Have you been wondering what you should really do with the 23andme genetic data that you’ve gathered? Wondering if you should even take the test at all? Or wondering what the future of genetic/epigenetic medicine is? This podcast is for you.
I am especially excited to bring you this conversation with epigenetic legend, Dr. Moshe Szyf. The study of epigenetics is continually breaking new ground in understanding how our environment dramatically influences our gene expression. With myriad published research studies and his ongoing work, Dr. Szyf is at the forefront in shaping this evolution.
The power of epigenetics to alter the course of our health is compelling, and I hope you will enjoy the discussion we had, which I hope will be one of many.
“Methylation is the punctuation which turns DNA into a language.” Dr. Szyf
In this podcast, you’ll hear us discuss:
- How DNA alone cannot explain variations in our development and health
- The concept of our ‘phenotype’, a marriage of genes PLUS environment
- Why the idea of genetic determinants of disease is too simplistic
- Why aberrant DNA methylation in cancer is EVERYTHING
- The “dirty” DNA de-methylating drugs used against cancer
- Big pharma’s disincentive to pursue natural, safe interventions
- Why life is much more complicated than science allows for and why we need to deal with it
- Analyzing epigenetic methylation through saliva or buccal swabs
- Why your 23andme data only has a small impact on your health outcomes
- The elephant in the room—environment and epigenetics as the bigger risk factor
- The BRCA gene story and how it supports a lifestyle connection moreso than genetic predisposition
Moshe Szyf received his Ph. D from the Hebrew University and did his postdoctoral fellowship in Genetics at Harvard Medical School, joined the department of Pharmacology and Therapeutics at McGill University in Montreal in 1989 and currently holds a James McGill Professorship and GlaxoSmithKline-CIHR Chair in Pharmacology and is a fellow of the Royal Society of Canada. He is the founding co-director of the Sackler Institute for Epigenetics and Psychobiology at McGill and is a Fellow of the Canadian Institute for Advanced Research Experience-based Brain and Biological Development program. Szyf has been the founder of the first “Pharma” to develop epigenetic pharmacology “Methylgene Inc.” and the first journal in epigenetics “Epigenetics”. Szyf lab has proposed two decades ago that DNA methylation is a prime therapeutic target in cancer and other diseases and has postulated and provided the first set of evidence that the “social environment” early in life can alter DNA methylation launching the emerging field of “social epigenetics”.
- Maternal Genistein Alters Coat Color and Protects Mouse Offspring from Obesity by Modifying the Fetal Epigenome
- Szyf: Reversal of Maternal Programming of Stress Responses in Adult Offspring through Methyl Supplementation: Altering Epigenetic Marking Later in Life
- Pregnant women’s cognitive appraisal of a natural disaster affects their children’s BMI and central adiposity via DNA methylation: Project Ice Storm
Podcast sponsored by Metagenics and Biotics Research Corporation
K. Fitzgerald: Hi, everybody. Welcome to New Frontiers in Functional Medicine. I am Dr. Kara Fitzgerald. It’s just my pleasure and honor to be podcasting today with Dr. Moshe Szyf. Dr. Szyf is a professor at McGill University, and a little bit of his rather remarkable background, he obtained his PhD from Hebrew University and did a post doc fellowship in genetics at Harvard Medical school, joined the Department of Psychology and Therapeutics at McGill University in 1989. Currently, holds the James McGill Professorship and Glaxo-Smith Kline CIHR Chair in Pharmacology and is a fellow of the Royal Society of Canada.
Very interestingly to me and my interest in epigenetics, Dr. Szyf has really been looking in this world, it appears to me to be longer than most. Currently, he’s the founding co-director at the Sackler Institute for epigenetics and psychobiology at McGill and is a fellow of the Canadian Institute for advanced research experience based brain and biological development program. Dr. Szyf is the founder of the first pharma to develop epigenetic pharmacology, MethylGene, Inc. and we’ll be sure to talk to him a little bit about that in the first journal in epigenetics, aptly titled Epigenetics.
The Szyf lab has proposed two decades ago that DNA methylation is a prime therapeutic target in cancer and other diseases and is postulated and provided the first set of evidence that the social environment in early life can alter DNA methylation, launching the emerging field of social epigenetics. Just a cursory search on PubMed, Dr. Szyf has hundreds of publications and really some of the earliest from the 1980’s looking at epigenetics. I had the honor of actually seeing Dr. Szyf present at Jeff Bland’s Personalized Lifestyle Medicine Institute in 2015 and was really blown away by the depth and breadth of his work in epigenetics in both animal and human studies.
Again, it’s just honor to have you join New Frontiers Today, Dr. Szyf. Thank you.
Dr. M. Szyf: Thank you very much for inviting me.
