Methylation, Epigenetics and Beyond with Carolyn Ledowsky

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Methylation, Epigenetics and Beyond with Carolyn Ledowsky

In Australia, if you've heard about MTHFR chances are you've come across the work of Carolyn Ledowsky. Carolyn is the founder of MTHFR Support Australia and has long been a trailblazer for personalised medicine using genetic testing.

Today Carolyn shares how MTHFR SNPs first came on her radar and how it changed the way she practiced and opened up the world of interpreting genetic results to maximise clinical outcomes. 

Covered in this episode

[01:19] Welcoming Carolyn Ledowsky
[01:40] From MTHFR to something much bigger
[04:21] The environmental epigenetic impacts on methylation
[07:34] Transgenerational impacts
[08:48] Finding answers to fertility issues
[12:12] What happens when methylation goes awry?
[16:51] Gene expression and uncovering weaknesses
[28:48] Pay attention to B12 SNPs
[32:31] Making sense of genetic reports
[41:13] Making empowered health decisions, based on genes
[43:38] A healthy microbiome makes a difference
[46:48] Looking to the future: genetics and personalised medicine


Mark: Hi, and a big welcome today to Carolyn Ledowsky, the founder of MTHFR Support Australia, in my own local area in Sydney in downtown Neutral Bay. She's a Naturopath, Herbalist, and Nutritionist, Bachelor of Herbal Medicine, Naturopathy, and Advanced Diploma in Naturopathy. Welcome this morning, Carolyn. 

Carolyn: Thank you, Mark. It's great to be here. 

Mark: I've got to ask you, it's MTHFR Support, but it has become so much more than that hasn't it? The MTHFR was the origins, and then you've moved outwards. Tell me a bit about how you started and how it's progressed from that time.

Carolyn: That's a really good subject in itself. 

Mark: Yeah. 

Carolyn: My mentor at the time was actually Rachel Arthur. 

Mark: Right. 

Carolyn: And we used to love delving into all the, you know, the bloods and having a look at the finite, you know, minute details and what it might suggest. And I kept seeing all the time, half of my patients would have these irregular red cell folates, and I kept thinking, "What is this?" And no one could tell me, literally it was just no one. I had interviews with doctors, I talked to professors, I rang the labs, and said, "Why would this happen?" And they said, "Well, it's a great thing. They're obviously eating a lot of leafy green veggies." And I knew that that wasn't the case because the patients sitting in front of me we're really sick, they were really ill, and they didn't have a particularly good diet. So it just didn't sit true to me. And that's what led me into the world of MTHFR. 

Mark: Right. 

Carolyn: Because I was asked for an answer as to why some people would have a disturbed folate and others would not. And when I found that I saw the MTHFR gene, because I started testing with all my patients, I started to see this pattern, that those with the MTHFR gene improved significantly when I actually took them off folic acid.

Mark: Right. 

Carolyn: Got the folic acid out, and tried to regulate and optimise their Methylfolate, and they improved nine times out of ten. 

Mark: Right. When was this? 

Carolyn: This was in 2010, '11. 

Mark: Right. 

Carolyn: And so, Ben Lynch at the time had just started posting about MTHFR and so I became really obsessed. That then led me into the world of methylation, which then led me into all the other folate genes, the genes in the methionine cycle, the CBS, and the transsulfuration. And I just started to then see that there were other genes outside MTHFR that we're obviously just as relevant. But for me, the linchpin seemed to be the MTHFR. It seemed to be where a lot of the stuff started, and that's what led me into the other world of all the other genes. 

Mark: It's a long journey then, isn't it? Because once you're led down that path, it was kind of similar feeling for me. People have mentioned MTHFR before then and there was a pattern of, you know, often the homozygous variants of that, doctors paid attention to homocysteine, but that’s all we paid attention to. 

Carolyn: That’s right. 

Mark: And so, if a person’s homocysteine wasn’t raised, we had no interest in this whole area. But there is a whole other story behind that. That, the reason doctors paid attention was, people had heart attacks if their homocysteine went high and they were males. And they had heart attacks very young. And we doctors thought, “Well, you treat the homocysteine, people will get better.” And it wasn’t a homocysteine treatment, it was an entire Pandora’s Box that opened when you get into methylation. 

Carolyn: Yes, exactly. And even today Mark, there’s so many doctors that still say, you know, ten years down the track from that, nearly ten years, they’re still saying, “Well, if homocysteine is not elevated, it’s not relevant.” And I think we just have to change the status quo and say, “Well, you know what? That’s actually not right.” 

We know that methylation can be disturbed, irrespective of an MTHFR polymorphism. And I think that’s what I’m trying to get the word out with all practitioners, is that, your environment, much like methylation, irrespective of any genetic SNPs. And so, we have to be aware of that. 

Because, I mean even as simple as a candida, and an increase in formaldehyde and acetaldehyde, you can get disturbance in methylation, quite significantly. Because it’s inhibiting a major gene that’s using folate. Your methionine synthase. 

