The paralyzed rat that walked

I am a neuroscientist

with a mixed background in physics and medicine.

My lab at Swiss Federal Institute of Technology

focuses on spinal cord injury,

which affect more than 50,000 people

around the world every year,

with dramatic consequences for affected individuals,

whose life literally shatters

in a matter of a handful of seconds.

And for me, the man of steel,

Christopher Reeve,

had best raised the awareness

on the distress of spinal cord injured people.

And this is how I started my own personal journey

in this field of research,

working with the Christopher and Dana Reeve Foundation.

I still remember

this decisive moment.

It was just at the end of a regular day of work

with the foundation.

Chris addressed to us, the scientists and experts,

"You have to be more pragmatic.

When leaving your laboratory tomorrow,

I want you to stop by the rehabilitation center

to watch injured people

fighting to take a step,

struggling to maintain their [??].

And when you go home,

think about what you are going to change in your research

on the following day to make their lives better."

These words, they stuck with me.

This was more than 10 years ago,

but ever since, my laboratory has followed

the pragmatic approach to recovery

after spinal cord injury.

And my first step in this direction

was to develop a new model of spinal cord injury

that would more closely mimic some of the key features of human injury

while offering well-controlled experimental conditions.

And for this purpose, we placed two [??]

on opposite sides of the body.

They completely interrupt the communication

between the brain and the spinal cord,

thus leaving to complete and permanent paralysis

of the leg.

But, as observed, after most injuries in humans,

there is this intervening gap of intact neural tissue

through which recovery can occur.

But how to make it happen?

Well, the classical approach

consists of applying intervention

that would promote the growth of the severed fiber

to the original target.

And while this certainly remained the key for a cure,

this seemed extraordinarily complicated to me.

To reach clinical fruition rapidly,

it was obvious:

I had to think about the problem differently.

It turned out that more than 100 years of research

on spinal cord physiology,

starting with the Nobel Prize Sherrington,

had shown that

the spinal cord below most injuries

contained all the necessary and sufficient neural networks

to coordinate locomotion,

but because input from the brain are interrupted,

they are in a non-functional state,

like kind of dormant.

My idea: we awaken this network.

And at the time, I was a post-doctoral fellow in Los Angeles,

after completing my Ph.D in France,

where independent thinking

is not necessarily promoted.

(Laughter)

I was afraid to talk to my new boss,

but decided to muster up my courage.

I knock at the door, my wonderful advisor,

Reggie Edgerton, to share my new idea.

He listened to me carefully,

and responded with a grin.

"Why don't you try?"

And I promise to you,

this was such an important moment in my career,

when I realized that the great leader

believed in young people and new ideas.

And this was the idea:

I'm going to use a simplistic metaphor

to explain you this complicated concept.

Imagine that the locomotor system is a car.

The engine is the spinal cord.

The transmission is interrupted. The engine is turned off.

How could we re-engage the engine?

First, we have to provide the fuel;

second, press the accelerator pedal;

third, steer the car.

It turned out that there are known neural pathways

coming from the brain that play this very function

during locomotion.

My idea: replace this missing input

to provide the spinal cord

with the kind of intervention

that the brain would deliver naturally in order to walk.

For this, I leveraged 20 years of past research in neuroscience,

first to replace the missing fuel

with pharmacological agents

that prepare the neural and in the spinal cord to fire,

and second, to mim the accelerator pedal

with electrical stimulation.

So here imagine an electrode

implanted on the back of the spinal cord

to deliver painless stimulation.

It took many years, but eventually we developed

an electrochemical neuroprosthesis

that transformed the neural network

in the spinal cord from dormant to highly functional state.

Immediately, the paralyzed rat can stand.

As soon as the treadmill starts moving,

the animals show coordinated movement of the leg,

but without the brain.

Here what I call "the spinal brain"

cognitively processes sensory information

arising from the moving leg

and takes decisions as to how to activate the muscle

in order to stand, to walk, to run,

and even here, while sprinting,

instantly stand

if the treadmill stops moving.

This was amazing.

I was completed fascinated by this locomotion

without the brain,

but at the same time so frustrated.

This locomotion was completely involuntary.

The animal had virtually no control over the legs.

Clearly, the steering system was missing.

And it then became obvious from me

that we had to move away

from the classical rehabilitation paradigm,

stepping on a treadmill,

and develop conditions that would encourage

the brain to begin a voluntary control over the leg.

With this in mind, we developed a completely new

robotic system to support the rat

in any direction of space.

