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All life,

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every living thing ever,

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has been built according
to the information in DNA.

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What does that mean?

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Well, it means that just
as the English language

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is made up of alphabetic letters
that, when combined into words,

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allow me to tell you the story
I'm going to tell you today,

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DNA is made up of genetic letters
that, when combined into genes,

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allow cells to produce proteins,

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strings of amino acids
that fold up into complex structures

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that perform the functions
that allow a cell to do what it does,

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to tell its stories.

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The English alphabet has 26 letters,
and the genetic alphabet has four.

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They're pretty famous.
Maybe you've heard of them.

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They are often just
referred to as G, C, A and T.

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But it's remarkable
that all the diversity of life

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is the result of four genetic letters.

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Imagine what it would be like
if the English alphabet had four letters.

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What sort of stories
would you be able to tell?

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What if the genetic alphabet
had more letters?

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Would life with more letters
be able to tell different stories,

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maybe even more interesting ones?

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In 1999, my lab at the Scripps
Research Institute in La Jolla, California

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started working on this question
with the goal of creating living organisms

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with DNA made up
of a six-letter genetic alphabet,

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the four natural letters
plus two additional new man-made letters.

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Such an organism would be

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the first radically altered
form of life ever created.

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It would be a semisynthetic form of life

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that stores more information
than life ever has before.

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It would be able to make new proteins,

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proteins built from more
than the 20 normal amino acids

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that are usually used to build proteins.

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What sort of stories could that life tell?

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With the power of synthetic chemistry
and molecular biology

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and just under 20 years of work,

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we created bacteria with six-letter DNA.

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Let me tell you how we did it.

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All you have to remember
from your high school biology

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is that the four natural letters
pair together to form two base pairs.

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G pairs with C and A pairs with T,

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so to create our new letters,

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we synthesized hundreds of new candidates,
new candidate letters,

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and examined their abilities
to selectively pair with each other.

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And after about 15 years of work,

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we found two that paired
together really well,

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at least in a test tube.

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They have complicated names,

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but let's just call them X and Y.

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The next thing we needed to do
was find a way to get X and Y into cells,

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and eventually we found that a protein
that does something similar in algae

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worked in our bacteria.

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So the final thing that we needed to do
was to show that with X and Y provided,

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cells could grow and divide
and hold on to X and Y in their DNA.

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Everything we had done up to then
took longer than I had hoped --

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I am actually a really impatient person --

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but this, the most important step,
worked faster than I dreamed,

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basically immediately.

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On a weekend in 2014,

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a graduate student in my lab
grew bacteria with six-letter DNA.

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Let me take the opportunity
to introduce you to them right now.

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This is an actual picture of them.

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These are the first
semisynthetic organisms.

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So bacteria with six-letter DNA,
that's really cool, right?

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Well, maybe some of you
are still wondering why.

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So let me tell you a little bit more
about some of our motivations,

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both conceptual and practical.

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Conceptually, people have
thought about life, what it is,

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what makes it different
from things that are not alive,

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since people have had thoughts.

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Many have interpreted
life as being perfect,

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and this was taken
as evidence of a creator.

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Living things are different
because a god breathed life into them.

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Others have sought
a more scientific explanation,

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but I think it's fair to say

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that they still consider
the molecules of life to be special.

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I mean, evolution has been optimizing them
for billions of years, right?

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Whatever perspective you take,
it would seem pretty impossible

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for chemists to come in
and build new parts

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that function within and alongside
the natural molecules of life

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without somehow
really screwing everything up.

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But just how perfectly
created or evolved are we?

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Just how special
are the molecules of life?

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These questions have been
impossible to even ask,

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because we've had nothing
to compare life to.

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Now for the first time, our work suggests

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that maybe the molecules of life
aren't that special.

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Maybe life as we know it
isn't the only way it could be.

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Maybe we're not the only solution,
maybe not even the best solution,

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just a solution.

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These questions address
fundamental issues about life,

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but maybe they seem a little esoteric.

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So what about practical motivations?

