the Origins of Molecular

I n 19.3 the Iiorrnn rlrmistirc a n s pro:~rh11:1cl l u m f n ~ i to s r r :I wide are:\, hut 1111- mow
aigncrl, \1011nt, ICvrrrst 1v:w rlimlwd, Q I I ~ ~Klimhrtlr II :~nil)itio~~s :~imof r r d n r i n ~t h r ~ procrssrs
r to moIrr111:w
I : r n v n l : I \V:~tson nnrl Crirk cliscovmd the vil,r:~tio~~.; not only provrd niislmding l ~ n 1v:1. t s I H I ~ I to
I~
s t n ~ r t n r cof DS.\. f : i .\t t h r ..:~nir timr. I ~ o w v r r ,mon likr 1:ritsrhr
1 %thr ~ l!lfiO's 1)S.k h:~dhrromr t h r golrlrn molrrnle wrrr s t ~ ~ d y i nrrll
g i n ~ l ~ ~ s i nhyn sthe :lid of ~ m I : ~ r i m I
of tlir l~iorl~t-mists; ~ n i r t i c i s t s: ~ n drl~rnrists,1vl10 for light. 'I'lwsr .duclirs did lrntl to tlw disrovrry of tlw
y m w Imd f:~ilrtltn rst:~I~lish :r common g r o w d of onclrr- clct:rih of ultr:~.itn~rtorr.in s1:lrrlr pnrinr, re11 \v:11Is, nnd
stnnding, fo~lndit in I)S.\. 1 ' 1 1 ~ yv:~r l!).j:$ srrms, n r ~ ~ s rlilwrs.
lc
thrn. in mark :I t n n ~ i n gpoint !vl~rn mnlrrnl:~rl~iology The Ultraslructvrish
c:mr of : ~ g r:IIICI tlw r s l m ~ ~ r n t igrnwt11 :~l of the sul~jrrt.
hrg:~n. ' h i s hrrnic pirtnrr, t~owrvrr r n n v i n r i ~ ~ g , I n 18.58 t h r Swiss hnt:~nist,C:rrl Siigrli. 1vI1ois k t t r r
1r:ivrr 11% in tlw d:~rk:IS In t h r n:~turrof thc conrrpt11:11 known :IS 3Irndrl's evil st:w for f:tiIing to :~pprrci:~tr
rrform whir11 lies lwl~indit. \Y:IS it ~ I I Pdiseovrry of tlw worthy monk's thrnry of hrrrdity, :wsrrtrd t l ~rrys- r
Imv-p:iirinp in DX;\ whir11 :~ltrrrdtlw cnnrw of l~in- t:lllinr nxtrirr of the l~oildii~p I~lorksor "molrrulr%,"
cl~rmi.stry,or wnirtl~ingrlsr? :IS hr c:~llrd thrm, of l v l ~ i r l11r
~ irr-lirvrd st:~rrhto lw
l'lw virw to Iw rspor~nclvcll ~ r wis thnt t h r trnnaition romlmsrcl (we 12ip. 1). At tl1:11 tinw tlir eoncrpt of the
frnni t h r sm:tll-molrrnlr rl~cmistryof t.lw ninrtrrnth
c n ~ t w yto t h r l:~rgr-molrr111rrl~rmislryof t h r I!UO's
onw:~rcls,rrsolvinp :IS it did t Iw p:~r:~dox of rolloid:~lIIC-
h:wior, rrprrwnts tlw i r : ~ l rrform. 'I'his hriug .;n, t h r
most mr:minpfnl drlinitinn nf # n n l r c ~ ~ lhiolngy :~r is onr
whir11 d:\trs t l ~ sul~jrrt
r h:wk to ill(. limv Illis ronrrptn:~l
r f r n I : I I If wr r:111 it thc d w c r i p t i n ~of~ form : ~ n d
fnnrtion : ~ tthe m o l r c ~ ~ I :Irwl. ~ r ~ I I I Y I t h r snl>jrrt 11:~s
h c w ~in r s i s t r t ~ r rfor ovrr 11hnrrclrrd yrars. I f \vr clv-
ni:ind t11:1t snrh rtudirs must Ii:wc~providrd kno\vlrdpc
of tlw tl~rrr-clinirr~sio~~:~l s l ~ : ~ pofr nrnlrrnlrs, then it is
d e w th:~t littlr n i n r t w n t l ~r w t u n work WIS prrrisr
rno11g11to qw~lify. I h t to t11r rstrnt tlmt trrhniqnrs
more powrrfnl thnn tl1:11 of t l ~ tn~dition:~l r lipl~tmicro- Figure I. Nb'gell'r pidvre of smmh micells in 18S8. showing wekm be-
sropr 1vrrr in n ~ t l, ~ r s rrnrly s t ~ ~ d i rrrprrsrnt < tlw h a e n lhe micclls, young s p h e r i d micellr, ond older anlorged m i 4 h
which ore polyhedrd in mngcntid ssrtion MI ond elongated in lhs rodiol
g s t h r snhjrrt whirl^ only rnmr into its own
h r g i n n i ~ ~ of section (81. A Iresh l a y e r of micalh has formed ncor h e b o n a ol %or-
with t h r clisrovrry of dilTr:~ctionof S - r : ~ y sI)?. cnst:du
rind t l ~ rinvrntion of t l ~ rlrrt r rnn mirrnsropr.
This hrnncl d r l i n i t i o ~of~ t h r snhjrrf r o n t n ~ s t swith
molecule \V:IS c o n f ~ ~ s nnnd l , it 1vnn not until the Knrls-
the mt~clin:rrrn\vrr nsr of t h r trrm hy t h r mirrnhinl : u ~ d rulw ('onferrncc of 18fi0 t11:rt i\vognclrnk 1,:tw won
virnl pI1ysinlogi4s. of w11nn1 Srymonr ( ' ~ I I ~ III:IS I s:~idin
srrious considrr:~t.ion :ind t h r molrrulr Iwc:imr :III
his .1rs1111I.rrtr~rrsth:lt they 11:wr nsrcl tlir lnhrl "to :~prrrcl entity v i t h t h r mr:~ning now :~ftnrhrclto it.
:~flirmt l ~ r i ri(1r11tity" n ~ t l ~th:~n r r to drlinr t11r sphrrr
S i i ~ r ltlam
i hnd to chnnpr his tcmn molrrnlr to micrllr
of thrir :rrtivitic*s. C;r:~ntcrl t11:lt thr trrm II:W romr (:I littlc m ~ m h to ) show thnt hr I I : I ~ in nrinrl :a1 nssori:~-
illto usr for soriolngic:~l:IS wrll :IS for srirntifie rc:~snns. tion of molrcr~lrs-111) to :IS many ns NKh3 of t l w n in
for 111r pilrpnrrs of this stndy wr will ~ : I S S ovrr tl~r rnrh mierllr, p i ~ r k n lin cryst:dIinr :irniy.
n:~rrn!v drlinitirnr :tnd t r w r instr:ul t h r oripins of t h r X?iprli i ~ ~ t r n d n r two
r d import:~nt c o ~ ~ c r p t x :(1) the
s ~ h j r c :IS
t morr 11m:idly r o ~ ~ c r i v w l . cryst:illinr s t : ~ tof
( ~the suh-units of sn-c:~llrd n m o r p h o ~ ~ s
sr~hst:rnrra,: I I ~(2) tlw ~rtstr~l:~tion of two lrvrls of
Early Biophysics
: c k i I m o l c r ~ ~ l:: ~ Ir I n ~ i r r l l ~ r :\t.
