A team led by scientists at the California
Institute of Technology (Caltech) have made the first-ever mechanical device
that can measure the mass of individual molecules one at a time.
This new technology, the researchers say,
will eventually help doctors diagnose diseases, enable biologists to study
viruses and probe the molecular machinery of cells, and even allow scientists
to better measure nanoparticles and air pollution.
The team includes researchers from the
Kavli Nanoscience Institute at Caltech and Commissariat à l’Energie Atomique et
aux Energies Alternatives, Laboratoire d’électronique des technologies de
l’information (CEA-LETI) in Grenoble, France. A description of this technology,
which includes nanodevices prototyped in CEA-LETI’s facilities, appears in the
online version of Nature
The device—which is only a couple
millionths of a meter in size—consists of a tiny, vibrating bridge-like
structure. When a particle or molecule lands on the bridge, its mass changes
the oscillating frequency in a way that reveals how much the particle weighs.
“As each particle comes in, we can
measure its mass,” says Michael Roukes, the Robert M. Abbey Professor of
Physics, Applied Physics, and Bioengineering at Caltech. “Nobody’s ever
done this before.”
The new instrument is based on a technique
Roukes and his colleagues developed over the last 12 years. In work published
in 2009, they showed that a bridge-like device—called a nanoelectromechanical
system (NEMS) resonator—could indeed measure the masses of individual
particles, which were sprayed onto the apparatus. The difficulty, however, was
that the measured shifts in frequencies depended not only on the particle’s
actual mass, but also on where the particle landed. Without knowing the
particle’s landing site, the researchers had to analyze measurements of about
500 identical particles in order to pinpoint its mass.
But with the new and improved technique,
the scientists need only one particle to make a measurement. “The critical
advance that we’ve made in this current work is that it now allows us to weigh
molecules—one by one—as they come in,” Roukes says.
To do so, the researchers analyzed how a
particle shifts the bridge’s vibrating frequency. All oscillatory motion is composed
of so-called vibrational modes. If the bridge just shook in the first mode, it
would sway side to side, with the center of the structure moving the most. The
second vibrational mode is at a higher frequency, in which half of the bridge
moves sideways in one direction as the other half goes in the opposite
direction, forming an oscillating S-shaped wave that spans the length of the
bridge. There is a third mode, a fourth mode, and so on. Whenever the bridge
oscillates, its motion can be described as a mixture of these vibrational
The team found that by looking at how the
first two modes change frequencies when a particle lands, they could determine
the particle’s mass and position, explains Mehmet Selim Hanay, a postdoctoral
researcher in Roukes’s laboratory and first author of the paper. “With
each measurement we can determine the mass of the particle, which wasn’t
possible in mechanical structures before.”
Traditionally, molecules are weighed using
a method called mass spectroscopy, in which tens of millions of molecules are
ionized—so that they attain an electrical charge—and then interact with an
electromagnetic field. By analyzing this interaction, scientists can deduce the
mass of the molecules.
The problem with this method is that it
does not work well for more massive particles—like proteins or viruses—which
have a harder time gaining an electrical charge. As a result, their
interactions with electromagnetic fields are too weak for the instrument to
make sufficiently accurate measurements.
The new device, on the other hand, does
work well for large particles. In fact, the researchers say, it can be
integrated with existing commercial instruments to expand their capabilities,
allowing them to measure a wider range of masses.
The researchers demonstrated how their new
tool works by weighing a molecule called immunoglobulin M (IgM), an antibody
produced by immune cells in the blood. By weighing each molecule—which can take
on different structures with different masses in the body—the researchers were
able to count and identify the various types of IgM. Not only was this the
first time a biological molecule was weighed using a nanomechanical device, but
the demonstration also served as a direct step toward biomedical applications.
Future instruments could be used to monitor a patient’s immune system or even
diagnose immunological diseases. For example, a certain ratio of IgM molecules
is a signature of a type of cancer called Waldenström macroglobulinemia.
In the more distant future, the new
instrument could give biologists a view into the molecular machinery of a cell.
Proteins drive nearly all of a cell’s functions, and their specific tasks
depend on what sort of molecular structures attach to them—thereby adding more
heft to the protein—during a process called posttranslational modification. By
weighing each protein in a cell at various times, biologists would now be able
to get a detailed snapshot of what each protein is doing at that particular
moment in time.
Another advantage of the new device is that
it is made using standard, semiconductor fabrication techniques, making it easy
to mass-produce. That’s crucial, since instruments that are efficient enough
for doctors or biologists to use will need arrays of hundreds to tens of
thousands of these bridges working in parallel. “With the incorporation of
the devices that are made by techniques for large-scale integration, we’re well
on our way to creating such instruments,” Roukes says. This new
technology, the researchers say, will enable the development of a new
generation of mass-spectrometry instruments.
“This result demonstrates how the
Alliance for Nanosystems VLSI, initiated in 2006, creates a favorable
environment to carry out innovative experiments with state-of-the-art,
mass-produced devices,” says Laurent Malier, the director of CEA-LETI. The
Alliance for Nanosystems VLSI is the name of the partnership between Caltech’s
Kavli Nanoscience Institute and CEA-LETI. “These devices,” he says, “will
enable commercial applications, thanks to cost advantage and process