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|3. Experiment and Theory|
|4. Medical Realism|
|8. Organizations and Funding|
|9. Science as a Social Process|
|10. Conclusion: Science as a Complex System|
My description of the cognitive processes involved in the discovery, development, and acceptance of the bacterial theory of ulcers might have left the impression that science is all in the mind (Thagard, forthcoming-b). But only part of the story of the bacterial theory of ulcers is psychological. This paper discusses the important role of physical interaction with the world by means of instruments and experiments, and the equally important role of social interactions among the medical researchers who developed the theory. The main questions I want to answer are the following:
1. What instruments contributed to the development and acceptance of the new theory?I conclude with a sketch of science as a complex system of interacting psychological, physical, and social processes.
2. What kinds of experiments contributed to the development and acceptance of the new theory?
3. How did theorizing and experimentation interact in the development of new experiments and hypotheses?
4. How did social processes such as collaboration, communication, and consensus contribute to the development and widespread acceptance of the bacterial theory of ulcers?
Gastric spiral bacteria were microscopically observed as early as the 1890s, and in the 1970s Steer and Colin-Jones (1975) reported the co-occurrence of gastric bacteria and ulceration.. They were unsuccessful, however, in attempts to culture the bacteria, which they identified as Pseudomonas aeruginosa. In 1979, Dr. Robin Warren was using an Orthoplan optical microscope at 250x magnification to examine histologic sections from patients with gastritis. He noticed the unexpected presence of spiral bacteria, and then used an oil immersion microscope capable of 1000x magnification to examine them more closely. In order to observe the morphology of the bacteria more clearly, he requested a Warthin-Starry silver stain on gastric biopsies and was able to see a large number of spiral organisms. He had previously used this kind of stain for observing the spirochetes that are responsible for syphilis. Staining of bacteria, which originated with Herman Hoffman in 1869, makes possible much clearer observation of their structure (Bulloch 1979).
All subsequent experiments observing the correlation of the bacteria and various diseases, as well as the experiments finding that eradicating the bacteria can cure diseases such as gastritis and ulcers, used microscopes to determine the presence or absence of bacteria in the gastric biopsies. Without microscopes, bacteria would never have been discovered, and the bacterial theory of ulcers would never have been developed and accepted.
Although most of the clinical research involving Helicobacter pylori has been performed using optical microscopes, electron microscopes proved very useful in identifying the detailed morphology of the newly discovered species of bacteria. In 1982, just after the first cultures of H. pylori were produced, Barry Marshall delivered specimens to an electron microscopist, Dr. John Armstrong, who produced the first electron micrographs of the bacteria (Marshall, 1989). Armstrong identified the essential morphological features, four or five sheathed flagella, that differentiated the gastric spiral bacteria from the species Campylobacter jejuni. Subsequent investigations, using electron microscopes and other technologies such as RNA sequencing, provided evidence that the bacteria did not belong in the genus Campylobacter and led to the naming of a new genus, Helicobacter (Goodwin and Worsley, 1993). Without these instruments permitting much more detailed observation of the structure and properties of the gastric bacteria, the conceptual change that produced a reclassification of the bacteria would not have been possible. Figure 1 is a photograph of H. pylori.
Figure 1. Microscopic photograph of H. pylori (arrows).Source: http://www.pds.med.umich.edu/users/greenson/HP-SILVER.GIF. Used by permission of Joel K. Greenson, M.D.
In the 1950s, a new technology for transmission of information became available. Hopkins and Kapany (1954) designed a flexible fiberscope that uses glass fibers encased in a cladding to direct light along a curved path. Fiber optics have since become the main medium for carrying all types of telecommunications, but one of their first applications was the manufacture of endoscopes for medical exploration. In 1957, Basil Hirschowitz and his colleagues produced the first fiber-optic gastroscope, and such instruments were in clinical use by the early 1960s. Improved instruments included biopsy channels for taking tissue samples from the stomach and, after 1983, video screens on which the endoscopist and others can observe the stomach.
By the 1970s, endoscopy had become a standard technique for gastroenterologists, who, by inserting a tube with fiber optics down the throat of patient, can view the inside of the stomach. An ulcer is immediately visible as a sore or hole in the lining of the stomach (gastric ulcer) or as a sore on the upper part of the intestine (duodenal ulcer). Endoscopy not only makes possible identification of ulcers, it also enables gastroenterologists to take samples of stomach tissue by means of a miniature pincer attached to the end of the endoscope. They can thus pass tissue samples to pathologists for further examinations. Robin Warren's observations of bacteria in stomach tissue in the late 1970s were done on samples obtained via endoscopy. Figure 2 shows an early gastroscope.
Endoscopy has also played a crucial role in all the experiments that have contributed to the acceptance of the bacterial theory of ulcers. Definitive diagnosis of a peptic ulcer is made by endoscopic observation of lesions, and endoscopically-gained samples are crucial for determining the presence or absence of Helicobacter pylori. The early experiments described below that found a correlation between the presence of bacteria and ulcers, and the later more conclusive experiments that showed that antibiotics can eradicate bacteria and cure ulcers, all depended on internal examination and tissue sampling using endoscopes. Without endoscopy to provide stomach samples, the bacterial theory of ulcers would never have been discovered or validated.
