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2008 EuropEan MolEcular Biology organization EMBo reports Vol 9 | no 12 | 2008 11

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The evolution of biologyA shift towards the engineering of prediction-generating tools and away from traditional research practice

Lawrence Kelley & Michael Scott

o

e f he ms ees eeeds he bsees hs beehe deveme f eseh meh-

ds h d dhee fm sddsf sef e. the d m fsef esehms b hs-shs bee mehesvedesd f heme d eee hheses h vde sme, w-ke d bd exs. cemeseh bfms s mked dffe-e: bfms e es e-e s mke e eds f esed e f heme, esevef he sm bde see. the ew devemes wh heb sees e s hd sqewh d a priori heesd-vsm, fsfsm feee hebes exh seve e hesdds f e sef mehd.

ths shf wds he eee fed-ee sd wfm d eseh e d hee f ve essbe ex-sshws h we eed ehk whembdes esebe sef e.the des f sm, w-keess d b desd wh s h mkese wk, e wde evedbh

wh d sde see mee s desbe d f sef ves-, b me s s he hess fsee h dssh fm feds shs he ee. i f, he med ex mse f f desd heme s sddme f ms eseh jes, bs mj se f eseh hs fd.

cseqe, hee s wdesedd exe h he b- sees d d shd vde

hee sh he wks fb heme, dese wbd f evdee he . ths -

de s b ssed, es ,b he sessf ed f he s-e f Dna b Fs ck (19162004)d Jmes Ws. the dsve, whhme e se he devemef mde b, hs ve de e-dee ms b fded beefh fhe eseh he b s-ees w ve sm fdmed sme shs.

B b ess d mehd-es, s he hve esed edve we, k ee kehe hee hes f hss. them es f hs devemes we hees he ems mex- f b sms, whh def em ex desd hems sme hheses mhemes. thee s w weess h hsmex eses sdebe h-ee he eds h b- (Mh, 2008; g, 2007).Hee, we fs he eve me dmms f sef mehd dffe d eve w f hkb d see, whh s fmed b

ev sdes.

the dvs he f he sefmehd hds h see shd -eed b see hse hees h

e bes fmed b s bsevs. asdd bem wh hs mehd, whhws sed b he as hsheK pe (19021994), s h ms se-f hees mke ees, bsed fe mbe f bsevs, whh hve fe mbe f ssbe ss(pe, 1963). n me hw fe we

he he es, we w eve be be vef s h f sf f ssbe ss. cseqe,

sef hees hve he ss f je-es: we mh be be ve hem fse,b we hve es hk h he ee, eve bb e.

the ise hss Dvd Deshdeded he dvs h bese fs ee he esse bem-sv e f sef q (Desh,1998). ised, he ed, see essesb d exemes, ee -jees, d e hem f he be fse. Hweve, dese s sessfhe f sme ses f se-f e es hssDeshsfsfsm shd hve e e fhe b sees. oe bem s h

s be wh bbs hh-eses. a hhess h ses Xs e ys be fsfed wh js e bsev h X s y. B, f he hhess ses h90% f Xs e ys, hw m bsevsd we eedd hw e shd he sm-e se bebefe we sfe deh he jee s fse? if he bes hh-ess esds ss eshdsveed bewee Xs d ys wh s-ess deem be sffe e sm-e, he Deshs efeedmehdwe e es fm d.

there is a widespread andcontinuing expectation that thebiological sciences could andshould provide theoretical insightinto the workings of biologicalphenomena, despite a growingbody of evidence to the contrary
http://www.emboreports.org/http://www.emboreports.org/http://www.emboreports.org/

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the m bem ehedvsm fsfsmd heeed a priori ss he b- sees s ehe eh- hsh. rhe, b ee hees he ee f he se-f mehd, hese ss e f d wh e sef e. ifhe sdds eqed b hese mehdswee ke ses, he mh eseh he b sees wd be deemedsef, d wh emed wdbe f ess effeve sv bems.We demse hs b desbhe deveme f eseh sees vs feds f b eseh.

csde, f exme, he feds fems d ems: he s

es hve see ems ese he m f exeme d vbe,whh s de whe-eme seqe,hh-hh s ems, m- eh d ee e- sss. Me h seve me seqees e w kw d meh 50,000 e ses hve beeexeme deemed. ths emsweh f d eqes he exesve se fme s f se, eev d,ms eev, ss d ed.

the hee-dmes se f e s deem f s b- f. ufe, he eexeme ehqes deeme hese f e e exesve, me-sm d smemes d de

ess . ths s e he se f membe-s esd exs wh he mbe f exe-me deemed e ses sw des f mde we h hembe f qe e seqees. tveme hs beek, bss dme exes hve bee deve- mehds ed he se f e fm s seqee.

ths s es dek. a e d hee d bewee1 10100 d 1 10500 fms. the

fd f e s f d vese s mex, e ddm e bewee he dvdm ds s eh d he s-d sve ess h vveshsds f ms e wh h-sds f we mees m hesin vivo. Eve f seqee e- wh eve he hh m-ex mb f ees fes,se effes d hde bd. thebs es h dve e fde esb we desd he evef hss d hems, b he se dmex f es mkes vesm mssbe; deed, me h20 es f ese eseh effs d eveme shsed me smshve fd shfwd e

bewee he m-d seqee f e d s e se.

