Automated science speeds solution of Human Genome data
ARGONNE, Ill. (Aug. 9, 2004) — Scientists in Argonne 's
Biosciences
Division are automating and
accelerating the complex processes that coax a protein to reveal
its structure so they can learn the role Nature assigned it.
Argonne is a leader in the world-wide scientific race to convert
data from the Human
Genome Project into three-dimensional images
that reveal how proteins function. Because proteins control everything
from breathing to digestion and sweating, this information can
help prevent or cure diseases in humans. Understanding other proteins
may help solve environmental problems.
The Biosciences Division plays many roles in piecing together
the meaning of the Human Genome data.
The division designed and operates the Structural
Biology Center (SBC) at the Advanced
Photon Source, the Western Hemisphere's
most brilliant source of research X-rays. The SBC beamline is the
world's most productive and efficient for solving protein structures
because it delivers the greatest detail to scientists.
For example, Argonne biophysicist and crystallographer Youngchang
Kim revealed a knot in an archaebacterium – the first ever observed
in this most ancient type of single cell organism and only the
second knot ever seen in a protein. Protein folding theory previously
held that a knot was not possible in a structure. Argonne 's brilliant
X-rays proved otherwise.
Argonne biologists managing the Midwest
Center for Structural Genomics (MCSG) determined and deposited
in the Protein
Data Bank 157 structures – as of
Aug. 1, 2004 – in less than four years of operation.
“When you consider it took seven years to determine the first
25 structures, you see how amazing the new processes are,” said
Structural Biology Center Director Andrzej Joachimiak. Joachimiak
also leads the Midwest Center fro Structural Genomics.
That number – 157 and growing fast -- is more than any of
the other nine structural genomic pilot centers funded by the
National Institute
of General Medical Science's pilot centers.
This National Institutes
of Health organization
leads the country's effort to determine the structures and functions
of the human genome.
The MCSG is composed of researchers from Argonne, Northwestern
University , Washington University School of Medicine, University
College of London, University of Toronto , University of Virginia
and the University of Texas Southwestern Medical Center at Dallas.
Argonne biologists and their colleagues use automation to dramatically
reduce the time and cost of cloning, expressing, purifying and
determining a protein's structure.
In the process, they are changing protein crystallography from
a one-lab, one-structure process into a highly automated production
line.
Since beginning research in 2000, MCSG biologists have used robotics
and computers to slash the cost of determining a structure from
$300,000 to $100,000 – they are planning to reduce it
further – and
the time from years and months to days and hours.
Protein crystallography poses difficult challenges because proteins
are unstable, soft molecules and require perfect conditions – temperature,
pH, salts and various additives – to crystallize. Hundreds of crystals
are created with the help of a robot in the hope of finding one,
perfect crystal that will reveal its structure. Converting a protein
into a crystal and then using X-rays to reveal its structure requires
at least 10 carefully controlled steps.
The Biosciences Division's old wet labs have been converted to
new labs with strict temperature and humidity controls that house
robots – many of which Argonne has designed with manufacturers.
Now Argonne researchers are cloning more than 1,000 genes a year – up
from 100 four years ago -- a 1,000 percent improvement.
Biologists developed a robotic purification system with the manufacturer,
Amersham Biosciences, and other labs are now buying the system
worldwide.
Researchers have even automated the process of loading the crystal
into the beamline for the X-ray study.
MCSG colleagues at the University
of Virginia and the University
of Texas ' Southwestern
Medical Center developed software to speed
data manipulation. The software automates the many computer steps
that convert the X-ray diffraction image of the protein crystal
to reveal its three-dimensional structure. This program has cut
the solution time from 8 hours to 2.5.
Center researchers based at the University
of London and Argonne's
Mathematics and Computer Science
Division are taking bioinformatics – the
combination of biology and computation -- to the next level by
creating structural bioinformatics. The London researchers are
developing computer analysis programs to identify potential targets
for comparative analysis. Researchers can save valuable research
time – and bypass
X-ray crystallography -- by predicting unknown protein functions
from structures already solved. London researchers are supplying
templates of the active site of solved proteins for comparison
that will be available to other researchers by the end of the summer.
The Biosciences Division's work for NIH has not gone unnoticed:
The U.S. Department of Energy is funding additional bioscience
automation research, and Argonne 's Biosciences Division is planning
to build the Advanced Protein Crystallization Facility to serve
as a regional, state-of-the-art resource for academic and industrial
biotechnology and biomedical researchers. The facility is planned
to have dedicated beamlines at the APS.
This facility may enhance Argonne 's opportunity to become home
to a $200 million Protein Production and Characterization Facility
recently announced as one of DOE's highest priority biotechnology
projects.
“Argonne is the world's most productive center for protein crystallizations
and structure determination,” said Biosciences Division Director
Lee Makowski . “We would love to build the Protein Production and
Characterization Facility here, because we developed and continue
to improve the automation process that is accelerating protein
structure determination.”
And the Advanced Photon Source is an incredible draw. While the
Structural Biology Center based at the APS is the world's best
in speed, resolution and quality, the APS also have 12 macromolecular
beamlines and several more are planned.
“With other facilities being planned at Argonne, such as the
Center for Nanoscale Materials and the University of Chicago's
Howard
T. Ricketts Regional Biocontainment Laboratory to study the
molecular mechanisms of infectious disease,” Makowski said, “we
will also have a strong microbiology facility, and we will be
able to make significant contributions to a wide range of biological
and medical problems, including new drug design ” — Evelyn
Brown
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