Figure 2. A modern fiber-optic endoscope.Originally, the only way to diagnose infection was by endoscopic biopsy of the gastric mucosa. But David Graham and his colleagues designed a non-invasive detection method based on the fact that H. pylori produces large amounts of urease that buffers it from gastric acid (Graham et al., 1987; see also Marshall et al. 1991). Patients suspected of having H. pylori in their stomachs are given a small quantity of urea containing an isotope of carbon. If urease is present, it reacts with the urea to form carbon dioxide containing the isotope, which is detected by having the patient breath into a balloon. Patients with stomach distress can be diagnosed as having H. pylori infection without undergoing the expensive and somewhat unpleasant experience of endoscopy, and immediately treated with antibiotics. Cutler et al. (1995) report that urea breath tests are as effective as endoscopic biopsy for diagnosing infection. Urea breath tests were not important in the discovery or validation of the bacterial theory of ulcers, but they promise to be of increasing importance in future treatment of gastritis and ulcers (1).
Source: http://www.mindspring.com/~dmmmd/atlas_1.html. Used by permission of David M. Martin, M.D.
1. Correlational studies use data from entire populations to compare disease frequencies between different groups during the same period of time or in the same population at different points of time. For example, there is a positive correlation across countries between high consumption of meat and colon cancer. Such correlational studies can be a useful source of hypotheses about the causes of diseases, but are weak for evaluating causal claims because of unknown effects of other variables.
2. Case reports and case studies consist of detailed descriptions of one or more patients with a particular disease. For example, the occurrence of a particular kind of pneumonia in five young, previously health young men in Los Angeles in 1980 suggested the existence of a previously unknown disease (AIDS) and led to the conjecture that the cause of the disease might be related to sexual behavior.
3. Cross-sectional surveys are large studies that collect extensive information from individuals at a particular point in time. They make possible calculation of the frequencies of various diseases in relation to age, sex, race, socioeconomic variables, medication use, cigarette smoking, and other risk factors. While such studies can be suggestive about the causes of disease, they are never definitive, since causes and effects are difficult to disentangle. For examples, when individuals with cancer are found to have lower levels of serum beta-carotene, it is not clear whether the lower levels are a cause or an effect of the cancer.
Hennekens and Buring (1987) contrast these three kinds of descriptive study with analytic studies in which an investigator assembles groups of individuals in order to make an explicit comparison of the risk of disease of those exposed to a factor with those not exposed.
4. Case-control studies select a group of patients that have a disease and compare them with a control group of patients without the disease. For example, a group of patients with a particular kind of cancer can be compared with a group of similar patients without cancer. The comparison can look at various potentially relevant variables such as diet, smoking, medication use, and so on.
5. Cohort studies differ from case-control studies temporally: subjects are classified on the basis of presence or absence of exposure to a factor and then followed over time to determine the comparative development of disease in each exposure group. For example, in the early 1950s the Framingham Heart Study established a cohort of more than 5000 people identified with respect to medical history, cigarette smoking, and a variety of laboratory variables. Reexamination of members of the cohort at regular intervals has identified numerous risk factors for cardiovascular disease.
6. Intervention studies (clinical trials) are a special kind of cohort study in which the exposure status of the individuals is randomly determined by the investigator. The advantage of random assignment to exposure and non-exposure conditions is that it controls for the effects of other risk factors, both recognized and unrecognized. For example, randomly assigning patients with hypertension into groups receiving a medication and not receiving it can provide evidence of the effectiveness of the medication. Hennekens and Buring (1987, p. 26-27) remark that "when well designed and conducted, intervention studies can indeed provide the most direct epidemiologic evidence on which to judge whether an exposure causes or prevents a disease."
The purpose of the 1982 experiment was not just to determine the medical significance of the bacteria but also to learn more about their nature. From each patient, two biopsy specimens were taken, one sent for microscopic examination to Robin Warren, the other transported to the microbiology lab in nutrient broth. After many tries, the organism was cultured for the first time in April, 1982. Sections were also sent to Dr. John Armstrong, the electron microscopist at Perth General Hospital, for ultrastructural examination. Thus the 1982 experiment involved all the major technologies describe in the last section: optical microscopes, light microscopes, and endoscopes. It also required the various technologies developed in the nineteenth century for culturing and observing bacteria, such as growth media, incubators, and stains.
Between April, 1985, and August, 1987, Marshall and numerous colleagues at Royal Perth Hospital examined 100 consecutive patients with both duodenal ulcer and H. pylori infection to see whether eradication of the bacteria affected ulcer healing or relapse (Marshall et al., 1988) (2). This experiment was double-blind, in that histology and microbiology findings were concealed from both the patients and the doctors managing them. Patients were randomly assigned to receive either the antacid cimetidine or colloidal bismuth subcitrate, and either tinidazole or a placebo. The four treatment groups were thus cimetedine+tinidazole, cimetidne+placebo, bismuth+tinidazole, and bismuth+placebo. Bismuth+tinidazole was by far the most effective combination, clearing the infection in 20 of 27 patients. After 10 weeks, patients underwent endoscopy, and healing of ulcers had taken place in 92% of patients in whom H. pylori were not detected, compared to only 61% of patients with persistent H. pylori. Marshall et al. (1988, p. 1441) concluded: "Our results imply that C pylori [H pylori] is the most important aetiologic factor so far described for duodenal ulcer." Many other researchers have done similar experiments that show that various kinds of antibiotic therapy are effective at healing both duodenal and gastric ulcers and at preventing their recurrence (Thagard forthcoming-b). The accumulated evidence provided by these intervention studies is such that in 1995 Barry Marshall was awarded the highly prestigious Albert Lasker clinical medical research award "For the visionary discovery that Helicobacter pylori causes peptic ulcer disease." I note again that endoscopes and microscopes were essential ingredients in these intervention experiments.
