[Script Info]
Title: 
[Events]
Format: Layer, Start, End, Style, Name, MarginL, MarginR, MarginV, Effect, Text
Dialogue: 0,0:00:01.29,0:00:05.32,Default,,0000,0000,0000,,The most important gift\Nyour mother and father ever gave you
Dialogue: 0,0:00:05.34,0:00:08.06,Default,,0000,0000,0000,,was the two sets\Nof three billion letters of DNA
Dialogue: 0,0:00:08.08,0:00:09.65,Default,,0000,0000,0000,,that make up your genome.
Dialogue: 0,0:00:10.01,0:00:12.49,Default,,0000,0000,0000,,But like anything\Nwith three billion components,
Dialogue: 0,0:00:12.52,0:00:13.92,Default,,0000,0000,0000,,that gift is fragile.
Dialogue: 0,0:00:14.82,0:00:18.36,Default,,0000,0000,0000,,Sunlight, smoking, unhealthy eating,
Dialogue: 0,0:00:18.38,0:00:21.37,Default,,0000,0000,0000,,even spontaneous mistakes\Nmade by your cells
Dialogue: 0,0:00:21.40,0:00:23.60,Default,,0000,0000,0000,,all cause changes to your genome.
Dialogue: 0,0:00:24.94,0:00:28.22,Default,,0000,0000,0000,,The most common kind of change in DNA
Dialogue: 0,0:00:28.24,0:00:32.47,Default,,0000,0000,0000,,is the simple swap of one letter,\Nor base, such as C,
Dialogue: 0,0:00:32.50,0:00:35.43,Default,,0000,0000,0000,,with a different letter,\Nsuch as T, G or A.
Dialogue: 0,0:00:36.74,0:00:37.90,Default,,0000,0000,0000,,In any day,
Dialogue: 0,0:00:37.93,0:00:40.36,Default,,0000,0000,0000,,the cells in your body\Nwill collectively accumulate
Dialogue: 0,0:00:40.38,0:00:44.78,Default,,0000,0000,0000,,billions of these single-letter swaps,\Nwhich are also called point mutations.
Dialogue: 0,0:00:46.15,0:00:48.68,Default,,0000,0000,0000,,Now, most of these\Npoint mutations are harmless.
Dialogue: 0,0:00:48.70,0:00:50.88,Default,,0000,0000,0000,,But every now and then, a point mutation
Dialogue: 0,0:00:50.90,0:00:53.88,Default,,0000,0000,0000,,disrupts an important\Ncapability in a cell,
Dialogue: 0,0:00:53.90,0:00:57.11,Default,,0000,0000,0000,,or causes a cell to misbehave\Nin harmful ways.
Dialogue: 0,0:00:58.10,0:01:01.10,Default,,0000,0000,0000,,If that mutation were inherited\Nfrom your parents,
Dialogue: 0,0:01:01.12,0:01:03.78,Default,,0000,0000,0000,,or occurred early enough\Nin your development,
Dialogue: 0,0:01:03.81,0:01:06.77,Default,,0000,0000,0000,,then the result would be\Nthat many or all of your cells
Dialogue: 0,0:01:06.80,0:01:08.71,Default,,0000,0000,0000,,contain this harmful mutation.
Dialogue: 0,0:01:09.15,0:01:12.42,Default,,0000,0000,0000,,And then you would be one\Nof hundreds of millions of people
Dialogue: 0,0:01:12.45,0:01:14.06,Default,,0000,0000,0000,,with a genetic disease,
Dialogue: 0,0:01:14.08,0:01:17.08,Default,,0000,0000,0000,,such as sickle cell anemia or progeria
Dialogue: 0,0:01:17.11,0:01:20.04,Default,,0000,0000,0000,,or muscular dystrophy\Nor Tay-Sachs disease.
Dialogue: 0,0:01:22.22,0:01:25.41,Default,,0000,0000,0000,,Gravest genetic diseases\Ncaused by point mutations
Dialogue: 0,0:01:25.43,0:01:27.42,Default,,0000,0000,0000,,are especially frustrating,
Dialogue: 0,0:01:27.45,0:01:30.35,Default,,0000,0000,0000,,because we often know\Nthe exact single letter change
Dialogue: 0,0:01:30.38,0:01:34.41,Default,,0000,0000,0000,,that causes the disease\Nand in theory, could cure the disease.
Dialogue: 0,0:01:35.27,0:01:38.12,Default,,0000,0000,0000,,Millions suffer from sickle cell anemia
Dialogue: 0,0:01:38.14,0:01:41.21,Default,,0000,0000,0000,,because they have\Na single A to T point mutations
Dialogue: 0,0:01:41.24,0:01:43.90,Default,,0000,0000,0000,,in both copies of their hemoglobin gene.
Dialogue: 0,0:01:45.53,0:01:47.03,Default,,0000,0000,0000,,And children with progeria
Dialogue: 0,0:01:47.05,0:01:52.14,Default,,0000,0000,0000,,are born with a T at a single position\Nin their genome where you have a C.
