0:00:00.760,0:00:02.096
All life,

0:00:02.120,0:00:03.856
every living thing ever,

0:00:03.880,0:00:06.816
has been built according[br]to the information in DNA.

0:00:06.840,0:00:08.216
What does that mean?

0:00:08.240,0:00:10.736
Well, it means that just[br]as the English language

0:00:10.760,0:00:13.976
is made up of alphabetic letters[br]that, when combined into words,

0:00:14.000,0:00:16.816
allow me to tell you the story[br]I'm going to tell you today,

0:00:16.840,0:00:20.936
DNA is made up of genetic letters[br]that, when combined into genes,

0:00:20.960,0:00:22.696
allow cells to produce proteins,

0:00:22.720,0:00:25.776
strings of amino acids[br]that fold up into complex structures

0:00:25.800,0:00:28.816
that perform the functions[br]that allow a cell to do what it does,

0:00:28.840,0:00:30.576
to tell its stories.

0:00:30.600,0:00:34.536
The English alphabet has 26 letters,[br]and the genetic alphabet has four.

0:00:34.560,0:00:36.936
They're pretty famous.[br]Maybe you've heard of them.

0:00:36.960,0:00:39.280
They are often just[br]referred to as G, C, A and T.

0:00:40.520,0:00:43.936
But it's remarkable[br]that all the diversity of life

0:00:43.960,0:00:46.040
is the result of four genetic letters.

0:00:47.240,0:00:51.256
Imagine what it would be like[br]if the English alphabet had four letters.

0:00:51.280,0:00:53.560
What sort of stories[br]would you be able to tell?

0:00:55.280,0:00:57.440
What if the genetic alphabet[br]had more letters?

0:00:59.440,0:01:02.416
Would life with more letters[br]be able to tell different stories,

0:01:02.440,0:01:04.440
maybe even more interesting ones?

0:01:06.480,0:01:10.296
In 1999, my lab at the Scripps[br]Research Institute in La Jolla, California

0:01:10.320,0:01:14.016
started working on this question[br]with the goal of creating living organisms

0:01:14.040,0:01:17.056
with DNA made up[br]of a six-letter genetic alphabet,

0:01:17.080,0:01:21.560
the four natural letters[br]plus two additional new man-made letters.

0:01:23.120,0:01:24.376
Such an organism would be

0:01:24.400,0:01:27.256
the first radically altered[br]form of life ever created.

0:01:27.280,0:01:29.216
It would be a semisynthetic form of life

0:01:29.240,0:01:33.120
that stores more information[br]than life ever has before.

0:01:34.120,0:01:35.976
It would be able to make new proteins,

0:01:36.000,0:01:38.736
proteins built from more[br]than the 20 normal amino acids

0:01:38.760,0:01:40.680
that are usually used to build proteins.

0:01:41.560,0:01:43.640
What sort of stories could that life tell?

0:01:45.400,0:01:48.216
With the power of synthetic chemistry[br]and molecular biology

0:01:48.240,0:01:49.816
and just under 20 years of work,

0:01:49.840,0:01:52.376
we created bacteria with six-letter DNA.

0:01:52.400,0:01:53.829
Let me tell you how we did it.

0:01:54.640,0:01:57.176
All you have to remember[br]from your high school biology

0:01:57.200,0:02:00.696
is that the four natural letters[br]pair together to form two base pairs.

0:02:00.720,0:02:02.976
G pairs with C and A pairs with T,

0:02:03.000,0:02:04.816
so to create our new letters,

0:02:04.840,0:02:08.376
we synthesized hundreds of new candidates,[br]new candidate letters,

0:02:08.400,0:02:11.448
and examined their abilities[br]to selectively pair with each other.

0:02:11.472,0:02:13.176
And after about 15 years of work,

0:02:13.200,0:02:15.776
we found two that paired[br]together really well,

0:02:15.800,0:02:17.496
at least in a test tube.

