and we're not women. The reason why we're different despite being so identical genetically is because of the word "epigenetics." Epigenetics is not the sequence of DNA that is the Watson and Crick model. It's actually a parallel universe. It's marks on the DNA. It's the way the DNA is coded to either become protein or not eventually. There's several systems in place that the body has to hide DNA from being made into other things. This is one of those systems that is specific in sperm in. Alan has studied this for years, and I've been interested in it for years. It's sort of the latest and greatest thing after DNA and genetics. It is probably the basis for many cancers, it's the base for autoimmune disease, it probably is the base for schizophrenia, autism, and other neurodegenerative disorders.

                                    It describes why a nose is a nose and an ear is an ear despite the fact that those cell types are identical. It's why organs are organs that they are. I think that's what we're talking about, right, Alan?

AH:                            It is indeed. A little bit about my background and how I got to this field, because it's a little strange, actually. My background, I'm a PhD in neuroscience. I actually became very interested in this through a conversation. This is where it started, with Andrew Smith, who is a computational biologist at USC. He's one of the co-founders of Episona as well. I was asking him about things he was working on, and he said, "I'm doing this work in epigenetics and sperm," which you know a little bit about now. He was looking to cross different species. In humans, in some of the samples, he saw some abnormalities in a gene region that was thought to be very important for neuro-development. My question was, is could you actually use that information to try to predict disease outcome in offspring? This, coming from a neuroscience perspective, that's what got me interested. That's clearly a very difficult thing to do, and so I started to think about it more broadly, about other opportunities in epigenetics.

                                    Is there more information there that we can use to help understand disease and human health in this case? Started digging around, immediately came across work from Doug Carol, who has been working on this. He's a professor, he's an andrologist from the University of Utah. He's been working in this field for probably several decades, but certainly in epigenetics for probably a decade. He has done a lot of work looking at how changes in this epigenetic profile can impact both fertility and early development, specifically the development of the embryo.

                                    We started to dig into it a little bit, and ask whether there was an opportunity for developing a diagnostic test for fertility based on the epigenetic profile. That's what we've been doing for the last couple years, which I can dig into here.

PT:                             Alan, I just want to say, I'm really happy you went from studying the real brain to studying the true brain of men.

AH:                            It's all connected. It's along the axis, right? I think one thing I'd like to talk about here is ... The audience, I think, is kind of a mix of both physicians and patients. I think we have to make sure that we're speaking to both groups. Paul, I would like you to describe, if you can, why we ... So the first question I asked Paul, when I first met him and talked to him about this, is do we need a better diagnostic for male infertility? Maybe you can start there, Paul, and I can help frame the rest of the conversation. Why bother with it, if that's making sense?

PT:                             Right. Doing a new mousetrap. The semen analysis is the single best measure that we have to predict male fertility. Unless it's zero, it's a terrible predictor of true fertility. Remember, fertility is not a semen analysis. Fertility is ability to conceive. It's a fifty to sixty-year-old test. It hasn't changed much. We've argued about what's normal and what's not, but it's been what I would call a blunt instrument. The ability to dissect out fertile men from infertile men, or to figure out why something maybe unexplained or explained. Of course, unless it's zero, which is true sterility, is truly an infertility problem. It's been really not very valuable in most cases, and it's nice to have a razor-sharp marker. A couple of other tough ... The other thing it doesn't do as a descriptive measure of semen, which is essentially putting order in the universe, like counting stars, which may never have meant to be counted. It doesn't tell you anything about how sperm functions, except motility, but it doesn't really tell you how well they work.

                                    When Alan approached me with this concept that there's something that looks deeper and maybe can describe how good sperm are, how well they work or if they're actually truly fertile sperm, or just bystanders. I went around and asked some prominent figures in the field a simple multiple-choice question. I was unsure of what its potential would be either, as an epigenetic test of sperm. I said, "If you could come up with an epigenetic test of sperm that was reliable to tell you something, what do you think it would tell you?" The options were A, whether a sperm is a fertile sperm or not, B, whether a man is fertile or not, if that's semen analysis, and C, whether that sperm could work with simple technologies like IUI and be successful, D, whether it would predict fertility with IVF, E, whether it would predict the ability of embryos to develop well in a dish after IVF, F, whether it would predict a successful pregnancy or miscarriage, G, whether it would predict any consequences to the child of health, because we know that epigenetic profiles can predict some awful things. Would this maybe predict the health of a child. I think the last one was G or H, was none of the above. There was another one, all of the above.

                                    Everyone chose all of the above. That's what we think we have with this test is, we don't even know its potential, but it could certainly do any one of a number of things. So far, it's been studied very specifically to try to assess its value for a couple of those things.

