Genetic Dark Matter: Decoding The Force Within [Functional Forum]

Genetic Dark Matter: Decoding The Force Within  [Functional Forum]


It’s my great pleasure to welcome for the first time, live at the Functional Forum, the Godfather of Functional Medicine, let’s have a big round of applause for Dr. Jeffrey Bland. 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 thought 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 saw 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 using 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 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. 2. 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 front-end of this curb. You don’t want to be on the
back-end. 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 wreceiving both electromagnetic radiation through moving of soundwaves that
I’m doing now to we’re 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 traveling 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 ….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; unintelligible
[00:10:46] 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, 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 dwarf, 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 1950s, 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. 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. Thanks so much for watching and for more great
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