Transcriber: Reviewer: Elisabeth Buffard
So in Feyman's famous lecture that we're celebrating today,
one of the things he foresaw
was that the computers of his time
could become incredibly more powerful by shrinking them
and increasing their paralellism with the components.
And that certainly came to pass,
and the invention that was key in doing that
is the integrated circuit, or - as we call it today - the computer chip.
And through the incredible paralellisation available
through the integrated circuit,
we now realise that these devices are useful.
They automate computation and they're useful for much more
than solving maths problems.
We use automated computation in virtually every area of our lives today,
from giving presentations to writing,
to communicating.
It's really amazing.
And what I've been interested in for the past decade or so
is trying to find the biological equivalent of the integrated circuit.
We're here... What we've been looking for are ways to automate biology.
And since the root of nearly every aspect of biology today
boils down to your ability to maneuver fluids around,
this means that instead of looking for devices
with transistors and wires on them,
we've tried to create devices that have pipes and valves
and pumps and so forth.
And back in the early 2000s,
my collaborators and I managed to do that,
and we were able to create fluidic circuits
which have, nowadays, up to tens of thousands of valves on them.
And I'll do decree any plumbers nightmare.
And it really is small plumbing.
In the spirit of getting the baloney out of the presentation:
you know: plumbing is one of the least glamorous of all the trades.
And, you know, if you've ever had the plumber in your house
versus your electrician,
you can tell that it's not nearly the same level of regard.
And... So trying to invent better plumbing is
not one of those mysteries of the universe
that generally keeps people up at night.
However, that being said,
plumbing - once you have this sort of automated plumbing in hand -
it allows you to explore a wide variety of problems
in biology, and to do so in a way that lets you ask questions
that aren't practical to do by just pipetting things by hand.
And in this movie you've been able to see,
one of these chips in action,
with the dimensions of the channels are about the size of a human hair,
and different colour food dyes are being manipulated in the device,
and this is something where the dimensions are much larger
than you see in a computer chip, and are correspondingly easier to make
and one of the fantastic things about this is you can make devices
of nearly arbitrary complexity with really a very small number of steps.
And I'm going to take you on a little tour of my laboratory,
and some of the things we've been doing over the past few years
to demonstrate what one can do with this plumbing in hand.
One of the first things we began to look at
is using these devices in structural biology.
So you've seen these beautiful pictures of proteins
that have been imaged with atomic scale resolution,
and the vast majority of those are obtained through crystallography,
where one has to grow the protein into a perfectly atomically ordered crystal,
and then diffract X-rays off of them.
And it turns out that one of the least scientific parts of this whole process
is getting the crystals to grow.
And we've spent quite a bit of time, trying to bring physics to that problem,
with some degree of success.
And it turns out, that these small volumes are useful,
not only for achieving engineering economies of scale,
but also the laws of fluid physics get into interesting new regimes
as you shrink the volumes down to nanolitres and below.
And so one can... one's intuition about how
fluids behave from the swimming pool and the ocean don't always apply,
and one can take advantage of novel behaviour
that's not available at the macroscale.
And in particular one can manipulate
the crystallisation of proteins in ways that aren't possible at the benchtop.
And so we took advantage of that to design a series of devices
that allow us to grow crystals and study them,
and parts of that became comercialised and
are used in labs around the world,
and there are now many structures that have been determined using these chips,
including ones of proteins that are involved in Ebola and Avian flu,
and therefore have potential health benefits
and the people who have done so,
- this has been reserved generally for the hardest proteins to solve -
and these people say they couldn't have done it without the chips.
Either because they didn't have enough protein to do it conventionally,
or they couldn't manipulate the crystallization kinetics.
Another area where we've used these devices,
has been to try to measure the interactions between molecules.
And to do so in a very highly parallel way.
And to do so at a scale where you can make measurements
that weren't possible to do before.
One area which we've done that has been looking at transcription factors,
which are the proteins that turn genes on and off in your cells, and
we've in fact have been able to measure the binding energies
of transcription factors to lots of different DNA sequences,
all possible combinations in fact.
And from those purely physical measurements
we've been able to show that you can
combine that with knowledge of the genome
to predict which genes are regulated by any given transcription factor.
That's been a very nice kind of basic science application of this,
in trying to understand how transcription factors work,
and what evolution has allowed them to do and not to do,
and how much of that capability has been explored.
But it's also lead to practical applications,
for example in drug discovery.
