Challenging Biology can we code human cells for health
[Music]
hi
my name is mark i’m a neurosurgeon and a
sensor biologist
and over the past 10 years i’ve become
an entrepreneur
i’d like to start telling you about my
work as a neurosurgeon
my focus are spinal cord injuries when
someone breaks
their neck in a car accident there’s a
high likelihood
that their spinal cord is damaged the
trauma disrupts the neural tissue
nerve cells and their connections are
lost
as well as the surrounding support cells
this can result in immediate paralysis
and loss of neurological function
as a neurosurgeon i’m called after the
patient arrives in the emergency room
and the injury is confirmed on imaging
my job is to manage
the next steps
many of my patients require urgent
surgery
i use state-of-the-art navigation
systems to place screws like this one
into the bony structures surrounding the
spinal cord
this stabilizes the spine but it doesn’t
repair the neurological injury
the spinal cord is unable to regenerate
the nerve cells that were lost
in the injury and their connections
most of my patients therefore remain
paralyzed
unable to use their hands or walk
and some of them are even unable to
breathe on their own
in fact i realize that many of the
conditions that i face
as neurosurgeon whether they are cancers
genetic or degenerative conditions
require more than a scalpel and screws
and they can’t be treated successfully
with conventional drugs either
because they require the regeneration of
lost cells
what we need is a revolution in medicine
a new set of sophisticated interventions
that
that can help these most difficult
medical problems
we need to move from small molecules and
biologics
to a new generation of intelligent
therapies
drugs that can interact with their
environment in other words
cell therapies the good news is that
this revolution is already on its way
the first cell therapies have been
approved
genetically engineered immune cells are
starting to transform the treatment of
cancer
as you can see on this video these
so-called car t cells
are able to identify tumor cells and
kill them
a meta study investigating 27 cd19 car t
cell therapy studies showed that 54.4
percent of patients experienced a
complete
response of their blood cancer
car t’s work when all other medicines
have failed
i believe that these astonishing results
are only the beginning the first wave of
cell therapies
and they give me hope when i think about
the number of patients
that i have operated on suffering from
brain cancer
like all tumors their condition starts
with a small number of brain cells
turning rogue
and these cells are extremely good at
escaping surgical tools
radiotherapy and chemotherapy
today there’s very little that we can
offer these patients despite
all the technical progress in
neurosurgery
their life expectancy is only about two
years my hope
is that car t and other cell therapies
will be similarly transformative for
these patients
or for example take the young boys
suffering from duchenne’s muscle
dystrophy
a horrible condition in which their
muscle cells
start to die due to imitation in a
specific
gene this leads to progressive muscle
weakness
and puts them into wheelchairs and the
condition progresses
until breathing becomes difficult what
their muscles need are healthy muscle
cells
again a problem that is best addressed
with cell
and gene therapy but so far there are
none
and what about the cell transplants for
parkinson’s
that have shown promising early effects
a decade and more ago
why is there still no treatment
why is it so difficult to get cell
therapies into the clinic
when it comes to cells there’s a
manufacturing crisis
cells are not easily accessible products
are inconsistent
and not scalable this is why today
there are only a handful of cell
therapies and why they cost
hundreds of thousands of dollars for a
single patient
the lack of a reliable source of human
cells also
holds back scientific discovery and the
development of more traditional drugs
to make cells available to everyone and
to treat
other conditions we need to manufacture
cells
at industrial scale so where do we get
cells for cell therapy
all cell types start as stem cells
which then go on to create all the cells
in our bodies
if you want to use cells for therapy you
can either take them
from people which is difficult and in
some cases not possible at all
or you can try and coax stem cells into
the right cell type
which after 20 years of research we know
is also very difficult
stem cell biologists study embryonic
development in order to obtain
cues of how stem cells can be turned
into the cell types required
for drug testing therapies and research
this approach has two problems it means
that you have to follow developmental
timelines
and these are long babies require nine
months until they’re born
and the approach is inconsistent because
it is based on stochastic events
in order to reach a particular cell type
stem cells have to undergo multiple
steps of differentiation
in which they produce slightly more
specific cells
this is a complex process
at each of these steps cells need to
make cell
fate choices they choose which cells
they actually produce
next and these choices are based on
chance events
during development this ensures that
really all cell types are generated
and the growing organism doesn’t miss a
cell or a tissue
or even an organ the particular cell
that we wanted to generate in my lab was
a human oligodendrocyte
these are support cells in the brain
that form insulating layers
around the processes of nerves they
facilitate rapid conduction of nerve
impulses
and provide nutrient support they are an
ideal cell for repairing
certain brain and spinal cord conditions
when we started out 10 years ago the
best protocol required more than 170
days of culture
during which we would feed and observe
the cells
change culture conditions add new
molecules
wait until the cell responded then again
change the media containing a new set of
molecules
and so on until we finally saw some
oligodendrocytes emerging
however we were never sure whether we
would actually be able to generate these
cells
and how many we’d be very happy if a
culture had
10 of cells
then i realized this is a common problem
in stem cell biology that nearly all of
us
working in this field were facing and
it’s an even bigger problem
if you want to manufacture cells at an
industrial scale
the inconsistency complexity and the
length of the protocols
means that they are very difficult to
scale so i had to look
for another way a radically new
perspective on biology
let’s just consider our current
situation
the reason why we’re not together in a
