SHz - The Accomplishments and Legacy of Saul Hertz

TheAccomplishmentsandLegacyofSaulHertz,MD

BennettS.Greenspan1,MichaelS.Hofman2,3,andJohnBuscombe4

1DepartmentofRadiology,AugustaVAMedicalCenter,Augusta,Georgia; 2ProstateCancerTheranosticsandImagingCentreof Excellence,DepartmentofMolecularImagingandTherapeuticNuclearMedicineCancerImaging,PeterMacCallumCancerCentre, Melbourne,Victoria,Australia; 3SirPeterMacCallumDepartmentofOncology,UniversityofMelbourne,Melbourne,Victoria, Australia;and 4DepartmentofNuclearMedicine,CambridgeUniversityHospitals,Cambridge,UnitedKingdom

Theearlyhistoryoftheuseofradioactiveiodine(RAI)iscomplicated andinteresting,andalsodifficulttodiscover,especiallysinceseveral historieshavepresentedinaccuratecontent.ThisarticleisacomprehensivereviewoftheaccomplishmentsofSaulHertz.Extensiveuse ofprimary-sourceverificationhasclarifiedseveralissues,including thequestionofwhetherHertzaloneconceivedandaskedthepivotal question: “Couldiodinebemaderadioactiveartificially?”;onwhat dateRAIwas firstusedtotreathyperthyroidism;andwhy2articleson the firstuseofRAIfortreatmentofhyperthyroidism,from2different setsofauthorsfromthesamedepartmentofthesameinstitution, appearedadjacenttoeachotherinthesameissueofthe Journalof theAmericanMedicalAssociation in1946.Ourreviewalsochronicles severalmajorchallengesthatHertzovercametoproducehispivotal work.HertzwasclearlytheoriginatorandavisionaryofRAItherapyin benignandmalignantthyroiddisease.Webelievehecanbeconsideredoneofthefathersofnuclearmedicine.Hertz’sparadigmchangingworkwasapivotalmedicaldiscoveryofthe20thcentury. ThelegacyofHertzcontinueswhiletheapplicationofRAItherapy continuestoevolve.RAItherapyremainsthepreferredtreatmentin mostsituationsforautonomousnodulesandtoxicmultinodulargoiter andremainsasafeandeffectivetreatmentforGravesdiseaseafter morethan80yofglobalclinicaluse.RAItreatmentofdifferentiated thyroidcancerremainsa first-linetreatmentformostpatientsafter surgery,especiallyforthosewithintermediate-orhigh-riskdisease.

KeyWords: SaulHertz;radioactiveiodine;hyperthyroidism;thyroid cancer;theranostics

JNuclMed2024;65:659–663 DOI:10.2967/jnumed.124.267524

Inthelandscapeofmedicalhistoryandinnovation,few figures exemplifytheblendofgroundbreakingscientificachievementand selflessserviceaswellasSaulHertzdoes.BornonApril20, 1905,Hertz’sjourneyinmedicinebeganwithhisgraduationfrom HarvardMedicalSchoolin1929,atimeofstrictquotasforoutsiders.HeservedaschiefoftheThyroidUnitatMassachusettsGeneralHospital(MGH)from1931to1943.Despitethepromiseofa burgeoningresearchandclinicalcareer,Hertz’spathtookadetour asheansweredthecallofduty,servingasacommanderinthe U.S.NavyduringthetumultuousyearsofWorldWarIIfrom 1943to1945.Tragically,hislifeandcareerwerecutshortwhen

ReceivedJan.26,2024;revisionacceptedJan.30,2024. Forcorrespondenceorreprints,contactBennettS.Greenspan(bengreenspan 0708@gmail.com).

PublishedonlineMar.7,2024.

COPYRIGHT 2024bytheSocietyofNuclearMedicineandMolecularImaging.

hepassedawayonJuly28,1950,attheageof45becauseofa myocardialinfarction,asconfirmedbyautopsy.ThisreviewarticleseekstoexplorenotjusttheprofessionalmilestonesofHertz butalsothepersonalandhistoricalcontextthatshapedhisremarkable,albeittoobrief,journeythroughlifeandmedicine(Table1).

