Don’t underestimate the power of food in our past, present and future evolutionary biology.
Today, Mark is talking with Dr Christine Houghton who has amassed over three decades of wisdom in clinical nutrition and has a passion for the interplay of nutrigenomics with the food and nutrients we consume. Christine takes us back to the basics with a review of the terminology that makes up the field of genetics in healthcare. She navigates us through the epigenetic and gene expression effects of the foods we eat, the microbiome and the influence our genes have on many pathways of the body including methylation, inflammation and detoxification. One message is resoundingly clear: when it comes to positively influencing our genes, there is no single supplementary intervention that can substitute for the complexities of the phytonutrients we obtain from having a diet rich in diverse foods.
Covered in this episode
[00:27] Introducing Dr Christine Houghton
[01:56] Terminology: the basics
[05:23] Biochemical individuality
[08:47] Genes and the microbiome
[21:14] Pharmaconutrition vs. Food as Medicine
[26:06] Genetics, ethnicity and heritage
[31:21] Detox pathways and Nrf2 activation
[39:57] Foods and cell signalling
[44:44] Is food enough to influence health?
[48:08] The problems with exclusion diets
Mark: Hi, everyone, and welcome. Today, we're talking with Dr. Christine Houghton, who is the managing director and chief scientific officer of Cell-Logic, a company specialising in nutrigenomics, functional foods, and nutriceuticals. She and Yael Joffe have created two online nutrigenomic courses for clinicians, Foundations in Nutrigenomics and Translational Nutrigenomics. Hi, and welcome, Christine.
Christine: Thanks, Mark. It's a pleasure to talk to you.
Mark: It's a pleasure for me as well. I've been busting to talk to you since last year's Genostics Conference. You gave a great talk there on sulforaphanes, and Nrf2, and things that we're going to get into in the nitty-gritty of this. And look, what I'm most excited about is the movement of nutrigenomics, and nutrigenetics, and genetics, and all of that, we're all learning this, and you seem to be at the forefront of very, very special parts of that, so it's great to be able to talk to you. And, in fact, we're planning a series of talks. So, today, I'm just going to try and cover a bit of an overview and the basics, and then we could go through way more detail as we go down the line of talks in the future, if that's okay with you.
Christine: That would be fine, given that it's my favourite topic.
Mark: Yes. In fact, my understanding is that you've also got the courses with Yael Joffe, the the nutrigenomic courses, "Foundations in Nutrigenomics" and "Translational Nutrigenomics." We might come to that at the end of today's talk.
But first of all, could you some basics for me? We have genetics, genomics, nutrigenetics, nutrigenomics. I still remain confused. Are these terms we can use interchangeably, or should we get a little bit precise? What's the differences between them?
Christine: Look, I think we're all a bit confused. The term nutrigenomics was coined in 2004, and it really was an overarching term that covers all of the other things that you mentioned and more.
But essentially the way I divide it up is nutrigenomics is nutri-genomics: food talking to your genes. So that's determining what food and other lifestyle factors related to food alter gene expression. And then the nutrigenetics is looking at an individual's pattern of polymorphism, or SNPs, that then determine how we respond to that particular food element.
Mark: Okay, so the nutrigenetics is the kind of genetic and biochemical individuality, and the nutrigenomics is, "How does the food and diet kind of interact with that to create outcomes?" Is that a kind of fair division?
Christine: Yes, I'd say that's a good way of summarising it.
So, the people who are looking at nutrigenetic profiles are practising nutrigenetics, but then they would make a nutrigenomic intervention.
Christine: Which is designed to modify gene expression in that patient, in other words, get the clinical outcome that you're looking for.
Mark: Which is what our listeners are, you know, as practitioners, are most interested in.
Mark: It can be a little bit overwhelming to be overloaded with genetic information, the knowledge that we need to know about genetics, and know where to enter that. Because we come from the other side of clinical work, where we give diets, we know that they work on some people, don't work on other people, we don't know why. And so this kind of expands that understanding a little bit, doesn't it? In fact, massively.
Christine: It does. It helps you to understand why. But there's another piece of the puzzle, and that is the biochemistry that underpins the genes. Because we have to look at the particular gene, we have to look at the enzyme it codes for, and therefore, "What is the biochemical pathway that's involved?"
Christine: So that sounds a little bit daunting at the outset, but that's the missing piece that helps the practitioner take the nutrigenetic profile and turn it into something that's clinically relevant. And that's what we teach when we're teaching our nutrigenomics work.
Mark: And that's where the epigenetics comes in, the ability to modify the genes that you are born with and will die with. The ability to make them act or not act in a different way than their fate would otherwise have been. So how we use stuff from the outside.
Christine: That's another level there. So that's another level of modification over and above the SNP. So you can have SNPs that are epigenetic modified as well.
Mark: Right, okay.
Christine: And so an epigenetic modification is like putting a paperclip on a gene, and it tells the gene whether it should be silenced and keep quiet, or whether it should act or not act. So that epigenetic regulation is a completely different level.
