Occasionally real science plays out just like the
movies: A brilliant experiment is followed by a "Eureka!"
moment, and a new vision of the future reveals itself. This
was the case in 1996 when the Northwestern University
chemist Chad Mirkin witnessed a solution of DNA-assembled
nanoparticles change from blue to red as it was heated.
Almost immediately, says Mirkin, he knew they had invented
the enabling technology for a whole new class of medical
diagnostics and perhaps even therapeutics.
Since then, Mirkin’s two initial papers on this work—"A
DNA-based method for rationally assembling nanoparticles into macroscopic
materials," published in Nature in 1996, and "Selective
colorimetric detection of polynucleotides based on the distance-dependent
optical properties of gold nanoparticles," published in Science a year
later—have each been cited more than 1,500 times (see table below).
The papers launched Mirkin on a path of technological innovation that is
unparalleled in modern chemistry—"A hell of a run," he says. "One
high-impact paper after another." According to the latest update of
Essential Science IndicatorsSMdatabase, based on papers
published and cited over the last decade, Mirkin is currently the
number-one ranked author in the Chemistry category, with 200-plus papers,
more than 18,000 collective citations, and an average of 85 citations per
Mirkin, 46, received his bachelor’s degree in chemistry from
Dickinson College in Pennsylvania in 1986, and his Ph.D. from Penn State
just three years later. He did a postdoctoral fellowship with
Mark Wrighton’s group at MIT. In 1991, he
joined the faculty of Northwestern University, where he is now director
of the International Institute for Nanotechnology and also the George B.
Rathmann Professor of Chemistry, Professor of Medicine, Professor of
Materials Science and Engineering, Professor of Biomedical Engineering,
and Professor of Chemical and Biological Engineering. In June of 2009,
Mirkin was awarded the $500,000 Lemelson-MIT Prize for his remarkable
record of invention.
Mirkin spoke with Science Watch
from his office in Evanston and, befitting his travel schedule of
giving 50 to 70 lectures a year, a hotel in Southern
Tell us about when you realized that the assembly
of nanoparticles into materials with DNA was the ideal platform for
I had asked two students, Bobby Mucic and James Storhoff, to synthesize
some DNA with an alkylthiol, a sulfur-containing group that sticks to
gold. We wanted to make gold nanoparticles with DNA on them. The idea
was to build materials using the DNA as a construction material, like
chemical-specific Velcro. So they synthesized the DNA and worked out
the chemistry to immobilize it on gold nanoparticles. They prepared a
second batch of particles with a non-complementary sequence. When a
third strand was added that could bring together both particles through
hybridization, a particle-assembly event took place. I’ll never
forget this. It was around 11 o’clock at night. Mucic came down
to my office and said, "You have to take a look at this. When I mix
them together, the solution turns blue. If I put it in the oven, it
turns red." This happened because the dispersed particles are red and
the assembled particles are blue. What we were watching with the naked
eye was, in effect, DNA raveling and forming the double helix and
unraveling again when it was heated. At high temperature, the particles
dispersed and were red again. Almost immediately, I remarked that this
was a new way of detecting DNA, a really simple way of doing so.
We then started to seriously pursue the question of whether these
particles offered a better means for detecting DNA. We began a ten-year
set of projects, mapping out the fundamental properties. We discovered
spectacular probes, not just for DNA and proteins, but for other
molecules. The probes have all kinds of advantages for developing
high-sensitivity platforms. And not just in terms of how low one can go
in detection—detecting the smallest number of DNA
strands—but also in the ability to get the right target and
differentiate it from all the wrong targets. Certain people have
genetic diseases, which are identified by single nucleotide
polymorphisms—one incorrect base in their DNA—and these
probes show the ability to identify DNA and differentiate from strands
with a single incorrect base, with near-perfect selectivity.
In 2000, you founded the company Nanosphere
Inc., which markets this technology as part of the Verigene
System. What’s the status of the Verigene System
It’s a commercialized system, now used in hospitals all around
the country. It’s in what I call a ramp-up stage. The company has
four FDA-cleared diagnostic tests, panel tests that are used for
diseases from cystic fibrosis to flu to predisposition to
thrombosis—for detecting people who have a genetic predisposition
to blood clotting—to a warfarin (blood thinner) metabolism assay.
It turns out that a significant number of people have a genetic
inability to metabolize warfarin, and this can lead to major problems
in terms of dosing them properly. If they’re not metabolizing the
warfarin, the more you give them, the more their blood thins. There are
other ways of doing DNA detection or genetic-based analysis, but the
Verigene System allows one to perform the analysis at the point of
care. It’s fast and accurate and doesn’t require a great
deal of expertise or complicated and expensive equipment. So instead of
sending samples to remote labs, the user can analyze them, for example,
in a hospital. It cuts out a middle man, gets the information to the
doctor in a shorter time, and does a lot of good for the patient.