1. Inductivist: scientists do experiments to collect data and then generalize the results. Good hypotheses and theories are derived from experimental results.The inductivist picture fits best with Marshall's and Warren's 1982 experiment where they sought to find out whether gastric symptoms and diseases correlate with the occurrence of gastric spiral bacteria. This experiment was not designed to test any specific hypothesis about the medical role of H. pylori. Nevertheless, the experiment did not operate in a theoretical vacuum either: Marshall did not know what diseases the bacteria might be associated with, but he did suspect, presumably by analogy with the disease-causing effects of some other kinds of bacteria, that H. pylori might be the cause of some diseases. The design of the 1982 experiment specifically looked for associations between presence of the bacteria and specific diseases of interest: gastritis, gastric ulcer, duodenal ulcer, and other stomach abnormalities. Marshall and Warren were neither simple-minded empiricists, merely collecting experimental data, nor theory-blinded deductivists, trying to confirm their own predictions. At this stage of the investigation, they had no clear predictions to test.
2. Hypothetico-deductivist: scientists start with hypotheses and then do experiments to test them. If the experiments come out as predicted, the hypotheses are confirmed; otherwise, the hypotheses are refuted.
3. Social constructivist: experiments are part of the social construction of scientific facts.
In contrast, the hypothetic-deductivist picture fits better with the intervention studies which were indeed designed to test the hypotheses that H. pylori causes peptic ulcers and that ulcers can be cured by eradicating the bacteria with antibiotics. The logic of the experiment that Marshall et al. reported in 1988 was something like: If H. pylori causes ulcers, then antibiotic treatment of people with ulcers and H. pylori infection should cure the ulcers. The experimental design, however, made matters much more complex than this simple conditional allows. The antibiotic tinidazole did not by itself cure ulcers, because the bacteria quickly adapted to become resistant to it. The combination treatment of tinidazole+bismuth was much more effective, a generalization that Marshall and his colleagues made from this study. Hence they were being simultaneously hypothetic-deductivist and inductivist, using experiments to test hypotheses and also deriving new hypotheses by generalization from new experimental findings.
Empiricists can accept the reality of ulcers, since lesions are observable by the naked eye, and stomach ulcers were identified in autopsies long before the microsope was invented. But bacteria cannot be observed without a microscope. Van Fraassen (1980) denies that scientists see through a microscope: his strict empiricism would prevent him from accepting as true the claim that bacteria exist. More plausibly, Hacking (1983, ch. 11) notes that very difficult physical processes, such as diffraction of light for optical microscopes and electron transmission for electron microscopes, yield identical results, so that denying the reality of bacteria and other structures observed through microscopes would make the common results of the different physical processes a "preposterous coincidence". The thousands of articles published on H. pylori reflect their authors' experiences of observing bacteria through optical and electrical microscopes, experiences made even more shareable by published photographs such as figure 1. The empiricist has no grounds for elevating unaided sense experience above the observational practice of microscopists: like ordinary observation, microscopy is not error-free, but it has a high degree of reliability shown by intersubjective agreement. Helicobacter pylori can be seen, even if it takes a microscope to do so.
Conceptualism is sometimes a useful antidote to a too simple empiricism, when it recognizes that understanding the world goes well beyond sense experience; but it can err in the other direction by downgrading the role of experiment in scientific change. The relation of hypothesis and experiment is reciprocal, involving a kind of feedback loop in which experimental results suggest hypotheses and hypotheses suggest experiments and so on. Experimental data are not theory-independent, but they are not completely theory-dependent either. Endoscopy and microscopy revealed gastric spiral bacteria even to researchers who thought that Warren and Marshall were wrong. The conceptual structures described in Thagard (forthcoming-b) do not determine what researchers will detect with their instruments. Some of Marshall's experiments, for example the early attempt to develop an animal model of disease production by H. pylori, were not successful. Even more remarkably, some researchers who set out to refute his claims about the link between bacteria and ulcers produced experiments that confirmed those claims. Scientists' investigations of nature depend heavily on the conceptual structures with which they design experiments, but experiments often display a recalcitrance to expectations that cannot be explained if one thinks of nature only as a mental construction.
