I turned 40 years of age in two weeks
time don’t worry no Portia no Botox no
lifts except for the ones I occasionally
get to work if I’m lucky I’m only
halfway through my life I have much to
achieve and I’m excited to see my two
daughters go into strong independent
women however this frame of mind and
this luxury of a long life hasn’t always
been the case in 1900 just over a
century ago we humans were living on
average to be just 50 if I as a woman
managed to even make it through
childbirth poor nutrition poor
sanitation pneumonia diphtheria would
have likely killed me but the good news
is we’re humans now are routinely living
to the 80 plus thanks to modern medicine
and science we have good sanitation we
have reduced infant and birth mortality
and we have fantastic vaccines against
many otherwise lethal infectious
diseases but now that we’re living
longer and we’re surviving these earlier
challenges we humans are faced with a
whole new enemy ourselves a new category
of disease is upon us
chronic inflammatory diseases something
only seen within our generations and
particularly in Western industrialized
societies so-called
diseases of affluence and age these
include allergies heart disease and a
slew of over 150 types of autoimmune
diseases where our mewn system becomes
disoriented and attacks us these include
multiple sclerosis rheumatoid arthritis
type 1 diabetes celiac disease and lupus
these diseases don’t get the attention
that say cancer or Alzheimer’s disease
may get but the current estimate is that
50 million Americans are afflicted with
an auto inflammatory disease one in five
of us have allergies I can’t put peanut
butter in my kids lunch
and the numbers of these diseases of
rising at unprecedented rates fatigue
swelling aching pain skin rashes people
don’t appreciate or understand the
difficulties of patients living with
you may have heard about some of these
diseases via afflicted celebrity tennis
players all those strange ads on TV
advertising drugs talking about
something called restless leg syndrome
but they’re impacting more people than
we know in particular there is a rapid
rise in what used to be considered a
rare disease of the gut inflammatory
bowel disease especially in
industrialized Western societies
inflammatory bowel disease currently
affects 3 million Americans that is the
number of school-aged kids and college
students in New England collectively
there currently is no cure strikingly
the rate of this disease has an almost
almost doubled in less than 20 years in
fact there are a hundred thousand new
cases of new new cases of inflammatory
bowel disease every year in the United
States and this is expected to keep
rising
imagine a packed Dallas Cowboys Stadium
being newly diagnosed with IBD this year
and next year and the year after that
and now imagine the rates of these
diseases rapidly rising in newly
industrialized China with 1.4 billion
people in India with 1.3 billion people
there currently is no cure inflammatory
bowel disease is a chronic relapsing
inflammation of the intestine there are
two types Crohn’s disease and ulcerative
colitis
you can’t tell they have it you can’t
see the abdominal cramps the bloody
stool the multiple trips to the bathroom
or the living in constant fear if
they’ll make it through a movie or a
work meeting the last days from school
or work
and the shock and stress that goes we’ve
been diagnosed with a chronic
inflammatory illness and the side
effects from drugs that try to alleviate
the disease so you might be wondering
what’s going on here
the rates of these chronic inflammatory
diseases is rising faster than can be
explained by genetics so clearly there’s
an environmental component that what our
diet our changing climate urban
environments there’s good evidence that
we’re not eating enough fiber and we’re
too damn clean and there’s good evidence
that these things disturb the microbiome
the ecosystem of bugs within our
intestine but precisely how these
environmental triggers are impacting
disease and if it’s the same
environmental trigger in every patient
is unclear and it frankly may never be
clear so you may ask how can we possibly
tackle a disease when we do not know the
cause and why and how does our immune
our beautiful immune system our white
blood cells about 10,000 of them per
drop of your blood they originate in the
bone marrow and circulate around our
bodies protecting us from infection and
most cancer we have the innate arm of
the immune system the first line of
defense the inventory in the trenches
that’s literally been event around for
about a billion years present in the
earliest organisms on earth and then
about 450 million years ago our adaptive
immune system evolved and this is more
like the Special Forces with a
sophisticated memory of past infections
to be called on again and both arms do
an incredible job of protecting us from
nasty bugs and keeping us alive so why
now does it start to make mistakes and
what makes it do this traditionally to
understand any disease we have used the
famous Koch’s postulates and that seemed
it states that if a pathogen is causing
a disease then it’s found in all
individuals with that disease and that
pathogen can transfer disease such as
influenza and we can train our special
forces to combat that pathogen and this
is exactly how vaccines work but we
don’t see the same pathogen in chronic
inflammatory disease patients nor does
it does it seem to be the exact same
environmental trigger so what about a
