Can we cure genetic diseases by rewriting DNA?
-
0:01 - 0:05The most important gift
your mother and father ever gave you -
0:05 - 0:08was the two sets
of three billion letters of DNA -
0:08 - 0:10that make up your genome.
-
0:10 - 0:12But like anything
with three billion components, -
0:13 - 0:14that gift is fragile.
-
0:15 - 0:18Sunlight, smoking, unhealthy eating,
-
0:18 - 0:21even spontaneous mistakes
made by your cells, -
0:21 - 0:23all cause changes to your genome.
-
0:25 - 0:28The most common kind of change in DNA
-
0:28 - 0:32is the simple swap of one letter,
or base, such as C, -
0:32 - 0:36with a different letter,
such as T, G or A. -
0:37 - 0:40In any day, the cells in your body
will collectively accumulate -
0:40 - 0:45billions of these single-letter swaps,
which are also called "point mutations." -
0:46 - 0:49Now, most of these
point mutations are harmless. -
0:49 - 0:50But every now and then,
-
0:50 - 0:54a point mutation disrupts
an important capability in a cell -
0:54 - 0:57or causes a cell to misbehave
in harmful ways. -
0:58 - 1:01If that mutation were inherited
from your parents -
1:01 - 1:04or occurred early enough
in your development, -
1:04 - 1:07then the result would be
that many or all of your cells -
1:07 - 1:09contain this harmful mutation.
-
1:09 - 1:12And then you would be one
of hundreds of millions of people -
1:12 - 1:14with a genetic disease,
-
1:14 - 1:17such as sickle cell anemia or progeria
-
1:17 - 1:20or muscular dystrophy
or Tay-Sachs disease. -
1:22 - 1:25Grievous genetic diseases
caused by point mutations -
1:25 - 1:27are especially frustrating,
-
1:27 - 1:30because we often know
the exact single-letter change -
1:30 - 1:35that causes the disease
and, in theory, could cure the disease. -
1:35 - 1:38Millions suffer from sickle cell anemia
-
1:38 - 1:41because they have
a single A to T point mutations -
1:41 - 1:44in both copies of their hemoglobin gene.
-
1:46 - 1:49And children with progeria
are born with a T -
1:49 - 1:51at a single position in their genome
-
1:51 - 1:52where you have a C,
-
1:53 - 1:57with the devastating consequence
that these wonderful, bright kids -
1:57 - 2:01age very rapidly and pass away
by about age 14. -
2:02 - 2:04Throughout the history of medicine,
-
2:04 - 2:07we have not had a way
to efficiently correct point mutations -
2:07 - 2:09in living systems,
-
2:09 - 2:12to change that disease-causing
T back into a C. -
2:13 - 2:15Perhaps until now.
-
2:15 - 2:20Because my laboratory recently succeeded
in developing such a capability, -
2:20 - 2:21which we call "base editing."
-
2:23 - 2:25The story of how we developed base editing
-
2:25 - 2:28actually begins three billion years ago.
-
2:29 - 2:32We think of bacteria
as sources of infection, -
2:32 - 2:35but bacteria themselves are also
prone to being infected, -
2:35 - 2:37in particular, by viruses.
-
2:38 - 2:40So about three billion years ago,
-
2:40 - 2:44bacteria evolved a defense mechanism
to fight viral infection. -
2:46 - 2:48That defense mechanism
is now better known as CRISPR. -
2:49 - 2:52And the warhead in CRISPR
is this purple protein -
2:52 - 2:56that acts like molecular
scissors to cut DNA, -
2:56 - 2:58breaking the double helix into two pieces.
-
2:59 - 3:03If CRISPR couldn't distinguish
between bacterial and viral DNA, -
3:03 - 3:06it wouldn't be a very useful
defense system. -
3:06 - 3:09But the most amazing feature of CRISPR
-
3:09 - 3:14is that the scissors can be
programmed to search for, -
3:14 - 3:17bind to and cut
-
3:17 - 3:19only a specific DNA sequence.
