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The most important gift
your mother and father ever gave you

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was the two sets
of three billion letters of DNA

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that make up your genome.

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But like anything
with three billion components,

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that gift is fragile.

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Sunlight, smoking, unhealthy eating,

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even spontaneous mistakes
made by your cells,

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all cause changes to your genome.

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The most common kind of change in DNA

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is the simple swap of one letter,
or base, such as C,

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with a different letter,
such as T, G or A.

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In any day, the cells in your body
will collectively accumulate

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billions of these single-letter swaps,
which are also called "point mutations."

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Now, most of these
point mutations are harmless.

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But every now and then,

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a point mutation disrupts
an important capability in a cell

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or causes a cell to misbehave
in harmful ways.

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If that mutation were inherited
from your parents

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or occurred early enough
in your development,

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then the result would be
that many or all of your cells

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contain this harmful mutation.

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And then you would be one
of hundreds of millions of people

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with a genetic disease,

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such as sickle cell anemia or progeria

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or muscular dystrophy
or Tay-Sachs disease.

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Grievous genetic diseases
caused by point mutations

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are especially frustrating,

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because we often know
the exact single-letter change

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that causes the disease
and, in theory, could cure the disease.

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Millions suffer from sickle cell anemia

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because they have
a single A to T point mutations

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in both copies of their hemoglobin gene.

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And children with progeria
are born with a T

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at a single position in their genome

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where you have a C,

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with the devastating consequence
that these wonderful, bright kids

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age very rapidly and pass away
by about age 14.

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Throughout the history of medicine,

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we have not had a way
to efficiently correct point mutations

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in living systems,

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to change that disease-causing
T back into a C.

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Perhaps until now.

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Because my laboratory recently succeeded
in developing such a capability,

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which we call "base editing."

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The story of how we developed base editing

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actually begins three billion years ago.

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We think of bacteria
as sources of infection,

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but bacteria themselves are also
prone to being infected,

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in particular, by viruses.

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So about three billion years ago,

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bacteria evolved a defense mechanism
to fight viral infection.

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That defense mechanism
is now better known as CRISPR.

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And the warhead in CRISPR
is this purple protein

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that acts like molecular
scissors to cut DNA,

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breaking the double helix into two pieces.

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If CRISPR couldn't distinguish
between bacterial and viral DNA,

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it wouldn't be a very useful
defense system.

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But the most amazing feature of CRISPR

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is that the scissors can be
programmed to search for,

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bind to and cut

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only a specific DNA sequence.

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So when a bacterium encounters
a virus for the first time,

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it can store a small snippet
of that virus's DNA

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for use as a program
to direct the CRISPR scissors

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to cut that viral DNA sequence
during a future infection.

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Cutting a virus's DNA messes up
the function of the cut viral gene,

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and therefore disrupts
the virus's life cycle.

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Remarkable researchers including
Emmanuelle Charpentier, George Church,

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Jennifer Doudna and Feng Zhang

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showed six years ago how CRISPR scissors
could be programmed

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to cut DNA sequences of our choosing,

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including sequences in your genome,

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instead of the viral DNA sequences
chosen by bacteria.

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But the outcomes are actually similar.

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Cutting a DNA sequence in your genome

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also disrupts the function
of the cut gene, typically,

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by causing the insertion and deletion
of random mixtures of DNA letters

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at the cut site.

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Now, disrupting genes can be very
useful for some applications.

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But for most point mutations
that cause genetic diseases,

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simply cutting the already-mutated gene
won't benefit patients,

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because the function of the mutated gene
needs to be restored,

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not further disrupted.

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So cutting this
already-mutated hemoglobin gene

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that causes sickle cell anemia

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won't restore the ability of patients
to make healthy red blood cells.

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And while we can sometimes introduce
new DNA sequences into cells

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to replace the DNA sequences
surrounding a cut site,

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that process, unfortunately, doesn't work
in most types of cells,

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and the disrupted gene outcomes
still predominate.

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Like many scientists,
I've dreamed of a future

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in which we might be able to treat
or maybe even cure

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human genetic diseases.

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But I saw the lack of a way
to fix point mutations,

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which cause most human genetic diseases,

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as a major problem standing in the way.

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Being a chemist, I began
working with my students

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to develop ways on performing chemistry
directly on an individual DNA base,

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to truly fix, rather than disrupt,
the mutations that cause genetic diseases.