more modern-day Koch’s postulates such
as a causative genetic mutation such as
Braca one for breast cancer current
evidence is that there are about 160
mutated genes that have been associated
with IBD but having one or many of these
does not guarantee you’ll get the
disease you have to have the bad
combination of genetics plus the
environmental trigger so what do we
scientists do and doctors do when we
don’t know the precise cause of a
disease and we may never know this and
it might be different for everyone
vaccines work when we know the pathogen
removing disease-causing genes can work
when we know the precise genetic
causative mutation we need fresh
thinking and new approaches to these
more complex diseases of affluence and
age I would like to propose that the
clues and answers may be in epigenetics
the interface of your genes with the
environment we are in the post genomic
era the human genome has been sequenced
a remarkable scientific feat and we
realized one major thing most of our DNA
is not genes it was somewhat like
Christopher Columbus who set up West
from Europe to find Asia and instead
landed in the New World
it was completely unexpected but we
couldn’t have known that unless we
embarked on that journey of your human
genome only 1% of it is actually
transcribed into genes that become
functional proteins in an immune cell as
little as 200 unique genes are used it
is actually the silencing of the
last majority of your DNA which actually
totals six feet in length that is
critical to how cells gain identity
behave and respond to the environment
that long strand of DNA needs to fit
into a microscopic cell and so here we
have a physical packaging problem income
histones which of those molecular spools
that DNA wraps around and in enables
efficient cramming of that DNA into this
tiny space and without them our cells
would look something like my four year
old sock drawer or if you ask my husband
my sock drawer these histones have
molecular tags on them that give precise
instructions that enable or prevent that
DNA from being expressed in a cell
type-specific manner and this we
collectively refer to as the epigenome
where epi is greek for outside of or
above its role in regulating the on and
off and timing of genes is partly
functional and partly structural I like
to use the analogy of music to describe
epigenetics mostly because my
grandmother pictured here
Cathleen was a pianist she also died of
complications of a classic disease of
effluents and age diabetes my wonderful
husband is also a talented musician and
pretty much everyone in my family
wonders what it is I do on a daily basis
so think of your human genome as a giant
piano and there’s about 20,000 separate
keys or genes and sitting at that piano
deciding which of those keys gets played
loudly or softly or remain silent in
different cell types is your epigenome
now think of the most famous music
sequence in a movie of all time
played in that way with the right timing
with all other keys silenced it’s so
powerful now in an innate immune cell
normally two keys are played and this
might go up to ten following an
infection but it will rapidly go back to
two but everything you can think of
sleep or lack of diet alcohol exercise
pollution and certainly the bacteria in
our guts has influence on our epigenome
and this is a key insight collectively
over time the music of our immune cells
is gradually changing in inflammation
it’s like a cell that used to play Jaws
is now playing more and more keys to
something like a piano concerto or
possibly something out of time and
completely nonsensical and in the last
few years we’ve just been able to
analyze the epigenome of our immune
cells and this is revealing amazing
insights a recent study in identical
twins found that by the time that we are
65 years of age 70 percent of our mewn
epigenome is derived from the
environment essentially the music of our
Moon cells is being played in a whole
different way not dictated by the DNA
you inherited from your parents but from
the environment in which you live so
what can we do with this knowledge and
how can we use this to treat or even
predict chronic inflammatory diseases
well the beauty of the epigenome unlike
the genome is that changes are
reversible and what’s more exciting for
the many patients suffering from chronic
inflammatory diseases is that epigenetic
enzymes can be manipulated with drugs my
research has shown that a molecule that
sits precisely in the pocket of a very
special class of epigenetic penis known
as the bromodomain epigenetic enzymes
could switch off inflammation
it stopped too many keys being played
and excitingly these drugs are now in
clinical trials for cancer because
cancer like inflammation cells lose
their identity through changes in their
epigenome and while these drugs are
offering hope to many cancer patients
these drugs could also be offering hope
to the millions of patients with chronic
inflammatory disease my lab at
Massachusetts General Hospital and
Harvard Medical School is seeking
designated epigenetic enzymes for the
immune system this is in the hope of
trying to find refined targets to
precisely reset the immune epigenome
back to jaws but we also wanted to
understand that if in like cancer
changes in our epigenome could actually
be a trigger of chronic inflammatory
disease what we found was that a very
specialized immune restricted epigenetic
enzyme it’s name is SP 140 was lost in a
subset of patients with inflammatory
bowel disease what happened in these
