so we’re gonna take a journey the
journey spans about 15 years of time
it’s gonna take us to multiple
continents of the world and as well as
hopefully scale a therapy using cells to
what we hope to see to be the next
global cell therapy that that really
gets distributed so this medicine is
something that as we’ve been working on
for about 15 years and it involves cell
communication and and so some of the
points that I want to get across our how
cells communicate why cell communication
is really important in health what
happens in disease to all of our cells
and their communication patterns and how
we’re gonna try to fix it using a cell
therapy so with that let’s begin and let
me start by the first revelation that I
had a long time ago which is that cells
communicate using cell phones right
obviously this should be nothing new to
everyone it’s it’s why we call them cell
phones no but in all reality cells
communicate using natural molecules okay
proteins fats sugars even genetic
material things like RNA and DNA are
made inside of cells they’re packaged up
and they’re secreted outside of those
cells through their cellular membranes
and if you have a not-so-great cell
phone plan those molecules only can act
and diffuse locally and we’re talking
about length length scales of about ten
to a hundred microns in size that’s the
size and width of a human hair
and unfortunately I don’t have a prop to
show you that that length today but
hopefully you get the point so this type
of local signaling it’s really nearest
neighbour signaling that’s taking place
inside of tissues very small
environments and we call this local
signaling Peregrine’s that it’s just to
define some terms now
if you have a even better cellphone plan
you will have the opportunity to do
long-range signaling distant signaling
and we call this endocrine signaling
this is a way where a cell from one
location in the body can secrete
something and have it travel all the way
to a distant part of the body the
classical examples are things like
hormones which are often made in the
pituitary gland they travel all
throughout the bloodstream and cause
physiological signals and other tissues
so great we’ve defined short-term
signaling long long-distance signaling
now as engineers which is really my
background where I’m trained or what I’m
trained in we like to think of really
the collection of cells really an
accounting problem how can we accumulate
all of these cell signals and understand
this as a system and so the aspect of
systems biology comes in
so let’s accumulate all of these cells
from all of these tissues secreting all
of these things traveling all around the
human body and that’s the type of
systems problem that engineers love to
study biomedical engineers left site and
so for a man who really likes silence
this is a very noisy system and mother
nature’s designed it that way so that
when there’s an actual signal when
there’s something that’s really
important that the body needs to respond
to it goes it breaks through that noise
and the system changes so one of those
signals unfortunately can be disease and
what happens in really severe cases of
disease significant injuries we’re
talking about car accidents gunshot
wounds drug toxicities things where a
life is lost and you never get to say
goodbye well the entire communication
network breaks down and there’s a lot of
dysfunction taking place at at multiple
organ levels and as well as
physiologically and so our mission from
a medicinal standpoint is to try to
correct this dysfunctional communication
pattern that’s our goal how are we going
to do it in such a
complicated systems Network well we
decided to fight fire with fire and
we’re using a cell there so introduce
the protagonist of the story these are
called bone marrow stromal cells and
we’ll use the acronym MSC s just for
brevity these bone marrow stromal cells
are found in the bone marrow of all of
us they exist there are very very few
numbers but in fact have are starting to
be developed as a cell therapy they have
great attributes actually that make them
have the potential to be a medicinal
product let me give you some examples so
these cells you can isolate them you can
get them from bone marrow you can
actually plate them in a petri culture
dish and you can expand them
tremendously to huge numbers so if I
need to make a medicine I need to make a
lot of it and so from a single bone
marrow donation you can make thousands
and thousands and thousands of products
of hundreds of millions of cells or
product so the ability for these cells
to grow makes them highly attractive as
a cell therapy
apart from that you’re able to freeze
these cells so you can freeze them and
ultimately create an inventory to
distribute to hospitals locally as well
as around the world so these are great
properties that enable these cells to
actually be a potential cell therapy but
it’s the utility that’s important so
when I first started research these
cells were being applied as an
intravenous medication to treat
inflammatory diseases they were shown
very promising signs in small animal
studies but then they started to be
applied to humans in clinical trials and
people observed a number of failures and
so I just started my research I was
excited by all the promising results
that were out there but I was faced with
this paradox how is this working in
small animals but not in human beings
and it led me to focus on the mechanism
of action and what I’m here to get
