DNA map IDs diseases

By Kimberly Patch, 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.

Timeline:   Now
Funding:   Private
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.


February 20, 2002

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