Christine: And we don't actually have the ability, at this point anyway, to determine for the particular patient whether those genes are epigenetically silenced or active.
Mark: Okay, so the individual, we can talk about biochemical individuality based on the genes that we do know about, and the SNPs and the variants that we are able to understand now. But the modification part is a level deeper that we're still working on?
Christine: That's right. So when we're using nutrigenomic interventions to modify a patient's gene expression, it may be, with that particular SNP, a gene is only acting at, say, 60% of its potential. So we're cranking it up. We probably don't get it back up to the 100% if this gene were completely the normal variant, but we can kick it along a fair bit further. And not only do we have polymorphism is that significant. As we get older or are unwell, we lose the efficiency of that gene expression process anyhow, and a whole lot of other associated factors.
So nutrigenomic activation of genes is beneficial just throughout the aging process, or for regulation of any illness regardless of your nutrigenetic profile.
Mark: So does that mean we kind of wind down as we age, that the kind of trap doors that are there in our youth which we're resilient enough to get through become more and more important as the years go by?
Christine: I believe so. If we wind down in life. Things just become generally less efficient. The ability of the food molecules we're eating to up-regulate a particular gene is just less and less efficient.
Christine: Finally, one day, I guess it doesn't work anymore.
Mark: Well, this does go right back to the very heart of what we call scientific medicine, where we kind of assume that all individuals are the same. And we do our studies, we kind of get coherent groups of people, without knowing anything about their genetics, and then test drugs, and test foods, and test diets and we have a statistical interpretation of the human race.
I think it's becoming a little bit more nuanced there. I think it's a well-established principle that biochemical individuality, which goes back to genetic individuality, means that every individual is different. And now we can take a little bit of a peek into the differences and act individually, rather than just on average, "This will work." Is that a fair...?
Christine: That is. That's a very fair summation of this whole new evolving field of personalised medicine.
Christine: That said, of the 25,000-odd genes within each of us, we don't have information on all of them. But the current focus is looking at those genes that are coding for those core cellular processes that govern the function of practically every cell in the body. And if you can enhance those core cellular processes, we tend to bring the body back to homeostasis. And after all, that's all mother nature has done for millennia. Whatever food we eat is modulating gene expression up or down, depending on what we eat.
Mark: Yes. We’ve kind of co-evolved with food, haven't we? It's all very well to talk about drugs, the kind of poisons that we manufacture to stop an enzyme pathway or to promote an enzyme pathway, they're all novel and new. But the co-evolution...
Mark: Yes, yes.
Christine: It's very recent. And we've now also got to look at the effect of the microbiome because it also is modulating gene expression.
Mark: Now, how does that happen? I am so interested in that. Because when you get a person's gastrointestinal tract back to function, lots of inflammatory, neurological, other consequences... It's like magic. You get the gut right, and so much else of health falls into place.
Christine: It is. I talk about trying to restore that ecology.
Christine: Because to me the players in there, the intestinal epithelial cell, which I have a particular love affair with because it's such a fascinating little entity, these little single-layered cells and the enormous capability that it has.
But those microbial creatures that are living in there too, they are cells in their own right. They're producing their own metabolites. They have a whole lot of signalling molecules which our intestinal epithelial cells can detect and respond to. So we're getting gene expression changes if we have a signalling molecule coming from a microbe that we detect. And that has this enormous effect at the gut-immune interface, which then can be translated right throughout the entire physiology.
Christine: That's magic. It's the whole microbiome story, which is really still in its infancy, without a doubt. But as you say, you get the gut right, all sorts of magic happens. And we certainly don't fully understand how that's working.
Mark: Yeah, we've managed as a population to get the gut very wrong in the first, where we have food-like substances sold in supermarkets, no seasonality, high carbohydrates, plenty of sugars, addictive properties. It doesn't resemble food of our ancestors whatsoever. So the surprise to me is that we're here at all, when we've got near-food products.
Christine: Exactly. Yeah. Well, there's some recent work being done on the effect of food additives on the microbiome. And some of the emulsifiers that are being used in food, some of which aren't even disclosed on the label, nor do they have to be by law, I believe, are contributing to enormous dysfunction. A lot of, you know, the so-called leaky gut which people attribute to gluten, gluten is just one small player in this whole panoply of additive chemicals, which are really quite toxic to the microbiome, and consequently, are affecting us as well.
Mark: Yeah, the whole thing of what we add to foods, preservatives, things that kill microbes, we have a bit of a passion for killing microbes all around the place. And I mean, even the use of glyphosate as a product, as a weedicide, and as a ripener of grains, has a highly toxic effect on the gut. To the extent that Bayer is now selling glyphosate as an antiseptic to clear the gut, which is after many, many years of treating crops and saying there's no effect on humans. If that modifies the gut bacteria in the way that it now appears they're selling it, then no wonder food can have an impact by just destroying particular strains of the microbes.
Christine: Absolutely. And health authorities sort of take this view that glyphosate can't affect human cells, because we don't have the shikimate pathway that glyphosate uses to do its herbicidal things. However, the microbes have the shikimate pathway, and that's the bit that's being ignored. That's the elephant in the room, as it were.
