|Popular introductions to nanotechnology usually crow about the minuteness of it all. Nano means small, we are told: really, really small. Think “teeny” and keep going.
Like a bolted morsel triggering the cough reflex, such naïveté forces
an involuntary guffaw out of Timothy Triche, chief pathologist at
Childrens Hospital Los Angeles and a member of the USC Provost’s
Biomedical Nanoscience Initiative. Nanoscale objects (a nanometer is a
billionth of a meter) are plenty big compared to, say, an atom. And
that’s a good thing, explains the physician-researcher who once dreamed
of becoming a particle physicist.
There is a reason no one has ever heard of quark-based medicine or
lepton therapy: nanoparticles in medicine need to hit a sweet spot.
Make them too big, above 100 nanometers, and they get trapped in the
bloodstream, unable to reach their target cells. Too small, below 10
nm, and the particles vanish into the churning waste-treatment plants
of the kidneys and liver. “These things are certainly not tiny like
elementary particles,” says Triche of the nanomedicines his lab is
currently developing. “These things at least have some discrete
One might expect the nano scale to be an attractive research area –
being so much more manageable than lab work at the atomic level. But
science does not always progress by the most direct route. In the first
half of the 20th century, Einstein’s famous formula (you know, that
one) and quantum mechanics worked like a gold rush, pulling scientists
from the East Coast of classical mechanics to the western ranges of
high-energy physics. Overlooked in the physics frenzy was that
nondescript land in the middle, a Nebraska of understated promise, an
Omaha waiting for its sage.
The sage has been slow in coming.
So far, nanotechnology has excelled at producing clever tag lines.
(“Nano: the next big thing.” “Size matters.” And Nobelist Richard
Feynman’s early entry, in a famous 1959 lecture predicting the age of
nano: “There’s plenty of room at the bottom.”)
The field also has scored impressive breakthroughs in funding.
(“Nanotechnology,” an Oxford don reportedly sneered, comes from a Greek
word meaning “grant.”)
What nanotechnology has not
yet done, for the most part, is produce really major advances in basic
science, engineering or medicine. A cynic, echoing the saw about
nations stuck on the verge of greatness, might say that nano is the
technology of the future, and always will be.
“But,” one might ask, “what about my nano-treated stain resistant
khakis from Gap? Or my nanosilver-enhanced antibacterial athletic socks
from Sharper Image, which cost four times as much as the regular kind?”
The marketing industry is not above exploiting nano for commercial
gain. This is not to deny that many products contain nanoscale
components, or that such components are useful – they do, and they are.
But the English chemist Michael Faraday was already making gold
particles a few nanometers across in a beaker back in the 1850s.
Nano-sized specks of titanium dioxide, with their unique reflective
properties, have been brightening white paint for decades – long before
a popular paint manufacturer began touting its “nano guard” process.
The truth is that making bits of matter on a nanoscale, especially
metals, can be surprisingly simple. With the cost of manufacturing
coming down and the understanding of nanoscale matter’s useful
properties going up, the use of nano in consumer products is taking off.
But actually making nanoscale structures, machines, engineered objects
with a specific function – that is the hard part, says USC chemist Mark
Thompson, who with Richard Cote of the Keck School of Medicine of USC
co-directs the Biomedical Nanoscience Initiative announced by Provost
C. L. Max Nikias in the fall of 2005.
Fittingly, for a major
research university, the USC initiative is focused precisely on the
hard part. Nanoscale biomedicine also happens to be the newest and most
“The excitement is that it’s a very
open area,” says Thompson, who specializes in molecular materials and
thin films. “There’s a lot yet to be learned, and a lot of techniques
to be developed before we can exploit things on the nanometer scale.
The biological aspect of nano is really quite recent.”
So recent, in fact, that Thompson knows of only one successful, truly
nano-engineered biomedical product: Abraxane, a new formulation of the
anti-cancer drug known as Taxol.
Taxol’s problem has been that it does not dissolve spontaneously in the
bloodstream. This was corrected by mixing the drug with a kind of
castor oil. But the additive made Taxol more toxic and caused allergic
reactions in many patients.
