OSWALD T, AVERY
his life and scientific achievements


OSWALD THEODORE AVERY


THE PROFESSOR,

THE INSTITUTE,

  AND DNA

BY RENE J. DUBOS

THE ROCKEFELLER UNIVERSITY PRESS

NEW YORK . 1976


CONTENTS

INTRODUCTION 3

CHAPTER ONE: The Professor and the Institute  5

    A dynamic institution
    Workshops of science
    The Professor and the genius loci

CHAPTER TWO: From the Bedside to the Laboratory  13

      The rise of scientific medicine in the United States
      The Rockefeller Institute for Medicial Research
     The Rockefeller Institute Hospital
I      From research institute to university
I  CHAPTER THREE: Chemistry in Medical Research 35
     Chemistry at the birth of the Rockefeller Institute
     Chemistry as a research tool
      The chemical view of life
     Interdisciplinary thinking

CHAPTER FOUR: Avery's Personal Life 47
   Private life and professional life
   Familial background
   The Colgate years
     Medical education
   The Rockefeller Institute years
    The Nashville years

CHAPTER FIVE: Avery's Life in the Laboratory 69
    The inwardness of research
   Picking other people's brains
   The protocol experiment
    The written word

The Red Seal Records

CHAPTER SIX: The Multifaceted Specialist 87


CHAPTER SEVEN: The Lure of Antiblastic Immunity
and the Chemistry of the Host  91
    Antiblastic immunity

Bacterial metabolism and the phenomena of infection
The chemistry of the host
Host-parasite relationships

CHAPTER EIGHT: The Chemical Basis of Biological Specificity  101
   Serum for pneumonia
    The specific soluble substances
    Immunity from sawdust and egg white
    Biological specificity

CHAPTER NINE: The Complexities of Virulence  113
   Virulence in nature and in experimental models
   The bacterial capsule and virulence
   The bacterial body and virulence

CHAPTER TEN: Bacterial Variability 125
   Polymorphism vs. monomorphism
   Phenotypic adaptations and hereditary changes
   The many facets of bacterial variability
   Transformation of types in pneumococci

CHAPTER ELEVEN: Heredity and DNA 139
   The transforming substance and DNA
    Scientific puritanism
    A premature discovery?

CHAPTER TWELVE: As I Remember Him  161
    Gentle mannered and tough minded
    Avery's consecutive persona
    An unspoken scientific philosophy
   Originality and creativity
   Experimental science as an art form

ENVOI 181
REFERENCES 183
CHRONOLOGIES 197
APPENDIXES 217
INDEX 229


ACKNOWLEDGMENTS

I would like to express my gratitude to the following col-
leagues, both in and out of The Rockefeller University,
who read all or part of the manuscript during its preparation
and who offered suggestions on various points or shared their
memories of 0. T. Avery: Saul Benison, Stuart Elliott.
Walther Goebel, Michael Heidelberger, James Hirsch, Mac-
lyn McCarty, Walsh McDermott. Robert Morison, Arnold
Ravin, and Norton Zinder. Joseph Ernst, Director of the
Rockefeller Archive Center, and Sonia W. Mirsky, Associate
Librarian, The Rockefeller University, were most generous
in helping me locate obscure source material.


THE PROFESSOR, THE INSTITUTE, AND DNA


INTRODUCTION

This book has two heroes: Oswald Theodore Avery (1877-1955) and The
Rockefeller Institute (1901-1955). I have had such close associations with
/  both of them that the objective description of facts and events concerning
them has often seemed to me less compelling than the subjective remem-
brance of things past.

I met Avery in 1927 and worked in a laboratory adjacent to his own for
the following 14 years. Our relations were so personal that he acted as
witness to my marriage in October, 1946, five years after I had left his
department. I have been continuously associated with The Rockefeller
Institute (now The Rockefeller University) since 1927, except for the years
1942-1944, which I spent at Harvard University Medical School. Since my
retirement in 1971, I have continued to occupy the office in which I
worked as a member of the scientific staff. There is no place in the world
where I have spent as much time as on the Rockefeller campus, and where
I feel more at ease. Whenever I approach the stalwart plane trees of the
66th Street entrance, I know "this is the place."
Many of the statements I shall make concerning Avery and the Institute
are not based on documents, but on personal observations and memories.
Whenever possible, I have checked their accuracy with the few surviving
friends and colleagues who, directly or indirectly, participated in the
experiences I report. It is obvious, however, that the very nature of my
relationship with the two heroes of this book colors my account of them,
perhaps at times to the point of distortion. I have tried to acknowledge this
difficulty by reporting in the chapter entitled "As I Remember Him" my
interpretations of Avery's attitudes as I perceived them during the years I
worked in his laboratory.

Documents concerning the history of The Rockefeller Institute are
available in the archives of The Rockefeller University and of The Ameri-
can Philosophical Society. I have consulted only a few of these primary
documents, and have derived most of my information from semiofficial
/ secondary sources and from persons who have been directly involved in the
Institute's affairs.


4     THE PROFESSOR, THE INSTITUTE, AND DNA

Some limited documentation concerning Avery has been deposited in
The Rockefeller University archives and in the Manuscripts Section, Ten-
nessee State Library and Archives in Nashville. I have received much addi-
tional information concerning his familial background and his private life
from his sister-in-law, Mrs. Catherine Avery (Mrs. Roy C. Avery), from a
few of his friends, from Mr. Howard Williams, archivist of Colgate Univer-
sity, and from Dr. Joseph Ernst, Director of the Rockefeller Archive
Center.

The development of Avery's scientific career can be followed, of course,
from his published papers, but more precisely and interestingly from the
detailed annual reports he submitted to the Board of Scientific Directors of
The Rockefeller Institute, as well as from reports to the Trustees of The
Institute, submitted by the Director of The Rockefeller Hospital. I have
quoted extensively from these documents, which are available in the
archives of The Rockefeller University.

During my two years at Harvard Medical School, I wrote a book
entitled The Bacterial Cell (1945)) which was profoundly influenced by my
earlier associations with Avery. I shall paraphrase below a few lines from
the preface to that book, because their spirit is as appropriate today as it
was three decades ago.

Those who have been connected with The Rockefeller Institute at some
time between 1920 and 1950, will undoubtedly recognize in the following
pages echoes of conversations held in the Institute lunchroom and espe-
cially in the Department of Respiratory Diseases. I shall be rewarded for
my efforts if my account helps them to recapture, and others to imagine,
the vital atmosphere of the Institute, and especially the smiling wisdom of
one whom we called with admiration, gratitude, and love "The Professor"
or, more familiarly, "Fess" Avery.


CHAPTER ONE

THE PROFESSOR

AND THE INSTITUTE

A Dynamic institution

From the windows of my office in the Bronk Laboratory building of The
Rockefeller University, I can see on my right, looking north, the four
buildings that constituted the original Rockefeller Institute for Medical
Research. The one nearest to me is the Hospital, where Oswald T. Avery's
department was located on the sixth floor.

These four buildings were erected between 1906 and 1938, and were
designed primarily as laboratories. Even in the Hospital, approximately
half of the floor space was assigned to laboratory work. The architectural
simplicity and uniformity of the initial Institute ensemble symbolize the
singular unity of purpose that presided over its creation- the conduct of
laboratory research focused on medical problems.
Several new buildings have been added since the Institute was metamor-
phosed into The Rockefeller University, and the grounds have been
arranged into a formal, parklike campus, the elegance of which calls to
mind an Ivy-League atmosphere. The new buildings are more diversified
than the old ones, and differ from them greatly in architectural style. The
various styles correspond not only to different periods, but, more impor-
tantly, to different types of functions, many of which were either nonexist-
ent in the old Institute, or little developed. In addition to the new labora-
tory buildings, a variety of structures now serve as residences for students,
staff, and visitors; as halls for lectures, conferences, concerts, and purely
social gatherings; as offices for the administrative requirements of modern
academe and for its complex social relationships.
The present character of the campus was determined in part by the
transformation of the medical research Institute into an educational institu-
tion. It reflects even more, however, changes that have occurred in science
and in society during recent decades. Most of the medical research insti-
tutes that were created in different parts of the world at the turn of the
century have retained their original character, and a few have gone out of


6     THE PROFESSOR, THE INSTITUTE, AND DNA
existence. In contrast, The Rockefeller Institute has continuously enlarged
the scope of its research fields and has undergone profound changes in its
physical and administrative structure-to the point of becoming a post-
graduate university in which medical sciences are only a part of a much
broader academic program. The reason for this continued vigor and ability
for self-renewal is certainly to be found in the initial policies that were
formulated for the Institute; they were so broad that they enabled it to
evolve rapidly by adapting to new scientific trends and new social de-
mands. Some aspects of this adaptability will be considered in Chapter
Two. Nowhere in this book, however, shall I have occasion to discuss the
University phase of the institution, because it began only in 1955, the very
year of Avery's death. In fact, I shall focus my interest on The Rockefeller
Institute for Medical Research, which came to an official end in 1953. The
qualification "for medical research" was dropped from the name five years
after Avery left the Institute for his final retirement in Nashville.
In this introductory chapter, I shall outline what could be readily seen
and learned of Avery and of The Rockefeller Institute for Medical Re-
search by an outsider or by a newcomer to the staff, as I was in 1927.

          Workshops of Science
At the time of Avery's birth in 1877, Louis Pasteur in France and
Robert Koch in Germany were in the process of demonstrating that
bacteria and other microorganisms can cause disease in animals and human
beings. Their findings had immediate practical applications in the control
of disease, and also had the broader social consequence of making the
medical and general public understand that progress in the practice of
medicine could be greatly accelerated by laboratory investigations that did
not involve the care of patients. Obvious as this view has now become, it
appeared far-fetched a century ago.
Interest in laboratory science spread so wide and so fast at the end of the
nineteenth century that it led to the creation of several medical research
institutes where scientists could devote all their efforts to the acquisition of
theoretical and practical knowledge. This new trend enabled Avery to
abandon clinical medicine at the age of 30 and to opt for a life of scientific
research, first at the Hoagland Laboratory in Brooklyn and then at The
Rockefeller Institute in Manhattan.
Details concerning the emergence of scientific medicine and the differ-
ent phases of Avery's life will be presented in subsequent chapters. The
emphasis here will be on those aspects of the Institute that made it an
environment ideally suited to Avery's life and to his work.


                The Professor and the Institute     7

William Blake's phrase "What is now proved was once only imagin'd"'
could well be applied to the medical research institutes created around
1900, because these were the incarnation of ideals formulated by Francis
Bacon and RenC Descartes in the seventeenth century, at the very begin-
ning of experimental science. In his book, The New Organon (1620),
Francis Bacon described a utopian scientific community that he called
Salomon's House, in which scholars devoted themselves to the search for
knowledge "for the benefit and use of life." The ultimate goal of the
experiments carried out in Salomon's House was the improvement of
man's estate, but Bacon recognized that not all experiments could be
expected to lead immediately to practical results. In his words, "Scientists
should be willing to carry out a variety of experiments, which are of no use
in themselves but simply serve to discover causes and axioms; which I call
experinenta lucifera, experiments of light to distinguish them from those
which I call jkctifera, experiments of fruit."2 Bacon's emphasis on the
importance of experimenta Iucifera provided the new research institutes
with their operational philosophy: the cultivation of theoretical science as
an essential step in the development of practical knowledge.
Descartes also contributed to this operational philosophy by affirming
that the best way to foster the advancement of knowledge was to provide
scientists not only with material facilities, but also with leisure, peace of
mind, and complete freedom. The view that scientists had a right to
leisure, even though they were supported by public funds, was truly a new
social concept.
  Two centuries later, Pasteur restated in memorable phrases Bacon's
dream of a Salomon's House and Descartes' plea for intellectual freedom
for scientists. Speaking of "these sacred institutions that we designate by
the expressive name of laboratories," he urged that they be multiplied and
well supported because they are "the temples of wealth and of the fu-
ture . . . where humanity learns to read in the works of nature." He
evoked the happiness that he had experienced "in the serene peace of
laboratories and libraries."3 The Rockefeller Institute for Medical Re-
search was created in 1901 by Mr. John D. Rockefeller, Sr., to provide for
scientists such an atmosphere of peace and serenity.
  During the early planning stages, there was a widespread belief that the
Institute should be linked to some well-established university, medical
school, or public health laboratory. However, this plan was vigorously
; rejected by Mr. Rockefeller himself, for reasons that were strangely
/ reminiscent of the opinions expressed by Bacon and Descartes in the
,.  seventeenth century. Mr. Rockefeller feared that clinical duties, the prepa-


8     THE PROFESSOR, THE INSTITUTE, AND DNA

ration of lectures, the conduct of examinations, and especially the adminis-
trative responsibilities associated with medical and educational practices
would distract investigators from their research.4 Unquestionably, other
reasons, such as matters of prestige and problems of funding, also played a
part in the final decision that The Rockefeller Institute should be com-
pletely independent from traditional academic or medical institutions, but
an important factor in the decision was Mr. Rockefeller's desire that the
Institute investigators have complete intellectual freedom and be protected
from extraneous pressures, whether academic or administrative.
The building site that was selected for the new Institute was quite
remote from what was then the center of New York City, as if to symbolize
the decision of its founders to make it intellectually independent of estab-
lished centers of medical research. It was situated between 64th and 68th
Streets along the East River, and formed on its eastern half a rocky bluff
about 40 feet high overlooking the river. The property was still farmland
when it was bought in 1901; goats were browsing on the gentle slopes
toward its western boundary, now occupied by York Avenue.
The instructions to the Boston firm of architects that was employed for
the construction of the Institute were that the style of the buildings should
be "as simple as is consistent with present purpose, future additions, and
general utility" (italics mine) .5 Just as the site selected for the Institute was
removed from the hustle and bustle of the city and from traditional
academic and medical influences, so were the buildings devoid of any
pretense to be anything other than places designed for work and thought.
Ground was broken for the first laboratory building, now called
Founder's Hall, in July, 1904. When the building was dedicated along with
an animal house and a powerhouse on May 11, 1906, not a word was said
about its architectural style "either in praise by the visitors, or vaunting by
their hosts."6 The reason for this tactful silence was that the main building
was far from sumptuous. It was large and well equipped by contemporary
criteria, but looked rather drab, especially in comparison with the new
buildings faced with white marble that had just been completed for the
Harvard Medical School in Boston.
In contrast to the lack of popular interest in the architecture of The
Rockefeller Institute buildings, there was much excitement at the time
about the skyscrapers that were being erected in downtown Manhattan-
especially about the Woolworth Building, which came to dominate the
Manhattan skyline in 1910. The Gothic frills that ornamented that sky-
scraper from top to bottom made it famous throughout the world as the


               The Professor and the Institute     9

"cathedral of commerce"-an international shrine to the gods of money
and technology.
Until 1957, none of the buildings that were erected on The Rockefeller
Institute grounds along East River was influenced by the modern architec-
tural styles. Each retained the same low profile and the same uniformly
prosaic institutional appearance that had been adopted for Founder's Hall.
The builders must have been instructed to use bricks that were neither red,
nor white, nor yellow in color, but nondescript. The buildings clearly were
not meant to be cathedrals of science, as the Woolworth Building pre-
tended to be a cathedral of commerce, but rather functional, unpretentious
workshops, designed for the prosecution of laboratory research.
The Rockefeller Institute Hospital, in particular, has an austere, func-
tional simplicity that makes it remarkably inconspicuous. It is not suffi-
ciently vast or high to be overpowering or physically inspiring; it is not
sufficiently small or cozy to give it an obvious emotional appeal. Despite its
outward simplicity, however, it was, at the time of its dedication on
October 17, 1910, a highly efficient structure, well suited to the methods
then known for the treatment of the sick and for scientific research on
disease.
The two thousand visitors who attended that dedication were somewhat
surprised, and probably many of them disappointed, to find that the
architects and builders had put up "a strictly utilitarian structure . . . space
and expenditure for artistic effect being strictly limited by the Directors."'
These are the very words of T. Mitchell Prudden, one of the initial
members of The Rockefeller Institute Board, who had taken a special
interest in the planning of the Hospital and of its activities. The visitors
were impressed, however, by the efficiency of the wards and of the
diagnostic services, by the diet kitchen, which was very unusual for the
time in its completeness and relative size, and especially by the importance
of the laboratories, with space and equipment far in excess of needs for
mere routine examinations and tests.
Today, the original buildings of The Rockefeller Institute for Medical
Research look much as they did at the beginning of the century, except for
the mellowness that they have acquired from the ivy that covers their walls
[ and from the greenery that surrounds them. They were so soundly built
j that they have proved adaptable to the changes in laboratory procedures
that have continuously transformed medical research during the past few
decades. I like to believe that they will serve for many more decades as
research laboratories and as shelters for scholarly thought. It is now almost


10    THE PROFESSOR, THE INSTITUTE, AND DNA
50 years since I first worked in them, and I still marvel at the quality of
their materials and at the soundness of the structure; I still make it a point
to walk up and down their broad stairways for the sheer enjoyment of
physical contact with their sturdy oak railings and their broad marble steps.
These old buildings call to mind the venerable institutions built in
Europe during earlier centuries, when good workmanship assured a quality
that transcended fashions and that improved with time. For example, the
Royal Institution of London is not remarkable for its architectural style,
but it was so well built that it has aged well and has become more appealing
with each generation. It still conveys the atmosphere of integrity it had
when Michael Faraday worked there until the end of his life. One century
after Faraday entered the Royal Institution, Oswald T. Avery joined the
Hospital of The Rockefeller Institute, where he stayed for the rest of his
professional life.

       The Professor and the Genius Loci
When The Rockefeller Institute Hospital opened its doors, Avery had
been working for several years on bacteriological and immunological
problems at the Hoagland Laboratory in Brooklyn. He was a physician,
but he already knew that he was more interested in laboratory investiga-
tions than in clinical work. The position offered to him at The Rockefeller
Hospital in 1913 did not involve taking care of patients; instead, he was
expected to participate as a bacteriologist and immunologist in the labora-
tory program on lobar pneumonia. He was technically well equipped for
this task and, more interestingly, he was admirably suited by temperament
to the intellectual and human atmosphere that he found in The Rockefeller
Institute.
Just as the planners of the Institute buildings scorned architectural
glamor, so did Avery shy away from public performances during his adult
life; everything about his person was in a low key that made him incon-
spicuous, like the buildings in which he worked and lived.
He was small and slender, and probably never weighed more than 100
pounds. In behavior he was low-voiced, mild-mannered, and seemingly
shy. His shirts, suits, neckties, and shoes were always impeccable, but were
as subdued as his physical person. His demeanor was charmingly cour-
teous, but in a conservative way that often called to mind a buttoned-up
petit bourgeois. I shall evoke in other chapters the richer and more unusual
aspects of his personality, but shall emphasize here the parallelism of his
scientific evolution with that of The Rockefeller Institute.


                The Professor and the Institute    11

For both Avery and the Institute, the point of departure had been the
awareness that the scientific basis of medicine was extremely weak and the
belief that the control of disease could be made more rational by knowl-
edge derived from laboratory investigations. In both cases, however, the
study of disease led to problems of a nonclinical character, especially
having to do with the chemical mechanisms of life processes. Instead of
being exclusively concerned with medical research, narrowly conceived,
the Institute became more and more chemically oriented. In a similar way,
Avery, who started with the study of lobar pneumonia, rapidly moved
toward the study of the chemical basis of biological specificity; he ended
with the demonstration that hereditary characteristics are transmitted by
molecules of deoxyribonucleic acid (DNA), his most celebrated achieve-
ment. By integrating his medical training with sophisticated laboratory
disciplines, he was a perfect representative of the intellectual attitude that
gave its shape to medicine during the first half of the twentieth century. An
outline of his scientific contributions is presented in Chapter Six. Technical
details are described and discussed in Chapters Seven through Eleven.
Thus, Avery and the Institute had much in common, because they were,
respectively, the human and institutional expressions of the same scientific
ttitudes. They both emerged and developed in the atmosphere of expect-
ncy generated by a few triumphs of scientific medicine at the end of the
nineteenth century; both followed an intellectual course that led them from
the study of specific diseases to large problems of theoretical biology; both
became part of a culture in which laboratory scientists were regarded as
members of a kind of priesthood, willing to accept social constraints for the
sake of intellectual privileges.
An Avery Memorial Gateway to the Rockefeller campus was dedicated
on September 29, 1965. Its great piers, made of red Laurentian granite
quarried in Avery's native Canada, bear the simple inscription:


                     IN MEMORY OF

          OSWALD THEODORE AVERY

                         1877-1955

            A MEMBER OF THE FACULTY OF

             THE ROCKEFELLER INSTITUTE

                        1913-1948

   ERECTED BY GRATEFUL FRIENDS AND COLLEAGUES

The Gateway is low-key, but bold in design, true to Avery's character.


12     THE PROFESSOR, THE INSTITUTE, AND DNA

It is the only entrance to the campus that has been given a name, an
indication of the uniqueness with which Avery represented the scientific
and social concepts that led to the creation of The Rockefeller Institute. As
I remember him, ardently involved in laboratory work, gently but intensely
discussing science with collaborators and friends, brooding at his desk, or
slowly walking on the grounds in a meditative mood, he symbolizes for me
the genius loci of The Rockefeller Institute for Medical Research.


CHAPTER TWO

FROM THE BEDSIDE

TO THE LABORATORY

The Rise of Scientific Medicine in the United States

When Avery entered medical school in 1900, the most influential physi-
cian in the United States was William Osler, who was then professor of
medicine at The Johns Hopkins University. Osler attributed his phenome-
nal success as a healer to the confidence he inspired in his patients through
psychological traits that were unrelated to his scientific knowledge of
disease. More generally, he believed that one of the most important
aspects of medical care was, in his words, "The Faith that Heals . Faith
in the gods or in the saints cures one, faith in little pills another, hypnotic
suggestion a third, faith in a common doctor a fourth." In his lectures and
writings, he emphasized time and time again the therapeutic effectiveness
of what he called "psychical methods of cure" or, more simply, faith
healing. What he really meant by these expressions is the effect of the
psychological influences through which physicians help the automatic proc-
ess of self-healing in their patients.

The original text of this book included some 10 pages devoted to the
place of the various practices of faith healing (self healing) in medical
history. However, the four persons who read the typescript felt that this
subject should be deleted because it had no "obvious relevance," either to
Avery or to The Rockefeller Institute. I have reluctantly followed their
advice and shall publish these pages elsewhere, but I must at least state my
opinion that, although the relevance of the psychological aspects of healing
to scientific medicine is not obvious, it is nevertheless extremely important,
nd may become even more so in the near future. Early in this century, in
act, this importance was explicitly recognized by William Henry Welch,
   Flexner, and Walter B. Cannon -physicians who cannot be sus-
   of antiscience bias, since they were among the chief architects of
entific medicine in the United States, and at The Rockefeller Institute.
I know from conversations with Avery that he, too, was much impressed
y the influence of the mind on the phenomena of disease. However, the


14     THE PROFESSOR, THE INSTITUTE, AND DNA

mystical and irrational character of most faith-healing practices was uncon-
genial to him, and he felt more at ease with medical problems that could be
studied in the laboratory by physicochemical methods. The spectacular
achievements of modern medicine are testimony to the effectiveness of this
orthodox scientific approach. On the other hand, the proliferation in our
times of ways of healing that have no rational basis in the conventional
natural sciences strongly suggests that medicine will not become fully
scientific until it has come to grips with what Osler called "the faith that
heals." A medicine based exclusively on the body-machine concept of
human nature may soon be as obsolete as is now the gold-headed cane of
the nineteenth-century European physician.
There was little doubt, however, about the direction that medical
sciences should take at the turn of the century. The most important
medical problems of the time involved infectious and deficiency diseases
that could not be significantly influenced by any form of faith healing or
self healing, but could be studied effectively by laboratory methods.
However, although this kind of experimental medicine had flourished in
Europe since the beginning of the nineteenth century, it was practically
nonexistent in the United States.
The general view among American physicians was that laboratory sci-
ence could never contribute anything of practical value to the practice of
medicine. Some American hospitals had modest laboratories, but these
were only for diagnostic work. Neither the universities nor the medical
schools nor governmental bodies were inclined to provide facilities or
personnel for medical research.
There were, of course, a few exceptions. A laboratory for experimental
medicine -the first in America-had been established at Harvard Medical
School in 1871 for the professor of physiology, Henry P. Bowditch, but it
consisted of only two small rooms in an attic. Furthermore, Dr. Henry J.
Bigelow, who was then the leading spirit of Harvard medicine, warned that
it would be dangerous to let students be distracted from useful knowledge
by theoretically interesting, but practically useless, learning. "The excel-
lence of the practitioner depends far more upon good judgment than upon
great learning," Bigelow wrote. "We justly honor the patient and learned
worker in the remote and exact sciences, but should not for that reason
encourage the medical student to while away his time in the labyrinths of
Chemistry and Physiology, when he ought to be learning the difference
between hernia and hydrocele"' (italics mine). In practice, the student of
medicine learned to take care of the sick by serving as an apprentice to an
experienced doctor, and the only worthwhile form of medical science was


              From the Bedside to the Laboratory    15

assumed to be the knowledge acquired by observation at the bedside.
The absence of research laboratories did not mean, however, that all of
nineteenth-century American medicine was backward, as Frederick Gates
erroneously assumed when he conceived the idea of the Rockefeller
Institute in 1901 (see page 20). As early as 1765, Dr. John Morgan of
Philadelphia had founded the first American medical school as part of
Benjamin Franklin College, and had based its curriculum on the scientific
experience he had gained in Europe. 2 European medical books were
rapidly translated for the American market.
Moreover, the science and practice of medicine had been advanced by
several American achievements of great importance-in surgery, in clinical
diagnosis, in genera1 anesthesiology, and in descriptive epidemiology. In
1809, for example, Ephraim McDowell performed the first ovariotomy on
record anywhere in the world. Between 1822 and 1839, William Beau-
mont took advantage of the large gastric fistula in his patient Alexis St.
Martin to conduct fundamental experiments on digestion. In 1837, Wil-
liam W. Gerhard differentiated typhus from typhoid fever. Between 1842
and 1846, both Crawford W. Long and William Thomas Green Morton
contributed independently to the demonstration that ether is highly effec-
tive for surgical anesthesia. Daniel Drake made elaborate epidemiological
observations that he summarized in Diseases of the Interior Valley of North
America, published in 1850. Important as these contributions were from
the practical point of view, however, they were not part of what came to be
known as scientific medicine because they had not required physicochemi-
cal understanding of pathological processes.

Here and there in North America, a few nineteenth-century physicians
began to investigate the causation and mechanism of disease by trying to
interpret careful observations made on patients in the light of what could
be learned from the study of post-mortem specimens. The most illustrious
representative of this attitude was William Osler. Born and trained in
Canada, then Professor of Medicine in Philadelphia and Baltimore, Osler
finally moved to England, where he became Regius Professor of Medicine
at Oxford University." He was knighted in 1911 and is now remembered as
Sir William Osler.

Osler had travelled in Europe and was familiar with the developments in
laboratory research. To the end of his life, however, he remained un-
shaken in his belief that medicine can be learned only at the bedside, and
that its most important aspect is the art of establishing the right kind of

personal rapport between physician and patient. His prodigious and lasting
fame as a clinician is evidenced by the fact that, 20 years after his death, he


16     THE PROFESSOR, THE INSTITUTE, AND DNA

was referred to as "that quasi-divinity of ours."4 Yet, the most important
advances of modern medicine emerged not from the kind of clinical and
pathological observations that he advocated, but rather from laboratory
investigations.
Throughout the nineteenth century, a number of young American
physicians had spent a few months, or even years, in Europe to familiarize
themselves with the new kind of medical science that was then flourishing
in the medical centers of Great Britain, France, Austria, and Germany.
Several of them contributed to the new learning through their own re-
search efforts while in Europe, but they discovered after their return home
that their native land offered no opportunities for laboratory research.
Referring to the bright young American physicians who had worked in his
laboratory, the German physiologist Karl Ludwig wondered why they were
never heard from again, even though they had done brilliant research work
while in Germany.5 Although otherwise typical, the particular case of
William Henry Welch has the special merit of referring to the same Welch
who eventually became the mastermind of laboratory medicine in the
United States-first at The Johns Hopkins Hospital and Medical School,
then at The Rockefeller Institute for Medical Research.`j
In the fall of 1872, Welch entered the College of Physicians and
Surgeons, then the best of the three medical schools in New York City.
After his graduation in February, 1875, he served an internship at Belle-
vue Hospital. There he gained some feeling for medical research from the
pathologist Francis Delafield, who had imbibed the teachings of the French
and German schools. In April, 1876, Welch sailed for Germany to get the
feel of the current situation in science and to try his hand at research. His
two years abroad were immensely successful from the scientific point of
view. He learned much from some of the most famous German patholo-
gists and carried out creditable research in several areas of pathology.
When he returned to the United States in February, 1878, he discov-
ered that the only laboratory positions available anywhere in the country
were for teaching elementary microscopy and pathology, without provision
for research of any sort. In a letter to his sister after his return home, he
discussed his scientific interests, but had to report that there was "no
opportunity for. nor appreciation of, no demand for that kind of work
here. . I sometimes feel rather blue when I look ahead and see that I am
not going to be able to realize my aspirations in life."r A similar discourag-
ing situation was experienced by other young American medical men
returning from Europe -for example, by T. M. Prudden, who was to
become, two decades later, part of the group that formulated the concept


From the Bedside to the Laboratory

af The Rockefeller Institute for Medical Research and an influential
member of its Board of Scientific Directors. The only solution for these
eager, idealistic, young men was to build a financially profitable consulting
practice that could finance their scientific interests.
The prospects for medical research thus looked very bleak in the United
States around 1880, but the situation changed dramatically for the better
within less than two decades. A few universities, medical schools, and
research institutes received financial support, chiefly from private funds, to
develop scientific programs modeled on the European examples. This
  found change of attitude was probably in part an expression of Amer-
s coming of age, but it was accelerated by two independent kinds of
uence that operated simultaneously at a critical time: the practical
pplications of the germ theory to the prevention and treatment of disease,
nd the emergence of social philanthropy as a result of the sudden accumu-
tion of great wealth by a few American families.
Although scientific medicine had advanced on many fronts in Europe
ing the first three-quarters of the nineteenth century, it had not contrib-
d much of practical use to either the prevention or the treatment of
  e. Its main achievements had been in the description, classification.
  atural history of pathological disorders. The new knowledge had
  clinicians more competent in diagnosis and prognosis, but not much
   effective in treatment. As a consequence of this limitation, scientific
   ne was not really meaningful to the general public or even to the
   e run of practicing physicians. Many of these, in fact, considered
   had only a negative effect, because it discredited some of the time-
nored practices by questioning their effectiveness and emphasizing their
angers. Such an attitude of therapeutic nihilism among scientific physi-
ians was, of course, largely justified during most of the nineteenth cen-
pry, but its unfortunate result was to retard the general acceptance of
cientific medicine by destroying confidence in old practices without offer-
ng anything better as a substitute.

A profound change in public attitude occurred during the last quarter of
he century, after the demonstration by Pasteur, Koch, and their followers
hat many types of disease were of microbial origin and could be prevented
i treated by measures directed against the microbes. Lister's application
I the germ theory to the control of surgical infections, the development of
itary practices, and the use of vaccines for prevention and of immune
1 for treatment proved that knowledge derived from laboratory re-
rch could be of practical usefulness. The germ theory thus provided the
t convincing and obvious evidence that laboratory research was helpful,


18     THE PROFESSOR, THE INSTITUTE, AND DNA

not only for understanding disease, but also, and more importantly, for the
control of disease. Scientific medicine was widely accepted by the general
public and by official bodies as soon as it became prescriptive instead of
merely descriptive.

Despite the public and official recognition of its practical value, scien-
tific medicine would probably not have developed as rapidly as it did if
public funds had constituted its only source of support. The promotion of 1
laboratory research would almost certainly have been handicapped by'
administrative difficulties and by the conservatism of medical and aca-
demic institutions. Fortunately, social changes that were then occurring in
the United States provided sources of private funds to catalyze scientific
programs and to experiment with new scientific institutions.

Great fortunes had been made during the second half of the nineteenth
century, and a few men of wealth decided to devote very large sums to
public ends during their own lifetimes. As they were eager that their
philanthropies be rational and creative enterprises instead of mere charity,
they sought the help of advisors committed to one or another type of social
cause. Thus emerged one of the most striking social phenomena of our
times-the use of private funds for the support and establishment of
libraries, educational institutions, research laboratories, hospitals, and
medical schools, as well as of concert halls, theaters, and artistic or
charitable programs. The new philanthropists shifted the emphasis from
traditional charity at the.individual level to programs for social improve-
ment.

Two cases of nineteenth-century social philanthropy had a direct rele-
vance to the topics of this book: The Johns Hopkins institutions in Balti-
more (Maryland), which prepared the ground for The Rockefeller Institute
for Medical Research; and the Hoagland Laboratory in Brooklyn (New
York), which provided Avery with experience in medical research.

At his death in 1873, the Baltimore Quaker merchant Johns Hopkins
left about $7,000,000-then a very large sum-for the establishment of
three institutions: a new type of university focused on research activities,
rather than on didactic undergraduate teaching; a hospital with facilities
for the investigation of disease; a medical school linked to both the
university and the hospital, and therefore of academic charactero8 The
university was established first; then an institute for research in pathology,
even before the hospital was ready to receive patients; and, last, the
medical school. William Henry Welch, who a few years before had de-
spaired of ever finding facilities in America for medical research compara-
ble to the ones he had known in Germany, was appointed the first director


             From the Bedside to the Laboratory    19

of the new Johns Hopkins Institute of Pathology in 1885, with the expecta-
tion that he would devote himself entirely to research and teaching in a
university environment. Thus began the phenomenal career which made
him the architect of American scientific medicine. Although his base
remained The Johns Hopkins Medical School, he played a crucial role in
the creation of The Rockefeller Institute for Medical Research and of
many institutions of a national character. The Rockefeller Institute was
organized by Simon Flexner, who had been one of Welch's favorite pupils;
in addition, Welch served as chairman of the Board of Scientific Directors
of the Institute from 1901 to 1933.
Whereas The Johns Hopkins University, Hospital, and Medical School
have long been in the limelight, few persons know of the Hoagland
Laboratory, which was incorporated in 1887. It has now been discontinued
and is almost completely forgotten, except by those who know that Avery
worked in it from 1907 to 1913. Yet, the Hoagland institution is histori-
cally important for having been the first privately endowed American
laboratory focused on bacteriological research. It was dedicated in 1888,
the same year as the Pasteur Institute in Paris.g


:  Cornelius Nevius Hoagland (1818-l 898) was a physician who practiced
edicine for 13 years. Then he went into business with his brother, and
ade a sizable fortune by promoting baking soda and creating the Royal
king Powder Company. In 1884, his grandson died of diphtheria, and
s tragedy reawakened his medical interests. He was aware of the spec-
cular advances made in medical bacteriology, and came to believe that
  science was the only one that offered mankind a real hope against
ase. He returned to medical practice and endowed a laboratory de-
  d to bacteriological research and teaching. Its first director was Dr.
rge M. Sternberg, major in the Medical Corps of the U.S. Army, who
ad achieved international fame for his work on yellow fever. He was
  inted in 1888 and remained Hoagland's nominal head until 1893,
n he resigned to become Surgeon General of the U.S. Army.
The Certificate of Incorporation of the Hoagland Laboratory stated that
s objectives were "the promotion of medical science and the instruction
f students in special branches thereof." William Henry Welch was to have
n the main speaker at the dedication of the new buildings on December
  1888, but he was prevented by a prior engagement. His place was
  by Dr. H. Newell Martin, professor of biology at The Johns Hopkins
  rsity, an Englishman who was one of the first men in the United
   to devote his entire time to teaching and research on a medical
   t. One of Martin's themes in his address was that "whereas in


20    THE PROFESSOR, THE INSTITUTE, AND DNA     I
Europe science was often directed from a government office and central- i
ized under bureaucratic control, in this country the . . . endowment of'
laboratories was being attained in a far better way-by private generosity
rather than by public subsidy." "Science," Martin said, "cannot for any
long period advance safely in chains even if those chains be golden.
Through private endowments-trusts as they are for the public welfare-
American science promised to attain a variety and independence of
thought such as no national science had ever attained in the past."`*
Martin's speech sounded a theme that was to be of great importance for the
development of medical research in America, and that is still timely today:
the independence of the scientist from bureaucratic control.
Because of shortage of funds, the Hoagland Laboratory was incorpo-
rated into the Long Island College of Medicine, which eventually became
the College of Medicine, State University of New York, Downstate Medi-
cal Center. But one fact deserves to be restated before taking leave of this
small, pioneering institution. In 1899, Dr. Sternberg, then U. S. Surgeon
General, stated that, as far as he knew, "The Hoagland Laboratory is the
first laboratory in the United States erected, equipped and endowed by
private means for the sole purpose of bacteriological research."" Admit-
tedly, bacteriological research and teaching had been conducted at the
Carnegie Laboratory of Pathology in New York City as early as 188.5, but
that laboratory, as its name indicates, was built primarily for pathology;
the bacteriology done there was largely incidental.
Avery, who worked in the Hoagland Laboratory for approximately six
years, was fond of saying that the professional associations and the intellec-
tual freedom he had enjoyed there had contributed greatly to his scientific
development.

    The Rockefeller Institute for Medical Research
The organizational patterns of medical research in the United States
appeared fairly well established by the last decade of the nineteenth
century. Research programs had been created and financed, first in a few
privileged medical schools, hospitals, and universities, then throughout the
land; public funding had followed private funding. The development of
scientific medicine probably would have continued along the same course
as part of an orthodox academic tradition. if it had not been for the
unexpected impact of a layman. His name was Frederick Taylor Gates, a
Baptist minister who acted as adviser to Mr. John D. Rockefeller in
matters of philanthropy. In addition to his crucial role in the creation of the
Institute, Gates engaged in many other activities that influenced the course
of modern medicine, for example the establishment of the Rockefeller


              From the Bedside to the Laboratory    21

Foundation and the development of "full-time" academic medicine.
The events, thoughts, and discussions that led to the establishment of
the Institute have been described in detail elsewhere, but some of their
aspects must be mentioned here, because they help to explain the social
and scientific atmosphere from which emerged the Institute's and Avery's
accomplishments.1*
Gates had always been interested in medical subjects. He was a physi-
cian's son, and had observed during his ministry as pastor of a struggling
Baptist church in Minneapolis that physicians were usually unable to deal
with serious medical problems. In 1897, he resolved to familiarize himself
with the state of medicine, and was advised by one of his young friends,
who was a medical student, that the most readable and competent source
of information was Osler's textbook The Principles and Practice of Medi-
cine.
Osler was acknowledged everywhere at that time as a physician of
; immense learning and ability, and also as a great teacher and skillful
i writer. His thorough training in pathology enabled him to supplement his
clinical descriptions with vivid pictures from first-hand knowledge of the
anatomical lesions characteristic of each disease. Furthermore, he was
extremely fond of medical history and of its heroes; he was also familiar
with the allusions to medicine that occur in poetry, novels, and other forms
ofliterature. Finally, he was so adept in the expression of his thoughts that,
: although his textbook was intended for medical students and physicians, it
had a literary and human quality that made it palatable to lay readers,
especially to Frederick Gates.
One aspect of Osler's book that was regarded as a weakness by many
physicians was skepticism concerning the prevalent forms of therapy and
the use of drugs, in particular. But it was this therapeutic nihilism that
impressed Gates and motivated him to work for the establishment of a
medical research institute and, later, for other massive investments in
biomedical research. Gates himself has given a detailed account of his
reaction to Osler's book in a memorandum that he prepared in 1897 from
his own recollections and from Mr. Rockefeller's private files:
  Osler's Principles and Practice of Medicine is one of the very few
[ scientific books that I have ever read possessed of literary charm. There
  ' was a fascination about the style itself that led me on and having once
  started I found a hook in my nose that pulled me from page to page, and
  chapter to chapter, until the whole of about a thousand closely written
  pages brought me to the end. But there were other things besides its
  style that attracted and constantly, in fact, intensified my interest. I had
  been a sceptic before. . . This book not only confirmed my scepticism,


22     THE PROFESSOR, THE INSTITUTE, AND DNA

but its revelation absolutely astounded and appalled me. . . . I found,
for illustration, that the best medical practice did not, and did not
pretend to cure more than four or five diseases. . . It was nature, and
not the doctor, and in most instances nature practically unassisted, that
performed the cures. . . . [Osler's] chapter on any particular disease
would begin with a profound and learned discussion of the definition of
the disease, of its extension throughout the world, of the history of
discovery about it, of the revelations of innumerable postmortems, of
the symptoms, cause and probable results of the disease, and the
permanent complications and consequences likely to follow, but when
he came to the vital point, namely, the treatment of the aforesaid
disease, our author . . . would almost invariably disclose a mental atti-
tude of doubt and scepticism : . . about all that medicine up to 1897
could do was to nurse the patients and alleviate in some degree the
suffering. Beyond this, medicine as a science had not progressed. I
found further that a large number of the most common diseases, espe-
cially of the young and middle aged, were simply infectious or conta-
gious, were caused by infinitesimal germs. . . I learned that of these
germs, only a very few had been identified and isolated. . . .

When I laid down this book, I had begun to realize how woefully
neglected in all civilized countries and perhaps most of all in this
country, had been the scientific study of medicine . . . while other
departments of science, astronomy, chemistry, physics, etc., had been
endowed very generously in colleges and universities throughout the
whole civilized world, medicine, owing to the peculiar commercial
organization of medical colleges, had rarely, if ever, been anywhere
endowed, and research and instruction alike had been left to shift for
itself dependent altogether on such chance as the active practitioner   1

might steal from his practice. It became clear to me that medicine could
hardly hope to become a science until medicine should be endowed and
qualified men could give themselves to uninterrupted study and investi-
gation, on ample salary, entirely independent of practice. To this end, it
seemed to me an Institute of medical research ought to be established in
the United States. Here was an opportunity, to me the greatest, which
the world could afford, for Mr. Rockefeller to become a pioneer. . . . I
knew nothing of the cost of research; I did not realize its enormous
difficulty; the only thing I saw was the overwhelming need and the
infinite promise,  worldwide, universal, eternal. Filled with these
thoughts and enthusiasms . . . I dictated to Mr. Jones, my secretary, for
Mr. Rockefeller's eye, a memorandum in which I aimed to show to him,
the to me amazing discoveries that I had made of the actual condition of
medicine in the United States and the world as disclosed by Osler's
book. I enumerated the infectious diseases and pointed out how few of
the germs had yet been discovered and how great the field of discovery,
how few specifics had yet been found and how appalling was the


             From the Bedside to the Laboratory    23

unreme.died suffering. I pointed to the Koch Institute in Berlin and at
greater length to the Pasteur Institute in Paris. . . . I remember insisting
in this or some subsequent memorandum, that even if the proposed
institute should fail to discover anything, the mere fact that he, Mr.
Rockefeller, had established such an institute of research, if he were to
consent to do so, would result in other institutes of a similar kind, or at
least other funds for research being established, until research in this
country would be conducted on a great scale and that out of the
multitudes of workers, we might be sure in the end of abundant rewards
even though those rewards did not come directly from the Institute
which he might found.13

From the beginning, Gates had visualized that medical research could
rest be carried out by "an institution in which whatever practice of
nedicine there is, shall be in itself an incident of investigation." Mr.
Rockefeller was much impressed by this view, and promised to provide
`unds for such an institution. He was the more receptive to the idea
)ecause his first grandchild, John Rockefeller McCormick, died of scarlet
!ever on January 2, 1901, when three years old. Mr. Rockefeller was
ihocked to learn from the doctors that the cause of scarlet fever was
unknown and that there was no method of treatment for the disease. It is of
interest that C. N. Hoagland also had been motivated to found the
Hoagland Laboratory by the death of his grandson from diphtheria, an-
other acute bacterial disease.
The Rockefeller Institute for Medical Research was incorporated that
same year. Its financial resources were small at first and were used to
support laboratory investigators in medical schools and hospitals through-
out the country. In 1903, the Institute established its own laboratories in
temporary quarters on Lexington Avenue in New York City. In 1906, the
laboratories were moved to the present site, as discussed earlier. The
begenesis, history, and administrative structure of the Institute have been
    in several books,14 and further details will be published in a
    of the first director, Simon Flexner, now in the course of
  ration by Dr. Saul Benison. One aspect of this history of direct
   e here is the scientific and administrative philosophy that presided
   organization of the Institute, because it was at least as important
   enerous funding and the talent of the scientists in determining the
   d success and the unique character of the enterprise.
  a clergyman, and as the externalized conscience of the Rockefeller
  , Frederick T. Gates saw medical research both as a search for
eventive and therapeutic measures against disease and as a way to probe


24     THE PROFESSOR, THE INSTITUTE, AND DNA

into man's nature. Addressing The Rockefeller Institute scientists on the
tenth anniversary of the opening of the laboratories, he told them that their
work went far beyond the study of disease. In his words, "Your vocation
goes to the foundation of life itself." lZ On another occasion, he asserted
that the Institute could be regarded as a "technological seminary" that
would provide material for a new form of religion. "I am now talking of the
religion, not of the past, but of the future. . . As this medical research
goes on you will . promulgate . new moral laws and new social laws,
new definitions of what is right and wrong in our relations with each
other. . . . You will teach nobler conceptions`of our social relations and of
the God who is over us a11."16 This euphoric and somewhat misty view of
the social role of science was, of course, foreign to most of the Institute's
scientists; yet it contributed to the success of the enterprise by dedicating it
to the search for knowledge, rather than to immediate practical applica-
tions.

The broad view of medical research held by the planners of the Institute
made it easier to avoid short-term utilitarianism. The Rockefeller family
and Mr. Gates had the wisdom not to expect quick results and not even to
"cherish extravagant dreams"; it is truly remarkable that, even though
they had little, if any, training in science and few contacts with scientists,
they rapidly came to realize that the best chance of success for the Institute
was to approach medical research from a theoretical point of view, instead
of looking for practical solutions to specific clinical problems. In the
expressed view of Frederick Gates, the chief hope of the founders was that
the Institute would serve as an example, and thus indirectly contribute to
the making of discoveries elsewhere. In fact, this hope was rapidly fulfilled,
because a multiplicity of other institutions patterned more or less after The
Rockefeller Institute were soon created to deal with the various aspects of
medical research.

A few remarks concerning the initial peculiarities of the Institute will
suffice to illustrate how the conceptual breadth of its organization enabled
it to evolve rapidly with the changes in science and thus to remain highly
productive, even though the problems of infectious disease, which had
motivated its creation in 1901, progressively became of less social impor-
tance.

Whereas the European institutes of medical research each were built
around a single remarkable scientist, such as Pasteur, Koch, Ehrlich, or
Pavlov, The Rockefeller Institute was organized as an association of
talented division chiefs. The authority of the director, Simon Flexner, was
very great indeed, but it was an authority of administrative, rather than


              From the Bedside to the Laboratory    25

scientific, nature. In Flexner's own words, the Institute "was not confined
in its growth by the interests . . . of a commanding personality; it could
look forward to a broader foundation of science . . .; its usefulness could
not be so seriously impaired by the death or retirement of one man.""
There is no doubt that such a structure, in which scientists were selected for
what they had produced or for what interested them and what they might
contribute, rather than because of the discipline they represented. made it
easier for the Institute to make rapid adaptations to changes in the social
and scientific atmosphere.
Even though the initial focus of The Rockefeller Institute was clearly
"medical" research, the documents concerning its organization made few
references to specific diseases. Laboratories were organized around inves-
tigators selected for their intellectual gifts and representing highly diversi-
fied areas of medical science. Microbiology and pathology were given a
prominent place at first, because these sciences had produced the most
spectacular results at the time the Institute was organized. However,
physiology, experimental surgery, and chemistry were emphasized from
the very beginning. As financial resources increased and as gifted investi-
gators revealed new, promising fields of research, the range of specialities
represented at the Institute came to include almost any kind of science that
might have a bearing on health and disease -from the study of populations
to that of physical laws.
The scientific basis of The Rockefeller Institute was thus initially, and
has remained ever since, broader than that of the other institutions created
before or after it to deal with medical research. This catholic approach is
the more remarkable because the scientists who were responsible for the
Institute's organization had been trained in specialized laboratories
abroad, particularly in the then-famous German institutes of pathology,
physiology, or chemistry. Despite this pervasive German influence, the
pattern of organization adopted for The Rockefeller Institute was closer to
the ideal of science that had been formulated in France by Claude Bernard.
Of special relevance in this regard is Bernard's last book, Leqons sur les
phinom&zes de la vie communs aux animaux et aux v@Ctaux,`" because its
very title conveys the belief that the fundamental processes of life are the
same in all types of creatures, from microbes to man. This scientific
philosophy was central to the organization and operations of The Rocke-
feller Institute. It led in 1910 to the appointment of the physiologist
Jacques Loeb as head of a new department of experimental biology,
created to deal with the contributions of physics and chemistry to all the
fundamental processes of life in all kinds of organisms. The scope of the


26     THE PROFESSOR, THE INSTITUTE, AND DNA

Institute was eventually further enlarged by the addition of units devoted
to animal and plant diseases. The Rockefeller Institute thus came to be
involved in most aspects of biological research.

       The Rockefeller Institute Hospital
There was nothing original in the idea that a hospital should be estab-
lished in close association with the Institute laboratories. The originality of
the enterprise emerged with the appointment of the first director and
physician-in-chief, Rufus Cole, who insisted that the Hospital should be
not an annex of the laboratories, but an independent unit completely
equipped to conduct its own research programs. This concept was so new
at the time that it justifies a few details concerning its origin, especially in
view of the fact that it had a profound influence on the subsequent
evolution of clinical research in North America.
In his initial 1902 plan for the organization of the Institute, Simon
Flexner had urged the establishment of a hospital, were it only to make
sure that problems of human disease not be forgotten by laboratory
scientists. He did not have a clear notion of how it should be organized,
and merely stated, "The hospital should be modern and fully equipped,
but it need not be large. It should attempt to provide only for selected cases
of disease ." lg This phrase "selected cases of disease" obviously meant that
the work of the Hospital was to be focused on specialized clinical research,
rather than on general medical care.
Physicians who are scientifically oriented now take it for granted that
clinical research implies laboratory research, but this view was still foreign
to the most illustrious representatives of scientific medicine less than a
century ago. Shortly after returning from his second trip to Germany in
1884, William Osler had stated that "the wards are clinical laboratories
utilized for the scientific study and treatment of disease."20 He shared the
opinion held by most physicians that biological and chemical laboratories
were needed only as diagnostic tools. Originally trained as a naturalist,
Osler carried this attitude into medicine. As a scientific physician, he was
primarily interested in the natural history of disease, and he derived his
knowledge from the careful observation of signs and symptoms in patients.
Medical science meant to him not experimental science, but clinical infor-
mation garnered at the bedside and interpreted in the light of data ob-
tained by bacteriological and chemical techniques, medical statistics, and
especially post-mortem examination of previous, similar cases.
Despite Osler's prestige, the attitude toward medical research changed
during his own lifetime. L. F. Barker, who succeeded him in the chair of


             From the Bedside to the Laboratory     27

nedicine at The Johns Hopkins Medical School in 1906, had first had a
:areer in laboratory research. Immediately after his appointment, he
:stablished, adjacent to his wards, biological and chemical laboratories
ntended for research by his clinical staff in the mechanisms of disease,
.ather than for diagnostic tests. Rufus Cole, who was the first head of
Sarker's biological laboratory, took advantage of the situation to carry out
:xperimental studies on typhoid fever.
From the beginning, the Rockefeller Hospital had been "designed
wholly for research in clinical medicine. Laboratories were provided on the
same scale as beds for the patients, and in proximity to them,"21 but it had
been assumed at first that the Hospital would be a place where the Institute
pathologists, physiologists, and bacteriologists could test ideas developed
in their own laboratories, or where they could obtain specimens for their
own investigations. Under such a system, the junior hospital interns were
expected to serve as medical attendants looking after patients for the sake
of scientific investigators-under the guidance of the physician-in-chief and
visiting physicians.
When Rufus Cole was invited to be physician-in-chief in 1908, he
proposed an entirely different plan. He wanted the physicians responsible
for the care of patients to be given the right to investigate the fundamental
,mechanisms of disease as deeply as their training allowed. Collaborative
/projects between the Institute laboratories and the Hospital might, of
rse, be extremely valuable but, according to Cole, the real point of a
arch hospital was that physicians could engage in fundamental studies
n the problems they dealt with in the wards.
Cole's point of view eventually prevailed, but there was much resistance
`t within the medical community, on the grounds that medicine was
   an art than a science. Whether medicine is an art or a science sui
  is was still hotly debated a few decades ago, and several of the senior
  ers of The Rockefeller Institute Hospital staff contributed actively to
he debate. In practice, however, from the time of its opening, the Hospital
rated in exactly the same spirit as the other Institute departments,
ept that the investigations carried out in its laboratories were chiefly
ived from clinical problems. 2z During the early years of the Hospital,
  main problems under study were lobar pneumonia, syphilis, poliomye-
  heumatic fever, heart disease, renal diseases - all pathological condi-
  that were prevalent at the time. The patients never numbered more
  60, and were selected as typical of the diseases under study. In
  quent years, other pathological conditions were studied when they
   e of greater social or scientific interest.









                                                ___~~


28    THE PROFESSOR, THE INSTITUTE, AND DNA

Granted the inescapable necessity for clinical specialization, there pre-
vailed among the Hospital staff a breadth of intellectual interests very
similar to that found in the rest of the Institute. A large percentage of the
staff did not have medical degrees, but instead were Ph.D.`s in theoretical
sciences, such as chemistry, physiology, or microbiology. Even more re-
markable was that the head of the department of renal diseases, Donald D.
Van Slyke, was not a physician. but a chemist.
Dr. Thomas M. Rivers, who replaced Cole as the director of the
Hospital in 1937, has this to say concerning the place of Ph.D .`s in clinical
medicine.

Although Van Slyke was a Ph.D., he had charge of all the kidney cases
in the hospital, and over the years I must say that he was a better
physician as far as his handling of nephritis and nephrosis was concerned
than most M.D.`s. Because Van Slyke was a Ph.D., he couldn't sign
orders in the order book for medicine and drugs, nor could he order
tests. However, most of the orders carried out by M.D.`s on the service
were usually done at Van Slyke's suggestion. . . . As far as I am con-
cerned no one in the United States has done as much as Donald Van
Slyke to unravel the riddles regarding the physiology and diseases of the
kidney.23

If I may be permitted to introduce a personal note, I, too, acted for a
few years as head of a clinical department of tuberculosis, even though I do
not have an earned medical degree.

While there was no real rivalry between M.D.`s and Ph.D.`s in the
Hospital, there were frequent discussions concerning the comparative
value of the two forms of training as a preparation for medical research.
Here, again, I shall let Dr. Rivers, who was an M.D., state the problem in
his own words:

The bald fact is that the Ph.D.`s never felt that the M.D.`s were
scientists. Just recently, I heard a young dot at the hospital complain to
one of the old Ph.D.`s at lunch that all the M.D.`s went around trying to
pass themselves off as Ph.D.`s and he wondered if it had always been so
at the Institute. "No," replied the old Ph.D. "Thirty years ago I tried to
pass myself off as an M.D. Then they were the kingpins around here,
you know."

In fact, Dr. Rivers continued,

. . . a large number of the doctors in the hospital . . . were made
members of the National Academy of Sciences. Cole was one, Avery
was one, Dochez was one, and I was one, and there were others. I



30    THE PROFESSOR, THE INSTITUTE, AND DNA

adopted a pattern of organization that gave almost complete autonomy to
each of the scientific departments. There was a danger that such a combi-
nation of diversity and autonomy would produce a heterogeneous institu-
tion, but The Rockefeller Institute was, in fact, a remarkably well-inte-
grated scientific organism.
The integration of the Institute's various departments was facilitated at :
first by the relatively small size of the initial staff, and also by the sense of
community that resulted from scientific pioneering - against the doubts,
and even the hostility, of a large part of the medical establishment. Of
greater and more lasting importance for the intellectual unity of the
Institute, however, was the administrative wisdom of its first director,
Simon Flexner. While acting as Eastman Visiting Professor at Oxford
University in 1937, Flexner discussed the general problem of organization
of university clinics in words that obviously reflected his long experience
with the problems of interdepartmental collaboration at the Institute. He
emphasized that the design and arrangement of buildings should encourage
"a spirit of easy and free cooperation. . . . At The Rockefeller Institute,
covered corridors, heated in winter, connect hospital and general laborato-
ries and passage from one to the other is made so easy that the effect is of
one common building for a11."26 He could have mentioned also the confer-
ences held every Friday afternoon, during which one of the staff members
presented the results of his investigations and at which all members of the
staff were expected to be present. Flexner himself was very much in
evidence at these staff conferences, always sitting in the front row.
Probably most important of all, there was the lunch room with its
comfortable chairs, its baguettes of French bread, its fresh butter, and its
endless supply of coffee served by quiet and obliging waitresses. The tables
accommodated eight persons, the right number to generate a conversa-
tional social unit in which all could participate. More often than not, the
conversation at one table was dominated by one particular person. If
Thomas M. Rivers was present, the talk at his table was likely to be about
viruses or hospital management; with Alfred E. Cohn, it was about the
history or philosophy of science; Avery spoke little, but listened and asked
a few pointed questions bearing on some scientific problem that preoccu-
pied him. It was in the lunch room that I was first introduced to Avery and
that we engaged in the conversation which eventually brought me to the
Institute.
Even Paul de Kruif, who did not think much of the Institute, wrote with I
warmth of its lunch room:

After a drab morning . . . at the lu


            From the Bedside to the Laboratory    31

discouragement. Here I could listen to the scintillating talk of my
betters, a scientific elite, a bevy of bacteriological, biological big names.
I was thrilled to sit at Jacques Loeb's table, listening to that parent of
fatherless sea urchins. . . . Those luncheon sessions were a kindergar-
ten in my stumbling study of character. I never tired of listening to the
philosophy of Alex Carrel. . . . Then at the luncheon table there might
be Dr. Peyton Rous, refined, gentle, exquisitely cultured. . . . In this
refectory there was an air of solemnity to be expected and appropriate
to the unveiling of mysteries.27

Wherever they meet, the alumni of The Rockefeller Institute evoke
with gratitude and fondness the lunch-room conversations which familiar-
ized them with the skills of their colleagues. This experience not only
provided factual information and a broader perspective of science; it also
generated collaborative projects with fellow scientists in other disciplines.
It can be said without exaggeration that there never was a symposium-in
the etymological sense of the word, namely, a convivial meeting for
drinking- that was more scientifically productive and intellectually
pleasurable than those held daily in the lunch-room of The Rockefeller
Institute, though coffee and ideas were the only intoxicants.
The Hospital had its own social institutions that facilitated scientific
contacts. Tea was served at 4:30 every afternoon in the residents' living
room, and this was an occasion for much professional interchange. There
was also the Hospital journal club that met for dinner, with wine or beer,
every other Monday from October to May. It was started by Alfred E.
Cohn, who faithfully presided over all its meetings until his retirement in
1944, and who introduced a subtle formality with certain traditions-for
example a special menu of English (Dover) sole for the first meeting in
October; of shad, asparagus, and strawberries in the Spring.
At each meeting, three or four papers were presented under a tacit set
of rules. Except in very special cases, one was not supposed to review
papers published in journals that we were all expected to have seen, such
as the Journal of Experimental Medicine, the Journal of Biochemistry, the
American Journal of Physiology, or the Journal of Clinical Investigation.
The papers selected had to have some bearing on experimental medicine
: very broadly conceived, preferably from the outer margin of the speaker's
1 research activities. Discussions were intense, and every member of the club
g could'participate in them because the group was rather small -fewer than
20 during the period of which I speak. It was bad taste, however, to use the
occasion for speaking of one's own research work and even for presenting
results obtained in the Hospital departments. Finally, Dr. Cohn made it a

point not to forewarn the persons who would be called on to speak-a


32    THE PROFESSOR, THE INSTITUTE, AND DNA

practice that caused much anguish among junior scientists. Month after 1
month, one came to the journal club dinner, wondering whom Dr. Cohn
had in mind for that particular evening. One was expected to have a new
paper to report at any meeting and, furthermore, one had to be prepared
to present it with style, because all the heads of departments, as well as the
Hospital director-first Dr. Cole, then Dr. Rivers-attended the
and certainly used the occasion to evaluate their junior staff.

Many examples could be given to illustrate the community of interest
that emerged from the focusing of thought on medical research and from
the ease of intellectual contacts within the Institute. Immediately after the
reference to the design of buildings that Flexner made in his Oxford
speech,  mentioned above, he went on to say, "Science thrives
best . . where research is in the air."28 But, he pointed out, each place
has a special research atmosphere of its own, determined by the goals of
the institution, and he chose the case of Donald D. Van Slyke to illustrate
how the "atmosphere of research" influences scientific creativity:

Van Slyke's original training was in organic chemistry, but he early
showed a special talent for physical chemistry. Had he developed out-
side the hospital, his interests would have been directed to the applica-
tion of physicochemical methods to structural chemistry. In the clinical
laboratory he was confronted with the problem of acidosis in diabetes
and he concentrated his attention on the development of methods of
blood analysis, which resulted in his discoveries in acid-base regulation
in health and in disease. As time went on other contributions to quanti-
tative clinical chemistry came from his laboratory, the responses to the
conditions arising within the clinic and the medical atmosl
rounding him .Oy

Flexner further illustrated the importance of the research at
by referring to the programs on animal and plant diseases at the
the Institute that had been created in Princeton in 1914. These programs
were conducted in two separate divisions, organized in such a manner that

each was complete and independent of the other. The staff of each worked I
in the atmosphere created by the subject, a clinical atmosphere of sick
animals or sick plants. On the other hand, there was close cooperation
between the two divisions, because they adjoined each other.

Human diseases, animal diseases, and plant diseases are but a few
among the research programs of the Institute that could have been selected
to illustrate how its administrative structure made it possible to reconcile a
unity of intellectual atmosphere with great diversity of scientific disciplines
and complete autonomy of departments. It would probably have been
difficult to maintain this unity if the work of the Institute had been directed
to applications of an immediately practical nature, but this was not the


              From the Bedside to the Laboratory    33

case. Many new products, techniques, and gadgets of practical utility were,
of course, developed by the Institute scientists. However, even in the
programs directly focused on practical problems, for example on a particu-
lar human disease, the emphasis was primarily on scientific understand-
ing-with the expectation that this understanding would eventually pave
the way for practical applications, as it did in many cases. The motto of the
Institute is Pro bono humani generis; its fundamental philosophy has
always been that the most important contribution that science can make to
iuman welfare is the kind of knowledge that facilitates a more intelligent
`onduct of life.
The Institute was not listed as an educational institution during the first
calf-century of its existence, but many young men, usually in their twen-
ies, joined it to work under the guidance of its scientists, either on
`ellowships or as junior members of the staff. In any research program,
caching inevitably becomes a desirable, as well as a pleasurable, aspect of
.he relationship between leader and neophyte. Thus, although the Institute
lid not give academic degrees. it helped many young men and women to
achieve superior preparation for a career in the field of science they
Lhemselves had selected. More importantly, perhaps, it provided an atmos-
phere in which they could discover themselves by being exposed to the
wide range of scientific disciplines and intellectual attitudes represented in
the laboratories, during staff conferences, and in the lunchroom every day.
From its very beginning and throughout its existence, The Rockefeller
Institute thus had certain general characteristics of a university. Its diver-
sity of disciplines and of administrative structures have probably played a
large part in assuring its continued scientific productivity and in making it
adaptable to changes in science. To summarize:
Instead of being focused on practical problems, the Institute cultivated a
broad approach to the understanding of biological principles, using what-
ever concepts and techniques were available at a given time. Instead of
being built around a single remarkable but dominant personality, as were
.&era1 of the other medical research institutes, it was organized as a
!commonwealth of scholars representing a great diversity of scientific disci-

  nes. Instead of training students by conventional teaching methods, it
  young scientists the opportunity to discover their own tastes and
  s by working in association with a self-selected master. Thus, while
  oning as a research center focused on medical problems, the Institute
  ayed some of the most desirable attributes of a university. Few
  ulties of adaptation were experienced when, in 1955, it was trans-
  ed into The Rockefeller University and had to enlarge still further the
nge of its research and teaching activities.


