TED in the Field

Craig Venter: Watch me unveil "synthetic life"

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Craig Venter and team make a historic announcement: they've created the first fully functioning, reproducing cell controlled by synthetic DNA. He explains how they did it and why the achievement marks the beginning of a new era for science.

- 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

We're here today to announce
00:16
the first synthetic cell,
00:18
a cell made by
00:21
starting with the digital code in the computer,
00:23
building the chromosome
00:26
from four bottles of chemicals,
00:29
assembling that chromosome in yeast,
00:32
transplanting it into
00:34
a recipient bacterial cell
00:37
and transforming that cell
00:39
into a new bacterial species.
00:41
So this is the first self-replicating species
00:44
that we've had on the planet
00:47
whose parent is a computer.
00:49
It also is the first species
00:52
to have its own website
00:54
encoded in its genetic code.
00:56
But we'll talk more about
00:59
the watermarks in a minute.
01:01
This is a project that had its inception
01:04
15 years ago
01:06
when our team then --
01:08
we called the institute TIGR --
01:10
was involved in sequencing
01:12
the first two genomes in history.
01:14
We did Haemophilus influenzae
01:16
and then the smallest genome of a self-replicating organism,
01:18
that of Mycoplasma genitalium.
01:21
And as soon as
01:24
we had these two sequences
01:26
we thought, if this is supposed to be the smallest genome
01:28
of a self-replicating species,
01:31
could there be even a smaller genome?
01:33
Could we understand the basis of cellular life
01:35
at the genetic level?
01:38
It's been a 15-year quest
01:40
just to get to the starting point now
01:42
to be able to answer those questions,
01:44
because it's very difficult to eliminate
01:47
multiple genes from a cell.
01:49
You can only do them one at a time.
01:51
We decided early on
01:54
that we had to take a synthetic route,
01:56
even though nobody had been there before,
01:58
to see if we could synthesize
02:00
a bacterial chromosome
02:02
so we could actually vary the gene content
02:04
to understand the essential genes for life.
02:06
That started our 15-year quest
02:09
to get here.
02:12
But before we did the first experiments,
02:14
we actually asked
02:16
Art Caplan's team at the University of Pennsylvania
02:19
to undertake a review
02:22
of what the risks, the challenges,
02:24
the ethics around creating new
02:27
species in the laboratory were
02:29
because it hadn't been done before.
02:31
They spent about two years
02:33
reviewing that independently
02:35
and published their results in Science in 1999.
02:37
Ham and I took two years off
02:40
as a side project to sequence the human genome,
02:42
but as soon as that was done
02:44
we got back to the task at hand.
02:46
In 2002, we started
02:50
a new institute,
02:52
the Institute for Biological Energy Alternatives,
02:54
where we set out two goals:
02:57
One, to understand
02:59
the impact of our technology on the environment,
03:01
and how to understand the environment better,
03:04
and two, to start down this process
03:06
of making synthetic life
03:08
to understand basic life.
03:11
In 2003,
03:14
we published our first success.
03:16
So Ham Smith and Clyde Hutchison
03:18
developed some new methods
03:20
for making error-free DNA
03:22
at a small level.
03:25
Our first task was
03:27
a 5,000-letter code bacteriophage,
03:29
a virus that attacks only E. coli.
03:32
So that was
03:36
the phage phi X 174,
03:38
which was chosen for historical reasons.
03:40
It was the first DNA phage,
03:42
DNA virus, DNA genome
03:45
that was actually sequenced.
03:48
So once we realized
03:50
that we could make 5,000-base pair
03:53
viral-sized pieces,
03:55
we thought, we at least have the means
03:57
then to try and make serially lots of these pieces
03:59
to be able to eventually assemble them together
04:02
to make this mega base chromosome.
04:05
So, substantially larger than
04:09
we even thought we would go initially.
04:11
There were several steps to this. There were two sides:
04:15
We had to solve the chemistry
04:18
for making large DNA molecules,
04:20
and we had to solve the biological side
04:22
of how, if we had this new chemical entity,
04:24
how would we boot it up, activate it
04:27
in a recipient cell.
