Subject: PCR Gene Technique Helps Physicians Diagnose Elusive Diseases Earlier 
Date: Published: 10/30/91 (159 lines)
Source:  Wall Street Journal.  Copyright Dow Jones & Co. Inc. 

    Medicine:
    Using PCR Gene Technique, Physicians
    Can Diagnose Elusive Diseases Earlier
    ----
    By Marilyn Chase
    Staff Reporter of The Wall Street Journal

    Gene amplification is transforming the way doctors detect
 dozens of ailments, including AIDS and cancer.
    The sleuthing technology, known as the polymerase chain
 reaction, or PCR, was invented in 1983 by scientists at Cetus
 Corp. and sold to Hoffmann-La Roche, a unit of Roche Holding
 Ltd.  of Switzerland, this summer.  Popularized outside
 medicine, PCR has yielded genetic "fingerprints" that have
 helped to identify criminal suspects, prehistoric animals and
 casualties of the Gulf War.
    But PCR is opening even more windows in diagnostic
 medicine, where its ability to pinpoint genes much more
 adeptly and quickly than other methods has aided researchers
 in identifying the bacteria, viruses and mutant genes that
 cause disease.  Starting as early as next year, PCR test kits
 may become commercially available to clinical labs, moving
 the technology further into the medical mainstream.
    "It's changed the way we think about diagnostic medicine,"
 says Jeffrey Cossman of Georgetown University School of
 Medicine, which this month co-sponsored a conference on the
 explosion in uses for PCR and some of the difficulties in
 harnessing the technology.
    PCR involves plucking a gene from a sample of blood or
 tissue through the use of DNA probes, which bracket the
 target much like bookends, and then replicating it as many as
 a trillion times.  This bit of medical alchemy permits
 detection of one cancer cell in a million, making it 1,000 to
 10,000 times more sensitive than earlier techniques.  That
 helps to alert doctors faster to relapses after treatment and
 serves as an early warning system for new viral infections
 too recent to have sparked symptoms.
    The speed of the technology tantalizes doctors who track
 contagious illness.  In the case of tuberculosis, says Jack
 Crawford of the Centers for Disease Control in Atlanta,
 "rapid detection using PCR offers the possibility of early
 intervention."
    Certainly, the tool isn't fail-safe.  PCR produces swarms
 of DNA copies that can overrun lab equipment and taint
 results of subsequent experiments, leading to as much as a
 30% rate of false-positive readings, warns Arthur Hooberman
 of the University of Chicago.  Cetus scientist John Sninsky
 unveiled a new sterilization technique that can prevent such
 contamination.  But the opposite problem -- that of false
 negative results -- occasionally troubles researchers, too.
    Some researchers also worry about some of the practical
 implications of PCR's ability to detect the presence of
 disease-bearing genes long before symptoms appear.  "The key
 question is what are we going to do with all this increased
 sensitivity," says Dr. Robert Yolken of the Johns Hopkins
 pediatrics department.  "Will we diagnose more people who are
 sick, or will we find out that everyone is carrying small
 amounts of virus and do more harm than good?  "
    For several years, PCR has been used to detect genes
 responsible for such diseases as sickle-cell anemia.  Now,
 cystic fibrosis, which damages the lungs, and Fragile-X
 syndrome, a type of retardation, have joined the list of
 genetic defects that PCR targets.  The National Institutes of
 Health recently funded a network of cystic fibrosis screening
 projects.  Johns Hopkins University geneticist Haig H. 
 Kazazian says he supports similar screening programs for such
 blood disorders as sickle-cell anemia and thalassemia, as
 well as for Tay-Sachs disease, a fatal enzyme deficiency.
    Oncologists are using PCR to detect cancer-causing genes
 as well as microscopic traces of disease that can lead
 malignancies to recur after treatment.  They can diagnose
 certain lymphomas and leukemias based on a telltale switch in
 the location of certain chromosomes.
    In the AIDS epidemic, PCR has a half dozen distinct uses,
 according to Gerald Schochetman of the CDC. It solved the
