[Colin MacLeod's remarks at the dedication of the Avery Memorial Gateway]
Like many remembrances of Avery, this one focused almost exclusively on his scientific accomplishments. McLeod's notes
of his remarks at the dedication of the Avery Memorial Gate at Rockefeller University outlined Avery's prominent place
in the still developing field of molecular biology.
I'm not sure whether Dr. Avery or I had a greater dislike to talk before an audience or was more intimidated by it. On
second thought I guess I'm not quite as reluctant as Fess was about "wasting people's time in listening to his
thoughts" - but the difference is not great. I went through two experiences of this kind with Fess: once when he was
President of the Society of American Bacteriologists and had to make the presidential address, and the second time on the
occasion of the 50th anniversary of the founding of the Hoagland Laboratory at the Long Island College of Medicine, where
Fess had worked with Ben White before Dr. Cole persuaded him to come to grace the Rockefeller Hospital. These were occasions
when Fess made his rare public appearances to address an audience as the principal speaker.
We had a great deal of fun about his talk to the Bacteriologists, which, as Fess would say, "was a pretty good talk, if
I say so myself, and I shouldn't." We talked about whether he should say that bacteriology is the "Queen of the
Biological Sciences", or, as I might suggest, the Grown Princess, because she hadn't arrived yet; and so we spent
the last half hour of the late afternoon, until Fess would say, "Let's go and see Do". And then a short three
and a half block walk across town to see Do, who would greet us, rubbing his hands and saying with enthusiasm, "Hey, you're
late, Fess. I'll make a Martini", which he would do forthwith, and when brought, would exclaim, "Fess, drink
it up before the bloom goes off it!"
And so then an extraordinary hour out of many, with these two wonderful gentlemen - bachelors - who knew about the goodness
of lift and of science and complemented each other in a way I have never seen elsewhere.
We might end up on this occasion declaring that bacteriology was not a Crown Princess or even a Cinderella, but more likely
a pumpkin. But you can be sure we had a stimulating time perhaps even blowing a few scientific bubbles, "which is all
right" as Fess was wont to remark, "so long as you prick them yourself."
Fess was fond of another and related small aphorism that many of you have heard him say and which expressed his distaste for
concepts that didn't lead to experiments. "Ideas are wonderful things," he would say, "the trouble with them
is that they don't work unless you do." - and he certainly worked at them, even to the final and almost uniquely painful
experience for him and for us of getting them on paper in clear, economical English sentences.
I would like to tell you briefly about some of the Professor's scientific interests that antedated the studies of genetic
transformation. I do so because of the threads that run through the work, and also so that the scope of his interests and
range of discovery will be appreciated.
My acquaintance with Dr. Avery included only 20 years of his enormously productive scientific life. There are more than 20
years going before that I don't know at first hand - except that listening to the Professor's tales about the development
of knowledge of pneumococcus and the diseases it causes, about streptococcus and its diseases, about the reaction of the body
to disease, and the development of clinical investigation in its modern sense - unless reliving these experiences with him,
and with Dr. Dochez, with Dr. Cole, Bill Tillett, Tommy Francis, Rebecca Lancefield and many other people, can be considered
almost as good as first hand.
It is well to remember that Dr. Avery was interested primarily in disease in pneumococcal pneumonia and the bacterium that
causes it, pneumococcus - and that his whole scientific life was devoted to understanding the disease, how pneumococcus is
able to exert its pathogenicity, the immune responses to it, how recovery takes place and how one can intervene. Through
his own work and that of the relatively small number of people who worked with him there was developed a truly remarkable
body of knowledge that illuminated the way for many other fields and has had a profound influence upon all of biology and
much of organic chemistry.
Let me emphasize that the Professor was interested in disease. I suspect, in our modern system of classification, that would
make him an applied scientist. If that be so, let's have more applied scientists.
As we said on many an occasion, disease is as natural a phenomenon as the freedom from it. There is also the more than valid
point of view that if you are going to work on the fundamental nature and reactions of a bacterial species, why not pick one
that has profound significance for human welfare: why work with E. coli when you can do just as interesting things with that
"lovely little bug, pneumococcus?"
The Professor had extraordinary respect, indeed almost affection, for pneumococcus and continually marveled as to how "that
little bug" could do all the things it is capable of doing.
He realized, with Dr. Cole and Dr. Dochez, before our entry into World War I, that to understand the disease process, pneumococcal
or lobar pneumonia, one must have a deep understanding of the causative agent, pneumococcus. It can be said without any hesitation
that the fundamental studies Dr. Avery and his colleagues carried out on pneumococcus had as their goal the understanding
of the disease. The disease was the rallying point; this kept everybody's eye on the ball.
Looked at in this proper light, the picture becomes clearer and more coherent. This accounts for the progression of observations
and concepts that began with the discovery of Dochez and Avery that the immunological specificity of pneumococcus is dependent
on the capsular polysaccharides that cloak the cell. That the virulence of the bacterium is dependent on these capsular substances
was shown shortly afterward and as a part of this demonstration, that antibodies specific for the capsule, protect against
the disease. All in all a very tidy picture, and one in which few of the implications were lost.
