— To investigate tumors, pathologists currently rely
on labor-intensive microscopic examination, using
century-old cell-staining methods that can take days
to complete and may give false readings.
A lightning-fast laser
technique, led by Sandia National Laboratories researcher
Paul Gourley, has provided laboratory demonstrations
of accurate, real-time, high-throughput identification
of liver tumor cells at their earliest stages, and
without invasive chemical reagents.
The technique generates
a laser beam in single human cells pumped from a flask
through tiny microchannels. The beam is altered by
what it encounters. These changes, registered by an
imaging spectrometer, instantly identify cancer-modified
mitochondria in cells gone wrong. Mitochondria are
known as the power pack of cells, energizing them
like batteries do flashlight bulbs.
"There are hundreds
of mitochondria, sometimes thousands, in a cell,"
says Gourley. "To see them in the old way requires
a time-consuming process like fluorescent tagging
or a chemical reagent. We've found we can see them
immediately by light alone."
The techniques could
be critical to advancing early detection, diagnosis,
and treatment of disease.
More technically put,
"To rapidly assess the health of a single mammalian
cell," says Gourley, "the key discovery
was the elucidation of biophotonic differences in
normal and cancer cells by using intracellular mitochondria
as biomarkers for disease. This technique holds promise
for detecting cancer at a very early stage and could
nearly eliminate delays in diagnosis and treatment."
The technique is effective
because "it measures changes in the cell architecture,
especially those arising from alterations in protein
density, cytoskeleton shape, and distribution of mitochondria
- changes that occur when a cell becomes cancerous,"
"One would think
that if a cell became nonfunctional, it would become
disorganized. In cancer, however, that's not the case.
A cancer cell is like an insurgent terrorist with
a very well-defined agenda. It rearranges the cytoskeleton
and the arrangement of mitochondria in the cell. It's
no longer a cooperative agent in a collection of cells
but becomes malicious, tries to get outside the area,
and hijacks the respiratory machinery of a cell."
The biocavity laser
It is these changes
- a kind of beefing-up of the criminal forces - that
Gourley's device, called a biocavity laser, detects.
A nano-thin layering
of gallium aluminum arsenide combinations send up
numerous tiny beams from a small cross-sectional generating
area. These beams are reinforced or thwarted by the
position and density of the mitochondria.
we get from normal and cancer cells are very different,"
says Gourley. "Mitochondria conspire to cluster
around the nucleus and work together to supply energy
to the healthy, functioning cell. In contrast, the
mitochondria in the cancer cell sit all over, isolated
and balled up in a quiescent, non-functioning state.
Apparently, the rapidly growing cancer cells derive
energy from an alternative source such as free glucose
in the cell."
Fortunately, the mitochondrion
is nearly the same size as the light wavelength of
about 800 nanometers, a frequency otherwise little
absorbed by the body. Because of this close match,
the laser is exquisitely sensitive to subtle changes
in the mitochondria size and effects of clustering.
To date, the research team has found that 90 to 95
percent of light scatter generated is from optical
properties of mitochondria.
Working with UCSD
According to Bob Naviaux,
professor at the School of Medicine at the University
of California at San Diego and co-director of its
Mitochondrial and Metabolic Disease Center, "What's
attractive about this novel optical method for identifying
cancer cells is it's a very rapid and general method
that potentially can be applied to cancer cells from
solid tumors as well as hematological malignancies
Naviaux looks forward
to examining a wider population of cancer cells to
validate the method, combining the resources of his
Center with Sandia's laser expertise.
A project proposal
has been filed with Sandia to support collaborative
work between the unique research capabilities of UCSD
and Sandia. "There are 300 different cell types
in the human body and different mitochondria for each
different shape and arrangement," says Naviaux.
"We want a library of spectra from different
cell types and their cancers."
Aiding stem cell research
Of further interest
is that the biocavity laser may be applied not only
to identifying the spectra associated with cancer
cells but also those associated with stem cells, and
how these optical signals change as they differentiate
into nerve, muscle, and other tissues. "At present,
there's no rapid method for identifying the transitional
states [of a stem cell] with the functional cell type
it eventually becomes. That process is a mysterious
sequence of metabolic and genetic changes." There
are, he says, metabolic similarities between stem
cells and cancer cells, and researchers would like
to clearly identify the differences.
"Stem cells are
therapeutic," says Naviaux. "How are their
spectra distinct from cancer?"
A difficulty still
ahead is viewing cancer cells in fluids taken directly
from the body, rather than isolated by type in a flask.
This problem will be solved by winnowing out unlikely
particles through size and frequency.
Sandia is a multiprogram laboratory operated by Sandia
Corporation, a Lockheed Martin company, for the U.S.
Department of Energy's National Nuclear Security Administration.
Sandia has major R&D responsibilities in national
security, energy and environmental technologies, and
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