DS6 FEC ig

STANLEY, WENDELL MEREDITH (b. Ridgeville, Indiana, 16 August 1904; d. ans

Salamanca, Spain, 15 June 1971) chemist, virologist, educator.

In 1935 Wendell Stanley crystallized tobacco mosaic virus, an achievement
which was awarded a Nobel Prize in 1946. This and subsequent findings
demonstrated that an infectious agent could have the properties of a chemical
molecule and posed the biochemical problems of the mechanisms of inheritable
duplicability. The initial observations were soon confirmed in England by F.C.
Bawden and N.W. Pirie, who showed also that this and other plant viruses
contained ribose nucleic acid (RNA). Their result, in its turn, set the
problem of the structural and functional roles of the nucleic acids in viruses.
The almost simultaneous discovery by M. Schlesinger of deoxyribonucleic acid
(DNA) in some bacterial viruses extended this finding. Thus, in the years 1935
and 1936, the biologists were startled to learn that some of the smallest

' were isolable by methods

organisms, in the group known as "filterable viruses,’
designed for proteins and were amenable to rigorous chemical and physical
characterization. The results at that time indicated that the viruses
contained both protein and a distinctive but little studied substance, a
nucleic acid. Early commentators on these findings called attention to the
similar reproductive capabilities of viruses and genes, and in 1937 E, Wollman
added "La possibilite d'"inoculer" des genes a des cellules ne nous semble pas
pouvoir @tre exclue a priori."

By 1944, these events culminated in the demonstration by O.T. Avery, C.M.
Macleod and M. McCarty that the Pneumococcal transforming agent was a
biologically specific DNA. Thus within the period of 1935 to 1944, the
fundamental problems of the nature of the gene, its duplication and mode of

action had been transferred to model systems of virology and microbiology. The

analysis of these systems over the next thirty years determined the course of

 
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biological science by facilitating the dissection of the mechanisms of
inheritance, and by leading to the integrative development of numerous
disciplines, i.e., biochemistry, genetics and structural chemistry, as
"molecular biology."

Wendell Stanley, the initiator of this modern era of biology, was the son
of James G. and Claire (Plessinger) Stanley. His parents published the local
newspaper, and as a boy, Stanley helped to collect news, to set type and to
deliver the final product. He attended public schools in the little town of
Ridgeville, completed the last two years of high school in Richmond, Indiana,
and entered Earlham College in Richmond, Indiana, in 1922. In addition to
academic majors in chemistry and mathematics and an active social life, Stanley
played football for all four of his collegiate years and captained a winning
team in his senior year. In a state known for several outstanding sports—
oriented colleges, the relatively slight Stanley was selected as end of the
All-Indiana State team. Nevertheless, Earlham College, which began as a Quaker
school, prided itself on the quality of its liberal arts education, stressing
the examination of values and moral commitments, as well as of "facts."

Several events in Stanley's later career suggest that the choice of Earlham and
his life there contributed significantly to his bearing and attitudes.

On graduation in 1926, Stanley aspired to be a football coach and in the
spring of that year visited the campus of the University of Illinois with this
future in mind. While there he met Roger Adams, a doyen of organic chemistry.
He learned of graduate work in chemistry and armed with his baccalaureate from
Earlham, entered the University of Illinois. Asa graduate student with Adams,
he worked on two types of problem, one on the stereochemistry of biphenyls and
the other on the synthesis and properties of compounds potentially bactericidal

for Mycobacterium leprae. He published eleven papers on these subjects with

 

 
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Adams between 1927 and 1933, obtaining an M.S. in 1927 and a Ph.D. in 1929,
Among these, Stanley and Adams synthesized hydnocarpylacetic acid and showed it
to be identical with natural chaulmoogric acid. Also all the bactericidal
aliphatic sodium salts were found to be marked depressants of surface tension.

A paper in this area was published in 1929 with Adams and another graduate
student, Marian S. Jay, who married Stanley in that year. The couple had a son
and three daughters, of whom the son, Wendell, Jr., is known for his work in
molecular biology. It may be relevant to Stanley's later success that the
single joint paper of Stanley, Jay and Adams in the Journal of the American
Chemical Society follows an early paper by J.B. Sumner and D.B. Hand on the
isoelectric point of crystalline urease, determined as the point of minimum
solubility. This is a method used by Stanley in his later crystallization of
tobacco mosaic virus.