K. Fitzgerald: I want to just jump right in. I know the term, epigenetics, I think clinicians are hearing and sort of becoming a little bit more familiar with but can you give me a basic overview of epigenetics and DNA methylation?
Dr. M. Szyf: Epigenetics is a concept that actually was coined by a British scientist in the 40’s, and he understood already then, as an embryologist, that the DNA sequence cannot explain the mystery of development. And specifically, how we have one set of DNA molecules and we have millions of different cells that have different forms and shapes and what we call phenotypes.
So there must be something between DNA and the phenotype that takes the DNA and gives a different interpretations in different contexts. And he called that epigenetics. This idea kind of fell out of favor, it was not of interest because the discovery of DNA structure and the sequencing of DNA, got us so excited about the gene sequence that we kind of put aside the fact that something else happens to the genes.
Actually in the early 40’s another scientist in the United States discovered that DNA is not just the four letters that we all know G, A, T, C, but that there is a minor base, a DNA, a methylated cytosine. And even that observation was left there with almost no attention paid to it until much later. And only later, in the early 80’s, people started to ask the question, “How are genes programmed? And how can the same gene do so many different things in different contexts?” And they went back to understanding how DNA methylation regulates genes. In a simplistic way, if the G, A, T, C, are the letters of the DNA language, methylation is the punctuation mark. It makes sense out of letters, it breaks up the words and sentences, overrides and under rides, and puts exclamation marks and question marks so that the letters become into a language.
So, DNA methylation is a very primary epigenetic mechanism that allows DNA to be flexible, and to do so much more than it can do just from the sequence itself.
K. Fitzgerald: It seems like the research into epigenetics is epically catapulted forward, and it seems like an impetus for that was around the disappointment for, maybe lack of a better word, that the human genome wasn’t telling us as much information about disease as we had anticipated. Is that true? Would you say that really pushed forward the research into epigenetics, or was that happening anyway?
Dr. M. Szyf: The research into epigenetics originally happened independently. The attention to epigenetics has changed around 2004 and if you look at the PubMed citations, you see an inflection in the curve. An exponential inflection. Where genetics is kind of stable and epigenetics is going up.
K. Fitzgerald: Yes, I observed too, that a lot of those papers are the conclusion of the abstract often is, “For the first time ever, we’ve shown …”. It’s pretty remarkable to see that.
Dr. M. Szyf: And what happened in 2004 is that I think that two papers came out, and one paper from our group that showed the Rat Maternal Care, that maternal care can change DNA methylation in the children. That was the first glimpse into social epigenetics. And Randy Jirtle, the same year, published a paper where you show that the maternal diets can change her offspring coat color and obesity and other things: the Agouti mice experiment. So for the first time, there was an awareness that it’s not just the sequence, it’s the context that can be very detrimental in how genes work.
Kara Fitzgerald: So, you pointed out, your study was amazing. I’ve actually used it. I’ve lectured periodically on the HPA axis and have cited that original work, where you were looking at vasopressin and glucocorticoid influence: genetic methylation marks in maternal care. So you’re looking at really clear environmental changes and behavioral and Jirtle was looking at nutrients.
Dr. M. Szyf: More diet, yeah.
K. Fitzgerald: Amazing.
Dr. M. Szyf: But it all happened at the same time, and you can see how it captured imagination of many scientists. And they started looking at similar things. Then thousands and thousands of papers have looked into how environment, whether behavioral, dietary, physical, could have long term impacts. So you eat the food today, but the impact are felt two generations down the line. And that has changed the way we think about how genes work.
K. Fitzgerald: Just incredible stuff! All right, I’m going to ask you a few questions about that. I know you’ve done number of publications on that fateful ice storm. And you had some really great observations that we’ll circle back to, but right now, your lab has done a number of publications looking at DNA, aberrant DNA methylation and cancer, and I know it’s an area of big, big, big, big drug development, etc. Can you talk, first of all, about, can you just define aberrant methylation and then DNA methylation specifically? And then cancer, and maybe expand it to other diseases because it seems to be a player in pretty much everything.
Dr. M. Szyf: Right. I think cancer is a good example of how the field evolved. I remember when I first proposed that DNA methylation is changing in cancer. I had some prominent scientists call it misguided attempt at scientific humor.
K. Fitzgerald: Oh really?
Dr. M. Szyf: Yeah. The idea was that cancer was all genetics. And until now there’s a tremendous investment in sequencing different tumors, and it’s called Personalized Medicine. For sure, it does provide some very important information. But, the idea was very simplistic. When I was a graduate student, and I looked at cancer and I said, the problem in cancer is that these cells are expressing a different genetic program than they should. Skin cells should remain in the skin, they should not metastasize to the lung.
