Breakthrough magazine, Spring 2023

Breakthrough magazineispublishedbyMEResearchUK,a ScottishCharitableIncorporatedOrganisationwiththeprincipalaimofcommissioningandfundinghigh-qualityscientific (biomedical)investigationintothecauses,consequencesand treatmentofMyalgicEncephalomyelitis/ChronicFatigue Syndrome(ME/CFS).Weinfluence,informandinvestinME researchgloballybyidentifyingpotentiallyimportantareasfor futurebiomedicalresearch,andbyproducinghighqualityprofessionalreviewsandreports. Breakthrough isanopen-access publicationand,apartfromimagesandillustrations,thecontentmaybereproducedfreeofcharge,subjecttotheterms andconditionsfoundatmeres.uk/bt-terms.

©MEResearchUK,2023–SCIOCharityNo.SC036942

TheGateway,NorthMethvenStreet, Perth,PH15PP,UK Tel:01738451234,Email:contact@meresearch.org.uk

Inthespotlight

What’shappeningintheworldofMEresearchandfunding

Editorial

WelcometoourSpring2023issueof Breakthrough magazine.

InSeptember2021,wewere delightedtoreachsomethingof amilestone,havingfunded£2.1 millionofresearchinour21 yearsasacharity.Justeighteen monthslater,wehavenowsurpassed£3millioninresearch funding,andhaveboththecapacityanddrivetokeepthisrateof progressgoing.

Ofcourseeverythingwedo isonlypossibleasaresultofyour support,andweareindebtedfor it.Thisissue,inparticular,highlightssomewonderfulexamples ofthefundraisingactivitiesundertakentoultimatelyprovideus withthemeanstocontinueour workonyourbehalf.Wehave alsoincludedaleafletwiththis issueexplainingmoreabouthow youcanleaveMEResearchUK agiftinyourWill,ifthatis somethingyouareabletoconsider.

Alongsideourcontinued fundingofestablishedresearchers(withasummaryofthelatest resultsfromJoNijs’sresearchin thisissue),thisyearhasseenour thirdPhDresearchgrantaward (inAustralia)withafourthinthe pipeline–ademonstrationof

ourcontinuedfocusonencouragingbrightyoungresearchers intothefield.

ThemajorDHSCinitiative startedbySajidJavidinMaylast yearisprogressing,andweremainactivelyengagedinthedevelopmentofaresearchstrategy toinformacrossgovernmentdeliveryplanforME.Wehaveno doubtthatmanychallengeslie ahead,butalongsidetherecent parliamentarydebateheldinthe ScottishParliament,weremain cautiouslyoptimisticthatthe landscapeischangingforthe better.CortJohnson’slatest‘postcardfromNevada’inthisissue reallyhighlightsboththeopportunitiesandchallengestheME researchcommunityfaces.

Thankyouforyourcontinuedsupport,andIhopeyouenjoythisissueof Breakthrough.

JonathanDavies Chair,BoardofTrustees

Facebook

Oneofthebestways youcanquicklyandeasilyraisefundsforME ResearchUKisviaa birthdayfundraiseron Facebook(seebit.ly/ 36d6o3hforguidance).

It’sagreatwaytoask friendsandfamilyto helpcelebrateyour birthdaybydonatingto acausethat’scloseto you,whileatthesame timeraisingawareness ofME/CFS.

Thebestbit?Thereare nofeesfordonations madetocharitieson Facebook,soallthe moneygoesdirectto thecauseyouaresupporting.

WalkforME

TeamWalkforME2023 hasnowbeenlaunched. Everyyear,thisamazing schemeencouragessupporterstowalk,run,swim andridetoraisemoneyfor researchintoME.

MEResearchUKisgrateful oncemoretobechosenas oneofthetwofeatured charities.

Sinceitstartedin2013, WalkforMEhasraisedwell over£200,000forcharity. Whereveryouare,we hopeyouwillbecomeinvolvedthisyear.

Youchoosewhenandhow fartowalk,andthecharity tosupport.Youwillbe supportingagreatcause andraisingawarenesswith everystride.

meres.uk/wfME2023

Scotland’sforgottenillness

ParliamentarydebateonME/CFS

On2February,inresponsetoa MotionputbySueWebberMSP, theScottishParliamenthelda debateonME/CFS,itssymptoms,andthefindingsofthe Scottishstakeholderreviewof theME/CFSNICEguideline.

Openingthedebate,Sue WebberdescribedME/CFSas “Scotland’sforgottenillness”and gavepersonaltestimoniesfrom herconstituents,illustratingthe realitiesoflivingwiththedisease,andthelackofempathy andknowledgesometimesshown byhealthcareprofessionals.