Mark: That is. You know, I do find that when people are very, very particular about moving to organic foods, I see people who are chemically very, very sensitive, who've been poisoned in the past. The one thing that they focus on, to the extent even if all the supplements, if everything drops away, organic food is the thing that keeps them safest. Fresh, organic food in season. And when they have non-organic food, they go down very, very quickly. They learn that pattern very quickly.
Christine: Yes, yes. I know there's probably some cell memory in there which is magnifying the response that certain individuals get over the rest of the population, who don't appear to be having an adverse effect to those chemicals.
Mark: Well, therein lies the problem. Because, you know, if you keep pushing towards the cliff, you only notice when you fall off. So it is the ones close to the edge that notice it early.
Christine: And you don't know whether you're halfway there or 9/10ths there.
Mark: That's right. And it's hard when you're young and otherwise fit to live with the idea that your diet should be really paid attention to, because you seem invulnerable. It's very hard to get that trajectory right. That's where mothers in families come in so importantly. They tend to have a more holistic understanding than fathers do of family health, and what's required for food and nutrition to keep children well.
So I would like to talk about something that, how do we, as practitioners, people coming to seek our help, we have concepts of using nutritional medicine, micronutrients in very, very high doses. And you would know this, but people who get even a single heterozygous MTHFR result, and suddenly the doctor or the naturopath is on to 5mg, 10mg of methylfolate and high-dose single nutrients to try and achieve something, versus phytochemicals, you know, herbs and the like, versus foods themselves. What should we know about that, if we're going to try and push things? Is it safe to go shoving away with one nutrient only and then step back, or should we be going for foods or phytonutrients?
Christine: It's interesting that you raised that issue. And the MTHFR is a case in point. But what I'm about to say about it applies to a lot of other genes and a lot of other related biochemical pathways.
So the issue with methylation is it's one process which cells use to maintain and restore homeostasis. So it's one cog in a big wheel. Unfortunately, it's being promoted as if it is the main function itself. I follow a couple of online blogs, and I see consumers frequently writing things like, "I've just been diagnosed with MTHFR, and now I know why I've been sick all my life, and now I know why this and that." Well, in truth, they don't know any such thing.
Christine: What then happens as a consequence is, say, they get some advice from wherever, probably online, about the need to have a special kind of methylfolate, which unblocks the block that they have in the pathway, so they understand. So, I think in the U.S. this has evolved because 15mg of folate is available…
Christine: And it's used post-chemotherapy. When people have had folate and taken this stuff they load them back up with methylfolate.
Christine: So anyway, they get a hold of 15mg, which is 15,000μg, not knowing the RDA for folate is around about 300 to 400μg a day. When you do the sums on that, 15mg is about 40-fold what the body approximately needs. So it's a huge dose.
So you do all sorts of things by overloading folate because folate is involved in a number of other pathways and cutting a long story short, what you end up doing is increasing the oxidative burden in the cell. So the folate is used, in part, to generate a compound called BH4. And BH4 is involved as a co-factor in endothelial nitric oxide synthase spinning off, which is a gene that will show up in the nutrigenetic profile. And when you increase the activity of that, you increase nitric oxide. And if you have a lot of superoxide floating around, as in, if you already had an oxidative burden, you now produce this highly toxic reactive oxygen species, a free radical called peroxynitrite. And it is a nasty little beast. It runs around and it damages DNA. It damages enzymes and other proteins and inactivates a whole range of important compounds.
So these people get themselves into lots of trouble very quickly. And these are the ones who sort of say, "I'm terribly sick. I'm much worse. This is happening, that's happening. I think I've got chronic fatigue."
Christine: What the proponents of the methylation process now advocate is that they give high-dose niacin to these patients.
Christine: Because niacin in its own metabolism uses folate. So this is the very model that lots of people rail against in pharmaceutical medicine. It's that we use one drug to counter the side effects of the first drug. Using high-dose niacin to counter high-dose folate, is no different.
This is not nutrition anymore, in my opinion. This is pharmaconutrition they do such a thing. And the side effects are quite horrendous. Wouldn’t it be much more sensible to understand how much folate is needed if one carries heterozygous or homozygous MTHFR variants. When you put in the methylated form of folate, you've basically jumped over the MTHFR fence, and now you've just made the same amount of folate in this new form that you would if you didn't have the SNP.
Christine: So there's no need for these megadoses. In fact, it's worse than no need. It's quite dangerous, in my opinion, to do this, because this is often happening in people who are already very ill in the first place. Now, we just slam them with this megadose of something which is allegedly safe. It's not.
Mark: Yeah. I have to admit, in the early days, I did exactly the same thing. You give a tool to a doctor, and they just escalate it by 100-fold because there is a quick effect.
But you're absolutely right, because, even the 5mg doses, there are plenty of patients who you know that there is a raised homocysteine, you know a job that you're wanting to do. But by racing in with something, it's almost like they've adapted to their stable state with that SNP. And when you jumpstart it, it's like 240V on a 12V system.
