Professor Stephen Arnold: But then there was a challenge that came from MIT and in University
California Santa Barbara. They said well we're
looking at experiments in this area and
what we see is that there are three
reports in the literature where they
predict based on theory that the binding
could not have been as fast as what as
what was being measured meaning there
were too many steps coming too fast
based on the concentration in solution
so and they sit and they're smart
enough to say such discrepancies suggest
that an additional as yet undetermined
ingredient must be present in the
experiments. So David happened to stop
into my office that same David Keng and
I said go into the lab and see if you
can see the scattering from the virus,
looked directly down on the micro cavity
inside the cell and see if you can see
the scattering about an hour later he
ran back into my office and he said
they're in orbit I said really
they're in orbit he says and I said well
when you double the amount of light do
they go faster in orbit he said yes so I
said you mean to say they're drawn in
and they're in orbit he said yes
there's David and and I said but you're
only operating with 30 micro watts of
light that's that's like a thirtieth of
what's coming out of this you know
radiation pressure the whole idea of
tractor beams like from Star Trek or
something being able to draw things in
with thirty microwatts of light sounded
impossible not only that but before
these particles got into the beam the
the wavelength wisconsin and then began
to chatter as it came in there. So he was
looking directly down from the top this
is what he saw and I'll just show you a
video of essentially what it looked like.
It's looking directly down on the top of
this thing and you can see we're not
resolving this but it's scattering from
some object which is going to the other
edge going down below coming around
coming up the other edge going around
again.
Going down this edge coming around again
he had created an orbital system in
solution or at least he discovered it
and it was sort of boggled the mind I
mean microfluidics had always been the
case where in fact if light was used it
was to illuminate things it wasn't being
used for the force that it could produce.
So all of fluidics was changed at that
point when we published this and now
then papers are coming out from
everywhere right after that he had
created light force fluidics a new area
and more importantly it generated
another three patents on all kinds of
things I can't go into all them but but
it was a very exciting time when we saw
that. In Star Trek I always remember the
spaceship could draw things in by using
a tractor beam we had created a tractor
beam. So you may wonder what was it
composed of so here's this light which
coming through a fiber that's
stimulating this spherical mode and
several things are happening first
there's a force called a gradient force
light particles like to be where the
intensity is highest so they tend to
move toward that surface that's called
the gradient force and we'll go through
the mathematical details this on silica
there's a charge on the surface because
at neutral pH it's deprotonated so
instead of having SI OHG of SiO - so
it's it's negatively charged and virus
are negatively charged so there's a
constant repulsion so repulsion here
attraction from the light and finally
there's a photon momentum flux moving
around because this is a traveling wave.
As it moves around they have enough sand
field travels with it and so this is the
kind of thing that was happening well
that's an illustration that's actual
data I mean we
kind of synchronized the to the ability
for an antigen to bind to an antibody is
now enhanced. Why, because we've created
dimensional reduction we have made a
railroad track okay a railroad track
that leads to an antibody watch. At least
as an illustration this thing gets
caught by that trap starts to move
around in order to find that particular
antibody it can find it much faster that
way than random diffusion or if it's
starting out up here I'm just showing it
now looking from the side it's going to
move around until it gets into that
track and then find that antibody much
more quickly or if you wanted to you
could invent a symbol I picked something
close to a field effect transistor the
this symbol light comes in to this
symbol the symbol is that which enables
this virus to move down to the antibody
right and now you can think of ways in
which you can make circuits of these
symbols right.
Therefore circuits of resonators this is
also a way to do fabrication suppose for
instance you wanted to put something on
the surface and you don't have the
fabrication tools or you want to do it
in a microfluidic cell right then how
would you do it? The answer is use light
forces we call that light force assembly
and we also issued a patent application
on that this is the person who
discovered a way to enhance signals well
beyond anything we could imagine right.