Sixty-oneMSPshadsigned theMotion,andmanyalsohighlightedthereal-lifeexperiences ofconstituentswithME/CFS whohadcontactedthem.

DonaldCameronMSPsummarisedtheissuesraisedbythese people,that:ME/CFSisalegit-

imateanddebilitatingillness,but isnotyetunderstoodfully;there isalackofaccesstoservices;and moreinvestmentisneededto findacure.Heurgedthatthis debateisthe“startofachange” inScotland.

JackieBaillieMSPgaveuseful backgroundtothesituationin Scotland.Thereisnospecialist ME/CFSconsultantandonly onespecialistnurse.Despitethe disease’sestimatedcosttothe Scottisheconomyof£360million,theScottishgovernmenthas fundedonlytwoME/CFS-relatedprojectsinthelastdecade.

OnbehalfoftheScottish Government,MareeTodd(MinisterforPublicHealth,Women’s HealthandSport)statedthat,“It isclearfromthevoicesthatwe haveheardthisafternoonthat manypeoplewithME/CFShave

feltstigmatisedordisbelievedby thosewhodonotunderstand theircondition.Therefore,the firstthingthatIhavetosayis thatIwantthatstigmaanddisbelieftoend.Wehavemadea visiblecommitmenttosupportingtherecentchangestothe ME/CFSguidance,andwecontinuetoworktoraiseawareness oftheconditionandtheimpact onthosewholivewithit.”

MEResearchUKwasinvited tosubmitaresearchbriefingto gotoMSPsaheadofthedebate, whichjoinedthoseonanumber ofME/CFStopicspreparedby othercharities.Theboxonthe rightsummarisessomeofthe pointsweraised.

However,onthesubjectofresearch,apartfrommentioning theDeliveryPlan’saspectslookingatwaystoimprovethenumberandqualityofresearch applications,theMinisterwas disappointinglysilent.

Keyresearchchallenges

•Biomedicalresearchhasidentifiedarangeofbiological abnormalitiesinpeoplelivingwithME/CFS,coveringdiversefieldssuchasimmunology,genetics,musclebiology,painmedicineandthecardiovascularsystem.

•Theexactbiologicalmechanismsdrivingthediseaseremainonlypartiallyexplained.

•Manycliniciansremainunawareofthisresearchandstill regardME/CFSwithscepticism.

•Thereislittleagreementontheappropriatenessofthe illnessname:ME,CFS,ME/CFSorothertermsinuse.

•Thelackofconsensusondiagnosticcriteriacanmakeit difficulttocomparethefindingsofdifferentstudies.

•Therearenotyetanyvalidatedbiomedicalbiomarkers toaidinthediagnosisandacceptanceoftheillness.

•TheMedicalResearchCouncil(MRC)recognisesthe needforbetterdiagnosisandtreatments,andhasmade ME/CFSahigh-priorityresearcharea.ButtheyhaveallocatedonlyasmallamountoffundingtoME/CFS,and manyscientistsfinditdifficulttosecuresupport.

•In2022,theUKGovernmentemphasisedthetenpriority researchquestionsthatneedtobeaddressed,andset outacross-GovernmentdeliveryplanforEngland, alignedwithplansintheScottishGovernment,todrive high-qualityresearchintoME/CFSandsupporttheresearchcommunitytobuildcapacityandcapabilityinthis field.

•TheMRCrecentlyawardedfundingforDecodeME,the world’slargestgenome-wideassociationstudyofME/ CFS,whichaimstoaidthedevelopmentofdiagnostic testsandtargetedtreatments.

•Despitethiswelcomedfunding,ME/CFSremainsaseriouslyunderfundeddisease,particularlywhencompared withcancer,diabetes,cardiovasculardiseaseandmultiplesclerosis.

MEResearchUKreachesnewmilestone

Morethan£3millioninvestedinME/CFSresearch

Aroundthebeginningofthis year,thetotalamountofmoney MEResearchUKhasinvestedin ME/CFSresearchduringthe charity’slifetimeexceededthe £3millionmark.

Thisisasignificantmilestone forusastheUK’slargestnongovernmentfunderofresearch intothisdisease,andonewe couldnothaveachievedwithout thegenerosityandhardworkof ourmanysupportersandfundraisers.

Sincetheestablishmentof MEResearchUKin2000,the charityhasreliedonthisfundraisingtoprovidefinancial backingtomorethansixtyresearchprojectstodateoverour 23-yearhistory.

Weonlyfundprojectswhich arebasedonsoundscienceand whichhavebeenpeer-reviewed andassessedbyourScience Committee.Andweonlyfund projectswhenwehavemoneyin thebanktopayfortheresearch

towhichwehavecommitted.