Fourscientificadvancementsanddiscoveriesprovidethebasis forthepivotalquestionandsubsequentresearchandclinicalwork ofHertz.Theseincludetheunderstandingoftheroleofiodinein thyroidmetabolismandfunction,thediscoveryofradioactivity, thedevelopmentofthetracerprinciple,andtheproductionofartificialradioactivity(1).

OnNovember12,1936,KarlCompton,presidentoftheMassachusettsInstituteofTechnology,presentedtothefacultyatthe HarvardMedicalSchoolaguestlectureentitled, “WhatPhysics CanDoforBiologyandMedicine” aspartofaweeklylecture seriesandluncheon.Attheconclusionofthelecture,Hertzsolely conceivedandspontaneouslyaskedthepivotalquestion “Could iodinebemaderadioactiveartificially?” KarlComptonwasuncertainandsaidhewouldlookintoit.HewrotebacktoHertzon December15,1936,apologizedforthedelayedresponse,and wrote, “Iodinecanbemadeartificiallyradioactive.” Infact,Enrico Fermihadproduced 128Iin1934,andearlierin1934,Frederic JoliotandIreneJoliot-Curiecreatedartificialradioactivity,for whichtheyreceivedtheNobelPrizeforChemistryin1935.LettersbetweenHertzandComptonmakeitclearthattheideaof usingradioactiveisotopestostudymetabolismcamesolelyfrom Hertz(1–4).ThefactthatHertzsolelyaskedthequestionwasconfirmedbyJamesMeans,chiefofmedicalservicesatMGH,ina lettertotheMarkleFoundation(Fig.3in(2))inwhichhestated, “whenitbecameapparentthattheremightberadioactiveisotopes ofiodine,itatonceoccurredtoHertzthatwemightmakeuseof themtosolveaproblemwewerealreadyworkingon” (1–5).RobleyEvans,directoroftheMassachusettsInstituteofTechnology RadiationLaboratory,alsowrotealetterofrecommendationto theNavyconfirmingthatHertzwastheonewhoconceivedthe ideaofusingradioactiveiodine(RAI)forresearchandtherapyof thyroiddisease(5).

HertzcollaboratedwithArthurRoberts,amedicalphysicist whowashiredatMassachusettsInstituteofTechnologybyRobleyEvans.EarleChapmanwasanendocrinologistintheMGH ThyroidClinic.WhenHertzwasleavingMGHtojointheNavyin 1943,HertzaskedChapmantosupervisetheclinicaltrialsandfollowtheestablishedprotocols,towhichChapmanagreed.However,Chapmanchangedtheprotocols.JohnStanburywasan endocrinologistintheThyroidClinic,whowroteabookonthe historyoftheMGHThyroidClinicfrom1913to1990.Unfortunately,thebookcontainedsignificantmisinformation.Roberts wrotealettertoStanburyonApril3,1991,inanattempttocorrect

TABLE1

AccomplishmentsofSaulHertz

Accomplishment

fi c

Scienti

Year

1932Firsttocombinethyroidmetabolismwithdiscoveryofradioactivity( fi rstpublicationonbloodpictureinexophthalmicgoiter)( 10 )

1936Conceivedandaskedseminalquestion: “ Couldiodinebemaderadioactivearti fi cially? ”

1937FirsttopublishpreclinicalstudyofRAImetabolisminrabbits*

FirsttopublishtraceruseofRAIinstudyingthyroidphysiology( 1 –3 )

1937FirsttoconceiveofusingRAIforbiomedicalinvestigation,andoneof fi rsttouseradiotracersastoolsforbiomedicalresearch( 1 –3 )

FirsttodemonstratelinkagebetweenRAIuptakeandthyroidfunction,includingeffectsofthyroid-stimulatinghormoneanddiet

Firsttoconceiveofusinguptakemeasurementfordiagnosisandforadministeredactivitycalculation

Firsttousemolecularlytargetedtherapy

FirsttouseRAIinpatients

FirsttouseRAIasboththerapeuticagentanddiagnosticagent(theranostics)

Firsttoconceiveofpharmacologicinterventionforresearchandclinicalstudies,extendingclinicalutilityofdiagnostictestsandenhancingth erapy