Mark: They get so sick so quickly.
Mark: But you have to back off. The other problem is...
Christine: And you knock out the circuit breaker, don't you?
Mark: Now, the other problem is sometimes even when you're doing sane stuff, and saying, "Okay, let's start at low doses." They feel so much better at the low dose that they think, "Woah, let's go harder. And more can surely be better. What can possibly be wrong with something as natural as a methylfolate?" And it is very, very difficult to kind of manipulate one gene at a time, and I have a feeling that we're thinking about it in medical terms, and we're just thinking about it the wrong way. It's not an MTHFR problem. It's a person problem of which that's one small cog.
Christine: It's also, if I crank up folate pathways, what else have I cranked up in the process?
Christine: That's the question, and that's not well-known. And this concept of using high-dose folate and then actually increasing the oxidative burden on the body, I would say, is very little-known and understood.
Mark: Yeah, we do have a bit of information that folate, folic acid anyway, when it was given as folic acid, is associated with increased polyps and possibly increased bowel cancer risk. And so promoting the growth of something and promoting a high use of folate, these are nutrients acting as, or being prescribed as drugs, we need to respect them in the same way we would a drug. We can't just race in because it's natural, multiplied by 100, and then say, "Well, it's obviously safe."
Mark: Right, okay.
Christine: And I think we need to understand the difference. Now, if we go back to your comment you've made a couple of times about biochemical individuality, that goes back to Dr. Roger Williams' work back in, I think, the '50s, late '50s? When he looked at this concept that we have this biochemical individuality and that's because the co-factor for that enzyme is either not there or not there in adequate quantity. So if we give a megadose, we can drive that enzyme reaction forward, and we can.
The problem with Roger Williams' theory and I just adored his work when I first heard it long, long ago. Is that we had absolutely no tools at the time to determine what anyone's biochemical individuality was.
Christine: So in the height of the megadose era, the megavitamin era, in the '70s I guess, it was just, "Give as much of the cofactor as possible, vitamin, or mineral, or trace element, and drive these reactions forward, and hope for the best."
Christine: And in truth, a lot of patients got better doing that. We'd been loading them up with vitamin-B6 in particular, and all sorts of wonderful things happening.
But in truth, we had no way of measuring what we were doing. There was no baseline measurement, and we had no way of assessing the response other than, "The patient feels better. The patient doesn't think they are."
Mark: We actually did call that orthomolecular medicine, because, you know, these were the molecules that could be found in nature. And one of the concepts was, "The body will be able to, therefore, get rid of any excesses." And with food, you may make a pretty good case for that. But I don't think you can make the case, that when you are using zinc at 200mg, that you can necessarily say zinc is non-toxic.
But when you're using Vitamin C at 30g intravenously, that's not the same as what you get from your food. So, I think it was medicine owning, "How do we use the individual nutrients as if they're drugs?"
Christine: Yeah, and the food comes armed with a whole battery of other molecules. And if we just look at cashews, or pumpkin seeds, which are two of my favourite recommendations to people, both of them are high in magnesium and it's quite possible to get your RDA for magnesium just with 30 or 50g a day of either of those. But they come with significant amounts of zinc…
Christine: And manganese, and iron, and a whole host of other nutrients which all will probably play into the same enzymatic pathways that we're giving them for the magnesium activity, for example.
So, I mean, I defer to Mother Nature. When I don't know, I often say, "What would Mother Nature do? How would Mother Nature restore homeostasis here?"
Christine: And, of course, it's with food, whole food, and enough of the right food. And you referred to the benefits of organic food earlier, and I totally agree with you. But what I do find happening is, because organic food is not always available across a range of different foods, and it's very expensive, some people will eat small amounts of organic vegetables. When, in fact, there's plenty of evidence to show that you need about 600 or so grams a day of total vegetable intake to get significant responses in reduction of inflammatory cytokines and other markers of disease.
Mark: Six hundred grams is a pretty decent amount of vegetables.
Christine: Six-hundred grams. Yeah. And I have to say to people, "Go to your fridge. Get your vegetables out, and put them on the bench, and weight out 600g, and just see what that is. It's a lot."
And it's not surprising when you look the traditional Mediterranean diet. Because they eat, on average, four to five times more fruit and vegetables a day than we in Australia and probably in America do. And, you know, a lot of the benefits of the Mediterranean diet are in that huge array of plant foods and the thousands of phytochemicals that come for the ride, not just nutrients. And I think that's where a lot of the benefits coming from. We like to say it's the red wine and the olive oil. They're just two food components. It's the total picture. In fact, it's not even the Mediterranean diet. It's the Mediterranean lifestyle.
Mark: Yes, having your siesta.
Christine: Having to walk through those little villages, the little winding, narrow streets. So there's the exercise, there's the fresh air, the sunshine, and the comradery because they're very social. So there's lots of things.
Mark: Which is, of course, where food, and socialisation, and meals...so it's not food. It's meals. It's the preparation, the growing.