Siyka Shopova, she imagined
using a gold nanoparticle and it's
plasmonics
so that when it's put on to the micro
cavity the field is further enhanced
where it's put on by the circulating
wave here's what our data look like. This
is the greatest signal we could ever get
from a distribution of particles of the
size which is being represented here a
size of dielectric particles she put
this plasmatic particle on and she
suddenly noticed that there are all
these that we couldn't explain. They were
due to an enhancement due to the
plasmatic particle so then in addition
to the small steps we could get gigantic
steps. It was only a factor of two or
three from the edge of this to the
largest thing you get here but in fact
it was a harbinger of things to come the
idea of adding nano optics to micro
optics to and to create a much bigger
signal and to see things we couldn't see
before. So here you plant this plasmatic
particle the form of something like a
sphere when light comes around and
drives it into resonance it creates a
big field on the top and the bottom of
this thing
and with this we managed to detect this
is when we put that system in we could
see that plasmatic particle on the
surface and then suddenly where we
couldn't possibly see MS2 before because
it was too small, much too small as a
matter of fact our our noise was on the
order of five femtometers and MS2 would
have generated on a bare cavity a
quarter of a femtometer we would never
been able to see it but yet there they are.
They appeared. The plasmatic particle
created a receptor which was an
amplifier and it was nanoscopic the
enhancement turned out to be 70
times so no longer four times now up to
70. You can just count them
this is taking a derivative of that
binding curve and you can see every one
of the viruses as they come in and then
over here there is no virus injected.
Cancer markers can also be detected one
at a time when you have thyroid cancer
they cut your thyroid out okay that's
what they do
supposedly they've cut the entire cancer
out. But there's a protein generated by
the thyroid so after two weeks or so
they begin looking to see if the protein
is there if it is there are remnants of
it in your system the cancer is still
there right now imagine being able to
see those protein one molecule at a time
one thyroglobulin protein at a time. So
here the maximum signal would have been
one hundredth of we could possibly detect
before but because of the plasmatic
particle we began to see steps you can
see them there okay from that plasmatic
particle known as a nano show now we
were up to 266
times. The reason we got so much higher
we didn't quite understand I mean after
all we didn't expect to get so much
higher we our theory was saying that we
shouldn't get this kind of thing. What we
hadn't realized is that these shells are
not perfect on their surface they're
bumpy when plasmonics particles are bumpy
they create hot spots that are very
close to the surface so they would react
to very small molecules more sensitively
than the react to of a virus which is
considerably larger so that's the reason
we managed to see them the bumps are
only four nanometers to ten nanometers
in size and this is what they do when
you do a calculation. It shows that as
you get close to the surface
get this big enhancement of potential
signal over what you would have had
before just due to a bump. Another
fortunate thing we published this in
2013 it's been taking off in the
literature and we're down to well below
where ever expected we would be we're
down to a sensitivity of eight Zepto
grams. Okay remember what I said when I
started this the protein on the surface
the epitopes single protein have a mass
of something on the order of 30
something like that that is 10 or
20 times higher than this our
sensitivity now here 8 zeptograms. Oh
so you want to know what that is and you
know you go attograms is 10^-18, Zeptograms 10^-21 grams.
We need more landing pads so at the
University of Michigan and also at Abu
Dhabi they're making rings based on
these designs where they're enhancing
signals by essentially putting plasmatic
particles on the rings okay this you'll
hear more about soon is for the people
at Abu Dhabi you began to finish also at
the University of Michigan so one of the
thank nature methods for publishing our technique.
An industry has come about a company Genalyte has created rings after
rings after rings a multiplexed types
sensor that can sense a whole slew of
different interactions and David Keng
has created something called mp3 laser
remember the name of our laboratory mp3
lab and we have one of these in our lab
and it's fantastic I mean I don't know
how he did all this I mean it was it he
he made it like an iPhone so when you
when you call him and you say look we'd
like to do this experiment but in fact
your system doesn't do it he sends us an
app we load it into this system and it
does that new experiment it's fantastic.
