Jeffrey Bland PhD presents: Genetic Dark Matter: Decoding the Force Within during the March 2016 Functional Forum.
JEFFREY S. BLAND, PhD, FACN, CNS, is an internationally recognized leader in the nutritional medicine field. He co-founded of the Institute for Functional Medicine in 1991 and is known to many as the “father of functional medicine.”
Well, thank you, thank you, thank you.
Gee, Star Warsian. You know, we are going to be talking about Dark Matter which fits in here but it’s really nice because on the 29th I can say anything and it will forever be forgotten because this is the day that doesn’t exist so that’s good.
As I was listening to this introduction from James and the wonderful rap video that we just saw what great creativity. It struck me that there is a metaphor here, isn’t there, that we all believe in or we wouldn’t probably be here tonight, and that is we have all been mired in the disease care system. Every metaphor is around disease, it’s all around pathology and we studied it deeply. We sat over microscopes or whatever our pathology based cytology courses were and we got a certain expertise but through that expertise, we also had a perspective and that is that the system is all around sadness, it’s around disappointment, it’s around tragedy. We took on that psychological profile and our medicine became very mired in that psychology.
If you just think of the energy that was brought into this room tonight that’s a different mentality, that’s a medicine of up and out, not down and in. That’s a medicine of hope and opportunity. That’s a medicine focused on function. That’s why I chose the term function because I thought it was a term that could be a rallying point for really quantifying feeling good rather than just defining feeling bad or pathology.
In fact, the funny story, you heard me maybe say this before but it actually was on my mind when I chose the term in 2000 because functional medicine already had some connotation in 2000; it was either psychosomatic medicine or it was rehabilitative geriatric medicine. So there was a lot of pushback by my colleagues in these meetings when we were kind of musing on founding the Institute for Functional Medicine and I made a funny statement, which I really believe I said so, if we had a thousand practitioners of various forms of disease care sitting in a room and they had all sorts of different pedigrees and backgrounds and training and so forth, and we ask the question, “How many of you want to practice dysfunctional medicine, please stand up?” So the counter point of that, right, was “Gee, I guess everyone would want to practice functional medicine.” That was the basic strategy.
So with that in mind, I really want to deal with three questions tonight. This is kind of the content portion of my musing because these are things that are on our radar screen either directly or indirectly through our patients which are “How does this Genomics Revolution really interface with Health Care? Is it just an epiphenomena that’s kind of fun and cute and it’s a new tool and we kind of a romance while the newness or does it really provide answers and solutions that we didn’t have before that could be meaningful in leading to actionable outcome that would improve patient outcome?”
The three questions I want to talk about to kind of overlay what I’m going to go through here about Dark Matter is:
Should we really be doing and advocating genetic testing at this point or is it too early to really be useful?
I’m going to say, “Yes, we should.” I’ll just put that out there and I’m going to say why I believe it should. Two – What are the interpretative guidelines then if we’re going to use genetic analysis? Is it a Bad News Bears story?
I’ll just tell you the story for those of you who won’t be to the end here in the next 27 minutes, so I’ll just tell you the end of the story.
The end of the story is if you think of the way that genetic testing is being used today and how it’s interpreted, it’s all around the bad news of pathology, it’s all around risk and I find this very interesting but I guess not surprising because if you think of the whole context of our system, it’s all tilted towards disease but yet in that genome, that book life those 23 chapters, there’s very little that actually codes for disease, it mostly codes for function and it mostly codes for the opportunity for high-level wellness for century or more.
So how do you access the good news in that system rather than constantly focusing on disease risk which just mires us back in the old model? I just want to throw that out as a construct and by the way, I think all the labs that are doing it are caught up in that same thing; it’s just like the term diagnosis.
Diagnosis should go out with disease. It’s prognosis. You want to be in the frontend of this curb. You don’t want to be on the backend. This is the difference between like accounting and financial planning. I mean, do you want really an accountant to be running your health? You want a financial planner, right? Someone is looking forward, not looking back and so that’s the model.