AH:                            Yeah. I think maybe I can talk a little bit about the goal of the test and what data we've acquired thus far. Maybe that'd be a good next step. I agree with Paul. I think that epigenetics holds a lot of promise, and there's a huge opportunity to ... it's an entirely new window into looking into human health that we really haven't dug into before. There's a lot of diseases and disorders that we've assumed are genetic in nature because they're heritable. There's an increased risk that someone will develop those diseases based upon the profile of their parents and grandparents and so on. The fact is, we've not found anything in the genetic profile. That suggests that there might be some other heritable element, which, now that we know a little bit more about epigenetics, really lends itself well to that as a possibility.

                                    With this test, one of the things that we're very interested in is understanding fertility. The first question that we tried to address is, "Can this epigenetic test, which we call SEED ..."

PT:                             Is that SEED or SEEP?

AH:                            SEED. S-E-E-D. Can we predict fertility status? What we did is we took men who were going through treatment with their wives at a fertility clinic, going through IVF, where both the male and the female have been worked up. Men went through the standard semen analysis. Many of them went through DNA fragmentation, which is exactly what it sounds like, for those that don't know. It's fragmentation rates in sperm DNA.

                                    The females go through a battery of upwards of eight different tests. There's potentially more information on the female side. The female factor in these cases was ruled out. We were left with about one hundred and twenty-seven men, where the infertility was likely to lie. Then we compared those men to a fertile donors. These are men with normal semen parameters, no infertility, they've produced offspring. We compared these two groups. To summarize, can we discriminate between normal, fertile donors and men that have fertility problems? The answer ...

PT:                             The infertility men had normal semen analysis.

AH:                            Well, most of them did, or half of them did. All of them did have sperm present, right, we couldn't look at anyone that wasn't producing sperm, for example. Half of them had normal semen parameters as defined by the World Health Organization. We could discriminate between those groups very well, so in the study we had eighty-two percent sensitivity, I'll describe what this means to most people, and ninety-seven percent specificity. What that say is that out of a hundred men with a fertility problem, we can recognize eighty-two percent of them. The ninety-seven percent is out of all fertile men, we can recognize ninety-seven percent. A very accurate test in that regard.

                                    The second part of that was looking at embryo quality. Could we predict the quality of the embryos before they go through IVF? By looking at this sperm epigenetic profile. This is very specifically dealing with methylation, which means methyl groups that bind on top of the DNA. One of the several different epigenetic mechanisms and whether we could predict the quality of the embryos. In those cases, in about fifty percent of the cases, we could determine whether there was going to be poor embryo development. Again, the specificity was very high, about a specificity of 98%.

                                    This was our retrospective study, and what we're doing now is a much larger validation study. We're nearing completion. We actually have the data in hand from several hundred subjects, through ...

PT:                             Let's take a minute and just recap those findings. You got scientific on us.

AH:                            Yeah, fair enough.

PT:                             You're saying that it's a powerful tool and it's precise and it's accurate because it could distinguish between fertile sperm and infertile sperm. Fertile men versus infertile men.

AH:                            That's correct. This is independent of the semen analysis, right?

PT:                             Right.

AH:                            I think one thing that we should mention here, too, is that many cases, up to twenty-five percent of cases, there are couples that have what is called unexplained infertility, right? Everything looks normal, but we don't know what the problem is. I think that's what many of these patients that we looked at represent, those cases.

PT:                             The other part of the study, this is the retrospective study of data, that material's never been collected before, is that when you looked at these sperm, you could predict the quality of the embryos that they would generate from IVF, be good or bad, which is a very important thing that ... It's a very important phenomenon to address called dissolving embryo syndrome. Which embryos are going to do well and which ones aren't? You looked at the sperm and the embryos and the outcomes and correlated them, and they correlated very well.

AH:                            Yes, that's correct.

PT:                             All right. That's not enough, because that's older stuff. You're now having a prospective trial where you're actually collecting samples as people are going through these technologies and you can design it more powerfully.

AH:                            Right. I think what's very important is to do a prospective study, where you actually ... you have people coming into the clinic. You don't know what their status is, in terms of their fertility status, and you don't know what kind of treatment they're going to go through, what the outcomes are going to be. You collect the sample before they go through their treatment, and then look at them after. That's what we've been doing over the last year and a half.

PT:                             In this study you're looking at the ability, you're not looking at natural pregnancies and natural fertility, you're looking at assisted reproduction and you're looking at IUI, so is the epigenetic sperm profile predictive of IUI success, and is the epigenetic profile predictive of IVF success? You're looking at embryo quality, embryo development, those are all the features.