S f, he esb sessfmehds f ed he se f e mke se f em d ss- mdes, mhe e, evd-m d he ss sm ffm se. these mehds ebem s me shsedd me sessf e e-d se, d hees dexemess ke e se heeds. Hweve, he m bje-ve f hese mehds s ehe desd f he fd mehsms, ex sme w-ke hh-ess b he esh bewee hese f e d s m-dseqee, b sed eee he mseffeve ed f h esh. theeds hemseves e, f se, e exeme vef. B es heeds des vef fsf he b hw e fd wks; meses he sess f he je f he sfwe h hseded he eds.

Mk eds bsed he vbe d wh bde hee desd-

s dffee ee hhesesb de mehsms, d sheefe sf se w fm hed sef mehd. oed esd h hs e shf sde eh bems sh s hes d eh f me eqed exe-me deeme e ses.afe , wh shd b ssems

be fdme dffee s ss-ems, f exme, whh ss f hembe f dffee bjes f v sed se? the es d mes s ssem bde b es de-sd d sme es, s wh shdhe sme be e f e fd?

ahe se esd hs h- e f b eseh s d

me mdes ms f wh bhees ex. Sme emhshes f see, wh kwedehe mex f b ssems dhe k f ves, w-ke esh de he behv, hve ed hbss ex heme b smehsms. the behv f hese meh-sms s edbe d sbje w-kees, b wh we e fs (Shffe, 1993; Sk, 1998;Wms, 1976; Mhme et al, 2000).

of se, deve he - dsve mehsm s hve sef se he b sees.F exme, e eh hs sbdved d me fm eses s vbe fm whh dwee es, mh be ssbe s es hheses b e fd-hh s dff see wh hsehheses wd k ke. B, he ee s h hh s d h s jees f sme bemss e ws f e hsss sh sge ge (15641642), is new(16431727) d abe Ese (1879

1955) s s he bes sef sv b bems. Meve,hee s me me sesh hs se s smeh h se-ss shd eve se whe mes k e bems.

lv sms hve evved ve eds f me esse h- evmes h mh hve bee

ee hem , f , mh e exs. ths seme desw se s. Fs, hee s k f

The planets and comets in oursolar system all abide by easilyunderstood and simple principles,so why should the same not betrue for protein folding?

The best possible biologicalaccount of an evolvedmechanism will probably beimmensely messy and offer nocognitively appealing insight intoits workings

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Photograph by Marietta Schupp | EMBL_Photolab

mve fm b whehe dhw es sms h e ddffee he e hbs f heEh d svve d fee Eh-ke evmes. Meve, we e be es whehe e sms wdhve evved he sme w f e de- ev de he sme ds(Seve, 2007). Sed, he svv f evv mehsm eqes sme eve ffde s ed, d bsesss evme hes d es e.

ye, hee s a priori es whhese fees shd ehe eqe beehed b e sme meh-sms. ths s e whewe sd ev he me eve,whee dm sed-dm v

ed wh -dm see hsdve he deveme f mex -sms. rdm vs svve seebese he e he e,dves sffe deees.Wh evdee h see fvssm, sm h hs evvedhh he m f dmhes w bb be mex. Weheefe k mh f he fm hwd he s wk wh smfs s des d wh evved hew dd.

ths mh seem be d es-sms k f he b s-ees ve h we fd mex hsses h eheess exhb w-kebehv. F exme, he es fmedb s f sd beh e hhmex, b he es f es eeve sme. i b, , hee se sme hh-eve ee: hehe f ev. Hweve, hs m-s bewee he ss f mex ss-ems hss d b qk beksdw whe we sde h, hs-s, ms ses exhb sm-

he eve whh we w desd he e.n sm es e v-be ex he behvf m b ssemsd ses.

tke ehe, hese bse-vs de h bssshd exe evvedb heme bemebe hee e-e bve he w-eve es f hems

d hss. the bes ssbe b f evved mehsm w b-b be mmese mess d ffe -ve e sh s wks.ths s s bed b e fee fds shw h, f fm v-e sme mehsms he fdsf b, we fd ssh deeef mex.

csde, f exme, he smehhess f e ee, e -e, e f. ths sms-

vew ws qk veed b hedsvees f eve s, rnaefeee, ssbe eemes dve ed fmes. We e sdsve h es exs esembe f vs fm ses

(gh et al, 2004) d h s sfeqe wh e dms (Beeet al, 2008). ams de eseqees d mee dffeefds d fs (aexde et al, 2007),whees ex-deede hmeeseqees de d hes d f deed hees wh he es (adeev& M, 2006). thee s s wdesedeme f hee ssems defd (H & He-H, 2002), mese f he mex d e-dbe e evme. We e sfd emes h exhb dbd ms, d mhes wh m fs deed he sbe ex (Mhet al, 2004).