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The results of our efforts
are molecular machines

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called "base editors."

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Base editors use the programmable
searching mechanism of CRISPR scissors,

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but instead of cutting the DNA,

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they directly convert
one base to another base

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without disrupting the rest of the gene.

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So if you think of naturally occurring
CRISPR proteins as molecular scissors,

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you can think of base editors as pencils,

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capable of directly rewriting
one DNA letter into another

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by actually rearranging
the atoms of one DNA base

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to instead become a different base.

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Now, base editors don't exist in nature.

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In fact, we engineered
the first base editor, shown here,

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from three separate proteins

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that don't even come
from the same organism.

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We started by taking CRISPR scissors
and disabling the ability to cut DNA

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while retaining its ability to search for
and bind a target DNA sequence

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in a programmed manner.

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To those disabled CRISPR
scissors, shown in blue,

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we attached a second protein in red,

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which performs a chemical reaction
on the DNA base C,

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converting it into a base
that behaves like T.

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Third, we had to attach
to the first two proteins

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the protein shown in purple,

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which protects the edited base
from being removed by the cell.

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The net result is an engineered
three-part protein

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that for the first time
allows us to convert Cs into Ts

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at specified locations in the genome.

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But even at this point,
our work was only half done.

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Because in order to be stable in cells,

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the two strands of a DNA double helix
have to form base pairs.

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And because C only pairs with G,

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and T only pairs with A,

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simply changing a C to a T
on one DNA strand creates a mismatch,

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a disagreement between the two DNA strands

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that the cell has to resolve
by deciding which strand to replace.

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We realized that we could further engineer
this three-part protein

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to flag the nonedited strand
as the one to be replaced

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by nicking that strand.

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This little nick tricks the cell

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into replacing the nonedited G with an A

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as it remakes the nicked strand,

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thereby completing the conversion
of what used to be a C-G base pair

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into a stable T-A base pair.

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After several years of hard work

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led by a former post doc
in the lab, Alexis Komor,

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we succeeded in developing
this first class of base editor,

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which converts Cs into Ts and Gs into As

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at targeted positions of our choosing.

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Among the more than 35,000 known
disease-associated point mutations,

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the two kinds of mutations
that this first base editor can reverse

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collectively account for about 14 percent
or 5,000 or so pathogenic point mutations.

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But correcting the largest fraction
of disease-causing point mutations

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would require developing
a second class of base editor,

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one that could convert
As into Gs or Ts into Cs.

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Led by Nicole Gaudelli,
a former post doc in the lab,

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we set out to develop
this second class of base editor,

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which, in theory, could correct up to
almost half of pathogenic point mutations,

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including that mutation that causes
the rapid-aging disease progeria.

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We realized that we could
borrow, once again,

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the targeting mechanism of CRISPR scissors

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to bring the new base editor
to the right site in a genome.

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But we quickly encountered
an incredible problem;

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namely, there is no protein

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that's known to convert
A into G or T into C

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in DNA.

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Faced with such a serious stumbling block,

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most students would probably
look for another project,

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if not another research advisor.

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(Laughter)

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But Nicole agreed to proceed with a plan

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that seemed wildly ambitious at the time.

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Given the absence
of a naturally occurring protein

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that performs the necessary chemistry,

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we decided we would evolve
our own protein in the laboratory

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to convert A into a base
that behaves like G,

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starting from a protein
that performs related chemistry on RNA.

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We set up a Darwinian
survival-of-the-fittest selection system

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that explored tens of millions
of protein variants

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and only allowed those rare variants

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that could perform the necessary
chemistry to survive.

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We ended up with a protein shown here,

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the first that can convert A in DNA

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into a base that resembles G.

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And when we attached that protein

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to the disabled CRISPR
scissors, shown in blue,

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we produced the second base editor,

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which converts As into Gs,

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and then uses the same
strand-nicking strategy

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that we used in the first base editor

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to trick the cell into replacing
the nonedited T with a C

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as it remakes that nicked strand,

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thereby completing the conversion
of an A-T base pair to a G-C base pair.

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(Applause)

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Thank you.

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(Applause)

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As an academic scientist in the US,

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I'm not used to being
interrupted by applause.

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(Laughter)

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We developed these
first two classes of base editors

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only three years ago
and one and a half years ago.

