Rockefeller strategies for scientific medicine: molecular machines, viruses and vaccines

Pergamon

Stud. Hist. Phil. Biol. & Biomed. Sci, Vol. 31, No. 3, pp. 491–509, 2000  2000 Published by Elsevier Science Ltd Printed in Great Britain 1369-8486/00 $ - see front matter

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Rockefeller Strategies for Scientific Medicine: Molecular Machines, Viruses and Vaccines Jean-Paul Gaudillie`re*

1. Introduction The Rockefeller Foundation has been granted a special status by historians of contemporary biology because of its role in the emergence and development of molecular biology. Although analysts disagree on the meaning and value of the molecular biology program the Natural Sciences Division of the Rockefeller Foundation supported in the 1930s and 1940s, most of them view this initiative as a turning point in the path toward the postwar approach to living organisms as information systems and more particularly toward the modern conception of macromolecules. A frequent assumption associated with this interpretation is that the activities of the Natural Sciences Division were highly insulated from the medical work supported by other Rockefeller institutions like the Rockefeller Institute or the International Health Division. Such isolation has usually been traced back to the reorganization of the Rockefeller philanthropic activities which took place during the late 1920s and early 1930s. The Rockefeller Foundation then experienced a transition from one regime of patronage to another.1 Men, management, targets and funding practices changed at the same time. The ‘old’ foundation was a philanthropic organization with interests in social hygiene and health care. Officers of the foundation shared the notion that medical progress—the end of epidemics and infectious diseases—was the key to the end of poverty and that it could be achieved by social and organizational means, among which public-health campaigns were of critical value. Priority investments of the Foundation targeted the domains of medical education, public-

* CERMES (CNRS-INSERM-EHESS), 182 Boulevard de la Villette, 75019, Paris, France (e-mail: [email protected]) 1 Kohler (1991).

PII: S1369-8486(00)00017-0 491

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health demonstration projects, and clinical research. They favored large donations aiming at institutional developments. The ‘new’ foundation was an organization aiming at the advancement of knowledge. Medical issues remained high on the agenda but the RF vision of the means by which to achieve progress changed. The laboratory was at the forefront. As illustrated by the creation of the Rockefeller Institute in New York, bacteriology and biochemistry had already been viewed as sites providing key technological resources for public-health programs. What was new, however, was the vision that the laboratory should be a knowledge factory producing claims of a biological nature which would later be put to use and lead to medical breakthroughs. Bio-medicine rather than social medicine became the slogan of the day. Within the Natural Sciences Division the emphasis on knowledge and basic research took the form of an attempt to shape the content of research and revitalize biology with an influx of physics and chemistry. The practice of patronage then shifted towards a centralized system of grants handled by activist program managers, usually former scientists who isolated the NSD from the publichealth orientation of other institutions within the Rockefeller system. This paper reexamines this history of ‘scientifization’ and ‘demedicalization’ of the Rockefeller strategies by investigating the connections between developments at the Natural Sciences Division, the International Health Division and the Rockefeller Institute. These connections revolved around the study of viruses which was, before and during the Second World War, at the very center of development in the three sectors of the Rockefeller complex. Though significant these connections have barely been analyzed. This paper therefore stresses the importance of viruses in the late Rockefellerian mode of articulating biology and medicine. In the 1930s viruses emerged as key targets within both the Natural Sciences Division and the International Health Division. The local form of virus research relied on a series of new machines for visualizing and studying macromolecules whose invention was strongly supported by the Foundation (with the ultracentrifuge in the leading role). The medical strategy focusing on the search for technical means of controlling microorganisms (rather than on epidemiological or clinical studies) was then articulated in terms of virus purification and ‘particle control’. This in turn boosted virus studies as a juncture between molecular biology and public health. 2. Viruses, Ultracentrifuges and the Rockefeller Research Complex The Rockefeller Institute for Medical Research had been established in 1901 through the philanthropy of John D. Rockefeller Sr. as a center for experimental research in New York, and had been modeled on the Pasteur Institute. But whereas the European laboratories built in honor of Pasteur and Koch were centered on bacteriology, the Rockefeller Institute was intended to support a wide range of research areas in medical science. Under the directorship of Simon Flexner, laboratories were organized around divisions of pathology and bacteriology, experimental

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surgery, physiology and pharmacology, and chemistry, with units of cancer research, biophysics, and animal and plant pathology being added over the years.2 The early years of the Rockefeller Institute’s development were the decades when filterable viruses became central to medical research and etiology. Flexner tended to view viruses simply as submicroscopic bacteriological agents, encouraging his co-workers Peter Olitsky and Hideyo Noguchi to pursue cell-free cultivation of the agents of viral diseases such as yellow fever and tobacco mosaic. But if Flexner did not view viruses as a separate category of infectious agents, he did make their study a priority among pathologists at the institute. In 1923, Flexner brought Thomas Rivers from Johns Hopkins with the mandate of developing a virus research program at the institute’s hospital.3 Five years later, five of the eight reviews in Rivers’ groundbreaking volume Filterable Viruses were written by Rockefeller Institute researchers specializing on human, animal and plant viruses. In the 1930s, viruses remained the most obvious source of laboratory-based medical innovations. This commitment to virus studies was echoed within the New York Laboratory of the International Health Division, which was located in the building of the RIMR.4 As the IHD 1936 report claimed: ‘The group of infectious agents known as filterable viruses have aroused much interest in recent years. A great deal is known regarding what they do when they attack a susceptible host, whether plant, animal or man. Nothing is known however of their exact nature. ...The chief reason why so little is known about this extremely important group of disease-producing agents is the lack of suitable methods and apparatus for their study. We believe that more precise knowledge regarding their nature is sorely needed, and until we have a more intelligent understanding of their physical nature and biological functions, many questions involved in infectious disease caused by filterable viruses will not lend themselves to clear explanations.’5 Much has been written about the diverging programs of a medically-oriented Rockefeller Institute and the reorganization of the Natural Sciences Division which took place in the early 1930s. Robert Kohler’s thorough examination of the emergence of Weaver’s attempt to support the ‘study of vital processes’, however, suggests that medical aims never disappeared from global views.6 Weaver’s claims about biological knowledge and medical progress have occasionally been interpreted as mere rhetorical moves made in order to sell his program to a board of 2

