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Nov 15, 2011 (Vol. 31, No. 20)

GEN's 30th Anniversary: Molecular Diagnostics

  • Editor's Note

    In this issue’s “Biomarket Trends” column, Frost & Sullivan analyst Jonathan Witonsky notes that revenues from worldwide sales of molecular diagnostics were estimated to reach $4 billion last year and to rise to $6 billion by 2014 based on a compound annual growth rate of over 11%. Witnosky goes on to point out that the two most common applications for molecular tests are: identifying and profiling infectious disease agents and monitoring patient therapeutic regimens.

    Contrast this current state of DNA-based or molecular diagnostic assays with the GEN article written in 1983, which appears below. Scientists and clinicians had their hands tied while trying to detect genetic diseases as early as possible, because no such tests existed back then.

    Nevertheless, what clearly comes across in the ‘83 GEN article was the understanding that DNA-based tests were near the top of the biomedical wish list and that research was taking place on a number of fronts to develop genetic tests for the diseases mentioned in the first part of the article. The result of all these early efforts can be seen in the fact that molecular diagnostic tests are now on the market for most, if not all, of these genetic diseases.

    —John Sterling, Editor in Chief

  • "As Seen in GEN"—Flashback Volume 3, Number 4, July/Aug 1983

    Click Image To Enlarge +

    DNA-Based Genetic Disease Tests Tantalize But Still Elude Biomedical Researchers

    By James Falkenstern

    Over 1,000 diseases are now known to be transmitted via defects or mutations in the genetic material, DNA. While most inherited diseases are extremely rare in the population, approximately 30 are relatively widespread, and of substantial concern to the medical community. Genetic diseases considered to be of greatest social importance include cystic fibrosis, Huntington’s chorea, certain forms of muscular dystrophy, sickle cell anemia, hemophilia and a variety of cancers and other metabolic disorders.

    Genetic diseases almost always are serious and often are incurable. Although some success in controlling these diseases has been realized through the efforts of genetic counseling services, public education, available diagnostic tests and the establishment of specialized disease programs, adequate means still do not exist to control those diseases of more widespread concern such as cystic fibrosis, Huntington’s disease, and some forms of cancer

    Recent advances in recombinant DNA technology, as well as focused research efforts to characterize the genetic defects involved in the transmission of inherited diseases, promise to make earlier diagnosis and disease prevention a reality.

    The technology is based on looking for genetic “markers” which are located close to the defective gene on a given chromosome. In order to make this type of testing accurate however, a significant number of family members must be tested and examined to determine the disease inheritance pattern within affected families. Eventually, scientists hope to pinpoint the exact DNA defects causing disease, and develop more specific, simpler tests.

    Diagnosing and preventing genetic diseases has been severely constrained by a lack of highly specific tools to allow precise, early diagnosis of disease in fetuses, children and adults.

    Biochemical and chromosomal tests vary in terms of quality and usefulness in diagnosing defects in an individual’s genetic make-up. Biochemical tests to detect female carriers of the muscular dystrophy defect have not been sufficiently reliable to use on a routine basis, and are not specific for the disease. Attempts to find a biochemical marker for carriers and patients afflicted with cystic fibrosis have also been unsuccessful thus far.

    The use of karyotyping to determine genetic defects is highly accurate for determining chromosomal abnormalities in individuals and prenatal fetuses. Quantitative changes in DNA can indicate whether a child is trisomic or afflicted with Down’s syndrome. The value of the technique, however, is limited to those diseases in which a physical derangement of the chromosomal material is apparent.

  • Case of Cystic Fibrosis

    Because it has been impossible to determine carriers of a genetic problem, the appearance of a genetic disease in a child often is the first indication an individual has that he or she may be carrying a defective gene. The problem is clearly illustrated in the case of cystic fibrosis.

    In the U.S., over 2,000 children are born each year with cystic fibrosis. It is estimated that one in 20 individuals in the general population carries a defective gene coding for the disease. Since two copies of the gene must be carried for the disease to be expressed (i.e.: the gene is recessive), these “carriers” do not exhibit any characteristics to distinguish them from the rest of the population. The chance of both members of a couple carrying the gene is one in 400 couples, and the subsequent chance of a child born to such a couple being afflicted with the disease is thus one in four.

    Cystic fibrosis is a life-threatening and costly disease. The burden of trying to have another child after having one afflicted child with cystic fibrosis is tremendous. The only information available to the couple regarding the chance of their having a second afflicted child is that the risk is 25 percent.

    Once markers and eventually the gene defect which causes cystic fibrosis are found, it will be possible to identify individuals carrying the defective gene and allow “carrier couples” to make informed decisions regarding reproduction. Prenatal diagnosis using DNA-based methods could conceivably be used to support a decision to abort an afflicted fetus, or continue the pregnancy of a healthy child.