Similarly, it is implausible to view the bacterial theory of ulcers wholly as a social construction. As we will see below, there were many social processes such as collaboration, communication, and consensus that were important to the development and acceptance of the new ideas. But these social processes operated in concert not only with the psychological processes in the minds of researchers, but also in concert with physical processes by which scientists used instruments to interact with the world. Financial, ideological, medical, or other interests do not suffice to enable medical researchers to see whatever they want to see through a microscope or to obtain whatever biopsy samples they want to obtain with an endoscope. Using commonly accepted instrumental techniques and experimental methods, scientists achieved consensus in part because of physical interaction with a world not generated by their mental and social processes. Anyone who believes that H. pylori and the diseases it causes are pure social or mental constructions might receive a useful dose of reality by replicating Marshall's self-experiment.
Note that the emphasis on instrument and experiment in this paper is not a competing explanation for scientific change to the cognitive explanations given in Thagard (forthcoming-b). The use of instruments in observation and the design and conduct of experiments all depend on mental representations for diseases and microbes. Interacting with the world depends on thinking, just as thinking depends on interacting with the world.
In sum, the ulcers/bacteria case has several aspects that support a realist interpretation: reliability of instruments, experimental recalcitrance, and causal efficacy. Unless one accepts as true the claims that H. pylori inhabit the stomach and can cause ulcers, there is no plausible explanation of why so many scientists have been able to observe the bacteria with microscopes, of why experimenters sometimes do not get the results they want, and of why antibiotics are such an effective cure for many cases of ulcers.
Like most scientists, medical researchers do not spend most of their time theorizing. They devote immense efforts to designing, conducting, and analyzing the results of experiments. Scientific experiments often involve instruments of varying degrees of complexity, from the multi-billion dollar accelerators needed for research in high-energy physics to the multi-million dollar brain scanning devices increasingly used in neuroscience to the computers used by cognitive psychologists to measure reaction times. In all these fields, there is great epistemological significance in the recalcitrance of nature, which often fails to provide researchers with the experimental results they expect. This recalcitrance, and the role of instruments and experimental design in enabling researchers to manipulate natural occurrences, renders implausible any attempt to construe the world purely as a mental or social construction. Understanding scientific change requires paying attention not only to the minds and social interactions of scientists, but also to the physical activities by which they intervene in the world and extract information from it. The development and acceptance of the bacterial theory of ulcers depended crucially on the use of instruments such as microscopes and endoscopes that are needed to observe bacteria and ulcers, and also on a series of experiments that were required to show that there is a causal relation between H. pyloriinfection and gastric ulcers. Scientific change is equally a mental, physical, and social process.
I will now describe several social processes that are part of an explanation of how the theory that most peptic ulcers are caused by Helicobacter pylori came to be formed and eventually accepted. First, research in this area, like most current research is highly collaborative, involving multiple scientists working together. Second, spread of the new ideas about ulcers required their communication through the medical community by various means, including personal contact, conferences, and publications. Third, the growing consensus that ulcers are caused by bacteria is the result of various social processes, including a Consensus Development Panel meeting convened by the U.S. National Institutes of Health in 1994. I will also describe more briefly other social aspects of scientific change, including funding of medical research and the role of pharmaceutical companies.
The first publication on ulcers and bacteria by Warren and Marshall has a curious structure. Under a common title, "Unidentified Curved Bacilli on Gastric Epithelium in Active Chronic Gastritis", Lancet published two separate letters, one by Warren and one by Marshall (Warren and Marshall, 1983 ) (3). Warren's letter described work on the bacteria that he had conducted before beginning collaboration with Marshall. Subsequently, Marshall and Warren published several joint papers reflecting their continuing collaboration.
We thank Dr T. E. Waters, Dr. C. R. Sanderson, and the gastroenterology unit staff for the biopsies, Miss Helen Royce and Dr. D. I. Annear for the microbiology studies, Mr Peter Rogers and Dr L. Sly for supplying the G & C data, Dr. J. A. Armstrong for the electron microscopy, Dr. R. Glancy for reviewing slides, Miss Joan Bot for the silver stains, Mrs Rose Rendell of Raine Medical Statistics Unit UWA, and Ms Maureen Humphries, secretary, and, for travel support, Fremantle Hospital.Notice the wealth of expertise required for the study: gastroenterology, microbiology, microscopy, statistics, etc. All of these specialties require years of intense training, so no individual researcher could have conducted the 1982 study alone.
Similarly, the 1984 attempt to fulfil Koch's postulates for bacteria and gastritis by Marshall's self-experiment required a team of researchers (Marshall, Armstrong, McGechie, and Clancy, 1985). This paper lists the specialties of the authors as follows:
Barry J. Marshall, registrar in microbiology,Marshall's self-administration of bacteria would have been uninformative without the assistance of various specialists to help determine whether the bacteria had infected his stomach. That additional help was useful for this project is clear from the acknowledgments (Marshall et al., 1985, p. 439):
David B. McGechie, microbiologist,
Ross J. Clancy, pathologist,
John A. Armstrong, electron microscopist.
We wish to thank Dr J. R. Warren for advice on the historical aspects; Dr I. G. Hislop for performing the gastroscopies; Mr N. Nokes for the cultures; and S. H. Wee (EM) and J. E. Holdsworth for the histological preparations.
