The structure and function of serpins

The Case of the MolectlEar Mowetnap:
The structure and function of serpins
3

4
The rerpinr are highly eifenive pmteaie inhibitm. tenaciously
gnpping their pmtcin target So ruccerrful is thc leipin mechanism
that an emodinanly diverie range of adaptations has
evolved. In some rerpinr inhibitoiy act~ily is anwaled by partimlii
ligands. In some ofthe rerpini' more disant mlatber.
inhtbtoiy artivly has been lost altogether and eherfunnronr
gained. II in the homone ciden thymxine- and cortiro.
stemid.binding globulini.
Serpinr aie partiwlady important in the conml ofpmteoiflic
carcadeder in the blood ansthmmbin inhibits blood clotting.
CI-inhibitor c~nmls mmplement anbation. and the inappmpnately
named SI -antitiypGn inhibits the elartare released by
inflammatoiy leukocltei. Abnomalitiei of plarma rerpini are
iurptisingiy common. and cause a vatiefy of direares - mainly of
the dmilation. Ai many as one in a loo0 people har an amnhmm.
bin abnomab, and ths a predspmiuon 10 thmmbosiit.
The best-studied abnormal sepini are ~ mam ofol-anti.
Wdn. Some IO per cent of Eumpeam rin is
wtheiized in homqgoter. it is ineiütiently secreted. Innead.

discovered this daes appearto happen: Z sntwrin rerdiiy
pobmerized imo bng fibnh. whale hepatmfie indw~ns were
found to conrirl of emangkd anutvpYin fibnb
The model could also explain the rapidly pmgreirive liver cirrhe~
(n 8nfancy. The foimation of pipmen ir highlyramperalure
mstne. and wen comparatively mall incream in the
range 37-41.C lead to vastly arreleraied rater of palymetira.
fion. Such temperature ChMgel an occur in childhood feuen
Indeed. m I pre~"ous tliniral nu* ofU infant$ two children
suddenly developed severe Iwr direaie ahv an unrelated fever.
Confimiatm that fever was a piiiemially rigmfirant ttiggenng
factor came fmm an unexpected IOYX~. DiJean-Yvvonne Bog
fmm Rouen in Fmce had rem the Cambo$e gmup blood
$amplel from pai,emi wnh familial thmmbdic direaie. In one
family. indmduais ruiiered ~ccasional episodes of severe
thromboiis aimciaed with plarma levels of amnhmmbin that
were sometimes IOW and mnetimei nmal. The abnomi
amiihmmbn turned out 10 comain an amino acid iubrtnuGon
wh-th created a coniomtional instability - a ~ uieln~ with
an oveneniilne tngger. In the t a tube. the abnoml
amlhmmim slowly Convened tothe inaLtive ïnpgereS fon
at 37'C but changed rapidly I 39'C polymenting in much the
sme way ai Z anutpmim
At fint these invertigattonr 01 mdividual mutations seemed to
pmvide an imereniog but anecdotal study of genetc disea$e
and moleiular m-hanirmr. Gradually. however. a pattern
was began lo emege. MI only fmm the dwene moleLulai
abnomaLUîS ofimnhmmbin identified m Cambndge and
elsewhere k m patiemr wnhthmmbotic dileale. but ab0 fmm
nudm dCImhbnwmcMt8om (n familsa1 angioedem. But
the patem was fninratinghl inmmplate: forexampk. mmc
rare al-amspmiin vaMnts had the rame ilinkal effects a$ the
Z vanant. and all0 omed a caniormatimal innabilny reruHing
in pelpme~tion. bin the molecular lnionr affeded qune di6
rent mgions ofthe motccuic
A SHARED PATHOLOGY
ihe explanation for this shared molemlar pathology recently
became apparent when &II the known piaims repin mutations
were plotted an the 1hree.dimenrionaI lemplate nmum
Over haK ofthe 100 mutationr dunered ~n fou? well-defined
domains The interpretation ofthii clme& WI greatly aisiil.
ed bythe completion ofthe rryslul slmcture oftwo funher
lam3 ofsnthhmmbin. eq~ivdlem 10 the paniy sprung and fuiw
lrggered mouretrap. The tmnmon between these WO fomr
rerub fmm P ttiggetinpindured change of iecondary wcture.
uling this reiw af~onbmationt. Anhw Lerk and graduate
nudent Jamer Mi$himotL produced I video showing how the
mobile region mwei dvnng mppiog. and how spontaneous
ttipgeting leads to polymercation. Amwding to thil Unetic
model. three ofthe mutaionil domains invobe regions ileidy
impliated in the trapping movements - the peptide loop con-
taining the ban region. and its pmximal and diml hinges The
founh me was qune unexpected and has identified the m ob
~bil~tch'
that cornroll the entry dthe bait reepioo into the
min body ofthe molecule.
Mut11i~1 h any ofthare domains lead to rpomaneour and
imppmpriate miornationai changer resulting, in the inhibitory
iepnr. in a shared pathology of inaaivation. pol)m&ation
and piarma deficiency. In paniwlar. the mutations in the 'Iatdi
Cod this tsmperature ~ensil~ny explain the unu~uaily severe
episodes ofthmmborir in the Rwen family! Th6 queRion domain that occur in the rare deficiency ~ tiimi af antnryprin
bm& an imediate faxed respame fmm France and pmvid. have the lame clinid dieai [ïier and lung areare) .a$ the
ed one of thore erquirncly warding mmem that .xur
only o~aiionalbf in a Lfetime of mearch. "Remakable ..,
exinodinary"- he ofthe Y>: episodes ofthmmborii in the
family occumd dunng petio& of fee< one in a 20 year old
mth pneumonia and four in family memben akei other fever-
,ndvting
mutation H the pmximal hinge in the 2 antnryprh vatianr
The ,demification ofthne mobile domaini has ~t only pmvided
a satisfying explanation afthe common mdecdarpathology
in the repin family but has also revealed the mechanisms (on.
tmiling cdonnaiond changes in these proteins. ~n parnutar,
dscare reruns from abmmal&rthat cause an inappropriate
or pmmture change in ~~nformatloh Thur the wlnerabiïny of
these mobile mechanisms in the $vins pdder a pmlotype
forthe much bmader group ofdiiodes now being recognized
as ionfomational direaies.
The Gas of L@:
The physiological and
molecular effects of oxygen
...
7