0:02:17.520,0:02:19.216
They have complicated names,

0:02:19.240,0:02:20.860
but let's just call them X and Y.

0:02:21.960,0:02:25.376
The next thing we needed to do[br]was find a way to get X and Y into cells,

0:02:25.400,0:02:28.936
and eventually we found that a protein[br]that does something similar in algae

0:02:28.960,0:02:30.336
worked in our bacteria.

0:02:30.360,0:02:34.856
So the final thing that we needed to do[br]was to show that with X and Y provided,

0:02:34.880,0:02:38.400
cells could grow and divide[br]and hold on to X and Y in their DNA.

0:02:39.880,0:02:42.976
Everything we had done up to then[br]took longer than I had hoped --

0:02:43.000,0:02:45.016
I am actually a really impatient person --

0:02:45.040,0:02:48.840
but this, the most important step,[br]worked faster than I dreamed,

0:02:49.840,0:02:51.040
basically immediately.

0:02:52.640,0:02:54.856
On a weekend in 2014,

0:02:54.880,0:02:57.960
a graduate student in my lab[br]grew bacteria with six-letter DNA.

0:02:58.800,0:03:01.776
Let me take the opportunity[br]to introduce you to them right now.

0:03:01.800,0:03:03.440
This is an actual picture of them.

0:03:04.880,0:03:07.320
These are the first[br]semisynthetic organisms.

0:03:09.480,0:03:12.256
So bacteria with six-letter DNA,[br]that's really cool, right?

0:03:12.280,0:03:14.720
Well, maybe some of you[br]are still wondering why.

0:03:15.680,0:03:18.856
So let me tell you a little bit more[br]about some of our motivations,

0:03:18.880,0:03:20.816
both conceptual and practical.

0:03:20.840,0:03:23.536
Conceptually, people have[br]thought about life, what it is,

0:03:23.560,0:03:26.176
what makes it different[br]from things that are not alive,

0:03:26.200,0:03:27.856
since people have had thoughts.

0:03:27.880,0:03:30.176
Many have interpreted[br]life as being perfect,

0:03:30.200,0:03:32.696
and this was taken[br]as evidence of a creator.

0:03:32.720,0:03:36.376
Living things are different[br]because a god breathed life into them.

0:03:36.400,0:03:38.736
Others have sought[br]a more scientific explanation,

0:03:38.760,0:03:40.136
but I think it's fair to say

0:03:40.160,0:03:43.056
that they still consider[br]the molecules of life to be special.

0:03:43.080,0:03:46.496
I mean, evolution has been optimizing them[br]for billions of years, right?

0:03:46.520,0:03:49.456
Whatever perspective you take,[br]it would seem pretty impossible

0:03:49.480,0:03:51.496
for chemists to come in[br]and build new parts

0:03:51.520,0:03:54.536
that function within and alongside[br]the natural molecules of life

0:03:54.560,0:03:56.920
without somehow[br]really screwing everything up.

0:03:58.400,0:04:01.456
But just how perfectly[br]created or evolved are we?

0:04:01.480,0:04:03.720
Just how special[br]are the molecules of life?

0:04:04.640,0:04:06.976
These questions have been[br]impossible to even ask,

0:04:07.000,0:04:09.120
because we've had nothing[br]to compare life to.

0:04:10.000,0:04:11.976
Now for the first time, our work suggests

0:04:12.000,0:04:14.696
that maybe the molecules of life[br]aren't that special.

0:04:14.720,0:04:17.760
Maybe life as we know it[br]isn't the only way it could be.

0:04:18.920,0:04:22.136
Maybe we're not the only solution,[br]maybe not even the best solution,

0:04:22.160,0:04:23.600
just a solution.

0:04:25.600,0:04:28.176
These questions address[br]fundamental issues about life,

0:04:28.200,0:04:30.056
but maybe they seem a little esoteric.

0:04:30.080,0:04:31.816
So what about practical motivations?

