Translator: Chryssa Takahashi Reviewer: Maria Pericleous
(Greek) Good afternoon.
I apologize I have to speak in English,
I have done my entire education in English,
but I hope everybody will be able to follow.
So thank you, Manoli, for the kind introduction.
It is very good to be with you.
Today, we are going to talk about one word, and one word only,
and that word is “Mutants.”
Now, let us all be honest with each other.
We do not bring positive images in our minds when we think about mutants.
We do not look at each other and say
“Oh, he looks so mutant” or “You are such a mutant”
as a term of endearment.
Before I go any further, I need to make sure
that you can tell everybody that you cannot catch a mutation,
and no, you do not get mutations by spider bites.
Just thought to put that out there.
But culturally, for a very long time,
we have considered a mutant to have a negative connotation,
and the picture that you will see behind me
are these horrible monster creatures in some cave.
In fact, as I was looking around to see appropriate pictures,
I actually found a mutant zombie.
As if being a zombie is not bad enough, you have to be a mutant zombie. OK.
(Laughter)
However, here is the thing.
It is all not true.
The word mutant
simply means a change in DNA,
and it does not have a positive or negative qualifier
about what it does.
All it talks about is the fact there is a position in your DNA
that is different from what is the reference position,
and we have known about this for the best part of 100 years,
since we started manipulating DNA in flies and other creatures.
And in many ways, we are all mutants, and I will come to that in a moment.
So, now we have the mutant misnomer.
There is a second misnomer I would like to talk about.
And the second misnomer is “Healthcare.”
This is where I work – this is where I am privileged to be able to work;
it is a wonderful place.
But I would like to ask if anybody here has gone to the doctor, lately,
and said, “Doctor, I am feeling really well today;
I am feeling really healthy. Please help me.”
(Laughter)
So in essence, healthcare is a beautification
because in reality it ought to have been “sickcare.”
We care for the sick, not for the healthy.
Yes, I understand that we aspire to be healthy,
but, really, we look after the sick.
So, let’s try to think about the problem of healthcare and sickcare
in a slightly different angle.
It is true and it is appropriate
that we spend significant amounts of effort and resources,
throughout the world, to care for the sick.
Indeed, some will say that we are not spending enough,
and I will agree with this.
However, I would pose it to you
that it is just as informative
not only to understand why people get sick,
but it is also to understand
why people who should be ill are not.
Think about this for a moment.
So here is a perhaps somewhat unsettling statement.
A subset of us probably should not exist
or should be very ill, as children, as neonates.
And the reason for this
is because some of the information that we carry in our genomes
is predicting a catastrophic disorder
from which we might not have been able to recover.
And yet, here we are, able to enjoy each other’s company.
I think that is wonderful, but I also think that it is interesting
because if we can understand what it is that protects us from illness,
maybe that will be our alternative path to new therapeutics,
to help people who are about to develop such illnesses.
And I would argue that this is an area that we are under-resourced
and we have under-considered.
OK.
So everybody’s going “Oh God, what is in the next slide.”
We are in Greece, my home country,
and sometimes when I think about the archetypal Greek,
what do I think about?
Here is one of our beloved children, Dimitri Mitropoulos,
but he seems to be doing a bit of this,
and it is true that many of us have a habit of smoking too much.
We also eat late, and some of the things that we eat are not particularly healthy.
There is gyro up there, there is kokoretsi.
We just had Easter, yes?
Some of you might know that the European Union
has issued an advice against eating kokoretsi
because it is considered to be deeply unhealthy for you.
But we do all these things, and we have been doing them for a very long time.
And yet, and yet, and yet,
we seem to enjoy among the largest longevity rates in Europe.
We have much lower cardiovascular disease rates
than you would have expected from our lifestyle,
and we are generally considered to be well hardy.
Why is that?
Well, there is a number of reasons.
Of course, before McDonald’s invaded our land,
we enjoyed the Mediterranean diet: oils, fruits, nuts, fish.
I cannot tell you anything more about this, because I am a geneticist.
I can tell you a little bit about this:
It is not just our diet that helps protect us
from the evils of smoking and kokoretsi and all the rest of it,
it is we now understand
that we have changes, mutations in our DNA,
that are protecting us from some catastrophic disorders.
Now, this is not new information, and it is a little bit puzzling
that perhaps we are not spending as much time as we should.