Corner (1964). Benison (1972, p. 318). Rivers’ influence went beyond the researchers in the Department of the Hospital; as he put it, ‘It is true that I proselytized for virology among young investigators, and that I did try to get people in the Institute laboratories, as opposed to the hospital, to work on things I was interested in.’ See Benison (1967, p. 131). 4 For the virus studies within the International Health Division, see Farley (forthcoming) and Lo¨wy (forthcoming) and Lo¨wy (2000). 5 IHD, New York Laboratories, report 1936, Rochefeller Archives Center (RAC), RG 5, Series 3, Box 1, pp. 20–1. 6 Kohler (1991). 3

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Trustees eager to see the pay-offs of basic research.7 One may argue that this was rhetoric but effective rhetoric nevertheless. Weaver’s activities as director of the NSD were manifold but the core of his investments were concerned with technical, methodological and theoretical research in biochemistry, physics, chemistry, physiology or mathematics that would shed some light on the nature, roles and production of ‘proteins’. Yet Weaver’s notion of proteins was a very large one. It included all sorts of large molecules that displayed some structural continuity and biological specificity. Accordingly, viruses and genes counted as proteins. As Weaver wrote in 1939: ‘One of the most interesting aspects of protein research, and one which has only recently emerged, is the indication that these huge molecules exhibit phenomena that we ordinarily consider possible only to living organisms. Thus “viruses” “reproduce” when in a suitable environment; and yet the brilliant researches of W. Stanley and others have shown that certain viruses which show this property so characteristic of life are nothing more than huge proteins.’8 Another widely-remarked aspect of the Natural Science Division in the 1930s was the scale of investments made in the development of physico-chemical apparatuses and instrumentation that might be employed in investigating biological processes. As analyzed by Robert Kohler, there was barely an instrument later associated with the rise of molecular biology whose invention was not supported by Weaver’s division. The list included the electrophoresis apparatus, the ultracentrifuge, all sorts of spectroscopes, electron microscopes, X-ray diffraction apparatus, cyclotrons and isotopes producers, etc. One way to investigate the connections between the various segments of the Rockefeller system may be to follow one of these ‘molecular’ devices—the ultracentrifuge—and its uses in virus studies. The genealogy of the centrifuge is currently traced to the work of Theo Svedberg in Upsala, whose prototype combined the motive power of an industrial centrifuge and an optical device for watching and photographing the rotating material. Svedberg’s first ultracentrifuges were highly complex tools for doing colloidal chemistry.9 Svedberg and his engineers developed two types of machines: one to visualize the materials as they sedimented in solutions at high speed, and one to gauge the position of materials which had already been spun to equilibrium at lower speeds. The first apparatus could reveal whether the material sedimented as one single component (as indicated by a sharp boundary) or as a series of components (revealed by several boundaries or a complete lack of boundary). The position of the particles measured in the second apparatus could be used to determine molecular weights. Svedberg’s instruments were tools visualizing large aggregates of molecules. As such, they were employed to study proteins. In Upsala this led to a 7

Kay (1993). Quoted in Kay (1993, p. 134). 9 Elzen (1988). 8

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series of surprising results, suggesting that some proteins like hemoglobin were not aggregates but behaved as single macromolecules possessing a singular molecular weight. From then on, Svedberg systematically examined all sorts of material of biological origin, elaborating a macromolecular theory of proteins which stated that such large molecules were made of a variable number of elementary units with the same molecular weight of roughly 16,000. Svedberg’s machine was an oil-driven ultracentrifuge. It was a huge and complex apparatus occupying a twostory space in the laboratory. In the 1930s, with the development of the protein program, three machines were run sixteen hours a day by a team of specialized technicians and engineers producing ‘data’ for further physico-mathematical analysis. This development would barely have been possible if not for the continued support of the Natural Science Division. Svedberg was already a Rockefeller fellow when he went for a few months to the United States and got the idea of using a derivative of an industrial cream separator in order to ‘centrifuge’ colloids. The building of the Upsala machine was an important aspect of the IEB support for European science when the NSD was established. Weaver simply took over with a more definite push towards the analysis of biological material. Although Svedberg remained in charge, the Rockefeller support was not without effect. This was especially visible in terms of ‘diffusion’. Svedberg had licensed some of his patents, but he was convinced that the apparatus and the skills necessary to use the ultracentrifuge were so complex that very few physico-chemists could successfully employ the machine. Weaver readily accepted this perception and, in the 1930s, the Foundation turned down most applicants dreaming of building their own version of Svedberg’s machine. The only exceptions were the Lister Institute in London and the University of Wisconsin. Interestingly, the Interational Health Division was involved in the origins of a very different system of ultracentrifugation. By the early 1930s, other physicists had begun to develop spinning machines. Jesse Beams, at the University of Virginia, adapted Henriot and Huguenard’s ‘spinning top’ design to make a centrifuge rotor supported and driven by air for experiments on optical phenomena.10 One of Beams’ graduate students, Edward G. Pickels, began developing the spinning-top kind of rotor further so that it could be used for measuring molecular weights. The addition of an optical system (to view the sedimenting material) was essential to this end, and Pickels sought to emulate key features of Svedberg’s oil-turbine apparatus in the air-driven spinning tops.11 10

