Nutrigenomics and the Future of Healthcare with Dr Yael Joffe

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Nutrigenomics and the Future of Health Care with Dr Yael Joffe

In the words of Dr Yael Joffe, health practitioners of all disciplines need to engage in learning about genetics and genomics or risk being left behind.

Tune in to today's episode as Mark and Yael discuss the differences between nutrigenetics and nutrigenomics, why nutrition is a more sustainable choice over drug therapies, the role of Nrf2 as a master regulator and why MTHFR was nutrigenomics 'darkest hour'.        

Covered in this episode

[01:11] Welcoming Dr Yael Joffe
[01:49] Becoming a nutrigenomic pioneer
[05:39] Working in genetics prior to the genome project
[07:31] PhD work: Uncovering answers in epigenetics
[10:43] Nutrigenetics vs. nutrigenomics
[18:32] Essential fatty acids
[22:28] Every mouthful of food changes gene expression
[25:53] Translating the science into healthcare
[28:28] Drugs vs. nutrition
[30:55] Nrf2: The master regulator
[35:45] MTHFR: "The darkest hour of nutrigenomics"
[38:29] Looking at both upstream and downstream effects
[40:58] Integrating genetic and functional testing
[45:35] Developing nutrigenomic education
[48:16] "Engage with genetics, or be left behind"

    


Mark: Hi, everyone, and welcome. Today, we're talking with Dr. Yael Joffe, a global expert in the field of nutrigenomics. 

Yael has co-authored two books, It's not just your Genes and Genes to Plate, and she and Dr. Christine Houghton have created two online nutrigenomics courses for clinicians; Foundations in Nutrigenomics and Translational Nutrigenomics. She's currently an adjunct professor teaching nutrigenomics at Rutgers University. 

Welcome Yael, how are you?

Yael: I'm good, thank you. Really happy to be here.

Mark: Yes, it's good to have you all the way from South Africa. 

Listen, we're going to be talking about nutrigenomics but there's a story behind this for just about everybody because the genomics and genetics story is a story of the 2000s. And I believe your career began before that as a dietician. Can you tell me how you moved from good old-fashioned kind of medical orthodoxy and adapted yourself to the genomics and genetics of today? What's the story? When did you become a dietician and how did you cross that divide?

Yael: Very good question. Well, I was lucky enough to cross the divide. I graduated as a dietician in 1993 and truth be told I think in the first like three weeks of starting my dietetics degree I realised that this was a major mistake. And that it wasn't really what I'd been looking for and I had been looking for a degree in health and how we could use nutrition to make people more healthy and prevent disease. And I was absolutely horrified to discover that dietetics really wasn't that at all. But, you know, that long ago, it really was appalling. 

And so there was kind of an immediate disillusionment and disappointment with the work that I was studying. I did go on to graduate as a dietician but I never really practised because I had the sense that something was missing and something was wrong. And that the nutrition we were practising just wasn't resonating with me as being anything to do with health. And I didn't not quite know what it was, and I was lucky to, I went travelling as we do when we finish our university degrees…

Mark: Yes. 

Yael: And I ended up in the UK, was kind of peddling some nutrition just to kind of make ends meet. And I was lucky enough to be invited to spend two days at a company called [?] in the south of England who were literally the first start-ups in the nutrigenomics space ever. And this was in 2000. Well the year 2000 was three years before even the human genome draft had been published. 

So basically it was an investor and a geneticist and they really had extraordinary foresight, they really were visionary. The really felt nutrigenetics were going to really play a significant role. When I met them, I thought they were quite crazy and I was like this is ridiculous, there's nothing going on here. Like there's nothing… genetics and nutrition has nothing to do with each other. And that itself was incredible because I joined them just really because it was the best offer I got, and it sounded quite intriguing. And I stayed with them for seven years. And I grew with the company and a couple of years into it I realised that I couldn't kind of do that any longer that I really needed to be able to put the kind of theoretical knowledge behind what had proven to be quite an interesting space to be working in. 

And so you know, dietetics not having prepared me very well I went back to university for my PhD. And, you know, my PhD started in the early 2000 as well like 2004. And in South Africa at the time there was no nutrigenomics academics at all. And so, I had no supervisors which was quite challenging. And so we kind of built a degree. You know, we got a geneticist and a nutritionist and an epidemiologist and a biostatistician and we kind of rolled them into one. And that's how I spent the next couple of years which is trying to really understand the kind of the hard science behind what was turning out to be a really interesting career for me which was in nutrigenomics.

Mark: How did that work? Without the genome project, it's like the days before and after computers, if the genome project had not produced much… genetics always seemed a pretty primitive area before that. Until we actually had the kind of 23,000 genes, it was invisible to doctors back at the time that you're talking about. So how was nutrigenomics emerging before the genome project had actually given something to work with?

Yael: That's a good question. So I'll have to say I think it's called invisible to doctors. So what the human genome project did was it created the draft of a sequence of entire genome. 

Mark: Right. 

Yael: As you said, 20-25,000, we're not exactly sure how many genes there are. They still say… but basically, they wrote down the code of the entire genome. 