. thc snmr
As rnrly ns the 1840's :I hnnd of hiophysirists rsistrcl timr IIC hrlcl t h r st:~rrlin~olrrulrto l ~ smnll r (formul:~
in the prrwns of C':irl Imlwip, 11rrm:11111Vnn Helm- ('lrllln()m). IIis :wrrtion of cryst:~lli~~ity !v:w rollr:Igr-
holtz, i h s t Rriirkr, nnd Ilmil ~ I IHois I ( r y n ~ o ~ ~ d o, w s i ~ ~hr c rh:d not rmployrcl t hr ~x~l:~rizing micrn'irq~r
wl~oscprogrnm it 1v:w to rrdurr :dl hiolopirnl prncrssra in warch of anisntrnpy :lnd wna un:wnrr nf Ilncn von
I X v t n i : n m r l ~ n ~ i r s Thry
. wrrr m r c r s s f ~ ~in
l 3lold's cvidrnrr of positive l~irrfringrnrr of stnrrh
shoving I t somr pl~y?;iolopic:~l prorcssrs olwy t h r gnrins, whirh :~ppr:~rrcl :lt the sxmr timr :IS his own
I:trvs of pl~ysirs.RIKI 11). the P I I of
~ t11r r r n t u n this n p 11:11)rron st:~rrhg n h * of 18%. In 18>!l SAprli fol-

168 / lwrml of Chemical Education

lo\vrcl VOII llohl's rx~ml~lc., :IIIII from thrn nn hirrfrin- t w y nf lifv Inv-:irnr :I p n ~ l h r nin the. colInicl:~lproprrtic-s
grnrr st.c~di~.s 11:1vr s r n w l widrly to givc i~~fnrm:It ion of pmtnpl:~smill111 its ~Ivriv:~tivrs.
:iIm~tt h r p:~ckingof m o l r c ~ ~ lin r s 1)ioIogird stnwturrs . \ t l r n ~ p t s to 11ri11gII:IIII~:II high polynirrs into t h r
I : I I I ~I o r i ~ ~ t : t i oofn i r I - I I ~ . Sligc4i's fnhl nf tllr org:~nirchrn~istII:III il~clrnl11rc.n ni:~clrIn11
s l ~ ~ ~ l r:\ni11rn1111,
nt, o l ~ t : ~ i rvi~lrncr
~ ~ r ~ l of 1111- rrys1:d- with11111s u c w s . I k c t u w frw ~mlynirrsdissolv~~ fr\v
linity of c r l l ~ ~ l o in s r I!llti, f m r yr:~rsIrforr Srhcwrr's ro111d hr cryst:~lIizr~l.:IIIII for t1111sr like I~rninglol~in
X-ray pirturr.; of mmir filrrs. ,\s r:~rly as I%%:% wl~irh~Iiwolvr~l :ind ~ryst:~llizwl tlwrr w:w no rrrI:iil~ty
;\rtln~rllc-yrr ~ ~ n t r~cPl : I I I I I ~ : I ~ ~ in I I I rhlorn111:1sts
I~ 1111(1rr 111:it 1111.y fnrmrd l ~ o n ~ o g r n r orryrt:~ls. ~~s So IIIIIK :L*
t I l r light mirmsrolw. l'hrsc~" ~ ~ I I I :wrrr I " r~di.;rovrrrd synthrsis of t h r sul,st:rt~rr I I ~:I known I~iorlirn~ir;~l
I I ~I k ~ ~ ~ t r r l i ginn c I~ :~ncl I!vn ycws I:llcr l;rry I : ~ I : rrni:iinrd
I i n ~ n s i l ~ l s~~spirions
r, :IS to 1111.
\\'yssling rrl~t:tinwl r v i l r ~ ~o rr I h y r r n l slnlrturr purity of the, rrystxls c m ~ t i n ~ ~tor din, voirrd I)?. t l i r
from hi.; hirrfri~~grnrr l y rhlornpl:~st.;. 111 I!KW
s t ~ ~ c of Ihrl~cwii*ts. TIIII*l,:mil I:iwlw~, who II:III s y ~ ~ t h ~ ~ s i z r d
II? ~ m s t ~ ~ l :I hr ~ I prrwnrr
r~l of :~Itrrn:~tr 1:iyrrs of p r n t r i ~ ~ :I sug:Ir ~Irriv:~tivv with n ~ o I r r ~ ~\vrigI~t
l : ~ r .lWl in l!Il:<,
:u~cllipid: t l ~ w wrrr r irlcwtilircl ill niorr (lrt:iil frcrni s111d- rrg:~rclrd this QIIIII,11.4 higl~rr~II:III t11:1t of nny ~ I I O W I I
i s w i g I r l r r t r ~n ~i i r r o ~ Ir 1 : l ' l ~ r: ~ t t : ~ r k 1m~tvi11,.\s for r r y s t : ~ l l i n ~hrnioglol~in,
~ vhirh el11
on 1111% s t n w t l ~ r rof I)S.\ \v:w likr\visr ~ ~ r r f : ~ I>y rrd i f f r n i ~ i r i r l f n : (~'~1211~~mS?~~S?II'~O?~s
I~irrfringcmrrs t ~ d i r swl~irhrrvr:~lrd t h r r ~ i s t r n r rnf II:II~t h r n ~ i l ~ i n nm ~ n l~r r ~ ~ l :w~ ~r i g l ~IIi,TOn.
t I:i*chrr
strnngly ~ml:~rizing groups whow p1:mrs w r r at right, clrrl:trrcl
:rnglw to t h r filwr :Isis : I I I I ~ i~:~rklmrw c h i n of t h r n~olr-
CIIIV. S-r:ty :~n:ilyrisI I .\stht~ry ~ :~ncl13141in 1WR rnn-
firnird this lincling. This is the ~msitivrsidr to S!igrli's
work. The 11rp:ltivr sirlr to his work rrntrrs on his
clisniiss:~lof thv rnnrrpt of 1:rrgr niolrc~~lrs : u d his in-
trnrl~~rtion in thrir 11l:trrof m i r r h r :iggrrg:~trs,:I con-
stnwt which provrcl i~~vnlu:~lrlr to t h r coll~~id rhrnlists,
l ~ whicl~t (lrl:rytvl t h r nerrpt:\nrr of t h ~m:~rmmolrrulr ,
cnncrpt .

Colloid Chemistry
W r h:wr notrcl th:~t t h r prngrnm of the hiophy~ieists
of 1x47 n r r r r rmlly got off i h r ~ M I I I I I I . It rnjoyrd
many sucrrssrs in t h r lirlds of IIII~I:III : ~ n dplant phys-
iology I I I I ~ :is :I t h n m ~ ~ g h - g n i] ~ ~n g~ g r : ~it n I1n11111lrrrcl
i
on t h r q ~ ~ i r k s : ~ofn :III d ~ in:111rq11:1trpl~ysirdr l ~ r n ~ i s t r y
: ~ n d:I n~isgt~iclrcl clc:votio~~ to ninlrrul:~rmntims. 'll~is
f:~ilurr11o11ri41rd1111. roots of :I l1ni1111of v i t : ~ l i mwhir11
wr mny e : ~ l l "rhrniir:~l vit:~lism" :~rrordinpto \vl~irh
I I : I ~ I I ~ : pro~llwts
I~ :ire to Ilr clistinpr~isl~r~l frcm t h r syn-
thrtir prndt~rtsof the I:~lmr:~t~~ry. \l:~ylw\Vihlrr h:d
s y ~ ~ t l i r s i Iz ~I ~~ ~: IlI I ~F:niil 1:isrhrr I I : pm1111rrd ~ wmr
s i r n l y ~ r ~ t i I~ l ~~sl y s : ~ r r I ~ : ~I r ti ~inl , sizr
: ~ n dI ~ r l ~ : ~ v ti nl ~r r s rwrrr :I f:ir rry from prntrins :md
n w l r i r nrids. T h r proprrtirs of thcw s111~t:1nrrsrr-
srn~l>lrcl tnnrr t l ~ o s rof t11r"rolloirl:~l" s o l ~ ~ t i ~411cliccl ~n.;
I,? (;r:rh:m~ th:tn the "rryst:~lloi~l:~l" sol111io11.iof tIic.ir
auhnnits.
;Is r:~rly:IS 1877 : \ I I ~ I S Iirk1116 ~ h:d vis11:11izrdh r g r
molrrr~lrs:IS net or slv~~lgr-likc. n i n s r r fornirrl I I tlw ~
I I I I ~ ~ IofI ni:Iny 11nivx1r11tninIrrul~*swit11 p l y v : ~ l r ~ ~ t .
