0:00:01.006,0:00:02.423
All life,

0:00:02.423,0:00:04.122
every living thing ever,

0:00:04.122,0:00:07.440
has been built according[br]to the information in DNA.

0:00:07.440,0:00:08.598
What does that mean?

0:00:08.598,0:00:10.991
Well, it means that just[br]as the English language

0:00:10.991,0:00:14.251
is made up of alphabetic letters[br]that, when combined into words,

0:00:14.251,0:00:16.926
allow me to tell you the story[br]I'm going to tell you today,

0:00:16.926,0:00:21.153
DNA is made up of genetic letters[br]that, when combined into genes,

0:00:21.153,0:00:23.384
allow cells to produce proteins,

0:00:23.384,0:00:26.425
strings of amino acids that fold up[br]into complex structures

0:00:26.425,0:00:29.574
that perform the functions[br]that allow a cell to do what it does,

0:00:29.574,0:00:31.307
to tell its stories.

0:00:31.307,0:00:35.058
The English alphabet has 26 letters,[br]and the genetic alphabet has four.

0:00:35.058,0:00:36.671
They're pretty famous.[br]Maybe you've heard of them.

0:00:36.671,0:00:40.976
They are often just referred to[br]as G, C, A and T.

0:00:40.976,0:00:44.272
But it's remarkable that all[br]the diversity of life

0:00:44.272,0:00:47.570
is the result of four genetic letters.

0:00:47.570,0:00:51.593
Imagine what it would be like[br]if the English alphabet had four letters.

0:00:51.593,0:00:55.556
What sort of stories[br]would you be able to tell?

0:00:55.556,0:00:58.721
What if the genetic alphabet[br]had more letters?

0:00:58.721,0:01:02.702
Would life with more letters[br]be able to tell different stories,

0:01:02.702,0:01:06.910
maybe even more interesting ones?

0:01:06.910,0:01:10.697
In 1999, my lab at the Scripps[br]Research Institute in La Jolla, California

0:01:10.697,0:01:14.221
started working on this question[br]with the goal of creating living organisms

0:01:14.221,0:01:17.555
with DNA made up of[br]a six-letter genetic alphabet,

0:01:17.555,0:01:23.504
the four natural letters plus two[br]additional new man-made letters.

0:01:23.718,0:01:27.216
Such an organism would be the first[br]radically altered form of life

0:01:27.216,0:01:27.653
ever created.

0:01:27.653,0:01:31.745
It would be a semi-synthetic form of life[br]that stores more information

0:01:31.745,0:01:34.434
than life ever has before.

0:01:34.434,0:01:36.323
It would be able to make new proteins,

0:01:36.323,0:01:38.906
proteins built from more[br]than the 20 normal amino acids

0:01:38.906,0:01:41.772
that are usually used to build proteins.

0:01:41.772,0:01:44.789
What sort of stories could that life tell?

0:01:44.789,0:01:48.891
With the power of synthetic chemistry[br]and molecular biology

0:01:48.891,0:01:50.304
and just under 20 years of work,

0:01:50.304,0:01:52.672
we created bacteria with six-letter DNA.

0:01:52.672,0:01:54.871
Let me tell you how we did it.

0:01:54.871,0:01:57.018
All you have to remember[br]from your high school biology

0:01:57.018,0:01:59.330
is that the four natural letters[br]pair together to form two base pairs.

0:01:59.330,0:02:03.329
G pairs with C and A pairs with T,

0:02:03.329,0:02:05.876
so to create our new letters,

0:02:05.876,0:02:08.833
we synthesize hundreds of new candidates,[br]new candidate letters,

0:02:08.833,0:02:11.804
and examined their abilities[br]to selectively pair with each other.

0:02:11.804,0:02:16.021
And after about 15 years of work, we found[br]two that paired together really well,

0:02:16.021,0:02:17.843
at least in a test tube.

0:02:17.843,0:02:20.537
They have complicated names,

0:02:20.537,0:02:22.309
but let's just called X and Y.

