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Stanley, Wendell Meredith

STANLEY, WENDELL MEREDITH

(b. Ridgeville, Indiana, 16 August 1904; d. Salamanca, Spain, 15 June 1971)

chemistry, virology, education.

In 1935 Wendell Stanley crystallized tobacco mosaic virus, an achievement that 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 ribonucleic 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 1935 and 1936, biologists were startled to learn that some of the smallest organisms, in the group known as “filterable viruses,” were isolable by methods 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, “The possibility of ‘inoculating’ genes into cells does not seem to us to be excluded 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, between 1935 and 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 biological science by facilitating the dissection of the mechanisms of inheritance and by leading to the integrative development of numerous disciplines (biochemistry, genetics, and structural chemistry) as “molecular biology.”

Wendell Stanley, an initiator of this modern era of biology, was the son of James G. Stanley and Claire Plessinger Stanley. His parents published the local newspaper, and as a boy Stanley helped to collect news, set type, and 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 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 on the Indiana All-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.” The choice of Earlham and his life there may have contributed significantly to his later bearing and attitudes.

On graduation in 1926 Stanley aspired to be a football coach, and he 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, he entered the University of Illinois. As a graduate student with Adams he worked on two types of problems, the stereochemistry of biphenyls and the synthesis and properties of compounds potentially bactericidal for Mycobacterium leprae. He published eleven papers on these subjects with Adams between 1927 and 1933, obtaining an M.S. in 1927 and a Ph.D. in 1929. 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 on this subject was published in 1929 with Adams and another graduate student, Marian S. Jay, who married Stanley in that year. The couple had three daughters and a son, Wendell, Jr., who is known for 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 a paper by J. B. Sumner and D. B. Hand on the isoelectric point of crystalline crease, 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 the academic year 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 City. 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 nonaqueous 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 pressure and of water entry. The entire system simulated accumulation in Valonia very well, permitting a comparison in the 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 Rockefeller Institute, established at Princeton, New Jersey, in 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 farmland on the outskirts of Princeton. Smith and the groups he assembled became active in the study of various protozoan, bacterial, and viral diseases of veterinary importance. In 1926 a group in 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 TenBroek, an early collaborator knowledgeable in virus infections. Under TenBroek, who helped to sustain the work of virologists such as Richard Shope and Otto Glaser, the Division of Plant Pathology was established in 1931 with Louis O. 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 the tobacco mosaic disease. In 1892 the Russian D. Ivanovsky 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. One virologist in Kunkel’s group, Francis Holmes, had developed a method of estimating infectious virus particles by counting the localized lesions arising 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.

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 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 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 Stanley introduced such a step in his initial successful purification. During purification steps the pH was adjusted at noninactivating 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 that 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 was then crystallized from this solution as small “needles” by the addition of acetic acid to a defined low pH in the presence of 20 percent saturated ammonium sulfate.

The initial report in 1935 described a product containing 20 percent nitrogen, but the first complete paper in 1936 reported nitrogen contents by two methods of 16.1–16.6 percent, 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. Numerous recrystallizations of the protein 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 of the infectious protein, indicating its multiplication. Antisera prepared against the virus in guinea pigs and rabbits 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 provirus that would be converted “autocatalytically” by the active virus to a serologically active virus? Significant amounts of comparable large molecules capable of serving as provirus were not present in the juice of normal plants. It was not until the late 1940’s, 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 1960’s, that the processes of synthesis of nucleic acids and proteins were composed of far more complex metabolic and synthetic events than that described for the conversion of trypsinogen to trypsin. In 1935 Stanley stated, “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 in 1946 and 1947, in studies with bacterial viruses, that the host cells continued to supply the energy, as 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 wondered 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.’” Summarizing the attributes of the many properties of organisms and substances, Pirie noted the lake 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 have 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 the English workers 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 needlelike “liquid” crystals or “paracrystals.” This occurred on precipitation by salts at a pH of minimum solubility 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; that is, 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.

Although the identity of Stanley’s initial product has been questioned, it should be noted that the high nitrogen content was corrected by the end of 1935, before the first paper in 1936 by the English group of Bawden, Pirie, Bernal, and Fankuchen. Furthermore, Stanley’s material was analyzed by an American crystallographic group, and the data published in November 1936 was described by the English group, in a note added on 3 December 1936, as follows: “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, 9, 12, 18) respectively.” Thus the material obtained by the English workers was identical to an early preparation of the virus obtained by Stanley, made before any publication by the former group.