The new drug, Abraxane, consists of Taxol enclosed in nanoparticles
that travel throughout the body, but that bind preferentially to
“The nanoparticle is designed to actually interact with a receptor that
is more highly expressed on cancer cells,” says Cote, who is a research
pathologist and urologist based at the USC/Norris Comprehensive Cancer
Center. The particle latches on to the receptor and gets absorbed by
the cell, he explains, multiplying the drug’s specificity compared to
How do you get the Taxol into the nanoparticles? Like a glass bottle
blown around a model ship, the nanoparticles are grown in Taxol instead
of in water or another solvent. Their insides can’t help but be full of
Even better would be a nanocapsule so specific that it binds only to
the cancer cell. That is the goal of Triche’s laboratory in its work
against Ewing’s sarcoma, a bone tumor found among children and young
adults. (Two of the researchers in Triche’s group are themselves
The laboratory has been encapsulating a standard chemotherapy drug,
brand name Irinotican, with a very non-standard nanocapsule. To
Triche’s knowledge, this is the first capsule designed to bind a
receptor specific to a tumor cell.
“Total specificity,” in which only cancer cells are harmed, is the great quest of chemotherapy.
“If you keep your relatively toxic drug in a nanoparticle, and the
nanoparticle goes to the tumor, and relatively little of it goes to the
bone marrow,” says Triche, you achieve that specificity.
To keep the patient’s immune system from attacking the nanoparticles,
they are coated with what Triche calls “stealthy liposomes” – sugars,
essentially – that fool the immune system but do not interfere with the
nanoparticle’s precision-guided targeting mechanism.
“The miracle to me is that it actually works,” he says.
Triche calls his method “targeted-targeted therapy” – targeted to find
the tumor, and targeted to kill it. In the interest of full disclosure,
he adds that the nanoparticle is not 100-percent specific: a small,
non-essential number of immune cells share the target receptor, as do
some cells in the testes. For the same reason, many other less-specific
chemotherapy drugs are known to compromise fertility.
“It was pretty successful,” deadpans Siwen Hu, a post-doc in Triche’s
lab who played a key role in developing the Irinotican-injected
nanoparticles. Her remark is an understatement. “It” turns out to be
not only a series of wildly successful experiments with nanoparticles
carrying the cancer drug, but also a bold extension of that concept
using silencing RNA (a 1998 discovery recently awarded the Nobel Prize
in Medicine). Just as they carry chemotherapy drugs, nanoparticles also
can smuggle siRNA into a tumor cell, turning off genes essential to
tumor growth. The smuggler, a protein that loads iron into cells, works
like a Trojan horse for the delivery of siRNA. Beware of nanoparticles
In experiments on mice with induced Ewing’s cancer, Triche’s lab achieved complete remission in 80 percent of cases.
“We conclude that this novel delivery system is a powerful and simple
method to induce gene silencing, with the potential to move to clinical
trials,” Hu said at a 2005 meeting of the American Association for
Cancer Research, which presented her with a scholar-in-training award.
Among others, The Economist covered the breakthrough.
Impressed by the initial results, the Nanoparticle Identification
Laboratory at the National Cancer Institute has commissioned huge
batches of nanoparticles, intending to perform all the tests required
by the Food and Drug Administration for a drug filing. It’s a win-win
proposition for Triche and USC. If the nanoparticles pass muster, the
university retains the right to submit the actual filing and to hold
The work at Triche’s
lab demonstrates another striking fact about nanotechnology: for all
the academic hype about interdisciplinary research, nano may be one
area where cross-campus collaborations are not just useful, but
indispensable. Triche works closely with Magnus Nordborg, associate
professor in molecular and computational biology in the USC College of
Letters, Arts and Sciences; his nanoparticle research group includes
another computational biologist, a graduate student of USC
math-biology-medicine polymath Simon Tavaré.
is the new face of biomedical research,” Triche says. “Statistics and
mathematical modeling become incredibly important.”
In that sense, the Biomedical Nanoscience Initiative formalizes and
supports what was already a university-wide movement.
“The initiative came along because when Max Nikias went into the
provost’s office he already had an understanding that nano was
important,” says Thompson, the chemist. (Nikias is an engineer and past
dean of the USC Viterbi School.)
But instead of starting a generic nanoscience program, the likes of
which exist elsewhere, Nikias searched for a synergy unique to USC. He
found it in a marriage of the University Park campus, the Keck School
and Childrens Hospital Los Angeles.
“If you really want to have a footprint, you have to pick and choose
your areas,” says Cote. “And where would USC have an advantage over,
for example, a Caltech, in nanosciences? What do we have that Caltech
“We have a huge biological and medical program. We have a medical
school. And, in fact, that has been a major attraction. It has
generated interest from the Caltech community and UC Berkeley.”