0:02:22.309,0:02:25.581
The next thing we needed to do[br]was find a way to get X and Y into cells,

0:02:25.581,0:02:28.870
and eventually we found that a protein[br]that does something similar in algae

0:02:28.870,0:02:30.694
worked in our bacteria.

0:02:30.694,0:02:32.849
So the final thing that we needed to do[br]was to show that with X and Y provided,

0:02:32.849,0:02:34.994
cells could grow and divide[br]and hold on to X and Y in their DNA.

0:02:34.994,0:02:37.469
Everything we had done up to then[br]took longer than I had hoped --

0:02:37.469,0:02:44.934
I am actually a really impatient person --

0:02:44.934,0:02:46.589
but this, the most important step,[br]worked faster than I dreamed,

0:02:46.589,0:02:51.653
basically immediately.

0:02:51.653,0:02:55.198
On a weekend in 2014,

0:02:55.198,0:02:58.991
a graduate student in my lab[br]grew bacteria with six-letter DNA.

0:02:58.991,0:03:01.615
Let me take the opportunity[br]to introduce you to them right now.,

0:03:01.615,0:03:04.208
This is an actual picture of them.

0:03:04.208,0:03:09.065
These are the first[br]semi-synthetic organisms.

0:03:09.065,0:03:12.627
So bacteria with six-letter DNA,[br]that's really cool, right?

0:03:12.627,0:03:15.737
Well, maybe some of you[br]are still wondering why.

0:03:15.737,0:03:18.317
So let me tell you a little bit more[br]about some of our motivations,

0:03:18.317,0:03:21.074
both conceptual and practical.

0:03:21.074,0:03:23.860
Conceptually, people have[br]thought about life, what it is,

0:03:23.860,0:03:25.937
what makes it different[br]from things that are not alive,

0:03:25.937,0:03:28.192
since people have had thoughts.

0:03:28.192,0:03:31.008
Many have interpreted[br]life as being perfect,

0:03:31.008,0:03:33.035
and this was taken[br]as evidence of a creator.

0:03:33.035,0:03:36.461
Living things are different[br]because a god breathed life into them.

0:03:36.461,0:03:38.766
Others have sought[br]a more scientific explanation,

0:03:38.766,0:03:42.720
but I think it's fair to say

0:03:42.720,0:03:43.388
that they still consider[br]the molecules of life to be special.

0:03:43.388,0:03:46.581
I mean, evolution has been optimizing them[br]for billions of years, right?

0:03:46.581,0:03:48.891
Whatever perspective you take,[br]it would seem pretty impossible

0:03:48.891,0:03:51.051
for chemists to come in[br]and build new parts

0:03:51.051,0:03:54.095
that function within and alongside[br]the natural molecules of life

0:03:54.095,0:03:58.120
without somehow really[br]screwing everything up.

0:03:58.120,0:04:01.763
But just how perfectly[br]created or evolved are we?

0:04:01.763,0:04:04.905
Just how special[br]are the molecules of life?

0:04:04.905,0:04:06.990
These questions have been[br]impossible to even ask,

0:04:06.990,0:04:10.330
because we've had nothing[br]to compare life to.

0:04:10.330,0:04:13.246
Now for the first time, our work suggests[br]that maybe the molecules of life

0:04:13.246,0:04:15.014
aren't that special.

0:04:15.014,0:04:19.309
Maybe life as we know it[br]isn't the only way it could be.

0:04:19.309,0:04:22.166
Maybe we're not the only solution,[br]maybe not even the best solution,

0:04:22.166,0:04:25.221
just a solution.

0:04:25.221,0:04:28.554
These questions address[br]fundamental issues about life,

0:04:28.554,0:04:30.079
but maybe they seem a little esoteric.

0:04:30.079,0:04:31.621
So what about practical motivations?

