Avery Gateway Dedication
September 29, 1965
Dr. Stanley
Friends of Dr. Avery: I came to the Rockefeller Institute in 1931.  For one year I had the great pleasure of walking the corridors of the Institute, having lunch and, as just a raw, new Ph.D., being just a little bit starry-eyed with people like Landsteiner, Levene and Dr. Avery, as well as some others who, because their interests were a little bit more diverse, I knew less well.  I then left and went down to Princeton.  There I had the good fortune of becoming acquainted with and knowing Dr. Theobald Smith.  So the Institute has given me an opportunity to be with and to remember and to walk with and to dine with, some of the really greats.  Dr. Avery will stand high among them.  And this afternoon I am going to attempt to help you understand, and perhaps it has helped me understand once again, why a discovery which is literally one of the greatest discoveries of this century was fully understood only by the three men who made the discovery, and why the full significance of it had so little impact on the rest of us at the time.  I'll have to talk a little bit about nucleic acids, but I'd like to quote from a paper that Dr. Bronk mentioned.  This is the famous paper of 1944 by Avery, McCarty, MacLeod.  I shall have quite a few quotations, as a matter of fact, to show the real conceptions and the misconceptions as they existed over the years with respect to this material, nucleic acid.  In their paper they stated: "Highly polymerized nucleic acid must be regarded as possessing biological specificity, the chemical basis of which is as yet undetermined."  Now that statement represented, I think, one of the landmarks in biological and the medical sciences.  And it came just a little less than a hundred years after the discovery of the material that we now call nucleic acid by Miescher in 1869, working initially with pus cells and then later
with the heads of salmon sperm.  Miescher identified the material reasonably well chemically; he understood the fact that there was a type of assault between nucleic acid and the protein material of protein, and he did some really remarkable chemistry.  [HANDWRITTEN NOTE: The tape is clear, but perhaps Dr. S. misspoke himself.] For about 30 years, the chemistry of nucleic acids was very good, and this includes the beginning of the work here at The Rockefeller Institute by Phoebus A. T. Levene.  Levene, I think, came to The Institute in 1907 [HANDWRITTEN NOTE: ? Corner says 1905], but had been working here in New York City on nucleic acid since 1901.  The structural organic chemistry which was done over those years, beginning With Miescher's more biological work and through the work of Levene and Jones at Hopkins, was top-flight organic chemistry.  And you would have thought that it would have worked out very well.  The biologists became interested in nucleic acid quite early, and here I would like to quote from a book written by E. B. Wilson just at the turn of the century, when he wrote that chromatin, a nucleic acid material, is known to be closely similar to, if not identical with, a substance known as nuclein, which analysis shows to be a tolerably definite chemical compound composed of nucleic acid and albumin.  Thus we reached the remarkable conclusion that inheritance may perhaps be affected by the physical transmission of a particular chemical compound from parent to offspring.  Contrast this with the strictly chemical work, where the relationship to biological specificity did not occur, apparently, to the chemists.  Yet the biologists of those years, in 1895 and continuing on with increasing fervor for about 20 years, re-expressed this general idea that nucleic acid had to have something to do with genetics.  And then came what, to me, is one of the most remarkable turn-arounds in medical science.  And I can again quote from E. B. Wilson in his book, The Cell, which he wrote in 1925.  He said, "Apart from the characteristic differences between animals and plants, the nucleic acids
of the nucleus are on the whole remarkably uniform (as the two preceding speakers have already indicated), showing with present methods of analysis no differences in any degree commensurate with those from the various species of cells from which they are derived.  In this respect, they show a remarkable contrast to the proteins, which, whether simple or compound, seem to be of an inexhaustible variety.  It has been suggested accordingly that the differences between different chromatins depend upon their basic or protein components and not upon their nucleic acids." This is diametrically opposed to what Dr. Wilson apparently thought and wrote 30 years earlier.  Can we explain this?  Well, I think we can.  And, being a chemist, perhaps I'm in a better position to attempt to explain it than is a biologist.  I think that it was due to the really great chemistry of a colleague of mine here at The Rockefeller Institute, and this is P. A. Levene. Levene was one of a very small number of people who did excellent work on structural nucleic acid chemistry.  After Miescher there was Posel, then Levine and Jones, and they had very few colleagues.  So all of the work on nucleic acids was in the hands of a very, very small number of people.  Levene was the leading proponent of the tetranucleotide theory of the structure of nucleic acids; in other words, that it's composed of four building blocks and that these are repeated over and over again.  I can quote, to try and give you a little bit of the flavor of the time, from a book which Dr. Levene wrote with Bass in 1931.  On page 276, for example, it's written: "Thus the tetranucleotide structure of yeast nucleic acid has been reestablished by the analytical method.  It will be seen later that the formulation of Levene has been confirmed by the physical chemical method."  On page 289, they state, with some reservations now, about the structure: "On the other hand, it must be borne in mind that the true molecular weight of the nucleic acids