across is that the mechanism of action
of these cells is really a form of
cellular communication so here’s really
the paradox that I was faced with when
these cells that can
mention was to intravenously administer
these cells with the thought the
prevailing hypothesis was that these
cells would find their target organ
that’s damaged locally and graphed in
that organ and sort of correct the
inflammation and really the tissue
damage that had occurred from a
significant injury but you know it this
just didn’t make sense to me the numbers
really didn’t work out when these cells
were being infused intravenously 99% of
them were were disappearing
they were vanished they were ultimately
getting destroyed in the blood
circulation and so very few cells
actually made it to a target organ and
to me it seemed insufficient to change
really the physiology of that organ let
alone the entire human body and so I
thought about the fundamental assumption
do these cells actually need to be in
the human body at all and we conducted
some proof-of-concept experiments where
we took these cells cultured in a dish
and collected the molecules these cells
produced and injected molecules instead
into an animal undergoing severe
inflammation and lo and behold we
reproduce the same therapeutic benefits
without the cells ever actually being
engrafted at all and so we proved this
concept that the mechanism of action of
this cell was not necessarily
Peregrine’s cell communication it was
more endocrine when these cells were
being administered intravenously they
were giving a short burst of molecules
and it’s really these molecules that
were causing the physiological changes
that we’re seeing improved that was the
therapeutic hypothesis the hypothesis
that really set me in a very different
direction about how to develop this cell
therapy so when we solved one problem
just like any good problem that solved
another three emerge so the question was
really about if these cells are
secreting things and trying to
communicate to the body to really
correct and bring back balance how do we
scale something like this this is a very
different type of mechanism it’s not
just a small molecule that you can
orally administer there’s only a few
routes of administration to get cells
into the human body
and we knew that intravenous
administration wasn’t going to get us
there and so we were we were stuck in
terms of how to get this therapy engaged
and interacting with the human body and
particularly the human bloodstream at
the scales that we needed to and so when
we looked around at all the different
routes of administration none really met
our criteria and so we had to think
outside of the box in fact we actually
ended up thinking outside of the body so
this is the technology that we developed
it’s an extra corporeal cell therapy and
what we fundamentally did was we flipped
the problem around instead of bringing
cells to the bloodstream we’re bringing
blood to these cells housed in a
biomedical device so what that means in
terms of what a patient experiences is
we’ve changed this from an intravenous
drip infusion to a dialysis like
procedure and this fundamentally makes
all the difference in terms of dosing so
as engineers we love widgets this is my
widget and I’m going to show you what’s
inside of this widget that where’s all
where all the magic is is happening but
in order to really advance this science
from a prototype stage that took place
in academic lab we had to build a
company we had to build a team around
this and that team is found in Lexington
Massachusetts right here now working
very hard at actually learning how to
manufacture this product distribute it
all around the country and eventually
the world if there’s success at the end
of the road so Centene is the name of
that company and its really a tremendous
team of hard-working individuals that
are really moving this forward now so
let’s look inside of this widget what’s
happening well blood is flowing through
this device and then coming back to the
patient in a circulate in a circulatory
manner and blood cells are travelling
through all of these thousands of fibers
that are within this device these are
hollow fibers so the blood cells are
traveling through them and we put em s
es on the other side of these fibers so
the MS CS are separated from blood by a
membrane and we have
effectively have given these cells which
were whispering by an intravenous
administration route we’ve now given
them a bullhorn and a pedestal so that
they can speak to the human bloodstream
in a really durable way what’s nice
about this from an engineering
standpoint is now we have full control
of the number of cells that are
interacting with the human blood
bloodstream as well as the duration of
therapy we can turn this on and off at
any point as we like and so it really
puts the control back in physicians
hands to find ways to administer to the
right disease at the right time so as
blood is flowing through MS ESR
secreting these molecules and it’s kind
of like a blood carwash if you think
about it where we’re trying to cleanse
and recondition and reprogram blood
cells as they continuously flow through
this device in these hollow fibers this
looks like a one-way conversation but in
fact it’s actually a two-way
conversation and this is where we
leverage the advantage of cells in their
ability to actually sense & react
dynamically to their environment so each
one of us when injured will all react