So, we’re so polluted, so many environmental toxins, and that’s what my Summit last year what about. How do we actually identify the key environmental factors that are stuffing up methylation? For want of a better word. 

Mark: Yeah. It is that predisposition. You can look at the genes, look at the SNPs, you can know all about that, but if you don’t know what puts the pressure on those, what makes them break, or what makes them fail? Missing the environment, nutrition, missing stress, missing all of those other factors. You may as well not know about the genes. The genes in isolation are not the answer here, are they?

Carolyn: No, no they’re not. And I think, you know, for me, when I’m doing my case histories, the first sort of, things I’m asking, particularly if I’m seeing MTHFR is, you know, what was mum doing when she was pregnant with you? Where did you live when you grew up? And I think these are really significant questions, that we need to realise, it actually goes back to, you know, fertilisation and what’s happening with the genetics and methylation when mum and dad are conceiving? This is huge, because methylation gets disturbed and then if you see MTHFR on top of it, and stress, you start to see these patterns emerge in family histories. 

Mark: It is involved in trans-generational changes too, isn’t it? 

Carolyn: Absolutely. 

Mark: So, the methylation, I think the dogma in medicine was always, “Oh well, sperm and ova will reset everything.” The histones and the methylation, it’s all cool, you start with a clean slate. But that’s not the truth anymore is it?

Carolyn: No. And in actual fact, what we’re seeing is these epigenetic effects can be trans-generational. So three, four generations. So it’s no longer what we do, it’s what our mums and dads and our grandparents did, that’s still affecting our offspring. And I think that, you know, it’s scary on the one hand, but on the other, we know just how important now, preconception is. And I have a huge preconception and fertility portion of my business. Because so many women with the MTHFR gene have terrible issues trying to conceive. 

Mark: Yeah. 

Carolyn: Whether it’s multiple miscarriage or failed IVF. And I can testify again and again and again, you get that methylation right, it’s absolutely fantastic. And successful. 

Mark: Yeah. I remember, and it wasn’t all that long ago, a few years ago, one of the fertility clinics grudgingly came to this idea that, “Oh, okay, methylation is a contributor to the relevant infertility.” What was the answer? 5mg of folic acid. That was it. There was no improvement in fertility. There’s no subtlety to the medical understanding of this. And so that infertility is a far more subtle process, and then the pregnancy, and the ongoing pregnancy, and the health of the foetus, and the ability to maintain progesterone, and to see you through the, first, you know, three to six to eight weeks of the pregnancy, they’re all critical factors based on simple biochemistry and genetic risk. 

So how do you do that? You bring people in who've been to the highest paid, you know, paid enormous amounts of money to get fertility advice, where they never mentioned any of these, and you come back to a clinic like yours with simple changes of diet, methylation, gene expression, and people get pregnant. It seems like it should be in the mainstream of medicine and it doesn't make it there.

Carolyn: Oh, you're so right, Mark. You're so right. And it's probably one of my greatest frustrations is that the standard protocol, as you said, in high-risk pregnancies, and usually they're all these people in the IVF clinics, is 5mg of folic acid, exactly what you said. There was a paper released even last week, to say that the five milligrams of folic acid is the wrong strategy. 

Mark: Yeah. 

Carolyn: And there's study after study showing that it decreases the methylation of sperm and egg. So why are we doing it? I mean, I can't believe that these IVF centres don't keep abreast with the research. It just seems crazy to me. 

Mark: I think there's a simpler explanation that there are high-cost procedures that can be done, and if it emerged that a very low-cost, simple mindset was able to get fertility up in say 30% or 40% of the people that would otherwise go to the high-cost options, then you've got your answer: follow the money. Fertility is the wild west of medicine right at the moment.

Carolyn: Oh gee, Mark, it's sad to think that. But look, you know what? I work with a fertility specialist from Genea, and she sends me a lot of her MTHFR patients and has done for a couple of years. 

Mark: Right. 

Carolyn: But she doesn't send them anymore because I never send them back because they fall pregnant. You know what I mean? So it's like, it's good, it's great that we're getting them pregnant, but I hate to think that you're right, but you may be to some degree.

Mark: I don't want to overstate it. I think people get into those high-tech things. But the business model of you know, $10,000 per cycle, if you found something that for $50, and a bit of education, made as much of a difference as your $10,000 per cycle, you wouldn't be in business very long. And so I think that it is subtly, and in the background, they disparage this as a trivial thing because to believe otherwise would be very difficult. 

Carolyn: Yeah, you're probably right. 

Mark: So can we go back a bit? Like, there's two things that I want to understand. First one, just getting a bit of a 101 on what is methylation? Like, the simple thing I remember back in the '90s, one-carbon metabolism became a big thing, and then it kind of faded. It wasn't called methylation, but shifting carbon and three hydrogen's around sounds like trivial work that goes on all the time. Tell us just a little bit, what does methylation do? A couple of examples, pull them out of what body functions are controlled by methylation. 