O X Y G E N
.. . -.
RV- Orrm~'Imn h ~ (ml o ID *cW ~
that rmtml them. A bener underrtanding would not jun have
implirationt for athletes and dimben: it could also have clinical - - ramifications forthe miilions dpeopie with 811neiie1 such II
anhma and emphylema, which nowk in IOW levels of oxygen in
the body, or commry anery direare and cancer. where pmitulac
tirruer are expored to hypoxid.
Nu
Two grnupi funded by the Weltome Tnin are continuing
ûxlodr Iradition of hypoxia reIeaKh. by loollng at two dinincl
aspess of oxygen renrinp the phyriologml mechanism that
regulate breathing and the molecular merhantrmr unde+$
oWen.dependent gene exprerrion.
A PHISlOLOGlCAL APPROACH
At the Vnwnny laboratory aï Phyliolqy in Oxford. Or Peter
Robbinr and deaguei areulhgto undenland how pmlonged
hypoxia afleni the breathing ai healthy humans. This queloin is
not 13 nraighüoFnard si n might seem. II the blood levels of
b31h oxygen and carbo dioide change when the oxygen level$
m the asr fall. and both thele biton sflecl brealhlng.
E
The immediate response to hypoxia il an inreare in vermla.
tim. the volume of air bmthed in and out per wit time. This
appears to be a dires ellecl Of lowered blood oxygen level$,
Ar ventilillion tirer. however. more arbon dioxide 1s exhaled.
IO le~ll in the blood fali: the cirdation becomes m m ilCa.
line. which. thmugh a reflex rerponre. causes venulatim ta fall
towadi 1:s rUning poinL In a third phare. venUlaiDn increais
again overthe ncn iew days, and !hi$ inmase il %stained
white the penon rrmaini at high al6tude -an cfl~t bown as
~entill~~ acdimtization.
O X Y G E N
Many hypotherer have been put ionvard to explain ventilatory
acdimatimion to hypoxu. and mon have pmpored that aliui.
Immtion ofthe blood and body times is a key phyriological
tngger. This may seem paradoxical since. in the rhon.tem.
rll

O X I G E N
Ifso, what orygen.renring mechanimi might be inwlved! A
L _ ~ Y. in D the USA wodinl .. on mat% has wideme that at lean
pan of ~cclimvza~on II due 10 pmgreriive incrediei in the
mfnMIy of camrid body chmoreceplos, There mepton.
located rlae to the camtid mer,, are activated by IOW oxygen
le~k. leading 10 an increaie in ventilalion A second US gmup
has pdflmmry endence that prolonged hypoxa induces the
expression of new membrane pmmn m camlid body cecep.
101 cells. which could increase their Ieninivny 10 oxygen Thus.
n il posible lhal at lean some ofthe physiological ellecti seen
in people breathing low omen are the relul4 of changer in
amid body ~enriiwy mediated by aatvation or imctwation
of p r by hypoxit.
"2:
, . . . .
encoding the hormone eyrhmpoietin which stimulatel red
blood cell production and thereby increasei the oxygenanying
capac~ty ofthe blood. Tranrcnption ofthe eryhmpoietin
gene has been found 10 be ~ttimulated by hypoxia - a rerponre
to hypoxia nieif. not one of its many metabolic ronrequenrer.
By tranrfening the eryhmpoietin gene imo mammalian tell
liner. and including dtflerent amounts of rumunding DNA.
DI Ratdille and colleaguer hive been able 10 identify DNA
~eqvencer required far !his hypoxieinduied conml oftranrcnption
of pamc~111 importance ira sequem at the 3' end
ofthe gene - the 3' enhancet. Under hypoxic tonditionS. this
$quem is bund by a ÿdm~riptionil activator pmtein known
a< hypoxially inducible nuclear factor (HIF.1).
10
Dr Ratdifle'r gmup ha$ lakm the DNA requencer cwiüolling
eyrhmpoietin tranrdpuon and linked them to 'eponef
genes, which encode pmleinr that ran readily be deleRed
when transcription ii activated. Under nomal ciriumrtanrei.
eryhmpoietin is pmduced in the liver and Kdney. but hypoxia
was found to induce repmw gene exprestian in 1 much
bmader range ofcell types - indeed every cell type tened IO
far has expressed the reponer gens in a hypmixically inducible
faihtoh and all these cell typer also contain HIF- I. Thur. there
appearr to be I similar mechanian for contmlling gene exprer.
sion in wpponre 10 hypoxia in most if not dl tirruer.
what other genes might be ieniitive to hypoxial Dr Ratclifle
$taled with some educated g u ~ ~ hypoxia r k might be
expected to ~timulle the pmdudon of gmwth facton
involved in bloodverrel formation and ofenrymei
involved in gl~olyrh. since glyrdpir cm be used to pmvide
cdldarenergl (ATP) iniheaben