Cote’s own research program exemplifies the marriage foreseen by the
provost. Cote, a urologist-pathologist from the Keck School of
Medicine; Thompson, a chemist-materials scientist from the USC College;
and Chongwu Zhou, an electrical engineer from the USC Viterbi School of
Engineering, are co-investigators on what may be the initiative’s
signature project: an effort to develop nano-sized sensors that would
screen for many types of cancers at once, with just a drop of a
patient’s blood, and in a single step.
To grasp the significance of such a sensor, it helps to understand the
current state of cancer screening. So-called early detection strategies
– mammograms, colonoscopies and such – detect tumor masses.
Unfortunately, by the time a tumor mass forms, millions or billions of
cells have already turned against the body. In the brave new nano
world, early detection means something different.
What if you could detect the very genesis of a cancer at the cellular
level? The difference between nanoscale cancer screening and today’s
idea of “early detection” is the difference between forecasting a snow
storm and waking up to four inches of the stuff.
One existing test approximates the nano ideal. Known as PSA, for
“prostate specific antigen,” it detects a protein expressed by prostate
tumors. Unfortunately, PSA is notorious for its high false-positive
rate: many biopsies come back negative, and many of the tumors are so
slow-growing they will never threaten the patient. The test also
requires a relatively large blood sample, says Cote, followed by up to
20 expensive and time-consuming steps.
“And that’s just for one disease,” adds the Keck School researcher,
whose specialty is in the detection of micrometastases in epithelial
“Now imagine that I can take a drop of blood, that I can put it on a
chip that’s two-by-two centimeters in dimension, and that I can run
hundreds or even thousands of reactions at once with that drop of
Great idea. But it requires sensing ability at the nano scale.
This is where Zhou’s
nanowires and nanotubes come in. In his gleaming white, deceptively
sparse laboratory in Tutor Hall, the USC Viterbi researcher leads
visitors in hospital slippers on a tour of the tools of nanoscience.
On a table nearest the security doors is an atomic force microscope:
essentially a very sharp needle, 10 nm in diameter at the tip, that is
repelled by the atomic force of other matter. By tracing a sample – say
a silicon wafer – with the needle and measuring the force pushing it
away, the microscope produces a textured map of the sample’s surface.
Down the hall to the right, past graduate students deep in analysis at
their workstations, Zhou points to his two workhorse instruments:
tabletop metal boxes facing each other across a small room.
One is a laser ablation system for making nanowires. The laser heats
the surface of a target, vaporizing some of the material. By supplying
the appropriate catalyst, usually a cluster of gold atoms, Zhou and his
students induce the vapor to reform into solid nano-sized wires or,
under different conditions, two- or three-dimensional wire structures.
Across the room is Zhou’s homemade device for growing carbon nanotubes.
Its name is descriptive to a fault: “carbon nanotube chemical vapor
deposition.” By flowing carbon-containing gases into the device –
providing a sapphire catalyst – and heating the chamber to around 900
degrees Celsius, Zhou and his team have found that the carbon
self-assembles into nanotubes, and that these nanotubes are ideally
oriented for conducting electricity. (Scientific American reported on the discovery earlier this year.)
Why do nanowires and nanotubes matter? In the semiconductor world,
conventional silicon circuits are approaching their physical limit. If
they could be mass-produced, nanoscale circuits would provide faster
conduction, lower heat loss, smaller circuit size and greater computing
More importantly for medical research, the unique properties of nano
structures seem tailor-made for sensor design. An effective sensor for
a cancer marker needs to find the target protein, capture it and
communicate its capture. Larger sensors can capture target proteins,
but the molecules are like fleas on an elephant – too small to be
noticed or to affect the mighty pachyderm’s gait.
As luck would have it, nanowires and nanotubes are similar in scale to
proteins. Moreover, as objects get smaller, the ratio of their
surface-area to their volume gets bigger and bigger. By analogy, a
nanoscale man would be all skin, with little or no muscle or bone.
Since the skin of the nanosensor is the part that interacts with target
proteins, even the binding of a single protein would feel less like a
flea bite than a mastiff’s chomp.
“The properties of the nanowire are very strongly influenced by
anything happening on the surface,” says Thompson, the chemist. “And so
now you can get a substantial change in your transistor response by
binding something to the surface of a nanowire, that you wouldn’t have
gotten with a larger sensor.”
Bye-bye clunky PSA test.