Carolyn: So essentially methyl groups act as master regulatory switches, and that's why they're so important. So the ability to turn proteins on and off, turn enzymes on and off, we rely on methylation to do that, specifically our methyl groups. We have essential enzymes within our biochemistry that can only work with methyls donating in methyl… like SAMe, donating it’s methyl group. 

Mark: Right. 

Carolyn: So for example, phosphatidylcholine, which we need for cellular membrane health. We need for memory, we need for myelination of nerves. Most, I would say, most MTHFR patients will have problems with one of those three. Because phosphatidylcholine is not being made. 

COMT, Catechol-O-Methyltransferase is our key enzyme that gets rid of toxic oestrogens. Again, people that have a lack of methylation have problems getting rid of their toxic oestrogen, so they'll have this imbalance between oestrogen and progesterone. 

Mark: Right. 

Carolyn: We have detoxification that is supported by methylation. We have creatine synthesis, so just having enough creatine for muscle development, essential. 

So these methyltransferases which run key biochemical pathways have to have these cute little methyl groups attaching to activate them and make them work better. Just being able to get rid of dopamine, you need your methyls. So, it's profound. 

Mark: It covers everywhere. I mean, it's also in an area that I deal with the chronic post-viral people, almost universally poor methylators. 

Carolyn: Yes. 

Mark: Methylation is an important part of preventing viruses from hijacking DNA and just perpetuating themselves as well. So it does strike me that in almost every aspect of our biochemistry, a failure, or a relative failure of methylation, is setting you up for failure in some other area. Or even just in the obvious areas, you know, as you said, the Catechol-O-Methyltransferase, the COMT are the specific areas that we kind of can pick up on testing. That's the tip of the iceberg. It percolates through the whole person, and you get whole person illnesses that are really difficult to disentangle. 

Carolyn: And I'm so glad you said that. Because that's exactly how I feel. 

Now, my gorgeous mentor, Rachel Arthur, will say to me "Carolyn, it's not all about methylation," but I actually think that it really is. It's the crux of why we have so many chronically ill patients. 

Mark: Yeah. 

Carolyn: Because our environment is disturbing it more, and more, and more. And if you look at the, just take the, you know, the idea about oestrogens. We have so many xenoestrogens in our environment, but it is putting that load on everybody, not just people with a COMT mutation. 

Mark: Yeah. However, the mutation is the weak spot. I tend to think of a lot of these SNPs not as... I mean, people do make the mistake of thinking of them as if they are mutation. They are variants, the SNPs the...

Carolyn: That's right.

Mark: The variation is a biological variation, it's like weak points that if you never put pressure on them, they don't break. 

Carolyn: Yes. 

Mark: But as soon as the pressure rises from environmental, nutritional stress or other sources, these are the weak spots, and they express themselves as illness that we see as practitioners. 

Carolyn: Yeah. And not all, polymorphisms are bad either.

Mark: No.

Carolyn: We adapt as we go as well. So even changes to the wild type can be positive, they don't all have to be negative. 

Mark: That's true. So then we go one layer even further then with the epigenetics of the expression of these genes. So there are modifications of not just the variants of the SNPs, and the genes, and the cells. But whether they're expressed or not expressed. Can you take us down that path a bit? You could have all the terrible genes, and if they've never expressed you seem to be able to go on with life. But if expression starts, and you find those weak spots and they're tested, what do you do as a practitioner when you discover that, and how do you manage that? What testing do you do? What kind of advice can you give there? 

Carolyn: What I will be always looking for in my first appointment, and I think the most important thing is looking at your timeline. So, in your questioning when you're talking about the patients, when did those fall ill? What was going on at the time? I think that gives you really good clues.

Mark: Yeah. 

Carolyn: And I think one of the best ones is looking at, for example, the PON gene, which helps detoxify pesticides and organophosphates. And I look at people who have had lots of problems with multiple chemical sensitivities, and I'll say to them often, you know, "When did this all start? What was going on in your life at the time?" And they'll invariably say, "Oh, well, you know, I was a young kid and I was probably, you know, in my primary school." And I'll say, you know, "And where did you live?" "Oh, we lived on a farm." "Oh, really? Okay. And what sort of crops, you know, we're in that area?" "Oh well, there was cotton crops beside it." "Okay. And was it aerial sprayed?" "Oh yes, it was aerial sprayed. There were a lot of...we used to see planes as kids, going over." So straight away you've now got your timeline, and you've got where the susceptibility and the environment interacted. 

Mark: Yeah. 

Carolyn: And then you can say, right. And I love talking biochemistry with my patients because if they can understand their susceptibility, and they can understand where the environment intersected with that, then the fixing of it, they become a lot more compliant because they understand why you're doing what you want to do. 

Mark: Yeah. 

Carolyn: And so, I will use a combination of very detailed case history, bloods, so what are the bloods? And I think the bloods are really insightful particularly if we can see elevated mean corpuscular volume and we know that perhaps B12 and folate are low. We can look at iron, and thyroid and put all that case together. And then say, "Okay. What are the symptoms? What other tests do I need to give me more information?" 