Consider this: red blood cells, they carry oxygen around your body –
you need them, trust me.
So we understand that when we have particular mutations
that cause these red blood cells to change shape,
we get things like sickle-cell disease,
and the oxygenation of our tissue is reduced.
That is a very bad thing; it is not comfortable.
Unless you happen to live in a place
in which malaria is endemic and has high frequency.
Because if that is the case,
those sickle-shaped cells actually protect you from malaria.
So let us take a step back for a moment.
We have a bad mutation that causes sickle-cell disease,
that becomes a good mutation
if you happen to live in an area where malaria is very prevalent.
I guess the point that I am trying to make is that there are no absolutes,
there is no absolute bad, there is no absolute good with mutations.
A mutation is a mutation,
and it depends in what context you evaluate the type of information
and help you might be able to get.
So then, is it possible for us to use our genome
not only to find these bad mutations,
but also to find some good mutations that can help us?
Well, it is.
I have aspirational goals toward this, but this is not science fiction,
this is happening in labs around the world right now,
and by the way, if my lab is watching, I hope you are going to work right now.
(Laughter)
Here are the covers of two very famous issues
of the very well-known journals “Nature” and “Science,”
that in 2001 published the first draft
of the blueprint of life, the human genome.
It was a draft, but it worked very well.
It took a best part of ten years to decode one genome,
and then what happened?
We did what we are really good at.
We scaled, we miniaturized, we made things cheaper.
It’s no different from the old Cray computers
to the thing that you got in your pocket now as your smartphone.
It used to cost millions and millions of dollars,
now it costs a few thousand dollars and the costs continue to crash.
As of right now,
there is tens of thousands of genomes that have already been sequenced,
and it is my prediction –
and I assure you it is not a visionary prediction –
that within the next few years,
we will have hundreds of thousands
and millions, and eventually billions of genomes.
Well, when that happens, we have an opportunity.
In addition to finding all the changes in the genomes that make us sick,
we can actually find
some of the changes that make us feel better.
Some of you might have heard about something called the blue zones.
Blue zones are areas in the planet in which people live longer,
and they don’t just live longer, they live longer, healthier.
The island of Ikaria, some of you will see on this map is one of them,
with a mean individual, the inhabitant of the island,
will live an average of ten years longer than elsewhere in Europe.
Yes, we should sequence those individuals,
but we should not just look for these blue zones.
So here is the thing.
As I look around you, I am confident to say
that there is at least two or three of you whose genome is containing something
that is deeply protective from a catastrophic disease.
I would actually argue
that there is more of you than that, but I don’t have enough of a sense yet.
So I’m thinking not just those who are on the blue zones,
but across the country, across the continent, across the globe.
As we start accumulating genomes,
we are going to start finding these good mutants,
people who should have been very, very ill but they are not,
and they are not,
because they have mutations in other genes, and they protect them.
OK, that is good, that is great.
You will say that is eight billion of us, and I will say, “Yeah that is good,
but I am a little impatient; it is not quite enough, give me more.”
What else can we do?
Well, we have been studying human genetic disorders
for the best part of 100-120 years.
And one of the things that we do is we model these genetic disorders
in a variety of animals: mice, rats,
fish, worms, flies, a whole host.
And what we typically like to do is say, “Aha, there is a gene
that when it is missing in a child,
is causing a very severe metabolic disease,
and I need to understand why.”
Well, I am going to go ahead,
and I am going to delete exactly the same gene in a mouse
or a fly or a worm or a fish.
And I am going to recreate this disease in this model
in such a way that I can study it.
And I must tell you, we get more excited when we achieve that goal
because now we have a malleable tool to study a disease.
I would argue that we should get even more excited,
that we delete those genes in these model organisms,
and we fail to generate this disease.
Why?
Because the question then becomes:
Why is it that when a little baby is missing a particular gene,
it is going to have a very dim future – and I consider that unacceptable –
[while] when I delete the very same gene in a rat or a mouse,
the mouse does not care?
My sense
is [that] understanding why these model organisms, these animals,
have the capacity to miss these genes and still be healthy
will surely help us, guide us, towards better therapeutics.
If we think a little bit broader – the planet –
there is an enormous number of species around the planet,
and we are well on our way of sequencing all of them.
We will have the genomes of thousands of species, very soon.
It is not a bold prediction to say
that among the species we are going to encounter mutations
that in the human being cause catastrophe,
but in those species they are fully tolerated.