0:04:31.621,0:04:34.593
Well, we want to explore[br]what sort of new stories

0:04:34.593,0:04:36.931
life with an expanded[br]vocabulary could tell,

0:04:36.931,0:04:40.294
and remember, stories here[br]are the proteins that a cell produces

0:04:40.294,0:04:41.707
and the functions they have.

0:04:41.707,0:04:44.411
So what sort of new proteins[br]with new types of functions

0:04:44.411,0:04:48.474
could our semi-synthetic organisms[br]make and maybe even use?

0:04:48.474,0:04:51.484
Well, we have a couple of things in mind.

0:04:51.484,0:04:56.146
The first is to get the cells[br]to make proteins for us, for our use.

0:04:56.146,0:04:58.324
Proteins are being used today

0:04:58.324,0:05:00.046
for an increasingly broad[br]range of different applications,

0:05:00.046,0:05:02.478
from materials that protect[br]soldiers from injury

0:05:02.478,0:05:04.832
to devices that detect[br]dangerous compounds,

0:05:04.832,0:05:06.011
but at least to me,

0:05:06.011,0:05:09.003
the most exciting application[br]is protein drugs.

0:05:09.425,0:05:10.851
Despite being relatively new,

0:05:10.851,0:05:13.082
protein drugs have already[br]revolutionized medicine,

0:05:13.082,0:05:15.967
and for example insulin is a protein.

0:05:15.967,0:05:18.567
You've probably heard of it,[br]and it's manufactured as a drug

0:05:18.567,0:05:21.410
that has completely changed[br]how we treat diabetes.

0:05:21.410,0:05:24.531
But the problem is is that proteins[br]are really hard to make,

0:05:24.531,0:05:28.500
and the only practical way to get them[br]is to get cells to make them for you.

0:05:28.500,0:05:32.479
So of course, with natural cells,[br]you can only get them to make

0:05:32.479,0:05:34.516
proteins with the natural amino acids,

0:05:34.516,0:05:36.535
and so the properties[br]those proteins can have,

0:05:36.535,0:05:38.676
the applications they[br]could be developed for,

0:05:38.676,0:05:41.520
must be limited by the nature[br]of those amino acids

0:05:41.520,0:05:43.194
that the protein's built from.

0:05:43.194,0:05:44.358
So here they are,

0:05:44.358,0:05:47.172
the 20 normal amino acids that are[br]strung together to make a protein,

0:05:47.172,0:05:50.069
and I think you can see, they're[br]not that different-looking.

0:05:50.069,0:05:51.847
They don't bring[br]that many different functions.

0:05:51.847,0:05:53.919
They don't make that many[br]different functions available.

0:05:53.919,0:05:58.155
Compare that with the small molecules[br]that synthetic chemists make as drugs.

0:05:58.155,0:06:00.874
Now, they're much simpler than proteins,

0:06:00.874,0:06:03.832
but they're routinely built from[br]a much broader range of diverse things.

0:06:03.832,0:06:05.490
Don't worry about the molecular details,

0:06:05.490,0:06:07.540
but I think you can see[br]how different they are.

0:06:07.540,0:06:10.819
And in fact, it's their differences[br]that make them great drugs

0:06:10.819,0:06:12.962
to treat different diseases.

0:06:12.962,0:06:17.169
So it's really provocative to wonder[br]what sort of new protein drugs

0:06:17.169,0:06:21.326
you could develop if you could build[br]proteins from more diverse things.

0:06:21.326,0:06:23.990
So can we get our semi-synthetic organism

0:06:23.990,0:06:27.335
to make proteins that include[br]new and different amino acids,

0:06:27.335,0:06:29.435
maybe amino acids selected[br]to confer the protein

0:06:29.435,0:06:31.877
with some desired property or function?

0:06:31.877,0:06:34.230
For example,

0:06:34.230,0:06:37.323
many proteins just aren't stable[br]when you inject them into people.

0:06:37.323,0:06:40.460
They are rapidly degraded or eliminated,

0:06:40.460,0:06:42.018
and this stops them from being drugs.

