Doctors to Turn Detective With ‘DNA Probes’

Armed with engineered molecules that turn them into DNA detectives, scientists working in San Diego say they are on the verge of a day when physicians will be able to use these sophisticated techniques to both diagnose and guide the treatment of human disease.

These “DNA probes” lock onto unique fragments of genetic material from invading viruses or bacteria. This enables laboratories to identify within hours pathogens that they otherwise could detect only with difficult or time-consuming techniques--if at all.

“This is totally going to revolutionize microbiology because it’ll give you the answer in one day--actually three hours,” said Dr. Robin Miller-Catchpole, associate director of microbiology for Evanston (Ill.) Hospital. “It’ll change everything virtually overnight. You’ll be treating a patient with an appropriate antibiotic right away.”

Currently, while a lab identifies microbes by taking days to weeks to grow them from a patient specimen, a doctor might have to hospitalize the patient or prescribe an expensive broad-spectrum antibiotic, Miller-Catchpole said. With a quick identification of the “bug,” a more specifically effective antibiotic could be used and hospitalization avoided altogether.

(DNA, or deoxyribonucleic acid, is often referred to as the body’s blueprint and holds the genes that tell the organism how to form and operate.) Within the next five years, DNA probes could enable physicians routinely to determine:

* If newborn babies are infected with the fatal AIDS virus and with cytomegalovirus, a herpes virus that can cause hearing problems and mental retardation if left unchecked. This application of the technology is being pioneered at UC San Diego Medical Center.

* Whether women are silently infected with venereal microorganisms that could kill them, make them sterile or give their children birth defects. Companies that have developed or are developing DNA probes for such diseases include San Diego’s Gen-Probe Inc. and Molecular Biosystems Inc.

* Whether blood cancers such as leukemia and lymphoma will be especially aggressive, and how well they are responding to treatment.

All this potential comes from a biotechnology that until recently had its most common practical applications in paternity testing and in the identification of criminal suspects from hairs or scraps of skin left at a crime scene. (See story on DNA “fingerprinting,” Page 3.)

But so far medical testing with DNA probes has remained within academic research laboratories.

That is because the complexity, the costliness of doing the tests in small batches and the use of radioactive isotopes have limited the usefulness of the handful of DNA probes available commercially, proponents admit. So far, these lab kits offer probes to detect respiratory infections such as Legionnaire’s disease and tuberculosis, as well as food and waterborne diarrheal diseases such as Shigella.

The technology’s future depends on how quickly biotechnology firms such as those that pepper San Diego’s booming biotech landscape can automate and simplify the many steps involved in the DNA probe process, the firms agree.

Nevertheless, even the most pessimistic observers predict DNA probes will play an increasing and dramatic role in diagnosing infectious diseases over the next five years. Market analyst Frost & Sullivan Inc. predicts the market for DNA probes will jump from $14.9 million this year to $203 million by 1992.

Miller-Catchpole, a senior scientist for the American Medical Assn., spoke at an AMA conference on DNA probes Nov. 3-4 in San Diego. Researchers and clinicians there and at another meeting the previous week, sponsored by the San Diego section of the American Assn. of Clinical Chemistry, agreed that DNA probes are within two years of being in general use by doctors. Within five years, the spectrum of tests available can be expected to broaden considerably, they say.

But that wait is likely to seem too long to physicians eager to improve the care their patients receive, said Vincent Frank, president of Molecular Biosystems. The San Diego firm sells 14 genetic probes for diagnosing disease, most of which are available only for research purposes.

“It’s exciting for the medical consumer, though it’s going to be frustrating for a while because . . . it’s going to be slow to get on the market” due to the commercial underpinnings, Frank said.

He predicts the first automated systems for conducting DNA probe tests will be available commercially in two to three years. This would open up the field to smaller laboratories that previously could not conduct the complicated tests.

One area of frustration for doctors and patients could involve DNA probe tests for human papilloma virus (HPV) infection, which the U.S. Centers for Disease Control says has reached crisis proportions across the country. As happened with anti-AIDS drugs, the DNA-based tests for HPV offer a potential tool against an epidemic before the tool has met government efficacy standards for commercial sale.