This Way Up, This End First:
The molecular basis of
axis formation in
Drosophila
MOSI orgmismr haw O &&y dirlinguithoblc hcod ond lai!,
~ ~ . ~ ~ ~ ~ ~ p h l r
fiont ond bob There oxet OIC citobiirhed early in embyonic
dcvciopmcnf hlil Tor most onimdr oimoil nothing it known
obovt the prc& mrchaoirmi invdvrd In the fmiffly,
Oiorqhh mymmety is codified in the developing egg, md
~ rcreorch ~ in Umbridgcir beginning to unrorcr~hcmoieculai
~ r ~ ~ p i U i r n n n . . f i h ~ ~ ~ ~ mechinisms ~ ~ , ~ bywhih ~ ~ i there , ~ me$ f ~ ors ~ tprcifed. * ~ ~ ~ i .
Theawad ofthe 1995 NobeIPtize for Phyiologyor Medrine
to Ed Lewir. Chtirliane Ntirdein4oihsd and Eti~ Wielchhaur
was recogn'~n ortheirpimemg or gmtis 10 a~tpe
eady development in Drnrophiio. But it also reIleued the piuoial
mie the fmMy has come 10 plsy in developmental biology.
HOW a fly is pui t~gether ii now undentood in iema?eble
detail. and many ofthe ptincipier discovered in OrniophiIo have
twned out to be widely appitable 10 other organism$.
One area of early development under cloie rcnniny ir the
mshanirm by which body axer are enab1,rhed nier are highly
arymmettical - heads facing fowads, wings on the back iegr
on the underride. and IO OR Inteming~. both head4a.tail
(antem.portetiot) and fmnt-to.batk (dom-mntial) poiltitiel
are already established in the unfeniïmed egg Atthe Wellcome
TdCancer Research Campaign Innilute for Cancer and
Deveiopmental Biology in Cambtidge. Dr Daniel 51 lohnrton
and cdieaguer are beginning 10 cianiy the moierdar mcchanimi
by which there asymmettiEI are mated.
I2
DROSOPHILA
A fmrhiy laid Drnrophiio egg il mvghly oval in shape and look
almort iymmem~al. in facc the inride of the egg is highly polar.
ized. owing to the localized dimbution of merrenger RNA$
encoding key pmteinr: bmd mRNA is localized to the anterior
and orbr mRNA $0 !he ponetior. In nom1 Ilia. biraid deliner
where the head will form and etkordicttatcr where the
abdomen will devebp.
How is this aiymmefry mated1 Eggs begin life in a ~flllmre
lvl~wn II the egg chamber. which is bmed when a Rem tell
divides four times 10 give a cyst of 16 ceilr: onne ofthere cells
develops into the wcyte - which will wmtually be the egg -
while the other 15 become 'nune celis', imerconnmed LeIli
fhl rvpply the ooqe With the matetialr 11 needs to gmw and
deveiop.Artheoo~ytegmwr.theegg chambertaker m a dirtincm
shape. with the ooqe iseifat the ponetior. the rime
celis atthe antetioranda tingl~.~diI~y~rofq~hhelium-f~llide
ceils - rumunding all I6 gemline celii. How the ooqe
ilimei to o~ccupy the ponm.oiend ofthe egg rhamberir not
dear. bu1 this positioning if eimtial to the ertabiithment of
both the antao.porletioi and dom-venml =CI.
WO* fmm Cr 51 Johnswn's and other labs ha revealed that
the key tD axis fomtion is a setier of signals relayed between
the developing oocyte and iumunding follide cell$. tek to
their own dwicer. ioliicie ceils I the portetior ofthe egg
rhamberaregeneti~aUypmgrammed to adopt an sntetiorfate.
A$ it develops. the Gcyte rends a signai to these follicle tells,
which stops them following the default anietioi pathway and
'
imtcad Commis them to a posterior fare.
Later. the ponetior foiiide ceils signal back 10 the oocyte The
eNea ofthi5 signal is 10 reorganize the intemal scaffolding or
~ y t ~ ~ ~ eooqe, i ~ IpeLiliaiiy t ~ ~ itr miuDtubu~e " krk
Unlike Icaliddmg. mimubules are directional: the labels 'pius'
13

D A D S O P H l L R
Iikeagmwth fmorandta$+d,emadaagmwth faaormeptor.
n is thought that Gurkm pmein pmduced by the oocyte
bmd to the Topedo receptoc M follicle cdlr ükimately. this
modilia g m expmrion in the foilitle relli and rommm
them 10 a doml fate.
FRONT FIRST
14
2
IS

From Frog Skin to Human Colon:
The mechanisms of epithelial crosstalk
16
We key nux in these cells is the abrqtion of sodium ions.
Sodim EIUI the cell through a sodium channel at the apical
membrane (the one facing the enema1 envimnmmt) and exits
at the baroiateral membrane (which facer body tirrues)
through a rodiumlpotarrium pump: the imported potassium
leak out thmugh a potassium channel ($te above). To replate
sdwm levl. the actiwtier oflhe sodium channel muR some.
haw be linked to those ofthe ion vansponen at the bardatatcr.
al membranc. A decade or rc'r work by Pmfmor han Harvey
and ioileaguer. fim in France but m m recently in Coh his
identified three mmponenu of lhir in~dcellulir imrnalk ryrtern:
pH, ATP 10 ADP ratio and calcium,
INTRACELLUIAR pH
We 6m edence that intracellular pH could be significant
sme in the 1980s. with the discovery that the sodium and .
poliiiium conductances dfmg Mn epithelia increased mth
increasing pH. Morewer, the efeN w e innaniamots and
occurred afierphyriologirally relevant Shi& in pH. Literpatch.
clamping rtudier revealed that individual potaiiium and sodium
cha~elr are directly modulated by pH. The $odiumlpotanium
pump. however. is relatively insemirive 10 intracellular pH.
Two a m ofthe ion transport rynem thus appear to be COY.
pled. via intracellular pH. How might this iwpling be linked to
the contml of ion tranipoTi1 Studies in fmg skin revealed that
in1racellulai pH is sensitive to m!ei of ion transort. We key
factor appearr 10 be a rodnrdpmton exchanger in the basola.
en1 membrane. whrh pumps pmtonr out ofthe cell and thus
increaser intraceiluIrpH. The exchangeri'doven by the rodium
gradient imii the membrane, IO any bdd.up of $odium
in the cell wII. thmugh ils eiTeitr on pH. inhiba funher $odium
17
inOvx lree abovel. In e kt 8 'ïeedback h W mmtes