0:04:31.840,0:04:34.616
Well, we want to explore[br]what sort of new stories

0:04:34.640,0:04:36.736
life with an expanded[br]vocabulary could tell,

0:04:36.760,0:04:39.976
and remember, stories here[br]are the proteins that a cell produces

0:04:40.000,0:04:41.376
and the functions they have.

0:04:41.400,0:04:44.496
So what sort of new proteins[br]with new types of functions

0:04:44.520,0:04:48.176
could our semisynthetic organisms[br]make and maybe even use?

0:04:48.200,0:04:50.160
Well, we have a couple of things in mind.

0:04:51.240,0:04:55.816
The first is to get the cells[br]to make proteins for us, for our use.

0:04:55.840,0:04:57.256
Proteins are being used today

0:04:57.280,0:05:00.016
for an increasingly broad[br]range of different applications,

0:05:00.040,0:05:02.296
from materials that protect[br]soldiers from injury

0:05:02.320,0:05:04.536
to devices that detect[br]dangerous compounds,

0:05:04.560,0:05:05.896
but at least to me,

0:05:05.920,0:05:08.320
the most exciting application[br]is protein drugs.

0:05:09.160,0:05:10.576
Despite being relatively new,

0:05:10.600,0:05:13.016
protein drugs have already[br]revolutionized medicine,

0:05:13.040,0:05:15.736
and, for example, insulin is a protein.

0:05:15.760,0:05:18.616
You've probably heard of it,[br]and it's manufactured as a drug

0:05:18.640,0:05:21.296
that has completely changed[br]how we treat diabetes.

0:05:21.320,0:05:24.296
But the problem is that proteins[br]are really hard to make

0:05:24.320,0:05:27.920
and the only practical way to get them[br]is to get cells to make them for you.

0:05:28.880,0:05:30.576
So of course, with natural cells,

0:05:30.600,0:05:34.096
you can only get them to make[br]proteins with the natural amino acids,

0:05:34.120,0:05:36.336
and so the properties[br]those proteins can have,

0:05:36.360,0:05:38.856
the applications[br]they could be developed for,

0:05:38.880,0:05:41.376
must be limited by the nature[br]of those amino acids

0:05:41.400,0:05:42.896
that the protein's built from.

0:05:42.920,0:05:44.136
So here they are,

0:05:44.160,0:05:47.416
the 20 normal amino acids that are[br]strung together to make a protein,

0:05:47.440,0:05:50.296
and I think you can see,[br]they're not that different-looking.

0:05:50.320,0:05:52.536
They don't bring[br]that many different functions.

0:05:52.560,0:05:55.216
They don't make that many[br]different functions available.

0:05:55.240,0:05:58.816
Compare that with the small molecules[br]that synthetic chemists make as drugs.

0:05:58.840,0:06:00.776
Now, they're much simpler than proteins,

0:06:00.800,0:06:04.216
but they're routinely built from[br]a much broader range of diverse things.

0:06:04.240,0:06:06.176
Don't worry about the molecular details,

0:06:06.200,0:06:08.416
but I think you can see[br]how different they are.

0:06:08.440,0:06:11.376
And in fact, it's their differences[br]that make them great drugs

0:06:11.400,0:06:12.776
to treat different diseases.

0:06:12.800,0:06:16.976
So it's really provocative to wonder[br]what sort of new protein drugs

0:06:17.000,0:06:20.360
you could develop if you could build[br]proteins from more diverse things.

0:06:21.840,0:06:23.776
So can we get our semisynthetic organism

0:06:23.800,0:06:27.016
to make proteins that include[br]new and different amino acids,

0:06:27.040,0:06:29.296
maybe amino acids[br]selected to confer the protein

0:06:29.320,0:06:31.400
with some desired property or function?

0:06:32.640,0:06:33.896
For example,

0:06:33.920,0:06:37.056
many proteins just aren't stable[br]when you inject them into people.

0:06:37.080,0:06:39.256
They are rapidly degraded or eliminated,

0:06:39.280,0:06:41.080
and this stops them from being drugs.

