TED2008
Paul Rothemund: DNA folding, in detail
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In 2007, Paul Rothemund gave TED a short summary of his specialty, DNA folding. Now he lays out in clear, abundant detail the immense promise of this field -- to create tiny machines that assemble themselves.
Paul Rothemund - DNA origamist
Paul Rothemund folds DNA into shapes and patterns. Which is a simple enough thing to say, but the process he has developed has vast implications for computing and manufacturing -- allowing us to create things we can now only dream of. Full bio
Paul Rothemund folds DNA into shapes and patterns. Which is a simple enough thing to say, but the process he has developed has vast implications for computing and manufacturing -- allowing us to create things we can now only dream of. Full bio
Double-click the English transcript below to play the video.
00:12
So, people argue vigorously about the definition of life.
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They ask if it should have reproduction in it, or metabolism, or evolution.
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And I don't know the answer to that, so I'm not going to tell you.
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I will say that life involves computation.
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So this is a computer program.
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Booted up in a cell, the program would execute,
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and it could result in this person;
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or with a small change, it could result in this person;
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or another small change, this person;
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or with a larger change, this dog,
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or this tree, or this whale.
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So now, if you take this metaphor
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[of] genome as program seriously,
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you have to consider that Chris Anderson
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is a computer-fabricated artifact, as is Jim Watson,
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Craig Venter, as are all of us.
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And in convincing yourself that this metaphor is true,
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there are lots of similarities between genetic programs
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and computer programs that could help to convince you.
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But one, to me, that's most compelling
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is the peculiar sensitivity to small changes
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that can make large changes in biological development -- the output.
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A small mutation can take a two-wing fly
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and make it a four-wing fly.
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Or it could take a fly and put legs where its antennae should be.
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Or if you're familiar with "The Princess Bride,"
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it could create a six-fingered man.
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Now, a hallmark of computer programs
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is just this kind of sensitivity to small changes.
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If your bank account's one dollar, and you flip a single bit,
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you could end up with a thousand dollars.
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So these small changes are things that I think
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that -- they indicate to us that a complicated computation
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in development is underlying these amplified, large changes.
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So now, all of this indicates that there are molecular programs underlying biology,
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and it shows the power of molecular programs -- biology does.
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And what I want to do is write molecular programs,
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potentially to build technology.
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And there are a lot of people doing this,
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a lot of synthetic biologists doing this, like Craig Venter.
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And they concentrate on using cells.
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They're cell-oriented.
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So my friends, molecular programmers, and I
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have a sort of biomolecule-centric approach.
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We're interested in using DNA, RNA and protein,
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and building new languages for building things from the bottom up,
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using biomolecules,
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potentially having nothing to do with biology.
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So, these are all the machines in a cell.
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There's a camera.
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There's the solar panels of the cell,
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some switches that turn your genes on and off,
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the girders of the cell, motors that move your muscles.
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My little group of molecular programmers
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are trying to refashion all of these parts from DNA.
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We're not DNA zealots, but DNA is the cheapest,
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easiest to understand and easy to program material to do this.
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And as other things become easier to use --
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maybe protein -- we'll work with those.
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If we succeed, what will molecular programming look like?
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You're going to sit in front of your computer.
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You're going to design something like a cell phone,
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and in a high-level language, you'll describe that cell phone.
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Then you're going to have a compiler
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that's going to take that description
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and it's going to turn it into actual molecules
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that can be sent to a synthesizer
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and that synthesizer will pack those molecules into a seed.
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And what happens if you water and feed that seed appropriately,
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is it will do a developmental computation,
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a molecular computation, and it'll build an electronic computer.
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And if I haven't revealed my prejudices already,
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I think that life has been about molecular computers
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building electrochemical computers,
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building electronic computers,
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which together with electrochemical computers
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will build new molecular computers,
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which will build new electronic computers, and so forth.
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And if you buy all of this,
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and you think life is about computation, as I do,
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then you look at big questions through the eyes of a computer scientist.
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So one big question is, how does a baby know when to stop growing?
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And for molecular programming,
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the question is how does your cell phone know when to stop growing?
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(Laughter)
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Or how does a computer program know when to stop running?
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Or more to the point, how do you know if a program will ever stop?
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There are other questions like this, too.
