From your club president, James Lee
James Lee (President)
James is a sophomore at SRHS and directed the magazine, looking over edits, finalizing articles and graphic design. Fun fact: if you text him and he doesn't respond, it is 95% likely that he is sleeping.
Adrian Mendez (VP)
Adrian is a sophomore at SRHS and is interested in many different areas of science; he enjoys studying quantum physics in his free time. He helped direct the overall magazine design. Also, he might be a communist.
Avaneesh Tisgaonkar (VP)
Avaneesh is a sophormore at SRHS and wrote an article, helped with the organizing and finalization of the article, and with graphic design. Fun Fact: 99% of the time he is listening to PSY songs (Gangnam Style).
Mayank Sharma (Secretary)
Mayank is a sophomore enjoys coding and anything computer science related. He helped set up the club discord server. Fun fact: he can solve a Rubik's cube in less than 20 seconds.
Veer is a sophomore at Scripps and is part of SRHS's cyberpatriot team, enjoying computer science and.. school dances?
Vivian Wang
Vivian made the cover. Fun fact: it was a good time.
Ryan Min
Ryan helped with editing. Fun Fact: Ryan loves studying Napoleonic history.
Rithvik Manikandan
Rithvik helps with editing. Fun Fact: Rithvik loves the milk and mocha cartoon.
Delbert Tran
Delbert edited many articles and helps with management. Fun Fact: he has a girlfriend.
Gautham Subramanian
Gautham helped with editing and design. Fun fact: Gautham likes Baby Shark. Gautham doesn't like coffee.
Michelle Cai
Michelle helped with editing the articles. Fun Fact: Michelle is a multi-sport athlete.
ABSTRACT
Tay-Sachsdisease(TSD),aneurodegenerativegeneticlysosomalstoragedisorder(LSD),isamongthe rarestofdiseases.Ofevery360,000births,onaverage,onlyonebirth,or0.00028%,willbeofachildwith TSD[1].ForindividualswithTSD,however,TSDwilldominate100%oftheirlives;initsmost commonform,TSDcausesrapidneurodegenerationanddeathinearlychildhood.Whilethereisno curetoTSD,therearemanytreatmentscurrentlyunderdevelopmenttoaidpatientswiththecondition. Inthisreport,wehopetoexploreoneofthesetreatmentmethods,knownasenzymereplacement therapy(ERT),andevaluateitsusefulnessandpracticalityforsuccessfullytreatingTSDinclinical settings.WewillfirstreviewTSDanditsunderlyingetiology,inheritance,andvariants.Wewillthen investigatethebenefitsanddrawbacksofERT.Finally,weshallexamineexamplesofongoingERT research.
KeyWords:Tay-Sachsdisease(TSD),lysosomalstoragedisorder(LSD),enzymereplacementtherapy (ERT),HEXAenzyme,GM2ganglioside,blood-brainbarrier(BBB)
AnOverviewofTay-SachsDisease
Tay-Sachsdisease(TSD)isararegeneticdisorderthatcausesthedeathofneuronsinthebrainand spinalcord[2].
TSDiscausedbytheaccumulationoftoxiclipidswithinthebrainandspinalcord.Undernormal conditions,theHEXAgeneproducestheα-subunitoftheβ-hexosaminidaseA(HEXA),whichisan enzymeinlysosomesthathelpsbreakdownGM2ganglioside,afattysubstancefoundincell membranes.InindividualswithTSD,however,theHEXAgenecannotproducetheα-subunit,ordoes soininsufficientamounts.Withoutthealphasubunit,theenzymeβ-hexosaminidaseAcannotbe createdinsufficientamounts,leadingtoadangerousaccumulationoftoxiclipidsinthelysosomes[2]. Furthermore,asmallaccumulationoflipidsoftencausesaccumulationofmorelipidsandhydrophobic proteins,whichclogslysosomesandimpairstheirfunctionandthefunctionoftheendolysosomal system.Insomecases,thisinhibitstheefficienttransferofnutrients,leadingtocellularstarvationand eventuallydeath[3].
InTSD,theinabilityoftheHEXAenzyme toproducetheHEXAenzymemost oftenstemsfrommutationsonchromosome 15,asseentotherightinFigure1.Tothis end,about130differentmutationsof varioustypes(ie.singlebasesubstitutions, smalldeletions,duplicationandinsertion splicingalterations,generearrangement,and partiallargeduplications)havebeen identifiedtocauseTSDinvariousgroupsof people,asseeninTable1below.Most mutationsthatcauseTSDare“outliercases”, inwhichthemutationiscarriedwithin asinglefamilylineage.Somemutations, however,arewidespreadacrossvarious communities[4]. Moreover,thereexist certaincommunitiesinwhichTSDdiseaseis moreprevalent.Thesecommunitiesinclude theAshkenaziJewish(rateofTay-Sachs carriersis1/30,~10timesthatofthegeneral populationrate),QuebecCanadianFrench, PennsylvaniaOldOrderAmish,Irish(rateof TSDcarriersis1/50,~6timesthatofthe generalpopulationrate),andLouisiana Cajunpopulations[2,5]. Despitebeing historicallyknowntohavehigherinstances ofTSDthanthegeneralpopulation,insome communitiesthatwereconsidered“high risk”(ie.AshkenaziJews),extensivetesting andscreeninghasreducedrates[2].
