| || ||Of Rice and Men:
One of the most important--and exciting--elements in guiding students through a historical scenario or case study is "not knowing the right answer"--that is, sharing a position of uncertainty with both students and the historical characters. How does a scientist reason, using only the materials and knowledge at hand? Further, how does one ensure the reliablity or certainty of a prospective answer? This is the crux of science. Student inquiry often leads them to ask for more information and the teacher equipped with a deeper perspective is better prepared to guide them. The additional information below addresses these pedagogical demands, while also allowing the teacher to extend discussion, once students have found what they consider to be good solutions to the questions in the text.
THINKing about Causes of DiseasesIn 1880-81, following one outbreak of beriberi, a doctor in the Japanese Navy (Takaki) collected data about the patients' clothing, living quarters, diet, occupation, economic status, and geographical region, and about seasonal frequency, hoping to find clues. Each, in a sense represented a hypothesis, in the form of a question, about what might have been a causal factor. Indeed, his methods largely reflect epidemiological methods today. Takaki found that:
In the late 1800s various reseachers, both Asians and Europeans working in Asia, explained the cause of beriberi differently. Some insisted that beriberi was not a specific disease at all, but a combination of other known diseases. Others claimed it was a form of poisoning. They disagreed about which toxin was responsible, however. Was it arsenic, oxalate, carbon dioxide, or some compound produced by a microorganism? Later, some viewed beriberi as an infection--but they disagreed whether a protozoan, a tiny worm, or a bacterium was responsible. Another blamed moldy rice. Yet other researchers implicated diet. But while some concluded that beriberi was due to a deficiency of fats, others thought it was phosphorus or proteins. For one researcher it was insufficient nitrogen, for another an improper balance of nitrogen among foods eaten. How does the scientist determine which of these many reported ideas to trust?
THINKing about ChickensThis is an ideal opportunity to introduce and discuss the role of animal models in studying human diseases. Some organisms are appropriate, others are not: why? For example, Eijkman eventually encountered many problems trying to persuade his peers that "chicken polyneuritis" was equivalent to human beriberi.
The applicability of animal models can also vary from disease to disease. The lack of suitable animals for studying HIV and AIDS, for example, has greatly shaped research on this disease.
THINKing about Unexpected CuresThis and the previous "accidental" discovery are excellent occasions to discuss the role of "chance" in science. Students may consider what features are necessary to "notice" chance events as significant. Louis Pasteur, for example, is noted for suggesting that "chance favors only the prepared mind." Molecular biologist Max Delbrück coined "the principle of limited sloppiness," suggesting that laboratories should operate with enough informality that careless errors "chance" events were likely to surface occasionally. happen. This was certainly true of Alexander Fleming's habits--and certainly contributed to his famous findings about penicillin. The series of chance events in Eijkman's case also shows how difficult it can be to proceed without any obvious clues, previous theories, or "working hypothesis."
THINKing about Eijkman's Interpretation of Chicken DietMany researchers failed to accept Eijkman's conclusions because they refused to believe that the disease in chickens was the same as the human disease beriberi. Eijkman then characterized the disease more fully. He examined the chickens' tissues and noted the same degeneration of the nerves that the medical commission had identified in human beriberi. Eijkman also tried to show the connection by transferring the disease from humans to chickens with injections of blood or other body fluids from beriberi patients--but with no luck. Nor was he able to transfer the disease directly from one chicken to another. Eijkman reasoned that the microorganism did not enter the blood itself. Instead, it might remain in the intestine where it would produce a toxin from something in the rice grain, perhaps starch. The toxin, rather than the microorganism, would then enter the body and poison the nerve cells.
Students have suggested other plausible hypotheses. For example, the milling (polishing) of the rice may have been unhygienic and introduced a "germ" into the starchy white rice, whereas unmilled rice would remain germ-free.