E P I T H E L I A L C R O I I I A L I :
CALCIUM
pmbh was resolved when ADP was included. which rhihr Eat wideme that ddiim was involved in cmrrtaik CamC fmm
the ~eninMty ofthe channel imo phfliobgial ATP toncenlra- nudies oftoid utinary bladder. in which sodium abroiplion il
lions ilk rmrnwe to ATPADP ratim rather thin ATP %reif. inhibited by calcium imophorer. Patch clamp nudier revealed
The ATPADP ratio ii integral to lhe coupling bnween the that caicium inhibiü both the sodium and the potasium chanpota~innn
charnel and the sodiumipotarrium pump. which is a nel, abhwgh in the former raie indredy, Cellvlw calcium lweli
w~i~~~mumerofATP:it~rnpomibleforuptoM)per ran 80 be InflUenCEd by sodium fluxes thmugh the aaRNticI of
cent of an epithelial cell's ATP UK, whui a is active. paariium ye1 another exchanger. I lodiudcalcium exchanger. which
ions flood imo the cell. ATP lwek dmp (and ADP levels ne). expels rikium and imporb radium. Thk pump is renritive IO
IO the pdar+m channel il opened. Cellular metabolism is inlraceilvlar radium. providing M addnional mechanism for
therefore a potent mxlalk signal.
leedbek CDmmlof sodium fluxer (se facing page).
Take lhe human col~n. As mmiioned above. aldonemm on
enhance sodium uptake by gut q%h& But il can dro inhibn
chlotide secretion, thereby exening I powedul influente on
body id1 leveli and on water retention. Sodium and chlotide
ion flow occur piedominamly in inioldi or'mpts', each containing
about 30 dlr. It has been rugpled that chidde is
secreted al the boum of oyps and sodium abrorted at the
top. but Pmferror Hakey believer that cells exponing chloride
are pedebly able IO absort $odium
It appearr that chlotide secretion is nomaliy dependat ai high
lweli olinuacelluiar calcium which aas indiredy through a cai-
ciumdependent pofariium channel: potadurn efbs *rough
these channeir are "red to mumtrtdance the mwement ol
negatkly charged cidoride ianr Now, immningly, this potarri-
um channel has an unurud pH renyiMry. It is oplimalh. aclke at
19

Mutation and Morphogentsis:
New insights from Apert syndrome
One ofthe bemm oflha Human Gnome PmJm is Ihm il ipreh
vp ideniijcorion of the moleciilor &sir ofinhetired diseoses by
suggesting 'condidate penet'ro moiyse. Ailhough such diremir
an rare. their rwdy bquea~@ prarider valuable indghU
into normd

EZ
nv

An Unwanted Defence:
Anti-ganglioside antibodies
and limb paralysis
Our immune sprjtemr pmiect us imm a huge range of organisms
u4irlkl

PROPERTIES OF THE ANTIBODIES
h theory, the cloned nntrganglioride amibodierdamage penph
era1 newel ladmg to muscle deymiion Ifso, the antibodies
hdd bind ganglioeder in nene Wrn For at lean me antibody,
this doer appear to be the case: 8mmunolocalmm studis
havc revealed thai a cloned antibody tan bind to gangiioiider
at munipie siter m nene fbm, including nides of Panvier. which
an as 'relay nation? in the tranrmirtion of mion potentiak
along myelinated newu.
,I 6 ml yet clear whnher or not all the other cloned atibodier
bind to neumni - and thus whether they actualt carne
dilese. The fact that the amtbq tha bin& to nodei of
Ranweralro induces i penpheral neumpathy-like *ilnerr when
lnjected into mce 6 good wsdmce of a ca~mtive link The
adds are thcs wry much in favour. but clear binding of other
antibodies to ~ner m the penpheral newous system would
pmvide rearrunng mnfimtion.
Hm do d.reactiue am,bod#er aflect the newel IO whkh hey
bind! AHhoqh mon anemion har been focuied on tmmune.
mediated damage. Dr Willnon bell- a rmmd pornbility
$ho& bt considered - that the aniibodler !Mead imeirere wnh
ganglieride fundon In elTeri they could act as phammlogd
reagent% either as 'blocken' that inhsbn gangloiide or PI anb.
10% Ahkugh there ir wdence of inflammatory damage to
new lib- there il dro suppm foi akematwe mechanisms for
example. some meu$ly 11 patients make enremely rapid RGW.
mer inwnrinem wnh the need for edemve mx~ural repair
but conrinmt wih a ~venicle response.
To explo~ these akemativei. Dr Wkon and (oliabomtm at
Strathclyde and Ohd are iening the elfe- OfaUtoantibOdy
O" a vanay or bi010g~~~i IPtem~. N O ~ or S bnvier are ti

ynemr d p a b with sud diiordm can reergar&e extensively.
and may explain why some patienü regain convol of
mwemen~ If parallel parhwayr do eriP could the damaged
brain be e@ohingthem dvnng recovery1
MODELS IN THE BSIN
Or Daniel Wolpen has memly returned to the LJK afier three
yeas at the Mariachhurenr Innitute dTKhnology in Bonan
At the lnnnute of Neumlagy. he II MW iheitigating the neural
comp~~tions invoked 3" two fundamema! aresi of motor con.
lml: how doer lhe brain imepte the intomation 11 recmier
fmm the eyes and other iemei (semonmoto? intepuon). and
then dire3 the body to aa accordingly (motor p1anning)l
n O V r M f N 7 C O N T R O L
To #&#gate there pmmrer. Di Wolpen has developed a
Ruble -mimental set-up that dlowr a n movement to be
wry fin& mmmiied Subjear hold a handle anached 10 a
lightweight robotic mnipUlatOn which BO eren compulelrontdled
totter on the hand duhg movement Vmd envi.
mnmenü' can th- be mated