patients was that the pause or the rest
in their DNA of their music cells was
eliminated and ultimately those cells
lost identity and a very specialized
innate immune cell the macrophage lost
its way it forgot to have a protective
role in the gut and ultimately over time
inflammation and shoes interestingly the
same epigenetic enzyme is also lost in
two other immune diseases multiple
sclerosis and an adult leukemia clearly
there must be a different environmental
trigger for three disease outcomes from
the same environmental change but now we
have the knowledge and possibly the
tools to predict this disease and try to
reset that immune epigenome back to
normal using epigenetic drugs the last
20 years we have witnessed a scientific
revolution with Boston and Cambridge
playing key roles the ability to
sequence the entire human genome for a
few hundred dollars we can literally
catalogue every single bit of DNA in
patients with and without disease
and now in the last five years we can do
something about that with CRISPR
molecular scissors to delete
disease-causing genes these two
scientific feats have undoubtedly
revolutionized modern medicine but as a
scientist it pains me to say it but they
may actually be largely worthless in the
context of these chronic inflammatory
diseases in order to truly understand
the intersection between our genes
environment and disease we need to be
looking at our epigenome and finding
ways to receive it epigenetics puts all
of that genetic information into the
right context and the way to slow or
reverse inflammation might be to tell to
change the epidemic genome and what it
tells certain genes to do Auto
inflammatory diseases are chronic and
incurable for inflammatory bowel disease
the current options are ineffective
drugs with bad side effects a scalpel to
remove the diseased intestine or
imagine a future if these chronic
diseases of inflammation continue to
as I celebrate my 40th birthday I see
new dangers in turning 40
but these dangers may be even greater
for my daughters and for your children
my hope is it in the future a trip to
the doctor will include an analysis of
your genetics and your epigenetics and
it will be this personalized medicine
that can create tangible links between
you your environment your lifestyle and
the chronic inflammatory diseases you’re
vulnerable to all on the cellular level
my ultimate hope is that we can identify
an epigenetic tipping point that we can
try and reset that immune epigenome back
to normal before it triggers disease
we’re not there yet but with the current
pace of science in this city and beyond
and the visionary leaders in this room
here tonight I have absolutely no doubt
that this can be achieved thank you [Applause]
time don’t worry no Portia no Botox no
lifts except for the ones I occasionally
get to work if I’m lucky I’m only
halfway through my life I have much to
achieve and I’m excited to see my two
daughters go into strong independent
women however this frame of mind and
this luxury of a long life hasn’t always
been the case in 1900 just over a
century ago we humans were living on
average to be just 50 if I as a woman
managed to even make it through
childbirth poor nutrition poor
sanitation pneumonia diphtheria would
have likely killed me but the good news
is we’re humans now are routinely living
to the 80 plus thanks to modern medicine
and science we have good sanitation we
have reduced infant and birth mortality
and we have fantastic vaccines against
many otherwise lethal infectious
diseases but now that we’re living
longer and we’re surviving these earlier
challenges we humans are faced with a
whole new enemy ourselves a new category
of disease is upon us
chronic inflammatory diseases something
only seen within our generations and
particularly in Western industrialized
societies so-called
diseases of affluence and age these
include allergies heart disease and a
slew of over 150 types of autoimmune
diseases where our mewn system becomes
disoriented and attacks us these include
multiple sclerosis rheumatoid arthritis
type 1 diabetes celiac disease and lupus
these diseases don’t get the attention
that say cancer or Alzheimer’s disease
may get but the current estimate is that
50 million Americans are afflicted with
an auto inflammatory disease one in five
of us have allergies I can’t put peanut
butter in my kids lunch
and the numbers of these diseases of
rising at unprecedented rates fatigue
swelling aching pain skin rashes people
don’t appreciate or understand the
difficulties of patients living with
you may have heard about some of these
diseases via afflicted celebrity tennis
players all those strange ads on TV
advertising drugs talking about
something called restless leg syndrome
but they’re impacting more people than
we know in particular there is a rapid
rise in what used to be considered a
rare disease of the gut inflammatory
bowel disease especially in
industrialized Western societies
inflammatory bowel disease currently
affects 3 million Americans that is the
number of school-aged kids and college
students in New England collectively
there currently is no cure strikingly
the rate of this disease has an almost
almost doubled in less than 20 years in
fact there are a hundred thousand new
cases of new new cases of inflammatory
bowel disease every year in the United
States and this is expected to keep
rising
imagine a packed Dallas Cowboys Stadium
being newly diagnosed with IBD this year
and next year and the year after that