CHAPTER THREE

CHEMISTRY IN

MEDICAL RESEARCH

   Chemistry at the Birth of The Rockefeller Institute
The Rockefeller Institute for Medical Research was conceived at a time
when infectious diseases were the most important medical problems in all
countries of Western civilization. Microbiological sciences were then the
most glamorous field of medical research because of their spectacular
contributions to the understanding and control of pathological processes.
This period has been called the golden era of microbiology, because each
year saw the discovery of new infectious agents and of new preventive and
therapeutic methods.

When Frederick T. Gates read Osler's textbook in 1897, he had been
,much impressed by the fact that "a large number of the most common
iseases, especially in the young and middle-aged," were caused by micro-
ial agents. In the plan he submitted to John D. Rockefeller for the
motion of medical research in the United States, he used as models the
steur Institute in Paris and the Koch Institute in Berlin, because these
  institutions were primarily concerned with infectious diseases.' It
  d have been natural, therefore, to focus the resources of the new
  tute on microbiology and immunology, as had been done in Paris and
rlin, and shortly after at the Lister Institute in London and the Kitasato

   oon as The Rockefeller Institute was created, the post of director
   red to Theobald Smith, who had achieved fame in infectious
   y by his brilliant studies on Texas fever of cattle. Smith declined
ffer for personal reasons, but as he was then a member of the Board of
tific Directors of the Institute, he took this opportunity to express the
mlon that the best policy for the Institute was to concentrate on "the
dy of infectious diseases from all points of view. They are the great
eatening dangers of our present social system."2 Following Smith's
fusal of the directorship, another member of the Board of Scientific
ectors, T. M. Prudden, drew up a statement of policy for the Institute,


36    THE PROFESSOR, THE INSTITUTE. AND DNA

and he, too. came to the conclusion that the major aim should be, at first,
the investigation of infectious diseases .3
In 1902, Simon Flexner was appointed director. As has been men-
tioned, he had been one of W. H. Welch's closest associates, and had made
his scientific reputation as a pathologist and bacteriologist. Yet, even
though he had been concerned almost exclusively with experimentation
and teaching in the field of infectious diseases, he decided that the scien-
tific scope of the Institute should be broader than had been recommended
by Smith and Prudden. From the time he assumed the directorship, he
acted on the conviction that medical research would, in the future, become
increasingly dependent on chemical knowledge. Evoking the early years of
the Institute, he wrote later, "In those days of rapidly advancing immunol-
ogy and chemotherapy, Ehrlich's Institute in Frankfurt was a great attrac-
tion. . .4 Biology as a whole . . . was fast taking on a chemical guise. . . .
The Rockefeller Institute took part in this growth by providing in its
original organization for biological chemistry . . . in its organic and physi-
cal forms. Biophysics, the corresponding new discipline, was added later."5
It is probable, however, that Flexner's belief that chemistry would play a
crucial role in medical research went further back in time than Ehrlich's
influence. It can be traced to his early association-first as a graduate
student, then as a colleague-with Welch at The Johns Hopkins Hospital
and Medical School.
Welch had begun to prepare himself for medical school in 1870 by
serving as an apprentice to his father, who was a medical practitioner, but
he did not enjoy the experience. The following year, he went back to Yale
University, this time to study chemistry at the newIy-created Sheffield
School. He did well in his chemical studies and, according to his biogra-
phers, Simon and James Flexner, there is evidence that he had even then
"an intuition of the role that science was to play in the healing art."" After
completing his chemical studies at the Sheffield School, Welch studied
medicine at the College of Physicians and Surgeons in New York City.
There again he did well, and a letter of the time to his father reveals how
intensely he responded to topics of a quasi-chemical nature that had no
direct relevance to the practice of medicine. He remembered to the end of
his life a lecture in which the professor of materia medica and therapeutics,
Edward Curtis, stated that protoplasm was "the physical basis of life in all
its manifestations animal or vegetable. . . . The theory was beautiful."'
Christian Herter is another physician who probably sensitized Simon
Flexner to the importance of chemistry in medical research. Herter was a
friend of Mr. Rockefeller and was himself a man of wealth. For sheer


              Chemistry in Medical Research    37

intellectual satisfaction, he had established and funded a chemical research
laboratory adjacent to his medical office in his midtown Manhattan house.
Since he was among the first persons to formulate plans for the proposed
Institute, and served from the beginning on its Board of Scientific Direc-
tors, one can assume that he was influential in making chemistry an
important part of the initial research program.6
Flexner was, in any case, so convinced that chemistry would play a
central role in medical research that, before undertaking his new duties as
director, he spent a year abroad to familiarize himself with "the rapidly
advancing science of physiological chemistry."g He studied in Berlin "with
Salkowski and, more important, with Emil Fisher, who was doing his basic
work in the chemistry of animal tissues and organs."`O Upon his return to
New York, his first administrative move was to appoint P. A. Levene as
head of the chemistry laboratory. Levene was a Russian who had worked
in Emil Fisher's laboratory and who "brought something of the problems
and atmosphere of that exciting place to the infant institute.""
After Rufus Cole was appointed director of the Hospital in 1909, he
also decided that he needed chemical knowledge to carry out his new
duties as a leader of medical research. He was primarily a clinician, with
some laboratory experience in pathology and bacteriology, but, instead of
taking time out to strengthen his experience in these fields, he spent the
year 1909-1910 working in Levene's department of chemistry at the
Institute during the period when the Hospital was being built. It was at that
time that he became acquainted with the organic chemist Donald D. Van
Slyke, whom he brought to the Hospital a few years later.
In 1927, John D. Rockefeller, Jr. presented to the Institute a magnifi-
cent painting of the chemist Antoine Lavoisier, by Jacques Louis David.
The painting now occupies the place of honor in the University library,
located in the Welch building. There could not be a truer symbol of the
Institute's scientific vocation, and of William H. Welch's influence on its
destiny. It was Lavoisier who placed chemistry at the center of the contem-
porary biological sciences, and it was Welch who, indirectly through Simon
Flexner, committed The Rockefeller Institute to the chemical view of
medical research.

        Chemistry as a Research Tool
A possible title for this chapter might have been "Better Life Through
Chemistry," to emphasize the importance of the chemical approach in the
development of scientific medicine. Unfortunately, the phrase has ac-
quired a meaning far too narrow for what I have in mind. When it was first


38    THE PROFESSOR, THE INSTITUTE, AND DNA
introduced as a publicity slogan by a large chemical firm a few years ago, it
referred to the social changes that had resulted from the mass production,
at fairly low cost, of a wide range of synthetic products such as plastic
gadgets, artificial fabrics, food additives, fertilizers, and pesticides. Then
the phrase was adopted by the youth culture to denote the various kinds of
emancipation that could be achieved with contraceptives and with the
immense variety of stimulating, relaxing, or mind-expanding substances
produced in the laboratory. These examples provide obvious illustrations
of the way in which modern life has been affected by chemical innovations.
But the transformations of medicine by chemistry have been even more
profound, and many of them have taken place in indirect ways that escape
attention.
A spectacular demonstration of the beneficial role that chemistry has
played in medicine is provided by the improvements it has made possible in
the design, production, and use of medicinal drugs. The old saying that
physicians put drugs of which they know little into human bodies of which
they know nothing is no longer quite as true as it used to be. Many drugs
are now specifically designed by chemical synthesis to fit certain physiolog-
ical needs or to produce desired reactions; furthermore, methods are
available to anticipate the biological and psychological effects of drugs
even before they are released for general use. Also thanks to chemistry,
vitamins and hormones have been isolated, identified, and synthesized; as
a result, they can be used to regulate vital functions according to nature's
own ways. Chemistry has put at the disposal of the physician powerful
substances that enable him to exercise much control over physical and
mental processes, in health and in disease.
The link between medicine and chemistry has been further strengthened
by the chemical study of substances and systems derived from living
organisms, and by the physiological study of the responses that the living
organisms themselves make to natural and synthetic compounds that have
biological activities. Chemists and biologists use a common scientific lan-
guage when they study how a class of chemical substances, derived from a
given biological system, sets in motion a certain type of physiological
response.
One of the most interesting aspects of the chemical approach to medical
research has been the possibility of reaching into all the regulatory proc-
esses that keep living organisms in a functioning order. The importance of
such chemical regulation was clearly implied in Claude Bernard's concept
that the stability of the internal environment is an essential condition of
free life. As is now well understood, this approximate stability of the milieu


               Chemistry in Medical Research    39

intirieur is achieved through a complex system of chemical feedbacks, each
step of which is controlled by hormones of exquisitely defined chemical
constitution, functioning under precisely defined chemical conditions.
The phenomenal specificity of most biological processes is a special
aspect of chemical regulation that deserves emphasis here because it
played a dominant role in Avery's scientific achievements. The belief that
biological specificity depends upon the molecular architecture of body
constituents was accepted as an article of faith long before it could be
scientifically demonstrated. For example, Paul Ehrlich had no precise
knowledge of the mechanisms involved in the operations of antiseptics or
antibodies when he boldly stated the problem in the famous phrases:
"Antitoxins and antibacterial substances are, so to speak, charmed bullets
which strike only those objects for whose destruction they have been
produced ."I2 And "only such substances can be anchored at any particular
part of the organism which fit into the molecule of the recipient combina-
tion as a piece of mosaic fits into a certain pattern."13
A similar attitude found expression in the picturesque image used by
Emil Fisher to account for the specificity of enzymatic reactions. Accord-
ing to him, the specific activity of each particular enzyme for a particular
substance reflects a reciprocal fitness of structure comparable to the lock-
and-key relationship.
Awareness of the chemical mechanisms of biological regulation and
specificity was certainly an important factor in the formulation of medical
research during the early days of The Rockefeller Institute. Paradoxically,
however, chemistry came to dominate the intellectual atmosphere of the
Institute, not through the achievements of the professional chemists, im-
portant as those achievements were, nor even through the preoccupations
of the physicians concerned with the chemical aspects of physiological
processes and of hormone, enzyme, or drug action, but through the
vigorous personality of Jacques Loeb-a general biologist intent on pro-
moting a philosophical theory of life based on physicochemical determin-
ism .

         The Chemical View of Life
Jacques Loeb was born in the Rhineland in 1859 and grew up during a
I period marked by the expression, among many young European scientists,
/ of unqualified materialism. In 1845, for example, a quadrumvirate of
rising German physiologists - H. Helmholtz, K. Ludwig, E . Dubois-Rey-
mond, and E. W. Brucke - had committed themselves in a famous mutual
oath to the demonstration that all bodily processes can be completely


40    THE PROFESSOR, THE INSTITUTE, AND DNA

accounted for in physicochemical terms. I4 Although they tempered their
materialistic view of life in their adult years, Loeb remained true to its most
extreme form, and eventually became its outspoken missionary.
As a youth, Loeb had read extensively in the eighteenth-century philo-
sophical literature on free will and consciousness. He entered the univer-
sity in Berlin with the intention of becoming a philosopher. Soon, how-
ever, he realized that professors of philosophy could not answer the
questions they delighted in posing, and he switched to science in the hope
that he could solve, by observation and laboratory experimentation, the
philosophical problems of the mind. I5 His life-long obsession with the
metaphysical issue of free will can be traced to his youthful interest in
Schopenhauer, with whom he shared a dogmatic conviction that individual
freedom is illusory. Like Schopenhauer, also, he had a passionate desire to
convey this unmitigated truth to others, an attitude that found expression
in his assertiveness as a teacher and publicist.`"
In 1880, at the age of 2 1, Loeb enrolled at the University of Strasbourg,
from which he obtained an M.D. degree in 1884. There, he worked in a
laboratory concerned with the localization of brain function, but again was
disappointed; in his quest for the understanding of free will, he did not get
from the neurologists any more enlightenment than he had from the
philosophers. He then moved to the University of Wurzburg, and joined a
group of experimenters who were working on the borderline between
biology and physics on the subject of tropism. or involuntary movement, in
organisms. Among these men, he found at last a congenial spiritual home,
because tropism was a kind of behavior that could be investigated in the
laboratory by experimental techniques.
In Wiirzburg, he became acquainted with the young Swedish chemist
Svante Arrhenius, or at least with his theory of electrolytic dissociation."
The discovery that complex chemical processes can be explained by simple
physical laws converted Loeb to the view that physical chemistry would
eventually explain all biological phenomena, including those of embryolog-
ical development. While working from this point of view at the Naples
biological station, Loeb succeeded in causing segmentation of sea-urchin
eggs by altering the osmotic pressure of the fluid in which the eggs were
immersed. This achievement was widely acclaimed as a triumph of mecha-
nistic physiology, and made him known throughout thepcientific world.
His further studies on artificial parthenogenesis reinforced his physico-
chemical view of biological determinism and, in addition, increased his
fame, especially among American biologists.
He moved to the United States in 1891, first to Bryn Mawr College,


               Chemistry in Medical Research     41

then to the University of California and the University of Chicago before
joining The Rockefeller Institute in 1910. Unceasingly, he channeled all
his knowledge and energy into the applications of physical chemistry to
biological processes, and he became the most effective spokesman- in-
deed an evangelist-for the "Mechanistic Conception of Life ." His book of
that title was published in 1912, and is one of the landmarks of twentieth-
century biology, if not by its purely scientific content, at least by the
influence it exerted on several generations of biologists all over the world.
Loeb believed that the physicochemical view of life was the key to
genera1 biology and to scientific medicine, as well. After being invited to
organize a new department at The Rockefeller Institute, he wrote Simon
Flexner that he wanted to develop experimental biology "on a physico-
chemical instead of on a purely zoological basis," and that "The experi-
mental biology of the cell . . . will have to form the basis not only of
Physiology but also of Genera1 Pathology and Therapeutics."`s He af-
firmed this scientific philosophy with such vigor that he soon became one
of the most influential members of the Institute staff. He left no doubt in
the minds of those who listened to him-and one could hardly escape
listening to him- that the only worthwhile kind of medical research was
the investigation of simple biological systems by the methods of physics
and chemistry.
The very logic of his physicochemical view of life led him from the study
of living organisms to that of chemical constituents separated from biologi-
cal materials, and eventually to that of simple colloidal systems- the
simpler the better. At the time of his death in 1924, he was investigating
the effects of various kinds of salts on gelatin under different conditions of
acidity and alkalinity. He had chosen to work with gelatin not because he
had a special interest in the biological role of that protein, but merely
because it provided him with a colloidal system of simple composition. He
believed, indeed, that he should have begun his study of life by investigat-
ing simple phenomena and substances, even though these were of limited
biological importance, because it is "more logical to commence with the
simple systems found in colloids than with such conditions as exist in
protoplasm ."lg
Loeb's analysis of biological processes was thus an almost infinite
regression. Believing as he did that one could not understand anything of
psychological or physiological behavior unless one knew everything about
molecular behavior, he tended to be contemptuous of orthodox biological
and medical research. His dogmatic attitude on this score naturally irri-
tated many of his Institute colleagues, but his intellectual prestige was so


42    THE PROFESSOR, THE INSTITUTE, AND DNA

great that he had devoted admirers, especially among the young members
of the staff, some of whom tried to ape his tart dialectic. In the words of
Paul de Kruif:

He gave the Institute a high scientific tone. . . . He was the peerless
leader of the militant godless. . . . He was the exponent of scientific
method as against the prevailing twaddle -that was his word- of medi-
cal science.

"Medical science? . . . Dat iss a contradiction in terms. Dere iss no
such thing. You should begin with the chemistry of proteins, as I do" he
admonished his table mates in the Institute lunch room.20

Despite, or perhaps because of, his scorn for medical research, he had
admirers even among physicians on the clinical staff of the Hospital. Many
of them, however, "were filled with a kind of consternation"21 on being
told by him that they could not find anything useful about disease until they
went much deeper into the intimate chemical mechanisms of the body.
Alfred E. Cohn, who was then in charge of the cardiology department at
the Hospital, reported their feelings later in his book No Retreat from
Reason: "We . . . trained as physicians, were made unhappy. Loeb, the
most accomplished, the most intelligent and we thought, the wisest man
with whom it was our privilege to come in contact, as we did daily in our
lunch room, we thought was laughing at us." The physicians on the clinical
staff were willing to accept that "ultimately a human body is a mass of
electrons," but they could not see how such knowledge would bring them
"a step nearer to being able to do anything about pneumonia or cardiac
disease ."22 On the whole, however, Loeb's faith in the physicochemical
approach to biological problems found a favorable response throughout
the Institute. Flexner, in particular, seems to have been receptive to that
scientific philosophy.

The word "philosophy" is the proper expression to denote the nature of
Jacques Loeb's influence on The Rockefeller Institute, because what he
did and what he taught were determined more by his a priori philosophical
view of life than by the study of actual processes in living things. Although
he thought that he had abandoned metaphysics once and for all during his
student years, in reality he had returned to it by his passionate espousal of
mechanistic biology. He saw in physics and chemistry the only rational
approach to the understanding of biological phenomena and of conscious-
ness and free will. Without any possibility of scientific proof, he did not
hesitate to affirm: " Not only is the mechanistic concept of life compatible

with ethics; it seems the only conception of life which can lead to an
understanding of the source of ethics."23 Parenthetically, it is entertaining


               Chemistry in Medical Research    43

to compare this dogmatic statement with the views expressed by Frederick
T. Gates when he told the scientific staff of the Institute (see Chapter Two)
that medical research could be regarded as a new form of religion from
which would emerge "new moral laws and new social laws"24 and even
nobler conceptions of God!
As mentioned earlier, Loeb's propensity to pronounce ex cathedra on
the most fundamental issues of philosophy, morality, politics, and science
irritated some of his colleagues, but not enough to nullify his influence on
the conduct of biological research at the Institute and in other scientific
institutions. By brazenly parading his mechanistic animus, he did more
than anyone else to foster the belief that the most effective approach to
biological and medical research is through physics and chemistry-a belief
that has left an indelible stamp on the scientific approach to medical
research at The Rockefeller Institute.
The year after Loeb's death in February, 1924, W. J. Osterhout was
appointed head of the Institute's department of general physiology.
Whereas Loeb had begun his scientific life as a zoologist, Osterhout was a
botanist, but this difference was inconsequential, because the two men had
the same fundamental interest-the desire to study the influence of physi-
cochemical factors on the biological activities of isolated tissues or cells.
Like Loeb, Osterhout was fond of simple experimental models, which,
irrespective of the extent to which they revealed new facts about life,
provided a framework for thinking about biological problems. For exam-
ple, he used large plant cells, such as those of the Nitella or Valonia genera,
for the simple reason that they permitted direct observation of the passage
of salts or dyes across their membranes under different experimental
conditions. He also devised artificial cell models, which were somewhat
similar to living cells in their ability to accumulate ions. The knowledge
derived from the study of such simple systems-natural or artificial-
guided physiological thinking about complex animal systems, such as those
involved in renal activity, muscle contraction, or the transmission of nerve
impulses. The subsequent scientific history of The Rockefeller Institute
was further influenced profoundly by the fact that these simple systems lent
themselves to analysis by physicochemical and mathematical methods, thus
making it easier for professional physicists and chemists to become in-
volved in biological problems,
Loeb and Osterhout naturally exerted a direct influence by their scien-
tific discoveries, but more important in the long run was their indirect
influence on the structure of the Institute's scientific staff. The very nature
of their studies made both of them dependent on the collaboration of


44    THE PROFESSOR, THE INSTITUTE, AND DNA       j

chemists and physicists, most of whom became interested in biological and
medical research while applying their professional skills to experimental
models. The physicists and chemists who came to work with Loeb and
Osterhout remained on the Institute staff after the two masters had disao-

peared, and several of them became heads of new departments. As a
result, the initial tendency of the Institute to approach medical problems
through physicochemical methods was greatly reinforced. Whereas pathol-
ogists, bacteriologists, and virologists constituted the largest percentage of
the staff during the early decades of the Institute, medical scientists
progressively came to be outnumbered by chemists, physiologists, and
biophysicists. In the 194Os, for example, there were six different labora-
tory groups working on the various ramifications of protein chemistry.
Jacques Loeb would probably have taken great pleasure in learning that, in
the 196Os, several biological departments that made intensive use of
physicochemical methods elected to be listed under the broad heading of
general physiology-the science that he had done so much to promote .25

Pure chemistry occupies only a rather small place in the present struc-
ture of The Rockefeller University, but the chemical approach is more
dominant than ever in fields such as cellular biology, genetics, immunol-
ogy, and experimental pathology. Chemistry as such has been replaced by
molecular biology.

Interdisciplinary Thinking

The mere enumeration of the biologists, chemists, and physicists on the
staff of the Institute does not give a true qualitative picture of its intellec-
tual composition. More interesting is that, whereas representatives of each
individual scientific discipline naturally retained their professional identifi-
cation with regard to theoretical knowledge and laboratory techniques,
many of them also developed lateral interests while collaborating on
biological problems unrelated to the traditional preoccupations of their
specialties.

For example, physical chemists working on electrophoresis became
interested in the peculiar problems posed by the fractionation of blood-
serum proteins; organic chemists working with nucleic acids learned to use
biological systems to determine the role of those substances in the transfer
and expression of hereditary characteristics. Conversely, bacteriologists
acquired knowledge of molecular structure in order to account for immu-
nological specificity; virologists learned to use ultraviolet absorption spec-
tra of proteins and nucleic acids in their attempts to purify viruses.

The few examples just mentioned will suffice to illustrate how the


               Chemistry in Medical Research    4.5

diversity of problems and techniques generated in the Institute a spectrum
f scientific interests much more complex and subtle than that defined by
he traditional scientific disciplines. Superficially, these examples seem to
se illustrations of what is now called interdisciplinary approach, but the
ctual scientific atmosphere did not result merely from the bringing to-
ether of specialists in different disciplines for the prosecution of well-
refined projects.
On the one hand, most cooperative research within the Institute
merged spontaneously without administrative planning. It was commonly
he outcome of lunchroom conversations - when clinicians and physical
hemists discussed the possibilities of serum fractionation; when immunol-
jgists heard about Pauling's views of antibody protein folding; when I, who
tad been trained in soil bacteriology, learned of the need in certain clinical
rroblems for specific chemical tests to which I could contribute by produc-
ng enzymes from bacteria. Thus, while most of the Institute's scientific
rrojects were indeed interdisciplinary, few of them were the outcome of
organization through administrative planning.
Even more important, however, was that some of the most striking
:xamples of interdisciplinary interplay took place within the mind of each
ndividual scientist, rather than among different scientists. The sensitiza-
:ion brought about by continued laboratory contacts made biologists think
n chemical terms, and encouraged chemists to focus their thoughts and
:heir techniques on the peculiarities of biological and medical problems.
For example, it was because Avery and his medical associates had learned
;o think chemically that they were able to demonstrate the nucleic acid
mature of the genetic material in pneumococci (see Chapter Eleven).
The mechanistic conception of life had led Jacques Loeb to formulate all
biological problems in physicochemical terms, and this attitude enabled
him to make a few startling prophecies. He believed, for example, in the
possibility of producing mutations by physicochemical means; this was
achieved in 1926 by the geneticist Hermann J. Muller through the irradia-
tion of fruit flies with X-rays. In 1911, Loeb stated that the main task for
students of heredity was to determine "the chemical substances in the
chromosomes which are responsible for the transmission of a quality."26
This was achieved three decades later by Avery and his group.
Loeb knew, of course, that the isolation and identification of the active
substance in the chromosomes would require the use of sophisticated
physicochemical methods; but he probably assumed that the work would
be done by scientists trained in the physicochemical aspects of general
psiology, the discipline he regarded as the fundamental biological sci-


46    THE PROFESSOR, THE INSTITUTE, AND DNA

ence. He would therefore have been surprised to learn that the achieve-
ment had been the feat not of physicists, chemists, or general physiologists,
but of physicians working in a hospital department dedicated to the study
of lobar pneumonia.

In a way, the DNA story can be regarded as a vindication of Jacques
Loeb's evangehsm. The forcefulness with which he had preached the
mechanistic gospel of life-to the point of intolerance - had created at The
Rockefeller Institute an intellectual environment in which biologists and
physicians took for granted that all their problems should and could be
formulated in physicochemical terms and investigated by physicochemical
methods. When Thomas Rivers stated that many of the Institute's M.D.`s
were scientifically as competent as the Ph.D.`s and that several of them
wanted to pass as such, he unconsciously reflected Loeb's view that there
was no worthwhile medical science other than laboratory science. In fact,
Loeb's intellectual influence has been so deep and lasting that it still
conditions the attitudes of biologists and physicians who never saw him and
are barely aware of his name. Because of it, ways of thinking about life,
including human life, that do not involve a physicochemical approach have
never found a congenial home within the walls of The Rockefeller Institute.

Exactly three decades after the publication of Loeb's The Mechanistic
Conception of Life, genetics emerged as a physicochemical science from
the work of Avery's group in the Hospital of the Institute, making this
crowning achievement of experimental medicine a spectacular testimony to
the explanatory power of the chemical view of life.


AV

CHAPTER FOUR                                      :`i
                                             i !9/

ERY'S PER

SON

AL

LIF

E

Private Life and Professional Life

The necrologies of its deceased members published by the National Acad-
emy of Sciences show that a large percentage of them came from rather

humble homes, and that many were the sons of Protestant clergymen. In
nineteenth-century America, a clergyman's way of life often seemed to
provide his children with an ethical and cultural environment favorable for
intellectual growth, leading eventually to membership in professional soci-
eties, including the Academy. This appears to have been true for Oswald
Theodore Avery, who was born on October 21, 1877, in Halifax, Nova
Scotia, four years after his parents had emigrated from England; his father
was pastor of a Canadian Baptist church.

Although Avery loved to tell stories about himself, he avoided conver-
sations of a'purely personal nature, in particular those involving his family
or the very early years of his life. He probably would have regarded any
search into his familial background as an unjustified intrusion into his
personal affairs; moreover, he would have felt that the information thus
obtained could not possibly throw useful light on his scientific achieve-
ments. His attitude in this regard is apparent in the obituary he prepared
for Karl Landsteiner, the somber genius who had been his colleague at The
Rockefeller Institute for Medical Research.' The original text of the
obituary that Avery submitted dealt exclusively with Landsteiner's scien-
tific life, but the editor of the journal in which it was to be published
requested that it be supplemented with details of the scientist's family life
and behavioral peculiarities. Avery refused, with the statement that such
personal details would not contribute to the understanding either of Land-
Steiner's scientific achievements or of his intellectual processes.
Claude Bernard had expressed similar views in Le Cahier Rouge, the

1  notebook to which he confided his casual thoughts. "A great man is not
great when he goes to bed, gets up, sneezes, etc., but only when he writes,
thinks, and even then it is only on special occasions, as is the case for an
actor. It is in these moments that man is truly great, and that we can reach
him through his works. We had better ignore the rest; it does not add
anything to the man."*


48    THE PROFESSOR, THE INSTITUTE, AND DNA
Claude Bernard and Avery may have been correct in believing that
familial background and behavioral characteristics have little bearing on
creativeness in science, the arts, or other intellectual pursuits. However,
familial and behavioral factors inevitably influence a person's way of life,
and thereby condition the manner in which creativeness is expressed, with
regard to both form and content. Such conditioning can be illustrated by
comparing the scientific careers of Avery and William Henry Welch. The
qualitative difference in the contributions these two physicians made to
biomedical sciences was not due to differences in their intellectual endow-
ment, but to choices they made with regard to their ways of life-choices
which probably originated from early familial influences and from temper-
amental peculiarities.
Both Welch and Avery studied medicine at the College of Physicians
and Surgeons in New York City, where they received the best clinical
training available at that time in the United States. Both did well in their
academic studies, had great charm and skill in human relationships, and
were judged by their teachers to have the attributes required for successful
careers in the practice of medicine. Both, however, were dissatisfied with
medical knowledge as it existed in their time, and abandoned clinical
medicine as soon as they had the chance to devote themselves to laboratory
research.
Although Welch and Avery took similar initial steps when they shifted
their interest from the bedside to the laboratory, their subsequent courses
were very different. Welch became more and more involved in medical
education and statesmanship; Avery moved increasingly toward theoreti-
cal scientific work. Their temperamental characteristics certainly ac-
counted in large part for this fundamental difference in their scientific
evolutions.
Welch had a Gargantuan appetite, and was fond of ice cream and other
sweets; he soon became obese. He loved the carnival aspects of life and to
mix with crowds in Atlantic City and on the New York beaches. In a letter
to his sister, written when he was over 50, he describes with gusto the
excitement he experienced riding the roller coaster. With these popular
tastes, it is not surprising that he found it easy to move into public life and
to spend an enormous amount of energy lecturing, organizing medical
groups, and engaging in medical or public health politics.3
In contrast, Avery ate very little, was extremely fastidious about the
nature of his food, shunned public gatherings, and resented being enter-
tained. Although he was a very effective lecturer, and loved to advise those
who came to him, he virtually gave up public speaking after joining the


                   Avery's Personal Life    49

research staff of the Institute. He kept shy of social responsibilities, and
instead devoted all his energy and talent to laboratory work in collabora-
tion with a small number of colleagues. Thus, Welch's extroverted person-
ality led him to the creation of a social environment in which medical
research became respectable and, indeed, fashionable, whereas Avery's
introverted attitude enabled him to take full advantage of this environment
to create new scientific knowledge.
Avery's natural endowments could certainly have enabled him to
achieve great worldly success in any of several different fields, but he
elected to withdraw almost completely from public life. He has left no
written document to account for this choice, nor does he seem explicitly to
have stated his reasons for it to either family or friend. His conversation
was always sparkling and often penetrating, but he was very selective in
what he revealed of his complex personality. To the end, he kept his own
counsel. I apologize to his memory for trying to uncover in the following
pages certain aspects of his personal life that he had chosen not to make
public.

          Familial Background
Avery's paternal grandfather, Joseph Henry Avery, was born and lived
in England, where he was a papermaker in charge of paper manufacture
for Oxford University. He must have had some inventive talent, as he was
the first to make the thin paper that could be printed on both sides and
used for the Oxford Bibles. On May 17, 1881, the delegates of the Claren-
don Press at Oxford presented Joseph with a Bible "in acknowledgement
of great services rendered by him to the Press during the publication of the
Revised Version of the New Testament."4
Avery's father, Joseph Francis Avery (1846-1892), was born at Nor-
wich, Norfolk. He had a mystical nature, and was not satisfied with the
profession of papermaker. Early in his life, he came under the influence of
a Baptist evangelist, C. H. Spurgeon, who was conducting a series of
religious meetings in England. Although Joseph had been raised in the
Church of England, he decided, on the basis of this experience, to prepare
himself for the Baptist ministry. In 1870, he married Elizabeth Crowdy
(1843-1910), who was three years his senior, and spent the first three
years of his married life in pastoral service in England. Then he and his
wife migrated to Canada, for somewhat obscure reasons. In his own words,
"a strange impression took possession of the writer, - `You are wanted and
must go to Nova Scotia.' Against the advice of friends, including Rev. C.
H. Spurgeon the desire and impulse grew; till in faith and not by sight, in


p 7             50    THE PROFESSOR, THE INSTITUTE, AND DNA
        May, 1873, it was determined to break up the home and if needs be, risk
        and sacrifice everything and go not knowing whither, trusting in God's
         leading. Confident a church and work awaited on the other side.`15
         As the steamer landed, a welcoming committee was at the pier, and
        asked the Reverend Avery to preach on the following Sunday at the North
        Baptist Church in Halifax. He accepted, and remained as pastor for a year
        and a half, when "providentially the way opened to organize a new cause
             and church ." The new Baptist church created by Joseph Francis Avery was
         called The Tabernacle, and he remained its pastor until 1887.
         All indications are that both he and his wife were popular and successful
         in Halifax, yet they pulled up stakes once more when he received an
        invitation to be pastor of a Baptist mission church in New York City.
        Again, the reasons for the move are far from clear; a spirit of restlessness
        probably played some role, along with the divine call to duty:
         It did at first appear, and even now does sometimes seem painfully
          strange, that our home and church life should again be disturbed, just as
         the homestead began to yield its fruits, and the church by the establish-
          ment and growth of time offered prospective easement from the neces-
         sary toil which comes to the pioneer worker. But knowing it is always
          safe to give heed to the voice of God, we have listened, watched, and
         prayed, and now, fully persuaded the Master in His providence has
         called us to the greater city of New York, we are resolved to go
            forward . . . ; the thought and expectation was to spend and be spent in
          building the upper structure of the Tabernacle, but the builder made a
         delay of several weeks in getting out his estimates. Meantime an increas-
         ing desire for more spiritual and direct evangelistic effort grew, and by
         reading an article in the Christian at Work a strange agitation of soul was
          created. The facts and figures given showed how vast the field, how
         great the need of direct, patient, continual pastoral effort in pastoral
           work amongst the multitudes of New York.6
         In 1887, J. F. Avery became pastor of the Mariners' Temple, situated
        on the lower East Side of New York City at 1 Henry Street, a section of the
        city that was notorious for its poverty and rowdyism. In the words of the
          Reverend Avery's wife:
         People, people everywhere. Crowded into the lofty tenement houses,
         burrowing in basements, packed in cheap lodging-houses, and swarming
         on the streets. To the casual observer the picture is bewildering. Even to
          the ordinary Christian worker the situation is one that would seem to
         defy all effort to improve it. Vice in a hundred repulsive forms holds
         many in its iron grasp. Relentless lust and passion hold captive many
                    . ..I.- ,,.e- ^_^ I. ^_.^ I--L AL- --...-.. A. ~--`-I AAl~    o.-_ ho1A ;m hnmrlnne


                    Avery's Personal Life    51

which if not so repulsive in its outward manifestation, is no less fatal in
its final influence on human destiny-that of religious superstition .?
The squalor of the Bowery did not dismay the Baptist Averys, who
accepted the challenge of having to deal with both Jews and Catholics, and
with a neighborhood which was a melting pot of sin. They made the
Mariners' Temple a lively center of religious and social activities until the
Reverend Avery's death from Bright's disease in 1892.
The peregrinations of the Reverend Avery and his wife strongly suggest
that they were enterprising persons, and this is confirmed by the wide
range of their activities in both Halifax and New York. J. F. Avery wrote in
the local newspapers about social problems; in 1876 he published an
edifying pamphlet entitled "The Voyage of Life"; until his death, he edited
a church paper, Buds and Blossoms, in which calls to worship and hymns
provided the framework for discussions of community and family affairs.
He must also have dabbled in medicine, or at least in pharmacy, as judged
from the fact that he patented a preparation called "Avery's Auraline,"
which he claimed was useful for the "relief and cure of deafness, earaches
and noises in the head." His wife entered into partnership with a certain
Jane Caroline Irish to promote "Avery's Auraline" commercially, but the
project failed.
The problems of daily life in New York were often difficult for the
Averys, living as they did on a small pastoral salary and using some of it for
the publication of Buds and Blossoms. Fortunately, the Baptist community
of the greater New York area was tightly woven, and was always available
for help and encouragement in times of trouble. This spirit of brotherhood
is illustrated by the account published in Buds and Blossoms of the fire that
destroyed the Avery home in December, 1890. All the community pitched
in; expressions of sympathy and financial assistance came from as far away
as North Tarrytown. In particular, Mr. John D. Rockefeller sent a friendly
letter and enclosed a check for $100.
Mr. Rockefeller was deeply involved in all activities of the Baptist
Church, and for this reason contributed now and then to the missionary
program of the Mariners' Temple. In letters to him that are as flamboyant
in style as in handwriting, the Reverend Avery suggested that he was in
need of some financial help to convert the Jews and Catholics of the
neighborhood. He also wished that the Mariners' Temple be made as
appealing to the Bowery derelicts as were the dens of sin among which it
was located. "The saloons are so brightening up around Chatham Square, I
am jealous for the Old Temple; it begins to look weather beaten."n Or
again, "1 wish we could out vie with attractiveness the brilliant but soul


52    THE PROFESSOR, THE INSTITUTE, AND DNA

cursing saloon."g While Mr. Rockefeller was much in favor of the Rever-
end Avery's efforts, he felt more at ease doing God's work through the
Baptist Mission. Nevertheless, he continued to help the Mariners' Temple
directly, as seen, for example, in a letter written to him by Mrs. Avery in
1893, one year after her husband's death.`O
A letter from Mr. Rockefeller to the Reverend Avery, dated December
30, 1890, reveals the closeness of the New York Baptist community:
Rev. J. F. Avery,
#l Henry St.
New York, NY
My dear Sir:
    I inclose herein a Christmas check for $50, for yourself and your
dear family and wish you all a happy New Year.
    We have skating at my house, and it occurred to me, that as you
moved down from the North, you might be skaters. Can you not all
come around and join us tomorrow afternoon between four and six?
You will find an entrance on either side of the house. Put your hand
through the gate, and pull the bolt.
                 Yours very truly,
                 (signed)    John D. Rockefeller"

According to John D. Rockefeller, Jr., "Father was always an enthu-
siastic skater." He arranged that a yard in back of his house at 4 West 54th
Street be converted into a basin that was flooded and used as a skating rink
when the weather was cold enough .I2 There he invited his Baptist acquaint-
ances, as well as churchmen and educators whose activities he valued.
Those were the happy days when the richest man in the world could simply
tell people to "put your hand through the gate, and pull the bolt" when he
invited them to his home!
Photographs of Mrs. Avery show her to be a small, strong-willed
person. As her son Oswald clearly resembled her physically, and perhaps
to some extent temperamentally, it seems worth mentioning a few facts
that suggest how she managed her life.
In New York, as well as in Halifax, she seems to have been the moving
spirit in making her husband's church a social center for the Baptist
community. She continued the mission work and the publication of Buds
and Blossoms after her husband's death. Her religious beliefs were com-
plemented by an earthy practical sense that led her to put pressure on the
readers of Buds and Blossoms for payment of their dues: "Please send the
amount due for your subscription at once; by so doing, I shall be relieved
of much care and anxiety."13
Among the many ordeals that she overcame, she once had the odd


                    Avery's Personal Life    53

experience of being considered dead for several hours. This happened in
Halifax in 1882, when she was 39 years old. After a few days of fever,
chills, and intense perspiration, she became so sick that, in the words of her
husband, "The death dew stood upon the face." Her two boys, Ernest and
Oswald, were called to her side as her end appeared near, and "she
charged [them] to do good and be good before they retired to the parlor
below and fell on their knees." She became completely unconscious.
Eventually "at 2 a.m. the form was stiffened and chilled, the jaw had
fallen. . . . `It is all over; she is gone,' said the doctor, `I may as well go
home' ." She was then prepared for the death linen she had carefully set
aside for such an eventuality, but two hours later she called for help and
said, "I have been dead, have I not? Yes, I remember, Jesus waved me
back and said `Not yet my child.' Oh! how disappointed I was." Soon she
took a cup of tea, "asked for a biscuit, and heartily enjoyed the same." She
lived for almost 30 years after this dramatic experience, but the story of her
"death" remained in the family, and it may have so affected the young
1 Oswald, who was five when he witnessed the event, that it played some
role later when he selected medicine as a profession.

After her husband's death in 1892, Mrs. Avery worked with the Baptist
City Mission Society, then located near the Manhattan Bridge. In her
work, she was associated with a great variety of wealthy people, among
whom were the Rockefellers, the Vanderbilts, and the Sloans. In particu-
lar, she was close to Emily Vanderbilt Sloan, who took an interest in the
two surviving sons. These social contacts made it possible for the boys to
spend some time on great estates (unidentified) in New York State. She
eventually moved to 1202 Lexington Avenue, where Oswald lived while
going to medical school; his Colgate roommate, William Parke, also lived

there as a boarder during his law-school years.
While in Halifax, the Averys had three sons. The oldest, Ernest, seems
to have had unusual intellectual gifts. "When but a toddler, he was fond of
getting on a stool, arrayed in his father's white collar and tie, and from an
open book preach to surroundings rather than to an audience. From the
start in life he had a stronger brain than physique."14 He died in 1892 of an
undefined illness, perhaps tuberculosis; the account of his death in Buds
and Blossoms reads like the hagiography of a medieval saint.
The youngest son, Roy, who was born in 1885, was also sickly during
his early years. Much can be learned in Buds and Blossoms of his mother's
struggle to protect his health, and he survived. As he was only six years old
when the Reverend Avery died in 1892, "he did not remember him so that
: his brother [Oswald] eight years his senior was more of a father than a


54     THE PROFESSOR, THE INSTITUTE, AND DNA

brother; he looked up to him and admired him greatly."`" Roy followed his
brother in the field of bacteriology, and eventually taught at Vanderbilt
University Medical School in Nashville, Tennessee. Much of the informa-
tion about the Avery family used in the present account was acquired by
him and transmitted to me by his widow, Mrs. Catherine Avery.
Oswald, the second boy, was born in 1877. He was then referred to as
"Ossie ," but the nickname does not seem to have stuck with him long.
Perhaps because his health did not generate as much concern as did that of
his brothers, and more likely because he was, from the beginning, a very
independent child, mentions of him in Buds and Blossoms are rather
casual. Small in stature, he had a strong and extremely intelligent face. He
began taking part in the activities of the church at a very early age, with the
same kind of determination that was to serve him well later in his scientific
work.`"
When the Averys arrived in New York, the organ of the Mariners'
Temple was in such poor condition that it could not be used, and there
were no funds to replace or repair it. Enterprising as usual, Mrs. Avery
managed to induce a young German musician to play his cornet in the
church. Soon, her two oldest boys, Ernest and Oswald, took advantage of
this new acquaintance to familiarize themselves with the cornet. Without
help or prompting from anyone, they "got hold of an old and inferior
instrument, and before we could believe they had, on the housetop,
without raising any protest, both learned to play this somewhat difficult
instrument."" The German cornetist was so impressed by the efforts of the
two boys that he volunteered to give them free lessons, and within three
months they were capable of playing with him in the church. When the
young German returned to his homeland, he arranged for another cornet-
ist to continue the musical education of the Avery boys. Eventually, they
both became so proficient with the cornet that they obtained scholarships
at the National Conservatory of Music.
Obtaining a good cornet was quite a problem for the Avery family. The
first-class instrument recommended by a famous Boston cornetist cost
more than $60. a large sum for a pastoral budget; but Ernest and Ossie
would have none other because "it did not take nearly so much effort to
blow, and produced a fuller, grander note."lX Fortunately, friends of the
Mariners' Temple became interested and contributed the necessary funds.
As early as July, 1889, Ossie had used the new instrument in the temper-
ance Sunday School and at the "regular meetings" of the church.
For a while, Ernest and Oswald made it a practice to stand on the steps
of the Mariners' Temple on Sunday afternoon, playing their cornets to


                   Avery's Personal Life    5.5

attract worshippers. The Reverend Avery mentioned this fact with pride in
his letters to Mr. John D. Rockefeller, asking for financial help. In 1891,
however, Ernest was so sick that he no longer had "the lung power for
successful and continued playing. "ls Another cornetist had to be found to
take his place, but Oswald continued until he left for Colgate Academy in
1893. Eventually, he became such an accomplished musician that he once
played in Antonin Dvoiak's Symphony No. 5, From the New World, with
the National Academy of Music, under the direction of Walter Damrosch.

The Colgate Years

Oswald Avery was ten years old when his family moved from Halifax to
New York City. Although he could not avoid coming into contact with the
riff-raff of the city all around the Mariners' Temple, there is no indication
that he was influenced in any way by this experience. He survived any
vicissitudes which the neighborhood might have presented, and attended
with success the New York Male Grammar School, from which he received
a diploma in 1893.

He then moved to the Colgate Academy, and in 1896 entered Colgate
University, from which he received the B.A. degree in 1900. He never
referred to his early childhood, but he frequently spoke of his Colgate
experiences, probably because the college years represented the beginning
of a new phase of his life, during which he achieved intellectual independ-
ence from his familial background.

Colgate Academy and Colgate University, both in Hamilton, New
York, had been founded in 1819 by the Baptist Education Society of the
State of New York; a theological seminary was attached to the Univer-
sity.*O The intellectual atmosphere of the school seems to have been
extremely liberal at the end of the nineteenth century. Harry Emerson
Fosdick, who was to become one of the most celebrated churchmen and
preachers of America and who was Avery's classmate, has written enter-
tainingly of the fact that his education at Colgate almost made him an
agnostic by the end of his sophomore year. In his words, "wild horses could
not have dragged me into church. . . . The old class prayer meetings saw
me no more."21 Although there is no information concerning Avery's
religious attitude, it is probable that he, too, came to question some of his
family's fundamentalist convictions.

The revolt against orthodoxy was very much in the air at Colgate at that
time. A group of six students, among them Avery and Harry Emerson
Fosdick, asked a young professor of philosophy to organize for them,
during the senior year, a special course of metaphysics in order that they


56     THE PROFESSOR, THE INSTITUTE, AND DNA

might examine the credibility of the Christian faith. One day, as the small
group stood on the steps of Alumni Hall after class, Avery concluded their
discussion with the startling pronouncement, "Fellows, you know there
really is a God."22 This from a boy who a very few years before had played
the cornet to lure the unbelievers to conversion and who, in his adult life,
made it a policy never to utter a statement that he could not document with
overwhelming laboratory evidence!
Life was rugged at Colgate at the turn of the century. The students were
expected to attend to their own housekeeping and to supply themselves
with cloths, mop, broom, bucket, and dust pan. From the top of the hill
where the college was situated, they had to walk down to the Hamilton
village store for their supplies, especially to secure kerosene for their
lamps; often the trip was made through unplowed snow.
Also during the winter, when the temperature hovered around zero
outside, the fire in the little iron stove in the dormitory often went out
during the night, and water froze in the pitchers. The students had to hustle
downstairs with the scuttle of ashes and get coal and kindling from the pile
outside the building. When the outdoor hand pump was frozen tight, the
ice had to be melted with a twist of blazing newspaper, and water had to be
found somewhere to prime the valve. Haste was essential, as breakfast and
morning classes started at an early hour.
Small and elfish as he was, Oswald seems to have fared remarkably well
under these rugged conditions. His schoolmates called him "Babe," proba-
bly because of his small size, but they also referred to his "aristocratic
daintiness," which they traced to what they mysteriously termed "his
residence among the dignitaries of the pie belt."23 He continued to play the
cornet (solo B flat) through his Colgate years and, in fact, became the
leader of the college band. The photographs of him among the other
members of the band show him to be small and slender of body, but with a
face giving an impression of alertness, intensity, forcefulness, and a touch
of youthful arrogance (Figure 4). During his junior year, it was said of
him in the yearbook that only the accident of having been born in Halifax
and therefore a foreigner prevented him from pursuing "his aspirations for
the Presidency."24 Parts of the yearbook characterization of Avery as a
college student are noteworthy because they present such a sharp contrast
with the adult man who became legendary in later years as a gentle,
retiring, and seemingly shy scholar.
"Being a minister's son, he is blessed with a faith in Providence, second
only to his faith in himself. . . . He iives in New York City, except in the
summer which he spends with the scions of America's saponaceous aristoc-


ersonal Life

57

racy. He believes in the Baptist doctrine, Free Trade, American expansion
and domestic finish"25 (italics mine). The mention of his "residence among
the dignitaries of the pie belt" and of the summers he spent "with the
scions of America's saponaceous aristocracy" probably refer to the fact
that, through his mother's social contacts, he had mixed with the well-bred,
prosperous classes and had acquired some of their behavioral patterns. The
"saponaceous aristocracy" included, in particular, Mr. J. P. Pyle, who
marketed the Pearline and other kinds of soap, as well as the Pearline
washtubs. Both Mr. and Mrs. Pyle were very active in the affairs of the
Mariners' Temple. Their names appear repeatedly in Buds and Blossoms,
both in church matters and because of their contributions to the familial
life of the Averys. Judging from the statement in the Colgate yearbook,
Oswald must have bragged about his social connection with such well-

From the beginning of his studies at Colgate Academy and University,
Avery made excellent grades in all his courses. At the University, his
average was 8.5 (out of 10) for the freshman year, and above 9 for the
other three years; he majored in the humanities, and took only the few
elementary courses in science that were compulsory.26

Paradoxical as it may seem for a person who later made it a point to
avoid public appearances, his best grades at Colgate were in public speak-
ing. Each of the four years he achieved grades of 9.5 in the subjects listed
as Public Speaking, Oration, or Debate. At Colgate in those days, oratori-
cal contests caused as much excitement as football games do today. On a
famous occasion, the judges announced that there would be no second
prize award; a tie for the first prize was to be shared by Harry Emerson
Fosdick and none other than Oswald T. Avery.*' Decades later, Avery was
still prone to declaim in the laboratory, with obvious pleasure, the sono-
rous phrases of a speech on Chinese civilization that had been one of his
college oratorical triumphs.

During the fourth year, which was then entirely elective, Avery took the
following courses, in all of which he made excellent grades: Philosophy,
Modern Philosophy, Ethics, History, English Literature, History of Art,
Economics, Political Economy, and of course Public Speaking, with De-
bate for good measure. Many elective courses were offered in scientific
subjects, but he did not choose to take any of them. This was the academic
preparation with which he graduated from Colgate University on June 21,
1900. He entered the College of Physicians and Surgeons of Columbia
University in New York City the same year.


            58    THE PROFESSOR, THE INSTITUTE, AND DNA

Medical Education

It can be surmised that when Avery first went to Colgate. his intention,
or at least that of his mother, had been for him to enter the ministry, as did
many of his classmates; this might explain his interest in public speaking
while at college. As mentioned earlier, his attitude in religious matters
seems to have changed profoundly in the course of his college years. Like
Harry Emerson Fosdick, he probably rebelled against "the kind of bibliol-
atry and theology" he had been taught. However, this alone does not
explain why he chose to enter medical school after having emphasized
philosophy, literature, and public speaking throughout his studies and, in
particular, during his elective senior year.

A possible explanation might be the contacts he had had with problems
of disease during his youth-his father's patent for ear ailments, his
brother's death. his mother's near-death. However, personal tragedies
were common at that time, and could hardly have been sufficient for
Avery's decision. A more likely reason may be that medicine provided him
with an outlet compatible with his familial missionary background and with
the rational philosophy he had developed at Colgate (see Chapter Twelve).

Furthermore, medicine enjoyed great prestige around 1900, because
recent spectacular discoveries in the field of infectious diseases opened
possibilities for effective action in the future. In his autobiography, Harry
Emerson Fosdick mentions that, after losing some of his original religious
faith, he himself had considered going into medicine upon graduation from
Colgate. According to the Colgate yearbook, four other students out of 30
in the class of 1900 expressed the intention to go to medical school. Three
of them, including Avery, did, and they all went to the College of Physi-
cians and Surgeons. At approximately the same time, the Reverend Gates
read Osler's textbook of medicine and concluded from it that the further-
ance of medical research would provide a worthwhile cause for Mr.
Rockefeller's philanthropic interests (Chapter Two). Medicine apparently
fitted well into the mood of the Baptist community at that time.

Whatever the reasons that led Avery to choose medicine as a profes-
sion, his deficiency in scientific training was not a handicap, as the scientific
entrance requirements of the College of Physicians and Surgeons were
virtually nonexistent. Courses in physics and chemistry were then part of
the first-year curriculum. The only records of his medical education that
have survived are course grades. These were good, except in bacteriology
and pathology, the sciences to which he was later to make such monumen-
tal contributions! The nickname "Babe" had followed him from Colgate,
and he was known by it during his four years of medical school. Dr.


Avery's Personal Life

Edwards A. Park (who became one of the foremost American pediatri-
cians) had been his schoolmate and has stated to at least two persons that
"Babe" was quite suitable to Avery as a medical student and a young
doctor because he appeared so immature and the most unlikely to suc-
ceed .zx

The College of Physicians and Surgeons had long been one of the
leading medical schools in the United States but, at the turn of the century,
it had not yet been much influenced by the scientific spirit. According to
Alfred E. Cohn, who was a student there at the same time as Avery, the
school was concerned almost exclusively "with the care of the sick." Since
Avery never spoke of his medical school years, it is probable that they did
not provide him with much intellectual satisfaction.
Immediately after receiving his medical degree in 1904, he joined a
group engaged in the practice of "general surgery" in New York City.
Around the turn of the century, this expression meant the general practice
of medicine. One of the few existing testimonies of that period, if not the
only one, is a thermometer in a silver case with the following inscription:

PRESENTED TO DR. 0. T. AVERY BY
NEW YORK CITY TRAINING SCHOOL
       JUNE 1, 1906

He remained in practice until approximately 1907, but found it upset-
ting to deal with patients suffering from chronic pulmonary disease and
intractable asthma for whom he could do nothing really useful. From his
own accounts, he was quite successful in his personal relations with pa-
tients, but clinical practice did not satisfy him intellectually and emotion-
ally, probably for the reasons mentioned earlier. In the words of his close
friend, Dr. A. R. Dochez, the experience "supplied him with some amus-
ing stories but did not attract him sufficiently to make a career in that
field.`lzg Fortunately for him, medical New York was then becoming
research-conscious, and he soon found an opportunity to shift from clinical
to laboratory work. As this part of his life is the only one for which he
himself has provided some documentation, it seems best to let him tell the
story in his own words:

Sir Almroth Wright came to New York from England and gave a lecture
at the Academy of Medicine on his newly invented opsonic technic. The
New York City Health Department was interested in this and arranged
to have a colleague of Sir Almroth give a short course of instruction to a
small group. [Dr. Wright was the prototype of the physician in G.B.
Shaw's play, The Doctor's Dilemma .]

I was one of those to take this course. At its completion, Dr. William


60    THE PROFESSOR, THE INSTITUTE, AND DNA

Park gave me a job doing opsonic indices for the Board of Health at a
stipend of $50 per month for part-time work. I also found part-time
employment doing milk bacteriology for the Sheffield Company. Pasteur-
ization of milk was just coming in; I made bacterial counts of milk before
and after pasteurization at a stipend that was also $50 per month.3"
The next important move in his professional life was his appointment to
the Hoagland Laboratory in Brooklyn, an institution which, as mentioned
earlier, has historical interest because it was the first privately endowed
laboratory for bacteriological research in the United States. The director,
Benjamin White, was not a physician. In 1903, he had earned a Ph.D. in
physiological chemistry at the Sheffield Scientific School of Yale Univer-
sity and progressively acquired practical knowledge of medical microbiol-
ogy, first in the United States, then in Germany, Austria, and London.
When he took over at Hoagland in 1907, his first administrative act was to
appoint Avery to the position of associate director at a salary of $1,200,
which was increased to $1,500 in 1909. This is how it happened, again in
Avery's words:
Benjamin White and I met in this way. While I was a student at the
College of Physicians and Surgeons, I roomed with a young law student,
William M. Parke, who after admission to the bar practiced for a time
on Remsen Street. It so happened that Benjamin White lived in the
same house, and thus we became acquainted. White mentioned to me
that he needed a young doctor to be his assistant director. I responded
enthusiastically and so I was invited over to the Hoagland Laboratory.31
It will be remembered that Parke had been Avery's classmate at Colgate
Academy and his roommate at Colgate University. While studying at the
New York Law School, he roomed in the apartment occupied on 1202
Lexington Avenue by Avery and his mother.
The six years Avery spent at the Hoagland Laboratory were of crucial
importance for his scientific development. Benjamin White, having been
trained as a chemist, could indoctrinate him in laboratory techniques and
in the chemical mode of thinking. Moreover, the responsibilities of the
department were wide, with regard to both research and teaching, thus
providing him with a highly diversified experience. He and White decided
at the outset that they would treat all bacterial cultures as if they were
plague bacilli. This set the stage for the exceedingly careful techniques that
characterized Avery throughout his professional life.
The first problem Avery had to deal with was the bacteriology of yogurt
and other fermented milks that were just becoming popular through the
work of Elie Metchnikoff at the Pasteur Institute in Paris. Metchnikoff


                   Avery's Personal Life    61

claimed that the consumption of these fermented milk products accounted
for the great longevity of populations in Eastern Europe, because they
prevented intestinal intoxication by controlling the putrefying bacteria of
the gut. As the Hoagland Laboratory was in a Syrian neighborhood where
the grocers prepared their own fermented milk, Avery developed a taste
for this product while studying it. He and White eventually recorded their
findings in a paper entitled "Observations on Certain Lactic Acid Bacteria
of the Bulgaricus Type." From 1909 to 1913, they carried out studies on a
wide variety of medical problems, which they approached by optical,
bacteriological, immunological, and chemical techniques. The subjects
ranged from the demonstration of Treponema pallidum in syphilitic lesions
to the analysis of the antigenic properties of certain plant proteins. Avery
thus received, during these few years, a very broad practical training in
various fields of bacteriology and immunology.
In 1910, White had a severe reactivation of tuberculosis, and went to
the Trudeau Sanatorium in Saranac Lake in the Adirondacks to take the
cure. Avery accompanied him on the initial trip, and later spent several
periods of vacation at the sanatorium. This experience naturally stimulated
in him an interest in tuberculosis, which he satisfied by working in the
Trudeau laboratory and library. His notebooks of the time were full of
extensive and carefully handwritten analyses of current publications on the
clinical and experimental aspects of tuberculosis.
Avery's publications during the Hoagland Laboratory period were
scholarly in approach and thorough in execution, but they exhibit little
originality and can be regarded as the products of a self-training period.
However, one of them deserves mention because it deals with a type of
systematic clinical testing which was of lasting practical value, but was very
different in research style from the more imaginative studies for which he
was to become famous a few years later. While "vacationing" at the
Trudeau sanatorium, he carried out 100 consecutive blood cultures of
tuberculous patients in the active phase of their disease without ever
recovering tubercle bacilli or observing evidence of secondary infection.
These negative findings were important for the understanding of tubercu-
losis, and they demonstrate his ability to carry out a systematic clinical
investigation. Although routine work of this kind was not his bent, it was
fortunate that he undertook it, because it caught the attention of Dr. Rufus
Cole, director of The Rockefeller Institute Hospital, and thus indirectly led
Avery into the scientific environment best suited to the unfolding of his
genius.
Some two years later, he carried out, in collaboration with Benjamin


g             62    THE PROFESSOR, THE INSTITUTE, AND DNA

White, a chemical and toxicological study of a product derived from
tubercle bacilli by extraction with alkaline ethanol. This investigation,
which was published in 1912, also was important in Avery's scientific
development. It was the beginning of a pattern that can be recognized
throughout his subsequent career at The Rockefeller Institute-the sys-
tematic effort to understand the biological activities of pathogenic bacteria
through a knowledge of their chemical composition. Another phase of his
training took place in 1911, when he spent his vacation at the biological
laboratories of the H. K. Mulford Comnanv. instructing its staff in bacteri-

Avery published nine papers during his Hoagland Laboratory period,
one of them a chapter on "Opsonins and Vaccine Therapy" that he
prepared in collaboration with Dr. N. B. Potter for Hare's Modern Treat-
ment, a text of clinical medicine that was then widely used. Here, again,
this publication contributed to his scientific career, because it prepared him
for the study of the role of phagocytosis in infectious processes.
The Hoagland Laboratory experience also provided Avery with the
chance to use in medicine the expository gifts he had displayed at Colgate
University. In collaboration with White, he worked on the bacteriology of
postsurgical infections and even planned to write a monograph on the
topic. To obtain material for this project, he encouraged clinicians of the
Brooklyn area to bring their bacteriological problems to his laboratory
and, when they did so, he gave them elaborate individual advice. Thus
began his practice of teaching by conversation, which he employed later
with great success at the Institute.
Another of his responsibilities at the Hoagland Laboratory was to run a
course for the student nurses. To impress the students with the dangers of
conveying respiratory germs by sneezing, he told them, "If your saliva
were blue, you would have to look at your patients through a blue fog."
From then on he was referred to as "The Professor" and later, more
familiarly, as "Fess," not only because of his skill as an expositor of
science, but also because of his wisdom in counsel.
The study on secondary infections in pulmonary tuberculosis, referred
to earlier, which Avery published in 1913, had greatly impressed Dr.
Rufus Cole. Late in the spring of that year, Cole paid a seemingly casual
.            . .-.          .     .^    . .         .    . . ..rl.

cultures of pneumococcus and testing their solubility in bile. He engaged


                   A very's Personal Life    63

the conversation with him by pointing out that, at the Institute, they
carried out the solubility test with buffered solutions of pure bile salts,
rather than with crude bile. The discussion that followed convinced Cole
that Avery had the proper scientific qualifications for the pneumonia
research program at the Hospital. This program involved a comparative
study of the different pneumococcal types, and could best be approached
by a scientist with knowledge of bacteriology, immunology, and chemistry.
This was precisely the unusual combination of skills that Avery had
acquired at the Hoagland Laboratory, under the guidance of White.

A few days after this meeting, Avery was invited to visit The Rockefel-
ler Institute, where he had lunch with Dr. Flexner, who also must have
been impressed. Shortly after, he received a letter from Dr. Cole with the
offer of a position as bacteriologist to the Hospital. In view of the prestige
of The Rockefeller Institute, and of the invitation to participate in the
program on lobar pneumonia, a disease of which his mother died in 1910,
he was certainly interested in the offer. However, according to his own
account, he did not reply, in part out of negligence and in part because he
was not eager to change positions. He liked his colleagues at the Hoagland
Laboratory and especially enjoyed the complete freedom to work at what
he wanted without ever being put under pressure. Dr. Cole wrote a second
letter and, receiving no reply, drove once more to Brooklyn, almost
apologizing to Avery for having offered him a position with inadequate
salary; the purpose of the second visit was to offer more attractive condi-
tions. Avery accepted, and joined the Hospital of the Institute in Septem-
ber, 1913. Only later did Dr. Cole realize that Avery tended to neglect his
correspondence, and that he had ignored the initial offer not because it was
financially inadequate, but because he had more urgent and more interest-
ing things to do than to acknowledge a business letter.

The Rockefeller Institute Years

Avery joined the Institute with the title of Assistant; he was promoted
to Associate in 1915, to Associate Member in 1919, and to full Member-
ship in 1923. He became Emeritus Member upon retirement in 1943 at
age 65. but continued working in his laboratory until 1948. Since the
scientific aspects of his New York phase will be presented at length in
subsequent chapters, it will suffice to outline here some facts of his private
life.

Shortly after his arrival in New York, Avery began to share an apart-
ment with Dr. A. R. Dochez, who was then his colleague in the depart-
ment of respiratory diseases at the Hospital and who was also a bachelor.


64     THE PROFESSOR, THE INSTITUTE, AND DNA

They continued this arrangement even after Dochez became Professor of
Medicine at the College of Physicians and Surgeons. As their apartment
was rather large, they took with them, for various periods of time, other
young medical scientists who were not yet married. In these early days,
their furniture consisted chiefly of odds and ends brought in and aban-
doned by each of the successive occupants.

