Creating Curative Therapies
i joined the stem cell institute over 15
years ago
and it wasn’t just the pleasure of
cutting my salary in half
as i left the for-profit sector but to
work with people like doug melton and
david skadden who are the two scientific
directors of the institute to set up
this new enterprise and what it was is a
virtual research center that spans
harvard the schools of harvard and the
harvard-affiliated hospitals harvard has
a unique footprint in not only this east
coast system but the world and having
eight hospitals affiliated with it and
so the idea here by building this what i
call virtual research center
where we could have a new way of doing r
d we didn’t need to own the assets but
we could have some of the world’s
leading experts and many diseases
work across
these different organizations and
departments and labs and disciplines to
go all the way from bench side signs to
treating patients where else in the
world can you do that so that that was
one of the the appeal the new business
model working with leading experts and
as john alluded to the ability to
actually take a serious go at some of
these diseases and conditions that are
affecting everyone not only some of the
aging issues you heard about from david
sinclair before
but conditions such as diabetes that
doug melton works on spinal cord injury
that my brother suffered from
parkinson’s disease that my
father-in-law
and we all have these stories right and
so far we’ve had no good treatments for
those so what we do we’ve grown that
center to now over 380 faculty across
the different institutions and the whole
point is interdisciplinary inner
organization interlab collaboration to
work on new cell and gene therapies this
is what most of you think about when you
think about stem cell science you think
about how do we fix broken cells i.e you
know the dopaminergic neurons that go in
parkinson’s the
eyelid cells that go on diabetes etc so
this is how do i replace the broken part
theory or fix the
the defective gene which we now can do
much more easily thanks to advanced like
crispr um and other another gene editing
tools but there are also
other mechanisms so stem cell science
has also led us into a whole new way of
thinking about how can we engage
endogenous repair capabilities in other
words how do we stimulate the body’s
internal ability to repair in a way that
it’s either lost because of age or lost
because of accident or disease so that’s
the second point and the third is
because now we’ve developed the tools
and i’ll talk about this a little bit
later where we can create human cells of
interest by mean if you want to study
a motor neuron or heart cell or muscle
cell or fat in a dish we now have the
tools that we can create those cells in
both 2d and three-dimensional systems to
help understand disease mechanism and
seriously change both the economics and
the approaches to drug discovery and
we’ll talk about why so we organized by
disease now that’s unique in an academic
setting because most people are looking
at technical problems but we wanted
people to look at technical problems but
aim them at having an impact on disease
we want the basic research but we don’t
want to be goal directed we also
deliberately set up so that we could
talk across disease categories so for
example that people studying the
autoimmune problem in diabetes where
once and type one diabetes that is where
your immune system attacks your own beta
cells what could they learn from the
cancer program where tumor cells are
really good at avoiding the immune
system that’s the whole issue so how can
they cross-pollinate
how do we also
understand processes that cut across
disease
diseases and organs and
even time such as fibrosis or aging so
think of fibrosis whether it’s
in the heart the kidney the lung the
skeletal muscle as a way where the body
doesn’t repair the way it should
what we can do because we’re people
studying those interact that process
from a molecular cellular level on up in
different organ systems is compare notes
so that we can see what are common
pathways what are common behaviors and
where do they differ so how can we take
you know what we learn in lung fibrosis
and apply it to say liver fibrosis or
vice versa similarly for those of you
who heard david sinclair
uh aging is a process basically of
losing our ability to repair and
regenerate over time
in utero if
a fetus has a skin wound it can heal you
know if there’s an in
intrauterine operation it can heal
scarlessly we
and infants can you know grow a
fingertip back children can grow a
fingertip back we lose that ability over
over time even certain body parts such
as blood skin hair that repair
themselves
every few days during life repair
themselves less and less well over time
why is that true and what can we learn
about the early ability to repair and
apply that to later stages in life
let me fast forward
from 15 years ago to today or actually a
couple weeks ago vertex pharmaceuticals
announced the results from the first
patient in a trial where stem cell
derived beta cell transplant so this is
work coming out of their acquisition of
semi-therapeutics a couple years ago
which itself had been formed five years
before that out of work coming out of
doug melton’s lab and we’re talking
about before so it took well over a
decade in the academic lab to figure out
how to turn an embryonic stem cell or or
pluripotent stem cell into a mature beta
cell in vitro
the startup company then further uh
refined that process and then vertex is
bringing it into the clinic
but what they’re able to do in this
patient and this is a brittle diabetic
an older man who had a type 1 diabetic
who’s been on insulin for 40 years was
hospitalized several times each year
because
is what they call brittle diabetic
because of the condition where his body
would just crash and in the 90 days at
half of their planned dose he was
basically off of insulin and this
remember is a disease that’s multi-genic
there are multiple genes impacting the
disease it’s environmental
and has many causes many different
manifestations but if it but it comes
crashing down on one cell type so gene
therapy isn’t going to fix but if you
can so this is shown at least
conceptually that if you can fix that
cell in question you can potentially
cure the disease potentially
now the next step many of you are going
to say well that’s type 1 diabetes where
your immune system attacks that cell