-
3:21 - 3:24So when a bacterium encounters
a virus for the first time, -
3:24 - 3:28it can store a small snippet
of that virus's DNA -
3:28 - 3:31for use as a program
to direct the CRISPR scissors -
3:31 - 3:35to cut that viral DNA sequence
during a future infection. -
3:36 - 3:41Cutting a virus's DNA messes up
the function of the cut viral gene, -
3:41 - 3:43and therefore disrupts
the virus's life cycle. -
3:46 - 3:51Remarkable researchers including
Emmanuelle Charpentier, George Church, -
3:51 - 3:54Jennifer Doudna and Feng Zhang
-
3:54 - 3:58showed six years ago how CRISPR scissors
could be programmed -
3:58 - 4:00to cut DNA sequences of our choosing,
-
4:00 - 4:03including sequences in your genome,
-
4:03 - 4:06instead of the viral DNA sequences
chosen by bacteria. -
4:07 - 4:09But the outcomes are actually similar.
-
4:10 - 4:12Cutting a DNA sequence in your genome
-
4:12 - 4:16also disrupts the function
of the cut gene, typically, -
4:17 - 4:21by causing the insertion and deletion
of random mixtures of DNA letters -
4:21 - 4:23at the cut site.
-
4:25 - 4:29Now, disrupting genes can be very
useful for some applications. -
4:30 - 4:34But for most point mutations
that cause genetic diseases, -
4:34 - 4:39simply cutting the already-mutated gene
won't benefit patients, -
4:39 - 4:43because the function of the mutated gene
needs to be restored, -
4:43 - 4:44not further disrupted.
-
4:45 - 4:48So cutting this
already-mutated hemoglobin gene -
4:48 - 4:51that causes sickle cell anemia
-
4:51 - 4:54won't restore the ability of patients
to make healthy red blood cells. -
4:56 - 5:00And while we can sometimes introduce
new DNA sequences into cells -
5:00 - 5:03to replace the DNA sequences
surrounding a cut site, -
5:03 - 5:08that process, unfortunately, doesn't work
in most types of cells, -
5:08 - 5:10and the disrupted gene outcomes
still predominate. -
5:12 - 5:14Like many scientists,
I've dreamed of a future -
5:15 - 5:17in which we might be able to treat
or maybe even cure -
5:17 - 5:19human genetic diseases.
-
5:19 - 5:23But I saw the lack of a way
to fix point mutations, -
5:23 - 5:26which cause most human genetic diseases,
-
5:26 - 5:28as a major problem standing in the way.
-
5:29 - 5:32Being a chemist, I began
working with my students -
5:32 - 5:37to develop ways on performing chemistry
directly on an individual DNA base, -
5:37 - 5:43to truly fix, rather than disrupt,
the mutations that cause genetic diseases. -
5:45 - 5:47The results of our efforts
are molecular machines -
5:47 - 5:48called "base editors."
-
5:50 - 5:55Base editors use the programmable
searching mechanism of CRISPR scissors, -
5:55 - 5:58but instead of cutting the DNA,
-
5:58 - 6:01they directly convert
one base to another base -
6:01 - 6:03without disrupting the rest of the gene.
-
6:05 - 6:09So if you think of naturally occurring
CRISPR proteins as molecular scissors, -
6:09 - 6:12you can think of base editors as pencils,
-
6:12 - 6:15capable of directly rewriting
one DNA letter into another -
6:16 - 6:20by actually rearranging
the atoms of one DNA base -
6:20 - 6:22to instead become a different base.
-
6:24 - 6:26Now, base editors don't exist in nature.
