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Genetic engineering for medicine - The BMJ
Genetic engineering for medicine "Breakthrough" is a word studiously avoided by most doctors, researchers, and respectable journalists; but Professor John
[PDF] GENETICS The Future of Medicine
Pharmacogenomics is a new word that scientists and drug developers use It describes the idea of tailoring drugs for patients, whose individual response can be
[PDF] Genetics, Medicine and Ethics - WHO World Health Organization
Genetics, Medicine and Ethics Research at present under genes function in order to prevent or nection with genetic engineering in medicine
[PDF] Application of Genetic Engineering - e-PG Pathshala
modified foods and medicines began • 1982: The first commercial development of GMOs (insulin-producing bacteria) • 1994: began to sell genetically modified
117057_3169_full.pdf BRITISH
MEDICALJOURNALLONDON,SATURDAY17JANUARY1981
Geneticengineeringformedicine
"Breakthrough"isawordstudiouslyavoidedbymostdoctors,researchers,andrespectablejournalists;butProfessorJohnPaulfromGlasgowuseditrecentlytodescribegeneticengineeringwhenaddressingtheSocietyforDrugResearch.Heisprobablyright.Geneticmanipulation,whichhasmostlydevelopedonlyinthepastdecade,istheprocessofchangingthegeneticmaterialofacell:genes(sequencesofDNA)fromonecell-forexample,ahumancell-canbeinsertedintoanothercell-oftenabacterium-andmadetofunction.Alreadywiththesetechniqueshumaninsulin,growthhormone,andinterferonhavebeenproducedbybacterialcells.Moreover,insightshavebeengainedintofundamentalcellfunctions,thebehaviouroftumourviruses,andthemechanismsofsomegeneticdiseases.Thesenewideashaveinfluencedallkindsofbiologicalwork;andtheirimpactwillsoonreachthegeneralpractitioner,whoshouldbeabletoprescribehumaninsulinmadebybacteria.Althoughthetechniquesaredauntinglycomplex,theprinciplesofgeneticengineeringaresimpleenoughforanydoctortounderstand.Therearethreeproblemstobeover-come:firstly,topreparetheappropriategenes;secondly,toinsertthemintothe"effecting"organism,sothattheyreplicateastheorganismreproduces;and,thirdly,toensurethattheinsertedgenesareexpressed-thatis,thattheeffect-ingorganismactuallymakesthecodedprotein.SegmentsofDNAforinsertioncanbepreparedbybreakinglongchainsintosmallerpiecesbytheuseofrestrictionenzymes,naturallyoccurringenzymesthatcleavetheDNAchainsatdefinedpoints.Alternatively,smallgenescanbesynthesised:nucleicacidscanbecombinedinthelaboratory,atthemomentforalengthofuptoabout100oftheconstituentbases,orsmalllengthsofDNAcanbesynthesisedfromtemplatesofmessen-gerRNAwiththehelpofreversetranscriptase(theenzymeproducedbysometumourvirusesthatcanmakeDNAfromRNAinsteadofviceversa).Thesegmentsareinsertedintotheeffectingorganism-usuallyEscherichiacoli-byusingplasmidsandbacteriophages.PlasmidsaresmallpacketsofDNAthatarefoundwithinbacteriaandcanbepassedfromonebacteriumtoanother;theyarebestknowntodoctorsfortheirabilitytotransferantibioticresistance.Byusingappropriateenzymes,sectionsofforeignDNAcanbeinsertedintotheDNAcontainedintheplasmid.Plasmidspassintothebacterialcelland,whileremaining
CBRITISHMEDICALJOURNAL1981.AUreproductionrightsreserved.separatefromthegenecomplement,theythenusethecellularmachinerytomanufactureproteins.AnotherwayofinsertingtheforeignDNAintobacteriaisbyfirstinsertingitintoavirus.Varioustechniquesareavailabletoselectoutthosebacteriacarryingtherequiredinsertedgenes(forinstance,genesforhumaninsulin),andtoencouragethebacteriatoreplicateandmaketherequiredproteininhighconcentration.Themolecularbiologists,whohavedevisedallthesetechniques,havebeenthefirsttobenefitfromtheirownwork.Geneticengineeringisproducingmanynewinsightsintotheworkingsofthegenesofbothprokaryoticcells(cellssuchasbacteriawithnotruenucleus)andeukaryoticcells(those,suchasanimalandplantcells,withatruenucleus).Manyofthegeneticmechanismsofprokaryoticcellshadbeenworkedoutbeforegeneticengineeringwasdeveloped,andmolecularbiologistshadtendedtoassumethateukaryoticcellswouldbesimilar.Geneticengineeringhashelpedtoshowthatthisassumptionwasfalse:asDrRAFlavellfromtheNationalInstituteforMedicalResearchsaidattheconference,themoremolecularbiologistslookatthetwotypesofcellsthemoredifferencestheydiscover.Thebeautyofthisfundamentalresearchisthatasgeneticengineeringteachesusmoreaboutthecellsothenewunderstandingcanadvancethetechniquesofgeneticengineering.Onefundamentalproblemwithclinicalovertonesnowripeforsolutionisthatoftumourviruses:whydotumourviruseswhichcanbequiescentinanimalcellssuddenlyturnthemmalignant?Morepressingtodoctors(andpatients)aretheproblemsofgeneticdiseases.Geneticengineeringmayhavemuchtocontributetotheseproblemsinincreasingunderstandingofthemechanisms,inimprovingmethodsofdiagnosis(par-ticularlyantenataldiagnosis),andperhapsinactuallytreatingsomeofthesediseases.AttheconferenceProfessorDavidWeatherallkepthisfeetfirmlyonthegroundandillustratedthepossibilitiesusingthethalassaemiasasanexample.AtthemomentP-thalassaemiacanbediagnosedantenatallyonlybyobtainingasampleoffetalbloodatabout15weeks'gestation.Thisdemandsfetoscopyandfetalbloodsampling,whichinthebesthandscarriesafetalmortalityrateofabout1-2%andofteninroutinepracticeofabout5%ormore.IthadbeenhopedthatgenemapsoffetalDNA(whichcanbeobtainedbyamniocentesis)wouldallowsaferandeasierdiagnosis.Sadly,thegenemapslookthesameinmostpatients
VOLUME282NO6259PAGE169 on 10 August 2023 by guest. Protected by copyright.http://www.bmj.com/Br Med J (Clin Res Ed): first published as 10.1136/bmj.282.6259.169 on
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withr-thalassaemiaasinnormalindividuals.Encouragingly,however,newtechniquesforbreakingupthegenesbytheuseofenzymesmayallowthegenesofpatientswithP-thalas-saemiatobedistinguishedfromnormalgenes.Butthisworkisatanearlystageandisapplicableforthediagnosisof3-thalassaemiaonlyincertainpopulations.Moreencouragingistherecentobservationthatthisapproachcanaccuratelyidentifyfetuseshomozygousforsickle-cellanaemia.Theproductionofhumanproteinsisthefirsttangiblebenefitfromgeneticengineering.Onedrugcompanyisalreadytestinginpatientshumaninsulinproducedfrombacteria,andotherproductsareinthepipeline.DrDDenner,ofEliLillyCompany,whohasexperienceoftryingtoproduceinsulinonacommercialscale,thinksthattheprospectsforproducingdrugsbygeneticengineeringmethodslieinmakinglargerquantitiesoffamiliarhormonesandenzymesratherthannewdrugs.Nevertheless,ProfessorDHopwoodfromNorwichthoughtthatgeneticengineeringcouldhelpeventuallyindevelopingnewantibiotics.Hepointedoutthat,unlikehormonesandenzymes,antibioticswerenotpuregeneproductsbutmetabolitesresultingfromreactionswithmanydifferentsteps.ButmanyofthetechniquesappliedtoEcoli-theusualmodelofmolecularbiologists-couldbeappliedtostreptomycetes,themicro-organismsthatproducemostofourpresentantibiotics;andnewantibioticsmighteventuallyresult.Oneproblemthatoverhangsthisexcitingworkisthatofregulation.Intheearlydaysofgeneticengineeringgovern-mentsandscientistswereworriedthatsomethingdreadful-suchasbacteriaresistanttoallantibiotics,orcancer-causingorganisms-mightresultfromthistinkeringwiththeverystuffoflife.Consequently,strictregulationswereevolved:therewereelaboraterulesonphysicalandbiologicalcontain-ment(biologicalcontainmentconsistsinmanipulatingbacteriainsuchawaythattheycannotsurvive outsidecon-trolledconditionsinthelaboratory).But,asProfessorJohnPaulobserved,thedangersarenowseentobethoseoftheorganismthatisbeingused-thuselaborateprecautionsareessentialforcontainingthesmallpoxvirusbutnotEcoli.Controlsarenowbeingrelaxed;buthedidpointoutthatagreementsareneededtolimittheuseofgeneticengineeringinmakingbiologicalweapons.Letushopethatthis"biologicalbreakthrough"isnotusedforharmasthe"atomicbreak-through"was.Evenforthemedicalusesofgeneticengineer-ing,thecomplexethicalquestionsshouldbeansweredbeforeandnotafterthetechniqueshavebeendeveloped.
