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A Closer Look at COMT and CBS Genes with Annalies Corse

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A Closer look at COMT and CBS Genes with Annalies Corse

The accessibility of genetic testing is on the rise, with a range of testing services now available world-wide.

Although our genes are the scaffold from which we are fundamentally built, genes are not as black and white as we're led to believe. They're simply one layer of the onion, or one piece of a very large puzzle and by all accounts, this area of science is still quite new.

The genes which encode for two important enzymes, catechol-O-methyltransferase (COMT) and cystathionine beta-synthase (CBS) are vital for healthy catecholamine, catechol estrogens, several drugs and homocysteine metabolism. They have been implicated in a range of health issues ranging from decreased fertility and pre-eclampsia to behaviour and mood issues, even cancer.

Today we are joined by medical scientist and naturopath, Annalies Corse, to tackle not only what the clinical relevance of these genes are, but Annalies and Andrew dive deep into the ethics and relevance of SNP testing and whether it alters the course of therapeutic interventions. 

Covered in this episode

[00:33] Welcoming back Annalies Corse
[01:25] Firstly, what are CBS and COMT genes?
[05:56] Understanding COMT SNPs
[08:24] Understanding CBS SNPs
[09:48] We have to remember, this science is new
[11:40] Where are these SNPs clinically relevant?
[23:55] How do patient's respond to testing?
[27:22] How often does a genetic test change treatments?
[34:15] Epigenetics and moving away from evolutionary diets
[43:22] The practicalities of diets and supplementation
[49:37] Quality and ethical considerations

Andrew: This is FX Medicine, I'm Andrew Whitfield-Cook. Joining us on the line again today is Annalies Corse. She's a medical scientist, lecturer, naturopath, and author who's based in Sydney. Annalise has worked as a medical scientist at Charles Sturt University, the Australian Institute of Sport, Australian Biologics, and both public and private hospital pathology laboratories. 

Annalies has been a practicing naturopath and lecturer since 2008. Annalies is a past board member of the NHAA and is on the Scientific Advisory Board for the Mindd Foundation. Most recently, Annalies has contributed to Leah Hechtman's textbook called "Clinical Naturopathic Medicine," due for publication in 2018. Welcome back to FX Medicine, Annalies. How are you? 
Annalies: I'm really well, Andrew. Thank you for having me again. 
Andrew: My absolute pleasure. And today, we're going to be diving into COMT and CBS genes. So I will ask you to lead me in this because I am not an expert. Firstly, what are we talking about here with COMT and CBS genes? 
Annalies: So most of the practitioners and students listening may have heard of them as being related to genes in our, not necessarily the methylation pathway, but biochemical pathway associated with methylation. 

Now, the problem is, is that these days, with all the sequencing tools that have been developing after the Human Genome Project, because it's now faster and cheaper to test all of these things going on in our DNA, it's blurred the lines with some of our terminology. So the definitions of mutations around COMT and CBS or polymorphisms associated with COMT and CBS is becoming problematic. Not just for scientists because there's a huge debate in the medical literature about what term to use, but also for clinicians in practice. We need to know, well, is this something I need to test for? Is this something I need to treat? These two particular enzymes or pathways, when I was studying naturopathy, we didn't cover them. There was simply not a single lecture even on this. Even in our advanced nutritional biochemistry subjects. 
So COMT is a gene for an enzyme known as catechol-O-methyltransferase. And it's particularly involved in the inactivation of the catecholamines and some neurotransmitters. So things like adrenaline, noradrenaline, and dopamine. It's also involved in the degradation of the catechol estrogen. So when we're degrading our estrogens in both the male and the female body, they need to be degraded in the liver, and COMT is involved in that, as well. It's also involved in the degradation of bioflavonoids, as well.  
So it’s, as an enzyme, or as a gene coding for a protein product, in this case, an enzyme, it's part of that group of methyltransferase enzymes. Because what it's doing is it's transferring methyl groups. And this is why, as an enzyme, it's linked with methylation pathways. Because it's taking methyl groups from that methionine cycle, particularly from SAMe, S-Adenosylmethionine, that people would remember from that methionine cycle. And it's taking those methyl groups in order to fulfill its role as a methyl donor and a degrader of catecholamines, catechol estrogens. 
The second one that we're going to be talking about today is cystathionine beta synthase. Again, there's a gene for this, the CBS gene, that codes for the CBS enzyme. Now, this particular enzyme, again, is involved in some of these methylation pathways or biochemical pathways that are, sort of, orbiting around that methylation-methionine cycle that everyone knows as being the most famous one. 

So CBS is actually the first enzyme or the step one enzyme in the transsulfuration pathway. So you might remember that one…

Andrew: Ahh, right. 