                                    There's a list of A through G. You're capturing about half of it.

AH:                            Yeah, I would say that that is where we're going, a lot of that. There's still lots of work to be done, but I think the first question, recognizing whether there's a factor or not, is what this test does even when the semen analysis looks normal. Secondly, there's a substantial amount of information about which genes appear to be abnormally methylated, or they look abnormal from an epigenetic standpoint and what they're important for.

                                    As an example, some of the samples that we've looked at, there are genes that are very important in regards to oxidative stress. Also in the acrosome reaction, which, for people that aren't familiar, that's when the egg and sperm connect and the sperm can drop off its DNA. If they can't make that connection properly, it's hard to fertilize the egg. We recognize that that can be a problem, too.

                                    This type of information can then be used to guide the treatment, right? If you start to understand, well, A, there's a problem, and then B, what might be causing the problem if you can have that information, then you can start to guide the care better. That's what we're trying to do. Not just tell you if there's a problem or not, but what might be causing it.

PT:                             How many marks are there in the genome? Are there millions of marks? How many did you look at, and how many do you think are important?

AH:                            To kind of give you a rough estimate, there are around twenty-seven million regions where there's methylation in the genome. That's across the genome. Now what we're looking at, we're looking at five thousand of them, using some technology from Ilumina. We're using a sub-set of those to make this prediction. We're using hundreds of them which encompass several hundred genes. We're looking fairly broadly.

PT:                             Yeah, so this is kind of technology that is informatics-based, massive cluster analysis, this is new biology. This is not something that could have been done ten or fifteen years ago, maybe twenty years ago, not done. This is pretty sophisticated informatics, and informatics and systematic biology or systems biology.

AH:                            That's correct, yeah. I think what we're trying to understand is that there's this entirely new layer of information. Well, it's always been there, but there's this new layer of information that we've just recognized, this epigenetic profile. We're trying to read it. We're trying to read that information to understand what might be going wrong. In this case, fertility.

PT:                             Yeah, and I think a test like this is totally different than anything we've ever seen, and it has more potential to explain many cases of currently unexplained infertility. About a quarter of human fertility, at least, is unexplained. That means nothing is abnormal on any evaluation, any of the routine stuff for men, a semen analysis, or any of the routine stuff for women. Yet we know there's a problem, and they're not conceiving. We also know that some couples, why are they doing poorly in IVF? Everything seems to be fine, and everyone blames sperm or they blame eggs or they blame this or that. This is actually going to be able to point fingers at things, and it's nice to be able to blame sperm because hopefully we can do something about it, too.

AH:                            Yeah. I think the problem has been that the sperm has always been thought of as just a vehicle for delivering DNA, and I think it's much more complicated than that.

PT:                             Yeah, sperm are people too!

AH:                            They've been just ignored through the years. I don't know if there's any ... Maybe we should take a moment. I don't know if there are any questions.

PT:                             It's a good time for questions.

AH:                            Do we have any questions right now? Okay. It looks like we don't have any questions at the moment. I have a question for you, Paul. Of the cases of unexplained infertility, which are many, you said there's about a quarter of all cases seem to be unexplained. How much of that is female-driven or male-driven or we just don't know? The right answer is probably we just don't know, but if you were able to make a guess on where that probably lies.

PT:                             To date, I would say that most of unexplained infertility has been ascribed to women. We haven't had the tools to blame men. That's too bad. The fertility potential of women changes so quickly over a ten or fifteen year period, where we don't believe a change in male fertility changes that much over the same time period. We've always said it's more robust, but I think there's enough data coming out from Carol's work that epigenetic changes to sperm could occur as men age too. Not only as they age, but as they get fat and eat poorly. What is exciting to me is that this is a mechanism by which your health can affect your fertility, which is what the National Institutes of Health, we just met about it last week in Washington talking about the relationship between health and fertility.

                                    We've always ignored a man's lifestyle, but this could be vocabulary of which we could speak about how is lifestyle, dietary habits, lifestyle issues, smoking could affect his fertility in a very substantial way. This, to me, is a keyhole into a whole other universe, I think it's going to be. I really do. You got something good here, Alan.

AH:                            Well, it's no small part to you as well. You've contributed significantly to this. One thing I maybe, a couple things, just a step back. You brought up this idea that the environment and health and behavior or activities can impact fertility, and aging too. I just want to point to the studies on that. When you brought up Carol, he's talking about Douglas Carol, up at U of Utah, he did the study looking at sperm and men at essentially day zero, and then ten years late and these same men. He was looking at changes and DNA methylation across the epigenome. He saw significant differences, both globally and locally. In the global sense, there was increased DNA methylation. Locally, it appeared that there were changes in genes that are very important to neuro-development, particularly implicated in schizophrenia and bipolar disorder. Which is again, very intriguing to me.

