- The Washington Times - Sunday, June 12, 2005

Gene chips, DNA scanning devices that can sort millions of fragments of genetic information, are a major advance in personalizing disease diagnoses and medical treatments, based on differences in each patient’s genes.

The thin glass chips, widely used in research laboratories for the past five years, may be commonplace in clinical practice in the not-too-distant future. They allow scientists to analyze thousands of human genes or gene fragments at once, rather than individually, so disease causes can be identified and therapies quickly applied.

Now some American scientists who have been on the cutting edge of this technology say it’s time to develop international standards for the use of the tools, also known as DNA microarrays.

Last month, more than 40 scientists, including some from the U.S. Department of Health and Human Services and several from Europe and Asia, met in Paris to brainstorm this issue.

“International standardization has to happen. If not, it will hold back modern medicine, because all medical research is focused on using genomic tools for early diagnosis and treatment,” said Dietrich Stephan, director of the neurogenomics division at the nonprofit Translational Genomics Research Institute, or TGen, in Phoenix.

Mr. Stephan said he is taking that position, even though the “vast majority of gene-chip use [to date] has been as a research tool,” rather than in clinical practice.

He predicts global standards for assessing the technical performance of these chips will be in place in a year or two.

Janet Warrington, vice president of emerging markets and molecular diagnoses at Affymetrix, Inc., a Santa Clara, Calif.-based firm that has been a leader in gene-chip research, believes that prediction is entirely possible.

Reasons for optimism

“This is a force that’s happening now. There are standard controls in development now, and it’s an international effort,” said Ms. Warrington, who organized and chaired the meeting in Paris.

Ira Lubin, a geneticist at the federal Centers for Disease Control and Prevention in Atlanta, who also attended the meeting, said in an interview there are “many reasons to be very optimistic” about the outlook for clinical effectiveness of DNA microarrays, based “on the work that already has been done.” He termed the time frame Ms. Warrington and Mr. Stephan suggested for international standards to be in place “quite reasonable.”

Officials of Affymetrix, co-developers of a DNA microarray test that’s been approved by the U.S. Food and Drug Administration, identified two international organizations — the Organization for Economic Cooperation and Development (OECD) and the Clinical and Laboratory Standards Institute (CLSI) — involved in this movement.

Relapse predicted, avoided

CLSI, a nonprofit group, is “at work designing a clinical protocol,” Ms. Warrington said in a telephone interview.

Mr. Stephan and other researchers atTGen have used gene chips to help determine the chances of relapse in children whose leukemia is in remission and to help select the best therapies for other cancer patients.

Mr. Stephan cites one man who, three years ago, was “on his deathbed with pancreatic cancer,” one of the deadliest forms of cancer. By monitoring the patient’s gene activity with DNA chips, Mr. Stephan said, it appeared he could benefit from a drug commonly used to treat breast cancer. The patient was put on that regimen.

“Today, he is healthy as a horse,” the researcher said.

Ethical issues possible

No one is saying DNA-based medical testing is always so beneficial. Research is still under way to determine its effectiveness, and, increasingly, it’s being tested in clinical trials.

“The bottom line is that we want to ensure that there is an appropriate level of quality” in DNA-based medical testing, as in other medical testing, said Mr. Lubin.

This is vital, he and other researchers say, because learning that someone is likely to suffer an incurable disease or could have family members with such a disease is fraught with ethical challenges.

“There is concern that overinterpretation of test results could lead to discrimination,” Mr. Lubin said, both in employment and medical decision-making.

So it’s important that centers providing such life-or-death information not only offer accurate test results, but also confidentiality, plus “genetic counseling and informed consent,” where appropriate, he said.

Mr. Lubin pointed out there have already been cases where information from DNA chips were used inappropriately. “For example, some companies have used genetic-test results to identify people at risk for carpal tunnel syndrome, but scientific evidence did not indicate genetic testing is useful for that purpose,” he said in a telephone interview.

In December, the FDA approved a diagnostic test called the AmpliChip CYP450, which was a collaborative effort by Affymetrix, Inc., in Santa Clara, and Roche, the Swiss pharmaceutical manufacturer. It was the first such DNA microarray test ever approved by the federal regulatory agency.

The benefit of this gene-chip technology is that it can identify specific sequence variations in an individual’s genes. “Some variations are thought to be associated with disease,” said Mr. Lubin.

Semiconductor technology

Gene chips are created using semiconductor manufacturing technology. The chips are a few centimeters in size, and each has a grove of short, single-stranded DNA segments spread evenly across the surface.

Researchers then drop marked RNA (ribonucleic acid) onto the chips. RNA serves as the messenger between DNA blueprints and a cell’s protein-making equipment. The portion of a chip on which genes interact with the RNA will be fluorescent, spotlighting mutant genes that may require more scrutiny: the sequential variations that might mean medical problems.

At present, gene chips are most often used to gauge metabolism rates to determine how quickly or slowly individuals can break down drugs. This information can let doctors know the appropriate drug dosage for a particular patient and avoid side effects.

At TGen, Mr. Stephan said, the technology helped researchers identify the best treatments available for most individuals included in a group of 250 advanced-cancer patients. The technique involved putting a piece of a patient’s malignant tumor on a DNA chip for analysis.

What’s more, he said, TGen investigators put bits of individual breast cancer tumors on the genetic chips and were able to inform women with that disease of their expected 10-year survival rates.

A main speaker at the recent meeting in Paris was Dr. Torsten Haferlach, a German physician, who heads the Laboratory for Leukemia Diagnosis in Munich. Mr. Lubin describes Dr. Haferlach as “one of the front-runners” in global gene-chip research, and someone who is bringing the technology into clinical situations.

Dr. Haferlach is “developing DNA-based testing he hopes will greatly streamline the diagnoses of various cancers,” said Mr. Lubin.

Leukemias ‘fingerprinted’

Ms. Warrington agreed. She said DNA chips have allowed Dr. Haferlach to get the same information from a single test that once took “12 or 15 different tests.”

By using DNA-based testing and by “fingerprinting” cancer cells, she said, Dr. Haferlach “has developed signatures that allow him to distinguish between different kinds of leukemia” with different outcomes.

This is information that can help an oncologist predict a patient’s life expectancy and choose the most suitable therapies.

One reason concerns are growing about the need for quality DNA-based medical testing is that it has become so widely affordable.

“It used to cost $2,500 to run these chips. But that changed in the last four or five years. Now we can run the same chip for $250,” said Mr. Stephan.

Affymetrix officials put the current price tag at $200 per chip. That’s the case, they said, even though a chip today can reveal 1.6 million bits of genetic information, 100 times more than chips made a decade ago.

Though many companies are developing microarray technology, the basic structure of these DNA chips remains the same. “Our technology is very reproducible,” Ms. Warrington said.

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