Commonly called genital warts, HPV is thought to have surpassed gonorrhea in the number of new cases annually--about 1 million by CDC estimates. The virus appears relatively benign in men--who can pass it on to their sex partners without knowing they have it--but has been associated with cervical and other genital cancers in women.

Of seven HPV strains that have been well characterized, two are strongly suspected to cause cell changes that can lead to cancer in women as young as their mid-20s. Three others are considered a moderate risk for inducing this condition, and two other strains are considered low risk.

HPV can be active in a woman without there being obvious symptoms. In addition, Pap smears sometimes fail to detect precancerous cell changes with which the virus has been linked. Consequently, using DNA probes to detect HPV and identify its strain could provide an adjunct to Pap tests in preventing cervical cancer.

But a doctor who diagnoses genital warts in a patient currently has no commercially available way to determine which strain she has.

The only DNA probe tests available, manufactured by Life Technologies Inc. of Gaithersburg, Md., are prominently marked “For research purposes only” while their efficacy for commercial use is shown to the U.S. Food and Drug Administration. The firm’s HPV detection kit is expected to be approved for commercial use soon. Its HPV typing kit is a year or more from approval, FDA spokesmen say.

Yet pathologists such as Dr. A. Bennett Jenson, pathology professor at Georgetown University School of Medicine, are adamant that women need the information such tests offer now.

In the Washington area, where Georgetown doctors have heightened physician and public awareness of HPV infection, Jenson said, worried women are beginning to demand HPV tests.

“It’s the patient who’s going for her normal workup who’s asking for it,” Jenson said. “It’s the women who are really spearheading it.”

DNA probes also are of pressing clinical importance in detecting human immunodeficiency virus in newborns whose mothers have AIDS, said Dr. Stephen A. Spector, who oversees treatment of children with AIDS at UCSD Medical Center.

In babies, the presence of HIV antibodies, the basis for current AIDS tests, cannot be used to diagnose HIV infection during the first several months after birth.

“If you see an infant that has antibodies, it’s virtually worthless to say that. Because all it tells you is that Mom is infected,” Spector said.

Spector’s research group has used DNA probes to detect HIV in samples that had very low concentrations of infected cells. But the methods are still technically quite difficult, he said.

Spector also is directing the UCSD portion of a recently inaugurated national study of the effectiveness of the drug AZT and other AIDS therapies in children. In that research, DNA probes for HIV might help identify babies who have escaped being infected by their mothers, so they won’t be subjected to anti-AIDS drugs they don’t need, Spector said.

In babies as well as adults with AIDS, Spector added, DNA probes might also eventually be useful for monitoring the effectiveness of anti-AIDS drugs. But clinical standards for measuring what is a “better” level of HIV in the blood must be developed first, he said.

“What we don’t know is what viral load means,” Spector said. “We know that we can culture virus from virtually anyone who’s infected. Is an increase in viral load significant? Or is a decrease in viral load significant? It may be that means the virus is just hiding somewhere, or it could mean that cells are being killed. We just don’t know.”

Biotechnology firms see their greatest commercial hope for DNA probes in developing batteries of tests that, all at once, will test a sample for several microorganisms that cause similar disease symptoms, Miller-Catchpole said.

In addition to offering hope of quick, accurate diagnosis of infectious diseases, DNA probes also are showing clear promise in detecting oncogenes, or defects in the genetic code that have been linked to certain cancers, said Dr. Carol A. Westbrook, who operates a hematology-oncology diagnostic lab at University of Chicago.

This kind of research is farthest along in blood cancers such as leukemia and lymphoma because they can be much more easily biopsied--by drawing a blood sample--than can other cancers, said Dr. Dennis W. Ross, associate professor of pathology at the University of North Carolina at Chapel Hill.

“Technology has always been dizzying for the physician,” Westbrook said. “Today it’s DNA probes. Yesterday it was monoclonal antibodies. Before it was antibiotics. But this is going to move even faster and have a bigger impact.”