                                    There's also another interesting study that came out fairly recently this year looking at what happens to the sperm epigenome as a function of significant changes in weight. These are guys where they measured the sperm epigenome, they were significantly obese, went through gastric bypass surgery, then measured the sperm epigenome again. Two weeks later, a month later, and then again six months later. Again, very significant changes across the genome as a function of that.

                                    There's probably a dozen papers out there now that show these environmental factors, behavioral changes, can ultimately lead to very large-scale and very dramatic changes in at least methylation and probably other epigenetic practices as well.

PT:                             It's organic, and it moves around. I have a question. What's the test we're talking about? Is it one test? How is it done? Is it hard, is it expensive? What do we know? Do you have the box that shows it? What does it look like?

AH:                            This is the box.

PT:                             That's nice.

AH:                            Your sample collection kit. It has all the details. You get this at your physician's office. You can take it home, collect a sample. You've got instructions here. You just collect in a container. You just seal it back up, double-sided tape, drop it in the mail, pre-paid shipping, and that's it. In terms of the actual test, just to be clear, we're still in validation mode. We expect that to be done relatively soon and we'd like to likely introduce this test later this year. That's all I'll say about that.

                                    The way it would work is you get the kit from your physician, take it home, supply a sample, we analyze it, and we then generate a report that goes back to the physician, the ordering physician and the patient can then go and review their position at the end of it.

PT:                             One of the things that's unique about this test is that when you send sperm for testing, it has to be frozen and handled very carefully, but this, what we're measuring here is so robust, is marks on DNA, that ... Am I wrong, you could leave it out on the sidewalk for a week or two and it'd still be okay. Is that right?

AH:                            Well, looking at Neanderthal, not us, but as a scientific community, we're looking at Neanderthal DNA methylation.

PT:                             Neanderthal?

AH:                            Yes.

PT:                             They haven't ejaculated in a couple of hundred thousand years.

AH:                            That's right. I don't know that it's sperm DNA, but it's definitely DNA methylation. It's actually very stable.

PT:                             It's a very robust test, so if you mailed it to the wrong address and then it got sent over it would still be okay.

AH:                            Yes.

PT:                             There's no test like this right now. Everyone treats sperm ... It's got to be alive, it's got be within twenty-four hours. This is a very hardy measure that is resistant to, well, like the post office, right? Gloom and sleet and ice ...

AH:                            Yeah, dramatic temperature tests don't seem to impact it at all, which is very good news. It allows you to ship it at ambient temperatures. We've seen exposures up to one hundred and thirty degrees and it's been just fine. I think that's an important point. This test is about providing a substantial increase in information while at the same time providing an entirely new layer of convenience for both physicians and patients, for that matter.

PT:                             If you want to ask a question of us, audience, you can add questions in the chat module, probably on the right side of your screen, or on Twitter. Use the hashtag #epigenetics. We'd love to hear questions. We want you questions. Now.

AH:                            There are a few questions.

PT:                             Good. See? That worked really well.

AH:                            We have a question. Do the sensitivity and specificity numbers hold if you have normal semen analysis parameters? That was with abnormal parameters. If I understand this correctly, I think what you're asking is are there ... Maybe two things. Yes, the sensitivity holds if the semen parameters are normal. That's what we showed in our retrospective study. We don't see any significant differences in our sensitivity and specificity for people that have normal semen parameters and abnormal semen parameters. If that makes sense.

PT:                             How about, maybe another question is, is there any correlation between, you don't have it yet, but is your gut that there might be a correlation between certain epigenetic patterns and certain semen analysis abnormalities?

AH:                            Yeah, I think that's likely the case. We don't see it with our tests right now. We're not looking for it. We're really focused on trying to understand problems that aren't recognized with the semen analysis. There was work done by Peter [inaudible 00:28:45]'s group at USC that looked at this, looking at epigenetic changes as a function of how well it correlated to the semen parameters. They did see stuff. It definitely exists. Right now, we definitely see things that are above and beyond the standard semen analysis.

                                    I'll take it one step further. In that study, we actually did a [inaudible 00:29:09] purification of those samples, and looked at them pre and post that purification. We can still see very clear epigenetic abnormalities. Our sensitivity and specificity is well-maintained, even after purification. It's not just that we're looking at work data or abnormal sperm, so these epigenetic abnormalities seem to be, carry through to the seemingly normal sperm as well. Hopefully that answers your question. If you don't think so, please jump in and ask some ...