differently they’re all be ranges in
different heterogeneity that are found
in all of individuals in terms of how
they deal with conditions and so in
order to manage that heterogeneity we’re
leveraging mother nature’s sensing
capabilities these cells have the
ability to actually respond in kind in a
time scale that’s relevant during this
treatment to help really sense the
inflammatory environment of that subject
and secrete things in a tailored way to
each individual so this is what’s inside
the black box we’ve been testing this
black box for for quite some time and I
want to show you some of the more latest
results this is through sentence
hardwork we learned how to take a small
prototype manufacturer to a large one
and test it in large animals and this is
some of our early efficacy data where we
took animals that were sick we treated
them continuously for 12 hours with a
cellular device or an acellular devices
of control and we start to save some of
these animals lives
this gave us
as a team tremendous confidence to move
forward into human trials and I’m really
excited to say that those trials have
already begun we are up and down the
eastern seaboard treating patients
during our first phase one B to a human
trial looking at both the safety of this
product as well as the efficacy in
patients with kidney injury these
patients already get continuous dialysis
the challenges their outcomes are very
poor about 50% of them die from this
condition and we’re hoping to make
improvements on their outcomes in this
early study and certainly there’s going
to be plenty more to follow as well as
expansion into other areas of injury
where this therapy could benefit this is
a large operation it’s taking place all
around the country and a lot of
individuals have come together to really
see this idea through and we’re really
excited to see the results next year
when they come out myself sentian these
researchers are not the only ones who
are playing around with cells and I
wanted to broaden the conversation to
include an emerging class of medicine
which are cellular medicines that I
think we’ll see a lot more over the next
decade or two the US fda has recognized
cellular medicines as regenerative
medicines and has actually sped up the
process to review and approve new
regenerative medicine technologies more
recently in the past year one thing to
bring to the attention is that this
month came the first approval of a
t-cell therapy that was engineered to
actually attack and fight against one’s
own cancer cells Novartis led this
effort and they just won approval for
the use of these engineer T cells for
the treatment of leukemia where they’re
seeing about 90% cures in a case where
with if left untreated there’s about 10%
folks who survived after five years so
at this point I’ve talked to you about
the what I’ve talked to you about the
how why did this start in the first
place and it’s really the last form of
cellular communication that I wanted to
get across and that’s a form
self communication this is called
autocrine signaling this is where a cell
secretes something and actually senses
itself
and I want to talk about this because
this work started over 10 years ago at a
moment where I was pretty torn about
what I was going to do for my career I
was training in medicine and in
engineering destined to go into my third
year of medicine and right before that I
found myself in India as part of an
observer ship I was acting as a
third-year medical student observing
this the healthcare system in this
country and during that period of time I
got to give research talks and at one
place in particular the Christian
medical college in south of India gave a
talk and it really changed the way that
I was thinking about my work and so
after presenting my research a doctor
came to me and said well it’s really
exciting you know this prototype looks
really cool what are you doing with it
are you gonna bring it forward and
advance it and you know I said no I’m
probably not I’m gonna go to medical
school and you know finish my training
and and you know I think I’ll work on a
new project at some point and so he took
me aside he brought me to the neonatal
intensive care unit of this hospital and
he showed me a baby boy that had just
been born and lost his mom
due to the pregnancy due to liver
disease something that I was working on
and it was a time where he said to me
and it was it was a hard thing to hear
but that if I had been thinking more
deeply about this and really trying to
push myself to challenge myself to see
how far I could take maybe someday a kid
like this wouldn’t be an orphan and I
tell you what that message burned a hole
in my soul and it’s with me here today
it’s in every single researcher that
works alongside of me and I think it’s
the motivation and really the energy
that we’ve been bringing to this work
for so many years so we’ve been trying
to make science come alive with these
types of innovations in these types of
medical products and there is actually
other ways to bring science to life and
we’ve been actually toying around with a
new one which is a science fiction
novel that’s gonna be coming out it’s
going to talk about cells it’s going to
talk about genetics and hopefully is
going to stimulate some excitement among
among the next generation of our youth
to get involved in science and help come
up with the the next innovations so with
that in cumulative all of my cells I
wanted to just say thank you very much
and
you