TSDisanautosomalrecessivedisorder (Figure2)[4].Thus, theallelesforthe HEXAgeneinvolvedinTSDarenotsexlinked;bothmaleandfemalechildrenof parentalcarrier(s)haveequalchancesof beingbornwiththedisease.Moreover,the mutantHEXAallele(TSD)isalsorecessive, meaningitseffectwillbemaskedif combinedwiththedominantwild-type HEXAallele(non-TSD)allele.While heterozygousindividualswillbecarriersof TSD,thesymptomsofthediseasewillonly showinhomozygousrecessiveindividuals.
Ethnic Community Prevalence (% of total Tay-Sachs patients)
Common Mutation(s)
Ashkenazi Jewish 94-98 •TATC sequence being inserted between segment 1277 and 1278 in coding DNA.
•Substitution of G with C in an intron near segment 1421.
•Substitution of G with A at segment 805.
French-Canadian N/A •Deletion of ~7,600 base pairs. This results in the deletion of exon 1 and someof the flanking sequences around it in the gene.
Japanese 80 •Substitution of G with T in an intron near segment571.
Key: G = Glycine, T = Thymine, A = Adenine, C = Cytosine
*Adapted from Shen, C.-H. (2019). Diagnostic Molecular Biology.
ThereareavarietyoftypesofTSD,eachwithdifferent symptoms.InfantileTSD,themostcommonform,isusually fatal,withindividualslivingonlytoearlychildhood.Other formsofTSD,however,suchasjuvenileTSDandlate-onset TSD,arelessaggressiveandareusuallynotfatal.Theseforms alsoappearlaterinlifethaninfantileTSD;thejuveniletype appearsfromroughly5yearsofagetolateadolescence,while thelate-onsettypeappearsinadults[2].Table2displaysthe differentsymptomsassociatedwitheachmaintype.
Symptoms
Cherry-red spot in the eye.
Symptoms setin at about 3-6 months of age.
Loss of basic skills suchas crawling, turning over, and sitting.
Exaggerated reactions to loud noise.
Involuntary muscle twitches (myoclonic jerks.
Seizures.
Difficulty swallowing (dysphagia).
Vision and hearing loss.
Intellectual disability.
Muscle weakness.
Loss of muscle coordination (ataxia).
Speech problems.
Psychiatric symptoms.
(Symptoms are more variable from person to person as opposed to in the infantile version)
*Adapted from U.S. National Library of Medicine. (n.d.). Tay-Sachs Disease: Medlineplus genetics. MedlinePlus. Retrieved December 31, 2022, from https://medlineplus.gov/genetics/condition/tay-sachsdisease/
Enzymereplacementtherapy(ERT)isamethodoftreatmentcurrentlythesubjectofmuch researchforuseinLSDssuchasTSD.UsingERT,enzymesaregiventopatientswholack them,usuallyviaIVinfusiondrips,inordertocombatconditionscausedbyenzyme deficiencies.ERThasshownpromisewhendeployedagainstLSDssuchasFabrydisease, Gaucherdisease,Mucopolysaccharidosis,Pompedisease,andNiemann-Pickdisease;itis hopedsuchbenefitscanbeextendedtotreatingTSDbyintroducingHEXAenzymesinto diseasedcells[6,7]. Vuetal.(2018)foundthattheintroductionof100nMofrecombinant humanHEXAenzymeintoTSDneuralstemcells(NSCs)whichhadbeendifferentiated frominducedpluripotentstemcellssignificantlyreducedtheaccumulationofGM2 gangliosidetonear-wildtypelevels.Inspecific,theTSDNSCstreatedwith100nM recombinantHEXAandlefttoincubatefor4hoursshowedNileRedIxA(anindicatorof GM2ganglioside)percentageslowerthan-5inthetreatedNCSswhenthepercentageswere normalizedtountreatedTSDcellsat100%andhealthy,wildtypecellsat0%.Furthermore,it hasbeenshownthatonlysmallamountsofHEXAactivity(aslowas10%comparedtowildtypelevels)areneededtosignificantlyreduceGM2gangliosideaccumulation[8].This suggeststhatTSDcanbetreatedwithverylittleHEXAenzyme,indicatingERThaspotential tobeanefficientremedyforTSD.
However,ERTwillneedtoovercomeanumberofobstaclestobefeasibleforclinicalusein treatingTSD,whichwewillexaminehere.ERTproducesseveraladversesideeffects,suchas headaches,nausea,rigors,fever,infectionfromtheIV,andlaboredbreathing;inmanycases, theimmunesystemmayreactagainsttheintroducedenzyme,leadingtofurtherhealth complications.Inaddition,ERTisextremelycostly,withannualpricesoftenexceedingone hundredthousanddollars,andtheefficacyofERTmaydecreaseovertimeifthebodyacquires resistanceagainstERTenzymes[6,7].Furthermore,duetothechronicnatureofmanyLSDs, ERTmustoftenbecarriedoutfrequentlyonaregularbasistocombatLSDs[8]. Thismay prolongtreatmentandincreasecostsfurther.Fortunately,ongoingresearchhasrevealedthat thecouplingofERTdrugs/enzymeswithtargetingmarkerscanincreasetheenzyme’saffinity forgeneraldestinations(i.e.addingpositively-chargedpeptidestoincreaseattractiontothe negatively-chargedcellmembrane)orspecificcellmarkers,suchascertainantibodies,sugars, andproteins.Suchattractionincreasesbio-adhesioninthebody,reducingthe amount/frequencyofdosesneededtoreplenishenzymelevels,whichisespeciallyusefulfor chronicLSDslikeTSD[9].Weshallnowexaminetwoofthemostpressingissuesaffecting ERTtoaidinourevaluationoftheefficiencyofERTintreatingTSD.