But it wasn't that we hadn't looked and been able to re-sequence any genomes. We just hadn't read the entire genome. So, if you look at a gene like MTHFR and look at the research and how far it goes back, you will see in the 1980s that they had studies on MTHFR. 

Mark: Yeah. 

Yael: So we knew where the gene was, we knew what the sequence was and we knew which chromosome that it was sitting on and we knew what the sequence around that gene was. 

So, we knew quite a lot of genes. And what the sequence of a lot of genes was, what we didn't know is orbit. And that's what shifted from...and also those sequences were sitting in a very academic space. They weren't open talk, they weren't available to the public, they weren't available to all scientists. So it's not that we didn't know the sequence of some genes, we didn't know the sequence of all the genes and that's essentially what changed when we did the draft genome.

Mark: So you had to pick your targets at that time I would imagine. So your PhD I believe was genetics and nutrition of obesity. So you had specific targets in mind and you were putting together nutrigenomics, the impact of nutrition and genetics and how that played out in obesity. Is that where your PhD went?

Yael: Yeah, that’s it. So actually there was another angle to it, and that angle was inflammation. So what happened in South Africa is we had identified quite an interesting conundrum in the South African obesity landscape. And that was that black women... So we have a huge problem with obesity in South Africa, same as American, same as Australia. And what we have identified was that when African black women because obese in South Africa then they in turn develop a comorbidity of diabetes. But when white Caucasian South African women became obese, they developed a cardiovascular kind of lipidemia. 

Mark: Right. 

Yael: And we were very interested to try and understand why was one group manifesting with a different comorbidity from another group. Even though ethnicity was kind of your core phenotype? 

So I was part of a big obesity research group where we all kind of brought our expertise and we all looked at this kind of interesting question in a different way. And my way was obviously to look at it through a nutrigenomic lens. So I wanted to understand were there any genes that were maybe in a different kind population frequency or expressing themselves differently in the obese population between the Caucasians and Africans? 

Mark: Right. 

Yael: And the other thing was diet playing a role? So was their diets different? Did their diet influence their gene expression? And so that was what we were looking at.

Mark: Again, from my perspective, the concept of genetics there was, you know, Watson and Crick version. It was a blueprint of life, basically the genes defined us. My understanding was the concept of epigenetics was not big at that time, the modifiability of genes was not thought to be a big thing. It was just, you got your genes, the environment played out on it. If you were lucky in the lottery of evolution you survived and if you were unlucky you were just selected against. 

So that sounds like your PhD was already looking at epigenetic expression, what changes the expression of something rather than just what genes are you lumbered with. Was that going on at that time?

Yael: I mean, I think you’re right. I don’t think I actually understood what I was doing at the time. I think that you’re a hundred percent right, that the conversation around epigenetics and gene expression wasn't actually happening. 

Mark: Right. 

Yael: And that we were more focused on the SNPs and gene variants. And there wasn't a lot of conversation about this idea that... I think our company understand it better now and I think it happens to be a really good topic, that different diets could really change the expression. We were much more focused on kind of the biochemistry and biomarkers and we didn't have anywhere being able to measure gene expression at the time. 

So we were a little bit ahead of our time but the question was right. I think we were asking the right questions. I don't think we understood fully the mechanisms. And what's really interesting is my first half of my career was firmly in what I call nutrigenetics. And nutrigenetics is really when you look at gene variance. Which is most of our genetic in the marketplace. Where we're testing if there's a “C” or a “D” or a DNA “AA,” and that really, where there is a sequence change, is really the field of nutrigenetics. And I think for the first half of my career I didn't go past that. I didn't actually think what else is there in this incredibly interesting field. And it was only later where I became a lot more interested in... You know, epigenetics is an interesting term because you can just talk about methylation, you can talk also about influences of diet, lifestyle, environment on gene expression. And I grew to understand that there was a field called nutrigenomics. And in my world we talk about nutrigenomics as gene expression.

Mark: Right. 

Yael: We talk about nutrigenetics as gene sequence. 

Mark: Right. 

Yael: I hope that makes sense.

Mark: Right. That does, because that was what my next question…

Yael: It does? Okay. 

Mark: Was really, what is that difference? I can understand the SNPs and the genes and the previous positions that fits the medical way of thinking. But the genomics, taking the whole of the genome and how it influences other parts of the genome and how external influences occur, that is much more difficult for me to understand yet that's the field we're in when we're in healthcare, isn't it?

Yael: Absolutely, and I'm going to try and make it a little bit more simple. And I'm going to try to keep it on the level of nutrigenomics. Because I think when you talk about the big genetic/genomics it becomes almost unfathomable. 

But we'll just kind of go back to this and I have to say that not everyone buys into my definition. You can still find people who will say, "Well, we can use genetics and genomics interchangeably." But I think it's extremely important that as students of nutrigenomics we understand the difference. And that we use the terms accurately and at the right time and in the right place.

So nutrigenetics is really what the genetic testing industry was built on.

Mark: Right. 