journey spans about 15 years of time
it’s gonna take us to multiple
continents of the world and as well as
hopefully scale a therapy using cells to
what we hope to see to be the next
global cell therapy that that really
gets distributed so this medicine is
something that as we’ve been working on
for about 15 years and it involves cell
communication and and so some of the
points that I want to get across our how
cells communicate why cell communication
is really important in health what
happens in disease to all of our cells
and their communication patterns and how
we’re gonna try to fix it using a cell
therapy so with that let’s begin and let
me start by the first revelation that I
had a long time ago which is that cells
communicate using cell phones right
obviously this should be nothing new to
everyone it’s it’s why we call them cell
phones no but in all reality cells
communicate using natural molecules okay
proteins fats sugars even genetic
material things like RNA and DNA are
made inside of cells they’re packaged up
and they’re secreted outside of those
cells through their cellular membranes
and if you have a not-so-great cell
phone plan those molecules only can act
and diffuse locally and we’re talking
about length length scales of about ten
to a hundred microns in size that’s the
size and width of a human hair
and unfortunately I don’t have a prop to
show you that that length today but
hopefully you get the point so this type
of local signaling it’s really nearest
neighbour signaling that’s taking place
inside of tissues very small
environments and we call this local
signaling Peregrine’s that it’s just to
define some terms now
if you have a even better cellphone plan
you will have the opportunity to do
long-range signaling distant signaling
and we call this endocrine signaling
this is a way where a cell from one
location in the body can secrete
something and have it travel all the way
to a distant part of the body the
classical examples are things like
hormones which are often made in the
pituitary gland they travel all
throughout the bloodstream and cause
physiological signals and other tissues
so great we’ve defined short-term
signaling long long-distance signaling
now as engineers which is really my
background where I’m trained or what I’m
trained in we like to think of really
the collection of cells really an
accounting problem how can we accumulate
all of these cell signals and understand
this as a system and so the aspect of
systems biology comes in
so let’s accumulate all of these cells
from all of these tissues secreting all
of these things traveling all around the
human body and that’s the type of
systems problem that engineers love to
study biomedical engineers left site and
so for a man who really likes silence
this is a very noisy system and mother
nature’s designed it that way so that
when there’s an actual signal when
there’s something that’s really
important that the body needs to respond
to it goes it breaks through that noise
and the system changes so one of those
signals unfortunately can be disease and
what happens in really severe cases of
disease significant injuries we’re
talking about car accidents gunshot
wounds drug toxicities things where a
life is lost and you never get to say
goodbye well the entire communication
network breaks down and there’s a lot of
dysfunction taking place at at multiple
organ levels and as well as
physiologically and so our mission from
a medicinal standpoint is to try to
correct this dysfunctional communication
pattern that’s our goal how are we going
to do it in such a
complicated systems Network well we
decided to fight fire with fire and
we’re using a cell there so introduce
the protagonist of the story these are
called bone marrow stromal cells and
we’ll use the acronym MSC s just for
brevity these bone marrow stromal cells
are found in the bone marrow of all of
us they exist there are very very few
numbers but in fact have are starting to
be developed as a cell therapy they have
great attributes actually that make them
have the potential to be a medicinal
product let me give you some examples so
these cells you can isolate them you can
get them from bone marrow you can
actually plate them in a petri culture
dish and you can expand them
tremendously to huge numbers so if I
need to make a medicine I need to make a
lot of it and so from a single bone
marrow donation you can make thousands
and thousands and thousands of products
of hundreds of millions of cells or
product so the ability for these cells
to grow makes them highly attractive as
a cell therapy
apart from that you’re able to freeze
these cells so you can freeze them and
ultimately create an inventory to
distribute to hospitals locally as well
as around the world so these are great
properties that enable these cells to
actually be a potential cell therapy but
it’s the utility that’s important so
when I first started research these
cells were being applied as an
intravenous medication to treat
inflammatory diseases they were shown
very promising signs in small animal
studies but then they started to be
applied to humans in clinical trials and
people observed a number of failures and
so I just started my research I was
excited by all the promising results
that were out there but I was faced with
this paradox how is this working in
small animals but not in human beings
and it led me to focus on the mechanism
of action and what I’m here to get
across is that the mechanism of action
