Cond MAY 9° 4 1978

Yale Universit y Box 1937 Yale Station, New Haven, Connecticut 06 520

DEPARTMENT OF MOLECULAR BIOPHYSICS
AND BIOCHEMISTRY

(203) 436- 4819

May 22, 1978

Dr. Joshua Lederberg
Department of Genetics
School of Medicine

Stanford University
Stanford, California 94305

Dear Josh:

Although you must be inundated with unsolicited advice for RU,
let me nevertheless toss my own into the hopper. Probably you would
agree with the premise that development 4s the central and most
germinal problem in biology today, I find it helpful to divide the
problem into two sequential domains, the first involving the establish-
ment of the developmental program, and the second the expression of
the program. This division is perhaps most clearly seen in Drosophila,
in which the transition occurs at the blastula stage. During oogenesis,
the developmental program is generated as a two-dimensional epigenetic
pattern in the oocyte, and afterwards the program becomes irreversibly
fixed at the cellular level when cell boundaries are demarcated in
the blastula. This phase, as you know, is still virtually a total
mystery, the oocyte remaining a black box. I expect the situation
will change dramatically soon as new techniques are exploited, parti-
cularly gene cloning and antibody cloning, which are ideally suited for
this purpose.

The subsequent expression of the developmental program appears
to involve both constitutive gene functions and inducible gene functions
that respond to extracellular signals, such as cell-cell surface
interactions and hormones. Recently, I have become interested in
the developmental role of hormonal signals, particularly of steroid
hormones as exemplified by ecdysone in Drosophila. I have enclosed
a reprint of our initial foray into the field. What has impressed me
about ecdysone, and I expect this applies to steroid hyOmones in
general, is its involvement in almost all aspects of development and
adult functions. Apparently, nature has chosen to use a ubiquitous
simple signal for ¢he. ,large variety of different responses. Specificity
is achieved by chastges in hormone titer during development, which allows
for different responses at different times in the same tissue, and
by tissue-specific receptors which allow for different responses at
the same time in different tissues. There is not much known about any
of the three principal aspects of steroid hormones, either regulation,
biosynthesis or response. One of the attractions of the problem is
the likelihood that the basic mechanisms are general for all eucaryotes.
Dr. Joshua Lederberg
May 22, 1978
Page 2

This glib overview of a complex topic is intended to bring to
your attention the possibility of establishing at RU a section,
that might be called Developmental Endocrinology, composed of three
laboratories, one interested in basic mechanisms probably best
studied in Drosophila, another in mammalian aspects for which the
mouse should be the best organism, and a third clinically oriented
towards human diseases resulting from steroid hormone malfunctions.
A tripartite section of this kind could be truly complementary, in
view of the commality of biological effects involved with all
steroid hormones.

If this approach interests you, we could discuss it further
after you and your family have resettled.

Cordially,

Mao.

Alan Garen

AG:m]
Encl.