Annalies: As the homocysteine down to cystathionine. 

Andrew: Yep. 

Annalies: And this is a gateway. This is an alternative pathway to methionine resynthesis, and it's the only route for homocysteine elimination. 

So the downstream products of this pathway include our sulfates, taurine, glutathione, so endogenous antioxidant synthesis, and ammonia. So I guess a lot of listeners will have done a lot of maybe, post-graduate study around, you know, MTHFR and those types of SNPs. These ones are starting to be mentioned, but they're still quite new. So in a nutshell, that's what they are. 
Andrew: Can I just ask, with regards to COMT, we always talk about it with regards to, you know, estrogen metabolism and other neurotransmitter metabolism. What's the active site? Is it in the liver only or is it elsewhere in the body, as well? 
Annalies: No, there's two. There's actually... There's two types of COMT that are synthesised. There's one which is the soluble form and then there's one that's known as membrane-bound COMT. 

Now, the soluble form has more of an activity on...or it predominates in the liver, the kidneys, and the GIT. So this is the one that's more associated with things like methoxy-estrogens and catechol estrogens, and the degradation of estrogens. 

Andrew: Yep. 

Annalies: The membrane-bound COMT is the major species in the brain. So they're slightly different in terms of their amino acid structure, and they have different sites and, therefore, different receptors in different parts of the body. But they would be… if we were to actually look at the amino acid sequence, they would be extremely similar with only subtle changes there to distinguish between the two types. 
Andrew: Okay, but when you're talking about a SNP, wouldn't you then be looking at a SNP that's relevant for either soluble or membrane-bound? 
Annalies: Yes. So there's different ones. There are many, many SNPs associated with COMT. It's not just one. There are some that are more common and some that are studied more. And those SNPs usually involve a different, or substitution, of valine to methionine. And usually, you'll see that occurring in both the soluble and the membrane-bound. 

Andrew: Ahh, okay. 

Annalies: So it can occur in both. That substitution might actually occur in different amounts in the S-COMT, so the soluble COMT, and the slightly different numbers of substitutions in the membrane-bound COMT, or position. It might even be position. So the valine might be...the methionine might be replacing the valine at a specific position along that peptide chain, and it differs between the S-COMT and the membrane-bound COMT, if that makes sense. 
Andrew: Okay. And what about the CBS gene? 
Annalies: Okay. So with the CBS gene, again, there are many SNPs that have been, I guess, discovered or associated with CBS. Again, this is one where we don't really understand just how clinically significant the SNP is. 

I guess the most important thing with this one is that it is, again, it's a very, very subtle change where you have a substitution of one amino acid to another. The interesting thing with CBS and where it differs a little bit to COMT is that the SNPs seem to either up-regulate or down-regulate the CBS activity. And some SNPs are associated with an up-regulation and some are associated with down-regulation. And that can also be manipulated by what's going on elsewhere in those methylation cycles. 

So I guess, if the question is how significant are the changes within an SNP, the changes are very, very subtle. 
Andrew: Does that lead to the, sort of, questionable significance of the CBS gene in a clinical situation? 
Annalies: Yeah, absolutely, because, I guess, the problem with all of this is, it's all very, very new. Even though these SNPs have been known about for a few decades now, we're still in the infancy with the research with regard to what does this actually mean in a clinical situation? 

A lot of SNPs, not just in COMT and CBS, but elsewhere in the wider genome, they might not have any clinical significance, whatsoever. It may just mean that you metabolise a particular drug differently, or you metabolise a particular hormone differently, or you might have an increased resilience to a particular set of pathology. 

So SNPs, in general, are not always associated with doom and gloom in terms of pathophysiology. And, I guess, the problem we now have is that SNPs are, sort of, almost being associated with problems, but that's not always the case. 
Andrew: No. 
Annalies: They are subtle changes. You would never just want to associate SNPs with disease. It may just mean variance. And that's the thing with the genome. All humans are different. And, you know, when you look at the Human Genome Project and its significance and its findings, you know, greater than 95% of human DNA between different individuals was the same. 

The difference is in that five or less percent, and that's often where a lot of these SNPs are, and that's what makes us different. It doesn't necessarily make us, these genetic mutants that are going around, having an increased susceptibility to terrible diseases. That's not always the case. 
Andrew: What are the conditions for which these SNPs are clinically relevant then? 
Annalies: Okay. Well, there's really broad categories. And first off of the bat is probably a bit more evidence for conditions associated with COMT than there is for CBS in general. 

So CBS, if we discuss that one first, that one seems to be more associated with fertility risks. There's a group of genes... CBS is one of the genes involved in folate metabolism. So I tend to think of it as this ‘less famous cousin’ of the MTFHR gene and the SNP associated with that. 