Dialogue: 0,0:01:53.12,0:01:56.56,Default,,0000,0000,0000,,With the devastating consequence\Nthat these wonderful bright kids
Dialogue: 0,0:01:56.59,0:02:00.32,Default,,0000,0000,0000,,age very rapidly and pass away\Nby about age 14.
Dialogue: 0,0:02:02.36,0:02:04.04,Default,,0000,0000,0000,,Throughout the history of medicine,
Dialogue: 0,0:02:04.06,0:02:07.12,Default,,0000,0000,0000,,we have not had a way\Nto efficiently correct point mutations
Dialogue: 0,0:02:07.15,0:02:08.92,Default,,0000,0000,0000,,in living systems,
Dialogue: 0,0:02:08.94,0:02:12.14,Default,,0000,0000,0000,,to change that disease-causing\NT back into a C.
Dialogue: 0,0:02:13.48,0:02:15.45,Default,,0000,0000,0000,,Perhaps until now,
Dialogue: 0,0:02:15.47,0:02:19.66,Default,,0000,0000,0000,,because my laboratory recently succeeded\Nin developing such a capability,
Dialogue: 0,0:02:19.69,0:02:21.49,Default,,0000,0000,0000,,which we call base editing.
Dialogue: 0,0:02:23.28,0:02:25.30,Default,,0000,0000,0000,,The story of how\Nwe developed base editing,
Dialogue: 0,0:02:25.32,0:02:27.100,Default,,0000,0000,0000,,actually begins three billion years ago.
Dialogue: 0,0:02:29.06,0:02:31.72,Default,,0000,0000,0000,,We think of bacteria\Nas sources of infection,
Dialogue: 0,0:02:31.74,0:02:35.05,Default,,0000,0000,0000,,but bacteria themselves are also\Nprone to being infected.
Dialogue: 0,0:02:35.08,0:02:36.81,Default,,0000,0000,0000,,In particular, by viruses.
Dialogue: 0,0:02:37.87,0:02:40.02,Default,,0000,0000,0000,,So about three billion years ago,
Dialogue: 0,0:02:40.05,0:02:43.93,Default,,0000,0000,0000,,bacteria evolved a defense mechanism\Nto fight viral infection.
Dialogue: 0,0:02:45.65,0:02:48.43,Default,,0000,0000,0000,,That defense mechanism\Nis now better known as CRISPR.
Dialogue: 0,0:02:49.01,0:02:51.83,Default,,0000,0000,0000,,And the warhead in CRISP\Nis this purple protein
Dialogue: 0,0:02:51.86,0:02:55.64,Default,,0000,0000,0000,,that acts like molecular\Nscissors to cut DNA,
Dialogue: 0,0:02:55.66,0:02:58.09,Default,,0000,0000,0000,,breaking the double helix into two pieces.
Dialogue: 0,0:02:59.32,0:03:03.30,Default,,0000,0000,0000,,If CRISPR couldn't distinguish\Nbetween bacterial and viral DNA
Dialogue: 0,0:03:03.32,0:03:05.83,Default,,0000,0000,0000,,it wouldn't be a very useful\Ndefense system.
Dialogue: 0,0:03:06.32,0:03:09.10,Default,,0000,0000,0000,,But the most amazing feature of CRISPR
Dialogue: 0,0:03:09.12,0:03:12.28,Default,,0000,0000,0000,,is that the scissors can be programmed
Dialogue: 0,0:03:12.31,0:03:16.61,Default,,0000,0000,0000,,to search for, bind to and cut
Dialogue: 0,0:03:16.63,0:03:19.18,Default,,0000,0000,0000,,only a specific DNA sequence.
Dialogue: 0,0:03:20.91,0:03:24.31,Default,,0000,0000,0000,,So when a bacterium encounters\Na virus for the first time,
Dialogue: 0,0:03:24.33,0:03:27.70,Default,,0000,0000,0000,,it can store a small snippet\Nof that virus's DNA
Dialogue: 0,0:03:27.73,0:03:31.37,Default,,0000,0000,0000,,for use as a program to direct\Nthe CRISPR scissors
Dialogue: 0,0:03:31.40,0:03:34.70,Default,,0000,0000,0000,,to cut that viral DNA sequence\Nduring a future infection.
Dialogue: 0,0:03:35.78,0:03:40.69,Default,,0000,0000,0000,,Cutting a virus's DNA messes up\Nthe function of the cut viral gene,
Dialogue: 0,0:03:40.72,0:03:43.18,Default,,0000,0000,0000,,and therefore disrupts virus's life cycle.