room is because the virus is hacking
into our cells to produce more virus
a virus is really little more than a
piece of genetic information
a program that contains a few genes
what can we learn from this does biology
run a sort of software
and if so can the same principles be
used to reprogram cells to another cell
type
in the 1980s when scientists first
figured out how to clone genes
harold weintraub identified a gene a
transcription factor
he called myod that when introduced into
other cells
turned them into muscle cell
unfortunately this piece of research was
long forgotten
harold died in early death from brain
cancer
in 2012 this concept that cells can be
reprogrammed has received renewed
attention
when shinya yamanaka and john garden
received the nobel prize for showing
that cells can be reprogrammed back into
stem cells
this is a true revolution because it
means that we can now
generate stem cells from every
individual and we don’t need to touch
any embryos
with all their ethical constraints
this inspired a handful of really
creative scientists
and amongst these marius wernick in
stanford to explore whether this concept
of celebrity probing
can be applied to other cell types
he showed that you can turn skin cells
into brain cells
and since then the field has taken off
and many more cell type programs
have been identified
however there was still a problem cell
reprogramming
relies on jump starting a new cell type
program
by the introduction of new genes in most
cases
scientists use a virus
in our lab we found that the cells
detect the genetic material introduced
by a virus
and that they do everything they can to
silence this new program
this means that the cells do not convert
so we had to design a different control
system
a hard problem i invested all my
resource
and the credibility of my group it was
really stressful
at the beginning of my scientific career
it took many years of work and the help
of multiple teams
and for the longest time we were only
making marginal improvements
until finally we designed a system that
relies on a direct intervention at the
dna
engineering a program into what are
called safe harbor sites of the cell
these are specialized areas in the dna
that are somehow protected
and they allow safe activation of genes
when we tested the system and activated
the first cell type program
encoding human brain cells i could not
believe my eyes
here you can see stem cells being
reprogrammed into brain cells
and what is remarkable is that every
stem cell in the culture seems to be
turning into a brain cell
at exactly the same time and once
they’ve reached a neuronal identity they
grow
processes that connect with each other
and form a neural network
and 10 days after initiating the program
the cells become
functional transmitting neural signals
this is one
order of magnitude faster than
traditional approaches
which often require 100 and more
the fact that all cells turned into
neurons was totally unexpected because
it went against
all the theories that certain cell
states were required to enable
reprogramming
in fact when we submitted our manuscript
for publication it first got rejected
because the reviewers did not believe
the data
and this is how it works all human cells
contain the same 20 000 genes which
cover
all genetic programs in a cell we
can call the entirety of these programs
the operating system of a cell
or life os at any given moment
only a subset of the genes a subset of
the genetic programs
is active in a cell the activity of
these programs is controlled by
transcription factors
like code words in a programming
language these
turn on networks of other transcription
factors and genes
and one to six of these transcription
factors encode the identity of the cell
every cell had its unique combination
and once you know that you can activate
it
and create a new cell type
our technology enables optimized over
expression of these transcription
factors in stem cells we call it optiox
it relies on engineering these code
words into the dna
so that they are not silenced and why is
the entire field thought
that for successful reprogramming cells
needed certain permissive states
our approach has proven that it is not
the case
and that all that is necessary for a
deterministic change in cell identity
is to control the activation of
transcription factors
this technology enables fast consistent
and scalable manufacturing of cells
it’s also truly a departure from biology
as we know it
and represents an approach to cells that
is much more like engineering
to leverage this opportunity and to
develop this technology
for the next generation of therapies i
became an entrepreneur
and i set up a company our mood shot
goal is to be able to
generate every cell in the body
and this is why it’s important having
access to a reliable and consistent
source of human cells is a game changer
a consistent source of human cells can
make scientific discovery more robust
this is a big problem in biology
experiments cannot be easily reproduced
and this has often to do with the
variability between the cells used for
experimentation
if scientists were able to include a
standardized set of cells in their
experiments in other words use the same
cells across the globe this would
greatly reduce this problem and it would
make experiments more interpretable in
order to develop a new drug
pharma companies screen millions of
chemicals and so far this has not been
possible in human cells
drugs are therefore developed using
animal models and cancer cell lines
however let’s take for example
alzheimer’s mice
don’t get alzheimer’s and cell lines
used for drug discovery
are very different from the brain cells
that the disease affects
so to generate better drugs and to do so
more efficiently
we need human cells that are actually
affected by alzheimer’s
and that can be used in high throughput
screens
finally what i’m most passionate about
are cell therapies
if we were able to manufacture the right
cells for the right conditions at scale
and perhaps even enhance their function
with the knowledge that we have gained
by understanding transcription factors
and the programs
they control we could generate new
intelligent
and curative medicines at a price point
where they become accessible to everyone
we could generate immune cells that are
able to dissolve
brain cancers or muscle cells that could
preserve the strength in boys suffering
from duchennes
and hopefully one day i will be able to
inject some cells into the spinal cords
of my patients
and perhaps connect them to electronic
devices
in order to make them walk again and
give them back
the use of their hands
you