Yael: You know we test for SNPs or deletions or substitutions and we understand how that change in sequence has an impact on the protein or the enzyme or the hormone. 

But actually, the magic, the real magic in this field is happening in what we call nutrigenomics. And we could define it again. When we look at nutrients or phytonutrients and environmental toxins and we understand how that trigger, that molecular basis, alters gene expression in some way. Either by switching it on or switching it off, or dimming it or increasing it. And I often talk about gene nutrition. You know, if dietetics was a great disappointment to you then what is the alternative? And for me the most exciting feature of nutrition is simply in the nutrigenomics space. That if we can practice nutrition and this is what we... I have a clinic here in Cape Town and this is what we try and do. We use nutrition and our nutrition process to impact gene expression. So, we use nutrigenetics as information and insight to give us information about the patients but we use the nutrigenomics to treat our patients as the intervention.

Mark: Okay. So that's moving it from SNPs which are, you know, nice to report, nice to see, homozygous, heterozygous, SNPs all around the place. And it moves it back into well, that's a kind of background, now how do you influence the risk maybe associated with that, how do you up-regulate or down-regulate something…

Yael: Correct, yes. 

Mark: ..So that you are not thinking I'm a genetic engineer but you're doing what we did through evolution. Which is the diet had to match our genome for our best survival. Coming back to that now, we're re-entering nutrition and environment as the expression of those genes. It's a pretty powerful thing if you can get hold of that to create a healthier human and also sometimes just to get around disease. 

So that's a transition that has amazed me that we can...always have been doing medicine effectively in nutrition we were doing something with diet that was making health but we didn't know how we were making health. 

Yael: Correct.

Mark: Now, we're putting kind of details behind it to say and this is how those things work and you can change your gene expression without changing your genome.

Yael: That's right. And that’s what people often get confused when they ask what I do and they think I'm actually trying to change, you know, gene therapy…

Mark: Yes. 

Yael: Like that’s what people think. But actually that's not what we're doing. What we're trying to do, is we're trying to impact gene expression in a way that it's more conducive to health. 

Now, you mentioned this concept of evolutionary biology and, I mean, one of the major problems we have in the world right now is why we see such a crisis around health, is we have an evolutionary genome, a sequence that hasn't really changed very much. But we have a feed system and a feed environment and an air pollution/environment which has changed radically. And the genome sequence, because it's evolutionary and doesn't change very quickly, has not been able to change, to be able to protect us against our food choices and our environment. 

So there's a huge conflict and clash between our older genome because our genome is very old, and our current gene system. And that's one of the reasons why we see so many health issues manifesting now especially around the cancers, the autoimmunes and because of this disconnect between them. 

So what we are trying to do is we're trying...because we can't go and change, we can't force evolution by changing the sequence. We won't be alive long enough to do that. But what we can do is try and manage the expression of the sequence that we have. So a perfect example is inflammation. So, we know the TNF-alpha gene is one of the genes that have been studied, probably, again, from the 1980s. This was one of the first genes that ever appeared in literature. And we know that when you have a gene variant that sits in the A transition we get a twofold increase in transcription. So we get an increased inflammatory response, it's kind of your chronic low grade inflammatory response. This would have been an extremely protective response in the time of evolution…

Mark: Yes. 

Yael: Kind of back when we were hunter/gatherers and we were living on the plains. The inflammation would have actually protected us.

Now, because we are exposed to a continuous and chronic amounts of inflammatory markers and triggers, we have a load of inflammatory triggers, plus we have a tendency and a susceptibility to have an inflammatory phenotype and obviously with the two together we get this kind of overall chronic inflammation. 

So we are out of sync with our genome at the moment and I see that changing anytime soon. But we need to work harder. How do we see that we can now up-regulate or down-regulate, whichever way we want to go, to be able to manage whatever evolution biology is essentially handed to us. I mean evolution biology functions on, reproduction and survival.

Mark: Yes. 

Yael: And we're not living in a reproduction and survival environment at the moment.

Mark: There was a time a hundred years ago, this is a thing that is definitely true in medicine, where the problem was lack of inflammation. You needed to have a strong inflammatory response to get your fight against the pathogens get under control. 

Yael: Yep.

Mark: And as you win the war, you know, with antibiotics, as medicine gets better at stopping the killers, the infections keeping them at bay, sanitation does its bit, the problem seemed to become that as food became less food-like and inflammation became the big new problem, and arthritis, cardiovascular disease, Alzheimer's, these have emerged, because we’ve control the infections that may be used to prune the population and what we're left with now is the survivors?

Yael: Exactly. And remember the other fundamental first, which formed my PhD work is that this huge pain between the omega 3s, 6s and 9s in our diet. I mean, it completely flipped on its head. So whereas our ancestors were sitting with a very high omega-3 and a very low omega 6, we have this incredible amount of omega 6 in our diet. 

And so when we put all of these in together, you know, the genetic kind of evolution with genetics, the change in the kind of fatty acid profiles in our diet, plus the… you don’t, you know, need that inflammatory response anymore, we end up with this kind of, severe kind of, health crisis. Which is what we're seeing in our patients.

