Remarks at Dedication of Avery Memorial Gate
       Rockefeller Institute, September 29, 1965
         Colin M. MacLeod, Deputy Director
           Office of Science and Technology
            Executive Office of the President
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  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
BacteriQlogists and had to make the presidential address, and the second time
on the occasion of the 50th anniversary of the founding of the Hoagland Labor-
atory 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. "
      lked about whether he should say that bacteriology is the "Queen of the
   Biological Sciences", or, as I might suggest, the Grown Princess, because shy
   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, Fes~~*~~ll make a Martini", which
   he would do forthwith, and wh_en brought, would exclaim, "Fess, drink it up
  before the bloom goes off it !y
  And solthen an extraordinary hour out of many,$ith these two wonderful
gentlemen - bachelors - who kncbw about the goodness of lift and of science and
complcmcntcd each other in a way I have never seen elsewhere.:
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We might end up on this occasion declaring that bacteriology was not a
\    Crown Princess or even a Cinderolla, but more likely a pumpkin.  But you can
                    .-perhaps-`&en-blowing a few scientific
~-??~~~Y$~~$?%%s was wont to remark, "so long as you
    prick them yourself. "
Fess was fond of anothcr'and related small aphorism.that many of you
I  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

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     with them is that they don't work unless you do," - and he certainly worked at
' 1" 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 rcmembcr 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
pncumococcus is able to exert its pathogenicity, the immune responses to it,
how recovery takes place and how one can intervene.  Through his own work ant1
that of the relatively small number of people who worked with him there was
dcvelopcd 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 mc cmphasizc that the Professor was intercstcd in disease.  I .susp~`~`:,
in our modern system of classification, that would make him an applied scienlic.'
If that bc 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 fundnlncntal nature and reactions of a bactcrinl
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 "lovc~J\~
little bug, pncumococcus ?`I
   The Professor had extraordinary respect, indeed almost affection, for
pneumococcus and continually marvellcd as to how "that little bug" could do
all the things it is capable of doing.
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1            He realized, with Dr. Cole and Dr. Dochez, before our entry into World
  War I, that to understand the disease process, pneumococcal or lobar pneu-
  monia, one must have a deep understanding of the causative agent, pneumo-
    coccus.  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
11  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 Dochex and Avery that the immunological speci-
ficity 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 pneumo-
coccus and in pneumococcal .disease was a far greater one than people now
realize.  Prior to this, it should be rccallcd, 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 bactcrio-
logists 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 polysaccharidcs was reminiscent of the outcry
about purified enzymes shortly before.  Sumner at Cornell had crystallized
jack bean urcase and Jack Northrop at the Princeton branch of the Rockcfcll(*r
Institute had isolated trypsin as a pure protein.  The difference in this casts,
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.
   Thcsc controversies wcighcd heavily on the Professor's mind t.hroughotlt
his scientific life.
   The Professor was marvcllously persistent, howcvcr, especially whc:n
his imagination was caught, and hc persuaded Michael Hcidclbcrgcr to cornet
and work with him on the chemistry and immunolbgy of `pnc-ococcal polysac-

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charides 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.  A4ichael was suc-
cceded 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 pneurnococcus 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 pneu-
monia 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 "schleim-
staff", is that it is antiphagocytic. Removal by digestion, theoretically, would
render the microorganism susceptible to phagocytosis and destruction. )
   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 IIl(type 3 polysaccharide)
as the sole carbon source', produces adaptively, or is induced to form, an
extraccllular enzyme, which specifically depolymcrizes S III both in growing
cultures in vitro as well as in experimental infections of animals.  The S III
          --
depolymcrase 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
knowlcdgc had progressed to the extent that would make a clinical test icnsiblt>,
chcmothcrapy of pneumonia by the sulfonamides had become a practical
reality, which we all welcomed with gusto.

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   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 pneurnococcus 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
t. triumphs.
   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 succcss-
fully 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
Ho spital.  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 -- nnd 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 acut{>
phase reaction of human and animal blood serum with the cellular or somatic
"C" polysaccharide of pneumococcus.  This reaction was discovered by Uill
Tillett and Tommy Francis and later a good deal of work was done to understn?"`
it and to purify the reagents by the special brand of "kitchen chemistry"
practiced on the 6th floor. After that good beginning, unfortunately little furtlll
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 bctwcc" 1938 and 1953.  Good photographs of him a~`('
uncommon, but some of these show the gentle little man in a way that publisl",`;
and official photographs fail to do.  (Slides).
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   1 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".