Whereas the 1982 experiment was done in one hospital, Perth Royal, the 1984 experiment required collaboration across two organizations. When it was conducted, Marshall, McGechie, and Clancy were all in the department of microbiology at Fremantle Hospital, while Armstrong was at Perth Royal. Note also how the need for collaborators often corresponds for the need for expertise with different instruments. This project needed gastroenterologists for expertise with gastroscopy, pathologists for expertise with microscopes, and microbiologists for expertise with stains and cultures, as well as an expert whose profession was defined by his instrument, the electron microscope.
In Thagard (forthcoming-b) I cited five additional papers that provide convincing evidence that use of antibiotics to eradicate Helicobacter pylori cures gastric or duodenal ulcers. All five papers are co-authored, with an average of more than five authors per paper. For example, the researchers who have collaborated with Dr. David Graham (e.g. Graham et al., 1992) include epidemiologists, pediatricians, and pathologists as well as gastroenterologists. Remarkably, one paper that found an association between Helicobacter pylori infection and gastric cancer lists as its author "The EUROGAST Study Group", which has more than two dozen members spread across many countries and institutions (EUROGAST Study Group, 1993).
It is thus obvious that the research that produced the evidential support for the bacterial theory of ulcers is not the product of individual minds working in isolation, but required the cooperative work of many teams of scientists. Figure 3 shows some of the social connections that contributed to the work of Marshall and Warren, grouped according to co-authorship. Such interconnections are typical of research in the natural sciences, as well as in some social sciences such as psychology. Hence the interactions of researchers in producing and interpreting experimental research must be taken into consideration in any adequate account of scientific change.
Figure 3. Research teams, as shown by the authorship of Marshall and Warren (1984), Marshall et al. (1985), and Marshall et al. (1988) (5).Philosophy of science is concerned not only with how science is done, but also with how it should be done. My conclusions concerning the importance of collaboration to the ulcers/bacteria case are both descriptive and normative. Descriptively, we must notice that collaboration did occur; normatively, it is clear that scientific research concerning peptic ulcers and H. pylori would have been much less effective, efficient, and illuminating without collaborations among pathologists, gastroenterologists, microbiologists, and other personnel. As with much other research in contemporary science, collaboration not only facilitates scientific change, but is essential to it. See Thagard (forthcoming-a) for further normative analysis of collaboration.
Once the new ideas about bacteria and ulcers began to gain acceptance, the main researchers such as Barry Marshall and David Graham became in great demand for speaking engagements, another kind of personal contact. In 1996, Marshall was booked 18 months in advance for personal appearances (6).
Strikingly, the hypothesis that the gastric spiral bacteria caused ulcers had a much more positive initial reception from medical microbiologists than from gastroenterologists, who had pre-existing ideas about acidity as the major causal factor in ulcers. Marshall and Warren's (1984) report of their 1982 study was not immediately accepted by the editors of The Lancet, who had received negative referee reports. But as the result of the 1983 meeting in Brussels a number of microbiologists such as Martin Blaser began finding the bacteria in patients with gastritis and ulcers. The growing recognition of the importance of Marshall and Warren's research made gastroenterologists take it more seriously. Using a football analogy, we might describe the acceptance of the bacterial theory ulcers as a kind of "epistemic end run": a direct assault on gastroenterology was unsuccessful because of entrenched ideas in that field, but an indirect pursuit of the new ideas was possible via microbiology.
It must be recognized, however, that in the mid-1980s the evidence for the claim that H. pylori causes peptic ulcers was meager. Even gastroenterologists who were very interested in the new hypothesis viewed it as lacking in scientific support, and were annoyed by conference presentations that aggressively pushed the hypothesis in the absence of careful experiments that supported the causal claim. By the 1990s, however, such experiments had been done by various researchers, and conference discussion shifted from the question of whether H. pylori causes ulcers to how it does so and how it can be eradicated.
Figure 4. Growth in the number of journal articles on the role of Helicobacter pylori in peptic ulcer disease and gastritis, adapted from Science Watch, vol. 1, no. 4, p. 7, published by Institute for Scientific Information.Unlike most scientific journals, medical journals such as The Lancet and The New England Journal of Medicine publish editorials along with research reports. The editorials allow experts in a field to comment on the clinical significance of recent findings. For example, David Graham (1993) wrote an editorial for The New England Journal of Medicine discussing recent studies and arguing that H. pylori infection is the most common cause of peptic ulcer and accounts for the majority of cases. Because such editorials are concise and less technical than research reports, they may have a substantial impact on belief change in medical researchers and physicians not directly involved with the topic.
Since 1977, NIH has conducted a Consensus Development Conference Program whose purpose is produce consensus statements on important and controversial statements in medicine. NIH's World Wide Web site describes the program as follows:
NIH Consensus Development Conferences are convened to evaluate available scientific information and resolve safety and efficacy issues related to biomedical technology. The resultant NIH Consensus Statements are intended to advance understanding of the technology or issue in question and to be useful to health professionals and the public.The 1994 consensus development conference on Helicobacter pylori in peptic ulcer disease was the ninety-fourth sponsored by NIH.
NIH Consensus Statements are prepared by a non advocate, non-Federal panel of experts, based on (1) presentations by investigators working in areas relevant to the consensus questions during a 2-day public session; (2) questions and statements from conference attendees during open discussion periods that are part of the public session; and (3) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government (7).