Stanley was an Instructor at Illinois in 1930, and won a National Research
Council Fellowship in Chemistry, which he took in 1930-1931 with Heinrich
Wieland in Munich, Germany. His work with Wieland was on the characterization
of the sterols of yeast.

The Stanleys returned to the United States during the Depression; he was
appointed to a position with W.J.V. Osterhout at the Rockefeller Institute in
New York. Osterhout, who had been studying the transport and concentration of
ions in plant cells, such as Valonia, had asked Stanley to develop a model
system to transport ions selectively across a membrane. Stanley, quite
unfamiliar with problems of this type, read extensively in the field and in
1931 helped to devise systems for the selective accumulation of potassium and
sodium. A non-aqueous medium representing the protoplasmic surface was
interposed between alkaline and acidic aqueous phases. An accumulation of the

cations occurs in the more acid phase, followed by an increase of osmotic

 
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pressure and of water entry. The entire system simulated accumulation in
Valonia very well, permitting a comparison in model and Valonia of the factors
modifying uptake. The work with Osterhout undoubtedly sharpened Stanley's
understanding of the biophysical chemistry of the time, and probably introduced
him to some current problems of plant physiology.

In 1932 he moved to the Department of Animal and Plant Pathology of the
Institute, established at Princeton, New Jersey, since 1916. This branch arose
in response to the principle that the Institute could not limit itself to the
study of human disease and to the proposal in 1914 to establish a Department of
Plant Pathology. The distinguished American microbiologist and comparative
pathologist, Theobald Smith, became Director. Laboratories were built on farm
land on the outskirts of Princeton. Smith and the groups he assembled became
active in the study of various protozoan, bacterial and virus diseases of
veterinary importance. In 1926, a branch of General Physiology, comprised of
John Northrop and Moses Kunitz, became part of Smith's administrative domain,
as had numerous other groups representing insect physiology, parasitology,
genetics and nutrition. By 1926, the size and diversity of the enterprise
became excessive for Smith, who was eventually replaced by Carl Ten Broek, an
early collaborator knowledgeable in virus infections. Under Ten Broek, who
helped to sustain the work of virologists such as Richard Shope and Otto
Glaser, a Division of Plant Pathology was established in 1931 with Louis 0.
Kunkel as its Head. He moved to Princeton in 1932 and brought Stanley there
shortly thereafter.

Kunkel had come from the Boyce Thompson Institute for Plant Research and
had been associated with C.G. Vinson and A.W. Petre, who had obtained promising
results in the chemical separation of tobacco mosaic virus. Kunkel asked his

entire group to focus on mosaic diseases, principally that of the tobacco

 
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mosaic disease. In 1892, the Russian, D. Ivanovski, had shown that this
disease could be transmitted by the sap of an infected plant after filtration
through porcelain. M. Beijerinck in Delft had made similar observations in
1898 and had postulated the existence of a pathogen smaller than bacteria,
i.e., a "filterable virus." Among several virologists in Kunkel's group,
Francis Holmes had developed a method of estimating infectious virus particles
by counting the localized lesionsarising after inoculating the leaves of
selected plants. Philip White was growing virus-susceptible tomato roots
aseptically in tissue cultures in order to dilute out possible secondary
invaders. Kunkel himself discovered related viruses and compared their host
ranges with that of tobacco mosaic virus. He is also known for the "heat-cure"™
of plants, including trees, thought to be infected by viruses. Some of these
infectious agents are known to be mycoplasmas and not to be viruses.

Beginning with the work of H.A. Allard in 1916, various investigators had
concentrated and purified the virus. Between 1925 and 1935, Vinson and Petre
had used lead acetate to precipitate the virus. The fact that the virus might
be handled as a chemical precipitable by protein precipitants led Stanley to
explore the possibility that this virus was a protein. In 1933 and 1934,
Stanley worked furiously to test the infectivity of fresh or partially purified
extracts exposed to more than a hundred reagents, including some proteolytic
enzymes, Such enzymes, including trypsin, had been isolated and crystallized
just a few years earlier by Northrop and Kunitz at the Institute in Princeton.
The successes and methods of this group were a continuing source of
encouragement in this early period. Stanley found that trypsin inactivated the
virus but that the latter could be reactivated. The enzyme affected the plant
more than the virus, and Stanley concluded that trypsin did not degrade the

virus proteolytically. On the other hand, a slow inactivation by pepsin in the

 
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range of hydrogen-ion concentration (pH) in which pepsin was proteolytic was
consistent with the idea that the virus was a protein. In general, infectivity
was lost at extreme pHs, or in the presence of oxidizing agents, or of protein
precipitants., Pursuing the results of Vinson and Petre, it was possible to use
a low concentration of lead acetate at high pH to eliminate colored materials
without reducing infectivity, and he introduced such a step in his initial
successful purification. During purification steps, the pH was adjusted at
non—inactivating levels, which facilitated solubilization or precipitation, and
which he had established earlier.