ForERTtobeusefulintreatingTSD,HEXAenzymesmustbeabletoenterintobraincells. However,duetothelargesizeoftheHEXAenzyme,ERTcurrentlyremainsimpracticalforuse inTSD.Specifically,themainobstacleforERTisthattherecombinantHEXAenzymeneeded totreatTSDistoolargetocrosstheblood-brainbarrier(BBB)andreachbraincells.TheBBB containstightjunctionsbetweencellsintheendotheliallayer,makingitdifficultforlarger molecules(suchasHEXAenzyme)topassthrough.Directintrathecalorintraparenchymal injectionsintothebrainhavealsobeenusedtocircumventobstructionbytheBBB,butsuch proceduresareoftenverycostly[8,9]. Unlessefficientmethodsofenzymeadministrationfor ERTcanbefound,itislikelyERTwillremainunavailableforTSDpatients.
ManytechniqueshavebeendevelopedinorderforERTtopassthroughtheBBB.Ingeneral, deliveryintothebrainandcentralnervoussystem(CNS)canbeperformedthroughtwo methods:localandperipheraladministration.Localadministration,inwhichenzymesareoften injecteddirectlyintothebrainorCNS,hasshownpotential.Forinstance,intraparenchymal administration(injectingdrugsintothebrainparenchyma)hasshownpromiseinex-vivorodent cellsfortreatingotherLSDssuchasMPSsyndromesandNiemann-Pickdiseasethroughenzyme andgenetherapy,whichcouldsoonbeextendedtosuccessintreatingTSD.However,local administrationandinjectionsintotheCNSarehamperedbythepoordiffusionofdrug contents,whichreducesefficiencyoftreatment.Furthermore,likelyduetoitsdirectnature,local administrationisinvasivetothepatientsandhasheightenedsafetyrisks[9].
Analternativetolocaladministrationisperipheral administration,inwhichenzymesareinjectedoutsidethe CNSandtransportedin,throughlessinvasivemethods,such asthroughcelljunctions(paracellularroute)or transmembranediffusion,saturabletransporters,and vesiculartranscytosis(transcellularroute).Oftheseoptions, vesiculartranscytosisisoneofthesafestandleast invasiveoptionsandworksforlargermolecules,whichisof greatimportancewhentreatingTSDwith large,recombinantHEXAenzymes.Vesiculartranscytosis functionsusingasystemofreceptorsandvesicles.When specificligandsbindtotheirvesiclereceptorsinthe endothelialplasmalemma,asequenceofreactionsoccurs, eventuallyresultinginmembranousvesiclestransportingthe enzymesintocells.Furthermore,vesiculartranscytosiscan eitherbecaveolar-mediatedorclathrin-mediated.In theformer,theprocessisregulatedbycaveolae,smallfolds ofthecellmembrane,whileinthelatter,whichismore commonlyusedtobypasstheBBB,theprocessisregulated bytheclathrinprotein[9].
Inadditiontolocalandperipheraladministration,muchresearchhasfocusedonmethodstomake theBBBmorepermeabletomoleculessuchastheenzymesinERT.StudiesbyAzminetal.(1985), Hanigetal.(1972),andKobileretal.(1989)haveestablishedvariouschemicals,suchasSDS, DMSO,ethanol,polysorbate-80,andglycerol,aspromotingeasiertransportofenzymesanddrugs intotheCNS.Suchchemicals,ifusedwithERT,couldenableHEXAenzymestopassthroughthe BBB.Whiletheuseofthesechemicalsremainsproblematicduetothelackofcontroloftheflow acrosstheBBB,theyholdgreatpotentialtoincreasetheefficiencyandefficacyofERTasa treatmentforTSD.Furtherresearchhasinvestigatedothermethodsinwhichtoincreasethe permeabilityoftheBBB,suchasusingultrasoundtotemporarilymaketheBBBmorepermeable, allowingenzymestopassthrough,anddecreasingtheefflux(outflow)oftransporterstoallowfor hydrophobicmoleculestodiffuseintocellsmoreeasily[8,9].Aswecansee,whileERTremains currentlyhamperedbytransportissues,ongoingresearchisrapidlyimprovingenzymetransport. GiventhatERThasbeendemonstratedtosuccessfullyreduceGM2gangliosidelevelsinpatients, continualresearchinERTisvital.
Inadditiontofunctionaltransportmechanisms,forHEXA-basedERTtobefunctional,boththeαandβ-subunitsofβ-hexosaminidaseA(HEXA)mustbeproduced.Theinabilitytosynthesizeboth subunitshasposedasignificantchallengetoimplementationofERT.Inspiteofthisobstacle, however,avarietyoftechniqueshavebeendevelopedtoenabletheproductionofbothα-andβsubunits[10].