So there are fertility risks in terms of increased risk of miscarriage, recurrent miscarriage. When a pregnancy is established, there is often an increased risk of pre-eclampsia. And generally, folate metabolism, in general. So the ability to activate folate for the growth and embryology of the growing baby. That does depend on this CBS gene. So CBS and fertility, does seem to be a fairly well-established like. 
Again, somebody would probably need to be homozygous for that SNP. So they would have had to inherit two copies of the SNP, one from their mother and one from their father. That is going to result in an increased likelihood that that SNP is going to be problematic as opposed to someone who's got a heterozygous status for the CBS SNP. 

Studies try to quantify how much of the increased or decreased enzyme activity there is based on heterozygosity versus homozygosity. It's a tricky thing to do. That's not established very well in the literature yet. 
Andrew: I guess with things like, certainly, fertility, you tend to hear of people having recurrent issues with fertility before they actually delve into the reasons why there's issues for fertility. But pre-eclampsia, I mean, that can be a really devastating condition. We're talking about safety of the mother here and, indeed, the baby. Where do you think the relevance is for pre-testing and/or, you know, testing, if there's an issue, you know, testing for subsequent pregnancies, for instance? 
Annalies: Well, I think, first and foremost, when someone is pregnant and they're in those early days, usually with her GP or her obstetrician, there's a lot of questions around family history. So they're asking about diabetes, did you mother have pre-eclampsia, clots, all of the things that can be associated with negative outcomes in pregnancy? 

So usually, things are questioned in those early stages of the pregnancy. But that doesn't really seem to address the problem. Because from our point of view, in naturopathic medicine, there's something that we could be doing beforehand in preconception care. So to my mind, we would need to be, at least, thinking about this in the pre-conception phase. And we all know that preconception is not a part of primary medical care. 
Andrew: No. 
Annalies: It's something from naturopathic medicine. So it's up to naturopaths, I think, and nutritionists and herbalists or whoever it is that's doing the preconception work, to identify with the lady who is thinking of conceiving, "Well, what… did your mother have pre-eclampsia? Do you have any sisters? Did they have pre-eclampsia? What about your grandmother?" And if you're getting strong indications of a family history, then it might be worth thinking about things like MTHFR, CBS, SNPs. 

Whether or not you test? That might be something that you decide to do or you don't decide to do, but it's definitely a question. And I think, for us, because we're working in the world of preconception, that's when it should be coming up. Because they're not really going to be getting these kinds of questions from GPs or obstetricians. 
Andrew: Look, I've got to ask the question here, though. Like, I'm always concerned about over-testing. But I'm also concerned about under-testing, where it's relevant. And where you can pick up a potentially serious condition and do something about it very early, rather than waiting till the horse has bolted. 

So when we're not talking about something like CBS gene, and you spoke about risk factors in the mother and siblings, what if they're heterozygous, though? And this patient is homozygous only by way of being the, you know, what is it, nine to three to three to one, the unlucky person that gets both chromosomes. 
Annalies: Yeah, yeah. So they're homozygous for the SNP. 

Andrew: Yeah, yeah. 

Annalies: Yeah, look. So look. I think if there's any family history and it's a strong family history, say the woman's mother, and if she had strong clinical conditions in her own pregnancy, such as hospitalisation from pre-eclampsia, diagnosed pre-eclampsia, embolus formation during her pregnancy, they are serious conditions. 

Andrew: Yeah. 

Annalies: They are serious. And they can lead to very, very, maybe even fatal outcomes for the mother, not so much in Australia these days. But worldwide. This is why women don't survive pregnancy in certain countries. So I would lump those in the category of serious conditions, strong family history. If that is there, then I would test. I wouldn't question it. I would definitely test. Because knowing if the woman in front of you who’s thinking about having a baby is homozygous or heterozygous, would that make you treat harder? Maybe? I think it would definitely, if she was homozygous for some of these SNPs, if it was CBS and MTHFR, for example, you know that you're going to have to be a little bit more robust with your treatment. 

If she is, say, heterozygous with CBS and no other polymorphisms related to these methylation pathways are present, you can think to yourself, "Well, there's a tendency, but she's not in the category of, say, other women who are compound homozygous or compound heterozygous for many different SNPs." 

So it is a spectrum. It's like most conditions. It's not black or white, but testing is available. It is cheaper. It is available to naturopaths. A lot of testing is so unavailable to us because we have to refer that to a GP or refer to a specialist and write a letter in order to get access to these tests. I think it's a matter of being able to really talk about the validity of the results with your patient and have that really good understanding and saying, "Look. Just because the genes are here doesn't necessarily mean that there's going to be a problem." And we have the tools in naturopathic medicine to, as best as we possibly can, not necessarily override these SNPs, but support your biochemistry and allow your enzymes and your genes and your biochemical pathways to do the right thing at the right time. 

