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TED2008

Craig Venter: On the verge of creating synthetic life

February 28, 2008

"Can we create new life out of our digital universe?" Craig Venter asks. His answer is "yes" -- and pretty soon. He walks through his latest research and promises that we'll soon be able to build and boot up a synthetic chromosome.

Craig Venter - Biologist, genetics pioneer
In 2001, Craig Venter made headlines for sequencing the human genome. In 2003, he started mapping the ocean's biodiversity. And now he's created the first synthetic lifeforms -- microorganisms that can produce alternative fuels. Full bio

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Double-click the English subtitles below to play the video.
You know, I've talked about some of these projects before --
00:19
about the human genome and what that might mean,
00:21
and discovering new sets of genes.
00:25
We're actually starting at a new point:
00:28
we've been digitizing biology,
00:31
and now we're trying to go from that digital code
00:35
into a new phase of biology
00:38
with designing and synthesizing life.
00:40
So, we've always been trying to ask big questions.
00:43
"What is life?" is something that I think many biologists
00:48
have been trying to understand
00:50
at various levels.
00:52
We've tried various approaches,
00:54
paring it down to minimal components.
00:57
We've been digitizing it now for almost 20 years;
01:01
when we sequenced the human genome,
01:03
it was going from the analog world of biology
01:05
into the digital world of the computer.
01:08
Now we're trying to ask, "Can we regenerate life
01:12
or can we create new life
01:16
out of this digital universe?"
01:18
This is the map of a small organism,
01:21
Mycoplasma genitalium,
01:24
that has the smallest genome for a species
01:26
that can self-replicate in the laboratory,
01:29
and we've been trying to just see if
01:32
we can come up with an even smaller genome.
01:34
We're able to knock out on the order of 100 genes
01:38
out of the 500 or so that are here.
01:40
When we look at its metabolic map,
01:43
it's relatively simple
01:45
compared to ours --
01:47
trust me, this is simple --
01:49
but when we look at all the genes
01:51
that we can knock out one at a time,
01:53
it's very unlikely that this would yield
01:56
a living cell.
01:58
So we decided the only way forward
02:01
was to actually synthesize this chromosome
02:03
so we could vary the components
02:06
to ask some of these most fundamental questions.
02:09
And so we started down the road of:
02:13
can we synthesize a chromosome?
02:15
Can chemistry permit making
02:19
these really large molecules
02:21
where we've never been before?
02:23
And if we do, can we boot up a chromosome?
02:25
A chromosome, by the way, is just a piece of inert chemical material.
02:28
So, our pace of digitizing life has been increasing
02:32
at an exponential pace.
02:35
Our ability to write the genetic code
02:38
has been moving pretty slowly
02:41
but has been increasing,
02:43
and our latest point would put it on, now, an exponential curve.
02:46
We started this over 15 years ago.
02:51
It took several stages, in fact,
02:53
starting with a bioethical review before we did the first experiments.
02:56
But it turns out synthesizing DNA
03:00
is very difficult.
03:02
There are tens of thousands of machines around the world
03:04
that make small pieces of DNA --
03:07
30 to 50 letters in length --
03:09
and it's a degenerate process, so the longer you make the piece,
03:12
the more errors there are.
03:15
So we had to create a new method
03:17
for putting these little pieces together and correct all the errors.
03:19
And this was our first attempt, starting with the digital information
03:23
of the genome of phi X174.
03:26
It's a small virus that kills bacteria.
03:28
We designed the pieces, went through our error correction
03:32
and had a DNA molecule
03:35
of about 5,000 letters.
03:37
The exciting phase came when we took this piece of inert chemical
03:40
and put it in the bacteria,
03:44
and the bacteria started to read this genetic code,
03:46
made the viral particles.
03:50
The viral particles then were released from the cells
03:52
and came back and killed the E. coli.
03:54
I was talking to the oil industry recently
03:57
and I said they clearly understood that model.
04:00
(Laughter)
04:03
They laughed more than you guys are. (Laughter)
04:06
And so, we think this is a situation
04:10
where the software can actually build its own hardware
04:12
in a biological system.
04:15
But we wanted to go much larger:
04:17
we wanted to build the entire bacterial chromosome --
04:19
it's over 580,000 letters of genetic code --
04:22
so we thought we'd build them in cassettes the size of the viruses
04:26
so we could actually vary the cassettes
04:29
to understand
04:31
what the actual components of a living cell are.
04:33
Design is critical,
04:36
and if you're starting with digital information in the computer,
04:38
that digital information has to be really accurate.
04:41
When we first sequenced this genome in 1995,
04:45
the standard of accuracy was one error per 10,000 base pairs.
04:48
We actually found, on resequencing it,
04:52
30 errors; had we used that original sequence,