And sometimes you're testing will be to improve compliance with the patient to help them understand where they are. So for example, organic acids, in that case, again, with PON 1, can often take up an elevated oxalic acid. And so you can say to your patient, "What our next step is, is to take oxalates out of the diet, improve the working of this PON1 gene to make sure that you are clearing these toxins and we support obviously phase two to go with that. 

So, the testing will obviously depend on what you've discovered in that original appointment. And sometimes, you know, if histamine is elevated, you’ll want to be looking at gut function. And is there some sort of dysbiotic bacteria that's potentially creating an excess of histamine that they haven't got the ability, you know, to break down. Or they're taking some medication that's affecting the DAO enzyme, which again, is affecting histamine breakdown. 

Mark: Right. 

Carolyn: So this fact-finding mission that you're doing at your first appointment is really giving you a very clear path, I believe, in what area you need to test. 

Mark: Yeah. I absolutely support you there. The history is critical. Lots of doctors, lots of people think, "Oh, genetics and this testing is the shortcut to taking a history." It's meaningless without a history. You can have any gene you like, but if there is no history that fits the timeline, you don't have a real reason to go and pursue that as your primary outcome, the cause of your illness. So that work, there's no way around asking the questions, getting the timeline, looking at the person. And it is what so many of us forget, that technology kind of replaces the clinical history and that timeline. It's a great way of getting to the bottom of it. 

One other example, the kids that are put on antibiotics all the way through their youth, or they're on acne for antibiotics, or they're on Roaccutane which is Isotretinoin for acne management later. But there is a clear... Before this point, I was, well, after this point, at some timeline, things started to fall apart. And that's the Sherlock Holmes work, isn't it? 

Carolyn: Oh, absolutely. That's what I say to my practitioners in my mentoring groups, you know, you need to almost be a medical detective.

Mark: Yeah. 

Carolyn: Yes, if you're seeing a variant report and you can look at their susceptibility, that can actually give you good clues as to where you need to go down as far as your questioning goes. 

So if you're seeing a COMT homozygous, you may well ask if there's any family history of oestrogen metabolism issues. Fibroids fibrocystic breast, endometriosis, breast cancer, prostate cancer. And so, it can give you clues, but it can't be, I agree with you, it can't be, “You have this,” and this is one of the things that annoys me, is that people go into health food shops, or wherever it happens to be, and they say "Oh, you're homozygous for MTHFR, you need buckets of methylfolate." It's not the case. 

Mark: Yeah. That is the other one of my concerns is that these days people bring in an entire genetic 140-page document and slam it on the desk, we've taken the scanning it. But the question that they will often start a consultation with is, "I'm sick and these my genes. Tell me how to fix it?" As if they are somehow separated from their history, from the events that they have been through. And without knowing the stressors, without knowing how and where those genes may fail, it's great to have that information, but overload of information can sometimes make us blind to the bloody obvious. 

Carolyn: Yeah. And I think... You know, Mark, one of the things that I think the practitioners do need to understand is that, this is the way we are going. This is the direction that we, as practitioners, whether we like it or not, this is where we're going. 

And I think it's because the patient, and particularly those that are chronically ill, are not getting much support from the medical model. We do acute care particularly well, but we're floundering in people who have chronic health conditions. And back for me in 2010, this was consumer-driven. It was not practitioner-driven. It was consumer-driven. And I knew like literally within a week of rechanging and redirecting my business to MTHFR support, which my husband thought I'd lost my mind. He seriously said, "You have got to be kidding. This is too niche. Absolutely no one's going to know what the heck you're talking about." But literally within three months, my business had increased by 300%. And it's because people were looking for things outside the norm to try and explain why they might be so chronically ill. 

Mark: Yeah. 

Carolyn: And look, I don't mind at all people throwing that report on my desk. Because for me, I feel like I'm delighted that they interested enough in their health to want to do it. 

Mark: This is true.

Carolyn: And I absolutely love their questions, and I love educating them to understand how their body and their history intertwines with their genetics. 

Mark: So many of them have actually got that help from you being there with MTHFR Support Australia. It has a mission also of education of the public so that the awareness is there to ask the right questions.

Carolyn: Yes. 

Mark: Rather than just to say, "I have a gene that may or may not be fixable. Please, you know, what do I do for it?" The subtleties and the awareness that diet, nutrition, lifestyle, stress reduction, that doesn't come by knowing the genes, that comes by knowing practitioners who know how to work with those genes, and how to escape from their, kind of, their destiny.

Carolyn: Yes. And you said before about expression, and I do think stress, just whether it be physical stress or mental stress, is really one of our key triggers. Because methylation is disturbed hugely because we use more methyl groups in our stress response. 

Mark: Right. 

Carolyn: And so, you know, just asking people about their stress, and when things happened, and when they became ill, you'll usually find that there's some sort stressor that happened at the time. And if then they have say a homozygous MTHFR polymorphism, then their ability to cope with that stress is worse than the person beside them. Because they just don't have what it takes to create enough methyls to support the stress response. 

Mark: Yes. 