In this early work, published in 1935, large batches of frozen infected
plants, ground in the frozen state, were thawed in a buffer containing sodium
phosphate (high pH) and the filtrate was precipitated at lower pH with a high
concentration of ammonium sulfate. This precipitate contained virus which was
extracted and reprecipitated. Lead acetate at high pH was used to remove
colored material and an asbestos powder adsorbed the virus at low pH. The
virus was eluted at high pH and the virus was crystallized from this solution
as small "needles" by the addition of acetic acid to a defined low pH in the
presence of 20% saturated ammonium sulfate.

The initial report in 1935 described a product containing 20% nitrogen but
the first complete paper in 1936 (accepted in November 1935) reported nitrogen
contents by two methods of 16.1-16.6%, values consistent with those of proteins
and most nucleoproteins. However, Stanley did not find phosphorus or sulfur in
the virus. The protein was recognized to be very large since it did not pass
through membranes that did not retain smaller proteins, such as egg albumin.
Resolution and recrystallization of the protein some ten times did not affect
the dilution of the virus used to produce local lesions. The extracts of

single lesions gave rise, in subsequent infections, to very much larger amounts

 
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of the infectious protein, indicating its multiplication, as befits a virus.
Antisera against the virus were prepared in guinea pigs and rabbits, and these
reacted specifically against purified virus preparations, as well as against
the juice of infected plants. Uninfected plants did not contain proteins
capable of reacting with these antisera. In a later study it’ was shown that
tobacco mosaic virus multiplied as such in tomato plants. Further, a
distinctly different strain of the virus, the aucuba mosaic virus, multiplied
as such in aucuba-infected tobacco.

In interpreting his results, Stanley was influenced by the results of
Northrop and Kunitz, who had described the existence of pancreatic proenzymes,
such as proteolytically inactive trypsinogen. This substance was converted by
proteolysis to active trypsin by adding a trace of the active proteolytic
enzyme. Could a plant contain a serologically inert pro-virus that would be
converted "autocatalytically" by the active virus to a serologically active
virus? It was shown very soon that significant amounts of comparable large
molecules capable of serving as pro-virus were not present in the juice of
normal plants, although various modifications of the precursor hypothesis were
not excluded. It was not until the late 1940s, in work with bacteriophage
systems, that it was shown that virus multiplication required extensive de novo
synthesis of proteins and nucleic acids, and very much later in the 1960s that
the processes of synthesis of nucleic acids and proteins were comprised of far
more complex metabolic and synthetic events than that described for the
conversion of trypsinogen to trypsin. In 1935 Stanley stated that
"Tobacco-mosaic virus is regarded as an autocatalytic protein which, for the
present, may be assumed to require the presence of living cells for
multiplication." It was shown a decade later, in 1946 and 1947, in studies

with bacterial viruses, that the host cells continued to supply the energy, as

 
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well as an extensive metabolic apparatus, for the multiplication of these
viruses. These conclusions are applicable similarly to plant and animal
viruses multiplying in their respective hosts.

In discussing the extraordinary result that an organism capable of
inheritable duplication could be defined as a relatively simple substance
capable of forming crystalline arrays, Stanley entered the morass of wondering
if the virus were "alive." His conclusion that this virus was not "alive"
elicited much discussion of the meaning of the term and, in particular, we can
note the important essay in 1937 by N.W. Pirie entitled "The Meaninglessness of
the Terms Life and Living." After a useful discussion of the attributes of the
many properties of organisms and substances, Pirie noted the lack of agreement
on the meaning of the word "living." He suggested that “it seems prudent to
avoid the use of the word 'life' in any discussion about border-—line systems,"
and indeed his essay squelched further discussion for about twenty-five years.
However, in later years, with the development of space programs, many |
individuals, including Pirie, have then had to attempt to define just which
characteristics ought to be sought in the samples to be collected on. Mars or
elsewhere.