04:54
it never would have been able to be booted up.
04:57
Part of the design is designing pieces
05:00
that are 50 letters long
05:02
that have to overlap with all the other 50-letter pieces
05:05
to build smaller subunits
05:08
we have to design so they can go together.
05:10
We design unique elements into this.
05:13
You may have read that we put watermarks in.
05:16
Think of this:
05:18
we have a four-letter genetic code -- A, C, G and T.
05:20
Triplets of those letters
05:23
code for roughly 20 amino acids,
05:26
such that there's a single letter designation
05:28
for each of the amino acids.
05:31
So we can use the genetic code to write out words,
05:33
sentences, thoughts.
05:36
Initially, all we did was autograph it.
05:39
Some people were disappointed there was not poetry.
05:41
We designed these pieces so
05:44
we can just chew back with enzymes;
05:46
there are enzymes that repair them and put them together.
05:50
And we started making pieces,
05:53
starting with pieces that were 5,000 to 7,000 letters,
05:55
put those together to make 24,000-letter pieces,
05:59
then put sets of those going up to 72,000.
06:03
At each stage, we grew up these pieces in abundance
06:07
so we could sequence them
06:09
because we're trying to create a process that's extremely robust
06:11
that you can see in a minute.
06:14
We're trying to get to the point of automation.
06:17
So, this looks like a basketball playoff.
06:20
When we get into these really large pieces
06:22
over 100,000 base pairs,
06:24
they won't any longer grow readily in E. coli --
06:28
it exhausts all the modern tools of molecular biology --
06:30
and so we turned to other mechanisms.
06:34
We knew there's a mechanism called homologous recombination
06:38
that biology uses to repair DNA
06:41
that can put pieces together.
06:44
Here's an example of it:
06:47
there's an organism called
06:48
Deinococcus radiodurans
06:49
that can take three millions rads of radiation.
06:51
You can see in the top panel, its chromosome just gets blown apart.
06:54
Twelve to 24 hours later, it put it
06:58
back together exactly as it was before.
07:01
We have thousands of organisms that can do this.
07:03
These organisms can be totally desiccated;
07:06
they can live in a vacuum.
07:08
I am absolutely certain that life can exist in outer space,
07:11
move around, find a new aqueous environment.
07:14
In fact, NASA has shown a lot of this is out there.
07:17
Here's an actual micrograph of the molecule we built
07:21
using these processes, actually just using yeast mechanisms
07:25
with the right design of the pieces we put them in;
07:29
yeast puts them together automatically.
07:32
This is not an electron micrograph;
07:35
this is just a regular photomicrograph.
07:37
It's such a large molecule
07:39
we can see it with a light microscope.
07:41
These are pictures over about a six-second period.
07:44
So, this is the publication we had just a short while ago.
07:47
This is over 580,000 letters of genetic code;
07:51
it's the largest molecule ever made by humans of a defined structure.
07:54
It's over 300 million molecular weight.
07:59
If we printed it out at a 10 font with no spacing,
08:02
it takes 142 pages
08:05
just to print this genetic code.
08:07
Well, how do we boot up a chromosome? How do we activate this?
08:11
Obviously, with a virus it's pretty simple;
08:14
it's much more complicated dealing with bacteria.
08:17
It's also simpler when you go
08:20
into eukaryotes like ourselves:
08:22
you can just pop out the nucleus
08:24
and pop in another one,
08:26
and that's what you've all heard about with cloning.
08:28
With bacteria and Archaea, the chromosome is integrated into the cell,
08:31
but we recently showed that we can do a complete transplant
08:35
of a chromosome from one cell to another
08:39
and activate it.
08:41
We purified a chromosome from one microbial species --
08:44
roughly, these two are as distant as human and mice --
08:48
we added a few extra genes
08:51
so we could select for this chromosome,
08:53
we digested it with enzymes
08:55
to kill all the proteins,
08:57
and it was pretty stunning when we put this in the cell --
08:59
and you'll appreciate
09:02
our very sophisticated graphics here.
09:04
The new chromosome went into the cell.
09:07
In fact, we thought this might be as far as it went,
09:10
but we tried to design the process a little bit further.
09:12
This is a major mechanism of evolution right here.
09:15
We find all kinds of species
09:18
that have taken up a second chromosome
09:20
or a third one from somewhere,
09:22
adding thousands of new traits
09:24
in a second to that species.
09:26
So, people who think of evolution
09:28
as just one gene changing at a time
09:30
have missed much of biology.
09:32
There are enzymes called restriction enzymes
09:35
that actually digest DNA.
09:37
The chromosome that was in the cell
09:39
doesn't have one;
09:41
the chromosome we put in does.
09:43
It got expressed and it recognized
09:45
the other chromosome as foreign material,
09:47
chewed it up, and so we ended up
09:50
just with a cell with the new chromosome.
09:52
It turned blue because of the genes we put in it.
09:56
And with a very short period of time,
09:59
all the characteristics of one species were lost
10:01