In2016,Tropaket.al,successfullycombinedα-andβ-subunitsoftheHEXAenzymetoformahybrid μ-subunitprotein.Theμ-subunitcombinesboththeactiveα-siteandstableβ-site,bothofwhichare favorableforeffectiverecombinantHEXAenzymes.Furthermore,Tropaket.alfoundthat,after beingpurified,thenewHexMhomodimer(adimerwhosesubunitsareidenticalproteins),inthe presenceofGM2A(gangliosideGM2activatorprotein,whichassistsintheprocessofbreakingdown GM2),wasabletohydrolyzethederivativesofGM2gangliosidebothinvitroandincellulo[10,11, 12].
Inotherstudies,Ogataeaminuta,amethylotrophic yeast(ayeastwhichprimarilyutilizesonecarboncompoundsfornourishment),wasfoundtobe abletosynthesizeboththeα-andβ-subunits, andwassuccessfullyusedtocreaterecombinantHEXA enzymes.Furthermore,ina2011study,Tsujiet aldemonstratedthetherapeuticefficacyofthenew recombinantHEXAenzymeintreatingHEXB-deficient housemice.Micetreatedwiththeenzymesexhibited improvedmotorfunctionandsurvivalrates,among otherimprovements,suggestingtherecombinant enzymesmayhaveuseintreatinghumanTSD[10,13].
Moreover,in2011,MatsuokaetalsuccessfullymodifiedthenucleotidesequenceoftheHEXB genewherethechimeric(agenewithpartsofvariousorigins)β-subunitisproduced,byinserting partialgenesfortheα-subunitthere.ThenewchimericHEXBenzymeperformedwellbothinvitro andinvivo.TheHEXBenzymesweresuccessfullyincorporatedintopatientTSDcellsinvitro,and loweredGM2gangliosidelevelsinthecells,whileexhibitingwild-typethermostablecharacteristicsin plasma.Similarly,uponbeinginjectedviaintracerebroventricularadministrationintoSandhoff (anotherLSD)modemice,decreasedGM2gangliosidelevelswereobservedinthemiceparenchyma. Additionally,Matsuokaetal.’sstudyisofparticularimportanceforourevaluationofERT,asit suggestsHEXBmaybeofbetterusefortreatmentforTSDthanHEXA[10,14,15].
Inthisreport,weexploredtheuseof enzymereplacementtherapyintreating Tay-Sachsdisease(TSD).TSDisan extremelyraregeneticneurodegenerative lysosomalstoragedisorder(LSD),caused byinsufficientlevelsoftheHEXA enzyme,andisusuallyfatal.Enzyme replacementtherapy(ERT)isone proposedtreatmenttoTSD,andseeksto reducefattyacidaccumulation byintroducingHEXAenzymesintothe body.
Despitebeingcurrentlylimitedbya varietyofissues,suchastheblood-brain barrier,whichpreventstheHEXA enzymefromreachingbraincells,ERT hasthepotentialtobeafeasible treatmentforTSD.Additionalresearch isrequiredtoexplorealternative methodsofenzymetargeting/delivery, subunitproduction,andtoreducesideeffects.Wehopesuchresearchwill reducecostsandincreasethesafetyand affordabilityofERT,andbelieveERT willsoonbeofgreatusetophysicians andpatientsinclinicalsettings.
1.Kaback, M.M.(2001). Tay–Sachs disease. Encyclopedia ofGenetics, 1941–1943. https://doi.org/10.1006/rwgn.2001.1273
2.U.S.National Library ofMedicine. (n.d.).Tay-Sachs Disease: Medlineplus genetics. MedlinePlus. Retrieved December 31, 2022, from https://medlineplus.gov/genetics/condition/tay-sachs-disease/
3.Schulze,H.,&Sandhoff,K.(2011). Lysosomal lipid storage diseases. ColdSpring HarborPerspectives inBiology, 3(6). https://doi.org/10.1101/cshperspect.a004804
4.Shen,C.-H.(2019). DiagnosticMolecular Biology.