0:06:42.018,0:06:44.361
What if we could make proteins[br]with new amino acids

0:06:44.361,0:06:45.990
with things attached to them

0:06:45.990,0:06:48.537
that protect them from their environment,

0:06:48.537,0:06:51.625
that protect them from[br]being degraded or eliminated,

0:06:51.625,0:06:54.060
so that they could be better drugs?

0:06:54.060,0:06:58.016
Could we make proteins[br]with little fingers attached

0:06:58.016,0:07:01.066
that specifically grab on[br]to other molecules?

0:07:01.066,0:07:04.239
Many small molecules fail[br]during development as drugs

0:07:04.239,0:07:07.009
because they just weren't[br]specific enough to find their target

0:07:07.009,0:07:09.533
in the complex environment[br]of the human body.

0:07:09.533,0:07:13.176
So could we take those molecules[br]and make them parts of new amino acids

0:07:13.176,0:07:15.406
that, when incorporated into a protein,

0:07:15.406,0:07:18.890
are guided by that protein[br]to their target?

0:07:20.139,0:07:22.576
I started a biotech company[br]called Synthorx.

0:07:22.576,0:07:25.089
Synthorx stands for synthetic organism

0:07:25.089,0:07:28.800
with an X added at the end because[br]that's what you do with biotech companies.

0:07:28.800,0:07:30.242
(Laughter)

0:07:30.242,0:07:32.552
Synthorx is working closely with my lab,

0:07:32.552,0:07:36.629
and they're interested in a protein[br]that recognizes a certain receptor

0:07:36.629,0:07:38.396
on the surface of human cells.

0:07:38.396,0:07:40.805
But the problem is that it also recognizes

0:07:40.805,0:07:43.640
another receptor on the surface[br]of those same cells,

0:07:43.640,0:07:46.057
and that makes it toxic.

0:07:46.057,0:07:48.069
So could we produce[br]a variant of that protein

0:07:48.069,0:07:52.209
where the part that interacts[br]with that second bad receptor is shielded,

0:07:52.209,0:07:55.566
blocked by something like a big umbrella[br]so that the protein only interacts

0:07:55.566,0:07:57.753
with that first good receptor?

0:07:57.753,0:07:59.944
Doing that would be really difficult

0:07:59.944,0:08:02.192
or impossible to do[br]with the normal amino acids,

0:08:02.192,0:08:06.217
but not with amino acids that are[br]specifically designed for that purpose.

0:08:06.217,0:08:11.825
So getting our semi-synthetic cells[br]to act as little factories

0:08:11.825,0:08:13.277
to produce better protein drugs

0:08:13.277,0:08:15.943
isn't the only potentially[br]really interesting application,

0:08:15.943,0:08:19.946
because remember, it's the proteins[br]that allow cells to do what they do.

0:08:19.946,0:08:23.795
So if we have cells that make[br]new proteins with new functions,

0:08:23.795,0:08:27.491
could we get them to do things[br]that natural cells can't do?

0:08:27.491,0:08:30.348
For example, could we develop[br]semi-synthetic organisms

0:08:31.220,0:08:33.094
that when injected into a person

0:08:33.094,0:08:35.609
seek out cancer cells[br]and only when they find them

0:08:35.609,0:08:38.505
secrete a toxic protein that kills them?

0:08:38.505,0:08:41.627
Could we create bacteria[br]that eat different kinds of oil,

0:08:41.627,0:08:43.583
maybe to clean up an oil spill?

0:08:43.583,0:08:45.907
These are just a couple[br]of the types of stories

0:08:45.907,0:08:48.754
that we're going to see if life[br]with an expanded vocabulary can tell.

0:08:48.754,0:08:50.276
So, sounds great, right?

0:08:50.276,0:08:53.490
Injecting semi-synthetic[br]organisms into people,

0:08:53.490,0:08:56.711
dumping millions and millions of gallons[br]of our bacteria into the ocean

0:08:56.711,0:08:58.386
or out on your favorite beach?

