The radical possibilities of man-made DNA

Every cell that has ever lived has been the result of the four-letter genetic alphabet: A, T, C and G -- the basic units of DNA. But now that has changed. In a visionary talk, synthetic biologist Floyd E. Romesberg introduces us to the first living organisms created with six-letter DNA -- the four natural letters plus two new man-made ones, X and Y -- and explores how this breakthrough could challenge our basic understanding of nature's design.

All life,

every living thing ever,

has been built according
to the information in DNA.

What does that mean?

Well, it means that just
as the English language

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

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

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

allow cells to produce proteins,

strings of amino acids
that fold up into complex structures

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

to tell its stories.

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

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

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

But it's remarkable
that all the diversity of life

is the result of four genetic letters.

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

What sort of stories
would you be able to tell?

What if the genetic alphabet
had more letters?

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

maybe even more interesting ones?

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

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

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

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

Such an organism would be

the first radically altered
form of life ever created.

It would be a semisynthetic form of life

that stores more information
than life ever has before.

It would be able to make new proteins,

proteins built from more
than the 20 normal amino acids

that are usually used to build proteins.

What sort of stories could that life tell?

With the power of synthetic chemistry
and molecular biology

and just under 20 years of work,

we created bacteria with six-letter DNA.

Let me tell you how we did it.

All you have to remember
from your high school biology

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

G pairs with C and A pairs with T,

so to create our new letters,

we synthesized hundreds of new candidates,
new candidate letters,

and examined their abilities
to selectively pair with each other.

And after about 15 years of work,

we found two that paired
together really well,

at least in a test tube.

They have complicated names,

but let's just call them X and Y.

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

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

worked in our bacteria.

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

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

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

I am actually a really impatient person --

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

basically immediately.

On a weekend in 2014,

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

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

This is an actual picture of them.

These are the first
semisynthetic organisms.

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

Well, maybe some of you
are still wondering why.

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

both conceptual and practical.

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

what makes it different
from things that are not alive,

since people have had thoughts.

Many have interpreted
life as being perfect,

and this was taken
as evidence of a creator.

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

Others have sought
a more scientific explanation,

but I think it's fair to say

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

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

Whatever perspective you take,
it would seem pretty impossible

for chemists to come in
and build new parts

that function within and alongside
the natural molecules of life

without somehow
really screwing everything up.

But just how perfectly
created or evolved are we?

Just how special
are the molecules of life?

These questions have been
impossible to even ask,

because we've had nothing
to compare life to.

Now for the first time, our work suggests

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

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

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

just a solution.

These questions address
fundamental issues about life,

but maybe they seem a little esoteric.

So what about practical motivations?

Well, we want to explore
what sort of new stories

life with an expanded
vocabulary could tell,

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

and the functions they have.

So what sort of new proteins
with new types of functions

could our semisynthetic organisms
make and maybe even use?

Well, we have a couple of things in mind.

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

Proteins are being used today

for an increasingly broad
range of different applications,

from materials that protect
soldiers from injury

to devices that detect
dangerous compounds,

but at least to me,

the most exciting application
is protein drugs.

Despite being relatively new,

protein drugs have already
revolutionized medicine,

and, for example, insulin is a protein.

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

that has completely changed
how we treat diabetes.

But the problem is that proteins
are really hard to make

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

So of course, with natural cells,

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

and so the properties
those proteins can have,

the applications
they could be developed for,

must be limited by the nature
of those amino acids

that the protein's built from.

So here they are,

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

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

They don't bring
that many different functions.

They don't make that many
different functions available.

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

Now, they're much simpler than proteins,

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

Don't worry about the molecular details,

but I think you can see
how different they are.

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

to treat different diseases.

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

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

So can we get our semisynthetic organism

to make proteins that include
new and different amino acids,

maybe amino acids
selected to confer the protein

with some desired property or function?

For example,

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

They are rapidly degraded or eliminated,

and this stops them from being drugs.

What if we could make proteins
with new amino acids

with things attached to them

that protect them from their environment,

that protect them
from being degraded or eliminated,

so that they could be better drugs?

Could we make proteins
with little fingers attached

that specifically
grab on to other molecules?

Many small molecules
failed during development as drugs

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

in the complex environment
of the human body.

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

that, when incorporated into a protein,

are guided by that protein
to their target?

I started a biotech company
called Synthorx.

Synthorx stands for synthetic organism

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

(Laughter)

Synthorx is working closely with my lab,

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

on the surface of human cells.

But the problem is that it also recognizes

another receptor on the surface
of those same cells,

and that makes it toxic.

So could we produce
a variant of that protein

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

blocked by something like a big umbrella

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

Doing that would be really difficult

or impossible to do
with the normal amino acids,

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

So getting our semisynthetic cells
to act as little factories

to produce better protein drugs

isn't the only potentially
really interesting application,

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

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

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

For example, could we develop
semisynthetic organisms

that when injected into a person,
seek out cancer cells

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

Could we create bacteria
that eat different kinds of oil,

maybe to clean up an oil spill?

These are just a couple
of the types of stories

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

So, sounds great, right?

Injecting semisynthetic
organisms into people,

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

or out on your favorite beach?

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

This dinosaur is really scary.

But here's the catch:

our semisynthetic organisms
in order to survive,

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

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

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

So when we prepare them,

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

we can feed them
lots of the unnatural food.

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

where they no longer
have access that special food,

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

maybe just long enough
to perform some intended function,

but then they start
to run out of the food.

They start to starve.

They starve to death
and they just disappear.

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

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

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

the creation of semisynthetic organisms
that store more information,

X and Y, in their DNA.

But all the motivations
that we just talked about

require cells to use X and Y
to make proteins,

so we started working on that.

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

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

And late last year,

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

Here they are, the stars of the show,

the first fully-functional
semisynthetic organisms.

(Applause)

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

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

that a lot of people use
in its natural form

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

But within every one of these proteins,

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

Every living cell, every living cell ever,

has made every one of its proteins

using a four-letter genetic alphabet.

These cells are living and growing
and making protein

with a six-letter alphabet.

These are a new form of life.

This is a semisynthetic form of life.

So what about the future?

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

including human cells,

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

Think semisynthetic worms.

The last thing I want to say to you,

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

is that the time
of semisynthetic life is here.

Thank you.

(Applause)

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

I just wanted to ask you,

what are the implications of your work

for how we should think
about the possibilities for life,

like, in the universe, elsewhere?

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

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

but is the possibility space
of self-replicating molecules

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

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

and I think what our work has shown,

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

that sort of we're perfect,

we're optimal, God created us this way,

evolution perfected us this way.

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

and I think that suggests
that any molecules

that obey the fundamental laws
of chemistry and physics

and you can optimize them

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

There's nothing magic there.

And I think that it suggests

that life could evolve
many different ways,

maybe similar to us
with other types of DNA,

maybe things without DNA at all.

CA: I mean, in your mind,

how big might that possibility space be?

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

or something radically different
that can still self-reproduce

and potentially create living organisms?

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

we might not even recognize it.

CA: So this obsession
with the search for Goldilocks planets

in exactly the right place
with water and whatever,

that's a very parochial
assumption, perhaps.

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

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

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

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

(Applause)