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Well, we want to explore
what sort of new stories

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life with an expanded
vocabulary could tell,

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and remember, stories here
are the proteins that a cell produces

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and the functions they have.

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So what sort of new proteins
with new types of functions

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could our semisynthetic organisms
make and maybe even use?

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Well, we have a couple of things in mind.

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The first is to get the cells
to make proteins for us, for our use.

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Proteins are being used today

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for an increasingly broad
range of different applications,

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from materials that protect
soldiers from injury

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to devices that detect
dangerous compounds,

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but at least to me,

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the most exciting application
is protein drugs.

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Despite being relatively new,

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protein drugs have already
revolutionized medicine,

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and, for example, insulin is a protein.

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You've probably heard of it,
and it's manufactured as a drug

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that has completely changed
how we treat diabetes.

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But the problem is that proteins
are really hard to make

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and the only practical way to get them
is to get cells to make them for you.

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So of course, with natural cells,

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you can only get them to make
proteins with the natural amino acids,

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and so the properties
those proteins can have,

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the applications
they could be developed for,

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must be limited by the nature
of those amino acids

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that the protein's built from.

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So here they are,

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the 20 normal amino acids that are
strung together to make a protein,

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and I think you can see,
they're not that different-looking.

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They don't bring
that many different functions.

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They don't make that many
different functions available.

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Compare that with the small molecules
that synthetic chemists make as drugs.

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Now, they're much simpler than proteins,

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but they're routinely built from
a much broader range of diverse things.

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Don't worry about the molecular details,

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but I think you can see
how different they are.

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And in fact, it's their differences
that make them great drugs

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to treat different diseases.

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So it's really provocative to wonder
what sort of new protein drugs

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you could develop if you could build
proteins from more diverse things.

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So can we get our semisynthetic organism

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to make proteins that include
new and different amino acids,

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maybe amino acids
selected to confer the protein

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with some desired property or function?

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For example,

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many proteins just aren't stable
when you inject them into people.

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They are rapidly degraded or eliminated,

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and this stops them from being drugs.

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What if we could make proteins
with new amino acids

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with things attached to them

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that protect them from their environment,

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that protect them
from being degraded or eliminated,

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so that they could be better drugs?

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Could we make proteins
with little fingers attached

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that specifically
grab on to other molecules?

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Many small molecules
failed during development as drugs

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because they just weren't
specific enough to find their target

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in the complex environment
of the human body.

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So could we take those molecules
and make them parts of new amino acids

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that, when incorporated into a protein,

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are guided by that protein
to their target?

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I started a biotech company
called Synthorx.

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Synthorx stands for synthetic organism

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with an X added at the end because
that's what you do with biotech companies.

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(Laughter)

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Synthorx is working closely with my lab,

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and they're interested in a protein
that recognizes a certain receptor

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on the surface of human cells.

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But the problem is that it also recognizes

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another receptor on the surface
of those same cells,

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and that makes it toxic.

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So could we produce
a variant of that protein

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where the part that interacts
with that second bad receptor is shielded,

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blocked by something like a big umbrella

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so that the protein only interacts
with that first good receptor?

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Doing that would be really difficult

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or impossible to do
with the normal amino acids,

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but not with amino acids that are
specifically designed for that purpose.

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So getting our semisynthetic cells
to act as little factories

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to produce better protein drugs

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isn't the only potentially
really interesting application,

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because remember, it's the proteins
that allow cells to do what they do.

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So if we have cells that make
new proteins with new functions,

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could we get them to do things
that natural cells can't do?

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For example, could we develop
semisynthetic organisms

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that when injected into a person,
seek out cancer cells

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and only when they find them,
secrete a toxic protein that kills them?

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Could we create bacteria
that eat different kinds of oil,

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maybe to clean up an oil spill?

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These are just a couple
of the types of stories

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that we're going to see if life
with an expanded vocabulary can tell.

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So, sounds great, right?

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Injecting semisynthetic
organisms into people,

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dumping millions and millions of gallons
of our bacteria into the ocean

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or out on your favorite beach?