So something is going on with the way the DNA is working that changes the program. And yes, you can change a program by changing the DNA, genetics. But, if DNA methylation indeed controls the way genes work, it stands to reason that it changes in cancer. This is the easiest way for a cancer to become cancer is to change the way genes are programmed by DNA methylation.
And there are multiple things happening in the DNA of cancer cells. They are so different as far as DNA methylation from their normal counterparts that we can say that thousands of genes alter their methylation pattern. So where as genetics is looking for one gene that got mutated, for the little leaf in the forest. The whole forest is changing.
So, thousands of genes are now programmed differently. Genes are supposed to work in the brain are working in the liver, or genes that are not supposed to work in the liver are working. The way I picture it, is that the change is not just one little thing. If you look at a cell as a corporation, the corporation has changed its strategy. It’s now doing something else. It’s not producing cars anymore, it’s producing airplanes. So when a corporation moves from producing cars for airplanes, it’s not just changing one gene. Yes, the CEO took a decision to change, but everything is changing. And this is what’s going on.
So the aberrant DNA methylation in cancer is everywhere. Almost probably half the genome has changed and it’s just doing different things. It’s now doing the stuff that it needs to do in cancer. So the idea was, that if we can tap into the machinery that makes this happen, we might cure cancer. What they discovered early on is that almost every genetic pathway that leads to cancer, goes through DNA methylation. So, they have to do that because they will not be a cancer if they don’t change DNA methylation. We will have to change the program. It really doesn’t make a difference how the cancer started. In the end, it has to change DNA methylation. Therefore, we have to target that. Because by targeting that, notwithstanding what was the cause, we will be able to cure cancer.
So, that’s one of the important aspects of DNA methylation in cancer. But, if you think about it, almost every disease involves a change in program. Obesity is a change in program, both in the brain and in the fat cells. The brain doesn’t think it’s satiated, it thinks it’s hungry. That involves changes in gene expression. That involves changes in how genes are programmed. The fat cells are now storing the fat, rather than burning the fat. That again is a change. And you can take any disease, from hypertension, to cardiovascular, to psychiatry diseases. They’re all the same. But all involve changes in gene regulation.
Therefore, the question is at three levels. First, can we prevent it? Why did it happen? Why did cancer cells change their program? Is it something normal that somehow wasn’t balanced properly? And why is it happening? Because it looks like a very sophisticated change. Is it just random noise, or is there something that is driving it? And we don’t know the answer for it. But now it is very much excitement with the immune system, so the immune system has to keep the cancer in balance. Why does the immune system fail in doing it? Did it also change its methylation pattern? And why did the methylation pattern change? Did it change because of some signals that came in by infection, by experience, by other things? How is stress connected to it?
So, that raises a lot of questions about the origins of that change. Now we know where to look. We see that change in gene programming and we can ask ourselves a question, “Why did it happen? Can we prevent this from happening?”
The next question is, we can use it as an enormous diagnostic tool. Because the methylation patterns provide essentially a fingerprint of the cell fate and the cell’s state. And we can map it. We have now the technology to map it. So, we can use it for early diagnosis. But, we can also use it for follow up. And what was suggested early in cancer is now being applied to psychiatry and to other situations.
And the third thing is, DNA methylation is controlled by proteins that are “druggable”. If we can interfere, we might be able to reverse the situation. The nice thing about epigenetic therapy is, if we can reverse it, we’ll reverse the underlying cause of the disease, not just a symptom of the disease. Because, once we remove that programming, we remove the disease, because the disease, unless something else happens, will not know how to put that program back again.
K. Fitzgerald: There are a number of de-methylating agents are already being used clinically, and there’s a whole bunch of them in various states of trials and the outcome on those? They’re being actively used, any comments?
Dr. M. Szyf: The current drugs are quite dirty drugs. They’re old drugs. It’s interesting, the drug that is now used in the clinic was invented in the 50’s by a Czech chemist. It also shows you how drugs has many lives, and it had many lives. Now it’s used mostly against blood cancers. It’s not very good against solid cancers. But I think because we don’t know enough, we’re still learning about the system, and these drugs are just not very specific. There’s a tremendous effort now to become more sophisticated with epigenetic drugs, but also to learn how to use them.
K. Fitzgerald: Yes. More tissue specificity, I would imagine and things of that nature.
Dr. M. Szyf: Dosing, scheduling and the other exciting thing is, can we use natural products to do the same?
K. Fitzgerald: Yes. Oh my gosh, yes.
Dr. M. Szyf: And I think that this is an area of medicine that was abandoned just because of the reward structure of pharmaceuticals.
K. Fitzgerald: Yes.
Dr. M. Szyf: It’s very hard to get a patent on a natural product. And it’s very hard to protect it. If you want to invest a billion dollar in research, you want to get some sort of reward. A return on investment. And that’s a major problem. Society hasn’t solved that problem. So, there’s a bigger incentive for a drug company to develop a new poison, than to reinvestigate some safe compounds. Because there’s no return on such an investment.