5.Tay-Sachs disease:Symptoms, cause,treatment. Cleveland Clinic. (n.d.).Retrieved December 31, 2022, from https://my.clevelandclinic.org/health/diseases/14348-taysachs-disease
6.Infusionteam. (2021, April 14).What isenzyme replacement therapy andhow does itwork? Infusion Associates. Retrieved December 31,2022, from https://infusionassociates.com/what-is-enzyme-replacement-therapy/
7.Enzyme replacement therapy forlysosomalstorage disorders.Infusion Associates. (2021, March 24).Retrieved December 31,2022, from https://infusionassociates.com/infusion-therapy/ert-for-lysosomal-storagedisorders/
8.Vu,M.,Li,R.,Baskfield, A.etal.Neural stem cells for disease modeling and evaluation oftherapeutics for Tay-Sachs disease. Orphanet JRareDis 13,152 (2018). https://doi.org/10.1186/s13023-018-0886-3
9.Muro, S.(2012). Strategies for delivery of therapeutics into thecentral nervous system for treatment of lysosomal storage disorders. DrugDelivery and Translational Research, 2(3), 169–186. https://doi.org/10.1007/s13346-012-0072-4
10.Solovyeva, V.V.,Shaimardanova, A.A.,Chulpanova, D.S.,Kitaeva, K.V., Chakrabarti, L.,&Rizvanov, A.A.(2018). Newapproaches totay-sachs disease therapy.Frontiers inPhysiology, 9.https://doi.org/10.3389/fphys.2018.01663
11.Wikimedia Foundation. (2022, November 15). Protein dimer.Wikipedia. Retrieved January 1,2023, from https://en.wikipedia.org/wiki/Protein_dimer
12.U.S.National Library ofMedicine. (n.d.). GM2A gene: MedlineplusGenetics MedlinePlus. Retrieved January 1,2023, from https://medlineplus.gov/genetics/gene/gm2a/
13.Wikimedia Foundation. (2022, February 10). Methylotroph. Wikipedia. Retrieved January 1,2023, from https://en.wikipedia.org/wiki/Methylotroph
14.Matsuoka, K.,Tamura, T.,Tsuji, D.,Dohzono, Y.,Kitakaze, K.,Ohno,K.,Saito, S.,Sakuraba, H.,&Itoh, K.(2011). Therapeutic potential ofintracerebroventricular replacement of modified humanβ-hexosaminidase Bfor GM2 gangliosidosis MolecularTherapy, 19(6), 1017–1024. https://doi.org/10.1038/mt.2011.27
NCIDictionary ofCancer terms.National Cancer Institute. (n.d.).Retrieved January 6,2023, from https://www.cancer.gov/publications/dictionaries/cancerterms/def/chimeric
Whydosomebecomeaddictedtogamingsoeasilywhileothersdon’t?Byexploring thisquestion,anotherquestionpressedindebatesarisesagain:areourcharacteristics formedbynatureornurture?Whilenumerousstudieshaveestablishedspecificgenetic markersforthecauseofaddiction,itisindubitablethatenvironmentalfactorsalsotake place.Bytargetingthebrainsoftheadolescentdemographic,anotherquestionis investigated:whyisgamingsoaddicting,andwhyareteenagersmuchmorevulnerable toaddiction?Allofthesequestions,collectively,leadtotheclaimsthat1)teens,inthe presenceofgaming,aremorevulnerabletoaddictionthanotherdemographics,and2) someteensaremoresusceptibletoaddictionthanothersinthesamedemographic.This paperraisespotentialethicalimplicationsfromtheideaofsomeonebeingmore susceptible.Addictsmaymisinterpretsusceptibilityasinevitable,discouraging themselves.Theymayalsomisusethisresearchasanexcusefortheiraddiction.Before thesemisunderstandingsandmisusesensue,societymustgofurtherthanmerely understandingthedifferentfactorsofaddictionandhelptoraiseawareness.
Ina2008report,97%percentofAmericanteensbetweentheagesof12-17playedgamesinat leastoneform(computer,console,etc.)[1].Inrecentyears,reportsanddatarevealthatchildren ages12-15spend12.2hoursaweekgaming[2].Thisfigureissignificantlyhigherforolderteens. A2021studybythejournalAddictiveBehaviorsdiscoveredthat26.8%of3000studentswere classifiedtohaveagamingdisorder[3].Byestablishinggamingasalifestyle,asignificantportion oftheseteens(asreferredtointhestatisticsabove)developapervasivegamingaddiction. Moreover,gamingaddictionhasbecomesoprevalentandintrusivethattheWorldHealth Organizationrecognizedgamingdisorderasadiagnosablementalhealthcondition.However, thesestatisticsalsorevealthatthereareteenagerswhodonotbecomeaddicted;forthepurposeof thisessay,thisexcludesthosewhodonothaveaccesstotechnologyorhavespecific circumstances. So,isitgeneticsorenvironmentthataffectone’slikelihoodtofallintoaddiction? Thesimpleanswer:both.
Natureandnurtureworkin intricateways,amultifactorial processoftenoverlapping todevelopwhatonecalls addiction[4].Inturn,itismore correcttodefinenatureasgenetics andnurtureasepigenetics. Geneticsandepigeneticsarenota rigiddichotomylikeblackand whitebutareinterrelatedin essence,workingtogetherina complexprocess.
Geneticsdescribestheheritability ofDNAcomponentsandvariants ingeneencodinginspecific receptors.Inthecaseofgaming addiction,2018researchinvolving Koreanmaleadolescentssuggests thatgenevariants(AAgenotype andAallele)ofthe CRHR1(CorticotropinReleasingHormoneReceptor1) geneareinvolvedwith susceptibilitytointernetgaming addiction[5].Anolderstudy, morefocusedonthegenesof thedopaminesystem,revealed thatagenevariant(Taq1A1allele) oftheDRD2 (DopamineReceptorD2) receptorgenewas“moreprevalent inanexcessiveonlinegaming groupthaninacontrolgroup” [6].
Epigeneticsstudiesthe“changesin phenotype,”howourbehaviors andenvironmentchangetheway ourbodiesreadtheexistingDNA [4][7].
Insimplerterms,the bodyholdsbackinherited dormantgenes,suchasaddiction genes.Thesepreexistinggenes arethentriggeredbythe environmentorcircumstance, changingtheexpressionofthe gene,anddevelopingadisorder suchasaddiction.