In addition to the clarification by Bawden, Pirie, and their crystallographic collaborators of the degree of order found in isolated viral arrays, their earliest paper records their discovery of the presence of 5 percent RNA in this virus, a result they soon extended to related viruses. Higher percentages of RNA were discovered later by Bawden and Pirie 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 A. F. 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 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 was prepared after heat denaturation.

As indicated above, the criticism of Stanley’s early studies had been severe. 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. From 1937 to 1942 the work of Stanley’s laboratory multiplied with the assistance of numerous younger chemists: H. S. Loring, A. F. Ross, M. A. Lauffer, G. L. Miller, C. A. Knight, and S. S. 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. Bawden and Pirie asked early on if the crystalline preparations of infectious protein contained only the distinctive rodlike 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 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 bush stunt virus, concluded that the diameters of the particles could deviate from the mean by no more than I percent. 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, and 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, G. A. Kausche, and H. Stubbe 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. The Rockefeller group 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.” Stanley’s group 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, with the entrance of the United States into World War II, the work of the laboratory was diverted to the isolation of influenza virus and the production of an influenza vaccine.

After the startling reports of Gierer and Schramm and of Fraenkel-Conrat in 1956, Bawden and Pirie undertook the testing of 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 problem 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 and was extended to animal cells infected in tissue culture in 1953 and finally to infection of separated plant protoplasts in 1967.

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 from Stanley’s laboratory 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. 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. Stanley also received an honorary degree from the University of California. Nevertheless, in 1947 the trustees of the Rockefeller Institute decided to close the Princeton laboratory.

In 1948 both Nobelists accepted positions at the University of California at Berkeley. Stanley joined the faculty as the founder of the Virus Laboratory and the chairman of a new department of biochemistry. 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 expected that the development of similarly wonderful drugs for the cure of virus disease was only a step away. Stanley began his second career as an educational administrator, in an optimistic university environment.

From 1948 to 1953 he recruited able young scientists for both departments, and in 1953 resigned as chairman of the department of biochemistry, as that developing unit was increasingly productive and independent. After that resignation 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 reestablished study of the plant viruses. H. K. Schachman, a physical chemist who had worked for years with Lauffer, 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. Delbrück. H. Rubin began a study of tumor viruses, and the animal virologists F. L. Schaffer and C. E. Schwerdt, concerned with the isolation of the virus of poliomyelitis, crystallized the virus in 1955. Also in that year 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 that had determined the complete sequence of the amino acids in the protein subunit.

Stanley urged the university to create the 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 science, as chairman of the editorial board of the Proceedings of the National Academy of Sciences, as a director-at-large 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. 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. 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 1960’s 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 this disease as well. In addition to awards from 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.

Stanley suffered several severe illnesses in his later years but continued to travel extensively. 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 that he built at the University of California is named the Wendell M. Stanley Hall.

BIBLIOGRAPHY

I. Original Works. “The Synthesis of Chaulmoogric Acid from Hydnocarpic Acid,” in Journal of the American Chemical Society, 51 (1929), 1515–1518, written with R. Adams; “The Preparation of Certain Octadecanoic Acids and Their Bactericidal Action Toward B. leprae, XV,” ibid., 1261–1266, written with M. S. Jay and R. Adams; “Zur Kenntnis der Sterine der Hefe, III , in Liebigs Annalen der Chemie, 489 , no. 1 (1931), 31–42, written with H. Wieland; “The Accumulation of Electrolytes, V, Models Showing Accumulation and a Steady State,” in Journal of General Physiology, 15 (1932), 667–689, written with W. J. V. Osterhout; Kinetics of Penetration, VII, Molecular Versus Ionic Transport,” ibid., 17 (1934), 469–480, written with W. J. V. Osterhout and S. E. Kamerling; “Chemical Studies on the Virus of Tobacco Mosaic, I, Some Effects of Trypsin,” in Phytopathology, 24 (1934), 1055–1085; “Chemical Studies of the Virus of Tobacco Mosaic, IV, Some Effects of Different Chemical Agents on Infectivity,” ibid., 25 (1935), 899–921; and “Isolation of a Crystalline Protein Possessing the Properties of Tobacco-Mosaic Virus,” in Science, 81 (1935), 644–645.