It’s a major step towards point-of-care molecular diagnostics.
You’ve suggested that this nanoparticle
technology can be used for gene regulation as well as diagnostics.
Is this the next step?
Highly Cited Papers by Chad A.
Mirkin and Colleagues, Published
by total citations)
C.A. Mirkin, et al., "A
DNA-based method for rationally
assembling nanoparticles into
Nature, 382(6592): 607-9,
R. Elganian, et al.,
"Selective colorimetric detection
of polynucleotides based on the
properties of gold nanoparticles,"
R.D. Piner, et al.,
Science, 283(5402): 661-3,
R.C. Jin, et al.,
"Photoinduced conversion of silver
nanospheres to nanoprisms,"
T.A. Taton, et al.,
"Scanometric DNA array detection
with nanoparticle probes,"
It’s the next big hurdle: moving this from diagnostics to
therapeutics. We’re now using these particles to go into cells
and turn off cancer genes, to turn off all sorts of diseases, so you
can think about enabling a whole new platform of gene-therapy
systems—systems that turn out to be non-toxic and highly
effective in terms of their ability to regulate these types of
Can you give us an example of how this might
Cancer is an obvious one. Cancer cells often over-express a gene called
survivin, which produces a set of proteins that stop the cell from
dying—they stop apoptosis. That’s what makes cancer cells
immortal. So the idea here is to design particles that can go into
these types of cells and turn off each cell’s ability to produce
those kinds of proteins, and therefore make it more like a healthy cell
that can then die via apoptosis.
Do you have to specifically target the cancer
The particles go into all cells, but only the cancer cells over-express
this particular type of gene. And that’s where the non-toxicity
comes into play. Because the particles aren’t toxic, you can
flood an area. One of the cancers we’re looking at is
glioblastoma, a brain cancer. A surgeon takes out a lethal tumor. If he
leaves even a few cells behind, that patient is likely going to die. In
fact 95% of these patients do die within five years. So the question
is, how do you make sure you clean up the last few cells? Well, here
we’re going to flood the area, and all the cells in the local
area will pick up these particles. But we will target the cancer cells
at the genetic level and therefore selectively kill them. We’re
targeting genes that are unique in cancers cells, so healthy cells will
Don’t get me wrong, though—it’s a long way away.
It’s too far right now to call it a real therapeutic. But these
particles look extremely promising. The beauty is that they don’t
require toxic materials to get into cells. All the other systems that
have been tried require the use of highly toxic lipid and polymer
carriers. Our particles naturally go into cells and do so in a very
stealth manner. Moreover, they can get the job done in a highly
selective fashion based on this genetic triggering.
How do the nanoparticles get into the cells?
Are they just small enough to slip through the membranes?
It’s not just their size—it’s what’s on their
surface. Their surface chemically triggers something called
endocytosis; it makes the cell pick them up. These particles are made
of gold and are decorated with DNA strands. The DNA is used for two
purposes. One is to trigger the endocytosis; it actually causes the
pick-up of signaling proteins from the extracellular matrix. But the
DNA is also the genetic-regulation mechanism. It goes in and is
designed to bind to mRNA, which then shuts down the ability of that
cell to produce a specific protein that the mRNA encoded for. The
particles also can deliver SiRNA, another potent nucleic acid-based
gene-regulation material. This is the next wave. We’ve actually
developed a new company, AuraSense, to develop the particle platform.
How long do you think it will take for this
technology to come to fruition, if it does?
It’s hard to predict, but I hope that within five to seven years,
we’ll have some very strong candidates for new kinds of therapies
In what other areas of medicine do you see this
having an impact?
Well, that’s also the beauty of it. You can begin to think about
targeting any disease that has a genetic basis, and a lot of diseases
do. Cure is in the cards in certain cases; managing is definitely in
How much do you still consider yourself a
chemist and how much a medical researcher?
I’m first and foremost a chemist. But my group at Northwestern
does everything. We’ve gone from chemistry all the way through
materials science and engineering and medicine. The group consists of
roughly 50 people, and there are a lot of chemists, but also many
biologists now, several materials scientists, and even a couple of
medical doctors. And that doesn’t include the researchers we have
at the three companies we’ve created—a workforce of over
200 people working on these problems.
What are you working on now that you’re really
excited about but haven’t yet published?