0:06:42.080,0:06:44.496
What if we could make proteins[br]with new amino acids

0:06:44.520,0:06:46.336
with things attached to them

0:06:46.360,0:06:48.336
that protect them from their environment,

0:06:48.360,0:06:51.536
that protect them[br]from being degraded or eliminated,

0:06:51.560,0:06:53.240
so that they could be better drugs?

0:06:55.560,0:06:57.976
Could we make proteins[br]with little fingers attached

0:06:58.000,0:07:00.480
that specifically[br]grab on to other molecules?

0:07:01.480,0:07:04.216
Many small molecules[br]failed during development as drugs

0:07:04.240,0:07:07.176
because they just weren't[br]specific enough to find their target

0:07:07.200,0:07:09.336
in the complex environment[br]of the human body.

0:07:09.360,0:07:12.976
So could we take those molecules[br]and make them parts of new amino acids

0:07:13.000,0:07:15.776
that, when incorporated into a protein,

0:07:15.800,0:07:18.160
are guided by that protein[br]to their target?

0:07:20.040,0:07:22.216
I started a biotech company[br]called Synthorx.

0:07:22.240,0:07:24.856
Synthorx stands for synthetic organism

0:07:24.880,0:07:28.536
with an X added at the end because[br]that's what you do with biotech companies.

0:07:28.560,0:07:29.976
(Laughter)

0:07:30.000,0:07:32.016
Synthorx is working closely with my lab,

0:07:32.040,0:07:36.376
and they're interested in a protein[br]that recognizes a certain receptor

0:07:36.400,0:07:38.096
on the surface of human cells.

0:07:38.120,0:07:40.576
But the problem is that it also recognizes

0:07:40.600,0:07:43.296
another receptor on the surface[br]of those same cells,

0:07:43.320,0:07:44.960
and that makes it toxic.

0:07:45.800,0:07:47.936
So could we produce[br]a variant of that protein

0:07:47.960,0:07:52.296
where the part that interacts[br]with that second bad receptor is shielded,

0:07:52.320,0:07:54.256
blocked by something like a big umbrella

0:07:54.280,0:07:57.360
so that the protein only interacts[br]with that first good receptor?

0:07:58.520,0:08:00.256
Doing that would be really difficult

0:08:00.280,0:08:02.536
or impossible to do[br]with the normal amino acids,

0:08:02.560,0:08:06.000
but not with amino acids that are[br]specifically designed for that purpose.

0:08:08.520,0:08:11.696
So getting our semisynthetic cells[br]to act as little factories

0:08:11.720,0:08:13.216
to produce better protein drugs

0:08:13.240,0:08:15.976
isn't the only potentially[br]really interesting application,

0:08:16.000,0:08:19.400
because remember, it's the proteins[br]that allow cells to do what they do.

0:08:20.320,0:08:23.616
So if we have cells that make[br]new proteins with new functions,

0:08:23.640,0:08:27.216
could we get them to do things[br]that natural cells can't do?

0:08:27.240,0:08:30.016
For example, could we develop[br]semisynthetic organisms

0:08:30.040,0:08:34.176
that when injected into a person,[br]seek out cancer cells

0:08:34.200,0:08:37.520
and only when they find them,[br]secrete a toxic protein that kills them?

0:08:38.400,0:08:41.336
Could we create bacteria[br]that eat different kinds of oil,

0:08:41.360,0:08:43.256
maybe to clean up an oil spill?

0:08:43.280,0:08:45.496
These are just a couple[br]of the types of stories

0:08:45.520,0:08:48.776
that we're going to see if life[br]with an expanded vocabulary can tell.

0:08:48.800,0:08:50.296
So, sounds great, right?

0:08:50.320,0:08:53.216
Injecting semisynthetic[br]organisms into people,

0:08:53.240,0:08:56.616
dumping millions and millions of gallons[br]of our bacteria into the ocean

0:08:56.640,0:08:58.136
or out on your favorite beach?