Christine: Yes, exactly.
Mark: There's more to food than just the food. But even going along that line, just parenthetically... I ask this all the time. With the biochemical individuality, evolutionary biology as well, is the Mediterranean diet for everybody? Like if you have Asian ancestors, if you have African ancestors, can we say that the Mediterranean diet is applicable to everybody because of the nutrient content, or should we be very specific according to the ethnic and racial origins of people?
Christine: The assumption… I'm sure you're right. And I have actually been heard to say MediterrAsian.
Christine: Because, really, there are elements of all food systems, and there are many ways we can combine foods to get to the same place. And that's an area, I don't think, that's well explored.
But most definitely, if you look at the nutrigenetic profile of an Asian population and put it up against a Caucasian population, you find numerous differences. So that means the response to a particular food is different from one ethnicity to another.
Christine: And so I believe you're asking me a question which I don't really have evidence for, but I would say one is better to stick to one's ethnic origin and optimise the dietary intake around whatever that tradition would say.
Chrsitine: But it's probably still possible to sort of adapt from one to another. Unfortunately, we know what happened to Japanese women when they went to live in the U.S. and ate the U.S. diet, you know, the study on breast cancer increase.
Mark: I do. Yes.
Christine: Yeah. So there's all sorts of examples of things like that, seeing Indians going to the live in the U.S. Practically, any population eating a standard American, standard Australian, modern diet is going to suffer in some way or another. Because with nutrigenomics, just as we talk about healthy food promoting gene expression of health-promoting genes, junk food, on the other hand, is switching on those disease-promoting genes. Of which many of them are related to the inflammatory process.
Mark: So, of course, in evolutionary terms, people didn't fly from country to country, and then take up, and live there. The whole genetic mix is not what the first million years of human evolution was. Which you migrated over thousands of years and there was time for kind of cordoning off. The culture, and the fermented foods, and the types of foods that were available varied according to geography, and now geography doesn't have the same boundaries that it used to have.
So I imagine that this mixing, the homogeneity, is not, you know, you can not now say there is one diet for everybody. But there is a need for a healthcare practitioner, and our listeners especially, to provide sensible advice. Which is not… We can't know each individual perfectly, but we need guidelines or rules about, "What do we do with food for a person who presents with this, who is, say, of Chinese descent?" Or, "Is there any difference between that and an Australian, you knoqw, three generations here and an Aboriginal Australian?"
So that kind of information is not at individual levels, but at population levels. And I don't see that we have all that much of a clue yet beyond just saying, "Well, what was the tradition of that culture?"
Christine: If we can look at their nutrigenetic profiles. Now, I can, just in theoretical terms, I can look at a nutrigenetic profile of the patient, let's say, zero in on the gene which are associated with the phase-II detoxification process.
Christine: And there are several key genes which we look at there. And, you know, if the person has SNPs in all of the major genes, we know their ability to detoxify chemicals is going to be more limited than someone who doesn't have SNPs there.
So this is independent of the ethnicity, except to say that genes like the gene coding for glutathione S-transferase, which is a major phase-II detoxification enzyme, that has significant variation in Asian populations compared with Caucasian, and that's one thing studied quite well. So that's interesting. And you can sort of predict the sort of exposures that might have adverse effects more on this race than that race. So our ethnicity… this is very much in its infancy, but there is considerable research going that way, keeping in mind that we've only been talking about nutrigenetics and nutrigenomics since the human genome approach at this completed in 2003. So it's very early days in terms of scientific discovery.
Mark: It is. And translating it to, you know, "What do we eat in food?" I know that what doctors are mainly interested with the cytochrome Ps is drug metabolism, you know, "Will a person be a fast metaboliser? What drugs are appropriate?"
Christine: And so, "What dose should I give this person?"
Mark: Yes, yes. So that's tended to be where doctors focused to know, "Why did chemotherapy fail in this person? They were a rapid detoxifier, because of a CYP that was up-regulated."
Christine: And I think that's very valid. I mean, that might be extremely valuable information.
Mark: It is. But those enzymes did not... The cytochrome P system is a hormone converter. It has multiple, multiple functions. It's not just a drug detoxifier. Nothing in evolution predicted methotrexate one million years in the future. So the general systems of genes that regulate the cytochrome P enzymes, and that is a mess and a web all in itself. Almost incomprehensible to me when I see those studies.
So it gets translated to, Here's the drugs you should have. Here's the drugs you shouldn't have." Could we do that same, just say, "Here's your CYPs and your MTHFRs and your VDRL." Could we do that and say, "Here's the type of diet that would be most appropriate for you as an individual," the same as we do for a chemotherapy patient, on the individual basis?
Christine: In a preliminary sense, you can.
Christine: Yeah, you can. I think that's the direction that we're moving towards.
Mark: We do have that problem of mismatch between the CYP of phase-I and the phase-II, as you were saying, the glutothione S-transferase.