and it converted totally into the new species
10:04
based on the new software that we put in the cell.
10:07
All the proteins changed,
10:10
the membranes changed;
10:12
when we read the genetic code, it's exactly what we had transferred in.
10:14
So, this may sound like genomic alchemy,
10:18
but we can, by moving the software of DNA around,
10:21
change things quite dramatically.
10:25
Now I've argued, this is not genesis;
10:29
this is building on three and a half billion years of evolution.
10:31
And I've argued that we're about to perhaps
10:36
create a new version of the Cambrian explosion,
10:38
where there's massive new speciation
10:41
based on this digital design.
10:45
Why do this?
10:47
I think this is pretty obvious in terms of some of the needs.
10:49
We're about to go from six and a half
10:51
to nine billion people over the next 40 years.
10:53
To put it in context for myself:
10:56
I was born in 1946.
10:58
There are now three people on the planet
11:00
for every one of us that existed in 1946;
11:02
within 40 years, there'll be four.
11:06
We have trouble feeding, providing fresh, clean water,
11:09
medicines, fuel
11:12
for the six and a half billion.
11:14
It's going to be a stretch to do it for nine.
11:17
We use over five billion tons of coal,
11:19
30 billion-plus barrels of oil --
11:22
that's a hundred million barrels a day.
11:25
When we try to think of biological processes
11:29
or any process to replace that,
11:31
it's going to be a huge challenge.
11:34
Then of course, there's all that
11:36
CO2 from this material
11:38
that ends up in the atmosphere.
11:40
We now, from our discovery around the world,
11:43
have a database with about 20 million genes,
11:45
and I like to think of these as the design components of the future.
11:49
The electronics industry only had a dozen or so components,
11:53
and look at the diversity that came out of that.
11:56
We're limited here primarily
12:00
by a biological reality
12:02
and our imagination.
12:04
We now have techniques,
12:07
because of these rapid methods of synthesis,
12:09
to do what we're calling combinatorial genomics.
12:12
We have the ability now to build a large robot
12:16
that can make a million chromosomes a day.
12:19
When you think of processing these 20 million different genes
12:23
or trying to optimize processes
12:26
to produce octane or to produce pharmaceuticals,
12:28
new vaccines,
12:31
we can just with a small team,
12:34
do more molecular biology
12:37
than the last 20 years of all science.
12:39
And it's just standard selection:
12:42
we can select for viability,
12:44
chemical or fuel production,
12:46
vaccine production, etc.
12:48
This is a screen snapshot
12:50
of some true design software
12:53
that we're working on to actually be able to sit down
12:56
and design species in the computer.
12:59
You know, we don't know necessarily what it'll look like:
13:03
we know exactly what their genetic code looks like.
13:06
We're focusing on now fourth-generation fuels.
13:09
You've seen recently, corn to ethanol
13:15
is just a bad experiment.
13:17
We have second- and third-generation fuels
13:19
that will be coming out relatively soon
13:21
that are sugar, to much higher-value fuels
13:24
like octane or different types of butanol.
13:27
But the only way we think that biology
13:30
can have a major impact without
13:33
further increasing the cost of food and limiting its availability
13:36
is if we start with CO2 as its feedstock,
13:39
and so we're working with designing cells to go down this road.
13:42
And we think we'll have the first fourth-generation fuels
13:47
in about 18 months.
13:50
Sunlight and CO2 is one method ...
13:52
(Applause)
13:54
but in our discovery around the world,
13:59
we have all kinds of other methods.
14:01
This is an organism we described in 1996.
14:03
It lives in the deep ocean,
14:07
about a mile and a half deep,
14:09
almost at boiling-water temperatures.
14:11
It takes CO2 to methane
14:13
using molecular hydrogen as its energy source.
14:16
We're looking to see if we can take
14:19
captured CO2,
14:21
which can easily be piped to sites,
14:23
convert that CO2 back into fuel
14:25
to drive this process.
14:28
So, in a short period of time,
14:31
we think that we might be able to increase
14:33
what the basic question is of "What is life?"
14:37
We truly, you know,
14:40
have modest goals
14:42
of replacing the whole petrol-chemical industry --
14:44
(Laughter) (Applause)
14:47
Yeah. If you can't do that at TED, where can you? --
14:50
(Laughter)
14:53
become a major source of energy ...
14:55
But also, we're now working on using these same tools
14:57
to come up with instant sets of vaccines.
15:00
You've seen this year with flu;
15:03
we're always a year behind and a dollar short
15:05
when it comes to the right vaccine.
15:08
I think that can be changed
15:10
by building combinatorial vaccines in advance.
15:12
Here's what the future may begin to look like
15:16
with changing, now, the evolutionary tree,
15:19
speeding up evolution
15:23
with synthetic bacteria, Archaea
15:25
and, eventually, eukaryotes.
15:28
We're a ways away from improving people:
15:32
our goal is just to make sure that we have a chance
15:34
to survive long enough to maybe do that. Thank you very much.
15:37
(Applause)
15:40