The first group to confirm Stanley's discovery included F.C. Bawden and
N.W. Pirie, who in earlier studies of the potato X virus had concluded that
this virus was comprised of proteinase-sensitive proteins. However, this
flexuous virus did not easily form crystalline arrays. Turning to tobacco
mosaic virus, they were able to isolate the "needles" observed by Stanley, but
with the aid of the X-ray crystallographers, J.D. Bernal and I. Fankuchen, it
became clear that the "needles" did not possess three-dimensional regularity.
The purified virus particles were relatively stiff rods of constant diameter,

which were aligned during flow, and packed in hexagonal arrays to form

 
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needle-like "liquid" or "para" crystals. This occurred on precipitation by
salts at a pH of minimum solubility, i.e., at the isoelectric point as
determined by Sumner and Hand in 1929, or by steric exclusion and the
abstraction of water to large foreign hydrophilic molecules. Bernal and
Fankuchen, in later detailed studies of the virus "paracrystals," described the
open-ended needles as "tactoids." Bawden and Pirie also showed that a further
purification of virus particles in concentrated suspension permitted a
separation into two phases, of which the bottom phase was spontaneously
birefringent in polarized light, i.e., the virus had crystallized in the arrays
represented by the smaller "tactoids." The top phase was now more dilute and
showed anisotropy of flow, becoming birefringent in polarized light in regions
of flow aligning the particles. Cycles of differential centrifugation effected
this degree of purification from both soluble contaminants and insoluble cell
fragments.

Although Bawden and Pirie have each questioned the identity of Stanley's
initial product, it should be noted that the high nitrogen content was
corrected by the end of 1935, before the first paper by the English group
(submitted on 17 November 1936 and published on 19 December 1936).

Furthermore, Stanley's material was analyzed by an American crystallographic
group, and the data published in November 1936 was described by the English
group as follows in a note added on 3 December 1936: "Wyckoff and Corey have
published an X-ray study of the ammonium sulphate crystals of tobacco mosaic
and aucuba protein. Their measurements of the intramolecular spacings obtained
with unorientated material agree with ours, notably the lines they record at
11.0, 7.44, 5.44 and 3.7 A correspond to our measurement of the planes (0006,

1

9, 12, 18) respectively." Thus the material obtained by the English workers

was identical to an early preparation of the virus obtained by Stanley, i.e.,

 
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made before any publication by the former group.

In addition to the British clarification of the degree of order found in
isolated viral arrays, their earliest paper records their discovery of the
presence of 54 RNA in this virus, a result they soon extended to related
viruses. Higher percentages of RNA were discovered later by this group in some
spherical viruses, such as the tomato bushy stunt virus and the tobacco
necrosis viruses. At first Stanley was unwilling to accept this result, which
had been communicated to him by Pirie early in 1936. Stanley considered the
RNA to be a disposable contaminant and disregarded the unusual ultraviolet
absorption spectrum of the virus, now known to relate to the presence of
nucleic acid. However, H.S. Loring, a collaborator of Stanley, found
phosphorus and RNA in organic combination with protein in several viruses, and
in 1938 Loring and Stanley corrected their earlier variable and confusing
values. Their report was extended in 1939 by F.A. Ross and Stanley to include
the presence of sulfur in the virus, exposed as sulfhydryl groups in side
chains of cysteine in the native protein.

The discovery of the presence of RNA in the virus and its solubilization
after denaturation of the virus protein by heat, detergents, alkali or acid
facilitated the characterization of this material. It had been suggested by
P.A. Levene that RNA was comprised of four different nucleotides to form a
tetranucleotide. The RNA of the virus contained the four classical nucleotides
but diffused more slowly than a tetranucleotide might. In 1942 the nucleic
acid, isolated after heat denaturation of the virus, was shown by S.S. Cohen
and Stanley, using measurements of diffusion, sedimentation and viscosity, to
be much larger, indeed, having an average molecular weight of 300,000. The
product was highly asymmetric and spontaneously birefringent, although it

slowly depolymerized on standing. The size and shape of this material
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suggested a lengthwise orientation within the virus, which also contained
linearly assembled smaller subunits of protein. The packaging of the protein
around the nucleic acid presumably rendered the latter insusceptible to
degradative enzymes. Although the largest weight of the product isolated at
this time was only an eighth of the total RNA of a virus particle, less drastic
methods have yielded RNA molecules of greater than two million daltons. Such
molecules of RNA are infectious themselves, and indeed some of this size were
probably among the mixture of molecules isolated in 1942, since some fifteen
years later infectious RNA has been prepared after heat denaturation.