Dialogue: 0,0:03:46.06,0:03:50.86,Default,,0000,0000,0000,,Remarkable researchers including\NEmmanuelle Charpentier, George Church,
Dialogue: 0,0:03:50.88,0:03:53.54,Default,,0000,0000,0000,,Jennifer Doudna, and Feng Zhang
Dialogue: 0,0:03:53.56,0:03:56.40,Default,,0000,0000,0000,,showed six years ago how CRISPR scissors
Dialogue: 0,0:03:56.43,0:04:00.14,Default,,0000,0000,0000,,could be programmed to cut\NDNA sequences of our choosing,
Dialogue: 0,0:04:00.16,0:04:02.53,Default,,0000,0000,0000,,including sequences in your genome,
Dialogue: 0,0:04:02.56,0:04:05.90,Default,,0000,0000,0000,,instead of the viral DNA sequences\Nchosen by a bacteria.
Dialogue: 0,0:04:06.55,0:04:09.08,Default,,0000,0000,0000,,But the outcomes are actually similar.
Dialogue: 0,0:04:09.61,0:04:12.07,Default,,0000,0000,0000,,Cutting a DNA sequence in your genome
Dialogue: 0,0:04:12.10,0:04:16.97,Default,,0000,0000,0000,,also disrupts the function\Nof the cut gene typically,
Dialogue: 0,0:04:16.100,0:04:19.15,Default,,0000,0000,0000,,by causing the insertion and deletion
Dialogue: 0,0:04:19.17,0:04:22.57,Default,,0000,0000,0000,,of random mixtures of DNA letters\Nat the cut site.
Dialogue: 0,0:04:24.62,0:04:28.74,Default,,0000,0000,0000,,Now, disrupting genes can be very\Nuseful for some applications.
Dialogue: 0,0:04:30.00,0:04:34.31,Default,,0000,0000,0000,,But for most point mutations\Nthat cause genetic diseases
Dialogue: 0,0:04:34.33,0:04:38.69,Default,,0000,0000,0000,,simply cutting the already mutated gene\Nwon't benefit patients,
Dialogue: 0,0:04:38.71,0:04:42.68,Default,,0000,0000,0000,,because the function of the mutated gene\Nneeds to be restored,
Dialogue: 0,0:04:42.70,0:04:44.17,Default,,0000,0000,0000,,not further disrupted.
Dialogue: 0,0:04:45.26,0:04:48.14,Default,,0000,0000,0000,,So cutting this already\Nmutated hemoglobin gene
Dialogue: 0,0:04:48.16,0:04:50.69,Default,,0000,0000,0000,,that causes sickle cell anemia
Dialogue: 0,0:04:50.71,0:04:54.23,Default,,0000,0000,0000,,won't restore the ability of patients\Nto make healthy red blood cells.
Dialogue: 0,0:04:55.63,0:04:59.97,Default,,0000,0000,0000,,And while we can sometimes introduce\Nnew DNA sequences into cells
Dialogue: 0,0:04:59.100,0:05:03.42,Default,,0000,0000,0000,,to replace the DNA sequences\Nsurrounding a cut site,
Dialogue: 0,0:05:03.44,0:05:07.76,Default,,0000,0000,0000,,that process unfortunately doesn't work\Nin most types of cells,
Dialogue: 0,0:05:07.79,0:05:10.53,Default,,0000,0000,0000,,and the disrupted gene outcomes\Nstill predominate.
Dialogue: 0,0:05:12.30,0:05:13.57,Default,,0000,0000,0000,,Like many scientists,
Dialogue: 0,0:05:13.60,0:05:16.38,Default,,0000,0000,0000,,I've dreamed of a future\Nin which we might be able to treat
Dialogue: 0,0:05:16.40,0:05:18.65,Default,,0000,0000,0000,,or maybe even cure human genetic diseases.
Dialogue: 0,0:05:19.14,0:05:22.94,Default,,0000,0000,0000,,But I saw the lack of a way\Nto fix point mutations,
Dialogue: 0,0:05:22.96,0:05:25.98,Default,,0000,0000,0000,,which cause most human genetic diseases,
Dialogue: 0,0:05:26.01,0:05:28.40,Default,,0000,0000,0000,,as a major problem standing in the way.
Dialogue: 0,0:05:29.43,0:05:32.10,Default,,0000,0000,0000,,Being a chemist, I began\Nworking with my students
Dialogue: 0,0:05:32.13,0:05:37.06,Default,,0000,0000,0000,,to develop ways on performing chemistry\Ndirectly on an individual DNA base,
Dialogue: 0,0:05:37.08,0:05:42.70,Default,,0000,0000,0000,,to truly fix, rather than disrupt,\Nthe mutations that cause genetic diseases.
Dialogue: 0,0:05:44.52,0:05:47.07,Default,,0000,0000,0000,,The results of our efforts\Nare molecular machines
Dialogue: 0,0:05:47.09,0:05:48.48,Default,,0000,0000,0000,,called base editors.