0:08:58.160,0:09:00.616
Oh, wait a minute,[br]actually it sounds really scary.

0:09:00.640,0:09:02.640
This dinosaur is really scary.

0:09:04.480,0:09:06.256
But here's the catch:

0:09:06.280,0:09:09.856
our semisynthetic organisms[br]in order to survive,

0:09:09.880,0:09:12.800
need to be fed the chemical[br]precursors of X and Y.

0:09:13.800,0:09:17.280
X and Y are completely different[br]than anything that exists in nature.

0:09:18.160,0:09:20.760
Cells just don't have them[br]or the ability to make them.

0:09:21.600,0:09:22.856
So when we prepare them,

0:09:22.880,0:09:25.816
when we grow them up[br]in the controlled environment of the lab,

0:09:25.840,0:09:27.936
we can feed them[br]lots of the unnatural food.

0:09:27.960,0:09:31.296
Then, when we deploy them[br]in a person or out on a beach

0:09:31.320,0:09:34.016
where they no longer[br]have access that special food,

0:09:34.040,0:09:37.136
they can grow for a little bit,[br]they can survive for a little,

0:09:37.160,0:09:40.656
maybe just long enough[br]to perform some intended function,

0:09:40.680,0:09:42.816
but then they start[br]to run out of the food.

0:09:42.840,0:09:44.176
They start to starve.

0:09:44.200,0:09:46.320
They starve to death[br]and they just disappear.

0:09:47.480,0:09:49.896
So not only could we get life[br]to tell new stories,

0:09:49.920,0:09:52.920
we get to tell life when and where[br]to tell those stories.

0:09:55.080,0:09:58.616
At the beginning of this talk[br]I told you that we reported in 2014

0:09:58.640,0:10:01.856
the creation of semisynthetic organisms[br]that store more information,

0:10:01.880,0:10:03.976
X and Y, in their DNA.

0:10:04.000,0:10:06.456
But all the motivations[br]that we just talked about

0:10:06.480,0:10:08.936
require cells to use X and Y[br]to make proteins,

0:10:08.960,0:10:10.640
so we started working on that.

0:10:11.600,0:10:15.296
Within a couple years, we showed[br]that the cells could take DNA with X and Y

0:10:15.320,0:10:18.160
and copy it into RNA,[br]the working copy of DNA.

0:10:19.560,0:10:21.376
And late last year,

0:10:21.400,0:10:24.536
we showed that they could then[br]use X and Y to make proteins.

0:10:24.560,0:10:27.216
Here they are, the stars of the show,

0:10:27.240,0:10:30.720
the first fully-functional[br]semisynthetic organisms.

0:10:31.560,0:10:36.200
(Applause)

0:10:38.040,0:10:41.536
These cells are green because[br]they're making a protein that glows green.

0:10:41.560,0:10:44.096
It's a pretty famous protein,[br]actually, from jellyfish

0:10:44.120,0:10:46.216
that a lot of people use[br]in its natural form

0:10:46.240,0:10:48.280
because it's easy to see that you made it.

0:10:49.280,0:10:51.176
But within every one of these proteins,

0:10:51.200,0:10:54.960
there's a new amino acid that[br]natural life can't build proteins with.

0:10:57.160,0:11:01.000
Every living cell, every living cell ever,

0:11:02.160,0:11:04.536
has made every one of its proteins

0:11:04.560,0:11:06.600
using a four-letter genetic alphabet.

0:11:07.720,0:11:11.856
These cells are living and growing[br]and making protein

0:11:11.880,0:11:13.776
with a six-letter alphabet.

0:11:13.800,0:11:15.200
These are a new form of life.

0:11:16.360,0:11:18.520
This is a semisynthetic form of life.

0:11:19.840,0:11:21.616
So what about the future?