Then lastly, how do we use biomarkers and other information to make the gene test more applicable to actionable things?
So this all starts as you know with this Rose Garden thing, the deciphering the human genome, we thought we had all these answers and then it led to this huge dissolution after spending like $3- or $4 billion, see people that, “Whoa, we got a kind of ripped off” because first, we thought there are going to be a hundred thousand genes in the human genome and the geneticist were disappointed because they didn’t have many things to play with and they said there’s only like 22,000 coding genes in the human genome and the pinot grape has 30,000 and rice has 50,000. What are we? It sounds like “Gee, this is a little bit confusing.”
We then they have learned from there and I’m kind of cutting to the chase making a lot of stuff kind of overly simple that it’s actually the genes that are sitting in resonance quite waiting to be influenced by the environment or the host so that they will be expressed in the way that the environment teases out those signals and we’re really kind of receptors of signals that come from the environment so all these things that we’re receiving both electromagnetic radiation through moving of soundwaves that I’m doing now to eating food, to breathing air, to all these things are signals that really create outcome in the way that our genes are expressed, and some are expressed in real time very rapidly, others over days or months or years, it depends on the process.
Functional Medicine as I said was developed really to try to codify this concept and I really want to give a lot of credit and attribution to my colleagues when we sat down. My wife’s real genius, after I’ve been travelling several million miles all over the world and she said, “Jeff, you know maybe you need to do something at home, wouldn’t that be interesting as an alternative?” Maybe if we form a group and why not we fund because we were in a position at that point with our little company that we could afford owning it to put our money where we wanted to, so why don’t we fund some of our friends and colleagues that you have seen around the world that are thought leaders to come in and I’ll put a meeting on, and let’s say this was 1989 in Victoria, Vancouver, British Columbia, and so we met for four days and we had a whiteboard. There was no obligation to go talk about reimbursement or licensure in to the realities. It was just about “What would a health care system look like if in the abstract it was to be perfect?” and so that led us in to really some deep conversation to and I had people from all different disciplines. I had informatics people from MIT and I had people that were biometricians and I had natural healers, and people that were all at the top of their games that were willing to entertain this kind of open landscape.
That led us in to some really interesting thoughts and then we went kind of in communication, this is pre-web, so we kind of use snail mail and we went back then the following year in ‘90 and we met again but now we had some guidelines and we got deeper in to the granularity of what would this look like.
Then on the Saturday night, right before the Sunday of our last day, I had this kind of dream, conception, whatever it was calculate dancing monkeys but it was basically the concept that we should call this Functional Medicine. As I already told you, we kind of then tested that with the group and David Jones my brother and I and Joe Pizzorno and a variety of other people; Leo Galland, Sid Baker, were all involved in these discussions and out of that then we decide, “Let’s give it a whirl, let’s try Functional Medicine on to see if it has any stickiness.”
Out of that was developed the tree that this I recall came out of our office in Gig Harbor in the early days of Functional Medicine, and you might recall that we had when we put our first training sessions, and I laugh at them now, there were two five-day training sessions we’re applying functional medicine, clinical practice that were separated by two months, so people had actually come in and live in Gig Harbor for a week twice and that was like a test right there (although some people like Gig Harbor it’s a little bit provincial) and then literally, we thought if we could get the 30 people to show up, we were really like this was a sign of success of which half were my family member, so that was kind of the early origin but out of that then was born, ultimately this kind of metaphor, the tree diagram and the question now that we take in our present parlance is “How do you convert the root thing, the kind of genetic potential in to the things up in the upper leaves fully to the tree to be healthy and robust, that would be the phenotype? How do you convert genetic potential into phenotypic high-level function?” That’s really the question.
The genetic information is clinically applied in the functional medicine system as an operating system, as I see it, it’s part of the portfolio of information that you can utilize in assembling a complex story about your patient. This is all about the story of the patient and the deep story from antecedents and the triggers, mediators and the science and symptoms.