Dialogue: 0,0:05:49.62,0:05:55.09,Default,,0000,0000,0000,,Base editors use the programmable\Nsearching mechanism of CRISPR scissors,
Dialogue: 0,0:05:55.12,0:05:58.05,Default,,0000,0000,0000,,but instead of cutting the DNA,
Dialogue: 0,0:05:58.08,0:06:01.02,Default,,0000,0000,0000,,they directly convert\None base to another base
Dialogue: 0,0:06:01.04,0:06:03.30,Default,,0000,0000,0000,,without disrupting the rest of the gene.
Dialogue: 0,0:06:04.67,0:06:08.83,Default,,0000,0000,0000,,So if you think of naturally occurring\NCRISPR proteins as molecular scissors,
Dialogue: 0,0:06:08.86,0:06:11.64,Default,,0000,0000,0000,,you can think of base editors as pencils,
Dialogue: 0,0:06:11.67,0:06:16.04,Default,,0000,0000,0000,,capable of directly rewriting\None DNA letter into another,
Dialogue: 0,0:06:16.07,0:06:19.90,Default,,0000,0000,0000,,by actually rearranging\Nthe atoms of one DNA base
Dialogue: 0,0:06:19.92,0:06:22.26,Default,,0000,0000,0000,,to instead become a different base.
Dialogue: 0,0:06:23.51,0:06:25.94,Default,,0000,0000,0000,,Now, base editors don't exist in nature.
Dialogue: 0,0:06:26.68,0:06:29.91,Default,,0000,0000,0000,,In fact, we engineered the first\Nbase editor, shown here,
Dialogue: 0,0:06:29.94,0:06:31.29,Default,,0000,0000,0000,,from three separate proteins
Dialogue: 0,0:06:31.32,0:06:33.55,Default,,0000,0000,0000,,that don't even come\Nfrom the same organism.
Dialogue: 0,0:06:34.15,0:06:39.25,Default,,0000,0000,0000,,We started by taking CRISPR scissors\Nand disabling the ability to cut DNA,
Dialogue: 0,0:06:39.27,0:06:43.81,Default,,0000,0000,0000,,while retaining its ability to search for\Nand bind a target DNA sequence
Dialogue: 0,0:06:43.84,0:06:45.37,Default,,0000,0000,0000,,in a programmed manner.
Dialogue: 0,0:06:46.35,0:06:49.19,Default,,0000,0000,0000,,To those disabled CRISPR\Nscissors, shown in blue,
Dialogue: 0,0:06:49.21,0:06:51.72,Default,,0000,0000,0000,,we attached a second protein in red,
Dialogue: 0,0:06:51.74,0:06:56.04,Default,,0000,0000,0000,,which performs a chemical reaction\Non the DNA base C,
Dialogue: 0,0:06:56.07,0:06:59.27,Default,,0000,0000,0000,,converting it into a base\Nthat behaves like T.
Dialogue: 0,0:07:00.96,0:07:04.10,Default,,0000,0000,0000,,Third, we had to attach\Nto the first two proteins
Dialogue: 0,0:07:04.12,0:07:05.47,Default,,0000,0000,0000,,the protein shown in purple,
Dialogue: 0,0:07:05.50,0:07:08.95,Default,,0000,0000,0000,,which protects the edited base\Nfrom being removed by the cell.
Dialogue: 0,0:07:10.47,0:07:13.31,Default,,0000,0000,0000,,The net result is an engineered\Nthree-part protein
Dialogue: 0,0:07:13.33,0:07:17.45,Default,,0000,0000,0000,,that for the first time\Nallows us to convert Cs into Ts
Dialogue: 0,0:07:17.47,0:07:19.94,Default,,0000,0000,0000,,at specified locations in the genome.
Dialogue: 0,0:07:21.49,0:07:24.52,Default,,0000,0000,0000,,But even at this point,\Nour work was only half done.
Dialogue: 0,0:07:24.55,0:07:27.17,Default,,0000,0000,0000,,Because in order to be stable in cells,
Dialogue: 0,0:07:27.20,0:07:30.86,Default,,0000,0000,0000,,the two strands of a DNA double helix\Nhave to form base pairs.
Dialogue: 0,0:07:32.12,0:07:35.78,Default,,0000,0000,0000,,And because C only pairs with G,
Dialogue: 0,0:07:35.81,0:07:39.15,Default,,0000,0000,0000,,and T only pairs with A,
Dialogue: 0,0:07:39.75,0:07:44.60,Default,,0000,0000,0000,,simply changing a C to a T\Non one DNA strand creates a mismatch.
Dialogue: 0,0:07:44.62,0:07:47.47,Default,,0000,0000,0000,,A disagreement between the two DNA strands
Dialogue: 0,0:07:47.50,0:07:51.61,Default,,0000,0000,0000,,that the cell has to resolve\Nby deciding which strand to replace.
Dialogue: 0,0:07:53.15,0:07:57.29,Default,,0000,0000,0000,,We realized that we could further engineer\Nthis three-part protein,
Dialogue: 0,0:07:58.65,0:08:02.52,Default,,0000,0000,0000,,to flag the non-edited strand\Nas the one to be replaced
Dialogue: 0,0:08:02.54,0:08:04.45,Default,,0000,0000,0000,,by nicking that strand.