:~torns: ~ e t h g:IS r r ~ ~ t rof r s : ~ t t : ~ r h n i rt1111s
~ ~ t ,giving riw
to t l ~ o s r"niolrrul:~r n1:wsrs w l ~ i r lrrsist ~ ~ ~ ~ T I I C: ~~nOd I I ,
w l ~ i r l ~: ~, r r n r c l i ~t~o g(;r:~h:~m'sprnpositinn, :Ire r:~Ilrd
colloi(l:~l." 15111Iirk1114<lidI I ( I ~:~rrivr:it t h r r o ~ ~ r r of pt
lcmg rh:~inniolrr~~lc.~. Ili.; thmry nf molcwl:~rni:issrs
did not g:Iin f:~vnr,instn~tlit \ w s the mirrll:w tl~rnrynf
S;igdi wl~irhW:IS :q~plird 111 t h r org:wir ~ I I I I I ~ I I Sof
grl:~tilw,rgg : ~ l l , u n ~ st:trrh i ~ ~ , : ~ n drcll~~losr.('l~rmists
f : ~ n ~ i l iwif : ~ r11 t111,ring s t n ~ r t ~ ~nfr IIIWWIII~
~*s clrriv:~tivrs,
sug:irs, :md :~ll~:~loids rs ~ I I V W
r o ~ ~ r r i v trh~rl n i n l r r ~ ~ l in
rollnicl:~l: ~ g g r r o ~ t:IS r s ryrlir ln~lymrrsof :I fcw rrsi(lrws
with :I molrrul:~r wright : I R I I I I I I ~ 1 0 . I%?. ronlnlrm
r t ~ ~ l a r Ill(.
n t 1,:1111to 1111. xtr~clyof n ~ r t : ~ l u ~prorrssrs
lic :III~~
1 0 tlrc- s t n ~ r t u r rof I I : I ~ I I ~ : Ip~ m ~ l ~ ~ Ir: tL c~ ~ I I I Y I I I t~h~ rI
p : ~ s t ~ ~of s r11I111icl
r r tht- rl~rmist. I l r ~ ~ r r f o r ttlh~r , nlys-
Volume 47, Number 3, Morch 1970 / 169
Thus Iiurt Hers quotcd molrculnr \wights for cellulose
k t w e r n 6000 nntl 10:1,000 from the liternturr of thc
fir.st t\vo drc:idrs of the p r r ~ e n tcrntury. T h e troul)Ie
wis thr~t.the I:~rgert.lw nrolccule the smnllrr is its os-
motic prcssurc nud drprrssinn of frrering p i n t . 1:or
m:~cmmolretrles the rxprrimrntnl rrrnrr excreclcd the
eflrct to he nie:wured.
J u s t how seriously hiochcmists took the hugr em-
piric:il fornntl:i of hcmoglohiu in the ninetrrnth crntury
it is difficult.to rwrss. \Vh:it is clc:~ris th:it :is s o w :I.* n uuelri I 1 I f n r n f l i . T l ~ c wh:d IWPII :i fruit-
t h r polyprptide t.l~mryof pmtciu s t n ~ c t u r rw:~s sd-
vancrd in I!KE hy 1:isrhrr : u ~ dIlofmristrr the p m l h n
posrcl hy these I:irgr m o l r n ~ l r sl n ~ n u n r:~cutc. \V:is it,
concriwhle thnt n molreulr with 711' r:irlmn ntoms in
one long chniu could rc.nuiin int:iet in :I cell :iud perform
sprcific functions? 15nril 1:isrhrr douhtetl it nnd Kurt.
Hew in his Htther I'rirr r s w y of I!VW wis cornl)lrtrly
convincrcl th:it i t could not. He s:nv :i w i y out of thc.
difliculty in the :~pprc'g:itchypnt hrsis nlrr:~clyrml~loyrd
in I!O.i hy H:irrirs tn :kccount for the colloidal prnper-
Cirs r ~ n dhigh rr:ictivity of ml>lwr. I'ollowiug .Joh:u~ncs
Thirlr he :~ttril)utrclthrsr pmprrtirs to t11c Iwesruce of
,' p:irti:\l vnlrncirc" t l ~ r s ehr suggrstrd held toprther
long cl~niusof isoprrnr molcculr.;. Kurt Iless drvrl-
oprd a similar idr:i of molccul:~r:ipgrrp:~trsfor cellulosr.
The Aggregate Theory
T h e principle of condrnsntion wherrhy s u r c r ~ ~ i v e l y of "p:~rti:~Iwlcury," whir11 II(> : d v x u r ~ di : ~lR!l!l to :LC-
Inrwr orgrmic molecules :in. formed WI?; first put for-
ward hy ('hrvrrul for f:~tsin 1816 where it led to the
postulntion of comlmuuds with molecul:~r wrights no
grcrlt(Lrthnn ROO, In11 with prnteins and csrlml~yclrntcs to prnlmw :nu :~ggn.p:~tc
:\ f i ~ rh r p r numlwr of I ~ u i l h g
hlorks are involvrcl in
thc form:ition of high molreul:~rcomlnnlnds in, to quote
Hesq, ":i downright s h ~ r k i n gm:rnnrr." T h e $:\me
principle n p p l i d to prntrins, he cleclnrcd, "would yield
chr~insof truly fnntnstic Irngths, thc cxistencr of which
cnn he n ~ s u m r dw r y impml):iI)lr nccording to our i d e m " Iinrrcr, Hnrrirs, nnd Rrrgm:u~n,nlthough \Vcmer h:~d
And in the e w e of ~mlys:~ccll;~rides he W:IS sure m~ch long
chnin structures "would couflict with the very c x c r p
tionrd physical prnpcrtirs of crllulose." When he cou-
sidercd the n ~ s with
e which crllulosr cnn he mcthyl:\td
nnd ncrtylntrd, ho\\, rrntlily glucose forms doul)lr s:~lts ist of t h s t perind nud to preserve the existing clnssi-
with metal s:~lts,he concluded th:it the chcmic:d :\finit?
of the plucosr residues in the crllulose molcculc is not.
snturntcvl. There is snmc rrsidunl nffinity left which
could :\ct hetween nrighlmring rcllulosc molrculrs to
form n pscudn-ginnt moleculr or : ~ g r e g : ~ t c .S o r did
he hnve to look far for :b precede~it for violnting the
rigid vnlcncy dogmn of liekulf. The f:imous chrmist
Alfrcd \Vrrner (18(iC,-l9l!)) hnd hrnkm n\vny fmm t h e
lic~kul6thrnry :is c:irly ns I891 nnil developed his own
throry of coordinntion to nccount for thc iwmerism of
complex snlts and for the prnprrtics of certain cyclic
orgnuic rnmlmunds. I n lU!IX h r put fonvnrd the con-
cel)t of primary nnd srconrlnry vnlency, the former
equnling in trnmeric:il valur the estel~liahecl iirkul6
v:ilencirs, the 1:itter h:iving a vnlue cnllecl the coordin:t-
tion n u m k r , nnd due to the rrsidunl nffinity iu the
ntom :rftcr the form:ition of primary Imnds.
T h e nnnlogy of complex snlts, :ilrencly hinted nt hy
Fischer whrn spenking of hcmoglohit~ cryst:tIs, was
chnmpionrcl hy \\'er~rrr's former s t o r l n ~zuid
t eollcngne,
1i11l I n in r i c h . He cnlnrged on thc views of
Iiurt Hers. I k s t m y the sernnd:wy forces in st:irch
und cellulosr, hr drrl:ired, : i d t h r t n w moleculrs of
crllulosr will he r r v ~ : ~ l e:wd \vcll-hch:~vecl l i f t lr rhnps,
soluhlr, of rnursr, iu a rwclily :~vr~il:~lilr snl\.eut.
The l a ~ pfrnm the coorclinntiou compnuncls of the
minernlogist.s to colloitl:~lst:irch :ind crllulosr srrms to
us nn u n w i r r d r c l oue, hut nnc must r r m e m l w lhnt~
crystnllopraphy Ix~cllong ~)rovidrdmodrls for the hiol-
ogist, t l ~ vmost not:il~lrrx:implc* Iring t h r Srhlriclrn-
S r h w n ~ ntlwory
~ nf ct.ll formatinn I I "cryst:~llil,ation"
~
ful "f:~llout" from mi!wr:~logy whicl~yirlclnl the 1wI:ir-
inwtcr for thosv studying l)inlnpie:~l 111tr:tstrurture;
strurtuml chcvnistry, c l v q ~ i t rit.; inf:~nry, I I : ~prowrl
inv:iIu:~lh 1,) men 1ik1. l':~strur :iud I ~ ~ h r l i r l ~Sow, .
iclms rrlmut the u:iture of iutc-rmolrcul:ir furre.; in c r y
t.:iIs wrrr hc.ing :ipplird to mncnimolwulrs.