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Oh, wait a minute,
actually it sounds really scary.

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This dinosaur is really scary.

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But here's the catch:

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our semisynthetic organisms
in order to survive,

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need to be fed the chemical
precursors of X and Y.

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X and Y are completely different
than anything that exists in nature.

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Cells just don't have them
or the ability to make them.

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So when we prepare them,

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when we grow them up
in the controlled environment of the lab,

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we can feed them
lots of the unnatural food.

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Then, when we deploy them
in a person or out on a beach

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where they no longer
have access that special food,

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they can grow for a little bit,
they can survive for a little,

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maybe just long enough
to perform some intended function,

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but then they start
to run out of the food.

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They start to starve.

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They starve to death
and they just disappear.

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So not only could we get life
to tell new stories,

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we get to tell life when and where
to tell those stories.

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At the beginning of this talk
I told you that we reported in 2014

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the creation of semisynthetic organisms
that store more information,

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X and Y, in their DNA.

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But all the motivations
that we just talked about

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require cells to use X and Y
to make proteins,

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so we started working on that.

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Within a couple years, we showed
that the cells could take DNA with X and Y

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and copy it into RNA,
the working copy of DNA.

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And late last year,

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we showed that they could then
use X and Y to make proteins.

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Here they are, the stars of the show,

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the first fully-functional
semisynthetic organisms.

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(Applause)

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These cells are green because
they're making a protein that glows green.

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It's a pretty famous protein,
actually, from jellyfish

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that a lot of people use
in its natural form

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because it's easy to see that you made it.

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But within every one of these proteins,

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there's a new amino acid that
natural life can't build proteins with.

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Every living cell, every living cell ever,

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has made every one of its proteins

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using a four-letter genetic alphabet.

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These cells are living and growing
and making protein

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with a six-letter alphabet.

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These are a new form of life.

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This is a semisynthetic form of life.

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So what about the future?

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My lab is already working on expanding
the genetic alphabet of other cells,

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including human cells,

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and we're getting ready to start working
on more complex organisms.

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Think semisynthetic worms.

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The last thing I want to say to you,

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the most important thing
that I want to say to you,

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is that the time
of semisynthetic life is here.

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Thank you.

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(Applause)

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Chris Anderson: I mean,
Floyd, this is so remarkable.

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I just wanted to ask you,

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what are the implications of your work

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for how we should think
about the possibilities for life,

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like, in the universe, elsewhere?

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It just seems like so much of life,
or so much of our assumptions are based

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on the fact that of course,
it's got to be DNA,

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but is the possibility space
of self-replicating molecules

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much bigger than DNA,
even just DNA with six letters?

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Floyd Romesberg:
Absolutely, I think that's right,

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and I think what our work has shown,

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as I mentioned, is that
there's been always this prejudice

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that sort of we're perfect,

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we're optimal, God created us this way,

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evolution perfected us this way.

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We've made molecules that work
right alongside the natural ones,

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and I think that suggests
that any molecules

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that obey the fundamental laws
of chemistry and physics

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and you can optimize them

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could do the things that
the natural molecules of life do.

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There's nothing magic there.

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And I think that it suggests

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that life could evolve
many different ways,

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maybe similar to us
with other types of DNA,

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maybe things without DNA at all.

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CA: I mean, in your mind,

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how big might that possibility space be?

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Do we even know? Are most things going
to look something like a DNA molecule,

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or something radically different
that can still self-reproduce

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and potentially create living organisms?

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FR: My personal opinion
is that if we found new life,

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we might not even recognize it.

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CA: So this obsession
with the search for Goldilocks planets

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in exactly the right place
with water and whatever,

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that's a very parochial
assumption, perhaps.

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FR: Well, if you want to find someone
you can talk to, then maybe not,

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but I think that if you're just
looking for any form of life,

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I think that's right, I think that you're
looking for life under the light post.

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CA: Thank you for boggling all our minds.
Thank so much, Floyd.

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(Applause)