Thismoneycomesfroma varietyofsources,includingdirectdonationsandthemarvelous effortsofourfundraisers.But oneimportantsourceislegacies.

Thisissueof Breakthrough isaccompaniedbyaleafletexplainingmoreabouthowyoucan leaveMEResearchUKagiftin yourWill,ifthatissomething youareabletodo.

Butitisalsoagoodopportunitytohighlightanumberofre-

centlyfundedprojectsallmade possiblethankstoalegacyfrom theFredandJoanDaviesBequest.

Todate,thisbequesthasenabledsurgeonMrJamesAllison toexploretheroleoftheautonomicnervoussysteminthe painfulsymptomsexperiencedby peoplewithME/CFS;Dr LeightonBarndentoinvestigate abnormalitiesinthebrainstem usingnewimagingtechnologies; andDrSarahAnnesleytolook morecloselyatchangesinmitochindrialenergyproduction.

What’smore,thereareatleast

threemorenewstudiesthatwe areplanningtoannouncethis yearthankstothisBequest.

Ofcourse,thisisnottheonly waypeoplecanhelpsupportour work,andwearesogratefulto everyoneraisingfundsinother wayssuchassponsoredand otherevents,someofwhichyou canreadaboutonpage20.

MEResearchUKremains committedtoourmissiontoinform,influenceandinvestinME research,andtomakeareal differencetothelivesofpeople withME/CFS,whichwecan continuetodowithyourhelp.

AmazonSmile

Wewouldliketosaya hugethankyoutoeveryonewhohasused AmazonSmileandselected MEResearchastheir chosencharity.

Wereceivedmorethan £1,900fromthisscheme overthelastthreemonths thankstosupporters.However,AmazonSmilesadly closedinFebruary.

However,therearestill otheronline,free-to-use fundraisingsitessuchas Easyfundraising,Givewith Bing,andGiveasyouLive.

Findoutmorehere: meres.uk/shopping

“Wecouldnot haveachieved thismilestone withoutour supporters’ generosity”

Cause and effect

AnewPhDprojectinAustralialooksat mitochondrialabnormalitiesinME/CFS inmoredetail

Wewerevery pleasedtoannouncethis yearanew awardforPhD-levelresearch. Thisprojectisbeingconducted atLaTrobeUniversityinMelbourne,AustraliabyPhDstudentTinaKatsarossupervisedby DrSarahAnnesley.

DrAnnesley’sresearchisfocusedonthemitochondria,the so-calledpowerplantsofthe body.Thesestructuresarefound

ineverycellinthebody,and theirroleistoconvertenergy fromourfoodintoaformour cellscanuse,namelymolecules calledATP(adenosinetriphosphate).

Themitochondria

Itisthereforenosurprisethata significantamountofresearch intoME/CFShaslookedat whetherthereareabnormalities inthemitochondriaandtheir productionofATP,sincethis

‘energycurrency’iscrucialto normalfunctioningofthebody.

Muchoftheresearchevidencesuggeststhatthemitochondriaareindeeddysfunctionalin ME/CFS,includingprevious workfromDrAnnesleyinwhich hergroupidentifiedtwospecific abnormalitiesinthefinalstage ofATPproductioninthemitochondria.

Inwhitebloodcellscalled lymphoblaststheyfoundthat:(1) anenzymecalledATPsynthase

producedATPlessefficientlyin ME/CFScellsthanincontrol cells,and(2)theactivityofan enzymecomplexcalledTORC1 (whichregulatesthisprocess)was increasedinME/CFScells.

MEResearchUKiscurrently supportingDrAnnesleytoinvestigatethisfurtherinother typesofcellscalledfibroblasts, whileTina’snewPhDproject aimstoinvestigatethemitochondrialabnormalitiesinmoredetail,andspecificallyhowthey interact.

Tinaplanstouseabatteryof differenttestsonlymphoblastoid cellsfrompeoplewithME/CFS andhealthycontrols,aswellas fromotherpatientswithgenetic mutationsknowntoaffectthe functionofATPsynthaseand

TORC1.Thetestsincludemeasurementsofmitochondrialrespiration,mitochondrialfunction andTORC1activity,aswellas somegeneticandproteomicassessments.

Themainquestionstheteam hopestoanswerarewhetherthe previouslyidentifiedATPsynthaseabnormalityand/orelevatedTORC1activitycauseother cellularabnormalitiesseenin ME/CFS.

Potentialtreatments?

Thehopeisthattheirfindings willhelpusunderstandmore abouthowthemitochondriaare affectedinpeoplewithME/ CFS,andhelpidentifywhich proteinsandprocessescouldbe targetedbypotentialtreatments.