of these cells is really a form of
cellular communication so here’s really
the paradox that I was faced with when
these cells that can
mention was to intravenously administer
these cells with the thought the
prevailing hypothesis was that these
cells would find their target organ
that’s damaged locally and graphed in
that organ and sort of correct the
inflammation and really the tissue
damage that had occurred from a
significant injury but you know it this
just didn’t make sense to me the numbers
really didn’t work out when these cells
were being infused intravenously 99% of
them were were disappearing
they were vanished they were ultimately
getting destroyed in the blood
circulation and so very few cells
actually made it to a target organ and
to me it seemed insufficient to change
really the physiology of that organ let
alone the entire human body and so I
thought about the fundamental assumption
do these cells actually need to be in
the human body at all and we conducted
some proof-of-concept experiments where
we took these cells cultured in a dish
and collected the molecules these cells
produced and injected molecules instead
into an animal undergoing severe
inflammation and lo and behold we
reproduce the same therapeutic benefits
without the cells ever actually being
engrafted at all and so we proved this
concept that the mechanism of action of
this cell was not necessarily
Peregrine’s cell communication it was
more endocrine when these cells were
being administered intravenously they
were giving a short burst of molecules
and it’s really these molecules that
were causing the physiological changes
that we’re seeing improved that was the
therapeutic hypothesis the hypothesis
that really set me in a very different
direction about how to develop this cell
therapy so when we solved one problem
just like any good problem that solved
another three emerge so the question was
really about if these cells are
secreting things and trying to
communicate to the body to really
correct and bring back balance how do we
scale something like this this is a very
different type of mechanism it’s not
just a small molecule that you can
orally administer there’s only a few
routes of administration to get cells
into the human body
and we knew that intravenous
administration wasn’t going to get us
there and so we were we were stuck in
terms of how to get this therapy engaged
and interacting with the human body and
particularly the human bloodstream at
the scales that we needed to and so when
we looked around at all the different
routes of administration none really met
our criteria and so we had to think
outside of the box in fact we actually
ended up thinking outside of the body so
this is the technology that we developed
it’s an extra corporeal cell therapy and
what we fundamentally did was we flipped
the problem around instead of bringing
cells to the bloodstream we’re bringing
blood to these cells housed in a
biomedical device so what that means in
terms of what a patient experiences is
we’ve changed this from an intravenous
drip infusion to a dialysis like
procedure and this fundamentally makes
all the difference in terms of dosing so
as engineers we love widgets this is my
widget and I’m going to show you what’s
inside of this widget that where’s all
where all the magic is is happening but
in order to really advance this science
from a prototype stage that took place
in academic lab we had to build a
company we had to build a team around
this and that team is found in Lexington
Massachusetts right here now working
very hard at actually learning how to
manufacture this product distribute it
all around the country and eventually
the world if there’s success at the end
of the road so Centene is the name of
that company and its really a tremendous
team of hard-working individuals that
are really moving this forward now so
let’s look inside of this widget what’s
happening well blood is flowing through
this device and then coming back to the
patient in a circulate in a circulatory
manner and blood cells are travelling
through all of these thousands of fibers
that are within this device these are
hollow fibers so the blood cells are
traveling through them and we put em s
es on the other side of these fibers so
the MS CS are separated from blood by a
membrane and we have
effectively have given these cells which
were whispering by an intravenous
administration route we’ve now given
them a bullhorn and a pedestal so that
they can speak to the human bloodstream
in a really durable way what’s nice
about this from an engineering
standpoint is now we have full control
of the number of cells that are
interacting with the human blood
bloodstream as well as the duration of
therapy we can turn this on and off at
any point as we like and so it really
puts the control back in physicians
hands to find ways to administer to the
right disease at the right time so as
blood is flowing through MS ESR
secreting these molecules and it’s kind
of like a blood carwash if you think
about it where we’re trying to cleanse
and recondition and reprogram blood
cells as they continuously flow through
this device in these hollow fibers this
looks like a one-way conversation but in
fact it’s actually a two-way
conversation and this is where we
leverage the advantage of cells in their
ability to actually sense & react
dynamically to their environment so each
one of us when injured will all react
differently they’re all be ranges in
different heterogeneity that are found