K. Fitzgerald: Well, yeah. So that’s what I’ve been thinking about in my world. Clinically, and then we’ve also been writing about it. There’s a big movement in integrative medicine to support, quote methylation. Lower homocysteine, people have a MTHFR mutation, etc. you know, depression. Very high dose methyl donors. So, folate went from micrograms to milligrams. Routinely we go very aggressively with it, as well as with methyl cobalamin and all of the other players.
As I started to unfold this epigenetic data, especially around this aberrant hyper-methylation happening in virtually every disease, I know hypo-methylation paradoxically happens as well. I get it. Both things are occurring in one gene. In one, probably relatively close regions. I know the promoters in the body of the gene. At any rate, as I started to read this data it occurred to me, maybe I was not doing my patients a service, especially if they had active cancers, by pushing methylation. So that was one question. And even using natural products. But then, as I started to dive there and it began to alter my thinking with regard to my patients, the other data that I began to read about that was incredibly compelling, and I think you’re alluding to it now, is the fact that there are these nutrients that we’ve used for millennia that have this sort of methylation balancing or remodeling capability.
Like, curcumin or many of the polyphenol compounds. Curcumin, luteolin, lutein, quercetin etc., all of these active constituents of foods that are included in any healthy and many traditional diets, actually are able to support balancing or remodeling the epigenome and in a healthy way. I don’t know, I have been doing that in my clinical practice now, and have started to write about it, and would actually like to research it to some extent. But are you, I mean, is that what you’re talking about? Actually considering some of these things? Some of these molecules?
Dr. M. Szyf: Yes. But I think the way I would have loved this to be done is a bit different. Is through really scientifically control clinical trials.
K. Fitzgerald: Absolutely.
Dr. M. Szyf: The problem is that they’re so expensive to do. The alternative option is to get some data from clinical practice. If we had a way to organize this, so we could have kind of meta-clinical trial, just by looking at what happens to people who do take these things.
So it might be a new way of doing clinical trials, because the classical way might be too expensive. And also, with computer technology with our ability to look at people in very faraway places using apps. It might well be, and I know that there are some companies working on this, which is looking at the effects of nutritionals and nutritional supplements on disease in this amateur kind of way, but by collecting data from a lot of people. That could then be statistically put together and compare to some control group that was not exposed to these compounds.
K. Fitzgerald: Well the other thing is, and what we’ve been looking at in our clinic, seriously, coming from your research, looking at behavioral modification of the epigenome and then looking at exercise, looking at exposure to toxins… I mean, you can cast a wide net on putting together a healthy living program that potentially augments the epigenome very favorably.
Dr. M. Szyf: Yes. I mean there’s evidence of exercise is working. And that it has changes on epigenetics. I think there’s quite good evidence. So, when we exercise, it’s not just we burn calories, that probably has a very small effect. It’s the system says, “Oh, this guy exercises, so I have to change everything to fix what this guy needs.” And these changes are most probably good for us. Although, perhaps, over-exercising is also not good.
K. Fitzgerald: Right!
Dr. M. Szyf: And that’s something that we never actually tested formally, right? How much exercising is good, how much exercise is really needed. And the same is true for methyl supplements and everything else.
K. Fitzgerald: Yes. It’s very interesting.
Dr. M. Szyf: Yes. So, the question is: How would research be done? If we do it traditionally, through academic or industrial traditional ways of doing medicine, this would be outrageously expensive to examine. And the only reward is that you make people healthier, but that doesn’t put money in your bank account. It doesn’t increase your pension funds and things like that.
So we need to think about the way of doing these things that gives some return on investment, but where the investment is smaller, because we take advantage of natural experiments. Like the ice storm, was a natural experiment. You medicating your patients is also an experiment, but it’s never documented. It’s never you know, you have your anecdotal experience and some other practitioner has his or her experience. But we don’t put it together.
I think today, with the technology, the media technology, the social media technology, we might figure out a smart way of putting together all this data and analyze it with the same rigor that we analyze the clinical trials. Where we have collected confounder data, other variables. We can do a co-variant analysis and we could perhaps tease apart and maybe we have the best clinical experiments in the world going on all the time, but we don’t get the data.
K. Fitzgerald: Yes. That’s right. I think now that we’re hopefully moving towards some user-friendly systems model, having cloud data and live, real time collection. I think you’re right. I very, very, very much want to research this and have gotten some, I know this is off topic, this is going off topic, but I just have to take advantage of your interest in this. I would very much like to do a trial and have some support.