Dialogue: 0,0:08:05.28,0:08:07.80,Default,,0000,0000,0000,,This little nick tricks the cell
Dialogue: 0,0:08:07.83,0:08:12.78,Default,,0000,0000,0000,,into replacing the non-edited G with an A
Dialogue: 0,0:08:12.80,0:08:15.12,Default,,0000,0000,0000,,as it remakes the nicked strand.
Dialogue: 0,0:08:15.15,0:08:19.18,Default,,0000,0000,0000,,Thereby completing the conversion\Nof what used to be a CG base pair
Dialogue: 0,0:08:19.20,0:08:21.28,Default,,0000,0000,0000,,into a stable TA base pair.
Dialogue: 0,0:08:24.58,0:08:26.18,Default,,0000,0000,0000,,After several years of hard work,
Dialogue: 0,0:08:26.20,0:08:30.14,Default,,0000,0000,0000,,led by a former post doc\Nin the lab Alexis Komor,
Dialogue: 0,0:08:30.16,0:08:33.35,Default,,0000,0000,0000,,we succeeded in developing\Nthis first class of base editor,
Dialogue: 0,0:08:33.37,0:08:37.04,Default,,0000,0000,0000,,which converts Cs into Ts and Gs into As
Dialogue: 0,0:08:37.06,0:08:39.22,Default,,0000,0000,0000,,at targeted positions of our choosing.
Dialogue: 0,0:08:40.63,0:08:45.86,Default,,0000,0000,0000,,Among the more than 35,000\Nknown disease-associated point mutations,
Dialogue: 0,0:08:45.89,0:08:49.67,Default,,0000,0000,0000,,the two kinds of mutations\Nthat this first base editor can reverse
Dialogue: 0,0:08:49.70,0:08:55.64,Default,,0000,0000,0000,,collectively account for about 14 percent\Nor 5,000 or so pathogenic point mutations.
Dialogue: 0,0:08:56.56,0:09:01.36,Default,,0000,0000,0000,,But correcting the largest fraction\Nof disease-causing point mutations
Dialogue: 0,0:09:01.39,0:09:05.02,Default,,0000,0000,0000,,would require developing\Na second class of base editor,
Dialogue: 0,0:09:05.05,0:09:09.13,Default,,0000,0000,0000,,one that could convert\NAs into Gs or Ts into Cs.
Dialogue: 0,0:09:10.85,0:09:14.54,Default,,0000,0000,0000,,Led by Nicole Gaudelli,\Na former post doc in the lab,
Dialogue: 0,0:09:14.57,0:09:17.72,Default,,0000,0000,0000,,we set out to develop\Nthis second class of base editor.
Dialogue: 0,0:09:17.74,0:09:23.87,Default,,0000,0000,0000,,Which in theory, could correct up to\Nalmost half of pathogenic point mutations,
Dialogue: 0,0:09:23.89,0:09:27.80,Default,,0000,0000,0000,,including that mutation that causes\Nthe rapid aging disease progeria.
Dialogue: 0,0:09:30.11,0:09:35.23,Default,,0000,0000,0000,,We realized that we could borrow,\Nonce again, the targeting mechanism
Dialogue: 0,0:09:35.26,0:09:40.19,Default,,0000,0000,0000,,of CRISPR scissors to bring\Nthe new base editor
Dialogue: 0,0:09:40.22,0:09:42.55,Default,,0000,0000,0000,,to the right site in a genome.
Dialogue: 0,0:09:43.54,0:09:46.49,Default,,0000,0000,0000,,But we quickly encountered\Nan incredible problem.
Dialogue: 0,0:09:47.90,0:09:51.06,Default,,0000,0000,0000,,Namely, there is no protein that's known
Dialogue: 0,0:09:51.09,0:09:55.25,Default,,0000,0000,0000,,to convert A into G or T into C in DNA.
Dialogue: 0,0:09:56.76,0:09:58.93,Default,,0000,0000,0000,,Faced with such a serious stumbling block,
Dialogue: 0,0:09:58.95,0:10:01.48,Default,,0000,0000,0000,,most students would probably\Nlook for another project,
Dialogue: 0,0:10:01.51,0:10:04.41,Default,,0000,0000,0000,,if not another research advisor,
Dialogue: 0,0:10:04.43,0:10:08.75,Default,,0000,0000,0000,,but Nicole agreed to proceed with a plan\Nthat seemed wildly ambitious at the time.