So like all great mysteries, riddles and puzzles, the human genome has layers of complexity, metaphoric trap doors and false walls and amazing hidden treasures and we’re only starting to learn the deep hidden mysteries, and I would be presumptuous to suggest I’m going to give you great insight that’s going to explain all aspects because I think that we’re really just in the early stages of our understanding, and the more we look, the more exciting it is, and we are in the depths of a revolution in biological science is second to none, it’s probably like what happened to the Pasteurian Vector Disease model at the turn of the last century where suddenly new ahas were coming out every day and it’s just the most exciting time to be alive right now because basically, all the old rules that I learned that were the maxims that we were tested on, are now like open for new discovery.
In fact, I had an alumni meeting with my class of seniors, we took our first molecular biology course in 1962 and we thought we were only a few years away from Watson and Crick, we thought we knew everything;…..and we had the triplet code and we understood how amino acids were coded for and proteins were assembled, this was the answer and so we all got in this after a few beers, into this discussion about “Gee whiz, if we took the same test we took back then and gave the same answers that got us good grades we’d all fail because most all of those things that we thought were true are now really changed.”
The key is the genetic code but there is a hidden genetic code below the way that we thought the genes work. This concept of the Mendelian fix structure of the genes and that they would always be monogenetic diseases were the primal scene, you have the molecular basis of genetic metabolism diseases that we could understand but those represent a small fraction of the way the genes ultimately regulate our function so it’s a whole new story of plasticity.
So we, as I said, have about 22,000 genes but the interesting part of this that I’ll be focusing on is that within the human genome, and by the way, yes you know there’s about 97.6 homology of the human genome in the coding regions of the gene with the chimpanzee so that’s like “Whoa, that’s a little too close.” What are the other things that differentiate us from rice that has 40 to 50,000 genes and us?
Well, basically the human genome in its entirety is huge compared to any other genome. It dwarfs, it makes the chimpanzee genome look just tiny in comparison and so all these other stuff that’s in there, all these other DNA that’s in there has been a question mark for some time. People knew it was in there but because it didn’t code for protein through normal mRNA transcription people said, “Well, okay what are we going to call it? Let’s just call it junk because it must be remnants, there’s a lot of repeating units in there and a lot of redundancy and so it must be stuff that’s not that important so we’re just going to call it junk.”
But I want to really remind us that I know I’m giving a quick reminder of maybe some things you prefer to forget but in the biology of the gene; the molecular biology of the gene, remember that there are these spacers in the genes and these are the introns, and those have to be pulled out in the splicing to give rise in to the parts of the genome that’s going to do the coding for the protein. So we assume for a long time that these green spots in there where kind of like just who knows what, they were like insulators or something and they weren’t providing any function.
Now, as I’ll go through, we recognize that they code for all sorts of information pertaining to the regulation of how genes are expressed as families and we don’t express genes one at a time; you have these families and that’s what really differentiates humans from others that the complexity of how you assemble and express these in groups.
So, if I ask a simple question, a kind of a statistical question, “How many permutations and combinations could you have of 22,000 genes take multiple at a time?”
Now, we get in to an infinite number virtually of possibilities. So that’s the diversity of the human species; the more way they can be assembled intelligently, the more diversity and control and fine structure you have.
The puffer fish is an interest, I actually studied tetrodotoxin and the puffer fish, I was doing neuroscience at one of my phases in my earlier life and it turns out the puffer fish genome is kind of interesting because it has 98% of its DNA it codes for protein so it’s very efficient but it doesn’t have much executive centers of what used to be called Junk DNA, so exactly the reverse of the human genome that’s only 2% coding and 98% other stuff.
What this is Junk DNA?
This wonderful book by the way, Nessa Carey is a really wonderful writer, she’s a molecular geneticist in England and so she talks about the fact that this Junk DNA contains within promoter regions of genes, a long sequence non-coding RNAs, telomeres (which we’re going to talk about in a moment), short inhibitory RNAs and microRNAs, so they’re all coded for out of the non-protein coding portion of what used to be called Junk DNA.