Carolyn: And, you know, I often say adrenal fatigue, there's no such thing. Which I think is very controversial in a way. 

But what I’ve seen Mark, which is quite amazing, is if someone comes in and you would classically look at them and go, "You know what? You would be the typical adrenal fatigue person." But if I get their methylation right, and they've got the right amount of nutrients, and the right amount of methylfolate, literally overnight, they'll come back in and go, "What stress?" Because their ability to cope with stress, has just been completely eroded. They don't have a problem anymore. They cope with stress like anyone else would. 

So, it made me think well, maybe that's all adrenal fatigue is, is this inability to control the stress response because of a lack of methylation. 

Mark: Maybe the mainstream is starting to join you in that. But I think the concept of adrenal stress, there's clearly the medical, you know, the adrenals fail and you get Addison's disease. There's clearly disease states of the adrenals. But the adrenals are the classic adaptive organism. They will close down at certain times, they go back to a hibernating state relatively regularly when they're unable to do anything else. 

And so adrenals when they fail, fail gracefully. We interpret it as adrenal stress, but it, in fact, is usually a metabolic stress and the adrenals are choosing the best path they can possibly work out to get through that, assuming it's a winter and in six months time will be fine, and that six months, that winter never ends and they never get back to fine. People stay in that chronic state of depressed health where every stressor now plays out dramatically on their health. 

Carolyn: Yes, exactly. 

Mark: It's a great area because I agree with you, managing their methylation at that point does allow them to resume function. I mean, we doctors have a favourite thing of jabbing people with high dose vitamin B12. There's about 20% or 30% of people who spring back to life with nothing more than a B12 jab, and we never understood why. It was done for the last 50 years. And I think we're getting some concepts that it's not for everybody, but for the right person, you kind of give a push start to the adrenals. And they go, "Oh, I've never noticed that before," and they come back to life in that same way. 

Carolyn: And I pay very close attention to the B12 SNPs. Because I really do believe there's significant information we can gain from that. 

Mark: Yeah. 

Carolyn: And I'm actually about to do a big presentation on B12 because for me, it's so important. And my father-in-law was a doctor, and his standard protocol was, you know, anyone over the age of 50 he gave them a B12 shot, as you said. And that's... I'm going back sort of 50 years, and he was considered to be, you know, quite ahead of his time. 

But it is so important. I think B12 is one of our key nutrients that we're just missing. And we go off the bloods and we go off, you know, testing, but it's the one place I really think we need to be going off our signs and symptoms. 

Mark: I think you're right, I mean, one thing that is true is if... livers are our major source of B12 storage, when there's any inflammatory gut issues and the liver is under load, the B12 initially gets liberated from liver, and you usually have high B12 levels that is unusable by the tissue. And so if you just simply measure the B12 you think all that's fine how could anyone need anything. Without asking the question now why would it be that high in a perfectly normal, healthy person? 

So I think you know, you can misread red cell folate, as you said before, we can misread a whole lot of those nutrients because we're watching the blood and the saying, that's okay. And that's not without a deeper understanding of biochemistry. 

Carolyn: Yes. And I've got some patients that have been diagnosed with MS, who I look at their genetic susceptibility to having low B12…

Mark: Yes. 

Carolyn: And when I really super load the B12, their MS symptoms pretty well disappear, in most cases. So I think... 

Mark: Isn't it fascinating?

Carolyn: Yeah. And I really think in some instances, where you're seeing this genetic susceptibility to B12 and they've been diagnosed with, you know, conditions like MS and etc, we can make significant difference. And I think a lot of the time you know, one of my patients said, "Well, I question if I have MS now, because my symptoms have you know, 80% gone." But I think the 20% residual was, you know, I guess a long term B12 deficiency and they've got, you know, irreversible neurological damage. 

So I think it's interesting and I love the insight that we can get by looking at the research, what it's telling us, and what I also love Mark is that because this is such an emerging science, everyday we're seeing patterns of SNPs they're having an effect on disease states. We're seeing different genes being identified, different combinations of genes being identified, and I find it really exciting. It just keeps me up and going every day. 

Mark: Carolyn is it exciting, but it's also confusing. I mean you're living in that area, living and breathing it, and I think you've got the best grasp of it. But for the average practitioner, we sit there thinking, we know there's something wrong, every week, there's another 40 units of information that we struggle to digest. How is it even possible? How do you stitch the diverse combinations, how do you get all that... for me is relatively incomprehensible, how do you turn it into advice for the person in front of you? What's your technique of grabbing the data, the genetics, the SNPs, the organic acids. How do you bring that together for the person in front of you without just going into overload and confusion? 

Carolyn: For the patient or the practitioner?

Mark: I'm talking for us, as practitioners. Your depth of involvement in this gives you special powers, like superpowers. But for those of us who are kind of dealing with say the chronic fatiguers, the autistic children… That, we get presentations, and there are so many possibilities in the genetics, that personalised medicine is sometimes very threatening to us, you know. How do we change our mindset? And how do we incorporate what is rapidly changing and vast information, from genetics, from SNPs? How do we turn that into sensible advice for a patient without becoming just overwhelmed and saying, I will pay no attention to it at all? 