And there's a lot of counseling that comes into this. You know, there's a whole area of medical science that was borne out of all the information in the Human Genome Project. It's called genetic counseling. And it's a whole area of specialization. Because it really dredges up a lot of information that we may not know a lot of what to do with it in a clinical situation. 

And on the other side of the coin, it creates decisions for a couple as to what treatment course they're going to take. And I think we're quite lucky in naturopathic medicine. Some of these SNPs that we investigate in clinic, they don't necessarily have to make huge decisions based on the information that's coming back. They just need to decide whether they're going to adopt the diet that you suggest. And they just need to decide if they're going to adopt the supplement regime that you suggest. They're not being asked to say, "Remove ovaries," or, "Remove breasts," or something, you know, really, really... 
Andrew: Devastating. 
Annalies: ...significant that the medical world has to deal with. 

So I guess, yes, if there's a strong clinical history, I would not be backward in testing. I would go for it. 
Andrew: It's one of those... Like, I'm still, sort o,f waxing and waning as to, if we don't know and if the SNP doesn't necessarily mean that that condition will present. In the face of having a strong family history, then, again, what's the point of testing, because you'd still be treating, even in the absence of testing? And conversely…
Annalies: Absolutely. 
Andrew: If you don't know that somebody's homozygous because they've got a heterozygous SNP from the mother, but you don't know what they're going to get from the father, then, you know, conversely, you don't know the seriousness of the potential condition. And it's like, "Argh! Which way do we go here?" 
Annalies: Yeah, of course. And I think the other thing to look at is, well, there's a whole layer on top of that genetics known as epigenetics. And the other thing that might make you lean towards testing would be what are the epigenetic factors that could be actually bringing these particular SNPs, if they're there, causing them to be more problematic? 

So if you've got that typical situation of long-standing poor dietary history, long-standing toxicity issues, environmental toxin exposure, a history of smoking, in particular, which is a huge drain on all our methylation pathways. Ethanol abuse, a huge amount of stress, a microbiome that has basically been deconstructed over decades because of all of those poor dietary habits, environmental, lifestyle factors. If that's all there and there is also a strong family history, again, testing may... 
Andrew: Testing, yeah. 
Annalies: Yeah, testing probably becomes important there. 

But having said all that, you do have... I need to have this tattooed some... If I ever get a tattoo, it's going to say, "Treat what's in front of you." There's two tattoos I'm going to get, and they're both about naturopathy. And that’s one of them, it's, "Treat what's in front of you." 

So if you can see that there's this couple or this woman who's thinking about having a child, having a baby, and you've got that diabolical back-story in her family history and a diabolical history of poor diet, poor health, etc., it probably won't change how you're going to treat her. 
Andrew: No, that's right. Yeah. 
Annalies: I think possibly it might come into play where you have to use your judgment and, possibly, the art of naturopathy in, is going to help with her compliance? Would having a test actually help with patient compliance? 

Andrew: Ahh, yes. 

Annalies: Because in many areas, not just in what we're talking about today, but in many areas of naturopathy and medicine, sometimes a test and having that in front of them, makes them follow your advice. 
Andrew: In your experience, do you find that testing can either cause guilt, if you like, "Oh my God, I'm going to hand over this gene to my baby," or do you find, as you've just mentioned, that it can actually help the person to say, "Right. I now know that there's something that I need to consider managing, and I now have the evidence to say, 'It could potentially be that way,' not that it is, but that it could potentially be that way?" In your experience, how do you find patients feel about testing? How do they respond? 
Annalies: Look. There's always apprehension with genetic testing. It's very different, isn't it? To just going and having a full blood count and being checked for anemia. Because it’s your genes. And a lot of people have that, you know, in the general population, when you talk about genetics, it's something you can't change. It's something you've inherited. It's something that you've got your quota of genes. You've got the information there in your genes. And whatever is there is present, and there's nothing you can do about it. So people are always nervous, I think, is the way that I've found. Is that if you say, "Look. Maybe we need to test for this, to see how you're going to say, cope, with a particular dietary change or whatever," so there is apprehension, no matter their background. 

