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By Carol Rados
Imagine that a swipe of the inside cheek or a stick of the little finger could be used to predict whether or not certain types of cancer may be in your future. Theoretically, both can. Thanks to the advances in genetics, and with the clearance by the Food and Drug Administration of a growing list of genetic diagnostic testing devices, doctors are beginning to understand how certain diseases, or increased risks for certain diseases, pass from generation to generation.
The Tag-It Cystic Fibrosis Kit is one such device. Cleared for marketing in May 2005, Tag-It finds genetic variations in what scientists now know is the gene that causes cystic fibrosis--the most common fatal genetic disease in the United States. Made by Tm Bioscience Corp. of Toronto, Tag-It will help diagnose cystic fibrosis in children and identify adults who are carriers of the gene.
Now that the mapping of the human genome is complete, scientists have a resource of detailed information about the structure, organization, and function of the entire set of human genes--all 30,000 to 40,000 of them--and an idea which ones affect health and disease. This genetic reference, coupled with a relatively new research tool called a microarray, provides a snapshot of which genes are active, or expressed, in both healthy and diseased cells. Microarrays allow scientists to view thousands of genes at once. In the past, researchers could study only one or a few genes at a time.
The concept of looking at hundreds or thousands of human genes at one time encompasses the field of science called genomics, and other scientific fields with the shared suffix, "-omics." Some examples include pharmacogenomics: why some drugs work better in some patients than in others; metabolomics: the study of body fluids to determine changes in metabolism; and proteomics: the study of proteins in an organism or tissues.
Building on previous knowledge of the life sciences, the idea is to use these new sciences to develop other ways to diagnose, treat, cure, and even prevent the thousands of diseases that afflict humans. New findings could allow doctors to understand many diseases in much more detail and could help manufacturers design better, faster, and more accurate tests with the ability to predict future health risks. This could mean that doctors will have access to tests that detect diseases before clinical symptoms appear. The -omics technologies currently are also being used by researchers and drug companies to help identify new drug candidates.
Experts at the Oak Ridge National Laboratory (ORNL)--a science and technology lab managed by a main contributor of the Human Genome Project, the U.S. Department of Energy--predict that it won't be long before doctors are able to select specific drugs and specific doses of drugs for an individual based on a decoded copy of his or her own genome. Conceivably, individual genomes could become an essential part of everyone's medical file.
But the road from identifying genes to developing effective drugs and diagnostic devices continues to be both tedious and challenging. Researchers hope that more discoveries made with microarrays in the laboratory will translate into improved genetic and genomic diagnostic tests that will eventually generate the promise of "personalized" medicine, or individually targeted treatments.
A microarray, or gene chip, is a tiny glass or plastic platform containing thousands of genes. It is similar to a computer microchip, but instead of tiny circuits, the chip contains "probes" or genes with a known identity, such as DNA or small pieces of DNA, which are arranged in a grid pattern on the chip. Whenever genetic material from a patient's blood or other tissue is placed on the chip, the probes react. Those reactions can be detected and used to screen for the presence of particular genetic sequences, such as those related to diseases, and how people will respond to certain medications. Microarrays also can enable researchers to see which genes are being switched on and off under different medical conditions.
"A small amount of body fluid has the ability to look at 35,000 genes that microarrays create," says Raj K. Puri, M.D., Ph.D., director of the Division of Cellular and Gene Therapies at the FDA's Center for Biologics Evaluation and Research. Microarrays can rapidly provide a detailed view of the simultaneous expression of all the genes in an entire genome, and provide new insights into gene function, disease pathology, disease classification, and drug development. "This is a new paradigm of understanding the biology of cells," Puri says.
Microarrays are especially useful because of their small size and because they can contain a very large number of genes. They come in many varieties, either individually created by scientists or produced commercially by a company. But they all share the same principle: a miniaturized slide that carries numerous probes that can measure the expression of genes. They differ in the way the probes are created, as well as in their content. Some of the main challenges in microarray technology result from the technical complexity of the process and the large amounts of data generated by the experiments.
With the development of DNA microarrays, scientists can now examine how active thousands of genes are at any given time. Studying which genes are active and which are inactive in different cell types helps scientists to understand both how these cells function normally and how they are affected when various genes do not perform properly. By comparing genes, scientists can link variations and mutations to many diseases.
Scientists at the FDA's Center for Devices and Radiological Health (CDRH) say that DNA microarrays hold a promise to become useful in earlier diagnosis of diseases such as lung cancer, which usually are not diagnosed until they are well-advanced and less treatable. In the future, microarray-generated data may help doctors with earlier lung cancer classification and diagnosis. But performance of a microarray-based method to test for cancer, the CDRH experts say, has to be properly evaluated before going into the clinic.
Complex techniques such as microarrays leave many opportunities for errors. The lack of standardization for naming and identifying the genes used on different DNA microarray platforms could cause potential errors. Before microarrays can be consistently and reliably used in clinical practice and in regulatory decision making as a diagnostic tool, Puri says that standards, quality measures, format, and interpretation issues still need to be settled.
"Diagnostic devices will lead to personalized medicine," says James C. Fuscoe, Ph.D., director of the Center for Functional Genomics at the FDA's National Center for Toxicological Research in Jefferson, Ark. For example, with these kinds of tests, it may be possible someday to tell, within a day or two and in some cases even faster, whether a drug is having the desired effect. This, Fuscoe says, is because the cellular changes that can be detected by an -omics test would occur before any treatment effect is evident in a patient. "If there is no drug response," he says, "the patient can be immediately put on another appropriate drug."