04:30
We had two teams working in parallel:
04:33
one team on the chemistry,
04:35
and the other on trying to
04:37
be able to transplant
04:40
entire chromosomes
04:42
to get new cells.
04:44
When we started this out, we thought the synthesis would be the biggest problem,
04:47
which is why we chose the smallest genome.
04:50
And some of you have noticed that we switched from the smallest genome
04:53
to a much larger one.
04:56
And we can walk through the reasons for that,
04:58
but basically the small cell
05:00
took on the order of
05:03
one to two months to get results from,
05:05
whereas the larger, faster-growing cell
05:08
takes only two days.
05:10
So there's only so many cycles we could go through
05:12
in a year at six weeks per cycle.
05:15
And you should know that basically
05:18
99, probably 99 percent plus
05:20
of our experiments failed.
05:23
So this was a debugging,
05:25
problem-solving scenario from the beginning
05:27
because there was no recipe
05:30
of how to get there.
05:32
So, one of the most important publications we had
05:34
was in 2007.
05:37
Carole Lartigue led the effort
05:39
to actually transplant a bacterial chromosome
05:42
from one bacteria to another.
05:45
I think philosophically, that was one of the most important papers
05:47
that we've ever done
05:50
because it showed how dynamic life was.
05:52
And we knew, once that worked,
05:55
that we actually had a chance
05:57
if we could make the synthetic chromosomes
05:59
to do the same with those.
06:01
We didn't know that it was going to take us
06:04
several years more to get there.
06:06
In 2008,
06:08
we reported the complete synthesis
06:10
of the Mycoplasma genitalium genome,
06:12
a little over 500,000 letters of genetic code,
06:15
but we have not yet succeeded in booting up that chromosome.
06:19
We think in part, because of its slow growth
06:22
and, in part,
06:26
cells have all kinds of unique defense mechanisms
06:28
to keep these events from happening.
06:31
It turned out the cell that we were trying to transplant into
06:33
had a nuclease, an enzyme that chews up DNA on its surface,
06:36
and was happy to eat
06:39
the synthetic DNA that we gave it
06:41
and never got transplantations.
06:43
But at the time, that was the largest
06:46
molecule of a defined structure
06:48
that had been made.
06:50
And so both sides were progressing,
06:52
but part of the synthesis
06:54
had to be accomplished or was able to be accomplished
06:56
using yeast, putting the fragments in yeast
06:59
and yeast would assemble these for us.
07:02
It's an amazing step forward,
07:04
but we had a problem because now we had
07:07
the bacterial chromosomes growing in yeast.
07:09
So in addition to doing the transplant,
07:12
we had to find out how to get a bacterial chromosome
07:15
out of the eukaryotic yeast
07:17
into a form where we could transplant it
07:19
into a recipient cell.
07:21
So our team developed new techniques
07:25
for actually growing, cloning
07:28
entire bacterial chromosomes in yeast.
07:30
So we took the same mycoides genome
07:32
that Carole had initially transplanted,
07:35
and we grew that in yeast
07:37
as an artificial chromosome.
07:39
And we thought this would be a great test bed
07:42
for learning how to get chromosomes out of yeast
07:44
and transplant them.
07:46
When we did these experiments, though,
07:48
we could get the chromosome out of yeast
07:50
but it wouldn't transplant and boot up a cell.
07:52
That little issue took the team two years to solve.
07:56
It turns out, the DNA in the bacterial cell
07:59
was actually methylated,
08:02
and the methylation protects it from the restriction enzyme,
08:04
from digesting the DNA.
08:08
So what we found is if we took the chromosome
08:11
out of yeast and methylated it,
08:13
we could then transplant it.
08:15
Further advances came
08:17
when the team removed the restriction enzyme genes
08:19
from the recipient capricolum cell.
08:22
And once we had done that, now we can take
08:25
naked DNA out of yeast and transplant it.
08:27
So last fall
08:30
when we published the results of that work in Science,
08:32
we all became overconfident
08:35
and were sure we were only
08:37
a few weeks away
08:39
from being able to now boot up
08:41
a chromosome out of yeast.
08:43
Because of the problems with
08:46
Mycoplasma genitalium and its slow growth
08:48
about a year and a half ago,
08:51
we decided to synthesize
08:54
the much larger chromosome, the mycoides chromosome,
08:57
knowing that we had the biology worked out on that
09:00
for transplantation.