Let us work together to understand the differences,
to understand why in a worm, or in a fish, or an ant, or a giraffe
and I do not care what,
a gene that causes a catastrophic disease in a human is actually tolerated.
And yet you will say, “Greedy, greedy, now all the species,
we have now eight billion humans and all the species on the planet”.
I hate to tell you this, but I am still not satisfied.
Scientists by definition are impatient, and we offer no apologies about this.
So here is the thing.
There is something else that we can do.
And the other thing we can do is go directly into cells.
The picture that you see behind [me] is just a picture of a cell,
and it is quite tenable for us to obtain ill cells from every human genetic disease
that has ever been discovered.
For rare human genetic disorders – and this is something that is my passion –
there is about 10,000-12,000 of them, give or take,
and if somebody said to me,
“Let us establish cells from 12.000 human genetic disorders,”
I would say, “Well that is hard,
but it is not impossible, by any stretch of the imagination.”
We do not need to invent technology, we just need to invest time.
And time is something we have a little bit of.
And then what are we going to do?
Well, we live in a brand new world.
Again, I am sure my predecessor and the ones before said the same thing,
and it is a wonderful thing about humanity,
but it is true, we live in a world where, for the first time ever,
we have the capacity to edit the genome.
Some of you might have heard about an enzyme, CRISPR-Cas9.
The bottom line is you can go ahead and at will direct it, you can delete genes,
you can change the lettering of genes, you can change the order of genes,
you can pretty much do whatever you do.
It is like Microsoft Word without the bugs, the hacking, and the virus threats.
But, we can do this.
So now, what you can do is you can take each of the 12.000 diseases that you have,
and in each cell go and systematically delete one gene at a time.
And you can discover which genes, when missing,
will actually protect, cure, restore the original dysfunction.
And when you actually combine that with a pharmacopoeia that we have,
you can have hyper accelerated drug discovery.
This is not going to work for every human genetic disorder,
but I am convinced is going to work for a significant fraction thereof.
And given that for genetic disorders right now
our therapeutic options are precious, few, and limited,
I strongly welcome this bold idea
because after all, sometimes it’s good to be a mutant!
Thank you.
(Applause)
(Greek) Good afternoon.
I apologize I have to speak in English,
I have done my entire education in English,
but I hope everybody will be able to follow.
So thank you, Manoli, for the kind introduction.
It is very good to be with you.
Today, we are going to talk about one word, and one word only,
and that word is “Mutants.”
Now, let us all be honest with each other.
We do not bring positive images in our minds when we think about mutants.
We do not look at each other and say
“Oh, he looks so mutant” or “You are such a mutant”
as a term of endearment.
Before I go any further, I need to make sure
that you can tell everybody that you cannot catch a mutation,
and no, you do not get mutations by spider bites.
Just thought to put that out there.
But culturally, for a very long time,
we have considered a mutant to have a negative connotation,
and the picture that you will see behind me
are these horrible monster creatures in some cave.
In fact, as I was looking around to see appropriate pictures,
I actually found a mutant zombie.
As if being a zombie is not bad enough, you have to be a mutant zombie. OK.
(Laughter)
However, here is the thing.
It is all not true.
The word mutant
simply means a change in DNA,
and it does not have a positive or negative qualifier
about what it does.
All it talks about is the fact there is a position in your DNA
that is different from what is the reference position,
and we have known about this for the best part of 100 years,
since we started manipulating DNA in flies and other creatures.
And in many ways, we are all mutants, and I will come to that in a moment.
So, now we have the mutant misnomer.
There is a second misnomer I would like to talk about.
And the second misnomer is “Healthcare.”
This is where I work – this is where I am privileged to be able to work;
it is a wonderful place.
But I would like to ask if anybody here has gone to the doctor, lately,
and said, “Doctor, I am feeling really well today;
I am feeling really healthy. Please help me.”
(Laughter)
So in essence, healthcare is a beautification
because in reality it ought to have been “sickcare.”
We care for the sick, not for the healthy.
Yes, I understand that we aspire to be healthy,
but, really, we look after the sick.
So, let’s try to think about the problem of healthcare and sickcare
in a slightly different angle.
It is true and it is appropriate
that we spend significant amounts of effort and resources,
throughout the world, to care for the sick.
Indeed, some will say that we are not spending enough,
and I will agree with this.
