map IDs diseases
Technology Research News
One of the problems with identifying bacteria
and viruses that cause diseases is finding them. The human body is full
of tiny cells and smaller organelles, or cell parts, that resemble each
other. In this crowded microscopic environment it is difficult to pick
out foreign pathogens that may be causing problems.
A group of Boston researchers have taken advantage of the human genome
project, which is mapping the exact sequence of base pairs in human DNA,
to form a new strategy for finding invading bacteria and viruses.
DNA is made up of four bases, or nucleotides, attached to a sugar-phosphate
backbone. The order of these bases is the genetic code containing a full
set of instructions to construct an organism. The bases pair up to form
the double helix of biological DNA, and unzip into single strands to replicate.
All life on earth, including bacteria and plants, uses DNA.
The researchers' subtractive DNA extracts all the DNA present in a sample
of diseased tissue, then compares it to the human genome, a series of
about 3 billion base pairs. Whatever doesn't match is likely to be foreign,
said Matthew Myerson, an assistant professor of pathology at Harvard University
and the Dana Farber Cancer Institute.
The inspiration for the scheme came when Myerson was looking for homologs,
or similar genes, of some bacterial genes in human DNA. "It made me think
you could find microbes, or pathogens by looking at genes that are in
diseased human tissues that aren't in the human genome," he said.
To carry out the scheme, the researchers first cloned the DNA they extracted,
then sequenced the DNA to find the order of the bases. Sequencing is a
standard process that involves using enzymes to cut the DNA in certain
places, and using florescent colors to detect certain portions of DNA.
The researchers then used a modified text comparison program to compare
the sequences they found to the sequences found in the human genome. In
principle, any sequence that does not match is from a foreign pathogen
in the tissue, but in practice it's more complicated than that, he said.
This is where the technical challenges of the method come in, he said.
"If it doesn't match... maybe the sequence qualities aren't good enough....
[or] maybe there is some kind of experimental contamination. A third possibility
is the mismatch comes from a region of the human genome that has not been
sequenced yet, he said. The human genome project has so far sequenced
95 percent of human DNA.
Until the human genome is finished, "most of what we see are actually
sequences of some regions of the genome that haven't been sequenced yet,"
and Myerson said. That problem will go away when the genome project is
completed, he said.
Identifying pathogens has historically been difficult for a couple of
reasons, said Myerson. "One of the biggest challenges in identifying pathogens
is when you have something, how do you prove it's really associated with
the disease? Our method doesn't really address that. This is basically
a way to get candidate pathogens," he said.
Traditional methods to find candidate pathogens, however, require knowing
something about the pathogen, which creates a kind of chicken and egg
problem. "In order to culture a pathogen, meaning grow it... you have
to figure out how to grow it and if you don't know what it is, it's hard
to figure out how to grow it," Myerson said. A second method requires
knowledge of the pathogens DNA sequence. "But if you don't know what it
is you... don't know its DNA sequence," he said. "With existing methods
you have to make a guess as to what the organism is," he said.
In contrast, with the subtractive DNA method a "you don't have to guess
at all," he said. This could speed the discovery process, he said.
The researchers are currently testing the scheme. "We're trying it right
now. We'll keep refining the method as we go," he said. The method will
remain a discovery method, and not a diagnostic method, he added.
The researchers are initially looking at three types of diseases for their
tests, Myerson said. "The general classes of diseases are going to be
cancers, autoimmune diseases and inflammatory diseases," he said. These
types of diseases are appropriate because there is specific diseased tissue
involved, he said. "You want something were there's a biopsy and you can
see something that's very clear on a biopsy to tell you what the disease
is," he said.
The researchers are looking for pathogens that may be either directly
or tangentially involved in these diseases. They are "basically interested"
in finding pathogens that directly cause a disease, but a disease could
also be helped along by a pathogen, he said. A third situation is that
the disease is encouraging pathogen growth by providing an environment
where it can thrive, he added.
The method can be used to find foreign organisms in any plant or animal
as long as its genome is known, said Myerson. "And eventually we're going
to know all the major genomes," he said.
Myerson's research colleagues were Griffin Webber of the Dana Farber Cancer
Institute and Brigham and Women's Hospital, Jay Shendure and George M.
Church of Harvard Medical School, and David M. Tanenbaum of the Dana Farber
Cancer Institute and Harvard Medical School. They published the research
in the January 14, 2002 online edition of Nature Genetics. The research
was funded by the Dana Farber Cancer Institute.
TRN Categories: Applied Computing, Biotechnology
Story Type: News
Related Elements: Technical paper, "Identification of Foreign
Gene Sequences by Transcript Filtering against the Human Genome," Nature
Genetics, online edition, January 14, 2002.
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