Carolyn: Yeah, that's a really good question. 

I actually set up a practitioner membership group, so this is what we go through on a monthly basis. We meet on, you know, Facebook twice a week, twice a month so that we can actually start talking about it and doing... So I do case histories, and basically what I say to the practitioner is, there are very simple things that you need to do. 

First of all, you do your timeline, you do a really good case history, and then you put the basic supporting nutrients in while you discover what you need to do. So, if you are looking at... Let's face it, probably the most important thing I'd say now is liver detoxification. Because our livers are inundated every second of every day. So I would say start with the basics. And we know that there's really good combinations of genes that we can start to look at that gives us a clue as to where we need to push our patients in the direction with nutritional advice, dietary advice, and lifestyle advice. 

So, for example, if you see combinations of CYP1B1 and COMT, then you're going to definitely improve oestrogen metabolism as one of your first steps. Improve glucuronidation, improve their ability to get rid of toxic oestrogens, and from a lifestyle point of view, counsel them in getting rid of xenoestrogens out of their environment, cutting out any endocrine disrupting hormones in personal care products. 

So it doesn't need to be complicated, Mark. I think the biggest issue for practitioners when they're new to this is you've got, even if you look at any genetic report, there's a multitude of stuff. 

Mark: Yeah. 

Carolyn: And so, for me, B12, I think is really significant and I definitely look at that first. Because without B12 pretty well methylation shuts down. So I look at are they vegetarian, are they vegans, you know, have they got problems with low hydrochloric acid? So I will evaluate those first. 

And then you just look at their timeline. As you said before, where's their susceptibility? That's what you should be concentrating on first. Plugging up that pothole of susceptibility and undoing what many years of, I guess, this susceptibility has potentially caused in a way of, either multiple chemical sensitivity, or oestrogen metabolism. 

So it doesn't need to be complicated. I do get why it is overwhelming. But I think the danger is we can be too clinical in presentations, and what I try and do is always give a clinical application. If you see this, I want you to be thinking about this. 

Mark: Right. 

Carolyn: And that's what we need to be helping practitioners with, really getting the initial connection, the initial important susceptibilities. And then what do we do in clinic and how do we explain that to our patients? I'm going to do it. Because I’m very basic with how I explain this to my patients. 

I basically say, “Right, you’ve got some genetics here, and from the timelines, I can see that this all started when you were living on the farm. So I suspect what was happening at the time, is that your ability to get rid of those pesticides that you were exposed on has put additional pressure on that liver to cope. You’ve also got a glutathione deletion gene, which means this PON 1 piggy-backs with your glutathione. So you have a double-whammy issue. So, our first port of call has got to be to improve that.”

Mark: Okay. 

Carolyn: And then they go, “Oh, okay, that’s great.” And then the next appointment, we’ll talk about something else. But usually at that first appointment, it’s giving them a bit of a background, giving them a diet and lifestyle that I want them to follow, and then just start putting in key nutrients. So, if B12 is low, I’ll start putting in B12. And then you can progress. 

Mark: Do you look just for clinical improvement, or do you use say, organic acids, do you use other biomarkers to assess how a particular intervention is going?

Carolyn: Oh, definitely. 

Mark: Okay, so what else do you use?

Carolyn: So I pretty well always do an organic acids, I find that that is a really lovely place to start. Because you’re looking at bacterial markers. I really want to see whether yeast is a problem. Because if arabinos is elevated, then I’m a bit suspicious that methionine synthase may be having a problem. 

I also look at.. you then get glutathione status, a lot of time you’re getting MMA, you’re getting all of your key nutrients, that are really important for, at least initially. Because if you’ve got a lot of nutritional deficiencies, you’ve got to address those first, haven’t you?

Mark: Yeah. 

Carolyn: And that is probably your most important thing. Balance what is out of whack and then… Because if you’ve got no zinc and no hydrochloric acid, you’re obviously going to have a problem. 

Mark: Yeah. 

Carolyn: And if you’ve got yeast, you’ve got to address it. I mean we’ve always talked about gut, gut, gut. But the more I get into methylation, the more I understand that disturbances in bacteria are going to have profound effects on methylation. And whether it’s a histamine problem, or an oxalate problem, or a yeast problem, it doesn’t matter, we’ve still got to address it. 

So organic acids is one of my favorites. Love doing it. I will then do oestrogen metabolism if I’m seeing issues with COMT and CYP1B1 and I know there’s a family history of oestrogen dominant conditions. And, if I need to, I’ll do gut, I’ll do a stool test, if I think I need to add that on. But I pretty-well would start with an organic acid, if money was an issue, that would be my go-to. 

Mark: And so, the urinary sterols are a part of your routine investigation, or only when you’ve got that specific set of genetic predispositions? Do you go down the sterol pathway all the time? 