Tinacompletedherhonours degreeunderthesupervisionof DrAnnesley,studyingcalcium signallinginParkinson’sdisease. Shedevelopedaninterestinthe ME/CFSresearchalsobeing conductedinthelaboratory,and nowhasadesiretomakeatangibleimpactinafieldaffectingso manypeople.

Leveragingherownpassion andexpertise,andthatofthe Annesleylaboratory,Tinastarts herPhDprojectwithhopesto betterunderstandthecause–effectrelationshipsbetweenenergypathwayabnormalitiesin cellsfrompeoplewithME/CFS.

MEResearchUKisdelighted tobeabletosupportTina’sfirst researchintoME/CFSatthis earlystageinhercareer.

TinaKatsaros

DrSarahAnnesley

Jo’sgenes

Are epigeneticalterations responsible forpaininME/CFSandfibromyalgia?

Lastyear,Prof.Jo Nijsandcolleagues atVrijeUniversiteit BrusselinBelgium publishedmoreresultsfromtheir MEResearchUK-fundedstudy lookingattheimpactofepigeneticsonpaininME/CFS.

Theserecentlypublishedfindings(inthe JournalofTranslational Medicine)relatespecificallytoa proteincalledcatechol-Omethyltransferase(COMT) whichisknowntohaveeffectson painandinflammation,bothof whicharekeyfeaturesinME/ CFS,aswellasinfibromyalgia.

Theinstructionstobuildproteinsarecontainedinourgenes, butalterationstothesegenescan changehowtheyoperate,and consequentlyhowtheproteins function.

Thesealterationscanbegeneticorepigenetic.Verysimply, ageneticalterationisachangeto theDNAinagene,whileanepigeneticalterationisachangeto

howthegenebehaves.

Theaimofthisstudywasto investigateanumberofgenetic andepigeneticalterationstothe COMT geneinpatientswith ME/CFSandfibromyalgia,and whethertheywereassociated withmarkersofinflammationor clinicalsymptoms.

Clinicalinformationand bloodsampleswerecollected from28patientsmeetingdiagnosticcriteriaforbothME/ CFSandfibromyalgia,andfrom 26healthycontrolsubjects.

Thebloodsampleswereanalysedtoassessanumberof factors:(1)polymorphismsinthe COMT gene(thesearegeneticalterations,ormutations);(2)DNA methylationinthe COMT gene (thisisanepigeneticalteration); and(3)levelsofseveralsubstances(cytokines)associated withinflammation.

Theresearchersfoundpolymorphismsinthe COMT genein patientswithME/CFSand

fibromyalgia,andalsotoasimilardegreeinhealthycontrol subjects.Thespecificpatternsof changescorrespondedtothe levelofactivityoftheCOMT protein.

However,thepatientswith ME/CFSandfibromyalgiahad aroundtwicethelevelofDNA methylation(theepigeneticalteration)aswasseeninthecontrols.

Thepatientsalsohadsignificantlylowerlevelsofinterferon gamma,whichisacytokine knowntoplayaroleininflammation.

Theresearchersbelievetheir findingsmaypointtothischange inthe COMT geneasbeingan importantfactorinthedevelopmentofME/CFSandfibromyalgia.

Highermethylationlevels mightbeassociatedwithlower activityoftheCOMTprotein andworsesymptoms,although moreresearchisneededtoexplorethismoreclosely.

Postcard from Nevada

Thegoodnewsis thatlongCOVIDis gettingalotof study,andnewinsightsareproducedseemingly everyweek.That’sencouraging giventhatrespectedresearchers likeAvindraNathhavestated theybelievethatifyousolveone oftheME-likediseases(long COVID,ME,fibromyalgia,etc.), you’llsolvethemall.

Thebadnews,though,isthat theME/CFSfield,withitsmeagrefunding,willlikelystruggleto

applytheinsightsgainedinan efficientandtimelymanner. Whilethelong-termtrajectoryis unquestionablygood,whowants, afteralltheseyears,towaitfor thelongterm?

Movingforwardrapidlyisgoingtorequirechangesthough. WhilethesmallME/CFSresearchfieldhasbeengreatat producingsmallstudiesthat providecrucialinsights,thefield hasbeenmissingavitalelement –bigfollow-upstudiesthatcan reallymoveafieldforward.

RecentstudiesfromtheUS NIHfundedME/CFSresearch centresdemonstratewhybig,expensivestudiesaresoimportant. SmallstudieshavebeenuncoveringgutissuesinME/CFSfor over10years,butitwasn’tuntil twolargeNIHfundedstudies–bothcontainingover200participants–producedsimilarresults thatthegutfindingsinME/CFS reallymadeabang.