Primarypulmonaryhypertension
Primarypulmonaryhypertension,firstdescribedclinicallybyPaulWood,'isarare,progressive,andusuallyfataldiseasewhichismorecommoninwomen.AThediagnosiscanbemadeonlybyexcludingthemanycausesofsecondarypul-monaryhypertension,startingwithleftventricularfailure,rememberingaorticstenosis,andworkingbackthroughmitralvalvediseaseandleftatrialtumourtocongenitalanomaliesofthepulmonaryveins,includingcortriatriatumandsupra-valvarstenosingring.Precapillarypulmonaryhypertensionmayconcealcongenitalseptaldefects.Rarelyfibrosingaveolitisoradvancedsarcoidosismaypresentwithseverepulmonaryhypertension.Inmanytropicalcountriespul-monarybilharziasiscloselysimulatesprimarypulmonaryhypertension,butinBritainpulmonarythromboembolismandveno-occlusivediseasearethemaindifferentialdiagnoses.
Attheextremesofagethesexincidenceisroughlyequal,butmostpatientswithprimarypulmonaryhypertensionarewomeninthechildbearingyears.Pulmonaryhypertensionisusuallyseverebythetimesymptomsdevelop.Patientsfrequentlypresentwithsyncopeoneffort.Allofthemarebreathless,andtheytendtoshowslightcyanosis.Considerablecentralcyanosismaybeseeninafewpatientswithadvanceddiseasewhomayshuntbloodfromtherighttotheleftsideoftheheartiftheforamenovaleispatent;peripheralcyanosismaybesevereinpatientswithaverylowcardiacoutput.
Thedisordermaybemisseduntilfaradvancedbecausethephysicalsignsaresometimessubtleandhardtoelicit-evenbytheexpertunlessaidedbytheelectrocardiogramandchestradiograph.Regularrhythmisusual;agiantvenousawaveintheneckmaybeprovokedbutisoftenabsentatrest;andtheremaybeaparasternalheave,arightatrialbeat,andaloud,evenpalpable,pulmonaryclosuresound.Anejectionclickcanusuallybeheardattheleftsternaledgeifthepatientholdshisbreathinexpiration.Splittingofthesecondsoundwithrespirationremainsnormaluntiltherightventriclestartstofail,whenpulmonaryclosurebecomesdelayedinrelationtoarelativelyearlyaorticvalveclosure.Adiastolicmurmurofpulmonaryregurgitationandamurmuroftricuspidregurgita-tion,oftenmisleadinglyloud,mayappear.Theelectrocardio-gramusuallyshowssinusrhythmwithrightaxisdeviationandalmostinvariableTwaveinversionintheright-sidedchestleads.Voltagechangesindicatingrightventricularhypertrophyvaryfromslighttoextreme,probablyreflectingthedurationofthedisease.Chestradiographsoftenshowanormalsizedheartbutwithadilatedmainpulmonaryarterytrunkandperhapsincreasedtransradiancyofthelungfieldscausedbynarrowingoftheperipheralbranchesofthepulmonaryartery.Lateronintheillnesstherightheartchambersdilate,butsuddendeathmayoccurbeforeheartfailuredevelops.
Exercisetoleranceisappreciablydiminishedwithanincreasedpulse-to-workratio,hyperventilation,andoftenafallinbloodpressure(thestrokevolumedoesnotrisetomaintainbloodpressureinthefaceofvasodilatationinexercisingmuscles)-theusualmechanismofsyncope.Lossofconsciousnessmaymistakenlybeattributedtosecondarycardiacarrhythmias;evenepilepsyhasbeenmimickedinsomecases.
Theechocardiogramisusefulinexcludingsilentmitralstenosisaswellasinshowinganormallycontractingleftventricleanddilatationoftherightventricularoutflowtract.Theremaybeincreasedthicknessoftheventricularseptumandoftheanteriorrightventricularwallaswellasabsenceoftheawaveinthepulmonaryvalveechoandanincreasedpulmonaryejectiontimeshownbyprolongedopeningofthepulmonaryvalve.Prolapseofthemitralvalveisoccasionallyseen;itmaybeattributedtothediminishedsizeofthe"starved"leftventricle.Cardiaccatheterisationshowsahighpulmonaryarterypressure,frequentlyatoraboutsystemiclevelwhenthediseaseisfirstrecognised.Apulmonarywedgepressurereadingmaybedifficulttoobtainbutthisorthedirectlymeasuredleftatrialpressureisnormal.Thecardiacoutputisusuallylow.Pulmonaryangiographyshowsnormalanatomybutwithdilatedproximalbranches,andmacro-angiogramsmayshowtheperipheralattenuationofsmallvessels-whichaccountsfortheblacKnessofthelungfieldsinx-rayfilms. on 10 August 2023 by guest. Protected by copyright.http://www.bmj.com/Br Med J (Clin Res Ed): first published as 10.1136/bmj.282.6259.169 on
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