In accord with NIH guidelines, this conference was organized around several groups of people. First a planning committee was established, chaired by Dr. Tadataka Yamada, Chair of the Department of Internal Medicine at the University of Michigan. The planning committee chair is required to be a knowledgeable and prestigious medical figure who is not identified with strong advocacy of the conference topic or with relevant research. The fifteen other members of the planning committee included researchers who were by then advocates of the bacterial theory of ulcers, including Martin Blaser, David Graham, and Barry Marshall, but it also included experts on digestive diseases who were not so directly involved. The consensus development panel consisted of fourteen people chosen for various kinds of expertise who were specifically not identified with advocacy or promotional positions with respect to the issues to be resolved by the conference.
Presentations to the panel were made by twenty-two researchers who were advocates for and against the claim that H. pylori are a causal factor in peptic ulcers. Martin Blaser, David Graham, and Barry Marshall were among those who argued for that claim, but more skeptical presentations had such titles as "Limitations of the Helicobacter pylori hypothesis" and "Current uncertainties about the impact of Helicobacter pylori on the complications of peptic ulcer disease." By 1994, however, the case for bacterial involvement in ulcers was strong, and most of the speakers at the consensus conference supported it. On February 9, 1994, the panel presented its statement concluding that ulcer patients with H. pylori infection require treatment with antimicrobial agents. This statement was later published in the widely read Journal of the American Medical Association (National Institutes of Health Consensus Development Panel, 1994).
The NIH panel was a formal version of a process that often happens informally in science, when relatively disinterested researchers can constitute a kind of jury for settling scientific controversies. For example, Kim (1994) describes how medical personnel provided a kind of neutral jury to evaluate disputes early in this century concerning the plausibility of Mendelian genetics, which had both advocates and critics. Similarly, the hypothesis proposed in 1980 that dinosaur extinction was caused by an asteroid striking the earth had vehement advocates and critics; but there were also many informed members of the scientific community who were not directly involved in the controversy and who were sufficiently well informed to provide objective assessment of the evidence. Science benefits both from diversity of approaches, when some researchers pursue new ideas even when there is limited empirical support for them, and from the social process by which researchers with no stake in or against those ideas provide an informed evaluation of them.
The 1994 NIH conference was only one of the social mechanisms that encouraged increased acceptance of the bacterial theory of ulcers. Some researchers and physicians learned about the emerging evidence for the theory from conferences, journals, and personal contacts. Consensus is by no means universal: John Graham (1995) rejects the claim that H. pylori has been shown to be the primary cause of peptic ulcers. As of 1996, many physicians are still treating patients with antacids instead of antibiotics.
Warren and Marshall's initial collaboration took place at the Royal Perth Hospital, where Warren was a pathologist and Marshall a trainee in internal medicine. Their early research does not cite any special funding sources, but was done with the resources of the Royal Perth and Fremantle Hospitals (Warren and Marshall 1983, Marshall and Warren 1984, Marshall et al. 1985). Subsequent larger-scale trials required greater resources, and the 1985-1987 research on eradication of H. pylori received funds from the National Health and Medical Research Council of Australia, the Royal Perth Hospital General Fund, Gist Brocades, and Pfizer (Marshall et al. 1988). After Marshall left Australia in 1986, his research was conducted at the University of Virginia Health Sciences Center. Today (1996), his World Wide Web page includes a disclaimer that indicates he consults with and accepts honoraria from Astra-Merck, Abbott, Glaxo-Wellcome, Eli-Lilley, Pfizer, Procter and Gamble and many other medical companies. In addition, he holds stock in several pharmaceutical and diagnostic companies, and has an interest in Tri-Med Specialties Inc. and Meretek, which are companies developing urea breath tests for H. pylori.
Clinical trials are very expensive, and usually require funding by pharmaceutical companies that have an interest in showing that a new drug is effective. Bradley (1993, p. 153) reports a survey that found that 89% of trials which were supported by the pharmaceutical industry had positive results in favor of a new treatment, but only 61% of trials not so supported found positive results. Because H. pylori infections can be cured with combinations of generic antibiotics in which no drug company has a proprietary interest, funding for research on this topic has been primarily obtained from other sources. Many of the early experiments on ulcers and H. pylori were done by interested researchers using funds redirected from other projects. The makers of Zantac and Tagamet, two of the most lucrative drugs ever produced, have an interest against the new treatment of ulcers which can actually eradicate the disease, but the drug companies mounted no resistance to the new theory of ulcers. Zantac and Tagamet have recently become available in the U.S. without a prescription, allowing people with gastric distress to alleviate their symptoms without consulting physicians concerning the possible presence of H. pylori infections. In the U.S., pharmaceutical companies have recently received approval for drugs that combine antacid and antibiotic treatments. These should make it easier for physicians to know what to prescribe to their ulcer patients.
In the U.S. and Canada, conservative government funding agencies were slow to appreciate the medical importance of Helicobacter pylori. The role of H. pylori in ulcers, gastric cancer, and other diseases is a socioeconomic issue as well as a medical one, since government health providers stand to save substantial amounts of money by eradicating H. pylori rather than pursuing traditional antacid treatment (O'Brien, Goeree, Mohamed, and Hunt, 1996).