In 1927, Avery and Dochez moved to 67th Street, between Lexington
and Third avenues, directly across the street from the fire station and
police precinct (the site is now occupied by a new building that houses the
Russian Embassy). They were joined at that time by one of Dr. Dochez's
brothers, who was a businessman and a widower and who brought with him
a great deal of fine household furnishings. This is the way Avery reported
the event in a letter to his sister-in-law, dated October 30, 1927:

. . . we have now a really delightfully equipped apartment with some
beautiful pieces - ranging from genuine Chippendale, original color
prints, and oriental rugs to Worcester Royal China and massive silver
service. It's really a great treat after years of association with an ill-
assortment of golden oak furniture and non-descript iron bedsteads of
the Early Wanamaker-Grand Rapids period.

When Dochez's brother remarried several years later, he took away all
the valuable pieces he had contributed, compelling the two bachelors to fill
the gaps with what they could find and afford at auction sales during the

a comfortable and carefree home. When the household was finally broken
up in 1948, Dochez took only a few items to the single room in which he
settled at the University Club in New York, and Avery moved the rest of
the furniture to the house he rented in Nashville, Tennessee.
The outward manifestations of Avery's life in New York were extremely

simple and frugal. Every day, just before 9 A.M., he walked the few blocks

from his 67th Street residence to the Hospital at 66th Street and York
Avenue. As soon as he reached his office on the sixth floor, he shed his
subdued gray jacket for an equally subdued light-tan laboratory coat. He
then took position at his desk, where one or several of us soon joined him
to begin the day with conversations, the tone of which I shall describe in

the next chapter. On special occasions, he put on a white laboratory coat
instead of a tan one, for example, when he had to call on Dr. Cole or Dr.
Flexner for some administrative problem, and every Wednesday morning

for the so-called "ward rounds," which, in reality, were held in the


                   Avery's Personal Life    65

dining room; on the first and third Monday of each month he faithfully
attended the dinner of the Hospital journal club. While he watched
carefully everything that was going on around him at these gatherings, he
seldom volunteered to participate in the discussions that took place. At
lunch, at ward rounds, or at the journal club, he talked only when asked                 !, Yi 1 (,/I
for his opinion, and even then his answers were short and to the point. The      i:j
great skill in public debate he had displayed at Colgate University never            , "i
expressed itself on The Rockefeller Institute campus.                                  :/ ~/)I
                                                                           III
                                                    ! -j,ml!
He was immensely popular among colleagues and outsiders, both men           i;ll::,
                                                                           .' 8'1
and women. Many were those who were eager to entertain him, and he                   ,/ t!
                                                                          c,!`;: ! I ! :
                                                                           il
could have spent every evening out if he had so desired; but, in fact, his                  t

social life was extremely restricted. Outside his laboratory, his most enjoy-                  :i
able moments appear to have been when Dochez returned home late at
night from one of his countless social engagements. Then talk would begin
on almost any topic, but preferably on one related to medical science and
to the theoretical problems of infectious diseases. Not infrequently, when
Dochez returned from the Metropolitan Opera, he found Avery reading
quietly in bed. Then he "would sit down in full evening dress and with
great animation describe to his old friend some of the illuminating thoughts
on the subject of microbiology which had occurred to him during the
second act of La Traviata, or whatever the evening's opera had been ."32
Both Avery and Dochez claimed that they derived much knowledge
from these midnight discussions. However, it is likely that the most profita-
ble result of their interplay was not what they learned from each other, but
that they used each other as perceptive sounding boards, better to define
whatever question each had in mind. These midnight discussions
sharpened their thoughts and gave them a form that could be successfully
communicated to other listeners and converted subsequently into labora-
tory tests.
The picture I have just drawn may give the impression that Avery's life
was rather drab, all work and no play. In reality, he managed to enliven
every moment of it with subtle attitudes and remarks that made his
company a pure delight. Dr. Colin MacLeod. who was one of his closest
associates around 1940, has given an amusing account of a typical after-
noon in 1941, while Avery was preparing the speech he had to deliver in
the month of May as president of the Society of American Bacteriologists:
We talked about whether he should say that bacteriology is the "Queen
of the Biological Sciences," or, as I might suggest, the Crown 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" [Dr.
Dochezj. And then a short three and a half block walk across town to


66     THE  PROFESSOR, THE INSTITUTE,  AND  DNA

see Do, who would greet us, rubbing his hands and saying with enthusi-
asm, "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 life
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.33

The even tenure of Averv's life was disturbed during the early 1930s
when he suffered from Graves' disease. He then frequently experienced
moods of depression and of irritation that he did not always manage to
conceal, despite valiant efforts. Finally, he underwent a thyroidectomy at
the Presbyterian Hospital in New York (either in 1933 or 1934-the
hospital records have been destroyed), and recuperated for several months
at the residence of his friend Dr. Harry Bray, who was superintendent of
the Raybrook Sanatorium in the Adirondacks. When he returned to the
Institute in the fall, he was once more his old self, but took advantage of his
medical condition to decrease still further his social commitments and
devote himself more comoletelv to his work and to his denartmental

Early during his New York years, he began to spend his vacation by the
seashore, and developed a great love of sailing. At first he went to
Gloucester, Massachusetts, where he was taken by his friend and colleague
Dr. Homer Swift, who owned property there. He rented a house on the
edge of the city at Stage Fort Park, which he shared with his brother's
family during the summer. While in Gloucester in 1929, he was invited by
Dr. Alan Chesney, who also had been his colleague at the Institute and was
then at The Johns Hopkins Medical School, to visit him on Deer Isle in
Maine. He immediately fell in love with the place, and from then on spent
every summer on Deer Isle, where several of his friends in scientific

medicine also spent their vacations.
One of his great measures was to eo sailing on Penohscot Bay on Dr.
Chesney's sloop. According to Dr. Chesney, "He never really tried to
master the art, but . . . rarely missed an opportunity to go for an afternoon
sail when the occasion offered. Short in stature and small in body as he
was-he could scarcely have weighed much over a hundred pounds-one
could not imagine him ever participating in any competitive sport."3" In
addition to sailing, he walked through the woods collecting ferns and


                 Avery's Personal Life    67

wildflowers; he observed the rapid growth and decay of toadstools, and
wondered at the enzymatic mechanisms involved in these biological proc-
esses; he painted landscapes and seascapes in watercolors of a subtle and
rather individual style.
Except for his annual summer trips to Gloucester and, later, to Deer
Isle, Avery did very little traveling. In 1932, he went to San Francisco to
deliver an important lecture, and came back via the Yosemite Valley, Los
Angeles, and the Grand Canyon. Upon his return, he wrote to his brother
that the trip had been "an unforgettable experience" and that he marveled
"at the gigantic sculpturing of Nature," but he never repeated the experi-
ence and never referred to it again. For a scientist of his fame, he attended
surprisingly few scientific meetings, even within the United States. He did
not go to Germany when he was awarded the Paul Ehrlich Gold Medal in
1933, or to England when he was proposed for a doctorate honoris causa
by Cambridge University in 1944 and awarded the Copley Medal by the
Royal Society in 1945, or to Sweden when he was awarded the Pasteur
Gold Medal by the Swedish Medical Society in 1950. He gave several
excuses for not traveling: lack of time, poor health, or financial cost, but
the only valid reason was that he restricted more and more the range of his
experiences to what he could find in his laboratory work, on Deer Isle, and
among his brother's family. In 1948, he decided that he had shot his bolt;
as he no longer felt able to function effectively in the scientific arena, he
retired to Nashville, Tennessee.

             The Nashville Years
Avery's reason for moving to Nashville was that he would find there his
brother Roy, who taught bacteriology at Vanderbilt University School of
Medicine, his sister-in-law Catherine, his niece Margaret, and his cousin
Minnie Wandell. Furthermore, he had several friends at the medical
school, in particular Dr. Ernest Goodpasture, chairman of the department
of pathology, and Dr. Hugh Morgan, chairman of the department of
medicine, who had once worked in Avery's laboratory at The Rockefeller
Institute.
Dr. Morgan persuaded Avery to continue with some laboratory work in
Nashville, and arranged that he be given a research grant by the Depart-
ment of Defense for the study of immunity to streptococcal infection. He
also arranged that Dr. Bertram E. Sprofkin, who had just completed his
medica residency at The Johns Hopkins, join Avery for two years as a co-
investigator. This program resulted in a joint report entitled "Studies on
the bacteriolytic properties of Streptomyces albus and its action on hemo-
lytic streptococci." According to Dr. Sprofkin, Avery often referred to the


68     THE PROFESSOR, THE INSTITUTE, AND DNA

work with which he had been associated at Rockefeller, and "his enthusi-
asm for any information concerning the nucleic acids remained at a high
level until his final illness."35 On the whole, however, Avery made little
effort to take advantage of the scientific facilities made available to him.
Throughout his years in New York, Avery always maintained contact
with his family, but almost exclusively by correspondence, except during
the summer vacations in Gloucester and on Deer Isle. In Nashville,
however, the familial atmosphere became much more intimate. He was
able to rent a fine stone house belonging to one of Roy's friends who had
moved to a farm in the country. The house was set on more than one acre
of land with beautiful trees, and had the additional advantage of being
situated but a few doors away from Roy's own home. His cousin Minnie
Wandell, "who adored him ," acted as his housekeeper.
Nearly every night Roy would walk up the street to join him for a game
of backgammon. It was a common sight to "see the two walking together
from one house to the other, obviously enjoying to be together."36 There is
no doubt that the possibility of close associations with his sister-in-law and
his niece provided him with the kind of emotional satisfaction from which
he had been deprived by his way of life in New York.
He became very much a part of his neighborhood, where he was known
not as a scientist but "as a very pleasant person to have around."37 Since he
had not previously lived in the South, he took great interest in the local
flowers and trees, learning their names and peculiarities. "His appreciation
of the flowers I shared with him from time to time would have warmed the
heart of any gardener."3h All accounts agree in giving the impression that,
during the last years of his life, Avery managed to create around himself
the atmosphere of the country gentleman. In fact, Dr. Sprofkin, who had
not known him before, felt that Avery spoke in Nashville with a slight
British accent, even though he had left Nova Scotia when he was ten years
old and had never returned. At times, Avery expressed the opinion that
"there was nothing so fine as a genuine British gentleman," and Dr.
Sprofkin felt that one of the reasons he loved his Nashville stone house was
that it embodied many of the most attractive features of an English
cottage.
While on Deer Isle during the summer of 1954, he noticed discomfort in
his right upper quadrant, and was examined first at The Rockefeller
Hospital and then in Nashville. The initial tentative diagnosis was gall-
bladder disease, but surgery revealed extensive hepatoma (cancer of the
liver). His terminal illness was very painful, but he bore it with his
characteristic patience. He died at the age of 78 on February 20, 195.5, and
was buried in Mount Olivet cemetery in Nashville.


CHAPTER FIVE

  AVERY'S LIFE

IN THE LABORATORY

The Inwardness of Research

Avery was a late starter in science. His research at the Hoagland I >abc ara-
tory had been thorough and diversified, but neither path-breaki ing  nor
even intellectually adventurous. He was almost 36 years old when he was
appointed to the staff of The Rockefeller Institute. The four papers he
published in 1915 dealt with the application of conventional serological
techniques to the biological classification of pneumococci isolated from
patients, and were of a routine nature. He was probably then regarded as a
competent medical bacteriologist, rather than as a creative scientist. In
1916, when he was 39 years old, there was nothing in his professional
achievements to indicate that, from the age of 40 to the age of 65. ) he
would continuously make major contributions to the biomedical SC :ien ces.
Graphologists, however, might have recognized in his handwritit "g u mu-

sual characteristics suggesting that he would go far if circumstances favored
him. Figure 9 represents a handwritten bacteriological report that he
prepared in 1916 on a pneumococcus culture isolated from a patient at
The Rockefeller Institute Hospital. Figure 10 is a letter to Simon Flexner,
written when Avery was ill with Graves' disease. In both cases, the script
reveals aspects of his temperament that could hardly be guessed at from
photographs of him taken during his adult life, or from descriptions of
his usual social behavior. The flourish of the script suggests enthusiasm,
versatility, and tenacity, a bold and imaginative mind, a love of form and
fantasy, an affirmative and almost daring self-confidence. These attributes
were concealed or muted in his public appearances, but they were fre-
quently expressed in his laboratory life and became evident in his creative
work after 1916. The bacteriological report is of historical interest for
another reason. The pneumococcus culture which it describes, labeled
D39, was widely used later by Avery and his collaborators in many phases
of their research program; in particular, it gave rise to the strains used in
the studies of transformation of pneumococcal types that led to the demon-


70    THE PROFESSOR, THE INSTITUTE, AND DNA

stration that deoxyribonucleic acid (DNA) is the carrier of genetic infor-
mation (Chapter Eleven).
The affirmative and almost exuberant character of Avery's script sym-
bolizes the boldness he began to display in his research style after joining
the Institute. Whereas his earlier work had been conventional, the papers
he published in collaboration with Dochez, first in 1916 on antiblastic
immunity, then in 19 17 on the soluble specific substances of pneumococci,
describe approaches to immunological problems that were then entirely
new-as original in execution as they were adventurous in interpretation.
One might assume that the profound change in Avery's research style
that began in 1916 was simply the consequence of his being provided with
generous budgets and elaborate resources for experimental work, but this
is not the case. As we shall see later, Avery never had a large laboratory at
the Institute, and he was always extremely frugal in the use of his research
facilities. He rapidly developed into a creative scientist not because he was
provided with funds and technical help, but because the Institute Hospital
provided an intellectual and human atmosphere that suited his tempera-
ment.
The type of scientific environment Avery found in the Hospital, and his
ideal of how biomedical research should be conducted, are lucidly ex-
pressed in the words he used in 1949 when he presented the Kober Medal
of the Association of American Physicians to Dochez. Both Avery and
Dochez were past retirement age at the time of the ceremony, but both had
exemplified throughout their professional lives the thoughtful and parsi-
monious attitude that Avery ascribed to his friend in the following words:
Throughout his [Dochez's] studies there is unique continuity of thought
centering in the dominant problem of acute respiratory diseases. The
results of his work are not random products of chance observation. They
are the fruits of years of wise reflection, objective thinking and thought-
ful experimentation. I have never seen his laboratory desk piled high
with Petri dishes and bristling with test tubes like a forest wherein the
trail ends and the searcher becomes lost in dense thickets of confused
thought. I have never seen him so busy taking something out of one tube
and putting it into another there was no time to think of why he was
doing it or of what he was actually looking for. I have never known him
to engage in purposeless rivalries or competitive research. But often I
have seen him sit calmly by, lost in thought, while all around him others
with great show of activity were flitting about like particles in Brownian
motion; then, I have watched him rouse himself, smilingly saunter to his
desk, assemble a few pipettes, borrow a few tubes of media, perhaps a
jar of mice, and then do a simple experiment which answered the very
question he had been thinking about when others thought he had been
idling in aimless leisure.'


                  Life in the Laboratory     71

Avery himself possessed to an extreme degree the qualities he attrib-
uted to Dochez. He exemplified the attitude he liked to call "the inward-
ness of research"- a phrase he borrowed from Theobald Smith-to denote
that scientific research implies both the establishment of facts through the
trained senses and the processing of these facts through the inner cogita-
tions of the intellect. He was scornful of ill-thought-out, busybody experi-
mentation, the kind he was wont to describe with a gentle smile as taking
something out of one test tube and putting it into another.
Whatever the importance or urgency of a problem, he never hurried,
because he believed that worthwhile answers could come only from orderly
thought based on careful observation and intellectual analysis. He was
prone to convey the importance of observing small details by quoting the
words of an old black patient who watched, with amused surprise, the
young doctors rushing about the wards of The Johns Hopkins Hospital:
"What's your hurry, Dot? By rushing that way, you passes by much more
than you catches up with." One of the reasons Avery was so effective in his
research is that he did not try to save time by being falsely efficient. He
knew that mechanical efficiency is not the same as effectiveness.
He conducted his investigations with the least possible expenditure of
physical effort, and with strict economy of materials, laboratory equip-
ment, and experimental animals. For him, the ideal experiment was one
that yielded a clear and inescapable conclusion from a limited number of
facts observed in a few test tubes or a few animals.
Avery had read widely and deeply into the literature of experimental
medicine before he joined the Institute. From the time he committed
himself to the study of respiratory diseases, however, he made little effort
to keep up with the details of other fields of science, let alone with other
intellectual disciplines. I worked in his department during a stage in my life
when I was under the illusion that one could assimilate the whole body of
biological sciences. I was often surprised, and at times almost shocked, by
the fact that his range of scientific information was not as broad as could
have been assumed from his fame and from the variety and magnitude of
his scientific achievements. Furthermore, his imagination did not seem to
me of the kind that soars far above the concrete facts revealed by straight-
forward observation or by simple laboratory experiments. I now realize
that these characteristics, which I regarded at the time as limitations in his
scholarship and imaginative power, were in reality great assets from the
point of view of his scientific creativity. Wordsworth's lines, "Wisdom is
ofttimes nearer when we stoop than when we soar," fits well the manner in
which Avery's imagination was intimately linked to the facts that he knew
from direct experience. He did not indulge in vague, sweeping generaliza-


72    THE PROFESSOR, THE INSTITUTE, AND DNA

tions, but he had an uncanny gift for transmuting the details he had
observed into an image of reality.
He had no taste for broad but shallow learning, and did not make
pretense to knowledge unless he had made it a constituent part of his own
intellectual fabric by using it in a creative way. For this reason, he tended
to focus his reading on the publications that were related to the experimen-
tal work in which he was engaged at any given time; in fact, he almost
limited his scientific contacts to those he could integrate into his own
research program. But the extent and thoroughness of his search for
information was truly phenomenal, once he had become committed to a
particular project. He assimilated abstruse aspects of organic chemistry
during the years he was involved in immunological studies with synthetic
antigens, and he became familiar with theoretical genetics when, late in his
professional life, he started the work that led to the identification of the
substance responsible for hereditary transformations in pneumococci.
He studied carefully the books and articles that had a direct bearing on
his problems, but he learned even more from personal contacts with
anyone who could provide him with theoretical knowledge or practical
information. I shall come back later to his skill in using conversation as an
educational process, but I want to emphasize at this point that it was
through his eagerness to learn from others that he developed a scientific
staff characterized by great diversity of professional specialization and, at
the same time, by a remarkable unity of purpose.

        Picking other People's Brains
Avery never referred to his collaborators as assistants, or even as
associates. When he wanted to mention the scientists, young or old, who
had participated in his research programs, he used circumlocutions to
indicate that they had been his friends, not subordinates - "the boys" or
"the people who have been in this laboratory." In his acceptance speech
for the Kober Medal in 1946, he gave credit for the success of his
department to the inspiration and wisdom that had been provided by Rufus
Cole, and he acknowledged the contributions of his associates with a
characteristic understatement: "Cole picked these men, and all I had to do
was pick their brains."2 It is indeed true that he used our technical skills
and derived many of his ideas from the theoretical knowledge and the
practical know-how of our diversified scientific disciplines. The more
interesting and important truth, however, is that it was he who formulated
the objectives of ,our collective enterprise and also set our very research
style.


                  Life in the Laboratory    73

The following two examples will illustrate how he "picked the brains" of

his collaborators and how he managed to integrate their specialized contri-
butions into his departmental program while helping each of us to discover
and develop a personal scientific identity.

In their early days at the Hospital, Dochez and Avery had prepared,
from broth cultures of the various pneumococcal types, crude fractions of
soluble materials that were specific for the particular type of pneumococ-
cus from which the material had been obtained. They referred to these
crude fractions as specific soluble substances (SSS), each of which is
specific for a particular pneumococcus type. They soon realized that it
would be of great importance to establish the chemical nature of these
substances, because this would explain the mechanisms of specificity and
throw light on the pathological behavior of pneumococci. Avery's first

I   Using simple techniques that he liked to refer to as "kitchen chemistry."                  `,,'
                                                                           .`,
                            i
                                                                           `,

substances that were endowed with specific immunological activity. In the
hope of finding a colleague who could help him to further the tasks of
purification and chemical identification, he constantly carried in his pocket
a small tube containing some of the mysterious powder. He had particu-
larly in mind the organic chemist Michael Heidelberger, who was then
working in the department of kidney disease on the seventh floor of the
Hospital. The following account is one that I heard many a time from
Avery, and that Dr. Heidelberger recently confirmed in all its details.

Every time he had a chance, Avery would agitate the tube of SSS in
front of Heidelberger and say, "Michael, the whole secret of bacterial
specificity is in this little tube. When can you work on it?" And Heidelber-
ger would answer, "Fess, this is a very interesting problem, but I have to
spend all my time making crystalline oxyhemoglobin. I shall look into your
problem when I have succeeded in obtaining for Van Slyke's team good
crystals of oxyhemoglobin." The scene repeated itself time and time again,
but finally, out of interest and friendliness, Heidelberger was able to work
on the specific soluble substance. Thus began a collaboration which even-
tually brought Heidelberger to join forces with Avery. He soon identified
the active material of SSS as a polysaccharide, and became thereby one of
the pioneers and great masters of immunochemistry.
The second example concerns the circumstances that resulted in my own
association with Avery, beginning in 1927. I was then a graduate student in


74    THE PROFESSOR, THE INSTITUTE, AND DNA

soil microbiology and soil chemistry at the New Jersey Agricultural Experi-
ment Station. Through a series of accidents, I found myself, during the

Rockefeller Institute for Medical Research. I knew nothing of his work
and, of course, he knew nothing of me. With his usual graciousness,
however, he inquired about my scientific interests and about the topic of
my Ph.D. thesis. I told him that I had been working on the microbial
decomposition of cellulose in soil, and had isolated several species of
bacteria and fungi that could destroy that substance. He immediately
became intensely interested, and invited me to continue the conversation
in his small office, where he asked for further details about my work. Then
he began slowly to suggest that my bacteriological studies with cellulose
were related to his own work with pneumococci. As I knew hardly any-
thing about medical microbiology, he patiently explained that these micro-
organisms owe their virulence to the fact that they are protected against the
defense mechanisms of the body by a mucilaginous envelope-the pneu-
mococcal capsule. This capsule, he told me, is made up of a polysaccha-
ride, a hemicelluloselike substance chemically related to the true cellulose
that I was using in my own experiments. And then, as if by a casual
gesture, but in fact deliberately, he took from the right-hand drawer of his
desk a little tube containing a white powder, labeled in his neat handwrit-
ing SSS III [Specific Soluble Substance of type III pneumococcus] and
shook it in front of me. Several years later he gave me this tube, still
containing some of the SSS III, and I have kept it ever since as a talisman.

While shaking the tube, Avery said. "This is the polysaccharide of
which the capsule is made. It is completely resistant to the body enzymes
and to all the other enzymes we have used. It can be decomposed only by
strong acid treatment. If only we knew of a way to decompose it with an
agent mild enough to be used in the body-an enzyme, for example - much
could be learned about pneumococcal infections." Even though I did not
understand all the details of the problem, I was fascinated by it and,
probably even more, by the scientific drama that emerged from Avery's
words and from the quiet intensity of his gestures and facial expressions.
Under the spell of his charm and contagious enthusiasm, I stated that, in
my opinion, it was possible to discover such an enzyme. I outlined how this
could be done, and even mentioned that I might find time to work on the
problem at the end of the summer.

In the course of that very same afternoon, Avery introduced me to two
persons whom I did not know; one was Rufus Cole, the other was Simon


                   Life in the Laboratory    75

ber, except for some general remarks about French bacteriologists and the
Pasteur Institute. I went back to the New Jersey Agricultural Experiment
Station and then traveled through the United States during the summer, as
I had planned. While in Fargo, North Dakota, I received a telegram
informing me that I had been granted a fellowship at The Rockefeller
Institute for Medical Research, to work with Avery. I had not applied
either for a job or a fellowship, but Avery had sensed that I could be of
help to his work and, without even corresponding with me, he had taken
the necessary steps for my appointment.
I joined his laboratory in September, 1927, and began to work on a
topic of pneumococcal physiology that had caught my interest, but that had
no relation to the search for an enzyme capable of decomposing the
polysaccharide. Now and then, Avery gently reminded me of the original
problem, and I finally began working on it during the summer of 1928. I
obtained active preparations of a bacterial enzyme early in the summer of
1929, while Avery was vacationing in Maine, and immediately wrote him
of my success. I mentioned especially that the enzyme had proved capable
not only of decomposing the capsular polysaccharide in vitro, but also of
destroying the capsules of pneumococci in Go, thereby curing mice suffer-
ing from experimental pneumococcal infection. Avery immediately re-
turned from Maine and together we repeated the experiments. The find-
ings were published in 1929.
I have told this story in detail to define the parts played by Avery and by
myself in this particular problem. There is no doubt that I contributed the
idea of how to discover a soil bacterium capable of decomposing the
capsular polysaccharide of type III pneumococcus; I also worked out the
techniques for the isolation of the bacterium, for making it produce large
amounts of the enzyme, for extracting and purifying the enzyme, and for
testing its activity in both the test tube and animals. But there is another
side of the story.
Now that I have read Avery's reports to the Board of Scientific Direc-
tors of the Institute, I know that, as early as 1923, he and Heidelberger
had tried without success to decompose the polysaccharide by using en-
zymes derived from animal tissues. They further stated that it had not been
possible to alter "the specific function [of the polysaccharides] by the
action of any molds grown in solutions of the active materials. Experiments
with molds, yeasts, and bacteria will be continued." 3 Although such
experiments also failed, it is obvious that my own studies were only a
continuation and extension of this initial program. The problem was still
very much in Avery's mind when he first talked to me in 1927, and it was


76     THE PROFESSOR, THE INSTITUTE, AND DNA

his vision of the potentialities of the enzymatic approach that set me on the
way. Furthermore, it was his teaching skill that enabled me to assimilate
rapidly the scientific lore and the techniques of his department, so that I
could apply my specialized knowledge to the large problem he had formu-
lated years before he began to indoctrinate me into biomedical research.
Such indoctrination of young scientists has been described by the late
Cohn MacLeod, who joined the department as a junior member of the
clinical staff in 1935, and who stayed long enough to be one of the co-
authors of the great DNA paper in 1944.
For a time, the recent arrival saw little of the Professor. In some, this
resulted in a sense of frustration at not being caught up immediately in
the scientific life of the active department around them or being made a
part of a current problem. Avery did not assign his associates to
problems. His approach was indirect and at times seemed excruciatingly
slow. After a week or two in the laboratory Avery commonly would
invite the new assistant into his tiny personal laboratory. . . . A morn-
ing or afternoon would be spent in describing the lore of pneumococcus
and in tracing the development of knowledge, the problems in which the
department was currently concerned and those in which it had an
interest. These soliloquies, prose masterpieces of high polish, were
widely known as "Red Seal Records" [of which more later] and Avery
was prone to repeat them as he sensed the necessity. If the candidate
showed interest and began to read and work under his own steam, he
was counselled and aided. A minimum of technical assistance was
provided and one swam or sank because of one's own efforts or the lack
of them. Avery placed emphasis solely on individual initiative and
spurned team projects.4

As is clear from MacLeod's account, there was no organized teaching or
training in the department; in fact, there was no formal organization of any
sort. Avery never asked or urged anyone to do anything, to participate in
any of his problems, or to initiate a new program. Consciously or uncon-
sciously, however, he had developed a very effective technique to create
unity of purpose among staff and visitors alike. The door of his office was
always open, and he was ready at all hours of the day to welcome questions
or statements from any one of us. In fact, except on very rare occasions, he
acted as if he believed that the concerns we brought him were of major
importance, but whatever the scientific problem discussed, he soon man-
aged to emphasize one aspect of it that had a bearing on some phase of his
own program. It did not matter whether the visitor's professional speciali-
zation was in clinical medicine, physiology, immunology, or chemistry, his
attention was soon focused upon some aspect of the departmental prob-


                   Life in the Laboratory    77

lems to which his particular skill was well suited. That is the way Avery
picked other people's brains, and also is the way he achieved unity of
purpose within the department. The newcomer became a part of the team
of his own volition almost unwittingly; he himself selected the area of work
best suited to his own taste and gifts, while being gently maneuvered into
one of the departmental problems.

This subtle manner of fostering cooperative action contributed greatly
to the effectiveness and variety of the departmental research program. Its
indirect consequences were even more important, for it gave each one of us
the opportunity to discover our individual attributes and to gain self-
confidence. Avery created an atmosphere in which our potentialities had a
chance to emerge spontaneously. His department was a nursery in which
any form of talent could unfold. One evidence that his teaching technique
was effective is the high percentage of his collaborators who came to
occupy important positions in medical schools or research institutes, and
who continued to be productive investigators wherever they went. Few
institutions can boast of such a large percentage of successful alumni!

The Protocol Experiment

As already mentioned, Avery was a late bloomer, but he moved fast
after 1916. By 1923, he had become a full Member of The Rockefeller
Institute, the highest rank in its scientific hierarchy. His fame was interna-
tional when I became part of his department in 1927, but the physical and
personal atmosphere in which he worked was still much the same as it had
been when he joined the Institute in 1913. In fact, it remained essentially
the same until he retired.

His laboratories were housed in a former hospital ward, still uselessly
ornamented with quaint marble fireplaces. The high-ceilinged rooms were
small and dissimilar in size; they were crowded with physicians and bacte-
riologists who were assisted by a few male technical helpers. Bacterial
cultures were transferred and examined and serological reactions were
carried out under conditions that would now be considered so primitive as
to be incompatible with careful scientific work.

Most experiments were conducted at simple wooden desks that had
been designed originally for office work and converted into laboratory
benches by equipping them with microscopes instead of typewriters. The
top of each desk accommodated a motley assortment of notebooks and
simple laboratory instruments- test tube racks, glass Mason jars, droppers
for various dyes and chemical reagents, tin cans holding pipettes and
platinum loops-in brief, any object that might serve in bacteriological and


78    THE PROFESSOR, THE INSTITUTE, AND DNA
serological manipulations. The same area was also used for handling
experimental animals, for inoculating, bleeding, and dissecting them, and
even for keeping some of them as pets.
The Bunsen burner on each desk served for aseptic transfer of cultures,
heat sterilization, preparation of culture media, and also for some chemical
operations. We used a great variety of kitchen utensils for many biological
and chemical experiments. Needless to say, the laboratories dedicated to
organic chemistry were equipped in a more sophisticated manner.
The larger pieces of equipment were situated in the middle of the rooms
or wherever they could be fitted between the desks; they consisted mainly
of a few simple incubators, vacuum pumps, and centrifuges. Each room
had a single porcelain sink that served for almost any operation requiring
the use of water, from staining slides for microscopic work to preparing
extracts of bacterial cultures for immunological tests.
Avery's own laboratory was the smallest; it had formerly been the ward
kitchen, and was equipped with the barest of bacteriological necessities.
His office was adjacent to his laboratory and was, like it, small and bare.
Both rooms were neat and clean, but kept as empty as possible, without
the photographs, pictures, momentos, unused books, and other friendly
items that usually adorn and clutter the working places of the white-collar
class. The austerity of his office and laboratory symbolized how much he
had given up in all aspects of his life for the sake of utter concentration on a
few chosen goals.
His laboratory techniques were extremely simple, and he seemingly
added to them only with hesitation and even reluctance. When the need
arose, however, he went out of his way to learn new experimental proce-
dures, as he did, for example, late in life during the phase of his work that
led to the chemical isolation and identification of DNA; techniques were
for him only a means to an end, and he never became a slave to them.
His kind of genius as an experimenter went far beyond that of the
competent tradesman of science. First and foremost, it was marked by the
thoughtfulness he applied to the selection of his distant goals, and the
meticulousness with which he conducted his experiments. Then, when the
results came in, he spent an incredible amount of time cogitating about
their significance and distilling from them new interpretations of earlier
knowledge and new ideas for further exploration.
Before deciding on any experiment. let alone starting it, he sat at his
desk for days, mulling over the problem with associates or friends, and
often alone. Among all the things that could be done, he was painfully
anxious to determine by thought the one, or the very few, that appeared


                   Life in the Laboratory    79

worth doing. He had developed an uncanny sense for recognizing what was
truly important. Then, once he had made his choices, he formulated them
over and over again, in as precise terms as possible. During that period, he
consulted with anyone who was likely to contribute information relevant to
the theoretical understanding of the problem at hand, or who was an
expert in procedures that might serve in the experimental study. This was
the time when he picked brains not only of his collaborators, but of anyone
he managed to enlist under his flag by his persistence, his charm, and his
enthusiasm.
Thinking, however, was never for him an end in itself. He had no taste
for concepts that did not lead to experimentation. "Ideas are wonderful
things," he would say, "but they don't work unless you work for them."
Not only did he work for them; he put as much intensity into actual
laboratory work as he did in thinking about experiments. The following
statement by Maclyn McCarty is of interest because ,it is typical of Avery's
attitude in the laboratory and because it refers to the period in the 1940s
when he was working on the transformation of pneumococcal types after
he had passed retirement age:
Each morning on arrival in the laboratory the results of the experiment
of the day before were waiting in the incubator to be read. Thus, when
things were going well, each day began with a new bit of information
that provided the stimulus and direction for further experiments. Fess
and I had an unspoken agreement that prevented either of us from
obtaining a sneak preview of the results before the other had ar-
rived. I recall the image of Fess as we converged on the incubator
each morning, and in particular I see his expression, which was a curious
mixture of eager anticipation and of apprehension for fear something
had gone wrong with our complex biological test system-which, alas,
was all too frequently the case.j
In view of this picture of Avery's childlike eagerness. it is rather
surprising to read the statement by the late Arne Tiselius, as an explana-
tion for the failure of the Nobel Committee to recognize Avery's DNA
work, that "he was an old man when he made his discovery." 6
Once experiments were under way, his obsession was to satisfy the most
exacting criteria of evidence. He did not consider the work to be complete
until all the results could be brought together in a perfect "protocol
experiment" - one which incorporated all the variables and controls and
which yielded the expected result without fail. The demonstration had to
be so obvious that there was no need for statistical analysis. When this
point had been reached, visitors and colleagues were invited to admire the


80    THE PROFESSOR, THE INSTITUTE, AND DNA

simplicity of the experimental set-up and the clarity of its results. As long
as Rufus Cole was director of the Hospital, he came down to the laboratory
whenever the results were especially interesting, and joined in the chorus
of admiration. We who had been involved in the excruciatingly slow, early
phases of the work knew that endless discussions and numerous prelimi-
nary tests had preceded the experimental design that now appeared simple
and decisive. For this reason, we were somewhat irritated to hear Dr. Cole
tell us that we should learn from The Professor the art of planning and
performing convincing experiments with small numbers of test tubes and
animals, but nevertheless we enjoyed the show. The final demonstration
with a few test tubes and a few animals never sacrificed any of the demands
of scientific integrity; it was high-class showmanship, and had the quality of
an artistic performance.
When an experiment failed to yield the expected results, extensive
discussions of the new findings would ensue, with head-scratchings and
exclamations of puzzlement. However, while the failure was the cause of
much perplexity, it rarely led to a long period of discouragement. Avery's
reaction was soon likely to be, "Now boys, whenever you fall, pick up
something." And he would try to find in the unexpected result new ideas to
be used for the problem at hand. In contrast to his cautious, conservative
attitude while preparing an experiment, or during its performance, he
would let his imagination be fired by any new challenge. During the initial
period of puzzlement, he would formulate and encourage new hypotheses,
some of them rather wild, in animated discussions and, even more often, in
animated soliloquies. Almost any fact, however small and especially if
unexpected, was likely to release in him a stream of theory.
Adrien Loir, Pasteur's nephew who assisted him in all his studies after
his paralysis, has left a picture of the master's life in the laboratory that
reminds me of Avery's behavior:
Whenever there was a result, he [Pasteur] would build a whole new
theory and expound it to anyone who was around; it is fortunate that
there were few of us because it was a true novel [un veritable ro-
man]. . . . He let his imagination run away when he was concerned with
a particular topic. He would discuss his idea in the laboratory, at home,
at the dinner table, everywhere. . . . He knew how to limit the numbers
of his experiments, but in such a way that they gave an answer to his
questions.7
When I read Loir's statement about Pasteur's "composition de ses
romans," I remember Avery's mental constructs about the antigenic disso-
ciation hypothesis that I shall discuss in Chapter Nine.
Even though he became readily intoxicated with his own ideas, Avery,


                   Life in the Laboratory     81

like Pasteur, always retained his discipline as an experimenter. An orgy of
talk was suddenly followed by phrases such as "We should be bold in
formulating hypotheses, but we must be humble in the presence of facts,"
an expression which I believe he derived from Thomas Huxley. After the
theoretical implications of new hypotheses had taken us into the strato-
sphere, he brought us back to a more sober view of reality with the homely
reminder that the blowing of bubbles is all right as long as one remembers
to prick them oneself. His eagerness to be the one to prick his own bubbles
remained to the end a dominant aspect of his scientific attitude, as seen in
the letter that he wrote to his brother Roy in 1943 to inform him of the role
of DNA in the transformation of pneumococcal types (see Appendix I).

The meticulousness that Avery brought to the design. execution, and
interpretation of experiments applied equally to the writing of scientific
papers and the preparation of his rare public addresses. The process of
organization, the balancing of one word or sentence against another, the
discarding of draft after draft until the final product satisfied both his
critical mind and his esthetic sense, brought him at times to a state
bordering on neurosis. He ruthlessly destroyed all his preliminary texts,
but fortunately Maclyn McCarty succeeded in salvaging one of the pencil
drafts of the famous 1944 DNA paper. A page of it is illustrated in Figure
20.

He gave very few public lectures after he ioined The Rockefeller

inflections of voice were tried repeatedly beforehand, using the laboratory
.P,. .          .  . . .          . .   `    . r..        .

indicated on the manuscript of the address (see Appendix II). The marvel
of it was that, at the moment of the public performance, the speech was
delivered in a quite natural tone, seemingly spontaneous. to such an extent
that many listeners believed that much of it was improvised in front of
them.

To submit a manuscript to him for discussion or approval was to impose
on him a task at which he worked as hard as had the author. He analyzed
the text for the quality of the scientific evidence and by identifying himself
with the potential readers. In the words of Rollin D. Hotchkiss:

One's eyes were likely to be opened to undreamed of ambiguities and
pitfalls that nest in the everyday language. A device he often used was to
read aloud the prepared text, in the most gracious tones. but slyly


82     THE PROFESSOR, THE INSTITUTE, AND DNA

emphasizing the wrong words, or pausing at the wrong places, so that
new linkages were created, hanging participles were absurdly exposed,
independent thoughts became comically interdependent, and the writer
learned from a subtle master actor how weak the connection between
thought and words can be.n

rarely, if ever, allowed his name to be listed as co-author unless he had
participated in the experiments with his own hands. Quoting Hotchkiss
once more:

I had always felt so deeply that I was an associate of Avery, that when
preparing this article it was with great astonishment that I realized for

gists who learned from him. Does the historian of science who leans

heavily upon the printed word always learn of these vital but undocu-
mented family pedigrees?s

After reading Hotchkiss's statement, I reviewed my own bibliography,
and discovered that Avery's name appears on only four of the many papers
that I published during the 14 years I worked in his department; these four
all deal with the effects of the bacterial enzyme that decomposes the type
III pneumococcal polysaccharide -a problem that he initiated and to
which he contributed directly, as I have reported. Yet he worked on all my
manuscripts, including two that he tactfully put to rest in one of his drawers
because he did not consider them worth publishing.

Avery derived much pleasure from the speculations that preceded and
accompanied the writing of scientific papers, but he disciplined himself to
indulge in such intellectual free-wheeling among only a few of his col-
leagues and friends, in unrecorded conversations. He saw no value in
informing nonspecialists of all the preliminary stages in the establishment
of facts or in the development of ideas. Just as he felt that scientific history

is not illuminated by details of personal life, so he believed that the
reporting of science is not served by the description of the uncertain steps
that may or may not lead to worthwhile knowledge. He hated scientific
gossip, and never repeated what he heard; nor did he ever make an unkind
or invidious remark about any of his colleagues, even when he knew that
they were critical of his work. Being acutely aware of human fallibility,
including his own, he never engaged in public criticism or controversies,
and he quietly ignored that which he could not believe.

Because "I" and "they" were words that had no place in his scientific


                  Life in the Laboratory    83

vocabulary and because he labored endlessly on his papers to polish them
and remove ambiguities, his style, though luminous, was rather imper-
sonal. But this was the way he wanted it to be-an almost anonymous
statement. By that very impersonal character, his style achieved a classical
and austere quality that was a true expression of the way he controlled his
nature and managed his life.

            The Red Seal Records
When the United States entered World War I in 1917, Avery sought to
obtain a commission in the Medical Corps of the U. S. Army, but this was
denied to him because he had been born of British parents and was still a
British subject. Even though he had lived in the United States for 30 years
by the time the war broke out, he had never taken the trouble to become
an American citizen! Eventually he enlisted as a private; because he was on
active duty during hostilities, he qualified for immediate naturalization,
and was commissioned captain.
He was fond of recounting his experiences of the period when, still a
private, he had to lecture on bacteriology and infectious diseases to
medical officers, many of whom held high military commissions. These
officers were at first surprised and amused at the thought of being lectured
to by such a small and unassuming teacher, but they soon recognized his
technical competence and marveled at his authority and skill as a lecturer.
He was dubbed once more "The Professor."
Although he retained the nickname "Professor" throughout his life, his
lectures to Army officers during World War I were his last experiences
with formal teaching. From then on, his influence was exerted almost
exclusively in private conversations with the scientists who came to work in
his department and with a host of people who were attracted by his
reputation for knowledge and wisdom. Naturally, he had many visitors
from other departments of the Institute and outside institutions, and from
nonscientific circles. People came to him for advice on specific scientific
problems and on personal matters, as well. I suspect, furthermore, that
many came just to hear him talk and to watch him convert any situation or
problem into an exciting display of words and gestures. He became a guru
before the word entered American consciousness. I have already referred
to him as a conversationalist, but I must come back to this aspect of his
personality because it played an enormous role in shaping the scientific
attitudes of his colleagues and, perhaps more importantly, in giving form to
his own thoughts.
Although reluctant to speak at public meetings, coquettishly so, Avery


84    THE PROFESSOR, THE INSTITUTE, AND DNA

was always eager to engage in conversations with colleagues, friends, or
strangers. In general, however, the conversation soon evolved into a
monologue, in the course of which his interests soon appeared more
compelling and glamorous than the visitor's own concerns. These mono-
logues had been thought out and were acted out in accordance with a
carefully practiced formula. They were virtuoso performances, in which
the theme was developed with logic and clarity, starting from the historical
background and ending with the rationale of possible scientific approaches.
The phraseology of these vignettes was remarkable. It included hesitations

these conversation pieces by heart. and we referred to them as the Red
Seal Records, after the name of the musical recordings that were then
considered top-grade. In truth, there were times when we became some-
what impatient at hearing The Professor's Red Seal Records. but we were
never bored by them, because we admired their artistic perfection. Fur-
thermore, we realized unconsciously that they played an important role in
the success of the department.

Avery's monologues certainly helped him to define his knowledge and
to give structure to his thoughts. The continuous effort he made to sharpen
and polish the language that he used to convey his concepts enabled.him to
recognize their ambiguities and inadequacies, and thereby facilitated the
formulation of working hypotheses sufficiently well defined to be amena-
ble to experimental testing.

My view of Avery's influence on the members of his department is
based entirely on my personal experiences during the years of continuous
and close association with him between 1927 and 1941. It is of interest to
compare it with the views expressed by Rollin Hotchkiss, whose scientific
background was very different from mine, and who worked with him
between 1943 and 1948, during a period when the laboratory was no
longer involved in problems of infectious diseases, but was concerned with
genetic phenomena in pneumococci. Hotchkiss's impressions of Avery's
attitude in the 1940s are so similar to what I remember of the 1920s and
1930s that I cannot refrain from quoting him at length at the risk of being
repetitious. About the Red Seal Records, Hotchkiss writes:

[Avery] successively played the parts of narrator, expositor, loyal oppo-
sition and finally attorney-in-summation. Even at the second or third
. .    I      ^ .                       . .             . .


                 Life in the Laboratory    85
surprised to find that dusk had fallen outside while the new inner light
was dawning.

These gems of perfection were continually revised and repolished.
The highly organized presentation was a kind of debate with himself,
punctuated with rhetorical questions like, "now, why should that be?"
or "what does that all mean?" The auditor who was moved to try to
respond, however, quickly found himself overwhelmed-and indeed
suppressed- by the ongoing flow of well-rehearsed logic, that even in
the voice of the man who seemed merely its spokesman, would brook no
interference. These dissertations probably played a great part in concen-
trating the attention of his younger collaborators on basic problems,
especially those involving that little gram-positive coccus which, he felt,
presented in small compass most of the basic questions of biology.rn

As we shall see, Avery did, in fact, touch on many crucial aspects of
general biology in the Red Seal Records, even though his ideas were
always based on the lore of the pneumococcus.


CHAPTER SIX

THE MULTIFACETED SPECIALIST

From 1913 to 1948, Avery occupied the same laboratory in the depart-
ment of respiratory diseases of The Rockefeller Institute Hospital. Most of
his experimental work was done with a single bacterial species: Diplococ-
cus pneumoniae. The limited studies that he carried out with other biologi-
cal systems were never far removed from pneumococcal biology. All his
own experimental findings were published in the Journal of Experimental
Medicine; the related aspects of his studies carried out by his chemist
collaborators were published in the Journal of Biological Chemistry. All his
public statements referred directly to his laboratory program, the only
exception being his speech as President of the Society of American Bacte-
riologists, which was of a general nature, but which he did not allow to be
published. It would be difficult, therefore, to imagine a more extreme case
of scientific specialization. A rapid overview of Avery's scientific career
will help to explain the paradox that, while he limited his investigations
almost exclusively to pneumococcal disease, he managed nevertheless to
throw light on a great diversity of theoretical problems in other fields of
pathology and biology.

Avery is now chiefly remembered as a theoretical scientist, but this was
only one aspect of his professional life. From the time he left medical
school until the late 193Os, his dominant interest was the field of infectious
diseases-how microorganisms invade the tissues and cause lesions; how
the infected body responds to their presence; how recovery from infection
takes place; how bacteriological and immunological knowledge can be
used to develop rational methods of prevention and treatment.

Now that pneumonia can be treated readily with penicillin and other
drugs, it is difficult to imagine what a distressing problem it was when the
Hospital opened its doors in 1910. More than 50,000 persons died of the
disease annually in the United States. It was more destructive than typhoid
fever had ever been, and it replaced tuberculosis as "the captain of the men
of death" among respiratory diseases. Physicians were so helpless against
lobar pneumonia that William Osler referred to it as "a self-limited disease
which can neither be aborted nor cut short by any means at our com-
mand." The patient either died irrespective of treatment or recovered


88    THE PROFESSOR, THE INSTITUTE, AND DNA

spontaneously after approximately one week of acute disease-by "crisis"
as the medical expression has been since Hippocrates. When Cole became
director of the Hospital, he therefore decided that one of his major
research goals would be to develop a therapeutic serum for pneumonia,
and it was to this end that he appointed Avery as the bacteriologist on his
team.
While working on the diagnosis and treatment of pneumonia, Avery
became interested in the broader aspects of susceptibility and resistance to
pneumococcal infections. He soon realized, however, that understanding
such problems would require detailed knowledge of the pneumococcal cell
itself, of its structure, its chemical composition, its physiological activities,
its immunological characteristics, its genetic stability and variability. The
systematic study of pneumococcal biology led him to deal with phenomena
that transcended pneumococcal infections and that had, indeed, theoreti-
cal significance for unrelated biological problems. The following are a few
of the discoveries he thus made:

-The virulence of pneumococci and of certain other bacterial species is
conditioned by their ability to produce an ectoplasmic layer, which consti-
tutes a cellular capsule. Encapsulated bacteria become avirulent when
they lose the ability to produce the capsular substance.
-The capsule contributes to virulence by protecting the pneumococci
against the defense mechanisms of the infected body, in particular against
engulfment (phagocytosis) by the cells of the blood and tissues.
-Encapsulated pneumococci can be separated into types which differ
chemically in the composition of their capsules. In all cases, the capsule is
made up of a polysaccharide (complex sugar) but, because of chemical
differences, each is immunologically specific for each pneumococcal type.
-The antibodies produced in the blood serum against the capsular poly-
saccharides protect against pneumococcal infection by neutralizing the
antiphagocytic property of the capsules. The protection is specific for each
pneumococcal type.
These facts, first established through the study of pneumococci, led to
broader generalizations applicable to all infectious agents, for example:
-Minute differences in the chemical composition of microorganisms have
profound effects on the response they elicit from animal and human
tissues. As a consequence, specificity can be defined in the precise terms of


                  The Multi-faceted Specialist    89

molecular chemistry, not only in the case of polysaccharides, but also of
other types of chemical substances.

-The ability of microorganisms to survive and multiply in the body
depends on their possession of specialized cellular structures. Virulence,
which used to be regarded as a mysterious attribute of certain microbial
groups, can be explained by the interplay of these structures with the
body's defense mechanisms.

These discoveries soon established Avery as one of the world's most
original investigators in the field of infection and immunity. Then he
progressively became involved in another line of work, which led to his
most spectacular achievement, this time in the field of genetics. He demon-
strated that bacteria can be made to undergo hereditary changes by
treating them with deoxyribonucleic acids (DNA) extracted from other
bacteria. This discovery turned out to be one of the landmarks of modern
biology, because other investigators soon established that DNA molecules
are the specific carriers of hereditary characteristics in all living things.
Remarkable as Avery's achievements were, they had no obvious inter-
est for the general public; there was nothing in them comparable in
excitement value to the discovery of a new drug or vaccine. Who but a
theoretical scientist could be impressed by the fact that subtle differences
in a sugar molecule condition the fate of microbes in the body? That
certain virulent bacteria become innocuous when they lose the ability to
produce an ectoplasmic layer or some other cellular constituent? That the
chemical composition of the pneumococcal capsule is genetically deter-
mined by a specific deoxyribonucleic acid?
When Avery died, the writers of newspaper obituaries tried to glamor-
ize his work by asserting that it had led to the development of miracle
drugs, but this was not true, and he would have been deeply embarrassed
by such a statement. In fact, his discoveries had only few and limited
applications of immediate practical importance. His contributions were to
the understanding of biological phenomena, and have influenced the prac-
tice of medicine only in an indirect manner. He advanced biological and
medical sciences by providing factual knowledge and thought patterns
applicable to the study of all living things; in particular, he demonstrated
the possibility of a chemical approach to the understanding of infection and
of heredity- hardly a topic to make newspaper headlines!
Avery's characteristic habit of intellectualizing a problem, then convert-
ing it into concrete chemical operations. is illustrated in the following


90    THE PROFESSOR, THE INSTITUTE, AND DNA

technical chapters, which deal with the bulk of the experimental work he
conducted at The Rockefeller Institute in the fields of immunity, virulence,
and heredity. Most of his findings have now been incorporated into
theoretical biology and medicine, but some have been questioned, or even
shown to be erroneous. For example, he failed to establish his early
hypothesis that resistance to infection with pneumococci results from the
inhibition of pneumococcal enzymes by the blood serum of infected per-
sons or animals. Although this metabolic approach to the immunity prob-
lem was abortive, it provides a useful introduction to his experimental
work at the Institute, in part because it was his first original investigation in
the field of pneumonia and, more interestingly, because it reveals how his
propensity to construct mental pictures of biological phenomena influ-
enced his vision of scientific reality.


CHAPTER SEVEN

THE LURE OF ANTIBLASTIC

IMMUNITY AND THE

CHEMISTRY OF THE HOST

Antiblastic Immunity

Avery was a persistent man. Once he became involved in a scientific
problem he pursued it doggedly, waiting, if need be, for many years until
he saw the way to a solution. He even pretended at times that he enjoyed
the failures that are inevitable in scientific life. "Disappointment is my
daily bread," he was wont to say. "I thrive on it." By this he probably
meant that his eagerness to overcome difficulties generated in him new
strength and new inspiration. However, there is at least one topic-
antiblastic immunity- that he seemingly abandoned after having affirmed
its importance in the annual reports to the Board of Scientific Directors of
The Rockefeller Institute for 1915 and 1916, and more publicly in an
article that he and Dochez submitted to the Journal of Experimental
Medicine in July, 1915, and that was published in 1916 .I He never again
mentioned antiblastic immunity in print after this publication, but he kept
it in mind to the end of his professional life.

In their Journal of Experimental Medicine paper, Dochez and Avery
defined antiblastic immunity as a resistance to pneumococci, resulting from
the inhibition of certain pneumococcal enzymes by the serum of the
infected person or animal. The origin of the theory can be traced to
experiments briefly mentioned in the report of April, 1915, in which
Avery appears for the first time as an original investigator.2

When he joined the Hospital staff in 1913, he was responsible for the
isolation of pneumococci from patients and also for the production and
testing of antipneumococcal sera. In the course of his routine duties, he
noticed that, although therapeutic sera do not kill pneumococci, they
retard their growth in culture media; he gave reasons to support his belief
that this growth-inhibitory effect was not due to agglutination of the
organisms by the serum. Shortly after this initial observation, Dochez and


92    THE PROFESSOR, THE INSTITUTE, AND DNA

Avery found that antipneumococcal serum "inhibits certain digestive and
fermentative properties of the pneumococcus, especially the formation of
amino acid from protein, and the fermentation of various carbohydrates.""
It is probable that Dochez was led to this enzymatic explanation because, a
few years earlier, he had collaborated with Eugene Opie on the enzymes of
inflammatory cells.
The facts observed by Dochez and Avery were few and limited in scope,
but the two scientists did not hesitate to elaborate from them a bold
metabolic concept of immunity. They based their argument on the hypoth-
esis that pneumococci could not multiply in vivo if they were not capable of
utilizing certain constituents of the infected host by means of enzymes
located at their cellular surface. They suggested, furthermore, that any
mechanism interfering with the action of these surface enzymes would
provide resistance to pneumococcal infection. In their words, "We have
chosen the term `antiblastic immunity' _ to indicate that the forces at
work are antagonistic to the growth activities of the organism ." (The word
antiblastic is derived from blastos, the Greek word for sprouting, or
growth.") This definition made it clear that the kind of resistance to
infection they had in mind was completely different in mechanism from
that induced by the conventional protective antibodies.
The experiments described in the 1916 paper unquestionably show that
addition of antipneumococcal serum to a broth culture of pneumococci
retards the growth of these organisms and partially inhibits some of their
enzymatic activities. They also establish that this so-called antiblastic
property appears in the serum of patients suffering from lobar pneumonia
at the time of the crisis, more or less concurrently with the appearance of
the type-specific antibodies usually associated with recovery from the
disease.
As judged from the annual reports, Dochez and Avery continued to
work on antiblastic immunity for at least several months after their paper
had been submitted to the Journal of Experimental Medicine. In the report
for 1916, they described the new finding that the metabolic functions of
pneumococci "recently isolated from the human body are more resistant to
the inhibiting factors of both normal and immune sera than are those of
organisms which have led a saprophytic existence for considerable periods
of time ."5 The obvious implication of this statement is that the virulence of
a microorganism is a consequence of its ability to resist the antiblastic
mechanisms of the human body.
In the 1916 Journal of Experimental Medicine paper, Dochez and Avery
stated that if the theory of antiblastic immunity turned out to be true,


The Lure of Antiblastic Immunity and the Chemistry of the Host    93

"considerable light would be thrown on the obscure mechanisms by which
parasitic bacteria establish themselves in animal tissues, and on the forces
mobilized by the animal body in opposition to such invasion."6 They also
formulated the more adventurous hypothesis that in pneumococci "capsule
formation represents on the part of the organism an attempt to protect the
function of its digestive zone." In the annual report for 1916, they made
the further unorthodox statement that "for the animal body to rid itself of
infection, the growth of the infecting microorganism must first be arrested
and that only afrer this has occurred do the more specific substances have
an opportunity to exert their full effect" (italics mine).7 This was a revolu-
tionary view of resistance to infectious disease, since it implied that the
hypothetical mechanisms involved in antiblastic immunity had to stop the
growth of the infectious agent by inhibiting its enzymes before antibodies
and other immunological mechanisms of resistance could come into play.
Ironically enough, Dochez and Avery themselves were soon to direct
the study of resistance into immunological channels by their 1917 discov-
ery of the specific soluble substances of pneumococci (see Chapter Eight).
Until 1916, however, they apparently believed that antiblastic immunity
was at least as important as conventional antibodies in providing resistance
to pneumococcal infection and in recovery from lobar pneumonia.
Some remarks made by Dr. Rufus Cole in his annual report for 1919
suggest that he had doubts concerning the significance of what he referred
to as "the question of so-called antiblastic immunity" (italics mine).8 In
1917, Francis Blake, who was himself at The Rockefeller Institute Hospi-
tal, published a paper denying that there was any such thing as antiblastic
immunity.g He had confirmed Dochez's and Avery's findings that, under
the conditions they used, antipneumococcal serum can indeed retard the
growth of pneumococci and depress their enzymatic activity, but he as-
serted that these effects were simply the result of agglutination of the
organisms, and did not involve inhibition of their enzymes. Equivocal
results were also published in 1919 by M. A. Barber, another bacteriolo-
gist working at the Hospital.`O
Neither Dochez nor Avery published anything to refute their col-
leagues' criticisms. In fact, they never mentioned antiblastic immunity
again in either scientific journals or the annual reports. One could there-
fore conclude that they rapidly lost interest in the subject and dismissed it
from their minds, but this is not the case.
On several occasions during the 193Os, both Avery and Dochez dis-
cussed with me the possible role of antiblastic immunity in pneumococcal
infections. Their reference to this topic may have been in part an expres-


94    THE PROFESSOR, THE INSTITUTE, AND DNA
sion of their usual graciousness, since they knew that the subject was close
to my own scientific interests and was, indeed, directly relevant to my
experimental work. However, I have been told by Dr. Maclyn McCarty
that he heard Avery mention antiblastic immunity during the 194Os, at a
time when the dominant concern of the department was the identification
of the substance responsible for the transformation of pneumococcal types.
There are reasons to believe that much of the experimental work in
Avery's department for almost 20 years derived from his early hunch that
the metabolic activities of pneumococci are an essential aspect of their role
in infection.
Before proceeding to that topic, however, I shall open a parenthesis to
express my personal view that the problem of antiblastic immunity should
be reinvestigated. Admittedly, the experiments published by Dochez and
Avery in their 1916 paper do not prove the validity of the hypothesis, but
neither do the papers published by Blake in 1917 and Barber in 1919 rule
the phenomenon out of existence.
During the past few decades, several experimental systems have been
studied in which control of experimental infection is brought about by
inhibition of the pathogen's growth, not by its destruction, and this is
precisely how antiblastic immunity is defined. Experimental infections
caused by certain protozoa and by tubercle bacilli are cases in point.
Furthermore, all enzymes that have been studied from the immunological
point of view have been found to be antigenic, and the antibodies that they
elicit have some inhibitory effect on their enzymatic activity." It is of
interest, in this regard, that such inactivation does not take place if the
enzyme is intracellular.`2 This gives added interest to the suggestion by
Dochez and Avery that the antiblastic effect takes place "at the surface of
the bacterial cell," and that the integrity of this zone "is essential to the
growth of the bacterium." While they had no evidence for their hypothesis,
their words acquire a prophetic quality when read in the light of present
information about the importance of the cell membrane in nutritional and
developmental processes. The plasma membrane, as is well known, is one
of the important organelles of the cellular structure. Thus, although anti-
blastic immunity was a hypothetical concept half a century ago, it can now
be reformulated in more precise terms and put to experimental tests.
Whatever its possible scientific importance for the understanding of
infectious processes, the subject of antiblastic immunity may have had a
decisive role in Avery's psychological development; it probably accounts in
part for his fear of making public statements that went beyond well-
established facts.


The Lure of Antiblastic Immunity and the Chemistry of the Host    95

The hypothesis that he and Dochez formulated in their Journal of
Experimental Medicine paper and in the annual reports for 1915 and 19 16
gives the impression that the two eager scientists had concocted the
antiblastic theory on the basis of abstract thought in the course of their
midnight discussions. As it turned out, the few laboratory tests they
conducted were sufficiently encouraging to give substance to the products
of their imagination; therefore, they felt justified to compound hypothesis
with hypothesis into a sweeping metabolic theory of virulence and immu-
nity. As we have seen, however, the interpretation of their findings was
questioned by some of their own colleagues, and they themselves soon
discovered new facts that pointed to a mechanism of resistance to pneumo-
cocci in which enzyme inhibition had no part.
Avery again published statements for which he had inadequate evi-
dence, and which were soon proved to be wrong, when he stated in 1917
that the specific soluble substances of pneumococci are of protein nature
and are responsible for the toxic effects of pneumococcal infections (Chap
ter Eight). But after these mistakes, he learned his lesson. Never again did
he mention in scientific journals the products of his imagination, unless
they had been documented by overwhelming laboratory evidence. He
continued to indulge in fanciful scientific theories throughout his profes-
sional life, but only in the course of private conversations among col-
leagues and a few friends, or now and then in the annual reports of The
Institute. It is probable that his experience of 1916 with antiblastic immu-
nity, then of 1917 with the specific soluble substance, contributed to his
conservative behavior in all his public statements and to his eagerness that
he should be the one to prick his own bubbles.

  Bacterial Metabolism and the Phenomena of Infection
Two high points in Avery's scientific life occurred in 1917, when he and
Dochez first reported on the specific soluble substances of pneumococci,
and in 1923, when he and Heidelberger demonstrated to everybody's
surprise that the immunological specificity of these substances was to be
found in their polysaccharide nature. One might assume that immuno-
chemistry had been his dominant scientific concern between these two
dates. In reality, more than 30 papers dealing with pneumococcal en-
zymes, accessory nutritional factors, and other topics of bacterial metabo-
lism were published from his laboratory in the six years between 1919 and
1925; his name appears as co-author in 23 of these studies, and it is certain
that he participated very directly in planning all the others and writing their
results.


