UNIVERSITY OF CALIFORNIA

DEPARTMENT OF ZOOLOGY
BERKELEY 4, CALIFORNIA

October 23, 1953

Dre Joshua Lederberg
Department of Genetics
University of Wisconsin
Madison 6, Wisconsin

Dear Dr. Lederberg:

I truly appreciate your letter of October 19, The ideas that
one admires most are those that he would never have created himself,
and this applies to your comments on the reversibility of transduction
effects in the cell that is the primary receptor. If the externally
introduced agent acts by some sort of competition with its counterpart.
that is already present, then it could only be fixed by being trapped
by cell division in a cell that has lost the normal counterpart. Do
I understand correctly that this is your picture of what happens? Re~
gardless of mechanism, those experiments on Salmonella that you describe
are most elegant.

The experiments on embryos were carried out at my Suggestion by a
graduate student of mine, Ruth Neff. While I find that graduate stu-
dents perform best in experimental work requiring strong motivation,

I feel that they earn proprietary rights to the problem in doing so.

In this case, the work has been delayed by the wanderings of Ruth Neff,
and I have done nothing myself until she could complete as much of her
plan as possible. She is now at Vanderbilt, where her husband is teach-
ing in the Zoology Department and has carried the work further. You
will recall that Brachet reported that he was unable to confirm our ex-
periments, On returning to the work, Ruth too began to encowmter in=
consistencies in her results. After a great deal of work, the reason
finally was discovered. It appears that the active agent, although in=-
sensitive to many other treatments, is extremely sensitive to conditions
of low pH. In ordinary work on the isolation of DNA, insufficient pre-
cautions are taken to prevent this. Zamenhof tells me that the same
situation holds for "transforming principles" that he has studied. He
finds that they are extremely insensitive to heat, compared to most pro-
teins, but, unlike many proteins quickly lose their biological activity
at pH levels not too far below neutrality.

Mrs. Neff still finds that the species-specific embryo~blocking
activity does not depend on a high polymer state of DNAe In fact, her
best method of preparation involves extraction with the aid of desoxy~
26

ribonuclease. We have found that DNAase ordinarily liberates very little
material other than DNA fragments. If the currently fashionable hypo~
thesis assigning the specificity of DNA to nucleotide sequences is true,

I don't see why the specific units need be very large. Whether a piece

of DNA retained its specificity or not would, it seems to me, depend less
on the size of the fragment than on the use of a technique that would pre-
vent uncoiling or separation of chains. The work that James and I did on
surface films of DNA indicated that a lowered pH did bring about an ir-
reversible decrease in the thickness of the molecule that could easily be
interpreted as an unravelling of chains.

If you do not mind, I would like to tell you about some other work I
am doing that relates to your interests. As you may know, I had worked
for a long time on the factors responsible for chromosome continuity, and
had been forced to the conclusion that we were dealing with a protein con-
tinuum because the only means that was found for "dissolving" the chromo-
some involved splitting of peptide bonds. Recently, some work done by
Bernstein in this lab, working with sperm heads, showed that the chromosomal
material could be dispersed into a solution of macromolecules containing DNA
and protein by the following sequence of operations. The material was ex-
posed to citrate, which presumably removed some divalent cation, then to a
medium containing no ions at all. If citrate was omitted, the material hy-
drated but the particles could not come ppart. We interpreted the citrate
effect as being possibly an effect on the membrane. But, now I personally
have done a series of experiments at the cytological level, using inter-
phase, mitetic, and meiotic chromosomes from a variety of sources. TI find
consistently that I can literally dissolve the chromosomes by application
of citrate and water, but not by either of them alone nor by the reverse
sequence,

This may seem like a pedestrian sort of experiment, but if one thinks
about it, it seems to mean that the chromosome is after all a fundamentally
particulate structure, with the particles being bonded by electrical and
ionic forces alone. (The ionic factor being intermolecular bridging by
divalent cations). The existence of identifiable chemical discontinuities
bears on a number of questions, including the ideas of my colleague Gold-
schmidt with whom I have not yet had the opportunity to discuss the matter.
It is conceivable that a point of attack for the mechanism of crossing over
or recombination phenomena can be found. It is even conceivable that some
sense could be made of the distinction between "point mutation" and "re=-
arrangements." At any rate, I am still doing the pedestrian part, trying
to identify the discontinuities, and would be interested in your reaction
to this development.

It is incredible that we are not better acquainted, considering our
common body of friends, and I hope that we can correct this before too
long.

With many thanks and best wishes,
Cordially yours,

Wana Mags

DM:th Taniel Mazia