Dialogue: 0,0:10:09.97,0:10:12.30,Default,,0000,0000,0000,,Given the absence\Nof a naturally occurring protein
Dialogue: 0,0:10:12.33,0:10:14.49,Default,,0000,0000,0000,,that performs the necessary chemistry,
Dialogue: 0,0:10:14.51,0:10:17.95,Default,,0000,0000,0000,,we decided we would evolve\Nour own protein in the laboratory
Dialogue: 0,0:10:17.97,0:10:21.81,Default,,0000,0000,0000,,to convert A into a base\Nthat behaves like G,
Dialogue: 0,0:10:21.83,0:10:26.48,Default,,0000,0000,0000,,starting from a protein\Nthat performs related chemistry on RNA.
Dialogue: 0,0:10:27.23,0:10:31.16,Default,,0000,0000,0000,,We set up a Darwinian\Nsurvival-of-the-fittest selection system
Dialogue: 0,0:10:31.19,0:10:35.18,Default,,0000,0000,0000,,that explored tens of millions\Nof protein variants,
Dialogue: 0,0:10:35.20,0:10:37.22,Default,,0000,0000,0000,,and only allowed those rare variants
Dialogue: 0,0:10:37.25,0:10:40.30,Default,,0000,0000,0000,,that could perform\Nthe necessary chemistry to survive.
Dialogue: 0,0:10:41.88,0:10:44.27,Default,,0000,0000,0000,,We ended up with a protein shown here,
Dialogue: 0,0:10:44.30,0:10:47.15,Default,,0000,0000,0000,,the first that can convert A in DNA
Dialogue: 0,0:10:47.18,0:10:49.27,Default,,0000,0000,0000,,into a base that resembles G.
Dialogue: 0,0:10:49.29,0:10:50.90,Default,,0000,0000,0000,,And when we attached that protein
Dialogue: 0,0:10:50.92,0:10:53.49,Default,,0000,0000,0000,,to the disabled CRISPR\Nscissors, shown in blue,
Dialogue: 0,0:10:53.51,0:10:55.52,Default,,0000,0000,0000,,we produced the second base editor,
Dialogue: 0,0:10:55.55,0:10:58.64,Default,,0000,0000,0000,,which converts As into Gs,
Dialogue: 0,0:10:58.66,0:11:02.51,Default,,0000,0000,0000,,and then uses the same\Nstrand-nicking strategy
Dialogue: 0,0:11:02.53,0:11:04.45,Default,,0000,0000,0000,,that we used in the first base editor,
Dialogue: 0,0:11:04.47,0:11:09.94,Default,,0000,0000,0000,,to trick the cell into replacing\Nthe non-edited T with a C
Dialogue: 0,0:11:09.96,0:11:11.64,Default,,0000,0000,0000,,as it remakes that nicked strand,
Dialogue: 0,0:11:11.66,0:11:15.74,Default,,0000,0000,0000,,thereby completing the conversion\Nof an AT base pair to a GC base pair.
Dialogue: 0,0:11:16.84,0:11:18.89,Default,,0000,0000,0000,,(Applause)
Dialogue: 0,0:11:18.92,0:11:20.09,Default,,0000,0000,0000,,Thank you.
Dialogue: 0,0:11:20.11,0:11:23.47,Default,,0000,0000,0000,,(Applause)
Dialogue: 0,0:11:23.49,0:11:25.83,Default,,0000,0000,0000,,As an academic scientist in the US,
Dialogue: 0,0:11:25.85,0:11:27.100,Default,,0000,0000,0000,,I'm not used to being\Ninterrupted by applause.
Dialogue: 0,0:11:28.02,0:11:31.17,Default,,0000,0000,0000,,(Laughter)
Dialogue: 0,0:11:31.20,0:11:35.60,Default,,0000,0000,0000,,We developed these\Nfirst two classes of base editors
Dialogue: 0,0:11:35.62,0:11:38.40,Default,,0000,0000,0000,,only three years ago\Nand one and a half years ago.
Dialogue: 0,0:11:39.27,0:11:40.82,Default,,0000,0000,0000,,But even in that short time,
Dialogue: 0,0:11:40.84,0:11:44.56,Default,,0000,0000,0000,,base editing has become widely used\Nby the biomedical research community.
Dialogue: 0,0:11:45.78,0:11:50.14,Default,,0000,0000,0000,,Base editors have been sent\Nmore than 6,000 times
Dialogue: 0,0:11:50.16,0:11:53.75,Default,,0000,0000,0000,,at the request of more\Nthan 1,000 researchers around the globe.
Dialogue: 0,0:11:55.48,0:11:58.99,Default,,0000,0000,0000,,A hundred scientific research papers\Nhave been published already,
Dialogue: 0,0:11:59.02,0:12:02.74,Default,,0000,0000,0000,,using base editors in organisms\Nranging from bacteria,
Dialogue: 0,0:12:02.77,0:12:04.90,Default,,0000,0000,0000,,to plants, to mice, to primates.
