By Matt Kelly
Small Times Correspondent

CAMBRIDGE, Mass., Jan. 18, 2002 — For almost two decades, pain has been Clifford Woolf’s obsession.

The Harvard Medical School researcher has spent nearly 20 years probing its causes, manifestations and treatments. In that time, pain has been elevated from an inevitable side effect of disease to an affliction all its own, to be diagnosed and treated.

Woolf’s quest has been to identify the cause of neuropathic pain, which can be felt in the nervous system but has no physical cause like, say, a broken arm. He sifts through the genome of rats, trying to determine which genes are expressed in nerve cells when rats are in pain.

It’s been slow work for the last five years. Woolf and his researchers at Harvard’s Neural Plasticity Research Group would creep along finding a few dozen expressed genes a year.

Then came a new gene chip technology from Affymetrix Inc..

Gene chips are essentially microscale comparisons of DNA. A control sample of DNA is first laid out on a chip, and the target DNA is spread on top of it. “Hits” happen when sample DNA bind with the normal DNA; hits are detected by exciting the samples with a laser.

Last year, Woolf’s group identified more than 1,000 target genes.

“We find that gene chip technology has proved to be the most useful method,” Woolf, a native of South Africa, said from his lab in Charlestown, Mass. “It’s a fantastic first step.”

Indeed, Woolf’s biggest problem now is how to analyze the vast amounts of data generated by the gene chip technique. The results only say whether a gene is expressed — whether a gene is “up” or “down,” in industry parlance — in a diseased state. How the gene is expressed, why it is or what to do about it are all open to question.

“The chips themselves don’t tell you if data is suggestive,” he said. “The difficult parts are determining what to put in and how to read what comes out.”

But gene chips, also known as microarrays, do tell researchers like Woolf where to start looking. Woolf is looking for certain sodium ion channels that appear as a result of neuropathic pain. He hopes to develop blocks for those channels, which could be delivered as an analgesic drug. With the channels blocked, the pain should stop.

Alternately, Woolf said, certain genes could essentially be “turned on” to produce therapeutic proteins, or to be used in some diagnostic capacity.

Affymetrix, based in Santa Clara, Calif., is a pioneer in the relatively young field of gene chip research. First-generation gene chips bedeviled researchers with false positives; data could be inconsistent or differ from day to day.

“The technique is not that new … the technology has improved dramatically,” Woolf said. “In the beginning, that number (of false positives) was quite high indeed.”

In the late 1990s, however, Affymetrix developed an improved method of creating the chips using photolithography. Since then, accuracy has increased dramatically and researchers have embraced the technology.

“Use of gene chips is a very important tool,” said Michael Lytton, general partner at Oxford Bioscience, a venture capital firm in Boston. “It’s only going to become more important.”

Lytton said that gene chips are especially useful in neuroscience research such as Woolf’s because they can examine many different genes at once. Afflictions such as neuropathic pain often involve many complex expressions across many genes, called a “pathway.” Gene chips help piece together how an analgesic would work in that pathway.

“You’re not entirely accurate on each gene,” Lytton said. “They give you a sense of the overall effect (a treatment) would have.”

Gene chips still do have some skeptics — more often clinicians than researchers. Michael Gold, a doctor with the University of Maryland School of Medicine who is acquainted with Woolf’s work, said the chief complaint is that the chips are not sensitive enough to detect miniscule changes.

“Very small changes are all you need,” Goldman said. “Especially in neuroscience, small changes can have profound effects.”

Goldman himself is not in the skeptics’ camp. He believes gene chip technology will usher in a new way of studying the genetic causes of disease. “It’s entering into the realm where lots of data can be generated by it,” he said.