Iibbruawy 14, 1946

      Hare just returned froan a trip east oWse raor ppore was to at-
tend the gsrrat-pansl rplagoriua oallud bg the HRC.
receive a sizable grant to grosecmu%e the prog~sus. I smbaritted,
retlslved offioirrl wad en St BO111.bter.

I was told that I rmld

IIaosn't an yet

f hare meen the %miman ppsr an tEte Daaslabsr 22 ism Q? Bature 814

found its major interest in ths fact that still anotlrsr person working oa
dlffersnt a&%rid8 problem has oome to the smm general a0~1~luoime~  3Lth
rofarensit to tho %%yoen oxld ltiOtVi8 wmk     lwry that we aonfirmd it Soon
riter Its publioatlon by produolag giant oells a%th the 1288 of aamphor. We
did not retain the atralns sin% phgsfologfoally they wers not rorg dtPferent
irm no~1. Should it be desiroblo to do samthb with tMm, It -11 bs
relatirely easy to peaover  the^.  ft is my Peeling that tho analom drawn
'phtman betresn theas types anl o82113er cells 1s not saffi91ently Pun3mmatal to
.warrant tM expanditme of nsh offart on then at Vescant without uome fntthet
evideaaa far a olomr aonaeotion.

     aith refemwe to Ylss Zo~roli, she  is LB Ph. D. in exporillleafa1
embryology with l%ttlo OP no baroXground in bioahemlstry OT snzpolugy. an
omission she 18 er~ger to recltiQ.
will probably not ret the i#ffld on fire but L aapable of paluohg roupL1 reaulta.

Shw is a pleasant and crowtent prronwho

-2-

Sincerely yooro,

s. Sgie;?;alsm

"I had set myself tb task of findins the suffioiont oonditfons for thd

'autoaynthetia' type of klnetlos in order to Bee what could be oonoltded. Of
oourse the moat trlvlal 1s the 80-oallsd autoaatalgtlo type exrrmpllfled by the pep-
sinogen pepsin trmaformatlon. ?his however la of little real interest to us (I
still believe in spite of Beadle's exoellent review) sinor pepsinogen already
c!ontains inherently all the sgeolrlotp of p8etpcin and haidea the trmaformatlon la
spontaneous. Another kind, however, 1s the fomtion"66 energy aoaumlators, 1. e.
units ahioh oontain tn their stmoture energy rlohbonda  the energy of vhloh oan be
used for the further rgnthesis of rlznilar unit$,
oonfer a type of speoifioity not merely on themselves, but far more impartant on
the energy oontained ln the enrgy rioh bonds, so as to sarmsrk it for mrtaln usee,
or for thw egpthesis of only gartiaular kinds of strwture.  the stsre@hemistry
muld determine to a large extent ths type of oonpound to whioh suoh energy omld
be effeotivsly transferred.  It fa relatively ea8y to show that tho grmth kinetios
of moh units :iould be of the autosynthetlo type althout involving the aonoept of
tautooatalgsist in the usual non-energetic dense of the term.

The bods in ruoh units would

Diaregerdlng the fanog mathemat ictal trimming9 the .vhole thing boils down

to this: in the uptheale of any oomgound, slmglo or omplex, whicth requires energy,
the energy required for the synthesis &ust be made SpQ3ifi3 for the partioular oom-
pound beinr?; formed. Put this way it srxlnds almost trlvlal and pobably Is, but It has
many experiniental ifapiioationa. It mans fundanrentally that it will be unllkely that
"ve wlll fiad d general energy pool in oella whioh can ~JQ te-ypecl: direotly for ell kind8
of synthetlo activity.  It means that :vhile the energy Obt3.it~d from tho oatabollo
breakdown of suoh things a$ oarbohydrate and fats may be slmilsr It muat be transferred
to many diverse aaoumulators eaoh of whlah supplles the enere for a speoifio type
of synthetlo seaotlon. ~nd the more alvmplsx the produat the severer the restraint8
on tho sgeoiflcltg of Its energy Iondtora. It means that if XQ Odn find the 1IXImediate
enetrigy donator for a partloular synthetl3 renction we all1 have at the 88138 tima, found
the dsterrnlnator of the spetolfioity of the prafuat of the reaction. From this point of
view the problem 04 energy supply L.r.ul spealPlbpY beaorne one and th3 ~81118. The lspll-
oatlone of thia for the problem of gene aontrol over eniymatlc oonstltution are

Obvious o

at any rate, from all this you can 80d qhy 1 .vent in the rllreotion I did.

I was not surprieed to firYf therefore that our search for the omrw ueed In enagme
furmatlon led ULS pest tho relatively slmple and non-speolfio Qnergy rioh oompounds of
th aTP group and ended up in the very xnucth more oomplex muoleogrotelns. I believe
we are on the right traok ad have the right methoris and wlll end up with 8 muoh more
unified picture of $ena adalon than m hlla last year. It beglna to look like
gene nualsoproteln enzyme with the nuoleoprotein as the moTe likely autoaynthetio
unit in the oytoplaam than the, enape. :i*> are a lon.?; .vays off bat we 8x8 have fun.

TIM results of the experiments in which P turnover in the different

fractions was stud ierl under different conditions may then by briefly summarized

by the following:

1. The phosphate turnover in the classical glyaolgt ic system is necessary but not

sufficient for enzyme format ion (as well as nitrogen assimilat ion) .

2. The phosphate bond energy in the form of adenosinetriphosphate is not directly

available for enzyme format ion.

3.

The phosphate bon3 energy of the above compound had  to be transferred to the

nuoleoprotein fraction before it oould be used for enzyme or proteh synthesis in

gener a1 .

4. ArrangQment of conditions which left the phosphate turnover in the glycolytic

system intact but hindered the flm of phosphate to the nucleoprotein fraction

stopped enzp format ion.

5.

     Compounds and conditions which increased phosphate turnover Its the nucleoprotei

fraotion imreaaed the rate and extent of enqyme formation.

6.

Prevention Of flow of P from the nucleoprotein fraotion stops enzyme formatimr

The above oonclusions are based on experiments with only one enayme in one

strain. It is imperative to extend these experiments to other strains arvl enzymes.

Thse results ma& understandable, in terms of a cummon factor, a whole host

of isolated findings collected during the study of the phsyiolbgy of the adaptive

pro ces s .

Of greater importanae however is the Implication that in the synthesis of a

complex compound upon whiah rigid restrictions of specifioity are imposed, a non-

specific soume or energy (as eb g, adenosinetriphosphate) is noT adequate.  It may

well be therefore that ths source of energy and swtcifioits come from the same cow

pound an8 the experiments indicate that this compound is a protein nuoleotide.

-7-

'These experiments also raiae the obvious question of whether we were not studying,

in our earlier experimnts, the selfduppication of these protein-nucleotide units

rather than melibiase. On theoretical grounds, the farmer would more likelu be

the cytoplasmio selfduplioating units since they oantain the necessary energy.

The melibiase enzyme would appear to be eelfduplicating if its synthesis closely

followed those of the oarrespond ing protein-nucleotide unit 8.