“If I functionalize this [nano]wire, and I bind something to it
specifically, I might need to only do that in order to detect a
specific reaction,” says Cote. “One step. We’ve in fact shown this.”
The team has already published some results and is awaiting word on a
series of grants to start moving the technology from the lab to the
The biggest remaining challenge, says Keck School doctoral student
Henry Lin, is to make the sensor work in the protein stew that is a
patient’s blood serum. “Non-specific binding,” in which a normal
protein manages to latch on to the nanowire, is always a concern. The
same challenge confronts a different nanosensor under development in
Cote’s lab: a cantilever – essentially a springboard – treated to bind
target proteins and to warp detectably from electromagnetic attraction
Once a cancer is
found, nanotubes also might figure in its elimination. Cancer kills
from within, so wouldn’t it be poetic justice for cancer’s killers to
do the same?
Zhou is investigating the use of
nanotubes as lethal vectors capable of infiltrating cancer cells but
not healthy tissue. This approach relies on a common trait of cancer
tumors: because they grow so fast, their structures develop gaps and
cracks. If nanotubes could penetrate the tumor through these cracks,
they could be heated with an infrared laser, says Zhou, destroying the
cancer cells without the side effects and potential for drug resistance
that plague chemotherapy.
All of these efforts share a common first step: Find a protein or other
molecule that will bind, or latch onto, a receptor on the cancer cell.
This is not always easy to achieve, especially if, to avoid false
positives, the desired molecule must be incapable of binding to other
There are almost as many ways to identify binding molecules, or
ligands, as there are cancers. All have their limitations. Richard
Roberts, a chemist in USC College, has a few trillion reasons to tout
his radical method.
Roberts specializes in “genetic evolutionary design.” The philosophy
behind his approach might be summarized thus: “Let’s not restrict
ourselves to molecules that exist today. Let’s try to find useful
molecules that evolution has not yet created, or that it should create
but might never get to.”
Roberts and his lab have built a library of trillions of molecules to literally throw at a cancer protein.
“We take the protein and we usually just use this library to target
different sites on it,” he says. “We just mix the two together and see
Though Roberts calls his approach “naïve,” it nevertheless delivers
molecules that are frequently useful or “functional,” in the jargon of
“It’s the brute force approach to being a locksmith,” says Roberts.
“You have a pocket with a trillion keys in it. Our strategy lets you
essentially test each key simultaneously.”
As a bonus, the approach also may deliver better formulations of common
drugs. One method, mentioned earlier, is to enclose a drug such as
Taxol in a protective nanocapsule. But there are other ways to skin a
nanocat. Roberts and his lab believe they can use their synthetic
library to make more durable versions of certain classes of drugs, such
as peptides, that fall apart quickly in the bloodstream.
Synthetic approaches are
hot in the fight against unnatural diseases, and Roberts’ “accelerated
evolution” looks almost natural compared to the armies of nanorobots
envisioned by computer scientist Aristides Requicha of the USC Viterbi
School. Together with Zhou and Thompson, Requicha runs the Laboratory
for Molecular Robotics, which is already working on components of
nanorobots, such as tiny transistors and actuators.
Instead of putting blood into the sensor, Requicha wants to put the
sensor in the blood. And not just one sensor, but a whole fleet – a
“sensor-actuator network” that could provide real-time monitoring of
the body’s health and carry out repair jobs.
While such nanorobots are a few years away – in Requicha’s most
optimistic estimate – his laboratory already has nano pseudo-bots that
could perform useful sensing and monitoring tasks in test tubes,
perhaps to study how cells interact or how healthy cells differ from
But the actual nanobot-in-body enterprise has what Requicha calls “a
big power problem.” Nobody has figured out how nanobots in the
bloodstream would power themselves or communicate wirelessly, both
among themselves and with an external computer.
Mark Humayun and Anupam Madhukar do not pretend to have solved that
problem, but their research on a different problem is revealing
surprising insights on how to harness a cell’s own power.
Humayun, professor of ophthalmology, biomedical engineering and cell
neurobiology in the Keck School, is best known to date for his retinal
implant – a micro-scale device that has returned a degree of sight to
some totally blind patients. Madhukar, professor of engineering at USC
Viterbi, is an expert in optical electronics at the nanoscale. One of
the earliest advocates of nano at USC, he proposed a program within
engineering in 1992.
