It's a great pleasure to be here. I speak to you today as a professor at University
of California, Berkeley, although I am a cofounder of some companies that are using gene editing
and, you know, I've been struck at this meeting by the incredible advances being made in information
technology, and certainly living in the Bay Area, we experience that very directly.
But I think what's really interesting to me is that there's a parallel explosion going
on in biology right now, and that's really what I want to talk to you about this morning,
a technology that is enabling manipulation of the information that controls biological
systems that, I think you'll see, very nicely parallels some of the things that we've heard
about earlier in the meeting. So to kick this off, you know, this is really
a technology that is about rewriting the language of life, rewriting the DNA that controls the
cells, organisms that we see around us and that are us, and it really begins with thinking
about the way that information is stored in biological systems.
So unlike in computers where we store information electronically, ones and zeros, in biology
information is stored chemically. It's stored in the information of DNA. And this is showing
you the beautiful structure of DNA, the double helix that was discovered back in the 1950s.
And in, in fact, when I was growing up in Hawaii, I was growing up in a rural town in
Hawaii. Nobody in my family was a scientist. But the way I got turned on to biology was
by reading a book my dad gave me about the discovery of the structure of DNA, and I was
so amazed by the fact that scientists could do experiments to understand the structure
of a molecule, that that's actually what got me excited about going into biochemistry and
structural biology. So, you know, when we look at the structure
like this, this is basically showing how information is stored in the form of letters of DNA. You
know that -- you might know that DNA has four letters, and the thing that makes it so useful
for storing information is that the letters pair with other letters to form the double
helix and that's how information can be replicated accurately and stored for future generations.
Now, ever since the discovery of the structure of DNA, scientists have been thinking about
how they could manipulate that molecule, how we could synthesize it, how we could make
copies of it, and also how we could change it. Could you actually alter the information
inside of a cell in a way that would allow manipulation of that information very precisely.
It sounds sort of like science fiction. But the idea really was, could you have -- could
you really create some kind of an editor for DNA, sort of analogous to the way that we
might have an editor in our -- to edit a document on our computer where we can move text around,
we can change it, cut and paste things, correct a typo. What if you could actually do that
in the DNA of a cell? It kind of sounds like science fiction, right?
But scientists have been thinking about this for the last few decades and sort of chipping
away at how to do this, and technologies have been coming along for making changes precisely
to the DNA of cells. The challenge has been that those technologies
have not been widely adopted. Why not? Because they were hard enough to
use and they -- there's sort of a high enough energy barrier that most scientists like me
had looked at those earlier technologies and said, "Well, that looks really exciting but
it looks too hard to use." And so the story that I want to tell you today
is about a technology for gene editing that came about from a very unexpected direction.
Research that I was doing with my collaborator, Emmanuelle Charpentier, that was directed
in a very different direction, we thought, than gene editing initially, and it was really
about a curiosity-driven project to understand how bacteria fight viral infection.
And it was through the course of that research that we uncovered a mechanism that cells use
to fight viral infection that could actually be repurposed, we harnessed as a technology
for gene editing. And it's a technology that's become known as "CRISPR."
So to explain how this works a little bit, I want to first show you that, you know, all
cells are susceptible to viral infection. So this is an example of a virus landing on
the surface of a bacterial cell, and in this example -- and this actually happens -- in
bacteria, the DNA of this virus is packaged inside the head, that sort of round structure
in the virus, under very high pressure, and when the virus lands on the surface of the
cell, it's literally like harpooning the cell, injecting the DNA into the cell, where that
DNA of the virus very rapidly takes over the machinery of the cell.
And this is true for any kind of viral infection in us or bacteria and other kinds of organisms.
In bacteria, when this process begins, the cell has very little time to defend itself
from the virus before it gets killed, so there's a really high selective pressure for cells
to come up with strategies to defend themselves, and one of those strategies is a system called
CRISPR. It's an adaptive immune system that allows cells to recognize this foreign DNA,
steal little pieces of it, store it in the DNA of the cell at a place in the genome called
CRISPR, so it keeps a genetic record of viruses that have infected these cells over time,
and then it makes a chemical copy of the DNA in the form of a related molecule called RNA
that provides the cell with a way to program its immune system to find and destroy viral
DNA that has a matching letter sequence. What does that mean?
Well, let me just show you -- [ Laughter ]
Let me show you the actual machinery that does this and then I'm going to show you a
little video that illustrates how it works. Okay. So this is a 3D printed model of the
actual molecule that carries out gene editing. It's a molecule -- it's a protein called Cas9
shown here in the -- it's the white molecule. And the great thing about this technology
is that this protein, Cas9, can be used for any experiment of gene editing in any cell,
and the reason it can work with any -- in any cell and recognize any sequence of DNA
is that it's programmed with a replaceable piece of RNA. That's the orange molecule in
this model. The orange molecule has a series of letters
that match the sequence of letters in DNA that a bacteria might want to find and destroy,
if it's a virus, but as a technologist we might want to use it to program -- to find
a certain sequence in the genome of a cell to make a change.
And the way this system works is that the protein, the white molecule, with its programmable
RNA orange molecule, searches through DNA in the cell, the blue double helix, to find
a sequence of letters matching the RNA sequence. And when that match occurs, this protein grabs
onto the DNA at that position and it makes a very precise cut in the DNA double helix.
Now, when that happens in animal and plant cells, the cell can actually take over, repair
the cut, and in the course of repairing the cut, make a change to the DNA at that position.