As Nessa said, in the Junk DNA book, I quote, “One shock from the sequencing of the human genome was the realization that the extraordinary complexities of human anatomy, physiology, intelligence, and behavior cannot be explained by referring to the classical model of the genes.”
Wow, that’s a pretty compelling statement, isn’t it, when we think of all the time we spent putting the stuff to memory thinking that we had answers that we could reproduce on demand and that would be of value. Now, we’re saying, “Well, maybe it’s only of limited value that we need to be looking farther down the story.”
So, you look at the ENCODE Project (I don’t know how many of you have followed this) but the ENCODE Project is very fascinating because it started looking at the full complex of information encoded in the genes, not just the coding portion for protein and the first published paper out of the ENCODE Project was in 2007 in which they were able to do a complete decoding of only 2% of the human genome; both in that 2% they found all these regions of non-coding portions of the genome that had functional characteristics.
I love this term because Functional Genomics has emerged now as the frontier of this genomic space. If genes can’t change but their expression does, then the Dark Matter in the genome is what controls the expression of gene. If you look at that kind of mass of DNA sitting in there, that’s obviously not ready to cell to divide that’s just kind of a distributed DNA. There is a huge amount of that 98% that’s related to regulation of how the message is going to be expressed in different environmental circumstances.
This book is another one, this is another British author, a very very well-written review really going back to the dawn of the study of DNA (and I won’t go through the whole history) but in this book he talks about the RNA as referred to as DNA’s cousin, some scientists however believe that RNA maybe the oldest form of genetic information.
As you probably know RNA is single stranded, it doesn’t and because of having rivals where then deoxy rivals, it doesn’t bent itself in to the triple helix efficiently but it does fall back on itself to form loops and to form these interesting fingers that then have topological structure-function relationships in opening or closing portions of the genome. Now that’s a very interesting thing, that’s a structure-function relationship. It’s the three dimensional genome basically, if you get where I’m going. So the way RNA can fold base upon its structure gives rise to the ability to shield or to mask or to open up certain portions of the genome for reading and that sounds like epigenetics, right, which it is. So your non-coding RNA has a big role to play in your epigenomic messaging and patterning over experiences.
When we look at then, as I think I’ve already said this that the RNA then is a single stranded, it has rivals; versus deoxy rivals and therefore it has also Uracil versus Thymine so there’s a nucleic acid change, and so when we start asking “What does it do?”
It has three major types of RNA that you’re familiar with; Messenger RNA that takes the message off DNA to make protein and the ribosome. But it also has Ribosomal RNA and then one of the members of my biotech company, one of the founders Transfer RNA; Paul Schimmel, which as you know pulls amino acids into the cytoplasm takes it to the messenger RNA and that whole process is one of the most intimate, beautiful, elegant dances that you can imagine as to how that whole process as nanomachine really works to make protein. But beyond those there are these other types of RNA that are within this non-coding region, the Mitochondrial RNA because remember we have genetic information within our mitochondria that’s passed on maternally and then the Small Nuclear RNA, and microRNAs.
John Mattick just wrote an article a couple years ago on The Rise of Regulatory RNA and he said, “RNA is the computational engine of cell biology; developmental biology, brain function and possibly evolution itself. The complexity and interconnectedness of the genetic code with the non-coding RNAs should not be the cause for concern but rather the motivation for exploring the vast unknown universe of RNA regulation, without which we will not understand biology.”
That’s really what the Dark Matter that we’re looking in to on February 29th is all about, right, we can’t because it’s an unusual day, this is the unusual day to be remembered because I think the structure of the nucleosome and how that three dimensional structure opens and closes to allow reader enzymes to come in to transcribe certain information is regulated by these non-coding regions which are in intimate contact with our lifestyle in our environment (as I’m going to show in a moment), including our thoughts, attitudes and beliefs which can change the three dimensional structure of the genome. So these are really, and these sounds like a little bit of woo-woo stuff but now we have the tools to really measure this, to quantify it, to replicate it and it become suddenly science. It’s now accepted.