The piece that I’ve been struggling with, as a clinician, is that I don’t have ready access to the epigenetic analysis. Specifically, looking at the regions of hyper and hypo-methylation and determining how we do that. I know some trials just look at this sort of global methylation…
Dr. M. Szyf: No, no, you can do that. And the technology is there.
K. Fitzgerald: Okay.
Dr. M. Szyf: Genomics technology has made these things do-able, they just cost money. And yeah, you can essentially answer whatever question you want about DNA methylation.
K. Fitzgerald: I would absolutely love to do that. And I think the time is now to start putting, us clinicians, to start putting our toes in this pond and collecting those data.
Dr. M. Szyf: Right. But I think collecting data from multiple places, finding some sort of way of connecting, linking them through the media. The available media applications, so that we collect data on everything that could go into the analysis. From lifestyle to food to, let’s say methyl. If we are interested in methyl supplementation, I’d guess that millions and millions of people in the world today are medicating themselves with methyl supplements.
K. Fitzgerald: Absolutely.
Dr. M. Szyf: But we have no idea what happens to them.
K. Fitzgerald: That’s right.
Dr. M. Szyf: And so, if we could collect all of this, and you know, if one could collect Isis across the world, we should be able to connect people who take methyl supplements across the world.
K. Fitzgerald: Yes!
Dr. M. Szyf: And then have them be our scientists, you know, document what’s going on. Measuring things that we decide are important to measure. Then eventually sending us the saliva, and then we do the methylation analysis. We have the clinical data, and we put together link their lifestyle to the medical records. For example, I think that SAM, which is a donor of the methyl group, is a very good compound to prevent breast cancer. I have animal experiments going on showing that. Liver cancer and PTSD and Alzheimer’s and there are millions of people taking them and I guess some of them have breast cancer and other things. And if we could collect all of this information to derive conclusions, at least guide us and say, “Ah, it’s worth spending a billion dollars in trying this.”
I think this is the challenge. I think it’s now do-able with the convergence of social media, ability to store huge amounts of data and crunch huge amounts of the data. And the readiness of people to do this, because people are now trained to work with this kind of thing. But as I said, you know, if evil people can use the media to do this, why can’t we use it for good purposes?
K. Fitzgerald: Yes.
Dr. M. Szyf: And actually address these questions critically, right? Rather than, you know one of the problems with a lot of nutritional stuff, is it becomes like a religion and there’s never a base line learning process where we see… We do it, then we see what happens. Then we change it. Then we do it again, and then we see what happens, and we change it again. So, there’s a training and machine learning in this process. Rather than having it as a religious, “Oh, it’s good to exercise.” Is it really good? Maybe, not always.
So a lot of these things are based on just beliefs. It’s cool. And people are doing it, but we don’t know what happens to them. We never measured that.
K. Fitzgerald: Yes.
Dr. M. Szyf: We don’t have the structure to measure it.
K. Fitzgerald: It’s all very personalized too. What’s a good exercise protocol for you, may be very different for me. Intensity level and duration and all of that.
But listen, I just want to circle back to a couple of comments you just made and then maybe talk a little bit more generally because I know that this is a new topic for a lot of people. But I’m on board with you. I am so on board with you and I will… it will just be great to share this conversation I’m having with you with some of my colleagues who are equally motivated in gathering these big, big, cloud-based systems data and see what we can do. So I’ll keep you… I’m very excited about it.
But anyway, just wanted to talk about S-Adenosyl Methionine is I think most of the listeners on this podcast are aware of is our major universal methyl donor. So you’re looking at your data, as I understand, you said, preliminary data in animal studies is showing it as a protective intervention against breast cancer, liver cancer, Alzheimer, PTSD. That’s huge! Again, underscoring the importance of healthy methylation. Sufficient methylation activity would be the case. And that, using SAMe. So we’re supporting active methylation.
Now, I just want to ask you though, so everybody, please, understand that. The importance of methylation in maintenance of fundamental wellness prior to the onset of disease. But once breast cancer is active, liver cancer is active, and we know that there’s aberrant methylation all over the place, and there are these regions of hyper-methylations. When the tumor is active do we then regroup, and reconsider SAMe? Correct?
Dr. M. Szyf: Yes.
K. Fitzgerald: Okay, all right. That has been my-
Dr. M. Szyf: And from a cell culture, human cell culture, and not just we, I think …
K. Fitzgerald: Excuse me?
Dr. M. Szyf: We somehow got disconnected.
K. Fitzgerald: Can you hear me?
Dr. M. Szyf: I don’t know what happened.
K. Fitzgerald: Can you hear me?
Dr. M. Szyf: Okay. Yeah. Now it’s back.
K. Fitzgerald: Okay. I can hear you okay.
Dr. M. Szyf: So we have data from a cell culture. Human cancers that we can treat with SAMe. And we changed the entire genetic program. We looked at the genome-wide methylation, we looked at genome-wide expression. It’s no question. And what’s interesting is that, for some reason that I don’t understand, it prefers cancer cells to change them. And causes less damage to normal cells.