The CDRH is now reviewing both genomic and genetic diagnostic devices. Genomic tests, for example, may look at the activity of many or all genes at the same time, while genetic tests, a subset of genomic tests, look for abnormalities in a person's genetic code. A breast cancer microarray chip that provides a snapshot of which genes are active in a group of 70 genes, for example, might be a genomic testing device. A chip that looks at the genetic code for these 70 genes might be considered a genetic test.
Genetic tests such as the Tag-It Cystic Fibrosis Kit involve DNA taken from a person's blood, saliva, or other body fluid that is examined for an abnormality and that flags a disease or disorder. The genetic abnormality associated with certain hereditary diseases can be relatively large--a piece of chromosome, or even an entire chromosome that's missing or added. Sometimes, the abnormality is very small--such as one extra, missing, or altered chemical base within the DNA strand. Genes can have too many copies, can be too active or inactive, or can be lost altogether. Sometimes, pieces of chromosomes mutate or change and become switched, transposed, or discovered in an incorrect location. If the mutated sequence is present in a patient's genome, the probe will find it and bind to it, flagging the mutation. But tests like Tag-It detect only a limited number of the hundreds of mutations in the gene that causes cystic fibrosis, Fuscoe says, "so the test is not perfect."
In the case of treating HIV infections, the virus often becomes resistant to drugs. When this happens, the drugs are not helping a patient. In fact, because of the significant negative side effects of these drugs, they are probably hurting the patient. The TRUGENE HIV-1 Genotyping Test, made by Visible Genetics Inc. of Toronto and cleared by the FDA in 2002, is a genetic test that allows doctors to determine from a blood sample whether a patient carries drug-resistant strains of HIV-1. If so, the patient can be given a different drug.
Similarly, some drugs require the body to metabolize them at just the right rate--not too quickly and not too slowly--to achieve the desired effect. The AmpliChip Cytochrome P450 Genotyping Test, made by Roche Molecular Diagnostics, is the first genetic lab test cleared by the FDA that uses DNA extracted from a patient's blood to detect variations in a gene that affects how certain drugs, such as antidepressants, antipsychotics, and some chemotherapy medications, are broken down and cleared from the body. Doctors can then adjust a drug's dosage for an individual patient.
In August 2005, the FDA cleared for marketing a genetic blood test called UGT1A1 Molecular Assay, which, like the AmpliChip, can significantly reduce the risk of ineffective or harmful therapies by telling doctors how to individualize drug dosing. The test is made by Third Wave Technologies Inc. of Madison, Wis., and specifically tests the action of an enzyme present in a drug used to treat colon cancer.
Since genomic tests often look at many hundreds or thousands of genes, the result may be a pattern of gene activation that also is designed to be diagnostic or characteristic of a condition. Genomics-based devices have the potential to become essential tools to identify patients at risk for developing life-threatening reactions to certain products. This information could be used to help make choices related to exposure, or to develop predictive tests for adverse responses.
One project being studied by the FDA is the diagnostic gene expression microarray for allergy to the proteins in latex, a complex natural product derived from rubber trees, most commonly found in medical gloves. "In our FDA lab we are applying new genomic technologies to try to understand why people become allergic to latex," says Rosalie K. Elespuru, Ph.D., of the FDA's Genomics and Genetics Laboratory in the CDRH. "We are also using the information to try to predict who will become allergic before it happens."
Elespuru takes blood from people who are allergic to latex and from those who are not and cultures the white blood cells that generate immune responses. She then exposes them in the laboratory to the latex proteins to which people are allergic. Once all the samples are obtained, Elespuru assembles a small microarray of just the genes she finds to be important. These then, she says, will be used to test more samples from those who are allergic and from those who are not "to see if it is truly representative of a genomic profile for latex allergy."
The expansion of microarray-based technologies will likely have a major impact on the regulatory practice of evaluating laboratory tests as diagnostic devices, according to the FDA.
Previous submissions for pre-marketing review of diagnostic devices by the CDRH have generally involved evaluating information on one or a few results per sample at a time. New -omics technologies will challenge the agency in that hundreds, thousands, or tens of thousands of results per sample will be generated. The FDA will need the necessary background for making regulatory decisions. The agency will also need to seek unique efficient and effective ways to evaluate the performance of diagnostic devices that use microarrays and other new technologies to ensure a seamless transition from laboratory study to product development, evaluation, and regulation and, ultimately, medical practice.
Projects like the latex allergy experiments provide a base for evaluating genomic and genetic device performance and for continuously updating the FDA's capability in new technologies as they evolve. Continually mastering genomic and genetic technologies involved in these projects will prepare the agency for possible future projects, such as those involving the rapid detection of bioterrorism agents and human responses to them.
The FDA has many ongoing activities to communicate with science and technology leaders to enhance its understanding of the new sciences, to gain experience, and to share knowledge in these important new, evolving areas of science. These activities include training initiatives, communications with everyone involved, in-house working groups, agency research, and improved pathogen detection, to name a few.
The FDA's mission is to ensure that safe and effective products are made available as soon as possible for consumer use, and to not become a barrier to product development. Although still early in its development, genome-based research shows promise that eventually it will enable medical science to develop highly effective diagnostic tools to better understand the health needs of people based on their individual genetic makeups.
Food and Drug Administration
www.fda.gov/cder/genomics/
The FDA's National Center for Toxicological Research
www.fda.gov/nctr/science/centers/functionalgenomics/index.htm
National Human Genome Research Institute
National Institutes of Health
www.genome.gov