Now the two are collaborating on a project that, if successful, would
make the retinal implant a true nanoscale device. And more broadly, it
would harness the cell as a power source for all kinds of nano
Humayun’s group has already identified a molecule naturally occurring
in spinach that makes nerve cells light-sensitive. The implications are
potentially staggering. Humayun’s retinal implant bypasses dead retinal
cells to electronically stimulate intact receptors in the eye. But from
a nano perspective, the implant is still unwieldy and primitive. The
molecule Humayun discovered might be able to do the same job as the
implant, without the awkward electronics and external power source.
But, he says, “we have to get this into the cell membrane.”
Madhukar and graduate student Siyuan Lu think they know how to use
nanotechnology to create protein-sized devices that can be embedded in
cells to restore or endow new function. Scientists already attach
fluorescent tags known as quantum dots to specific ligands, which then
bind to desired proteins on the cell surface. Humayun, Lu and Madhukar
propose replacing the fluorescent tag with an “active” device that will
perform the desired function. Making the nerve cell light-sensitive, as
for the retina, is just one of many possible applications.
“We can use these functional active nano devices, or FANS, by putting
them directly at appropriate places in the cell,” says Madhukar, who
holds faculty appointments in materials science, biomedical and
chemical engineering and physics.
Details are still confidential – the researchers are filing for a
patent – but Humayun can barely contain his enthusiasm. “Once you have
control over the cell with a receptor, now you got ’em. You can drive
the energy harnessed in the cell. It’s very powerful.”
It is a short hop
from Madhukar’s active nano devices to Requicha’s robotic legions to
Zhou’s nanowires and carbon nanotubes. The existence of such closely
related projects in one university, with synergies yet unexplored,
argues for a structure to bring them together. The Biomedical
Nanoscience Initiative is an obvious start, but the provost also is
considering the establishment of a biomedical nanoscience institute, as
yet unnamed and unfunded, to coordinate projects, encourage
collaborations and just gather USC nano scholars under one roof for a
few hours a month.
In addition, USC may have room for a few more outstanding scientists.
“We would like to bring in, not just one or two, but a group of
individuals who can really push the university forward in this field,”
says Randolph Hall, vice provost for research advancement.
Meanwhile the university is already busy with major upgrades to its
nanotechnology capability: millions of dollars for “core labs” (shared
by all interested researchers) to acquire the latest fabrication
equipment, microfluidic devices, electron microscopes and other basic
tools of nano.
In the late 19th century, universities around the world upgraded their
laboratories with stunningly powerful optical tools that afforded
glimpses of matter at the micro scale – hence the name “microscope.”
Is nanotechnology the destination or a way station? Will mankind
someday need even smaller tools to fix the nanomachines that fix the
“In the Reign of Harad IV” – a short story by noted American fiction
writer Steven Millhauser – tells of a miniature maker so accomplished
that he begins to work in the invisible realm, confidently assembling
minuscule masterpieces by feel even as his students and patrons write
him off as insane. At the story’s conclusion, two students bestow
exaggerated praise on his latest creation, an invisible kingdom.
The maker of miniatures, knowing that [the students] had seen nothing,
that their words were hollow, and that they would never visit him
again, returned with some impatience to his work; and as he sank below
the crust of the visible world, into his dazzling kingdom, he
understood that he had traveled a long way from the early days, that he
still had far to go, and that, from now on, his life would be difficult
and without forgiveness.
Particle physics may yet return to haunt medicine’s miniature makers.
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In his Tutor Hall lab, electrical engineer Chongwu Zhou (left) confers
with chemist Mark Thompson and pathologist Richard Cote, co-directors
of the USC Biomedical Nanoscience Initiative.
Photographs by Mark Berndt
|Trojan Horse Breeders
Siwen Hu, a postdoctoral fellow at USC-affiliated Childrens Hospital
Los Angeles, reviews the progress of tumors in lab rats receiving
chemotherapy via a revolutionary nanocapsule that she helped develop in
the lab of CHLA chief pathologist Timothy Triche (left). Their new
delivery system may be on the market soon; tests needed for an FDA
filing have been commissioned by the National Cancer Institute.
|At the Forge
Chemical engineer Ted Lee (right) fires up a laser light and detector
capable of measuring particles in a solution. Lee teaches a new
undergraduate class in “nano-blacksmithing” offered through the USC
Viterbi School. With him (from left) are journeymen nanosmiths Panteha
Mirarefi and Anne-Laure Leny, both doctoral students in chemical
engineering, and junior Jonathan Lo, an aspiring apprentice from Lee’s