96    THE PROFESSOR, THE INSTITUTE, AND DNA

The introductory statements of Avery's papers on bacterial metabolism
and nutrition, as well as the discussions and summaries that conclude them,
are written as if the motivating force behind this impressive amount of
experimentation was his interest in the characteristics of pneumococci
considered as independent organisms. A different interpretation emerges,
however, from his statements in the annual reports to the Board of
Scientific Directors.
The section dealing with antiblastic immunity in the annual report for
1916 emphasizes the difficulties that Dochez and Avery experienced when
they tried to quantitate the inhibitory effect of serum on the enzymatic
activities of pneumococci. The major source of these difficulties was that,
under the conditions of their tests, the enzymes themselves underwent
spontaneous inactivation because of the rapidity with which living pneumo-
cocci disintegrate and autolyse in artificial media. In order to deal with this
problem, Avery decided to separate the enzymes from the bacterial cells,
on the assumption that he could obtain them in a stable form. He was
sufficiently successful to express the view in the 1916 report that "much
more reliable" results could be expected in the future because he had
obtained from pneumococci a "proteolytic enzyme" that was "active in the
absence of the living ce11."13 This statement reveals an attitude toward
biological work that he was to maintain in all his subsequent investiga-
tions-that the way to study a biological phenomenon is to obtain the
substance responsible for it in an active, stable form, and to determine its
chemical activities under controlled conditions. From a more limited and
immediate point of view, his attempts to measure antiblastic immunity by
chemical methods, as described in the 1916 report, heralded a long
program of biochemical studies encompassing topics ranging from meta-
bolic equipment of pneumococci to bacterial nutrition to oxidation-reduc-
tion processes.
From 1918 to 1925, Avery devoted a very large percentage of his time
to biochemical studies of bacteria in collaboration with G. E. Cullen, T.
Thyotta, H. J. Morgan, and J. M. Neill. When I joined his department in
1927, he encouraged me to develop this program on my own. He himself
could no longer participate directly in its execution because of his involve-
ment in immunochemical studies, but he was intensely interested in its
progress, and gave extensive coverage to it in his annual reports.
Much of the departmental work on bacterial nutrition and metabolism
was focused on problems of immediate practical importance in laboratory
experiments. In particular, it aimed at improving culture media either for
diagnostic purposes or for producing large quantities of bacteria, and later


The Lure of Antiblastic Immunity and the Chemistry of the Host    97

at assuring the genetic stability of bacterial strains. Some of the findings,
however, had a larger biological significance. Avery himself worked in-
tensely on the recognition in bacteriological culture media of two accessory
growth factors that he designated as the X and V factors, and that were
later identified in other laboratories as heme and cozymase. Commonplace
as this knowledge is today, in 1921 the recognition of the X and V factors
was an important step in the development of the science of bacterial
nutrition.
There was always in the background, furthermore, the hope that studies
of bacterial metabolism would eventually contribute to the understanding
of pneumococcal disease - of natural resistance to it, of recovery from it, of
its pathogenesis and its epidemiology. This hope can be illustrated by many
statements taken from the annual reports.
In the April section of the 1920 report, a series of papers from Avery's
group, published in the Journal of Experimental Medicine under the gen-
eral heading "Studies on the enzymes of pneumococcus," was justified as
follows: "With the hope of acquiring a more definite understanding of the
way in which pneumococci adapt themselves to various environments, a
study is being made of the enzymes of pneumococcus."`" In the October
part of that report, Avery expressed the belief that "these studies are
important, not only theoretically because of the added knowledge gained
concerning life processes of the organism, but also clinically."`5 In the
1923-24 report, he again justified his interest in bacterial metabolism with
the statement that enzymatic and metabolic studies had "yielded certain
facts which are not only of interest with reference to the physiology and
chemistry of the bacterial cell, but which give promise of wider significance
in the interpretation of the process of infection in the animal body."`" He
was aware that experiments carried out in other institutions had shown that
the activity of certain enzymes can be inhibited by antibodies prepared
against them, as he and Dochez had postulated in their 1916 paper.

         The Chemistry of the Host
A favorite subject of laboratory discussion in the 193Os, and one
commonly mentioned in the annual reports, was that even the most
virulent pneumococci are incapable of initiating infection until the normal
defensive mechanism which guards the lower respiratory tract has been
broken down. There was no understanding of the factors involved in this
breakdown except that the general physiological condition of the host was
involved. It was known, for example, that the incidence of lobar pneu-
monia was in some way correlated with attendance at football games, and


98    THE PROFESSOR, THE INSTITUTE, AND DNA
probably with the excessive consumption of liquor on such occasions.
Many experiments were performed with a variety of animals in an attempt
to overcome the normal resistance of their lungs to pneumococci. For this
reason, mice intoxicated with alcohol and exposed to sprays of pneumo-
cocci were a common sight in E. G. Stillman's laboratory across the hall
from Avery's office. Although the results of this type of experimentation
were meager, they provided food for much thinking and guessing about the
interplay between the physiological characteristics of pneumococci and the
chemical conditions in infected organs.
From 1925 on, the pressure of the immunochemical studies with capsu-
lar polysaccharides and with synthetic antigens, and the phenomenal suc-
cess of these studies, prevented Avery from developing further his interest
in the metabolic and physiological aspects of infection, but he came back to
the subject through an accidental discovery.
While following the development of specific antibodies in the serum of
pneumonia patients, he and T. J. Abernathy recognized the occurrence of
a peculiar serum protein not normally present in the blood. This substance
did not behave like an antibody, because it appeared very early during the
acute phase of the disease and disappeared within 24 hours after recovery.
The newly discovered serum factor was dubbed the "C-reactive protein" in
laboratory parlance, because it precipitated in contact with the so-called
"C polysaccharide" of pneumococci. Avery saw in this unexpected obser-
vation an opening into aspects of the infectious process that transcended
the classical antigen-antibody reactions, and that might eventually throw
light on the physiological responses of the body to pathological phenom-
ena. An indication of his interest in this new aspect of host-parasite
relationship appears in a small item reported by Rollin Hotchkiss: "In
1938 . . . I begged for an opportunity to work on transformation but he
[Avery] was anxious to further the work on blood proteins in acute
infections and asked me to wait ."l' Avery certainly welcomed the prospect
of being able to anchor the physiological problem of host-parasite relation-
ship on a substance that could be isolated and chemically characterized.
Although he and Abernathy had first detected the new protein in the
serum of pneumonia patients, they soon found that it also occurred in the
serum of patients suffering from many acute infections caused by other
pathogens. Three papers published in 1941 defined the characteristics of
the C-reactive protein, and established that it was not an antibody. They
provided evidence, instead, that it was released from tissues in the course
of infection, probably as a result of some cellular damage, and that it
therefore represented a nonspecific reaction of the tissues to injury. The C-


c   The Lure of Antiblastic Immunitv and the Chemistrv of the Host    99                 : 1

reactive protein was isolated as a highly purified, immunologically homo-
geneous protein by Avery and MacLeod in 1941, and crystallized shortly
after by McCarty.

Avery never discussed the C-reactive protein without turning the con-
versation to what he was wont to call "the chemistry of the host." Al-
though he never spelled out what he meant by that expression, he clearly
had in mind all the unidentified body substances and mechanisms of a
nonimmunological nature, both protective and destructive, that come into
play in the course of infectious processes. Along with the C-reactive
protein, he probably would have listed in this category other products of
cellular damage or stimulation, the multiple aspects of the inflammatory
responses, and-even though he rarely mentioned them- the mechanisms
responsible for antiblastic immunity.

Host-Parasite Relationships

The intensity of Avery's interest in the physiological determinants and
products of host-parasite relationships comes to light in a written text on
which he worked for many days but refused to publish-the speech he
delivered in 1941 as President of the Society of American Bacteriologists
(Appendix II).18 In it, he quoted at length from the prophetic words of the
seventeenth-century English chemist Robert Boyle, who guessed as far
back as 1660, two centuries before Pasteur, that the mechanisms of disease
would eventually be explained through an understanding of fermentations.
In Boyle's words:

He that thoroughly understands the nature of ferments and fermenta-
tions shall probably be much better able than he, that ignores them, to
give a fair account of divers phaenomena of several diseases (as well
fevers as others) which will, perhaps, be never thoroughly understood,
without an insight into the doctrine of fermentation.lg

After quoting Robert Boyle, Avery went on to discuss the wide range of
interplay between chemistry and microbiology; this gave him the opportu-
nity to emphasize the solidarity of the different fields of natural science and
the dangers of scientific specialization. I shall come back later to the
general aspects of this speech (Chapter Thirteen).

Contrary to what could have been expected from a scientist who had
devoted most of his professional life to the study of specific immune
mechanisms, Avery did not mention antigen-antibody reactions or cellular
immunity. Instead, he forcefully stated that the best chance for progress in
the control of microbial diseases "lies not alone in the discovery of ways
and means of fortifying the natural and specific defenses of the host -


100   THE PROFESSOR, THE INSTITUTE, AND DNA
important as these are- but in a better insight into the structural and
cellular mechanisms of host and parasite" (italics mine) .`O
He concluded this section of his speech bv paraphrasinp Rohert Bode to

predict that the phenomena of infectious diseases will never be "thor-
oughly understood without an insight into the life processes of the host and
parasite _ "*I This statement calls to mind similar ones that he and Dochez
made in their 1916 paper on antiblastic immunity, when they tried to
explain in metabolic terms the phenomena of bacterial virulence and host
resistance.

The members of the Society of American Bacteriologists who listened to
Avery's speech in 1941 knew, of course, that his most spectacular achieve-
ments at that time had been in the field of immunochemistry; many of
them also were familiar with the work of his department on bacterial
transformation. They were probably surprised and, perhaps, disappointed
that he did not refer to any of those fundamental studies, but chose instead
to discuss in rather vague terms the cellular structures and metabolic
activities of microorganisms and the chemistry of the host. Yet, what they
heard was far more important than what they had expected, and also a far
more revealing expression of Avery's genius as a scientist. He could have
discussed conventional knowledge and theories, but he pointed instead to
problems that had not yet been defined; he could have reminisced about

In expressing his faith that studying the interplay between the life
processes of the host and those of the parasite was the way of the future, he
was continuing the midnight discussions he had begun 30 years earlier with
Dochez. He was still cogitating about the precise nature of the physiologi-
cal processes that determine the outcome of host-parasite relationshios and

that he had symbolized by the expressions antiblastic immunity and chem-
istry of the host.


          Serum for Pneumonia
As mentioned in Chapter Six, one of the chief projects at the Rockefeller
Hospital was the development of a therapeutic serum for lobar pneumonia.
The problem appeared well defined in 1909, when Cole first formulated
his research program. Most cases of lobar pneumonia were known to be
caused by the pneumococcus, a delicate microbe that had been described
in 1881 by Pasteur in France and almost simultaneously by Sternberg in
New York-the same Sternberg who was, for a while, director of the
Hoagland Laboratory where Avery began his scientific life. The causative
role of the pneumococcus in human pneumonia had been demonstrated
between 1884 and 1886 in Germany. Good techniques were available to
isolate the microbe from patients, to cultivate it in vitro, and to produce
with it an experimental disease in animals. The problem selected by Cole
thus appeared straightforward: to immunize horses against pneumococci
and to administer the antipneumococcal serum thus obtained to patients
suffering from pneumonia.
An unexpected difficulty arose just as the work was being planned. In
1909 and 1910, Neufeld and Handel, of the Robert Koch Institute in
Berlin, reported that they had found subtle, but important, differences
among the various cultures of pneumococcus isolated from patients. What
had been regarded as the pneumococcus species turned out to consist of a
variety of strains, which, although similar in appearance and in general
characteristics, differed in immunological properties. The German workers
divided the pneumococcus group into three well-defined types and a
heterogeneous subgroup. These findings greatly complicated the problem
of serum therapy, because the serum prepared against any one particular
pneumococcal type was inactive against the other types.
Dochez was given the task of comparing the distribution of pneumococ-
cal types in New York with that found by Neufeld and Handel. In 19 13. he
reported that the cultures he had studied could be divided into three main
types identical with those found by the German workers, plus a fourth


102    THE PROFESSOR.  THE INSTITI'TF   AND DNA

group, made up of poorly characterized subtypes; this fourth group was
dubbed by some English bacteriologists, somewhat contemptuously, as the
American Scrap Heap.

Therapeutic trials conducted in the Hospital with antipneumococcal
sera soon gave encouraging results in type I lobar pneumonia. As serum
was not commercially available, a program of production was developed at
the Institute. Avery was given the responsibility for the vaccination of
horses, the processing of serum, and the measurement of its antipneumo-
coccal activity. He was also made responsible for much of the diagnostic
work, and developed a rapid culture method for determining the pneumo-
coccal types recovered from patients. The mastery and authority he ac-
quired within a few years can be measured from the fact that in 1917, less
than four years after joining the Hospital, he was the senior author of a
classic monograph entitled Acute Lobar Pneumonia: Prevention and Serum
Treatment, published by The Institute .I In this monograph, he, in collabo-

had learned about lobar pneumonia from their practical experience in the
laboratorv and on the wards: the relative nrevalence of the various oneu- I

mococcal types; how to prepare an effective serum against type I; and how
to treat the disease.

Avery's preoccupations with pathological processes were at the basis of
the biochemical investigations mentioned in the preceding chapter and of
the immunological investigations that will be considered. Much of his work
was conditioned by his desire to produce effective therapeutic sera. Until
the advent of chemotherapy, this was the rallying point in his department;
it kept everybody's eyes on the ball. Many abstruse studies on "antigenic
dissociation" and on the autolytic system of pneumococci, which will be
discussed later, appear far removed from the clinical problems of disease,
but they were, in reality, steps toward a better understanding of the factors
involved in immunity to pneumococcal infection and in the production of
therapeutic sera.

In the 1936-37 annual report to the Corporation, Dr. Cole detailed
some of the theoretical factors that had led the Averv denartment to shift

from horses to rabbits for the production of antipneumococcal sera. The
technical aspects of this problem cannot be discussed here, but the clinical
results deserve to be mentioned, because they demonstrate that Avery's
continued interest in serum production had important practical conse-
quences. Cole reported:
Among more than fifty patients suffering with lobar pneumonias due to
pneumococcus Types I, II, V, VI, VII, XIV, XVIII there has been but


         The Chemical Basis of Biological Specificity   103

one death and this occurred in a patient five weeks convalescent from
pneumonia. In untreated patients with similar type distribution the
death rate would have amounted to about 34 percent. . . . In the last
several cases treated with immune rabbit serum in this hospital, the
average time from the first injection of serum until the crisis was less
than five hours. In many patients normal temperature, pulse and respi-
ration were regained in as short a time as five hours after serum was
administered.2

Admittedly, the therapeutic results were not satisfactory in pneumonia
caused by type III pneumococci; furthermore, the need for rapid typing of
the pneumococcus cultures in each individual patient and other practical
problems still stood in the way of the widespread use of antipneumococcal
sera in general practice. Admittedly, also, the introduction of sulfa pyri-
dine and other sulfa drugs in the late 193Os, then of penicillin in the early
194Os, made serum therapy obsolete within a very short time after it had
been perfected. This, however, does not detract from the scientific and
practical quality of the research program that led to the development of
antipneumococcal sera; in fact, the achievement remains one of the finest
examples of the application of orderly, rational thought to a therapeutic
problem.

        The Specific Soluble Substances
During late 1916, Dochez discovered in the filtrate of a pneumococcus
culture a soluble substance that flocculated in the antiserum prepared
against the particular type of pneumococcus growing in the culture. Fur-
ther tests soon revealed that this was a general phenomenon. Each of the
various types of pneumococci isolated from patients was found to produce
in culture media a soluble substance that possessed its own type specificity.
Avery soon joined forces with Dochez in the analysis of the phenomenon,
and together they established that the specific soluble substances, desig-
nated SSS in laboratory parlance, were released in solution early during
the life of the pneumococci, and therefore were not the products of
bacterial disintegration.
Dochez and Avery also established by immunological techniques that
the SSS passes into the blood and urine of patients during the acute phase
of pneumococcal pneumonia. Both were fond of telling how, after having
first detected the substance in the blood, they reasoned that, since it was
soluble and diffusible, it might filter through the kidneys into the urine.
They accordingly requested from the ward a urine specimen from a patient
with a severe type II pneumonia and tested it with type II antipneumococ-
cal serum. To their great disappointment, no flocculation occurred. They


104   THE PROFESSOR, THE INSTITUTE, AND DNA
sat glumly looking at the tubes, which had remained clear, wondering what
was wrong with their reasoning. After a while, Avery walked to the vase of
urine received from the ward, picked it up, and looked at the label; to their
relief, it turned out that the specimen was from the wrong patient. The
precipitin test was positive when carried out with the proper specimen. SSS
did indeed pass through the kidneys into the urine.
The discovery of SSS, and the demonstration of its presence in the body
fluids of patients, were published in 1917 by Dochez and Avery in two
papers that are now classic. 3 As Dochez was away in France during the
early part of 1917, Avery was left alone to continue the work. He obtained
further evidence that SSS can usually be found in the urine of pneumonia
patients, and he made use of this observation to develop a diagnostic test
that in many cases permitted rapid identification of the pneumococcal
type, even before the culture was recovered from the patient.
The annual report for April, 1917, shows that he had already been
bitten by the desire to know the chemical nature of the specific soluble
substances. He separated serologically active material from the urine "by
repeated precipitation with acetone and alcohol," 4 and the simple chemi-
cal analyses that he carried out on it led him to state in the report: "The
determination of total nitrogen and nitrogen partitions . . . shows that this
substance is of protein nature or is associated with protein" (italics mine).
This statement, which he himself, with Heidelberger, later proved was
erroneous, found its way onto page 493 of "The elaboration of specific
soluble substances by pneumococcus during growth," a paper he published
with Dochez in the Journal of Experimental Medicine in 1917 .5
The first World War naturally disrupted the research program at The
Rockefeller Institute. Until January, 1919, Avery ran a course for Army
medical officers on the "etiologic diagnosis of acute respiratory diseases."
The epidemic of so-called Spanish influenza compelled The Rockefeller
Institute Hospital group, under the leadership of Rufus Cole, to become
involved in studies of influenza bacilli and hemolytic streptococci, orga-
nisms that were frequently found in the pneumonia outbreaks studied first
in Army camps, then in the civilian population. Avery published papers on
the bacteriology of these two species in 1918 and 1919. Then, immediately
after the war, he turned his attention to the metabolic studies that have
been discussed in the preceding chapter.
Six years elapsed between the original publication on the specific solu-
ble substances in 1917 and the paper on the chemical nature of these
materials that Avery published with Heidelberger in 1923. He had not
been idle during that period; he published 14 papers on several entirely


         The Chemical Basis of Bioiogical Specificity    105

different topics, but none of these dealt with immunological problems.
One can surmise from indirect evidence, however, that he had become
convinced in the meantime that the specific soluble substances are the
main, if not the only, components of the capsules that surround the cells of
virulent pneumococci. It is certain that he continued to work on the
purification of the capsular substances by his simple techniques of kitchen
chemistry, and it is probable that he came to question the validity of his
1917 statement that they were "of protein nature." There is no doubt that
he was asking himself the kind of question that henceforth would remain
the leitmotiv of his research. When studying a biological phenomenon, he
would always wonder, "What is the substance responsible?" and "How
does it work?" As I have recounted in a preceding chapter, this is the kind
of question he had in mind when, in 1922, he finally managed to secure the
collaboration of Michael Heidelberger .
The rapid success of the Avery-Heidelberger collaboration is demon-
strated by the fundamental papers on immunochemistry that they pub-
lished together between 1923 and 1929 (Heidelberger left The Rockefeller
Institute in 1927 for The Mount Sinai Hospital in New York). These
papers are readily available, but in discussing the experimental work on
which they are based, I shall quote chiefly from the annual reports, which
give a clearer impression of Avery's hopes and of his constant worries
about the significance of his work.
From the beginning, he was interested not only in the chemical nature of
the capsular substances, but also in the general problem of biological
specificity, a concern clearly formulated in the annual report for 1922-23.
In it, he recalled his 1917 investigations, which had established "that the
specific substance . . . is precipitable in acetone, alcohol and ether; that it
is precipitated by colloidal iron and does not dialyze through parchment;
that the serological reactions of the substance are not affected by proteo-
lytic action by trypsin ." 6 He saw in these properties "an ideal basis for the
beginning of a study of the relation between bacterial specificity and chemi-
cal constitution" (italics mine).7 He expressed the same view in the annual
report for 1923-24, in which he stated that the specific soluble substance
"was selected as a basis for the present studies on the chemistry of bacterial
specificity because it was not only highly type-specific, but also possessed a
stability to heat, enzymes, and many chemical reagents that augured well
for its suceptibility to study by the methods of organic chemistry" (italics
mine).* This phrase makes clear that his goal was not merely the chemical
isolation of the substance, but the establishment of the molecular basis of
immunological specificity.


             106   THE PROFESSOR, THE INSTITUTE, AND DNA

          Avery and Heidelberger started their work with the type II specific
          soluble substance, and soon established that the preparations possessing
         specific immunological activity consisted predominantly of complex poly-
          saccharides. They felt, however, that this was not sufficient evidence to
          prove the chemical nature of the active material, because, in their words,
         "it seemed possible that the polysaccharide . . . might be a tenaciously
         adhering impurity, and that the actual specific substance might belong to
          some other class of organic substance."g After submitting the active
         material to a variety of purification procedures and chemical analyses, they
          finally concluded "that the low nitrogen content, 0.1-0.2 percent, and
          absence of reactions for protein split products exclude relationships with
                  . . proteins and their derivatives." They noted furthermore "that by all
          the methods hitherto used for purification . . . essentially the same type of
          polysaccharide is recovered. It is, therefore, becoming increasingly diffi-
         cult to believe that the carbohydrate present can be merely a tenaciously
I           adhering impurity." lo
           I have quoted these passages to illustrate that Avery was acutely con-
         scious of the possibility that the immunological specificity of the soluble
         substance was due to a contaminating protein; the phrase "tenaciously
          adhering impurity" occurs twice in the report.
          The announcement in 1923 that the immunological specificity of type II
         pneumococcus is due to a polysaccharide was greeted with wide skepticism
         and even sarcasm. It went counter to the orthodox view that only proteins
         are sufficiently complex in structure to allow for the enormous degree of
         diversity required to account for immunological specificity. But Avery and
~          Heidelberger refused to become involved in controversies; they eventually
         convinced their critics by the sheer accumulation of new facts.
           Within a year, work with type III specific soluble substance "showed
          that marked chemical differences existed between it and the corresponding
         substance of type II." The type III substance appeared to be "an optically
         levorotatory strong acid, hydrolyzing to reducing sugars, chief of which is
         perhaps glucuronic acid or an analog, and not glucose, as in type II.""
         Thus was laid the groundwork for all the immunological studies which led,
          a decade later, to the synthesis of artificial antigens.
           In 1924, Avery and Heidelberger were joined by the organic chemist
          Walther Goebel, who determined with greater precision the molecular
I
I          structure of the various pneumococcal capsular polysaccharides. Another
         bacterial species, Klebsiella pneumoniae (designated Friedlander bacillus
E
i          in the Avery publications), was added to the immunochemical program
         because the virulent forms of this organism are occasional causes of lobar


         The Chemical Basis of Biological Specificity    107

pneumonia and are encapsulated as are pneumococci. The capsular poly-
saccharide of Friedlander bacilli not only proved to be the carrier of
immunological specificity, but turned out to exhibit a close chemical
resemblance to the capsular polysaccharide of the type II pneumococcus.
This finding immediately suggested a new experiment, which is explicitly
stated in the annual report for 1924-25 :
Because the two specific substances, although of widely different biolog-
ical origins, resembled each other so closely in some of their chemical
properties, the Friedhinder polysaccharide was tested with type II anti-
pneumococcus serum and a precipitin reaction was found to occur. On
the other hand, there was absence of precipitation when this substance
was tested with antipneumococcus serum of the other two types.lg

Even more spectacular was the discovery that mice could be protected
against type II pneumococcal infection by treatment with the serum of
rabbits which had been vaccinated with encapsulated Friedlander bacilli
and that, vice versa, mice could be protected against Friedlander infection
by treatment with type II antipneumococcal serum. Clearly, then, immu-
nological relationship was not the consequence of biological derivation,
but instead was determined by chemical configuration of the capsular
substance.
The widespread occurrence of specifically reacting polysaccharides
among microorganisms of different biological groups suggested that such
polysaccharides might also be found among plants. Indeed, chemical frac-
tionation of gum arabic yielded fractions that reacted with type II anti-
pneumococcal serum and, to some extent, with type III, but not with type
I.13 Furthermore, immunological relationships were found between the
pneumococcus type III polysaccharide and certain plant pectins .I4
The atmosphere of intellectual excitement created by these discoveries
can be recaptured from the style of the reports to the Board of Scientific
Directors for the period 1924-25. Some of the passages are worth quoting,
because they forcefully express Avery's belief that protective immunity is
the expression of the response that the body makes, not so much to a
certain microbial species as to a particular molecular configuration, irre-
spective of the biological origin of the material possessing the configura-
tion. After recalling "the surprising fact that the analogous specific soluble
substance of such closely related organisms as the three types of Pneumo-
coccus should be so strikingly different ," Avery found it "equally remarka-
ble that the analogous specific soluble substances of such widely different
organisms as this strain of the Encapsulatus group [the Friedlander bacil-
lus] and the type II pneumococcus should be so similar." I5 Commenting


108   THE PROFESSOR, THE INSTITUTE, AND DNA

on the chemi

cal differences between the Friedlander and

the type II

pneumococcus capsular polysaccharides, he stated further, "it seems rea-
sonable to assume that both contain in a portion of the complex molecule
the same or a closely similar steric configuration of atoms. This essential
similarity in molecular group would then determine the immunological
similarity of the two substances." I6 Thus, the origin of immunological
specificity was pushed back from the microbial species to certain molecules
that it contains, and from the molecule to the steric configuration of a
particular group within the molecule. As will presently be discussed, this
concept was soon to be converted into fascinating experimental models by
the synthesis of artificial antigens.

Immunity from Sawdust and Egg White

In his speech of acceptance of the Landsteiner Avery Award in 1973,
Walther Goebel referred to the 1920s and 1930s as "The Golden Era of
Immunology at The Rockefeller Institute." I7 And for good reason. Karl
Landsteiner had become a member of The Institute staff in 1922, the very
year that Heidelberger joined with Avery in the immunochemical program'
that was to be so brilliantly developed by Goebel himself. Although both
the Avery and Landsteiner departments were intensely involved in immu-
nochemistry, their approaches to the field were at first rather different.
Until 1930, Avery and his group were primarily concerned with immuno-
logical phenomena as they occur in natural systems, especially in infectious
processes. In contrast, Landsteiner emphasized immunochemical reactions
in artificial systems using, instead of bacteria or their products, antigens
that he synthesized to elicit antibody production. After 1930, however,
these approaches were integrated in Avery's department, largely through
Goebel's imaginative immunochemical studies with artificial antigens that
had activities similar to those of bacterial products.

While working as a pathologist in Vienna around 1920, Landsteiner
produced artificial antigens by combining simple molecules with proteins.
Whereas the simple molecules by themselves could not elicit the produc-
tion of antibodies when injected into animals, they acquired this ability
after having been combined with proteins. Landsteiner coined the word
"hapten" as a general term to designate substances which cannot act as
antigen (i.e., cannot elicit the production of antibodies) by themselves, but
acquire this ability when they are part of a larger molecular complex. The
capsular polysaccharides of pneumococci fitted well into Landsteiner's
hapten concept, since they reacted avidly with sera prepared by immuniz-
ing animals with whole pneumococci, yet by themselves were incapable of
. . . .    *      - . ,. . . . . . .        . *..

etictting the productton ot antioooies in norses and raboits.


        The Chemical Basis of Biological Specificity    109

Taking their lead from Landsteiner's work, Avery and Goebel started,

          - ----a -----
   d-artificial   -_ -,. -I-------- ,         -.-r- ..___ -...-,    _..-.. . . . . .
        antigens made up of proteins combined with simple
sugars, sugar derivatives, or the capsular polysaccharides of pneumococci.

By immunizing animals with such artificial antigens, they obtained sera
that enabled them to determine the effect of each chemical group on
immunological specificity and, thus, to understand the molecular basis of
both the immunological differences between pneumococcal types and the
immunological similarities between type II pneumococcus and the

I

4
I


Friedlander bacillus. They could thus confirm by the methods of synthetic
chemistry the assumption made in the 1925-26 report that substances of
different biological origin would exhibit immunological similarity if they
had the same molecular configuration.
While it would be out of place to review here these very specialized
studies, it seems worthwhile to present in Appendix III a simplified
account of them prepared by Avery in 1930-31'* for the lay members of

The Rockefeller Institute Board of Trustees. The very fact that he was

! j
i

asked to prepare this account is evidence of the interest aroused by the
demonstration that it is possible to prepare at will, by chemical means,

k

j
/ :

complex substances (antigens) that have immunological properties similar
to those of pathogenic bacteria.

In later experiments, Avery and Goebel synthesized an artificial antigen
containing the sugar derivative cellobiuronic acid, a substance which they
knew had a close chemical similarity to the capsular polysaccharides of
types III and VIII pneumococci. The immune serum prepared against this
synthetic antigen reacted not only with cellobiuronic acid, but also with the
various pneumococcal polysaccharides; furthermore, it protected mice

,I





'


1

against infection with certain types of pneumococci. After describing these

!


spectacular experiments in his book The Speci@city of Serological Reac-
tions, Karl Landsteiner added that this was "the first time an immune
serum produced by means of a synthetic substance acted upon a natural

antigen and protected against an infectious disease." I9 The production of
immunity against a microbial infection with a synthetic antigen is, unques-
tionably, the most startling and finest intellectual achievement of medical
immunology.



The Avery and Goebel experiments on synthetic antigens found their
way into one of the popular weekly magazines under the intriguing title
"Immunity from Saw Dust and Egg White." There was more scientific
truth than appeared at first sight in this eye-catching headline. In theory,
sawdust could be used as raw material for the synthesis of a variety of


110   THE PROFESSOR, THE INSTITUTE, AND DNA

tures of pathogens. These molecules, in turn, could be combined with the
protein egg white to produce artificial antigens and, finally, these artificial
antigens could be used to elicit immunity against certain infectious dis-
eases. In addition to sawdust and egg white, what is needed to develop a
rational approach to immunization based on the use of synthetic antigens is
a group of immunologists and chemists sophisticated enough to devise the

The title of this chapter, "The Chemical Basis of Biological Specificity,"
is obviously far too sweeping and may even appear misleading, because the
text is focused on a limited topic- the role of polysaccharides in immuno-
logical specificity. However, the very limitation in the range of subjects
discussed, when contrasted with the breadth of their implications, con-
forms well to Avery's style in scientific research.
During the 193Os, several laboratories were investigating the molecular
basis of the specificity of the effects exerted by hormones, vitamins, or
enzymes. At The Rockefeller Institute, for example, Max Bergmann and
his group of organic chemists were trying to define, in terms of chemical

         configuration, the lock-and-key image that Emil Fisher had used to de-
         scribe the specific relationship between an enzyme and the substance it
         attacks. Avery could have discussed the results of his immunological
         studies within the larger concepts of specificity that were emerging from
         the analysis of such biochemical systems, but this was not his bent; he stuck
         to his lathe. Goebel's discovery in 1925 that two organisms as biologically
         different as type II pneumococcus and the Friedlander bacillus produced
         polysaccharides with the same immunological specificity, pointed to the
/          fact that both polysaccharides contained "in a portion of the complex

b          molecule the same or a closely similar steric configuration of atoms." z"
         Obviously, Avery could have extrapolated from this observation to other

types of biochemical phenomena. Instead, he limited the discussion of its
significance to the field of bacterial immunology, using his new insight to
undertake the synthesis of artificial antigens that had some of the immuno-
logical properties of capsular polysaccharides produced by bacterial patho-
gens.
This limitation was self-imposed, and did not mean that his experience

with polysaccharides in immunological phenomena had made him blind to
the role of other kinds of chemical compounds in biological specificity. His


         The Chemical Basis of Biological Specificity    111

his own work, which proved that proteins or nucleic acids are responsible
for the specificity of certain biological phenomena.
Early in the 192Os, he and Heidelberger separated from the cells of
pneumococci an immunologically active protein that was chemically unre-
lated to the capsular polysaccharides, and differed from them in other
respects. Whereas the capsular polysaccharides are specific for each pneu-
mococcal type, the protein fraction is immunologically the same in all
types. However, it is different from protein fractions separated by similar
chemical methods from other bacterial species. Thus, Avery himself estab-
lished that a protein determines the immunological specificity of Diplococ-
cus pneumoniae.
The widespread occurrence of hemolytic streptococci in the pneumonia
associated with viral influenza during and after the first World War led
Avery to become involved in the identification of these organisms. Al-
though his name appears on only two papers concerned with streptococci
(in 1919)) his views and advice influenced profoundly the classic contribu-
tions that Dr. Rebecca Lancefield and her associates made to streptococcal
immunology. As mentioned earlier, he had made it a strict policy not to be
listed as co-author of a publication unless he had participated in the
experimental work with his own hands. Dr. Lancefield, however, would be
the first to acknowledge the crucial role of his constant advice in the studies
through which she demonstrated that the specificity of group A strepto-
cocci is determined by proteins, and not by polysaccharides.
From his early days as bacteriologist to the Hospital, Avery had been
interested in antibodies, and had accepted the general view that they are
proteins belonging to the group of serum globulins. He published a minor
paper on this topic in 1915, when he was trying to concentrate the active
fraction of antipneumococcal serum for therapeutic use. Although he did
not continue to work actively on the problem, he frequently talked about it
in the laboratory and encouraged Goebel, who, in collaboration with John
H. Northrop,"' crystallized the protein antibodies. Avery hoped that the
availability of such materials in a pure form would help to identify the
steric groups involved in specific reaction with the relevant antigen, as has
been done to explain the relationship between enzyme and substrate.
These studies did not go far, in part for lack of time, in part because
protein chemistry was not then sufficiently advanced for such an analysis,
but they provide further evidence that he was not blind to the role of
proteins in immunological specificity.
Finally, there is the fact, to be discussed at length in Chapter Eleven,
that he devoted an immense amount of effort to the identification of the


substance responsible for the transformation of immunological types in
pneumococci. He ended his professional life with the demonstration that
this genetic phenomenon is not brought about by polysaccharides or
proteins, but by deoxyribonucleic acids endowed with specificity.
Thus, his work on specificity ranges over three very different classes of
chemical compounds and two classes of biological phenomena. In the
laboratory, his experimental material was the pneumococcus but, in his
      lings were incorporated in a much broader concept of biologi-


CHAPTER NINE

THE COMPLEXITIES OF

    VIRULENCE

Virulence in Nature and in Experimental Models

Avery, who was so careful in his use of the English language and so
meticulous in the expression of his thoughts and feelings, was paradoxically
rather casual, at times to the point of carelessness, when it came to the
scientific jargon of medical microbiology. Whereas all modern textbooks
discuss at length the concept of virulence in an attempt to define the many
different shades of meaning the word conveys, he was prone to use it
conversationally in its narrow etymological sense, which refers only to the
severity of disease. At times, he would speak of virulence as did the
physicians of the pre-microbiological era, who could not possibly have
known that, when the word is applied to microbial pathogens, it subsumes
the multiple mechanisms involved in the complex processes of tissue
invasion and of pathological disturbances- mechanisms that differ from
one microbial strain to another. This linguistic casualness was not due, of
course, to lack of intellectual discipline on his part or to the fact that he
underestimated the complexity of virulence. It resulted from the dual
manner in which he approached scientific problems.

When Avery became interested in a biological phenomenon, he first
observed it for the sheer fun of it, as a naturalist. He took delight in
watching almost any manifestation of life, including the pathological ones.
At this initial phase of observation, he reported what he perceived in a
language that appeared nonscientific because it was not analytical. He
simply wanted to convey his direct perception of facts and events, just as he
apprehended them. For example, when first describing the pathogens
recovered from patients with lobar pneumonia or septic sore throat, he
called virulent, without further qualification, the pneumococci, Fried-
lander bacilli, influenza bacilli, or hemolytic streptococci responsible for
the lesions and toxic effects in these diseases. The degree of virulence of a
given microbe then meant to him its ability to cause disease, mild or
severe, under this or that set of conditions. When looking at infectious

;
i 1.
3



images without concern for precision. He would playfully speak of the
pneumococcus as that cunning little fellow which behaves now as a peace-
ful citizen, then as a vicious character, depending upon the circumstances.
Once he took the problem of virulence to the laboratory bench, how-
ever, this playful posture was replaced by a strictly analytical attitude.
Instead of studying virulence in its complex manifestations, as they occur in
disease under natural conditions, he tried to reproduce limited aspects of it
in one or another experimental model of infection where he could control
the variables. He thus explored separately the various facets of virulence
from a multiplicity of viewpoints in a number of consecutive steps. A
review of these steps, taken in a fairly well-defined chronological order
from 1916 to 1942, will bring out his continuity of purpose, even though
his approach changed considerably in the course of those 2.5 years.
As mentioned in Chapter Seven, Avery first considered the problem of
virulence from a metabolic point of view. He argued that, since the
multiplication of bacteria in viva depends upon the operation of their
enzymes, virulence implies that their enzymatic equipment is protected
  .    . .^        _ .     ^.. -.     .    ^..^

then to a series of studies on bacterial metabolism, and finally to his 1941
speech before the Society of American Bacteriologists.'

The discovery of the specific soluble substances of pneumococci in 1917
and of their polysaccharide nature in 1923, encouraged Avery to focus his
attention on the antiphagocytic activity of these substances, and of the
bacterial capsule of which they are the chief, if not the only, constituents.
This facet of the virulence problem is the one he explored most completely,
in both its chemical and morphological aspects. He demonstrated that
capsular polysaccharides play an essential role in virulence by protecting
pneumococci against engulfment and destruction by phagocytes.

Many strains of pneumococci that are fully encapsulated and produce a
capsular polysaccharide known to have antiphagocytic activity, neverthe-
less are not virulent for certain animal species. In other words, while the
production of capsular polysaccharide is a necessary condition of virulence,
it is not a sufficient condition. About 192.5, Avery postulated that the
capsular polysaccharide is an effective factor of virulence only when com-
bined with some other component of the bacterial cell; he assumed also
that animal tissues contain an enzyme which, although inactive against the
polysaccharide itself, "dissociates" it from its cellular combination. In the
light of this dual hypothesis, virulence appeared to him to depend upon the


The Complexities of Virulence   115

ability of pneumococci to resist the process of antigenic dissociation. He
termed this resistance "tissue fastness."

Throughout these studies, Avery was impressed by the fact that pneu-
mococcal strains can undergo reversible hereditary changes in virulence.
For example, they can go from the encapsulated form, which may be
virulent if other conditions are fulfilled, to the nonencapsulated form,
which is never virulent, and vice versa. Similarly, a strain can be made to
acquire or lose the tissue fastness essential to virulence for certain animal
species. Thus, one of the most intriguing aspects of virulence is the
independence and reversible variability of its determinant factors.

The last phase of Avery's exploration of virulence was the genetic
analysis of its variability. The gene for each determinant of virulence can
be taken from one pneumococcal cell and incorporated into another
through the techniques that have come to be known as bacterial transfor-
mation (see Chapter Eleven). For example, pneumococci that have lost the
ability to produce a capsular polysaccharide can be made to recover
virulence by providing them with the genetic equipment needed for the
production of that substance; pneumococci that produce one certain type
of capsular polysaccharide can be made to produce another type; the tissue
fastness that confers virulence for a particular animal species can also be
transferred from one pneumococcal strain to another.

Thus, whereas virulence once was regarded as a property pertaining to
bacterial cultures considered as a whole, Avery emphasized that it depends
on the simultaneous operation of several distinctive attributes of the
bacterial cells; he demonstrated that virulence can be altered at will, both
qualitatively and quantitatively, by manipulating each of these attributes
separately.

Avery's analytical concept of virulence was derived chiefly from his
extensive studies of pneumococcal infections, but he applied the same
analytical approach to a few other bacterial species, either through his own
work or by advice to his colleagues. The most spectacular and best known
of his discoveries relating.to virulence is that polysaccharides, not proteins,
are the substances responsible for the immunological specificity and the
antiphagocytic activity of the capsule in pneumococci and Friedlander's
bacilli. Of less obvious, but broader, significance is his demonstration that
virulence can be analyzed in terms of other chemically defined structures
and components of bacterial cells. This concept had, of course, long been
established with regard to diseases in which toxin production is the domi-
nant factor of the infectious process, as in diphtheria. Avery's work
revealed that the same concept applies to conditions in which virulence


116    THE PROFESSOR, THE INSTITUTE, AND DNA

depends chiefly upon the ability of the microorganisms to invade tissues.

He showed, furthermore, that there are profound differences in the
chemical nature of the factors responsible for invasiveness, even between
closely related bacterial groups. Whereas in pneumococci, for example,
immunological specificity and antiphagocytic activity are located in the
polysaccharide capsule, the analogous role in hemolytic streptococci of
group A is played by proteins (the so-called M substances) on the bacterial
surface. In hemolytic streptococci of group C, however, invasiveness de-
pends upon the possession of a hyaluronic acid capsule. Although the
factors to which Avery attributed tissue fastness are still unidentified, there
is reason to believe that they, too, differ in location and chemical charac-
teristics from one bacterial strain to another.

These different facets of the virulence problem were so clearly set apart
in Avery's mind that even his speech mannerisms changed, depending
upon the aspect of the problem he wanted to emphasize at any given time.
If the conversation was focused on the capsular polysaccharide, he would
refer to the pneumococcus as this "sugar-coated microbe," whereas he
would compare it to Dr. Jekyll and Mr. Hyde if he wanted to discuss
reversible changes in virulence.

In a general report to the Corporation of The Rockefeller Institute in
1930, Avery stated that the efforts of his department were centered on an
attempt to construct for the pneumococcus a "precise knowledge of the
biological properties peculiar to it and the nature of the protective proc-
esses which the animal body develops against it."2 He had begun this
program in 1915, and was still deeply involved in it at the time of his
retirement. Yet, much of this work has been forgotten. After the advent of
the sulfonamides in the mid-1930s and of other antibacterial drugs in the
194Os, the problems of virulence appeared to be of only remote and
esoteric interest to most students of infectious disease. Since some of
Avery's contributions to the problem have not reached textbooks dealing
with mechanisms of infection, it seems justified to present them here in
some detail, at the risk of repetition, in part because of their historical
interest, and also because they may once more become of practical interest
if chemotherapy does not continue to fulfill its promises.

The Bacterial Capsule and Virulence

Ever since 1881, bacteriologists have known that pneumococci re-
covered from human disease or animal tissues are surrounded by a thick,
mucoid envelope. Pasteur called this structure an "aureole," but the more
generally accepted name is "capsule." Until approximately 1920, there


The Complexities of Virulence   117

was no precise knowledge concerning either the chemical composition or
the biological properties of the capsule, except that it seemed to be related
to virulence. The following quotation from The Rockefeller Institute
monograph on "Acute Lobar Pneumonia," which was written largely by
Avery, states the consensus on this matter around 1917:

The exact significance of the capsule of pneumococcus is not known.
That it may serve as a protective mechanism of the organism and that it
may in some way be related to virulence, is suggested by the fact that
capsular development is always much more marked when the organism
is grown in animal tissues in which presumptively there is some opposi-
tion to its development. . . . In addition, it seems to be true that the
greater the amount of capsular development the less the amount of
passive protection afforded by immune serum (italics mine).3

These statements could be read as a preview of Avery's scientific
program for the rest of his professional life, but there are indications that,
at the time the monograph was published, he was still far from having a
clear view of the role that the capsule plays in virulence and immunity.

His first original suggestions concerning a possible mechanism for the
protective role of the capsule occurs in the paper on antiblastic immunity
that he and Dochez published in 1916. As mentioned earlier, one of the
hypotheses presented in the paper is that the capsule protects the enzymes
located on the membrane of pneumococci against the effect of the serum
antiblastic factors. There is probably a remnant of this hypothesis in the
remark quoted above that, in animal tissues, the pneumococcus "encoun-
ters some opposition to its development." However, this is the last time in
Avery's writings that the capsule is linked to the metabolic activities of the
pneumococcus.

In the lobar pneumonia monograph, he referred to the specific soluble
substances of pneumococci that he and Dochez had just discovered, but he
did not relate them to the capsules. He suggested instead that they might
be "responsible for the intoxication which attends pneumococcus infec-
tion." While he acknowledged that their "toxicity is in no way comparable
to that of diphtheria toxin," he felt, nevertheless, that they possess "a
degree of toxicity which, exhibited through the course of an infection,
might account for the signs of intoxication in lobar pneumonia."" The
importance of this hypothetical toxicity appeared to him even greater
in view of the fact that the specific soluble substances are released into the
infected body as soon as the pneumococci begin to multiply. Thus, his
second published hypothesis was that the specific soluble substance con-
tributes to virulence through its toxicity.


118   THE PROFESSOR, THE INSTITUTE, AND DNA
It is probable that, after these erroneous hypotheses, his understanding
of the role of the capsule in virulence finally emerged from a scientific
interest that he had acquired at the beginning of his medical life. While still
engaged in the practice of medicine, he received, as mentioned earlier, a
small grant to study the relationship between phagocytic index in patients
and their susceptibility to infection. This experience made him become co-
author in 1910, while at the Hoagland Laboratory, of "Opsonins and
Vaccine Therapy" (see Chapter Four). He was, therefore, intellectually
prepared to imagine that the specific soluble substances contribute to the
virulence of pneumococci by rendering them resistant to phagocytosis, and
that the protective antibodies in antipneumococcal serum act as opsonins
by combining with the soluble substances.
The phagocytosis-opsonin theory of virulence and immunity is not
mentioned in Avery's writings until 1923, either in his publications or the
annual reports; nor does the word capsule appear in any of these docu-
ments. His silence on these matters is probably explained by the fact that
all his papers and reports between 1917 and 1923 dealt with the enzymes
of pneumococci and their metabolic activities. In contrast, there was a
complete change of scientific content in his writings after 1923. As soon as
he and Heidelberger began to report their findings on the chemical compo-
sition of the specific soluble substances, they referred to them as capsular
polysaccharides, and to the capsule as a structure that protects the pneu-
mococci against phagocytosis. Everything had fallen into place. It is cer-
tain, therefore, that Avery had developed an integrated concept of the role
of the antiphagocytic role of capsular substances before he resumed publi-
cation in this field.
There is other unpublished evidence that he had long been interested in
the mechanisms that render virulent pneumococci resistant to phagocyto-
sis. In conversation, he referred now and then to some of his early
experiments, in which he had tested various chemical compounds for their
ability to neutralize the antiphagocytic power of the capsule. For example,
he carried out phagocytic tests in virro and protection tests in mice with a
variety of mineral salts and organic substances that he found, by micro-
scopic examination, to be capable of reacting with the capsule. He had
hoped that the neutralization of antiphagocytic power by chemical sub-
stances would open the way for a rational chemotherapy. All these experi-
ments failed, and he did not even mention them in the annual reports, but
they testify to the constancy, intensity, and diversity of his interest in the
role of the capsule in pneumococcal infections.
The discovery that the specific soluble substances in the capsules are


The Complexities of Virulence    119

made up of polysaccharides probably made him feel that conditions were
now right for a more searching analysis of virulence and immunity. He
began his presentation of the problem to the Board of Scientific Directors
with an understatement of what he knew and believed: "The synthesis of
this polysaccharide is a cellular function highly developed in those strains
of pneumococci which are most capable of multiplying in animal tissues.
This substance apparently bears a significant relationship not only to type
specificity but to virulence and capsular development" (italics mine) .j The
word "apparently" means here that, although he was convinced, he did not
regard the evidence as final proof until he could illustrate it with one of his
demonstrative "protocol experiments" (see Chapter Five). In fact, evi-
dence for the theory of a relationship between capsular polysaccharide and
virulence rapidly became so overwhelming that it was accepted as textbook
knowledge within a few years.

The theory was clear, but it had disturbing practical limitations. From
the beginning of the pneumonia work at the Hospital, highly effective
therapeutic sera against type I pneumococci had been consistently ob-
tained by the immunization of horses, but the results had been far less
satisfying with other types, and entirely negative with type III. This failure
certainly accounted for the interest Avery took in me during the meeting
recounted in Chapter Five. He hoped that if one could find an enzyme
capable of decomposing the type III capsular polysaccharide, and if this
enzyme could be shown to destroy the capsule itself and thereby render the
pneumococci susceptible to phagocytosis, his theory would be vindicated.
In fact, the results of the enzymatic approach went beyond expectation.
The bacterial enzyme that we found to be capable of decomposing the
specific polysaccharide of type III pneumococci did not interfere with the
growth of pneumococci in vitro, but, when it was injected into infected
animals, it destroyed the bacterial capsules so rapidly and completely that
the phagocytes could immediately engulf the bacteria and kill them. Mice,
rabbits, and monkeys suffering from advanced infection with type III
pneumococci promptly recovered after treatment with the enzyme. This
provided further proof, if any was needed, of Avery's doctrine concerning
the role of capsular polysaccharide in virulence.

The Bacterial Body and Virulence

In their purified soluble forms, all the capsular polysaccharides react
avidly with the corresponding antibodies of antipneumococcal sera that
have been obtained either from pneumonia patients or from animals
vaccinated with the killed cells of virulent pneumococci of the proper type.


120    THE PROFESSOR, THE INSTITUTE, AND DNA

However, while such cells can act as antigens, none of the capsular
polysaccharides is capable by itself of eliciting the formation of antibodies
when injected into horses or rabbits; it behaves as a hapten. From these
facts, Avery concluded that the capsular polysaccharides exist in the
pneumococcal cells as a part of complex structures that confer upon them
the antigenicity they do not possess after they have been separated in pure
form. The analysis of the factors involved in the antigenicity of the capsular
polysaccharides was for many years one of his most constant preoccupa-
tions.
The point of departure of the analysis was the observation that, when
encapsulated pneumococci are allowed to disintegrate by autolysis before
being used as vaccines, they do not elicit the formation of antibodies
against their capsular polysaccharides, even though these substances per-
sist in the autolysate. Avery assumed that the polysaccharide was sepa-
rated during autolysis by some pneumococcal enzyme from the hypotheti-
cal cellular structure which endows it with antigenicity- what he called the
complete capsular antigen. He referred to this separation or splitting as
"antigenic dissociation." The tables of contents of the annual reports for
1930-1931 and 1936-1937 give an idea of the enormous amount of
experimental work that was devoted for several years to this hypothesis
(Appendix IV).
The program on antigenic dissociation involved extensive studies of the
autolytic system of pneumococci and of the effects exerted by various
enzymes on the antigenic activities of the bacterial cell. The results were
disappointing from the theoretical point of view, because they did not
elucidate the chemical composition of the complete capsular antigen or the
mechanisms of antigenic dissociation; nevertheless, they had great practi-
cal utility. Despite this failure, it was still possible to develop empirical
means that prevented, or at least minimized, autolytic processes. This led
to the production of highly effective vaccines for the preparation of thera-
peutic sera. By 1935, as mentioned in Chapter Eight, successful results
were obtained in the Hospital with serum treatment of many types of
pneumococcal lobar pneumonia.
Even with the best vaccines, however, it was more difficult to obtain
sera containing a high level of specific antibodies against type II and,
especially, type III pneumococci than against type I. To explain this
anomaly, Avery postulated that there exist in the animal body certain
enzymes capable of splitting the complete capsular antigen, and that this
splitting occurs more rapidly in type II and type III than in type I. Here,
again, he referred to the hypothetical splitting as antigenic dissociation, but


The Complexities of Virulence   121

in this case brought about by the enzymes of animal tissues, instead of by
the pneumococcal enzymes.

Carrying his speculations still further, he suggested that "the factors
which make for dissociation of the antigen after injection into the animal
body . . . appear to be related to what is commonly called natural immu-
nity, for animals which are most resistant to pneumococcus infection are
just those animals which have been found to possess the greatest capacity
to split the antigen and consequently to yield the least potent serum.""
According to this mental construct, certain animal species are endowed
with natural resistance to a given type of encapsulated pneumococcus
because they possess an enzymatic machinery that rapidly dissociates the
complete capsular antigen of this particular type. In the light of this
hypothesis, the difficulty experienced in obtaining sera with a high level of
antibodies against type II and type III pneumococci came from the fact that
the complete capsular antigens of these types were rapidly dissociated,
either by the pneumococcal autolytic enzymes or by the enzymes of the
animal tissues.

Avery thought at first that the differences in antigenic stability of the
various pneumococcal types could be traced to chemical differences in the
capsular polysaccharides themselves:

The fact that this splitting of the specifically immunizing complex of
pneumococci occurs so readily, particularly in the case of organisms of
Type II and III and the fact that under these circumstances the stimulus
to specific antibody production is lost so quickly in these two instances
affords a possible explanation of the lack of success in obtaining an
antiserum of high potency against these types. It seems not unlikely that
the relative differences in the rate and degree of splitting of the specific
antigens in the three types of pneumococcus are in each instance
referable to known differences in the chemical structures of the specific
sugar components. Antigenic stability, like specificity itself, then rests
upon the chemical constitution of these unique and specific substances
(italics mine) .7

New findings, however, revealed that this hypothesis was erroneous.
Some strains of type III pneumococcus were found to be virulent for
rabbits and others not, even though they produced equally large amounts
of the same capsular polysaccharide. Even if it were true that the virulence
characteristics of the two strains could be explained by the rates of anti-
genie dissociation, the difference between them was obviously due to some
factor other than the polysaccharide itself, since this was the same in both
cases.


122   THE PROFESSOR, THE INSTITUTE, AND DNA

Instead of being discouraged by the finding, Avery formulated a further
hypothesis. He assumed that certain strains of type III pneumococci had
become virulent for rabbits through a change that had rendered their
complete capsular antigen more resistant to the enzymes of the rabbit. He
imagined that the "rabbit virulence factor" was the cellular expression of
some kind of tissue fastness-to use his own words- that had its site not in
the capsule, but in the body of the pneumococcus; it was a "somatic"
factor. He assumed also that the mechanism responsible for the degree of
virulence in some way determined the ability of the culture to elicit in
rabbits the formation of antibodies specific against type III pneumococci.

It is probably impossible for anyone who was not a member of Avery's
department during the late 1920s and the 1930s to follow the succession of
hypotheses he formulated to explain in immunological and enzymatic
terms the complexities of the virulence problem- hypotheses that were
more remarkable for their imaginative exuberance than for their value as
guides to experimentation. An idea of the multiple experimental ap-
proaches that were developed in the department during that period can be
had from the table of contents of the annual report for 1926-27 (Appendix
V>.

Despite extensive experimentation by most of us, the findings were
never sufficient to evaluate the validity of the hypotheses formulated to
explain antigenic dissociation or to isolate the somatic virulence factor. For
this reason, the only aspects of the annual reports that found their way into
scientific journals are those that yielded clear-cut experimental facts with a
straightforward interpretation, independent of any hypothesis concerning
the mechanism of virulence. For example, although the phrase "tissue
fastness" occurs repeatedly in the annual reports, and although I have used
it in these pages, I do not believe that it occurs in any of the papers
published from the department.

Avery's failure to identify the nature of the rabbit virulence factor did
not cause him to lose interest in the problem. In fact, he came back to it in
the 1940s when the techniques of bacterial transformation (Chapter Ten)

made it possible to put to the test his hypothesis that, in pneumococci of
type III, virulence for rabbits depends upon a somatic factor completely
independent of the capsular polysaccharide. Although the principle of the
"transformation" technique will not be presented until the next chapter, it
seems worthwhile to describe this particular experiment here, because it
reveals that one of the determinants of rabbit virulence persists, in an
unexpressed form, in certain nonvirulent pneumococci.

Two strains of type III pneumococci, both fully encapsulated, but one


virulent for rabbits and the other nonvirulent, were caused to undergo a
genetic change that resulted in the loss of their ability to produce a capsule.

transforming material prepared from these organisms. When the cultures
of type II pneumococci thus artificially produced by the transformation
technique were tested in rabbits, it was found that they differed in viru-
lence- their ability to establish disease in rabbits corresponded to that of
the particular type III strain from which they had been derived; one was
virulent for rabbits and the other was not. The importance of this finding is
the demonstration that one of the determinants of rabbit virulence is
associated with a cellular factor which persists in the noncapsulated form,
independent of the production of capsular polysaccharide.

The experimental feat just described was performed by MacLeod and
McCarty and published by them in 1942 under the title "The relation of a
somatic factor to virulence of pneumococci."* Avery did not want to have
his name entered as co-author of the article because he had not actually
participated in the experiments, but the genetic transfer of the rabbit
virulence factor was obviously the experimental demonstration of the
mechanism he had postulated 10 years before under the name of tissue
fastness. It is not unlikely that, in a similar way, his mental constructs
about antigenic dissociation will acquire a concrete meaning if techniques
ever become available to determine how the capsular polysaccharide is
bound in the intact cellular structure of pneumococci.


CHAPTER TEN              I

Polymorphism vs. Monomorphism

During the two centuries that elapsed after Leuwenhoek first saw bacteria,
probably about 1675, these organisms were studied almost exclusively by
microscopic examinations; naturalists were primarily interested in their
occurrence, shapes, and motility in different natural fluids and products, or
in the bodies of human beings and animals. The paper on lactic acid
fermentation published by Louis Pasteur in 1857 is the first well-docu-
mented report of a study in which a bacterial culture was manipulated
under controlled conditions to measure its chemical activity, rather than to
observe its morphological appearance .r Pasteur was intensely interested in
what bacteria do and in the specificity of their chemical and pathological
effects, but he paid little attention to their cellular organization and other
purely biological characteristics.

Until the middle of the nineteenth century, in fact, most microscopists
believed that bacteria were extremely primitive organisms, so simple as to
be little more than poorly organized chunks of protoplasm. "They form the
boundary line of life; beyond them, life does not exist," wrote the botanist
Ferdinand Cohn in a short, classic essay published in 1866 under the title
"Ueber Bacterien, die kleinsten lebenden Wesen."2 Such assumed simplic-
ity of structure led many biologists of the time to believe that the various
bacterial forms seen under the microscope were but the different manifes-
tations of only one or a very few elementary protoplasmic structures that
could change in appearance and other characteristics, depending upon
environmental conditions. This now-discredited theory, which has been
called the doctrine of bacterial polymorphism, was asserted in one form or
another by many of the most famous biologists and physicians until a
century ago-for example, by Thomas Huxley in 1870,3 by Edwin Klebs in

ness and biological stability of the different bacterial types.
An elaborate statement of the doctrine of bacterial polymorphism was


126   THE PROFESSOR, THE INSTITUTE, AND DNA

published in 1877 by the botanist Carl von Nageli in his book Die Niederen
Pilze,8 in which he introduced the word Anpassung (adaptation, acclimati-
zation) to express his view that bacteria were primitive fungi capable of
changing from one morphological or physiological type to another as they
adapted to new external conditions. Ntigeli's thesis had a peculiar fate.
Even before it was published, bacterial polymorphism was being aban-
doned and replaced by an opposite doctrine of strict bacterial monomorph-
ism. Yet the concept of Anpassung survived and was used extensively a few
years later to account for the discovery that bacterial species do, in fact,
continuously give rise to many variant forms in response to environmental
changes.

I

From the time of his first biological studies in 1857, however, Pasteur
believed that, for each kind of fermentation and each kind of contagious

disease, there exists a particular type of microorganism that retains its
fundamental characteristics under all conditions, but he could not provide
biological evidence to prove his point. Having been trained in physics and
chemistry, and having only limited knowledge of conventional biology. he
could not give morphological descriptions of the microorganisms he stud-
ied; instead, he put his emphasis on their functional attributes, such as
their ability to perform certain chemical reactions or to cause certain
pathological disorders. Evidence for the distinctiveness of bacterial types
required the use of biological criteria such as those introduced in the 1870s
by Ferdinand Cohn and by Robert Koch.

Many different scientific forces, acting over several decades, played
roles in discrediting the doctrine of bacterial polymorphism. They can be
symbolized by three very different types of studies that were published
during 1876, each contributing in its own way to the demonstration that
bacteria are well-defined biological entities, stable in their fundamental
characteristics.

In 1876, Ferdinand Cohn published the fourth of his Untersuchungen
iiber Bacferien,Y in which he gave precise descriptions of the morphological
appearance of various bacterial cells as seen under the microscope, and
suggested that they could be classified in four morphological groups, each

consisting of several genera. He thus introduced into bacteriology taxo-
nomic criteria similar to those used in other biological fields. In 1876,
Koch published Die Aetiologie der Milzbrandkrankheit,`O in which he
described the life history of the anthrax bacillus and its role as an agent of
disease. Also in 1876, Louis Pasteur published his Etudes sur la bitre . . .

avec une tht!orie nouvelle de la fermentation." In this work, he presented in
their final forms the views on the biological specificity of fermentative


Bacterial Variability    127

processes and on other chemical aspects of microbial life that he had been
expounding for some 20 years.

The distinctiveness and stability of bacterial species-the so-called doc-
trine of bacterial monomorphism - had thus been fully demonstrated by
1876, or so it was believed. There is no doubt that the very rigidity of this
doctrine helped to create bacteriological science by introducing discipline
into the intellectual approach to problems and into the design of tech-
niques. The subsequent triumphs of the germ theory of fermentation and
disease would not have been possible without this discipline. As we shall
now see, however, the doctrine of monomorphism did not last long in its

I   discredited, many bacteriologists became aware that each bacterial species

Ironically, Pasteur, who had been the first to affirm that bacterial
species are distinct and stable, was also the first to recognize bacterial
variability during his work on fermentation and infection. Furthermore, he
came to regard bacterial variability as a manifestation of the adaptive
phenomena that Carl von Nggeli had designated by the word Anpassung.
Nageli's interpretation was faulty, because what he thought to be transfor-
mation of one species into another was, in reality, a succession of different

organism can undergo by phenotypic adaptation in direct response to a
change in its environment. In the Etudes sur la bitre, for example, Pasteur
had shown that, whereas yeast cells are globular during fermentation, they
become somewhat elongated in the presence of oxygen; conversely, the
fungus Mucor, which usually grows as a mycelium, becomes globular and
yeastlike under anaerobic conditions. Pasteur also showed that the
amounts of CO*, alcohol, organic acids, and protoplasmic material pro-
duced by yeast from a given amount of sugar differ greatly according to the
oxygen tension in the culture medium. Although such morphological and
metabolic changes can be profound, they are not lasting; they correspond


128   THE PROFESSOR, THE INSTITUTE, AND DNA

to a phenotypic response of the individual organism, and are not transmis-
sible to its descendants.

In other cases, Anpassung denotes adaptive changes which, in contrast
to phenotypic adaptations, are hereditary. Examples of such hereditary
adaptive changes among bacteria were first observed by students of experi-
mental infections,

As early as 1872, three years before Koch and Pasteur had published
anything on the anthrax bacillus and before the pathogenic role of this
organism had been established, C. J. Davaine had discovered that the
"virulence" of the blood of rabbits infected with anthrax could be spectac-
ularly increased by the technique he introduced under the name "animal

    Y       ,
smaller amounts of infected blood. Davaine observed that the causative
agent progressively increases in activity as it passes through living animals
("acquiert done une plus grande activite en passant par l'economie d'un
animal vivant").`* Shortly after he began to work with bacteria1 diseases,
Pasteur himself postulated that bacteria become more virulent by animal
passage because they undergo a process of biological adaptation to the
animal through which they are "passed." Referring to fowl cholera, he
postulated that its bacterial agent "having multiplied for numerous genera-
tions [in the bodies of chickens] becomes more and more capable of

fundamentally different from phenotypic adaptation because they are
transmissible from one bacterial culture to the next.

In 1880, Pasteur observed accidentally that the causative agent of fowl
cholera commonly becomes nonvirulent when cultivated in vitro; he re-
ferred to this phenomenon as "attenuation" of virulence.r3 In 1881, he
developed techniques by which he could at will cause cultures of the
anthrax bacillus to lose the ability to produce spores and simultaneously to
lose virulence for cattle.14 He used attenuated forms of these two bacterial
species to develop vaccines that conferred immunity to fowl cholera and to
anthrax respectively, thereby opening a general approach to vaccination by
means of living, attenuated cultures.

Because of their relevance to disease, the changes resulting in exaltation
or attenuation of virulence were the two kinds of hereditary variation in
bacteria that were at first most widely recognized and most extensively
studied. However, other kinds of hereditary changes also were described
by the early bacteriologists. In 1888, for example, G. Firtsch recognized



3 * O.cwald AI'EY~. thctl about
      I?, and his brother
   Ernest, wxith the c0rnet.T
they played at the Temple.





lfitlitrir-itrtr iiflrs.