However, I would pose it to you
that it is just as informative
not only to understand why people get sick,
but it is also to understand
why people who should be ill are not.
Think about this for a moment.
So here is a perhaps somewhat unsettling statement.
A subset of us probably should not exist
or should be very ill, as children, as neonates.
And the reason for this
is because some of the information that we carry in our genomes
is predicting a catastrophic disorder
from which we might not have been able to recover.
And yet, here we are, able to enjoy each other’s company.
I think that is wonderful, but I also think that it is interesting
because if we can understand what it is that protects us from illness,
maybe that will be our alternative path to new therapeutics,
to help people who are about to develop such illnesses.
And I would argue that this is an area that we are under-resourced
and we have under-considered.
OK.
So everybody’s going “Oh God, what is in the next slide.”
We are in Greece, my home country,
and sometimes when I think about the archetypal Greek,
what do I think about?
Here is one of our beloved children, Dimitri Mitropoulos,
but he seems to be doing a bit of this,
and it is true that many of us have a habit of smoking too much.
We also eat late, and some of the things that we eat are not particularly healthy.
There is gyro up there, there is kokoretsi.
We just had Easter, yes?
Some of you might know that the European Union
has issued an advice against eating kokoretsi
because it is considered to be deeply unhealthy for you.
But we do all these things, and we have been doing them for a very long time.
And yet, and yet, and yet,
we seem to enjoy among the largest longevity rates in Europe.
We have much lower cardiovascular disease rates
than you would have expected from our lifestyle,
and we are generally considered to be well hardy.
Why is that?
Well, there is a number of reasons.
Of course, before McDonald’s invaded our land,
we enjoyed the Mediterranean diet: oils, fruits, nuts, fish.
I cannot tell you anything more about this, because I am a geneticist.
I can tell you a little bit about this:
It is not just our diet that helps protect us
from the evils of smoking and kokoretsi and all the rest of it,
it is we now understand
that we have changes, mutations in our DNA,
that are protecting us from some catastrophic disorders.
Now, this is not new information, and it is a little bit puzzling
that perhaps we are not spending as much time as we should.
Consider this: red blood cells, they carry oxygen around your body –
you need them, trust me.
So we understand that when we have particular mutations
that cause these red blood cells to change shape,
we get things like sickle-cell disease,
and the oxygenation of our tissue is reduced.
That is a very bad thing; it is not comfortable.
Unless you happen to live in a place
in which malaria is endemic and has high frequency.
Because if that is the case,
those sickle-shaped cells actually protect you from malaria.
So let us take a step back for a moment.
We have a bad mutation that causes sickle-cell disease,
that becomes a good mutation
if you happen to live in an area where malaria is very prevalent.
I guess the point that I am trying to make is that there are no absolutes,
there is no absolute bad, there is no absolute good with mutations.
A mutation is a mutation,
and it depends in what context you evaluate the type of information
and help you might be able to get.
So then, is it possible for us to use our genome
not only to find these bad mutations,
but also to find some good mutations that can help us?
Well, it is.
I have aspirational goals toward this, but this is not science fiction,
this is happening in labs around the world right now,
and by the way, if my lab is watching, I hope you are going to work right now.
(Laughter)
Here are the covers of two very famous issues
of the very well-known journals “Nature” and “Science,”
that in 2001 published the first draft
of the blueprint of life, the human genome.
It was a draft, but it worked very well.
It took a best part of ten years to decode one genome,
and then what happened?
We did what we are really good at.
We scaled, we miniaturized, we made things cheaper.
It’s no different from the old Cray computers
to the thing that you got in your pocket now as your smartphone.
It used to cost millions and millions of dollars,
now it costs a few thousand dollars and the costs continue to crash.
As of right now,
there is tens of thousands of genomes that have already been sequenced,
and it is my prediction –
and I assure you it is not a visionary prediction –
that within the next few years,
we will have hundreds of thousands
and millions, and eventually billions of genomes.
Well, when that happens, we have an opportunity.
In addition to finding all the changes in the genomes that make us sick,
we can actually find
some of the changes that make us feel better.
Some of you might have heard about something called the blue zones.
Blue zones are areas in the planet in which people live longer,
and they don’t just live longer, they live longer, healthier.
The island of Ikaria, some of you will see on this map is one of them,
with a mean individual, the inhabitant of the island,
will live an average of ten years longer than elsewhere in Europe.