-
6:27 - 6:30In fact, we engineered
the first base editor, shown here, -
6:30 - 6:31from three separate proteins
-
6:31 - 6:34that don't even come
from the same organism. -
6:34 - 6:39We started by taking CRISPR scissors
and disabling the ability to cut DNA -
6:39 - 6:44while retaining its ability to search for
and bind a target DNA sequence -
6:44 - 6:45in a programmed manner.
-
6:46 - 6:49To those disabled CRISPR
scissors, shown in blue, -
6:49 - 6:52we attached a second protein in red,
-
6:52 - 6:56which performs a chemical reaction
on the DNA base C, -
6:56 - 6:59converting it into a base
that behaves like T. -
7:01 - 7:04Third, we had to attach
to the first two proteins -
7:04 - 7:05the protein shown in purple,
-
7:05 - 7:09which protects the edited base
from being removed by the cell. -
7:10 - 7:13The net result is an engineered
three-part protein -
7:13 - 7:17that for the first time
allows us to convert Cs into Ts -
7:17 - 7:20at specified locations in the genome.
-
7:21 - 7:25But even at this point,
our work was only half done. -
7:25 - 7:27Because in order to be stable in cells,
-
7:27 - 7:31the two strands of a DNA double helix
have to form base pairs. -
7:32 - 7:36And because C only pairs with G,
-
7:36 - 7:39and T only pairs with A,
-
7:40 - 7:45simply changing a C to a T
on one DNA strand creates a mismatch, -
7:45 - 7:47a disagreement between the two DNA strands
-
7:47 - 7:52that the cell has to resolve
by deciding which strand to replace. -
7:53 - 7:57We realized that we could further engineer
this three-part protein -
7:59 - 8:03to flag the nonedited strand
as the one to be replaced -
8:03 - 8:04by nicking that strand.
-
8:05 - 8:08This little nick tricks the cell
-
8:08 - 8:13into replacing the nonedited G with an A
-
8:13 - 8:15as it remakes the nicked strand,
-
8:15 - 8:19thereby completing the conversion
of what used to be a C-G base pair -
8:19 - 8:22into a stable T-A base pair.
-
8:25 - 8:26After several years of hard work
-
8:26 - 8:30led by a former post doc
in the lab, Alexis Komor, -
8:30 - 8:33we succeeded in developing
this first class of base editor, -
8:33 - 8:37which converts Cs into Ts and Gs into As
-
8:37 - 8:39at targeted positions of our choosing.
-
8:41 - 8:46Among the more than 35,000 known
disease-associated point mutations, -
8:46 - 8:50the two kinds of mutations
that this first base editor can reverse -
8:50 - 8:56collectively account for about 14 percent
or 5,000 or so pathogenic point mutations. -
8:57 - 9:01But correcting the largest fraction
of disease-causing point mutations -
9:01 - 9:05would require developing
a second class of base editor, -
9:05 - 9:09one that could convert
As into Gs or Ts into Cs. -
9:11 - 9:15Led by Nicole Gaudelli,
a former post doc in the lab, -
9:15 - 9:18we set out to develop
this second class of base editor, -
9:18 - 9:24which, in theory, could correct up to
almost half of pathogenic point mutations, -
9:24 - 9:28including that mutation that causes
the rapid-aging disease progeria. -
9:30 - 9:33We realized that we could
borrow, once again, -
9:33 - 9:37the targeting mechanism of CRISPR scissors
-
9:37 - 9:43to bring the new base editor
to the right site in a genome. -
9:44 - 9:47But we quickly encountered
an incredible problem; -
9:48 - 9:50namely, there is no protein
-
9:50 - 9:54that's known to convert
A into G or T into C -
9:54 - 9:56in DNA.
-
9:57 - 9:59Faced with such a serious stumbling block,
-
9:59 - 10:01most students would probably
look for another project, -
10:02 - 10:03if not another research advisor.
-
10:03 - 10:04(Laughter)
-
10:04 - 10:06But Nicole agreed to proceed with a plan
-
10:06 - 10:09that seemed wildly ambitious at the time.