area ofthe brain that was lell actwe in Pahmon's patients
than in noml rubjecü (see above). Could underadmy m this
are& known as the %upplememary motor area undcdie the
motorabnomalnies seen in ParCimon'i patiemr?
The neural dirniptionr leen in Parkinrotir dseare ruggert a
possible cause forthis underacttivhy. The rupplememury mmor
ares rends mnnect8om both 10 the mmor mnex and to the
spinal cord. 1s sctMty il influenced by the putamen (pan of the
baral panplta). which in Paf6hon'r dseare il innervated by 1
greliy reduced -ber ddopamuie-rmiaYimg nemm This
losi of dopaminegie input appeari 10 affect the rupplememsry
molw area: act% in this area WI found to be more nomd
when palientr had taken apomoiphine.which i~reareithe
levels of dopamine in the pUtMlen.
E l O V E M f N i C O N T R O L
These nudei wggen that the supplementary -tor area my have P $pedal mle in the performance 01 relf.genented movements
and nudm M macaques have rdmed UUS theory.
The macaques were cim trained to pdom an arbnrary mvem
m whenevw they raised thek am. a panut was ddivered
10 a faad hopper. Animals in one group were trained 10 raire
their arm wheneverthey wan1ed:the movements were selfinfliated
Thoie in a second group were mined to nise their
am when iky heard a tone: the movemem wre enemalh/
uiggered. men the supplementary mmor conex mi
I -' -
removed however. Lnimali in the fml gmup initiated few
movcmcmi, while those in the setond gmup were much less
aifected (see below).
The supplementary motor area is therefore mcial 10 the
direction ofrelFgenerated movementr. It il there movement$
thl are paniculady affected in Parkinron'l pstienü. But why
are patiems leii impaired when enemii cues are provided!
Dr Parrineham turned hi% attenlion to thc lateral nremotor
conex. Like the suppiemernary mmor conex this area rends
connections both to the mmer conex and to the spinal cord.
but PEI nudier suggested lhl h was activated namaily or
near normally in Pa+inion'r patiemi. Wovid leions in the
bted premotorcanex akt motor performance m macaques?
The animals were trained 10 pull I handle when presented wnh
one ~OIOUL and to move h to the leh when presented whh
another. When the brai premolor conex was removed. the
macaques made many ems (see below). ruggening that ihir
area plays an imponant mle in the guidance of m~ement by
extemal cue%.
32
PET studies in homm an im$iftenl with this idea Nomi
subject$ were asked to use a computer mouse 10 move a
pointer almg lines - a task in which viruai WEI guide tracking
movements. AI expected. the lmral prrmotor conex was
activated but the rupplemfntary motor canex vm not.
Activation was also noted in the cerebellum. which an influ-
ence the mmor caltex via a relay thmvgh the lateral pmotor
c on ex. This pathway may explain the abilny of Palünron'r
patients 10 use visuai CUE$, since the cerebeiium 6 not sliected
in ParCinroin'r diieare.
The Oxford and London nudiei am helping 10 cianfy the way
the brain commir movement in heakh and direare. A clearer
piaure WIII. in time. not only help U$ to undernand one ofthe
mon fundamental human skills but dis0 to devire more ratiltlonal
therapies forthore who have. unfanunately. lost such rkdk.
Unwanted Repeats:
b
Fragile sites, mental impairment
r
and ovarian failure
33

MUTATIONS AT FRAGILE SITES
34
Also of interen are the chmmosomal suroundingr ofthe frag.
ile riter By characfetiting genetic makers doie 10 the fragile
riter, the gmup hopes to idemay makes or gmups of makers
that are Co-inhemed with unnuble rnei. Thur. the Salisbury
nvdy II a 1hree.pmnged invenigation: how is repeal innabilny
Iinkd 10 the number ofrepeats. 10 the inteml mur re of
the repeats and 10 the chmmosomal comext afthe fragile riter
THE FIRST THOUSAND
A preliminav anslyrii of the first IWO children has jus been
F R A G C L E X SYNDROME
FRAXA sile, and the allela cm%d by an individual at these But phapr the mon im'guing dixovay concas mdiualr
mahrriterpmvide acharacleridc'labd'oflhntchmmo with?~pennumbabortki(ine~~~andprrmu.
soma1 region. The mon common pmem at F W 7-3-4+ tation. Thse allder have bem sdgned to a newgoup. the
(each number representing the allele at each maker rite). il 'intemediale' allder (40-60 repals). In the Fm IWO boy.
iamed by mughly halithe population. In irapile X indiduais
this and previous mdiei haw uncaverd a &d over
reprerentation Ofthree pallerns - 2-1-3 and the related
64-9 and 6-44 These chmoroml typer thus seem to
c~ntiln FRAXA sites prediipsed 10 mutation.
The 2-1-3 FRAXA d e LI pmbably unmble because it cdnr
a relatively large number of CCG repeats. The 6-4-5 and
6-44 pli?. by tonMn. caw 1 nmcfural change: tw, dthe
AGG impuntier M reparaed by more than 10 CGCr and this
may mnder FRAXA suscepuble to full mmtbn. i?tenningif,
about a third oiFRAXA cale$ involve maker combination$
x