The discovery of the role of the capsule in the immunology of pneumococcus and in pneumococcal disease was a far greater one
than people now realize. Prior to this, it should be recalled, immunological specificity was safely and somewhat smugly categorized
as a property unique to proteins. That any other substance could have such specificity was simply heretical and the concept
was roundly denounced by some of the most prestigious bacteriologists of the day. "Contamination by protein" was
the cry (and one to be echoed and re-echoed many years later when we announced that DNA was the bearer of genetic specificity
- the prime mover}.
The rumpus about the polysaccharides was reminiscent of the outcry about purified enzymes shortly before. Sumner at Cornell
had crystallized jack bean urease and Jack Northrop at the Princeton branch of the Rockefeller Institute had isolated trypsin
as a pure protein. The difference in this case, however, was that the detractors insisted that the purified proteins were
not the specific catalysts but rather that some unrecognized substance present in very small amount possessed the observed
catalytic activity of the highly purified protein.
These controversies weighed heavily on the Professor's mind throughout his scientific life.
The Professor was marvelously persistent, however, especially when his imagination was caught, and he persuaded Michael Heidelberger
to come and work with him on the chemistry and immunology of pneumococcal polysaccharides and their antibodies. The whole
modern science of immunology stems from that association and the determination to understand the chemical basis of immunological
specificity of both antigen and antibody. Michael was succeeded in Dr. Avery's laboratory by Wally Goebel who carried
the work forward with imagination and devotion, as Michael himself has also to this very day.
By this time, in the late twenties and early thirties, the role of the capsular polysaccharides in the virulence of pneumococcus
was thoroughly established as was also the knowledge that anticapsular antibodies protect against the experimental disease
in animals and can be used therapeutically in treating the human disease. Although remarkably effective, antibody treatment
was not easy to apply because protection is type specific. Moreover, in pneumonia caused by some types, especially pneumococcus
type 3, with its huge, juicy, polysaccharide capsule, the therapeutic effect of antibody was simply poor.
With the firm knowledge that the capsule is necessary for virulence, the nature of the capsule well-known and methods worked
out for its preparation from cultures in large amounts, a very imaginative approach to the therapy of type III pneumonia was
undertaken. There was conceived the brilliant idea that an enzyme might be found in nature which could specifically hydrolyze
the type 3 polysaccharide on the surface of living cells and thus render them susceptible to phagocytosis and destruction.
(I should note that the main function in virulence of the capsular material of pneumococcus, the "schleimstoff", is
that it is antiphagocytic. Removal by digestion, theoretically, would render the microorganism susceptible to phagocytosis
It was at this time that Rene Dubos joined the laboratory and brought to bear his knowledge of soil microbiology on the problem.
A bacterium was isolated from bog soil, which in the presence of S III (type 3 polysaccharide) as the sole carbon source,
produces adaptively, or is induced to form, an extracellular enzyme, which specifically depolymerizes S III both in growing
cultures in vitro as well as in experimental infections of animals. The S III depolymerase was shown by Dubos, Francis, and
their associates in the laboratory to have a remarkable protective effect in infections of experimental animals.
The enzyme was never tested in human disease because by the time knowledge had progressed to the extent that would make a
clinical test feasible, chemotherapy of pneumonia by the sulfonamides had become a practical reality, which we all welcomed
The S III enzyme story is a particularly interesting one, however, because it represents a truly rational approach to chemotherapy,
based upon knowledge of the unique structure of pneumococcus which determines its virulence. In a sense, the fact that it
was not applied to treat human disease is by the way, because the conception and demonstration of the principle remain intellectual
The threads that link this story together are two, a preoccupation with the disease, lobar pneumonia, and the role of the
capsular polysaccharides in infection and immunity. Many facets of these and other problems were successfully attacked by
Dr. Avery and his associates over the period of some 40 years during which he was active in the laboratory.
The phenomenon of capsular transformation first reported by Griffith in England in 1928 was greeted with some skepticism on
the 6th floor of the Hospital. However, Henry Dawson was able to confirm it and with Richard Sia demonstrated that, under
appropriate circumstances, the phenomenon takes place in vitro -- a large step forward. A little later Lionel Alloway was
able to show, although not very reproducibly, that the active substance could be separated from the whole cells and passed
through a filter that holds back the bacteria. It took quite a long time after that to understand the process and to identify
and characterize the active material. That story I don't intend to tell, however, because many of the points that arc
most interesting to me would be least interesting to you -- and there are other people who will speak this afternoon from
a more important point of view, namely the impact on biology.
There are other scientific interests that I could recount such as the acute phase reaction of human and animal blood serum
with the cellular or somatic "C" polysaccharide of pneumococcus. This reaction was discovered by Bill Tillett and
Tommy Francis and later a good deal of work was done to understand it and to purify the reagents by the special brand of "kitchen
chemistry" practiced on the 6th floor. After that good beginning, unfortunately little further progress has been made
in understanding its relation to disease processes -- the "why" of it is still unknown.
I would like to take the opportunity to show you a few pictures of the Professor, mostly taken between 1938 and 1953. Good
photographs of him are uncommon, but some of these show the gentle little man in a way that published and official photographs
fail to do. (Slides).
I believe Fess would have liked this gate. He would find it hard to believe, I'm sure, and would be inclined to mock
it gently in his whimsical way, "Hmm - a gate - do you suppose it's to keep 'em in or keep 'em out?"
It's good that the Rockefeller Institute has honored its most original and productive son and we are grateful to share
in dedicating the "Fessgate".