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One of them is Craig Venter's question.
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Turns out I think he's actually a computer scientist.
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He asked, how big is the minimal genome
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that will give me a functioning microorganism?
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How few genes can I use?
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This is exactly analogous to the question,
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what's the smallest program I can write
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that will act exactly like Microsoft Word?
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(Laughter)
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And just as he's writing, you know, bacteria that will be smaller,
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he's writing genomes that will work,
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we could write smaller programs
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that would do what Microsoft Word does.
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But for molecular programming, our question is,
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how many molecules do we need to put in that seed to get a cell phone?
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What's the smallest number we can get away with?
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Now, these are big questions in computer science.
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These are all complexity questions,
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and computer science tells us that these are very hard questions.
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Almost -- many of them are impossible.
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But for some tasks, we can start to answer them.
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So, I'm going to start asking those questions
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for the DNA structures I'm going to talk about next.
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So, this is normal DNA, what you think of as normal DNA.
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It's double-stranded, it's a double helix,
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has the As, Ts, Cs and Gs that pair to hold the strands together.
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And I'm going to draw it like this sometimes,
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just so I don't scare you.
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We want to look at individual strands and not think about the double helix.
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When we synthesize it, it comes single-stranded,
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so we can take the blue strand in one tube
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and make an orange strand in the other tube,
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and they're floppy when they're single-stranded.
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You mix them together and they make a rigid double helix.
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Now for the last 25 years,
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Ned Seeman and a bunch of his descendants
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have worked very hard and made beautiful three-dimensional structures
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using this kind of reaction of DNA strands coming together.
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But a lot of their approaches, though elegant, take a long time.
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They can take a couple of years, or it can be difficult to design.
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So I came up with a new method a couple of years ago
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I call DNA origami
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that's so easy you could do it at home in your kitchen
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and design the stuff on a laptop.
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But to do it, you need a long, single strand of DNA,
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which is technically very difficult to get.
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So, you can go to a natural source.
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You can look in this computer-fabricated artifact,
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and he's got a double-stranded genome -- that's no good.
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You look in his intestines. There are billions of bacteria.
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They're no good either.
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Double strand again, but inside them, they're infected with a virus
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that has a nice, long, single-stranded genome
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that we can fold like a piece of paper.
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And here's how we do it.
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This is part of that genome.
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We add a bunch of short, synthetic DNAs that I call staples.
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Each one has a left half that binds the long strand in one place,
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and a right half that binds it in a different place,
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and brings the long strand together like this.
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The net action of many of these on that long strand
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is to fold it into something like a rectangle.
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Now, we can't actually take a movie of this process,
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but Shawn Douglas at Harvard
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has made a nice visualization for us
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that begins with a long strand and has some short strands in it.
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And what happens is that we mix these strands together.
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We heat them up, we add a little bit of salt,
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we heat them up to almost boiling and cool them down,
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and as we cool them down,
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the short strands bind the long strands
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and start to form structure.
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And you can see a little bit of double helix forming there.
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When you look at DNA origami,
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you can see that what it really is,
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even though you think it's complicated,
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is a bunch of double helices that are parallel to each other,
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and they're held together
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by places where short strands go along one helix
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and then jump to another one.
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So there's a strand that goes like this, goes along one helix and binds --
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it jumps to another helix and comes back.
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That holds the long strand like this.
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Now, to show that we could make any shape or pattern
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that we wanted, I tried to make this shape.
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I wanted to fold DNA into something that goes up over the eye,
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down the nose, up the nose, around the forehead,
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back down and end in a little loop like this.
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And so, I thought, if this could work, anything could work.
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So I had the computer program design the short staples to do this.
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I ordered them; they came by FedEx.
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I mixed them up, heated them, cooled them down,
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and I got 50 billion little smiley faces
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floating around in a single drop of water.
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And each one of these is just
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one-thousandth the width of a human hair, OK?
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So, they're all floating around in solution, and to look at them,
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you have to get them on a surface where they stick.
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So, you pour them out onto a surface
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and they start to stick to that surface,
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and we take a picture using an atomic-force microscope.
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It's got a needle, like a record needle,
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that goes back and forth over the surface,
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bumps up and down, and feels the height of the first surface.
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It feels the DNA origami.