“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,” in Phytopathology, 26 (1936), 305–320; “Isolation of Crystalline Tobacco Mosaic Virus Protein from Tomato Plants,” in Journal of Biological Chemistry, 117 (1937), 733–754, written with H. S. Loring; “Properties of Virus Proteins,” in Cold Spring Harbor Symposia on Quantitative Biology, 6 (1938), 341–360, written with H. S. Loring; “The Sulfur and Phosphorus Contents of Tobacco Mosaic Virus,” in Journal of the American Chemical Society, 61 (1939), 535–540, written with A. F. Ross; “The Physical Chemistry of Tobacco Mosaic Virus Protein,” in Chemical Reviews, 24 (1939), 303-321, written with M. A. Lauffer; “Studies on the Sedimentation Rate of Bushy Stunt Virus,” in Journal of Biological Chemistry, 135 (1940), 463–472, written with M. A. Lauffer; “The Chemical Composition of Strains of Tobacco Mosaic Virus,” in Cold Spring Harbor Symposia on Quantitative Biology, 9 (1941), 255-262, written with C. A. Knight; and “A Study of Purified Viruses with the Electron Microscope,” in Journal of Biological Chemistry, 139 (1941), 325–344, written with T. F. Anderson.

“Derivatives of Tobacco Mosaic Virus. II, Carbobenzoxy, p-chlorobenzoyl, and Benzenesulfonyl Virus,” in Journal of Biological Chemistry, 146 (1942), 331–338, written with G. L. Miller; “The Molecular Size and Shape of the Nucleic Acid of Tobacco Mosaic Virus,” ibid., 144 (1942), 589–598, written with S. S. Cohen; “The Preparation and Properties of Influenza Virus Vaccines Concentrated and Purified by Differential Centrifugation,” in Journal of Experimental Medicine, 81 (1945), 193–218; “Biochemical Studies on Influenza Virus,” in Chemical and Engineering News, 24 (1946), 755–758; “The Isolation and Properties of Crystalline Tobacco Mosaic Virus,” in Les prix Nobel en 1947 (Stockholm, 1949), 196–225; “Virus Composition and Structure: 25 Years Ago and Now,” in Federation of American Societies for Experimental Biology, Federation Proceedings, 15 (1956), 812–818; “The Potential Significance of Nucleic Acids and Nucleoproteins of Specific Composition in Malignancy,” in Texas Reports on Biology and Medicine, 15 (1957), 796–810; “Relationships, Established and Prospective, Between Viruses and Cancer,” in Annals of the New York Academy of Sciences, 71 (1958), 1100–1113; and “The Complete Amino Acid Sequence of the Protein of Tobacco Mosaic Virus,” in Proceedings of the National Academy of Sciences of the United States, 46 (1960), 1463–1469, written with A. Tsugita, D. T. Gish, J. Young, H. Fraenkel-Conrat, and C. A. Knight.

II. Secondary Literature. G. C. Ainsworth, Introduction to the History of Plant Pathology (Cambridge, England, 1981); F. C. Bawden, N. W. Pirie, J. D. Benial, and I. Fankuchen, “Liquid Crystalline Substances from Virus-infected Plants,” in Nature, 138 (1936), 1051–1052; F. C. Bawden, Plant Viruses and Virus Diseases, 4th ed (New York, 1964); S. S. Cohen, “Some Contributions of the Princeton Laboratory of the Rockefeller Institute on Proteins, Viruses, Enzymes, and Nucleic Acids,” in P. R. Srinivasan et al., eds., The Origins of Modern Biochemistry (New York, 1979), 303–306; G. W. Corner, A History of the Rockefeller Institute, 1901–1953: Origins and Growth (New York, 1965); and John T. Edsall, “Wendell Meredith Stanley (1904–1971),” in American Philosophical Society, Year Book 1971 (Philadelphia, 1971), 184–190.

J. S. Fruton, Molecules and Life (New York, 1972); N. W. Pirie, “The Meaninglessness of the Terms ‘Life’ and ‘Living,’” in Joseph Needham, ed., Perspectives in Biochemistry (Cambridge, England, 1937), 11–22; R. E. Shope, “In Honor of Wendell M. Stanley,” in Gustav Stern Symposium on Perspectives in Virology, V (New York, 1967), xv-xxi; R. L. Shriner and V. Du Vigneaud, “The William H. Nichols Medalist for 1946,” in Chemical and Engineering News, 24 (1946), 750–755; A. Tiselius, “The Nobel Prize for Chemistry, 1946,” in Les prix Nobel en 1946 (Stockholm, 1948), 29–32; A. P. Waterson and L. Wilkinson, An Introduction to the History of Virology (Cambridge, England, 1978); and “Wendell Meredith Stanley,” in Nature, 233 (1971), 149–150.