you’re reading the fine print there you
notice this guy is on immunosuppressive
therapy the next step and this is what
people are working on how do you
encapsulate those cells or gene edit
those cells so that they are invisible
to the immune system or can protect
themselves from the immune system if
some of you were here for uh
john’s conversation with pardesa betty
earlier from the broad in harvard here’s
a paper that she and amy wagers from
harvard led a multi-disciplinary team
working on namely what’s the next stage
in gene therapy many of you have heard
over the last couple of years about car
t therapy for cancer that’s basically
you take cells
the t cells out of the body engineer
them put them back into the body so it’s
essentially gene editing cells for uh
for blood blood-borne cancers there’s
also work where you can um where people
are shown that you can gene correct
blood stem cells such as in sickle cell
anemia that’s in the clinic today
and there have been gene correction
therapies for certain genetic eye
diseases where the local delivery of the
of that gene is is important but the
boss have been cases where patients have
had gene therapy and have had toxic
results because the gene products
accumulate in the liver and have
negative
side effects and
some quite serious
what these labs did together was
essentially create
miniature versions of the gene delivery
vehicle these aav capsids
and could modify them to preferentially
home to a tissue of interest in this
case they’re going after genetic muscle
diseases and they prove the point with
functional recovery in a mouse model
duchenne
muscular dystrophy as well as a very
rare genetic
muscle disease so this is the next wave
of gene therapy is not
gene’s sort of injunctive very
specifically but how do you get it to a
broader system without having the toxic
side effects and to enable potentially
redosing
more broadly
stem cells have opened a whole new
window you heard again david sinclair
talk about aging i won’t talk about
sirtuins here it was clear to me very
painfully a couple of weeks ago when i
ran a half marathon and i ran a lot
slower and it took me longer to recover
than the 20 and 30 year olds
one of the things uh that particulars
research coming in both out of stanford
and harvard has looked a lot at
understanding the differences between
young and old mice and how they repair
or don’t repair over time
one of the avenues that they use to look
at it was what they call parabiotic
mouse models so this image on the left
shows you an old and a young mouse
joined in a way so that they share a
circulatory system and the point of this
is to understand what is it in the blood
if there are if there are factors in the
blood
that enable the old mouse to repair in a
way that they are not because what
they’ve proven if you look on the left
the positive effects on the older mouse
show up in the heart in the brain the
bone and muscle and in different tissue
systems in different ways the converse
is also true where the blood from the
old mouse is negatively affecting the
young mouse the idea is not to give you
know
blood transfers from young people to old
people but what the idea this model has
been used to look at what are the
individual factors and see if we can
tease out from this what is it that’s
driving that repair that regeneration
process and how do we lose that over
time so for example there was a startup
company that spun out of harvard several
years ago called alevian
that
identified a circulating protein in the
animal that is also human protein and
they’re now working their way toward
toward a clinical trial comparably on
the right there’s a recent article
showing the benefits of exercise which
we all know
not only in terms of you know heart
muscle etc but even on indirect effects
such as cognitive function which has
been well documented what this study
showed is that they looked again at
different factors and showed that a
hormone that had been discovered a
decade ago also in a lab in the harvard
system
that is released by the muscles during
exercise if they
created a small peptide version of that
a small protein version of that hormone
they could deliver it systemically they
could replicate the effect of exercise
and they tested that not only in terms
of general effects but also on a an
alzheimer’s mouse model now humans and
mice are very different but the concept
um holds true and so this is leading us
not only to think about conditions like
aging but also leading us to think about
systemic approaches to disease so rather
than thinking about alzheimer’s or
thinking about cardiac can we look at
interventions that have partic
potentially system-wide effects in the
alzheimer’s example maybe untangle us if
you will from the plaques and tangles
debate that sort of wrap treatments of
that disease up in a bit of a quandary
so far
this is all possible because there have
been
major scientific advantages in the last
decade namely uh
yamanaka’s discovery of how to reprogram
cells so can you turn the sands of time
back on individual cells he showed that
you could take an adult cell adult
meaning a mature in this case skin cell
or blood cell and with only four factors
turn that cell back to an embryonic-like
state what they call induced pluripotent
stem cells
then what people can do like the melton
lab spend a lot of time figuring out the
recipe the cookbook for turning that
cell into the cell that’s either impact
you know of interest to the organ or
disease of interest in other words the
forward programming of that into like a
neuron muscle cell uh blood cell
whatever and then you can use that again
either for in vitro experiments under
same disease mechanism or potentially
for cell therapy for example as you know
bayer pharmaceuticals is now
engaged in a parkinson’s clinical study
where they’re making dopaminergic
neurons from ips cells you combine that
with
the
work that jennifer doudna and emmanuel
charpentier received the nobel prize for
in 2020 on crispr and gene editing and
the increasing ability to edit genes
um either
ex vivo
in vitro or ultimately in vivo
combine that with stem cell technology
and open a whole new window for for
curative therapy i mentioned the sickle
cell example before and that’s exactly a
combination of these two technologies
this just shows an optically stimulated
and recorded stimulation of a motor
neuron so what we now have is ability
not only make individual cells in a dish