I see a lot of women from scientific backgrounds in my clinic, and they're apprehensive. Even people that work in genetics, they're apprehensive. So there's a lot of, like I said, genetic counseling that comes into this. And you do have to explain things like, "Well, just because it's there doesn't necessarily mean a clinical outcome is going to be a problem, okay?" 
We talk about epigenetics a lot. I talk about epigenetics a lot with clients. And I give them information to read about epigenetics. I talk about that this is the layer above our genetics that we still know virtually nothing about. So it's all about things like diet, lifestyle, stress, sleep, whether or not we smoke, whether or not we do a lot of alcohol and drugs, etc. So there is a lot of talking and a lot of counseling that comes into this. And usually, if they're worried about passing something on, we also talk about the fact that whatever it's likely to be doing in you, it is also likely to be doing in your offspring, but at the same time, we can talk about the right type of diet, the right type of lifestyle, that's going to nullify any potential risks associated with an SNP. 
And I also talk about the fact that these things have probably been in the human population for, goodness knows, how long. And it's only now that because we know about it, and we can test it, that we're even having this conversation. But at the same time, knowledge is power. And if we know that it's there, the way that we address it is simple. There are simple things that we know that can address these issues. A lot of people think that they're mutants. And I have to just basically describe what a mutant is and that they're not one of them, as well. 
Andrew: You know, again, I'm vacillating because you have, on the one hand this, as you say, ‘knowledge is power’. And yet you have on the other hand this fear, given even in, you know, people that are ofay with genetics because they have this preconception of what genetic testing tells you about. With regards to, you know, serious conditions like cystic fibrosis, Huntington's chorea, that sort of thing. 

Now, we're getting into the thing of potential, not necessarily actual. And it's sort of... I don't... You know, I don't... One minute I will be saying, "Yes, test." And the next minute I will go, "Really?" So let's take it this way. If I could say, okay, your total patient population, how many genetic tests have you done, percentage wise? 
Annalies: Oh, look. I would say it's probably less than 20%. 
Andrew: And how many has it changed the treatment of? 
Annalies: Gosh, probably even less than that, maybe 10%... 
Andrew: Ten percent. 
Annalies: ...of the people I've seen. And where it has changed things has more been around diet. More so than anything else, more so than a heavy dose supplementation in that supra-physiological level, which, I don't really go to anyway in clinic. But really it's more been around dietary changes and permanent, so lifestyle changes. 
Andrew: Okay. So here's my take on it then. If diet is always the foundation of naturopathic natural treatment and supplements are used judiciously, then if you're using this, sort of thing, to solidify or cement the importance of a good, well-balanced vegetable-based diet, then I can only see this as being good for those people that you've done testing for. 
Annalies: And if you talk to any practitioner that does or has used genetic testing in their clinic, you almost have to... You're never going to use it with all of them. You base it always on the family history, the clinical history, but also things like physical examination, their dietary history, the types of medications they're currently on or that they've been on long-term in their past, any questions that come up for you related to their nutrient assimilation. Only then when you've done all of that background do you then even think about ordering some of these tests. 

And in many cases in clinic, I would actually order routine pathology as surrogate testing and surrogate markers, before I ever thought about doing genetic testing. 
Andrew: What do you find the concordance is when you're looking at SNPs with regards to your functional pathology tests? Let's say the hydroxy-methoxy estrogens, the 2 to 16, the 4 series? 
Annalies: Look. I think, usually, if you're seeing abnormalities in more routine or more orthodox testing, or even functional pathology testing, if you're seeing imbalances there or abnormalities there, then most of the time, you're going...if you went looking, you would find a SNP. I don't know what...I couldn't say what the concordance it's with most of them are homozygous or most of them are heterozygous, or they're compound heterozygous for many SNPs. So I couldn't even think about what the percentage would be there. But if you're seeing abnormalities on routine and functional pathology, if you went looking, you'd probably find a SNP. 
That's not to say that you would go looking for a SNP, if you had abnormalities here. But particularly with routine pathology, as most of the listeners would know, usually if something's showing up on a routine pathology test like bloods or homocysteine being abnormal or even methoxyestrogen, something like that. Usually there's a fairly decent amount of pathology underlying that, because the body does really like to keep things healthy and keep things balanced. 

So if something’s showing up in, say, blood or serum or even urine, then usually there's a problem. You know, homeostasis has gone awry somewhere. So I actually find that routine pathology's a great tool to just start with, to start there. You know, just do some serum B12, red cell folate, red cell zinc. A full blood count, looking for things like macrocytosis to give you an idea whether or not B12 and folate is deficient. Just doing homocysteine levels on blood, just starting with something like that. 

And again, doing it based on clinical history. You know, these are not just screening tests that you do with every patient that comes in. It's because you suspect that methylation pathways, COMT, CBS might be implicated here. So yeah, these surrogate tests. Even B6, I didn't even mention B6. But you can do B^... 
Andrew: The much maligned B6. 
Annalies: Yeah, exactly. So you can do these tests in routine pathology. And that can sometimes add weight to your decision with your patient to actually do further, say, genetic testing. 

I find the problem, the biggest problem in clinic, is when people come to me with their genetic testing. 

Andrew: Oh, okay. 