  • Awareness of Genetic Diseases

    Over the past decade, the link between genetics and disease has grown increasingly strong. Research has demonstrated a genetic link in many diseases once thought to be caused solely by external factors. Major diseases now known to have a strong familial pattern include diabetes, certain forms of cancer including colon and breast cancer, and mental disorders such as schizophrenia.

    Similarly, the public’s awareness of the genetic link to diseases has also grown. According to C. Raczenback, a genetic counselor at North Shore Hospital on New York’s Long Island, “more and more people are calling in asking about genetic services.” The North Shore Hospital Genetics Clinic as well as other clinics are getting a growing number of requests from the public regarding the familial risks of cancer, kidney disease and heart disease.

    But definitive diagnostic and predictive tools do not yet exist to accurately define the risk of disease among the population. Genetic counseling still is limited to assessing family history, performing tests which are subject to interpretation and defining possible risks to concerned individuals.

    Other professionals feel the role of public information dissemination has been particularly strong in educating people about the link between disease and family inheritance patterns, and encouraging use of procedures such as amniocentesis for women who might be at risk of having a child with chromosomal defects.

    Genetics also is expected to play an increasingly important role in medical education and in clinical practice. With the advent of new technological developments and awareness of genetics, “physicians are becoming more aware of the exciting potential for treatment and testing; now genetics is becoming more and more a part of other medical specialties,” according to Dr. J. Davis, director of the Child Development Center at North Shore Hospital.

  • Technical Advances

    In combination with highly specific restriction enzymes, known sequences of DNA (DNA probes) can be used to look for genetic markers in an individual’s DNA which are located near disease-producing DNA defects. Inheritance of the marker can be used to infer inheritance of the gene defect. Even more specific tests can be designed once the mutation responsible for a given disease is known.

    The feasibility of this approach has already been demonstrated with the sickle cell diseases: sickle cell anemia and b-thalassemia. Sickling of red blood cells in these diseases is caused by a defect in the hemoglobin molecule, which in turn is encoded by a mutant globin DNA sequence.

    The amount of research devoted to the study of hemoglobinopathies, and in particular the globin gene, along with advances in DNA probe technology has facilitated the development of a refined, DNA-based diagnostic test for sickle cell disease which can discern the point mutation causing the defective hemoglobin.

    The sickle cell test is now being used to designate couples at risk of having an affected child, and to then analyze amniotic fluid in the pregnant woman carrying a child at risk, to determine whether the fetus will be affected with the disease.

    For many genetic diseases, little is known about how the disease is caused. It is generally agreed among researchers that finding useful DNA markers to diagnose disease, and eventually characterize and locate the DNA abnormalities responsible will involve a substantial research effort. Similarly, DNA-based testing may lead to the discovery of genetic links to disease not heretofore known to have a familial basis. According to Dr. M. Swift, professor of medicine at the University of North Carolina, ataxia telengectasia may be just such a disease. While individuals carrying two copies of the defective gene are severely afflicted with disease, less is known about the heterozygous state (where one copy of the gene is carried in an individual’s DNA). It is now believed that heterozygotes are prone to certain types of cancer. Dr. Swift feels that a genetic test of ataxia telengectasia would be very valuable for prevention or early therapy of cancers towards which an individual may be disposed.

  • Applicability of Genetic Testing

    The ability to diagnose genetic disease is especially valuable for making informed reproductive decisions, as well as to diagnose a disease or predisposition to disease so that appropriate management or preventive measures can be initiated early on. How a genetic test is used will probably depend on the characteristics of individual disease.

    Couples at risk of having a child afflicted with a serious genetic disorder such as cystic fibrosis or muscular dystrophy would be able to make informed reproductive decisions with the availability of accurate DNA-based tests. Prenatal diagnosis would permit a couple to both ensure the birth of a healthy child or provide definitive grounds for early termination of a pregnancy.

    In other diseases, such as neurofibromatosis and colon cancer, the ability to detect a genetic predisposition towards these diseases could allow institution of earlier monitoring and surgical intervention to prevent disease progression.

    Both academic and corporate research efforts are under way to find the genetic basis of diseases such as cystic fibrosis, Huntington’s disease, muscular dystrophy, cancer and diabetes. Companies known to have efforts in the area of genetic diagnosis include Enzo Biochem, Integrated Genetics, Cetus, AMGen and Molecular Diagnostics.

    A combination of biochemistry and molecular biology will be required to permit an improved understanding of these diseases, and to make development of DNA-based tests a reality.


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