While noticing the importance of social processes such as collaboration, communication, consensus, and funding to scientific research, it is important not to succumb to the slogan that science is a social construction. Proponents of that slogan tend to ignore both the psychological processes of theory construction and acceptance that I described in Thagard (forthcoming-b), and the physical processes of interaction with the world via instruments and experiments that I described in sections 1-2 of this paper. Undoubtedly interests and social networks abound in the ulcers case as in other episodes in the history of science. But explaining scientific change solely on the basis of social factors is as patently inadequate as purely logical and psychological explanations.
Latour (1988, p. 229) says that science is politics by other means. He depicts research as a Machiavellian series of trials of strength in which scientists attempt to recruit allies to vanquish their foes. A Latourian history of the bacterial theory of ulcers would ignore the cognitive processes of scientists, since Latour (1988, p. 218) says that we do not think, only write. It would also misconstrue the role of instruments and experiments, as when Latour (1988, p. 73) explains Pasteur's laboratory work by saying: "To win, we have only to bring the enemy to where we are sure we will be the stronger. A researcher like Pasteur was strongest in the laboratory." This is nonsense; microbiologists go to the laboratory because it enables them to study organisms under controlled conditions with the appropriate instruments. Of course, science does have a political side, evident in the operations of funding agencies, consensus panels, and other social operations such as Marshall's working with microbiologists in the face of opposition from many gastroenterologists. But science also has cognitive and experimental sides that must figure in explanations of scientific change.
Figure 5. Science as a complex system. Arrows indicate mutual causal influences. Reprinted from Thagard (1995).Although it has been convenient to organize this paper and its companion in terms of mind, nature, and society, we must not forget the interactions among these elements. Mind affects nature through the mental processes crucial to the use of instruments and the design of experiments, at the same time as nature affects mind by producing observations and experimental results which may or may not conform with expectations. Society affects mind through the goals and interests that motivate scientists and through the organizations and social networks that make modern science possible, at the same time as mind affects society when organizations are affected by the discoveries of individuals (8). Society affects nature through the contributions of needs, organizations, and networks to experimental research, at the same time as nature affects society when scientific organizations contribute to new discoveries arising from interactions with the world.
In accord with figure 3, my account of the emergence in the past decade and a half of major new views about the causes of ulcers has described science as a complex system. The system is simultaneously: psychological (involving individual scientists' cognitive processes for discovery and acceptance), physical (requiring scientists to interact with the natural world using instruments and experiments), and social (involving the interaction of scientists with each other). Only by attending to all these aspects of the growth of knowledge can we fully explain scientific change.
(1) For details on how the urea breath test works, see the World Wide Web page of Barry Marshall's Helicobacter Foundation: http://www.helico.com/.
(2) This paper has nine authors. See section 5 below for details of the nature of the collaboration between members of several different medical specialties.
(3) The two letters are usually cited as one publication. Goodwin and Worsley (1993, p. 3) state that the unusual format was suggested by the electron microscopist J. A. Armstrong because Warren and Marshall could not agree on the wording of a joint letter. However, according to Warren (personal communication), the letters were kept separate because the first one reflected work he had done alone; the second letter, which lists Marshall as author, described joint work. Marshall (personal communication) reports that the two-letter format was suggested by the Lancet editor who thought that an original single letter was too long.
(4) The ninth researcher, Michael Phillips, is listed as being at Curtin University in Perth.
(5) In the terminology of social network analysis, collaboration can be understood as a kind of affiliation network, and figure 1 can be interpreted as a hypergraph (Wasserman and Faust, 1994). A much more complicated graph would be needed to display all of the relevant collaborations.
(6) See Marshall's World Wide Web page: http://www.vianet.net.au/~bjmrshll/.
(7) Source: Web page: http://text.nlm.nih.gov/nih/upload-v3/About/about.html.
(8) One aspect of mind that I have neglected in these papers is personality. Personal characteristics such as aggressiveness, tenacity, and conservatism were undoubtedly of some importance in the roles that different researchers played. This case does not support the claim that scientific change is primarily supported by later borns, since Warren and Marshall are both eldest children.
Bradbury, S. (1968). The microscope past and present. Oxford: Pergamon.
Bradley, G. W. (1993). Disease, diagnosis, and decisions. Chichester: John Wiley & Sons.
Bulloch, W. (1979). The history of bacteriology. New York: Dover.
Cutler, A. F., Havstad, S., Ma, C. K., Blaser, M. J., Perez-perez, G. I., & Schubert, T. T. (1995). Accuracy of invasive and noninvasive tests to diagnose Helicobacter pylori infection. Gastroenterology, 109, 136-141.
Dobell, C. (1958). Antony von Leeuwenhoek and his 'little animals'. New York`: Russell & Russell.
EUROGAST Study Group (1993). An international association between Helicobacter pylori infection and gastric cancer. Lancet, 341(8857), 1359-1362.
Forbes, G. M., Glaser, M. E., Cullen, D. J. E., Warren, J. R., Christianson, K. J., & Marshall, B. J. (1994). Duodenal ulcer treated with Helicobacter pylori eradication: Seven year follow-up. Lancet, 342, 258-260.
