ability of molecular biologists to sequence the human
genetic code promises to usher in a new era of genetic
medicine, but that doesn't mean current science can
accurately read your personal genetic code. The sequencing
of the DNA comprising the code is still far too slow,
costly and inaccurate to allow the kind of accurate
sequencing of specific tissues that is necessary to
understand many of particular genetic problems of
radical new method of DNA sequencing currently being
explored by Stuart Lindsay, Director of the Center
for Single Molecule Biophysics in the Biodesign Institute
at Arizona State University and Professor of Physics
at ASU, could make the long-dreamt-of era of true
genetic medicine possible with extremely rapid, accurate
and low cost sequencing of single DNA molecules. However,
a number of significant technical hurdles still need
to be overcome before the idea can be considered a
the goal of overcoming these technical challenges,
the National Human Genome Research Institute (NHGRI)
of the National Institutes of Health has awarded a
$550,000 three-year grant to Lindsay to further develop
a nanotechnology project for rapid genetic profiling.
The award is just one of seven given this year in
NHGRI's "Revolutionary Genome Sequencing Technologies"
grant program, which the Institute says is aimed at
"the development of breakthrough technologies
that will enable a human-sized genome to be sequenced
for $1,000 or less."
a scientist, however, Lindsay is careful in not claiming
a breakthrough yet. "There is still a fair amount
of harsh reality to deal with," he said. "As
we work harder on the project, we haven't yet encountered
any fundamental problems that say this is impossible
but we have encountered lots of challenges that still
need to be solved. But this is what scientific research
is about. We are making solid progress and every time
a new problem has come up, we have found a way around
it. This grant is a wonderful opportunity to continue
new sequencing technology involves using Atomic Force
Microscopy (AFM), which is customarily used to analyze
the surface structure of materials at molecular resolution
with the ultra-small tip of a sensitive probe, in
combination with naturally occurring ring-shaped sugar
molecules called cyclodextrins. Lindsay believes that
the ring molecules, when paired with the AFM probe
tip, can effectively be used as sensors to "read"
the sequence of amino acid code (DNA "bases")
in the human genome that comprises many millions of
are Mother Nature's little molecular rings,"
explained Lindsay. "They are just big enough
to slide a strand of DNA through. Conveniently, Mother
Nature also makes them with neat little reactive groups
on the side, so you do chemistry with them."
the reactive groups on the side of the rings, Lindsay's
technology proposes to attach the ring to the sensitive
AFM tip, which would thread an anchored DNA molecule
into the ring and pull it through, recording the subtle
differences in the "bumps" resulting from
the friction of the different DNA bases with the ring.
The resulting data could thus be translated into the
precise sequence of the DNA molecule.
thread the DNA through the cyclodextrin molecular
ring, the cyclodextrin molecules are first assembled
around a long, straight molecule, like beads on a
wire. The "wire" molecule is then attached
to a surface at one end, and to the end of a DNA molecule
at the other by chemical bonds. The AFM tip bonds
to the "bead" and by its movement rapidly
pulls first the "wire" and then the DNA
molecule through the ring.
Lindsay's proposed sequencing method can be made towork,
it would be remarkably faster and more accurate than
current sequencing technology.
increases in technology, there is no reason that you
couldn't read bases in microseconds, in which case
you could get the time for sequencing the whole human
genome down to hours," he said.
first sequencing of the human genome, completed in
2002, took two teams 11 years to do and cost $1 billion.
Lindsay's method could make the same genome sequencing
feat possible at less that $1,000.
other advantage is that this method can be used for
a single molecule," Lindsay notes. "You
could take a piece of DNA out of a cancer cell and
get its coding sequence, and take the DNA out of an
adjacent normal cell and ask what its sequence is
can do this without modifying the DNA. Current sequencing
techniques, which are very slow, require you to take
the DNA and copy it through the polymerase chain reaction,
which is error prone. Subtle, single base differences
that may have to do with the disease, can easily get
the concept sounds relatively straightforward, making
things work in the nanospace of individual molecules
is very difficult and there are numerous technical
hurdles that Lindsay and his team still have to get
the challenges, Lindsay is encouraged that NHGRI has
selected his proposal for funding along with a very
small number of other competing ideas in an area that
is critical to the future of bioscience. The award
is one 19 grants the institute announced, and one
of two given to ASU researchers in a round of NIH
funding totaling $38 million.