Thank you all.
The sessions have been
extraordinarily stimulating
and I've made many decisions here, today.
The first one is that
I will be joining a political party
first thing on Monday.
(Laughter)
The second one is that we are going to redefine a little
our perspectives --
our research priorities
and we are going to try to clone Mr. Joaquim Casado.
(Laughter)
And we will try to make
10,000 Joaquim Casados.
(Applause)
And in that way, really
transform Portuguese local politics.
What I will try to do here, today,
is to explain very complex things,
in the simplest way possible.
I will talk about genes.
And many of you don't even know
what a gene is.
A gene is the basic unit
of heredity
that exists in all of our cells.
And our genetic information
is all contained in a wonderful molecule
called DNA, or ADN in Portuguese.
And it contains a kind of mold
to build many, many proteins.
And the proteins -- those are the functions
that our body is able to accomplish.
And our genes -- we are very much
what our genes are,
especially as a species.
We are human because
we have a certain genome
that is common to all.
In fact, it is surprising that
there are only small differences between us
and chimpanzees,
from a genetic point of view,
and there are, in fact, many modifications
of form and function in these organisms.
Therefore, in fact, everything that we are
is, really, coded in the genes.
Of course there are many
environmental circumstances
that are very important.
But the genes are, really, the basis of us,
of ourselves.
What are genes for?
Genes make proteins.
Proteins -- a group of proteins
forms entities
called cells.
And an organized set of cells
forms tissues.
An organized set of tissues
forms organs.
And an organized set of organs
forms organisms,
just like us.
And, coming down to the cell,
to simplify
because it's the most basic unit
of our organism.
Each cell is composed of
about 10,000 pieces.
10,000 proteins -- so,
10,000 genes coded 10,000 proteins,
that all work together.
And a cell is like a city:
it contains everything.
It contains highways,
the microfilaments.
It contains country roads,
the microfilaments. --
The microtubules are the highways.
It contains a thermal power station,
the mitochondria.
It contains an import/export trading market,
the mechanisms of endocytosis
and secretion.
It contains all kinds --
everything that a city needs
is within a cell.
And that is why they are extraordinarily
complex structures.
They can also be compared,
the cells,
to an engine.
An extraordinarily sophisticated engine
that has many functions.
And here, I use this analogy,
to try to explain
what a genetic disease is.
A hereditary genetic disease,
the simplest,
is one in which a person
inherits a spoiled gene,
a gene that doesn't work.
And you can imagine an engine,
with a defective part,
or, many times, missing a part.
It's either damaged or it doesn't exist.
Well, if that part
is absolutely fundamental
for the engine to work,
then the engine won't work, right?
Therefore,
that fetus, that child
who inherited that spoiled gene
has no chance, dies, and therefore
does not become a medical problem;
it's a pre-medical problem, essentially.
But in many cases,
we have damaged parts
that are not absolutely essential,
so the engine works.
But obviously, it won't work
to the same capacity
that a normal engine can.
And so,
the existence of a bad part
is going to compromise the function of that engine,
throughout the lifetime
of the car, or the organism
of which it is a part of.
So, the main idea here
is that if we could,
through special techniques,
introduce in these engines
the missing part, we would be able, in fact,
to correct what was wrong with the engine,
and it would work perfectly.
So, gene therapy
is trying to do exactly that.
It's a technique that aims at replacing genes
to treat and prevent disease.
But we have a fundamental problem,
which is how to insert the genetic material
inside the cell.
Now, the average person
is often exposed to genes.
We have genes and we're exposed to genes.
For example, every day we eat genes.
We eat lots of genes, through food.
And if, by chance, as we eat fish,
if we had the ability
of acquiring fish genes,
we would be able to actually transform,
and start to present
some fish characteristics,
as time passed,
and as we ate more fish.
And instead of fish, I could say vegetables.
Vegetables have, in fact, many genes,
contrary to what many people think.
Tomatoes and carrots
also have genes.
(Laughter)
And they would also be able
to alter us, genetically.
So, we are -- the lesson here,
what I wanted to say is that
we are prepared to resist
the entrance of new genes
into our organism;
to keep our genome intact,
so that we don't transform into other things
that we are not.
So, what is --
this is the big challenge we face
in gene therapy.
So what is the solution for this?
There is a solution.
And it's a biological solution.
It's a natural solution.
Because there are some naughty
microorganisms
that have found --
they have resolved, naturally, the problem.
Those little crooks are viruses.
Viruses are the simplest living beings
and they are, in essence, a shell
with DNA inside.
And what are they able to do?
They are able to penetrate --
they attach to the cells,
they're inserted inside these cells,
they break those membranes
that keep the virus away, and really go
deep inside the cell, and then
they can manipulate the cell
into using their DNA
for their own advantage.
In the case of viruses, it's to make more viruses.
They use the cell
as a factory for new viruses.
And when there are many viruses in that cell,
it bursts,
the viruses move on to other cells
and so on,
and the virus is dispersed.
Well, we can use this
in a therapeutic way.
And the key here is to remove from those viruses
the bad genes, that is,
those genes that make it so
the virus can self-perpetuate.
So, we are trying to make
non-replicative viruses,
that will not be able to
replicate inside this cell.
We remove the bad genes and in their place,
because the genome is very compact --
the virus genome --
we will insert the gene of interest
and introduce it in the cell.
So, in that case, we have a virus,
by genetic engineering,
with a sequence of DNA
with the gene we want to insert
in the cell.
So, that's the principle.