Beams and Weed (1931) and Elzen (1988, Chapter 3). Beams, Weed and Pickels (1933), Elzen (1988, pp. 156–7), where he includes this quotation from Pickels’ Ph.D. thesis: ‘Recent years have witnessed a rapidly increasing interest in the production of high rotational speeds and large centrifugal forces. Perhaps the most outstanding example of practical application is the work of T. Svedberg and his collaborators who have used high speed centrifuges of the electrically driven and oil turbine types to determine the molecular weights of a great many organic 11

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Beams and Pickels’ efforts attracted the attention of Johannes Bauer, an M.D. on the research staff of the Rockefeller Foundation’s International Health Division laboratory in New York. Bauer was interested in the utility of the air-driven ultracentrifuge in his efforts to isolate and study the yellow fever virus, and he arranged for Pickels to work with him during the summer of 1934.12 Pickels’ vision of the ultracentrifuge was increasingly shaped by its potential uses in biomedical laboratories, particularly for virus research; to this end he designed the rotor to accommodate larger volumes of liquid so that the ultracentrifuge could be used to prepare as well as analyze materials.13 In addition, Pickels devised a vacuum rotor chamber which solved many of the design problems (especially the disturbance of even sedimentation by convection currents) and made the machine usable for determining the purity and sedimentation constants of large molecules. Pickels concluded his dissertation with a remark on his prospects of contributing to biomedical investigations: ‘For the study of biological materials, particularly filterable viruses and bacteria, the contributions may be a definite step in opening an entirely new field of research.’14 After filing his Ph.D. in Virginia in 1935, Pickels joined the staff of the Rockefeller Foundation’s International Health Division to resume his work on viruses with Bauer and develop the biophysical instrumentation of the IHD.15 Because the Virus Laboratory of the International Health Division was housed at the Rockefeller Institute, the presence of Pickels brought a diverse groups of medical researchers into contact with the possibilities of the ultracentrifuge. The head of biophysics at the Rockefeller Institute, Ralph W. G. Wyckoff, had already been developing techniques for using X-ray diffraction, ultraviolet microscopy and radiation for medical research, and he was eager to expand his program to include development of the air-driven ultracentrifuge.16 Since Wyckoff already possessed the best machineshop facilities at the institute, he suggested that he and Pickels collaborate, but Pickels preferred to work independently and exchange information.17 They published two papers together in 1936, the same year that Bauer and Pickels published materials, particularly proteins. The fixing of the molecular weight of haemoglobin as approximately 69,000 is indeed one of the classical experiments of modern times. The particular disadvantages of the higher speed ultracentrifuges are the excessively high costs of construction and operation, and the fact that the design is not so easily varied to meet the needs of different investigators.’ See Pickels (1935). 12 Elzen (1988, p. 161). 13 Early in 1935 Pickels redesigned the air-driven ultracentrifuge. Rather than resting on the stator and being driven directly by air jets, the rotor was hung in a vacuum chamber from a piano wire in a thin shaft below the air-driven turbine. The thermal isolation of the vacuum chamber helped overcome earlier problems associated with convection currents, and the chamber could be water-cooled to keep biological materials from heat-induced denaturation. Elzen (1988, pp. 167–8). 14 Elzen (1988, p. 173), quoting Pickels (1935, p. 56). 15 ‘Mr. Pickels—Appointment’, September 19, 1936, RAC RU 5, Series 4, box 22, folder 260. 16 In 1939, Wyckoff claimed that ten years earlier he had ‘suggested to Dr. Rivers that if the pathologists at the Institute would utilize [the ultracentrifuge’s] possibilities, my department of biophysics would undertake to make one. We received no encouragement.’ 17 Memorandum to Dr. Arthur F. Coca, May 2, 1939, Francis Peyton Rous papers, folder Ralph Wyckoff #2, America Philosophical Society, BR77.

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on their ‘high speed vacuum centrifuge suitable for the study of viruses’.18 Virus researchers were strongly represented among the laboratories of the institute, and Pickels was already collaborating with Thomas Rivers and Joseph Smadel of the institute’s hospital.19 Wyckoff was keenly interested in the application of the ultracentrifuge for virus research. After the publication of Wendell Stanley’s isolation of crystalline tobacco mosaic virus (TMV) in the summer of 1935, Stanley and Wyckoff began to collaborate on ultracentrifugal studies of TMV.20 In the spring of 1936, Stanley was sending Wyckoff samples of TMV, including variants from hosts other than tobacco as well as from different strains of the disease. Despite recurrent equipment problems,21 Wyckoff’s runs showed TMV to be a homogeneous protein with a molecular weight between 15 and 20 million daltons.22 Partly in response to this promising collaboration, Wyckoff closed down his X-ray diffraction program and moved his centrifuges to Princeton to work with Stanley, who became an aficionado of the machine.23 Around the same time, an unexpected finding by Wyckoff and his co-worker Robert Corey opened up another possible use of the ultracentrifuge for virus work. They found that when they centrifuged clear juice from Stanley’s mosaic-infected tobacco plants at 25,000 r.p.m., a pellet of fibrous material sedimented to the bottom of the cell, that, when analyzed in a microscope, was seen to be composed of crystals.24 Thus the ultracentrifuge could be used to isolate viruses from serum or sap. This method was especially promising for plant viruses that were too dilute or fragile to withstand chemical extraction.25