14 -  MICHAEL HEIDELBERGER               15 *  WILLIAM H. WELCH

16 *  RUFUS COLE


r '        .,  --l --         /, --   '


STUDIES ON THE CHEMICAL NATURE OF THE SUBSTANCE
INDUCING TRANSFORMATION OF PNEUMOCOCCAL TYPES

INDUCTION OF ~ANSFO~ATION BY A DESOXYRIBON~CLEIC ACID FRACTION
         ISOLATED FROM PmrJbfococcus TYPPE III

BY OSWALD T. AVERY, M.D., COLIN M. MncLEOD, M.D., mm
         MACLYN MCCARTY,' M.D.
(From the Hospifal of The Rockefeller It&l& for Medical Research)
               PLATE 1

(Received for publication, November 1, 1943)

Biologists have long attempted by chemical means to induce in higher
organisms predictable and specific changes which thereafter could be trans-
mitted in series as hereditary characters.  .4mong microijrganisms the most
striking example of inheritable and specific alterations in cell structure and
function that can be experimentally induced and are reproducible under well
defined and adequately controlled conditions is the transformation of specific
types of Pneumococcus.  This phenomenon was first described by Griffith (1)
who succeeded in transforming an attenuated and non-encapsulated (R)
variant derived from one specific type into fully encapsulated and virulent (S)
cells of a heterologous specific type.  -4 typical instance will suffice to illustrate
the techniques originally used and serve to indicate the wide variety of trans-
formations that are possible within the limits of this bacterial species.

Griflith found that mice injected subcutaneously with a small amount of a living
R culture derived from Pneumococcus Type II together with a large inoculum of
heat-killed Type III (S) cells frequently succumbed to infection, and that the heart's
blood of these animals yielded Type III pneumccocci in pure culture.  The fact that
the R strain was avirulent and incapable by itself of causing fatal bacteremia and the
additional fact that the heated suspension of Type III cells contained no viable or-
ganisms brought convincing evidence that the R forms growing under these condi-
tions had newly acquired the capsular structure and biological specificity of Type III
p*NllOCOCCi.

The original observations of GritXth were later confzrmed by Neufeld and Levin-
thal(2), and by Baurhenn (3) abroad, and by Dawson (4) in this laboratory.  Sub%-
quently Dawson and Sia (5) succeeded in inducing transformation in vitro. This
they accomplished by growing R cells in a fluid medium containing anti-R serum and
heat-killed encapsulated S cells.  They showed that in the test tube as in the animal
body transformation can be selectively induced, depending on the type specificity
of the S cells used in the reaction system.  Later, Alloway (r-) was able to cause

*Work done in part as Fellow in the Medical Sciences of the National Research
COUnCiI.
                     137

19 - Opening page of the DNA paper, published in
  1944 in the Journal of Experimental Medicine.


,                        I
!
I
\  2. . Avery,s handwrirten teXt of the discussion section of the paper On fhe facing page'


21 * Colin M. MacLeod, left, and Maclyn McCarty at the dedication of the Avery
  Memorial Gateway at The Rockefeller University on September 29, 196.5.


                    Bacterial Variability   129

                                                                           /
colonial variation in Vibrio15 ; in 1901, Martinus Beijerinck published
photographs illustrating a wide range of variations in cellular and colonial
morphology.i6 Max Neisser in 1906i7 and R. Massini in 1907ix described
the spontaneous appearance of lactose fermenting organisms in cultures of
the nonlactose fermenter Escherichia coli mutabile. Similar examples of
hereditary changes in biochemical properties were soon reported in the
scientific literature and made it obvious that phenomena akin to mutation
are common in bacteria.
In 1921, there came to light a morphological expression of bacterial
variability that was destined to have a deep influence on medical bacteriol-
ogy and, later, on genetics. While comparing the virulent strains of Shiga
dysentery bacilli with the nonvirulent forms that appear spontaneously in                 /
laboratory cultures of this species, the British bacteriologist J. A. Ark-
wright noticed that the colonies of the virulent forms are regular in shape,
dome-shaped, and with a smooth surface, whereas the colonies of nonviru-
lent forms are irregular, granular, and flat.19 He introduced the terms
Smooth and Rough (respectively abbreviated as S and R) to describe the
colonial appearance of the culture, then eventually to denote the culture
itself. He postulated that persistent variations in virulence and colonial
morphology correspond to genetic mutations.
Arkwright also noticed that R forms occur frequently in cultures grown
under artificial conditions, but not in infected tissues. From this he con-
cluded that a Darwinian process of natural selection is at work in determin-
ing whether S or R forms gain the upper hand. In his words, "The human
body infected with dysentery may be considered a selective environment
which keeps such pathogenic bacteria in the forms in which they are usually
encountered ."*O The importance of Arkwright's discoveries and interpreta-
tions was immediately recognized, and several authors in different coun-
tries, working with other bacterial pathogens, confirmed that loss of
virulence was commonly associated with a change in colonial morphology.
The expressions S and R thus came to be associated with both the colonial
morphology of the culture and its virulence; the reversible change SGR
came to be regarded as a process involving mechanisms of mutation and
Darwinian selection.

      The Many Facets of Bacterial Variability
Mendelian genetics had at first little influence on the scientific climate in
which the understanding of bacterial variation progressively emerged dur-
ing the first half of the twentieth century. By 1900, the original doctrine of
bacterial polymorphism had been completely discredited. Bacteriologists


130   THE PROFESSOR, THE INSTITUTE, AND DNA

were convinced that bacteria breed true like other living things; they tried
to classify and name the best-defined organisms according to the Linnean
system, using names such as Lactobacillus bulgaricus and Lactobacillus
acidophilis; Streptococcus hemolyticus and Streptococcus fecalis; Mycobac-
terium tuberculosis and Mycobacterium bovis. Complications appeared
now and then, but they did not affect the belief that, on the whole,
microorganisms are stable biological entities possessing distinctive func-
tional attributes.

However, even the most orthodox and conservative among bacteriolo-
gists could not help noticing that the doctrine of bacterial monomorphism
failed to account for a multiplicity of variant forms that constantly appear
under natural conditions, as well as in the laboratory. Even pure cultures-
clones- issued from single cells commonly undergo modifications in some
of their morphological, biochemical, and pathological attributes. Such
modifications appear spontaneously or can be brought about deliberately
by experimental procedures; some persist in subcultures and thus seem to
be hereditary, whereas others are extremely transient. As the phenomenon
of bacterial variability was observed under a great variety of ill-defined
conditions without any understanding of its mechanisms, it gave rise to a
confusing terminology that reflected a confusion of thought in the bacterio-
logical community.

Individual bacteriologists, however, had fairly well-formulated views of
bacterial variability. Some considered it as the outcome of "training" or
"adapting" cultures to new substances or to new animal hosts and, more
generally, to new environmental conditions. Others used names such as
saltation, Dauermodifikation, phase variation, bacterial dissociation, etc.
Still others borrowed the terminology of classical genetics, and referred to
mutations, genotypes, and phenotypes.

In most cases, the diversity and complexity of the changes observed, the
rapidity with which they occurred, and the ease of their reversibility made
it difficult to believe that the classical concepts of genetics sufficed to
explain the variability of bacteria. This skepticism was strengthened by the
fact that nothing was yet known concerning the existence of nuclei, chro-
mosomes, or genes in bacteria. When I wrote The Bacterial Cell" between
1943 and 1945, I could find in the literature only a few sketchy experi-
ments to support the view that, despite obvious differences between
bacteria and other living things, some phenomena of bacterial variability
nevertheless probably fall within the fold of classical genetics; I had to print
an addendum to the book, at the page-proof stage, to describe the evi-
dence published in late 1944 that the cells of several bacterial species do


_..----            -~ __.I___..    I -_Y-----  __------  -rr------     ___-_ -
precisely, a nucleoid body. As was shown later, the cell's DNA is concen-
trated in this body.
It is now clear that, as used in the past, the expression "bacterial
variability" included several kinds of unrelated phenomena; the multitude
of names that were used to describe the different kinds of variations can
probably be classified under two general headings, phenotypic excursions
and genetic mutations. Each of the bacterial species has a wide repertoire
of phenotypic expressions affecting its morphological, physiological, and
pathological characteristics. The conditions under which the species is
grown, and the stage of its development at which it is observed, determine
which aspects of its repertoire are expressed or repressed. In the 193Os, for
example, certain bacterial enzymes were termed "adaptive" because they
were found to be produced in significant amounts only as a specific
response to the presence of the homologous substrate in the culture
medium."-25 Such adaptive enzymes are now called "inducible," and the
mechanism of their induction has been traced to the fact that the proper
substrate acts by neutralizing the product (repressor) of a regulatory gene
that otherwise prevents enzyme synthesis.`"
Just as interesting as the effect of the composition of the medium on
phenotypic expression, but less well known, is that the individual cells of
bacterial cultures undergo profound changes in the course of their growth
cycles. This topic is discussed at some length in The Bacterial Cell under the
name "cytomorphosis" n7; it proved of great importance with regard to the
conditions under which bacterial cells acquire the "competence" to incor-
porate the DNA of another cell and thus undergo transformation.`*
Except for a few special cases, such as enzyme induction. the develop-
ment of competence, and the effect of certain substances and conditions on
cellular characteristics, the field of phenotypic variations in bacteria has
been neglected. In contrast, the transmission of hereditary characteristics
has been studied extensively during the past three decades, and has been
shown to take place through genetic mechanisms analogous to those
operating in other organisms. Unexpectedly, this aspect of bacterial knowl-
edge emerged from the study of the pneumococcus, an organism so
delicate that it would have seemed unsuited a priori for the complex
laboratory operations involved in this kind of study. Also unexpectedly,
the understanding of the chemical processes involved in heredity was
developed initially not by theoretical biologists or even by general bacte-
riologists, but by students of infectious processes. Bacterial genetics, which
led to modern chemical genetics, emerged in large part from the analysis of


132    THE PROFESSOR, THE INSTITUTE, AND DNA

virulence and of colonial variation in pneumococci, first by an epidemiolo-
gist in England and, shortly after, by young physicians working on lobar
pneumonia under Avery's leadership in the Hospital of The Rockefeller
Institute for Medical Research.

     Transformation of Types in Pneumococci

Fred Griffith, a medical officer who worked in the pathology laboratory
of the British Ministry of Health, was the first to describe the S and R
forms of pneumococci. Like Avery, whose contemporary he was, Griffith
was a quiet and retiring bachelor, a recluse, known to few. In the words of
one of his students, he was the most English of Englishmen. He was small
and of slight build, with a long, thin face. He spoke with great precision,
but in a whisper. At an international meeting of microbiologists in 1936,
he presented an important paper on the classification of streptococci by
talking down to his manuscript in such a low voice that nobody heard a
word he said. According to one of his American friends, however, he
became a lively companion and a better conversationalist when vacationing
on the Downs near Brighton. He had there a house that looked so modern
for the time (1936) that it shocked his conservative friends. He would walk

briskly on the Downs, and this ultracautious scientist drove his car along
narrow streets at a speed that frightened his American visitor.2s

Griffith loved bacteriology and epidemiology, but, above all, "He was a
civil servant, and proud of it. He had that kind of a mind and the integrity
that often goes with it. He did not allow his fancy to roam . . . and being
employed by the Ministry of Health to do a specific job, he believed in
fulfilling his contract however frustrating that might be,"30 and however
limited the working conditions put at his disposal. His laboratory facilities
were limited, indeed, but he "could do more with a kerosene tin and a
primus stove than most men could do with a palace."31 Especially, he made
up for limitation of equipment by the ingenuity and meticulous care with
which he conducted his experiments. According to Stuart Elliott, who
worked with him for many years, he was "fanatic about techniques," and
wanted his associates to carry out tests exactly according to his teachings.
His meticulousness "sometimes aroused the exasperation, if not the fury,
of his associates and assistants."

Griffith was so retiring that he could rarely be persuaded to attend
scientific meetings, let alone to present a paper, but he was always willing
to help, at whatever cost of time and trouble. "It did not matter if the
visitor were the veriest tyro humbly seeking an introduction to a particular


                    Bacterial Variability   133

technique, or a senior of repute wishing to discuss some intricacy of public
health bacteriology, all came away impressed" with the compendium of
knowledge and the wealth of practical experience that he used in his own
work and generously made available to others.32

In his scientific life, Griffith followed a single star. He believed that
progress in the epidemiology of infectious diseases could come, and only
come, with better knowledge of the microorganisms involved, and with
better ways of differentiating one strain from another. To this task, he
devoted the thirty years of his professional life, quietly accumulating
observation after observation, with a clear end in view. He wanted to

classification of pathogenic species. In addition to his work with pneumo-
cocci, he introduced a practicable system for typing hemolytic streptococci,
and thus made possible the epidemiological study of infections caused by
these microorganisms. He was killed in 1941 during an air raid over
London, not in a shelter or even indoors, but while "fire-watching." To the
end, he had done the job that he felt his duty to perform as a public
servant.

Griffith's discovery of the S and R forms of pneumococci was made in
1923 .33 He made the further fundamental observation that, when large
numbers of avirulent R cells are injected into mice, it is often possible to
recover from the heart blood of these animals S cells which are fully
virulent, and which possess a capsular polysaccharide with the same immu-
nological type as the S cells from which the R cells were orginally derived.
He concluded from these and other observations that the potentiality for
virulence persists in the nonvirulent cultures, and that the animal body acts
as a selective medium in which only the S forms can multiply. Step by step,
Griffith developed techniques that enabled him to transform at will one
colonial form of pneumococci into another, both in vivo and in vitro. In
particular, he found that the R form can be transformed into the S form in
vitro by adding anti-R immune serum to the culture medium. These
experiments led him to postulate that the S & R variation is a reversible
mutational change.

While he regarded the reversibility from S to R, and vice versa, as a
mechanism by which the organisms adapt themselves to new environmen-
tal conditions either in vitro or in vim, Griffith took it for granted that the
changes remained within the limits of the species. He probably had not
envisaged that one pneumococcus type could be transformed into another,
as this was then regarded as the equivalent of transforming one species into
another-a phenomenon never observed. Yet, such a transformation is


134   THE PROFESSOR, THE INSTITUTE, AND DNA
precisely what he himself observed in 1Y28,"4 thus exploding a bombshell
in the field of pneumococcal immunology.

The experiment by which Griffith demonstrated that pneumococci can
be made to change types deserves to be described in some detail because of
its historical importance and because the discovery of the new phenome-
non is a striking example of serendipity. It also provides an illustration of
the fact that, while progress in science often depends on interesting acci-
dents, these can be recognized and exploited only by investigators en-
dowed with theoretical knowledge and experimental skills. In Pasteur's
words, chance favors only the prepared mind.

One of the empirical techniques used by bacteriologists to establish
experimental infection in laboratory animals is to inject the infective
inoculum along with a mucilaginous substance, such as gastric mucin,
which acts as an adjuvant, or assistant, of virulence. In a particular
experiment, Griffith infected mice subcutaneously with nonvirulent R
pneumococci derived from type I, but instead of using gastric mucin as an
adjuvant, he mixed the inoculum with a thick suspension of S pneumococci
of type II that had been killed by heat. He probably wanted to see if the
killed S cells would facilitate infection by contributing to the system a heat-
resistant "aggressin" - a hypothetical substance assumed by many bacte-
riologists to be responsible for virulence.

Whatever the exact reason that motivated Griffith to use heat-killed
type II pneumococci as adjuvant material, the experiment was successful in
the sense that the mice died of pneumococcal infection. However, the
pneumococci that he recovered from the heart blood of these mice did not
belong to type I, as he had expected, but to type II. Not only had the killed
S pneumococci of type II helped the nonvirulent R cells to become
virulent; in so doing, they had endowed the changed cells with their own

recovered from the infected mice continued to grow as S forms of type II
when cultivated in vitro, even though no further type II material was added
to the culture medium. The change was hereditary.
Griffith was so surprised by his unexpected findings that, according to a
colleague who wrote his obituary notice in The Lancet, "he hesitated
longer than most workers would have done before publishing these obser-
vations. He always took the line, `Almighty God is in no hurry, why should
1 be?' "35 Avery commonly took the same attitude, using almost the same
                   . . .    *.            . .                1 P


I       _---.--V---.---V -- .Y
    Griffith had achieved the hereditary transformation of pneumococcal
    type by "accident," but he would not have recognized the accident or its

implications if he had not been a keen observer and if he had not been
extremely familiar with the behavior of pneumococci, both in vitro and in
vivo. There is evidence, furthermore, that some of his earlier speculations
had prepared him to accept the unexpected result. In the course of
extensive epidemiological studies, which will not be reported here, he had
been much impressed by the fact that, although pneumococcal types differ
immunologically one from the other, there are great similarities among
them. In his own words: "The various races of pneumococci resemble each
other so closely in appearance of colonies and in the characteristic of bile
solubility that there can be no doubt that they belong to one species" (italics
mine).3" He regarded all pneumococci as different breeds of a single
species, which probably made it easier for him to believe that, under the
proper conditions, they can produce one or the other material responsible
for immunological specificity.

   After having established that R cells derived from type I could be
  transformed into S cells of type II, Griffith suggested a Lamarckian
  explanation of the phenomenon. In his words, "the R pneumococcus in its
  ultimate form is the same, no matter from what Type it is derived; it
  possesses both Type I and Type II antigen in a rudimentary form or, as it
/   may be differently expressed, it is able to develop either S form according
    to the material available."37 He went so far as to suggest that the living R
  cells could use the components of the killed S cells "as a pabulum from
   which to build a similar antigen and thus to develop into an S strain of that

of the phenomenon. What happens in reality is that the gene correspond-
ing to type II replaces the gene corresponding to type I in the cells
undergoing transformation; these two genes exclude each other recipro-
cally, as if in competition for the same receptor. However, this mechanism
could not be understood until the material responsible for type transforma-
tion had been isolated and shown to behave as a gene.

Griffith believed that the transformation phenomenon could explain
obscure epidemiological aspects of lobar pneumonia, in particular the
change of types that commonly occur from one outbreak to another:
epidemiological problems were always his primary concern. Although he
did try to reproduce the transformation phenomenon in vitro, he gave up
after a few failures, probably because this did not appear to him to have
crucial relevance to epidemiological problems.


136    THE PROFESSOR, THE INSTITUTE, AND DNA
Griffith's speculations on the epidemiological significance of the inter-
convertibility of pneumococcal types remained virtually unnoticed, and
have been largely forgotten, but his experimental findings had an immedi-
ate, enormous impact on immunologists all over the world. Within a few
months after their publication, they were confirmed at the Robert Koch
Institute in Berlin by Neufeld and Levintha1,3g the same Neufeld who had
first demonstrated the existence of different pneumococcus types 19 years
earlier. Further confirmation came in 1929 from Hobart Reimann,40 who
was then working at the Peking Union Medical College, but was well
known at The Rockefeller Institute, where he had served on the Hospital
staff between 1923 and 1926.
Needless to say, Griffith's experiments were also widely discussed in
Avery's department, but we did not even try to repeat them at first, as if we
had been stunned and almost paralyzed intellectually by the shocking
nature of the findings. Avery, in particular, found it impossible to believe
that pneumococci could be made to change their immunological specificity.
This reluctance was only natural on the part of a person who had devoted
so much time, skill, and critical judgment to the doctrine of the fixity of
immunological types. Furthermore, he was not the only one to be skepti-
cal. Even in England, the Griffith phenomenon was not widely accepted;
the 1933 edition of the immensely influential textbook on bacteriology and
immunity by Topley and Wilson made only a hesitant mention of it in a
short paragraph.
There were technical reasons for this skepticism. Griffith's method
involved the subcutaneous injection into mice, along with the living R
cells, of huge amounts of virulent pneumococci that had been heated at
60oC. Even though control tests seemed to prove that this temperature was
high enough to kill all the virulent cells, Avery wondered whether a few
might not have recovered their viability in the animal environment. These
doubts were made more plausible because, in Griffith's own experiments,
suspensions of S cells lost their ability to induce transformation when the
temperature used to kill them was raised from 60oC to 80oC.
Although Avery had never met Griffith, or even corresponded with
him, he greatly admired the latter's earlier scientific contributions, which
were in fundamental agreement with his own views of pneumococcal
biology. For example, Griffith's discovery that the colonies of virulent
pneumococci are "smooth ," whereas those of the nonvirulent forms are
"rough," fitted well into Avery's scheme of virulence; colonial smoothness
could be explained by the existence of a polysaccharide capsule around the
cell. The change from R to S, described earlier by Griffith, was also


compatible with the concc
study, reversion had resulted in the production of a culture immunologi-
cally identical with that of the S type from which the R form had origi-
nated.
The reversion of R to S of the same original type was indeed of such
interest to Avery that, in 1926, he had encouraged M. H. Dawson, a
young Canadian physician who had just joined his department, to investi-
gate the conditions most favorable for the occurrence of the phenomenon.
Dawson first approached the problem by trying to determine whether all
the cells of a given R culture were capable of reverting to the S form. To
this end, he first prepared cultures derived from single R cells in order to
work with what he called "pure line strains"; he then subcultured these
clones in several different culture media. His results led him to conclude
that "the great majority if not all of avirulent R cells have the ability, under
the proper conditions, to revert to virulent, type specific capsulated orga-
nisms."41 The phrase "proper conditions" meant that reversion was greatly
facilitated by the presence in the culture medium of growth-promoting
factors and of serum-containing antibodies to pneumococcus proteins.
Dawson's results, which confirmed and extended those of Griffith, thus
provided further evidence for the fundamental fixity of the specific types,
as they demonstrated that the attribute responsible for immunological
specificity and for type-specific virulence persisted in the R forms even
when it was not expressed.
The transformation problem was eventually taken up in Avery's labora-
tory by Dawson on his own initiative, simply because he believed almost a
priori that work done in the British Ministry of Health had to be right, and
that therefore Griffith's conclusions were valid. At first, he simply re-
peated Griffith's experiments, satisfying himself that pneumococci heated
at 60" and 70" could not multiply in mice, yet were capable of bringing
about type transformation in viuo. This initial part of his experimental
work was completed in late 1929 and published in 1930.42
Dawson then tried to carry out the transformation of types in vitro. In
collaboration with R. H. P. Sia, he cultivated R pneumococci in rich
culture media that contained antipneumococcus serum and heat-killed S
pneumococi. After several passages in such media, transformation oc-
curred in vitro.43 The success of this new experiment was due in large part
to the experience Dawson had gained in 1926 while repeating Griffith's
initial reversion experiments and studying the conditions under which R
organisms revert in vitro to S organisms of the original type.
In 1930, Dawson moved to the College of Physicians and Surgeons in


I         New York, where the pressure of clinical duties prevented him from
        continuing work on transformation. Avery, however, was now convinced
        that pneumococci could indeed be made to undergo transmissible changes
        in immunological specificity, and he encouraged J L. Alloway, the young
        physician who had taken Dawson's place, to pursue the study of the
        phenomenon in vitro. Alloway soon demonstrated that transformation can
        be brought about, not only with whole, killed S cells, but also with a
        soluble fraction prepared from S pneumococci by "dissolving" the living
        cells in sodium deoxycholate, then passing the material through Berkefeld
I
        filters to remove cellular fragments. Furthermore, he found that the active
        material could be precipitated with alcohol, and thus obtained as "a thick
        syrupy precipitate" that was fairly stable.44
         Alloway was an extremely shy person, little given to talk or to emotional
        expression, but he could not refrain from displaying his excitement when
        he noticed the extreme viscosity of active preparations containing the
        material that was then referred to in the laboratory as the "transforming
        principle." Alloway was thus the first person to handle the active, fibrous
         substance that was to be identified as DNA 10 years later. It should be
        mentioned in passing that, although Alloway's procedure is of great histor-
        ical importance because it yielded the first soluble preparations of the
        transforming substance, it is extremely unreliable, because the prepara-


CHAPTER ELEVEN

HEREDITY AND DNA

The Transforming Substance and DNA

After Alloway's departure in 1932, Avery began to devote some of his
own time to experiments on transformation, even though he was then
actively involved in several other immunological studies. His initial goal
was to improve the techniques for the preparation of the transforming
substance and for the quantitative assay of its activity, but the work was full
of frustrations. The irreproducibility of the transformation experiments
during the 1930s was often punctuated with his remark, "Disappointment
is my daily bread; but I thrive on it." When recalling this difficult period
later, he was wont to say, "Many are the times we were ready to throw the
whole thing out of the window." However, he did not give up. because he
was served once more by his gentle stubbornness in the face of a problem
of which he sensed the broad significance.

As on earlier occasions, he decided that the first essential task was to
isolate the active material and determine its chemical nature. This does not
mean that he shunned discussions concerning the mechanism of the trans-
formation phenomenon or its bearing on other biological problems. The
late Dr. James Murphy, for example, discussed with him some similarities
between the transforming principle of pneumococci and the filterable
agent that causes chicken sarcoma, referring to both of them as examples
of "plasmagens." The relevance of type transformation to changes of a
genetic nature, or to alterations caused by viruses, was frequently dis-
cussed in the laboratory. An echo of these discussions can be heard in the
letter that Avery wrote his brother Roy early in 1943, at a time when much
evidence was at hand that the transforming substance was a deoxyribonu-
cleic acid (Appendix I). After describing in his letter what was then known
of the material, he added playfully, "Sounds like a virus-maybe a gene.
But with mechanisms I am not now concerned. One step at a time and the
first step is what is the chemical nature of the transforming principle." He
was excited by the fact that "the problem bristles with implications," but,
with his usual discipline, he did not let speculations deter him from
establishing the chemical identity of the active material.

Dawson had postulated that transformation was brought about by the


capsular polysaccharide itself, acting as a template for its own replication.
Later, Alloway suggested that the active material was a protein-polysac-
charide complex that existed in the intact cell in the form of the complete
capsular antigen. Avery considered all these possibilities, but some of his
statements in the annual reports indicate that, as early as 1935, he had
obtained the transforming material in a form essentially free of capsular
polysaccharide and protein. Quoting from his own personal notes of 1936,
Hotchkiss writes: "Avery outlined to me that the transformin;

nucleic acid at that stage of the work probably did not have much signifi-
cance. Some of us were then working with a ribonucleic-acid component of

     ,ccal cell, and had found that it was attacked by the ribonu-
clease present in animal tissues .* It is therefore probable that Avery
mentioned nucleic acid in passing, among many other possibilities that he
had in mind. In any case, his fundamental strategy was to obtain the active
material in a pure form, before attempting to determine its chemical
nature.

Progress toward this goal was very slow for several years because of
    stations that will be discussed later and, in particular, because

of two technical difficulties. Alloway's method for producing the trans-
forming substance gave such erratic results that many preparations were
essentially inactive. Furthermore, the assay method for determining activ-
ity was also undependable, and almost useless for evaluating quantitatively
the concentration and purification procedures. These difficulties were
resolved in the late 1930s and early 1940s when new methods were
developed, especially through the work of Colin MacLeod, who had joined
the department in 1935.

Techniques were developed for the production and centrifugation of
very large volumes of pneumococcus cultures from which sizable amounts
of transforming substance could be prepared. Instead of obtaining the
material by dissolving the living pneumococci in deoxycholate, as Alloway
had done, MacLeod first killed the organisms by heat and only then treated
them with sodium deoxycholate. This procedure had the advantage of
avoiding inactivation of the transforming substance by the p
enzymes, and thus gave more active and more stable preparations.

The discovery that the various R strains differ in the readiness with
which they undergo transformation led to the selection of o
strain which was particularly efficient in this regard, and which was used
consistently from then on as a test organism in all the measurements of
transforming activity. By several such technical improven        _ .


Heredity and DNA    141

`------J---b  -__-                           ",
ceeded in working out a dependable assay dilution technique that permit-
ted an approach to a quantitative evaluation of the various procedures used
for concentrating and purifying the transforming substance.
These technical advances were not published at the time, nor were the
initial discoveries to which they led concerning the properties of the
transforming material. Yet, progress was extremely rapid, as can be seen
from the facts described under the somewhat misleading title, "Studies on
capsular synthesis by pneumococci ," in the annual report to the Board of
Scientific Directors for the  vear 1940-l 941 -3 The  rennrt         the

preparation of the transforming substance by extracting heat-killed pneu-
mococci with deoxycholate, precipitating the active material with alcohol,
redissolving it in slightly alkaline salt solution, and shaking it with chloro-
form to remove proteins and other impurities. Preparations thus obtained
appeared to be essentially "protein-free and lipid-free," yet they retained
most of the original transforming activity.

The report stated also that "the transforming activity of purified extracts
[is] resistant to the action of the crystalline proteolytic enzymes trypsin and
chymotrypsin," as well as to the action of "a purified phosphatase pre-
pared from swine kidney." Although the original extracts contained "con-
siderable amounts of nucleic acid," this substance could be "almost com-
pletely removed by digestion with crystalline ribonuclease without affect-
ing the transforming potency." There was no mention of deoxyribonucleic
acid in the 1940-1941 report, but some of the observations prepared the
ground for the later definition of this substance. MacLeod noticed that
sodium fluoride protected the transforming material against the inactivat-
ing effect of pneumococcal enzymes, a fact he considered of interest
because fluoride "is known to inhibit the action of esterases." Because
animal serum and tissues rich in esterases also destroyed the transforming
activity, there was some reason to believe "that the transforming principle
may be an esterified compound"-a hypothesis formulated in the report
for 1940-1941.

In the summer of 1941, MacLeod left The' Rockefeller Institute to
become Professor of Bacteriology at the New York University School of
Medicine. He was replaced by Maclyn McCarty, a young pediatrician with
extensive biochemical training. In some ways, McCarty's role in the identi-
fication of the transforming substance can be compared to that played by
Michael Heidelberger 20 years before in the demonstration that the spe-
cific soluble substances of the pneumococcal capsules are complex polysac-
charides.

Now that dependable methods had become available for the production


i'
I

142   THE PROFESSOR, THE INSTITUTE, AND DNA
of the transforming substance in a stable form and for its quantitative
assay, McCarty could apply his chemical skills to the identification of the
active material, under the guidance of Avery, with the help of MacLeod,
who frequently returned to the Rockefeller laboratory, and with the
encouragement of the Hospital director, Dr. Thomas Rivers. The outcome
was that, within an incredibly short time, the transforming activity was
shown to reside in a highly viscous fraction that consisted almost exclu-
sively of polymerized deoxyribonucleic acid (DNA).

Surprising as it may seem, the Avery group never published a complete,
detailed account of the steps that led them to this remarkable and unex-
pected conclusion. The facts are available in the laboratory records, but
the pace of experimentation was so rapid during the last phase of the work

that, according to Maclyn McCarty, who was then responsible for most of
it, he himself now has difficulty in restructuring from his notes the intellec-
tual processes that ended with the identification of the transforming sub-
stance as deoxyribonucleic acid. Since only he could tell the story, and
should soon do it, I shall limit myself to the briefest summary of the
different lines of evidence that began to accumulate after he started work-
ing with Avery.

One of McCarty's first experiments was to study the sedimentation of
the active material in the high-speed analytical centrifuge, in collaboration
with Alexandre Rothen. The results suggested that the molecular weight of
the transforming substance is approximately 0.5 1 million.
All qualitative chemical tests on the sedimented material were essen-
tially negative, except for those which suggested deoxyribonucleic acid.
The results of quantitative elementary analysis, in particular the phospho-
rus-nitrogen ratio, also corresponded to deoxyribonucleic acid.
These findings were compatible with the results of earlier enzymatic
studies and of new ones carried out by McCarty. Whereas, as has been
mentioned, the activity was left unimpaired by treatment with a great
variety of enzymes, including ribonuclease, the material was rapidly inacti-

vated by all enzyme preparations capable of attacking authentic samples of
deoxyribonucleic acids. As Avery was to write his brother Roy a few
months later, the substance conformed "very closely to the theoretical
values of pure desoxyribose nucleic acid (thymus type).* Who could have
guessed it? This type of nucleic acid has not to my knowledge been
recognized in pneumococcus before." Indeed, who could have guessed it?

* Desoxy- became deoxy- in the late 1950s or early 1960s. The decision to drop the s was
made by an international nomenclature committee.


                     Heredity and DNA   143

In early 1943, Avery, MacLeod, and McCarty presented all their
findings to Drs. Jack Northrop and Wendell Stanley at the Princeton
section of the Institute, but these experienced and famous chemists had no
suggestions for further lines of evidence. Avery, however, still felt uncer-
tain. When MacLeod asked him on the train ride back from Princeton.
"Fess, what more do you want?" he could only shake his head; he wished
for tests with a more purified preparation of deoxyribonuclease; this was to
be satisfied by McCarty three years later. (Subsequently, Moses Kunitz of
the Princeton group achieved the crystallization of this enzyme.)
The classic paper by Avery, MacLeod, and McCarty describing their
extraordinary findings was submitted to the Journal of Experimental Medi-
cine in November, 1943, and published in 1944.' However, all the basic
experimental information had been accumulated much earlier, as shown by
the mass of detailed evidence in the annual report submitted to the Board
of Scientific Directors in early April, 1943.
It would be out of place to describe here the experiments that led to the
identification of transforming activity with a DNA preparation, but it
seems worthwhile to emphasize that the authors of the discovery owed
much of their success to their skill in using a great diversity of techniques,
ranging from the most physical to the most biological. The following
outline of the preparative procedures described in the 1944 paper gives an
idea of their technical ingenuity and boldness.
The pneumococci (type III) were grown in batches of 50 to 75 liters and
separated by centrifugation in a steam-driven Sharples centrifuge. The
cells were heated at 65oC to destroy the pneumococcal enzyme that was
known to inactivate the transforming material. (In a later phase of the
work, McCarty found that this enzyme requires magnesium and therefore
is ineffective in the presence of citrate, which binds this metal. Addition of
citrate to the medium thus resulted in much larger yields of the transform-
ing substance.) The heated cells were washed repeatedly with salt solution,
which removed large amounts of proteins, polysaccharides, and ribonu-
cleic acid. The washed cells were then shaken with 0.5 percent deoxycho-
late, which extracted the active material. This material was separated from
the deoxycholate solution by precipitation with alcohol. It was dissolved in
salt solution and shaken with chloroform to remove most of the remaining
proteins. Concentrated solutions of the active material were then treated
with a series of enzymes capable of hydrolyzing proteins, ribonucleic acid,
and the type III capsular polysaccharide; then they were once more shaken
with chloroform to remove the last traces of proteins.
The final step was the repeated precipitation of the extract by the


144   THE PROFESSOR, THE INSTITUTE, AND DNA
dropwise addition of one volume of absolute ethyl alcohol, with constant

.,L I..... 6' 1 L.                                               ..-----,
extremely fine "fibrous strands that wind themselves around the stirring
rod." All those who have witnessed this delicate operation remember the
excitement at the sight of the beautiful fibers, which were the purified
forms of the viscous material that Alloway had first perceived 10 years
before.

The fibrous character was due to the fact that the preparation consisted
of highly polymerized deoxyribonucleic acid - DNA! Its biological activity
was so great that it was capable of bringing about the transformation of R
pneumococci into encapsulated type III pneumococci, even when used in a
final dilution of less than 1 in 100,000,000 in the reacting system. The R
pneumococci that had been transformed into type III pneumococci re-
tained this newly acquired immunological specificity from generation to
generation, even though no further transforming material was added to the
culture medium. The transformation induced was therefore hereditary.

The statement that DNA was responsible for transforming activity had
staggering implications. The effect observed was type-specific, so it fol-
lowed that each type of pneumococcus had to have its own nucleic acid

acting as a genetic bearer of immunological specificity; but this conclusion
was incompatible with what was then taught concerning the chemical struc-
ture of deoxyribonucleic acid. P. A. Levene, the organic chemist of The
Rockefeller Institute, was considered the world expert on the structure of
this substance. He regarded DNA as a simple arrangement of nucleotides,
and could not see how specific biological activity could reside in such a
repetitious assemblage of phosphate, sugars, and nitrogen bases. He there-
fore concluded, as did many other chemists and biologists, that the speci-
ficity of the preparations was due to some contaminating substance.

announcement by him and Heidelberger, exactly 20 years earlier, that
polysaccharides, and not proteins, were responsible for the immunological
specificity of pneumococcal types. And he anticipated that even greater
skepticism would now greet the claim of genetic specificity for deoxyribo-
nucleic acid. For this reason, the manuscript of the paper reporting the
claim was sent for publication only after it had been submitted for many
months to the critical review and adverse criticism of associates and
friends. Furthermore, the conclusions were presented with several caution-
ary statements. The authors recognized that it was "of course" possible
that "the biological activity of the substance described is not an inherent
property of the nucleic acid, but is due to minute amounts of some other


                     Heredity and DNA    145

substance adsorbed to it or so intimately associated with it as to escape
detection."5 This was a way of acknowledging the possibility that traces of
some very active protein might account for transformation.
The mood of excitement tempered with caution that existed in 1943 in
Avery's laboratory, and especially in his own mind, is well conveyed in his
letter to his brother. Avery was then 65 years old and, having reached
retirement age, had planned to join his brother's family in Nashville.
However, the eagerness to complete his investigations on the transforming
substance made him change his mind and stay in New York for a while
longer. Although Avery ends his letter by characteristically apologizing for
its lack of clarity and referring to it as "a rambling epistle," the document
is, in fact, of considerable importance, because it was obviously composed
with great care and presents many examples of the Professor's mannerisms
(Appendix I). Here I shall mention only his emphasis on the need to
document further the validity of the experimental findings, and his aware-
ness of their large biological implications.
He emphasized that the thymus type of nucleic acids "were known to
constitute the major part of the chromosomes but have been thought to be
alike regardless of origin and species" (italics mine). This made it difficult
to imagine how nucleic acids "protein-free could possibly be endowed with
such biologically active and specific properties and this evidence we are
now trying to get" (italics mine). After having described the work in detail,
he asked Roy not to "shout it around" because "It's hazardous to go off
half-cocked-and embarrassing to retract later. . . . It's lots of fun to blow
bubbles-but it's wiser to prick them yourself before someone else tries
to." (That he should be the one to prick his own bubble had long been an
obsession with Avery.) In any case, the criticisms leveled against the claim
that DNA was the transforming agent appeared to him sufficiently valid to
warrant further studies.
Alfred E. Mirsky, who was working on biochemical genetics at The
Rockefeller Institute, had pointed out that the evidence from enzymatic
studies was not as convincing as was suggested in the 1944 paper.6 Among
his objections were that certain proteins are resistant to the proteolytic
enzymes used by Avery and his colleagues, and that other proteins resist
enzymatic action until they have been denatured. The illustrious geneticist
H. J. Muller was so impressed by Mirsky's arguments that he wrote to the
English geneticist C. D. Darlington in 1946: "Avery's so-called nucleic
acid is probably nucleoprotein after all, with the protein too tightly bound
to be detected by ordinary method . . free chromosomes."'
Avery was, of course, aware of the criticisms leveled against the DNA


146    THE PROFESSOR, THE INSTITUTE, AND DNA

theory, even though they were rarely expressed in public. That he resented
them is indicated by the following statement in his 1946-7 annual report to
the Board of Scientific Directors: "From the beginning we ourselves have
been keenly alert to the possibility that the presence of some substance
other than the desoxyribonucleate in our preparations may be responsible
for the biological activity ."(( Even when, a few years later, Hotchkiss
reported that the protein content of the most active preparations was
below 0.02 percent, it remained possible, by interpreting this figure in the

was focused on the accumulation of additional evidence for the role of

Lest the phrase "his department" conjure a large and highly organized
team of investigators, a few words should be said here concerning Avery's
group during his last five years in New York. In addition to himself, the
"team" consisted at any given time of only one or two scientifically trained
persons, plus two technicians. As in the past, the unity of purpose in the
laboratory emerged from casual conversations, rather than from formal
organization.

McCarty was the only official member of the staff from 1943 to 1945;
Harriett Taylor joined him in 1945, immediately after receiving her docto-
rate in genetics from Columbia University. McCarty left in 1946 to take
charge of the rheumatic fever division in the Hospital, and elected not to
continue working on the transformation problem because of the demand-
ing nature of his clinical studies. Rollin Hotchkiss, who had long been
interested in the transformation phenomenon, joined forces with Avery.
He carried on after Avery left New York in 1948, whereas Harriett Taylor
continued her work in France, where she moved in 1948 (she married the
geneticist Boris Ephrussi). MacLeod, in his new professorial appointment
at New York University, developed special biological aspects of trans-
formation, enlisting as coworkers M. R. Krauss and R. Austrian. The
contributions of this very small disseminated "group" confirmed the spe-
cific biological activity of DNA and enlarged the significance of the trans-
formation phenomenon.

Briefly, the technique for assaying DNA activity was made simpler, and
more reproducible, by two unrelated discoveries. It was found that serum
albumin is required for transformation, and that the "competence" of R
pneumococci to undergo transformation depends not only on the strain
used in the test, but also on the phase of the growth cycle during which the
organisms are exposed to the transforming material.


                              /
Heredity and DNA    147

Tests with the purest preparations of crystalline deoxyribonuclease,
obtained from the pancreas, showed that transforming preparations are
inactivated by this enzyme, as it depolymerizes the nucleic acid, thus
clinching the evidence for the essential role of the latter substance in
transformation. Furthermore, a long series of elaborate chemical studies
proved that proteins are not involved in the phenomenon.

Comparative analyses of DNA showed that the preparations derived
from pneumococcus differ chemically from the classical thymus nucleic
acid in having more thymine, less adenine, less cytosine, and a lower

once thought, these findings made it more plausible that DNA can exhibit

biological specificity.

Transformation was extended to characteristics other than the capsular
polysaccharide, for example to somatic components of the pneumococcus,
to its fermentative activities, and to its resistance to various antibacterial
agents. The latter properties lent themselves to the first truly quantitative
assays measuring the numbers of cells actually transformed under varied
conditions.
Genetic analvsis of these nhenomena indicated that transformation

which the material pairs with the homologous region of the recipient
           -    . . . .     .        ..^r

I have listed chronologically, in references 9 to 42, 33 articles ranging
from 1945 to 1960, by the four scientists- Colin MacLeod, Maclyn Mc-
Carty, Harriett (Ephrussi-) Taylor, and Rollin D. Hotchkiss-who were at
one time or another directly associated with Avery in the transformation
problem.

It is impossible to state precisely when the evidence became sufficient to
convince the scientific public that DNA is involved in specific hereditary
transformations. In fact, there was no way to obtain absolute proof by
chemical techniques. Contamination of the most purified preparations by
minute amounts of very active protein or other substance could not be
ruled out entirely. Even the destruction of transforming activity by crystal-
line deoxyribonuclease was not foolproof evidence; despite its crystalline
state, the nuclease might still have been contaminated with some other
enzyme, as had been found for crystalline trypsin that turned out to
contain some ribonuclease; in any case, the deoxyribonuclease might have
acted on some hypothetical nucleoprotein involved in the transformation
phenomenon.


148    THE PROFESSOR,  THE INSTITUTE, AND DNA

It took an experiment, outside of the Institute, with a biological system

completely different from that used by Avery to win universal acceptance
for the genetic role of DNA. Using coliphage marked with 32P (restricted
to the DNA component of the virus) and with 35S (restricted to the protein
component), Hershey and Chase at the Cold Spring Harbor Laboratory
showed in 1952 that most of the viral DNA penetrates the infected
bacterium, whereas most of the protein remains outside. This finding
suggested that DNA, and not protein, was responsible for the directed
specific synthesis of bacteriophage in infected bacteria. In reality, the
interpretation of this wonderful experiment was just as questionable on
technical grounds as was the chemical interpretation of pneumococcal
transformation, but its results were so completely in agreement with those
obtained by Avery 10 years before, that the few remaining skeptics were
convinced. The case for the view that DNA is the essential and sufficient
substance capable of inducing genetic transformations in bacteria was not
won by a single absolute demonstration, but by two independent lines of
evidence.

Granting the importance and elegance of the Hershey-Chase experi-
ment, the genetic role of DNA had become widely accepted before its
results became known. In 1948, the year Avery left the Institute, an
international congress was held in Paris, during which the problems of type
transformation were presented by Rollin Hotchkiss and Harriett Taylor.
At the end of the conference, Andre Lwoff of the Pasteur Institute

for the specificity of nucleic acids. Once the transforming principle of
pneumococcus is introduced into a bacterium it confers on it perma-
nently a given specificity. But this principle is susceptible of modifica-
tion and even at the present time we know of two varieties of specific
nucleic acid of type III pneumococcus. They have been compared to
allelomorphic genes.43

Thus, DNA had been incorporated into orthodox genetic theory five
years before the Watson-Crick announcement of the DNA double-helical
structure in 1953 started the deluge of work concerning the central role of
DNA in genetic determinism.

During the 1940s and early 195Os, several lines of investigation that
were seemingly unrelated to the transformation problem provided further
indirect evidence for the role of DNA in the transmission of hereditary


                      Heredity and DNA   149

Rockefeller Institute, it seems best to present them in an appendix, along
with a few remarks concerning the large biological implications of Avery's
original work on DNA (Appendix VI). As already mentioned, however,
these implications were apparent to Avery and his colleagues long before
the role of DNA in the transformation of pneumococcus types had been
accepted as a landmark of biological history. Avery's very last annual.
report to the Board of Scientific Directors was still conservatively entitled
"Studies on transformation of pneumococci," and in it he affirmed once
more that the objective of his work was to achieve a better definition of the
chemical and biological factors involved in the phenomenon. However,
this expressed only one aspect of his personality: his puritanical discipline
as an investigator. Several years earlier, he had revealed another aspect
when he had boldly and proudly announced to his brother and a few
intimates that he and his colleagues had achieved, for the first time, a

way's second paper in 1933 and the classic paper by Avery, MacLeod,
and McCarty in f 944. This long period of silence has been interpreted by
several authors as due to a failure by Avery to appreciate the full biological
significance of the phenomenon, an interpretation seemingly justified by
the fact that the 1944 paper includes only the barest mention of genes or
viruses. Avery never made any public statement about the large biological
implications of his findings, so it was assumed that, like Griffith, he was
more interested in the immunological aspects of the transformation phe-
nomenon than in its genetic aspects. Having been a member of Avery's
department until July, 1941, and having remained in very close contact
with him until he left New York, I know that this interpretation of his
public silence is erroneous. From the time of Griffith's publication in 1928,
the transformation phenomenon remained a constant topic of conversation
in the laboratory. As to its significance for genetic theorv and for viral

deficiencies in our collective knowledge of these fields and Avery's intel-
lectual discipline, which kept unbridled intellectual free-wheeling under
control.

I shall now present, on the basis of personal memories, the reasons for
the apparent lack of progress during the decade between 1933 and 1943,
and for the paucity of public statements regarding the great significance of
the experimental findings.

During the 193Os, all members of the department were engaged in a


150   THE PROFESSOR, THE INSTITUTE, AND DNA

large variety of investigations. most of which were extremely productive.
Avery's own name appears on 25 papers between 1929 and 1941, and his
actual participation in the laboratory work was considerable in all cases,
although he was suffering from Graves' disease during the earlier part of
that period. I can mention only briefly some of the fields of study that
yielded results of theoretical and practical importance during that period:
the chemical characterization of capsular polysaccharides; the synthesis
and immunological study of artificial antigens; the autolytic processes in
pneumococcus cultures and their bearing on the production of therapeutic
sera; the recognition of the so-called C-reactive protein in the serum of
patients during the acute phase of infection; the skin reactivity of animals
and human beings to various components of the pneumococcus cell; the
production and activities of a bacterial enzyme capable of hydrolyzing the
type III capsular polysaccharide; the production and activities of the
antibiotics gramicidin and tyrocidine (Appendix IV and Chronology II).
To this list must be added the studies on streptococci that were carried out
in the rheumatic fever department at the other end of the floor and in
which Avery, as well as the rest of us, took a lively interest.

All the different projects in Avery's department were conducted in
three small general laboratories and one chemical laboratory. All investi-
gators participated in most of the experiments and in the interpretation of
the results, regardless of their professional specialization and individual
interests. As I try to evoke this period, I wonder how we could have found
time to keep informed about the affairs of the outside world. But we did,
especially when they had a bearing on our own scientific interests, as was
obviously the case for Griffith's 1928 paper.

It could be argued that the slow pace of the work on transformation
during the mid-1930s cannot be justified by the diversity of research
projects, and that it suggests instead a failure to appreciate fully the
importance of the phenomenon. In the words of one of my colleagues,
"Generally when something as important as this is found, there is a
concentration of effort to the exclusion of other avenues of research." The
difficulty with this argument is that opinions concerning the importance of
a problem depend upon the point of view from which that problem is
considered.

Avery's department was in the Hospital; its staff was responsible for the
care of respiratory diseases; its goal was the development of therapeutic
sera and other procedures that offered hope for the control of lobar
pneumonia. Much of the early work on transformation was carried out
before the days of chemotherapy. Mortality rates were extremely high


_ Y .  . 1                                                ---- ---..
made toward the development of techniques for the production of sera
effective against the other types. Under these conditions, I doubt that it
would have been possible for anyone working in a hospital in direct contact
with patients to concentrate all effort on transformation. and neglect the
departmental commitment to the control of lobar pneumonia. What I find
remarkable is that the problem was often given priority over the other
urgent tasks.

(It is interesting to note in passing that the first important elaboration of
the Avery findings on the genetic role of DNA was also due to a physician
actively engaged in clinical work. Dr. Hattie Alexander was a pediatrician
at the Babies Hospital of P&S when she demonstrated that strains of

topic were published between 1930 and 1933. Then the work slowed down
because of technical difficulties. Even though transformation could be
achieved in vitro with a cell-free material, the results were erratic. As has
been pointed out, the methods developed by Dawson and Alloway were
inadequate on two different grounds: the transforming material was unsta-
ble and the R strain used for the assay technique often lacked "compe-
tence" to undergo transformation. The countless experiments performed
beween 1934 and 1940 to extend Alloway's findings did not lead at first to
a systematic program, simply because the results were not reproducible.

In the late 193Os, the use of sulfapyridine and related drugs made it
much easier to treat lobar pneumonia. This decreased the pressure for the
development of therapeutic sera. Furthermore, World War II compelled
the abandonment of certain research projects. As a consequence. it was
easier for Avery and for MacLeod, who did not serve in the Armed Forces,

then on, Avery and MacLeod, then McCarty after 1941, devoted much of
their time to work on transformation, with the result that it took less than
two years to isolate and characterize the active material.

In their 1944 paper, Avery, MacLeod, and McCarty expressed them-
selves in a very muted manner concerning the relevance of their work to


               ..-. y Y..U.-      . . . . y.`s"""""
texts avidly." Avery's reticence was an expression of his intellectual self-
discipline, which applied not only to modern genetics, but to much simpler
biological problems, and was reflected in his scientific language. A few
examples taken from daily conversations in the laboratory may help to
establish the depth of his scientific puritanism.   I

that reason, he seldom, if ever, used the names Diplococcus pneumoniae,
Klebsiella pneumoniae, Mycobacterium tuberculosis; pneumococci,
Friedlander bacilli, and tubercle bacilli were good enough for him. For
similar reasons, he did not use the classical jargon of genetics when
discussing hereditary processes in bacteria. He spoke of transmissible
properties, of bacterial dissociation from S to R, of reversion from the R
form to the encapsulated form. It was certainly because the classical
concepts of genetics had not yet been proved to be applicable to bacteria
that, as late as 1948, he continued to use phrases such as "transformation
of types" or "intraconvertibility of types" when referring to the phenome-
non discovered by Griffith. As to the material responsible for the transfor-
mation of types, he was aware of its likely relation to a gene, but he felt
more comfortable referring to it in cautious terms-first as the transform-
ing principle, then as the transforming substance, and later as desoxyribo-
nucleic acid, or DNA. In any case, he preferred the concrete meaning

genetics. From 1930 to 1948, "he collected, read, and commented on,
with great interest and some amusement, the conjectures of many leading
geneticists and biologists about transformation ." In 1954, he turned these
notes over to Hotchkiss44; they record, naturally, the reactions to
Griffith's and his own paper, with suggestions by several geneticists that
DNA was a chromosomal fragment acting a genetic role. He obviously had
all these facts in mind when he stated in his letter to Roy, "By means of a
known chemical substance it is possible to induce predictable and heredi-
rary changes in cells. This is something that has long been the dream of
geneticists. The mutation they induce by x-ray and ultra-violet are always
unpredictable, random, and chance changes." But while he enjoyed such
speculations, he considered it indecent to make them public if they went
far beyond established facts. In the absence of really convincing evidence,


I    it seemed to him merely clever, vainglorious, and indeed irresponsible to
   extrapolate from limited laboratory findings, however well documented, to
   sweeping statements that created false illusions in an impressionable pub-

1    lit.

E     In his own subdued and smiling way, he showed signs of irritation when

took at my French quotation of the Arab saying "Les chiens aboyent. la
caravane passe" (The dogs bark, the caravan moves on), because it
conveyed so well his deep feelings about the contrast between talkers and
doers. But it is only since reading his annual report to the Board of
Scientific Directors for 1946-1947 that I have come to realize the intensity
of his irritation. There he clearly expressed in print, for the first and last
time, his annoyance at those who assumed that he was not fully aware of

I     factors involved in the reaction. This is not to say that we are indifferent

I     the relation of the problem to other similar phenomena in related fields

He had enjoyed, as much as anyone, indulging in speculation and
discussions concerning the relevance of his experimental work to other
fields of biology, but only with associates and close friends- "among
ourselves ." Hotchkiss, who was his last collaborator, discussed the process
of scientific discovery in words that would have been very congenial to The
Professor. According to Hotchkiss, the first stage in making a discovery is
one in which "faint evidence and speculation are encouraged," shared with
associates and friends but "not the public"; in the second stage, the
investigator should be overcritical, and communicate his findings in a way
that will inform, but "not misinform or overinform . . . the people not
fully able to evaluate the conclusions."46
Of course, the price of such thoroughness is some loss in the spectacular
value of "discovery," and this was precisely the price Avery had to pay.
His intellectual puritanism won him the admiration of those who were in
. .            . . . .   .             . . .         . .   P..       . .


When Avery finally decided to retire in 1948, it had become clear that
the method developed to isolate the DNA resonsible for the transforma-
tion of capsular polysaccharides could also be used to isolate other prepa-
rations of DNA capable of inducing other types of transformation. More-
over, great progress had been made toward defining the chemical and
genetic aspects of the transformation phenomenon. In brief, the pneumo-
coccus cell had been shown to contain a multiplicity of different forms of
deoxyribonucleic acids, each endowed with a distinct biological specificity
and located on chromosomes with functions similar to those of the classical
chromosomes in the cells of higher organisms. It had become justified to
equate the expression DNA with the word gene, both being abstract
statements of the various chemical structures and genetic functions respon-
sible for the specific distinctness of hereditary characters and for their
transmission. Within less than 10 years after the type transformation of
pneumococci by DNA had first been established-and regarded by many
as a biological freak-the phenomenon had been incorporated into ortho-
dox genetic doctrine. Furthermore, the discovery that DNA is the bearer

minism, and thus created the new science of chemical genetics.
Most of the findings summarized in the preceding pages were published
after Avery's retirement; his name does not appear as co-author of the
publications in which they are described. However, much of the informa-
tion is either reported or suggested in the annual reports that he continued
to submit to the Board of Scientific Directors until 1948. The last phases of
the experimental work carried out in his laboratory involved techniques
that he did not have time to master, but the over-all program reflects his
influence on the goals and general design of the experiments. In fact, he
remained an actual participant in the laboratory work until he left the
Institute, as reported by Rollin Hotchkiss:

In his last two years at The Rockefeller Institute, Dr. Avery began his
self-disciplined withdrawal from participation. At first he would disap-
pear only when we (by that time only Harriett Ephrussi-Taylor and the
writer) were planning experiments. I believe that he was determined not
to be observed in any of the stages of ageing when he might be losing
some of his mental faculties, as he had seen others do. This precaution
was unjustifed, for his remarkable acuity and ability to focus never
diminished. But the delight of performing experiments and observing
the results he could not forego, and he would appear at the moment we
commenced the work, asking "What are we doing today?" and start to
help. We still enjoyed his influence at the time of discussing and inter-
preting the outcome. But this participation too he began to surrender,


                    Heredity and DNA   155

especially in the last year, when I was attempting new chemical analy-
ses, although all of his friends tried to make him welcome in the
laboratories."7

A Premature Discovery?

Avery's work on DNA was published during a period of great excite-
ment in theoretical biology -a period marked by new concepts of theoreti-
cal genetics and, in particular, by the flamboyant theoretical declarations
of the "phage group."4R,4g Several schools of biologists, inspired by
physicists who had moved into biology, made it fashionable to think about
biological problems in terms of theoretical constructs, rather than of ana-
tomical structures, physiological processes, and behavioral patterns; some
biologists talked as if they were more concerned with cosmic riddles than
with living organisms.

In contrast, Avery questioned the validity of biological generalizations
and was even reluctant to use the word gene. He was virtually ignored by
the theoreticians of genetics, precisely because he made no effort to
communicate with them or, more exactly, to communicate to them what he
had discovered by working at the bench instead of speculating about the
secret of life. This peculiar scientific apartheid was still painfully evident as
late as 1972, when Gunther S. Stent, an early member of the "phage
group" published in Scientific American an essay entitled "Prematurity and
Uniqueness in Scientific Discovery."5u The theme of the essay is that "for
many years" Avery's work on DNA "had little impact on genetics. The
reason for the delay was not that Avery's work was unknown or mistrusted
by geneticists but that it was premature . geneticists did not seem to be
able to do much with it or build on it." The caption for the diagram that
explained the experimental proof of the role of DNA ends with the phrase,
"The significance of Avery's discovery was not appreciated by molecular
geneticists until 1952," more than eight years after the details of the work
had been made public.

As evidence for this extraordinary statement, Stent refers to the sympo-
sium, "Genetics in the 20th Century," held in 1950 to celebrate the golden
jubilee of genetics."' He points out that, in the proceedings of the sympo-
sium, "Only one of the 26 essayists saw fit to make more than a passing
reference to Avery's discovery, then six years old. He was a colleague of
Avery's at The Rockefeller Institute, and he expressed some doubt that the
active transforming principle was really pure DNA. The then leading
philosopher of the gene, H. J. Muller of Indiana University, contributed an


interpretation appears in a different light when one knows-as Stent knew
and should have mentioned- that the only member of The Rockefeller
Institute staff present at the symposium was A. E. Mirsky, who still
believed at that time that Avery's DNA preparations might contain small
amounts of active protein. As to H. J. Muller, he had refrained from
mentioning DNA in his formal lecture not for lack of awareness of its
potential relevance to genetics, but because Mirsky's objections had made
him uncertain concerning the chemical nature of the transforming sub-
stance. In the course of the general discussion, he did refer to a possible
relationship between genes and DNA, but he added that "as yet no one has
been able to correlate these features of chemical structure with the gene's
peculiar property of self-reproduction ." This was as positive a statement as

(italics mine) is to quote verbatim a few of the many statements made by
leading geneticists and theoretical biologists during the 1940s concerning
the potential significance of the DNA work.
According to the account of Theodosius Dobzhansky, the eminent
classical geneticist, he visited Avery's laboratory at least one year before
the publication of the 1944 paper "and tried to argue that what were being
observed were mutations like the mutations in Drosophila."53 In the
introduction to the second edition of his widely read book Genetics and the
Origin of Species, dated March, 1941, Dobzhansky referred to pneumo-
coccal transformation as follows: "We are dealing with authentic cases of
induction of specific mutations by specific treatments-a feat which geneti-
cists have vainly tried to accomplish in higher organisms."s4 Within a year
after Avery's original publication, G . E. Hutchinson ,55 A. Marshak and A.
C. Walker,56 and Sewall Wright5' suggested that DNA might be a chromo-
somal fraction acting a genetic role. G. W. Beadle was even more specific
in his 1948 Silliman Lecture: "Pneumococcus transformations, which ap-
pear to be guided in specific ways by highly polymerized nucleic acids, may
well represent the first success in transmuting genes in predetermined
ways ."58

Sir MacFarland Burnet visited Avery's laboratory in 1943 and immedi-
ately wrote his wife about the discovery, because he regarded it as "noth-
ing less than the isolation of a pure gene in the form of desoxyribonucleic
.1.. .   . .     . .   r        . .    1  ./`.l 1.        .* .-..I.


       a-------
heralded the opening of 1
nated scholarly thought in biology ever since ."5g In 1948, as already men-
tioned, Andre Lwoff had concluded the Paris Symposium on "Biological
Units Endowed with Genetic Continuity"6o with remarks expressing an
attitude similar to that of Burnet. From these examples, it is clear that,
contrary to Stent's assertion, the "general discourse of genetics" was
immediately affected by the view that DNA is involved in genetic phenom-
ena.
In his 1946 presidential address to The Royal Society, which included
the citation of Avery for the Copley Medal, Sir Henry Dale stated that the
transformation of pneumococcus type should be given "the status of a
genetic variation; and the substance inducing it -the gene in solution, one
is tempted to call it - appears to be nucleic acid of the desoxyribose type.
Whatever it be, it is something which should be capable of complete de-
scription in terms of structural chemistry"61 (italics mine). Here was a
clear call to action, and it was answered at once by several chemists and
biologists. At the Institute, Hotchkiss was beginning to study the compara-
tive structure of deoxyribonucleic acids of different origins. Mirsky himself
stated in 1947 that Avery's findings "have caused chemists to consider
critically the evidence for uniformity among nucleic acids, and the gener-
ally accepted conclusion is that the available chemical evidence does not
permit us to suppose that nucleic acids do not vary."62 E. Chargaff stated
emphatically that Avery's 1944 paper had been "the decisive influence"
that led him to devote the major part of the activities in his department to
the chemistry of nucleic acids.63
Awareness of the role of DNA in pneumococcal transformation led
Hershey and Chase to design the ingenious experiment which established
that, in bacteriophage infection, most of the viral DNA penetrates the
infected bacterium, whereas the viral protein remains outside. Finally, it is
certain that the findings of the Avery group were responsible for James D.
Watson's decision to engage in the chemical program which culminated in
the recognition of the double helix. According to Watson, his teacher,
Salvatore Luria, had realized very early that "Avery's experiment made it
[DNA] smell like the essential genetic material. So, working out DNA's
chemical structure might be the essential step in learning how genes
duplicated." When Watson arrived in England, he found that Francis
Crick himself "knew that DNA was more important than proteins."64
In view of all these facts, it is obvious that the 1944 paper by Avery,
MacLeod, and McCarty had a rapid and profound influence on both the


           158    THE PROFESSOR, THE INSTITUTE. AND DNA
~I

thoughts and the laboratory programs of geneticists and other scientists.
Apparently, certain members of the "phage group" regarded the orthodox
chemical approach to the understanding of biological phenomena as pedes-
trian, too slow, and not revolutionary enough for their intellectual ambi-

tions. They "did not seem to be able to do much with or build on it,"65
because it did not fit their particular approach to genetics. It has been
reported that Delbrtick, the leader of the group, "deprecated biochemis-
try"66 and even influenced some of his followers to avoid it. He "wanted

to . . . go straight to the problems of gene replication and gene action"67
and the "informational" approach seemed the most promising to this end.
According to Stent, Delbrtick and other members of the informational
school even doubted that biological phenomena could be explained by the
known laws of physics and chemistry; instead, they "were motivated by the
fantastic and wholly unconventional notion that biology might make funda-
mental contributions to physics."68 At least they hoped that information
theory would give them rapidly, in the simplest possible way, some insight
into the universal phenomena of life and especially into the mechanism of
gene replication.

