November 22, 1955

Dr. Clifford Grobstein
National Cencer Institute
Bethesda 14, Maryland

Dear Cliff:

It has taken m this long to get around to the Medical Library so that
I could answer your letter the 2d.

I must say I am not mch impressed by Paschkis' arguments—- they take no
account af the possibility that the still viable cells are slightly altered
in their physiological capabilities by the treatment, or by the residue of
DNA with which they are mixed. Klein's argument is not irrefutable (as he him-
self was careful to point out) but 1t certainly seems to pit Pastis et al.
under some burden of proof, I have talked this work over in some detail with
Klein and Hauschka— perhaps it would help if I esimply enclose a short ms.
that I wrote (as a so-called discussion of Klein's paper) for a NYAS conference
on ascites tumors. Please send it back at your convenience, ds I think this is
my only copy.

To my mind there are two issues: the physical dimensions of the agent (par-
ticularly is it as big as a cell, nucleus, etc.), and its genetic scope. I think
it would be very hard to get a convincing result on the former even by filtwation/
methods, though this can well be worked up. I do think a very easy experiment
would be to verify whether DNAase inactivated the chromatin {‘and(presumably ) not
control cells; the same could be done with other enzymes or combinations of enzymes.
Enzymatic treatments might also help to clear up the mess to tell whether there
Were actually som cells in the soup/

As to the second question, one should expect to find some MBER separability
of markers, if the transductive interpretation is correct. Novikoff is, I think,
confused: the point is not shat different markers are sometimes linked, but that
they usually are not. Klein's experiment tried to demonstrate a separation of
tumorigendsis from histocompatibility, and failed. Why not try other markers? Would
not the lymphosarcoma be amenable to the use of drug-resistance as another marker?

If no separation of markers can be found in these supposed transductions, there
is still the problem of identifying the agent. It would hot have to be the intact
cell— it might be a nucleuad or large niclear fragment. But I think the most con-
servative reaction now is that probably there are cells, perhaps damaged in some
way, in the chromatin preparations.

Give my best to Lloyd Law..; Sincerely,

Josgua Lederberg