This is a photograph of the Columbia Engineering team’s custom multichannel CMOS preamplifier chip, attached to a circuit board with thin gold wirebonds. Credit: Columbia Engineering

As
nanotechnology becomes ever more ubiquitous, researchers are using it
to make medical diagnostics smaller, faster, and cheaper, in order to
better diagnose diseases, learn more about inherited traits, and more.
But as sensors get smaller, measuring them becomes more difficult—there
is always a tradeoff between how long any measurement takes to make and
how precise it is. And when a signal is very weak, the tradeoff is
especially big.

   

A
team of researchers at Columbia Engineering, led by Electrical
Engineering Professor Ken Shepard, together with colleagues at the
University of Pennsylvania, has figured out a way to measure
nanopores—tiny holes in a thin membrane that can detect single
biological molecules such as DNA and proteins—with less error than can
be achieved with commercial instruments. They have miniaturized the
measurement by designing a custom integrated circuit using commercial
semiconductor technology, building the nanopore measurement around the
new amplifier chip. Their research will be published in the advance
online publication on Nature Methods‘ website at 2 p.m., March 18, 2012.

   

Nanopores
are exciting scientists because they may lead to extremely low-cost and
fast DNA sequencing. But the signals from nanopores are very weak, so
it is critically important to measure them as cleanly as possible.

   

“We
put a tiny amplifier chip directly into the liquid chamber next to the
nanopore, and the signals are so clean that we can see single molecules
passing through the pore in only one microsecond,” says Jacob
Rosenstein, a Ph.D. candidate in electrical engineering at Columbia
Engineering and lead author of the paper. “Previously, scientists could
only see molecules that stay in the pore for more than 10 microseconds.”

   

Many
single-molecule measurements are currently made using optical
techniques, which use fluorescent molecules that emit photons at a
particular wavelength. But, while fluorescence is very powerful, its
major limitation is that each molecule usually produces only a few
thousand photons per second.

“This
means you can’t see anything that happens faster than a few
milliseconds, because any image you could take would be too dim,”
explains Shepard, who is Rosenstein’s advisor. “On the other hand, if
you can use techniques that measure electrons or ions, you can get
billions of signals per second. The problem is that for electronic
measurements there is no equivalent to a fluorescent wavelength filter,
so even though the signal comes through, it is often buried in
background noise.”

   

Shepard’s
group has been interested in single-molecule measurements for several
years looking at a variety of novel transduction platforms. They began
working with nanopore sensors after Marija Drndic, a professor of
physics at the University of Pennsylvania, gave a seminar at Columbia
Engineering in 2009. “We saw that nearly everybody else measures
nanopores using classical electrophysiology amplifiers, which are mostly
optimized for slower measurements,” notes Shepard. “So we designed our
own integrated circuit instead.”

   

Rosenstein
designed the new electronics and did much of the lab work. Drndic’s
group at the University of Pennsylvania fabricated the nanopores that
the team then measured in their new system.

   

“While
most groups are trying to slow down DNA, our approach is to build
faster electronics,” says Drndic. “We combined the most sensitive
electronics with the most sensitive solid-state nanopores.”

   

“It’s
very exciting to be able to make purely electronic measurements of
single molecules,” says Rosenstein. “The setup for nanopore measurements
is very simple and portable. It doesn’t require a complicated
microscope or high powered instruments; it just requires attention to
detail. You can easily imagine nanopore technology having a major impact
on DNA sequencing and other medical applications within the next few
years.”

   

Shepard’s
group is continuing to improve these techniques. “With a
next-generation design,” he says, “we may be able to get a further 10X
improvement, and measure things that last only 100 nanoseconds. Our lab
is also working with other electronic single-molecule techniques based
on carbon nanotube transistors, which can leverage similar electronic
circuits. This is an exciting time!”

   

This
research has been funded by the National Institutes of Health, the
Semiconductor Research Corporation, and the Office of Naval Research.

Source: Columbia University