Apersonwithafamilyhistory ofaddictionhasan increasedchance around40 to60% ofdevelopingan addiction[4].Thisisevident throughthe studiesmentionedabovewith differentvariantgenesinvolved withaddiction.Studieshave shownthatastressfullifecauses onetobesusceptibletoepigenetic changes[4].Inotherwords,stress actsasatriggertohowaddiction genesareexpressed.Stress releasessteroidhormones
calledglucocorticoidsthrough asystemknownas thehypothalamic-pituitaryadrenal(HPA)axis[7].This axisinvolvesthe complexinteraction betweenthethreeregions: thehypothalamus,pituitary gland,andadrenalglands. Thesestressinducedhormones“affect theriskofaddictionby affectingthebrain’sreward center”[8].Thisexplainswhy teenagers,whomostlikely pursueastressfulacademic standard,aremorevulnerable toaddiction.Forthosewitha familyhistoryofaddiction,if placedinacompetitive environment,theyundergo changesthat triggerthegeneticmarkers ofaddictionthatareencoded inthem.
Whyisgamingsoaddicting,especiallytoteenagers?
Dopamineandteenagers’vulnerabilityto therewardsystem:
Thedarkblueregionsshowahighstatistical significanceoraverygoodpossibilityofusingthe brainregion.Theseusedregionsrepresentthe abnormalintegrityofthebrain’swhitematter. Otherresearchsuggestshowwhitematter plasticityholdsimplicationsforaddiction[10]. Thiscomparisonshowshowinternetaddiction andopiateaddictionusethesameneural mechanismsanddopaminergicregions.Asthe studystates:internetdisorders,substance addiction,andpathologicalgamblinghave similarstructuralabnormalitiesinthebrain,a neuralsignatureforaddiction[11].Thisstudy firmlyestablishesgamingasaseriousaddiction, althoughtoalesserextent,asgamblingand substanceabuse.
Thebrainreleasesdopamine,areliefhormone, duringgaminginsimilarwaystoopioid addiction.Dopaminecontributestoareward system,thusmakingitaddictive.Thisis especiallytrueinthecaseofteenagersastheir rewardsystemis“verysensitivewhilecircuits involvedinself-controlarenotfullydeveloped” [13].Duringadolescence,thestriatum,aregion involvedwithrewardprocessing,is“hyperresponsive”torewards,meaningtheyhavean “increasedreward-seekingbehavior”[14].The teenagebrainduringitsdevelopmentalphaseis vulnerable,malleable,andeasilylatchedtoseek “rewards,”thusdevelopingaddiction[14].
Withthehighlyaddictive componentofgaming, genetics,andenvironment playingamajor factorinaddiction,there isampleevidenceto establishthataddiction formanyteenagers inthosecircumstancesis veryprobable.Ifteenagers aremoresusceptible togamingaddiction thanotherdemographics, orifsometeenagersare moresusceptiblethan otherteenagers,isittheir fault?Allthreefactorsof addictioncannotbe controlledbythe individual;whatis society’sduty torecognizethis?With this knowledge,individuals shouldrestructurethe perspective ofunderstanding theaddictedteen.It mustchangefrom blamingtheperson’s identitytounderstanding the combinationofcompone ntsthatresultin addiction.
However,thereis anothersideofpotential ethicalimplicationsthat arisewith theprocessofunderstan ding.Thisresearch wouldserveasatoolfor peopletouseas anexcusefor theiraddiction.Itcan potentiallybe counteractive labeling addictionas“inevitable” willdiscouragepeopleto workoutofit.Inthe scopeofthegenetic factor,individualsmay alsoblameotherpeople fortheiraddiction. Offeringthisideawould takethe responsibilityoffoftheir conscience.
Thus,theactof understandingcan becomeapoison,making itimperative thatwithunderstanding comesaidandgenuine care.Solely understandingis superficial;it iswhatoffersaddictiona scapegoat.“Highly probable”shouldnotbe interpretedasfate,but ratheracallingto recognizethesepeople andsuccorthem,more thanweoriginallyhave.
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[8] Can You Pick Your Poison? The Effects of Genetics on Addiction. The Yale Ledger. https://campuspress.yale.edu/ledger/can-you-pick-your-poison-the-effectsof-genetics-on-addiction/. Retrieved: 17/06/2022.
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Given any Jordan curve, is it possible to draw a rectangle, such that each of its vertices is on that curve?
A checklist:
That question leaves a lot to be desired: what is a Jordan curve? How does one define a rectangle, in a way helpful to the problem? And, last but not least, how would one even solve something like this?
The first and second questions are fairly simple. A Jordan curve (Image 1) is any squiggly line through space that is continuous, without any gaps, at every point. Another, analogous, term for a Jordan curve is a “closed curve”.
The traditional definition of a rectangle—a quadrilateral with 3 (not 4!) right angles, and parallel sides that are opposite to each other is not very helpful. Another way to define a rectangle is by the properties of its diagonals. Each diagonal of the rectangle must be equal, and the midpoint of one, must be the midpoint of another.
Now onto the last part—how to solve it. Rephrasing the problem would help with that. On any Jordan curve, is it possible to find two pairs of two points on said curve, such that the middle of the line connecting paired points is the same, as well as the distance between paired points? A simple checklist can be used to approach this!