If tlw conec.pt nf pnlymrriz:~tinn I)?- t h r S I I P C P S ~ ~ V P
ndclitiou of n~rmnmerrto :i long eh:~inn~olreulc.scww so
ol~viousto IIS 1011:1y, OIIP must rrnmmlm 111:1t,:irnuucl
1!)00. q u r d i m s :~Imutthe 11:iturcb of the eh~mic:tI I X I I I ~
wrrc d~mvingthr o r t l ~ o ~ lvie\\.
m t o Iw II:I~VP, 1111- nr:d~(-u1r
roncrpt In*g:in to look uns:~fe,:md it \v:w not uutil tlw
rntirc. thrnry of tlw atom 11:id Iwcn eh:u~grrl:~nclthe
elrrtmn tlwory r)f v:ilrney rst:~l)lichcrltI1:it. t h r w 1111-
cc.rt:iintics.; \vcbrr rrwlvrcl. \Vrrner'.d prinmry : U I ~ +PC-
o n d a y wlrneirs could i h ~ 11r n .wrn :IS : I C I I I I ~ I I > ~ : Iof
~~~II~
cov:tlrut :ud ionic l x ~ ~ ~ cend ..
l * , Jol~:int~r.: I I~ic+'s tlicwry
couut fnr thv w r y n w t i v r n:~turvof unr:~tur:ite~l nr-
g:n!ic romlmunds, could In* srcm 10 wnt:iin :i r n d v i c l r : ~
of rrson:inrr. l%utiu l!W 1I:irrirs usc~lp:irti:tI x ~ l r u r y
stnlcturr for n ~ h h r r .
Cncertnint- over the molcculc concept, cnmc nt. the
snmc time :w clrtcrmined :~ttrmptswere k i n g madr to
study nntur:il lmlymrw hy the trchniques of t h e t e e n t h
century chrmiatry. I:mm 1!Ml o n w ~ r d sthe iden of
secondnry or pertinl vnlrncirs W:IS pushecl hy Hes-,
given u p I\ fundnmentnl distinctio~r \wt\vem~prim:wy
:~ncl sccondnry v:~lcncy in 1!l1:1. Clearly these hi*
chemists w r e nnxious to keep the molcculc concept
within the scope of the techniques of the organic chcm-
lic:ltion of these insoluhle rrntur:~lnnd synthetic pol?-
mcrx RS ~ollnidswhosr s u p p o ~ r dn t y h d Iwhnvior is
due to their ngyrrp:rtc state. Some properties of poly-
mers nrr of C O I I ~ S C due
* to \venk Imnds such :IS the hy-
drogen lmud : ~ n d\vr mny conjecture t11:1t w m e t l h g
like n hydrngeu lmnd may h w e heen in the hnck of t.hc
minds of Rcss nncl I<:irrcr. It is :iIso true th:rt. mnnv
comlmml.; which form crystnls hnve rxtnrsive systems
of hydrogen Imtals hrt\veen neighlmring molcculcs in
the cryst:d, : u d these lmnds nre tlrstmyed when thc
crystnl dissnlves. Also the insnluhility of cellulose in
wntcr conrp:irrd with that of strirch is due to hydrogen
hnuding l~etwrensuccrssivc ch:iins which hidrs the
hydmphilic groups frnm the mlvcnt.. liot i t is not, true
th:it the grc:it chnin lengths of starch :rud cellulo?lc nrc
due to simil:tr lmnds or :iflinities which the :tct of dis-
wlving will destroy.
T h e ft~lsedistinction twt,\+een cnlloid chemistry nnd
chcmistn prnprr, with its rntionnlc--the formntion of
:~ggrrg:~tes-wns ovrrrnme by thrcc lines of wiclence.
.\lich:~rlis nnd Sflrenwn sho\wd thnt pmteins, though
colloid:il, kh:ivr ILS ~mlyrlrctrolytesnnd thnt whwe
d o t i o n s :rrr formed the phnw n ~ l eis ohryrd. S v d -
Iwrp and his nswcistrs showrd th:~t.hemoplotin d v e s a
clwr 11:1nc1 in t h r ~ ~ l t n ~ c r n t r i f ucrll,.i~~clicativc
gc of n
monoclisprrsr systrm with uniform pnrticlr size, whrrrns
nggrrgxt ion shoulcl givr :I nmgr of p:~rt,iclrsires, hrncr n
~wlycli.;prrsrsystrm. Also in 19'2.i Gillwrt iltlnir hecl,
u n k n n \ r ~to ~ Svrelhrrg, ohtninnl from w r y c:lN~flll0s-
niotic nir:wurrmrnts of hrnroglohin :r molrcular weight.
of lifi,700, \vhirh w:~sw r y clwr to Svrulln~rg'svnlur of
fX,ooO oht:~inrd :I year Inter. Corrnlmrntion in this
W : I ~from cliflrrrnt mrtl~oclsof rstimntion clirrchrd the
d r l ~ n t rin f:~vnrof grnuinr rnncrnniolrcules whore col-
Ioitl:d ~ ~ r q r r t i:trr
r s ;I rrflrction mrrrly of t hrir size and
c o ~ ~ s t i t u r n:ind
t s not of :I slrri:d npgrrgntr eonstn~ction.
13111 t h r tr:~inof rrnroning rrhich lrcl to this ronrlr~sion
was not. st n ~ i g h t f o n v ~ ~:rucl
r d ,it rrquirnl:r w r y nrtirul:~tc
:~nclprrsistr111 clrhntrr to tlrmolish the ngprrg:rtr the,-
or?. SIICII:r m:ur \rns t h r Grrmnn pidytnrr rhrmist,
Ilrrm:rnn S t : ~ u d i ~ ~ g(1RRl-l!I(i.',),
rr nncl it was hr who
coinrul the trrm ".llnkrn~~~ol~l;a(r."
The Macromolecule Concept
Stnuclingrr's study of polymers h e w n in 1920 n h r n
h r xrns at the S\riw 1:rulrr;d T n h r ~ i r n lUnivrmity in
Zurich. ' h r t ycrr h r clrlivrrrul :I spiritnl nttnek on
the rrcent nusumption of srconclnry forcrs of a.wxintion
in polymrrs, himself favoring primsry IickulE lmncla
throughout. T\ro ycnm 1:rtc.r hc usnl the term rn:lcm
n i o l r r ~ ~ lnncl
r , in IVZI he clrfinrul it 11sthose p:rriirlrs in
xvllirh the inclivicl~~alntonis nrc tmrrnd hy normnl
valrnry forcrs. \Vhrn Iw left Zurich in IV2.7 to 1:rke
t h r rhnir of rhrtnistry nt the <krmnn univcmity of
Frri1)rlrp-im-Rrrisg:~~~ he clrvotnl his lrctr~rrat tlrr
Ziirirh C'hrmirnl Sorirty to his rvidrnrr in f:~rorof t h r
mecromolrc~~lv co~lcrpt. This formrtl the snl~jrct.of
his :iddrrss in Diissrldnrf n yr:w 1:rtrr.
011 1~1th oer:~sinnshe m r t with n hostilr rrrrl)t.ion.
T h r Ziirieh m r r t i ~ ~finishrrlg in uprnnr :rnd S1:111clingrr
conrl~~cl(d t h r stormy discl~asiondrfi:~nt hut not :~g-
grrssirr, quoting tlw w m I s of Imthrr, "Herr I st:ind, I
emnot (lo othrrwisr." I d me q r ~ o t rsnmr of t h r :ul-
vier Iw rccrivrd
Ilmr CoIIrn~~e, 1 . m ~the ~ mwept of I R W ~mnlec~dwrell
nlone; orl(artir rnolc~wlnw i l h a molrmrlnr wripht sluwc .XHHl
do no! rxi.:. l'wify yuw pmdurts, WCII 8s ruihw, tlwn tlwy
will c.ryr:;,llirerttd lmvr tolw hwrr m~,l~n~lnrsf~l~stn~~cw.
Orpnir molrn~lmwith more t h n n 40 rnrlmn nlom* do not
cGt.
3lolcnllw mmot he larpcr i h n n the rryatnllopphir snit. rell,
r ~ ,thew rnn l w n o r ~ i r bIhinp; RS R mncmrnolrc~~lr.
