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]