0:11:21.640,0:11:25.216
My lab is already working on expanding[br]the genetic alphabet of other cells,

0:11:25.240,0:11:26.456
including human cells,

0:11:26.480,0:11:30.136
and we're getting ready to start working[br]on more complex organisms.

0:11:30.160,0:11:31.960
Think semisynthetic worms.

0:11:33.360,0:11:35.096
The last thing I want to say to you,

0:11:35.120,0:11:37.536
the most important thing[br]that I want to say to you,

0:11:37.560,0:11:39.920
is that the time[br]of semisynthetic life is here.

0:11:40.760,0:11:42.016
Thank you.

0:11:42.040,0:11:46.720
(Applause)

0:11:53.480,0:11:55.976
Chris Anderson: I mean,[br]Floyd, this is so remarkable.

0:11:56.000,0:11:58.736
I just wanted to ask you,

0:11:58.760,0:12:01.256
what are the implications of your work

0:12:01.280,0:12:05.136
for how we should think[br]about the possibilities for life,

0:12:05.160,0:12:07.416
like, in the universe, elsewhere?

0:12:07.440,0:12:11.576
It just seems like so much of life,[br]or so much of our assumptions are based

0:12:11.600,0:12:14.456
on the fact that of course,[br]it's got to be DNA,

0:12:14.480,0:12:18.736
but is the possibility space[br]of self-replicating molecules

0:12:18.760,0:12:21.856
much bigger than DNA,[br]even just DNA with six letters?

0:12:21.880,0:12:24.256
Floyd Romesberg:[br]Absolutely, I think that's right,

0:12:24.280,0:12:26.016
and I think what our work has shown,

0:12:26.040,0:12:29.736
as I mentioned, is that[br]there's been always this prejudice

0:12:29.760,0:12:31.136
that sort of we're perfect,

0:12:31.160,0:12:33.736
we're optimal, God created us this way,

0:12:33.760,0:12:35.856
evolution perfected us this way.

0:12:35.880,0:12:39.160
We've made molecules that work[br]right alongside the natural ones,

0:12:40.440,0:12:43.656
and I think that suggests[br]that any molecules

0:12:43.680,0:12:46.336
that obey the fundamental laws[br]of chemistry and physics

0:12:46.360,0:12:47.616
and you can optimize them

0:12:47.640,0:12:50.376
could do the things that[br]the natural molecules of life do.

0:12:50.400,0:12:52.136
There's nothing magic there.

0:12:52.160,0:12:53.536
And I think that it suggests

0:12:53.560,0:12:55.616
that life could evolve[br]many different ways,

0:12:55.640,0:12:58.496
maybe similar to us[br]with other types of DNA,

0:12:58.520,0:13:00.240
maybe things without DNA at all.

0:13:01.120,0:13:02.376
CA: I mean, in your mind,

0:13:02.400,0:13:05.736
how big might that possibility space be?

0:13:05.760,0:13:09.416
Do we even know? Are most things going[br]to look something like a DNA molecule,

0:13:09.440,0:13:12.376
or something radically different[br]that can still self-reproduce

0:13:12.400,0:13:14.336
and potentially create living organisms?

0:13:14.360,0:13:16.856
FR: My personal opinion[br]is that if we found new life,

0:13:16.880,0:13:19.096
we might not even recognize it.

0:13:19.120,0:13:22.056
CA: So this obsession[br]with the search for Goldilocks planets

0:13:22.080,0:13:24.496
in exactly the right place[br]with water and whatever,

0:13:24.520,0:13:26.816
that's a very parochial[br]assumption, perhaps.

0:13:26.840,0:13:30.256
FR: Well, if you want to find someone[br]you can talk to, then maybe not,

0:13:30.280,0:13:33.176
but I think that if you're just[br]looking for any form of life,

0:13:33.200,0:13:37.096
I think that's right, I think that you're[br]looking for life under the light post.

0:13:37.120,0:13:40.456
CA: Thank you for boggling all our minds.[br]Thank so much, Floyd.

0:13:40.480,0:13:43.120
(Applause)