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Craig Venter - Biologist, genetics pioneer
In 2001, Craig Venter made headlines for sequencing the human genome. In 2003, he started mapping the ocean's biodiversity. And now he's created the first synthetic lifeforms -- microorganisms that can produce alternative fuels.

Why you should listen

Craig Venter, the man who led the private effort to sequence the human genome, is hard at work now on even more potentially world-changing projects.

First, there's his mission aboard the Sorcerer II, a 92-foot yacht, which, in 2006, finished its voyage around the globe to sample, catalouge and decode the genes of the ocean's unknown microorganisms. Quite a task, when you consider that there are tens of millions of microbes in a single drop of sea water. Then there's the J. Craig Venter Institute, a nonprofit dedicated to researching genomics and exploring its societal implications.

In 2005, Venter founded Synthetic Genomics, a private company with a provocative mission: to engineer new life forms. Its goal is to design, synthesize and assemble synthetic microorganisms that will produce alternative fuels, such as ethanol or hydrogen. He was on Time magzine's 2007 list of the 100 Most Influential People in the World.

In early 2008, scientists at the J. Craig Venter Institute announced that they had manufactured the entire genome of a bacterium by painstakingly stitching together its chemical components. By sequencing a genome, scientists can begin to custom-design bootable organisms, creating biological robots that can produce from scratch chemicals humans can use, such as biofuel. And in 2010, they announced, they had created "synthetic life" -- DNA created digitally, inserted into a living bacterium, and remaining alive.

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