in all of individuals in terms of how
they deal with conditions and so in
order to manage that heterogeneity we’re
leveraging mother nature’s sensing
capabilities these cells have the
ability to actually respond in kind in a
time scale that’s relevant during this
treatment to help really sense the
inflammatory environment of that subject
and secrete things in a tailored way to
each individual so this is what’s inside
the black box we’ve been testing this
black box for for quite some time and I
want to show you some of the more latest
results this is through sentence
hardwork we learned how to take a small
prototype manufacturer to a large one
and test it in large animals and this is
some of our early efficacy data where we
took animals that were sick we treated
them continuously for 12 hours with a
cellular device or an acellular devices
of control and we start to save some of
these animals lives
this gave us
as a team tremendous confidence to move
forward into human trials and I’m really
excited to say that those trials have
already begun we are up and down the
eastern seaboard treating patients
during our first phase one B to a human
trial looking at both the safety of this
product as well as the efficacy in
patients with kidney injury these
patients already get continuous dialysis
the challenges their outcomes are very
poor about 50% of them die from this
condition and we’re hoping to make
improvements on their outcomes in this
early study and certainly there’s going
to be plenty more to follow as well as
expansion into other areas of injury
where this therapy could benefit this is
a large operation it’s taking place all
around the country and a lot of
individuals have come together to really
see this idea through and we’re really
excited to see the results next year
when they come out myself sentian these
researchers are not the only ones who
are playing around with cells and I
wanted to broaden the conversation to
include an emerging class of medicine
which are cellular medicines that I
think we’ll see a lot more over the next
decade or two the US fda has recognized
cellular medicines as regenerative
medicines and has actually sped up the
process to review and approve new
regenerative medicine technologies more
recently in the past year one thing to
bring to the attention is that this
month came the first approval of a
t-cell therapy that was engineered to
actually attack and fight against one’s
own cancer cells Novartis led this
effort and they just won approval for
the use of these engineer T cells for
the treatment of leukemia where they’re
seeing about 90% cures in a case where
with if left untreated there’s about 10%
folks who survived after five years so
at this point I’ve talked to you about
the what I’ve talked to you about the
how why did this start in the first
place and it’s really the last form of
cellular communication that I wanted to
get across and that’s a form
self communication this is called
autocrine signaling this is where a cell
secretes something and actually senses
itself
and I want to talk about this because
this work started over 10 years ago at a
moment where I was pretty torn about
what I was going to do for my career I
was training in medicine and in
engineering destined to go into my third
year of medicine and right before that I
found myself in India as part of an
observer ship I was acting as a
third-year medical student observing
this the healthcare system in this
country and during that period of time I
got to give research talks and at one
place in particular the Christian
medical college in south of India gave a
talk and it really changed the way that
I was thinking about my work and so
after presenting my research a doctor
came to me and said well it’s really
exciting you know this prototype looks
really cool what are you doing with it
are you gonna bring it forward and
advance it and you know I said no I’m
probably not I’m gonna go to medical
school and you know finish my training
and and you know I think I’ll work on a
new project at some point and so he took
me aside he brought me to the neonatal
intensive care unit of this hospital and
he showed me a baby boy that had just
been born and lost his mom
due to the pregnancy due to liver
disease something that I was working on
and it was a time where he said to me
and it was it was a hard thing to hear
but that if I had been thinking more
deeply about this and really trying to
push myself to challenge myself to see
how far I could take maybe someday a kid
like this wouldn’t be an orphan and I
tell you what that message burned a hole
in my soul and it’s with me here today
it’s in every single researcher that
works alongside of me and I think it’s
the motivation and really the energy
that we’ve been bringing to this work
for so many years so we’ve been trying
to make science come alive with these
types of innovations in these types of
medical products and there is actually
other ways to bring science to life and
we’ve been actually toying around with a
new one which is a science fiction
novel that’s gonna be coming out it’s
going to talk about cells it’s going to
talk about genetics and hopefully is
going to stimulate some excitement among
among the next generation of our youth
to get involved in science and help come
up with the the next innovations so with
that in cumulative all of my cells I
wanted to just say thank you very much
and
you
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