HARVARD UNIVERSITY
THE BIOLOGICAL LABORATORIES

       16 DIVINITY AVENUE

CAMBRIDGE, MASSACHUSETTS 02138
  March 31, 1965

Dr. Francis H. Crick
M. R. C. Unit for Molecular Biology
The Medical School
Hills Road
Cambridge, England

Dear Francis:

   I was at Ma,dison several da.ys ago,  where Khorana. now ha.s evidence tha.t
AGA = arginine and GAG = glutamic.  There are thus increa.sing hints that
A will be found to equal G for most 3rd positions.  My impression of the
solid fa#cts is shown in the enclosed picture.  The only item which really
bothers me is the mechanism by which arginine can mutate to serine, a very
frequent result observed by Yanofsky.  This is a crucial point since it is
involved in his genetic data' which suggests that the direction of tra.ns-
la,tion 1s 5' to 3'.  I thus wonder if there is any good evidence against
believing that AUA or AUG codes for serine. If so, then it is understandable
why cell-free extracts from su- strains incorporate some serine (result of
Haselkorn) when an AGU copolymer is used.

  Here our main excitement comes from the study (by my students Mario
Capecchi and Gary Gussin) of the template activity of RNA from a sus-
mutant of the RNA phage R17.  They have an in vitro system which tells us
that the ~~63 suppressor gene causes the production of a new type of SRNA.
This, if added to a sus- in vitro system,
the production of coat prxein)     causes suppression (as shown by

  On the E. coli mutant front, Wally now a.t last may have evidence tha,t
polynucleoti??e phosphorylase breaks down RNA in viva, Our hunch now, however,
                                                          v-
is that it cannot be the sole answer to mRNA breakdown, but that it works
only if another enzyme working from the 5' end starts the breakdown process
by nibbling off the nucleotides at the 5' end. When this happens, no new
ribosomes can attach, thus leading to an a.bsence of ribosomes at the 3' end.
Then polynucleotide phosphoryla,se attacks the 3' end. In this way the polar
mutants, as well as modulation, may find a. simple explana.tion.  To prove
this we must find an E. coli enzyme which works from the 5' end.
                           --

1 hope by now that Odilie is fully recovered.

Regards to all,

   \
     I* -

James D. Wa,tson

JDW:jb


GENETIC CODE AS OF WFCH 30, 1965:

u








C



1st*



A








G

-

PHE (B)**
PHE (B)     iz3.m 09
        SER (B) i  TYR (B)
               'ixft (B)   CYS(B) u!
                  CYS b) C 1
LEU (B)                                 A 1
        SER (B)                 TRYP    G f

        PRO 09     HIS           I

LEU       PRO (B)                  u ;
                       HIS                  c ;
                       GLUJ!?
                       GLUN        : .A i
                                  .'  G '

;----I

ILEXJ (B)      THR?
SLEU (B) :          Q3PN (B)
           THR?      ASPr? (B)      ; u j

          TRR '  LYS (B) ' .Q?G    ; c ;
                                          : 4
               LYS (B)      j G )

                                                                     pl   I

-- -1--v

VAL (B)
VAL
VdL'!
VlrL

ALA?     !   ASP         GLY
!u&~!.? :   ASP         I     ; u 1
                     GLY
ALA? '
ALA?    GW (B) i GLY   I A 1

          GLU        ' c i
                              G !
         1

*the order of each triplet is 5' to 3'
+N (B) denotes sRNA binding data

Copolymer Results of Khorana:

ARG     GLU
A&.GAGAGAGAGAGAGAGAGAGAG

Lq?     SEX
cucucucucu&Jcucucucucucu

CYS     V.4L
UGUGUGUGUGljGUGUGUGUGUG~JG

TKR     HIS
ACACACACACACWACACACkCAC