FirsttouseRAIasbiomarker

1937FirsttosuggestthatRAImayalsobeusedtotreatthyroidcancer( 1 , 2 ) †

1941FirsttousetherapeuticRAIinclinicatMGH( 1 , 8 )

FirsttodemonstratesafetyandsuccessofRAItherapyforhyperthyroidism

1942FirsttouseRAItotreatpatientwiththyroidcancer

FirsttopresentRAItreatmentofhyperthyroidism(alongwithArthurRoberts,presentedtoMarkleFoundationresultsoftreatmentof fi rst10hyperthyroid patients)

JournaloftheAmericanMedicalAssociation ( 8 )

1946Publishedresultsof fi rst29patientsin

Administrative

1943ServedasdirectorofMGHThyroidUnit

1931 –

1937 –1946Oneofthe fi rstphysicianstocollaboratewithamedicalphysicist(ArthurRoberts)

1946FounderofRadioactiveIsotopeResearchInstitute

StrongproponentofmakingRAIwidelyavailablebyurgingAtomicEnergyCommissiontodoso

HelpedpromotepeacefulusesofatomicenergybydevelopingeffectiveusesofRAI,advocatingwidedistributionandavailabilityofRAIwithreasona blecost, andissuingguidelinesforsafety

Developedcurriculum(togetherwithArthurRoberts)inappliednuclearphysicsforphysiciansandbiologists

1949Established fi rstnuclearmedicinedepartment(atMassachusettsWomen ’ sHospital)

*Hertzdemonstratedremarkabledisciplineinproceedingsystematicallyfromexplorationofconceptinpreclinicalanimalstudies,includingstu diesoffunctionandsafety,tosuccessful clinicaluseofRAIinpatientsfordiagnosisandtreatment.Hertz ’ suseofdosimetry,RAIuptaketesting,andRAIastracerandbiomarkerareenduringessentialsofprecisiontargeted approach.

† HertzsuggestedthatRAItherapyofthyroidcancerwasamodelforradiopharmaceuticaltherapiesforcancerandthattherapyofothertypesofcancerm ightbeaddressedinthe future. “ MynewresearchisinCanceroftheThyroidwhichIbelieveholdsthekeytothelargerproblemofCanceringeneral. ” LetterbyHertztoMGH( 4 ).

TABLE2

versionmadeusing hotpot.ai deeplearning.)

themisinformation.Robertsalsostatedintheletter, “Evansmade itaconditionofmyemploymentthathisnamewastoappearon allpublications” (2).HertzandRobertsincludedEvansonthe first 2papers,butnotafterthat,sinceEvansneverparticipatedinany ofthestudies(5).ItistobenotedthatHertzandRobertsdesigned theresearch,executedthework,analyzedthedata,andwrotethe papers(4).Evanswasnotinvolvedinanyofthoseactivities. Evansdirectedthelaboratorythatinitiallyprovidedtheneutron sourcetoproduceRAI.TheMassachusettsInstituteofTechnology cyclotronproducedgreaterquantitiesofRAIthatwerecritically importantforRAItherapy.

Althoughitisoftenassumedscienceandscientificendeavor occurinaworldisolatedfromtheprejudicesandmoresofthe time,thisissadlyhardlyeverthecase.AtthetimeHertzwas workingandpublishinghisresearch,hewaslivingandworkingin acityinwhichantisemiticopinionandactionshadbecomecommonplace.Inthe1930s,Bostonwasthemostanti-Jewishcityin theUnitedStatesandtheheadquartersofanorganizationcalled theChristianFront(6).Until1941,thisorganization,atthevery

AwardsandHonorsReceivedbySaulHertz

YearAwardorhonor

1931–1933DaltonScholar,MGH

1935–1937HenryPickeringWolcottFellow,Harvard MedicalSchool

1940KeytoScience/SigmaXiChapterof MassachusettsInstituteofTechnology

1941ElectedmemberofAmericanSocietyfor ClinicalInvestigation(“YoungTurks” Society)