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There's the atomic-force microscope working
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and you can see that the landing's a little rough.
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When you zoom in, they've got, you know,
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weak jaws that flip over their heads
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and some of their noses get punched out, but it's pretty good.
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You can zoom in and even see the extra little loop,
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this little nano-goatee.
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Now, what's great about this is anybody can do this.
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And so, I got this in the mail about a year after I did this, unsolicited.
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Anyone know what this is? What is it?
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It's China, right?
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So, what happened is, a graduate student in China,
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Lulu Qian, did a great job.
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She wrote all her own software
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to design and built this DNA origami,
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a beautiful rendition of China, which even has Taiwan,
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and you can see it's sort of on the world's shortest leash, right?
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(Laughter)
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So, this works really well
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and you can make patterns as well as shapes, OK?
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And you can make a map of the Americas and spell DNA with DNA.
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And what's really neat about it --
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well, actually, this all looks like nano-artwork,
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but it turns out that nano-artwork
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is just what you need to make nano-circuits.
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So, you can put circuit components on the staples,
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like a light bulb and a light switch.
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Let the thing assemble, and you'll get some kind of a circuit.
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And then you can maybe wash the DNA away and have the circuit left over.
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So, this is what some colleagues of mine at Caltech did.
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They took a DNA origami, organized some carbon nano-tubes,
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made a little switch, you see here, wired it up,
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tested it and showed that it is indeed a switch.
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Now, this is just a single switch
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and you need half a billion for a computer, so we have a long way to go.
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But this is very promising
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because the origami can organize parts just one-tenth the size
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of those in a normal computer.
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So it's very promising for making small computers.
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Now, I want to get back to that compiler.
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The DNA origami is a proof that that compiler actually works.
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So, you start with something in the computer.
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You get a high-level description of the computer program,
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a high-level description of the origami.
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You can compile it to molecules, send it to a synthesizer,
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and it actually works.
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And it turns out that a company has made a nice program
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that's much better than my code, which was kind of ugly,
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and will allow us to do this in a nice,
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visual, computer-aided design way.
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So, now you can say, all right,
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why isn't DNA origami the end of the story?
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You have your molecular compiler, you can do whatever you want.
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The fact is that it does not scale.
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So if you want to build a human from DNA origami,
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the problem is, you need a long strand
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that's 10 trillion trillion bases long.
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That's three light years' worth of DNA,
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so we're not going to do this.
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We're going to turn to another technology,
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called algorithmic self-assembly of tiles.
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It was started by Erik Winfree,
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and what it does,
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it has tiles that are a hundredth the size of a DNA origami.
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You zoom in, there are just four DNA strands
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and they have little single-stranded bits on them
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that can bind to other tiles, if they match.
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And we like to draw these tiles as little squares.
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And if you look at their sticky ends, these little DNA bits,
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you can see that they actually form a checkerboard pattern.
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So, these tiles would make a complicated, self-assembling checkerboard.
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And the point of this, if you didn't catch that,
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is that tiles are a kind of molecular program
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and they can output patterns.
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And a really amazing part of this is
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that any computer program can be translated
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into one of these tile programs -- specifically, counting.
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So, you can come up with a set of tiles
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that when they come together, form a little binary counter
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rather than a checkerboard.
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So you can read off binary numbers five, six and seven.
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And in order to get these kinds of computations started right,
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you need some kind of input, a kind of seed.
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You can use DNA origami for that.
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You can encode the number 32
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in the right-hand side of a DNA origami,
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and when you add those tiles that count,
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they will start to count -- they will read that 32
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and they'll stop at 32.
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So, what we've done is we've figured out a way
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to have a molecular program know when to stop going.
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It knows when to stop growing because it can count.
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It knows how big it is.
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So, that answers that sort of first question I was talking about.
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It doesn't tell us how babies do it, however.
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So now, we can use this counting to try and get at much bigger things
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than DNA origami could otherwise.
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Here's the DNA origami, and what we can do
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is we can write 32 on both edges of the DNA origami,
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and we can now use our watering can
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and water with tiles, and we can start growing tiles off of that
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and create a square.
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The counter serves as a template
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to fill in a square in the middle of this thing.
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So, what we've done is we've succeeded
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in making something much bigger than a DNA origami
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by combining DNA origami with tiles.