09:03
And Dan led the team for the synthesis
09:05
of this over one-million-base pair chromosome.
09:07
But it turned out it wasn't going to be as simple in the end,
09:12
and it set us back three months
09:15
because we had one error
09:17
out of over a million base pairs in that sequence.
09:19
So the team developed new debugging software,
09:22
where we could test each synthetic fragment
09:25
to see if it would grow in a background
09:28
of wild type DNA.
09:30
And we found that 10 out of the 11
09:33
100,000-base pair pieces we synthesized
09:36
were completely accurate
09:39
and compatible with
09:41
a life-forming sequence.
09:43
We narrowed it down to one fragment;
09:47
we sequenced it
09:49
and found just one base pair had been deleted
09:51
in an essential gene.
09:53
So accuracy is essential.
09:55
There's parts of the genome
09:58
where it cannot tolerate even a single error,
10:00
and then there's parts of the genome
10:03
where we can put in large blocks of DNA,
10:05
as we did with the watermarks,
10:07
and it can tolerate all kinds of errors.
10:09
So it took about three months to find that error
10:12
and repair it.
10:15
And then early one morning, at 6 a.m.
10:17
we got a text from Dan
10:20
saying that, now, the first blue colonies existed.
10:23
So, it's been a long route to get here:
10:26
15 years from the beginning.
10:29
We felt
10:32
one of the tenets of this field
10:34
was to make absolutely certain
10:36
we could distinguish synthetic DNA
10:39
from natural DNA.
10:42
Early on, when you're working in a new area of science,
10:44
you have to think about all the pitfalls
10:47
and things that could lead you
10:50
to believe that you had done something when you hadn't,
10:52
and, even worse, leading others to believe it.
10:55
So, we thought the worst problem would be
10:58
a single molecule contamination
11:00
of the native chromosome,
11:03
leading us to believe that we actually had
11:05
created a synthetic cell,
11:08
when it would have been just a contaminant.
11:10
So early on, we developed the notion
11:12
of putting in watermarks in the DNA
11:14
to absolutely make clear
11:16
that the DNA was synthetic.
11:18
And the first chromosome we built
11:21
in 2008 --
11:24
the 500,000-base pair one --
11:26
we simply assigned
11:28
the names of the authors of the chromosome
11:31
into the genetic code,
11:34
but it was using just amino acid
11:37
single letter translations,
11:39
which leaves out certain letters of the alphabet.
11:41
So the team actually developed a new code
11:45
within the code within the code.
11:48
So it's a new code
11:51
for interpreting and writing messages in DNA.
11:53
Now, mathematicians have been hiding and writing
11:56
messages in the genetic code for a long time,
11:59
but it's clear they were mathematicians and not biologists
12:02
because, if you write long messages
12:05
with the code that the mathematicians developed,
12:08
it would more than likely lead to
12:11
new proteins being synthesized
12:13
with unknown functions.
12:16
So the code that Mike Montague and the team developed
12:19
actually puts frequent stop codons,
12:22
so it's a different alphabet
12:24
but allows us to use
12:27
the entire English alphabet
12:29
with punctuation and numbers.
12:32
So, there are four major watermarks
12:34
all over 1,000 base pairs of genetic code.
12:36
The first one actually contains within it
12:39
this code for interpreting
12:42
the rest of the genetic code.
12:45
So in the remaining information,
12:49
in the watermarks,
12:51
contain the names of, I think it's
12:53
46 different authors
12:56
and key contributors
12:58
to getting the project to this stage.
13:00
And we also built in
13:04
a website address
13:06
so that if somebody decodes the code
13:09
within the code within the code,
13:11
they can send an email to that address.
13:13
So it's clearly distinguishable
13:15
from any other species,
13:18
having 46 names in it,
13:20
its own web address.
13:23
And we added three quotations,
13:27
because with the first genome
13:30
we were criticized for not trying to say something more profound
13:32
than just signing the work.
13:35
So we won't give the rest of the code,
13:37
but we will give the three quotations.
13:39
The first is,
13:41
"To live, to err,
13:43
to fall, to triumph
13:45
and to recreate life out of life."