Yes, we should sequence those individuals,
but we should not just look for these blue zones.
So here is the thing.
As I look around you, I am confident to say
that there is at least two or three of you whose genome is containing something
that is deeply protective from a catastrophic disease.
I would actually argue
that there is more of you than that, but I don’t have enough of a sense yet.
So I’m thinking not just those who are on the blue zones,
but across the country, across the continent, across the globe.
As we start accumulating genomes,
we are going to start finding these good mutants,
people who should have been very, very ill but they are not,
and they are not,
because they have mutations in other genes, and they protect them.
OK, that is good, that is great.
You will say that is eight billion of us, and I will say, “Yeah that is good,
but I am a little impatient; it is not quite enough, give me more.”
What else can we do?
Well, we have been studying human genetic disorders
for the best part of 100-120 years.
And one of the things that we do is we model these genetic disorders
in a variety of animals: mice, rats,
fish, worms, flies, a whole host.
And what we typically like to do is say, “Aha, there is a gene
that when it is missing in a child,
is causing a very severe metabolic disease,
and I need to understand why.”
Well, I am going to go ahead,
and I am going to delete exactly the same gene in a mouse
or a fly or a worm or a fish.
And I am going to recreate this disease in this model
in such a way that I can study it.
And I must tell you, we get more excited when we achieve that goal
because now we have a malleable tool to study a disease.
I would argue that we should get even more excited,
that we delete those genes in these model organisms,
and we fail to generate this disease.
Why?
Because the question then becomes:
Why is it that when a little baby is missing a particular gene,
it is going to have a very dim future – and I consider that unacceptable –
[while] when I delete the very same gene in a rat or a mouse,
the mouse does not care?
My sense
is [that] understanding why these model organisms, these animals,
have the capacity to miss these genes and still be healthy
will surely help us, guide us, towards better therapeutics.
If we think a little bit broader – the planet –
there is an enormous number of species around the planet,
and we are well on our way of sequencing all of them.
We will have the genomes of thousands of species, very soon.
It is not a bold prediction to say
that among the species we are going to encounter mutations
that in the human being cause catastrophe,
but in those species they are fully tolerated.
Let us work together to understand the differences,
to understand why in a worm, or in a fish, or an ant, or a giraffe
and I do not care what,
a gene that causes a catastrophic disease in a human is actually tolerated.
And yet you will say, “Greedy, greedy, now all the species,
we have now eight billion humans and all the species on the planet”.
I hate to tell you this, but I am still not satisfied.
Scientists by definition are impatient, and we offer no apologies about this.
So here is the thing.
There is something else that we can do.
And the other thing we can do is go directly into cells.
The picture that you see behind [me] is just a picture of a cell,
and it is quite tenable for us to obtain ill cells from every human genetic disease
that has ever been discovered.
For rare human genetic disorders – and this is something that is my passion –
there is about 10,000-12,000 of them, give or take,
and if somebody said to me,
“Let us establish cells from 12.000 human genetic disorders,”
I would say, “Well that is hard,
but it is not impossible, by any stretch of the imagination.”
We do not need to invent technology, we just need to invest time.
And time is something we have a little bit of.
And then what are we going to do?
Well, we live in a brand new world.
Again, I am sure my predecessor and the ones before said the same thing,
and it is a wonderful thing about humanity,
but it is true, we live in a world where, for the first time ever,
we have the capacity to edit the genome.
Some of you might have heard about an enzyme, CRISPR-Cas9.
The bottom line is you can go ahead and at will direct it, you can delete genes,
you can change the lettering of genes, you can change the order of genes,
you can pretty much do whatever you do.
It is like Microsoft Word without the bugs, the hacking, and the virus threats.
But, we can do this.
So now, what you can do is you can take each of the 12.000 diseases that you have,
and in each cell go and systematically delete one gene at a time.
And you can discover which genes, when missing,
will actually protect, cure, restore the original dysfunction.
And when you actually combine that with a pharmacopoeia that we have,
you can have hyper accelerated drug discovery.
This is not going to work for every human genetic disorder,
but I am convinced is going to work for a significant fraction thereof.
And given that for genetic disorders right now
our therapeutic options are precious, few, and limited,
I strongly welcome this bold idea
because after all, sometimes it’s good to be a mutant!
Thank you.
(Applause)
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