Seymour S. Cohen

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Stanley, Wendell Meredith (1904-1971)

Stanley, Wendell Meredith (1904-1971)

American biochemist

Wendell Meredith Stanley was a biochemist who was the first to isolate, purify, and characterize the crystalline form of a virus. During World War II, he led a team of scientists in developing a vaccine for viral influenza . His efforts have paved the way for understanding the molecular basis of heredity and formed the foundation for the new scientific field of molecular biology . For his work in crystallizing the tobacco mosaic virus , Stanley shared the 1946 Nobel Prize in chemistry with John Howard Northrop and James B. Sumner.

Stanley was born in the small community of Ridgeville, Indiana. His parents, James and Claire Plessinger Stanley, were publishers of a local newspaper. As a boy, Stanley helped the business by collecting news, setting type, and delivering papers. After graduating from high school he enrolled in Earlham College, a liberal arts school in Richmond, Indiana, where he majored in chemistry and mathematics. He played football as an undergraduate, and in his senior year, he became team captain and was chosen to play end on the Indiana All-State team. In June of 1926, Stanley graduated with a Bachelor of Science degree. His ambition was to become a football coach, but the course of his life was changed forever when an Earlham chemistry professor invited him on a trip to Illinois State University. Here, he was introduced to Roger Adams, an organic chemist, who inspired him to seek a career in chemical research. Stanley applied and was accepted as a graduate assistant in the fall of 1926.

In graduate school, Stanley worked under Adams, and his first project involved finding the stereochemical characteristics of biphenyl, a molecule containing carbon and hydrogen atoms. His second assignment was more practical; Adams was interested in finding chemicals to treat leprosy , and Stanley set out to prepare and purify compounds that would destroy the disease-causing pathogen. Stanley received his master's degree in 1927 and two years later was awarded his Ph.D. In the summer of 1930, he was awarded a National Research Council Fellowship to do postdoctoral studies with Heinrich Wieland at the University of Munich in Germany. Under Wieland's tutelage, Stanley extended his knowledge of experimental biochemistry by characterizing the properties of some yeast compounds.

Stanley returned to the United States in 1931 to accept the post of research assistant at the Rockefeller Institute in New York City. Stanley was assigned to work with W. J. V. Osterhout, who was studying how living cells absorb potassium ions from seawater. Stanley was asked to find a suitable chemical model that would simulate how a marine plant called Valonia functions. Stanley discovered a way of using a water-insoluble solution sandwiched between two layers of water to model the way the plant exchanged ions with its environment. The work on Valonia served to extend Stanley's knowledge of biophysical systems, and it introduced him to current problems in biological chemistry.

In 1932, Stanley moved to the Rockefeller Institute's Division of Plant Pathology in Princeton, New Jersey. He was primarily interested in studying viruses . Viruses were known to cause diseases in plants and animals, but little was known about how they functioned. Stanley's assignment was to characterize viruses and determine their composition and structure.

Stanley began work on a virus that had long been associated with the field of virology . In 1892, D. Ivanovsky, a Russian scientist, had studied tobacco mosaic disease, in which infected tobacco plants develop a characteristic mosaic pattern of dark and light spots. He found that the tobacco plant juice retained its ability to cause infection even after it was passed through a filter. Six years later M. Beijerinck, a Dutch scientist, realized the significance of Ivanovsky's discovery: the filtration technique used by Ivanovsky would have filtered out all known bacteria , and the fact that the filtered juice remained infectious must have meant that something smaller than a bacterium and invisible to the ordinary light microscope was responsible for the disease. Beijerinck concluded that tobacco mosaic disease was caused by a previously undiscovered type of infective agent, a virus.

Stanley was aware of recent techniques used to precipitate the tobacco mosaic virus (TMV ) with common chemicals. These results led him to believe that the virus might be a protein susceptible to the reagents used in protein chemistry. He set out to isolate, purify, and concentrate the tobacco mosaic virus. He planted Turkish tobacco plants, and when the plants were about 6 in (15 cm) tall, he rubbed the leaves with a swab of linen dipped in TMV solution. After a few days, the heavily infected plants were chopped and frozen. Later, he ground and mashed the frozen plants to obtain a thick, dark liquid. He then subjected the TMV liquid to various enzymes and found that some would inactivate the virus and concluded that TMV must be a protein or something similar. After exposing the liquid to more than 100 different chemicals, Stanley determined that the virus was inactivated by the same chemicals that typically inactivated proteins, and this suggested to him, as well as others, that TMV was protein-like in nature.