PT:                             Yeah, I think sensitivity and specificity are difficult concepts for the public. In sensitivity, and these are talking eighties to nineties, that means that of all the people with a problem, this would pick up so much of it. Ninety percent of it, right?

AH:                            Yeah.

PT:                             Specificity would be ... no, is that ...

AH:                            That's right, that's right. I'll say it a different way. If you have a hundred infertile men and you knew this, I know this, our test can pick up eighty-two percent of them. If you have a hundred fertile men, we can accurately classify them as fertile ninety-seven percent of the time. We really weigh on the specificity, because what we don't want to do is call a fertile man infertile.

PT:                             You have your priorities straight. That's good.

AH:                            I think that's right. I think we better do that. Another question, are you suggesting that targeted methylation abnormalities will lead to identification of potential treatments targeting those methylated genes? You understand the question, Paul?

PT:                             Yeah! Yeah, that's the big one.

AH:                            Well, okay. If I were to wax philosophical and get a little dreamy, I'd say that that's a potential down the road. Particularly with CRISPR/Cas9 technology, which it's basically a gene-editing technology, which now has been proven to work with DNA methylation as well. Well, works at least partially with DNA methylation. There's a potential, say, if we see an abnormal DNA methylation profile in a region, we may say, "Oh, that's wrong. We know how to change that." CRISPR/Cas9 it. Boom, we're there. Decade away, if that.

                                    What I was really referring to is the potential of using the information that we've gathered to help address how you might help treat the patient with current available treatments. In the case there's a gene called Caspard, which is a, I'm going to get technical on you, it's a calcium ion that helps, is important for the acrosome reaction. Now if we know that's abnormally DNA methylated, right, then we know that there's probably a problem with that gene and that the acrosome reaction may be compromised.

                                    In those cases, what he might recognize is like, "Oh, well we failed at IEY a few times, then we recognize that this might be the problem. Maybe what we need to do is go straight to Ixy IVF. We're injecting the sperm straight into the egg to get around that problem, so we have to deal with the problem of compromised acrosome reaction." That's the kind of information that we're hoping that this test will provide.

PT:                             I love it when you use big words, Alan.

AH:                            You're supposed to pull me back from the [inaudible 00:32:47].

PT:                             I mean, that question was definitely ... That was one smart reader who asked that question. Holy ... They were out there. They were definitely following along.

AH:                            Okay.

PT:                             Mark clarified his question. He asked, "Will there be different patterns of methylation that pinpoint specific focus?" Cosign. Does that mean genetic cosign? I would say yes is the answer. You've selected a panel of epigenetic marks that don't represent genes right now. They represent a picture, an array which you think is highly predictive of fertility, right? That's what you've done.

AH:                            Right.

PT:                             Just a huge pile of them.

AH:                            Right, but the DNA methylation that we're looking at does reside in specific gene [inaudible 00:33:57], right? That gives us information about what's happening at the gene level.

PT:                             There is potential to pinpointing this to specific genes, like you're [inaudible 00:34:05].

AH:                            Exactly.

PT:                             So there, everybody.

AH:                            Mark, does that answer your question?

PT:                             Maybe that's Mark Hughes.

AH:                            No, it's Mark Perlo, down in Atlanta.

PT:                             That's great. Beautiful.

AH:                            I think he has another question for us. Do environmental factors like smoking marijuana and heat exposure affect methylation patterns? I think the answer is yes, but we don't have ... I think that's a story that's still being played out.

PT:                             I can imagine when you use the word lifestyle, that's what you're talking about. Diet, social, recreational drugs, I think that's the mechanism by which they can cause infertility.

AH:                            Yeah, and I think that's what that gastric bypass thing showed pretty clearly is that if you have very dramatic shifts in environment, which, you know, the body, as weight changes is an environmental factor, at least on the epigenome, then the environmental factors do play a part. There are lots of studies being conducted to understand how smoking affects the epigenome.

PT:                             Is this actually evolution?

AH:                            No. No, I'm not biting. I think it's perhaps an adaptive mechanism, right? I think it's a way for our body to respond to its environment. Things of adaptation, right?

PT:                             Why would you put those things in sperm? You're looking at the sperm of men who lost a lot of weight, and their genetic profile. You're looking at men at one age and then ten years later you've got them when they're ten years older and the sperm are different. The epigenetic marks are different. Is that evolution? That's evolution! Come on, it's got to be! What else is there? That's evolution. The genetics hasn't changed.