So what I like to thank people at
Rockefeller University who's helped us
near the beginning David Keng our
highlight here Frank Vollmer was a grad
student there is a biochemist who wanted
to learn physics so I mentored him
Stephen Haller contributed he was one of
our students interesting guy he created
a company a sensor company and sold it
for 26 million dollars in his
30s so he did all right and then all of
these people are people at the
Polytechnic who contributed to the work
you can visit us on YouTube this is a
short I'm never sure whether web pages
will change their names here so instead
a place in Texas runs this page it's mp3l.org and you can visit visit our
youtube at which is mp3 l wgm so mp3 l4
micro particle photo physics lab and WGM
for whispering gallery mode
and that's it. So do you have any
questions or anything you should be a
short of the fact that I'm dumb as a
rock
so cut so you can ask any question what
you got yes yes yes it can in fact
that's how we put it on the surface we
put on a surface but by drawing it in
from an orbit with little pulses of
intensities so we could get it close
enough to stick yeah that's a very good
question yes yeah yes gentle aid okay so
there silicon which is very high
refractive index on silica silicon on
the silica so silica has a refractive
index about 1.45 but silicon is is way
over two so the light is confined within
the silicon ring and then of course
there's evanescent fields around the
ring yeah that's a very good question
thank you yes.
Of the of the orbit you mean, about lightforce fluidics this new subject
I'm not quite getting
it but the gold particle will will be
grabbed on to by the tractor beam the
light force and be drawn to the surface.
If there's a repulsion between the
surface as there was in the case of
these negative particles and the
negative surface then it can remain out
there and and orbit.
A bump in yeah yeah, okay so the normal
sensitivity of of the bare cavity was
not sufficient to see a single molecule.
But when you put a plasmatic particle on
it has this property that a particular
frequency and it's pretty broad
frequencies spectrum there's a large
field created on the north and south
pole of this nanoscopic thing okay so
that if you're sending a particular
field in you get a much larger field and
therefore that remember that principle
that I had which the sensing principles
said that the amount to which you
polarize the energy that polarizes the
particle is the wavelength shift of the
photons and the mode. So if you have a
higher field you polarize them more
strongly I hope that helps and if, yes.
Sorry, I'm sorry.
Yes, from Genalyte.
Right it is you know they're they're
putting in into hospitals, yeah yes.
Yeah, some people use narrow rods which are
you know rod shapes. Some people use
nanoshells which are gold on the outside
and they have glass on the inside and
some people use just solid gold.
Yes apparently just recently single
atomic ions were detected inside of the
fluid right not by our group but by
group in Germany. So yeah it enhances the
sensitivity tremendously that used gold
nanorods yes.
Yes, yes so it turns out
what you do is you put specific
antibodies on the surface. Now you can
generate the antibodies by essentially
poisoning bacteria with with virus and
then harvesting the antibodies and then
binding those the surface.
No no you
should be able to distinguish different
things if you can if you can identify
the spatial regions where you put those
those antibodies yes that's another subject yeah.
Well and the micro cavities or our
dielectric they're they're glass because
the metals have too much loss so you
don't want to make a solid micro cavity
out of metal. It's it's fine if you just
use nanoscopic metal particles.
Nanoscopic meaning of nanometers in size
but the micro cavities we were using
were typically 40 micrometers. Okay so
they are they are a thousand times the
size of those little gold nanoparticles
that are put on the surface okay the
nano particles act as receptors so if
you then put antibodies on the nano
particles they're specific to a certain
virus then the signal gets enhanced when
the virus reaches that plasmonics
particle a little particle the
nanoscopic particle which is on the
micro cavity.
Yeah I mean the the problem with with
soft materials for the micro cavity is
that they will tend to because they're
elastic coefficients are not very stiff
they will tend to fluctuate on their
surface. That will broaden these
resonance lines okay and so not as
useful but we've made them out of PDMS
which is soft and they're pretty good.
Yes.
How do we avoid it okay so I mean
typically what you do and these these
systems is you try to block all parts of
this surface you block it chemically
except for the places where you want the
receptors to be you don't want
nonspecific adsorption. Okay so you have
a problem you know I mean if you if you
have a well well-designed surface
okay so surface science comes into this
then you can block all the parts of the
surface deceptive where you where you've
put your receptors okay any others okay
so what I'm saying here aside from this
guy who's who's ready now.
The guys are being beaten here all these girls who
they they're asking all kinds of
questions, yeah?
