Challenging Biology can we code human cells for health

[Music]

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

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

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