0:08:58.386,0:09:00.776
Oh, wait a minute,[br]actually it sounds really scary.

0:09:00.776,0:09:04.337
This dinosaur is really scary.

0:09:04.747,0:09:06.491
But here's the catch:

0:09:06.491,0:09:10.095
our semi-synthetic organisms[br]in order to survive

0:09:10.095,0:09:14.102
need to be fed the chemical[br]precursors of X and Y.

0:09:14.102,0:09:17.765
X and Y are completely different[br]than anything that exists in nature.

0:09:17.765,0:09:21.747
Cells just don't have them[br]or the ability to make them.

0:09:21.747,0:09:23.217
So when we prepare them,

0:09:23.217,0:09:24.954
when we grow them up in[br]the controlled environment of the lab,

0:09:24.954,0:09:27.608
we can feed them lots[br]of the unnatural food.

0:09:27.608,0:09:31.595
Then, when we deploy them[br]in a person or out on a beach

0:09:31.595,0:09:34.319
where they no longer[br]have access that special food,

0:09:34.319,0:09:36.380
they can grow for a little bit,

0:09:36.380,0:09:37.666
they can survive for a little,

0:09:37.666,0:09:41.032
maybe just long enough to perform[br]some intended function,

0:09:41.032,0:09:43.151
but then they start[br]to run out of the food.

0:09:43.151,0:09:44.564
They start to starve.

0:09:44.564,0:09:47.779
They starve to death,[br]and they just disappear.

0:09:47.779,0:09:50.233
So not only could we get life[br]to tell new stories,

0:09:50.233,0:09:54.124
we get to tell life when and where[br]to tell those stories.

0:09:54.124,0:09:58.711
At the beginning of this talk[br]I told you that we reported in 2014

0:09:58.711,0:10:02.223
the creation of semi-synthetic organisms[br]that store more information,

0:10:02.223,0:10:04.077
X and Y, in their DNA.

0:10:04.077,0:10:06.395
But all the motivations[br]that we just talked about

0:10:06.395,0:10:09.341
require cells to use X and Y[br]to make proteins,

0:10:09.341,0:10:11.959
so we started working on that.

0:10:11.959,0:10:15.641
Within a couple years, we showed[br]that the cells could take DNA with X and Y

0:10:15.641,0:10:17.294
and copy it into RNA,[br]the working copy of DNA.

0:10:17.294,0:10:20.971
And late last year,

0:10:20.971,0:10:24.706
we showed that they could then[br]use X and Y to make proteins.

0:10:24.706,0:10:27.141
Here they are, the stars of the show,

0:10:27.141,0:10:31.631
the first fully-functional[br]semi-synthetic organisms.

0:10:31.631,0:10:35.067
(Applause)

0:10:37.146,0:10:41.170
These cells are green because[br]they're making a protein that glows green.

0:10:41.170,0:10:43.906
It's a pretty famous protein[br]actually from jellyfish

0:10:43.906,0:10:46.072
that a lot of people use[br]in its natural form

0:10:46.072,0:10:49.034
because it's easy to see that you made it.

0:10:49.034,0:10:51.407
But within every one of these proteins,

0:10:51.407,0:10:56.954
there's a new amino acid that[br]natural life can't build proteins with.

0:10:56.954,0:11:02.168
Every living cell, every living cell ever,

0:11:02.168,0:11:04.823
has made every one of its proteins

0:11:04.823,0:11:07.973
using a four-letter genetic alphabet.

0:11:07.973,0:11:12.117
These cells are living and growing[br]and making protein

0:11:12.117,0:11:14.094
with a six-letter alphabet.

0:11:14.094,0:11:16.538
These are a new form of life.

0:11:16.538,0:11:20.071
This is a semi-synthetic form of life.

0:11:20.071,0:11:21.928
So what about the future?

0:11:21.928,0:11:24.856
My lab is already working on expanding [br]the genetic alphabet of other cells,

0:11:24.856,0:11:26.382
including human cells,

0:11:26.382,0:11:29.835
and we're getting ready to start working[br]on more complex organisms.