Annalies: And they've ordered it over the internet or somewhere. They've had it done. And then they come to you with a paper or a result sheet saying, "I've got this. What do we do about it?" And then you're, sort of, working backwards. You then have to do everything that you might not have ever needed to do with them, had you seen them at the beginning of the journey and didn't have any genetic testing to go on. 
So there's a lot of genetic counseling that comes into that. There's a lot of backtracking that comes into it. You might then have to talk about routine pathology as a way of seeing, "Well, okay. You've got these SNPs, but let's actually see if they're causing a problem for you. If you're concerned, we can do the routine pathology and see if it's actually manifesting in a physiological sense and we can pick up deficiencies in your blood or your urine," but at the same time, the treatment also will be the same. It will still be dietary prevention and lifestyle intervention and looking for any kind of epigenetic factors that might tip the balance in favour of the abnormal effects of the SNP. 
Andrew: You were talking before about epigenetics. I guess we've got to go there with regards to diet, nutrition, lifestyle. I remember Mike Ash saying, "If nutrition is really where the pedal hits the metal, should we just be talking about nutrition anyway with regards to epigenetics because we're doing it anyway? We should be advocating a good, healthy diet and lifestyle anyway." 

So what, therefore, is the facility of testing? However, there's this back flip about, it gives you knowledge to say, "I should be leaning this way with regards to my diet." So with regards to epigenetics, how do you decide what focus to take with regards to diet? 
Annalies: I think it depends. There’s a little bit of how someone practices that comes into this a lot, I think. For me and how I practice, diet is everything. No matter what. No matter what treatment you need to do for someone or what conditions need to be corrected. It's always diet first. 

Now, my belief is that because we've gotten so far away from our evolutionary diet, and this is just all my theories, because we've gotten so far away from our evolutionary diet, these SNPs have more of a chance to cause problems. Now, the problem I'm finding is that when people present and then you start talking about getting back to, say, a more evolutionary-based diet, there are compliance issues. There are issues around time and how long it takes to actually prepare meals that allow you to follow an evolutionary diet. There are social issues that surround why people won't follow an evolutionary diet. 

But I truly believe, there's no science to back this up, but I truly believe that if we were supplying our body with, you know, great quality food, the correct amount of protein, fat, good carbohydrates, if we didn't have all the issues that we have with the food supply that we now have, I really don't think that the SNPs would be really manifesting clinically as much as they are now. 
Andrew: Oh, for sure. 
Annalies: Yeah. So what we have is a bit of a conundrum. Because there's all these different reasons why people can't or won't follow an evolutionary diet. And so that's why we're having to talk about things like, say, epigenetics. And, you know, stress comes into this, as well. And that's why we're, sort of, talking about the idea of maybe having to go and modify enzyme activity with high dose supplementation. 

So for me, I think, the epigenetic storm that can happen from this is never going to be as problematic if the foundation underneath, which is food, it’s not, you know, for me, herbs and medicine, they're not something that provide the foundation to our health. It’s not, you know, nutrition provides the substances that actually build our body, that builds our genes, that builds our enzymes, that builds our neurotransmitters. And if that foundation is correct, then the epigenetic insults usually wouldn't be as severe when they come. And the other thing is modifying those epigenetic insults as much as we possibly can. 

Nutrition and sound nutrition is the buffer that allows us to deal with those epigenetic insults that are going to come. There's always going to be times of stress. There's always going to be times of imbalance. But if that foundation is solid, we tend to weather those storms a lot more easily. 
Andrew: You mentioned getting way from our ancestral diet. We've also gotten away from our ancestral lifestyle, as well, though. The production of adrenaline in ancient times would have been rather acute to save your body from death. To get away from that lion. 
Annalies: Yes, of course. 
Andrew: Nowadays, it's to get away from rent or marital stress or, you know, work stress. 
Annalies: Yes, yes, yes. It's all of those factors, food and lifestyle and the types of stressors. The way we sleep, everything. Everything is involved. 
Andrew: Yeah. So then can I ask you, when you're talking to patients about dietary intervention, do you ask them how much they're willing to give, how much they're willing to change? 
Annalies: Yes. 
Andrew: How do you approach that? And I've got to ask, how do you get them to commit? And how successful do you find that? 
Annalies: Usually, a little bit of, I guess, getting way from the whole, "This is all my knowledge in the sciencey part of it," and just talking to them as one human to another. And it's almost like you just want to take the practitioner hat off for a little while and say, "Look. These are not easy things to do." People being asked to change their diet, possibly for the rest of their life, these are not easy things to do. 