There finding fvggened that intermedate expmiom at
FRAYA Could have an etTea on cames. Funhermore. th- is
some evidence that the numberoinon.identicaI wins born to
carrier women il also anomalouily high. Interrnin& the hodence
of divgow winning is known te increase with matemil
age. and premture ommn failure is also age-related - in efien.
the ovay N ~T ou7 of egg% abnormaUy early. Could both these
erects dcct premature ageing ofthe waq in FRAYA carrien!
36
To shed light on lhk issue. Pmrerrorjambi is beginning a
study d 60 aflecled familier 10 detcmine the inodence of
(I) premature wanan railure. (2) iwinniog and (3) milcarriaga
and ttiromler (enra copia O( a panicuI&r chmmmome. I in
Down 3pdmme):the lattertwo efiects am dm thought to be
indicalon of ageing ovatier. lithe inadence of some or all of
lhefe factam is inueaied. this Would pmvide iunher evidence
that iuppriiediy harmless npat expsnrion is in facl dettimen.
1.1 - atrelenting ageing in the ovary. How might this ariw!
In mowe embyogcnerir FMR-i is expressed in the gonads ai
the sex cells undergo mitotic dwirion. Pehapr. rvgaertr
Roierrorjacobr. cell division if slowed during this peiiod. due
ta the presence oi the addnional repem or their eliea on
fMR4. 10 fewer eggs than normal ire pmdured. The wpply of
eggr mightthcn be exhauned prematurely,
Insulin-Dependent Diabetes:
Exploring the land of NOD
37

SVan of mice that rpominaouriy develop IDDM - nondese
dlabeiic (NOD) mice.
MECHANISMS OF AÏTACK
By SIX memhi of age. mvghb 70 per cent of female and 10 per
cHn of male NOD mice show features vep~ similar to thoie of
human IDDM. IDDM ran a110 be induced byvanrferd reif.
reactive immuns cells imo idvh or newborn NOD mice Sinre
na 41 NOD mice succumb to diabetes. and the incidence of
IDDM vatis signifanUy R lab populations amund the WO&. it
s a*

L@, Death and Happiness:
A new role for proenkephalin?
hornlr~hiPMn"~fn~~~~-~~k'
W*nkN*NmrQf*mddm*ceZ
Wellme /"lYI"Ie Lim
eitherruwive whenthey should die. ordre whenüiq are till
needed-indeed. abnomailyregdated apoptorir plqr a mie
in many direarer. Not rurpnsiogly. *en. apoplorii nrearch has
undqone a ~peaamlar boom and oiïen exoling new oppor.
tunilier for fundamental and clini

A MArKR OF LICE AND DEATH
h &I bcroming increamby apparent that rbrely related molecules
- and romesme pmdum aftk same gene - can.
depending on the Liriurnstaocei. pmmotc either death or $UP-
+al Cell$ are thus precanourly poised beween life and death.
On the po~il~ve fide. however, a relatwely small change may be
fuflicient 10 tip the mlei in favour of IUNIV~I OT death. and
these changes muld be therape~tically useful.
Pmenkephalin can now be added to ihti list oilwoke& mol.
eculer. For. as well as promoting rvwival, pmenkphalm can
allo be lethal. The key to this dual mie appeari to lie in the
invdceikilailocation ofthe protein: the Dundee gmup ha$ found
that in 3 numberofcell types, such II embryonic (ibroblartr
P R O E N X E P H A L l N
42 43
h l been implicated in amer. in the insppmpMie p"nenrc
of sdCreacÜve lymphmltei in ayv)immyne direse. and in persinent
inflimmtion aher iniea8m Converidy. inappmptisle
spoptorir has been implicated in the delnion of beneliaal lym
phocre populéonr in AIDS, and in neuronal lmi in diKars
such a$ Altheimeir or aherhin injury. There M tmuldng
gmundr for investigating the potentid mle of pmenhphalin in
there diiedief. since many ofhe cell typu inwlved romdy
exprerr pmenkephalin.
Fvnherin~nigation of pmenkephalin my thedore have
practical benefnnr. But the ceneal bioiqigid quenion -8unanswered
why does the pmtein have such difieren1 der?
One pombility is that d celiectt a Lm of'pae btinf. as
exemplified by the lkm r*F-Jllinr which CUI act &er as NYC-

Philanthropy in Action:
The Hodgkin family collection

individual about whom there II substantial doLumentition in
the aKhive II Thomas Hodgk8n.r father, John Hodgkm of
PemoOwlle (17661845). who left Waw,cksh$re for London
and set up II afutor. He and his wife Elzabeth (1768-1833)
(née RiChan: some papes ofthis Sussex Quaker famvly are
1110 m the collection) had two rurriumg sons. The elder.
Thomas Hodghn MD or 'Uncle Doctor' 1s he was known to
succeeding generations. was the 6m Hodgbn to enter medicine.
Trarained is 1 doctor in Edinburgh and Pans. fmm I 825 he was
employed at Gv'r Hmpiidl os lnrpector ofthe Dead and Curator
ofthe Muieum. conduiting f ut op si el and creating I coliection
of specimens iiiuitrative a system of pathology. H,I obrewa.
lion of morbid gmmhr m the lymphatic rynem led 10 the lint
deanpiion of what was later IO be named Hodgkin's direare in
his honour. However. a tlah with the horpitdr auÿ~crat~
Treasurer. Eeniamin Hamion. reruked in his being parred over
for pmmolion and he resigned ~n 1837. Increasingly. he gave his
enw 10 the philanthmpr caulel that had ~Iways occupied hi$
spare time. interests ceninng on inuemgation Ofthe cult~ies d
conquered people5 and advo

From Hippocrates to Harugr and Beyond
The Western Medical Tradition
800 BC -AD 1800
PmieawVw$an NUiTON
W*l