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Biscoe, Pickels and Wyckoff (1936a,b); Bauer and Pickels (1936). This resulted in four joint publications: the two parts of Smadel, Pickels and Shedlovsky (1938), Smadel, Rivers and Pickels (1939), Smadel, Pickels, Shlovsky and Rivers (1940). 20 Wyckoff and Stanley first collaborated on X-ray diffraction studies of crytalline TMV. Ralph Wyckoff to W. M. Stanley, 22 Jan 1936, carton 14, folder Wyckoff. Wyckoff went ahead with some runs of TMV, and he was at the same time trying to get X-ray diffraction patterns from the material, to no avail. Wyckoff to Stanley, 13 Feb 1936, carton 14, folder Wyckoff. Stanley’s 1935 publication was Stanley (1935). 21 Wyckoff to Stanley, May 6, 1936, Stanley papers, 78/18c, carton 14, folder Wyckoff. 22 See Wyckoff, Biscoe and Stanley (1937) Stanley had also collaborated with Svedberg, who determined a molecular weight in the same range but found that the virus was not chemically homogeneous. Stanley interpreted this unfortunate result to be the result of degradation of the preparation through the chemical precipitation of the virus and through its travel to Sweden. See Eriksson-Quensel and Svedberg (1936), and Stanley to Svedberg, July 9, 1936, Stanley papers, carton 13, folder Svedberg. 23 Wyckoff was also sensing that he would not be kept on the Institute staff beyond 1937 in accord with the normal termination of a research associate’s contract. Memorandum to Dr. Arthur F. Coca, May 2, 1939, Francis Peyton Rous papers, folder Ralph Wyckoff #2, America Philosophical Society, BR77. 24 Wyckoff and Corey (1936). 25 With Stanley, Wyckoff used the ultracentrifuge to isolate potato X-virus and tobacco ring-spot disease; with another Princeton plant pathologist, W. C. Price, he isolated two strains of cucumbermosaic disease and tobacco-necrosis virus. See Stanley and Wyckoff (1937) and Price and Wyckoff (1937, 1939). 19

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3. War, Molecular Machines and Mass-produced Vaccines The NSD ultracentrifuge and the IHD ultracentrifuge never converged but by the late 1940s, Beams and Pickles’ version of the machine had superseded Svedberg’s. This outcome was by no means inevitable. It was rooted in shifting uses of ultracentrifugation during the Second World War. The war medical mobilization strongly reinforced the preparative value of the apparatus and linked the ‘molecular’ machines with public-health vaccination programs as illustrated by the International Health Division’s influenza research. The possibility of an influenza epidemic was a major concern for American military doctors because of the high toll taken by such epidemics in 1918–9. Work on influenza at the New York laboratory of the IHD began in the mid-1930s when Andrewes and a team of British scientists discovered that influenza might not be caused by bacteria but might be the consequence of an infection by a new type of virus. In 1936, Thomas Francis, the first American bacteriologist to confirm Andrewes’ discovery, was hired to run an influenza project. The enterprise aimed at the bacteriological and immunological study of the new agent with a view towards the development of methods for prevention. Francis organized the collection of throat washings and sera from patients affected with influenza-like diseases in various parts of the country. Following the exemplar of Andrewes, the animal model used was the ferret.26 Special quarters and isolation units into which filtered air was forced were designed at the Rockefeller Institute because of the assumed susceptibility of these animals to contact infection.27 One of Francis’ achievements was to establish the virus in a cheaper and more readily available host, namely in the white laboratory mouse. This made possible two developments: a) a new isolation procedure which combined the sequential use of ferrets and mice in order to pursue immunological characterization of various geographical strains of influenza viruses; b) the mass culture of the agent by passage from mouse to mouse and consequently the putative isolation of an attenuated form of the virus.28 A critical change of staff took place in 1938 when Francis moved to New York University (with another later move to Ann Arbor, Michigan). He was replaced by Frank Horsfall, who had been working with Pickles and was just returning from a long stay in Svedberg’s laboratory to learn the practice of electrophoresis. Horsfall was commissioned to take charge of the influenza project.29 Isolation and immunological studies were pursued in two different directions. First, Horsfall set up a long-term epidemiological and etiologic study of a small community in New York State where the inhabitants would be regularly checked and where biological material (sputum, throat washings and sera) would be collected if an epidemic 26

Smith, Andrewes and Laidlaw (1933). F. Horsfall to F. Soper, June 1, 1939. RAC, RG 5, Series 4, Box 33, Folder 359. 28 IHD report for 1937. RAC, RG 5, Series 3, Box 1, 77–82. 29 Bauer to Horsfall, July 5, 1938, RAC, RG 5, Series 4, Box 14, Folder 155. 27

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of acute respiratory diseases broke out. Second, Horsfall sought the Rockefeller Foundation officers in the West Indies, and in Central and Southern America to participate in the influenza research, either by sending human material in time of epidemics or by looking for animals susceptible to infection by the influenza virus.30 This sort of immunology-based natural history was no trivial matter, since the relationship between the presence of an influenza-like virus and various symptoms of severe infection (acute fever, nausea, sore throat, respiratory infection etc.) was unclear.31 It seemed that influenza could appear with no virus present and that different viruses might well be responsible for the same clinical disorder. The collection and exchange of strains and antiserum was then considered normal practice.32 Work on prevention started in 1939 when the IHD team began preparing inactivated vaccine from strains stabilized in mice. For reasons unknown to the investigators, preparation of mouse-adapted influenza viruses inactivated by a classical formaldehyde treatment did not induce the formation of specific antibodies in ferrets unless another sort of animal virus—the so-called distemper virus infecting dogs and ferrets—was added.33 Small groups of volunteers (presumably in penal institutions) were inoculated with the mixture and evaluation was based on two parameters: the existence of adverse reaction (none was reported) and the formation of antibodies against influenza virus A. The measurement of the latter was based on a tedious in vivo procedure. Dilutions from each sampled serum were prepared and each dilution was injected into a mouse infected with a standard amount of testing virus. This resulted in the consumption of between ten and fifteen mice for every surveyed patient, so that the size of the group given a peculiar vaccine preparation was ten individuals and no more. This was enough to claim that the complex vaccine was a good candidate but not strong enough to consider massive use. As Horsfall wrote in July 1940: ‘I do not believe that we have sufficient evidence regarding the actual efficiency of the complex vaccine to begin mass production of it as yet.’34 Expectations were actually not very high because all the workers in the field viewed the relationship between protection and the presence of antibodies against the virus as a complex one.35 In the context of the war in Europe and the mounting scientific mobilization in the United States, cautionary statements were soon obsolete. By the time he was writing the above-mentioned letter, Horsfall was already looking for a larger experiment. One idea was to use the complex vaccine for inoculation in the course of a