Mark: It's the doctor's curse at the moment because we keep looking to drugs to control inflammation. If you ever look at that on drug books the basic thing is the exact mechanism of action is unknown. I have a suspicion sometimes that the drugs are fiddling with epigenetic expression and the tricks are being played. And some of those are being derived from the omega 3s and it seems strange to me that we have the potential for diet to make a huge impact, yet we keep turning to drugs as if, well the diet, the supermarkets, the lack of omega 3s, that inverted ratio.. From what I understand now omega 3's have gone from 1 to 1 to about a 10 to 1 ratio in favour of omega 6. 

Yael: I think that’s.. .yeah…

Mark: But rather than reversing that, that what we're doing is we're trying to say, "Oh we can make a drug that imitates the biological products of an omega 3, the resolvins and protectins. They're great to know about, but it's not food. And coming back to something that could be population delivered, is food, isn't it?

Yael: Yeah. I mean, they say that it used to be 1 to 2.

Mark: Right. 

Yael: It used to be a 1:2 ratio. And that’s… it’s not even possible even if you grew your own food. Even if you went and got your grass-fed kind of meat, you still would not be able to get below like, 1:7 or something or other. It's just physically not possible in our environment anymore. And in fact, 1:10 would be a fantastic outcome. I think most countries, are sitting at about 1:15, 1:17. 

Mark: Right. 

Yael: And in South Africa, in their research we are sitting at...in the African population about 1:28, can you imagine that? 

Mark: Right.

Yael: So you're right, and that's something about the new nutrition. You know, we talk about this new nutrition science. Where we have to look at everything from genome, right to kind of, you know, biology, but then right through to our food system. Because they’re all so connected. That if we don't think about where our food is coming and what is being manufactured and produced and how that works with our genome, we don't have a complete solution. We don't really have an answer. 

We can't just kind of...we say now in our training is never look at genetics in isolation. It just doesn't exist in isolation and one of the, you know, I have this course with a fellow Australian and Christine Houghton from Brisbane, an extraordinary nutritional biochemist. 

Mark: Yes. 

Yael: And what Christine taught me and what she brought to my work is the nutrigenomics gene expression. I really do think she's one of the experts in that space. And we try to bring both of them together to be able to create a new way of thinking about nutrition. That whenever you actually choose a food, whatever nutrient… every single time we eat, you change gene expression. It's not like, "Ooh I ate well this month, I think I changed my gene expression." It's not like that at all. It's actually every single mouthful, at that time changes gene expression.

Mark: I have argued with my wife on many occasions. I've said for years, it's the average of what you eat. It's you know, "I don't need a salad every night," and her answer was, "You didn't raise children. You don't know what it's like." There's a concept I think as well that women are moving into this field and science has been a fairly male dominated field in the analytical side of honing down to a specific question without paying attention to the whole. 

The paradox here for me is as we hone down onto the tiniest detail of genetics, it in fact expands out to the whole environment of breastfeeding a child, delivering a baby, an environment of toxins, eating for health and life. And that it being a, you know, a joyful expression of growing healthy babies. And I think women have a much better grasp of the whole than... I think our brains are a little bit focused on the task at hand whereas they don't expand out necessarily.

Yael: I won't argue with that. I'll take that one, I won't argue with that.

Mark: Okay. And I'll hand in my card, you know, as a practising male people have said, "You traitor." But changing that, what I was meaning is, the paradox is as you go further into the genes you think that's being highly specific. But like a fractal, it opens up to say, "Hey everything is important."

Yael: Absolutely. Everything we put in our mouth. Yep

Mark: That idea that every meal is important is... Yeah, I'd love you to expand on that. Really? At the meal level, there are changes going on meal by meal, is that true?

Yael: Yup. Meal by meal. Meal by meal, you are changing gene expression. There isn't a delay in the impact. So every time you eat, every nutrient that passes your lips, it has an immediate effect on switching on and switching off genes. 

Mark: Wow.

Yael: And I think this is...you're 100% right. If I only pass on one thing today, it's that idea that this is not a generalist kind of average out experiment. And we talk about here, in South Africa, we talk about health is a daily choice and we say that because of that concept. That every decision, when you go in the morning and go to your coffee shop and you make a decision of what coffee to choose, what coffee you choose, will change gene expression at that time. When you decide to meditate before you go to work, you're changing gene expression. And this is when we come to that full solution that you mentioned. Whether it's meditation and some kind of stress management, whether it's a kind of exercise that you choose, one kind of exercise will change gene expression in one way, but is all happening in real time. It's just constant switches going on and off, on and off all the time. If we can understand that it's extremely powerful in terms of impacting behaviour...

Mark: It makes the science very difficult. I mean, we still think of science as aggregated statistical science but really this is playing out per individual, with their individual genetics, biochemistry, their stressors in the environment, their nutrition in the environment. How do you turn that into a science and how do you provide advice for the individual and their family when each one is so different from another? Is there a practical way that we can translate that into healthcare that is meaningful at the individual level?