T h r r r wrrr thrrr rr:l.wnr for this violent. opposition
t o St:ruclingrr's m:~crnmolrculr concrpt. The. :Iggrr-
gntr throry wr h:ivr srru h:~rmonisrelwith tlrr m11rrpt
of rolloicl:~lprnprrtirs 21s Iring supr:unolrcul:~r in oripin,
~ r h i c l~~r : ~ s orthotlos virw :rt th:rt timr. T h r w w
tlrr
srirucr of N - n ~ yrryst:rllopr;rldry, ~vhirhlrncl only just
Iwrn npplird surcrssfully to crllulosr hy Ilrrsnp : I I ~
Iris rollr:~pl~rs :ti tlw 11cw1y for~nelcdlinisrr \Vilhrlrn
Institutr for f i t r r rhrn~istry,n.ns niist:~krnlythortglrt
to s t l p p r t t h r eonrrpt of smnll lmlymrr nrolrculr~. A
molrrulr t)igprr 1 1 1 t ~h r rryst:~llogr;~phie unit rrll C:III-
rot rsist. 'l'l~ird. S t : a ~ d i ~ ~ g r most
r ' s imlmrtnnt mi-
drnrr--rh:~i~~lrrrgth of pnlymrm-elid not rest on :I
tl~re~rrtic:~l rrl:rtien141ipdrrivrcl f m m first pri~wiplr*hut
on hi.; mipirir:rl Sl:~r~cliugrr llulr for slrrrilir riwosity.
Hnd h r hrrn drnling with sphrricnl moleculrs which in
snlution o t r y the I~:i~~strinSmol~~cI~o~rski rqrlntion, thrn
Irr could hnve drrivrcl molrel~l:~r wrights, or rnther
p:~rtirlr wrighta, in a lopir;tl nrnnnrr from viscosity
me:rsurrrnruts,' hut prrcisc4y hrcnusr hr w:rs tlrnling
with long rhnin molrcutcs his viscosity w:rs of the non-
Sr\vtoni:\n typr, : u d l ~ w:ts r forced to extr~rlmlntrto
small p+lymrrs : ~ c c r d ~ tl or tr:~clitionnlly acrrpt:~hlr
nirthods of m o l r r ~ ~ l awr i g h t rstimation in orelrr to
e:rIilr:~tc i s rr:~lings. It is intrrcsting to notr here
thnt St:ruclingrr h:uI nrriwrl :kt tlw rr1ntionsl1ip for
sprcilic visrosily in a f i t of dcsprnrtio~rI~rnr~ght :~hout
I)y ttrr rrfwrl r ~ ft h r nuthoritirs to supply him with the
funds necrss:wy to pnrrh:~sean ultrarrntrifuge (Dr. .\I.
St:ruclingrr, personal commnnicntion).
c e thnt mrthylntion, ncrt-
His othrr linr of r v i d r ~ ~\\.:IS
rl:rtion, t ~ r o m i ~ ~ n t i o:md
n , hytlrngrnntion of polymrn
hoes not nltrr thrir molecul:~r w i g h t snhstantinlly.
How, h r nrpltrd, could thry rshihit this idrntity if thry
arc- hrlcl togrthrr I)? r r r o n d ~ ~ rforrrsy which must lx?
clc*strnyeclIwforr the chrmir:il rri~ctioncnn t : ~ k rpl:~cr?
,lnd had not t l ~ csmrcg:itr theory uphol(lrrs nt trilmtrd
thc rrmnd:iry forcw to re411:d :iffinit irs whirh :rrr u r d
up in nrrtt~yl:~tionand l~yclrngrn:~tion?How thrn
could n~hlwr,:UI un?i:rtr~r:~trdhy(lrnr;~rlmn, s n d Iry-
clrngrn;rtnl mhhrr, :I s:ltllr:~trd ollr, t)oth hnvr sreon-
d:~ry forrrs in them? Ilrsis1:rncr mnlinurcl, nntl i t
\r;~s not r~ntil19.53, 83 y r : w :dtrr h r h:wl intrn(lucrd the
trrm "mecrnmolrculr" t11:1t the 72-ycrr-old St:rudingrr
rrrcivrtl t h r S n h r l I'rirr for chrmistry.' Altlrm~glrhe
is rrmrmlwml for his work em n . g r ~ ~ c r n t n:mtl l syn-
thrtic p + n r r s it is noteworthy tl1:11 he h:d t l ~ l~iolo-
r
gists' virwlwiub. Consiclrr t h r fe~llowingcluot;~tio!~
Ilitherfo the ownnic chemist hn* worked lar& on sahlnnew
x t a l h ? nt rrlntiv~lyhiph (100-20fl'C) tmtprntttlrp?r. This ir
wtmrrh*l w i l h lltc pnn.nll:m rnqdoyed 111, t i l l now fnr i s h -
i n I i l i i t i O r ~ m n i cs:rwtw(Li which rnn only
l r ~far more Wlrnt~mwn l d rrml-
exist ,,I. 1owc.r l r m ~ r n ~ l l:Ire
plcx. Tlwir *ttaly i* mndr dillicdt I,y t h ~ i riwren*inp,r~n-
rilivity. 1)npitv the litrge tnitmlwr of ~rxnnir ?;III~S:A~IC(S
which aw nlrr;tcly know Icdny w? lnw m l y rtnlldill~I,II the
thrr.-ls,ld of l l w chrmistry 01 I na onnnir crmpol~lal.;:md h w e
KOI nctwltew nc:w R UWIIL-~OIL
I t wrs no :recidrnt, hr :rrgrtrd, th:rt, hiolopic:~lm o l r c ~ ~ l r s
:lrr MI rrrsist:int to l h r tcrlrnicli~rsof tlrr cl:c~~icnl ehem-
ist., for thrsr 1:lrge "rurolloiel:d" srtt~stnnces
c m rsist
only :11 normnl living tmq)rr:~tun.s.
St:tudingrr first rcalirnl t h r rignificnnce of his work
\ v l r r ~h~ r mrt his futurr wifr, t h r pl:rnt physiologist,
Dr. .\l:~gd:~ Woit, in August, 1!Ei shortly : ~ f t r tlw
r pul)-
lieation of his l,:qwr "l'11lyn1rr For~n:rlcldrydr,:I .\lodrl
nf ('rllulose." \Vhen 1)r. Wait clrsrrilml her virrvs
--
I I k w with sph~riml pnrlirln t h ~ wis lhc pnhlcrn o f wlvntio:l
whirh r n w n II dwi:~timfmnl thn,ry.
I'tu1I li:wrrr mwivc4 i h r Sd,cl I'rirrforC!hrmir:ry i t ) 1043.
Volume 47, Number 3, Morch 1970 / 171
on the permenhility of nlgnl cell wnlls he dismi~seclthem
wit11 n smile snying, "It is nll quite ditlcrent!" Then
hr clcscri1)crI his own views on the p l y m e r fiber struc-
ture of cellulose, nnd
. . .gazing m t over the sen, RS if in a trance, hespokeof the sub-
stonre of living mntter: only n marn~molec~ilnr mnstrurt.ion
of the anmr w o ~ ~ bel d rapnldc of brirying ntmat the orgnnirs-
lion of events it, the living cell; rhtmicnl cw~llitutiwIme
mmt~ld he of primary irnprtnwe, not ccdloidnl phrnomeun,
r h i r h have n*rr*mdnrysi~uifimnre.*
With this interest in hiologienl pmblems Stnudinger
hoped to tnke up the structure of pmtrins nt his insti-
tute in l ~ r e i h u qhut
, the d r s t r ~ ~ c t i oofn thclntter during
t h r Alliwl homhing of the to\vn mennt 1)eginning from
scrntch which hy Ihc time it l m n m e possihlr wns t w
nnluous nn undcrt:\king for the nging Stnuclinger.
The Shape of Macromolecules
T h e nccrptnncr of the mncromolecule concept ex-
ploded the myth thnt the secrets of life arc hidden in
t h e "follilorr" r ~ colloid
f chemistry, hut the prohlcm of
whnt. to clo wit11 t h r ung:~inlychnins t h r ~ sg r n r m t d rr-
mnincrl. This had hem :In emhnrrnwnent to St:~uding-
er who nskrd Rurlolph Signer, now pmfrssnr of rl~em-
istry nt l % m ~to, clrvclop :III intlrprnrlrnt m ~ t h o dfor
rstnhlishi~~p t h r sizr nncl if pssihle t h r shnpe of p l y -
mrrs. H r chow t h e opticnl t r r h ~ ~ i q of u r hirrfringrncc
n ~ ~ huilt
d 11 w r y writ little n p p n ~ : ~ t ufor s prnerh~p;
hiph flow grndirnts. Thus rquiplwd he rstimntrd t h r
lrngth/l)rrndth r:~t.io of mnny r n r includhg
Dl'.\,nnd sho\vrd t h : ~ tthey nrr irvlrrd prrwnt :L< Img
i I I s t r I s . S~uctheIessit. wemrd
i ~ ~ r r r d i lthnt
~ l r the pmtrins of whir11 r11zy111rsnre com-
posrcl r1~11ldfunction in the form of Ionp chains-they
must S I I W I ~ hnvrsomr spcrilic conformntion.