Dialogue: 0,0:12:07.95,0:12:09.50,Default,,0000,0000,0000,,While base editors are too new
Dialogue: 0,0:12:09.52,0:12:12.47,Default,,0000,0000,0000,,to have already entered\Nhuman clinical trials,
Dialogue: 0,0:12:12.49,0:12:17.61,Default,,0000,0000,0000,,scientists have succeeded in achieving\Na critical milestone towards that goal,
Dialogue: 0,0:12:17.64,0:12:20.48,Default,,0000,0000,0000,,by using base editors in animals
Dialogue: 0,0:12:20.51,0:12:24.42,Default,,0000,0000,0000,,to correct point mutations\Nthat cause human genetic diseases.
Dialogue: 0,0:12:25.82,0:12:26.98,Default,,0000,0000,0000,,For example,
Dialogue: 0,0:12:27.01,0:12:30.78,Default,,0000,0000,0000,,a collaborative team of scientists\Nled by Luke Koblan and John Levy,
Dialogue: 0,0:12:30.81,0:12:33.22,Default,,0000,0000,0000,,two additional students in my lab,
Dialogue: 0,0:12:33.24,0:12:37.36,Default,,0000,0000,0000,,recently used a virus to deliver\Nthat second base editor
Dialogue: 0,0:12:37.39,0:12:39.58,Default,,0000,0000,0000,,into a mouse with progeria,
Dialogue: 0,0:12:39.60,0:12:43.46,Default,,0000,0000,0000,,changing that disease-causing\NT back into a C,
Dialogue: 0,0:12:43.48,0:12:47.39,Default,,0000,0000,0000,,and reversing its consequences\Nat the DNA, RNA and protein levels.
Dialogue: 0,0:12:48.88,0:12:51.63,Default,,0000,0000,0000,,Base editors have also\Nbeen used in animals
Dialogue: 0,0:12:51.65,0:12:55.62,Default,,0000,0000,0000,,to reverse the consequence of tyrosinemia,
Dialogue: 0,0:12:55.64,0:12:59.26,Default,,0000,0000,0000,,beta-thalassemia, muscular dystrophy,
Dialogue: 0,0:12:59.28,0:13:02.97,Default,,0000,0000,0000,,phenylketonuria, a congenital deafness,
Dialogue: 0,0:13:02.100,0:13:04.94,Default,,0000,0000,0000,,and a type of cardiovascular disease,
Dialogue: 0,0:13:04.96,0:13:09.82,Default,,0000,0000,0000,,in each case by directly\Ncorrecting a point mutation
Dialogue: 0,0:13:09.85,0:13:12.65,Default,,0000,0000,0000,,that causes or contributes to the disease.
Dialogue: 0,0:13:13.69,0:13:15.74,Default,,0000,0000,0000,,In plants, base editors have been used
Dialogue: 0,0:13:15.77,0:13:19.84,Default,,0000,0000,0000,,to introduce individual\Nsingle DNA letter changes
Dialogue: 0,0:13:19.86,0:13:21.83,Default,,0000,0000,0000,,that could lead to better crops.
Dialogue: 0,0:13:22.25,0:13:24.78,Default,,0000,0000,0000,,And biologists have used base editors
Dialogue: 0,0:13:24.81,0:13:26.84,Default,,0000,0000,0000,,to probe the role of individual letters
Dialogue: 0,0:13:26.87,0:13:29.68,Default,,0000,0000,0000,,in genes associated\Nwith diseases such as cancer.
Dialogue: 0,0:13:31.05,0:13:35.61,Default,,0000,0000,0000,,Two companies I cofounded,\NBeam Therapeutics and Pairwise Plants,
Dialogue: 0,0:13:35.64,0:13:39.46,Default,,0000,0000,0000,,are using base editing\Nto treat human genetic diseases
Dialogue: 0,0:13:39.49,0:13:41.29,Default,,0000,0000,0000,,and to improve agriculture.
Dialogue: 0,0:13:41.95,0:13:43.92,Default,,0000,0000,0000,,All of these applications of base editing
Dialogue: 0,0:13:43.94,0:13:47.04,Default,,0000,0000,0000,,have taken place in less\Nthan the past three years.
Dialogue: 0,0:13:47.06,0:13:50.71,Default,,0000,0000,0000,,On the historical timescale of science,\Nthe blink of an eye.
Dialogue: 0,0:13:52.66,0:13:53.91,Default,,0000,0000,0000,,Additional work lies ahead
Dialogue: 0,0:13:53.93,0:13:56.97,Default,,0000,0000,0000,,before base editing can realize\Nits full potential
Dialogue: 0,0:13:56.99,0:14:00.43,Default,,0000,0000,0000,,to improve the lives of patients\Nwith genetic diseases.
Dialogue: 0,0:14:01.24,0:14:04.02,Default,,0000,0000,0000,,While many of these diseases\Nare thought to be treatable
Dialogue: 0,0:14:04.05,0:14:05.90,Default,,0000,0000,0000,,by correcting the underlying mutation
Dialogue: 0,0:14:05.92,0:14:09.44,Default,,0000,0000,0000,,in even a modest fraction\Nof cells in an organ,
Dialogue: 0,0:14:09.46,0:14:12.44,Default,,0000,0000,0000,,delivering molecular machines\Nlike base editors
Dialogue: 0,0:14:12.46,0:14:15.17,Default,,0000,0000,0000,,into cells in a human being\Ncan be challenging.