And we know that because people are taking SAMe for now decades and we don’t have many problems. So obviously it’s not very toxic. And what I want to share this with journalists and others, we always have a problem because SAMe is an old stuff, you know? Tell me something new. Tell me some new molecule. And my argument is, why do I have to tell you something new if the old stuff is actually better?
K. Fitzgerald: Yes.
Dr. M. Szyf: And so we have a misunderstanding of what “new” is. New is needed if you
need better things. But, sometimes, you can used new techniques like media, and new genomic technologies to examine old ideas. And it might be actually extremely good.
SAMe, I think has tremendous potential. It was under-utilized because it was never tested in a clinically acceptable way. And I tried, I tried to do a study. I convinced a colleague to give it to patients with major depression and it would work very well, and then I said, “Why don’t we do a study? A real clinical study.” Because, if it works on a patient, you never know. Did it work just because God helped the patient? Or was it just a random change that happens? Nothing in medicine is perfect. You have people with the worst cancers, they get cured. But you don’t know, is it because of your drug, or is it because it’s just the statistics? One percent get cured.
K. Fitzgerald: Yes, right.
Dr. M. Szyf: And that’s why we need a clinical study. And he answered and said, “Who’s gonna pay for it?” You know? Even though the drug is cheap, you can buy it in a health store. But, you need the nurses, you need the hospital, you need to document it, you need the regulatory work. So, we need to find another way of going about it. And in the end he said, [inaudible 00:33:16]. Granting agencies want to sponsor new stuff. Because they always have to say, “We’re novel and creative.” I think there’s tremendous creativity in finding all this stuff that actually works. But this is not the way we understand creativity.
And drug companies will never support it because we’re not rewarding them for that. So we’re stuck. But, I think there is some overwhelming data with SAMe. The only problem with SAMe is it’s not a poison. And therefore you can’t make money out of it.
But I guess, that out there in Chinese traditional medicine, in extracts from cells, there’s a whole slew of things we can do. And we have now the technology to check it. I can tell you, this thing changes methyl. And that’s the difference. You see?
K. Fitzgerald: Yes.
Dr. M. Szyf: Like, 20 years ago we could guess, we could believe in it. Today we can actually critically test it. So I think we are ready to screen millions of natural compounds and find the balance that can actually work.
K. Fitzgerald: Well, and also I think in this systems model, that we have to embrace and expand our research structures around to honor. We need to look beyond just a single molecule intervention, I think, to the whole dance of life.
Dr. M. Szyf: Of course, of course! And we see it everywhere. You know, whatever I do, even for diagnostic, you think one marker doesn’t work, you take a few… it’s amazing. Because systems don’t work as single genes. They work as systems. And there are multiple ways by which a system can work to get the same output. And therefore, it’s never one gene, it’s never… it’s a systemic approach, and that goes against very much of what we have done in science. Because science was focused on a reductionist approach, on making a knockout mouse with one mutation, or better a yeast with one mutation. But life is much more complicated, and you need to deal with it.
K. Fitzgerald: Don’t you think, again circling back to sort of the disappointment, I don’t know if that’s the right word, around when we completed mapping the human genome, and I see that humorous quote out there where it’s, “less than a grape, but more than a chicken…” the number of our genes. So, we couldn’t find this reductionistic one gene, one disease. We had to really blow up and think about the exposome and all of this, and it just seemed to me that we basically answered that we have to embrace this bigger thinking.
Dr. M. Szyf: Of course. I think it’s accepted at a theoretical level, but at the practical level, most scientist are still trained to look for single genes. And they get very confused when they see a mixture, and they don’t believe it, and they don’t fund it and they don’t like it. So, it will take some time.
K. Fitzgerald: Let me guess. Well in our world, in this functional medicine integrative world, this is where we think, and what we attempt to actualize. And I know there isn’t money for this, but we’re certainly always pondering it. There are some systems in Gig Harbor, I think, or not Gig Harbor in Seattle, the Institute for Systems Biology, I think that they have some interesting larger projects going on collecting this data.
But listen, I wanted to ask you a couple questions here. You mentioned saliva as a specimen for analyzing the epigenome. So saliva is adequate?
Dr. M. Szyf: Yes, and buccal swab are even better. They are better.
K. Fitzgerald: That’s great. It’s very, very easy. Anybody can do it.
Dr. M. Szyf: But it’s do-able, yeah.