Yael: Well, you know, I think we're finding our way in that. Christine and I will argue that we think that we do have the answer to that. I mean, I am lucky enough to have my own clinic where I can practice and play around with that. As well as an education program that trains practitioners. And we've been training practitioners for quite some time now to be able to put genetics into its context. 

So what we're trying to teach is this concept of how do we take everything that we know, it doesn't matter if you're a naturopath or doctor or a dietician or homeopath. How do you take what we know, both in the insight of the nutrigenetics, the information we can get about an individual, but what areas might we be really concentrating on, where some choices might be quite powerful. And then how do we...we could bring in functional testing, biomarkers and all of that. And then how do we use that information to make the best decision possible for our patient? 

Mark: Right.

Yael: And we believe that we can train practitioners to be able to make that kind of decision making process. It's not something that's taught at universities, it's not something taught in dietetics or medicine. 

Mark: Right. 

Yael: It's really something that we have to almost re-train practitioners. And we, you know, we always laugh and say like it's almost the ones we need to train the most of the dieticians. Because we almost have to.. and the Doctors, unlearn what we were taught…

Mark: Yes.

Yael: And kind of re-learn it. Because what we're teaching now is the power of nutrition. Nutrition now stands above everything else, in terms of power. 

Now, medicine does the same thing but what medicine does, we talk about the difference to modulation and activation. What medicine does is it goes in and it just like knocks everything over, puts all the switches up and with a mode of activation. But it's got no signature, it's got no signaling, it's got no… a little bit… where the medicine holds you back.

Mark: Most of medicine as well, most of the drugs we have, are typically enzyme poisons that, you know, when an imbalance occurs between pathways, we know how to find a chemical that will blockade one pathway to allow for an evening-up. And so blockading prostaglandins gives you an anti-inflammatory response…

Yael: Yep, yep. 

Mark: That medicine is the science of poisons used at a dose that you hope does not poison.

Yael: Correct. That doesn't always kill the patients, yeah.

Mark: Yes. One of the problems with that is, drugs are, in my experience, not sustainable. Diet and nutrition of course is. Right?

Yael: Exactly.

Mark: But if you take the approach of we knock out an enzyme you find the consequences downstream of that. Whereas if you take a diet, you don't find those negative consequences downstream. So in that sense, nutrition is far more powerful because it's sustainable. And it may be more powerful for another reason that it's affordable?

Yael: Well, yeah. I mean, there's so many good reasons. But yeah, it's affordable. It's accessible and available. But so nutrition can never knock something out. 

Mark: Right. 

Yael: Nutrition works on a more signaling level and it modulates.

Mark: Right. 

Yael: And modulation is what you what. So when you're using the cruciferous vegetables, you can...which is full of all these lovely isothiocyanates, and the kind of, sulphoraphanes, you are modulating the expression of genes. There are much more powerful compounds that you can take as a medicine that they actually almost overwork and they actually wipe out the whole signalling system. 

Mark: Yes. 

Yael: So this is the sophistication of nutrition. This is the nutrition that we need to be learning in our degrees. Where we can become masters with nutrients to be able to impact signalling more than anything. You know, the concept of using co-oxidants as antioxidants. 

Mark: Yes. 

Yael: You know, whereas at university I was taught just throw all the antioxidants you can possibly imagine into a supplement and take it. And now we understand that actually what you want to do is you want to create almost a light, mild, pro-oxidant environment as a signal to be able to switch on your antioxidant endogenous system. There's a way nutrition is starting to become a really exciting science.

Mark: That area fascinates me. We've had this concept of hormesis going back a century. 

Yael: Yes. 

Mark: The idea that a mild poison can in fact induce the most powerful pharmacology, which is one's own pharmacology. And this Nrf2 kind of expression.

Yael: Yes. 

Mark: Something that can trigger through the diet, a plant poison triggering an effect in the host, that is protective antioxidant and that signals cells rather than biochemically doses you to a certain point. It's such a nonlinear way of thinking about it, that I can understand a little how the, you know, each meal can actually make that difference. 

Can you go into that a little bit? The Nrf2, I'm not sure I or anyone else truly understands all the details but you seem to have a good grasp of that. Christine and you have a bit of a course in that.

Yael: Yes. So I would say that, I'm going to say that Christine is probably the greatest expert on Nrf2 of anyone I know. 

Mark: Okay, I shall ask her.

Yael: And really, it's her space. So I mean, I can give you an answer but she's going to do it so much better. 

But I will say, I mean, what's so exciting about the course that we teach is, you know, I was building a course in nutrigenetics, that was really my expertise. And then Christine and I met each other at a conference in Italy standing in the cue waiting and kind of eyed upon the wine on the table and thought let’s just go and have some wine so, you know, Italian conferences, they give you wine at lunch time. 

And we got talking and we realised that were coming to this story around nutrigenomics in a completely different direction. Me from a very dietetic, nutrigenetic and her from a very nutritional biochemistry. And we discovered that when we put our two... We call ourselves, you know, like nutrigenomics soul mates. That when we put our two sets of knowledge together, we had an incredibly powerful answer. 

