The radical possibilities of manmade DNA Floyd E. Romesberg

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’re often just

referred to as GC a and T but it’s

remarkable that all the diversity of

life is the result of for 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 semi synthetic 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 lifestyle 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

eight pairs with T so to create our new

letters we synthesized hundreds of new

candidates new candidate letters in exam

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 on 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 in the 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 that

we’ve done up to then took longer than I

had hoped I’m 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 blew

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 semi synthetic

organisms so bacteria was 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 is 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 evolutions

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 so

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 semi synthetic 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 the 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’s completely

changed how we treat diabetes but the

problem is 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 proteins built from

so here they are the twenty 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

semi synthetic 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

when you inject them into people they’re

rapidly degraded or eliminated and to

stop 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 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 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 synth

racks synth X stands for synthetic

organism with an X added at the end

because that’s what you do with biotech

companies synth Rex is working closely

with my lab and they’re interested at a

you know in a protein that recognizes a

certain receptor on the surface of human

cells but the problem is 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

semi-synthetic 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’re making 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 semi synthetic

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 create

pect area 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 gonna see if life

with an expanded vocabulary can tell so

sounds great right injecting

semi-synthetic organisms and the people

dumping millions and millions of gallons

of our bacteria into the ocean or out on

your favorite beach oh wait a minute

actually sounds really scary this this

dinosaur is really scary but here’s the

catch

our semi-synthetic 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 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 to that special food they can

grow for a little 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 news 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 semi synthetic 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 semi synthetic

organisms

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 semi

synthetic form of life so what about the

future my labs 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 semi-synthetic

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 semi

synthetic life is here thank you

I mean this Freud this is so remarkable

I 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 just

it just seems like so much of life is

based or so much of our assumptions are

based on the fact that it’s 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 they absolutely I

think that’s right and I think what were

what our work has shown as I mentioned I

think 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 any molecules that

obey the fundamental laws of chemistry

and physics then 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 may be similar to us with other

types of DNA may be things without DNA

at all I mean in your mind how like how

big might that possibility space be do

we even know of most things gonna look

something like a DNA more I color them

I’m saying really radically different

that can still sell for produce and

potentially create living organisms my

personal opinion is that if we found new

life we might not even recognize it

so this obsession with the search for

Goldilocks planets and in exactly the

right place with water and whatever that

that’s a very parochial assumption

perhaps well if you want to find someone

you can talk to then maybe not but you

know I think that that if you’re just

looking for any form of life I think I

think that’s right I think that you’re

looking for life under the light post

thank you for boggling all our minds

thank you so much

[Applause]