Okay. So let me show you a video that illustrates how we imagine that this actually works inside
of an animal or a plant cell. So we're looking at a cell, and of course
in animals and plants the DNA is actually packaged inside the nucleus of the cell, so
we're zooming in here to the nucleus. And you'll see that the blue DNA is wrapped
around some green proteins that allow the DNA to be highly compacted inside the nucleus.
Now, the amazing thing about the CRISPR technology is that this programmable enzyme, Cas9, searches
through all of the letters of the DNA in the nucleus to find a single set of letters -- 20
letters -- that match the letters in the RNA. And when that match occurs, the DNA opens
up, this protein cuts the DNA, and then it hands off those broken ends of the DNA to
repair enzymes in the cell that can fix the break. And in this example, we're seeing actually
insertion of a new piece of information at the site of the break. That's what makes this
very powerful. You can control where changes occur in the DNA by triggering this repair
pathway by introducing a break. Now, the remarkable thing about this technology
is that it works in essentially any kind of plant or animal or fungal or any other type
of organism where it's been tested, so it's very powerful.
It's a democratizing technology because it's simple to deploy. Any student -- we've had
high school students come to the lab. They can take out their iPhone, they can type in
a sequence of letters that they want to synthesize in the form of RNA, they can order it from
a company, and within a couple of days they can be programming this enzyme, Cas9, to make
genetic changes to human cells or any other kind of cells that they are -- they're interested
in studying. So it's a really remarkable, really powerful
technology for doing something that not long ago seemed like science fiction.
So where do we go from here? I want to point out that -- you know, the
way that this technology is being deployed right now. So we're already seeing multiple
clinical trials that have started already to test this, initially in cancer patients
but probably in the not-distant future to test this system also for treating genetic
diseases in mouse models of muscular dystrophy or HIV/AIDS infection. We've already seen
efficacy using the CRISPR technology to treat these animal models of disease.
So there's tremendous excitement about this. And also, of course, in agriculture, excitement
about being able to engineer plants precisely to allow them to adapt to climate change and
other kinds of attacks that are happening, pathogens that might attack plants.
All of these types of changes, at least -- certainly in clinical medicine right now are being done
in cells that we call somatic cells. They're fully differentiated cells, cells that exist
in kids or adults. They're not cells that are going to pass changes on to the future
-- future generations. But one of the things to appreciate about
this technology is because it works in effectively any cell type, it can also be done -- this
kind of gene editing can be done in what we call the germline. And this is an example
of germline editing. So what you're seeing here is a pipette on the left-hand side that's
holding on to a fertilized egg -- this is actually a fertilized mouse egg -- and a needle
coming in from the right that's injecting the gene editing molecules into this fertilized
embryo. And when that animal then develops, it will have changes that are induced by this
-- by the injected CRISPR Cas9 molecules. Those changes will be transmitted to all of
the cells of the organism. And not only that, to their children, children's children, et
cetera. So these become heritable changes.
And it was appreciated early on with this technology that this works very nicely in
mice. It turns out it works in lots of other kinds of organisms.
I wanted to show you one example of sort of illustrating how simple this is to do and
also how beautiful a result one can get with this kind of germline editing.
So this is an experiment that was done by a first-year graduate at the University of
Texas and she was kind enough to share this with me. Sunada Khadka.
And what Sunada did in this experiment is she took frog embryos. These are two-cell
embryos, so they have two cells and the cells are split right -- round embryos, there are
two cells on each side of the round embryo. And she injected the CRISPR molecules into
one of the two cells in such a way that she removed a gene important for making the brown
color of these frogs and replaced it with a gene that makes the frog -- makes the cell
glow green. And so you see these beautiful embryos with one cell glowing green, the other
cell unedited, and when these animals -- these animals are otherwise completely normal, these
are allowed to develop, these are the tadpoles that develop. And you can see that in the
image on the -- on your left, these animals have a split right down the center, with the
normal brown color is gone from the cells on the bottom of the animal and, you see on
the right-hand side, replaced by the green gene.
So it's a very, very interesting, very powerful technology, and this is something that was
done by a first-year graduate student. So it turns out that this kind of germline
editing works in other animals. It also works in mammals. It works in -- in monkeys. And
an experiment that was published in early 2014 illustrated this, in which monkeys that
were treated in the same way that I just showed you with the frog embryos were edited in the
germline, so that the resulting animals could pass on those genetic changes to their progeny.
And for me, this was kind of the moment when I realized that as excited as I was about
this technology, I started to feel a little bit nervous because, you know, this technology
is powerful enough that it can also allow changes to be made, heritable changes to be
made, in human beings. And this was actually a cover of "The Economist" from about a year
ago under the banner, "Editing Humanity," with the article talking about the exciting
challenges that we now face where we have a technology that can allow correction of
mutations that would cause disease, but also potentially introduce changes to human populations
that lead to changes in traits that some might consider enhancements, and should we go there,
is this something that should happen. And just to give you a flavor of how fast
the technology is moving, so I -- I spoke about this last year, last summer at Google
Camp, and just in that -- in that amount of time, so it's not quite a year, this technology
has now moved to the point where it's possible now to make cells from human somatic cells,
so fully differentiated cells. It's now possible to make eggs and sperm, certainly in mice
and probably very soon in human beings that will obviate the need to do embryo editing.
We won't have to do that. We can edit eggs and sperm of people and then use those edited
germ cells to -- for fertilization, if that were desired.
So the pace of the technology is unbelievably fast, and I think that, you know, it's really
important for scientists and, frankly, all of us to appreciate the wonderful opportunities
it offers but also the real challenges that we face now with ethical decisions about how
to use this technology appropriately. Thank you very much.