There are other ways, without viruses,
but this one is, really,
the most effective one,
and it is, really,
the ideal system, for the moment.
I'll tell you about practical applications
of this therapy.
And I will tell you about the eye.
The eye is the ideal organ for this therapy
because it's a small organ.
It's a very important organ, but it's not vital.
It's not a question of life or death,
but people value their vision a lot,
obviously.
And it's relatively confined
so it's very --
it's kept away from the rest of the body, let's say.
And so, the eye becomes --
the eye is a fascinating organ
that is able to detect light, detect photons
and transform photons
into electric impulses
that are then read by our brain
and then registered as images.
And that goes on in this orange
sheath that you see here, in this picture,
and that is called the retina.
Obviously, when there are problems
in these retina cells, there are vision diseases,
and blindness problems.
There are two essential kinds:
one kind is mainly hereditary
and it's called -- it's a big group
called retinitis pigmentosa,
in which, what the patients see
is shown here
on the top part of the slide.
So, normal vision is on the left,
and vision of a patient
with one of these diseases is on the right.
In other words, there is initially a loss
of peripheral retina
and what is called tunnel vision,
and also loss of sight at night.
But eventually, even that central spot
disappears in the end.
There is another, very common disease,
it's a disease related to aging,
it's complex and multi-genic,
in which there is also --
there is also a degeneration of the retina.
That one is a little bit different
and there is, above all,
a problem of central vision,
while peripheral vision remains
more or less intact.
This was just to give you an idea,
really, of the common problems
that exist in the diseases of vision.
Well, what do we need to do?
We need to insert
these recombinant viruses --
that's what we call them --
that contain that gene
that we want to insert in the retina,
and that is achieved
through eye surgery techniques
that are relatively standard.
So, none of this is too spectacular,
these are things eye doctors already do
and they're going to be able to put --
to inject a bunch of viruses
exactly in the retina cells
so that they can then --
so the viruses can infect those cells
and lead them to express --
they start using that DNA,
and start expressing that part that is missing
and that is damaged in those patients.
Of course, this takes years
to be accomplished;
these are slow processes
that involve many studies,
to find which viruses are ideal
to do these things.
Some are, some aren't.
Some attack the cells too much,
some too little, and so on.
There are many complications,
and it took 20 to 30 years
to get where we are now.
There are also problems with testing animals,
and now we have a wonderful technique
that allows us to do -- it's called
a knockout -- and allows us
to delete a gene in a mouse
and replicate the human disease.
In other words, we have an exact model
of the human disease, in mouse,
and then we can test lots of things.
And that's what has been done,
that is what has been done for a disease
that has a very complicated name,
it's called LCA, Leber's disease
and it leads to a degeneration
quite catastrophic and precocious
of the retina, in patients.
I will show you now
the results of a gene therapy study
done at the Hospital of Philadelphia,
by an American group,
but, in fact, there is a group in London
that has done the same thing,
and another American group that has already done it
for that disease, in particular,
and they all get amazing results,
as you will see.
So, this is just to indicate
what I will show you,
I will show you a patient,
this is, in fact, the youngest patient
that was treated with this disease,
because the earliest we intervene
with this disease, the better.
And the patient -- one eye is covered
and they ask that the non-treated eye --
because they only treated one eye,
as this is a clinical trial, obviously,
so everything is experimental --
they cover one eye, and the patient
has to follow an obstacle course
just like the one indicated here.
Now, let's show
the video, please.
So, the patient - it was asked that --
he has the treated eye covered,
the non-treated eye open
and he's having trouble finding
his way.
There are a few obstacles
but there are also some arrows on the floor
that indicate the right way.
There are subtitles; we don't need sound.
But the kid is, in fact, having a lot of trouble
and he's saying "This IS hard."
"This is really hard, and I really
I can't solve this.
I can't see, I can't go through."
This video, I had to cut it because he takes
about four minutes, trying
with some corrections
and some help
to complete the course.
Now, they've covered the other eye
and this is the treated eye.
And here, there is, in fact,
a spectacular improvement.
Corey, that's his name,
is able to overcome the obstacles,
he sees where he's going
and, really, can complete the course
in a few seconds,
open the door and leave.
So, this is a first evidence
that ocular gene therapy --
There have been
very promising results
with hematopoietic diseases,
bone marrow diseases,
but in which that is possible
because they remove the bone marrow cells,
do the genetic manipulation in vitro,
and then put back the cells
into the organism.
This is, really, the first good evidence
that we can do
gene therapy in situ.
We are collaborating on a project
to try the second genetic disease,
in London, with University of Oxford
and Imperial College,
which I'm associated with.
And we will start, until the end of the year,
a clinical trial,
similar to these ones,
in a disease that is a lot slower
and for which the therapeutic potential
of acting early is excellent.
I didn't say, but it's obvious,
gene therapy is going to stop
the progression of a disease and it's going to cure it
in that moment, but it will not regenerate
a tissue that is already dead.
That is what stem cell therapies are for,
which we'll leave for another talk.
So, the earlier we stop it, the better,
and so, this disease has two --
this new disease, called choroideremia,
has two very good things.
It has, exactly -- it is much slower,
and so, the patients only around 40 years old
will show this visual deficit
that we see in 10-year-old children
with this other disease.
So, we will be able to act sooner.
And then it is also much more common,
I mean, among rare diseases,
it's a lot less rare than this one,
which is, in fact, extremely rare.
So I'll end here. Thank you very much.
(Applause)
Translated and subtitled by Inês Pereira