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]