As indicated above, the criticism of Stanley's early studies had been
severe. Nevertheless Stanley did not respond in kind. The dialogue, criticism
and competition led in many instances to stimulated efforts and new results.
Before 1937, Stanley had obtained collaborative assistance from physical
chemists in New York, R.W.G. Wyckoff, J. Biscoe and G.I. Lavin. In the period
of 1937 to 1942, the work of Stanley's laboratory multiplied with the
assistance of numerous younger chemists, H.S. Loring, Frank A. Ross, M.
Lauffer, G.L. Miller, C.A. Knight and 5.5. Cohen. The physical biochemist, Max
Lauffer, was particularly important in formulating approaches to defining the
molecularity of tobacco mosaic virus and of tomato bushy stunt virus, and in
characterizing macromolecules generally. The English group asked early on if
the crystalline preparations of infectious protein contained only the
distinctive rod-like particles, and both groups used physical and chemical
methods in developing the affirmative answer. Was the infectivity a function
of a singularly~sized rod? Lengthwise aggregation occurred under many
biological and chemical conditions, but careful sedimentation studies by
Lauffer revealed that monomeric rods were the infectious entity. Rods of

shorter length were seen in electron microscopy of infectious samples, but

 
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these are now known to be derived from longer rods broken in the preparation of
the sample for microscopy. How homogeneous was a population of virus
particles? Lauffer, analyzing the spreading of a sedimenting boundary of
tomato busy stunt virus, concluded that the diameters of the particles could
deviate from the mean by no more than 1%. In an exuberant moment, Lauffer
referred to "living molecules."

Nevertheless, it is of considerable interest that neither group tested the
infectivity of viral RNA before 1956. Despite the availability of appropriate
viral RNA after 1936 and inactivating crystalline ribonuclease in 1940, despite
the demonstration of DNA as Pneumococcal transforming agent in 1944 and the
apparent infectivity of phage DNA, accepted by the community of phage workers
in 1953 following the discovery of the Watson-Crick model, the thought that the
viral RNA might be the genetic element of this virus was not tested before
1956.

In 1940 E. Pfankuch et al. had studied X-ray induced mutations of the
virus and had attributed differences in the phosphorus contents of the parent
and mutant strains to irradiation-induced alterations in the nucleic acid part
of the virus. These data were not considered convincing in 1941 by C.A. Knight
and Stanley who had found differences in the amino acid compositions of various
strains. They had concluded that “the chemical differences between strains
probably lies not in the nucleic acid but rather in the protein part of the
virus molecule." They apparently did not consider the possibility that the
nucleic acid might determine the composition of the protein. Following this
line of thought, Miller and Stanley modified amino acid residues with a variety
of reagents but found that, although many groups could be modified without loss
of biological activity, the virus propagated was normal virus. At this point

in the work, early in the entrance of the United States into World War II, the

 
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work of the laboratory was diverted to the isolation of influenza virus and the
production of an influenza vaccine.

Nor is the record of Bawden and Pirie more enlightening on this question.
Only after the startling reports of Gierer and Schramm and of Fraenkel—-Conrat
in 1956 did these workers undertake to test the infectivity of RNA
preparations. Finding low levels of such activity in an inefficient assay by
their RNA samples, they were suspicious initially of the meaning of their
results. However, as the mechanisms of virus multiplication and of the roles
of the nucleic acids were clarified, they eventually accepted the concept that
the RNA or DNA of a particular virus can constitute its genetic element.

Although Stanley had defined the reproductive process as one requiring the
participation of cells, his approach to the problems of virus multiplication,
as well as that of Bawden and Pirie, focused on the nature and structure of the
virus particle. This approach provided unique materials for the development of
electron microscopy, and for some years the well-defined tobacco mosaic virus
served as the yardstick for the standardization of the magnification in the
microscope. Neither group ever attempted to analyze the multiplication of a
virus in its cellular site, because it appeared too difficult to obtain tissue
in which a high percentage of cells were infected. This had led a few workers
to begin to reexplore the long-known bacteriophage systems, in which it was
possible to time the initiation of infection, the duration of the
multiplication process and the yield of virus per infected cell. Furthermore,
it was possible to infect all the bacteria of a population simultaneously to
provide a system for the study of chemical events during bacteriophage
multiplication. This type of chemical study of virus multiplication began in
1946, was extended to animal cells infected in tissue culture in 1953, and

finally to infection of separated plant protoplasts in 1967. It is now known

 
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that certain virus infections of plants permit the growth of virus-infected

cells, which can be isolated in high yield and with which processes of virus
multiplication can be studied. In retrospect it can be seen that this late

development could have been sought in the late 1930s.