So you have to talk about things like willpower and commitment. And I actually read a lot. I'm reading more… To help me be a better practitioner, I'm reading more about how to talk to people, as opposed to all my biochemistry stuff. Because I'm finding that that makes so much more of a difference. 
So I recently read about this idea in psychology that willpower is absolutely bullocks. It's not going to get people anywhere, and that the way that you can get people to adopt any kind of change, whether it's more exercise, changing your diet, getting to bed earlier, whatever it is? Giving up alcohol, whatever it is? It's not about willpower. It's actually about working at your ‘why’. And saying, "Well, why do you want to do this," and make that decision, make it public, have people that make you accountable for this. Don't just decide in your head, "Oh, I'm going to have really high willpower. And I'm not going to... You know, all this stuff's going to be in front of me, but I'm going to try really hard to not do this." 

I talked to people about their environment. And I've started doing this a lot more recently, where I talk about the fact that you can create your own environment. If you want to change and that's your ‘why’, your ‘why’ is because you want to be healthier and be around your kids and be alive for as long as possible or whatever it is. You have to change your environment because willpower is really hard to stick to long-term. It might work for a few months, but it may not work forever. 

That’s about changing the environment and getting people on board with you and not just, sort of, making that decision in your head. But telling people around you, telling your family, telling your friends. And often, you find that if there's one person in the family that you're treating, I try and focus on what are the rest of the family doing. Because sometimes by default, if the family comes on board with a change in diet, the whole family gets better by default, which a lot of practitioners know anyway. 
Andrew: Yeah. I'm so glad you said that, though, that sentence about find your ‘why’. That's, indeed, how I gave up smoking. I remember exactly the time. Because I found my ‘why’. 
Annalies: Yes. I can't even think of who the author is at the moment because I'm reading a whole bunch of stuff and I don't know who's who. But it's Find Your Why
Andrew: Find your why. I'll find the book. 
Annalies: Yeah. We sit in clinic, and I say, "If you don't know what your why is at the moment, that's okay. You might have an epiphany on the train on the way home. Or in two weeks' time, you might in a situation you think, 'Well, this is my why.' And, you know, next time we speak, let's talk about it or, you know, send me an email and tell me then your why." And that's fantastic. But at least have a think about it, because if we don't really know our why for doing something, we don't change the environment to set ourselves up for that success. 

And yeah, there's a lot of human psychology that goes into... As we all know, that's the art of naturopathy and nutrition, which we couldn't... That's a life-long skill. That's not something that we get great at just because we've graduated or been in practice for 20 years. We're constantly, constantly working on it. 
Andrew: But it's such beautiful art that you practice. Well done. I've got to ask regarding diet. And if we're talking, again, about epigenetics and we're talking about modifying the activity of SNPs or the downstream issues of the SNPs, how hard do you go with diet? How long do you treat? Do you ever do a short-term intervention and then modulate the diet longer-term? 
Annalies: I guess the short answer to that is if... So say it's a scenario where you don't have any genetic testing in front of you. And you're just going based on a clinical hunch, or not even a hunch, but clinical evidence of the person in front of you. Always diet and always hard in those first few months, and then modified as you, I guess, get feedback from the person as to... You know, you have to think about why they're coming in. So they might be coming in for a mental health issue. They might be coming in for fertility issues. They might be coming in for any number of reasons related to COMT, CBS, methylation. 

And if you don't have that genetic information in front of you, you start with diet. I wouldn't even start with supplements at this stage. You'd start with diet, and you get feedback. You start to get feedback on just the things that you're measuring. So you might be measuring anxiety or you might be measuring something like... If it's a fertility thing, you might be measuring menses and regularity. You've always got those things that you're trying to modify, and you're measuring those outcomes. 

So definitely always diet. You would go harder, I think, in terms of supplementation, if you had something like seriousness of condition. So something like history of embolus formation. Or, really, if it was severe anxiety, maybe severe ADHD, severe maybe depression, if you're suspecting COMT and these sorts of thing and you've got some testing in front of you. That's when you might start thinking about supplementation. 
For me personally, I don't really go into that super physiological dosing range. But it's very, I won't say popular, but it's out there. There's been some great research on modifying enzyme activity, either up-regulating or down-regulating with just super physiological dosing regimens with supplements. But, for me, I think you... And I've seen it in clinic, you can still get really good results. If you're working on the diet and the compliance, you don't need to go down that path of really hitting it hard with supplementation. 
And the other thing with that really heavy high dose supplementation is that it often can make people worse. And I've seen it. Particularly if you're talking about COMT and anything to do with mental health issues. Often their anxiety worsens, their depression worsens, their panic disorder worsens. And then you've actually go to pull back. 

The other thing that happens is, particularly with something like COMT and it's a mental health issue, if you've also got an inflammatory issue on top of that, say, joints or arthritis or something, if you start going in with something like…

Andrew: Ahh, yes, it can flare.