Avery's goal was less ambitious but more concrete. As in his earlier
studies, he was interested in both the chemical composition and identity of
the substances responsible for biological phenomena and in the mechanism
through which they affect living processes. His years of experience in
chemical immunology were his only contact with anything that might
suggest an "informational" approach to biological phenomena, but he had

not forgotten the lesson. He had assimilated Paul Ehrlich's classical (even  I

immunological work done in Landsteiner's laboratory and in his own at
The Rockefeller Institute transmuted this crude picture into a refined
analysis of the specific relationship between the molecular structure of the
antigen and the corresponding antibody. He was therefore not unprepared
for the view that a nucleic acid of a certain molecular structure could
instruct the pneumococcus cell to synthesize a polysaccharide endowed
with immunological specificity. Hotchkiss has pointed out that, even
though Avery was not a chemist and was unfamiliar with information
theory, he nevertheless viewed biological problems in a very modern
chemical light:

. the specificity (now "information") was assumed to reside in indi-
vidual molecular structures ("messages") capable of influencing (being


"translated") or interacting with (complex forming, repressing, etc.),
cellular enzymes responsible for growth (biosynthetic systems). The

mechanism, turned out to be far more complex than expected, almost as
complex as a fruit fly. In contrast, Avery's down-to-earth chemical ap-
proach led, through DNA, to the formulation by Watson and Crick eight
years later of the double-helix molecular structure70 that provided the first
material for effective thinking about biological information, thus making
the dream of the "phage group" finally come true; but through the
conventional channel of structural chemistry.

During the late 193Os, Avery had been nominated for the Nobel Prize
in recognition of his immunochemical studies. After the 1944 paper, the
Nobel committee was immediately alerted to the fact that he had once
more made a fundamental contribution to biological science. But the 1944
paper was ineffective from the public relations point of view; it left open
the possibility that some substance other than DNA might conceivably be
involved in transformation; if failed to extrapolate from the role of DNA in
a single bacterial species to the role of DNA in other living things. In other
words, it did not make it obvious that the findings opened the door to a
new era of biology. The Nobel committee, probably not accustomed to
such restraint and self-criticism bordering on the neurotic, "found it desira-
ble to wait until more became known about the mechanism involved in the
transformation ."il Yet, the very phenomenon of transformation, repre-
senting as it did the first example of directed change in hereditary charac-
teristics, was in itself a biological landmark worthy of the Nobel Prize,
regardless of the precise chemical nature of the transforming substance.
But neither Fred Griffith nor Avery was a person who makes himself or his
work obvious to international committees. They were not followers of
fashionable scientific trends, nor did they attempt to create a fashion by
broadcasting that they had reached a major turning point in the search for
the secret of heredity. A day may come when the Nobel Foundation will
review its errors of omission and write of Avery, as the Academic
Francaise once wrote of Moliere: "Rien ne manquait a sa gloire, il man-
quait a la notre."


I               CHAPTER TWELVE

Gentle-Mannered and Tough-Minded

From 1927 to 1942, I worked in the laboratory adjacent to the one
occupied by Avery at The Rockefeller Institute. He never closed the door
of his own laboratory and but rarely that of the small office attached to it,
so that I was witness to most of his activities at the bench or in conversa-
tion, and also to his interludes of day-dreaming. As I was a rather quiet
person, he was hardly aware of my presence, and often behaved as if he
were alone. This gave me a chance to observe certain aspects of his
personality quite different from those that appeared on the facade he
exposed to the public under the normal conditions of everyday life. Some
of the moods he displayed puzzled me at the time, but I understand them
better now that I realize how much his quality as a person depended upon
the constant discipline he exerted over himself.

The appellation "Fess" brings to mind, first and foremost, a slender
man always dressed in a neat and subdued style; his conservative appear-
ance added to the charm of his lively and affable behavior. The most
dominant features of his physical being were his sparkling and questioning
eyes surmounted by the bulky dome of a head that appeared too volumi-
nous for the frail body. In repose, his face expressed a gentle, quiet
wisdom, which was enlivened by a warm smile of welcome and by effusive
greetings as he met colleagues, friends, or strangers. He transformed even
the most casual conversation into an artistic performance by a panoply of
words and gestures that managed to be simultaneously spirited and re-
strained. Each of his statements was spiced with mimicry, pithy remarks,
verbal pyrotechnics, and picturesque analysis. The extroverted playfulness
of his nature, and his phenomenal empathy for every person or situation
that engaged his interest, made any contact with him an intellectually
rewarding experience, always entertaining and often enchanting.

,    Now and then, however, he displayed other patterns of behavior that
/
t   seemed rather disconcerting and at first sight less attractive, yet had a
  haunting quality. On the rare occasions when he was alone, he was prone

I   whistling to himself the lonely tune of the shepherd's song from Tristan und


162    THE PROFESSOR, THE INSTITUTE, AND DNA

Isolde. His gaze was then focused inward, and his brooding forehead
appeared almost to dwarf his body. For a few fleeting moments, he seemed
to be a melancholy figure out of contact with the external world, but this
attitude of inwardness vanished as soon as an occurrence brought him back
to reality.
If a colleague or a visitor walked into his room during one of these
moods of withdrawal, he would immediately be welcomed with Avery's
usual warm smile. If the telephone rang, commonly for an invitation to
dinner or to some other social event, his response was instantaneously one
of joyful thanks or of profuse regrets, couched in endearing or apologetic
terms. These interruptions, however, did not really break the spell of his
inward mood. Once the visitor had walked out of his office or the tele-
phone conversation had ended, an expression of lassitude was likely to
reappear on his face, as if a smiling mask had been removed. He would
push the telephone away from him in an abrupt gesture that suggested
irritation against encroachment into his privacy. His smile was replaced by
a tortured expression of protest against the need to play a social role that
he resented because it did not fit his present mood. He certainly suffered
from his own attitude on these occasions, because, as he was wont to say,
obviously referring to himself, resentment hurts the person who resents,
much more than the person who is resented.
While he never engaged in criticism or unkind gossip, he manifested his
feelings of censure in other ways. What he did not approve, he simply
ignored. His eagerness to avoid certain social roles probably accounted for
some of his behavioral peculiarities. For example, he left many letters
unanswered and did not want to have a secretary, even though the large
number of scientists in his department would have justified one during the
1930s. The departmental manuscripts and administrative matters were
handled in the office of the Hospital director. He refrained from reviewing
or sponsoring scientific papers unless he had had a direct part in the
performance of the experiments; I can still see him graciously but firmly
pushing back under the arm of a visiting bacteriologist, whom he had
courteously entertained for more than an hour, the manuscript of a paper
that the visitor wanted him to endorse for a certain journal. He was
extremely selective in what he gave of himself, even to his colleagues; for
example, he would act as if he had not noticed the presence of one of his
young associates who tried to approach him, but whose attitude he found
distasteful or simply irritating.
Thus, while he was exquisitely gentle-mannered, he was tough-minded;
in his own subdued way, he was indeed ruthless with regard to what he
elected to do or not to do. Once he had decided on a course of action, he


As I Remember Him   163

did not allow any external influence to deter him from reaching his goal or
to force him into an activity he did not desire.
These different views of Avery's behavior-his extroverted attitude and

plementary aspects of his nature. His effusive welcome, his receptiveness

accounted for his ability to identify himself with new scientific problems or
new ways of life. In contrast, most of his introverted moods probably

the phenomena he had observed became integrated with his own substance
in the patterns that formed his self-created persona. He had been endowed
by nature with many intellectual gifts, great sensitivity, and an immense
skill in dealing with people, and could thus have been successful in many
different types of activities and environments. Indeed, one of the most
interesting aspects of his life is that each period of it provided him with the
chance to give successful expression to one or another facet of his rich
personality.

Avery's Consecutive Persona

Avery's neighbors during his retirement years in Nashville must have
wondered why such a kind and attractive gentleman had remained a
bachelor. In fact, there were other mysteries in his life. After having
majored in humanistic subjects at Colgate University until the age of 23,
how did he manage, within a few vears, to redirect all his energy and talent

to the study of biomedical problems ? Since he emphasized declamation
  .  . .      . . .      . .       . .   . .     . .  . .        * .

own research after he became a famous scientist? He was an extrovert in
youth, as shown by his eagerness to play the cornet in front of the
Mariners' Temple, by his position as leader of the college band, by his
participation in college debates and his dramatic proclamation concerning
the existence of God on the steps of the Colgate Alumni Hall. What
circumstances made him an introvert and shun public appearances during
his mature years? Avery did not discuss the reasons for these extraordinary
mutations of his persona, even with his closest associates. The mysteries of
his behavior call to mind Dr. William Henry Welch, whose inner life also
remained a closed book, even to those who knew him best and whom he
regarded as his trusted friends.

While a student at Yale, Welch had desired to become a professor of


164   THE PROFESSOR, THE INSTITUTE, AND DNA

Greek, but when the opportunity came to him to fulfill this wish, he elected
instead to go into science. He enjoyed social contacts and was extremely
popular with women, as well as men, but he never married and had very
few, if any, really intimate friends. He came to be known all over the world
as the congenial and jovial Popsy, but no one had access to his private
world. Dr. Simon Flexner, who had been closely associated with Welch for
some 50 years, stated in the biography he wrote in collaboration with
Thomas Flexner that aloofness was at least as much a characteristic of
Welch as was his congeniality, and that he never allowed social relation-
ships to intrude into his privacy or overcome his emotional reserve.
Welch's life was governed by this aloofness until the very end, as shown by
the account of his death from cancer in the Flexner biography:

Welch was holding to his lifelong habit of not confiding in anyone,
irrespective of who that person was or what he knew. Always he had
been surrounded with people, and during most of his life he had moved
on a public stage toward public ends, but always he had kept the inner
core of his being inviolate. And when the final trial came, he did not
change. While his body suffered, his mind struggled to maintain before
the world the same placid exterior that had been his banner and his
shield. Popsy, the physician who had been so greatly beloved, died as he
had lived, keeping his own counsel, essentially alone' (italics mine).

Judging from Avery's behavior in difficult periods of his life, it is certain
that he, too, wanted to keep his own counsel and face his destiny alone. He
did not discuss his health when he was suffering from Graves' disease,
except to answer his friends' questions with the statement that he was
feeling much better. He never mentioned concern for members of his
family, even though their problems were much on his mind. He did not
express irritation at criticisms of his work, even when these were unjusti-
fied. Since he left no record of his personal thoughts, I shall attempt to
imagine, from very tenuous clues, some of the factors that may have
influenced important decisions of his life. One justification for this ques-
tionable exercise is that it will provide an opportunity to bring out a few
more aspects of his many-faceted and endearing personality.

On an early spring day in 1934, I informed him that I was about to get
married. He immediately rejoiced at the news, and described with anima-
tion how this change would enrich my life. At one point in our conversa-
tion, he slowly walked to the window and looked outside, lost in thought
for a few seconds. Coming back to his chair, he casually mentioned that he,
too, had contemplated such a move years before, but that circumstances
had stood in the way of his plans. Then he turned the conversation back to


, -..__ ----, --`----by- ___" -____--- ---- `-~          - .-.. b---b --. -_-- ___-.- --
:imate companionship which he had not known. One of the great joys of
life, he remarked in passing, is to go home to someone who would rather
see you than anybody else.
I have recently been told that, while talking to the wife of one of our
colleagues, he referred on several occasions to a certain nurse who had
meant a great deal to him. To this information, I can add that he took
special pleasure in mentioning the course he gave to student nurses at the
Hoagland Laboratory, at the time when the success of his lectures won him
the appellation "The Professor." He was then 32 or 33 years old, and it is
not unreasonable to imagine that he developed an emotional attachment to
one of these young women.
His years at the Hoagland Laboratory, however, must have been an
anxious period of his life. He was training himself for laboratory research
and, although he was involved in several scientific problems, his profes-
sional future was still uncertain. He felt responsible both for his young
brother Roy and for his orphaned first cousin Minnie Wandell, whom he
supported for the rest of his life. Throughout the years, his correspondence
with his brother Roy and his sister-in-law Catherine leaves no doubt that
he was willing to sacrifice his personal desires to the welfare of his family.
One of the reasons he remained a bachelor may therefore have been that
he thought this was the only way he could properly fulfill the familial
obligations he had inherited. It is also probable that he eventually found it
increasingly distasteful, and even painful, to accept any commitment,
except those he took for granted as head of his family, that would impinge
on his intellectual and emotional freedom.
Avery always retained a profound sense of responsibility toward others,
but he displayed throughout life a remarkable ability to change his persona
according to circumstances and to the roles he elected to play.
He had joined the Baptist church at the unusually young age of eight
years and had taken an active part in its activities at the Mariners' Temple.
His father was dead by the time he entered college, but his mother was
then heavily involved in the affairs of the Baptist Mission Society. It would
therefore have been natural for him to train for the ministry, as did many
of his classmates at Colgate. However, his religious beliefs evolved during
his early college years, and he probably found it impossible, or at least
intellectually dishonest, to follow in his father's footsteps. A career in
medicine may have seemed to him a proper substitute for the Baptist
ministry.
From his own accounts, he was soon disappointed by medical practice.


166    THE PROFESSOR. THE INSTITUTE. AND  DNA

By necessity, the clinician and the public health officer must act even when
they do not understand the inevitable complexity of the disease process
with which they are dealing. For lack of sufficient information, they must
commonly make value judgements on the relative importance of the
multiple factors that impinge simultaneously on the patient or population
group for which they are responsible. This situation must have been

19OOs, at a time when an educated physician had enough general scientific
knowledge to be aware that few of his interventions were scientifically
justifiable and usually were, at best, completely empirical.
As he worshipped rational thought, he probably turned to laboratory
research both because this offered the best approach to progress in medical
practice, and because it provided him with the opportunity to deal with
experimental situations that he could understand and control. Whatever
the state of knowledge, the experimenter has the freedom to separate from
the complexity of natural phenomena a few limited aspects that he chooses
to investigate; instead of dealing directly with the confusing complexities of
natural processes as he encounters them in the raw, he can often create

experimental models simple enough to be controlled and manipulated at  1
will-although at the risk of working with artificial situations far removed   i

- _-.---.- -

in natural situations, but when it came to the systematic study of them, and
particularly to active intervention into them, he suffered acutely, and was
almost paralyzed until he had reduced the complexity of the system so as to
control its variables. Once he had made this choice, he settled into the wav
of life of a laboratory scientist, and never departed from it until the time of
his retirement.

particularly difficult for Avery, who practiced medicine during the early

Another aspect of his personality may have been influential in his
decision to shift from clinical medicine to laboratory research. Because
there were few really effective therapies in the early 19OOs, taking care of
the sick largely meant providing them with psychological comfort. In the
words of Francis Peabody, the most important aspect of the care of the
patient is caring for the patient. Avery was certainly capable of the human
understanding and sympathy implied in Peabody's phrase; this compas-
sionate approach to medicine, however, is emotionally demanding of the
physician if he identifies himself completely with his patients. Indeed,
many physicians experience difficulties on this score during their early
clinical experience, but most learn by practice to display kindness without
becoming emotionally involved; they develop the skill to turn emotional
involvement off and on as needed. It is possible that Avery's temperament

made it difficult for him to achieve this protective kind of behavior. The


As I Remember Him   167

facts that, despite his great sensitiveness and his ability to inspire affection
in all the persons with whom he came into contact, he never married and
had very few really intimate friends, suggest that he tried to avoid deep
emotional commitments. He may have found it painful to achieve the right
balance of involvement and detachment that is essential in clinical practice.

Avery always had a whimsical smile when, in the course of laboratory
conversations, his young associates made dogmatic statements about such
nonscientific topics as social problems, the management of institutions, the
characteristics or activities of important persons. I can still hear the gentle
irony in his voice when he asked us on such occasions, "Now, are you really
sure of that?" He was probably the more amused by our cockiness because
he remembered that he, too, had often been guilty of unwarranted state-
ments during his youth and early adulthood. In college, as already men-
tioned, he had engaged in brash talk on almost any subject. At The
Rockefeller Institute, he had published in 1916 and 1917 hasty conclusions
that were soon proved to be erroneous (Chapters Seven and Eight). He
therefore knew from experience the human propensity to use facts solely
for the sake of rhetorical effects and to ignore facts when they stand in the
way of one's prejudices.

Self-knowledge had made him wise, but he understood that wisdom, far
from being an innate attribute, must be constantly gained by the mistrust of
spontaneous impulses and by self-mastery. He was always immensely
successful on the few occasions when he accepted invitations to give public
lectures, so it is unlikely that fear of public reaction made him try to avoid
this kind of activity during his late professional life. It is more probable that
he was afraid of himself and, especially, of exerting an influence that did
not correspond to what he considered as really significant truth. There may
have been an element of conceit in this attitude, since it implied that
anything he said was likely to receive public attention and to have public

humanistic studies and other interests from which he could have derived
satisfaction. Increasingly, he refused to consider any commitment, to
either a person or a cause. that would interfere with the few roles he had
accepted or elected to play. This refusal even extended to honors that he
greatly valued. In 1944, he was proposed for an honorary degree by
Cambridge University; in 1945, he was awarded the Copley Medal by the
Royal Society of London. Even though he was a great admirer of British


168    THE PROFESSOR, THE INSTITUTE, AND DNA

culture, he refused to go to England on both occasions, saying that his state

foundations would have been willing to finance his trip.
As he did not go to England, he could not receive the honorary degree
from Cambridge University, but Sir Henry Dale, who was then President
of the Royal Society, decided to bring him the Copley Medal at The

Rockefeller Institute. Dale was accompanied by Dr. Edgar Todd, who
knew Avery and who has told the story of the occasion. The two English
visitors arrived at the Institute unannounced, and went directly to Avery's
department, with which Dr. Todd was familiar. As they approached, they
saw Avery, alone in his laboratory, manipulating pipettes and test tubes
and transferring bacterial cultures. As they retreated without letting their
presence be known, Sir Henry Dale said simply to Dr. Todd, "Now I

except for his familial responsibilities, which are repeatedly mentioned as
taken for granted in his correspondence. What remained constant was his
determination to be what he wanted to be, at any given time. This spirit of
determination can be read in all photographs of him, even those taken
when he was very young. It found expression in the several consecutive
social roles that he played-as the child intensely involved in the activities
of the Mariners' Temple; as a humanist and public figure at Colgate
University; as the scientific investigator who emerged at the Hoagland
Laboratory and came to flowering at The Rockefeller Institute; finally as
the country gentleman, who delighted his family and his neighbors during
his retirement years in Nashville.

Both his singleness of purpose and his ability to adapt to new circum-
stances are obvious throughout the 35 years he spent at the Institute. His
scientific achievements during that period naturally brought him many
offers from other institutions, but he ignored them. The Institute provided
for him an ideal environment, because, although he was responsible for a

An Unspoken Scientific Philosophy


  method or the social obligations of scientists was in the 1941 speech he
  delivered when he was president of the Society of American Bacteriolo-
  gists." The speech was well-received, yet he refused to publish it or even to
  deposit it in the archives of the Society of American Bacteriologists, as is
  the usual practice. I retrieved a copy of it from a waste basket where he had
  discarded it in 1948 while clearing his desk before retiring to Nashville.
  The speech is of interest, not for the originality of the ideas it presents, but

I   for what it reveals of Avery's mannerisms and attitudes.
I     The typescript I recovered is fortunately the one from which he spoke.

ing and also numerous indications in pencil as to nuances of expression,
almost like musical notations (Appendix II). Looking at the script, I can
hear the points of emphasis and of query, the linkages between words and
phrases, and inflections of voice that enabled Avery to convert the some-
what artificial and labored text into an exciting and seemingly spontaneous
performance.

The theme of the second half of the speech, which is of little interest
because it is conventional and stereotyped, deals in abstract terms with the
comparative importance of theoretical and practical science, and with the
moral and social obligations of scientists. Most of the views expressed in
this section are quoted from Sir Robert Gregory, who had just retired as
President of the British Association for the Advancement of Science, and
more extensively from Raymond B. Fosdick, who was then President of
The Rockefeller Foundation and the brother of Avery's classmate at

expected from such orthodox officials.

tional as those he quotes. According to him, scientists in general, and
microbiologists in particular, "have undeniably and always been in the
service of human welfare. . . It is the ancient tradition of the spirit of
science that it follows no flag, recognizes no geographical boundaries, and
sets up no trade barriers. Complete freedom of scientific thought, and the
free interchange of knowledge are prerequisites for the survival of the
spirit of free inquiry. They are to the Commonwealth of Science what the
Bill of Rights is to the life of democracy."

I   obvious from his abstract formulation of them, so different from the
   sparkle of his usual manner of speech, that he was not much interested in
   the topic and, in any case, had no desire to challenge conventional social


had about people and institutions he kept to himself. He gave the impres-
sion that he had decided irrevocably, at some time in the past, not to
attempt to change the world of men (except himself) and instead to focus
his attention on understanding other forms of life, the smaller the better.
Judging from the notations for emphasis on the typescript of the speech,
the statements made by Fosdick that were most meaningful to Avery were
those concerning science as a way of thinking about the world:

Science is more than the technologies that cluster about it -more than
its inventions and gadgets. It is even more than the discovery and
correlation of new facts. Science is a method, a confidence and a
faith. , . . It is a confidence that truth is discoverable. It is a faith that
truth is worth discovering

Avery may have doubted that all forms of truth are really worth discover-
ing, but the belief that the scientific study of medicine can lead to the
discovery of large biological truths was the faith by which he functioned in
the laboratory. It was therefore proper for him to conclude with the
statement that "science, in obeying the law of humanity, will always labor
to enlarge the frontiers of knowledge"- an irreproachable platitude he had
borrowed from Pasteur.

He was truer to himself in the first half of the speech, where he
expressed some of his characteristic attitudes as a laboratory worker. He
wanted to convey the view that no one should regard his "own corner of
knowledge as the source and directive of all biological thought ." Instead of
stating this truth in abstract academic sentences, however, he took an
obvious pleasure in quoting the words that Fosdick had used to make fun
of those scientists who believe in the unique importance of their own
discipline:

Choose off the shelves a group of learned treatises and sample the
prefaces: Mathematics: - it is the queen of sciences; Physics: - it is the
source of the basic laws for the behavior of all matter; Chemistry:-a
recent text says, "Chemistry touches all human interests. It is the central
science"; Biology: - it assaults the greatest mystery of all, the mystery of

Philosophy: - it is an examination of the ultimate questions which give
life meaning. And so one could expand the list, with brave and startling I


                ---- -.----- -- -_-- Y ---r-I-        )     .___-* ----. __
the potentialities of which challenge the human intellect." But while he
spoke with tongue in cheek of certain excessive claims made for microbio-
logical sciences by some of his colleagues, later in his text he,could not
refrain from quoting example after example illustrating how microbiologi-
cal studies have, in fact, illuminated a wide range of biological problems.
Addressing physiologists and biochemists, he admonished them jokingly,
"Go to the microbe, thou scientist, consider its ways and be wise." This
paraphrase of the Biblical saying was obviously meant to entertain his
listeners, but it expressed also his scientific philosophy as a biologist. He
believed in the interdependence of all natural sciences; he regarded chem-
istry as playing an essential role in biological progress; he was convinced
that the chemical unity of life could best be documented through the study
of microorganisms.
Avery always refrained from extending scientific concepts into domains
where they could not be converted into experimental laboratory tests. In
particular. he avoided scientific discussions of a philosophical character
about the human condition or the origin of life. This restraint was not due
to lack of interest in these problems, or to ignorance of them. In his early
years at The Rockefeller Institute, he had been exposed to Jacques Loeb's
assertions that free will and ethical attitudes can be explained by physico-
chemical mechanisms. In the 1930~4, he had been witness to free-wheeling
discussions about the origin of life, generated by the finding that the
tobacco mosaic virus can be obtained in a crystalline form. At the time he
delivered his presidential speech before the Society of American Bacteriol-
ogists, he was in the process of demonstrating that DNA is the bearer of
hereditary characteristics in pneumococci, and he certainly realized that
this discovery would lead to speculations about the "nature" of life. In
other words, he was fully aware of the general tendency to read philosophi-
cal implications into any new form of biological knowledge. However, the
way he shook his head when such discussions went on around him made it
clear that he did not have as grandiose and sweeping a view of these
implications as did some of his colleagues. In my judgment, he felt that
certain aspects of life and certain areas of human concern are outside the
domain of science because they cannot be formulated in such a manner as
to be put to the test of verification or falsification. Because he did not
explicitly state his opinions on such matters, I shall try to imagine them, as
much from his silences as from fragmentary statements he made now and
then concerning the limitations and potentialities of the scientific ap-


/ i          stract terms, but through illustrative examples. For example, he might
i'         have said that the phrase "God exists" is a statement which has meaning
         for those who make it, but is not scientific because there is no conceivable
4         way that it can be proved right or wrong. Similarly, when Gauguin
         inscribed on his famous Tahiti painting "Where have we come from? What
          are we? Where are we going?" he was asking questions which are of
        universal significance, but which are not answerable in scientific terms at
I         the present time . if ever. In fact, there is probably no way to give
         scientific answers to such questions as What is the nature or purpose of the
          universe? Of life? Of consciousness? Of free will? These are truly meta-
         physical, in the Greek sense of the word.
          While Avery never discussed such questions, he did believe that scien-
;         tists can provide knowledge relevant to them by converting them into other
i          questions amenable to experimental tests. For example, scientists cannot
         usefully discuss the nature of the universe, but they can make testable and
         falsifiable statements about its components and its development; they
        cannot discuss the nature of life, but they can investigate the mechanisms of
        growth, self-reproduction, and evolution in living things; they cannot
        discuss the nature of free will, but they can determine the influence of prior
        conditioning, of the state of health, and of the total environment on the
         ability of human beings to make choices and decisions.
          Avery also shunned theoretical discussions about the scientific method.
         If he had been familiar with Karl Popper's writings, he would have agreed
         with him that the method involves a number of different consecutive steps,
         such as the recognition of a problem; imagining solutions to it in the form
         of hypotheses; deducing testable propositions from these hypotheses;
         trying to confirm and refute the hypotheses by experiments and arguments;
         selecting among competing theories. But he would have suggested gently
         that effective scientists intuitively go through these steps without bothering
          to formulate them in philosophical terms.
,
          His own way of acknowledging the existence of a philosophy of the
         scientific method was to indoctrinate his young associates with picturesque
         admonitions. For example, he would welcome any failure or inconsistency
         in experimental results with the remark, "Whenever you fall, pick up
         something." When in search of an explanation, he would assert, "Be
         fearless when it comes to hypotheses, but humble in the presence of facts."
         As to Karl Popper's famous law that falsifiability is the criterion of
          demarcation between science and nonscience, he would have stated it in
          the form of his favorite phrase, "It is great fun to blow bubbles, but you


As I Remember Him    173

must be the first one to try to prick them." Without taking the trouble to
say it, he would also have agreed with Sir Peter Medawar that science is
"the Art of the Soluble," 5 and he would have especially emphasized that
good scientists have the wisdom not to deal with problems that lie beyond
their competence or outside the domain of science; they intuitively elect to
study the most important problems they can solve.

On the other hand, solving problems simply because they can be solved
did not seem to him a reasonable occupation. It was the kind of activity
that he described with a smile as "pouring something from one test tube
into another." His attitude toward busy-ness in science was much the same
as that expressed by Sir Joshua Reynolds about painting: "A provision of
endless apparatus, a bustle of infinite inquiry . . . employed to evade and
shuffle off real labor . . . the real labor of thinking." Avery, as mentioned
earlier, symbolized the very opposite of this attitude. He spent countless
hours debating what was really important among the countless things that

Originality and Creativity

Watching Avery at work in the laboratory was an unforgettable experi-
ence. Because he abhorred complex situations and a plethora of equip-
ment, his own presence was the essential part of the show. His gaze was
intensely focused on the operation being carried out or on the phenome-
non under observation; his movements were limited, but of extreme
precision and elegance; his whole being appeared to be identified with the
sharply defined aspect of reality that he was studying. Confusion seemed to

I   that of the hunter in search of his prey. For the hunter, all the compo-         I

penetrate the world of the phenomena he studied. He invested his whole
attention so completely in the problem at hand that he became inattentive
to extraneous matters. When at work in the laboratory, he found it difficult
to concern himself with the questions asked of him unless he could relate
them to his own problem.
Like the hunter, also, he took more pleasure in the pursuit of the prey
.    .            n. .     -.     .     ^     . .    .     .   . .


174   THE PROFESSOR, THE INSTITUTE, AND DNA
only transient satisfaction; he was chiefly attracted by the unknown, and
found charm in established knowledge chiefly to the extent that it helped
him in his own research. Thus, he continued to stalk new phenomena for
the sake of the hunt itself. One could have applied to him Pascal's
paradoxical saying that he was not so much in search of truth as in search of
the search for truth.
Since the search as a process, rather than the product of the search, was
the more appealing aspect of scientific work for Avery, he could
honestly say, as he was prone to do, that he would have been just as
interested working with the hay bacillus as with the pneumococcus. In fact,
many of the problems on which he worked were not of his own choice. He
did not imagine them; at the most, he selected among those provided by
the conditions of his time and of his milieu. To a large extent, indeed, his
scientific problems were almost forced on him by his social environment.
When he began working at the Hoagland Laboratory, for example,
acidified milks of the yogurt type had just become popular and were
important commercial products in his Syrian neighborhood; he therefore
studied the lactobacilli involved in the acidification of milk. Tuberculosis
was then one of the most important infectious diseases, and his Hoagland
Laboratory colleague Benjamin White had to take the cure at the Trudeau
sanatorium; Avery therefore worked on tubercle bacilli. When he joined
The Rockefeller Institute Hospital, lobar pneumonia was the problem
under investigation in the Department of Respiratory Diseases; he there-
fore became a specialist in the bacteriology of pneumococci. The approach
to the control of pneumonia at The Rockefeller Institute was through the
development of therapeutic antisera; he therefore studied the immuno-
chemical processes that might contribute to vaccination and serotherapy.  ;
The success of chemotherapy, first with the sulfa drugs in the late 193Os,   1
then with penicillin in the 194Os, made the immunochemical approach less  I
urgent, so that he could concentrate his efforts on the isolation of the
substance responsible for the transformation of pneumococcal types; in
this case, again, he did not create the transformation problem, but rather
faced up to it because Griffith's discovery had threatened the doctrine of   ,
immunological specificity to which he had become commited.
The methods that he used in his research also were provided by his time   i
and, in particular, by the scientific environment in which he worked. Both
at the Hoagland Laboratory and at The Rockefeller Institute, most of his
colleagues believed that biological phenomena are only complex expres-
sions of physicochemical processes, and that physics and chemistry offer
the only pathways leading to a real understanding of animate nature. In
agreement with this view, Avery made it his scientific ideal to formulate


As 1 Remember Him   175

pathological and biological problems in physicochemical terms, and to
define chemically the substances and reactions involved in the phenomena
that he studied.

His originality and creativity did not reside in the kinds of problems on
which he worked or in the development of new laboratory methods, but in
the intellectual style of his investigations. He accepted the practical prob-
lems that came his way, but he recognized and emphasized certain aspects
of them that had large biological significance; he used conventional labora-
tory methods, but he designed original and artistic experiments. For
example, the immunological specificity of bacterial strains was a widely
recognized phenomenon when he began his immunochemical studies, but
he gave it a broader and richer significance by relating specificity to certain
anatomical structures of the microorganisms and to certain chemical con-
figurations of these structures. Whereas the transformation of pneumococ-
cal types was regarded by most microbiologists as an oddity of little
interest, he had the persistence and the vision to convert type transforma-
tion into a precise and elegant laboratory model of a phenomenon with
great significance for theoretical biology.

I   associates whenever an important phenomenon seemed to escape his
   control: "Let us do the same experiment over again; the essential is never
   to leave the subject ."6 This was Avery's attitrlde, as most strikingly demon-
   strated during the 10 years of heart-breaking failures that preceded the

continue a line of experimentation against odds; it meant pursuing a
problem beyond the point of initial success. This attitude conditioned his
pragmatic philosophy of the experimental method, as he expressed it
during a conversation he had around 1935 with the young Dr. Barry
Wood, who had come to him for advice before beginning his research
career. Scientific investigators, Avery told Dr. Wood, can be divided into
two classes. There are those, the most numerous, "who go around picking
up the surface nuggets, and wherever they can spot a surface nugget of gold
they . . . grab it and put it in their collection." On the other hand, there is
the more unusual investigator "who is not really interested in the surface
nugget. He is much more interested in digging a deep hole in one place,
hoping to hit a vein. And of course if he strikes a vein of gold he makes a
tremendous advance." 7 This statement, made by Avery years before he


176   THE PROFESSOR, THE INSTITUTE, AND DNA

had established the role of DNA as the bearer of hereditary characteristics,
reveals how clearly he realized that persistence was probably one of his
most important assets as an investigator.
His persistence also accounts for the fact that he remained scientifically
productive into very late in life. According to the English mathematician
G. H. Hardy, "A mathematician may still be competent enough at sixty,
but it is useless to expect him to have original ideas." 8 Thomas Huxley is
reputed to have gone even further, and stated that "a man of science past
sixty does more harm than good." g William Osler once facetiously re-
ferred to the admirable scheme of a college into which, at sixty, men
retired for a year of contemplation before a peaceful departure by chloro-
form.`O These statements express the commonly held view that creativity in
science decreases rapidly after early adulthood.
Avery was past 6.5 when he published the DNA work, which is com-
monly regarded as his greatest achievement. Therefore, his case seems to
be an oddity in the annals of science. The fact is, however, that this
achievement did not depend on "original ideas" as commonly thought of,
and as understood, for example, in Hardy's phrase. The transformation of
pneumococcal types had been known for 15 years; the isolation and
identification of the substance responsible for transformation did not
require originality of concepts, but rather the disciplined and critical
application of known laboratory techniques. A similar situation is pre-
sented by the case of the English physicist Lord Rayleigh. He, also,
remained productive in classical science until his late 60's, and gave an
explanation that is applicable to Avery's continued scientific creativity.
When asked to comment on Huxley's remark that a "man of science past
sixty does more harm than good," Lord Rayleigh replied, "That may be, if
he undertakes to criticize the work of younger men, but I do not see why it
need be so if he sticks to the things he is conversant with." I* This is, of
course, exactly what Avery did. He had a deep knowledge of pneumococ-
cal biology; he was familiar with the technical problems of type transforma-
tion; and he sensed that, in some way, these problems had broad theoreti-
cal significance. A large part of his creativity thus resided in his wisdom.
He knew that by "digging a deep hole in one place" he had a good chance
to hit a vein, even though he could not predict what he would discover.

       Experimental Science as an Art Form
Avery's advice to Dr. Barry Wood was a picturesque way of acknowl-
edging that persistence had been an essential factor in his own success, but
there was much more than that to his genius as an investigator. Before
deciding where to dig the hole, he spent much time surveying the terrain


                      __ ____          .._-
acted as if he did not believe that truth would automatically emerge from
those facts. His approach to knowledge was not through compulsive
scholarship and the accumulation of data, but rather through an imagina-
tive vision of reality expressed in hypotheses derived from a few carefully
selected facts.

All experimenters worth their salt go, of course, through the process of
hypothesis-making in the course of their work; furthermore, all believe
that a hypothesis can be useful, irrespective of its validity, because the very
findings that show it to be erroneous commonly suggest new lines of
investigation. However, this orthodox view of the experimental method,
conceived as a continuous interplay and feedback between hypotheses and
experimentation, does not do full justice to Avery's way of dealing with
scientific problems. He was as much interested in constructing elegant
mental models of the truth as in describing reality.

His formulation of scientific problems had some analogy to the wonder-

way as to create a composition more interesting and more compelling than
the actual occurrence. Similarly, he loved to create theoretical images out
of the scientific facts provided by observation and experimentation.
Throughout his scientific career, for example, he composed hypotheses in
the form of short phrases, the meaning of which could almost be visualized
from his choice of words. The following are a few of the word images on
which he focused his thoughts, and around which he organized his experi-
ments.

Antiblastic immunity: the metabolic processes of the host which inhibit
the multiplication of parasites.

Host chemistry: the various chemical changes that occur in the body as a
consequence of infection.

Specific soluble substances: the substances produced by the various
types of pneumococci that determine the immunological specificity of each
particular type.

Capsular antigen: the cellular complex of which each type of capsular
substance is a part in virulent encapsulated pneumococci, and which is
responsible for the ability to induce specific immunity.
Antigenic dissociation: the enzymatic processes caused either by pneu-
mococci or by infected hosts that separate the capsular substance from the


178    THE PROFESSOR, THE INSTITUTE, AND DNA

complex structure of which it is a part in the virulent encapsulated cell.

Rabbit virulence factor: a cellular substance, other than the capsular
polysaccharide, which determines the ability of encapsulated pneumococci
to cause disease in rabbits.

Transforming agent: the component of a pneumococcal cell that enables
the cell to transfer its immunological specificity to other pneumococci.

As we have seen in preceding chapters, Avery converted many of these
word images into laboratory operations that established the existence of
each of the phenomena symbolized by the image. In several cases, his
experimental studies led to the chemical isolation and identification of the
substance responsible for the phenomenon.

The occasions when experimental findings revealed the factual basis of
one of his word images and thus gave it a concrete meaning were, for
Avery, moments of childlike pleasure that he wished to share with his
colleagues and, indeed, with a broader public. On these occasions, The
Professor became the showman.

The quality of his showmanship had much in common with the spectacu-
lar demonstrations staged by Pasteur during the early days of the contro-
versies about the germ theory of fermentation and of disease. Best known
is Pasteur's famous experiment at the farm at Pouilly le Fort, where he
arranged for a widely publicized field demonstration of the fact that sheep
can be protected against anthrax by vaccination. More similar to Avery's
case, because on a smaller scale and for a more specialized audience, was
the demonstration Pasteur staged before the Paris Academy of Medicine
with four chickens of different plumage to convince his colleagues that
these birds can be made susceptible to anthrax by lowering their body
temperature .I2

The spectacular demonstrative value of Pasteur's public performance
depended, of course, upon his complete mastery of experimental condi-
tions. Numerous prior trials had made it safe for him to eliminate all
unnecessary details of the experiment and thus to increase its impact when
it was performed in public. Avery, also, would first work out the precise
requirements for a foolproof demonstration of the phenomenon he consid-
ered of importance, and then design tests as simple as compatible with
providing irrevocable evidence. These final tests would include a few
control animals or test tubes showing no effect whatever, a few others
placed under such limiting conditions that the effect was apparent but
minimal, and finally a few others in which the ideal conditions assured
unequivocal and striking results, whether the phenomenon being demon-
strated was acute death of an animal or its resistance to disease, formation
of a precipitate in a test tube or its inhibition. As discussed in Chapter Five,


As I Remember Him    179

These protocol experiments certainly had a meaning that transcended
the pleasure he derived from the demonstration. They symbolized for him
some of the values that had made him choose a life of science. in particular
the serenity, security, and order that can be found in the world of experi-
mentation, where much can be understood and controlled. Einstein has

flight from the eve&day life, with its painful harshness and wretched
dreariness, and from the fetters of one's own shifting desires. .
With this negative motive there goes a positive one. Man seeks to
form for himself, in whatever manner is suitable for him, a simplified

olaces the center of eravitv of his emotional life, in order to attain the         I

In his protocol experiments, Avery behaved much as artists do in their
efforts to convey their response to the external world. Artists deal with
limited aspects of reality. selecting from it only what they need to express
an inner vision or concept. Furthermore, they deliberately impose on
themselves limits as to their mode of expression -for example, a sonnet or

itself or the painting itself-as a new creation and as a personal vision of
reality. The frame placed around a picture symbolizes that the painter has
elected to separate from the cosmos a fragment of nature and to make of it
a self-sufficient entity through his own interpretation and vision. Similarly,
the design of an experiment provides a pattern of reality controlled and
shaped by the mind of the experimenter.

When Avery displayed a phenomenon with a few test tubes or animals,
he gave an independent existence to a fragment of reality and created his
view of scientific truth. For him, science was more than problem-solving or
the accumulation of facts. It meant recognizing patterns in the apparent
chaos of nature and composing the raw materials of nature into artistic
creations.


ENVOI

I   The spirit of scientific research which emerged in American medicine
   around the turn of the century was incarnated in The Rockefeller Institute
   for Medical Research. A letter written by Simon Flexner shortly after
   retiring from his directorship of the Institute shows that Avery was for him

I      Institute . that you came there so early in the Hospital's history and
    are still there to carry on your most important and original work, which
    no one else could possibly have done as you have done it. . . . There is
    no one that I have got more pleasure and stimulation in talking with
       .l                      P      . .a     . 1           1 .   I'

extraordinary statement of what Avery meant to the Institute. Avery, on
the other hand, knew that the Institute had been for him an ideal spiritual
home, one in which he had discovered himself or, more exactly, made
himself into what he wanted to become. In 1945, two years after his own
official retirement, he wrote Flexner, "No words of mine can ever convey
to you my gratitude for all you have done and made possible for me these
many years" 2 (italics mine). What Flexner and the Institute had made
possible was to cultivate in full freedom a few characteristics that gave a
distinctive and unique quality to Avery's scientific style and personal life.

Avery was remarkable as a scientist by his ability to recognize important
problems and by his mastery of the experimental method, but even more
by his research style. Everything he did in his adult life had an artistic
quality governed by a classical taste and a strict discipline. He shunned
uncertainty, vagueness, and overstatement in scientific matters as much as
in everyday life.

He did not have a robust enough temperament to deal effectively with
complex, ill-defined situations, such as those commonly presented by
clinical and social problems, but he had immense intellectual vigor in
selecting from the confusion of natural occurrences the few facts most
significant for the problems he elected to investigate, and he had the
creative impulse to compose these facts into meaningful and elegant
structures. His scientific compositions had, indeed, much in common with


182    THE PROFESSOR, THE  INSTITUTE,  AND DNA

Avery applied disciplined creativeness both to his scientific work and to
the development of his personality. He retained throughout his life the
perceptive, intelligent, determined, and also impish and whimsical expres-
sion that had characterized him during his youth and college years. In
adulthood and old age, however, his face radiated, in addition, tolerance,
sympathy, wisdom, and a romantic inwardness. "At 50, everyone has the
face he deserves." 3 This was especially true of Avery, whose adult face
achieved a rich mellowness that testified to the prodigious control he
exerted over all aspects of his temperament. He certainly believed with
Montaigne that each of us can "discover in himself a pattern all his own"
and that "to compose our character is our duty." 4 In the end, his most
glorious masterpiece was the persona he created by cultivating at e;ich
phase of his intellectual and emotional development those aspects of his
nature that made him function best in each particular situation.

Those who have known The Professor admire him for what he com-
posed as a scientist; but they remember him even more vividly for the art
with which he composed his character and his life.


Board of Scientific Directors of The Rockefeller Institute.

The Professor and the Institute

I, Blake. William. 1965. The Marriage of Heuven und Hell. Pinto, Vivian, Ed.
  New York: Schocken, p. 101.
2. Bacon, Francis. 1960. The Nerz? Organon and Related Writings. Anderson. F.
  H., Ed. New York: Liberal Arts Press, p. 96.
3. Pasteur, Louis. 1926. Oeuvres de Pasteur. Vol. 7. Paris: Masson et Cie.. pp.
   200, 327.

4 Corner. George. 1964. A History of The Rockefeller Institute. New York: The

  Rockefeller Institute Press. pp. 39-41.
5. Ibid., p. 55.
6. Ibid., p. 64.
7. Ibid., p. 94.

1. Flexner. S. and Flexner, J. T. 1941. William Henry Welch and the Heroic Age
  of American Medicine. New York: Viking, p. 230.
2. Corner, G. W. 1965. Two Centuries of: Medicine: A History of the School of
  Medicine, University of Pennsylvnnia. Philadelphia: J. B. Lippincott. Chap-
  ter 2. See also: Fleming, D. 1954. Wiflium H. Welch and the Rise of Modern
  Medicine. Boston: Little. Brown, p. 4.
3. Gushing. H. 1925. The Life of Sir William Osler. Vols. I and II. Oxford:
  Clarendon, p. 546.

4. Cohn, Alfred. 1948. No Rerreat from Reason. New York: Harcourt. Brace. p.
   34.

5. Flexner and Flexner. Op. cit., p. 291.
6. Ibid.
7. Ibid., p. 112.

8. Fleming, D. Op. cir., p. 7.
9. Eggerth. Arnold. 1960. The History ofthe Hoagland Laboratory. New York:
    n.p.
IO. Ibid., p. 43.
11. Ibid., p. 110.

I?. Flexner and Flexner. Op. cit., pp. 269-296. See also: Corner, G., 1964. A
  History of the RockefelIer Institute. New York: The Rockefeller Institute
    Press.


184   THE PROFESSOR. THE INSTITUTE. AND DNA

13. Ibid., pp. 578-580.

14. Flexner and Flexner. Up. cit., and Corner. Op. cir.
15. Corner, G. W. Op. cit., facing title page.
16. Fleming, D. Op. cit., p. 153.
17. Flcxnrr and Flexner. Op. cir., p. 289.
18. Bernard. Claude. 1885. Lqnns .SUY le.7 phhnom&~es de la vie ~wr7m~t7~ aux
  unimaux et UUY v~g~taux. Paris: J. B Bailliere.
1Y. Corner, G. W. Op. cit., p. 89.
20. Flexnrr, Simon. lY3Y. The Evolution and Organization of the Universit)
   Clinic. Oxford: Clarendon Press. p. 18.
21. Ibid., p. 26.

22. Swift. Homer. 1928. The art and science of medicine. Science 68: 167. See
   also: Cohn, Alfred, 1931, Medicine, Science and Art: Studies in Interrela-
  tions. Chicago: Univ. of Chicago Press. Also: Rivers, T. 1950. Concepts
  and Methods of Medical Research. The George R. Siedenburg Memorial
  Lecture. In: Frontiers in Medicine. New York: Columbia Univ. Press, p.
    120.

23. Benison, S. 1967. Tom Rivers: Reyections on a Life in Medicine ond Science.

  Cambridge, Mass.: M.I.T. Press. p. 200.
23. Ibid., p. 196.

25. Flexner. Abraham. 1 Y 10. Medical Education irr the United States and Cunada.

  Carnegie Foundation. Bulletin Number 4.
26. Flexner, Simon. Op cit., p. 37.
27. de Kruif, Paul. Op. cit., p. 16.
28. Flexner. Simon. Op. ci/., p. 37.
29. Ibid., p. 3.5.

CHAPTER THREE

Chemistry in Medical Research

1. Corner, George. 1964. A History of The Rockefeller Institute. New York: The
  Rockefeller Institute Press. pp. 578-580.
2. Flexner, S., and Flexner, J. T. 193 1. William Hemy Welch and the Heroic Age
  of American Medicine. New York: Viking, p. 280.
3. Ibid., p. 282.
4. Ibid., p. 276.
5. Ibid., p. 289.
6. Ibid., p. 55.
7. Ibid., p. 63.

8. Corner, G. W. Op. cit., p. 13. See also: Hawthorne, Robert. lY74. Christian
  Archibald Herter, M.D. (1865-1910). Perspect. Biol. Med. 18: 24-39.
Y. Flexner and Flexner. Op. cit., p. 283.
10. Ibid.
11. Ibid., p. 284.

12. Quoted in Dubos, R. 194.5. The Bacterial Cell. Cambridge: Harvard Univ.
   Press, p. 229.


13. ibid., p. 92.

14. Fleming. Donald. 1964. Introduction to Lo&, Jacques. The Mechunistic
  Conception of Life. Cambridge: Harvard Univ. Press. p. viii.
15. Ibid. See also: Osterhout, W. J. V. 192X. Jacques Loeb. J. Germ. Physiol. 8:
  ix-Iv. Also: Reingold, Nathan. 1962. Jacques Loch, the Scientist. Library
   Congr. Quart. J. 19: 119-l 30.
16. Fleming, D. Op. cit., p. xiii.
17. Ibid., p. xviii.

18. Osterhout, W. J. V. Op. cit., p, xviii.
19. Ibid., p. Ii.

20. de Kruif. Paul. 1962. The Sweeping Wind. New York: Harcourt, Brace and
   World, p. 16.

21. Cohn, Alfred. 1948. No Retreat from Reason New York: Harcourt. Brace.
   p. 263.
22. Ibid., p. 264.

23. Osterhout. W. J. V. Op. cit., p. xxiii.
24. Fleming. Donald. 1954. William H. Welch and the Rise of Modern Medicine.
   Boston: Little. Brown. p. 153.
25. Corner, G. W. Op. cit.. pp. 328-329.

Avery's Personal Life

1. Avery. 0. T. 1044. Karl Landsteiner. J. Pathol. Bacterial. 56: 592.
2. Bernard. Claude. 1942. Le Cahier Rouge. Paris: Gallimard. p. 119.
3. Flexner. S., and Flexner, J. T. 194 1. William Henry Welch and the Heroic Age
   of American Medicine. New York: Viking.
4. Unless otherwise noted, the material concerning the Avery family is in the
   personal collection of Mrs. Roy Avery. or The Manuscript Unit. Archives
  and Records Services Section, Tennessee State Library and Archives, Nash-
   ville, Tennessee. Accession Number 70-I 28.
5. Buds and Blossoms, Vol. X. Jan., 1886.
6. Buds and Blossoms, Vol. XI. Aug., 1887.
7. Buds and Blossoms. Vol. XV, May, 1891.
8. Rockefeller Family Archives, New York. Record Group I, March 12, 189 1.
Y. Ibid., December 2, 1890.
10. Ibid., December 29, 1893.
1 I. Ibid., December 30, 1890.

12. Flynn, J. 1932. God's Gold. New York: Harcourt. Brace, p. 26Y. See also:

   Nevins, Allan. 1959. John D. Rockefeller. New York: Scrihner's, p. 224.
13. Buds and Blossoms, Vol. XVI, Dec., 1892.
14. Buds und Blossoms, Vol. XVI. Apr., 1892.
15. Letter to author, dated October 6. 1975.
16. Buds and Blossoms, Vol. XVI, Apr.. 1892.
17. Ibid.


186   THE PROFESSOR, THE INSTITUTE, AND DNA

18. Buds and Blossoms, Vol. XIII, June, 1889.
19. Buds and Blossoms, Vol. XVI. Apr., 1892.
20. Williams, Howard. 1969. A History of Colgate University, IRlY-lY69. New

    York: Van Nostrand Reinhold.
21. Fosdick, Harry Emerson. 1056. The Living of These Days. New York: Har-
   per, p. 53.
22. Ibid., p. 58.

23. Salmagundi 1900. Colgate University Yearbook, p. 28.
24. Ibid., p. 31.
25. Ibid.

26. Colgate University Archives, Hamilton, New York.
27. Cofgute Alumni News, August. 1965, p. 22.
28. Coburn. A. F. lY74. Commitment Total. New York: Walker, p. 186.
29. Dochez, A. R. 1958. Oswald Theodore Avery. National Academy of Sciences
   Biogruphical Memoirs. Vol. 32. New York: Columbia Univ. Press, p. 31.
30. Eggerth, Arnold. 1960. The History ofthe Hoagland Laboratory. New York:
   n.p.. p. 125.
31. Ibid., pp. 125-26.

32. Heidelberger. M., Kneeland, Y.. Jr., and Price, K. 1971.Alphonse Raymond
   Dochez. National Academy of Sciences Biographical Memoirs. Vol. 42. New
   York: Columbia Univ. Press, p. 39.
33. MacLeod, Colin. September 29, 1965. Remarks delivered at the dedication of
   the Avery Gateway. Rockefeller University Archives.
34. Chesney, Alan. 1957. Oswald Theodore Avery. J. Pathol. Bacterial., 74: 454.
3.5. Letter to author dated November 7. 1975.
36. Letter to author, from Mrs. Margaret Brearley. dated November 14, 1975.
37. Ibid.
38. ibid.

  R. Dochez. Trans. Assoc. Am. Physicians 62: 28.
2. Avery, 0. T. 1946. Acceptance of the Kober Medal Award. Trans. Assoc.
  Am. Physicians 59: 45.
3. BSD. 1923-24. Vol. 12, 138.
                   p.
4. MacLeod. Colin. 1957. Oswald Theodore Avery, 1877-1955. J. Gen. Micro-
   biol. 17: 543.

5 McCarty, Maclyn. 1965. Oswald T. Avery and his scientific legacy. Rockefel-
  ler University Reviertf, Sept.-Oct.. p, 12.
6. Quoted in Scientific Research, October, 1967, n.p.
7. Loir, Adrien. 1938.A I'ombre de Pasteur. Paris: Le Mouvement Sanitaire, pp.
   2X. 50.


8. Hotchkiss, R. D. 1965. Oswald T. Avery. Generics 51: 3
9. Ibid., 4.
     p.

I    IO. Ibid., p. 3.

CHAPTER SEVEN

and the Chemistry of the Host

I. Dochez, A. R.. and Avery, 0. T. 1916. Antiblastic immunity. J. Exp. Med.

    23: 61-68.
2.  BSD. April. 1915. Vol. 4. 108.
                    p.
3. ibid., p. 73.
4. Dochez and Avery. Op. cit., p. 67.
5.  BSD. 1916. Vol. 4, 253.
               p.
6. Dochez and Avery. Op. cit., p. 68.
7.  BSD. IYI 6. Vol. 4. 252-253.
               p.
8.  BSD. 1910. Vol. 7. 368.
               p.
Y. Blake, F. G. 1017. Studies on antiblastic immunity. J. Exp. Med. 26: 563.
IO. Barber, M. A. 1919. A study by the single cell method of the influence of

I I, Marrack. J. R. 1950. Antibodies to Enzymes. In: Myrb%ck, K.. and Sumner,
  J. B., (Eds.). The Enzymes. Vol. I. New York: Academic Press. See also:
  Sevag, M. G. 1951. Immune-catulysis. Springfield, Ill.: C. C Thomas.
12. Krebs, E. G., and Najjar. V. A. 1948. The inhibition of D-glyceraldehyde 3-
  phosphate dehydrogenase by specific antiserum. J. Exp. Med. 88: 569-577.
13. BSD. 1916. Vol. 4, p. 253.

14. BSD. April, 1920. Vol. 8, p. 101.
IS. BSD. Oct., 1920. Vol. 8, p. 248.
16. BSD. 1923-24. Vol. 12, p. 130.
17. Hotchkiss, R. D. 1965. Oswald T. Avery. Generics 51: 5.
18. Avery, 0. T. 1941. The Commonwealth of Science. Presidential Address

   before the American Society of Bacteriologists. Unpublished typescript.
   personal property of author.
19. Ibid., p. 1.
20. Ibid., p. 8.

The Chemical Basis of Biological Specificity

1. Avery, 0. T.. Chickering, H. T.. Cole, R.. and Dochez, A. R. 1917. Acute


188   THE PROFESSOR. THE INSTITUTE, AND DNA

   Lobar Pneumonia: Prevention und Serum Treutment. New York: The
  Rockefeller Institute for Medical Research. Monograph No. 7.
2. BSD. 1936-37. Vol. 25, 314-15.
                    pp.
3. Dochez. A. R.. and Avery, 0. T. 1917. Soluble substance of pneumococcus
  origin in the blood and urine during lobar pneumonia. Proc. Sot. Exp. Biol.
    Med. 14: 126.

Dochez, A. R.. and Avery, 0. T. 1917. The elaboration of specific soluble
  substance by pneumococcus during growth. J. Exp. Med. 26: 477.
4. BSD. April, 1917. Vol. 5. 137.
                     p.
5. Dochez and Avery. Op. cit., J. Exp. Med., p. 493.
6. BSD. 1922-23. Vol. 11, 145.
                    p.
7. ibid., 146.
       p.
8. BSD. 1923-24. Vol. 12, 136.
                    p.
9. Ibid.. 137.
       p.
10. Ibid., 140.
       p.
11. Ibid., 142.
       p.
12. BSD. 1924-25. Vol. 13, 306.
                   p.
13. BSD. 1925-26. Vol. 14, 622.
                   p.
14. Ibid., 624.
       p.
15. BSD. 1924-25. Vol. 13, 312.
                    p.
16. Ibid., 310.
       p.
17. Goebel. Walther. 1975. The golden era of immunology at The Rockefeller
   Institute. Perspect. Biol. Med. 18: 419-426.
18. BSD. 1930-31. Vol. 19, 412-413.
                   pp.
19. Landsteiner, Karl. 1962. The Specificity of Serological Reactions. New York:
   Dover, p. 176.
20. BSD. 1924-25. Vol. 13, 310.
                    p.
21. Northrop, J. H., and Goebel, Walther, F. Crystalline pneumococcus antibody.
   J. Gen. Physiol. 32: 705.

CHAPTER NINE

The Complexities of Virulence

1. Avery, 0. T. 1941. The Commonwealth of Science. Presidential Address
  before the American Society of Bacteriologists. Unpublished typescript,
  personal property of author.

2. BSD. 1930-3 1. Vol. 19. p. 406.
3. Avery, 0. T., Chickering, H. T., Cole. R.. and Dochez, A. R. 1917. Acute
  Lobar Pneumonia: Prevention and Serum Treatment. New York: The
  Rockefeller Institute for Medical Research, Monograph No. 7. p. 10.
4. Ibid., p. 16.

5. BSD. 1923-24. Vol. 12, p. 339,
6. BSD. 1926-27. Vol. 15, p. 519.
7. ibid.

8. MacLeod, C.. and McCarty, M. 1942. The relation of a somatic factor to
  virulence of pneumococci. J. C/in. Invesf. 21: 647.


      I.                                                    A.. , .C..U.
/         Sci. 45: 913-16.

1     2. Cohn, F. 1866. Ueber Bacterien, die kleinsten lebenden Wesen. Berlin: Samml.
j       gemeinverst8;ndl. wissenschaftl. Vortrage. hrsg. v. R. Virchow ii. Fr. v.
        Holtzendorff. no. 165.

3. Huxley, T. H. 1870. On the relations of Penicillium, Torula. and Bacterium.

!       Q. J. Microsc. Sci. N. S. 10: 355-62.
/    4. Klebs, E. 1873. Beitrage zur Kenntniss der Micrococcen. Arch. Exp. Parhol.
        Pharmakol. 1: 3 l-64.
/
/    5. Lankester. E. Ray. 1873. On a peach-coloured bacterium-Bacterium rubes-
      tens. Q. J. Microsc. Sci. N. S. 13: 40825.
   6. Billroth, T. 1874. Untersuchungen iiber die Vegetations formen von Coccobac-
      teria septica und den Antheil, welchen sie an der Entstehung und Verbreitung
        der accidentellen Wundkrankheiten haben. Berlin: Reimer.
,

   7. Lister. .l. 1873. A further contribution to the natural history of bacteria and
      the germ theory of fermentative changes. (2. J. Microsc. Sci. N. S. 13; 380-
        408.
/         -. 1876. A contribution to the germ theory of putrefaction and other
      fermentative changes and to the natural history of torulae and bacteria.
      Trans. R. Sot. Edinb. (1872-h). 27: 313-44.
   8. Nageli. C. von. 1877. Die niederen P&e in ihren Beziehungen zu den Infec-
      tionskrankheiten und der Gesundheitspflege. Munich: R. Oldenbourg.
   9. Cohn, F. 1876. Untersuchungen iiber Bacterien. IV. Beitrtige zur Biologie der
        Bacillen. Beitr. BioL. Pflanz. 2 (No. 2): 248-76.

tion. Paris: Gauthier-Villars.

12. Davaine, C. 1872. Recherches sur quelques questions relatives a la sep-
   ticernie. Bull. Acad. MPd., 2nd ser. 1: 907, 976.
1.3. Pastcur. L. 1880. De I'attenuation du virus du cholera des poules. C. R. Acad.
   Sci. 91: 673-80.
14. -. 188 1. De I'attenuation des virus et de leur retour a la virulence. C. R.
   Acad. Sci. 92: 429-35.

15. Firtsch, G. 1888. Untersuchungen iiber Variationserscheinungen bei Vibrio
  proteus. Arch. Hyg. 8: 369-401.

16. Bcijerinck, M. 1901. Mutation bei Mikroben. Versl. Afd. Natuurkunde,
   Akad. Wetznsch (Amsterdam) 9: 3 10.

17. Neisser. M. 1906. Ein Fall von Mutation nach De Vries bei Bakterien und
   andere Demonstrationen. Cent. Bukt. I. Ref. 38: 98.
18. Maxsini. R. 1907. Ueber einen in biologischer Bezeichnung interessanten


1 90    THE PROFESSOR. THE INSTITUTE.  AND  DNA

19. Arkwright, J. A. 1921 Variation in bacteria in relation to agglutination both
   by salts and by specific serum. J. Parhol. Bacterial. 24: 36-60.
20. Ibid., p. 55.

2 1. Dubos, R. 1945. The Bacteriul Cell. Cambridge: Harvard Univ. Press.
22. p. 1932. Factors affecting the yield of specific enzyme in cultures of the
   bacillus decomposing the capsular polysaccharide of type 111 pneumococcus.
   J. Exp. Med. 55: 377-391.
23. p. 1940. The adaptive production of enzymes by bacteria. Bacterial.
    Rev. 4: I-16.

24. Spiegelman. S.. and Campbell, A. 1956. The Significance of Induced Enzyme
   Formation. In: Green, D. E. (Ed.), Currents in Biochemical Research 1956.
   New York: Interscience, pp. 1 15-l 61
25. Karstrom. H. 1937-38. Enzymatische Adaptation hei Mikroorganismen. Er-
   geh. Enzymforsch. 7: 350-376.

26. Jacob. F., and Monod, J 1961 Genetic regulatory mechanisms in the synthe-
   sis of proteins. J. Mol. Biol. 3: 318-356.
27. Dubos. R. 1945. The Bacteria/ Cd/. Cambridge: Harvard Unrv. Press, pp.
    137-143.

28. Ravin. A. 1961. The genetics of transformation. Adv. Genet. 10: 61-l 63.
2Y. Coburn. A. lY74. Commitment Total. New York: Walker. p, 167.
30. Elliott, S. (quoted in Olby, R. lY74. The Path to the Double Helix. Seattle:
   Univ. of Washington Press). p. 170.
31. H. D. W. 1941. Frederick Griffith. Lancer 1: 588.
32. Ibid., p. 589.

33. Griffith, F. 1923. The influence of immune serum on the biological properties
  of pneumococci. In: Reports on Public Hrulth und Medical Subjects. No. 18.
   Bacteriological Studies. London: H. M. S. 0.. pp. 1-13.
34. p. 1928. The significance of pneumococcal types. J. Hyg. 27: 113- 159.
35. H. D. W. Op. cit., p. 588.

36. Griffith, F. 1922. Types of pneumococci obtained from cases of lobar pneu-
  mania. Reports on Public He&h and Medical Subjects. No. 13. Bacteriologi-
  cal Studies. London: H. M. S. 0.. p. 36.
37. -. Op. cit., p. 153.
38. Ibid., p. 153.

39. Neufeld, F., and Levinthal, W. 1928. Beitrage zur Variabilitat der Pneumo-
   kokken. Z. Immunitiitsforsch. 55: 324-340.
40. Reimann, H. 1929. The reversion of R to S nneumococcus. J. Exe. Med. 49:

41. BSD. 1926-27. Vol. IS, p. 269.
42. Dawson, M. 1930. The transformation of pneumococcal types. 1 and 11. J.
   Exp. Med. 51: 99-122 and 123-147.
43. Dawson. M.. and Sia. R.  1931. In vitro transformation of nneumococcal

of different specific types by the use of filtered pneumococcus extracts. J.
El-p. Med. 55: 91-99.