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But even in that short time,

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base editing has become widely used
by the biomedical research community.

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Base editors have been sent
more than 6,000 times

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at the request of more than
1,000 researchers around the globe.

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A hundred scientific research papers
have been published already,

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using base editors in organisms
ranging from bacteria

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to plants to mice to primates.

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While base editors are too new

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to have already entered
human clinical trials,

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scientists have succeeded in achieving
a critical milestone towards that goal

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by using base editors in animals

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to correct point mutations
that cause human genetic diseases.

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For example,

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a collaborative team of scientists
led by Luke Koblan and Jon Levy,

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two additional students in my lab,

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recently used a virus to deliver
that second base editor

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into a mouse with progeria,

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changing that disease-causing
T back into a C

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and reversing its consequences
at the DNA, RNA and protein levels.

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Base editors have also
been used in animals

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to reverse the consequence of tyrosinemia,

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beta thalassemia, muscular dystrophy,

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phenylketonuria, a congenital deafness

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and a type of cardiovascular disease --

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in each case, by directly
correcting a point mutation

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that causes or contributes to the disease.

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In plants, base editors have been used

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to introduce individual
single DNA letter changes

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that could lead to better crops.

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And biologists have used base editors
to probe the role of individual letters

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in genes associated
with diseases such as cancer.

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Two companies I cofounded,
Beam Therapeutics and Pairwise Plants,

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are using base editing
to treat human genetic diseases

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and to improve agriculture.

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All of these applications of base editing

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have taken place in less
than the past three years:

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on the historical timescale of science,

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the blink of an eye.

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Additional work lies ahead

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before base editing can realize
its full potential

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to improve the lives of patients
with genetic diseases.

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While many of these diseases
are thought to be treatable

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by correcting the underlying mutation

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in even a modest fraction
of cells in an organ,

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delivering molecular machines
like base editors

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into cells in a human being

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can be challenging.

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Co-opting nature's viruses
to deliver base editors

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00:14:20,359 --> 00:14:22,557
instead of the molecules
that give you a cold

250
00:14:22,581 --> 00:14:25,268
is one of several promising
delivery strategies

251
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that's been successfully used.

252
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Continuing to develop
new molecular machines

253
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that can make all of the remaining ways

254
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to convert one base pair
to another base pair

255
00:14:35,465 --> 00:14:39,845
and that minimize unwanted editing
at off-target locations in cells

256
00:14:39,869 --> 00:14:41,069
is very important.

257
00:14:41,782 --> 00:14:46,488
And engaging with other scientists,
doctors, ethicists and governments

258
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to maximize the likelihood
that base editing is applied thoughtfully,

259
00:14:51,327 --> 00:14:53,708
safely and ethically,

260
00:14:53,732 --> 00:14:55,732
remains a critical obligation.

261
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These challenges notwithstanding,

262
00:14:59,160 --> 00:15:02,815
if you had told me
even just five years ago

263
00:15:02,839 --> 00:15:04,490
that researchers around the globe

264
00:15:04,514 --> 00:15:08,053
would be using laboratory-evolved
molecular machines

265
00:15:08,077 --> 00:15:11,074
to directly convert
an individual base pair

266
00:15:11,098 --> 00:15:12,280
to another base pair

267
00:15:12,304 --> 00:15:14,923
at a specified location
in the human genome

268
00:15:14,947 --> 00:15:18,772
efficiently and with a minimum
of other outcomes,

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I would have asked you,

270
00:15:19,988 --> 00:15:22,462
"What science-fiction novel
are you reading?"

271
00:15:23,706 --> 00:15:27,166
Thanks to a relentlessly dedicated
group of students

272
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who were creative enough to engineer
what we could design ourselves

273
00:15:31,674 --> 00:15:34,599
and brave enough
to evolve what we couldn't,

274
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base editing has begun to transform
that science-fiction-like aspiration

275
00:15:39,687 --> 00:15:41,544
into an exciting new reality,

276
00:15:42,250 --> 00:15:45,481
one in which the most important gift
we give our children

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00:15:45,505 --> 00:15:48,530
may not only be
three billion letters of DNA,

278
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but also the means to protect
and repair them.

279
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Thank you.

280
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(Applause)

281
00:15:58,040 --> 00:15:59,190
Thank you.