Christine: Yes, definitely. And then there are those who formed the very toxic intermediates. So, as you know, with the story, the phase-I is fast and the phase-II is too slow to metabolise those intermediates. But that's where enzymes like superoxide dismutase come in and can deal with a lot of that intermediate metabolism. That one often gets overlooked.
Christine: But that's very important. But I think what gets overlooked to a large extent when we're talking about phase-II detoxification is the primal enzyme in that process, which stops the formation of DNA adducts, is an enzyme called quinone reductase. And quinone reductase is such a clever little enzyme. It kind of goes right through the process of the detoxification, from the CYP1B1 section, you were mentioning the P450s, through to COMT where that compound becomes methylated. And then it goes through a series of intermediates. And then finally, quinone reductase says, "If I don't stop you, you're going to produce DNA adducts which are mutagenic."
So, now, what quinone reductase does is it pulls that metabolite that's about to damage the DNA, pulls it back, and takes it right around and represents it to COMT and says, "Okay, COMT, you've had a bit of a chance here to catch up now. You need to do some more methylating." So it just keeps recycling those metabolites back through the system until finally it's completely dissipated and the DNA can take a deep breath and relax.
Mark: We have clever biochemistry.
Christine: It is. It's fascinating. And the other thing quinone reductase can do is it can stand in for superoxide dismutase as well. Not quite as efficiently, so when the superoxide radicals are excessive, quinone reductase can put its hand up and go, "Hey, I can give you a hand here. Just let me help," and it's does.
But it's the same enzyme that takes oxidised coenzyme-Q10 and reduces it, so it recycles your oxidised CoQ10, makes it active again. So I think a lot of these high doses of CoQ10 that people take are probably not necessary if the recycling process was working properly.
Mark: So how do we increase the efficiency of that recycling of the quinone reductase? That process had its own support system.
Christine: Yeah. So quinone reductase is… the gene is an Nrf2 target gene.
Mark: Ahh, I see.
Christine: So if you can upregulate Nrf2, then you’re going to be.. well, if you can activate Nrf2 then you’re going to up-regulate your quinone reductase. And the beauty of activating Nrf2 is it governs a whole battery of hundreds and hundreds of cytoprotective genes. So I liken it to putting the switch on the wall to light up the Christmas tree. I just have to put on one switch, and hundreds of bulbs light up on my Christmas tree. That's the power of Nrf2 activation.
Mark: It is, to me, the most fascinating area at the moment. But what we have is this idea of hormesis, we've heard for 100 years, of a little stimulus, not withdrawal from every poison, but the poisons have an effect of telling the body, "Hmm, here's something you can handle." But can you switch on protective effects there? It seems almost like magic that you have to test the body a little. You have to push it into a state for it to say, "Okay, we'll activate our own defences," rather than having to get everything as a nutrient from the outside.
Christine: Exactly. Exactly. It's about signals and switches.
Christine: Really, that's where it's come to. And the interesting thing with Nrf2 activation is it responds to a stressor.
Christine: So, you know, whether it's a toxin in the food, whether it's excessive ultraviolet radiation, whether it's exercise that’s pushing you to exhaustion, those stressors are what activate Nrf2.
So basically the body says, "Hey, we're going to be in trouble here. There's a stress, something attacking us. Hop over there and switch on your defences," and that's how Nrf2 works.
Mark: You don't want to overdo that though, do you? You don't want the attack to be fatal. That's always a bad outcome.
Christine: Yeah, but the thing about Nrf2 activation is… the body is so clever, because there are so many other little regulating control mechanisms that are in there that say, "Okay, that's enough. No more. Back over here, back over there." It will regulate itself until you do something really stupid, like was done in a clinical trial a few years ago. So the power of Nrf2 was found to be so wonderful in chronic kidney disease patients that a drug called bardoxolone methyl was developed. And it was used in the chronic kidney disease patients over a four-year study. The study had to be stopped at 21 months, because patients were going into heart failure.
Christine: It's not surprising they would go into heart failure because one of the preliminary studies showed that the serum magnesium levels had dropped significantly. And I remember looking at that preliminary study, going, "Hey, you're going to have trouble here," and that's exactly what happened. But when I tell you what badoxolone methyl did, you wont be surprised.
So sulforaphane, the cruciferous vegetable compound that is the most potent Nrf2 activator known amongst natural sources. This bardoxolone is 830 times more potent in its Nrf2 activating-ability than sulforaphane.
So that's what you get when you really want to mess with the body's biochemistry. I mean, that is just ridiculous. And it's not surprising what the outcome actually was.
Mark: Yeah. So instead of tickling the system, it sledgehammers the system.
Christine: Absolutely. You know, a thumbtack would have done, but we had to get the sledgehammer out there.
Christine: Mind you, in CKD patients, there's not an easy fix anyway as you know, and I understand the logic. But I just think, "This could have been titrated up slowly," and it's just insane. And you may not have even heard of that study.
Mark: I haven’t.
Christine: Because I'd only heard about it because I was following it. But it kind of disappeared into oblivion. You'll find the papers if you look for them, but they weren't publicised.
Mark: It's not going to be a very successful drug at the other end of it, if it causes that.