Stanley then turned his attention to obtaining a pure sample of the virus. He decanted, filtered, precipitated, and evaporated the tobacco juice many times. With each chemical operation, the juice became more clear and the solution more infectious. The result of two-and-one-half years of work was a clear concentrated solution of TMV that began to form into crystals when stirred. Stanley filtered and collected the tiny, white crystals and discovered that they retained their ability to produce the characteristic lesions of tobacco mosaic disease.

After successfully crystallizing TMV, Stanley's work turned toward characterizing its properties. In 1936, two English scientists at Cambridge University confirmed Stanley's work by isolating TMV crystals. They discovered that the virus consisted of 94% protein and 6% nucleic acid, and they concluded that TMV was a nucleoprotein. Stanley was skeptical at first. Later studies, however, showed that the virus became inactivated upon removal of the nucleic acid, and this work convinced him that TMV was indeed a nucleoprotein. In addition to chemical evidence, the first electron microscope pictures of TMV were produced by researchers in Germany. The pictures showed the crystals to have a distinct rod-like shape. For his work in crystallizing the tobacco mosaic virus, Stanley shared the 1946 Nobel prize in chemistry with John Howard Northrop and James Sumner.

During World War II, Stanley was asked to participate in efforts to prevent viral diseases, and he joined the Office of Scientific Research and Development in Washington D.C. Here, he worked on the problem of finding a vaccine effective against viral influenza. Such a substance would change the virus so that the body's immune system could build up defenses without causing the disease. Using fertilized hen eggs as a source, he proceeded to grow, isolate, and purify the virus. After many attempts, he discovered that formaldehyde, the chemical used as a biological preservative, would inactivate the virus but still induce the body to produce antibodies. The first flu vaccine was tested and found to be remarkably effective against viral influenza. For his work in developing large-scale methods of preparing vaccines, he was awarded the Presidential Certificate of Merit in 1948.

In 1948, Stanley moved to the University of California in Berkeley, where he became director of a new virology laboratory and chair of the department of biochemistry. In five years, Stanley assembled an impressive team of scientists and technicians who reopened the study of plant viruses and began an intensive effort to characterize large, biologically important molecules. In 1955 Heinz Fraenkel-Conrat, a protein chemist, and R. C. Williams, an electron microscopist, took TMV apart and reassembled the viral RNA , thus proving that RNA was the infectious component. In addition, their work indicated that the protein component of TMV served only as a protective cover. Other workers in the virus laboratory succeeded in isolating and crystallizing the virus responsible for polio, and in 1960, Stanley led a group that determined the complete amino acid sequence of TMV protein. In the early 1960s, Stanley became interested in a possible link between viruses and cancer.

Stanley was an advocate of academic freedom. In the 1950s, when his university was embroiled in the politics of McCarthyism, members of the faculty were asked to sign oaths of loyalty to the United States. Although Stanley signed the oath of loyalty, he publicly defended those who chose not to, and his actions led to court decisions which eventually invalidated the requirement.

Stanley received many awards, including the Alder Prize from Harvard University in 1938, the Nichols Medal of the American Chemical Society in 1946, and the Scientific Achievement Award of the American Medical Association in 1966. He held honorary doctorates from many colleges and universities. He was a prolific author of more than 150 publications and he co-edited a three volume compendium entitled The Viruses. By lecturing, writing, and appearing on television he helped bring important scientific issues before the public. He served on many boards and commissions, including the National Institute of Health, the World Health Organization , and the National Cancer Institute.

Stanley married Marian Staples Jay on June 25, 1929. The two met at the University of Illinois, when they both were graduate students in chemistry. They co-authored a scientific paper together with Adams, which was published the same year they were married. The Stanleys had three daughters and one son. While attending a conference on biochemistry in Spain, Stanley died from a heart attack at the age of 66.

See also History of immunology; History of microbiology; Viral genetics; Viral vectors in gene therapy; Virology; Virus replication; Viruses and responses to viral infection

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Wendell Meredith Stanley

Wendell Meredith Stanley

The American virologist Wendell Meredith Stanley (1904-1971) convinced the world that viruses are physicochemically definable particles showing some properties of living material.