1946HonorableMention,AmericanGoiter AssociationVanMeterAward

2021*HonoredbyAmericanChemicalSociety withNationalHistoricalChemical landmarkdesignationatMGH

HonoredbyU.S.Congressforpioneering workindevelopingmedicalapplications forRAI

2023*Asoriginatorofprecisiontargeted personalizedmedicine,honoredby NortheasternChapterofAmerican ChemicalSocietywithSaulHertz MemorialSymposium

*Posthumouslyhonored.

timethatHertzwasworkinginBoston,was financedandledby thenationalsocialist(Nazi)governmentinGermany.Evenafter theUnitedStatesenteredthewaragainstGermany,theorganizationcontinuedto flourishandorganizeantisemiticprotestmarches throughthestreetsofBoston.Theorganizationwasimplicatedin physicalattacksonJewishmenandboysuptotheendof1943.

Hertzfacedandovercameseveralmajorchallengesduringhis career:pushbackfromsurgeons,whowereconcernedthathewas takingbusinessfromthem;interruptionofhisclinicalstudiesby WorldWarII;questionableethicsinmedicalpublishing(ghost authoring);otherstryingtostealcreditforhiswork;andconfrontationwithstrictquotasandrestrictions hewasatargetofpersonalandsystemicantisemitism.

ThetruestoryofHertzincludeselementsofexploitation,failure tohonorthosewhoservedinthewar, greed,stolenintellectualproperty,and antisemitism.Evansdeliberatelymuddied thewatersastothetruthregarding whetherHertzwastheonewhoaskedthe pivotalquestion.Thetruthwasexplained inApril2016byMGH’schairmanemeritusoftheDepartmentofRadiology, JamesThrall,whostated, “… Chapman andEvanshadbasicallystolenHertz’s work themost flagrant,unethical,academicallyreprehensiblebehavior … worst yet .ChapmanandEvansspenta greatdealoftimeandeffortrewritinghistory” (7).

FIGURE2. BostonTraveler newspaperofSeptember30,1949,announcingnewresearchdivision whereradioactiveisotopesweretobeusedinstudyandtreatmentofdisease.

In1946,therewere2adjacentpublicationsinthesameMay11issueof Journal

FIGURE1. Hertzwithhisassistantandmultiscalerprobe.(Colorized

CategoryLegacy

Revolutionizingof ThyroiddiseasemanagementwithuseofRAItherapy,whichhasbecomestandardofcarefor benignthyroiddisease(hyperthyroidism)andfordifferentiatedthyroidcancer(papillaryand follicularcell)

Establishmentof

Developmentof

Cultureofcollaboration(betweenphysiciansandphysicists,betweendepartments,between institutions,andwithgovernmentagencies)

Cultureofsafety(patientsafetyandproposalofreviewprocesstoinvestigateinfringementof rightsofphysiciansbyhospitalboards)

Theranosticapproachforcancertherapy

Nuclearmedicineasmedicalspecialty

Detectiondevice(multiscaleruptakeprobe,whichisbelievedtohaveinfluenceddevelopment ofrectilinearscanner[BennedictCassen,1950]and g-camera[HalAnger,1958])

Radiotracerfordetectabilityandlocalization,andsubsequentuseofmanydifferent radiotracersindiagnosisandtreatment

Realizationof Useofdosimetryforeffectivetreatmentusingpersonalizedtargetedtherapy

Increasinguseof

Continuingevolutionof

Eponymof …

Radiopharmaceuticaltherapyformanydifferentcancers*

ApplicationsofRAItherapy,whichremainspreferredinmostsituationsforautonomous nodulesandtoxicmultinodulargoiter,remainssafeandeffectiveforGravesdiseaseafter morethan80yofclinicaluseworldwide,andremains first-linetreatmentformost differentiatedthyroidcancerpatientsaftersurgery,especiallythosewithintermediateor high-riskdisease(useofdosimetryisincreasinglyrecognizedasvaluableintreatmentof thyroiddisease;tumorheterogeneityhasbeenidentifiedaskeyfactorlimitingresponseto targetedtreatmentssuchas 131I;andimagingwith 124Iand 18F-FDGPET/CThasrolein selectingpatientsanddirectingtherapy,markingnewareaofpersonalizedmedicine)