In any case the exigencies of World War II altered the priorities of
Stanley's laboratory, and with the participation of Miller, Lauffer and Knight,
Stanley developed an inactivated vaccine for viral influenza. A Sharples
Super-centrifuge, found to be useful in sedimenting various types of particles,
was applied to the study of the concentration of influenza virus grown in the
allantois of the embryonated chick. The large capacity and efficiency of this
equipment made this the method of choice for a large-scale preparation of
virus. The size, stability and chemical inactivation of the virus were
studied, as well as its immunizing potency. The general procedure has proved
to be useful in the development of several commercial vaccines. Stanley became
a consultant to the Secretary of War and a member of the U.S. Army Commission
on influenza. In 1948 he received a Presidential Certificate of Merit for his
work in vaccine development.

The many exciting and important results of Stanley and his early
collaborators led to his election to the American Philosophical Society and
National Academy of Sciences in 1940 and 1941 respectively. He had won many
prizes and academic honors, including honorary degrees from Earlham, Harvard
and Yale before the beginning of the War. At the end of the War, a new round
of awards began in 1946, including the Nichols Medal of the American Chemical
Society and the Nobel Prize, shared with J.B. Sumner and John H. Northrop, for
their crystallization of enzymes, and Stanley also received an honorary degree
from the University of California. Early in 1947, the Trustees of the

Rockefeller Institute decided to close the Princeton Laboratory, announcing

 
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this in the press without the prior knowledge of the Director, Carl Ten Broek,
and senior Members including Stanley and Northrop at the Princeton branch.
Individuals were offered the opportunity to renew their work in New York.
Although this was acceptable to Kunkel who kept his home in New Jersey and
Kunitz who moved to New York, many others, including Stanley and Northrop, left
the Institute.

In 1948 both Nobelists accepted positions at the University of California
in Berkeley, California. Stanley joined the Faculty as the founder of the
Virus Laboratory-to-—be and the Chairman of a new Department of Biochemistry.

He moved at the peak of his career to a University which, as a matter of
policy, had frequently recruited the most eminent professorial stars to build
new areas or Institutes in the University complex. The move occurred at the
end of a strenuous War, in which scientists of the Berkeley campus had
contributed in an outstanding way to the magical thunderclaps that had
precipitated the final collapse of the Japanese. Penicillin, which produced
miraculous cures of many bacterial diseases, had also become a major product in
the course of the War. Science was perceived as an enormous force in the
future of the planet, and, although the development of penicillin had not
solved the problem of virus infection, it was well known that knowledge was
power and the development of similarly wonderful drugs for the cure of virus
disease was only a step away. The soldiers were going to return to college and
to the University, the fruits of the baby boom were to appear at its doors only
ten years after that, and growth of the University was essential, particularly
in areas of science, to prepare for the glorious future. Stanley began his
second career as an educational administrator, in an optimistic University.

From 1948 to 1953, he recruited able young scientists for both

Departments, and in 1953 resigned as Chairman of the Department of

 
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Biochemistry, as that developing unit was increasingly productive and
independent. In a period in which the enzymological basis of intermediary
metabolism was being explored increasingly in microbial systems, members of
that Department, such as W.Z. Hassid and H.A. Barker, were recognized as
leaders in such studies. After his resignation as Chairman of Biochemistry,
Stanley focused on the tasks for which he had been recruited. The Virus
Laboratory became an assembly of leaders in disciplines crucial to the
development of virology. C.A. Knight had come with Stanley and had
reestablished study of plant viruses. H.K. Schachman, a physical chemist who
had worked for years with Lauffer at Princeton, had organized the laboratory
concerned with the physical characterization of macromolecules. Schachman was
to become Director of the Virus Laboratory after Stanley's death. R.C.
Williams, a distinguished electron microscopist, had been recruited, as had the
protein chemist, H. Fraenkel-Conrat, and G. Stent, a phage worker, who had
studied with M. Delbruck. H. Rubin began a study of tumor viruses, and several
animal virologists, F.L. Schaffer and C.E. Schwerdt, concerned with the
isolation of the virus of poliomyelitis, crystallized the virus in 1955. In
that year also, Fraenkel-Conrat and Williams had reassembled the RNA and
protein subunits of tobacco mosaic virus to form an infectious product, and in
the following year the former showed that the RNA alone was active and had been
protected by its protein coat. In 1960 Stanley participated in a group which
had determined the complete sequence of the amino acids in the protein subunit.
He urged the University to create a Department of Virology, which he
chaired from 1958 until 1964. In this period Stanley wrote many reviews and
participated in many symposia related to viruses. In 1959 he and F.M. Burnet
edited a three-volume compendium entitled "The Viruses." Before and during