and now imagine the rates of these
diseases rapidly rising in newly
industrialized China with 1.4 billion
people in India with 1.3 billion people
there currently is no cure inflammatory
bowel disease is a chronic relapsing
inflammation of the intestine there are
two types Crohn’s disease and ulcerative
colitis
you can’t tell they have it you can’t
see the abdominal cramps the bloody
stool the multiple trips to the bathroom
or the living in constant fear if
they’ll make it through a movie or a
work meeting the last days from school
or work
and the shock and stress that goes we’ve
been diagnosed with a chronic
inflammatory illness and the side
effects from drugs that try to alleviate
the disease so you might be wondering
what’s going on here
the rates of these chronic inflammatory
diseases is rising faster than can be
explained by genetics so clearly there’s
an environmental component that what our
diet our changing climate urban
environments there’s good evidence that
we’re not eating enough fiber and we’re
too damn clean and there’s good evidence
that these things disturb the microbiome
the ecosystem of bugs within our
intestine but precisely how these
environmental triggers are impacting
disease and if it’s the same
environmental trigger in every patient
is unclear and it frankly may never be
clear so you may ask how can we possibly
tackle a disease when we do not know the
cause and why and how does our immune
our beautiful immune system our white
blood cells about 10,000 of them per
drop of your blood they originate in the
bone marrow and circulate around our
bodies protecting us from infection and
most cancer we have the innate arm of
the immune system the first line of
defense the inventory in the trenches
that’s literally been event around for
about a billion years present in the
earliest organisms on earth and then
about 450 million years ago our adaptive
immune system evolved and this is more
like the Special Forces with a
sophisticated memory of past infections
to be called on again and both arms do
an incredible job of protecting us from
nasty bugs and keeping us alive so why
now does it start to make mistakes and
what makes it do this traditionally to
understand any disease we have used the
famous Koch’s postulates and that seemed
it states that if a pathogen is causing
a disease then it’s found in all
individuals with that disease and that
pathogen can transfer disease such as
influenza and we can train our special
forces to combat that pathogen and this
is exactly how vaccines work but we
don’t see the same pathogen in chronic
inflammatory disease patients nor does
it does it seem to be the exact same
environmental trigger so what about a
more modern-day Koch’s postulates such
as a causative genetic mutation such as
Braca one for breast cancer current
evidence is that there are about 160
mutated genes that have been associated
with IBD but having one or many of these
does not guarantee you’ll get the
disease you have to have the bad
combination of genetics plus the
environmental trigger so what do we
scientists do and doctors do when we
don’t know the precise cause of a
disease and we may never know this and
it might be different for everyone
vaccines work when we know the pathogen
removing disease-causing genes can work
when we know the precise genetic
causative mutation we need fresh
thinking and new approaches to these
more complex diseases of affluence and
age I would like to propose that the
clues and answers may be in epigenetics
the interface of your genes with the
environment we are in the post genomic
era the human genome has been sequenced
a remarkable scientific feat and we
realized one major thing most of our DNA
is not genes it was somewhat like
Christopher Columbus who set up West
from Europe to find Asia and instead
landed in the New World
it was completely unexpected but we
couldn’t have known that unless we
embarked on that journey of your human
genome only 1% of it is actually
transcribed into genes that become
functional proteins in an immune cell as
little as 200 unique genes are used it
is actually the silencing of the
last majority of your DNA which actually
totals six feet in length that is
critical to how cells gain identity
behave and respond to the environment
that long strand of DNA needs to fit
into a microscopic cell and so here we
have a physical packaging problem income
histones which of those molecular spools
that DNA wraps around and in enables
efficient cramming of that DNA into this
tiny space and without them our cells
would look something like my four year
old sock drawer or if you ask my husband
my sock drawer these histones have
molecular tags on them that give precise
instructions that enable or prevent that
DNA from being expressed in a cell
type-specific manner and this we
collectively refer to as the epigenome
where epi is greek for outside of or
above its role in regulating the on and
off and timing of genes is partly
functional and partly structural I like
to use the analogy of music to describe
epigenetics mostly because my
grandmother pictured here
Cathleen was a pianist she also died of
complications of a classic disease of
effluents and age diabetes my wonderful
husband is also a talented musician and
pretty much everyone in my family
wonders what it is I do on a daily basis
so think of your human genome as a giant
piano and there’s about 20,000 separate
keys or genes and sitting at that piano
deciding which of those keys gets played