Iimned in scope. and the dircovetier ~fmtural scientin%
although interenmg an thmirelver. had not contributed much
10 the maimeMnCe or recovery of heahh.
04 hile the nie and fall of lhu lamed tradnion formi lhc vine
of oar hstw d Western d i c m equal anmtim is &en to
nr imemction wRh other foml Of healing. and 10 RI development
again? 1 Ihihing social and whural barkgmund. There
are iMematke medical theories that were once in favour but
were lhen excluded - Empindrm and Methodilm in Antiquity.
IatmphricI ~n the ievemeemh century - a$ well as authos
and movementi whose place in the medical pantheon has only
been achieved by omming mixh. The Greek Eraiisratur.
8.280 BC. il accepted as a great experimental anatomin. but
forgotten 1s a tlinuin: Panireliur and his followerr (n the sixteenth
~enlury are praised fortheirpmtodemirtry.while their
radical mysticirm is r0nven8ently ignored
In all th,% surgery 01c~piei an ambiguous poiition: elite pni~iit-.
an FRC5 n a myal lugeon. are eiieemed, their more
humble quwalemr dirmirred as bonc.renen or wen quacks.
Yet some oftodais 1pecid1RteL mcluding dentistry and ophlhalmdow.
were once regarded II the province of quack. and
for many ofthe rick the miniitratmnr of a travelilng drug-rcller
or local blaikrnnh or barmaid might be dl that was available.
Fared ,a,lh ,he ainhonty OfmDdem medr,ne it ir 111 elly
10 iorgct the ml1 pan played in healing in the pdn by phyri.
(Sni, and, ~anverrely, ,he impomn~e of med,tine -
previous major histotier ofmedicine in that none d its authon
- 1 tlifsicisL 1" arabis and three hinotianr - was trained in
medicine. They have come 10 the Weitem medical tradnian II
outside-. II patients not practnionem. They have not themielv~i
shared in the pm

From Deontology to Discipli,
! German medical ethics, 1800-19
I
I ' "
__
Debotes about medicd ethics open hmk bock to ihc oncirni
prcreplr orthe Hippirmtic oath, such 01 nonmoiefiirenre. confi.
dcniidiry and prcrervoiian ofhumin bfe. Fmm this pcrtpmire,
the dcreiopmenr almid!al ethics may oppeor 0 scrm ofdcvio.
tien$ from a iimeierr idrrri. In meni yecm howewr, hirtorionr
hove begun to erpiore the toiid proferrionof ond intcileauoi
conditions that *hoped medimi cihirr in defined periods. AL the
Univerriry ofourham Dr AndreorHoiger Modile il mmpormg
Germon and Bnti$h medid ethics in Ihe IBOOi and miy
1900s. and hem he prcrenir some inilid infighli. firuring an
Gcrmon drvriopmenir.
In the early nineieemh centuq German docton expetienced
profound pmrernonai change. a relull of mduittializa1,on.
uri>aazation and paupenzation. Al warken migrated to indurinal
regionr. hospmi medme expanded 10 cope and towns
created publicly funded pmi for phyrcianr 10 treat the poor.
Cornpired 10 their predecerran in the eighteenth mtuq,
dmon were ranfmnted with patients from a broad 10m1
spectrum. indudinglhe lower clai~e~. Cholera epldemiir in the
Memnhcna, v , ~ / ~ thrTr, ~ ~ ~ dareare. Sooally-minded phywani. such as Rudoif Vmhaw.
admanirhed thetc colleaguer 10 act as 'advocate$ of the pooi
At the same lime. demands on practical competence in rugeq
and ObnetncI increased. culminating sn the so.cnlied uniGed
rncdiial pmferrion (onIlicher Einheitrriand). Fint iamduced in
P ~ w 8n a 1852. it abolished the dichotomy of lppreni#Celh!P
trained iuqeonr and academ8cnlly educated physician$.
Moreover. dmon had new publx health duties to periom. II
54
were expressed. foi innançe. in theloumrl der pmnisdw
Heilhnde. edited by the Mnyential hnian COU~ physician and
Min pmielror Chnnoph Wilhelm Hufeland. Even the old s p
lem of remunerating donon with an amual lump rum began
10 fail. In 1823 the Bonn dinidan oitinim Friednch Narre rug
gened that medical iocietier should be founded to collect and
redinnkne fees. Dlhen favoured the example re1 by the
Kingdom of Hanover, which paired I law in 18 18 to limit
licenser for practice in re*m that already had noqh donon
Againnthir bacligmund. doct~nincre8sing~wmteabouttheir
pmrerrional obügatimr. ertablirhing a ïnemv genre that
became known as 'medical deontology' (i&nnic ofthe doaofr
duties). This lnerature fomr I major area of DI Msehle'r
research. The pmtotype was Hufeland's elhical essay 'Die
Verhdirnirre der Amer', which detailed the physician's obliga
tiom to patienü. deaguer and roiiay. and CM be seen 8s the
bke Pm'val'r Eth:~, Hufelanüs deonlolqy &ad a
~onxwative effort Io uphold &id Mddom in the face of
pmlarimd conflid and %cial change Forthe PwYan dortor
anNim was the fovndation of the di pmfprbh and
atit it ion of human life iü MY a~me Acmidmgly. he
rejected abonion and my life-horlmhg memm in dying
patiemr. Though refang m the Hipppo~tic oah in this mn-
55
tuL he chiefly wed vrhat pment4ay efhiN rail a 'dippy
slope' argumm ifa doMImade iudgemü ab- the nh
andrrcerrityofhuman1ife.hcw8s bwndtobecomeWe
dangernus Inthe -'.
The bmdw r-1 rpccuvm of patients was &ed in
Hufcland's mng plea for equal mmmt hdcpndm of
we& and rtatm Echoing Kantisn nhx* he fustheradnuin-
iBed doam nwerto rrgard a patim 8s a 'means' or'merr
objeect of a naluml up&mem'. but ahnp asharm's highnt

end'. Smce mlprartice was unlikely to be punished thmvgh the
legal ryrtem. docton vere exhoned 10 linen 10 the mice of
their 'inner inbunaS. fmally, mniemporaiy mmpetn,~ wnhm
tne pmfewon and tanrem foi ils public image was expreried
10 lhe warning newerr0 dtrparage a cdieague. In essence.
Hdeland tned 10 maintain the ideal ofthe 'gentleman dartaf.
.