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And the neat thing about it is, is that it's also reprogrammable.
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You can just change a couple of the DNA strands in this binary representation
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and you'll get 96 rather than 32.
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And if you do that, the origami's the same size,
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but the resulting square that you get is three times bigger.
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So, this sort of recapitulates
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what I was telling you about development.
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You have a very sensitive computer program
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where small changes -- single, tiny, little mutations --
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can take something that made one size square
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and make something very much bigger.
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Now, this -- using counting to compute
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and build these kinds of things
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by this kind of developmental process
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is something that also has bearing on Craig Venter's question.
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So, you can ask, how many DNA strands are required
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to build a square of a given size?
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If we wanted to make a square of size 10, 100 or 1,000,
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if we used DNA origami alone,
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we would require a number of DNA strands that's the square
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of the size of that square;
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so we'd need 100, 10,000 or a million DNA strands.
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That's really not affordable.
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But if we use a little computation --
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we use origami, plus some tiles that count --
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then we can get away with using 100, 200 or 300 DNA strands.
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And so we can exponentially reduce the number of DNA strands we use,
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if we use counting, if we use a little bit of computation.
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And so computation is some very powerful way
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to reduce the number of molecules you need to build something,
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to reduce the size of the genome that you're building.
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And finally, I'm going to get back to that sort of crazy idea
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about computers building computers.
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If you look at the square that you build with the origami
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and some counters growing off it,
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the pattern that it has is exactly the pattern that you need
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to make a memory.
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So if you affix some wires and switches to those tiles --
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rather than to the staple strands, you affix them to the tiles --
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then they'll self-assemble the somewhat complicated circuits,
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the demultiplexer circuits, that you need to address this memory.
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So you can actually make a complicated circuit
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using a little bit of computation.
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It's a molecular computer building an electronic computer.
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Now, you ask me, how far have we gotten down this path?
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Experimentally, this is what we've done in the last year.
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Here is a DNA origami rectangle,
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and here are some tiles growing from it.
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And you can see how they count.
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One, two, three, four, five, six, nine, 10, 11, 12, 17.
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So it's got some errors, but at least it counts up.
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(Laughter)
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So, it turns out we actually had this idea nine years ago,
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and that's about the time constant for how long it takes
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to do these kinds of things, so I think we made a lot of progress.
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We've got ideas about how to fix these errors.
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And I think in the next five or 10 years,
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we'll make the kind of squares that I described
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and maybe even get to some of those self-assembled circuits.
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So now, what do I want you to take away from this talk?
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I want you to remember that
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to create life's very diverse and complex forms,
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life uses computation to do that.
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And the computations that it uses, they're molecular computations,
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and in order to understand this and get a better handle on it,
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as Feynman said, you know,
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we need to build something to understand it.
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And so we are going to use molecules and refashion this thing,
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rebuild everything from the bottom up,
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using DNA in ways that nature never intended,
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using DNA origami,
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and DNA origami to seed this algorithmic self-assembly.
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You know, so this is all very cool,
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but what I'd like you to take from the talk,
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hopefully from some of those big questions,
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is that this molecular programming isn't just about making gadgets.
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It's not just making about --
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it's making self-assembled cell phones and circuits.
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What it's really about is taking computer science
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and looking at big questions in a new light,
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asking new versions of those big questions
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and trying to understand how biology
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can make such amazing things. Thank you.
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(Applause)
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ABOUT THE SPEAKER
Paul Rothemund - DNA origamistPaul Rothemund folds DNA into shapes and patterns. Which is a simple enough thing to say, but the process he has developed has vast implications for computing and manufacturing -- allowing us to create things we can now only dream of.
Why you should listen
Paul Rothemund won a MacArthur grant this year for a fairly mystifying study area: "folding DNA." It brings up the question: Why fold DNA? The answer is -- because the power to manipulate DNA in this way could change the way we make things at a very basic level.
Rothemund's work combines the study of self-assembly (watch the TEDTalks from Neil Gershenfeld and Saul Griffith for more on this) with the research being done in DNA nanotechnology -- and points the way toward self-assembling devices at microscale, making computer memory, for instance, smaller, faster and maybe even cheaper.
Paul Rothemund | Speaker | TED.com