THINKing about Vorderman's StatisticsEach part of the supplemental investigation represents a variable that Vorderman wished to rule out as a possible cause. The Eijkman/Vorderman study is classic in exhibiting the idea of a controlled study--not "controlling" the variables in the lab, but comparing two parallels sets of data that each differing by a single variable.
THINKing about Vorderman's ResultsVorderman's results addressed many objections about the relationship of chicken polyneuritis to human beriberi. Once the results became widely known in the early 1900s, more research began to focus on rice in the diet. Large-scale studies, like Vorderman's, continued through 1912--in each case confirming the findings on rice. Between 1905 and 1910 major institutions--armies, navies, prisons, insane asylums, and leper colonies(!)--finally began to change their primarily white-rice diets.
Nevertheless, as noted in the text, several researchers also continued to search for the bacterium responsible for something in the rice.
THINKing about Communicating Eijkman's FindingsThis case underscores the importance of communication among members of a scientific community. Journals, of course, are the primary channels for formally reporting results. Most journals in the late 1800s were European and even the work of researchers from colonial powers working in Southeast Asia were typically published in these European journals. In addition, Eijkman chose to publish his article in his native Dutch--hardly a language used universally, even at the time.
Students might imagine the various forms by which scientists communicate today (e-mail, telephone, correspondence, local and international conferences) and contrast these with what was available in Eijkman's era. This can highlight further the general cultural and technological contexts of science on a "mundane," but clearly influential level.
THINKing about Bacterial Causes and Burden of ProofAs suggested in the question, this case is an excellent occasion to discussion asymmetries in experimental reasoning and the corresponding notion of the "burden of proof." Philosopher Karl Popper is widely known among scientists for his idea of falsification: that we can never logically prove a theory in all cases, but that we can rule it out based on a single counterexample or "falsifying" instance. This may be true logically, but the beriberi case demonstrates the additional experimental dimensions of the problem: how does one know that one has a definitive falsifying instance? If one is searching for an unknown (of unknown properties--and hence, hard to find or identify), for example, how exhaustive must one make the search?
In some cases, by contrast, single specimens or events have been influential scientifically ("golden events" in particle physics; fossils; phylogentically unprecedented animals). In these cases, an individual piece of evidence can demonstrate the plausibility of a previously "improbable" hypothesis or "prove" the existence of an important class of previously unknown phenomena. Both cases--falsification and demonstration--raise the question of expectations, null hypotheses, and burden of proof. This can be especially important in cases of social decision-making under scientific uncertainty.
THINKing about Decision-Making in Scientific and Policy ContextsThe first decision underscores that scientists do not have unlimited resources for pursuing various investigations. Scientists must make choices about which problems to pursue or which hypotheses to test. Further, they must make these choices without the advantage of hindsight--that is, they cannot know which path is the "right" path to pursue in advance. The beriberi case illustrates that a scientific community, through its diversity, might be able to "hedge it bets," by pursuing several different lines of investigation simultaneously. If so, then disagreement in a scientific community may be a productive force, rather than a sign of weakness.
The second decision highlights how public policy must often be decided in contexts of scientific uncertainty. Scientists may have the luxury of witholding judgment; public policy-makers, generally, cannot "wait and see." They have many factors to consider and, therefore, may not always follow the "weight of the scientific evidence." They may need to consider equally avoiding the consequences of possible error. Such cases of uncertainty confront us today. While evidence for global warming and climate change is accumulating, for example, critics readily point out that the dire predictions rely very much on modeling and educated speculation, not "hard data." Even professional scientists disagree over interpretations of the evidence. How do we decide the best policy in the meanwhile?
THINKing about Human Subjects and Research EthicsAn obvious approach to investigate beriberi in humans is to control the diet of two groups of poeple. In fact, based on Eijkman's work, in 1906 two researchers (Fraser and Stanton) took a healthy workforce to a previously isolated area of Javanese forest. They fed one half of the workers white rice, the others a more complete diet. They continued until the workers that were fed only rice became ill with beriberi. They then switched diets between the two groups. The first group was cured, while second group became ill. Reversing the diet of the same two groups is an elegant example of the use of control. From today's perspective, there are also obvious ethical problems with Fraser and Stanton's study. What is needed to justify the design of an experiment?