I                            References    191

    -. 1933. Further observations on the use of pneumococcus extracts in
       effecting transformation of tvpe in vitro. J. EXD. Med. 57: 265-278.

Heredity and DNA

1. Hotchkiss, R. 1965. Oswald T. Avery. 1877- 1955. Genetics 5 1: S.
2. Dubos. R., and Thompson, R. lY38. The decomposition of yeast nucleic acid
  by a heat-resistant enzyme. J. Biol. Chem. 124: 501-510.
3. The following discussion is taken from BSD. 1940-41, Vol. ZY, p. 141-146.
4. Avery, 0. T., MacLeod, C.. and McCarty, M. 1944. Studies on the chemical
  nature of the substance inducing transformation of pneumococcal types. J.
  Exp. Med. 79: 137-158.
5. Ibid., p. 155.

6. Mirsky. A. 1947. Contribution to the discussion of Boivin's paper. Co/r1
  Spring Harbor Symp. Quant. Biol. 12: 15-16.
7. Darlington. quoted in Olby, op. cit., p. 192.

I      mation of pneumococcal types. J. Exp. Med. Xl: 501-514.
   10. -. 1946. Purification and properties of desoxyribonuclease isolated from
       beef oancreas. J. Gen. Phvsiol. 29: 123-139.

I      inducing transformation of pneumococcal types. Bacterial. Rev. 10: 63-7 1 .
  12. McCarty. M., and Avery. 0. 1946. Studies on the chemical nature of the
       substance inducing transformation of nneumococcal  tvnes. 11. Effect of

  desoxyribonuclease on the biological activity of the transforming substance.
   J. Exp. Med. 83: 89-96.
13. -. 1946. Studies on the chemical nature of the substance inducing
  transformation of pneumococcal types. Ill. An improved method for the
   isolation of the transforming substance and its application to pneumococcus
   types II. III. and VI. J. Exp. Med. X3: 97-104.
14. McCarty, M., Taylor, H. E., and Avery, 0. T. 1946. Biochemical studies of
   environmental factors essential in transformation of pneumococcal types.
   Cold Spring Harbor Symp. Quunt. Biol. 11: 177-l 83.
15. MacLeod, C. M., and Krauss, M. R. 1947. Stepwise intra-type transformation
   of pneumococcus from R to S by way of a variant intermediate in capsular
   polysaccharide production. J. Exp. Med. 86: 439-453.
16. Hotchkiss, R. D. 1048. Etudes chimiques sur le facteur transformant du
   pneumocoque. In: Lwoff, A. (Ed.). L . ey unit&s biologiques do&es de contin-
   uitP ginh'que. Paris: C. N. R. S., pp. 57-65.
17. Austrian. R., and MacLeod. C. M. 1949. Acquisition of M protein bv
             . .     .                     .  -      . ,. ,.  - _  . , ,.-

I   18. Taylor, H. E. 1949. Transformations reciproques des formes R et ER chez le


192    THE PROFESSOR, THE INSTITUTE, AND DNA

19. Taylor, H. E. 1949, Additive effects of certain transforming agents from some
   variants of pneumococcus. J. Exp. Med. 89: 399-424.
20. Ephrussi-Taylor, H. E. 1951. Transformations allogenes du pneumocoque.
   Exp. Cell Res. 2: 589-607.
21. -.  1951.  Genetic asnects of transformations of oneumococci.  Cold

22. Hotchkiss, R. D. 1951. Transfer of penicillin resistance in pneumococci by the
    desoxvribonucleate derived from resistant cultures. Cold Saring Harbor

23.

24.

25.

26.

21.

28.

29.

30.

31.

32.

33.

34.

Hotchkiss, R. D., and Ephrussi-Taylor, H. E. 1951. Use of serum albumin as
source of serum factor in pneumococcal transformation. Fed. Proc. 10: 200.
Hotchkiss, R. D. 1952. The role of desoxyribonucleates in bacterial transfor-
mations. In: McElroy. W., and Glass, B. (Eds.). Phosphorus Merubolism.
Vol. II. Baltimore: Johns Hopkins Univ. Press, pp. 426-436.
Ephrussi-Taylor, H. E. 19.54. A new transforming agent determining pattern
of metabolism and glucose and lactic acids in pneumococcus. Exp. Cell Res.
6: 94-116.

Hotchkiss, R. D. 1954. Cyclical behavior in pneumococcal growth and trans-
formability occasioned by environmental changes. Proc. Natl. Acad. Sci. 40:
49-55.

Hotchkiss. R. D., and Marmur. J. 1954. Double marker transformations as
evidence of linked factors in deoxyribonucleate transforming agents. Proc.
Natl. Acad. Sci. 40: 55-60.

Ephrussi-Taylor, H. E. 195.5. Current status of bacterial transformations.
Adv. Virus Res. 3: 275-301.

Hotchkiss, R. D. 1955. The Biological Role of the Deoxypentose Nucleic
Acids. In: Chargaff, E., and Davidson, J. N. (Eds.), Nucleic Acids. Vol. II.
New York: Academic Press, pp. 435-473.
-_ 1955. Bacterial transformation. J. Cell. Camp. Physiol. 45: (Suppl. 2)
1-14.

Marmur, J., and Hotchkiss, R. D. 1955. Mannitol metabolism a transferable
property of pneumococcus. J. Biol. Chem. 214: 382-396.
Hotchkiss, R. D. 1956. The Genetic Organization of the Deoxyribonucleate
Units Functioning in Bacterial Transformations. In: Gaebler. 0. H. (Ed.).
Enzymes: Units of Biological Structure and Function. New York: Academic
Press, pp. 119-130.

MacLeod, C. M., and Krauss, M. R. 1956. Transformation reactions with two
non-allelic R mutants of the same strain of pneumococcus type VIII. J. E?rp.
Med. 103: 623-638.

Ephrussi-Taylor. H. E. 1957. X-ray inactivation studies on solutions of trans-
forming DNA from pneumococcus. In: McElroy. W., and Glass, B. (Eds.),
Chemical Basis of Hereditv. Baltimore: Johns Hopkins Univ. Press, pp.

35. Fox, M. S., and Hotchkiss, R. D. 1957. Initiation of bacterial transformation.
    Nature 179: 1322-1325.

36. Hotchkiss, R. D. 1057. Criteria for Quantitative Genetic Transformations of
   Bacteria. In: Chemical Basis of Heredity, op. cit.. pp. 321-325.


37. Ephrussi-Taylor, H. E.

   induced Transformations. In: Tunevalle, G. (Ed.).
   crobiology. Springfield, Illinois: C. C Thomas, pp.
38. Hotchkiss, R. D. 1958. Size limitations governing the incorporation of genetic
   material in bacterial transformations and other nonreciprocal recombina-
   tions. Symp. Sot. Exp. Biol. 12: 49-59.
39. Hotchkiss. R. D., and Evans, A. H. 1958. Analysis of the complex sulfon-
  amide resistance locus of pneumococcus. Cold Spring Harbor S,vmp. Quant.
    Biol. 23: 85-97.

40. Ephrussi-Taylor, H. E. 1960. On the biological functions of deoxyribonucleic
   acid. Symp. Sot. Gen. Microbial. 10: 132-154.
41. p_ 1960. L'Ctat du DNA transformant au tours des premieres phases de
    la transformation bacterienne. C. R. Sot. Biol. 154: 1951-1955.
32. -_ 196 1. Recombination Analysis in Microbial Systems. In: Growth in
   Living Systems. New York: Basic Books.
43. Lwoff, A. 194'). Unites biologiques do&es de continuite genetique. Colloq.
   Int. Cent. Natl. Rech. Sci. No. 8, p. 202.
44. Hotchkiss, R. D. 1966. Gene, Transforming Principle, and DNA. In: Cairns,
   J.. Stent, G., and Watson, J. (Eds.). Phage and the Origins of Molecular
  Biology. Cold Spring. N. Y.: Cold Spring Harbor Laboratory of Quantita-
   tive Biology, p. 194.

45. BSD. 1946-47. Vol. 35. pp. 126-l 27.
46. Hotchkiss. R. D. 1966. Op. cit., pp. 193-194.
47. -. 1965. Oswald T. Avery, 1877-1955. Generics 51: I-10, p. 6.
48. Fleming. D. 1969. Emigre Physicists and the Biological Revolution. In:
   Fleming, D., and Bailyn, B. (Eds.). The lntellecfuaf Migration. Cambridge:
   Harvard Univ. Press. pp. 152-189.

4Y. Olby, R. 1974. Intellectual Migrations. In: The Path to the Double Helix-.
   Seattle: Univ. of Washington Press, pp. 223-320.
50. Stent. G. S. 1972. Prematurity and uniqueness in scientific discovery. Sci. Am.

5 I Dunn, L. C. 195 I Genetics in the Twentieth Century: Essays on the Progress of
   Genetics during its First Fifty Years. New York: Macmillan.
52. Stent, G. S. 1972. Op. cit., p. 84.
53. Dobzhansky. T.. quoted in Olby, 1974, op. cit., p. 189.
54. Dobzhansky. T. 1941. Genetics and the Origin of Species. New York: Colum-
   bia University Press.
55 Hutchinson, G. E. 1945. The biochemical genetics of pneumococcus. Am. Sci.
    33: 56-57.

56. Marshak, A.. and Walker, A. C. 1945. Mitosis in regenerating liver. Science
    101: 94-95.

57. Wright, S. 1945. Physiological aspects of genetics. Ann. Rev. PhysioL. I: 79,
    83.

58. Beadle, G. W. 1948. Genes and biological enigmas. Am. Sci. 36: 71.
50. Burnet. Sir F. M. 1968. Changing Patterns: An Atypical Biography. London:
   Heinemann. p. 81.
60. Lwoff, A. 1949. Op. cif.


185A: 128.

62. Mirsky, A. 1947. Contribution to the discussion of Boivin's paper. Cold
   Spring Harbor Symp. Quant. Biol. 12: 15-l 6.
63. Chargaff, A. Quoted in Olby. Op. cit., p. 21 1.
63. Watson, J. D. 1968. The Double Hefix. New York: Atheneum. pp. 23, 48.
65. Stent, G. S. 1972. Op. cit., p. 84.
66. Benzer, S. 1966. Adventures in the rI1 Region. In: Cairns, J., et al. (Eds.).
   Phage and the Origins of Molecular Biology. Op. cit., p. 158.
67. Kalckar, H. M. 1966. High Energy Bonds: Optional or Obligatory. In: Phage
   and the Origins of Molecular Biology. Op. cit., p. 46.
68. Stent. G. 1966. Waiting for the Paradox (Introduction). In: Phage and the
   Origins of Molecular Biology. Op. cit., p. 4.
69. Hotchkiss. R. D. 1965. Op. cit., p. 2.
70. Watson. J. D., and Crick, F. 1953. Molecular structure of nucleic acids. A

-_ 1953. Genetical implications of the structure of deoxyribonucleic acid.
    Nuture 17 1: 964-967.
71. Schuck. H., et al. 1962. Nobel, the Man and his Prizes. New York: Elsevier, p.

CHAPTER TWELVE

As I Remember Him

1. Flexner, S., and Flexner, J T. 1941. William Henry Welch und the Heroic Age
  of American Medicine. New York: Viking, pp. 455-56.
2. Dr. Stuart Elliott, private communication.
3. Avery, 0. T. 1941. The Commonwealth of Science. Presidential Address
  before the American Society of Bacteriologists. Unpublished typescript,
  personal property of author. All following quotations are taken from this
  typescript.

4. Magee. Bryan. 1973. Popper. London: Collins, Chapter 3.
5. Medawar. P. B. 1967. The Art of the Soluble. London: Methuen.
6. Pasteur, Louis. 1926. Oeuvres de Pasteur. Vol. 7. Paris: Masson et Cie., pp.
   363-64. 390.

7. Wood, W. Barry, Jr. 1971. "Leaders in American Medicine," audiovisual
  memoir T/V2107. Alpha Omega Alpha Honor Medical Society and Na-
  tional Library of Medicine/National Medical Audiovisual Center.
8. Quoted in Chandrasekhar, S. 1975. Shakespeare. Newton and Beethoven. or
  Patterns of Creativity. The Nora and Edward Ryerson Lecture. Chicago:
  University of Chicago Center for Policy Study, p. 28.

10. Cushing, H. 1925. The Life of Sir William Osler. Oxford: Clarendon. Vol. I.,
      I I <>


I?. Dubos, R. 1976. Louis Pasteur, Free Lance of Science. New York: Scribner's
   (reprint).

13. Einstein, A. 19.55. Ideus and Opinions ofAlbert Einstein. New York: Crown,
   pp. 224-227.

1. Simon Flexner Papers. American Philosophical Society Library, Philadelphia,
  letter dated January 20. 1936.

2. Ibid., letter dated April 9, 1945.
3. Orwell, George. 1968. The Collected Essays, lourna~ism and Letters. IV. In
  Front of Your Nose 1945-l 9.50. Orwell, Sonia, and Angus, Ian (Eds.). New
  York: Harcourt, Brace and World, p. 515. See also: Camus. Albert. 1962.
  La Chute. Paris: Pleiade, p. 1502.

4. Montaigne, Michel de. 1958. The Complefe Essays (Translated by D. Frame).
   Palo Alto: Stanford Univ. Press. D. 615.

1. Ravin, A. 1961. The genetics of transformation. Adr. Genet. IO: 61-163.
2. Ibid.

3 Chargaff. E. 1950. Chemical specificity of nucleic acids and the mechanism of
  their enzymatic degradation. Experientia 6: 201-209.
p. 1957. The Base Composition of Desoxyribonucleic Acid and Pentose
  Nucleic Acid in Various Species. In: McElroy, W., and Glass. B. (Eds.). A
  Symposium on rhe Chemical Basis of Heredity. Baltimore: Johns Hopkins
  Press, pp. 521-527.

4. Chargaff, quoted in Robert Olby. 1974. The Path ro the Double He/ix. Seattle:
  Univ. of Washington Press, p, 21 1.
5. Robinow, C. 1942. A study of the nuclear apparatus of bacteria. Proc. R. Sot.
   Lond. B. Biol. Sci. 130: 299-324.

6. Tulasne, R. 1947. Sur la mise en evidence du noyau des cellules bacteriennes.
   C. R. SPances Sot. Biol. 141: 41 l-413.
7. Tulasne. R.. and Vendrely, R. 1947. Demonstration of bacterial nuclei with
   ribonuclease. Nature 160: 225-226.

8. Hershev, A., and Chase, M. 1952. Independent functions of viral proteins and
nucleic acid in growth of bacteriophage. /. Gen. Physiol. 36: 39-56.
9. Boivin, A.. Vendrely, R., and Vendrely. C. 1948. L'acide desoxyribo-
  nucleique du noyau cellulaire, depositaire des caracteres hertditaires; argu-
  ments d'ordre analytique. C. R. Hebd. Se'ances Acad. Sci., Paris 226: 1061-
   1063.


196   THE PROFESSOR, THE INSTITUTE, AND DNA

10. Mirsky, A., and Ris, H. lY49. Variable and constant components of chromo-
   somes. Nature 163: 666-667.

Il. Luria, S., and Delbriick, M. 1943. Mutation of bacteria from virus sensitivity
   to virus resistance. Genetics 2X: 491-511.
12. Tatum. E.. and Lederberg, J. 1947. Gene recombination in the bacterium
   Escherichia coli. J. Bacferiol. 53: 673-684.

_ __  -.. .--. .
        ) ,
   Bacterial. 64: 679-699.
14. Zinder, N. lY55. Bacterial transduction. J. Cell. Comp. Physiol. 45 (Suppl.
   2): 23.
15. Lederberg, J. 1956. Genetic transduction. Am. Sci. 44: 264-280.
16. Ravin. A. 1960. The origin of bacterial species. Bacterial. Rev. 24: 201-220.
-. 1961. The genetics of transformation. Adv. Genet. IO: 61-163.


  I .  SOME EVENTS OF AVERY'S LIFE

ARRANGED IN CHRONOLOGICAL ORDER

Oct. 21. 1877
     1887
      1893
  1893-1896
  18Yh-lY00

1900- 1904

lYO3-I907
  c. 1906

1907-1913

1913-1948

lY17
1918

      1948
Feb. 20, 1955

1921
1933
1947
1950
1954

Born in Halifax

His family moves to New York City
Graduates from New York City Male Grammar School
Attends Colgate Academy in Hamilton, New York
B.A. from Colgate University vvith emphasis on humanistic

studies and public speaking
M.D. from Columbia Universitv College of Physicians and

           _   --...  -..,
Medical practice (general surgery) in New York City
Given a research grant from New York City Board of Health to
work on opsonic index
Worked on milk pasteurization in bacteriological laboratory at
the Sheffield Dairy Company, Brooklyn
Associate Director of bacteriological department at the Hoag-
land Laboratory, Brooklyn
The Rockefeller Institute for Medical Research, New York
1913-1915 Assistant, Department of Hospital
1 Y 15-l 919  Associate, Department of Hospital
191 Y-lY23 Associate Member
1923- 1943 Member
1943-l 948 Emeritus Member
Private, U.S. Army

Acquires American citizenship
Captain, U.S. Army

Leaves New York for final retirement in Nashville, Tennessee
Dies of cancer of the liver
Buried in Mt. Olivet Cemetery, Nashville

HONORARY DEGREES

Sc.D., Colgate University
L.L.D.. McGill University
Sc.D., New York University
Sc.D., University of Chicago
Sc.D., Rutgers University


1930
1932
1933
1944
1945
1946
1946
1947
1949
1950

AWARDS

Joseph Mather Smith Prize, Columbia University
John Phillips Memorial Medal, American College of Physicians
Paul Ehrlich Gold Medal (Germany)
Medal of the New York Academy of Medicine
Copley Medal, Royal Society of London
Kober Medal, Association of American Physicians
Charles Mickle Fellowship, University of Toronto
Lasker Award, American Public Health Association
Passano Award, Passano Foundation
Pasteur Gold Medal, Swedish Medical Society of Stockholm

   SCIENTIFIC ORGANIZATIONS

Domestic

American Academy of Arts & Sciences

(President, 1934)
American Society of Clinical Investigation

Harvey Society

National Academy of Sciences
New York Academy of Medicine
Society for Experimental Biology and Medicine
Society of American Bacteriologists (President, 1942)
Society of Experimental Pathology

Foreign

Academic Royale de Medecine de Belgique
Der Norski Videnskaps Academi, Oslo
Pathological Society of Great Britian and Ireland
Royal Danish Academy of Science and Letters
Royal Society of London
Societe Philomatique de Paris
Society of General Microbiology, England

1942   Consultant to Secretary of War and Member of Board for Study
     and Control of Epidemic Diseases, U.S. Army.
1943   Member of Sub-Committee on Infectious Diseases, National
      Research Council
1948   Consultant and Member of Commission on Streptococcal Dis-
             -.. __.._    .". .     ,_


II .  SCIENTIFIC PUBLICATIONS OF AVERY

      AND HIS COLLABORATORS

Work done at The Hoagland Laboratory
           1909

White, B., and Avery, 0. T. The treponema pallidum; observations on its occur-
rence and demonstration in syphilitic lesions. Arch. Int. Med. 3:411.
                         1910

Potter, N. B., and Avery, 0. T. Opsonins and vaccine therapy. In: Modern
Treatment, edited by Hare. Philadelphia and New York, Vol. I, p. 515.
White, B., and Avery, 0. T. Observations on certain lactic acid bacteria of the so-
called Bulgaricus type. Cbl. Bakt., Abt. II. 25:161_
Ager, L. C., and Avery, 0. T. A case of influenza meningitis. Arch. Pediat.
24:284.

White, B., and Avery, 0. T. Concerning the bacteriemic theory of tuberculosis. J.
Med. Res. 23105.
                        1912
White, B., and Avery, 0. T. The action of certain products obtained from the

26:317. -

1913

Avery, 0. T., and Lyall, H. W. Concerning secondary infection in pulmonary
tuberculosis. J. Med. Res. 28: 111.
White, B.. and Avery, 0. T. Some immunity reactions of edestin. The biological
reactions of the vegetable proteins. III. J. In5 Dis. 13: 103.
                         1914

North, C. E., White. B., and Avery, 0. T. A septic sore throat epidemic in
Cortland and Homer, N. Y. J. mf. Dis. 14:124.
    Work done at The Rockefeller Institute for Medical Research

1915

Dr. Avery became a Member of the Institute in 1923. From then
on, the names entered in parentheses for each academic year (July 1
to June 30) are those listed in the Annual Report to the Board of
Scientific Directors. The list includes the departmental members of
the scientific staff (M.D.`s, Ph.D.`s, and Guest Investigators) dur-

ing the designated years; it does not include laboratory technicians
or other helpers. (Inconsistencies in the original lists are reproduced
here .)

Dochez, A. R., and Avery. 0. T. Varieties of pneumococcus and their relation to
lobar pneumonia. J. Exp. Med. 21:l 14.
Avery, 0. T. The distribution of the immune bodies occurring in antipneumococ-
cus serum. J. Exp. Med. 21:133.

Dochez, A. R.. and Avery, 0. T. The occurrence of carriers of disease-producing
types of pneumococcus. J. Exp. Med. 22: 105.


200   THE PROFESSOR, THE INSTITUTE, AND DNA

Avery, 0. T. A further study on the biologic classification of pneunococci.J. Exp.
Med. 22:X04.
                         1916

Dochcz, A. R., and Avery, 0. T. Antiblastic immunity. J. Exp. Med. 23:hl.
Dochez. A. R.. and Avery, 0. T. Soluble substance of pneumococcus origin in the
blood and urine during lobar pneumonia. Proc. Sot. Exp. Biol. and Med.
14: 126.

1917

Avery, 0. T.. Chickering. H. T., Cole, R., and Dochez. A. R. Acute lobar
pneumonia: prevention and serum treatment. Monogruphs of The Rockefeller
lnstirute for Medical Research, No. 7, N. Y.
Dochez. A. R., and Avery, 0. T. The elaboration of specific soluble substance by
pncumococcus during growth. J. Ewp. Med. 26:477. Trans. Assoc. Amer. Phys.
32:281_

1918

Avery, 0. T. Determination of types of pneumococcus in lobar pneumonia: a rapid
cultural method. J. Amer. Med. Assoc. 70:17.
Dernby, K. G.. and Avery, 0. T. The optimum hydrogen ion concentration for the
growth of pneumococcus. J. Exp. Med. 2X:345.
Avery, 0. T. A selective medium for B. influenzae. Oleate-hemoglobin agar. J.
Amer. Med. Assoc. 71:2050.

1919

Avery. 0. T., and Cullen, G. E. The use of the final hydrogen ion concentration in
differentiation of streptococcus haemolyticus of human and bovine types./. Exp.
Med. 29:21.5.

Dochez, A. R., Avery, 0. T., and Lancefield, Rebecca C. Studies on the biology
of streptococcus. I. Antigenic relationships between strains of streptococcus
haemolyticus. /. Exp. Med. 30: 179.

Avery, 0. T., and Cullen, G. E. Hydrogen ion concentration of cultures of
pneumococci of the different types in carbohydrate media. J. Exp. Med. 30:359.
Avery, 0. T., Dochez. A. R.. and Lancefield, Rebecca C. Bacteriology of strepto-
coccus hemolyticus. Ann. Otol. Rhinol. Laryngol. 28:350.

1920

Avery, 0. T., and Cullen. G. E. Studies on the enzymes of pneumococcus. I.
Proteolytic enzymes. J. Exp. Med. 32:547.
Avery, 0. T.. and Cullen, G. E. Studies on the enzymes of pneumococcus. II.
Lipolvtic enzymes: esterase. J. Exp. Med. 32:571.

Thjiitta. T., and Avery, 0. T. Growth accessory substances in the nutrition of
bacteria. Proc. Sot. Exp. Biol. and Med. 18:197.


Chronologies    201

Esp. Med. 34:4SS.

Avery. 0. T., and Morgan, H. J. The effect of the accessory substances of plant
tissue upon growth of bacteria. Proc. Sot. Exp. Biol. and Med. 19: 1 13.

1923-24

      (with M. Heidelberger, H. J. Morgan, J. M. Neill)
Heidelberger, M., and Avery, 0. T. The specific soluble substance of pneumococ-
cus. Proc. Sot. Exp. Biol. und Med. 20:434.
Avery. 0. T., and Heidelberger, M. Immunological relationships of cell constitu-
ents of pneumococcus. Proc. Sot. Exp. Biol. and Med. 20:435.
Heidelberger. M., and Avery, 0. T. The soluble specific substance of pneumococ-
cu. J. Exp. Med. 38173.

Avery. 0. T., and Heidelberger, M. Immunological relationships of cell constitu-
ents of pneumococcus. J. Exp. Med. 38:El.
Avery. O.T.. and Cullen, G. E. Studies on the enzymes of pneumococcus. IV.
Bacteriolytic enzyme. J. Exp. Med. 38:199.
Avery. 0. T., and Morgan, H. J. Studies on bacterial nutrition. IV. Effect of plant
tissue upon growth of pneumococcus and streptococcus. J. Exp. Med. 38:207.
Avery. 0. T.. and Morgan, H. J. Influence of an artificial peroxidase upon the
growth of anaerobic bacilli. Proc. Sot. Exp. Biol. and Med. 21:59.

1924-1925

  (with M. Heidelberger and W. F. Goebel, W. S. Tillett, L. A. Julianelle)
Avery. 0. T.. and Morgan, H. J. The occurrence of peroxide in cultures of
pneumococcus. J. Exp. Med. 391275.

Avery, 0. T., and Morgan, H. J. Studies on bacterial nutrition. V. The effect of
plant tissue upon the growth of anaerobic bacilli. J. Exp. Med. 39:289.
Morgan, H. J.. and Avery, 0. T. Growth-inhibitory substances in pneumococcus
cultures. J. Exp. Med. 39:335.

Avery. 0. T., and Neill, J. M. Studies on oxidation and reduction by pneumococ-
cus. I. Production of peroxide by anaerobic cultures of pneumococcus on expo-
sure to air under conditions not permitting active growth. J. Exp. Med. 39:347.
Avery, 0. T., and Neill, J. M. Studies on oxidation and reduction by pneumococ-
cus. II. The production of peroxide by sterile extracts of pneumococcus. 1. Exp.
Med. 391357.

Avery. 0. T., and Neill, J. M. Studies on oxidation and reduction by pneumococ-
cus. III. Reduction of methylene blue by sterile extracts of pneumococcus. J.
Exp. Med. 39:543.

Avery, 0. T.. and Neill. J. M. Studies on oxidation and reduction by pneumococ-
cus. IV. Oxidation of hemotoxin in sterile extracts of pneumococcus. J. Exp.
Med. 391745.

Neill. J. M., and Avery, 0. T. Studies on oxidation and reduction by pneumococ-
cus. V. The destruction of oxyhemoglobin by sterile extracts of pneumococcus. 1.
Exp. Med. 39~757.

Heidelberger, M., and Avery, 0. T. The soluble specific substance of pneumococ-
cus. Second paper. J. Exp. Med. 40:301_
Neill. J. M., and Avery, 0. T. Studies on oxidation and reduction by pneumococ-


202    THE PROFESSOR, THE INSTITUTE, AND DNA

cus. VI. The oxidation of enzymes in sterile extracts of pneumococcus. J. Exp.
Med. 40:405.

Neil], J. M., and Avery, 0. T. Studies on oxidation and reduction by pneumococ-
cus. VII. Enzyme activity of sterile filtrates of aerobic and anaerobic cultures of
pneumococcus. J. Exp. Med. 40:423.

1925-1926

         (with M. Heidelberger and W. F. Goebel)
Neill, J. M., and Avery, 0. T. Studies on oxidation and reduction by pneumococ-
CUS. VIII. Nature of oxidation-reduction systems in sterile pneumococcus ex-
tracts. J. Exp. Med. 40:285.

Avery, 0. T., and Morgan, H. J. Immunological reactions of isolated carbohydrate
and protein of pneumococcus. J. Exp. Med. 42~347.
Avery, 0. T.. and Neill, J. M. The antigenic properties of solutions of pneumococ-
cus. J. Exp. Med. 421355.

Avery, 0. T., and Heidelberger, M. Immunological relationships of cell constitu-
ents of pneumococcus. Second paper. J. Exp. Med. 42:367.
Heidelberger, M., Goebel. W. F.. and Avery, 0. T. The soluble specific substance
of a strain of Friedlander's bacillus. Paper 1. J. Exp. Med. 42:701.
Avery. 0. T., Heidelberger, M.. and Goebel, W. F. The soluble specific substance
of Friedlander's bacillus. Paper II. Chemical and immunological relationships of
pneumococcus Type II and of a strain of Friedlander's bacillus. J. Exp. Med.
42:709.

Heidelberger, M., Goebel, W. F., and Avery. 0. T. The soluble specific substance

Heidelberger, M., Goebel, Wl F., and Avery, 0. T. The soluble specific substance
of a strain of Friedlander bacillus. Proc. Sm. Exp. Biol. nnd Med. 23:l.
Avery, 0. T., Heidelberger, M., and Goebel, W. F. Immunological behaviour of
the "E" strain of Friedhinder bacillus and its soluble specific substance. Proc.
Sot. Exp. Biol. and Med. 23~2.

Neil], J. M. Studies on the oxidation-reduction of hemoglobin and methemoglobin.
I. The changes induced by pneumococci and by sterile animal tissue. J. Exp.
Med. 411299.

Neill, J. M. Studies on the oxidation-reduction of hemoglobin and methemoglobin.
II. The oxidation of hemoglobin and reduction of methemoglobin by anaerobic
bacilli and by sterile plant tissue. J. Exp. Med. 41:535.
Neill, J. M. Studies on the oxidation-reduction of hemoglobin and methemoglobin.
III. The formation of methemoglobin during the oxidation of autoxidizable
substances. J. Exp. Med. 41:551,

Neil], J. M. Studies on the oxidation-reduction of hemoglobin and methemoglobin.
IV. The inhibition of "spontaneous" methemoglobin formation. J. Exp. Med.
41:561.

In the Annual Report for 1926-27, no publications are listed for
any department. The publications listed on this page are taken from
"The Semi-Annual List of the Publications of the Staff of The
Rockefeller Institute for Medical Research," May 1926-Novem-


Chronologies

203

                                        L.V.w...Y-.,
1927.

(with M. Heidelberger. W. F. Goebel, W. S. Tillett, L. A. Julianelle, M. H.
           Dawson. and E. G. Stillman)

Julianelle, L. A. A biological classification of Encapsulnfus pneumoniae (Fried-
hinder's bacillus). J. Exp. Med. 44: 113.
Goebel, W. F. On the oxidation of glucose in alkaline solutions of iodine. J. Biol.
Chem. 72:801.

Goebel, W. F. The preparation of hexonic and bionic acids by oxidation of aldoses
with barium hypoiodite. /. Biol. Chem. 72:809.
Heidelberger, M. The chemical nature of immune substances. Physiol. Rev. 7:107.
Heidelberger, M. immunologically specific polysaccharides. Chem. Rev. 3:423.
Heidelberger, M., Goebel, W. F. The soluble specific substance of pneumococcus.
IV. On the nature of the specific polysaccharide of Type III pneumococcus. J.
Biol. Chem. 70:613.

Julianelle, L. A. Immunological relationships of encapsulated and capsule-free
strains of Encupsularus pneumoniae (Friedlander's bacillus). J. Exp. Med.
43:683.
Julianelle. L. A. Immunological relationships of cell constituents of Encar~u/arus

pneumoniue (Friedhinder's bacillus). .I. Exp. Med. 44:735.

N&l. J.-M. Studies on the oxidation and reduction of immunological substances.
V. Production of antihemotoxin bv immunization with oxidized pneumococcus

Stillman, E. G., and Branch, A. Susceptibility of rabbits to infection by the
inhalation of virulent oneumococci. J.     Med. 44:581-587.

Tillett, W. S. Studies on immunity to pneumococcus mucosus (Type III). I.
Antibody response of rabbits immunized with Type III pneumococcus. J. Exp.
Med. 45:713.

Stillman, E. G. The development of agglutinins and protective antibodies in rabbits
following inhalation of pneumococci. /. Exp. Med. 45:1057.
                     1927-1928

(with W. S. Tillett, L. A. Julianelle. W. F. Goebel,
     R. J. Dubos, M. H. Dawson)

Tillett. W. S. Studies on immunity to pneumococcus mucosus. I. Antibody re-
sponse of rabbits to Type III Pneumococcus. J. Exp. Med. 45:713.
Tillett, W. S. Studies on immunity to pneumococcus (Type III). II. The infectivity
of Type III pneumococcus for rabbits. J. Exp. Med. 45:1093.
Tillett, W. S. Studies on immunity to pneumococcus mucosus (Type III). III.
Increased resistance to Type III infection induced in rabbits by immunization
with "R" and "S" forms of pneumococcus. J. Exp. Med. 46:343.
Goebel, W. F. The soluble specific substance of Friedlander's bacillus. 1V. On the
nature of the hydrolytic products of the specific carbohydrate from Type Il. J.
Biol. Chem. 74:619.

Heidelberger, M.. and Goebel. W. F. The soluble specific substance of pneumo-


204   THE PROFESSOR, THE INSTITUTE, AND DNA

coccus. V. On the chemical nature of the aldobionic acid from the specific
polysaccharide of Type III pneumococcus. J. Biol. Chem. 74:6 13.
Goebel, W. F., and Avery, 0. T. The soluble specific substance of Friedlander's
bacillus. III. On the isolation and properties of the specific carbohydrates from
Types A and C Friedlander's bacillus. J. Exp. Med. 46:601.
Julianelle, L. A.. and Reimann, H. A. The production of purpura by derivatives of
pneumococcus. III. Further studies on the nature of the purpura producing
principle. J. Exp. Med. 45:609.

Dawson, M. H., and Avery. 0. T. Reversion of avirulent "Rough" forms of
pneumococcus to virulent "Smooth" types. Proc. Sot. Exp. Biol. Med. 241943.
Goebel. W. F. The preparation of hexonic and bionic acids by oxidation of aldoses
with barium hyporodite. J. Biol. Chem. 72:8OY.

Goebel. W. F. On the oxidation of glucose in alkaline solutions of iodine. J. Biol.  I

Chem. 72:801.

1928-1929

(with E. G. Stillman. W. S. Tillett, L. A. Julianelle, W. F. Goebcl, R. J. Dubos.
          M. H. Dawson, T. Francis, Jr.)

Avery, 0. T.. and Tillett. W. S. Anaphylaxis with the type-specific carbohydrates
of pneumococcus. J. Exp. Med. 49:251.
Dawson, M. H. The interconvertibility of "R" and "S" forms of pneumococcus. J.
Exp. Med. 47:577.

Dubos, R. J. Observations on the oxidation-reduction properties of sterile bacteri-
ological media. /. Exp. Med. 49:507.
Dubos. R. J. The initiation of growth of certain facultative anaerobes as related to

oxidation-reduction processes in the medium. J. Exp. Med. 49:559.

Dubos, R. .I. The relation of the bacteriostatic action of certain dyes to oxidation-
reduction processes. J. Exp. Med. 49~575.        I

Goebel. W. F.. and Avery, 0. T. A study of pneumococcus auto1ysis.l. Exp. Med.
491267.

Julianelle, L. A. Bacterial variation in cultures of Friedlander's bacillus. J. Exp.
Med. 47:88Y.

Julianelle, L. A., and Avery, 0. T. Intracutaneous vaccination of rabbits with
pneumococcus. I. Antibody response. II. Resistance to infection. III. Hypersen-
sitiveness. Proc. Sot. Exp. Biol. Med. 26~224.

Tillett. W. S. Active and passive immunity to pneumococcus infection induced in

rabbits by immunization with "R" pneumococci. J. Exp. Med. 4X:79 1.
                     1929-1930

(with E. G. Stillman, W. S. Tillett, L. A. Julianelle. W. F. Goebel, R. J. Dubos, T.
          Francis. Jr.. W. Kelley, F. H. Babers)

Avery, 0. T.. and Goebel, W. F. Chemo-immunological studies on conjugated
carbohydrate-proteins. II. Immunological specificity of synthetic sugar-protein
antigens. J. Exp. Med. 50:521.

Dawson. M, H. The transformation of pneumococcal types. I The conversion of R

forms of pneumococcus into S forms or the homologous type. J. Exp. Med.

Dawson. M. H. The transformation of pneumococcal types. II. The interconverti-


Dubos, R. J. The role of carbohydrates in biological oxidations and reductions.
Experiments with pneumococcus. J. Exp. Med. 50:143.
Goebel, W. F.. and Avery, 0. T. Chemo-immunological studies on conjugated
carbohydrate-proteins. I. The synthesis of p-aminophenol P-glucoside p-amino-
phenol fi-galactoside, and their coupling with serum globulin. J. Exp. Med.
50:535.

Heidelberger, M.. Avery, 0. T., and Goebel, W. F. A soluble specific substance
derived from gum arabic. /. Exp. Med. 49:847.
Julianelle, L. A. Reactions of rabbits to injections of pneumococci and their
products. 1. The antibody response. J. Exp. Med. 51:441.
II. Resistance to infection. J. Exp. Med. 51:449.
III. Reactions at the site of injection. J. Exp. Med. 51:463.

. ,  . ..- ..- .-.Vy...Q..'   IL . . . .     . ..,
    Med. 51:625.

V. The development of eye reactivity to derivatives of Pneumococcus. /. Exp.
   Med. 51:633.

VI. Hypersensitiveness to pneumococci and their products. J. Exp. Med.
    51:643.

Stillman, E. G., and Branch, A. Early pulmonary lesions in partially immune
alcoholized mice following inhalation of virulent pneumococci. J. Exp. Med.

Tillett, W. S., Avery. 0. T., and Goebel. W. F. Chemo-immunological studies on
conjugated carbohydrate-proteins. III. Active and passive anaphylaxis with syn-
thetic sugar-proteins. J. Exp. Med. 50:551.
Tillett. W. S., and Francis. T., Jr. Cutaneous reactions to the polvsacchartdes and

(with E.G. Stillman, W. F. Goebel. R. J. Dubos, T. Francis, Jr., W. Kelley, F. H.
          Babers, K. Goodner. J. L. Alloway)
Avery, 0. T., and Dubos. R. J. The specific action of a bacterial enzyme on
pneumococci of Type III. Science 72: 151.
Babers, F. H.. and Goebel, W. F. The molecular size of the Type III specific
polysaccharide of Pneumococcus. J. Biol. Chem. 893387.
Dubos, R. J. The bacteriostatic action of certain components of commercial
peptones as affected by conditions of oxidation and reduction. /. Exp. Med.
52:331.

Francis, T., Jr.. and Tillett, W. S. Cutaneous reactions in Pneumonia. The devel-
opment of antibodies following the intradermal injection of type specific polysac-
charide. J. Exp. Med. 521573.

Goebel. W. F. The preparation of the type-specific polysaccharides of Pneumococ-
cus. J. Biol. Chem. 89:395.

Julianelle, L. A. The distribution of Friedlander's bacilli of different types. J. Exp.
Med. 52:53Y.

Stillman, E. G. The effect of the route of immunization on the immunity response


206   THE PROFESSOR, THE INSTITL
Stillman, E. G. Susceptibility of rabbits to infection by the inhalation of Type 11
pneumococci. J. Exp. Med. 52:2 15.

Stillman, E. G. Development of agglutinins and protective antibodies in rabbits,
after inhalation of Type II pneumococci. J. Exp. Med. 52:225.
Tillett, W. S., and Francis, T., Jr. Serological reactions in pneumonia with a non-
protein somatic fraction of Pneumococcus. J. Exp. Med. 53:561; J. Cfin. Invest.
9:ll.
Tillett, W. S.. Goebel. W. F., and Averv, 0. T. Chemical and immunological

                                  "1
52:X95.

(with E. G. Stillman, W. F. Goebel, R. J. Dubos, T. Francis, Jr., F. H. Babers, K.     /

different specific types bv the use of filtered uneumococcus extracts. J. EXD.

Med. 55:91.

Avery, 0. T.. and Dubos, R. The protective action of a specific enzyme against
Type III pneumococcus infection in mice. J. Exp. Med. 54:471.
Avery, 0. T., and Dubos, R. The specific action of a bacterial enzyme on Type III
pneumococci. Trans. Assoc. Amer. Phys. 46:216.
Avery, 0. T., and Goebel, W. F. Chemo-immunological studies on conjugated
carbohydrate proteins. V. The immunological specificity of an antigen prepared
by combining the capsular polysaccharide of Type III Pneumococcus with foreign
protein. J. Exp. Med. 54:437.
Dubos, R., and Avery, 0. T. Decomposition of the capsular polvsaccharide of

Dubos, R. Factors affecting yield of specific enzyme in cultures of the bacillus
decomposing the capsular polysaccharide of Type III Pneumococcus. /. Exp.
Med. 55~377.

Finkle, P. Metabolism of S and R forms of Pneumococcus. J. Exp. Med. 53:661.
Francis, T., Jr., and Tillett, W. S. Cutaneous reactions in rabbits to the type-
specific capsular polysaccharides of Pneumococcus. J. Exp. Med. 54:587.
Francis, T. Jr., and Tillett, W. S. The significance of the type-specific skin test in
the serum treatment of pneumonia, Type I. J. Clin. Invest. 10:659.
Francis, T., Jr. The identity of the mechanisms of type-specific agglutinin and
precipitin reactions with Pneumococcus. J. Exp. Med. 55:55.
Goebel, W. F.. and Avery. 0. T. Chemo-immunological studies on conjugated
carbohydrate proteins. IV. The synthesis of the p-aminobenzyl ether of the
soluble specific substance of Type III Pneumococcus and its coupling with
protein. J. Exp. Med. .54:451.

Goodner, K. The development and localization of the dermal pneumococcic lesion
in the rabbit. J. Exp. Med. 54:847.
Goodner, K., Dubos, R., and Avery, 0. T. The action of a specific enzyme in Type
III pneumococcus dermal infection in rabbits. J. Exp. Med. 55:393.
Rhoads, C. P., and Goodner, K. The pathology of experimental dermal pneumo-
coccus infection in the rabbit. J. Exp. Med. 54:41.
- .


Stillman, E. G., and Branch

partially immunized mice following inhalation oipneumococci. J. Exp. bed.
541623.

1932-1933

(with E. G. Stillman, W. F. Goebel, R. J. Dubos, T. Francis, Jr., F. H. Babers, K.
          Goodner, E. Terrell, E. Rogers)

Avery. 0. T. The role of specific carbohydrates in Pneumococcus infection and
immunity. Annals Int. Med. 6:l (John Phillips Memorial Prize).
Avery. 0. T., Goebel. W. F., and Babers, F. H. Chemoimmunological studies on
conjugated carbohydrate-proteins. VII. Immunological specificity of antigens
prepared by combining (Y and p glucosides of glucose with proteins. J. Exp. Med.
551769.

Alloway, J. L. Further observations on the use of Pneumococcus extracts in
effecting transformation of Type in virro. J. EXP. Med. 57:265.
Baudisch. 0.. and Dubos, R. Uber Katalasewirkung von Eisenverbindungen in
Kulturmedien. Biochem. Zeit. 245:278.
Francis. T., Jr. The value of the skin test with type-specific capsular polysaccharide
in the Serum treatment of Type 1 Pneumococcus pneumonia. J. Exp. Med.
57:617.

Goebel, W. F.. Babers, F. H., and Avery, 0. T. Chemo-immunological studies on
conjugated carbohydrate-proteins. VI. The synthesis of p-aminophenol a-gluco-
side and its coupling with protein. J. Exp. Med. 55:761_
Goodner, K. A test for the therapeutic value of anti-pneumococcus serum. (Pre-
sented before the American Public Health Service, Washington, D. C., October
24, 1932) J. Irnmunol. 25:199.

Goodncr, K.. and Dubos, R. Studies on the quantitative aCtiOn Of a Specific
enzyme in Type III Pneumococcus dermal infection in rabbits. J. Exp. Med.
56:521.

Julianelle, L. A., and Rhoads, C. P. Reactior
injections of pneumococci and their products. VII. The relation of hypersensi-
tjveness to lesions in the lungs of rabbits infected with pneumococci. /. EXP.
Med. 551797.

Ke]]ey. W. H. The antipneumococcus properties of normal swine serum. J. EXP.
Med. 551877.

Stillman, Ernest G. Reaction of rabbits following inhalation of Type III pneumo-
cocci. J. Infect. Dis. 501542.
                    1933-1934

(with T. Francis, Jr,, T. J. Abernethy, E. G. Stillman, R. J. Dubos, W. F. GoebeI,
          F    RnhPrc  K Gnndner. E. Ropers. E. Terrell)

I    Averv. 0. T. Chemo-immunoloaische Untersuchungen an Pneumokokken-infek-

Goebel, W. F., and Babers, F. H. Derivatives of glucuronic acid. I. The prepa
tion of glucuronic acid from glucuron and a comparison of th
values. J. Biol. Chem. 100:573.
Goebel, W. F., and Babers, F. H. Derivatives of           _  _ _  _ .


tion of glucuron. J. Biol. C/rem. 100:734.
Goebel, W. F., and Babers, F. H. Derivatives of glucuronic acid. III. The synthesis
of diacetylchloroglucuron. 1. &of. Chem. 10 1: 173.
Avery, 0. T., and Goebel, W. F. Chemo-immunological studies on the soluble
specific substance of Pneumococcus. Isolation and properties of the acetyl
polysaccharide of Pneumococcus Type I. J. Exp. Med. 58:73 1.
Goodner. K.. and Stillman, E. G. The evaluation of active resistance to Pneumo-
coccus infection in rabbits. J. Exp. Med. 58:183.
Goodner, K. The effect of Pneumococcus autolysates upon pneumococcus dermal
infection in the rabbit. J. Exp. Med. 58: 153.
                      1934-1935

(with T. J. Abernethy, F. H. Babers, B. Chow, R. J. Dubos, W. F. Goebel, K.
   Goodner. F. L. Horsfall, Jr., C. M. MacLeod, and E. G. Stillman)
Babers. F. H., and Goebel, W. F. The synthesis of the p-aminophenol ,%glycosides
of maltose, lactose, cellobiose and gentiobiose. /. Biol. Chem. 105:473.
Francis, T., Jr., and Terrell, E. E. Experimental Type III pneumococcus pneu-
monia in monkeys. I. Production and clinical course. J. Exp. Med. 59:609.
Francis, T.. Jr., Terrell, E. E., Dubos, R., and Avery, 0. T. Experimental Type

decomposes the specific capsular polysaccharide of Pneumococcus Type III. J.

Goebel, W. F., Babers. F. H., and Avery, 0. T. Chemo-immunological studies on
conjugated carbohydrate-proteins. VIII. The influence of the acetyl group on the

specificity of hexoside-protein antigens. J. Exp. Med. 60:85.
Goebel, W. F.. Avery, 0. T., and Babers. F. H. Chemo-immunological studies on

glucuronic acid methyl ester. J. Biof. Chem. 106:63.
Goodner, Kenneth. Studies on host factors in pneumococcus infections. I. Certain
factors involved in the curative action of specific antipneumococcus serum in
Type I pneumococcus dermal infection in rabbits. J. Exp. Med. 60:9-18.
Goodner, Kenneth. Studies on host factors in pneumococcus infections. II. The
protective action of Type I antipneumococcus serum in rabbits. J. Exp. Med.
nn.10

hydrate of hemophilus influenzae. Type B. J. Immunol. 29:239.
Stillman, E. G. Duration of demonstrable antibodies in the serum of rabbits
immunized with heat-killed Type II and Type III Pneumococci. J. Infecf. Dis.
571223.

Stillman, E. G., and Schulz, R. Z. The reaction of partially immunized rabbits to
inhalation of Type I pneumococci. J. Infect. Dis. 57:233.
Stillman, E. G., and Schulz. R. Z. The reaction of normally and partially immu-
nized rabbits to intranasal instillation of Type I pneumococci. J. Infect. Dis.
_- ^_-


(withT. J. Abernethy, R. J. Dubos, W. F. Goehel, K. Goodner, R. D. Hotchkiss,
     F. L. Horsfall, Jr., C. M. MacLeod, and E. G. Stillman)
Abernethy, T. J., Horsfall, F. L., Jr., and MacLeod, C. M. Pneumothorax therapy

Exp. Med. 621259.

Dubos, R., and Bauer, J. H. The use of graded collodion membranes for the
concentration of a bacterial enzyme capable of decomposing the capsular poly-
saccharide of Type III Pneumococcus. J. Exp. Med. 62:271.
Goodner, K., and Horsfall, F. L., Jr. The protective action of Type I antipneumo-
coccus serum in mice. I. The quantitative aspects of the mouse protection test. J.
Exp. Med. 62:359.

Goodner, K., and Miller, D. K. The protective action of Type I antipneumococcus
serum in mice. II. The course of the infectious process. J. Exp. Med. 62:375.
Goodner, K., and Miller, D. K. The protective action of Type I antipneumococcus
serum in mice. III. The significance of certain host factors. J. Exp. Med. 62:393.
Horsfall, F. L., Jr., and Goodner, K. Relation of the phospholipins to the reactivity
of antipneumococcus sera. Proc. Sot. Exp. Biol. Med. 32:1329.
Swift, H. F., Lancefield, R. C., and Goodner, K. The serologic classification of

horse and rabbit sera. J. Exp. Med. 62:485.
Goebel, W. F., and Babers, F. H. Derivatives of glucuronic acid. V. The synthesis
of glucuronides. J. Biol. Chem. 110:707.
Goebel, W. F., and Babers, F. H. Derivatives of glucuronic acid. VI. The prepara-
tion of cy-chloro- and a-bromotriacetylglucuronic acid methyl ester, and the
synthesis of /3-glucuronides. J. Biol. Chem. 111:347.
Goebel, W. F. Chemo-immunological studies on the soluble specific substance of
Pneumococcus. II. The chemical basis for the immunological relationship be-
tween the capsular polysaccharides of Types III and VIII Pneumococcus. J. Biol.
Chem. 110:391.

Chow, B. F., and Goebel, W. F. The purification of the antibodies in Type I
antipneumococcus serum, and the chemical nature of the type-specific precipitin
reaction. J. Exp. Med. 62:179.
                     1936-1937

(with R. J. Dubos, W. F. Goebel, K. Goodner, F. L. Horsfall, Jr., R. D.
       Hotchkiss, C. M. MacLeod, and E. G. Stillman)
Abernethy, T. J. Concentrated antipneumococcus serum in Type I pneumonia.
Control of dosage by skin tests with type specific polysaccharide. N. Y. State J.

Abernethy , T. J., and Francis, T. Jr. Studies on the somatic "C" polysaccharide of
pneumococcus I. Cutaneous and serological reactions in pneumonia. J. Exp.
Med. 65:59.


210   THE PROFESSOR, THE INSTITUTE, AND DNA

Abernethy, T. J. Studies on the somatic "C" polysaccharide of pneumococcus II.
The precipitation reaction in animals with experimentally induced pneumococcic
infection. .I. Exp. Med. 6.5:75.

Dubos, R., and Miller, B. Enzyme for decomposition of creatinine and its action
on the "apparent creatinine" of blood. Proc. Sot. Exp. Biol. Med. 35:335.
Dubos, R., Meyer, K., and Smyth, E. M. Action of the lytic principle of pneumo-
coccus on certain tissue polysaccharides. Proc. Sm. Exp. Biol. Med. 34:816.
Dubos, R., Meyer. K., and Smyth, E. M. The hydrolysis of the polysaccharide acid
of vitreous humors, of umbilical cord, and of streptococcus by the autolytic
enzyme of pneumococcus. J. Biol. Chem. 118:71.
Goebel, W. F. Chemo-immunological studies on conjugated carbohydrate-pro-
teins. X. The immunological properties of an artificial antigen containing glucu-
ronic acid. J. Exp. Med. 64:29.

Goebel, W. F., and Reznikoff, P. The preparation of ferrous gluconate and its use
in the treatment of hypochromic anemia in rats. J. Pharmacol. Exp. Ther.
59:162.

Goodner, K., Horsfall, F. L., and Bauer, J. H. Ultrafiltration of Type I pneumo-
coccal sera. Proc. Sm. Exp. Biol. Med. 34:617.
Goodner, K., and Horsfall, F. L. The protective action of Type I antipneumococ-
cus serum in mice. IV. The prozone. V. The effect of added lipids on the
protective mechanism. J. Exp. Med. 64:369 and 377.
Goodner, K.. and Horsfall, F. L. The complement fixation reaction with pneumo-
coccus capsular polysaccharide. J. Exp. Med. 64:201.
Horsfall, F. L., and Goodner. K. Lipids and immunological reactions. II. Further
experiments on the relation of lipids to the type specific reactions of antipneumo-
coccus sera. J. lmmunol. 3 1: 135.

Horsfall, F. L., and Goodner, K. Lipids and immunological reactions. III. Lipid
content of specific precipitates from Type I antipneumococcus sera. J. Exp. Med.
64:583.

Horsfall, F. L., and Goodner, K. Lipids and immunological reactions. IV. The
lipid patterns of specific precipitates from Type I antipneumococcus sera. /. Exp.
Med. 64:855.

Horsfall. F. L.. Goodner, K., and MacLeod, C. M. Type specific antipneumococ-
cus rabbit serum. Science 84:579.

Hotchkiss, R. D., and Goebel. W. F. The synthesis of the aldobionic acid of gum
acacia. J. Am. Chem. Sot. 58:858.
Hotchkiss, R. D., and Goebel, W. F. The synthesis of the heptacetyl methyl ester
of gentiobiuronic acid. Science 83:353.
Hotchkiss, R. D., and Goebel, W. F. Derivatives of glucuronic acid. VII. The
synthesis of aldobionic acids. J. Biol. Chem. 115:285.

1937-1938

  (with P. B. Beeson. R. J. Dubos, W. F. Goebel, K. Goodner, C. L.
  Hoagland, F. L. Horsfall, Jr., R. D. Hotchkiss, C. M. MacLeod, R.
  Reeves, E. G. Stillman and R. H. S. Thompson)
Beeson, P. B., and Hoagland, C. L. Use of calcium chloride in relief of chills
following serum administration. Proc. Sot. Exp. Biol. Med. 38:160.
Dubos, R. J. The decompositon of yeast nucleic acid by a heat resistant enzyme.
Science 85:.549.


                         Chronologies    211

Dubos, R. J., and MacLeod. C. M. Effect of a heat-resistant enzyme upon the
antigenicity of pneumococci. Proc. Sot. Exp. Biol. Med. 36:696.
Dubos, R. J., and Miller, B. The production of bacterial enzymes capable of
decomposing creatinine. J. Biol. Chem. 121:429.
Dubos, R. J. The effect of formaldehyde on pneumococci.J. Exp. Med. 67:389.
Goebel, W. F. The chemical constitution of benzoyl glucuronic acid. Science
86:105.
Goebel, W. F., and Hotchkiss, R. D. Chemo-immunological studies on conjugated
carbohydrate-proteins. XI. The specificity of azo-protein antigens containing
glucuronic and galacturonic acids. J. Exp. Med. 66: IY 1.
Goebel, W. F., Reeves. R.. and Hotchkiss, R. D. The synthesis of a1dobionides.l.
Am. Chem. Sot. 59:2745.
Goebel, W F. Derivatives of glucuronic acid. VIII. The structure of benzoylglucu-
ronic acid. J. Biol. Chem. 122:649.
Goodner, K., and Horsfall, F. L. Jr. Properties of the type specific proteins of
antipneumococcus sera. I. The mouse protective value of Type I sera with
reference to the precipitin content. J. Exp. Med. 413:66.
Goodner, K., and Horsfall, F. L. Jr. Properties of the type specific proteins of
antipneumococcus sera. II. Immunological fractionation of Type 1 antipneumo-
coccus horse and rabbit sera. J. Exp. Med. 66:425.
Goodner, K., and Horsfall, F. L. Jr. Properties of the type specific proteins of
antipneumococcus sera. III. Immunochemical fractionation of Type I antipneu-
mococcus horse and rabbit sera. J. Exp. Med. 66:437.
Goodner, K., and Horsfall, F. L. Jr. Passive anaphylactic sensitivity to pneumococ-
cal capsular polysaccharides. J. Zmmunol. 33:2.59.
Goodner, K., Horsfall, F. L., Jr., and Dubos, R. Type specific antipneumococcic
rabbit serum for therapeutic purposes. Production, processing and standardiza-
tion. J. Immunol. 33:279.
Goodner, K., Horsfall, F. L., Jr. The purpuric reaction produced in animals by
derivatives of the Pneumococcus. Proc. Sot. Exp. Biol. Med. 37:178.
Horsfall. F. L. Jr. The control of lobar pneumonia. Can. J. Public Heafth, Ocfober,
476.
Horsfall, F. L., Jr., Goodner, K., and MacLeod, C. M. Antipneumococcus rabbit
serum as a therapeutic agent in lobar pneumonia. II. Additional observations in
pneumococcus pneumonias of nine different types. N. Y. State J. Med. 38:l.
Hotchkiss, R. D., and Goebel, W. F. Chemo-immunological studies on the soluble
specific substance of Pneumococcus III. The structure of the aldobionic acid
from the Type III polysaccharide. J. Biol. Chem. 222:195.
MacLeod, C. M., and Farr. L. E. Relation of the carrier state to pneumococcal
peritonitis in young children with the nephrotic syndrome. Proc. Sot. Exp. Biol.
Med. 37:556.
Miller, B. F., and Dubos. R. Studies on the presence of creatinine in human blood.
J. Biol. Chem. 121:448.
Miller, B. F., and Dubos, R. Determination by a specific, enzymatic method of the
creatinine content of blood and urine from normal and nephritic individuals. J.
Biol. Chem. 121:457.
Reznikoff, P., and Goebel, W. F. The use of ferrous gluconate in the treatment of
hypochromic anemia. J. Clin. Invest. 16:547.


212   THE PROFESSOR, THE INSTITUTE, AND DNA

Stillman, E. G. The susceptibility of mice to inhaled Type III pneumococci. /.
Infect. Dis. 62~66.

                 19381939
(with M. H. Adams, P. B. Beeson, C. Cattaneo, G. Daddi, A. W.
Downie, T. Dublin, R. J. Dubos, W. F. Goebel, K. Goodner, R.
Heggies, C. L. Hoagland, R. D. Hotchkiss, C. M. MacLeod, R. E.

tracted from pneumococci. .r. Eip. Med. 67~799.
Dubos, R. J. The bactericidal effect of an extract of a soil bacillus on Gram positive
cocci. Proc. Sot. Exp. Biol. Med. 40:311.
Dubos, R. J., and MacLeod, C. M. The effect of a tissue enzyme upon pneumo-
cocci. J. Exp. Med. 67:791.

Dubos, R. J., and Miller, B. F. A bacterial enzyme which converts creatine into its
anhydride creatinine. Proc. Sot. Exp. Biol. Med. 39:65.
Dubos, R. J ., and Thompson, R. H. S. The decomposition of yeast nucleic acid by
a heat-resistant enzyme. J. Biol. Chem. 124:.501.
Goebel, W. F. The isolation of the blood group A specific substance from commer-
cial peptone. J. Exp. Med. 68:221.

Goebel, W. F. Chemo-immunological studies on conjugated carbohydrate-pro-
teins. XII. The immunological properties of an artificial antigen containing
cellobiuronic acid. J. Exp. Med. 68:469.
Goebel, W. F. Immunity to experimental pneumococcus infection with an artificial
antigen. Nature 143:77.

Goebel, W. F., and Reeves, R. E. Derivatives of glucuronic acid. IX. The synthesis
of aldobionides and the relationship between the molecular rotation of deriva-
tives of acetylated aldoses and uranic acids. J. Biol. Chem. 124:207.
Goodner, K., Horsfall, F. L. Jr., and Bauer, J. H. Some factors which affect the
ultrafiltration of antipneumococcal sera. J. tmmunol. 35:439.
Hoagland,C.L.,Beeson,P.B.,andGoebel, W.F.Thecapsularpolysaccharideof
the Type XIV Pneumococcus and its relationship to the specific substances of
human blood. Science 88:261.

Horsfall, F. L. Jr. The characteristics of antipneumococcus sera produced by
various animal species. J. Bacterial. 35:207.
Lavin, G. I., Thompson, R. H. S., and Dubos, R. J. The ultraviolet absorption
spectra of fractions isolated from pneumococci. J. Biol. Chem. 125:75.
MacLeod, C. M. Treatment of pneumonia with antipneumococcal rabbit serum.
Bull. N. Y. Acad. Med. 15:116.

MacLeod, C. M., Hoagland, C. L., and Beeson, P. B. The use of the skin test with
the type specific polysaccharides in the control of serum dosage in pneumococcal
pneumonia. J. Clin. Invest. 171739.

Stillman, E. G. Viability of pneumococci in dried sputum. J. Infect. Dis. 63:340.
Thompson, R. H. S., and Dubos, R. J. Production of experimental osteomyelitis in
rabbits by intravenous injection of staphylococcus aureus. J. Exp. Med. 68:191.
Thompson, R. H. S., and Dubos, R. J. The isolation of nucleic acid and nucleopro-
tein fractions from pneumococci. J. Biol. Chem. 125:65.


                        Chronologies   213


                     1939-1940

  (with M. H. Adams, P. B. Beeson, C. Cattaneo, E. C. Curnen, G.
   Daddi, T. Dublin, R. J. Dubos, W. F. Goebel, K. Goodner, T.
  Heggies, R. D. Hotchkiss, C. M. MacLeod, G. S. Mirick, and E. G.
   Stillman)
Beeson, P. B ., and Goebel, W. F. The immunological relationship of the capsular
polysaccharide of Type XIV Pneumococcus to the blood group A specific
substance. J. Exp. Med. 701239.
Dubos, R. J. Enzymatic analysis of the antigenic structure of pneumococci. Er-
gebn. Enzymforsch. 8:135.
Dubos, R. J. Studies on a bactericidal agent extracted from a soil bacillus. I.
Preparation of the agent. Its activity in vitro. II. Protective effect of the bacteri-
cidal agent against experimental pneumococcus infections in mice. J. Exp. Med.
7O:l and 11.
Dubos, R. J., and Cattaneo. C. Studies on a bactericidal agent extracted from a soil
bacillus. III. Preparation and activity of a protein-free fraction. J. Exp. Med.
701249.
Goebel, W. F. Studies on antibacterial immunity induced by artificial antigens. I.
Immunity to experimental pneumococcal infection with an antigen containing
cellobiuronic acid. J. Exp. Med. 69:353.
Goebel, W. F. Immunity to experimental pneumococcal infection with an artificial
antigen containing a saccharide of synthetic origin. Science 91:20.
Goebel, W. F., Beeson, P. B., and Hoagland, C. L. Chemo-immunological studies
on the soluble specific substance of pneumococcus. IV. The capsular polysaccha-
ride of Type XIV Pneumococcus and its relationship to the blood group A
specific substance. J. Biol. Chem. 129:455.
Goodner, K., Horsfall, F. L. Jr., and Bauer, J. H. The neutralization of pneumo-
coccal capsular polysaccharide by the antibodies of type-specific antisera. J.
immunol. 351451.
Hotchkiss, R. D., and Dubos, R. J. Fractionation of the bactericidal agent from
cultures of a soil bacillus, J. Biol. Chem. 132:791.
Hotchkiss, R. D., and Dubos, R. J. Chemical properties of bactericidal substances
isolated from cultures of a soil bacillus. J. Biol. Chem. 132:793.
MacLeod, C. M. Chemotherapy `of pneumococcic pneumonia. J.A.M.A.
113:1405.
MacLeod, C. M. Metabolism of "sulfapyridine-fast" and parent strains of Pneumo-
COCCUS Type I. Proc. Sot. Exp. Biol. Med. 41:215.
MacLeod, C. M., and Daddi, G. A "sulfapyridine-fast" strain of Pneumococcus
Type I. Proc. Sot. Exp. Biol. Med. 41:69.
Reeves, R. E. Saccharolactone methyl ester. J. Am. Chem. Sot. 61:664.
Smadel, J. E., Lavin, G. I., and Dubos, R. J. Some constituents of elementary
bodies of vaccina. J. Exp. Med. 71:373.
Stillman, E. G., and Schulz, R. Z. Difference in virulence of various types of
pneumococci for mice. J. Infect Dis. 65:246.