On Aug. 16, 1904, W. M. Stanley was born in Ridgeville, Ind. At the age of 16 he entered Earlham College in Richmond, Ind., where he majored in chemistry and mathematics and excelled in football. Upon graduating, he considered a career as an athletic coach. A visit to the University of Illinois at Urbana in connection with his contemplated football career culminated in a fortuitous interview with Roger Adams, professor of chemistry. Three years of graduate work under Professor Adams followed.

After graduating, Stanley married a collaborator, Marian Jay, and they spent a year at the University of Munich. In 1931 he joined the Rockefeller Institute in New York City. The following year he transferred to its newly established laboratory of plant pathology at Princeton, N.J., where he did his important research, the crystallization of the tobacco mosaic virus, which within 3 years led to a short epoch-making paper in Science and to many more publications, lectures, and world renown within 6 years.

Origin of Molecular Virology

Viruses differ from bacteria and other microorganisms in replicating not on nutrient media but only in living cells. Stanley, as a chemist, knew that purification should lead to pure and usually crystallizable materials. He was working at a time when mysterious enzymes were proved to be crystallizable proteins. He employed these protein methods and succeeded in 1935 in obtaining pure tobacco mosaic virus, free from plant material and infective when introduced into susceptible plants. The crystals seen by Stanley are now called paracrystals because the rod-shaped virus particles are arranged in only two-dimensional order (lengthwise).

All-important was Stanley's recognition that viruses could be obtained in pure form and studied by physical and chemical methods, like proteins and other simpler biologically active compounds. And, more important than this recognition, in which he was not alone, was his willingness and ability to "sell" this concept to the scientific community, and his success in overcoming the skepticism of those virologists and biologists who retained vestiges of vitalist philosophy and wanted the seemingly living viruses to retain a shroud of mystery and to resist the efforts of chemists. Concerning the question whether viruses are living or not, we now know that they carry the same principal genetic capabilities as living cells but lack all metabolic capabilities. Thus viruses need the energy and materials produced in living cells for their replication. They are half alive.

Move to the West

The next turning point for Stanley came about through another fortuitous circumstance. Gordon Sproul, president of the University of California, was looking for a man to head a new biochemistry department at Berkeley. He and Stanley met when their planes were grounded by fog, and they agreed in principle on a joint future. The creation of a separate research laboratory, the Virus Laboratory, by the California Legislature was part of the deal. In 1948 Stanley moved to Berkeley, successfully staffing both the biochemistry department and the Virus Laboratory in the course of the next 5 years.

Stanley's interest had turned from plant viruses to human pathogens, particularly influenza virus. During World War II his prime aim was the development of a vaccine against this virus. At Berkeley, research proceeded on plant, bacterial, and animal viruses; Stanley's greatest interest was in animal viruses, with poliomyelitis as the focal point. In subsequent years his interest turned more toward tumor-causing viruses. Several of these had been described as having elicited tumors in chickens or rabbits that resembled human malignant tumors. The belief that many or all malignant tumors might be due to viruses found a new proponent and prophet in Stanley. This aspect of his career received crowning recognition when he served as president of the Tenth International Cancer Congress in 1970.

Stanley received many honors and awards. Besides the Nobel Prize in chemistry in 1946, shared with John Northrop and James Sumner, there was a Presidential Certificate of Merit and the Franklin Medal in 1948, an American Cancer Society award in 1959, and over a dozen honorary doctorates. Stanley retired as director of the Virus Laboratory in 1969. He died in Salamanca, Spain, on June 15, 1971.

Further Reading

Stanley's perspective on virology is illustrated in a book by himself and Evans G. Valens, developed from a series of filmed lectures by staff members, Viruses and the Nature of Life (1961). A biographical sketch of Stanley is in Nobel Foundation, Chemistry: Including Presentation Speeches and Laureates' Biographies (3 vols., 1964-1966). Stanley's career and researches at the Rockefeller Institute are discussed in detail in George W. Corner, A History of the Rockefeller Institute, 1901-1953: Origins and Growth (1964). A more personal viewpoint is expressed by R. E. Shope in volume 5 of Perspectives in Virology (1967), an issue dedicated to Stanley. A recent textbook on molecular virology by Heinz Fraenkel-Conrat, The Chemistry and Biology of Viruses (1969), describes the development of this research field since it was opened up by Stanley in 1935. □

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