Dialogue: 0,0:14:16.96,0:14:20.34,Default,,0000,0000,0000,,Co-opting nature's viruses\Nto deliver base editors
Dialogue: 0,0:14:20.36,0:14:22.56,Default,,0000,0000,0000,,instead of the molecules\Nthat give you a cold,
Dialogue: 0,0:14:22.58,0:14:25.27,Default,,0000,0000,0000,,is one of several promising\Ndelivery strategies
Dialogue: 0,0:14:25.29,0:14:27.29,Default,,0000,0000,0000,,that's been successfully used.
Dialogue: 0,0:14:28.27,0:14:30.63,Default,,0000,0000,0000,,Continuing to develop\Nnew molecular machines
Dialogue: 0,0:14:30.66,0:14:32.52,Default,,0000,0000,0000,,that can make all of the remaining ways
Dialogue: 0,0:14:32.55,0:14:35.44,Default,,0000,0000,0000,,to convert one base pair\Nto another base pair,
Dialogue: 0,0:14:35.46,0:14:39.84,Default,,0000,0000,0000,,and that minimize unwanted editing\Nat off-target locations in cells
Dialogue: 0,0:14:39.87,0:14:41.07,Default,,0000,0000,0000,,is very important.
Dialogue: 0,0:14:41.78,0:14:46.49,Default,,0000,0000,0000,,And engaging with other scientists,\Ndoctors, ethicists and governments
Dialogue: 0,0:14:46.51,0:14:51.30,Default,,0000,0000,0000,,to maximize the likelihood\Nthat base editing is applied thoughtfully,
Dialogue: 0,0:14:51.33,0:14:53.71,Default,,0000,0000,0000,,safely and ethically,
Dialogue: 0,0:14:53.73,0:14:55.73,Default,,0000,0000,0000,,remains a critical obligation.
Dialogue: 0,0:14:57.52,0:14:59.14,Default,,0000,0000,0000,,These challenges notwithstanding,
Dialogue: 0,0:14:59.16,0:15:02.82,Default,,0000,0000,0000,,if you had told me,\Neven just five years ago,
Dialogue: 0,0:15:02.84,0:15:04.49,Default,,0000,0000,0000,,that researchers around the globe
Dialogue: 0,0:15:04.51,0:15:08.05,Default,,0000,0000,0000,,would be using laboratory-evolved\Nmolecular machines
Dialogue: 0,0:15:08.08,0:15:11.07,Default,,0000,0000,0000,,to directly convert\Nan individual base pair
Dialogue: 0,0:15:11.10,0:15:12.28,Default,,0000,0000,0000,,to another base pair
Dialogue: 0,0:15:12.30,0:15:14.92,Default,,0000,0000,0000,,at a specified location\Nin the human genome
Dialogue: 0,0:15:14.95,0:15:18.77,Default,,0000,0000,0000,,efficiently and with the minimum\Nof other outcomes,
Dialogue: 0,0:15:18.80,0:15:19.96,Default,,0000,0000,0000,,I would have asked you,
Dialogue: 0,0:15:19.99,0:15:22.46,Default,,0000,0000,0000,,"What science-fiction novel\Nare you reading?"
Dialogue: 0,0:15:23.71,0:15:27.17,Default,,0000,0000,0000,,Thanks to a relentlessly dedicated\Ngroup of students,
Dialogue: 0,0:15:27.19,0:15:31.65,Default,,0000,0000,0000,,who were creative enough to engineer\Nwhat we could design ourselves,
Dialogue: 0,0:15:31.67,0:15:34.60,Default,,0000,0000,0000,,and brave enough\Nto evolve what we couldn't,
Dialogue: 0,0:15:34.62,0:15:39.66,Default,,0000,0000,0000,,base editing has begun to transform\Nthat science-fiction-like aspiration
Dialogue: 0,0:15:39.69,0:15:41.43,Default,,0000,0000,0000,,into an exciting new reality.
Dialogue: 0,0:15:42.25,0:15:45.48,Default,,0000,0000,0000,,One in which the most important gift\Nwe give our children
Dialogue: 0,0:15:45.50,0:15:48.53,Default,,0000,0000,0000,,may not only be\Nthree billion letters of DNA,
Dialogue: 0,0:15:48.55,0:15:51.46,Default,,0000,0000,0000,,but also the means to protect\Nand repair them.
Dialogue: 0,0:15:52.34,0:15:53.49,Default,,0000,0000,0000,,Thank you.
Dialogue: 0,0:15:53.51,0:15:58.02,Default,,0000,0000,0000,,(Applause)
Dialogue: 0,0:15:58.04,0:15:59.19,Default,,0000,0000,0000,,Thank you.