                     1940-1941

  (with M. H. Adams, A. Coburn, E. C. Curnen, R. J. Dubos, W. F.


214   THE PROFESSOR, THE INSTITUTE, AND DNA

   Goebel. K. Goodner, R. D. Hotchkiss. C. M. MacLeod. G. S. Mirick.
   and E. G. Stillmanl

Beeson, P. B ., and Goebel, W. F. Immunological cross-reactions of Type B
Friedlander bacillus in Type II antipneumococcal horse and rabbit serum. /.

Immunol. 38:231_
Beeson, P. B., and Hoagland, C. L. The use of calcium chloride in the treatment of
chills. N. Y. State J. Med. 40:803.
Dubos, R. J. The effect of specific agents extracted from soil microorganisms upon
experimental bacterial infections. Ann. Inr. Med. 13:2025.
Dubos, R. J. The adaptive production of enzymes by bacteria. Bacterial. Rev. 4: 1.
Dubos. R. J. The utilization of selective microbial agents in the study of biological

problems. Harvey Lectures, Series 35, 223.
Erf, L. A., and MacLeod, C. M. Increased urobilinogen excretion and acute
hemolytic anemia in patients treated with sulfapyridine. J. Clin. Invest. 19:451.
Goebel. W. F. Studies on antibacterial immunity induced by artificial antigens. II.
Immunity to experimental pneumococcal infection with antigens containing
saccharides of synthetic origin. J. Exp. Med. 72:33.
Hotchkiss, R. D.. and Dubos. R. J. Bactericidal fractions from an aerobic sporulat-
ing bacillus. J. Biol. Chem. 136:803.

Little, R. B., Dubos, R. J.. and Hotchkiss, R. D. Action of gramicidin on
streptococci of bovine mastitis. Proc. Sot. Exp. BioL. Med. 44:444.
Little, R. B., Dubos, R. J ., and Hotchkiss. R. D. Effect of gramicidin suspended in
mineral oil on streptococci of bovine mastitis. Proc. Sot. Exp. Biol. Med.
451462.

Little, R. B.. Dubos, R. J., and Hotchkiss, R. D. Gramicidin. Novoxil, and
acriflavine for the treatment of the chronic form of streptococcic mastitis. J. Am.
Vet. Med. Assoc. 98(No. 768):189.

MacLeod, C. M. The inhibition of the bacteriostatic action of sulfonamide drugs by
substances of animal and bacterial origin. J. Exp. Med. 72:217.
MacLeod, C. M., and Avery, 0. T. The occurrence during acute infections of a
protein not normally present in the blood. II. Isolation and properties of the
reactive protein. J. Exp. Med. 73:183.

MacLeod, C. M., and Avery, 0. T. The occurrence during acute infections of a
protein not normally present in the blood. III. Immunological properties of the
C-reactive protein and its differentiation from normal blood proteins. J. Exp.
Med. 73:191.

MacLeod. C. M., and Mirick, G. S. Bacteriological diagnosis of pneumonia in
relation to chemotherapy. Am. J. Public Health 31:34.
MacLeod, C. M., Mirick, G. S., and Curnen. E. C. Toxicity for dogs of a
bactericidal substance derived from a soil bacillus. Proc. Sot. Exp. Biol. Med.
43:461.

Reeves, R. E. The structure of trimethyl glucurone. J. Am. Chem. Sot. 4:l.
Reeves. R. E., Adams, M. H., and Goebel, W. F. The synthesis of a new dimethyl-


                         Chronologies   215

P-methylglucoside. J. Am. Chem. Sot. 62:2881.
Stillman, E. G. The viability of pneumococci in dried rabbit blood. J. Infect. Dis.
66:171.
Stillman, E. G., and Schulz, R. Z. Susceptibility of mice to intranasal instillation of
various types of pneumococci. J. Infect. Dis. 66: 174.
                      1941-1942
(with M. H. Adams, E. C. Curnen, W. F. Goebel, F. L. Horsfall, Jr.. M. McCarty,
       C. M. MacLeod, G. S. Mirick, and E. G. Stillman)
Adams, M. H., Reeves, R. E., and Goebel, W. F. The synthesis of 2,4-dimethyl-P-
methyl-glucoside. J. Biol. Chem. 140:653.
Curnen, E. C., and MacLeod, C. M. The effect of sulfapyridine upon the develop
ment of immunity to pneumococcus in rabbits. J. Exp. Med. 75~77.
Horsfall, F. L.. Jr. Recent studies in influenza. Am. J. Public Health 31:1275.
Reeves, R. E.. and Goebel, W. F. Chemoimmunological studies on the soluble
specific substance of pneumococcus. V. The structure of the Type III polysaccha-
ride. J. Biol. Chem. 139:511.
Stillman, E. G. A comparison of antibody production by rabbits following injection
of pneumococcus vaccines heated at 60oC. or autoclaved. J. lmmunol. 41:343.
Stillman, E. G. The preservation of pneumococcus by freezing and drying. J.
Bacterial. 421689.

                      1942-1943
  (with M. H. Adams. 0. Binkley, E. C. Curnen, W. F. Goebel. F. L.
  Horsfall, Jr., M. McCarty, G. S. Mirick, E. Perlman, E. G. Stillman,
  and J. E. Ziegler, Jr.)
Adams, M. H. The reaction between the enzyme tyrosinase and its specific
antibody. J. Exp. Med. 76:175.
Horsfall. F. L. Jr. The present status of the influenza problem. J. A. M. A.
120:284.
Horsfall, F. L. Jr. Human Influenza. Cornell Univ. Press, New York. 1942.
Horsfall, F. L. Jr. The effect of sulphonamides on virulence of pneumococci. J.
Clin. Invest. 21:647 (Abstr.).
Horsfall. F. L. Jr.. Curnen, E. C., Mirick, G. S., Thomas, L., and Ziegler, J. E.,
Jr. A virus recovered from patients with primary atypical pneumonia. Science
97:289.
MacLeod, C. M., and McCarty, M. Relation of a somatic factor to virulence of
pneumococci. J. Clin. Invest. 21:647 (Abstr.).
MacLeod, C. M., and Mirick, G. S. Quantitative determination of the bacterio-
static effect of the sulfonamide drugs on pneumococci. J. Bacterial. 44:277.
Mirick, G. S. Mode of action of the sulphonamide drugsin vitro. J. Bacterial. 45:66
(Abstr.).
Mirick, G. S. Enzymatic identification of p-amino benzoic acid (PAB) in cultures
of pneumococcus and its relation to sulphonamide-fastness. J. C[in. invest.
21:628 (Abstr.).
Thomas, L., Curnen, E. C., Mirick, G. S., Ziegler, J. E.? Jr., and Horsfall, F. L..
Jr. Complement fixation with dissimilar antigens in primary atypical pneumonia.
hoc. Sot. Exp. Biol. Med. 52:121.


216   THE PROFESSOR, THE INSTITUTE, AND DNA

  1943-1944
(with M. McCarty)

Avery, 0. T. Karl Landsteiner. J. Path. Bact. 56:592.
Avery, 0. T., MacLeod, C. M., and McCarty, M. Transformation of pneumococ-
cal types induced by a desoxyribonucleic acid fraction isolated from Pneumococ-
cus Type III. J. Exp. Med. 79:137.
                    1944-1945
              (with M. McCarty)

McCarty, M. Reversible inactivation of the substance inducing transformation of
pneumococcal types. J. Clin. Invest. 231942 (Abstr.).
                    1945-1946

         (with M. McCarty and H. F. Taylor)
Avery, 0. T. Acceptance of the Kober Medal Award. Truns. Assoc. Amer. Phys.
59:43.

McCarty. M. Purification and properties of desoxyribonuclease isolated from beef
pancreas. J. Gen. Physiol. 29:123.

McCarty, M., and Avery, 0. T. Studies on the chemical nature of the substance
inducing transformation of pneumococcal types. II. Effect of desoxyribonuclease
on the biological activity of the transforming substance. J. Exp. Med. 83:89.
McCarty, M., and Avery, 0. T. Studies on the chemical nature of the substance
inducing transformation of pneumococcal types. III. An improved method for
the isolation of the transforming substance and its application to Pneumococcus
Types II, III and VI. J. Exp. Med. 83:97.
                    1946-1947

     (with R. D. Hotchkiss, M. McCarty and H. F. Taylor)
McCarty, M. Chemical nature and biological specificity of the substance inducing
transformation of pneumococcal types. Bacteriof. Rev. 10:63.

1947-1948

       (with R. D. Hotchkiss, and H. F. Taylor)
Hotchkiss, R. D. The assimilation of amino acids by respiring washed staphylo-
cocci. Fed. Proc. 6:263.

Hotchkiss, R. D. A microchemical reaction resulting in the staining of polysaccha-
ride structures in fixed tissue preparations. Arch. Biochem. 16:131.
Hotchkiss, R. D. Review of Modern Development ofchemotherapy, Havinga, E.,
et al., Amsterdam, 1946. J. Appl. Physics 18:1135.
McCarty, M., Taylor, H. F., and Avery, 0. T. Biochemical studies of environmen-
tal factors essential in transformation of pneumococcal types. Cold Spring Har-
bor Symp. 11:177.

                        1950
Avery, 0. T., and Sprofkin, B. E. Studies on the bacteriolytic properties of
Streptomyces albus and its action on hemolytic streptococci. Semi-Annual Prog-
ress Report, Department of Defense (DDRDB-3). (Unpublished report)


APPENDIXES

              APPENDIX I

A Letter from Avery to His Brother Roy, Dated Mav 26, 1943

I    of the handwritten text were written on May 13, 1943; they are not reproduced
    here because they deal with family affairs in relation to Avery's proposed move
    from New York to join his family in Nashville, Tennessee. In fact, the entire letter

I    mandatory retirement age of 65 at The Rockefeller Institute for Medical Research
     and was to become Emeritus Member in Julv. 1943.

The second part of the letter, dated May 26, is here reproduced. Although it is

mentioned in the letter are reported at length in the annual report that was
submitted to the Board of Scientific Directors in the early spring of 1943.

I       some properties of the transforming substance he adds, "Sounds like a virur

lots of fun to blow bubbles- but it's wiser to prick them yourself before someone
else tries to. It's hazardous to go off half cocked-and embarrassing to have to

I      The letter was terminated "long after midnight" and Avery apologizes for its
    deficiencies. "I'm so tired and sleepy I'm afraid I have not made this very
      clear. . . Forgive this rambling epistle." In reality, the letter is far from rambling.

months earlier and are presented with precision and clarity. Even when writing to
his brother, the Professor could not avoid playing one of his Red Seal Records! He
also ended the letter with Dickens' phrase that he loved to use in the laboratory:

I    Dr. Gasser and Dr. Rivers have been very kind and have insisted on my staying on,

I've been studying. I've not published anything about it -indeed have discussed it

I    evidence. However, I did talk to Ernest [Dr. Ernest Goodpasture, Vanderbilt
    University Medical School] about it in Washington and I hope he has told you-for
    I have intended telling you first of all. I felt he should know because it bears directly
    on my coming eventually to Nashville.


218   THE PROFESSOR, THE INSTITUTE, AND DNA

It is the problem of the transformation of pneumococcal types. You will recall
that Griffith, in London, some 15 years ago described a technique whereby he
could change one specific type into another specific type through the intermediate
R form. For example: Type II + R + Type III. This he accomplished by injecting
mice with a large amount of heat killed Type III cells together with a small
inoculum of a living R culture derived from Type II. He noted that not infrequently
the mice so treated died and from their heart blood he recovered living, encapsu-
lated Type III pneumococci. This he could accomplish only by the use of mice. He
failed to obtain transformation when the same bacterial mixture was incubated in
broth. Griffith's original observations were repeated and confirmed both in our
Lab and abroad by Neufeld, and others. Then you remember Dawson with us
reproduced the phenomenon in vitro by adding a dash of anti-R serum to the broth
cultures. Later Alloway used filtered extracts prepared from Type 111 cells and in
the absence of formed elements and cellular debris induced the R cultures derived
from Type II to become typical encapsulated III pneumococcus. This you may
remember involved several and repeated transfers in serum broth-often as many
as 5-6 -before the change occurred. But it did occur and once the reaction was
induced, thereafter without further addition of the inducing extract, the organisms
continued to produce the Type III capsules; that is the change was hereditary and
transmissible in series in plain broth thereafter. For the past two years, first with
MacLeod and now with Dr. McCarty I have been trying to find out what is the
chemical nature of the substance in the bacterial extracts which induces this specific
change. The crude extract (Type III) is full of capsular polysaccharide, C (somatic)
carbohydrate, nucleoproteins, free nucleic acids of both the yeast and thymus type,
lipids and other cell constituents. Try to find in that complex mixture the active
principle!! Try to isolate and chemically identify the particular substance that will
by itself when brought into contact with the R cell derived from Type II cause it to
elaborate Type III capsular polysaccharide. and to acquire all the aristocratic
distinctions of the same specific type of cells as that from which the extract was
prepared! Some job-and full of heartaches and heart breaks. But at last perhups
we have it. The active substance is not digested by crystalline trypsin or chymotryp-
sin-It does not lose activity when treated with crystalline Ribonuclease which
specifically breaks down yeast nucleic acid. The Type III capsular polysaccharide
can be removed by digestion with the specific Type III enzyme without loss of
transforming activity of a potent extract. The lipids can be extracted from such
extracts by alcohol and ether at -12" C without impairing biological activity. The
extract can be de-proteinized by Sevag Method (shaking with chloroform and amyl
alcohol) until protein free and biuret negative. When extracts treated and purified
to this extent. but still containing traces of protein, lots of C carbohydrate and
nucleic acids of both the yeast and thymus types are further fractionated by the
dropwise addition of absolute ethyl alcohol, an interesting thing occurs. When
alcohol reaches a concentration of about 9/10 volume there separates out a fibrous
substance which on stirring the mixture wraps itself about the glass rod like thread
on a spool-and the other impurities stay behind as granular precipitate. The
fibrous material is redissolved and the process repeated several times-In short, the
substance is highly reactive and on elementary analysis conforms very closely to the
theoretical values of pure desoxyribose nucleic acid (thymus type). Who could have


Appendixes   219

Of a number of crude enzyme preparations from rabbit bone, swine kidney, dog

1.1. -IL...-1        YI." y,.LM"&"C"CC`,                   "1
rabbit, only those containing active depolymerase capable of breaking down known

principle as isolated may belong to this class of chemical substance. We have
isolated highly purified substance of which as little as 0.02 of a microgram is active
in inducing transformaiion. In the reaction mixture (culture medium) this repre-
sents a dilution of 1 part in a hundred million -potent stuff that -and highly
specific. This does not leave much room for impurities-but the evidence is not
good enough yet. In dilution of 1:lOOO the substance is highly viscous as an
authentic preparation of desoxyribose nucleic acid derived from fish sperm. Prelim-

500.000 -a highly polymerized substance.
We are now planning to prepare new batch and get further evidence of purity

and homogeneity by use of ultracentrifuge and electrophoresis. This will keep me
here for a while longer. If things go well I hope to go up to Deer Isle, rest awhile-
Come back refreshed and try to pick up loose ends in the problem and write up the

by means if a known chemical substance it is possible to induce predictable and

dictable, random, and chance changes. If we are proven to be right-and of course
that's a big
is known al
former being thymus nucleic acid-the latter Type III polysaccharide. And both
are thereaf
and withou
transformir
to induce tt
am not now

nature of the transforming principle? Someone else can work out the rest. Of
course, the problem bristles with implications. It touches the biochemistry of the
thymus type of nucleic acids which are known to constitute the major part of the
chromosomes but have been thought to be alike regardless of origin and species. It
touches genetics, enzyme chemistry, cell metabolism and carbohydrate synthesis,
etc. today it takes a lot of well documented evidence to convince anyone that the
sodium salt of desoxyribose nucleic acid, protein-free. could possibly be endowed
with such biologically active and specific properties and this evidence we are now
trying to get. It's lots of fun to blow bubbles-but it's wiser to prick them yourself
before someone else tries to. So there's the story Roy-right or wrong it's been
good fun ar ..    ^    . -.                    .            

of other ir


220   THE PROFESSOR, THE INSTITUTE, AND DNA

understand. Talk it over with Goodpasture but don't shout it around-until we're
quite sure or at least as sure as present method permits. It's hazardous to go off half
cocked-and embarrassing to have to retract later.

I'm so tired and sleepy I'm afraid I have not made this very clear. But I want you
to know-and sure you will see that I cannot well leave this problem until we've got
convincing evidence. Then I look forward and hope we may all be together- God

and the war permitting-and living out our days in peace. What a lovely picture of
dear Margaret. How is she and Cath-wish we could all meet in Deer Isle. I know

Minnie has kept you all posted. Things go well with us despite this cruel war but

Victory must come and I'm optimistic enough to look forward to happier days even
if they are not perfect-We can take it-and still be happy.

Forgive this rambling epistle-with it goes my love and thought and hope of
better things ahead -

"With heaps and heaps of love"
   Affectionately and faithfully,
           OTA

[A P.S. but not so designated]

If the Board in the Surgeon General's office meets at Camp Bragg as I think
they may later on I shall take the opportunity of running over to Nashville for I
want to talk over future plans and possibilities with you and Catherine. Do write if

just a line-1 want to know your reaction and don't hestitate to talk to Ernest-he
knows it all and we talked it over very frankly.
Good night -it's long after mid-night and I have a busy day ahead. God bless us,
one and all. Sleepy, well and happy-


APPENDIX II

Appendixes   221

  Typescript Used by Avery when He Delivered His Address "The
Commonwealth of Science" in May, 1941, as President of the Society of
           American Bacteriologists

-IA

\

of the spirit of inquiry.  They are to the Gxmonwealth of Science what the Bill
             -

of Rights is to the life of democracy.

On that occasion Sir Richard Gregory, President of the British Association

presented the following charter of science whboh was -imously adopted by the

                            A     -1
Conference.  Its swen articles represent mpt a creed but a policy; they posssaa no

          \               l--------l
sanctity or finality, but they do represent the spirit of science.
                    -

DECLARATION OF SCIENTIFIC PRINCIPLES

             /              /              /
1. Liberty to learn, opportunity to teach and power to understand are necessary for

            \           -A
the extension of knowledge and we, a8 men of scisncs, maintain that they cannot

       I                \
be sacrifioed without degradation to human life.

                         -         -        /
2. Communities depend for their existence, their survival and advancement, on

knowledge of t+aelves, and of the properties of things in the world around them.
                                   ---
'1 #-------
3. All nations and all o-8 of society have contributed to the laowledge and
              I------W
utilization of natural reaoucea, and to the understanding of the influanca they
                                                     -
                   \

exemise on human development.

4. The service of science requires independence combined rith cooperation and its

  structure is influenced by the progressiva needa of humanity.
                               -

5. Yen of science are among the trustees of each generation'rr inheritance of natural

              A /
  hOWledgO.  They are bound, therefore, to foster and increase that heritag.


APPENDIX III

  The Lore of the Pneumococcus, as Presented by Avery
in an Annual Report to the Board of Trustees of The Rockefeller
        Institute for Medical Research

(This text is taken from an essay prepared by Avery in the spring of 1931 as a
supplement to the more technical annual report submitted at the same time to the
Board of Scientific Directors of the Institute [see Appendix IV]. The essay was
probably written at the request of Drs. Simon Flexner and Rufus Cole for the lay
members of the Board of Trustees of the Institute. It presents in general terms
Avery's views of the role of the capsular polysaccharides in the virulence of
pneumococci. It also provides the background for the efforts to control type III
pneumococcal infections by vaccination with a synthetic antigen. Later in the text,
but not reproduced here, it discusses treatment with an enzyme capable of hydro-
lyzing the type III capsular polysaccharide.

Although the essay was written as part of the annual report for 1931, it can be
read as an expression of the so-called "Red Seal Records," through which Avery
presented the lore of the pneumococcus to his colleagues and to visitors.)

222   THE PROFESSOR, THE INSTITUTE, AND DNA

It has long been recognized that simple sugars such as glucose do not possess the
property of an antigen, that is, they are incapable of stimulating the formation of
antibodies in the animal body. However, it is now known that if these sugars are
combined by chemical means with a protein, that is, with a substance naturally
endowed with antigenic properties, the new sugar compounds thus formed incite
the formation of antibodies that are specific for the particular sugar used. The study
of synthetic antigens prepared by combining a simple sugar with protein has shown
that the specificity of the newly formed compounds is determined by the chemical
individuality of the reactive carbohydrate irrespective of the protein to which it is
attached. Antisera produced by immunization with these conjugated sugar-proteins
invariably reflect the controlling influence of the carbohydrate on the specificity of
the whole compound. The studies on the simple non-bacterial sugars emphasize
again the significance of carbohydrates in orienting the specific immune response of
the body to substances of this class.

The results of this work led us to test the possibility of synthesizing an artificial
pneumococcus antigen by combining the capsular polysaccharide with a foreign
protein. For this purpose the polysaccharide of Type III was chosen since in its
purified form it contains no nitrogen and represents a definite chemical entity.
Further, if results were obtained with this particular sugar, they would be all the
more interesting since the isolated pure substance itself has never been found to
elicit antibodies in rabbits and even the intact cells from which it is derived
frequently fail to incite antibody formation in these animals. By an intricate
chemical synthesis, the details of which need not concern us here, it was found
possible to combine the Type III capsular polysaccharide in stable chemical union
with an unrelated protein of animal origin. This artificial antigen has in common
with Type III Pneumococcus only the capsular polysaccharide, the protein with


                         Appendixes   223

which it was combined being of widely remote biological origin. Rabbits injected
with this artificial antigen were actively immune to subsequent infection and their
serum specifically agglutinated living cultures of Type III Pneumococci, precipi-
tated solutions of Type III polysaccharide, and protected mice against Type III
Pneumococcus infection. In other words, this synthesized compound, containing
only a single component of the pneumococcus cell, called forth an immune re-
sponse as specific in nature as that induced by the whole microorganism.

APPENDIX IV

The Problems under Investigation in

Avery's Department during the 1930s

(The two documents presented here are the outlines of the annual reports submit-
ted by Avery to the Board of Scientific Directors of the Institute in the springs of
193 1 and 1937. These outlines, which are typical of those for the other years of the
193Os, give an idea of the wide range of theoretical and practical problems under
investigation in the department during that period.

The 1931 report presents the first attempts to achieve the transformation of
pneumococcal types with cell-free extracts of pneumococci. The 1937 report

I     Report of Dr. Avery with Drs. Stillman, Goebel, Dubos, Francis, Kelley, Babers,
                Goodner, and Alloway [I 930-311

cus by a Bacterial Enzyme.
I. Methods for obtaining potent, non-toxic preparations of the enzyme.    I

1. The determination of the molecular size of the capsular polysaccharide
  of Type III Pneumococcus.
2. The specific carbohydrate of two strains of Pfeiffer's bacillus.
3. The somatic carbohydrate of Pneumococcus.
4. Studies on synthetic carbohydrate derivatives.
   a) Synthesis of LY para-amino phenol glucoside.
   b) Glucuronic acid.
-.     

I       VI. Studies on Natural Resistance and the Immunity induced by R pneumococci.
    VII. Principles Governing the Precipitin and Agglutinin reactions with Pneumo-


(Avery devoted the entire annual report that he submitted in the spring of 1927 to
the analysis of the problems of virulence and antigenicity. He formulated in
particular the hypothetical concept which he called "antigenic dissociation"-
namely, the set of phenomena that, either in vitro or in vivo, bring about the
separation of the capsular polysaccharide from the complex cellular structure of
which it is a part in the pneumococcal cell. According to this hypothesis, antigenic
dissociation is in some way associated with loss of antigenicity and loss of virulence.

The following is the table of contents of the section of the report dealing with
antigenic dissociation. Although the hypothesis was never fully substantiated, it
provided the framework for much of the immunological program carried out in
Avery's department during the late 1920s and through the 1930s.)

224   THE PROFESSOR, THE INSTITUTE, AND DNA

VIII. Studies on Epidemiology of Pneumonia.
   1. Antibody response to immunization by different routes.
   2. Production of experimental pneumonia in animals.
IX. Antipneumococcus Immune Reactions of Normal Hog Serum.
X. Pathogenesis of Experimental Intradermal Pneumococcus Infection.
   1. Intradermal infection with a rabbit virulent Type III Pneumococcus.
XI. Studies on the Transformation of the Specific Types of Pneumococcus.
XII. Significance of Oxidation-Reduction Processes in Bacterial Growth.
   A. Purification of a brand of commercial peptone.
   B. Preparation of peptones from pure proteins.
XIII. Publications.

Report of Drs. Cole and Avery (assisted by Drs. Dubos, Goebel, Goodner,
    Horsfall, Hotchkiss, MacLeod and Stillman) [I 936-371

1. The chemical and specific properties of pneumococcus antibodies.
2. Antipneumococcus rabbit serum as a therapeutic agent in lobar pneumonia.
3. The autolytic system of pneumococci and its reaction to the antigenicity of the
  cells.

4. The action of tissue enzymes upon bacteria.
5. The production of specific enzymes by bacteria as a tool in biochemical analysis.
6. The transformation of specific types of pneumococcus.
7. The antigenic mosaic of pneumococcus - the so-called Z substance.
8. Comparative virulence of pneumococcus implanted on the mucous membranes
of mice by the inhalation method.

9. Conjugated carbohydrate-protein antigens containing glucuronic and galactu-
ronic acids.

APPENDIX V

The Theory of Antigenic Dissociation


    _Y..l_.     -`--.`----`, -..-                     -, .
Report of Dr. Avery, with Drs. Heidelberger, Goebel, Tillett, Julianelle, and
                    Dawson

STUDIES ON ANTIGENIC DISSOCIATION:
1, Pneumococcus as "Complex Antigen"
2. Consideration of the Cell as      .

     a. Two distinct and Seuarate antigenic svstems.

a. Qualitatively different antibodies stimulated by intact and dissolved
cells.

b. Relative differences in the dissociation of Types I, II, and III.

c. Relation of antigenic dissociation to production of antipneumococcus
  sera.

d. Antigenic potency inversely proportional to rate and extent of dissocia-
  tion.

5. Factors relating to the Animal:

7. Concept of Virulence:
   a. As tissue fastness.
  b. Relationship between Virulence and Antigenicity.

From Bacterial Transformation to Genetic Engineering

After Griffith's initial discovery, the transformation phenomenon acquired a life of
its own within the walls of The Rockefeller Institute. There, DNA emerged as the
transforming substance in Avery's laboratory, not through a planned, detailed,
experimental program based on prevailing genetic theories, but as the result of a
disciplined trial and error approach, a persistent day-to-day, step-by-step work at
the bench, seemingly unaffected by outside influences.
This does not mean that the studies on transformation proceeded in an intellec-
tual vacuum. Although Avery's laboratory was the only place where research was
       .              . .   .                      .   .


226   THE PROFESSOR, THE INSTITUTE, AND DNA

tions were involved during that period in problems that appeared unrelated to
transformation, but eventually proved to have a direct bearing on the interpreta-
tion of the phenomenon and on its general significance. I shall mention a few of
these problems in the following pages, not to present a documentation of the
studies that preceded and followed the discovery that DNA is responsible for
genetic specificity, but to evoke the intellectual atmosphere in which the discovery
was made. The references that I have listed are not inclusive; they have been
selected merely to illustrate the wide range of biological and chemical studies
which, during the 194Os, created a scientific climate favorable to the conversion of
such a crude biological phenomenon as pneumococcus type transformation in the
mouse into the highly sophisticated science of molecular genetics.

Within a few years after the demonstration that pneumococci can be made to
incorporate DNA from a different immunological type and thus undergo hereditary
change in the chemical structure of their capsular polysaccharide, other phenomena
of transformation were recognized in several other bacteria1 species. In little more
than a decade, it had been shown that transformation can involve a great diversity
of characters completely different from those that govern the synthesis of the
capsular polysaccharides-for example, cellular morphology, production of many
different enzymes, resistance to antibacterial agents, virulence for certain animal
hosts. In brief, the transformation of immunological type in pneumococci proved to
be but a special case of a very general phenomenon in the bacterial world. The
rapidity with which the field developed is illustrated by the huge size of the
bibliography in a review, "The Genetics of Transformation," that was published in
1961, 15 years after the publication of the original findings on the genetic role of
DNA (reviewed in reference 1 to this Appendix).

Although many bacterial species have been shown to be capable of incorporat-
ing foreign DNA, recognition of the phenomenon in the laboratory is often made
difficult by the fact that the recipient cells must be in a physiologically "competent"
state before incorporation can take place; this state of "competence" exists for only
a short period of the cell's growth cycle. Moreover, the ease of transformation is
conditioned by a multiplicity of subtle environmental factors which differ from
species to species (reviewed in reference 2). These experimental difficulties, how-
ever, are of minor importance when compared with the much larger conceptual
difficulty posed by the chemical nature of the transforming substance.

The general view among geneticists then was that proteins are the only sub-
stances with a sufficient degree of chemical complexity to account for the immense
diversity of hereditary processes. This view was challenged by the claim that
hereditary characteristics can be transferred by molecules of deoxyribonucleic acid,
but such a claim was chemically untenable as long as DNA was believed to be built
up from simple tetranucleotides, which could not possibly provide the chemical
diversity required for biological specificity. Next to the discovery of the transforma-
tion phenomenon itself, and its identification with DNA, the most fundamental
step in the development of chemical genetics was therefore the demonstration that
the molecular structure of DNA differs according to the biological source of the
material.3 It is of interest that E. Chargaff, whose role was crucial in discrediting
the tetranucleotide doctrine, has repeatedly acknowledged Avery's influence on his
own work:


                        Appendixes   227

"In 1944 Avery, MacLeod and McCarty published their famous paper on the
transforming principle of pneumococci. This was really the decisive influence, as
far as I was concerned, to devote our laboratory almost completely to the chemistry
of nucleic acids. . . ."4
Once it had been shown, largely through Chargaff's work, that the distribution
of bases differs from one biological type of DNA to another, it became possible to
envisage chemical mechanisms for the specificity of genetic information, deter-
mined by the sequence of the four nucleotides along the polynucleotide chain.
Several other lines of studies which came to fruition during the 1940s made it
possible to visualize how DNA functions as bearer of hereditary characteristics in
the bacterial cell. New histological techniques were used to establish beyond doubt
the existence of a nucleoid body in bacteria and to show that the cellular DNA is
localized in this very structure. 5-7 Further evidence, even though indirect, for the
genetic role of DNA was provided by two different kinds of findings, namely: the
demonstration that this substance is the active infectious component of coli T-
phage" and that diploid cells contain twice as much DNA as haploid cells.9, I"
During the 1940s also, it became increasingly apparent that the fundamental
genetic mechanisms of bacteria are very similar to those in the cells of higher
organisms. First came the demonstration that when hereditary changes take place
in pure cultures of bacteria, they occur as discrete spontaneous events, resembling
the mutations of classical genetics. I1 The relation between genes and transforma-
tion became even clearer in 1951, when it was shown that the very steps experi-
enced in the mutational history of a bacterium could be faithfully recapitulated as
discrete stages of transformation which its DNA could bring about. By this time,
the discovery had been made that mating (conjugation) does occasionally occur in
bacterial cells and results in exchange of genetic material between mated cells.`* A
few years later, it was found that genetic material can be introduced into bacteria
through the agency of temperate phage, by a mechanism that has come to be
known as transduction.*3l'4 Conjugation, in particular, eventually revealed that
bacteria possess chromosomelike structures which are linear arrays of many
genes-a fact compatible with the view that the process of transformation in
pneumococci is not really a mutation, but rather involves transfer of chromosomal
material from donor to recipient cells.15
Transformation, conjugation, and transduction are thus three different mecha-
nisms through which new genetic material can be introduced into the bacterial cell.
To the extent that these mechanisms operate in nature-an extent which has not
been determined quantitatively-they increase genetic variety by facilitating re-
combination of spontaneously occurring mutants. In this manner, they play a role
in haploid, asexually reproducing bacteria similar to that of genetic recombination
between chromosomes in diploid, sexually reproducing organisms. By increasing
the flow of genes through populations of bacteria and probably between different
species, transformation, conjugation, and transduction tend to produce a continu-
ous spectrum of genetic differences, and thereby to blur species distinctiveness. If
the flow of genes through these mechanisms were to occur widely on a large scale,
the nineteenth-century doctrine of bacterial polymorphism might be reappearing
under a new guise, but this is obviously not the case.`"
For practical reasons, bacteriologists have found it useful to classify bacteria


228   THE PROFESSOR, THE INSTITUTE, AND DNA

according to the Linnean system on the assumption that genetic discontinuity in
these organisms is as marked as it is among higher organisms. Bergey's Manual of
Determinative Bacteriology could not have been prepared without this assumption.
There are many cases, of course, in which the conventional classification of bacteria
in neatly defined genera and species appears to be more an exercise in textbook
taxonomy than a reflection of the manner in which these organisms are related in
nature. Nevertheless, practice shows that a number of bacterial groups are suffi-
ciently stable and distinct from each other to make possible a fairly dependable
system of classification. Such genetic discontinuity implies, of course, that there
exist in bacteria certain mechanisms which act as barriers to gene flow and which
thus play the same role as do genetic isolating mechanisms in higher organisms.
Little is known concerning the mechanisms responsible for such interference to
gene flow, but granted that genetic transfer between bacteria can be achieved by
laboratory procedures, there is no evidence that the phenomenon occurs frequently
in nature.

The very knowledge that foreign genetic material can be incorporated into a
bacterial cell and that the genetic endowment can thus be modified has naturally
encouraged investigators to pursue the problem beyond the limits of naturally
occurring processes. Despite public alarm about the potential dangers of manipu-
lating the genetic endowment of bacteria and other cells, it can be taken for granted
that the biological methods of transformation, conjugation, and transduction will
be used to "synthesize" composite cells possessing desired associations of proper-
ties. Such "chimera" are even now being produced in the laboratory, and will
certainly continue to be produced. Furthermore, chemical manipulation of the
DNA molecule may permit modifications of the genes themselves and thus lead to
directed chemical mutation, for good or evil.

Genetic engineering, which is the popular name of this science, thus appears
superficially to be a man-made reincarnation of bacterial polymorphism, one
century after Louis Pasteur, Ferdinand Cohn, and Robert Koch had affirmed that
bacterial species are stable and cannot change one into the other. The potentialities
of genetic engineering are immense, and it is certain that, with all the genetic
material of the world's biotype available, many creatures will be built that genetic
isolation mechanisms would prevent from occurring in nature. But I doubt that,
outside the laboratory, such genetic chimera will be a match for the products of
bacterial variability as they occur under natural conditions. As I terminate this
essay-at the end of my professional life-1 experience as deeply as ever a feeling
of humility before the inventiveness of nature, but also a sense of pride at man's
ability to manipulate nature.


INDEX

A

Abernathy, T. J. 98
Acute Lobar Pneumonia 102, 117
Aeiologie der Milzbrandkrankheit 126
Alexander, Hattie 15 1
Alloway, J. L. 29, 139 ff.

transformation experiments 138, 140 ff.,
  151, 218

American Philosophical Society 3
"animal passage"
adaptive changes produced by 128
virulence and 128
Anpassung
concept of 126
anthrax

virulence increase in 128
antiblastic immunity 91 ff., 96, 114
critics of 93-94

definition of 91-92, 177
publication on 70, 117
antibodies

against capsular polysaccharides 88
Avery's interest in 111
formation of 120 ff.
synthetic antigens and 222-223
antibodies, protein
crystallization of 111
antigenic dissociation 120
Avery's constructs on 80, 123
Avery's annual report on (1927) 224-225
definition 177

pneumococcal resistance to 115
antigenic stability
differences in 121
antigenicity

capsular polysaccharides and 120
antigens, synthetic 98, 108 ff.
antibody formation and 222-223
immunity via 109, 222-223
via virulent pneumococcal cells 119 ff.
antiphagocytosis

capsular polysaccharides and 114 ff.
in pneumococci 116
Arkwright, J. A.

Shiga dysentery bacilli and 129
Association of American Physicians
Kober Medal of 70, 72
Austrian, R. 146

"Avery's Auraline" 51
Avery, Catherine (Mrs. Roy C.) 4, 67
Avery, Elizabeth Crowdy 49, Fig. 1
and Baptist Citv Mission Societv 53

Buds and Blossbms and 52 ff. d
comments on New York 50-51
illness of 52-53
personality 52 ff.

Avery, Ernest 53, Fig. I
cornet purchase for 54-55, Fig. 3
death of 53, 55

music scholarship 54
Avery, Joseph Francis 49 ff., Fig. 1
in Baptist community 51 ff.
Buds and Blossoms and 51

death 51, 53
in Halifax 49-50

at Mariners' Temple 50 ff.
Avery, Joseph Henry 49
Avery, Margaret 67
Avery Memorial Gateway dedication 11-12,
  Fig. 21
Avery, Oswald Theodore Frontispiece, Figs,
  I, 3, 4, II, 13; see also Rockefeller
Institute for Medical Research; Hospi-
  tal; transformation, etc.
academic record 57
analysis of SSS 104 ff.
annoyance at criticism 153
antiblastic immunity and 70, 91 ff., 114,
   117,177

and antipneumonia sera 102 ff.
appearance 10, 12, 161 ff.
appointment to Hospital 63, Fig. 8
approach to science 71-72
avoidance of controversy 82
bacterial terminology 152
behavioral mysteries 163 ff.
birth 54

"bubble-pricking" 145, 217, 219
captain in World War I 83, Fig. 11.
and chemical basis of biological specificity

  111
childhood 49-55, Fig. 1

chronology and honors 197-198
citation for Co&v Medal 157

Cole, Rufus, and ?l
at Colgate 55 ff.
at College of Physicians and Surgeons

57 ff.

concepts of virulence 113 ff.
as conversationalist 83 ff
cornet purchase for 54-55, Fig. 3
cornetist under Damrosch 55
cornetist with Colgate band 56, Fig. 4
C-reactive protein and 99
death 68, 89

at Deer Isle 66-67
departmental investigations (1930s) 223-
  224

departmental members Fig. 23
DNA publication (1944) 143, 227, Figs.
  19,20

cautions on 145-146
DNA studies 89; see also biological speci-


postsurgical infection studies by 62
presents Kober Medal to Dochez 70-71
presidential address to Society of Ameri-
  can Bacteriologists 65, 99-100, 114,
  169 ff., 221
private life of 47 ff.
professional life of 47 ff.
The Professor 62, 83-84; see also Avery,

230    INDEX

Avery, Oswald T., (conr.)
   ficity, transformation, etc.
Dochez and 63 ff.;see also Dochez, A. R.
enters private practice 29
as experimenter 77 ff.
religious faith of 55-56
familial background 49 ff.
fear of premature publication 94-95
genius loci of the Institute 10 ff.
at Gloucester, Mass. 66
Graves' disease 66, 150
handwriting 69-70, Fig. 9.
  to Flexner Fig. 10
in transformation text Fig. 20
see also letter to Roy C. Avery
at Hoagland Laboratory 20, 60 ff.
  publications from 62
honors 67, 167-168
Hospital appointment 63
influence on associates 84-85, 166-167
intellectual economy 71-72
Kober Medal recipient 72
laboratory techniques 69 ff., 75-77
Landsteiner obituary by 47
letter to Flexner Fig. 10
letter to Roy C. Avery re DNA (1943) 81,
  139, 145, 152, 217-220, Fig. 18
mannerisms of 145, 161 ff.
as manuscript critic 81-82
meaning of, to Institute 181
medical career 58 ff.
member, National Academy of Sciences
   28

as multifaceted specialist 87 ff.
in Nashville 67-68
National Conservatory of Music scholar-

ship 54

natural immunochemical systems and 108
the naturalist 113
nicknames 4, 54,56,58-59,62, 83-84
nominated for Nobel Prize 159
opsonin publications 62, 118
as orator 57

organization of department 76
originality and creativity 173 ff.
pathogenic bacteria research 62 ff.
persona of 47 ff., 161 ff.
"picking brains" 72 ff.
pneumonia studies 10 ff., Fig. 9
popularity of 65

  nicknames
publications 69, 87, 95-96, 102 ff., 150
  ff., 199-216
philosophy on 82

as-public speaker 57, 83-84
Red Seal Records 76. 83-85

relationship to Instituie 10 ff.
relationship to Roy C. Avery 53-54, 68
report to Board of Trustees (1931) 222-

223

reputation at Colgate 56-57
research style 110 ff.
resistance to travel 67, 168
retirement 67, 154, 217
Rockefeller Institute and 11, 63 ff.
schooling 55 ff.

scientific career 48-49
scientific environment of 70
scientific philosophy of 78 ff., 168 ff.
scientific puritanism of 149 ff.
as a showman 178-179
simple life style 64-65
skill in public debate 65
specific soluble substances and, see SSS
speech mannersisms of 116

staff responsibilities in Hospital 150
as teacher 62, 76, 83, 104
as theoretical scientist 87 ff.
training in bacteriology and immunology

61

transformation, doubts on 136, 139 ff.
tuberculosis studies of 61 ff.
word images of 177 ff.
writing methods of 81 ff.
Avery, Roy C. 53, Fig. 1
bacteriologist 54

letter from Oswald T. (1943) 81, 139,
145, 152, 217-220, Fig. 18
in Nashville 67-68

Oswald T. Avery's influence on 53-54

B

Babers, Frank H. Fig. 13
Bacon, Francis
science concepts of 7
bacteria

biochemical studies of 96 ff.
classification of 126. 130. 152. 227-228

DNA incorporation'in ljl
encapsulated 88 ff.
genetics of
mechanisms 227
mutations 131
transfer 227-228
variations 128-129
influenza 104
nucleoid bodies in 130-131
nutrition of 95


Index   231

Boyle, Robert 99-100
Bray, Harry 66

Bronk Laboratory Building 5
Brucke, E. W.

physicochemical theory of 39
"bubble pricking" by Avery 145,217,219
Buds and Blossoms
published by Averys 51 ff.
Burnet. Sir MacFarland 156-157

phenotypic excursions of 131
Shiga dysentery

smooth and rough forms 129
transformation of 225-228
bacterial body

virulence and 119 ff.
bacterial capsule
virulence and 116 ff.
see also capsular polysaccharides
Bacterial Cell, The 4, 130-131
bacterial cells

exchange of genetic material between 227
bacterial genetics 131-132; see also DNA;
  genetics; heredity
bacteria1 metabolism 95 ff., 114 ff.
bacterial monomorphism 130
demonstration of 127
bacteria1 polymorphism 125, 228
discredited 126

bacterial specificity 73; see also biological
  specificity

bacterial transformation
genetic engineering and 225-228

see also transformation
bacterial variabilitv 125 ff,. 228

morphological expression of 129

bacteriological report (1916) Fig. 9
and DNA 69-70

bacterioligy

Avery's training in 60-61
Baptist City Mission Society
patronage of 53
Baptist community, N.Y. 51 ff.
medicine and 58
Rockefeller, John D., and 51-52
Barber, M. A. 93
Barker, L. F. 26-27
Beadle, G. W. 156
Beaumont, William
digestion experiments 15
Beijerinck, Martinus 129
Bellevue Hospital
William Welch at 16
Benison, Saul ix, 23
Benjamin Franklin College 15
Bergmann, Max 109
Bernard, Claude 25, 38-39, 47-48
Bigelow , Henry J.
and experimental medicine 14
Biggs, Herman M. Fig. 7
Billroth, Theodor 125
biological specificity 110 ff.
chemical basis of 101 ff.
of fermentative processes 126-127
Blake, Francis 93
Board of Scientific Directors 4, Fig. 7
Bowditch, Henry P.
laboratory at Harvard 14

C

Cannon, Walter B. 13
capsular antigen
definition of 177
capsular polysaccharides 88, 98
activity in 116
antibody formation and 120
hapten concept and 108
transformation and 140
type III 119 ff., 222-223
virulence and 114 ff., 222-223
capsular substances
antiphagocytic role of 118
chemical nature of 105 ff.
Carnegie Laboratory of Pathology
bacterial research in 20
Carrel, "Alex" 3 i
cellobiuronic acid 109
Chargaff, E. 157, 226-227
Chase, Margaret 148
chemical genetics 131
as new science 154
chemistry
in medical research 35 ff.
molecular 88-89
see also Loeb, Jacques
chemistry of the host 91 ff.
chemotherapy
for pneumonia 102
Chesney, Alan 66
chicken sarcoma
filterable virus of 139
Chickering, H. T. 102
chronology, Avery
life 197-198
publications 199-216
clinical research
vs. laboratory research 26-27
clinical specialization
in Hospital 28 ff.
Cohn, Alfred E. 30-32, 59
Loeb and 42
Cohn, Ferdinand 125-126, 228

bacterial classification and 126
Cole, Rufus 72, 88, 102. Fip. 16

antiblastic immunity and 53
clinical research and 26 ff.


232    INDEX

Cole, Rufus, (cont.)
director of Hospital 26 ff.
hires Avery 63
interest in Avery 61
Hospital physician-in-chief 27, 63
Levene, P. A., and 37
member, National Academy of Sciences
    28

pneumonia research program 101 ff.
protocol experiments and 80
tuberculosis studies and 62
Colgate Academy 55
Colgate University
Avery's life at 55 ff.
College of Physicians and Surgeons 16,59
Welch, Avery, and 48-49
"competence"
cellular 226
conjugation 227-228
C-reactive protein 98-99
crystallized 99
isolated 99
cozymase 97
Crick, Francis 157
Crowdy, Elizabeth 49; see also Avery, Eliza-
  beth
Cullen, G. E. 96
cytomorphosis 131

D

Dale, Sir Henry 157, 168
Darlington, C. D. 145

Davaink, C. J.
"animal passage" and 128
Dawson, M. H. 29,137-138, 218
transformation studies 139 ff.
Deer Isle 66-67
de Kruif, Paul 30
Loeb and 42

Delafield, Francis 16
Delbriick, M. 158
deoxyribonucleic acid, see DNA
Descartes, Rent
science concepts of 7
Diplococcus pneumoniae
Avery's studies on 87 ff.
specificity 111
diseases

microbial origin of 17 ff.
DNA 70, 79

Avery and 11, 142 ff., see also Avery
activity assay of 146-147
biological implications 149
double helix announced 148
doubts re genetic specificity 144-145
first isolation of 138
genetic role accepted 148, 227

hereditary changes and 89
heredity and 139 ff.
incorporation into cells 131
implications of transformation 144 ff.
procedures for identification 143 ff.
publication (1944) on transformation 142,
  143, 157, 158, Figs. 19, 20
specificity of 226
as vindication of Loeb's philosophy 46
viral 148

Dobzhansky, Theodosius 156
Dochez, A. R. 59, 63 ff., 102, Fig. 17
antiblastic immunity and 91 ff.
Avery and 63 ff.
lobar pneumonia studies 117
member, National Academy of Sciences
    28

pneumococcal types and 101 ff.
publications 102 ff.
receives Kober Medal 70
SSS and 70, 74, 95; 103 ff.
see also Avery, Oswald T.
Drake, Daniel
epidemiologist 15
Dubois-Reymond , E
physicochemical theory 39
Dubos, Rene J. 3, 4, 96, 130, Fig. 13
Avery and 74-75
Bacterial Cell, The 4, 130- 13 1
Rockefeller Institute Fellowship 75

E

Ehrlich, Paul 36, 39, 158
Einstein, Albert 179
Elliott, Stuart ix, 132
encapsulated pneumococci; see  capsular
  polysaccharides; pneumococci
enzymes
adaptive 131
inducible 13 1
Ernst, Joseph ix, 4
Etudes SW la bitire 126-l 27
experimental medicine
in Europe 14
in U.S. 14 ff.
see also medical research
experimental science
as an art form 176 ff.

F

faith healing 13-14
"Fess," see Avery, nicknames
Firtsch, G. 128
Fisher, Emil 109
enzymatic specificity and 39
teaches Flexner 37
Flexner, Abraham 29


Index   233

i

Flexner, James 36
Flexner Report 29
Flexner, Simon 13,19,23-24,74,164, Fig.
  7

as administrator 30
Avery and 63, 181
Avery letter to 69, Fig. 10
chemistry in medical research and 36 ff.
Hospital and 26
organizer of Institute 19
scope of Institute`and 30
Fosdick, Harry Emerson
Avery's classmate 55
as orator 57

Fosdick, Raymond B. 169-170
Founder's Hall 8
Francis, Thomas, Jr. Fig. 13
Friedlander's bacilli
antiphagocytic activity and 115
similarity to type II pneumococcus 109
virulent form of 106 ff.

G

Gasser, Herbert S. 217
Gates, Frederick T.
adviser to John D. Rockefeller 20 ff.
conceives idea of Institute 15
on infectious diseases 35
Osler influence on 21 ff., 58
research concepts of 23 ff.
gene modification
via DNA 228

genetic engineering 225-228
genetics
bacterial 13 1
bacterial variability and 129
chemical 131, 226
"informational school" of 159
molecular 226
as physicochemical science 46
see also heredity
"Genetics of Transformation" 226
genetic specificity
DNA and 226
Gerhard, William W.
differentiates between typhus and typhoid
    fever 15
germ theory
influence on laboratory research 17 ff.
Gloucester, Mass.
Avery and 66-67
Goebel, Walther F. ix, Fig. I3
and molecular structure of pneumococcal
   polysaccharides 106, 109 ff.
receives Landsteiner-Avery award 108
Goodner, Kenneth Fig. 13
Goodpasture, Ernest 67, 217, 220
Gregory, Sir Robert 169

Griffith, Fred 225
Avery resemblance to 149 ff.
pneumococci studies 132 ff.
  S and R forms 133 ff.
type transformation and 218

H

hapten 120

definition 108

Hardy, G. H. 176
heart disease 27
Heidelberger, Michael ix, 73, 75, 141,
  Fig. 14

analyzes SSS 104 ff., 118
immunological specificity and 95
Helmholtz, H.
physicochemical theory 39
heme 97

hemolytic streptococci 104, 111
group A 116
group C 116

hereditary changes 127 ff.
reversible 115
heredity 90

chemical processes in 13 1
DNA and 139 ff.
see also genetics; DNA; transformation
Hershey, A. 148
Herter, Christian A. 36-37, Fig. 7
Hirsch, James G. ix
Hirst, George K. 82
Hoagland, Cornelius Nevins 19
Hoagland Laboratory 18, 23, 101, 118
Avery and 6, 10
Avery appointed to 60
bacteriological research in 20
founding of 19

White, Benjamin, director of 60 ff.
Holt, L. Emmett Fig. 7
Hopkins, Johns 18
Horsfall, Frank L. 82
Hospital 4 ff., 26 ff., Figs. 6 and 12
architecture 9
Avery and 10

Avery's appointment to 63
Avery's laboratory in 77 ff.
clinical specialization 27-28
dedication 9

disease problems, early years 27 ff.
journal club 31-32, 65
pneumonia research in 101 ff.
origin of 26 ff.
host chemistry
definition 177

host-parasite relationships 99-100
Hotchkiss, Rollin C. 140
comments on Avery Sl-82,84-85, 154
joins Avery's department 146 ff.
studies on DNA structure 157


234    INDEX

Hutchinson, G. E. 156
Huxley, Thomas 125, 176
hyaluronic acid capsule
virulence and 116

1

Kunitz, Moses
crystallizes deoxyribonuclease 143

             L

laboratory science

1

immunity 90, 108 ff.
metabolic concept of 92 ff.
phagocytic-opsonin theory of 118
via synthetic antigen 109
immunochemistry
Avery-Heidelberger papers on 105
Avery's achievements in 100
immunological specificity 88
molecular basis of 105 ff.
of pneumococci 144
polysaccharide capsule and 116
steric configuration and 108
immunological types
transformation of 112
immunology

Avery's training in 61
infection

phenomena of 95 ff.
infectious disease
Avery's studies of 87 ff.
resistance to 93
studied at the Institute 35-36
in Western civilizations 35
influenza bacilli 104
interdisciplinary thinking at Rockefeller In-
  stitute 44 ff.

Irish, Jane Caroline
"Avery's Auraline" and 5 1

             J

Journal of Experimental Medicine 31, 87,
  91-92,97,104,143

Johns `Hopkins Institute of Pathology 19
Johns Honkins Medical School 19

chemi&y in 36
see a/so Welch, William H.

            K

Kitasato Institute 35
Kitchen chemistry 73

Klebs, Edwin 125

Klebsiella aneumoniae 106: see also

Friedlander's bacillus
Kober Medal
awarded to Avery 72
awarded to Dochez 70
Koch Institute 35
Koch, Robert 126, 228
Aetiologie der Milzbrandkrankheit 126
disease control and 6
germ theory and 17
Krauss, M. R. 146

beginnings of 6 ff.
Lancefield, Rebecca C. 111

Landsteiner, Karl 158
artificial immunochemical systems and
    108 ff.

obituary by Avery 47
Lankester, Ray 125
Levene, P. A. 144
head, chemistry laboratory 37
Lister Institute 35
Lister, Joseph 125
germ theory of 17
lobar pneumonia 27 ff.
caused by Friedlinder's bacillus 107
research on 29
serum treatment of 120
sulfapyridine treatment of 151
therapeutic serum for 101 ff.
types of 102 ff.
virulence of 87
Loeb, Jacques 25, 31, 171
academic background 40
chemical view of life 39 ff.
DNA as vindication of 46

influence on Institute 42 ff.
Mechanistic Conception of Life 41-43

physicochemical philosophy 41-43
sea-urchin studies 40
Loir, Adrien 80
Long, Crawford W.
and ether as anesthetic 15
Ludwig, Karl 16
physicochemical theory 39
Luria, Salvatore 157
Lwoff, Andre 148, 157

M

MacLeod, Colin 29, 65, 76, Fig. 21
chemical analysis of transformation 218
C-reactive protein and 99
DNA publication (1944) 143, 227
production methods for transforming sub-
   stances 140 ff.

rabbit virulence and 123
Manual of Determinative Bacteriology 228
Mariners' Temple Fig. 2
Avery, J. F. pastor at 50 ff.
cornet-playing at 54-55
Marshak, A. 156
Martin, H. Newell 19
Massini, R. 129

McCarty, Maclyn ix, 29, 79, 81, 94, Fig. 21
chemical analysis of transformation 218


C-reactive protein and 99
DNA publication (1944) 143, 227
joins the Institute 141 ff.
methods in DNA identification 142 ff.
rabbit virulence and 123
McCormick, John Rockefeller 23
McDermott, Walsh ix
McDowell, Ephraim
performs first ovariotomy 15
Mechanistic Conception of Life 41, 46
medical research
Avery's career and 29
chemistry in 35 ff.
Gates' concept of 23
at Institute 25 ff.
in United States 15 ff.
  germ theory and 17
  philanthropy and 17 ff.
medical science
in 1900 14 ff.
medicine

scientific basis of 11
medicine, European
influence of 14, 16 ff.
metabolism, bacterial, see bacterial metabo-
    lism

Metchnikoff, Elie

fermentation studies 60-61
Mirskv. Alfred E. 156-157

doubts on DNA findings 145
Mirsky, Sonia ix
molecular biology
at Institute 44
molecular chemistry
specificity and 88-89
molecular genetics
transformation and 226
Morgan, Hugh 67, 96
Morgan, John
founds first U. S. medical school 15
Morison, Robert ix
Morton, William Thomas Green
and ether as anesthetic 15
Muller, Herman J. 45, 155-156
doubts on DNA findings 145
and physicochemical mutations 45
Murphy, James 139

N

Nggeli, Carl von
Anpassung and 126-127
Nashville
Avery in 67-68
Neil], J. M. 96
Neisser, Max 129
Neufeld, F.
confirms Griffith's findings 136
pneumococcus studies 101

Index

Niederen Pilze, Die 126
Nobel Committee 79
Nobel Prize
Avery nominated for 159
Northrop, John H. 111, 143
nucleic acids
cell biochemistry and 219
nucleoid body
DNA concentration in 131

0

Opie, Eugene 92
opsonins 59-60
Avery publishes on 62. 118

vaccine therapy and 118
Osler. William 87. 176

faith-healing and 13-14
influence of 15
  on Frederick T. Gates 21 ff.
laboratory research and 26
Osterhout, W. J.


236    INDEX

pneumococci, (conf.)
Avery's group studies of 29
biochemistry of 96 ff.
capsule formation 93
C-polysaccharide of 98
capsular polysaccharides of 108 ff.
encapsulated 114 ff.
  types of 88
immunological specificity and 116
metabolism of 94
nonencapsulated 115
"proteolytic enzymes" in 96
smooth and rough forms of 133 ff.
sss of 117
transformation of 132 ff., 139 ff., 144
type changes of 134 ff.
types of 74, 102 ff., 119, 120-123
type specificity of 103
virulence in 88 ff., 123
pneumococcus
chemistry of 225
culture report I?&. 9
immunological properties of 225
lore of 222-223
species variation 101 ff.
pneumonia
chemotherapy for 102
research on 62 ff.
serum for 101 ff.
pneumonia, see lobar pneumonia
poliomyelitis 27
polysaccharides
in SSS 118-119
see also capsular polysaccharides
Popper, Karl 172
postsurgical infections
bacteriology of 62
Potter, N. B
Avery collaboration with 62
"Professor," see Avery, nicknames
proteins
determinants of specificity 111
proteolytic enzymes 96
protocol experiments 77-81, 119, 179
Prudden, T. Mitchell 9,16-17,35-36, Fig. 7
publications
Avery and collaborators 199-216
Avery philosophy on 82
see also Avery, publications
Pyle, J. P. 57

R

rabbit virulence factor 122

defined 178

Ravin, Arnold ix
Rayleigh, Lord 176
Red Seal Records 83 ff., 217, 222

renal diseases 27
research atmosphere
importance of 30 ff.
resistance

to disease 91 ff.
to encapsulated pneumococcus types 121
Reynolds, Sir Joshua 173
rheumatic fever 27, 146
Reimann, Hobart
confirms Griffith's findings 136
Rivers, Thomas M. 28-30, 142, 217
director of Hospital 28, 30
laboratory science and 46
member, National Academy of Sciences
    28

Rockefeller Institute Hospital, see Hospital
Rockefeller Institute for Medical Research
   3, 20 ff., Fig. 6
ambience of 30 ff.
architecture 5, 8 ff.
chemistry at 35 ff.
creation of 7

Department of Respiratory Diseases 4,
   174

as educational institution 33
formation of 33
intellectual freedom in 8
interdisciplinary thought in 44 ff.
laboratory organization in 25 ff.
Loeb's influence on 42 ff.
lunchroom of 30-31
original site of Fig. 5
philosophy of 20 ff.
Princeton branch 32
scientific medicine in 6
scope of 25-26
William Welch and 19
see also Avery, professional life; Hospital;
   etc.

Rockefeller, John D., Jr.
Lavoisier portrait presented by 37
Rockefeller, John D., Sr. 35, 58
aid to Avery family 51-52
creates the Institute 7, 20 ff.
skating invitation 52
see also Gates, Frederick T.
Rockefeller University 33
archives 4

chemistry at 44
Rothen, Alexandre 142
Rous, Peyton 31

             S

Salomon's House 7
scientific medicine
European 13 ff.
private support of 18 ff.


self-healing, see faith-healing
serum. therapeutic
antipneumococcal 101 ff,
Sia, R. H. P.

transformation experiments 137
Sloan, Emily Vanderbilt 53
Smith, Theobald 35-36, Fig. 7
social philanthropy '
medical research and 18 ff.
Society of American Bacteriologists
Avery's presidential address to 6.5, 99-
   100, 114, 169 ff., 221
species specificity
transformation and 226
specific soluble substances, see SSS
Sprofkin, Bertram E. 67-68
Spurgeon, C. H. 49
SSS (specific soluble substances) 103 ff.
antiphagocytic activities of 114 ff.
definition 177

discovery of 114
first report on 95
polysaccharide composition of 73 ff., 118-
  119

publication on 70
purification of 73
in type II and III pneumococcus 106 ff
virulence 117
Stanley Wendell 143
Stent, Gunther S. 155 ff.
Sternberg, George M.
describes pneumococcus 101
director of Hoagland Laboratory 19-20
Stillman, E. G. 98
streptococci

hemolytic 104, 111, 116
specificity of group A 111
sulfapyridine

in pneumonia treatment 151
sulfonamides

advent of 116
Swift, Homer 66
synthetic antigens, see antigens, synthetic
syphilis 27

T

Taylor, Harriett (Ephrussi) 146 ff.
Tennessee State Library and Archives 4
Terrell, Edward E. Fig. 13
tetranucleotide doctrine

discrediting of 226
Thyotta, T. 96
Tiselius, Arne 79

tissue fastness 122
Todd, Edgar 168
transduction 227-228
transformation 131 ff., 227-228

Index

237

Avery-group publications on 147
Avery laboratory methods on 137 ff., 218
  ff.

bacterial 225-228
capsular polysarcharides and 139-140
DNA and 225-228
environmental effects on 226
genetic diversity and 226
implications of 2 19
and species specificity 226
see also transforming agent; transforming
  substance; etc.

transforming agent
definition 178

transforming substance
assays for 140 ff.
chemical identification of 142
identification as DNA 142 ff.
production methods 140 ff.
tubercle bacilli
Avery's work on 61-62

U

Untersuchungen iiber Bacterien 126

V

vaccination

by synthetic antigens 222
vaccines

against pneumococcal types 120
Vanderbilt University Medical College 54
Van Slyke, Donald D. 28, 37
research atmosphere and 32
virulence 90

"animal passage" and 128
"attenuation" of 128
Avery's concepts of 113 ff.
bacterial body and 115, 119 ff.
bacterial capsule and 116 ff.
capsular polysaccharide role in 88, 114 ff.,
  118 ff.

cell specialization and 89
complexities of 113 ff.
and enzymatic activities of bacilli 114 ff.
in experimental models 113 ff.
and genetic variability 115 ff.
in nature 113 ff.
phagocytosis-opsonin theory of 118
pneumococcal 222-223

W

Walker, A. C. 156
Wandell, Minnie 67-68
Watson, James D. 148, 157
Welch, William Henry 13, Figs. 7 and 15
behavioral mysteries 163-164
influence on medical research 16 ff.


238    INDEX

Welch, William Henry, (cont.)
at Johns Hopkins 18-19

Woolworth Building
architecture 8-9

personality of 48-49
professional background of 36
scientific career 48-49
White, Benjamin
director, Hoaaland Laboratory 60 ff.

Wright, Sir Almroth
influence on Avery 59
opsonic techniques and 59
Wright, Sewall 156
             "

indoctrinates Avery in laboratory tech-                 1
   niques 60 ff.                yogurt
at Trudeau Sanatorium 174
tubercle-bacilli studies 61-62         bacteriology of 60-61

Williams, Howard 4                                Z
Wood, Dr. Barry 175-176            Zinder. Norton ix