loudly or softly or remain silent in
different cell types is your epigenome
now think of the most famous music
sequence in a movie of all time
played in that way with the right timing
with all other keys silenced it’s so
powerful now in an innate immune cell
normally two keys are played and this
might go up to ten following an
infection but it will rapidly go back to
two but everything you can think of
sleep or lack of diet alcohol exercise
pollution and certainly the bacteria in
our guts has influence on our epigenome
and this is a key insight collectively
over time the music of our immune cells
is gradually changing in inflammation
it’s like a cell that used to play Jaws
is now playing more and more keys to
something like a piano concerto or
possibly something out of time and
completely nonsensical and in the last
few years we’ve just been able to
analyze the epigenome of our immune
cells and this is revealing amazing
insights a recent study in identical
twins found that by the time that we are
65 years of age 70 percent of our mewn
epigenome is derived from the
environment essentially the music of our
Moon cells is being played in a whole
different way not dictated by the DNA
you inherited from your parents but from
the environment in which you live so
what can we do with this knowledge and
how can we use this to treat or even
predict chronic inflammatory diseases
well the beauty of the epigenome unlike
the genome is that changes are
reversible and what’s more exciting for
the many patients suffering from chronic
inflammatory diseases is that epigenetic
enzymes can be manipulated with drugs my
research has shown that a molecule that
sits precisely in the pocket of a very
special class of epigenetic penis known
as the bromodomain epigenetic enzymes
could switch off inflammation
it stopped too many keys being played
and excitingly these drugs are now in
clinical trials for cancer because
cancer like inflammation cells lose
their identity through changes in their
epigenome and while these drugs are
offering hope to many cancer patients
these drugs could also be offering hope
to the millions of patients with chronic
inflammatory disease my lab at
Massachusetts General Hospital and
Harvard Medical School is seeking
designated epigenetic enzymes for the
immune system this is in the hope of
trying to find refined targets to
precisely reset the immune epigenome
back to jaws but we also wanted to
understand that if in like cancer
changes in our epigenome could actually
be a trigger of chronic inflammatory
disease what we found was that a very
specialized immune restricted epigenetic
enzyme it’s name is SP 140 was lost in a
subset of patients with inflammatory
bowel disease what happened in these
patients was that the pause or the rest
in their DNA of their music cells was
eliminated and ultimately those cells
lost identity and a very specialized
innate immune cell the macrophage lost
its way it forgot to have a protective
role in the gut and ultimately over time
inflammation and shoes interestingly the
same epigenetic enzyme is also lost in
two other immune diseases multiple
sclerosis and an adult leukemia clearly
there must be a different environmental
trigger for three disease outcomes from
the same environmental change but now we
have the knowledge and possibly the
tools to predict this disease and try to
reset that immune epigenome back to
normal using epigenetic drugs the last
20 years we have witnessed a scientific
revolution with Boston and Cambridge
playing key roles the ability to
sequence the entire human genome for a
few hundred dollars we can literally
catalogue every single bit of DNA in
patients with and without disease
and now in the last five years we can do
something about that with CRISPR
molecular scissors to delete
disease-causing genes these two
scientific feats have undoubtedly
revolutionized modern medicine but as a
scientist it pains me to say it but they
may actually be largely worthless in the
context of these chronic inflammatory
diseases in order to truly understand
the intersection between our genes
environment and disease we need to be
looking at our epigenome and finding
ways to receive it epigenetics puts all
of that genetic information into the
right context and the way to slow or
reverse inflammation might be to tell to
change the epidemic genome and what it
tells certain genes to do Auto
inflammatory diseases are chronic and
incurable for inflammatory bowel disease
the current options are ineffective
drugs with bad side effects a scalpel to
remove the diseased intestine or
imagine a future if these chronic
diseases of inflammation continue to
as I celebrate my 40th birthday I see
new dangers in turning 40
but these dangers may be even greater
for my daughters and for your children
my hope is it in the future a trip to
the doctor will include an analysis of
your genetics and your epigenetics and
it will be this personalized medicine
that can create tangible links between
you your environment your lifestyle and
the chronic inflammatory diseases you’re
vulnerable to all on the cellular level
my ultimate hope is that we can identify
an epigenetic tipping point that we can
try and reset that immune epigenome back
to normal before it triggers disease
we’re not there yet but with the current
pace of science in this city and beyond
and the visionary leaders in this room
here tonight I have absolutely no doubt
that this can be achieved thank you [Applause]
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