Inscribed Rectangle Problem:
• Is the middle of the lines between paired points the same?
• Is the distance between each pair of points the same?
It might be helpful to find some way to identify the midpoint, therefore, let’s introduce a function. Imagine the Jordan curve on a 2D xy plane. Let’s move the midpoint of each possible diagonal up, on the z-axis, a certain amount, to be able to identify them (Image 2). If the x and y coordinate of any two midpoints match, the first task is complete!
• Is the middle of the lines between paired points the same?
Now, some of you might be wondering how far to move each point up on the z axis. That leads to the second task by moving the midpoints up by the length of the diagonals they are on, the diagonals with the same length will all have the same z-coordinates. Matching z-coordinates represents the completion of the second task, because the corresponding diagonals would be the same length.
• Is the distance between each pair of points the same?
But wait a second. If the x, y and z coordinates are all the same, then all one must find is any point that can be identified by using two different sets of points on the curve. Therefore, all that needs to be done to solve the problem is to plug every possible points into the function, and to find any you can get from two points on the curve.
Now, this section’s namesake: the mountain. Applying this function to every point on the Jordan curve moving up the midpoints, by the length of the diagonals they bisect, and plotting that point we get a “mountain” (see image 2).
This mountain is just one way to define the problem. The next section will focus on another, equally useful, way to visualize the problem.
Now, instead of thinking about what happens in 3D, we’ll go down to 1D. How? Scissors!
Let’s take that Jordan curve from earlier and cut it (See image 1). Then, let’s straighten it (See image 3a). On that straight line (think of the number line on the wall of your elementary classroom!), let’s choose a point, and cut it with scissors. Now, instead of an enclosed shape, it is just a curvy line.
This is the confusing part: We can turn this into a straight line by moving each point on the curvy line to a 1D plane, while maintaining the order (See image 3a). The point where the shape was cut will appear twice, at each end of the straight line.
A point on the straight line corresponds to a single one, on the Jordan curve, but there needs to be two points on the Jordan curve to create a rectangle. To solve this, duplicate the straight line to make a square (see image 3b). This square is special, as each point on the square corresponds to a possible rectangle. This can almost be used to compare with our previous, 3D model.
However, another problem arose.
For the sake of objectivity, let’s observe point A and point B, two random points on the shape. On the Jordan curve, any two choices for A and B will result in a single rectangle. However, on the square from earlier, A and B result in two points: (C, B) and (B, C) (see image 3b). Two distinct points on the square will map to the same rectangle. As a side note, if the pair of points on the Jordan curve are the same, the two resulting points on the square will map onto the same point, but that doesn’t matter, due to reasons which will be explained shortly.
Now comes the topology: as long as the overall essence of the shape is preserved, we can draw a number of conclusions. While this may seem broad, imagine you have some paper, scissors and glue; anything you can do to that paper, you can do to this square. The first change to the shape, or transformation, will be to “flip” half of the square onto the other half, in order
to remove the second, redundant, ordered pair, turning the square into a triangle with only unordered pairs (see image 3c). Now, there is only a 2D triangle, but two more problems remain!
First, it is only 2D, but it needs to be 3D to compare it to our 3D mountain. We also have to make sure the order of the line is the same, and two points overlap only if they represent the same thing. In other words, we need to make sure the arrows always map onto each other facing in the same direction (See the arrows in image 3c).
There is a solution to both! First, split the triangle in two, based on its altitude (see image 3c). This leaves us with 2 smaller triangles, which account for ¼ of the total area of the original square. By “flipping” one of the triangles and “gluing” it to the next (see image 3d), such that the green line and purple line are coincident, our final 2D polygon is achieved
Now, our final step is to make it 3D. Fairly simple: just connect the left and right sides of this smaller square. However, notice that we still have to be careful; the arrows are facing in opposite directions (see image 3d), therefore, they can’t be connected normally. Instead, they have to be “flipped” once more. This will create a Möbius strip (see image 4).
Now the last phase: connecting the pieces.
Both the mountain and the Möbius strip represent the same set of all possible rectangles. Remember, if any point on the mountain is the output of two different pairs of points on the Jordan curve, or a single point on the Möbius strip, the theorem is proved.
From here, all that is left is proving the Möbius strip cannot map onto the mountain, without intersecting itself. A Möbius strip has a “flip”; it switches direction midway through, creating a 1-sided, yet 3D shape. That flip ensures it cannot map onto the mountain. Try it yourself! Take a piece of paper, flip it once, and connect the two ends. Now see if you can map that onto a rock, such that the rock is completely covered, and the paper never overlaps. And with that, the theorem is proved. The underlying motif throughout this proof was topology: it was used in creating the mountain, creating the Möbius strip, and combining the two shapes. The abstract nature of topology, unbounded by restrictions, such as exact length and angle, can lead to many, otherwise unreachable, conclusions.