30 A good example of this unequal form of collaboration was the relationship of Horsfall with Weir in Bogota. 31 Horsfall (1940). 32 F. Horsfall to C. H. Andrewes, November 1938; March 6, 1939 and April 14, 1939, RAC, RG 5, Series 4, Box 1, Folder 8. 33 Horsfall and Lennette (1940); Horsfall to Andrewes May 9, 1940. 34 F. Horsfall to C. H. Andrewes, July 16, 1940. RAC, RG 5, Series 4, Box 1, Folder 8. 35 F. Horsfall, ‘The status of the influenza problem’, 1940. RAC, RG 5, Series 4, Box 1, Folder 8.

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deadly epidemic. The ideal location would be a country in Central or South America where a vaccination campaign and an immunological follow-up could benefit from the previous work of International Health Division envoys. Puerto Rico might be the ideal candidate: ‘A recent development might give us an opportunity for an actual test of the efficacy of the vaccine under field conditions. We learned only a few days ago that an epidemic of clinical influenza began in the islands of PuertoRico about three weeks ago. To date there have been 27,000 cases with 65 deaths and not for pulmonary infections. Dr. Lennette has flown to Puerto-Rico with all necessary equipment and we will together make an effort to determine the etiology of this epidemic.’36 With the news of the Puerto-Rico outbreak, planning was running fast within the IHD. The same day, Bauer sent Sawyer a memo listing the material required for ‘preparing 200,000 doses of influenza vaccine per week for Puerto-Rico’.37 Unfortunately, the throat washings collected by Lennette and sent back to the New York laboratory to be examined failed to reveal the target of the vaccine, i.e. the influenza virus A: ‘It may be of course that we have been unfortunate in the choice of the throat washings though these have probably been taken from typically severe and early cases. It is hard for me to think that we have chosen fourteen washings in series which did not contain the etiologic agent. At the moment I am wondering whether these epidemics may have not been due to an agent we have not encountered before.’38 Mass vaccination was of course out of question. Another epidemic soon reached Cuba. The reaction was more immediate: as the neutralization test done with a handful of sera received from the RF officer in Cuba revealed antibodies against influenza A, the vaccination material previously prepared for Puerto Rico was sent to the Caribbean. Vaccination was completed on a limited scale: in asylums, hospitals and prisons. Even in these controlled institutions, Horsfall reported to Andrewes that, in most cases, the results showed a higher incidence of influenza among the vaccinated population because ‘temperature was routinely taken on the vaccinated group and resulted in picking up mild cases’ which were unnoticed in the control group. Horsfall did not believe that ‘the incidence in the two groups was any different’ even though results from one institution were ‘mildly suggestive that the vaccine may have some efficacy since after 13 days of vaccination, cases among the vaccinated group almost disappear in contrast to the unvaccinated group’.39 Viewed from Britain, where war emergency was at its highest, the meaning of these results was different. In London, Andrewes had already launched attempts to produce an analog of the IHD complex vaccine which could be given to the British troops defending the British Islands against a massive German attack. On 36

Ibid. J. H. Bauer to W. A. Sawyer, July 16, 1940. RAC, RG 5, Series 4, Box 26, Folder 295. 38 F. Horsfall to C. H. Andrewes, August 31, 1940. RAC, RG 5, Series 4, Box 1, Folder 8. 39 Ibid., September 14, 1940. RAC, RG 5, Series 4, Box 1, Folder 8. 37

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September 16, 1940, Andrewes received a cable from the IHD: ‘Important letter sent by air summarizing vaccination results. Cuba results suggestive one case in vaccinated against twenty four in controls same institution. Apparently immunity develops earliest two weeks after vaccination. Our vaccination lab nearing completion and could supply England large quantities if desired.’40 Andrewes immediately cabled: ‘Crucial discussion of plans will follow receipt of your letter. Can you meanwhile estimate roughly your maximum output of vaccine.’41 The question was legitimate since the Rockefeller Institute was not known to be a drug or vaccine production center. But times were changing. The new vaccine laboratory Horsfall was alluding to had not in the first place been designed for producing the influenza vaccine but to produce massive amounts of yellow fever vaccine for the U.S. Army.42 It could, however, accommodate the two types of production since many features were common, including the use of virus cultures in chicken eggs. One peculiar aspect of the new laboratory was therefore the organization of a system for inoculating and incubating thousands of chicken eggs, followed by semi-automatized collection and treatment of amniotic fluid. On that basis, Horsfall could immediately assure Andrewes that ‘if desired could supply two hundred fifty thousand doses monthly beginning middle October. Later increase possible’.43 The decision to import was made by the British Medical Research Council following Andrewes’ advice. The latter played a decisive role since epidemiologists and statisticians sitting on the committee ‘were not disposed to put much stress on the Cuba results’, as Andrewes put it.44 In the following months, roughly 500,000 doses of the complex vaccine were shipped from New York, two-thirds of which were used in Britain.45 Following this industrial enterprise, influenza vaccination was no longer an idea or a possibly feasible project but a system of production. For the IHD workers this implied that all opportunities for advanced testing of the complex vaccines in the United States should be exploited. During the winter of 1940–1, distribution through the U.S. Army and various state health departments was achieved while a few thousand controlled inoculations were completed in closed institutions. In February 1941, Bauer became rather skeptical about further use: ‘on the whole the present evidence seems to indicate the vaccine has not lived up to our expectations as an effective measure for completely preventing influenza ... (although) we feel at the present time we do not have enough negative results on hand to condemn definitely the vaccine as a complete failure.’46 The public assessment was more balanced, since a 50% reduction of the incidence of influenza A infection in the 40