this period he had become increasingly active in the affairs of national

 
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science, as Chairman of the Editorial Board of the Proceedings of the National
Academy of Sciences, as a Director of the American Cancer Society, and as a
member of the Board of Scientific Counselors of the National Cancer Institute.

He was also deeply and consistently occupied in campus life, as an officer
of the Faculty Club and in the Faculty Senate. In the period of a developing
Cold War, the influence of McCarthyism had led to an imposition of loyalty
oaths on the Faculties of many Universities, including that at Berkeley.
Stanley served as Chairman of the University Senate Committee on Academic
Freedom. He signed the California oath himself, but publicly defended the
rights of others who refused to sign oaths as a matter of conscience. He
vigorously opposed this imposition as a condition of employment and
participated in the work of groups of academics in resisting oaths and in
bringing the legal issues to the courts. A court decision eventually declared
the unconstitutionality of the oath.

Stanley was convinced of the need to communicate current advances and
perspectives of science to lay and medical groups. He helped to organize a
television series on viruses. His efforts in addressing the public led to his
election as an honorary member of the National Association of Science Writers.

After 1964, when the Department of Virology was enlarged to become the
Department of Molecular Biology, Stanley was relieved of some administrative
duties and shifted his interests even more extensively to the national scene.
In this period of the growth of the National Institutes of Health, he served as
a member of the Advisory Committees to the director, James A. Shannon, and to
the Secretary of the Department of Health, Education and Welfare. In the 1960s
also, the work on avian and mammalian tumor viruses had increasingly created
the sense that such viruses might be etiological agents of human cancer, and

the feeling grew that Stanley's contributions might relate to the control of

 
-~18-

this disease as well. In addition to awards by the American Cancer Society, he
was selected as President of the Tenth International Cancer Congress in 1970.
The hypothesis that tumor viruses, responsible for human cancer, might be
isolated and used in the development of immunizing vaccines, was one
perspective leading to the passage of the National Cancer Act in 1971. The
expanded national effort, which attempted to document the concept, discovered
in the next five years that this idea was much too oversimplified, but in its
turn discovered new facts concerning the genetic relations of tumor viruses
which have led to new rounds of excitement and hope.

Stanley suffered several severe illnesses in his later years but continued
to live a full and vigorous life, which included extensive travel. He died of
a heart attack in Spain where he had attended a scientific conference and had
discussed tumor viruses. He is buried in California. The laboratory which he

built at the University of California is named the Wendell M. Stanley Hall.

 

Bibliography

1. Original Work:

A list of Stanley's publications until 1948 is obtainable from the
Archives of the Rockefeller University. A more complete list until 1970 is
available in the Archives of the University of California at Berkeley. Key
publications to which reference has been made include: The Isolation and
Properties of Crystalline Tobacco Mosaic Virus, p. 196 in Les Prix Nobel en
1947 (Published Rung. Boktryckeriet, P.A. Norstedt and Souer, Stockholm, 1949);
(With R. Adams) The synthesis of chaulmoogric acid from hydnocarpic acid, J.
Am. Chem. Soc. 51:1515 (1929); (With M.S. Jay and R. Adams) The preparation of
certain octadecanoic acids and their bactericidal action toward B. leprae, XV,