AH:                            Well, I tell you I think it's reflective of, it's a map of environmental exposures. They can probably alter gene function appropriately to deal with that. That would be my guess.

PT:                             We know that about half of human evolution is neuro-developmental. You see movies, martian movies with big heads and big eyes, that's exactly where we're evolving. We're not evolving fingers and toes. We're evolving in our brains, and it looks like from Doug Carol's study, in sperm from ... That's where it was happening, in those same neuro-developmental genes, like autism and schizophrenia. It's just fascinating. That's heritable, right? That can be passed down if it's in your sperm.

AH:                            Yeah, there's lots of debate. I think we should be honest here and say there's lot of debate about how heritable this stuff can be. There's very clear evidence that that pattern of DNA methylation goes through the erasure. It gets wiped out. Everybody, for many, many years, thought that it was just completely cleaned out like a disc. It was completely erased and it was reprogrammed once the embryo started developing. Now, what we know now is that that's not entirely true. Actually, about twenty percent of DNA methylation is maintained after that full-scale "erasure." It's still maintained, right?

                                    Whether that's meaningful information or not, I think that's still playing with [crosstalk 00:37:40].

PT:                             Oh, I'm sure it's meaningful somewhere. I'm sure there's a recent ...

AH:                            Yeah, I think the evidence is beginning to roll in that's really supporting this concept that these things are absolutely occurring. In fact, that's what epigenetics by definition is. It's these marks on top of DNA that are ultimately heritable.

PT:                             Epigenetics is actually any alteration of DNA that doesn't alter its sequence.

AH:                            Yeah, that's right. That's right. That's right.

PT:                             This is a parallel universe. How old is it? How old is epigenetics? How old is this study, this field?

AH:                            Well, the feel of epigenetics ... Charles Darwin had an interesting term for it called gemmules. These were different little factors that would flow through the bloodstream to the gamuts and change how the gamuts were and then ultimately heritable. That's how you inherited changes from acquired traits. It really became much more ... After the genome was mapped, right, I think then we came to develop technology. The ability to actually do anything with epigenetics is only several decades old. It's not a particularly old science. I think there is a lot of uphill battle to deal with the ... Up through the nines and oughts for that matter, genetics is where it's at. Genome studies was ... You couldn't throw a rock without hitting a principal investigator of genome study, right? Those were common.

                                    Those are a little less popular now. Those were genome-wide association studies. We're trying to understand how the genome makes us who we are and how [inaudible 00:39:34]. That's what those studies were about. The problem was is that many of the things we were looking at were complex diseases like autism, which doesn't play out very well with genetics. I mean, I heard there were genetic components to it, most certainly, right? I think that epigenetics is going to be a lot more informative.

PT:                             I was listening to David Page at MIT talk at DNH last week on how men and women have sex-specific differences in response to disease.

AH:                            Yeah.

PT:                             He's saying that the same mutation in a woman and a man would lead to different diseases and different trajectories of disease. We should start thinking about them as not having the same genome, or having the same genome but different expressions of it. He went on forever, and it was an absolutely humiliatingly beautiful talk about his thought for the last twenty years. The meeting was about how fertility could predict your health, how it could be a bio marker. He ended up saying as his last sentence that he thought it was epigenetics that would seal the deal on being able to figure this out. Why we have differences in response to diseases or gene mutations, and why women get lupus than men, and why men get more ... schizophrenia than women. Et cetera. It's fascinating that the father of the Y chromosome and the Human Genome Project thinks that the future in figuring out disease and health is in epigenetics. Fascinating.

AH:                            That is fascinating, yeah. What do we have? We have ... I'm looking at more questions. We have lots from Mark.

PT:                             We love questions. We know all the answers too.

AH:                            Well, you might. I'm a scientist. I continue to look for answers. "I think you said that with fixing the acrosome is affected, so that reports will not be a simple yes or no. Your report known gene issues." Yes, that's right, Mark. If I can just kind of describe what our report might look like, and it's still something we're working on, I just want to be clear if there are people tuning in that wanted to know a little bit about our validation study, we do have much of that data in hand. We look forward to sharing that with people, but we're just not at a point where we can discuss the results yet.

                                    We have been working on developing a report. Basically what you'll have is you'll have a score at the top saying are you fertile or are you infertile. Kind of a scale, it's from -1 to 1. If you're above zero to one, you're in the fertile category. Depending on how close you are to one ... The closer you are to one, the more confident we are that you're part of that fertile group. Same thing with the negatives. If you're in the negative category, you're infertile. The close you are to negative one, the more confident we are that you're part of that infertile group.