TheconservativeNIHhailed thefindingstwice–inanewsreleaseandanNIHDirector’sblog

Inhislatestpostcard, CortJohnson talks about“ridingthelongCOVIDwave”to ensurelarge-scalefundingforME/CFS

–andsuggestedthatalongsought-afterbiomarkermayhave beenfound.Theresultswere subsequentlypickedupbymany newsoutlets.

IntheNIHDirector’sblog, LawrenceTabakclearlyilluminatedtheproblemME/CFShas faced.Tabakpointedoutthat “whileearlierstudiesalsohad pointedtoaroleforthegutmicrobiomeinME/CFS…those studieswerelimitedintheirsize andabilitytoteaseoutprecise microbialdifferences”.Thebiggerstudies,though,provideda “solidlead”whichTabaksuggestedcouldleadtotreatmenttrials –ararestatementfromariskaverseNIHwhichdoesnotcurrentlyallowitsME/CFSsection tofundtreatmenttrials!

Thesebigstudiesblowahole intheideathatME/CFSissome sortof“wastebasketdisease” thatisnotamenabletostudy, anddemonstratethat,ifME/ CFSresearcherscangettheir

handsonthe resourcesthat otherdiseases typicallyget, thenswifter progresscan bemade.

Theyalso demonstrate howcritical governmental fundingis. Whilecharities cananddo providecrucial insightsinto diseases,onlygovernmentagenciesliketheMedicalResearch CouncilintheUKandtheNIH havetheresourcestoturnthose insightsintobroadandsustained researchefforts.

Yet,whileinterestinME/ CFShasmushroomed,funding forthediseaseintheStatesand elsewherelargelyremainsatthe samelowlevel.IntheStates,this ispartlybecauseofanarchaic

andinefficientfundingmechanismthatreliesonthegoodwillof itsInstitutes–noneofwhich have(orwant)responsibilityfor ME/CFS.IntheUK,theMedicalResearchCouncil’sstatementthat“Supportingand enablingastrongportfolioof ME/CFSresearchhasbeena highpriorityfortheMRC” seemsalmostlaughablegivenits pitifulfundingovermanyyears.

Unfortunately,ME/CFSbelongstoasuiteofdiseases(also includingfibromyalgia,irritable bowelsyndrome,migraine,environmentalillness,interstitialcystitisandvulvodynia)thathave historicallybeenwoefullyneglectedbygovernmentalfunders. Thesediseasesarealsoprevalent, primarilyaffectfemales,cause highratesofpain,fatigueand economiclosses,arelargelyinvisible,andrarelyresultindeath.

TakeME/CFS–priortothe COVIDpandemicitwasestimatedtoaffectroughly1to2millionpeopleintheUSA,and causeupwardsof$25billionof economiclosseseveryyear.Itreceives$17millionorroughly$10 perpersonperyearinNIH funding.ME/CFS’ssisterillness, fibromyalgia,affectsroughly4 millionpeopleandreceives about$14millioninNIHfundingorroughly$3perpersonper year.

Comparethattomultiple sclerosis(MS),avisiblydisabling diseasethatissignificantlyless functionallyimpairingthanME/ CFS.MSaffectsaboutamillion

CortJohnson

“Only government agencieshave theresources toturncrucial insightsinto sustained research efforts”

peopleintheUSA,andreceives $131millioninNIHfundingor about$130perpersonayear–thirteentimesasmuchasME/ CFSand40timesasmuchas fibromyalgia.

Therearesigns,though,that thingsmayslowlybechanging. The£3.2million2020DecodeMEstudy–theworld’s largestME/CFSgenomicstudy whichisco-funded,itshouldbe noted,bytheMRCandtheNIH –standsoutasthekindoflarge, ambitiousfederallyfundedstudy thisdiseaseneeds.

Recenteventsalsosuggest thatthemessagethatsomemajordiseasesareseriouslyunderfundedmayslowlybegetting through.Thenewbillion-dollar AdvancedResearchProjects AgencyforHealthorAPRH-A agencyintheUSAwasdesigned tobeamorenimbleandequitablealternativetotheNIH.

TimewilltellwhatwillhappenwithME/CFSandthis

agency,butoneofitsmandated requirements–toprioritizeits investmentsbasedon“disease burden,includingunmetpatient need(s)”–wouldseemtoplace ME/CFSrightinitscross-hairs.

Similarly,onesectionofthe EuropeanParliament’sHorizon Europe2023–24workprogrammefocuseson“insufficientlyresearched”diseasesthat demonstrate“highprevalence”, are“insufficientlyunderstood, inaccuratelydiagnosedor treated”andwhich“representa highburdenforpatientsandsociety”.Thethreeexamplesgiven arechronicfatigue(ME/CFS), Lymediseaseandbackpain. Thetotalbudgetforthe2024 program–€25millionor£22 million)suggeststhatME/CFS maysoonbegettingsomemore attention.