Mark: There is this issue of cell signalling. It's become a much bigger issue. The old concept was biochemistry it's a kind of bag of chemicals in our body, and somehow magic just separates them into the right components. And that's part of where orthomolecular medicine ran, you know, "Dump everything in there in excess, the body will get rid of the rest, and then you'll be left with enough."
But there is a far more subtle system that I think everyone's now aware of, of the cell signaling. Which isn't kind of concentration dependent. Tiny amounts of nitric oxide, tiny amounts of certain chemicals, initiate a cascade of responses that you don't need much of a product. It's not a dose that has to be higher to be better. You just need to switch on the signals.
Christine: That's right. You need to switch on the signal. But the thing about signalling is that Mother Nature switches it off too.
Christine: When it's done its job, because there will be counter-regulatory processes there. Whereas when we want to dump a whole lot of, let's say, a nutrient style chemical, it can't switch it off when we want to, and cells don't work like that. There's this constant modulation, up and down, of every process that's going on in the cell, assuming all of the processes work properly.
But that fine-tuning is there, but signalling is about fine-tuning. But it's also about negative feedback loops, so that when one molecule tends to accumulate slightly above its required level, a negative feedback mechanism falls into place and something shuts down, and you stop producing it. But, you know, we're only scratching the surface there.
Mark: I know, we are. Can foods do that? The variety of chemicals in foods, is there a kind of signalling effect, or is foods just nutrients that go into the body?
Christine: No, not at all. So if we just go back historically to sort of, about the '60s and so on. When epidemiological studies were showing that the healthiest populations in the world had lots of fruits and vegetables, the conclusion that was drawn out of that was that that was because of the vitamins and the antioxidant vitamins in those foods. So we spent years and years going down that track, using vitamins to see whether we could prevent chronic diseases like cancer, heart disease, diabetes, and so on, there are simple large-scale meta-analyses looking at hundreds of thousands of people, and they weren't ever able to show that those antioxidant vitamins had the same benefit that people had by eating those foods.
And it was around about the same time it became apparent that there's somewhere between 5 and 10 pounds in different phytochemicals in the food supply, and possibly it's those phytochemicals that are really doing the work, and not the vitamins.
Christine: And that's sort of been the evolution now of the way the science is going. We certainly acknowledge the need for nutrients, macro/micro-nutrients, without question, and that's a given. But that is no substitute for the whole various molecules that are found in foods, and, in particular, plant food.
Christine: And that's why I think no multivitamin mineral supplement will ever replace what's in the food.
Mark: Yes. The only multivitamin would have to be the size of a rock. You couldn't swallow it whole.
Christine: Then you might as well eat the food anyway.
Mark: That's right. And the food, at a meal, with other people in the Mediterranean, with this nice sunset.
Christine: Oh, that sounds good.
Mark: That seems to be better for you than just about anything else.
The ability of the diet, I know Yael Joffe has talked about, you know, the first mouthful of food can have a signalling effect that can be effects with a single meal. It's not doing well over 6, 12, 24 months, or 10 years, which is important. But that the food acts as a signal, mouthful by mouthful. That creates a whole different level. If the body's getting the signals that way, it suggests an obligation to get eating, and meals, and chewing, and digestion...focusing on the gut would seem to be…gut, food, diet, and the life, would appear to be the best way for prevention, in principle. Rather than having to do lifestyle studies to say that something is right, that signalling seems to be, in an evolutionary term, the way that we survive the time we do.
Christine: Oh, I agree, totally agree. Yeah.
Mark: So how do we translate that? How do we turn food back into the medicine? It's a Hippocratic ideal. Like, there was a doctor a couple of thousand years ago who, you know, "let the food be your medicine." It's become unfashionable now. But is that a realistic concept, if we could get back to eat food?
Christine: Oh, I think that's where we need to go back to Mark. More and more, the more I study nutrigenomics, the more convinced I am that you have to look at food first.
Christine: Unfortunately, there's this thinking that's become entrenched that says there's nothing left in our soil, and therefore there's no point. It's simply not true. There's no doubt that we've had degradation in food and nutrients in soil over time, no doubt.
But this notion now that, "There's no point, really, worrying too much about what you eat because there's nothing in it, anyway," is a nice little marketing ploy that was started by the early multivitamin manufacturers back in the '70s. That's really when it started. There's an element of truth, yes, but it's gotten out of control. And I find with some people, they just laugh if you talk about eating food, "What's the point? It's full of toxins. It's got no nutrients." I think we've got to get this into proper perspective.
Christine: There was a study done in 2010 by an author Hermsdorff. This is the one that took the 600g of vegetables, actually, took three different quantities of vegetables. I forget what the first one was, but it was 300 and 600g, and looked at biochemical markers of redox imbalance and inflammation. And without a doubt, 600g of vegetables made a marked impact on anti-inflammatory responses. And these were not organic vegetables. They were just whatever vegetables was available in the place where they did the study. So that had quite an impact on me. Because we can still do it with food.
