Download Worm research hits the fast lane

Decenber 2007 • www.BioscienceTechnology.com
Crystallization
Screens
Biological Computing
®
E N A B L I N G
L I F E
S C I E N C E
R E S E A R C H
PROTEIN RESEARCH FOCUS
These non-ionic
detergents are
suitable for isolating membrane-protein
complexes.
CELL RESEARCH FOCUS
Worm
Research
Hits the Fast Lane
Laser microdissection system
extracts small
biomaterials
from heterogeneous tissue
and cell
colonies.
FILTRATION FOCUS
Ultrasound
biomicroscopy
system is
offered for inutero mouse
brain embryonic
imaging.
SNAPSHOT
Types of Automated Lab Systems Being Used
by Tanuja Koppal, PhD
T
he nematode C. elegans
has been a geneticist’s
friend since the early
1960’s. The simplicity, transparency and speed of its biological functions have made C. elegans an ideal model organism
for studying genes and their
function. However, working
with C. elegans is not easy. It
requires a lot of time and
effort, as many assays remain
fairly archaic, involving manual
handling, picking and sorting of
the tiny organism. The largescale genome-wide assays using
C. elegans often take months or
even years to complete.
Mehmet Fatih Yanik, Ph.D., an
assistant professor in the department of Electrical Engineering
Continued on page 12
Figure 1. High-throughput in vivo
screening using microchamber
technology. A live worm (C. elegans) is immobilized in a
Dedicated Workstations
34.9%
Application Specific
Workstations
33.9%
Microplate Readers
31.7%
microfluidic chip by fluidic pressure in order to image its neu-
Mass Spectrometry
30.1%
rons at sub-cellular resolution.
Fluorescence and white-light
images are taken simultaneously.
Image Analysis
28.5%
Centrifugation
25.8%
Part of the microfluidic device,
the animal’s body, its green fluorescent protein (GFP) expressing
HTS Systems
neurons and their axons are all
Library
Management
visible in the same pseudo-col-
Sequencers
19.9%
16.1%
15.1%
ored image. (Source: Yanik, MIT)
Source: Bioscience Technology’s “Trends in the
Use of Laboratory Automation: 2007”
12
Cover Story
www.BioscienceTechnology.com
Continued from cover
at the Massachusetts Institute of
Technology (MIT) in Cambridge,
MA is using C. elegans as a
model to study genes involved in
neural regeneration and degeneration. “I started looking at how
people did assays using C. elegans and one of the things that
became clear is that people
Mehmet Fatih Yanik, Ph.D., an
assistant professor in the department of Electrical Engineering at
the Massachusetts Institute of
Technology (MIT)
(Cambridge) is using C. elegans
as a model to study genes
involved in neural regeneration
and degeneration. “I started looking at how people did assays
using C. elegans and one of the
things that became clear is that
people are still manipulating this
organism using manual techniques, transferring worms from
one plate to another by hand,”
says Yanik. Some genetic screens
using C. elegans have been performed in a high-throughput
fashion by modifying technologies developed for screening and
sorting cells. However, these
techniques are fairly limited in
their use. “[Using these techniques] you can tell that the fluorescence is coming from the
head of the worm but the head
contains hundreds of cells,” says
Yanik. “It doesn’t show any cellular resolution.”
To overcome this limitation
Yanik, who has a background in
Figure 2. Figure 2: An image
showing the microfluidic screening chambers where one of the
chambers is filled with a different
color dye than the other chambers to show selective addressing
of each chamber for drug/compound/RNAi delivery. This technology can be used to perform
large-scale RNAi and drug
screens. (Source: Yanik, MIT)
engineering and physics, has
proceeded to develop a microfluidic chip that offers both
speed and resolution. This technology promises to automate
and accelerate most of the
genetic screens currently performed using C. elegans. The
chips are designed and fabricated in Yanik’s laboratory using
polymers that are transparent to
light and keep the worms
healthy. The details of the chip
design and its applications are published in the August
2007 issue of the
Proceedings of the
National Academy of
Sciences of the USA.
Yanik’s laboratory is
now developing
methods for highthroughput, largescale screens using
this microfluidic
chip.
By changing its configuration,
the chip can be modified to perform various types of fluorescence-based genetic screens. For
instance, the chip can be used
as an automated sorter device
By changing its configuration, the microfluidic
chip can be modified to perform various types
of fluorescence-based genetic screens.
for genome-wide mutagenesis
screens. A mutagenesis screen
involves randomly mutating
genes in the worms and examining the phenotypes of the
mutants. Using the sorter
device, the worms are sucked
into the microfluidic chamber
one at a time and immobilized
to obtain a high resolution
image to examine its phenotype.
“This way, if you have 40,000
mutagenized worms, the sorter
Mehmet Fatih Yanik is an assistant professor in the department of
Electrical Engineering and is a member of the Computational and
Systems Biology program at Massachusetts Institute of Technology
(MIT). His research expertise lies at the confluence of applied
physics, bioengineering and neurobiology. He received his B.S. and
M.S. degrees in Electrical Engineering and Physics from MIT. He
went to Stanford University for his Ph.D. in Applied Physics and continued his postdoctoral work in Bioengineering and Neurosurgery there. Yanik is “one of the world’s
top 35 innovators under the age of 35” according to MIT’s Technology Review magazine. His work related to the development of the microfluidic chip for high-throughput, whole-animal screening was recently awarded the NIH Director’s New Innovator
Award. This award will provide Yanik’s lab with nearly $2.5 million dollars in funding
over the next five years.
can go through it really fast, in
fractions of a second,” says
Yanik. “You can potentially
screen the entire genome in a
few hours and you can do this
at a very high resolution to see
the cellular detail.”
The microfluidic device can
also be used to perform largescale RNA interference (RNAi)
assays and compound screens.
For RNAi screens, the microfluidic chip is divided into several
microchambers. One worm and
one RNAi vector that is specific
for silencing a single gene is
delivered to each chamber and
the phenotypes are observed
under a microscope. “We know
what gene is targeted and so
we can map out what phenotype is observed when that gene
is silenced,” says Yanik. The
same methodology can also be
used to perform drug and
compound screens. He is also
looking to extrapolate this technology to other model organisms, such as zebrafish and
others that grow in liquid culture. “But we cannot extend it
to Drosophila because it cannot
be cultured in liquid,” says
Yanik.
This technology is drawing a
lot of interest in the C. elegans
community, where researchers
are always on the lookout for
means to accelerate their
research. Yanik is also talking
to some companies that have
expressed an interest in commercializing the technology.
"The challenge of running a
system like this right now is
[it’s] like driving a Ferrari," he
says. "A Ferrari is a fast car, a
ncie car, but it's not practical.
What we want to do is make it
like a Toyota and make it easy
to run so that we can send it to
someone and they can run it
very rapidly without our help."
12/2007 • Bioscience Technology