. .

Dear Dr. Edmrds:

  It was most gratifying to hear from you, 2nd to find your interest
in our work. It is particularly fortunate,1 think, that we do differ in
our formulations of the 5nlmoneU.e story, re~lizihg that I have had to
approach the matter on a entirely a priori basis with some genetic ideas

transported from other organisms, while you have shd all the practical

and experimental aontz&t tvith these org+nisms.

  The cultures &d serums which you sent have been received in good
condition, r;rld we are set to go to work with them iBiaed3.atel.y. However,
a new tack has suggested ifself which modifies somewhat the approach I
suggested previously, There seema to be already available in msny Salmonella
types a diversity of nutritional requirementls, which should be as usable
a3 induced nutritional mutants in detecting gene recombin~&iona. Therefore,
instead of selecting, at this .x&z atage of the game a particular antigenic
type+, a -large series def Salmonellas will be workdd over for their
nutriti&al requirements, nnd those selected lzhich will be on that basis

most. convenient. I have been able to obtain it fe-# varieties alrend from

the Columbia cLnd Yale Laboratories, and have enlAsted Dr. :iheeler!s

cooperation in extending that Ust,

  There seems to be a most striki@g analogy between phase vririation
in Salmonellti and some features in the inheritance of mating type in
Paramecium bursaria as described by Jennings (Proc. Amer.Philos. SOC.,
85:25, 19fJ.j, in particular the phenomenon of 'self-differentiation'.
Jennings finds that a clone of a given rating type (of which there are
four alternativesj may give rise to org<tirnns of a different type; dif-


ferent clone8 of a given mating type characteristicaUy ~aelf-differentiate~

to a given alternative, which may be different for different clones. The

czone OCFkained in this way may In turn 'self-differentiate', always to

tile original type . Although F'ara:.scium i6 a 8cxL131. Ibr@nism, the gek%'biC

bsxi.ti of this phenornen@ 18 still quit.6 Obsxr6, and hybridization experixmnts

so far hhve shed no great light on the matter. 1 do not know whether any

attempt has been made to characterize =ti.ng type seroiogicaXLy.

It will be some tisrs before the survey of nutritional requirements in

Salmonella will be com&eted, but we shall, of course, keepciyou informed in

detail of our progrese. Whd.le Dr.  "heeler's collection should be adequate,

we would appreciate the opportunity to ascertain the nutritional requirements

of any strains 3x1 which you may be particular interested.

Re-reading my original letter to you, there

that I did not expreea quite clearly, In order

standing, the situation should be reviewedi

a) The E. coli xork dtmanstr&& that Qere

    detenaine such chwactera as nutritional

   tibility.

seem to be some considerations

thattheremaybs no misunderdr-

are genes in bacteria which

reqtireinents , and phage suecep-

bj In IL coli, different substrsins can be hybridized giving rise to new

types, characterizable as recombinations of the different characters

as the parents.

Ke ha\:e no avid~nco as yet as to the inheritance of antigens, nor as

to the occurrence of gene recombination in, or Between Salmonella

strains. In ii. co& the recombintltion of nutritional requiremanta can

be used as a b&.a for aeleciing out of a large number of cells those

few in which recombination has occu'reci. In such cells1 the segregation

of other genes can be determine&

In Salmonella, recombination of nutritional requirements must first be

detersdned. If this occurs, we are in a position to study the inheritance

of other characters (such as antigens).


Only if a system of inheritice of antigens can be formulated on the basis of
lcrossest can the problem of phase variat&on be studied. It probably will. be
beat to use a form which is normally almost entirely monophasic, but in which
the alter=tive phase can be ciotected ana selected for by well-know1 methods.
Pwenthetic~lly, the expression 'inauced Variation' has a rather different
connotation in genetics Irom ti2.d in bacteriology. It is taken to i.x@y a direct
action of the inducing agent on Lhe hereditary materials of the organina. Unless
there is direct evidencs to the contrary, cases of apparent induced variation
are formulated as instances of selection in favor of a small proportion of
spontzneuusly occurring variants. Your own work seems to bear this out in balmonella.
In the bacteria, only the pneumocaccus transformations have been accepted by
most geneticists as bona fide examples of 'Induced Varaltion~. There may of course

be others.

It would be most convenient to have a set of specific Salmonella phages. Can
you suggest where ~hqy might be ob-dine d, arid rrhat references there may be in the

liteaature?

Finally, I hope that I shall &ve :an opportunity to vi& your laboratory

sometime -in the next year, but thaw is nothing definite in sight RS yet.

                       Very ahcorefy yours,

. Joshue Lederberg.