is as yet unknown.  The tetranucleotide theory is the minimum molecular weight and the nucleic acid may well be a multiple of it."  You see, there is still no idea of biological specificity.  They're thinking just about four things tied together over and over again in a monotonous polymer.  This, I think, was the feeling of the times.  As Dr. McCarty and Dr. MacLeod have already indicated, when they began to work on the transforming principle, it was a very different and a very difficult scientific atmosphere.  I can well remember those days, because, as Dr. McCarty has already indicated, I was interested in this phenomenon from the standpoint of the possibility that they might have a bacterial virus.  I remember writing in those days -- 1937, this was: "It is obvious that there is a factor which may be obtained from any one of the S-type organisms that is normally absent from the type-R cells, but when added to such cells induces their conversion into the same type of S organisms in which the factor was derived, with the very important result that more of the factor is produced in the induced S Cells."  Then I state: "This phenomenon is virus-like, and it is because of this and the fact that it may become important from the standpoint of the chemistry of viruses that a discussion of it is included here."  Then I went ahead with the same sort of story that has already been presented to you, and ended up by: "No chemical tests at that time had been made, hence nothing is known about the nature of the active agent.  It is to be hoped that the study of this agent will be continued because of its virus-like nature.  Well, as you well know, within a very few years after that, the three scientists did obtain definite information concerning the fact that it was deoxyribonucleic acid.  You would have thought, and I must say reminiscing can be very damaging to your ego, you would have thought that with this and my knowing about it in 1944, and having obtained tobacco mosaic virus as a nuclear protein a few
years earlier, this would have impressed me tremendously.  I have delved deep into my brain to try and explain why it didn't.  I don't know whether it was because tobacco mosaic virus had RNA in it instead of DNA, but DNA was supposed to be the genetic material and RNA was thrown over to one side as being different.  I sometimes wonder if, because the war came on at this particular time, we dropped all of our fundamental work and went into the work for the Armed Forces.  In any case, it is a sad commentary on my own intelligence that this did not have the effect that it should have had in 1944 and few years after that.  I simply cannot explain it, except that I am in a company of a few other people who took almost ten years before the significance of this really remarkable discovery was fully recognized.  It took, in my own case, the isolation of tobacco mosaic-virus nucleic acid, and the proof that this RKA had biological activity, to really shake me up and force me to go back and realize how fully I had been missing a real pearl, which was right here at The Rockefeller Institute over these many years.  You see even the work of Alexander and Lidy [HANDWRITTEN NOTE: Hattie Alexander?  Leidy?] on the transforming of the influenza bacillus still didn't shake up the scientific world very much.  The later work of Hershey and Chase [HANDWRITTEN NOTE: Is this J. Chase?], which was as late, I think, as 1952 and the work that Hotchkiss did here, started the rumbling that finally resulted in the beginning of the recognition that should have come many years before.  There was the discovery by Lederberg and Zinder of the transduction phenomenon, which was even before the isolation of tobacco mosaic-virus nucleic acid.  But then a literal revolution has taken place in the last 15 to 18 years.  There's been an accumulation of a half, almost three-quarters, of a century of welling up of information.  At long last, sorting things out the way they belong, scientists have finally realized the great significance of the 1944 discovery.  This now, with tremendous work in molecular biology, is one of
the most active fields in all of science.  I think also it is one of the fields of greatest potential benefit for mankind, as we learn more about the tremendous information which can be wrapped up in nucleic acid in the way of genetic material.  As has been stated, perhaps by one of the members here at The Institute, there is the potential eventually of controlling the messages that are contained in nucleic acid, and I think you may learn from Dr. Holley in just a moment or two about some of the progress that has been made in elucidating the structure of the nucleic acids.  There has been, in the last 6 or 7 years, a tremendous amount of excellent work on viral nucleic acids and, as you probably know, quite a number of the viral nucleic acids have been isolated in pure form.  It has been discovered, first in Sinsheimer's laboratory and then again in Ochoa's laboratory here in collaboration with our laboratory, that nucleic acid, be it RNA or DNA, can act as genetic material; that when it is reproduced, it can form a helical double structure in a ring-type form, which, from the standpoint of nature, makes it a beautiful way to reproduce its own kind.  You put a little polymerase [HANDWRITTEN NOTE: Should this by polymeric?  Tape note clear] molecule on the ring and it can run right around and read off all of the messages you see there.  In the case of these viral nucleic acids, they themselves are the messengers, if you are familiar with the current dogma with respect to DNA, RNA, and protein.  Now we can go back to this discovery of Avery, MacLeod, and McCarty in 1944.  If you read the scientific literature as it exists today, you will see that this tremendous discovery is receiving, at long last, the recognition that it truly deserves.  The impact comes slowly sometimes, but it comes with resounding force when it does happen.  I appreciate very much the chance to come back and, in some small way, participate in this tribute to Dr. Avery.  I never worked with him, but he was one of the greats whom I liked to brush close to as I walked the halls here in 1931.  Thank you.