J. Am. Chem, Soc. 51:1261 (1929); (With H. Wieland) Zur kenntnis der sterine

 
~19-

der hefe, III, Liebigs Annalen der Chemie 489(1):31 (1931); (With W.J.V.
Osterhout) The accumulation of electrolytes, V, Models showing accumulation and
a steady state, J. Gen. Physiol. 15:667 (1932); (With W.J.V. Osterhout and S.E.
Kamerling) The kinetics of penetration, VII, Molecular versus ionic transport,
J. Gen. Physiol. 17:469 (1934); Chemical studies on the virus of tobacco
mosaic, I, Some effects of trypsin, Phytopath. 24:1269 (1934); Chemical studies
on the virus of tobacco mosaic, IV, Some effects of different chemical agents
on infectivity, Phytopath. 25:889 (1935); Isolation of a crystalline protein
possessing the properties of tobacco-mosaic virus, Science 81:644 (1935);
Chemical studies on the virus of tobacco mosaic, VI, The isolation from
diseased Turkish tobacco plants of a crystalline protein possessing the
properties of tobacco-mosaic virus, Phytopath. 26:305 (1936); (F.C. Bawden,
N.W. Pirie, J.D. Bernal and I. Fankuchen) Liquid crystalline substances from
virus infected plants, Nature, Lond. 138:1051 (1936): (With H.S. Loring)
Isolation of crystalline tobacco mosaic virus protein from tomato plants, J.
Biol. Chem. 117:733 (1937); (With H.S. Loring) The properties of virus
proteins, Cold Spring Harbor Symposia on Quant. Biol. 6:341 (1938); (With F.A.
Ross) The sulfur and phosphorus contents of tobacco mosaic virus, J. Am. Chen.
Soc. 61:535 (1939); (With M.A. Lauffer) The physical chemistry of tobacco
mosaic virus protein, Chem. Rev. 24:303 (1939); (with M.A. Lauffer) Studies on
the sedimentation rate of bushy stunt virus, J. Biol. Chem. 135:463 (1940);
(With C.A. Knight) The chemical composition of strains of tobacco mosaic virus,
Cold Spring Harbor Symposia on Quant. Biol. 9:255 (1941); (With T.F. Anderson)
A study of purified viruses with the electron microscope, J. Biol. Chem.
139:325 (1941); (With G.L. Miller) Derivatives of tobacco mosaic virus, II,
Carbobenzoxy, p-chlorobenzoyl and benzene sulfonyl virus, J. Biol. Chem.

146:331 (1942); (With S.S. Cohen) The molecular size and shape of the nucleic
~20-

acid of tobacco mosaic virus, J. Biol. Chem. 144:589 (1942); The preparation
and properties of influenza virus vaccines concentrated and purified by
differential centrifugation, J. Exp. Med. 81:193 (1945); Biochemical studies on
influenza virus, Chem. Engineering News 24:750 (1946); Virus composition and
structure--25 years and now, Fed. Proc. 15:812 (1956); The potential
significance of nucleic acids and nucleoproteins of specific composition in
malignancy, Texas Reports on Biol. and Med. 15:796 (1957); Relationships,
established and prospective, between viruses and cancer, Ann. N.Y. Acad. Sci.
71:1100 (1958); (with A. Tsugita, D.T. Gish, J. Young, H. Fraenkel-Conrat, and
C.A. Knight) The complete amino acid sequence of the protein of tobacco mosaic
virus, Proc. Nat. Acad. Sci. U.S. 46:1463 (1960).

Ti. Secondary Literature:

G.W. Corner, A History of the Rockefeller Institute, 1901-1953, Origins

 

and Growth (The Rockefeller Institute Press, 1965); John T. Edsall, Wendell
Meredith Stanley (1904-1971) Year Book of th American Philosophical Society,
184 (1971); Obituary, Wendell Meredith Stanley, Nature 233:149 (1971); R.E.

Shope, In Honor of Wendell M. Stanley, Perspectives in Virology V, XV (1967); A.

 

Tiselius, p. 29 in Les Prix Nobel en 1946 (Imprimerie Royale, P.A. Norstedt and

 

Souer, Stockholm, 1948); R.L. Shriner and V. Du Vigneaud, The William H.
Nichols Medalist for 1946, Chem. Engineering News 24:750 (1946); G.C.
Ainsworth, Introduction to the History of Plant Pathology (Cambridge University
Press, Cambridge, 1981); A.P. Waterson and L. Wilkinson, An Introduction to the
History of Virology (Cambridge University Press, Cambridge, 1978); J.S. Fruton,
Molecules and Life (Wiley~Interscience, New York, 1972); S.S. Cohen, Some
Contributions of the Princeton Laboratory of the Rockefeller Institute on
Proteins, Viruses, Enzymes, and Nucleic Acids, Annals N.Y. Acad. Sci. 325:303

(1979); N.W. Pirie, The Meaninglessness of the Terms J.ife and Living, p. 11 in
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Perspectives in Biochemistry (Cambridge University Press, Cambridge, 1937);
F.C. Bawden, Plant and Viruses and Virus Diseases, 2nd Edition (Chronica
Botanica Company, Waltham, Mass., 1943) and 4th Edition (The Ronald Press

Company, New York, 1964).