So I’ll give you an example around Nrf2. Nrf2 is like a master regulator. And we know that’s critical for our hormone metabolism. We know that in hormone metabolism and oestrogen metabolism, is a whole phase 1, phase 2 intoxification. There's a whole lot of genes that can kind of cause chaos with how you metabolise those endogenous and exogenous hormones. Like the GSTs, we talk about even COMT, obviously having a significant impact. And then there's some kind of peripheral ones, like your MTHFR and your methylation genes. And then a cheaper one that Christine and I both like, NQO1, quinone reductase, amazing gene, absolutely fascinating.

Now, all of these genes have to work up to...for us to be able to metabolise and manage how oestrogens are processed in our bodies. And at any point, obviously you can have like a dysfunction in one of our SNPs which is causing kind of change in metabolism. And this is where the sulphoraphane and glucoraphanin are incredibly powerful in up-regulating. 

So what Christine and I did, is we took something like oestrogen metabolism and we actually gave a presentation on this a couple of years ago, where we presented together. And we took one pathway which was quite a complicated pathway and I gave the presentation on how different nutrigenetic gene variants in the metabolism of hormones could create a kind of a dysfunction in the process that might land us with kind of different, you know, the oestrogens going down different kind of pathways. 

Mark: Right. 

Yael: And then what Christine did when she came in and she said, “Well, if we know through using nutrigenetics that NQO1 isn’t functioning optimally and that we might have a homozygous and in fact, we’ve got a very, very low NQO1 activity. Now we need to up-regulate, we need to switch on. And know that Nrf2 switches genes. We think it switches on about two thousand protective genes.

Mark: Wow.

Yael: So, if I know that oestrogen metabolism is suboptimal, what you want to do now is you want to go and impact gene expression in a way, that switches on all these protective genes. And that's where Nrf2 comes in. 

Then Christine came in and gave this wonderful presentation on how we can use nutrition to switch on things like Nrf2. To up-regulate the rest of the GST family, the one that hasn't been potentially knocked out. To provide that kind of reservation support around COMT. And this is one of the... I would say to anyone who's listening to this that if you ever have an opportunity to be involved in nutrigenomics you must always ask yourself the question, have they covered both nutrigenetics and nutrigenomics? Because if you only have a conversation about the one and not the other, then you're not actually getting the full beauty of the field. 

Mark: Right. The nutrigenetics seems to be the easier one to grasp, especially for us limited male minds. Because there's a heterozygous, homozygous, we name a gene and as you would probably know, one of the flaws of medicine is you get something like MTHFR and we flog it to death as though it was the only gene worth knowing about. 

Yael: Oh yes, yeah. 

Mark: And you see these...and I've done it myself in enthusiasm, in the early days, load up with methylfolate, load up with methyl b12 and make the person sicker than they have ever been in their whole lives. 

Yael: Yeah, absolutely. 

Mark: And we back off a little bit and say, "Well why didn't that work?" And so doctors love an easy answer. You have a headache, here is paracetamol. You have arthritis, here is celecoxib. It doesn't work that way, does it? When you're thinking of nutrigenetics and nutrigenomics, the nutrigenetics part is only a data point. It's not a treatment. It doesn't describe a treatment. You have to move to the whole of genome and the expression before you have a concept of how would I manage this? Is that what your course does?

Yael: Yeah, I mean, there’s so many levels. I mean, the MTHFR fiasco has been, for me, the darkest hour of nutrigenomics. And I know I'm being a bit dramatic, but I really do believe that. 

You know what happened was, we have this really exciting field, a couple of practitioners who market themselves extremely well we’re like, “MTHFR, the mutation is the answer.” You know, it defines everything about us, autism, ADHD, depression, anxiety, pretty much everything. 

And what we need to understand is that in each new variant, these SNPs, that we talk about in nutrigenetics are what we call low penetrant..

Mark: Right. 

Yael: By themselves they do not cause disease. All they are is a marker of biochemistry. They give us an insight where a biochemical pathway may be working sub-optimally. 

Mark: Right. 

Yael: The other very important thing to know is that most variants work in pathways. They don't work in isolation. So, if you think about methylation, they’re kind of pre-transsulfuration pathways. Not one.  And MTHFR is only one part of it. And MTHFR 677 is only one SNP in the one pathway. 

And what happened was everyone, as you say, got onto the MTHFR bandwagon. They started giving these extremely high doses of folates, we started pushing everyone into this really like horrible over-methylation, their symptoms were actually worse than the entire symptoms before they started taking the folate. So it really has been quite… I mean, it’s still in that space. I mean, we still encounter a great deal. 

So what we teach in the course is a completely different approach. Which is gene variants and nutrigenetics, by themselves, are not that powerful. But they are extremely informative. When you take a whole bunch of low penetrant gene variants and you look at them in terms of biochemical pathways, this is why Christine and I love biochemistry so much. When you look at them in terms of biochemical pathways you start to make sense of the impact of those variants on the quality of the biochemical pathway. Once you have an understanding that perhaps that biochemical pathway is not working optimally, you can then think what are the interventions that I can go to to up-regulate? And that's why we, you know, very much on the principles of functional medicine that we go upstream. 