Carolyn: No, I don’t. If they don’t have a family history of oestrogen dominance, if they don’t have their own history of oestrogen dominance and if I’ve… however, if I see CYP1B1 and/or glucuronidation genes, and COMT, I’m going to do it. Yes I am. Because even though they may not have symptoms, if they’ve got an incredibly elevated 4-hydroxy, I need to deal with that.

Mark: You have the job of preventing their future health problems, not just the current ones, don't you?

Carolyn: Absolutely. And Mark, my family history is really interesting. Because I ended up with endometriosis at 22 which is quite young. And I knew that with my girls, I didn't want them to go there. And so for me, being able to give them things, you know, as teenagers, indole-3’s and calcium d-glucarate, and really help that liver get rid of those, has been fantastic. Because I'm sure if I hadn't have done it, they would have ended up the same place as me. And I find this incredibly powerful. 

Mark: It is, to be able to use your own history, a parent informing the entire family history, or a child sometimes. Children often are the place where the genetics become apparent, and you can make sense of other family members and even relatively distant members, it's a very powerful technique beyond the individual involved as well. 

Carolyn: Absolutely. Yes, definitely. 

Mark: The tragic thing is often, you know, the mother and the grandmother's breast cancers, no doctor thinks that we can do anything about it. But the understanding of the predispositions, not just BRCA1, BRCA2, but the understanding of these dispositions of the toxic oestrogens, and what can be done about it. I find one of the tragedies of medicine, we wait for the cancer, and then do something that should have been done 30 years before, as you've done with your children. 

Carolyn: And Mark, I I think the whole Angelina Jolie thing was just so unnecessary. Because what it basically said to everybody is, if you've got the BRCA gene, you're going to end up with ovarian cancer or breast cancer. And it's not right. As you know, and we've said many times in this interview, the environment plays such a huge part. 

Mark: Yeah. 

Carolyn: And so just because your mother or your grandmother had breast cancer, it does not mean that you will get it. 

Mark: Yeah. 

Carolyn: It means you might have a susceptibility, and so we can do really powerful stuff to prevent that. And I agree with you, I think it's a shame that every GP and every specialist out there doesn't understand that and go, "Okay, we're going to make sure you don't end up that way."

Mark: One big question. I mean, I've discovered this, doctors always come late to the party that the naturopaths knew for decades or even 100 years before. 

But it does strike me that the gut, the microbiome, the liver, the kind of unit of function, has been so disregarded buy medicine, and is so critical to whether our genes are expressed and in what way, and how we detoxify. To me, it almost seems routine that if the gut is managed, 50% of predicted risk, probably disappears with nothing more than really, really good look-up management. Do you have a similar experience, or is that a little bit on the soft side? 

Carolyn: No, I really do agree with you. I mean, think about, even stress. Stress really affects gut function. Because you're decreasing hydrochloric acid in the first point, and you're disturbing all your neurotransmitters, your serotonin, your cortisol and everything else is affecting gut function. And we know that there is such a huge interaction between the gut and brain. 

I think the biggest issue we've got is parents not understanding a lot of the time that, A) massive doses of antibiotics regularly is obviously having a profound impact on everybody's gut. But even things like, you know, now it's regulation, in a lot of schools, that you have to use that stupid looking antibacterial wash before you walk in. I mean, we are... And we're not allowing our kids to play, so the diversity of the gut is being affected. 

Mark: Yes. 

Carolyn: And I think it's a multitude of things that are really affecting gut function. And we all know that if gut is good, the chances of other things being then affected are much less.

Mark: Yeah. You bring your candida, you bring other things back under control, the Clostridium settled down. And a lot of the signaling seems to be settled, a lot of the inflammation on the gut and the gut permeability. If you get control of those, they seem very powerful moderators of the genetic predispositions that we may carry. 

Carolyn: Incredibly.

Mark: It is.

Carolyn: And, you know, with all the work on the microbiome, and, you know, medicine now discovering how important it is, you're right. It's probably 100 years after most naturopaths, and nutritionists have, you know, realised it, but at least they're getting there. 

And I think that it's only going to open up to the average GP and doctors out there that it is important, and we need to be thinking about antibiotic use and antibacterial use, I guess, is really important. 

Mark: We have 150 years of making every microbe our enemy, only to find out that the vast, vast, vast majority were the thing separating us from ill health the whole time. 

Carolyn: Yes. 

Mark: So getting a new relationship with our bugs it seems to be one thing and it's happening slowly in medicine, but at least is happening. 

On that, where do you see the future? Like, you've been at this for around about the last eight years, is there a direction emerging? Do you see anything of doctors awakening to what is going on with say, methylation, gut, gene expression? Is this still a hard slog? Do you see the future as opening up a little with medicine, genetics predispositions actually talk the same language? 

Carolyn: Right now, it's a very hard slog.

Mark: Is it?

Carolyn: And I have a lot of my patients that end up saying "Look you know what? This discussion is just too hard. I'm getting fought on every single front. And quite frankly, I'm over it, so I'm just not going to say anything." And what we actually find is that they are pretty well healthy, going forward, and then they just go to the doctor, you know, if they need something. 