at xhaal: today's young people we not only going 10 gmw up
ma society markedly dilierem fmm !hat of earlier geneniionr.
rheyarealrogoinglorhapeil.
GZNETlC FUTURES
Genetic$ iprer pmminemly in the Nmmd Cilnimlum. By the
age of lb. rtudents should have been taught many of the basic
concepr of genetics. ruth as the chemical barir of genes. fhe
inhenlance of some direaser and the pnncipler of genetic en@
neenng. But how well do Ithod nudents undentand generic
pnncipler indsppreDatP the likely impact ofthe new genetic$!
Do they appmve of genetic manipulation of plant5 and animai$!
To what eneni do they need 10 appreciate the unddying Ici.
ence m order10 come 10 1 conridered viewpoint'kh quer-
1,om ace aff~d~mentalimpartanreifme nun geneialh of
adults is going 10 coninbule meaningfully to debutel about 1hE
mle and scope of genetic lechnolo@er in the 21 11 centuv. Yet
we have vev IilUe idea about the bowledge bare of young
pei>p!efheirpeicepti~omofthene>v~t*r.andwhat they
identify II the maior ilsues.
58 59

i
and yiewpoim~ ran be explored they engage the stvdenis and
therefore. the team belieucr. more reaiin~cally reflect annuder
and l ~eli of undemanding of he ihwti involved.
hpoci~emembenofthe~eciteamwahthraghhepmber
wnh ~ cbd biology clailei. and Shen more detailed iollowvp
intewiewr are held with I sele~tion of students in grnupr of
four. to expbre 8" greaer depth mme of the ihei raised in
the clau exerme$. The pmjea his generated an em>my)ui
amOum ofinbmation. whxh mu* now be analysed. Ahhough
iome qumlmwe data have been amassed. the team ha Concentmod on drawing oui general ihemn imm nudemi
respoma. m oderto ademify concepts that they tend 10 find
lmubleromeandto exploretheirwayr olthinking-facton
that more Iimplistlic IYN~S might oveiioolc while fl II too eady
m drawirmtanlmnr. iomeprrlimiraiypanmha~ emmed.
The bel of undemanding of nudemi in th$ age range II, L
be% vanable: the National Curnrulvm oken makes
demands on nudenis that are not earily met. given the
wide range oilheir eiirting Ideas. A iurptiringly large
range olm%rcm

R E P E * R C "
Nevenheleu. the way h which roentific dimuenes amally
lead 10 marXetable pmducti - 'innovation' - or impmvemenli
m heakhcare II not well undeotood. The IradiiiOnal modcl of
innovation has been of P lin~ai pmcerç pure rereanh (reatcr
a ioune 01 new knowledge. appited reieanh exploiir thii new
afomiaton 10 tackle 1 rp~ific problem. and a devebpment
Sage grnerater the pmdvn iticif. Yet II many poliiy
rescanhen and anaiyrti have 'ontluded. thii type of model I$
to0 ~impiair ln ihe Uaii for Policy Rerearch in Science and
Mediane (PRISM) at the Wellcome Tm11, models are being
develaped 10 pmuide P bener deitnption of innovalion. For if
steps are 10 be faken 10 intenene m the exploifati~n of ICImie.
it II ellenila1 that the pricer5 !< fully undemood. IO the
ektr Of such llew-enltoni can acruraieir be predicted
PRISM'S APPROACH
A key challenge II the developmen1 oftaair 10 moniforthe flow
of knowledge withm the innovdim p mes The fis1 outpyt
from funding basic Wence II new howledge. al evidenced by
the publiraiion d mearch papes. Secondary efieitr can
include new patents. and m Ihc mediial dmm these may be
followed by new diagnostic and iherapeutvc pmduttr leading
10 impmuemcnrr n healihcire. PRISM 81 developvig techniques
10 quwbfy thew effçctr r and rnnprehenine way
To measure the eflenr of fundtng nntegier an the publication
of pope". PRKM has developed the Reearth OUfplr Database
(ROD). ROD was established 10 enable funding bodies. and
a b mearrh m$ttilyliom thcmrelver. to msww a vanety Of
queaionr. includag.
*
.
What cemnbinion does our oqmzauon make to the
pmduflian of knowledge in panicularrerearch fields m the
UK and woddrnde?
Which types of funding have been panrulady ruirerrfui in
terms of knowledge pmduflon?
'Nha1 II the geographical dirtnblsn of outputs fmm
rneanh rondvned by ourgmntholdm and what impan
don !his have on idunna1 aiiiuity?
ROD includes full bibliographi( details of a11 allitleS. noter and
WNS by UK biamedral siienii~ts. together with delads of
the Io~nel of funding knowl led god in each paper. If coven
aboyt 25 WO papes per year fmm 1988 onwardr Smpie
lemhes

organaalioni that pmcnr. tranrfom or modify research res~lll
before pariing them on 10 Other usen.
Fmm thil model emerges the concept of 'pmximal uren'
(dore te the sotne of knowledge pmduclion) and 'diilal
uim' (those funher away). Since new knowledge may flow in
a vansy of ways between proxmal and diml uren. this model
ofihe innovation pmcelr more cloiely resemble5 a web or
nelwotklhma lhearrhiin.
The dlagram on page 63 ii a simplified innovation web for
phamCeUiiLdl dmgr meaith hi thtl example the pool of
knowledge emegingfmm h w rereanh lr used not only by
the pharmareutral industry but a110 by regulator/ bodies and
leNiie indvlüiel(e8. tmumce companier). Phamceeutral
cornpanier both use this pool of knowledge and. through their
own subrraniial R8D pmgrammer. add to 11.
This example, wifh nr numemus