Themassiveanduniquepool ofresourcespresentingovernmentalinstitutesdemonstrates whyadvocacyeffortstargeting

theseresourcesareessential.Left tothemselves,organisationslike theNIHorMedicalResearch Counciltendtobeconservative, buttheycanbemovedbylegislativeeffortsandstrongadvocacy.Itshouldbenotedthat the$1.15billiontheNIHis spendingonlongCOVIDcame notfrominsidetheNIH(which didnothingforlongCOVIDon itsown)butfromconcerned membersofCongress.

SimplygettingME/CFScohortsintomajorlongCOVID studiescouldmakeahugedifference,andeffortsareunderwayto dothat.WithlongCOVIDfundingboomingandinterestinME/ CFSup,wemustcontinueto makeclearthecompellingconnectionsbetweenME/CFSand longCOVID,andfindawayto ridethelongCOVIDwaveto plentifulfunding.Forthefirst timeever,ME/CFScouldbeon theroadtofinallygetitsproper shareofthemedicalpie.

Researchbites

Ourround-upofrecentresearchfromaroundtheworld

EndothelialdysfunctioninME/CFS

Sandviketal.,PLOSONE,2023

Thereisconsiderableevidenceofcardiovascular abnormalitiesinpeoplewithME/CFS,including dysfunctionoftheendothelium.Theendothelium formstheinnerliningofeverybloodvessel,andis involvedincontrollingthebloodflowingthrough them.ThisnewstudyfromNorwayusedtwo differenttechniques (flow-mediateddilatationand post-occlusivereactivehyperaemia) tomeasurethe functionofbothlargeandsmallbloodvesselsin39 peoplewithME/CFSandagroupofhealthycontrols.Thesemeasuresofbloodvesselfunctionrely onadequateendothelialfunction.

Bothlargeandsmallblood-vesselendothelial functionwereimpairedintheME/CFSpatients,

andthesefindingsconfirmthoseofapreviousME ResearchUK-fundedstudyusingthesametechniques.Importantly,thisprovidesgreatercertainty thattherereallyisaconsistentabnormalityinendothelialfunctioninpeoplewithME/CFS.

Theresearchersalsoassessedthepatientsafter theyhadbeentreatedwithrituximabfor18 months.Althoughrituximabisnoteffectiveasa treatmentforME/CFS,thepatientsdidexperience asmallimprovementinclinicalsymptoms,and therewassimilarlyasmallimprovementinblood vesselfunctionoverthetreatmentperiod.TheauthorsconcludethatatleastsomepeoplewithME/ CFShavereducedvascularendothelialfunction.

Humanherpesvirusespart1

Rasa-Dzelzkalejaetal.,JTransl.Med.,2023

ViralinfectionshavelongbeensuggestedasatriggerofME/CFS,andhumanherpesvirusesare particularlyimplicated.ResearchersfromLatvia havereportedthatinfectionswithtwotypesof herpesvirus(HHV-6A/BandHHV-7)andone typeofparvovirus(B19V)weremorelikelytobein anactivephaseinME/CFSpatientsthancontrols. Patientsalsohadahigherviralloadandhigher levelsofpro-andanti-inflammatorycytokines. Theyconcludethattheseinfectionsmayinfluence thedevelopmentandseverityofME/CFS.

Humanherpesvirusespart2

Kasimiretal.,Front.Mol.Biosci.,2022

DrBhupeshPrustyandcolleaguesinWürzburg, Germanyarealsointerestedinhumanherpesviruses.OneoftheirideasisthatHHVreactivation leadstotheexpressionofmicroRNAs,whichin turncauseareductioninmitochondrialfunction. Theyrecentlyexaminedbraintissuefromthree ME/CFSpatientsandfoundabundantHHVmicroRNAinvariousregions(butnotincontrols). HHVactivityinthebraincoulddisruptnerve functionandaccountforsomeofthesymptomsof ME/CFS,includingbrainfog,tirednessandpain.

TranscriptomicsofPEM

VanBoovenetal.,Int.JMol.Sci.,2023

Post-exertionalmalaise(PEM)isacardinalsymptomofME/CFS,andistopoftherecentPSPlist ofprioritiesforresearch.ThisstudyfromtheUSA soughttoinvestigatethetranscriptomicchanges (whichcellularprocessesareactive)occuringduringexerciseandtheonsetofPEM.Oneimportant findingwasthatME/CFSpatientshaddysregulatedimmunesignallinganddysfunctionalcellular responsestostressintherecoveryperiodaftermaximalexercise–thisistheperiodwhenPEMstarts. Theseresultsarehopefullyagoodbasisforfurther researchandtoidentifytreatmentsforPEM.