\VII in (:hin:~, A s t h ~ ~ ri lyl l~ngl:~nd, : ~ n d>firsky nnd
I'nuling in t h r I'nitcd Stntrs put fonwrcl the idrn of the
prrrisc* folding or rnnformatio~~ of polypeptide chnins
to solve this pmhlrm nncl to e s p l n i ~why ~ an enzyme,
whrn rlrnntt~rrdlry hr:~t,is hiolopirnlly innctivr. S o w
long c h : h s :w rcnlly !?-rlimrnsinnnl corwtmctn, hut
fol~lcrl rhnins r e : - I i m e n s i ~ ~ ~nud : l , thry grnerntc
stnlcturrs for which it is 111:u1sihlrto conrrivr specific
hiolopienl functio~~s.This i h , I hrlicvr, c o n t n i ~ ~the s
essrnrr of n~olrertlnrhiology. .\lirsky's ~lmmonstrntion
of t11v rrwrsihility of t h r clrnnturation proerss \ ~ n tsh r
s r m i ~ ~dailw ~ v r r yI w h i ~ ~t hd r idrn of c n ~ ~ f o r n ~ n t ihut,
on,
S-r:iy r n d : ~ l l o g r n p I ~of y pmtcins hnd 1)y this time
inclic~trd.mmr r~xuI:~rIy folclrd .srcon(l:~rystn~ctures.
;\s won ns thr- irlr:~ W I . rstnt~lishrd
~ tllat :I long chain
n ~ r ~ l r r urould
lr 11:1ssthrnuph s ~ ~ r r r s s i v unit
r cell* in :I
rryst:il nr lilwr : I I I ~wrll ~ from o w cryrtnllitc to nnother
it h r r ; ~ m r h r to Astln~ryth:tt m m y li111nuspmteinn
nrr fol~lccls t n ~ r t ~ ~ r rTIC s . r x t r ~ ~ d rthis
d iden to t,hc
gIohul:~rp m t r i ~ in ~ sI!):%:, : ~ n dit WIS m n g i v w qunlitn-
t i w suplmrt. from t h r S - m y pictures tnkrn of the lirst.
rryst:~lsof prpsin, insulin, n11d 1:vloplohulin.
T h r linking of hinlopirnl function with thrrcclimrn-
siim:d s t n ~ c t u r rin this wty, I rrpanl ns t l ~ ex-cncr r of
n ~ o l r c ~ ~hiology.
lnr .\[nny lines of cvidrnce mntrihutnl
11) thi* ronrlusion hut ntmve nll it 1v:w the product of
a Trnnslntiott of nn ext.mrt from a letter fnm Pmfexwr
Slnwlingcr 10Sir Ilnw limb*.
172 / Jourml of Chemical Edumtion
the converarncr of t,he concept of the mncromolecule
with the enrly results of the X-rny study of nnt.urnI
fihrrs rind of single crystnls of glohulnr proteins. This
nswcintion of t h r work of biochemists nnd rrystnllog-
rnphrrs is to 1% dist.inguished. from the i n t m d u c t i o ~of~
pl~ysicnltechniques into pl~ysiology whirl^ cl:~tcsfrom
t h r prriod of 1.11chvig nnd his contrmpornrirs in the lntr
1840's. The virw tnkrn hew is thnt such cxnmplcs of
biophysics nntedntr n~oleculnr 1)iology by n e r :I
crlltllry.
This distinction cnn be i l l n s t r n t ~ lhy the following
exnmples. I n Inlo A. 1'. Hill intcrprctd the oxygen
disweintion curve of hemoglo1)in ns due to the revrrsil)le
chnnpc of hemoglobin :~ggrrgntenwith an nvrrngr of 2.5
molrrulrs per p:~rticlcinto t h r single molrculrs. Con-
sidcwd in isolation this t l ~ m r yhnq the chnrncter of
molrculnr hiolopy only in n very crude scnsr, h r ~ when t
lntrr irlrns wrrr e o m h i n ~ l with s t n ~ c t u m l drtnils
supplied hy .I. 13. Conent, Linus I'nnling, nnd C. D.
Coryrll in the 1930's the thmry Iwcsme n pnrt of
molrrulnr binlog?., for function WE t,hen corrclntccl with
the nrrnngemcnt in spncc of the molerule's const ituents.
I n n similnr wny Spnnrlrr rind 1)ore8s stnrcturr for
cellulose in I92fi nccountcrl for mnny of the proprrties of
the crllulose lihrr. \V. 1'.~\stl)ury'snlphn-lwtn trnns-
formntion of krmtin did the snnw for hnir, nntl he
npplird it to musclr fihrrs, cilin, nnd fln~.ellnr(.we Fig.
?). I.nter rrsenrrh sho\vcd Anthuy's rxpl:mntions t o
Alpha Keratin Beta Keratin
be right. in principle thoc~gh not in detnil, nnd this
daring venture into moleculnr s t n ~ c t u r e~ t i m d n t e d
othen.
Among these cnrly nttemptv n t moleculnr stn~ctures
the most noteworthy is C. S. Ilnnes' hrlicnl model for
nmylo-r (stnrch) in 19%' (see 1:ig. 3). Six years Inter
this conformntion was cstnl~lishrclfmm S-rny pictures
by Rnnclle nnd Edwnrdn. Though little known outsidc
polysncchnriclr circles thin hclie:d s t n ~ e t u r rnccountd
for the t ~ h n v i o rof stnrch to iodine nnd its snluhility
rhnrnctcristirs, nlm Hnnes wn* nhlc to suggest how
enzymic hrr:~kdo\vnof n hrlix conld lend to t h r produe-
tion of t h r two Shnrdinger tlrxtrins present in the
hydmlysnte.
Residue Sequence in Macromolecules
T h e discovery of the size and overnll shnpe of n
mncmmoleeulr w ~ uof little help in elucidnting t h r
wquenm of subunits within it. In the nhwwe of such
 trtr:~nurlmtirlr. wit 11 nsymmrtrir crrlmn ntoms ns t h r
only snurrr of i.onwrim. 'l%:~t thv iclr:~ of vnrirtl
r r ~ ~ I I - I I I I ~ I~nd
s n l ~ ~ r n e of ~ . ; not ocrurrnl to t h r I I ~ I I ~
trt-nth rn~trlly i~iologids who diw~sscrl rhrmirnl
clivrr.;ily of the pnwtir rn:~trri:~l(lVri.;n~nnn, lX!l2,
1Iirsrlwr. lX9'2) is Imrn o11t 11y tl~rf:lrt t11:it thry CWI-
firtr~lt hrir fli.srus.;ion of i ~ o m r r i mto tlir :~symmrIric
r l n ton^. Vir\vnI from t IIP :~*pwtof synthr*is, of
rourw. :I IIOII-~IPIII:I~ ~ ~ I I I P I I sWr r n ~ n li~nlikrlyif t h r
cwrymf. clifl 1111 n ~ o r rt1x111c:~lnlyzsrl l ~ pnlynl~~ris:~tiot~
r
rcwtinn in !vhirl~ the 1rrn1i11:dr r 4 1 1 r of the g r m v i ~ ~ p
r11:tin d r t w n ~ i n r dwhir11 rrsidlw sho11I~1 follnw it. This
ro11rq1111:1l 11:lrric.r r f m n i ~ ~ lmtil
n l tIw trnq~l:itrnlrrl~:~-
11isn1r : ~ l ~ g ht th r i m : ~ g i ~ ~ :of ~ tl~iorhm~ict*
io~~ in t11r1:11r
1!).10's.