-
10:10 - 10:12Given the absence
of a naturally occurring protein -
10:12 - 10:14that performs the necessary chemistry,
-
10:15 - 10:18we decided we would evolve
our own protein in the laboratory -
10:18 - 10:22to convert A into a base
that behaves like G, -
10:22 - 10:27starting from a protein
that performs related chemistry on RNA. -
10:27 - 10:31We set up a Darwinian
survival-of-the-fittest selection system -
10:31 - 10:35that explored tens of millions
of protein variants -
10:35 - 10:37and only allowed those rare variants
-
10:37 - 10:40that could perform the necessary
chemistry to survive. -
10:42 - 10:44We ended up with a protein shown here,
-
10:44 - 10:47the first that can convert A in DNA
-
10:47 - 10:49into a base that resembles G.
-
10:49 - 10:51And when we attached that protein
-
10:51 - 10:53to the disabled CRISPR
scissors, shown in blue, -
10:54 - 10:56we produced the second base editor,
-
10:56 - 10:59which converts As into Gs,
-
10:59 - 11:03and then uses the same
strand-nicking strategy -
11:03 - 11:04that we used in the first base editor
-
11:04 - 11:10to trick the cell into replacing
the nonedited T with a C -
11:10 - 11:12as it remakes that nicked strand,
-
11:12 - 11:16thereby completing the conversion
of an A-T base pair to a G-C base pair. -
11:17 - 11:19(Applause)
-
11:19 - 11:20Thank you.
-
11:20 - 11:23(Applause)
-
11:23 - 11:26As an academic scientist in the US,
-
11:26 - 11:28I'm not used to being
interrupted by applause. -
11:28 - 11:31(Laughter)
-
11:31 - 11:36We developed these
first two classes of base editors -
11:36 - 11:38only three years ago
and one and a half years ago. -
11:39 - 11:41But even in that short time,
-
11:41 - 11:45base editing has become widely used
by the biomedical research community. -
11:46 - 11:50Base editors have been sent
more than 6,000 times -
11:50 - 11:54at the request of more than
1,000 researchers around the globe. -
11:55 - 11:59A hundred scientific research papers
have been published already, -
11:59 - 12:03using base editors in organisms
ranging from bacteria -
12:03 - 12:05to plants to mice to primates.
-
12:08 - 12:10While base editors are too new
-
12:10 - 12:12to have already entered
human clinical trials, -
12:12 - 12:18scientists have succeeded in achieving
a critical milestone towards that goal -
12:18 - 12:20by using base editors in animals
-
12:21 - 12:24to correct point mutations
that cause human genetic diseases. -
12:26 - 12:27For example,
-
12:27 - 12:31a collaborative team of scientists
led by Luke Koblan and Jon Levy, -
12:31 - 12:33two additional students in my lab,
-
12:33 - 12:37recently used a virus to deliver
that second base editor -
12:37 - 12:40into a mouse with progeria,
-
12:40 - 12:43changing that disease-causing
T back into a C -
12:43 - 12:48and reversing its consequences
at the DNA, RNA and protein levels. -
12:49 - 12:52Base editors have also
been used in animals -
12:52 - 12:55to reverse the consequence of tyrosinemia,
-
12:56 - 12:59beta thalassemia, muscular dystrophy,
-
12:59 - 13:03phenylketonuria, a congenital deafness
-
13:03 - 13:05and a type of cardiovascular disease --
-
13:05 - 13:10in each case, by directly
correcting a point mutation -
13:10 - 13:12that causes or contributes to the disease.
-
13:14 - 13:16In plants, base editors have been used
-
13:16 - 13:20to introduce individual
single DNA letter changes -
13:20 - 13:22that could lead to better crops.