0:11:29.835,0:11:33.514
Think semi-synthetic worms.

0:11:33.514,0:11:35.516
The last thing I want to say to you,

0:11:35.516,0:11:37.797
the most important thing[br]that I want to say to you,

0:11:37.797,0:11:40.863
is that the time[br]of semi-synthetic life is here.

0:11:40.863,0:11:42.376
Thank you.

0:11:42.376,0:11:44.913
(Applause)

0:11:50.445,0:11:55.895
Chris Anderson: I mean, Floyd,[br]this is so remarkable.

0:11:55.895,0:11:57.815
I just wanted to ask you,

0:11:57.815,0:12:01.142
what are the implications of your work

0:12:01.142,0:12:03.535
for how we should think about

0:12:03.535,0:12:05.928
the possibilities for life,

0:12:05.928,0:12:07.869
like, in the universe, elsewhere?

0:12:07.869,0:12:10.029
It just seems like so much of life,[br]or so much of our assumptions are based

0:12:10.029,0:12:14.599
on the fact that of course[br]it's got to be DNA,

0:12:14.599,0:12:19.053
but is the possibility space[br]of self-replicating molecules

0:12:19.053,0:12:22.189
much bigger than DNA,[br]even just DNA with six letters?

0:12:22.189,0:12:24.087
Floyd Romesberg: Absolutely,[br]I think that's right,

0:12:24.087,0:12:26.764
and I think what our work has shown,[br]as I mentioned, is that I think that

0:12:26.764,0:12:30.769
there's been always this prejudice[br]that sort of we're perfect,

0:12:30.769,0:12:33.687
and we're optimal,[br]God created us this way,

0:12:33.687,0:12:36.166
evolution perfected us this way.

0:12:36.166,0:12:39.865
We've made molecules that work[br]right alongside the natural ones,

0:12:39.865,0:12:43.821
and I think that suggests[br]that any molecules

0:12:43.821,0:12:46.760
that obey the fundamental laws[br]of chemistry and physics

0:12:46.760,0:12:48.578
and you can optimize them

0:12:48.578,0:12:50.382
could do the things that[br]the natural molecules of life do.

0:12:50.382,0:12:52.439
There's nothing magic there.

0:12:52.439,0:12:54.084
And I think that it suggests

0:12:54.084,0:12:55.781
that life could evolve[br]many different ways,

0:12:55.781,0:12:58.803
maybe similar to us[br]with other types of DNA,

0:12:58.803,0:13:00.939
maybe things without DNA at all.

0:13:00.939,0:13:02.645
CA: I mean, in your mind,

0:13:02.645,0:13:06.055
how big might that possibility space be?

0:13:06.055,0:13:08.997
Do we even know? Are most things going[br]to look something like a DNA molecule,

0:13:08.997,0:13:12.790
or something radically different[br]that can still potentially self-reproduce

0:13:12.790,0:13:14.285
and potentially create living organisms?

0:13:14.285,0:13:16.867
FR: My personal opinion[br]is that if we found new life,

0:13:16.867,0:13:18.697
we might not even recognize it.

0:13:18.697,0:13:22.047
CA: So this obsession with the search[br]for Goldilocks planets

0:13:22.047,0:13:24.649
in exactly the right place[br]with water and whatever,

0:13:24.649,0:13:27.126
that's a very parochial[br]assumption, perhaps.

0:13:27.126,0:13:29.472
FR: Well, if you want to find something[br]you can talk to, then maybe not,

0:13:29.472,0:13:33.301
but I think that if you're just[br]looking for any form of life,

0:13:33.301,0:13:37.305
I think that's right, I think that you're[br]looking for life under the light post.

0:13:37.305,0:13:40.881
CA: Thank you for boggling[br]all our minds. Thank so much, Floyd.

0:13:40.881,0:13:43.131
(Applause)