F. Horsfall to C. H. Andrewes, September 16, 1940. RAC, RG 5, Series 4, Box 1, Folder 8. C. H. Andrewes to F. Horsfall, September 24, 1940. RAC, RG 5, Series 4, Box 1, Folder 8. 42 See I. Lo¨wy’s essay in this issue. 43 F. Horsfall to C. H. Andrewes, September 26, 1940. RAC, RG 5, Series 4, Box 1, Folder 8. 44 C. H. Andrewes to F. Horsfall, October 8, 1940. RAC, RG 5, Series 4, Box 1, Folder 8. 45 Hudson to Bauer, April 3, 1941. RAC, RG 5, Series 4, Box 33, Folder 630. 46 Bauer to Sawyer, February 7, 1941. RAC, RG 5, Series 4, Box 26, Folder 295. 41

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vaccinated group and an equal incidence for influenza of unknown causes was claimed.47 But the complex vaccine was already doomed by laboratory tinkering. Stressing the need for tight virus control, the IHD workers reasoned that increasing efficiency could be attained if larger amounts of inactivated virus were injected. Horsfall and his collaborators—particularly a young biologist named G. Hirst— started to work on various means of concentrating the viral particles in the allantoid fluid of chickens. All sorts of adsorbing material were thought of (and occasionally tested): alum, precipitated allantoic proteins, red blood cells, etc. In the fall of 1941 they settled for a method based on the concentration of virus from the allantoic fluid of infected chicken eggs by means of adsorption on red blood cells.48 A vaccination program of twelve thousand individuals in mental institutions was envisioned. Meanwhile the IHD was no longer an isolated player in the field. The declaration of war with Japan accelerated the scientific mobilization. Influenza was of such concern within the Army that a board on the disease was established in February 1941. As discoverer of the second influenza virus (influenza B, unrelated to the form discovered by Andrewes), Thomas Francis was mandated to head an investigation commission gathering civilian researchers and members of the Army reserve. Part of the IHD staff was mobilized for this commission. The first task of the Army commission was to make recommendations about the standardization of laboratory procedures for the diagnosis of influenza and for epidemiological studies. In October 1941, Francis endorsed a new agglutination test for measuring the quantity of antibodies against the influenza virus, which originated in Hirst’s work at the Rockefeller Institute. ‘...[T]he test seems so accurate it should be a great advantage over the ordinary mouse neutralization. If we are to have much activity in the Army camps this winter, I thought we might also use it. For that reason it seems to me that we should follow exactly the same procedure that Hirst does rather than use some unessential modification. If you feel any objection to this do not hesitate to say so.’49 It was made routine procedure in the Army.50 The second task Francis assigned the Army Commission was a vaccination campaign using the IHD concentration method.51 Horsfall and Hirst’s technique was passed to commercial firms which would produce the vaccine for the Army to be used solely in military camps. The goals of the Army Commission were theoretically not limited to the cataloguing of virus strains and the development of vaccines. They also included epide-

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Horsfall (1941). Bauer to Sawyer, December 8, 1941. RAC, RG 5, Series 4, Box 26, Folder 295. Details of the method in Hirst to Francis June 3, 1942. RAC, RG 5, Series 4, Box 12, Folder 123. 49 Francis to Bauer, October 8, 1941. RAC, RG 5, Series 4, Box 12, Folder 122. 50 Hirst to Francis, October 14, 1941. RAC, RG 5, Series 4, Box 12, Folder 123. 51 Francis to Hirst, May 20, 1941. RAC, RG 5, Series 4, Box 12, Folder 123. 48

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miological surveillance and therapeutic evaluation.52 It is, however, a testimony to the strength of consensus regarding the Rockefeller-based strategy of ‘viral control’ that these topics were rarely addressed. Moreover, as medical mobilization escalated, the molecular redefinition of the viruses, enhanced by the Rockefeller complex, pervaded the military approach to influenza control. In 1942, when Thomas Francis launched his own big ‘influenza laboratory’ at the University of Michigan, he inquired whether the IHD would build an ultracentrifuge for him. The ‘ultracentrifuge situation’ at the Rockefeller Institute (as Bauer called it) was complex. First, Pickels had been assigned other tasks beginning with the development of new tools for large-scale production of vaccines. For instance, he had just built a new machine for freezing yellow fever vaccine preparations. Second, ultracentrifuges were now built for many war-related research projects under the umbrella of OSRD or other military bodies, and appropriation problems were mounting. As Bauer put it: ‘It is true that we have avoided building centrifuges for other labs for two reasons. The first is that such a procedure would turn our lab into a service station for other institutions and would seriously interfere with our own research program. The other is that all high speed centrifuges utilize features that are patented. For example, in the concentration centrifuge the angle used is patented by the Swedish Angle Centrifuge Company. In the analytical centrifuge the optical system is patented by Svedberg and the Sharples company owns this patent at present.’53 Francis was a former fellow, and he was becoming an influential science organizer. In spite of all their reservations, the IHD managers finally agreed to have Pickles build a machine for the Michigan laboratory.54 Why was it so important to get such an instrument? The answer lies in the changing meaning of the machine. The ultracentrifuge was then being incorporated in a series of projects as a tool crucial to characterizing macromolecules and decisive to purifying and isolating proteins or viruses. In short, the ultracentrifuge was gradually becoming a preparative rather than an analytical apparatus. This shift is easy to perceive in influenza studies. In 1942–3, the first papers associating ultracentrifuges and influenza viruses were published by the two branches of the Rockefeller scientific personnel: Friedewald and Pickels for the IHD laboratories, Lauffer and Stanley for the Princeton branch of the Rockefeller Institute.55 They focused on the determination of size. They were soon followed by other members of the Army commission,56 with the latter arguing against the former that the influenza viruses did not behave like one single macromolecule but like a