                                    You'll also see all the people that we've looked at. You'll see the histograms of the different populations of people that we've worked with. Below that, I think, Mark, this is what you were pointing out and you'd be interested in, we'll have this list of genes that we use to classify people. The genes will show you if your DNA methylation in that gene is normal or abnormal. We'll tell you a little bit about what those genes are important for.

                                    Many of the genes that we've looked at thus far that contribute to the score pretty significantly appear to be very important for fertility, maybe not surprisingly. I should say that's actually fairly comforting, because we approached this study that we did very differently. We basically said, "Look. We don't care what genes are involved. We're going to be very agnostic. We're just going to say, are there differences in DNA methylation between fertile and infertile men. We don't care where they are, and the most important differences, we'll look at those and we'll use that to create this algorithm for discriminating between the two populations."

                                    We had no idea. We didn't go in saying, "We're going to look at this gene and that gene." We didn't do that. We acted completely agnostic. We said, "What genes seem to be most important for that discriminating method?" It just so happened that many of these genes are an important for fertility. Then again, we'll talk more about this as we talk about our evaluation data, but many of the genes that we believed to be very important for making that discrimination were very important for fertility in very different ways.

                                    Everything from the acrosome reaction to oxidative stress to other developmental stuff, too. I look forward to sharing that in more detail.

PT:                             Yeah, I think that each of these genes is someone's career in science. I mean, this is a whole new thing and you're just doing the thirty thousand foot view. If there's any relevance to the whole field, then your study was incredible. The one published in Fertility and Sterility showing these precision and accuracy and the power of it. Now it looks like the prospect of study, can you say? Is it backing up what the retroactive study's doing? Does it look as good? Does it look as strong?

AH:                            Nice try. I can't said. I'd rather not now. Things are going well. I mean, things have gone very smoothly with the study. We've been very, very appreciative of the clinics we're working with, with Mark's group particularly down in Atlanta. They've been very, hugely contributive to what we're doing. It's been a huge effort amongst many clinics, and that's gone very smoothly, and we are very happy with how the results are coming in.

PT:                             You know, one of the most important things when you're introducing a brand-new test that's once in a generation, maybe, is it applicable to all patients in all geographic regions, right? You want it to be generalizable. That's really important that these specimens come from all over the country in groups and not just sort of LA or San Francisco or Colorado, but that's what you have is a very good distribution, wide distribution around the country of different samples. You could even do that analysis, but that is going to make it much more generalizable.

AH:                            Yeah, one thing we tried to do is make it both geographically quite diverse and I think it's very ethnically diverse as far as we can see. We also asked a number of questions of the patients too, about obviously their fertility history, but also general health history, exposure histories, environmental exposures, and then also wellbeing. We captured a lot of additional data about things that might affect the epigenome too. We look forward to linking a correlation between those data as well as the epigenome.

PT:                             We've gone really deep, and I guess I want to bring it back to, why would I order this test? You have a little box there, and it looks cute, like a Tiffany's box, but why would I order it? I was thinking, you know, as we've gone through the evolution of this product is, it's ordered if you can't explain why a couple can't conceive naturally. That would be one of the test questions. That would be B. I don't know if I'd order it to see why my semen analysis is abnormal, because I don't have that information. If the couple's having trouble for no apparent cause, unexplained infertility, that would be a reason. If a man, I might go out off route for this, if a man is smoking pot and cigarettes and has a terrible lifestyle and is failing to conceive and has a low sperm count, it may be able to explain functionally what is happening to his sperm because of lifestyle issues. Maybe that would an inspiration for men to change the toxicity profile for their life and clean it up a little bit. Men need numbers to do that. We don't know if that's going to help, but it's something that I'd think about.

                                    I would think about if you go through IVF and it doesn't work, and it might be characterized by poor embryo development, and if you don't embryos to transfer, you might consider it instead of a fragmentation rate. Sperm fragmentation rate has been around for ten or fifteen years, but I don't know if it's been all that valuable in that situation. I think for most of us, reproductive endocrinologists and reproductive urologists, it hasn't really been a go-to explanation for things in many cases, even though it would seem to be. This might be a more powerful tool for that, and I think it will probably explain more cases. Can you think of other reasons why a doctor or provider would order this test? Those were three reasons.

AH:                            I think much of what you said is correct. I think the other scenario is upfront, right? If you're doing an initial workup, you know as a couple, you come in, you do have a fertility problem. That's relatively easy to diagnose. You haven't been able to conceive over the course of a year. Understanding why is where it gets tricky. Understanding why can really inform the path of treatment. I think if you were to take this test right up at the beginning, you might understand a little bit more about what might be causing the infertility within the couple. Then you could use that information to guide the treatment and help counsel the patients as well.