Misdiagnosis

Malatoetal.,Diagnostics,2022

MisdiagnosisisacommonprobleminME/CFS, andstudieshavereportedthatasignificantproportionofpatientsareeventuallydiagnosedwithother conditions.HowmightthisaffectthevalidityofresearchintoME/CFS?ThisanalysisfromPortugal usedstatisticalmodellingtoshowthataresearch studyinvestigatingassociationswithME/CFS wouldneed500to1,000individualsineachstudy grouptocompensateforthepossibilitythatsome participantshavebeenmisdiagnosed.FurtherconfirmationthatfindinganswersinME/CFSneeds largestudies,andthereforelarge-scalefunding.

Agutbiomarker?

Guoetal.,CellHost&Microbe,2023

Themicrobiomereferstothecollectionofaround100trillionmicroorganisms,includingbacteria,thatliveonorinsidethehuman body.Manyofthesebacteriaarebeneficialtousandessentialtoour survival.Inthegut,theyliveonthemembranousliningandbreak downourfoodandhelpprotectusagainstinfection.Thiswholearea hasbecomeahottopicofresearchinmanydiseases,includingME/ CFS,butcouldthegutmicrobiomeprovideabiomarkerforthedisease?

That’sthetantalisingprospectofanewstudyfromresearchersin theUSAwhofoundthatmultiplemeasuresofthegutmicrobiome werealteredinME/CFSpatientsversuscontrolsubjects.Inparticular,levelsof Faecalibacteriumprausnitzii and Eubacteriumrectale werereducedinME/CFS.Thesebacteriaarebothinvolvedinthe productionofbutyrate,ananti-inflammatorythathasasignificant impactonguthealth.Oneconsequencemaybeanimpairedinability tocontrolbacterialgrowth,andtheresearcherstalkaboutamicrobial networkdisturbanceinME/CFS.CortJohnsondiscussesthesefindingsinmoredetailonhisHealthRisingblog:bit.ly/3EqKJ5r

Riskfactors

Palaciosetal.,ScientificReports,2023

ScientistsfromtheUSAhavebeenexploringthe potentiallycontroversialquestionofwhetherME/ CFSisjustamoreextremeformoffatigue.They conductedaquestionnaireonsymptomsinUSfemalenurses,andfoundthattheriskofseverefatiguewasincreasedinindividualswhowereolder, hadahigherBMI,usedhormonetherapy,andhad anincreasedalcoholintake.Theseriskfactorswere notassociatedwithME/CFS,however.Theauthorsconcludethat“ME/CFShasaqualitatively differentunderlyingbiologyfromthemorecommonstateofseverefatigue”.

Alteredlymphocytes

Mayaetal.,Int.JMol.Sci,2023

AnewstudyfromresearchersatCornellUniversity tacklestheincreasinglyrelevanttopicoftheimmunesysteminME/CFS.Theyconductedanumberofexperimentsonlymphocytes(atypeofwhite bloodcell),specificallylookingatfattyacidoxidation,whichisastageinthemetabolismofthecell. ThisprocesswasalteredinthreetypesoflymphocytefromME/CFSsamples,particularlywhenenergydemandwashigh.Theauthorssuggestthat theirfindingssupporttheideaofmetabolicdysfunctioninME/CFSimmunecells,whichhavean impactonthecells’immunologicalfunction.

MicroRNAbiomarker?

Nepotchatykhetal.,Sci.Rep.,2023

WhileME/CFSandfibromyalgiaaredistinctconditions,theydohavemanyoverlappingsymptoms. Sinceneitherdiseasecurrentlyhasanyvalidated biomarkers,theyarebothoftenmisdiagnosed.Canadianresearchershavenowidentifiedapatternof 11microRNAexpressionprofilesthattheysaycan discriminatebetweenpatientswithME/CFS,those withfibromyalgia,andthosewithbothconditions. MicroRNAsaremoleculeswhichhelpcellscreate proteins,andtheonesusedherehaveallpreviously beenassociatedwithME/CFS.Wewillwaittosee whethertheyreallycanformausefulbiomarker.

Gastrointestinalsymptoms

Steinsviketal.,Scan.JGastroenterol.,2023

AlthoughnotconsideredacoresymptomofME/ CFS,gastrointestinalproblemsarereportedby peoplewiththedisease,andtheyarenotwellunderstood.ResearchersinNorwayexamined20patientswithME/CFSandabdominalcomplaints, andperformedultrasoundmeasurementsofthe stomach.Thekeyfindingwasthatthepatients showedsignsofimpairedgastricaccomodation afteraliquidmeal.Thisessentiallymeansthatthe stomachwasnotabletorelaxproperlytoallowfor theintakeinfood,leadingtoafeelingoffullness andbloating.