One understands the ethics more clearly when one views these studies--and the whole Dutch effort to cure beriberi--from a Javanese perspective. First, why were so many prisoners available for scientific study by the Dutch? The Dutch were managing over one-quarter million prisoners on one island! In the late 1800s Java was one of the most densely populated areas in the world, with between 30 and 35 million inhabitants, yet almost 1% of the population was in prison. Vorderman's survey clearly took advantage of the Dutch colonial presence. From the local perspective, was that ethical? Should this matter to "science"? Second, one may consider the Javanese perspective on who would benefit most from a cure to beriberi. More Javanese than Dutch suffered from the disease, but because the disease took its toll on the local workforce, the Dutch Colonials certainly valued a cure for economic, not merely humanitarian reasons. They had more at stake than simply aiding the indigenous population. For example, no one had offered the Javanese the tools or resources to study the disease on their own.
For Further Thinking: Are there other cases today where availability of research funds for medicine (or other sciences) may be shaped by economic or political concerns?
THINKing about Grijns's InterpretationGrijns's notion of a deficiency rather than an active cause required a conceptual "gestalt switch"--seeing background as foreground.
For further discussion, consider how Grijns's might have interpreted Takaki's findings, if he had known about them (see above).
To pursue his alternative hypothesis, Grijns examined the ability of other starchy foods to produce "beriberi" in chickens. Diets of either tapioca root or sago (the starchy pith of a palm) could also produce the disease. Grijns also looked for other sources of the curative or missing factor. He tested each one by adding it to a chicken's diet of polished white rice. He found that several beans, notably the mongo bean, known locally as kachang-ijo, could "cure" or prevent beriberi.
THINKing about the Significance of Vorderman's StudyIt is hard to find a better example that demonstrated both the power and the limit of scientific investigation. The conclusions of a controlled experiment or controlled study are only as good as the controls investigated. Yet this does not invalidate a study in the context where the controls apply. One may contrast the dramatic decrease in beriberi throughout Asia based in changes of diet with the later discovery of thiamine itself.
THINKing about Discovery and Nobel PrizesHistorian Thomas Kuhn has argued that discovery is a fuzzy concept and that we cannot pinpoint a specific date, time, or place for most discoveries. They are not single events, but complex shifts in conceptual understanding. For example, can Eijkman be credited with discovering vitamins, if he could cure beriberi, but at first rejected the explanation of deficiency diseases? Does Hopkins earn recognition, even though he did not connect specific molecules with specific diseases, as Funk and Suzuki did? Jansen and Donath were the first to actually isolate thiamine, but would they have done so without earlier findings? Nobel Prizes tend to reinforce a common notion that science relies on genius and individuals of exceptional talent. How does the case of beriberi fit with this image of science?
Credit in science is often portrayed as a significant motivating factor, if not for research, then for publicizing findings as soon as they are publically defensible. How does the system of credit motivate scientists? What other motivations might exist? Why do we credit only the first person to publish a discovery? Are there any disdvantages to our system of credit? Should we give prizes or awards in science? --If so, on what basis?
THINKing about "the" Cause of BeriberiHere, causes seem to operate on at least three levels simultaneously. This challenges many conventional notions of causality as single, linear and deterministic--proceeding in billiard-ball-like fashion, from one cause to the next.
Reductionistic thinking further leads us to consider the lack of vitamin B1 as "the" cause of beriberi. Yet many were able to cure beriberi using Eijkman's (erroneous?) conclusions, long before anyone understood the concept of a vitamin. Why might we tend to privilege one explanation over another?
Link to main case study.
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