A surprise it was! Your gift arrived intact and was received with great pleasure by all of us in the family. As you can
see it also brought forth a letter from me, admittedly long overdue and with apologies. No excuses, although you must know
that I wouldn't forget to write in due time.
We are working hard in the lab these days with a sense of excitement that we may shortly have some important answers to the
question of how hormones activate adenylate cyclase systems. The clue to this mechanism is the role of nucleotides, particularly
GTP, in this process. We are fairly certain that GTP acts at a regulatory site that mediates the actions of all hormones
operating on adenylate cyclase systems and that the regulatory site is proximal to the catalytic site where ATP is utilized.
Based on kinetic analyses of substrate utilization, our tentative conclusion is that GTP probably alters the conformation
of the catalytic site in a manner that reduces the inhibitory action of free ATP (uncomplexed with Mg) and increases the binding
of Mg at a site involving a crucial sulfhydryl group at the active center. Computer fitting of our glucagon binding data
coupled with studies of the effects of sulfhydryl agents on this sulfhydryl group indicates that glucagon induces a change
in subunit interaction resulting in increased reactivity of the regulatory site with GTP. We have also discovered a universal
"hormone" in the form of Gpp(NH)p, the analogue of GTP. This nucleotide is not metaolized and causes the same increase
in rate of adenylate cyclase seen by addition of maximal concentration of hormones in the several types of adenylate cyclases
systems we are examining (adrenal, salmon red cell, frog red cell, hepatic membranes, and fat cell membranes). The nucleotide
causes the same effects on all these systems. With this nucleotide, we now are getting close, as stated above, to the realization
of the final stage in the regulation of adenylate cyclase activity. Hopefully our computer modelling will fit our experimental
data in a meaningful manner. If so, we will then be prepared to look at the chemistry of the adenylate cyclase system with
a sure background of what we are doing.
Perhaps in five years or so we will have the important answers available on hormone action. Not a long time considering that
man has been around for millions of years. Of course we could say that what man didn't know didn't seem to hurt him.
The search for knowledge is a wonderful way of spending your life, even if the final outcome is misunderstood or misused by
society at large. We, as scientists, must take that risk. After all, the only unique feature of the human is the ability
to integrate information. Considering the total human nerve cell capacity on this planet, it is surprising how long it takes
man to achieve a rational approach to an understanding of himself and his relationship to the universe. Sad to state, he
hasn't yet learned how to overcome his emotions. War, plague, famine hover around us continuously. Collectively, we
should be capable of preventing such catastrophes. The point is that man hasn't learned to use the essential conflict
of motion and reasoning in a constructive manner. So, we see the best of Israel and Arab youth succumbing on the battlefield.
I hope that your studies in Bangalore are going fine. I will be visiting Irving Fritz over the Christmas Holidays. It would
be wonderful if you can come to Canada in the near future. Meanwhile, keep up your spirits as always.
With fondest regards, I remain
Martin Rodbell, Ph.D.
Chief, Section on Membrane Regulation
Laboratory of Nutrition & Endocrinology
National Institute of Arthritis, Metabolism and Digestive Diseases