This other book by Nessa Carey, The Epigenetics Revolution talks about how genetic expression is controlled by the epigenome and how small RNAs play a role in masking and opening up certain portions of the genome.
So if you look at the full genome and you ask, “In a chart, how do you divide up the coding versus the non-coding region?”
So that little blue slice up there that’s the percentage of coding region and then that kind of purple that’s the so called introns, those were the spacers that are the regulatory regions like the transcription factors and the promoter regions of genes and then you get to the unique non-coding RNAs that then regulate the structure of the genome and the nucleosome which are playing very important roles in how we express messages.
What are the actionable opportunities within the Functional Medicine model for all this information? This sounds pretty esoteric at this point, so what do we do with it?
Let’s start with Telomeres.
Can we influence in telomeres which are the ends of the chromosomes, these repeating units that then are shortened with age in all animals with replication? Remember Leonard Hayflick in the ‘50s, cell doublings and you get to a certain doubling number and then the cells expire because you shorten the telomeres so much that you did a genomic stability is lost and those genes now open up to all sorts of damage in the universe, so entropy wins in the end that’s called aging.
Can you influence then the telomeres? The answer is yes you can because we know that healthy lifestyle, now we have with Elizabeth Blackburn’s Nobel Prize winning work, we have the ability to measure the amount of the links of telomeres and the telomeres enzyme so people can say, “Wow, if you really just do the right things that speaks with harmony to your genes that you can actually preserve the integrity of the protective ends of your chromosomes which is akin to reducing biological agent, yes, you can. That’s an actionable thing. You can measure telomeres and you can do something and you can measure them again. So this makes the science a little bit more quantifiable.
Same thing as you know Dean Ornish worked with Elizabeth Blackburn with prostate cancer, these are the males and again who go on the lifestyle program pretty intensively and they show that their telomerase activity goes up, their telomerase shortening goes down and so with better outcomes.
When I look at cancer as kind of the model threshold of how we’re using this information, I think it’s the first beachhead, it’s very very fascinating because if we go back to the Twins Study done in Sweden, it was published a number of years ago in New England Journal, you recall, they pointed out with identical twins that there was no more concordance in cancer than there was with the population at large, so if it was all a genetic disease like inherited disease, we would have much more concordance.
Now, we would say that cancer is a genetic disease but at a somatic cell level not at the germ level. It’s not inherited in the normal sense. That means that the genomic stability becomes very very important.
Now, there are ways of measuring genomic stability in humans. Yes, you can take buccal cells and look at cytology or leukocytes and there are ways of actually simply getting some qualitative information about genomic stability from fairly simple test. So if you put telomeres shortening or telomeres link together with the buccal cell cytological analysis of genomic stability, and what did we see win the Lasker Award in medicine this year; DNA-damage response element.
What is a DNA-damage response?
Well, BRCA1 and 2 are DNA-damage response genes, aren’t they? They are regulatory genes in men and women that control damage to genes. So women who have BRCA1 and 2 homozygous mutations that lead to higher incidence of breast and ovarian cancer, they don’t have cancer genes; they have lost their protection against their DNA by a loss of function condition which is increased genomic instability.
In looking at the serum of Chinese subjects, what has been found on rice-based diet, this is another actionable part of my story because what they found is at lo and behold, they could find in their plasma specific examples of rice non-coding RNA after they eat rice. Are you familiar with this work? This is highly controversial by the way and it’s created a big stir in the field because what happens if you can eat information in such a way that your epigenetically modifying gene expression.
Now, in this particular case, they even went on to say that the stable microRNAs are secreted and found in the serum and this exogenous plant microRNAs from the consumption of rice were found in the serum, that this microRNA 168a actually has an effect on the LDL receptor expression. So it has something to do with cholesterol feedback processes and how this relates to cholesterol genesis and high cholesterol, so this is a pretty dramatic thing if you start thinking.