Annalies:  Yeah, heavy SAM-e or something, it flares up. And I'm a fan of the ‘gently, softly approach’. That's just me and how I've always practiced. I'm not particularly gung-ho with high dose supplementation. 
So you have to get a lot of feedback. You need to be in close, I guess, communication with someone and asking them, sometimes even on a daily basis, just checking in with a quick phone call. "How are you feeling today or call me at this time, you know, every couple of days. And just let me know how you're going." Because that's the feedback that we need. We can't just say to someone, "See you in a month or two or see you in two months. Come back." If you are hitting hard because you've got genetic evidence or really strong clinical manifestation of a serious problem, you do need to be in that really, really close contact. 
The other time that I would suggest maybe hitting something hard with, say, diet or supplements is if other treatments have failed. If they have tried diet alone and they're being really compliant and they've tried it for a while and they've got at least say 6 to 12 months of dietary change and you think that their compliance has been good and they're telling you it's been good and they've tried other things and it's not working, diet alone, then you might think, "Okay. Well, now we need to talk about supplementation. And we need to go a little bit harder here." But in terms of high dose supplementation long-term, I really don't think that there's any real evidence for that. 
You know, there's clinicians all over the world and researchers working on this. And we still... A lot of this is still weak genetic data, to be honest. It's not strong genetic data. We don't know the long-term safety of these super physiological doses, if people were to follow it for five years, for example. We just don't know. Yet, we're being expected to adopt it in our clinic. That's the hard thing. So it's almost like the information's coming out so fast. And every six months, there's new studies and new seminars and new protocol, but we don't know. 
Andrew: And so I do totally agree with you, that we should always be checking in with our patients and finding out if, you know, what little they can be on, if at all. 

I have to ask just as a last question, we spoke about ethical issues just previously. And I have this question; if somebody does present to you with their already-done test, is that considered a pre-existing condition because they now know what their genetics are, even given that the SNP may or may not have an effect? Is that considered legally a pre-existing condition? 
Annalies: That's a very good question, that I don't know the answer to. 

I think because it's a SNP, I doubt that it would be considered a pre-existing condition. To my scientist mind, I would be looking for… if I had to make an evaluation on this as a medical ethicist, I'd be thinking, "Well, is it homozygous? What's the evidence?" If there's not a lot of scientific evidence out there, it weakens the argument for pre-existing condition. 

And the other thing is we need to be looking at who did the testing and the methodology that they used? So who was the lab that offered the test? Was it a bit of a garden variety or even, sort of, a backyard setup where the testing methodology wasn't legitimate? Or is this a legitimate laboratory offering legitimate genetic testing? Because they're not all the same. 
Andrew: Now, that's very interesting. There is a can of worms that I didn't know about. I thought it was all, you know, "Here's your chip." And it's, sort of, basically, that's what you get your testing done on. So it's not that. There is variance. 
Annalies: No, there are definitely some services out there that, sort of, these... Well, they're laboratories, but there's all different methodologies for this. And some of the methodologies have been superseded by more accurate methodologies. And the older ones might still be in use. 
Andrew: Right. So false positives, false negatives? 
Annalies: Both... 
Andrew: Wow. 
Annalies: ...to be honest, but more often than not, it might be something like a false positive, more often than not. 

And we're also talking about things like, within laboratories, as you would know, quality control is a huge issue. So laboratories that are part of a formalised quality control program are expected to have their own internal quality control that they then report to the overseeing quality control body. So that they are monitored. So there are laboratories out there that might be offering legitimate methodologies, but the accuracy of their results may decline over time because they don't have that strong quality control process internally. And, you know, it costs money to be part of such a program, but obviously, you should be part of that, sort of, program as a lab because we're talking about people's health data here. 
Andrew: Health, yeah. That's right. That's exactly right. Annalise Corse, thank you so much again. I mean, this is...you talk about a tip of the iceberg with this, and we've just covered two genes. And even then, we've just really tapped it on the outside of the iceberg. 
Annalies: Scratched the surface. 
Andrew: Yeah, we've scratched the surface, not even the tip of the iceberg. We've only scratched the surface of the tip of the iceberg. But I do thank you for taking us through, you know, the relevance, if you like, of testing. And I do really admire you for teaching us the real ethical stance that one should take as a practitioner when you're looking at, you know, whether you're going to test or not. And indeed, how you're going to treat people. So thank you very much for taking us through this today. 
Annalies: Thank you so much. Thanks for the opportunity. 
Andrew: This is FX Medicine, I'm Andrew Whitfield-Cook. 

Additional Resources

Annalies Corse
The Human Genome Project
Book: Find Your Why by Simon Sinek

Other podcasts with Annalies include:


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