52 Preliminary Plan of Investigations for the Commission on Influenza. RAC, RG 5, Series 4, Box 33, Folder 630. 53 Bauer to Sawyer, April 24, 1941. RAC, RG 5, Series 4, Box 26, Folder 295. 54 Francis to Bauer, October 8, 1941. RAC, RG 5, Series 4, Box 12, Folder 122. 55 Friedewald and Pickels (1943) and Chambers et al. (1943). 56 Beard (1944).

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micro-organism of variable size, better described with photographs taken with electron microscopes than with ultracentrifugation pictures.57 By the end of 1943, the Rockefeller core set was thinking of other uses: the ultracentrifuge might be enlisted to solve the vaccine efficiency problem. Just as with the complex vaccine, the concentrated vaccine gave mixed, ‘though promising’, results.58 The alliance of scaling-up and technological fix favored by the war mobilization was evolving into a strategy. In the case of influenza this move was reflected in the quasi-natural idea of improving the vaccine by inoculating larger amounts of purer antigenic materials. Within the Rockefeller circles, the virus was identified with a protein, and it was not a big step to considering ultracentrifugation as a means of concentrating and purifying large amounts of influenza viruses. This move was first taken by the biochemist and ultracentrifuge enthusiast Wendell Stanley, then under OSRD contract. Late in 1943, Stanley made arrangements for the testing of his centrifuge-based virus preparations without any consultation with Francis and the Army Commission.59 Given the history of the ultracentrifuge at the IHD, one may wonder why such a procedure was not developed within the IHD laboratory. Two features are worth mentioning in this respect. First, in 1944 Pickles left the IHD for a research center in Maryland where he built ultracentrifuges for the Navy. Second, Stanley’s conjunction of the ultracentrifuge and influenza emerged quite early. In 1942, Stanley had secured a major contract with the OSRD for influenza studies. By mid-1943, he was advocating the use of the ultracentrifuge for purity reasons rooted in his knowledge of the influenza virus molecule: ‘the purified products obtained by methods involving only the use of red cells or the freezing and thawing techniques [the IHD techniques] were found to contain 80 per cent of non-virus proteins’; furthermore, obtaining a homogeneous viral macromolecule ‘appears to be of importance in connection with the prevention or control of influenza ... Irrespective of the mechanism by means of which a solid immunity to influenza is achieved, the importance of securing concentrated virus preparations is indicated by the findings of Hirst and co-workers that the average antibody response of human beings is directly related, though not strictly proportional to the amount of virus administered.’60 In all probability, Hirst and Bauer did not fully agree with this radical molecular redefinition of the prevention problem which left immunological studies out. Nonetheless they agreed to participate in the testing of a product prepared according to Stanley’s specifications. This experiment, conducted in 1944, led the IHD to endorse the Stanley-CMR vaccine and to condemn the Army vaccine. Following the reception of two drafts on immunization written by Friedewald, the head of 57 On the problematic juxtaposition of ultracentrifuges and electron microscopes, see Gaudillie`re (1998). 58 IHD laboratory reports 1943 and 1944. RAC, RG 5, Series 3, Box 1. 59 Francis to Stanley, February 9, 1944. Bancroft Library, University of California, Stanley papers, Box 8, Folder Francis. 60 Stanley (1944).

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the Influenza Board, Col. Bayne-Jones angrily wrote back to Bauer: ‘The part of the paper which troubles me is the discussion in which the vaccine made by elution from red cells is rather severely condemned in comparison with straight infected allantoic fluid and virus concentrated by high speed centrifugation ...There have been no actual tests of human immunization with centrifuged vaccine while there have been extensive tests of the eluted vaccine with results highly favorable ... Obviously my concern about this comes particularly from the fact that the Army is getting a stock of the eluted type vaccine to be used in case of need...’61 Francis soon echoed these views. As a consequence, Friedewald deleted the contested results ‘until further evidence can be obtained’.62 Such evidence was already in the making. In November 1944, Hirst sent Stanley the first report of his investigation of the CMR vaccine, with a copy to Francis and the Army Board. The main comment was not only that ‘I personally have no doubt that vaccine prepared by centrifugation will be as efficient in preventing clinical influenza as similar amounts of virus prepared by any other method of concentration’, but that ‘the commission product supposedly concentrated ten times is equivalent to a centrifuge concentrated two times and a half’.63 Stanley immediately mobilized this evaluation to complement his own results on the purity of the preparation and its antigenic potency in mice. Early in 1945, Stanley entered into thorough negotiations with Francis, the Army Influenza Commission and the War Production Board to have his vaccine approved 64, a step which was taken by the summer. One irony of the story, however, is that the ‘molecular’ vaccine developed and claimed as more efficient by Stanley and the IHD did not really take over. By 1945, the Commission vaccine was reported ‘effective in reducing the incidence of influenza’ although with variable rates and duration of protection.65 One issue in the assessment of this variability was the making of the diagnosis. Since mild infections eventually caused by the influenza virus were not surveyed, the level of protection remained uncertain. Since neither the IHD nor the Commission organized significant clinical and epidemiological surveys of the target populations, such questions (as well as the problems of local variability of the influenza viruses) were left unanswered. Irreversible use was nonetheless achieved: the Commission vaccine was already being produced by commercial firms such as Lederle laboratories, and distributed to a broad network of military doctors. It became the basis for further developments and an international reference.66 The medical mobilization of World War II made a significant impact on the Rockefeller strategies. Before the war, the ultracentrifuge (and other molecular 61