Mark: Yeah. 

Carolyn: So essentially, no. I don't feel like the medical world is coming to the party at all. I think you've definitely got your researchers that are saying, "Hey, the genetic susceptibility is a real thing, and we need to be taking note of it." But I think the average medical professional is saying, "Oh, this is all hoo-ha, and really, we can't do anything about it." 

Mark: Yeah. We have to break that habit, don't we?

Carolyn: We do. And I think where we're going, though...and one of the reasons why, you know, integrative doctors are so busy and so flat out, and I'm really pleased that the integrative doctors are really excited about what I'm teaching, and I've just come back from Chicago to teach 150 doctors in the U.S. on how to get involved with methylation. And I'll tell you what, the excitement in the room was so good. They were so interested, they were so into it, and they just want to learn this stuff. Because I think they to really see that this is going to make huge inroads into their practice and how they improve the health of their patients. 

But outside the integrative world? It's not happening. So where will we be in 10 years? I think in 10 years time, every patient will be at some point coming in and saying "Here are my genes, I'm really not well. What do I need to do?" And I think the medical world will come into this sphere because they'll have to. Because they will be completely left behind if they don't. 

Mark: There's a lot of work to do on the computing side of that. Doctors, they love to see results on a piece of paper and treat diseases where there's big asterisks. And we are over at genome one, looking at when whole of genome testing becomes a $200 test. When you can actually nominate every single gene and variant and every SNP. Then what you next need is the computing power to say, well, it's not just the things that cause disease, it's those predispositions. How do you put the greys together to say what's turning black and what's turning white? 

And that's a lot of technical work. I suspect the science and the biology have to go hand in hand. And the doctors, often, are a decade behind or two decades behind, for when the solution is fixed and a piece of paper comes out, says, consider the following. 

Carolyn: Yep. 

Mark: Can you see us being there in 10 years time where a summarised genetic report changes the way a doctor views their job? You know, I can prevent something, I can help this person, I don't have to give a drug to try and change them to some way that I want them to be? 

Carolyn: Yes, I do actually.

Mark: You do.

Carolyn: I do feel like that's where we're going. Again, it's going to take interpretation to some degree, but I do think it will be, “Here's this person genetic susceptibility, I've plugged their family history,”

Mark: Yes, yes!

Carolyn: “And therefore here is the key gene that I really need to keep my eye on and perhaps here's the nutrients that support it.” That's where I think it would go because then it makes it more relevant to the average GP. 

Mark: Yeah. It's clinically relevant, it fits with what we understand, and it gives us new tools to do good, rather than wait for harm to happen and then try and patch it up at the end. I think there is a turning point, and I'm hoping that it's not 10 years. 

I want to thank you very much for the talk and to say congratulations. The bringing of awareness, not just in the area of methylation, but in the area of susceptibilities. You're doing a marvelous job. You turn up everywhere. Everybody has heard about you. And for something that started only eight years ago, that is magic all by itself. 

So, you know, I honour you, you, Ben Lynch, others, Elizma. There's a group that are taking this forward. And you will be attacked, but I honour you for the work that you're doing. It's necessary and we have to change that direction. So thank you. 

Carolyn: Thank you, Mark. It's been great talking to you. I just love it. And as you can probably tell, I get so excited about it because it's just such a powerful tool that we've got to be able to put all this together and see really amazing clinical changes. There's nothing more exciting, as a practitioner, to have someone that's been sick for 30 or 40 years, to be able to see a difference in a few months, is not only so exciting for the patient, but also I think to the practitioner. 

Mark: It's so rewarding for the practitioner. It makes me feel that our medical education, not wasted, we're good at fixing diseases, as you said, patching people up. But it's an unsatisfying profession when you know we should have done better. And what you've told us today, I think is, you know, part of that story. How do we learn the tools of doing better preserving and maintaining health, and not allowing these diseases to progress? 

Carolyn, thank you so much for joining us on FX Omics today. 

Carolyn: Thank you


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Carolyn Ledowsky

Carolyn Ledowsky is the founder of MTHFR Support Australia. She is a naturopath, herbalist and nutritionist who has a Bachelor of Herbal Medicine, Bachelor of Naturopathy, Advanced Diploma of Naturopathy and Diploma of Nutrition. She has also studied courses in genetics at Duke University (Genetics and Evolution) and The University of Maryland (Genes and the Human condition – from behaviour to biotechnology) . 

Carolyn’s debut into the world of MTHFR commenced when she noticed that so many of her patients had high red cell folate levels in their blood work. She embarked on a mission to discover the significance of this and this led her to the MTHFR gene. Carolyn now sees chronically ill patients who have searched, sometimes for decades, to find the reason behind their ill health. Most of her patients have MTHFR mutations and/or associated methylation disturbances. These disturbances then go on to affect thyroid, adrenals, hormones, detoxification and energy pathways and often neurotransmitters. Her expertise is in understanding these highly complex biochemical pathways. Carolyn’s strength lies in her ability to reveal layers of dysfunction and not give up until results are seen.