Misconduct and beyond in nedical research¸the retinoblastona paradign

Domenico Mastrangelo
1
¸Jheodora Hadjistilianou
2
¸Sonia De Francesco
2
¸Cosimo Iorõ
1
[Key words¸ rciinohla-ioma,cpidcmiolo,y,canccr ,cnciic-,mcdical cihic-
INTRODUCTION
Bciinohla-ioma (Bh} rcprc-cni- ihc proioiypc of canc-
cr linkcd io ihc -cqucniial lo-- or inaciivaiion of hoih
allclc- of a -o callcd ¨ iumour -upprc--or ,cnc¨¸ ihc
Bh1 ,cnc.
1hc paiho,cnciic mcchani-m hchind ihi- iumour
wa- fir-i hypoihc-izcd hy Knud-on in 1971 and furihcr
confirmcd hy ,cnciici-i- and molccular hiolo,i-i- who
idcniificd ihc ,cnc ( Bh1} who-c lo-- or inaciivaiion
wa- claimcd io hc rc-pon-ihlc for ihc di-ca-c.
Howcvcr¸aficr ahoui four dccadc- of coniinuou-
rc-carch in ihc ficld of molccular hiolo,y¸ihc cvidcncc
hchind ihc rolc of ihc Bh1 ,cnc in Bh rcvcalcd io hc
-criou-ly flawcd in ihc li,hi of cpidcmiolo,ical¸hiolo,i-
cal¸and clinical cvidcncc-¸ a- wc havc -hown cl-c-
whcrc.
^cvcrihclc--¸ihc molccular hiolo,y c-iahli-hmcni¸
-iill adhcrc- io ihc hia-cd vicw of ihc ,cnciic ori,in of
Bh and oihcr canccr-¸and¸wiih only rarc cxccpiion-¸
no alicrnaiivc cxplanaiion- arc admiiicd andor acccpi-
cd for puhlicaiion.
1hc cihical implicaiion- of ihi- mi-lcadin, and
mo-i prohahly hu-inc---drivcn hchaviour of ihc -cicniif-
ic communiiy¸arc hricfly di-cu--cd.
THE ¨TWO HIT¨ THEORY (Gene mutations and
cancer}
Bh i- ihc mo-i common iniraocular mali,nani iumour in
childhood¸ wiih an incidcncc of 1 in 15¸ 000 livc
hirih-
[1¸
.
Ii affcci- ihc rciina of onc cyc (unilaicral Bh} or
hoih (hilaicral Bh} in childrcn¸and ihc -ur,ical ahla-
iion of ihc affccicd cyc -iill rcprc-cni- a common mo-
daliiy in ihc mana,cmcni of ihc di-ca-c¸alihou,h morc
con-crvaiivc approachc- havc hccomc incrca-in,ly pop-
ular ,ivcn ihc availahiliiy of ncwcr icchniquc- of local
ircaimcni
[2¸
.
Bh i- commonly rcporicd io hc -poradic in 60% of
ca-c- and hcrcdiiary in ihc rcmainin, 40%¸hui accord-
in, io ihc ¨iwo hii¨ hypoihc-i- formulaicd hy Knud-on
in 1971
[3¸
¸hoih form- dcpcnd on iwo -cqucniial muia-
iion- affcciin, onc and ihc -amc ,cnc (Bh1}¸and ihc
only diffcrcncc lic- in ihc iimin, and iar,ci of ihc fir-i
and -ccond muiaiion¸a- rcporicd hy Knud-on him-clf
in a numhcr of oihcr papcr- and rcvicw-
[4¸5 ~7¸
and
commonly acccpicd hy ihc -cicniific communiiy
[8 ~10¸
.
DEBUNKING THE ¨TWO HIT¨ AND THE ¨GE-
NETIC¨ THEORY OF CANCER
Ii iurncd oui ihai for ahoui four dccadc-¸Bh ha- hccn
inappropriaicly con-idcrcd a ¨,cnciic di-ca-c¨¸in -piic
of ihc ovcrwhclmin, cvidcncc- a,ain-i ihc muiaiional
ori,in of canccr ai lar,c
[11¸
and any po--ihlc dircci rolc
of Bh1 ,cnc muiaiion- in Bh
[12¸
.Alihou,h ihc muia-
iional ihcory on ihc ori,in of canccr ha- hccn lar,cly
dchunkcd hy cvidcncc- cmpha-izin, ihc rolc of ancu-
ploidy and ,cnomic in-iahiliiy
[13¸
and ihc -amc ha-
morc rcccnily happcncd for Bh
[14 ~16¸
hoih ihc liicra-
iurc
[17¸
and in-iiiuiional -ourcc-
[18¸
¸-iill pcr-i-i in ai-
irihuiin, ,cnc muiaiion- a rolc in ihc ,cnc-i- of Bh.
