Transcriber: Mary Lopez Reviewer: David DeRuwe
Suppose you’re working for an automotive company
that wants to offer the best electric cars to customers.
You spend 10 years developing 20 different highly innovative car models.
Once you test them, one out of 20 makes it out of the garage.
The other 19 don't drive at all or are not safe to drive.
10 years of work designing 20 new cars, and only one goes to the market.
Would you be satisfied?
Well, this is precisely what happens in innovative drug development.
93% of new drugs developed in laboratories
fail when tested on patients in clinical trials.
That’s about one out of 20 drugs in development.
They simply don’t work as expected or are unsafe for use due to side effects.
Consequently, developing a new drug nowadays costs around three billion euros,
primarily due to the many failures and unforeseen circumstances
across the drug development journey.
Firstly, this is a waste of effort and money,
ultimately leading to more expensive medicines for everyone,
and secondly, the patients taking part in clinical trials to test new drugs
may be at risk of experiencing side effects,
no matter how carefully monitored.
On top of this, for vulnerable people such as cancer patients
who may have only one single shot on receiving an effective therapy
to help treat the cancer, it would be incredibly disheartening
to receive an experimental drug that doesn’t work at all.
Yet, drug developers are smart scientists. So where does it go wrong?
Drug developers must deal with biology, which is obviously not a car.
Biology is instead a complex system that we simply do not fully grasp.
It has evolved to be adaptive.
Cells, tissues, and organisms adjust to adapt to changing circumstances.
We call this homeostasis, maintaining conditions that keep us safe and healthy.
We regulate homeostasis with complex biological networks
that are interconnected inside our cells,
between cells in our organs, and between organs in our body.
For example, when we run away from danger,
our body produces hormones that make us more alert and increase our muscle power.
Our muscles start using more oxygen, which makes us breathe faster,
and when we run out of sugar as fuel, our metabolism changes
to use other energy sources, such as fat and proteins.
This chain of effects works to our advantage.
It makes us flexible, able to cope with a wide range of conditions.
However, it can also work against us.
When people receive a drug that changes the activity of a cell or protein,
it may lead to adaptive changes that reduce the effectiveness
of the drug on the cell, tissue, and body level.
This is because our adaptive biological systems are wired to compensate
for changes, sometimes even when these changes are good for us.
Knowing this,
wouldn’t it be possible to take these adaptive systems into account,
thus reducing the number of failed drugs?
In fact, we can, with the latest 3D tissue culture technology
called “organs-on-chips.”
But let’s first look a bit deeper into drug development.
As a matter of fact, biology gets even more complex
when things go wrong, when we get ill.
Diseases we deal with now
often have multiple causes and take decades to develop.
For example, if I get Alzheimer’s disease in 20 years,
I’m probably developing it right now without even being aware of it.
Cardiovascular disease takes over 30 years
to develop into actual disease without any symptoms.
The same is true for diabetes, autoimmune diseases, cancer,
and many other conditions.
They develop over the years, leading to adaptive changes in our bodies,
such as hormonal, immunological, and tissue architecture changes.
We don’t feel ill yet, but once the disease surfaces,
these changes have led to a new normal, the diseased state.
At that point, the systems that used to keep us healthy
may now keep us ill, in a bid to adapt to the changes they’re facing.
To cope with the complexity of biology and diseases,
drug developers use models to test their new compounds.
They usually start with finding a target for the new drug.
This is typically a protein whose activity can be blocked or sometimes activated.
Through years of research, we learn which proteins play a role in a disease,
and which of these are the most likely candidates to be druggable.
In other words, a druggable target is a protein whose activity we can change.
We assume that changing that activity offers some benefit
to a patient with a particular condition.
The models used to test this assumption are typically human cells
cultured in petri dishes or laboratory animals.
Cultured cells may be human,
but they don’t look at all like the cells in our body,
Usually only one cell type is used in a non-natural two-dimensional environment.
The cells are kept alive under carefully optimized conditions,
unlike our own disease cells that are surrounded by other cell types
embedded in a tissue-specific matrix in various local micro-environments.
Animal models are way more complex, but they are not human.
As a result, predictions of animal models about drugs are often wrong.
In other words, the wrong model leads to the wrong drug,
a drug that doesn't work in our complex bodies.
In the end, more and more drugs fail when tested in patients.
To solve this, we need to correct the system.
We can’t just put our horse blinkers on
and focus on one protein to correct with the drug.
We need to focus on the disease and tissue holistically,
in addition to compounds and targets.
What if, rather than testing new drugs in the current non-natural
two-dimensional cultures in a petri dish, we created human tissue models
that capture disease processes with all their complexity?
Thankfully, this technology has arrived.
This is an OrganoPlate.
It looks like a standard well plate used in laboratories worldwide,
well known by any biologist.
However, we developed it into an organs-on-chips device
with up to 96 biological culture chips
that organize cells to closely resemble human tissues.
In each of these chips, we grow a tiny tissue
with a volume of a few hundred nanoliters or one hundredth of a droplet.
Why are these so special?
Well, let me give you an example: the wall of the human gut.
It contains multiple cell layers.
On the inside, you find the covering layer or epithelium.
It separates the gut contents from the inside of our body.
Underneath this layer are fibroblasts, blood vessels, and immune cells,
surrounded by a protein matrix.
A bit deeper, you find more blood vessels,
muscle cells, neurons, and other cell types.
All these cells interact, exchanging signals
to monitor the status of the tissue and respond to changing conditions,
for example, the damage of the gut epithelium.
Immune cells move in and out to fight infections;
the blood vessels bring oxygen and take nutrients from our food
to the rest of our bodies.
In classical, two-dimensional human cell models,
a single cell type is cultured on a plastic surface,
no interactions between different cell types,
no moving immune cells, and no blood vessels.
This is miles away from natural gut tissue.
In a gut model in OrganoPlate,
we combine the essential cell types in a three-dimensional culture,
including the epithelium, blood vessels, immune cells and fibroblasts.
We get the cells from real people, for example, rest materials from surgery
from patients with Crohn’s disease, of course, with their permission.
We organize these cells in an OrganoPlate
such that the model closely resembles natural gut tissue.
Moreover, the cells interact in the tissue, immune cells move around, -
have a look at the green cells behind me -
and blood vessels bring nutrients,
oxygen, and drugs with the red tubule behind me.
In these human gut models, we observe inflammation in Crohn’s disease,
blood vessel leakage, and immune activation.
You could see this as photocopying a tiny piece of diseased tissue.
The OrganoPlate can perform this thousands of times over.
We now routinely do this for a range of tissues and diseases,
including liver and kidney disease,
vascular damage, immunological diseases, and a range of tumors.
Compared to classical models, these models are more than human.
Imagine what this can do for the efficiency of drug development.
Now we can genuinely mimic the response of diseased human tissues to drugs
and better understand the downstream effects on our complex biology.
We can incorporate long-term adaptive changes
by using patient cells and carefully tuning the tissue environment,
all of this in the high numbers crucial to modern drug development.
Could 50% instead of 5% of new drugs leave the garage,
leading to a dramatic cost reduction of drug development?
With these new technologies, I absolutely think so.
We will put fewer patients at risk in trials
and sacrifice fewer laboratory animals in the process,
but most importantly, we will be able to successfully treat more patients
suffering from currently incurable diseases with genuinely innovative drugs
that embrace, rather than ignore, the complexity of human disease biology.