Branden TarlowMay 28, 2002Biochemistry 118QDr. Doug BrutlagFinal PaperIt's not just your genes: using genomics to identify,trace, and treat foreign pathogensWith the announcement that the first copy of the human genome has beencompleted, many eyes have turned to the genomic field. One bi-product of humangenome research is the availability of a vast new set of technological tools. Because ofthe human genome project, genotype screening techniques have greatly proliferated —they are more widely used and widely available for a growing number of researchers andmedical professionals. In the last decade a combination of new genomic strategies,classic molecular fingerprinting techniques of restriction fragment-length polymorphismanalysis (RFLP), and epidemiological strategies have helped us better understand disease.Elucidating the genetic sequence of individual pathogen strains can help deliver the mostefficacious treatment to patients, trace diseases in populations in order to design betterpublic health policy, and lead to wrongful death convictions. In this paper, I will discussthese applications in addition to ethical and technical concerns relating to public healthand the legal arena where applicable.To begin with, genotypic identification of pathogen strains allows offers thepossibility to better understand the mechanisms of bacteria or viruses. Though thistechnology is not new or novel, it has been used in new ways to identify the properties ofun-culturable bacteria. For example, by amplifying the DNA with PCR, scientists wereable to identify and characterize the bacterium associated with Whipple’s disease, asystemic illness affecting the nervous and gastrointestinal system.i In addition, genotypicscreening has allowed doctors to distinguish between separate diseases with similarphenotypes—a growing trend in biology. In the 19th century, a variety disease that wenow may call cancer and heart disease (and many others) were clumped under thecommon title “consumption,” which was treated by bloodletting. While this now seemsabsurd, the progress in medicine is a macrocosm of how molecular epidemiology willrefine the treatment of pathogens. A more modern corollary can be found in thediscovery of hepatitis. Molecular analysis identified patients afflicted with “hepatitis” toshow that hepatitis A, B, C, D, and E are separate diseases.ii Identifying variation in thegenotypes of diseases with similar phenotypes allows medical professionals to bettertrack the spread of disease. By knowing what strain of a disease a patient has, doctorscan prescribe the most efficacious drug to fight that disease. This approach is especiallyuseful in treating drug resistant bacterial infections. In the worst of infections, initiallychoosing the correct drug (that the bacterium is not resistant to) instead of operating bytrial and error may make a life and death difference. Doctors, however, must ask whetherrunning such an assay is time-effective or cost-effective. Though the host environment isa great variable in disease characteristics, understanding of the pathogenesis of thedisease can greatly aid treatment.Genotype identification is especially applicable in treating humanimmunodeficiency virus (HIV). Though it is believed to be an incurable disease, theprogression of the illness can be treated with a variety of drug cocktails to enhance andlengthen the life of an afflicted person. A major problem in administering HIV drugs isthat the drug targets constantly change: HIV has an extremely high mutation rate due tothe inexact nature of the reverse-transcriptase enzyme; nearly 1 in a 1000 base pairs isincorrectly copied. For many years, HIV has been treated with protease inhibitors, drugsthat prevent HIV proteins from being correctly divided and AZT, a drug that inhibitsreverse-transcription and therefore slowing retrovirus action. But in its hyper-evolution,HIV quickly develops drug resistance. Consequently, to have the most efficacioustreatment of the retrovirus, it is important to know which drugs the HIV strain is resistantto and which one work the best. For example, a doctor might enter the RNA sequence ofa patient’s HIV into the computer and receive an output that says that AZT is only 20 %effective on that patient while another drug works is 80 % effective. Currently, databaseswith this information receive thousands of scan per day from all over the world. Thistechnology uses bioinformatics to predict the most likely match based upon alignments inthe database.iiiBecause HIV has a great number of nucleotide polymorphisms, it is difficult totreat. But by the same token, the strains take on a personalized aspect that allowsepidemiologist to track its evolution. For example, HIV on the African continent is easilydistinguished from that in Europe or Asia. Thus, by simply looking at a strain andcomparing it to a database, researchers can roughly identify the source of the virus. Evenin a smaller cluster of people, a high degree of genetic relatedness of HIV strains cansuggest common infection sources.Several years before the O.J. Simpson trial, genetics, molecular biology, andepidemiology joined forces to help demonstrate that a dentist infected several of hispatients with HIV. The dentist, who was symptomatic with AIDS, continued to practiceand five of his patients who had very low risks for HIV infection, were found to have thevirus. Molecular analysis of highly variable regions of the HIV genome were analyzed toshow a very significant correlation between the doctor and his patients. In the study,investigators identified eight signature nonconsecutive nucleotides in a region called C2-V3 sequences. The theory is that mutations randomly arise in the genetic code in theretrovirus action of HIV. Thus, when a mutation occurs in one host, it is hereticallytransferred from one HIV molecule to a daughter HIV molecule. Thus, a newly infectedperson will receive the same strain of HIV as their host. After the moment of infection,the genomes will diverge from each other in an essentially random manner (thismicroevolution is influenced by the host’s immune system, drugs, and other variableenvironmental factors). By means of a statistical comparison, it was shown that fivedental patients shared 7 or more of the signature nucleotides with the dentist while localcontrols (HIV-positive people in the same geographic area who didn’t have contact withthe dentist or the
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