Mark: Right. 

Yael: We start at cellular systems. We don't talk about the disease. We look at inflammation, detox, methylation, oxidative stress… Because that's where, where we have kind of a dysfunctional biochemical situation, if they happen to have upstream at that level, we'll never solve anything downstream. 

So then once we've understood that and that's where in nutrigenetics is so helpful in identifying an individual where we need focusing our attention. And then nutrigenomics is how do we do nutrition to be able to impact that biochemistry? And what is unique about the course that we were able to build, Christine and I, is we were able to build both sides of the coin. We were able to build how do we use nutrigenetics to identify in our patients which area we need to work in? And then what do with nutrition to be able to up-regulate or down-regulate genes to be able to compensate for what we found in the nutrigenetics?

Mark: Does your course also give us tools to identify when we have been successful in that nutritional approach? So are there... I'll give you the example that I'm thinking of. Part of the reason the MTHFR, one particular genetic SNP, was important is doctors noticed high homocysteine in males who had heart attacks in their 40s and 50s. And there was a concept of, "Oh homocysteine causes heart attacks.” What can we do to reduce homocysteine? Without knowing genetics people just took B vitamins. And B vitamins were used to lower homocysteine and 30 years later we said, "Well the heart attack rate didn't really change. You know, what we did was we changed a homocysteine which is a kind of biomarker of that gene." 

Yael: Right. 

Mark: And then the enthusiasm was lost entirely but what doctors always crave is, okay you've told me what the problem is. How can I intervene? Now doctors think drug-wise but if the new doctor is thinking nutrition, not only how do I intervene but how do I know I've been successful? How do I not let this person run down the path that they were otherwise biochemically disposed to through their genes? So what's the markers that we can say, "Are we successful or not?"

Yael: Yeah, I think that is one of the great challenges that we have I think in the field of medicine and nutrition at the moment, is biomarkers. And I really do think that some of the most exciting developments in the next decade will come from biomarker development. And you’re a hundred percent right, that's exactly our challenge here is how do we measure if we’ve actually impacted the genes? 

Mark: Right. 

Yael: Now, we have this wonderful thing called functional testing, which I know you have a lot of in Australia as well. Where we can use things like the DUTCH Test, we can use organic acids and other testing to be able to get a baseline in terms of biomarkers and be able to measure it once we've done the intervention. 

Mark: Right. 

Yael: I mean, the DUTCH test is a perfect example of how when I was talking about oestrogen metabolism.

Mark: And the DUTCH Test is the urinary test to measure all the metabolites of most of the steroid hormones…

Yael: Correct, correct. 

Mark: And do it over a 24 period. So you know, not just to get one static picture how the body manages it over the days. So how will we use that test for example? Get a baseline and then intervene and then remeasure?

Yael: Yeah. So I'll give you an example. We use this quite a bit.

Mark: Okay. 

Yael: We use it quite a bit, for exactly that reason. So if we have a patient who comes to us for any reason, why.. when we suspect… So the difference is, we use genetic testing as a starting point because functional testing is extremely expensive. 

Mark: Yes. 

Yael: So we always… we use these genetics as a screening test to see what areas may be areas that we need to investigate further. 

If a patient comes to us with a strong family history of breast cancers or any kind of menopausal hormone issues, we might...what we'd first do is we would do an nutrigenetic test to see if there's any genes significantly impacting hormone metabolism. And then, if we felt that this was an area that needed further investigation we would do the kind of the DUTCH urine hormone test. Which is one of the better ones and more recent ones in the market. Where we could really get a sense of the pathways of oestrogen metabolites and what the issues are. 

And only I did mine quite recently and found that my oestrogen metabolism was actually pushing toward E4, so I was not aware of. Like I couldn't have guessed that. If I had gone to a normal gynaecologist in South Africa I would have had my kind of total oestrogen, total testosterone, or progesterone and known nothing.

Mark: Right.

Yael: And then I have choices. I can look at my genes, I can see where in that nutrigenetic profile I perhaps have a deletion in GST, perhaps my NQO1, my quinone reductase is not good, and then I can choose the supplements and nutrition, a plan, to be able to up-regulate. I can then in three months to six months time take the DUTCH test again and be able to see whether that oestrogen pathway is now moving to a different place. 

Mark: Right. 

Yael: So that's an example where you can functional testing together with nutrigenetic testing, together with nutrigenomic intervention which is extremely powerful. 

That isn't always... I mean functional testing as I said, it can be quite expensive especially when you have to repeat the test. So this is where we would like to be. We're definitely doing it at the moment but we're not using functional testing as much as we'd like just because of the cost barrier. 

Mark: Right. 

Yael: But that definitely is going to be an answer.

Mark: Like most things, when they become more common in medicine the costs come down once you commoditise it a little. 