 problem of diagnosing newborns, who carry maternal antibodies
 that mask their condition in conventional tests.  PCR can also
 detect HIV, the virus that causes AIDS, in newly infected
 adults before they make antibodies.  Further, PCR can help
 track disease progression by measuring how much virus a
 patient is carrying.
    PCR is also emerging as a tool for screening donated blood
 for HIV.  The American Red Cross is planning to use the
 technology in its central laboratory in Washington.  Says
 Gerald Sandler of the Red Cross:  "There are 50,000 people to
 whom we've said:  `You test false-positive so you can't donate
 blood.' We'll put in PCR not to detect more {HIV} but to work
 toward reinstating those people as blood donors."
    PCR is having a major impact on more common infectious
 diseases, too.  For herpes virus infections, Thomas Smith of
 the Mayo Clinic says, "PCR gives us more diagnostic options"
 because it can pick up such hard-to-detect herpes family
 members as the Epstein-Barr virus, linked with mononucleosis
 and lymphoma, and the papilloma viruses, linked with genital
 warts and tumors.  Dr. Yolken of Johns Hopkins says PCR can
 also detect cases of virusborne diarrhea before antibodies
 are produced, making it potentially easier to curb outbreaks
 in hospitals and day-care centers.
    For David Persing of the Mayo Clinic, PCR has shed
 unexpected historical light on Lyme disease.  After combing
 through insect museums, he performed PCR on tick specimens
 dating from the 1940s, and concluded that the ailment was
 around decades earlier than doctors had thought.
    Next month, Roche is launching clinical trials of its
 first commercial PCR candidate, a test for chlamydia, a
 common sexually transmitted infection, and the company hopes
 to file for market approval in the first quarter of 1992.
 According to Dr. Yolken, people with infectious chlamydia can
 test negative in conventional tests.  What's more, the company
 says, its test takes only four hours, compared with two days
 for other tests.
    Roche has also slated clinical trials for a second
 commercial PCR venture, a confirmatory test for HIV, in the
 first half of 1992.  Further into the future, Roche scientists
 are developing a test that can distinguish between the benign
 and cancerous types of the papilloma virus.
    Roche says it owns the rights to all present and future
 uses of PCR by virtue of a $300 million deal with Cetus in
 July.
    Eastman Kodak Co. has asked for a preliminary injunction
 to block Cetus's sale of the technology, and a hearing has
 been set for Nov. 19 in Delaware.  Kodak claims it retained
 broad rights to PCR technology from a 1986 contract with
 Cetus.  Cetus terminated that contract in 1989, when it
 licensed diagnostic rights to Roche.
    Would-be competitors are now developing potential
 second-generation diagnostic tests similar to PCR. They
 include Abbott Laboratories of Abbott Park, Ill., which calls
 its technology the ligase chain reaction.  Amoco Corp. is
 working on another potential contender called
 Q-beta-replicase.  So promising is the market for such
 gene-based tests that Thomas MacMahon, president of the Roche
 Diagnostics Group, predicts, "Any major company in the
 diagnostics field will want to compete."
    Roche, meanwhile, expects a bonanza from PCR. Mr. MacMahon
 predicts that the world-wide market for gene-based diagnostic
 tests will reach $500 million by 1995 or 1996 and double to
 $1 billion by the year 2000.
    Along with opening up new treatment options for patients,
 PCR may also open up business opportunities for drug
 companies.  Harley Rotbart of the University of Colorado,
 Denver, notes that there are 75,000 cases of viral meningitis
 and encephalitis annually that can leave their victims --
 especially children -- brain-damaged or dead.  Because there
 was no practical way to test for the enteroviruses at fault
 in such cases, a number of companies shelved potentially
 helpful drugs.
    With PCR, "now there is a way to test," says Dr. Rotbart.
 He hopes to launch clinical trials of antiviral drugs by
 Schering Plough Corp., the G. D. Searle unit of Monsanto Co. 
 and the Sterling Winthrop unit of Kodak.

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