but the ability to analyze them and
because we can make them we’re using
that reprogramming technology from
people with different genetic
backgrounds we can understand for
example how what the electrical firing
pattern of a motor neuron from a healthy
person is versus say someone with als
that then can be scaled up it’s we used
to think of als as a one disease
category but now we’re realizing there
are actually many different genetic
backgrounds in als there’s actually
another company spun out of the harvard
ecosystem that is specifically doing
that and what they’re doing is not to
replace a motor neurons but to say look
for drugs use this as an in vitro model
in petri dish to look for drugs that can
restore a normal firing pattern and
restore health to those neurons and
hopefully make them live longer and
realize that patients with different
diseases
can treat differently now many of you
said but many diseases aren’t single
cell diseases that they’re
multiple cellular and you’re right cells
do live in 3d environments so the topic
of organoids was mentioned briefly
before
we now can create brain organoids kidney
organoids tumor organoids etc in vitro
to understand how they behave look for
interactions we can combine them with
materials and electronics as you see on
the upper right is a joint project
between someone at the engineering
school and a cardiac developmental
biologist saying how do i integrate nano
electronics into a cardiac organoid in
order to mature heart cells potentially
use them for for cell therapy purposes
and then people have incorporated them
into chips so that what you can do is
then for example in the lung chip we’re
coming out of the vesa institute
at harvest shown how you can take lung
cells put them in a chip flow air and
blood through them and in the covet
example introduce a virus and say how
does a virus impact the lung tissue in
in a living environment again it’s not
the same as a whole body but we now can
study these things with human cells of
interest a human the relevant human
cells that are affected in a
particular disease that’s an ability we
didn’t have a decade ago how do we
repair complex organs that don’t have a
stem cell that can’t repair themselves
the ancient greeks i don’t know if they
knew about stem cells but the myth of
prometheus exists because the liver
repairs itself right
half the liver won’t grow back every
single night that’s asking a little too
much of it um and you don’t want an
eagle cruising around your innards
anyway
however in diseases like the kidney we
found there are no stem cells in the
kidney there was a big argument about
whether there are
but it has a very complex architecture
the bioprinting technologies today are
not going to solve that which means that
hemodialysis as a disease looks today
exactly like it did 70 years ago the bed
frame has changed and the tubing is
probably a little better plastic but the
guy actually looks pretty much the same
it’s an expensive proposition and
transplants don’t save this problem
because in the us only one out of five
people in transplant list gets gets a
transplant so there’s another startup
out of the harvard ecosystem coming out
of mgh aviva medical that’s trying to
work on how do you create a biological
replica of the kidney without
replicating the complexity of the
architecture but taking biologic
material putting cells in the relevant
cells in the relevant channels and
essentially creating a biologic device
that can provide enough kidney function
to get people off of
dialysis and off of transplants
and our purpose in life at hsci was not
to start companies but the science has
accelerated so over the last decade
there have been some 40 companies
started by hsci scientists and more are
happening
some of them you’ve actually heard about
such as moderna i daresay is on some of
your lists
but these are in a range from
drug screening to cell therapy to gene
therapy to mrna a whole range of
technologies but all aimed at this
regeneration and repair one of the
reasons we can do this is because we can
draw on resources like the wet lab
incubator on the business school campus
we live in a town surrounded by other
life science incubators and those
incubators live in an environment
surrounded not only by the venture
capitalists who are deep in life
sciences but by the biotech companies
and by big pharma a decade ago novartis
was the only large pharma had r d here
now essentially all the large pharma
companies have r d either headquarters
or major offices so boston right now in
the particular last decade has really
become the center of gravity in uh in
life sciences but it’s not all about
science so i’ll leave you with this one
cautionary note that stephen johnson
pointed out in his book that he wrote
about major medical interventions and
what’s taken them to succeed as we live
longer and healthier lives and that is
around the social and political and
economic
policies that have to be in place one of
the examples in his book is louis
pasteur it took 50 years from his
discovery of pasteurization to actually
pasteurize milk being on the shelf
that’s not a science problem that’s a
social problem
similarly in walter isaacson’s book
about crispr they centered around
jennifer doudna’s story and crisper cast
9 has now turned into crispr 13 and 14
and crisper phi and g prime editing and
base editing etc so they’ve been huge
advances since but
they won’t be socially useful clinically
use until we can agree on what as we
again increase the capability even
even better and better gene editing
until we agree on what’s a right thing
to do and what’s wrong where are the
lines to draw on gene on what we should
be doing with the technology
that came to the fore a couple years ago
with that case in china where a guy did
in vivo gene editing but that technology
will be driving us down the path and we
need to think programmatically about
what are the right applications of it
and related to that is also what will
health care systems reimburse and how do
we pay for that
because if we can have these gene
correction therapies out there and solve
these problems at scale we also have to
have a way to pay for them in a health
care system that isn’t designed for it
today so i’ll leave you with that
thought because that is a collective
problem it’s not just a science problem
cool things are happening on the science
more is to be done thank you very much
[Applause]