So this is, you know, the big argument, medicine tends to wait for the early expression of disease, the pathology test become positive at a point where you wish you had acted earlier. But every time medicine which is good as disease treatment, every time it fiddles with prevention it tends to get it wrong. It tends to, you know, give drugs when a person does not need drug therapy.

Yael: Absolutely.

Mark: So cholesterol management, inflammation management, blood pressure management..

Yael: Yep. 

Mark: Where there are other options we tend to apply medicine that's great and extremist but it's not good for a person who's going to live the next 40 with the medication. So that transition I think will happen as we get better and better at understanding it. And I've got to say this, apart from, well, let's say doctors should come and do yours and Christine's courses. I understand they're online courses aren't they? The foundations of nutrigenomics and translational nutrigenomics.

Yael: Yeah. We have two courses. We have our first course which we built translational nutrigenomics which we really say is, you know, if you want to be an expert in nutrigenomics, if you want to differentiate yourself from the marketplace in nutrigenetics, it's a brilliant course. It's very high level, you really delve deeply and you really become an expert in the space. 

Mark: Right. 

Yael: Then we realised that not everyone wanted to be an expert. So we built what’s called the foundations course. Also though, for those that just want to kind of, get a sense of the field and not sure whether they want to be an expert, we built the foundations course. And I kind of, it goes under the brand of Manuka Science. 

Mark: Rght. 

Yael: It was named after the Manuka honey, from down the road from me.

Mark: Ahh right? No, it is the whole new science of the whole of life and the influences from every direction. But Manuka, that concept of using something like honey, my own mother had to go through wound management. The best of science, the best of hospitals could do nothing about her wounds and her ulcers on her legs. The Manuka Honey was the difference and the turning point for her.

Yael: Amazing.

Mark: Yes. It was amazing to me as well. And as her diet failed her, it was external application. And it does lead me back to that concept that yes we're humans. We live in a world of plants, of biology, of things around us. We've co-developed and co-evolved with those. It should have been obvious to us that the molecules of life have got a higher capacity for sustained treatment and help and benefit than the drugs that we manufacture in a laboratory. But that was the very first practical experience that I had of that.

Yael: Yes. That was right there. I mean, it's an amazing story and now we know the science. 

So in the time… and what’s interesting, is when they were using it for wounds, they didn't clearly understand why it was able to do what it was doing. Now because we know, you know, the molecular level. But it still extraordinary, that's an extraordinary story. That should be teaching us, this concept again, of mother nature, where the plants and the foods around us are much more powerful at talking to our bodies than drugs. Which kind of just go in and kind of shoot everything down.

Mark: So a final question is if you had to give just one or two pieces of advice to our listeners, to practitioners who are looking to understand nutrigenetics, nutrigenomics, what would it be? Would it be to be educated? Is there a way of immersing ourselves in this safely and understanding it? Is there a simple trick that we should know about with, you know, eat a salad everyday? Would you give a kind of potent piece of advice or do we have to immerse ourselves in this whole thing?

Yael: You know, I wish I could say there was an easy way. I don't think there is. I think the most important thing is to acknowledge and understand that this is not knowledge we were given at university. That we have a knowledge gap, I call it the knowledge gap. That we have to go back and add, study again to fill the gap. 

But then I would also say that what waits on the other side is so exciting and engaging that it's like having… it's just walking through the looking glass in Alice in Wonderland.

Mark: Right. 

Yael: Where you kind of, you think you’re a certain way, and then you study something like this and you come out the other side. Like, you know, gene expression, it’s such a mouthful. And you can see the work you to and it doesn't matter whether you're a homeopath, whether you're hydrotherapist, if you are a dietician, your view changes. And unfortunately, I really do believe that education has to be the first step. It doesn’t have to be the big course. You can do a short course. But start learning. Start engaging, start learning, start reading, get the terminology because you don't want to miss out. The reality is genetics is mainstream.

Mark: It's the new medicine, isn't it? And it's being handed back beyond the doctors.

Yael: Yes. And this is where the power lies and if you're not going to engage with genetics you're being left behind. And I know it's a very harsh thing to say but it's the absolutely truth. If you're not in it will be like you are the dinosaur, you will be left behind. Because genetics is now just part of what to do, it's not an add-on. 

Mark: Dr. Yael Joffe, it has been delightful to talk with you. I hope to talk with you again soon. You and Christine, between you, I'd like to have more conversations on this. There's so many areas we haven't touched, but thank you it's been delightful today.

Yael: Thank you Mark, it has been fascinating hasn’t it? It was very interesting to meet you, I really enjoyed it. And yeah, I look forward to any other time.

Mark: This is FX Omics and I'm Dr. Mark Donohoe.



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The information provided on FX Medicine is for educational and informational purposes only. The information provided on this site is not, nor is it intended to be, a substitute for professional advice or care. Please seek the advice of a qualified health care professional in the event something you have read here raises questions or concerns regarding your health.

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FX Omics Podcast

The FX Omics podcast is hosted by renowned Australian integrative medicine expert, Dr Mark Donohoe. Join us as we explore the emerging research and clinical application of genetics, epigenetics and metabolomics and why this is the future of personalised medicine.