The Delay in the Establishment of Molecular Genetics
T h e nssumpt ion that DS;\ rnneists of m m y iclrnticnl
trtr:~~turlcntirlr~ *wms to l~nvchwn t h r rhirf rr:lron for
t h r f l r h y (srr'V:~l~lc 2 ) . ,\clclwl to this was thccvirlrnrr
from ultr:~violrt mirrosropy. With this trchniclue
'I'orl~jorr~~ C:~sl~rtsson II:LII i:tilwl to detect contim~ityin
the clistrihutinn of l)S:\ :dong thc lrl~gthof the rl~rnmo-
some nf t 11rl ~ r o . ~ ~ ~ s:~Iiwry p l ~ i / o ~I:IIIII rrll, : ~ n ftlhrmph-
out the in~clr:wcyclv, I ) S h , it scrmcrl, was ton tr:u~si-
tory ill the in~rlcusto net 21s repository of thc prnrtic
inforn~stion. Yet high r n ~ ~ c crxtiot~s nt of DS:\ wrrr
1111v:~ysfnund whrrr rl~rntnosnmrs:irv rrplie:~ting,: I I ~
.\s0111r:. fn1111f1 tl1:11the r 1 4 1 1 rr r p ~ i l of l 1)S;\ r q ~ ~ : ~ l l w I
lh:~tof pnlyprpl i ~ l win the. f111Iyrxtonded r o n f o r n ~ : ~ t i ~ m
(:.I ) llrncr Asthnry rsprrssrd t h r view th:~tI)SA
n~ight:wt :IS tlw nlirrnr inl:~gcof t h r origi~xdpolyprp-
tidv, so 1h:~t:I ropy of t h r 1:lttcr rnulfl III* prnrr:~tcrlon
tlw other side of the DSA rr~ltunn. T h f w i ~ h IIII s thc
function of I S in rhrnmnsomc rr~Iic:tinn were
Table 2. The letronuclcotide Hypothesis sumnic~l1111 I)?. ('. I). I)nrlingto~~ iu the lhr:~sc"~nidwife
n~olrrule."
;\ltla~uphu v microsropy mislwl hiolodsts ns to the
-- -- -- distril~t~tinn of I)S.\ within l h r chron~o*onw, trr~cli-
IW I.0(?) n.98 ...I.li (hbrn & RSA tinn:~lrylnlopirnl s1uflit.s of mriosis : u d mitosis in tlw
llnrris lx~nd*nf l ~ : ~ r I i ~ ~ g: w l iim1.n ('nur pni11tr11In the prfbs-
190; 0.47 0.23 I.% 1.0 lrvrnc DSA
I ~.:m I . I 1.m S I ~ W I P I IISA enrc of l~rlir:~l I I I O I W I I I ~ ~ . l):~rlinpto~~'s l!l:<.-~p p w s on
I!aly I n.w I .1r2 I . w I..-WW & I)S:\ I s ~ j :~ttrilwtfvl
r I r o i l i ~I I r~nroilit~g of
~In,,dd r h r n ~ n n n nI I i i s i l ~ 'l n i n I ~ l : ~s irr : ~ I . " ;\t
IW 1.0 1.3 1.7 ? lrvrnr RSA
I!I-I; nu-0.9 I .(I I .]-I .? I . O ( ; u I I : ~ IISA t h r 15ritisI1;\wori:~tion in I!% hrflwrrihw~l)X:\ in the
I!IIV O N 2.11 1.0 0.2.; r ~ , : , ~ : , t r I ~ S A cl~romosnmc~ :IS :I ro111m11,"likr pwnic*.;, :IS ;\r;tlwry
I ! 1.6 1.11 1.0 I.:, (~I.K:LIT IISi
I!I.-,o n.:q 0.18 n . 1 ~ o.:~I r l ~ m g : t t-r - I I S A - 1111tsit, nr prrI1:111*rvrn morr Iikra spir:d st:~irc:~sror t he
- --- rills of n coll:~psil~lr f:~n."
Aminrt Arid % t r n r ~ *
IMP Pmlein Autl~~~rs Squenres Two m ~ ~ f r r c . ~hrfore ~ e r s the war wrrc nrg:~nizwI:1nd
- suppnrt~rl11y I I I V Rnrkrfrllrr l ~ n ~ ~ n d : ~In t i ohni n g I n -
grtlwr I~inpl~ysiri.;Is,rytolopists. I~iorhmmists. :IIIC!
gem-tirixt-i for 1 1 1 rsprrss ~ I I I I ~ I H I Wof snlving ~ I I P11rn11-
Ivms nf rhromosnmr n ~ r r h : ~ n i:ind r + g~nc* strurturr. 111
I!! I i f r n :i n I o r g : n i ~ lI tlw 1ntc.r-
n:ttio~~:~l ('n~~grw.; nf (;1.11rlirs:it I.Xi11lmrg11ri~llnlt h r
"(;rnr (;rn111,." It is trur t h t in I I I V fIis?ussin~~s 11ntI1
:it tlw Ilnrlid~4lw('nnfrrrnew :\I S ~ : I:IIIII l i l : ~ n ~ p ~ m -
Iwrg :IIIII : ~ ttl~rl<fIinln~rgh (;rnr (;rnup I I I P :~ssuny~tint~
lh:it thrb gwws :Irr p r o t ( h s w:is nnt ~ [ I I P S ~ ~ O I I M ['Vhr .
p:~rtiril~:u~ls trinl tn :~c(r~unt for the I~IIC-P:III~I* :lttr:lc-
tinn of I~nrnolngnwr l ~ r n t n ~ ~ w for n ~ fr~: s~ r lnlhrr,
~ : ~ t d
thoupht 1 1 ~ 1 1sinrv i t i* w l y t h r homolops wl~irhenmr
t.ng~'tlwr, r~.plir:ltiot~of thf. grnc..; m114 :~lsohr n likr
with like prrwc.~.*. S o n 1 4 h c h s , h f I thc* inlrl~sityof
1111-i ~ ~ t r r w: ~t ttliis tinw I I ~ I > I enntinuwl,
I it wf111If1 hnvr
crc*:~trd:I rIin~:itf* ni npinifm more s f w i l i v ~to t l ~ first r

Volume 47, Number 3, March 1970 / 173

clrmo~~strntion of the pewtic rnlr of DS;\ hy Avrry,
XIacI,rnd, sod XIrChrty in 191-1. Rut lrforr t h r irclin-
I)urgh ('ongrws ~ v n ovor s war 11:tdhrokrn out.
The inhihitory effect of the s n r r x t r n d d fnr beyond
thnt of prrwnnl contact hrt~vernscirntisls of diflrrrnt
c o ~ n t r i . It hrld up the estnhlishn~rntof instilutm
for molecular hiology rnmrch. The dates of the
foundinp of the A s t h r y lliophysics llepnrtmrnt, the
XIIK! 13iophysies Ul~itnt King's Collwf~.1m1do11nnrl
the XII<C 1,nhorntory of llolrct~lnrl3iology nt. Cnm-
hridpr nrc nll 1N7. n u t molrcnlnr 1)iolngy rnrnrch
I , ~ ~ : I I in
I L ~ l nss n rrsult of :I rrnsmsmrnt of t h r stntc
of the trxtilc~,liysicsdepnrtmentI)? thr then \'icr-Chnn-
rrllor i n 101'7. Asthury's nuclric ncid work thrrr
r r n r h d n penk in l!l:W nncl might well hnvr e o n t i n ~ ~ n l
nnd hrrn (Irveloperl hy othrrs hnd not the war impawl
routine work of militnry imlwrt:u~cc.