                                    I think this is probably a test that would be ... In the beginning, I think it's going to be used for those hard to understand cases, so people that failed IUI several times, failed IVF several times. I think in the end, I think it's going to be very informative and useful when applied at the very beginning of the treatment process, when you're still doing the diagnostic workup. I think then you can have a full picture of what's happening both for the male and the female. That way, they can understand which treatment options they have.

PT:                             Right. There you might be able to streamline the care a little bit and avoid certain things that are probably not likely to work, and go to things that might work. It could relieve a lot of frustration. It could save money. Straightline care is always encouraged. It reduces morbidity in a sense of quality of life issues, because some couples go on for years and some of them can't move forward without a good explanation.

AH:                            Right.

PT:                             We're always scratching our heads. I'm going bald, scratching my head. We need something.

AH:                            You look like you have a full head of hair there. Yeah, that's what I've heard a lot of, both from the treating physicians and from the patients. It's very frustrating not to understand why this might be a problem for you, or what might be causing the infertility, particularly in cases of unexplained infertility, it sounds like it's very frustrating. We will have at least shed more light on that.

PT:                             Alan, I'm going to be giving a big Keynotes speech to the traditional Chinese medicine and alternative medicine complimentary medicine group in Vancouver next weekend in a fertility symposium basically mostly on epigenetics. Not a lot on this essay. The question is, could they order this too? Who can order this?

AH:                            I think what we're thinking of right now is that this would be a physician-ordered test. It needs to be an MD. That being said, if someone doing alternative forms of medicine is collaborating with someone that's an MD, then I think that's a possibility. Right now, what we're planning to do is provide this test to people working fertility clinics, so reproductive endocrinologists, urologists such as yourself, and OB/GYNs will understand this as well. I think that's a possibility as well. Primarily, people focused around fertility. I think as we move up and we move more broadly, I think it's other physicians that have an interest in understanding what might be at hand for patients suffering from infertility. I think primary care physicians could order if they want to. Right now, we're planning this to be a physician-ordered test.

PT:                             Okay.

AH:                            I think we've been rambling for nearly an hour. I know, Mark, you asked ...

PT:                             Some damn good questions!

AH:                            Really good questions. "Is epigenetic variation seen in bacteria?" Do bacteria have DNA methylations? Do they? Okay. Yeah, I don't know. I don't know the answer to that, to be honest. Can't speak any more to that.

PT:                             I think I want to thank everyone for listening to our breakfast conversation about a very sophisticated field in genetic medicine and genomics called epigenetics. Now we're applying it to potentially figure out whether sperm are fertile or not with the CEO of Episona, which is the epigenetics company that's the vanguard of offering this. I'll be available certainly over the weekend in Vancouver if you want to talk about, answer questions. My blog has something about epigenetics, it's a terrific blog on Google, and my site has a lot about infertility at theturekclinic.com. Alan, do you want to say anything in parting?

AH:                            Like Paul, I appreciate everyone taking the time to listen to us talk about this. We're excited about this test. I think hopefully it'll provide a lot of promise, a lot of hope and opportunity for people. Once again, if you're interested in following along as we finish this validation study, you can go to our website and sign up on our product page. We can send you updates as things move along. We'll certainly be updating people and we'll be talking about it at upcoming conferences as well.

PT:                             Episona.com is a very informative site. It's got good English language, non-scientific language to explain things.

AH:                            It's far less scientific than me. It's less science-y than me, right?

PT:                             Yeah, it's great. Episona.com is excellent, and you'll probably have the trends. There's a blog on there so you can keep in touch. This is a game-changer, everybody. We're really happy you joined us today. It's really a very new thing.

AH:                            Thanks, everybody. I really appreciate your time.

PT:                             We'll also be available on demand, this webinar.

AH:                            I think we'll post it on our mutual blogs, right?

PT:                             Yes.

AH:                            We'll definitely have it on ours.

PT:                             Thank you very much!

AH:                            Thank you so much, guys. Take care.


 

 



Featured Speakers

Alan Horsager PhD 

Alan_Horsager.jpg

Dr. Horsager is the President and CEO of Episona,  

a molecular information company developing 

personalized diagnostics using epigenetics.

 

Paul Turek MD, FACS, FRSM

      Paul_Turek.jpg       

Dr. Turek is an internationally renowned expert in male infertility

and men's sexual health. He is the founder and medical director

of The Turek Clinics, located in Beverly Hills and San Francisco.

                                                        

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