Galison, P. (1987). How experiments end. Chicago: University of Chicago Press.
Gooding, D. (1990). Experiment and the nature of meaning. Dordrecht: Kluwer.
Goodwin, C. S., & Worsley, B. W. (1993). The Helicobacter genus: The history of H. pylori and taxonomy of current species. In C. S. Goodwin & B. W. Worsley (Eds.), Helicobacter pylori: Biology and clinical practice (pp. 1-13). Boca Raton: CRC Press.
Graham, D. Y. (1993). Treatment of peptic ulcers caused by Helicobacter pylori. New England Journal of Medicine, 328, 349-350.
Graham, J. R. (1995). Helicobacter pylori: Human pathogen or simply an opportunist? Lancet, 345, 1095-1097.
Graham, D. Y., Klein, P. D., & Evans, D. J. e. a. (1987). Campylobacter pylori detected non-invasively with the 13C-urea. Lancet, 1, 1174-1177.
Graham, D. Y., Lew, G. M., Klein, P. D., Evans, D. G., Evans, D. J., Saeed, Z. A., & Malaty, H. M. (1992). Effect of treatment of Helicobacter pylori infection on long-term recurrence of gastric or duodenal ulcer: A randomized, controlled study. Annals of Internal Medicine, 116, 705-708.
Hacking, I. (1983). Representing and intervening. Cambridge: Cambridge University Press.
Hennekens, C. H., & Buring, J. E. (1987). Epidemiology in medicine. Boston: Little, Brown.
Hirschowitz, B. I. (1993). Development and application of endoscopy. Gastroenterology, 104, 337-342.
Hopkins, H. H., & Kapany, N. S. (1954). A flexible fiberscope using static scanning. Nature, 173, 39-41.
Kim, K. (1994). Explaining scientific consensus: The case of Mendelian genetics. New York: Guilford.
Kuhn, T. (1970). Structure of scientific revolutions (2 ed.). Chicago: University of Chicago Press.
Latour, B. (1988). The pasteurization of France (Sheridan, A. and Law, J., Trans.). Cambridge, MA: Harvard University Press.
Marshall, B. J. (1989). History of the discovery of C. pylori. In M. J. Blaser (Eds.), Campylobacter pylori in gastritis and peptic ulcer disease (pp. 7-22). New York: Igaku-Shoin.
Marshall, B. J., Armstrong, J. A., McGechie, D. B., & Clancy, R. J. (1985). Attempt to fulfil Koch's postulates for pyloric campbylobacter. Medical Journal of Australia, 142, 436-439.
Marshall, B. J., Goodwin, C. S., Warren, J. R., Murray, R., Blincow, E. D., Blackbourn, S. J., Phillips, M., Waters, T. E., & Sanderson, C. R. (1988). Prospective double-blind trial of duodenal ulcer relapse after eradication of campylobacter pylori. Lancet, 2(8626/8627), 1437-1441.
Marshall, B. J., Plankey, M. W., Hoffman, S. R., Boyd, C. L., Dye, K. R., Frierson, H. f., Guerrant, R. L., & McCallum, R. W. (1991). A 20-minute breath test for Helicobacter pylori. American Journal of Gastroenterology, 86, 438-445.
Marshall, B. J., & Warren, J. R. (1984). Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet, 1(8390), 1311-1315.
National Institutes of Health Consensus Development Panel (1994). Helicobacter pylori in peptic ulcer disease. Journal of the American Medical Association, 272, 65-69.
O'Brien, B., Goeree, R., Mohamed, H., & Hunt, R. (1996). Cost-effectiveness of Helicobacter pylori eradication for the long-term management of duodenal ulcer in Canada. Archives of Internal Medicine, 155, 1958-1964.
Olbe, L., Hamlet, A., Dalenbäck, J., & Fändriks, L. (1996). A mechanism by which Helicobacter pylori infection of the antrum contributes to the development of duodenal ulcer. Gastroenterology, 110, 1386-1394.
Steer, H. W., & Colin-Jones, D. G. (1975). Mucosal changes in gastric ulceration and their response to carbenoxolone sodium. Gut, 16, 590-597.
Thagard, P. (1988). Computational philosophy of science. Cambridge, MA: MIT Press/Bradford Books.
Thagard, P. (1995). Explaining scientific change: Integrating the cognitive and the social. In D. Hull, M. Forbes, & R. Burian (Eds.), PSA 1994, vol. 2 (pp. 298-303). East Lansing, MI: Philosophy of Science Association.
Thagard, P. (forthcoming-a). Collaborative knowledge. Noûs.
Thagard, P. (forthcoming-b). Ulcers and bacteria I: Discovery and acceptance.
van Fraassen, B. (1980). The scientific image. Oxford: Clarendon Press.
Warren, J. R., & Marshall, B. J. (1983). Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet(8336), 1273-1275.
Wasserman, S., & Faust, K. (1994). Social network analysis: Methods and applications. Cambridge: Cambridge University Press.
Woolgar, S. (1988). Science: The very idea. Chichester, Sussex: Ellis Horwood. EUROGAST Study Group (1993). An international association between Helicobacter pylori infection and gastric cancer. Lancet, 341(8857), 1359-1362.