SaulHertzWorldTheranosticsDay(celebratingongoinginnovationandadvancementin field ofnucleartheranostics)†

SaulHertzAwardandSymposium,SocietyofNuclearMedicineandMoleculeImaging(lifetime achievementawardforoutstandingcontributionstoradionuclidetherapy)

SaulHertzYoungInvestigatorAward,SouthAfricanSocietyofNuclearMedicine

SaulHertzYoungInvestigatorAward,IndianSocietyofNuclearMedicine

SaulHertzYoungInvestigatorAward,PakistanSocietyofNuclearMedicine

SaulHertzMemorialPrize,BritishNuclearMedicineSociety(bestoralpaperandbestpaper concerningscienceordeliveryofradionuclidetherapy)

SaulHertzMemorialLecturePreceptorship,ProstateTheranosticsandImagingCentreof Excellence

*Hertzwasquotedin TheAmericanWeeklyMagazine onJune2,1946,assaying “… demandisexpectedinthe fieldsofcancerand leukaemiaforotherradioactivemedicines.”

†OnMarch31,1941,usingMassachusettsInstituteofTechnologycyclotron-producedRAI,Hertzinitiallyusedmixtureof 130I(90%) and 131I(10%)totreatGravesdiseasepatientElizabethD.ThisdateisnowestablishedasSaulHertzWorldTheranosticsDay.He presentedresultsof first10patientsin1942toMarkleFoundation.Initially,29patientsweretreated,andresultswerepublishedin5-y follow-upin JournaloftheAmericanMedicalAssociation in1946.Twentyof29wereconsideredcured,and6othershadpartialresponse toRAItherapy(1–3).

oftheAmericanMedicalAssociation, fromthesamelaboratoryon thesametopic the firstsuccessfuluseofRAItotreathyperthyroidism.Theeditorofthatjournalfrom1924to1950wasMorris Fishbein,whowasawareoftheprevious6papersbyHertzand Roberts.He firstreceivedapaperfromChapmanandEvans.Fishbeinsentitbackforrevision,sinceitwastoolong.Fishbeinwas alsoconcernedthatthestudiesonthesametopicfromthesame laboratorydidnotincludeHertzandRobertsanddidnotevenreferencethem.FishbeincontactedMeans,whoassuredFishbeinthat theChapmanandEvansarticlewaslegitimateandthattheirarticle wasbasedonaseriesofdifferentpatients.Fishbeincontacted Hertzandaskedhimtosubmithispaperwiththeresultsofhis first clinicaltrial,whichhedid.Afternegotiation,Fishbeinpublished

bothpapersnexttoeachotherandplacedtheHertzandRoberts paper first,toacknowledgetheirpioneerstatus,sincethosestudies weredone first(8,9).Thisissueisdiscussedfurtherinapaperby ObaldoandHertz(5).

HistoryrecordsHertz,withRoberts,asapioneerofRAItherapyandasestablishingnuclearmedicineasanewspecialtyof medicine(Figs.1and2).Hertzcreatedadynamicandenduring fundamentalchangeinmodernmedicine.Heinfluencedtheconvergenceofthesciencesandcollaborativeteamsaswellastheuse ofuptaketestinganddosimetrytodevelopprecisiontargetedmedicine.Hislegacylivesontoday(Tables2and3).

WealsoacknowledgeJohnLawrenceforuseof 32Pfortreatmentofleukemiain1936andpolycythemiaverain1937.Atthe

LawrenceBerkeleyNationallaboratory,Lawrence’steamwas alsoinvestigatingRAIinthelate1930sandearly1940sandbegan treatinghyperthyroidpatientsinOctober1941(1).AlsoacknowledgedisCharlesPecherfortreatmentofbonesarcomawith 89Sr in1941.Today,westandontheshouldersofthesegiantsaswe continueoureffortstodevelopnext-generationtheranostics.

DISCLOSURE

Nopotentialconflictofinterestrelevanttothisarticlewasreported.

ACKNOWLEDGMENT

WeacknowledgeBarbaraHertz,whoprovidedthe2 figuresand primarysourcematerialforthisarticle.

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