But once again
if unless you have a way of the the rate
will the rate will be conditioned by the
on compare to off time so that remember
most of these antibodies physically bind
right the the antigen to the antibody. So
there's a certain time over which
they'll remain there before they come
off there are some things that bind very
nicely like streptavidin and biotin
right things like that very strong but a
lot of things you know basically have an
on to off rate so the answer is yeah the
reason why people would want a thing
like this is because they want to test
antibodies and see which ones that are
most effective. The ones that are most
effective would have an on rate much
greater than their off rate so you've
hit on a very important purpose of this
overall thing to test basically the
quality of antibodies for particular
antigens. Does that help? Any any other
questions? Guys come on I mean you guys
look I don't know about this usually, yeah go ahead.
Well that's where the light is moving
right at least on what I what I
demonstrated right. It is possible by
using different frequencies to move the
light to different places but no if it
if the neat thing about this is that
what we call that carousel trap we call
it that because it's like a carousel
right. It can draw things to the surface
and then they stick at a particular
latitude right so thinking about the
earth is having an equator a North Pole
South Pole the only difference between
our micro world and that is that our
micro world is only 80 millionths of a
meter
and the earth is 8,000 miles across but
aside from that the geometry is the same
right so yeah so what you what you'd
want to do is pull the particle to
precisely where the light is and that's
exactly what this carousel trap does.
It's very fortunate I hope that helped
okay any any other questions guys what's
happening here how do you solve yes yes
well okay let me let me since that's a
very hard question I answer right and I
recognize that but I wanted to point out
something inside of your system right
now right now okay and my friend here
can tell us just how many interactions
are occurring per second with the DNA
right and there are a lot of impurities
in there right
and and the you can recognize the
right protein based on receptors which
are in the biological system. So you're
depending really on this idea of using
biology to create the stickiness of that
surface that's specific to particular
antigen okay and and it's pretty
selective otherwise you wouldn't be here
right think about that.
I never heard of it I never heard of a
crap protein I'm now alright so
obviously that's indeed oh the word crap
anyway who's on first yes yes yes yes
yes I can't I can't do that but I had
not done that so I'm gonna I'm gonna
take us all away from from London to
Beijing. It's not gonna take too
long okay so if you if you go to London
and you go up into St. Paul's Cathedral
and it's about one level up there is a
gallery which is completely round it has
sort of a concave walls a bit and if you
whisper into the corner then you can be
heard 40 metres away on the other side
by a person standing there putting his
ear toward the surface because what
happens is the acoustic wave comes
around so obviously this is not acoustic
right but it seemed like the right title
for it because it was already a
phenomenon that people knew they called
it a Whispering Gallery now I'm gonna
take you to Beijing. In Beijing there's a
place called the Temple of Heaven okay
guys tell us about the Temple of Heaven.
What do they have there?
Just like London but much much larger
everything is larger in China and that's
okay
much much larger right and people stand
at the wall and they whisper to each
other I think it's more than 70 meters
or more across I mean it's really
incredible I'm sorry I should have put a
slide in on that.
Right, but Grand Central
is not a complete. Okay so what happened
in Grand Central I think now I'm
interpreting this is that Vanderbilt so
man wealthy man gave the property to the
people to build a Grand Central but he
demanded only one thing that in the
basement of Grand Central there'd be an
oyster bar where he could have his
oysters okay
the sealing of the oyster bar was like
this okay the story is whether I don't I
don't know if it's entirely true that he
would sit as competitors at one side and
he would sit himself on the other
because he remained quiet and that's
called a Whispering Gallery but it's
it's you might call it semicircular
you're right so not resonant in the same
way yep.
Just on the outside. Well in this
case around a hemispherical tomp. Guys
you're still being beat here.
I mean why it's inverted yeah yeah it's because
there's the like one way to think of it
as the light this generates the
resonance the lot that the energy goes
into the seer and not into the rest of
the fiber that's one way to think of it.
We see a dip okay well I want to I can
see it's been very participatory and I
thank you for that and that's a little
hand for our professor some sometime in
the future.
you