-
13:22 - 13:27And biologists have used base editors
to probe the role of individual letters -
13:27 - 13:30in genes associated
with diseases such as cancer. -
13:31 - 13:36Two companies I cofounded,
Beam Therapeutics and Pairwise Plants, -
13:36 - 13:39are using base editing
to treat human genetic diseases -
13:39 - 13:41and to improve agriculture.
-
13:42 - 13:44All of these applications of base editing
-
13:44 - 13:47have taken place in less
than the past three years: -
13:47 - 13:49on the historical timescale of science,
-
13:49 - 13:51the blink of an eye.
-
13:53 - 13:54Additional work lies ahead
-
13:54 - 13:57before base editing can realize
its full potential -
13:57 - 14:01to improve the lives of patients
with genetic diseases. -
14:01 - 14:04While many of these diseases
are thought to be treatable -
14:04 - 14:06by correcting the underlying mutation
-
14:06 - 14:09in even a modest fraction
of cells in an organ, -
14:09 - 14:12delivering molecular machines
like base editors -
14:12 - 14:14into cells in a human being
-
14:14 - 14:15can be challenging.
-
14:17 - 14:20Co-opting nature's viruses
to deliver base editors -
14:20 - 14:23instead of the molecules
that give you a cold -
14:23 - 14:25is one of several promising
delivery strategies -
14:25 - 14:27that's been successfully used.
-
14:28 - 14:31Continuing to develop
new molecular machines -
14:31 - 14:33that can make all of the remaining ways
-
14:33 - 14:35to convert one base pair
to another base pair -
14:35 - 14:40and that minimize unwanted editing
at off-target locations in cells -
14:40 - 14:41is very important.
-
14:42 - 14:46And engaging with other scientists,
doctors, ethicists and governments -
14:47 - 14:51to maximize the likelihood
that base editing is applied thoughtfully, -
14:51 - 14:54safely and ethically,
-
14:54 - 14:56remains a critical obligation.
-
14:58 - 14:59These challenges notwithstanding,
-
14:59 - 15:03if you had told me
even just five years ago -
15:03 - 15:04that researchers around the globe
-
15:05 - 15:08would be using laboratory-evolved
molecular machines -
15:08 - 15:11to directly convert
an individual base pair -
15:11 - 15:12to another base pair
-
15:12 - 15:15at a specified location
in the human genome -
15:15 - 15:19efficiently and with a minimum
of other outcomes, -
15:19 - 15:20I would have asked you,
-
15:20 - 15:22"What science-fiction novel
are you reading?" -
15:24 - 15:27Thanks to a relentlessly dedicated
group of students -
15:27 - 15:32who were creative enough to engineer
what we could design ourselves -
15:32 - 15:35and brave enough
to evolve what we couldn't, -
15:35 - 15:40base editing has begun to transform
that science-fiction-like aspiration -
15:40 - 15:42into an exciting new reality,
-
15:42 - 15:45one in which the most important gift
we give our children -
15:46 - 15:49may not only be
three billion letters of DNA, -
15:49 - 15:52but also the means to protect
and repair them. -
15:52 - 15:53Thank you.
-
15:54 - 15:58(Applause)
-
15:58 - 15:59Thank you.
- Title:
- Can we cure genetic diseases by rewriting DNA?
- Speaker:
- David R. Liu
- Description:
-
In a story of scientific discovery, chemical biologist David R. Liu shares a breakthrough: his lab's development of base editors that can rewrite DNA. This crucial step in genome editing takes the promise of CRISPR to the next level: if CRISPR proteins are molecular scissors, programmed to cut specific DNA sequences, then base editors are pencils, capable of directly rewriting one DNA letter into another. Learn more about how these molecular machines work -- and their potential to treat or even cure genetic diseases.
- Video Language:
- English
- Team:
- closed TED
- Project:
- TEDTalks
- Duration:
- 16:12
Brian Greene edited English subtitles for Can we cure genetic diseases by rewriting DNA? | ||
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Ivana Korom edited English subtitles for Can we cure genetic diseases by rewriting DNA? |