Imagine, this is really cool.

So imagine the little 200 gram rat

attached at the extremity of this 200 kilo robot,

but the rat does not feel the robot.

The robot is transparent,

just how you would hold a young child

during the first insecure steps.

Let me summarize: the rat received

a paralyzing lesion of the spinal cord.

The electrochemical neuroprostheses enable

highly functional state of the spinal locomotor networks.

The robot provides the safe environment

to allow the rat to attempt anything

to engage the paralyzed legs.

And for motivation, we used what I think

is the more powerful pharmacology of Switzerland:

fine Swiss chocolate.

(Laughter)

Actually, the first results were very, very,

very disappointing.

Here is my best physical therapist

completely failing to encourage the rat

to take a single step,

whereas the same rat, five minutes earlier,

walked beautifully on the treadmill.

We were so frustrated.

But you know, one of the most essential qualities

of a scientist is perseverance.

We insisted. We refined our paradigm,

and after several months of training,

the otherwise paralyzed rat could stand,

and whenever she decided,

initiated full weight-bearing locomotion

to sprint towards the rewards.

This is the first recovery ever observed

of voluntary leg movement

after an experimental lesion of the spinal cord

leading to complete and permanent paralysis.

In fact --

(Applause)

Thank you.

In fact, not only the rat could initiate

and sustain locomotion on the ground,

they could even adjust leg movement,

for example, to resist gravity

in order to climb a staircase.

I can promise you this was

such an emotional moment in my laboratory.

It took us 10 years of hard work

to reach this goal.

But the remaining question was, how?

I mean, how is it possible?

And here, what we found

was completely unexpected.

This novel training paradigm

encouraged the brain to create new connections,

some relay circuits

that relay information from the brain

past the injury and restore cortical control

over the locomotor networks below the injury.

And here, you can see one such example,

where we label the fibers coming from the brain in red.

This blue neuron is connected with the locomotor center,

and what this constellation

of synaptive contacts means

is that the brain is reconnected with locomotor center

with only one relay neuron.

But the remodeling was not restricted

to the lesion area.

It occurred throughout the central nervous system,

including in the brain stem,

where we observed up to 300 percent increase

in the density of fibers coming from the brain.

We did not aim to repair the spinal cord,

yet we were able to promote

one of the more extensive remodeling

of external projection ever observed

in the central nervous system of adult mammal

after an injury.

And, you know, there is a very important message

hidden behind this discovery.

They are the result of a young team

of very talented people:

physical therapist, neurobiologist, neurosurgeon,

engineers of all kinds.

We have achieved together

what would have been impossible by single individuals.

This is truly a trans-disciplinary team.

They are work so close to each other

that there is almost like a transfer of DNA.

We are creating the next generation

of MDs and engineers,

get a bit of translating discoveries all the way

from bench to bedside.

And me?

I am only the maestro who orchestrated this beautiful symphony.

Now, I am sure you are all wondering, aren't you,

will this help injured people?

Me too, every day.

The truth is that we don't know enough yet.

This is certainly not a cure for spinal cord injury,

but I begin to believe that this may lead

to an intervention to improve recovery

and people's quality of life.

I would like you all

to take a moment and dream with me.

Imagine a person just suffered spinal cord injury.

After a few weeks of recovery,

we will implant a programmable [??]

to deliver a personalized pharmacological cocktail

directly into the spinal cord.

At the same time, we will implant an electrode array,

a sort of second skin

covering the area of the spinal cord controlling leg movement,

and this array is attached to an electrical pulse generator

that delivers stimulations that are tailored

to the person's needs.

This defines a personalized electrochemical neuroprosthesis

that will enable locomotion

during training with a newly designed supporting system.

And my hope is that after several months of training,

there may be enough remodeling of residual connection

to allow locomotion without the robot,

maybe even without pharmacology or stimulation.

My hope here is to be able to create

the personalized condition

to boost the plasticity of the brain

and the spinal cord.

And this is a radically new concept

that may apply to other neurological disorders.

What I termed "personalized neuroprosthetics,"

where by sensing and stimulating neural interfaces,

I implanted throughout the nervous system,

in the brain, in the spinal cord,

even in peripheral nerves,

based on patient-specific impairments.

But not to replace the lost function, no:

to help the brain help itself.

And I hope this enticed your imagination,

because I can promise to you

this is not a matter of whether this revolution will occur,

but when.

And remember, we are only as great

as our imagination, as big as our dream.

Thank you.

(Applause)