Christine: Maybe that's not enough on its own, maybe you have to eat more vegetables than you otherwise feel comfortable doing, but it is possible to do it with food.
Christine: And the other thing that sticks in my mind, because I started practising it a really long time ago in the '70s, we had so few supplements on the market at that time in Australia, what we did with patients, you had to do with food. So I have every confidence that I can get sick people well by manipulating their diet, alone.
Christine: And I can't ever forget that. And, you know, we're in an era now where a lot of the practise of nutrition has really become surrogate medicine. You know, you run a whole stack of blood tests, most of them are mainstream tests, and then you want to prescribe a whole stack of isolated nutrients…
Christine: To change the effect of that test, and it makes no sense to me. This is not nutritional medicine as I understand it. It's fast becoming a variant of pharmaceutical medicine.
Mark: It is, isn't it? It is, "Here's the symptom list. Here's the nutrient missing. Here's the symptom list. Here's the nutrient missing."
Mark: And think of them as though they're drugs that we're putting back in therapeutic dose.
Mark: Yes, tell me about that. Right.
Christine: And some of the things we're replacing those food groups with have issues of their own. I mean, I think people who are relying on commercially available gluten-free foods are going to wind up with all sorts of problems. I don't know whether we're seeing them yet, but it's only a matter of time. Someone will do a study on it.
Mark: Yeah, you can have junk food that's gluten-free, and that's one of the problems. Is when you say something's evil, what you replace it with had better be healthier, not just missing a nutrient.
Mark: All you're doing is subtracting, if that's the case.
Christine: But when you've got a gluten-free bread that's basically refined tapioca flour and rice flour, or something along those lines. You might as well eat the packet it was made.. it was stored in, I mean, it's nothing in it, it's empty calories of the very worst kind.
Mark: I do want to address that one item, the restrictive diets. It's a medical problem, it's a naturopathic problem. It can be impressive how well a person feels when you restrict their diet artificially because the gut is doing less. It's like a rest for the gastrointestinal tract. And the bane of my existence is two of them, the FODMAP diet and the low-salicylate diet. And the reason I say that is not that they don't work, but it's not a lifelong diet. They are a method of changing something temporarily in order for a person to resume a diet that's going to be healthy. Neither of them are healthy diets.
And our job as health practitioners of getting people back onto as much food, not fearing every mouthful that goes in. Because I'm convinced that if you fear your food, you're not eating meals with family in the way that the gastrointestinal tract and the autonomic nervous system are meant to work. You're eating in fear. Your digestion will be abnormal.
So, yes, while it's important to get people off something, get an outcome, it's just as important to find the healthy foods and the whole diet that they're going to be able to resume as soon as possible afterwards. So that that whole signalling, the nutrients, the phytonutrients, get back in, and we're not left with a, "Have lamb and a celery," and that's your diet for the rest of your life.
Christine: Totally agree. And the other group is the ones who exclude histamines. And, again, I'm on one of these online forums where I watch people and I hear people ranting, like, you know, "I used to be able to eat 12 foods. Now, I'm down to five foods."
Christine: And not understanding that the very fact that they're having this adverse response to food needs to be fixed. The more you exclude foods from your diet, the more difficult it is to obtain the healing factors out of that food that will repair whatever it was, or is, that's causing the problem, which is most likely at the gut-immune interface. But this is where the power of the internet can really work against people.
Mark: Yeah, panic can occur, and it can run in, you know, very powerful lines can be made that ultimately oftentime do have commercial interests behind them to drive people to a particular product, service or perk. And paranoia can create a bit of a problem that way.
Christine: Yes. And while, as you're suggesting too, you need to exclude certain things in the short term, there's no point in exacerbating symptoms in the short term. But as you said with FODMAP, it was only ever designed to be six weeks, mind you. But people feel, "Right now, I'm feeling so much better because I'm not getting this reaction from eating those foods," so they stay on it. Little knowing, that those FODMAPs are the very foods that the microbiota love to eat.
Mark: I know.
Christine: And the less you give them FODMAPs, the more you starve them and the more issues you cause long term with the microbiome.
Mark: Yes, it can be self-perpetuating, but coming off it after a while is a very difficult thing to do. We have so much to talk about, Christine. I want to thank you for today. But I would love to go into the kind of nutrient immunological, gastrointestinal kind of interface, with a single cell that keeps us from devastation.
Christine: My favourite little intestinal epithelium.
Mark: Yes. Yes, it's one of my favourites as well.
Christine: A day in the life of.
Mark: And on the other side of it, the immunology of the body that is so profound, and triggers signals at the vagus nerve, and the effect on the brain. We have so many areas to cover, and I'd love to talk with you at length about those in the future, if we can...
Christine: Well, I'd very much like to chat about that too, Mark. Yes.
Mark: Okay. Well, we'll work our way through that in the future. And I thank you very much for your time today. It's been delightful to talk with you, and I hope to talk with you again very, very soon.
Christine: Thank you. My pleasure.
Mark: This is FX Omics, and I'm Dr. Mark Donohoe.