And we were able to discover an interaction that was
- with a collaborator, J eff Glenn at Stanford, -
that an interaction that is important for the replication of Hepatitis C virus,
we used chips for the first time,
to biochemically prove that that interaction happens,
and then screen small molecules on a chip
to try to inhibit the interaction.
And in doing so, discovered a new drug for Hepatitis C,
which is now in clinical trials.
And so, one practical application of this plumbing,
and its use to measure interactions has been in drug discovery.
Let me take you to another application,
and this is going to require a small digression.
We got interested in using the plumbing to count molecules.
It turns out that it's fairly challenging to do precise quantitation of DNA.
What's generally done is to use a biochemical amplifier called PCR,
but because the amplifier is non-linear it's difficult to do it precisely,
and there's this beautiful idea that's been floating around
for a number of years, called digital PCR,
and it's reached sort of its fullest fruition in the microfluidic context.
And the idea is very simple:
if you have a test tube full of molecules,
and then you dilute them into many different test tubes,
so that on average each test tube has one molecule or zero molecules in it,
and then you do this amplification process in every test tube,
and don't worry about trying to do it quantitatively, let it run non-linearly.
What you'll see at the end of the day
is test tubes that either have amplified product in or don't.
And if you count up all the ones that have amplified product in,
that tells you how many molecules you started with.
And this so-called digital PCR provides a beautifully precise way
to do DNA quantitation.
As you can imagine, this is not something you'd want to do by hand,
and it lends itself very well to automated plumbing.
And in fact, if you look at this image here,
each bright spot you see is the amplified product of a single molecule,
and these panels are loaded with increasing concentrations of molecules,
and you can see that one can just count up what was there.
What's the use of this?
Well, one practical application has to do with making babies.
For those of you who are parents, you know it's one of the most
remarkable things you can go through,
but it's also somewhat terrifying when doctors want to stick needles in.
And I had this done to my wife and unborn kid,
and it really made me think there must be a better way
to do diagnostics of the baby.
And it turns out that gross chromosomal disorders
like Down's Syndrome affecting about 1% of live births,
and these invasive tests have their own risks associated with them.
And it happened one day, when I was sitting in my office, reading an article,
and discovered that a certain amount of the baby's DNA
floats around in the mum's blood,
and I realised that by using this molecular counting we've been working on,
you can actually measure, whether or not the baby has Down's syndrome
non-invasivaly, simply by having a little bit of mom's blood,
which is drawn from her arm where there's no risk,
and you're not putting the needle anywhere near the baby.
And so we published a proof-of-principle study of this some years ago,
and now others have gone on and used this method
on real clinical samples to show that you can in fact diagnose Down's syndrome
and other genetic disorders non-invasively,
and it's something that's moving very quickly towards the clinic.
So a diagnostic application of small plumbing and counting molecules.
(Applause)
So in the last minute here I'll give you one more biological example,
which is using the plumbing to analyse single cells.
We built this device, shown here, with which you take a single human cell,
digest it, and distribute its chromosomes randomly across those different chambers.
And then we use very similar amplification processes to amplify
those single molecules, and then recover the components independently.
And what that allows you to do,
is analyse an individual's genome with sort of exquisite sensitivity,
and in fact, as you know, you get one chromosome from each...
one copy of each of your chromosomes from each of your parents,
and virtually all of the genomes published today
have sort of not been able to deconvolve that in any meaningful way.
And being able to separate those molecules and amplify,
and analyse them independently,
lets you look at a synthetic karyotype like this,
and say for a given person, which chromosome came from your mom,
which came from your dad.
And in fact you can do even better than that.
If you analyse a few cells from the mom and the dad,
you can work out exactly how their chromosomes
were mixed together in the particular sperm and egg that created that child,
so a chance to look back in time,
and look at the specific genetics of those single cells
that created that individual.
And this sort of haplotype measurement
is something that is gonna to be
an important part of genome analysis going forward.
The last example is leaving biology and moving to chemistry,
another area where the ability to manipulate fluids really matters.
The ability to use microfluidics in this field has just had it's beginning,
and you may ask, why would you want to make nanolitres of stuff?
Turns out for areas like gene and genome synthesis
and medical imaging for cancer,
PET imaging,
you want small amounts of stuff,
and we've been able to demonstrate in principle you can do that,
and that's something we look forward to seeing developed.
And so, I'll just summarize here, by saying
we've had a lot of fun, exploring different areas,
and you can see there's applications of this plumbing
in both basic science and in diagnostics and drug discovery,
and the hope is that in the near future these devices will be in labs everywhere,
and liberate graduate students from the tyranny of pipetting.
Thank you!
(Applause)