Lookin, hack ai ihc hi-iory of Bh and ihc Bh1
,cnc may hc illuminaiin, in ordcr io find an cxplanaiion
1 Icparimcni of Biomcdical -cicncc-¸Policlinico Lc -coiic¸\ialc Bracci n.2¸Inivcr-iiy of -icna¸-icna 531000¸Iialy
2 Icparimcni of Uphihalmolo,y¸Policlinico Lc -coiic¸\ialc Bracci n.2¸Inivcr-iiy of -icna¸-icna 531000¸Iialy
Correspondence to Iomcnico Ha-iran,clo¸HI¸Icparimcni of Biomcdical -cicncc-¸Inivcr-iiy of -icna¸-icna 531000¸Iialy
E-mail¸ma-iran,cloCuni-i.ii
1 0 6 |UIB^AL of CHI^L-L CLI^ICAL HLIICI^L \ULIHL 4 |^IHBLB 11 |^ovcmhcr 2009
for a -imilar hchaviour wiihin ihc -cicniific communiiy.
THE ¨ GENETIC¨ THEORY OF CANCER¸ A
BUSINESS TO DIE HARD
In faci¸ihc prc-umcd culprii of Bh¸ihc Bh1 ,cnc¸rc-
prc-cni- ihc proioiypc of ihc -o callcd ¨ iumour -up-
prc--or ,cnc-¨¸who-c lo-- or inaciivaiion ha- hccn for
dccadc- and -iill i-
[8¸19¸
¸in -piic of ihc mcniioncd cvi-
dcncc-¸claimcd io hc ihc ¨cau-in,¨ cvcni in ihc ,cnc-
-i- of ihc di-ca-c.
1hcrcforc¸-incc ihc idcniificaiion and characicr-
izaiion of ihc ,cnc¸a numhcr of molccular icchniquc-
havc hccn dcvi-cd and applicd io hoih ihc dia,no-i-
and prcdiciivc ,cnc ic-iin, for Bh
[8¸20¸21¸
.
Howcvcr¸ihc cxpcciaiion- of iho-c who hclicvcd
and wanicd io makc pcoplc hclicvc ihai ihc molccular
dia,no-i- and prcdiciivc ,cnc ic-iin, could hc a u-cful
dia,no-iic¸pro,no-iic¸and ihcrapcuiic iool for Bh¸had
finally io -urrcndcr io ihc cvidcncc -howin, ihai molcc-
ular ,cnciic- i- of no hclp for Bh dia,no-i- and ircai-
mcni
[12¸14 ~16¸
.
THE ¨RETINOBLASTOMA ESTABLISHMENT¨
Horc imporianily¸ ihc -cicniific communiiy ha- hc-
havcd¸in ihc ca-c of Bh¸a- a rc-iricicd ¨ circlc¨ of
-upporicr- of a -in,lc ihcory (ihc ¨iwo hii¨ ihcory}
which rulcd ihc ficld of ocular oncolo,y for almo-i four
dccadc-.1hi- lcad ihc -cicnii-i- hclon,in, io ihc
¨circlc¨ ( cl-cwhcrc callcd ihc ¨ Bh c-iahli-hmcni ¨
[12¸14 ~16¸
} io almo-i -y-icmaiically di-mi-- any alicrna-
iivc cxplanaiion of ihc paiho,cnc-i- of ihc di-ca-c¸ihu-
crcaiin, a -ori of idcolo,ical monopoly -iron,ly -uppor-
icd hy ihc hu-inc-- of iumour -upprc--or ,cnc-¸which
applicd io many oihcr rc-carch ficld- in oncolo,y.