K. Fitzgerald: No phlebotomy necessary!
All right, what else, I wanted I know we’ve got so much to cover, but I think we’re heading towards the end here. Why don’t you talk a little bit, because it was just powerful, such powerful work you’ve been doing on these behavioral changes. Maybe give us some of, actually, wait… let me just ask you one question before we go there and then we’ll go there. Again, in our world, Integrative Medicine, there’s lots of us, and lots of our patients. Actually many of my patients come to me having obtained a “23andMe” data. Single nucleotide polymorphism, thousands data set of their particular SNPs. There’s a lot of emphasis put on these mutations as dictating disease pretty profoundly. And people will take many, many supplements and do… design pretty involved, expensive protocols with really no evidence behind them.
And I know there are some genome wide associations studies that are pretty good. Particularly as they look at groups of SNPs, but in light of really understanding the epigenome and how and I know with regard to cancer, the epigenome is a bigger deal than mutations. What do you think about this movement towards analyzing and treating or addressing single nucleotide polymorphisms?
Dr. M. Szyf: I think it will work on very few, rare cases. There are cases where there is a mutation in one gene that causes cancer like breast cancer 1 and there are retinal blastoma. There are a few. But I think even in these cases probably a good epigenetic strategy might overcome that, because BRCA1 also has to go through epigenetics. And so, in the end, even if there is a genetic cause, manipulating the epigenome is worthwhile. But, I think what people don’t understand is to actually read the data that they get from 23andMe. The risks are very small. Therefore, we should focus on the big risks. And the big risks are probably, in the end, environmental.
If you become overweight, and you don’t exercise, your chances of getting disease, whatever genes you have, are very high. I think, notwithstanding, we all carry some genetic baggage that changes our risk for disease slightly. But they were not overwhelmingly change our future. I think we need to focus on the large effects. And the epigenetics effects are large. They happen in every cancer. You cannot avoid them. These are much more important.
K. Fitzgerald: Yes. Well, in fact, circling back to the BRCA mutations, we know that environment is massive with them because the incidents associated with cancer and BRCA mutations decades ago was much, much, much, much lower than it is now. Of course, you’re familiar with the data around, well you know, hyper-methylation of the BRCA gene. So, it doesn’t even take a mutation, the BRCA mutation to shut that suppressor gene down.
I agree with you. It certainly makes more sense to me that the epigenome is playing a bigger role. And, I think the thing that’s really heartening for me, as a doctor, is we can do it, do stuff about supporting healthy epigenetic balance or remodeling, etc. It just feels like there’s much more I can do as a physician in advising and supporting my patients towards wellness. When I think about the epigenome versus genetics. Can you talk about the ice storm? I know you’ve published a whole bunch of papers on it. Maybe just a couple of the takeaways from that really interesting research? And then we’ll wrap up and, again I appreciate your time.
Dr. M. Szyf: The ice storm of ’98 in Quebec, which was a major natural disaster, allowed us for the first time, to me to look at the impact of adversity early in life in a random way. Because most of the criticism of our work and other work in this area is that, let’s say we found DNA methylation differences in people who were abused as children. So, they have adversity, now we find the DNA methylation, and we connect it to some psychiatry condition, or heart condition, or something. How do you know that it’s causal? How do you know that this methylation change was not caused just by underlying genetic differences?
Everything is genetic anyways, and therefore, you don’t add much to it. With animals, we can control for it. Because, we can take one group of animals, and expose them to adversity, and another group, not. And see what happened. Then we know that what happened was because of adversity. It wasn’t because they carried bad genes. It’s because they had the bad childhood.
So, here, the ice storm was a random occurrence. People were inflicted by, not because of their genetics, not because of their inheritance, not because of their history, just because they happened to live in Quebec and they were damaged in very different ways. So the whole quantitative distribution of how much stress you have.
K. Fitzgerald: Well how long was it? How many days was this ice storm? I mean-
Dr. M. Szyf: Oh, the whole thing took a few, the ice storm was a few days. But the power loss was could take anything between one hour to six weeks. So people suffered to different extents.
K. Fitzgerald: But even still, six weeks is not a ton of time for the kind of changes you saw.
Dr. M. Szyf: Exactly. But this stress was significant, but normal stress. These are the kind of stresses we always go through in life. Having to move somewhere else, not having power, things like that.
But even that, which is, I agree with you, it’s not enormous stress, it’s kind of moderate stress, had a huge impact on the mothers that were pregnant at the time and their children. So, for the first time, we could look at changes in methylation as a function of a random stress that we know was not caused by their genetics or, by money, or by their inheritance or anything else. Just randomly they happened to be in a place where they got more stressed than others. And we can ask the question, “How does this change methylation in your children 15 years down the line?” And we looked at the methylation 15 years down the line, and we found very distinct differences.
And the other thing that Suzanne King did, who was running this study, she looked at the health and behavioral parameters. And what we saw was, three kinds of health challenges. Behavioral health challenges, like very high rate of autism. We saw high rates of auto-immune disease, the immune system, and metabolic issues, the cardiovascular system.
