(gentle music)
- The thing that that really excites me
is the experience and the adventure of doing science.
Even though we can't visually see it,
if we look at this test tube,
we know that there are billions of molecules in there,
diffusing, colliding, vibrating.
Sometimes when they collide into another molecule,
they will stick to that molecule,
and then that's when a reaction will happen.
Oftentimes we're exploring questions
that no one has really explored before.
You are the first person in the world,
and probably in the universe,
to really see that.
Working in the lab takes a certain amount of focus,
but when you're focused on that,
it helps you not think about anything else.
And it's also just fun.
(gentle music)
In middle school, I really didn't like biology.
It was mostly about taking a really smelly
paraformaldehyde-fixed frog and dissecting it,
and then labeling its different anatomical parts.
And when they showed us the movie "Jurassic Park,"
that really captured my imagination
- [DNA Strand] A DNA strand like me
is a blueprint for building a living thing.
- The concept that you can alter DNA,
that DNA is a blueprint for life, really resonated with me.
And so I thought it'd be great
to learn more about biology from that point on.
In order to treat diseases,
we need to know more about how genes underlie human health
and how mutations lead to disease.
The beauty of the scientific ecosystem is
that we build our work on the shoulders of giants.
- [Narrator] Research on DNA
is one of the great new challenges in science.
Using modern techniques, the chromosomes can be removed
from the nucleus and chemically analyzed.
- [Reporter] Since 1986,
scientists have been mapping and sequencing
the 3 billion nucleotides contained in the human genome.
- One of the major advances that we have made in biology,
over the past couple decades,
has been a completion of the human genome.
- [Reporter] It's an incredibly detailed blueprint
for building a human cell.
- A revolution in medical science
whose implications far surpass
even the discovery of antibiotics.
- So now we know every single letter in the human DNA.
One tantalizing thought is
"Why don't we go into our DNA,
replace the deleterious genes,
and then also put in the beneficial ones?"
Turns out that's where gene editing comes in.
Gene editing allows us to perturb one gene at time,
and that makes it possible
to study more complex gene interactions in cells.
First and foremost, we need to be able to cut DNA
before we can edit the genome.
You can think of it like a cursory Microsoft Word.
Wherever you make a cut, you can backspace and delete,
and you can type in a new word.
When I first started working on genome editing,
our ability to cut DNA
in specific spots in the genome was pretty challenging.
The tools compared to what I have today
are not nearly as easy to use, not nearly as efficient.
One of the methods we used was called "Zinc Finger Nucleus."
Zinc-finger proteins are found
in many different types of organisms,
including the human genome.
They naturally bind DNA sequences.
But by engineering the zinc-finger protein,
it is possible to change what sequence it recognizes.
We can use it to then bring nucleuses,
which are scissors for cutting DNA, to a specific spot.
(gentle music)
But engineering the zinc-finger protein
turned out to be really challenging.
Around that time, a couple groups of plant biologists
had described a new protein called "TALE,"
which modulate genes in plants.
(gentle music)
I have worked with these proteins,
changed their compositions, so that they would recognize
a new sequence of DNA in the human cell.
And I found out that the TALEN system
can cut DNA pretty well,
much better than using finger proteins.
But even though it can work, it's still pretty cumbersome.
To engineer a zinc-finger or TALEN protein,
you have to make a brand new protein.
This is usually done by taking an existing protein
and then introducing many many mutations
to randomly change this protein,
and then select from that whole pool
of many different proteins,
hoping that one of them will work.
That is a very laborious procedure.
It will take even an expert many months
to perturb a single gene.
And so, I was on the lookout for new systems,
where you don't have the engineer the protein,
which is what makes TALEs and zinc-fingers so difficult.
(wind swooshing)
(cars driving)
I first learned about CRISPR in this room here.
I had just started my lab here
at the Broad Institute in the beginning of 2011.
There was a scientist talking about his research
in enterococcus bacteria,
and I was sitting in the back of the room
sort of dozing off, but he mentioned
that "there are also these CRISPR nucleuses" in his system.
At the time I was working on TALE nucleuses,
so when I heard the word "nucleus"
that immediately caught my attention.
CRISPR is a very abundant system
that protects bacteria from viruses.
You can find them in over 60% of bacteria
that live in this world.
The CRISPR system has a protein called, "CAS-9."
CAS-9 is guided by a RNA
that's programmed to recognize virus DNA.
And when that RNA guide matches the target,
CAS-9 will be programmed to cut DNA.
And once it makes the break,
it doesn't do any more damage than that.
What's so exciting about CRISPR
is that we can easily reprogram CAS-9
to recognize a different DNA sequence.
And so I thought, "This is really cool."
Let's test it to see if we can transfer it to human cells
and engineer it so that we can edit the genome.
And it worked.
The CRISPR system was able to edit the DNA in the human cell
much more efficiently than zinc-fingers or TALE nucleuses.
Zinc-finger proteins recognize DNA
through protein interaction with DNA,
and there isn't a one-to-one correspondence.
There are 20 different amino acids
that you can find in the protein,
and it's hard to know which one and in which context
the amino acid will recognize that specific DNA letter.
In the context of CRISPR,
you are using RNA to recognize DNA,
and so there is a correspondence,
A base pairs with a U,
and then G base pairs with a C.
And so if you know the DNA sequence,
you can very quickly write out
what the RNA sequence should be.
The difference is really night and day.
CRISPR is one of many tools
that are making biological research faster and more precise.
We can modify multiple genes at once in multiple cell lines
all in a matter of a couple weeks.
And that kind of acceleration is what's really exciting.
In the future, we'll be able to understanding more,
and we'll be able to engineer more.
And through that, new ways of therapeutics
that really go at the root cause of disease,
rather than just the symptoms, will become a reality.
And of course, I think we need to proceed cautiously.
Biology is very complicated.
Most of the mutations that we have found
that reduce disease risk,
also have complex interactions with other disease processes.
Let me give you one example.
There's a gene called CCR5,
and there's a small percentage of individuals
that naturally don't have it,
and they are immune to HIV infection.
So you may think that we can get rid of this CCR5 gene
and then make people no longer susceptible to HIV.
If that's true, that's good,
but turns out that this particular mutation
makes someone more susceptible to West Nile virus.
And that trade off is something
that I don't think we are equipped to make that judgment.
Even though we don't have
a West Nile virus epidemic right now,
it doesn't mean that there won't be one in the future.
There's just so much more that we don't know,
and we don't know what we don't know.
And that's what makes biology so fascinating,
but also treatment of disease so challenging.
As we go forward, there will be many new tools
that we need to develop to understand biology.
We need to know more.
(gentle orchestral music)
(gentle orchestral music continues)