13:47
It's a James Joyce quote.
13:49
The second quotation is, "See things not as they are,
13:53
but as they might be."
13:56
It's a quote from the "American Prometheus"
13:58
book on Robert Oppenheimer.
14:01
And the last one is a Richard Feynman quote:
14:03
"What I cannot build,
14:06
I cannot understand."
14:08
So, because this is as much a philosophical advance
14:13
as a technical advance in science,
14:16
we tried to deal with both the philosophical
14:19
and the technical side.
14:22
The last thing I want to say before turning it over to questions
14:24
is that the extensive work
14:26
that we've done --
14:29
asking for ethical review,
14:31
pushing the envelope
14:33
on that side as well as the technical side --
14:35
this has been broadly discussed in the scientific community,
14:38
in the policy community
14:41
and at the highest levels of the federal government.
14:43
Even with this announcement,
14:46
as we did in 2003 --
14:49
that work was funded by the Department of Energy,
14:51
so the work was reviewed
14:54
at the level of the White House,
14:56
trying to decide whether to classify the work or publish it.
14:58
And they came down on the side of open publication,
15:01
which is the right approach --
15:04
we've briefed the White House,
15:07
we've briefed members of Congress,
15:09
we've tried to take and push
15:12
the policy issues
15:14
in parallel with the scientific advances.
15:16
So with that, I would like
15:20
to open it first to the floor for questions.
15:22
Yes, in the back.
15:25
Reporter: Could you explain, in layman's terms,
15:27
how significant a breakthrough this is please?
15:29
Craig Venter: Can we explain how significant this is?
15:33
I'm not sure we're the ones that should be explaining how significant it is.
15:35
It's significant to us.
15:38
Perhaps it's a giant philosophical change
15:41
in how we view life.
15:44
We actually view it as a baby step in terms of,
15:46
it's taken us 15 years to be able
15:49
to do the experiment
15:51
we wanted to do 15 years ago
15:53
on understanding life at its basic level.
15:55
But we actually believe
15:58
this is going to be a very powerful set of tools
16:00
and we're already starting
16:04
in numerous avenues
16:06
to use this tool.
16:08
We have, at the Institute,
16:10
ongoing funding now from NIH
16:12
in a program with Novartis
16:15
to try and use these new
16:17
synthetic DNA tools
16:19
to perhaps make the flu vaccine
16:21
that you might get next year.
16:24
Because instead of taking weeks to months to make these,
16:27
Dan's team can now make these
16:30
in less than 24 hours.
16:33
So when you see how long it took to get an H1N1 vaccine out,
16:36
we think we can shorten that process
16:39
quite substantially.
16:41
In the vaccine area,
16:43
Synthetic Genomics and the Institute
16:45
are forming a new vaccine company
16:47
because we think these tools can affect vaccines
16:49
to diseases that haven't been possible to date,
16:52
things where the viruses rapidly evolve,
16:55
such with rhinovirus.
16:58
Wouldn't it be nice to have something that actually blocked common colds?
17:00
Or, more importantly, HIV,
17:03
where the virus evolves so quickly
17:06
the vaccines that are made today
17:08
can't keep up
17:10
with those evolutionary changes.
17:12
Also, at Synthetic Genomics,
17:15
we've been working
17:17
on major environmental issues.
17:19
I think this latest oil spill in the Gulf
17:21
is a reminder.
17:23
We can't see CO2 --
17:25
we depend on scientific measurements for it
17:27
and we see the beginning results
17:29
of having too much of it --
17:31
but we can see pre-CO2 now
17:33
floating on the waters
17:35
and contaminating the beaches in the Gulf.
17:37
We need some alternatives
17:40
for oil.
17:43
We have a program with Exxon Mobile
17:45
to try and develop new strains of algae
17:47
that can efficiently capture carbon dioxide
17:50
from the atmosphere or from concentrated sources,
17:53
make new hydrocarbons that can go into their refineries
17:56
to make normal gasoline
17:59
and diesel fuel out of CO2.
18:01
Those are just a couple of the approaches
18:03
and directions that we're taking.
18:05
(Applause)
18:08

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About the Speaker:

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.