On the pure chemistry side of things, what we want to do is learn how
to make molecules that do what PCR [the polymerase chain reaction]
does, but for things other than nucleic acids—asking the
question, how can one synthesize molecules that can recognize other
molecules and make more of them? PCR is an incredibly powerful
technology, but it only works for nucleic acids. Therefore, one of the
grand challenges is to design molecules that have nothing to do with
biology but are inspired by biology: they will be able to do what PCR
does, and allow one to recognize a small molecule—say, a
medically relevant diagnostic indicator—and trigger some sort of
conformational change that then turns over a catalytic reaction that
generates more of the molecule that the complex originally recognized.
In this way, one can create a cascade-amplification system, which has
all sorts of implications for diagnostics and therapeutics. If you look
at what PCR did for molecular biology and medicine, it really changed
the way we think about what we can detect. With PCR, researchers can
now analyze and identify a few molecules in a sample. Before PCR, those
molecules would have passed beneath the radar screen of the
conventional diagnostic tools we had at the time. I now want to be able
to develop the chemistry, and then ultimately the technology, to create
similar capabilities for other molecules beyond nucleic acids.
Your other great innovation, the one that
cemented your reputation, was dip-pen lithography. Can you tell us
how that came about?
Dip-pen was interesting. We weren’t trying to create a
lithographic tool when we invented it. We were actually studying water
transport from an AFM [atomic force microscope] tip to a surface. It
was hypothesized for a long time that when you bring a tip in contact
with a surface in air, water will collect at the point of contact.
That’s called the capillary effect. It turns out that
that’s a thermodynamic minimum for water in the system;
that’s the energetically preferred site for the water.
"One of the grand challenges is to design molecules
that have nothing to do with biology but are inspired
by biology," says Chad Mirlin of Northwestern
University, Evanston, Illinois."
I had a post-doc, Richard Piner, who was studying this water-transport
process. He was a pipe smoker, and during a routine experiment he left
the AFM tip in contact with the surface and went outside to smoke his
pipe, and when he came back, he pulled the tip away and did a survey
scan of the surface and saw what looked like a droplet. That droplet
turned out to be water. And that’s the first time anybody had
actually imaged what’s called the meniscus—the droplet of
water that forms at the point of contact between tip and surface. He
then discovered that when you move the tip across the surface, one of
two things happens: either you deposit water on the surface or you
deplete water from the surface. You create either a raised pattern or a
recessed pattern from that water transport. That’s
temporary—eventually, it simply fades away as everything returns
to equilibrium. And Richard, being a physicist, thought this was
absolutely fascinating, and it was.
But, as I told you earlier, I’m a chemist at heart. I said,
"Richard, this is fascinating, but nobody’s going to be really
interested in it, at least from the chemistry side, unless we can
actually make something with it. So why not try to put molecules on
that tip; say, alkanethiols, and see if they transport to gold, and use
the little droplet of water—turning a lemon into
lemonade—as a transport vehicle." Now, if we move the tip across
the surface, the molecules can move across or through the water, and if
they have a functional group that can react with the surface,
they’ll form a single layer on the surface that should be stable
and should last for a long time. And that was really the birth of
dip-pen nanolithography. Later, we found that this process is highly
controllable, and in fact you can use environmental humidity and the
water as a way of regulating how fast the molecules move from tip to
So, with water-soluble molecules, you can ratchet up the humidity and
increase their rate of transport or you can ratchet it down and
decrease it. And, in fact, the commercial systems that are now sold are
in controlled-humidity chambers. Then we started thinking about all of
the different things one can do with dip-pen, looking at the mechanisms
of transport, and it really gave birth to a whole area of nanoscale
molecular printing that now involves the patterning of just about
everything from DNA to proteins to viruses to small molecules to
catalysts to really anything one would like to study on the nanoscale.
It’s become, I think, one of the workhorse tools, if not
the workhorse tool, for nanotechnologists to study the
consequences of miniaturization and how chemically controlled surfaces
and interfaces can be used to study and regulate many processes in
chemistry and biology.
Considering that you now have over 350 patents
and technological innovations spanning, as you say, a wide variety
of fields, do you have a philosophy of invention that you can tell
us about? A way of thinking about problems that leads to
I see it as similar to composing. You get in, you start
looking—for instance, at some of the unusual characteristics of
materials, unusual properties—and you just connect the dots. You
say, "How can I use those new properties for developing tools that will
make a difference? Not just another way of doing things, but a much
better way of doing things?" I think that’s where a lot of people
miss the boat. The world doesn’t want just another way of
diagnosing or treating disease—it wants a better way of doing it.
So you really have to see what the analytical benchmarks are, what the
current ones are, and how you can exceed them with the new properties
or the new materials you’re making.