Mr,Ri&mrdMorgm
27418 sixth Avenue
Sacramento, call.fornia

Dear Richard?

      I have been thinking &out the matter that we discussed on
your lad trip here 0 the quertion of our collaborating with your de-
partment in sn attack on mental disease.

      I think that it would be possible to fonmrlate a program
that would be of intereat to you and would also fit Zn satisfactorily
with our facilities and interests.  The proposal is that we would carry
on 5ome fundamental studies relattPd to the possibility that some mental
diseases are Lmolecular diseases.

      You know &bout the discovery of' molecular diseases - our work
an sickle cell anemia, published in 1349, and the nor& recent develop-
ments.  I enclose two copies each of our first paper and a review
artlcla, my Harvey Lecture, given last year. The history of 11101ecular
diseases is that, although all hereditary diseases may be cslled moleeu-
lar (fieeaae6,in that It is likely that &z&es are molecules, and heredi-
tary diseases may be a:scribed to sbncmnalitiea of genes, and possibly
to abnormalitfes of other rpolecules manufact*ured under the guidance of
genes, sickle cell anemia was in fact the first disease shown clearly
to be caused by c&mwmal molecules, present Pn the bodies of patients
in place of normal adult human henmglobin molecules.  In the Harvey
Lecture mention is msde of other diseaseee, due to the abnorm5J. hemo-
globins C, D, and E, whtch were discovered after the work on 5ickle-cell-
an&a hem&&bin.  During the past year several mre abnomal hem-
globins have been discovered.

     In 1934 it was found by F&ling that a considerable nu&er of
indivfduals showi% idiocy, or imbclicity, or occs&onally feeble-minded-
ness, excrete large amounts of phenylpyruvic acid in their urine. This
biochemical. abnorsnslity, which seems clearly to be the cause of the mental
deficiency, is presumably the result of the inability of the individual
to carry out the axichtion of phenyltianlne to tyrosine.  I think that it
would be worth while, in ord5r to verify this a.5 a molecular diisease,
which it presumably is, to attempt to izaolate a protein similar to but
somewhat different from a protein normally present, which is involved in
this oxidation - that is, one of the enzymes. If this protein could be
isolated, Its inveetigation might provide valuable information about
the nature of the disease.  It is, of eourae, not to be expected that a
study of this sort would leaia &mediately to a therapy for the disease -
we would be interested primarily in obtaining basic information about the
nature of mental disease, which would later be useful in the effort to
develop new therapeutic methods.


Mr. #organ

2w55

      I may ss~ that there Is some evidence that the enzymes
involved are in the liver and not in the bloodstream. Fremmably
our inveetigation along theee lines would, have to begin with the
study of the enzyme-catalyzed oxldation of phenylalanine, probably
with beef liver as the starting materisl, and only later would
human enzyme be studledr

      A sacondpart ofcmrpropomlmightbethe search for
other biochemical abnormalities in mental patients. This part
has, I think, significant possibilities, but it would, of course,
be a big job.  I think that it would begin with the study of samples
of blood and ur&$e*  It ira impossible to make an exhaustive study of
this sort, because of the labor involved; : we wou.$d try to move in
the directions that seemed to us to offer the greatest chance of
leading to a eignlfieant discovery.

      f should not went to e&ark on a program of this sort
unlessl there were fund8 available for support of more than one fuU-
time research maxa (perhaps two or three) and for the equipment neces-
sary for the work, and also, over a continued period of tine. I
would look on the job as a &year job ; that is, as extending until
my retirement, inlS)tjg, aad Z gmobablywould notwantto embark upon
it unless there was defi4te indication of support over at least a
%year period.

        Fleas,> L let me kuob if you want my mm information -
more copies of these reprints or of others of our papers, for
-pie .  I shall Look forward to having a confereuccl? with you and
other zezibers of your departmat later on.

Sincerely yours,

Linus Pauling:W
Encls .