THERAPEUTIC DRUG MONITORING People vary in their ability to metabolize drugs. Some drugs become active only if metabolized; in other cases, a drug can build up to toxic levels if it is not metabolized. Knowing how a patient metabolizes a drug can help prevent toxicity and predict whether the patient will respond. Drug metabolic pathways commonly involve the cytochrome oxidase family of enzymes. The genes that code for them can already be analyzed, and we can predict how rapidly someone will metabolize a drug based on whether he or she has specific genetic abnormalities. One example of this application is in cardiology, where it’s been discovered that patients who have had a cardiac stent placed and who metabolize Plavix (clopidogrel) abnormally have an increased incidence of stent thrombosis.
Another useful application may be testing to evaluate metabolism of the anticoagulant warfarin, for which more than 32 million prescriptions were written in 2010. If you’re a slow metabolizer, the consequences can be quite severe, since the complications of over-anticoagulation include severe hemorrhage and death. In the hospital, where we track adverse drug reactions, that’s one of the more common serious adverse drug reactions. Under-anticoagulation is equally a problem,
organisms opens up whole new areas of exploration, with great significance for our health and the importance of the bacteria to our normal functioning. Genetic sequencing will also identify unusual or fastidious disease-causing organisms. Imagine, for instance, an anaerobic joint infection with one of these unusual organisms that cannot be isolated by traditional means. Using genetic fingerprinting we may be able to identify it and select appropriate therapy.
LIMITS OF GENOMIC MEDICINE Although we have high expectations for this new technology, it is only a piece of the puzzle. Identical twins, with the exact same genetic makeup, don’t always develop the same diseases. Environmental factors are obviously critical, but our DNA also changes throughout our lifetimes. Although the primary sequences don’t generally change, post translational modifications like methylations occur and can influence gene expression. Genetics can help us identify a disease predisposition, but it can’t
predict for certain whether someone develops the disease. Most diseases are influenced by multiple genes with complex interactions that are further influenced by those environmental factors and post-
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will sequence A pAtient’s entire genome sequence for less thAn us$10,000, A stAggeringly low cost
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because patients will be more susceptible to thrombosis. Warfarin dosing has to be just right. One pharmacy benefit manager routinely offers to test patients being put on warfarin, but so far, genetic testing for warfarin metabolism hasn’t gotten a lot of clinical uptake, even though the FDA has added verbiage to the packaging for the drug suggesting that patients should screened. I believe this is related to the cost and lack of rapid availability of screening results. As the technology becomes more available and the cost decreases, genetic screening will be much more accessible and will help us select not only the right drug but also the right dosage – both essential to safe and effective treatment.
MICROBIOLOGY We’re only beginning to learn about the vast number of organisms that live in and on us. We usually think about them in terms of the diseases they cause, but they are critically important to facilitate normal body function as well. The Human Microbiome Project is exploring human microbial communities in five areas, including the nasal passages, oral cavities, skin, gastrointestinal tract, and urogenital tract, and analyzing the role of these microbes in human health and disease. The complexity of the microbiome is astonishing. In the intestinal tract, for example, we have previously been unable to isolate the majority of organisms, because they’re not very hardy. They die quickly and can’t be cultured using normal media. Consequently, we really have had no idea about the makeup of the intestinal flora. Genetic identification of these
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translational changes. Understanding the basic genetic sequence is a critical first step, but we need to learn far more about these other interactions. We’ll also need to examine other pathways involving RNA, proteins, and small molecules to find abnormal metabolic activity that may be diagnostically useful or reveal a pathway that can be targeted with drug therapy. Such explorations could also dramatically alter our treatment of many disorders.
WHAT THIS MEANS FOR PATHOLOGISTS Pathologists can have a key role in genomic medicine, teaming with molecular biologists to offer the treating physician guidance on diagnostic and treatment options. The current diagnosis and treatment of leukemia offers insights into this future role. Nowadays, when we get a bone marrow sample from a patient with acute leukemia, the pathologist looks at smears the traditional way and formulates a differential diagnosis. Based on that initial examination, the pathologist may order flow cytometry, cytogenetics, or single gene studies and integrate all the information to characterize the leukemia. In the future, we may do whole genome sequencing or a proteomic analysis to type the leukemia or suggest targeted therapy. Pathologists will need to select the appropriate studies and integrate this increasingly complex information.
CHALLENGES FOR THE LAB Currently, only highly specialized centres provide whole genome sequencing. The technology will eventually be available at the local
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