Feb. 2, 1960

Mahlon B. Hoagland, M.D
Massachusetts General Hospital
Boston th, Mass.

Dear Dr, Hoarland:

The question I had raised in my letters to Mr. Pfeiffer and your father was not
intended to concern itself with how mutations were produced or teok effect but with
how the mechanism you deseribe in your fascimeting recent article in the Seientific
American could have evolved. I intended to convey the idea that neither the presence
of transfer ribonucleic acid nor of protein enzymes specialised for the separate
amino acids could have been necessary in the first place for the stringing together
of amino acids into protein in the earliest forms of life in which protein was manu-
factured according to specifications set by nuclectide-chains. There must be a much
simpler though doubtless much less efficient and reliable method by which the nucleotide
chains are able, in the most primitive forms, to string the amino acids together to
form protein, otherwise the system could never have evolved. At least, according to
the view which © have put forward for nearly forty years, the most primitive thing
deserving of being called living, namely, the zene or primitive virus, now to be iden-
tified with a nucleotide chain, must have been able, with the help only of fortuitously
preformed organic molecules (such as addnogine pyrophosphate) floating in the mediun,
to synthesize (after scitable mutations in the arrangement of nucleotides in the chain
hed oceurred) heloful companion substances, among the first of which would have been
proteins. (ne cannot suppose specific proteins that would serve as enzymes for the
amino acids had been fortuitously formed first and were at hand for th- further pro-
duction of proteins, with the cooneration of the nucleic acid chain, for that would
tie the cart and the horre un together in a circle.

It happens by a coincidence dhat exactly the thought I hed in mind was much bet-
ter expressed in the article by Lederberg (his Nobel lecture) thot appeared in the
last iseve of Science. It ecmes just at the close of his articl«. I think that most
geneticists would agree with Lederberg and myself on this point. It is, of course,
by no means an objection te your findings or theory, but only means that the circle
of formation of proteins cannot really be a closed one even though it now works in a
pretty much closed way; that is, there must have been methods, no doubt less effective
ones, of gettin the same end result, the orotein, without the intermediation of a pre-
existing protein, and possibly even without the intermediation of the transfer nucleic
acid unlese perhans that originally represented only blocks cut out of the original
nucleotide chain, that is, out of some of the examples of that chain.

It is very presumptuous of me to write you in this way since i am not a biochemist.
Let me assure you that i have the higheet regard for the work you have been dcins along
these lines and for the whole body of recent werk on this topic. I think that in the
natural course of biochemical progress the questions i hav:. alluded tc will become re-
solved, but it is just as well that they be recognized sc that clues to them may be
picked up when found. ot: a. .)

With perscnal regards,

Yours sincerely,

Teen tye !

HJMetelh : H. J. Muller

ec: Nr. John Pfeiffer V
Dr. Hucson Hoagland Or. Lederherg