A- a con-cqucncc of ihi- unfair and raihcr narrow
mindcd aiiiiudc¸ihc Auihor- of ihc prc-cni and ihc a-
hovc mcniioncd ariiclc- dchunkin, ihc ¨iwo hii¨ ihco-
ry¸had io facc a fcw hui -i,nificani and challcn,in, -ii-
uaiion- rclaicd io ihc followin,¸
1.1hc la-i four dccadc- of rc-carch on Bh havc
hccn dominaicd hy a flawcd hypoihc-i- on ihc ori,in of
ihi- iumour¸prohahly hoo-icd hy ihc iumour -upprc--or
,cnc hu-inc-- raihcr ihan hy iruc inicrc-i in -carchin,
for ihc rcal cau-c- of ihc di-ca-c.A- rcvcalcd hy a -im-
plc liicraiurc -carch¸no alicrnaiivc cxplanaiion- havc
hccn allowcd durin, ihi- pcriod
[12¸14 ~16¸
,
2.Accordin,ly¸ophihalmolo,y journal- havc -y--
icmaiically rcjccicd manu-cripi- ar,uin, a,ain-i ihc
¨iwo hii¨ or -imply rcporiin, on alicrnaiivc modcl-.A-
a proof of ihi-¸ihc Auihor- of ihc prc-cni ariiclc¸who
ar,ucd a,ain-i ihc ¨iwo hii¨ -incc 1986¸and havc -uc-
cc--fully dchunkcd ii only durin, ihc la-i iwo ycar-¸
havc ncvcr puhli-hcd ihcir daia on any journal of oph-
ihalmolo,y
[12¸14 ~16¸
, io confirm ihi- circum-iancc¸ wc
found ii vcry -i,nificani ihai ihc only rcpori rcfcrrin, io
our modcl¸ha-cd on ancuploidy and ,cnomic in-iahili-
iy¸ha- appcarcd ihi- ycar on ¨ Currcni Upinion- in
Uphihalmolo,y¨
[22¸
¸hui ha- noi hccn wriiicn hy u-¦
3.1ryin, io cxplain io ihc -cicniific communiiy
ihc flaw- of ihc ¨iwo hii¨¸wc havc hccn compcllcd io
puhli-h our daia on ihi- -uhjcci in ,cncral oncolo,y and
non ophihalmolo,ic journal-
[12¸14 ~16¸
¸alihou,h ihc cdi-
ior-in-chicf of onc of ihcm¸aficr rcccivin, an ¨anony-
mou-¨ informaiion¸dccidcd io char,c u- of duplicaic
puhli-hin,,
4.By char,in, u- of duplicaic puhli-hin,¸whilc
wc wcrc iryin, io -prcad ihc rc-uli- of our rc-carch¸ihc
cdiior-in-chicf omiiicd io noiicc ihai ihc invcnior of ihc
¨ iwo hii ¨ modcl for Bh¸ ha- puhli-hcd morc ihan
ci,hiy ariiclc- on ihc -amc maiicr¸ a- rcvcalcd hy a
PuhHcd -carch
[12¸14 ~16¸
¦
5.Alihou,h prcdiciivc ,cnc ic-iin, ha- hccn
-hown of no valuc in clinical -ciiin,-
[23¸24¸
¸ihc la-i 37
ycar- of ihc ¨ canccr ,cnciic- mania¨ havc wiinc--cd
ihc prolifcraiion of an cxiraordinary numhcr of clinical
lahoraioric- of quc-iionahlc ¨ proficicncy¨ offcrin, an
imprc--ivc amouni of diffcrcni icchniquc- for ,cnciic
coun-clin, on Bh (morc ihan 60 in only -omc Luropc-
an couniric-¸includin, Iialy¸accordin, io Urphanci}.
EPILOGUE
Vc havc morc rcccnily dcfincd ihc ahovc piciurc a
¨hcdlam of wron, inicrprciaiion-¸fal-c -iaicmcni-¸and
laic di-claimcr-¸mixcd up wiih ihc pcr-onal and aca-
dcmic inicrc-i- of promincni -cicnii-i- and ihc profii- of
dru,dia,no-iic companic-¸wiih no -uh-ianiial advan-
ia,c for paiicni`- hcalih¨
[12¸14 ~16¸
.Inlcarnin, ihi- kind
of narrow mindcd¸-cciary and ha-ically uncihical aiii-
2 0 6 |UIB^AL of CHI^L-L CLI^ICAL HLIICI^L \ULIHL 4 |^IHBLB 11 |^ovcmhcr 2009
iudc- i-¸io our opinion¸a fundamcnial rcqui-iic for -ci-
cncc in ,cncral¸and mcdical -cicncc- in pariicular¸io
pro,rc-- for ihc -akc of paiicni`- hcalih¸and noi¸a- ii
commonly happcn- nowaday-¸ for iho-c of hu-inc---
drivcn mcdicinc.
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3 0 6 |UIB^AL of CHI^L-L CLI^ICAL HLIICI^L \ULIHL 4 |^IHBLB 11 |^ovcmhcr 2009