Works Cited
Sanderson, Grant. “Who Cares about Topology? (Inscribed Rectangle Problem).” 3Blue1Brown, https://www.3blue1brown.com/lessons/inscribed-rectangle-problem. Ye, Tomáš.“RectanglesInscribedin JordanCurves.” Mathematical Institute of Charles University, Charles University, 2018,pp.2427 https://dspace.cuni.cz/bitstream/handle/20.500.11956/99757/130
In 1969, NASA’s Apollo guidance computer was a “technological beast” of its time. A cubic foot in volume, with a whopping 64KB of memory, and the ability to perform one hundred thousand operations per second, this supercomputer sent humans to the moon (Zmescience). Just half a century later, we have miniscule smartphones dwarfing the capabilities of the guidance computer . Able to perform nearly 17 trillion operations per second, Apple’s iPhone 14 pro is infinitely faster than NASA’s once-great behemoth.
The secret lies in the microscopic size. The growing interest in miniaturization produces components that are smaller, faster, cheaper. At the base level, the transistor is the data processing component of computers. In simple terms, a transistor is like a switch, either blocking or opening the way for information to pass. Based on the signal received, by electricity– the flow of electrons– a transistor will relay information, which is then stored in bits. Conceptually, these bits have a binary value of a 1 or a 0. Transistors are then packed by the millions into the computer’s processing unit: the CPU. The individual transistors convey these basic, simple bits to other transistors, allowing for a coherent transfer of signals, allowing classical computers to do large numbers of operations.
However, as transistors shrink to the atomic level, we run into a unique phenomenon: quantum tunneling. Electrons transfer themselves through the physical boundary of a transistor, changing the intended result of the electrical signal. Although this may not get you through the wall to Platform 9 ¾, tunneling results in unique signal transfers, where electrons, the quantum unit of electricity, can bypass and even reach an endpoint faster than normal routing. Quantum computers aim to exploit quantum tunneling and other quantum properties to effectively perform calculations and solve problems.
One such quantum property is quantum superposition. In the quantum world, the value of an electric signal does not have to be exactly 0 or exactly 1. Qubits, the quantum equivalent of a classical bit, can exist in any linear combination of the two states at once. This is superposition. Too complicated? Here is a simple analogy: If a quarter is placed on a table, an observer will easily be able to identify if the quarter is facing “heads” or “tails.” This is a classical bit. However, for a qubit, imagine the quarter is rapidly spinning on the table. Now, an observer cannot distinguish if the quarter is exactly facing “heads” or “tails.” The quarter is spinning in a special state, on its side a combination of both “heads” and “tails.” This is called superposition. Until the quarter stops spinning, whether or not it is “heads” or “tails” is just a probability, and nothing definite. Similarly, until a qubit is measured, the qubit is in a combination of probabilities for 0 and 1. The exact combination is unknown. This property allows an exponential increase in the sets of data that bits can hold.
Image 4: Quantum Tunneling
Another unique property of qubits is entanglement. Quantum entanglement is the phenomenon when two particles [electrons] link together, no matter how far apart they are in space (Space.com). Think of it like a long-distance relationship, it lasts indefinitely, at any distance, until they break apart from external forces. Even Einstein described this common-sense defying property as “spooky,” as it implies that one electron is sending information to another electron instantaneously. An invisible information transfer is occurring, faster than light. Today, quantum entanglement is widely accepted and has been proven by scientists, to be in fact, possible. In a practical sense, measuring just one of the qubits at any point in time will give the exact details of the entangled qubit. Quantum entanglement allows data correlations to be inferred, otherwise impossible to achieve with classical computers (linkedin). The number of qubits and electrical signals that can be processed simultaneously is augmented to a groundbreaking amount.
A third quantum property is used in quantum computers: interference. Interferenceis essentially combining two waves, so they either constructively interfere, and the waves’ amplitude increases, or they destructively interfere,and simultaneously cancel. Interference allows us to predispose the measurement of a qubit toward a desired state or set of states, by amplifying a signal leading to the “right answer” and killing the signal leading to the undesired state.
Quantum computing, in all its majesty, is just like communism and social utopia. While it is idealistic, it is incredibly difficult to achieve. The aspect of quantum physics that hinders the progress of quantum computing is called decoherence (educative.io).When a qubit is exposed to an external environmental factor, most notably: temperature fluctuations or electromagnetic waves, the superposition state has a high chance of collapsing, resulting in an uncontrollable alteration, and catalyzing the destruction of the quantum information (Scientific American).
Scientists and engineers have deduced ways to manipulate quantum particles, minimizing decoherence. For instance, quantum computers often hold qubits at freezing temperatures, minimizing temperature fluctuations and decoherence (Educative). Others hold qubits in a vacuum-state, reducing vibrations and balancing the state of the qubits. Decoherence still hinders progress, as the methods of scientists are at times faulty, or difficult to scale. The frigid conditions or vacuum-state make them unusable as regular tools in our lives.
As with the early supercomputers, quantum computers remain in their earliest stages, and, therefore, are gigantic in size and incredibly costly. The state-of-theart quantum computer (as of December2022),IBM’s Osprey, is a cubic yard in volume and costs millions of dollars. Such factors make quantum computers impractical and inaccessible for most people.
“Quantum computers” symbolize futuristic, out-of-reach ideals. However, once problems like decoherence, size, and cost are solved, the numerous advantages of quantum computers can be applied to the real world. The increase in speed and power is applicable to various careers:AI and machine learning, computational chemistry, cybersecurity,and drug development. We do not know when – years, decades, maybelonger – but quantum computing is sure to offer endless possibilities for the realm of technology.
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