Bayne-Jones to Bauer, 26 August 1944. RAC, RG 5, Series 4, Box 33, Folder 361. Friedewald to Bayne-Jones, 19 September 1944. RAC, RG 5, Series 4, Box 33, Folder 361. 63 Hirst to Stanley, 30 November 1944. RAC, RG 5, Series 4, Box 12, Folder 122. 64 Thomas Francis, memo on Stanley’s vaccine, 27 January 1945. Bancroft Library, University of California, Stanley papers, Box 8, Folder Francis. 65 Francis (1945). See also the detailed reports in the same special issue. 66 Abaza (1946). 62

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machines such as the electrophoresis apparatus) had been associated with the shift from an approach to viruses as small bacteria to a vision of viruses as big proteins. This displacement of scientific practices and theories was, however, loosely connected to the control of viruses through the notion that a better knowledge of the structure and mode of replication of viruses would facilitate medical innovations. Accordingly, the search for vaccines revolved around ‘bacteriological’ practices such as the so-called ‘passage’ of viruses in animals or immunological tests. During the war, vaccine production became a major emergency enterprise based on the search for quick technological means of control and scaling-up. Practices much closer to industrial research emerged. Within the Rockefeller complex, they were juxtaposed with the culture of biophysical instrumentation which characterized the molecular biology of the 1930s, with the result that the ultracentrifuge became a focus for projects of ‘virus control’ conceived as projects of ‘particle control’. During the postwar era, this conjunction of health policies, macromolecules and industrial engineering was endorsed in several domains of American biomedical research, including cancer research and the fight against polio. As recounted by J. Smith or A. Creager, the National Foundation for Infantile Paralysis supported at the same time the development of vaccines by means identical to the war influenza research and the molecular study of the polio viruses.67 The former line of work was exemplified by Jonas Salk’s laboratory, where a killed vaccine was invented and tested in the early 1950s and then produced and trialed on a large scale in 1954 under NFIP supervision. The latter line of work was illustrated by Stanley’s new Virus Laboratory at the University of California Berkeley, where the polio viruses were centrifuged, measured with the electron microscope and finally crystallized. Links between these two lines of work were numerous, including the circulation of virus batches from NFIP contractors to Stanley’s laboratory, and the use of Stanley’s electron micrographs of the polio virus by NFIP officials and vaccine makers. In spite of these exchanges, the development of Salk’s vaccine did not owe much to the molecular biology of polio viruses. The means and tools employed by Salk were those of classical bacteriology (with the exception of the cell cultures techniques). Yet, such restricted use of molecular concepts and molecular machines did not imply that the ‘control of particles’ style of work was irrelevant to the polio project. The industrial and molecular cultures of the NFIP hinged on three aspects of the previous influenza vaccine project: scale, standardization and scientific advertising. 4. Conclusion In 1946–7, the head of the Pasteur Institute’s virology laboratory, Pierre Le´pine, was visiting the United States for the first time since the war began. His concluding

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Smith (1990) and Creager (forthcoming).

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comment to his IHD colleagues as he returned to Paris was about instrumentation: ‘...the visit confirmed me in the opinion that the three items most urgently needed here for virus work, which we are unable to get now in France at present or to buy abroad, are, by order of urgency...the Sharples and Sorvall ultracentrifuges and a deep freezer.’68 Lepine’s comment highlights the specificity of the biomedical strategies which dominated the Rockefeller complex in the 1930s and 1940s, as viruses emerged as key targets within both the Natural Sciences Division and the International Health Division. The Rockefellerian form of virus research relied on a series of new machines for visualizing and studying macromolecules, machines whose invention was strongly supported by the Foundation (with the ultracentrifuge in the leading role). The medical meanings of the Rockefeller ‘molecular’ culture became more specific and visible during the Second World War when these machines and the Rockefeller scientists were mobilized and participated in the development of the influenza vaccine. The medical strategy focusing on the search for technical means of controlling micro-organisms (rather than on epidemiological or clinical studies) was then articulated in terms of virus purification and ‘particle control’ based on the use of the ultracentrifuge. This in turn boosted virus studies as a juncture between basic biology and public health. The irony of the story is, however, that such reshaping of means and targets led the Rockeller Foundation into quasi-industrial ventures aiming at the production of vaccines while leaving medical practices almost untouched. The story of the influenza vaccine highlights a peculiar conjunction of molecular machines, industrial research practices and mass production which became an integral component of postwar American biomedical culture. With the war mobilization, public-health issues were (re)defined in terms of means for handling, producing, changing or standardizing viral particles. This shift maintained the links between vaccine development and molecular biology even if the connections were often more cultural than practical, as illustrated by the history of the Salk polio vaccine in the 1950s.69 Acknowledgement—Section 2 of this paper is adapted from a forthcoming article on cancer viruses by A. Geager and J.P. Gaudilliere. I thank Angela Geager for her willingness to see this material employed here.

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