Hweve, he bem s sdeb me mex: -sm s hh dm ewk f h-sds f ees wh exesve feedbkd e mehsms. the eeshemsevesd ees, es,

ees d membese dmesembes f sef e-shs. the mex f b s- ewks, f exme, s deemedb fs sh s he mbe f m-es d he f he efesbewee hem, he mbe d f d bhes, he deee fes d he es f d se. idd, hee e he sses f dmssemb, s, ded dhe he f hem es. af hese ves smesd eh me es sevedffee ves (We et al, 1999).

ah he sbje fm e-ee vew, csee & De (2002)e h hs ems mex s hees f ev de-ff bewee

bsess, feedbk d f. ised,we m h mh f hs mexess fm he dmess f he ev- ess b whh beefdes e eed, edess f hee fe shms; ev see he fe. if me sf-we wee desed hs w, he es- ms wd be mex d mess,be effeve, s hs bee fd hefed f ev m.

i s heefe ss h we es be desd f he me- bss f ms mmdseses, dese he e-ms effs f b-med esehes d s (Hb,2001). i mses s eve s-sbe

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see he he effe f ee kk(pes, 2002) sm bese he ees e hws mesef mss ees bese he heees de e evmeds. We shd s be ssed he s fe f he hmeeseh eff (Hb, 2001), f hew dbs b he ve f he ed-s hes h fs he sefees he me mes f b ssem d vek s memex d ssem es (vreeme, 2004; Keebee, 2004).

i smm, we see vewhem m-ex, d mxe f se dse ms fdme esses

me bs, s-

d fdhh he evef dm s d meb e-wks, d bed h he hee.these mehsms exs sm besehe wk, bese he hve wked he s; smemes, s wh sss,he mh e hve f-. the es s h bss hve f mh sed fm be be mke fmve jees evehhe h he sdd hems hs-s h de sef eswh se f be vefbe e.Meve, we s hve e f-m b he ex whh hesemehsms evved kw wh djee mh k ke, d we hve ds beeve h he wks fevved mehsms shd be edb e e es.

of se, vew f hs bemd he wh dm ew ds-vee fe, f exmeb e fm d kwede bev esses ve s es hk h evved mehsms shd beexbe hhe eve h he wsf hss d hems. ad e, wh-sd he k f sme exs dhees, edve mdes hve ved be emkb effeve.

csde, f exme, he se fedve ss d mhee ehqes. gee-fd,

mde ee ewks, ed fhe sed d e se f -es, e f se ses, ee es, e e m exemes, e dss,m ssf, mf dsve, ddes d hees e exmes whh esehes hve deveed m- ehqes h mke edswh ffe exs f hw hemehsms de ves f(l et al, 2006). a f hese hvemde se f m ehqes se hewse smbe q f d,d e ewks, s vemhes, Bes es, ss es,

ee hms, dm fess, sm-ed e, Me c sm dhdde Mkv mdes.

le s sde e exme f hwhese edve mehds wk: he se fsevsed e fd Dna seqeesh e vved he f eeexess. Fed wh vs m fexeme d he bsee f e-e he, s sef seh f ses h mh de sme dese. F exme, we hve exeme- fm h e seqees evved he f ee s,b we e fe be see e -es wh sh seqees h wd df-feee hem fm he, -fseqees. We hve, hweve, d es ssme h hee ms be sme es he e mhe s be eee seqees.

Bfms mm se fmf sevsed mhe e shses. ths vves e sef sve d eve exmeskws f bd ses d -bd ses, f exmed s

hem b s wde e f hms eee xme fs h -e ssf he exmes wh ee esse . these e fs he be ed ew exeme df m ssf d ed.aeve, sevsed e meh-dssh s gbbs sms wh d ses h e beeved, he bssf deede evdee, h-es b kw ede e,whh mh eese bd se (tmet al, 2005).