So essentially what we saw, that a stressful environment really coordinates three kinds of responses in the body: an immune response, a metabolic response, and a behavioral response. And if you remember my talk, I talked about the fact that you can’t break psychiatry from physical health. They’re coordinated. When something stressful or threatening happens, it’s not just our brain that is involved. We have to recruit everything from the immune system, to the fat system, to the heart. And therefore, what I believe is early in life, is children are getting this information, “Life is going to be tough.” And they are kind of altering multiple systems to deal with hard life. And hard life involves social threat, it involves food threat, lack of food. It involves bacterial infestation, so it prepares for all of this.
And this is why I told you, you can do epigenetics not necessarily in the brain, even if you want to look at the brain, because the entire body is responding together. Therefore, it measures in saliva could be telling us something that happens, not just in saliva, but in the brain, in the fat tissue and other places.
K. Fitzgerald: Yes. That’s amazing. Thank you. That’s just very, very interesting. I want to just ask you though on that, I know some people will hear this, especially moms or women getting ready to conceive, or families, etc. and there’s a lot of anxiety. “Well, geez, you can’t avoid stress!” And you certainly can’t do anything if you happen to live through an ice storm. I mean that’s random in a way, to an extent.
So what about, so piggy backing on this was a really interesting study I read where they gave mice a single high glucose meal or exposure, I think they injected them with a whole bunch of glucose, or something like that. Or maybe they gave them a high glucose meal. And then they showed that epigenetic changes occurred for I think, quite a while. They showed differential methylation patterns for up to six days. I guess, my question around all of it is, “okay, so we initiate these aberrant changes that are disease promoting, but now we want to reverse them.” And these women who are pregnant want to not have their babies be at higher risk for autism, etc. because they’ve gone through stressors.
So again, so what do we do? What would you say about how they’re going to support…
Dr. M. Szyf: I think I would love to have two kinds of tools that I think the new science of epigenetics can develop. One set of tools will be to find the people who are at risk because humans are remarkably resilient. We should remember that. Our system, our epigenetic system, knows how to deal with adversity. And in most cases, it will deal with it well. So the epigenetic response will not promote disease, it will promote resilience. I think this will happen in 90% of the cases, hopefully. And, or 70%. But we want to identify those who somehow missed that resilient response and are vulnerable.
So, I am hoping that one day we, or our colleagues of the scientific community, will be able to develop DNA methylation diagnostics. That we can, maybe at the placenta, maybe at the core blood, maybe later. Find babies that, they are at risk. As you said, many things could have happened during pregnancy. Had a fight with your spouse, you lost a parent, or a close relative, you were fired, you lost money in the stock market, so there’s a lot of things that can cause stress.
K. Fitzgerald: Always. Yeah.
Dr. M. Szyf: All we care about… so, I would say, to the modern psychiatrist, rather than talking to the patient about all the terrible things that happened during the pregnancy, is doing a simple test. And seeing “oh, there’s something that happened. I’m not sure I want to know whether it was sexual abuse, or physical abuse, or verbal abuse, or natural abuse. Your child is at risk.”
It’s like your physician telling you, you have high blood pressure. You are at risk. You don’t know why it was caused, but we know that high blood pressure is something that we need to take care of. And at that point, the question is, “Okay, let’s say we have kids at risk, how can we intervene very early to prevent that risk from manifesting itself?” We need to think about the kinds of intervention, behavioral intervention, some sort of an enrichment environment that will send the opposite signals to what was sent.
K. Fitzgerald: And I just want to hit this home to our listeners that will indeed augment the epigenome. As powerfully as some of the other interventions.
Dr. M. Szyf: Right.
K. Fitzgerald: The behavioral piece is extremely important.
Dr. M. Szyf: Right. Because through behavior we can tap into the chemistry of the body and the body itself will take care of things. Sometimes we might have to supplement, have a nutritional strategy. Then, the third strategy, sometimes it has to be pharmacological, depends on the risk and the cost and benefits of each of these.
At certain points, unfortunately you need pharmacology, because either we don’t know how to do it, or the system is so convoluted that you need a real push to change it. And I think all three are possible. And I think they will happen. I think research, clinical research and hopefully one day, a public experience will kind of join together. Our clinical research will not be just controlled clinical trials, but what actually happens in the wild, you know? Amongst people who are exposing themselves to these different interventions. How they work.
K. Fitzgerald: I’m with you. That is so exciting. Geez. Well, that’s a good place I think for us to end. Dr. Szyf, again, just an honor to have you on New Frontiers.
Dr. M. Szyf: Thank you. You’re welcome. Yeah, bye, bye.
K. Fitzgerald: Yeah, take care.
Dr. M. Szyf: Bye.