Could we actually measure then theoretically these microRNAs that come from our diet and how they’re influencing gene expression and epigenetically modifying a phenotype?
Now just think about that if you talk about food is information. I mean we’re really getting down to a pretty fundamental level of understanding.
So the microbiome plays a role in our epigenetics as well because it’s sending out signals through the immune system and through the release of various agents from its own genome; unintelligible [00:25:18] that are influencing the gene expression as well. This is a whole frontier that just now in the early stages are really starting to understand and we’ll have tools to measure this in the near future. So when we eat, we produce all sorts of byproducts that then have effects on these regulatory processes that ultimately cause our genes to alter their functional status.
Moshe Szyf’s said, a good colleague and friend at McGill University, the Father supposedly of Behavioral Epigenetics, he was a pharmacologist by training, Israeli-trained PhD pharmacologist, so social epigenetics is looking at the environment and how that influence is going from energy force field called behavior to a covalent bond of molecular groupings such as methylation; the promoter regions of genes.
Now, can you actually measure quantitatively the effect of a disharmonious environment such that the psycho-social energy is captured by the genome and it alters its methylation patterns?
The answer is yes, it is and there’s a huge amount of work that’s done on this actually, he and many others.
One of the studies he did was what is called the Ice Babies. Maybe you’re familiar with this where there is a huge huge cold snap in Canada a few years ago and so people were just locked into their places with no electricity and it was very very stressful and many of these people were in jeopardy to lose their life from hypothermia. So there’s a lot of stress and women who were pregnant at that time were under a lot of stress.
So the question was, these babies that were born, what are their methylation patterns of their genomes? They say were born of mothers that were in some of these very fearful environments and they found lo and behold, they’re called the ice babies, they have methylation patterns that are trigger to methylating regions that control stress response. So these are now hyper-reactive stress children, is what they’re finding.
These constructs that you can have in an environment that could create a molecular change in the way your DNA can be expressed and it can be unintelligible [00:27:25]. By the way, that’s the other part of this, it can be transmittal, this is totally Lamarckian so that’s a whole another like “Oh, I can’t even believe it.” So that then you probably know the work was done right over here at unintelligible [00:27:36] and this is really fascinating example of that with second generation descendants of people that were intern during the Holocaust, and looking at the methylation patterns and again, showing similar methylation patterns of this gene that is a controller gene; a reporter of a regulatory gene for stress response showing that they have inherited this through their epigenetic patterning.
What does these all mean?
I’ve given a lot of stuff, just throwing kind of to the wind here on February 29th a bunch of thoughts but I think this is a frame shift in the way we actually see biology which influences the way we see health and disease, which influences ultimately the way that medicine will be practiced and I am so proud that we have this Functional Medicine Operating System because it’s at least a formalized system to take all this information in, it’s a system’s biology approach of collecting data so that we have an intelligent way of analyzing it and come to a conclusion that can lead to personalize precision health care.
We are much more than DNA that codes for protein in our genome, that’s obvious.
The major difference between humans and all other plants and animals is the large amount of what used to be called Junk DNA or Dark Matter.
The Dark Matter of the genome is where the regulation of complexity of life really resides. We are much more complex because of that than other plants.
The Dark Matter takes its message from the environment, diet and lifestyle.
Functional Medicine, I believe, is the system that incorporates the effects of Genetic Dark Matter in its assessment and treatment approach. It is the frontier way that we can throw through this lens the ability to understand this information and make it clinically valuable.
Thanks for listening. I’ve enjoyed it.
James: Wow. That was really amazing. There is some great information on the screen right now about some other resources Dr. Bland’s book; The Disease Delusion is awesome. The series actually, here you can find at FunctionalMedicine.org about functional medicine genomics is really incredible too, so check it out on the internet forever for free for everyone, awesome.
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