“Multiple measuresof thegut microbiome werealtered inME/CFS”

Fundraisingstories

Recentfundraisingactivitiesbyoursupporters. TosupportMEResearchUK,pleasevisitourwebsiteforideas.

Ultramarathon

LizzyHodcroftistacklingthe inaugural50kmYorkshireWolds UltrainJulyinaidofME ResearchUK.Theevent’s circularroutestartsandendson theedgeofPocklington,and takesinsomeofthebestpartsof theWolds,includingthevillages ofBishopWiltonandKirby Underdale.Lizzyisrunningfor usbecausehersisterhasME and,asshesays,“Runningan ultramarathonisanincredibly challengingandrewarding

experience.Itismuchlonger thanastandardmarathonand caninvolveclimbingmountains, navigatingruggedterrain,and runninginhot,coldandwet conditions.Itrequiresagreat dealofmentalandphysical preparation,andtherewards comefrompushingyourselfto yourphysicalandmentallimits.” bit.ly/3HZyoWR

BlueSunday

AnnaRedshaw’sannualBlue SundayTeaPartyForMEwill

beheldthisyearonSunday14 May,andistakingplaceinaidof variousMEcharitiesincluding MEResearchUK.Thereisno settimeandtheeventrunsall day.Participantsareencouraged towearsomethingblue,enjoy someteaandasliceortwoof cake,anddonatethepricethey wouldnormallypayinacafé toanME/CFScharityinstead. Youcanalsojoinothersonlineas theydothesame,andshare photosonFacebook. bit.ly/3YW78PX

Leedsmarathon

LauraWilkinsonHewittwillbe runninginMay’sinauguralRob BurrowLeedsMarathon2023in aidofMEResearchUK.The eventisnamedinhonourof formerLeedsRhinosrugby playerRobBurrowwhowas diagnosedwithmotorneurone diseaseinDecember2019.The marathonwillseeover10,000 participantstakeonabrandnew

routethroughLeedsthatstarts andfinishesatHeadingley Stadium–thehomeofLeeds Rhinosrugbyleagueclub. bit.ly/3xps7i9

Londonmarathon

Anotherofthisyear’smarathon runnersisMarkGodsalvewho willberunningtheTCSLondon Marathonon23Apriltoraise moneyforMEResearchUK,

01 Lizzy, Laura and Mark are allrunning marathonsthis year

02 Treat yourselfto someteaand cakeinMay

03 Mark Godsalve has sethimselfa challenging target

andinmemoryofhislatefather whoranthemarathonin1995. Mark’sbrother,Tim,hassuffered fromMEfor34yearsandsoME researchisacauseclosetohis heart.Ultimately,Markhopesto gettheLondonClassicsmedal forfinishingallthreeofthe LondonMarathon, RideLondon-Essex100and SwimSerpentinetwo-mileswim. bit.ly/3YvVWJL

RunforME

RunforME2023hasbeen launchedbyClaireCarter.“We areasmallgroupofparents, friendsandfamilyofsomeone livingwithME/CFS.InMay,as partof‘WalkforME’,wewillbe doingasponsoredrunorwalkto raiseawareness,showsupport andraisefundstowardsmuch neededresearch.”

Penguinchallenge

CélineMoyes’‘Pengiun ChallengeinaidofME

ResearchUK’justgotalot harderasshehasalsotakenon theGoldPenguinChallenge whichrequireshertowildswim throughoutthewintermonths, coveringatleast1,000mper monthandincludingatleasttwo 250-mswims.Swimminginthe NorthSeaintheEastNeukof Fifethisiscertainlynotforthe faint-hearted.bit.ly/3Ecgtv4

BigGive

Werealiseditwasabigaskfor lastNovember’sBigGive,but

01 Participants inaprevious RunforME

02 Celine Moyes braves theNorthSea thiswinter

03 Thankyouto allwho supportedthe BigGive

ourwonderfulsupporterstopped thefundraisingtargetwehadset of£7,000.Thisisourbestresult yetfromtheannualfundmatchingscheme,andwhenthis totalwasaddedtothatmatched byourpledgers,thetotalamount raisedwasafantastic£19,410! Thankyousomuchtoeveryone whopledgedanddonated,and helpedmaketheBigGivea rousingsuccessforMEResearch UK,raisingvaluablefundsfor thecharityandallowingusto supportmorecrucialresearch.

Tosupportourwork,pleaseconsidersettingupastandingorderbycompletingthisformand sendingitto: MEResearchUK,TheGateway,NorthMethvenStreet,Perth,PH15PP

Pleasetickthisboxtoindicateyouarehappyforustocollectandstoreyourpersonal information,inaccordancewithourPrivacyPolicyatmeresearch.org.uk.

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