F m es, he mhe emm hs bee deve es-sve me wef hms. ukee ems, ms mde e -ms e med sme e f-s b s e e fs e-dmes ses wh hh deeef d m effe.Hweve, he vs mj f sh -hms de bk bx h fe -sss f hdeds hsds f mees bs se, he h e, - s se; s ee mssbe evese-eee hese ss mef e e.

i

he fed f e se ed-, he sdd e s se dm d-m ehqe sh

s pSi-BlaSt (ash et al, 1997) ex eev d fm he seqeedbses, e ewk shs pSiprED (Mgff et al, 2000) s-ess h d, d he se ef ss deved ses f meesehe wh sed-dm smedes eee e hee-dmes mdes f e. nef hese ses eed be hs ee-v he e de sd, d heess vde ex f he s-es. neveheess, hese edes ed exeme effe eds h ef e se he b mm.

i f, he deveme f deves sss he ed f he behvf b smshe h desd hems sdd m-e f b eseh. a sf

f bshed eseh hsesed fm hese es f eees ed bems. We shd f seves exe meve e ess: deeedesd f he wks f b- sms mh be desbe, b heev hs ves s es ssme h we w sh deeeh he eve f bs hem hses. these ss e ssmed he eved eseh ef bss.

It is therefore not the methodthat should control ourconception of what counts asgood science, but rather themeasure of success

Scientific research itself canbe thought of as a type ofevolved organism

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o he fe f , hs mh ese m hee -e f wh s d see.

the s f he sef mehd hwe desbed ee hs e weemved b he beef h see hs dsve mehd d h we e js-fed beev h sef veseds kwede. B f, s we hve ed,hs e f b see s esse- he bsess f v s heesd exs, he wh ds d wehve f fdee s ess? Meve,wh mehd, wh shd he- s be ebe fmf sef ves?

t swe he sed qes fs: e f he dsve ws f k- bems b sees, d

he ws whh he dveefm he d e f seefded hss, e mses bd-e f e f wh s sd see. B des fw hh es. Wh he b s-ees hve esse mm whhe feds f see s he fs e-d d m he hemede ves. i s heefe hemehd h shd ef wh s s d see, b hehe mese f sess. Fd he hexs hw smeh wks s ew f mee hs sdd. Eee m ed hw smeh behvess he wes mm bf hev he sme es.

the de h see ms exhbsdds f sess s , f se, ew e (See, 2006). B se-

ss hve ssmed h sessfeds ms emee fm heedesd f he heme deves. Hweve, w bd feseh b eees mehsms

h eee eds wh sh hee ex, d hs s sfdee bh e f hwsee shd be de d he w h s de he es f see.

ye, he k f fed eseh mehdshd ed s db h see -vdes ebe kwede. Sef esehsef be hh f s e f evvedsm: s sbje vs seeessessh s he eed de s-essf ess d bshbe wkds s bed d mdfedb he f esehes. c, dehese mses, e desebe ess, d s hs eb hdes jdeme h hh s-ee we kw he wd. Whe heevme ems meve d s-ee ese, we hve fdee he ess h eds.

rEFErEncESaexde pa, He y, che y, ob J, B pn

(2007) the des d he f

w es wh 88% seqee de bdffee se d f. Proc Natl AcadSci USA104: 1196311968

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Acids Res25: 33893402adeev a, M ag (2006) Ev f

e fd he esee f fss. Curr Opin Struct Biol16: 399408

Bee F, csb F, zmme r (2008) aeves d e se ev. Nucleic

Acids Res36: 550558csee ME, De Jc (2002) revese eee f

b mex. Science295:16641669

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g F (2007) t mex mehed?EMBO Rep8: 705

gh cS, Mb D, gese M (2004)cfm hes ssed whee es.Curr Opin StructBiol14: 104109

H Fu, He-H M (2002) Mehees he s: fm se h fded e. Science295: 18521858

Hb DF (2001) resm d dsved cssd be h? Nat Biotechnol19:10991100

Keebee E (2004) the ev f meb. EMBO Rep5: 564569

l p et al(2006) Mhe e bfms. Brief Bioinform 7: 86112

Mh a, nbe i, th JM (2004)ld seev d me beweeemes in silico. Nat Biotechnol22:10391045

Mhme p, Dde l, cve cF (2000) thkb mehsms. Philos Sci67: 125

Mh F (2008) cmex b.EMBO Rep9: 1014

Mgff lJ, Bs K, Jes Dt (2000) thepSiprED e se ed seve.Bioinformatics16: 404405

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Sk S (1998) Genetics and Reductionism.cmbde, uK: cmbde uves pess

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Lawrence Kelley (left) is at theStructuralBioinformatics Group, Division of MolecularBiosciences at Imperial College London, UK.E-mail: [email protected] Scott is at the Centre for Philosophy,

School of Social Sciences, University ofManchester, UK.E-mail: [email protected]

doi:10.1038/embor.2008.212

Published online 14November 2008
http://www.emboreports.org/http://www.emboreports.org/mailto:[email protected]:[email protected]://www.nature.com/doifinder/10.1038/embor.2008.212http://www.nature.com/doifinder/10.1038/embor.2008.212mailto:[email protected]:[email protected]://www.emboreports.org/

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