The study of the s t r ~ ~ c t uof r e protein crystnls hegnn
i n ('nmhridgc in I!%$ whrn .I. D. Brrnnl and 1)ornthy
Crnwfoot took the first S-rny pictures of pepsin. Such
stutlin wcrr continutrl in the crystnllopnphy drpnrt-
mrnts of h t h Oxford nnd Cnmhridpr, i n thr formcr hy
Xliss Crowfoot (now l'rofrssor Hodgkin) nnd i n the
lnttrr hy 13rrnnl. In 19:iO Xlnx I'rrutz nnd I. Fnnkr~-
chrn cnmr to C!nmhridgr nnd togrthrr thry took the
firxt X-my picturn of rhymotrypsi~~ nnd hemo~lohinin
I . This work wns continr~nlundrr Sir 1,awrcnce
I 3 m rind ~ wns the rrnl stnrt of whnt nfter the lvnr hr-
e:lnir the fnmous XIRC 1.ahorntory. I3rrnnl has thus
p l n y d n lending role in the wtnhlishmn~tof the Cnm-
hridgr school of molrculnr liology, originntinp thesinple
crystal study of protrins nnd with F:~nkucl~en mnkinp
the first S-rny cliNr:~rtion study of Tohnccn Xlosnic
K r o s rrystnls. The XIRC l3iophysir* [.:nit nt King's
C:ollrge, Ifinclon xvns :un nml,ition which its prrsrut.
dirrctor, Sir .lo11111?:1nd:lll, hncl i l l the rnrly yenrs of the
wnr, hitt the n m l to rrly on Aclmirnlty grants for rr-
sr:~rchfnrals nnrl t h r lark of n suitnhly sitnntnl physics
deportmrnt prevrutnl him from rr:~lising his drmm
until 39-17. 1,inos I?iulinp's work on t h r protrins at
the G n t n nnrl Crrllil~I.nlmrntorirs, Cnlifornin lnstitntc
of Trrhnology, hegnn ~ v h nCorry ~ cnmr to join him
from the Ilockefrdlrr Institute i n IIK37. i\lthouph
Corey hnd :rrr:~nged to IIC nwny from the Rockrlrllrr
for only one yew hc hns remninnl nt Cnl Tcdi rvrr
rincr, Iwt the w:~rrflort .won divrrtnl him to clirrct n
rwr:~rchtram \vorking on the proprrtirs of rocket pro-
prllnnts. l'n~~linghimsrlf \vns for some timc w r y ill
wit11 n rnrrnnd hit herto f:~tnldisrnxcof the kidneys. nnd
when he returnnl to science h r took up the study of
nnli-ner:~.
Soeiologistn of ncirncc hnvc emphnsirnl t h r n m l
which :I IIPW suhjwt hns for n rcspnnsivc nnd influentinl
n~rdirncc,if it is to prow. This nurlirncc must consist of
pr:lrtitionrrs who follo\v the pnprrs p11hlish~1 n11d nre
mmprtrnt to criticizr thrir content. 13rforr the. war
molrcul:~rhiolopists were :I s c n t t r r l hnrd hnving 110
sorirty or jonrn:~lof thei,. own, l n ~ tns we hnvr sern, :I
merging of the sevrrnl strands of t h r suhjrct wn.. undrr
a n y on the rvc of the outhrmk of wnr. The wnr nippnl
this process in the bud, prrvrntnl intcrnntionnl m t l ~ r r -
ings of scientists, nnd trrminntcul the fruitful coll:~horn-
tion of l3er11nlnncl I'n~~korhrn, r\sthury nnd 1ldI. : ~ n d
I'nuling nnd Corey. Germ:~n seirnti?its were rut ofl
from tl~eircollmpurs i n 11rit:1in nnd the UnitnI Stntn.
174 / Jwrml of Chemiml Mumtion
1;ri~lrieh-Frrksn's pnprr IIII the temphtr synthnis of
n s Srhrnmni'x paper on t h r wlx~rnlionof n
~ ~ r o t ~ . inml
virw into pmtrin rnnt rind ~nrrlrirnrid rorr, thr former
Iwing non-infwtivr, wrrc. virtr~nllyI I I I ~ I I ~ ~nl1t4dr I I
(irrmnny nntil :~ftvrthe w ~ r . \Inn? nhlr C i r r m : ~ ~ ~
nrirntists wrrc deprivrd of their johs in the Snei PEL
whicl~prrcrtlrcl thr. w r , :uxl in the nnwttlcul yr:v.; tllnt,
follo\vnl thry fnilrcl to nchievr the f n ~ i t f resr~lts
~ ~ l lh:11
r d i n G I ~ ~ : IWOIIICI
~ ~ n ~ l i s t n r hwork I I ~ hnvr :~fforclcd
thrm.
Thnt fnndnmentsl resrarch of no forrsernhlr militnry
nncl ecnnomir valw wns in prneri~lheld up hy the \var
is n trnisrn. TIN,xim of clrt:~ilinpits impnrt. in o w firld
hem is to sho~vth:~t.m o l r r ~ ~ l :hiolog? ~r ~ v n s:I y o n ~ ~ g
suhjcct, in t l r 1930's whir11 i n I!):+!) tv:w p & w l rr:111?
for n big exp:~nsion,nnd the fnct tl~ntno such prow111
took 1,I:1ce until the lntr I!)lO's was due to thr itnpnrt
of thr 1v:ir nnfl 1101to the sul~ject'snonnistencc.
A certnin drprce of clisrontinuity ivns thrrefore in-
cvitnl)lr i n the s ~ h j e c nt s it rrnergnl nftcr tlw w:w. Its
prnctitioners hm1 little rnvnrrness of t h r nchievements
of thrir llre-1v:lr preclwrssors. The victory of the
mnrroniolecnlr concept wns tnkrn for gr:~ntnl,1,111 if
wr :trr to find :I clrrisivc phnsr in the prowth of thc
suhjrrt i t is surely i n the yr:m nround 1!t:10 lvhen two
schools of thoupl~twere i n oplwsition-tl~c nggreKatr
nncl the mncromoleenlc school*. l'hc virtory of the
Inttrr nncl the clrmise of the fornirr providrs :I goal
ernmplc of the p:~r:uligm trnnsfer clescril~eclI I Thoni:~s ~
1iul111; h11t there nrr ~ l i l i r : ~ t i ~ ~ s nwnhrr :-:~ of
m:~cnnnolrc~~lrs I I : since
~ t u r ~ ~out
n l to he :\ggrepatrs.
1'hw insulin rrnlilccl with tnolccolnr weipl~t.i:IS high ns
.IR,000 hns sincc shnwn from srqorncc a ~ d y s i . a; KIIIIC
of ~i000. The ~ ~ l ~ r n o m r nofo nngprep:ition is :I per-
fectly :wccptnl~lrfnet today nncl (lor.; 11n1interfere with
thr rxistrnrc- of m:~crnmnlrculrs. In the ninre prrrisc
f m n of V:IIIcler \\'n:lls forcrs : ~ n dI~ydrnprnhonds, thc
roncept. o f swoncl:wy forrcs has plnyrcl :I dcrisivr part in
molc.enlnr biolopy. T l ~ cdistinrtion l)etwrn ILII nggrc
g:rtr nnrl rr molc.eole is often :~rhitr:lry ns witnrss the
delinition of the cheniicnl h n d in Linus I':~ulinp's
"l'l~r Chemicnl I1on1l."
In the field ol diNr:~ction nnalysis thcrc 1x1s hwn n
continunrru incrensc i n the power of trrht~iqursn ~ x l
q u i p m r n t from the timc of the discowry of S-r:q
cliflcwtion onwnrrls. This hns Iwn ~4 cloewnentnl
i n "l:ifty Ymrs of X-Ray Cryatnlln~n~phy," cvlitnl I)?
I ' d ICwslcl. For fihrons prnteil~snnil nnrleir nrids
the most rrlevnnt, devrlnpn~f.ntwas the rlrrivntiol~of
thc Inyrr line concrpt 11y I'olnnyi in I!VL'O fr~lln\vrdby
thnt of the Fourier transform nf :I helix t l~irty-onryr;m
lntrr hy Coehrnnr, Crick, nnrl Vnnd nnrl hy Stokrs.
'I'hi~m i w l the pmlictivc prnvcr of cliNr;~ctiont l ~ m r y
to :I level of rophistirntion far nhovc t h t of the oldrr
throry. Fonrirr thew-y, compntrr scirncr, and thr
clcsipn of S-my tnhrs 11:n.run~lorhtnllypl:tynI clrrisivr
role* i n thc flrvelnpn~entof ~nolecl~l:~r 1)iology.
Thirty yenr* :\go tlw strurtrlrc of the prnr p m r n t ~ l
I i n t ~ c t r: o~ h m 1'r~I:ty its s t r ~ ~ r t l l :~ppr:~rs
rc~
.wlvnI. I'ct thr rf~l:itionof t l ~ molecnlnrr nioclrl to the
nltn~stmrturcnnfl pl~ysiolnpyof the rhromoson~rrf.-
mains nlmnst ns mycteriow :IS ever. I h r e we hope to
see the oldrr tmclitinn of rell physiolopy do more thnn
ncerpt the now I n s i c n ~lisrnveric~*of n i o l r r ~ ~ l : ~ r
hicrlngy:-m:rk tlwm fully n p:wt of l~iolog??