René Dubos, the Autochthonous Flora, and the Discovery of the Microbiome.

Now characterised by high-throughput sequencing methods that enable the study of microbes without lab culture, the human "microbiome" (the microbial flora of the body) is said to have revolutionary implications for biology and medicine. According to many experts, we must now understand ourselves as "holobionts" like lichen or coral, multispecies superorganisms that consist of animal and symbiotic microbes in combination, because normal physiological function depends on them. Here I explore the 1960s research of biologist René Dubos, a forerunner figure mentioned in some historical accounts of the microbiome, and argue that he arrived at the superorganism concept 40 years before the Human Microbiome Project. This raises the question of why his contribution was not hailed as revolutionary at the time and why Dubos is not remembered for it.

The Rise and Fall of the Neurotic Housewife: Patient Sex in Psychotropic Drug Advertising to Physicians 1946-1990.

Previous studies have demonstrated a sex bias when it comes to the portrayal of men and women in medical journal advertisements for prescription drugs for psychiatric conditions. However, these studies have typically looked at ads over a restricted time period and often for a single diagnosis. Here we focus on ads for 3 diagnoses - anxiety, depression, and a combination of anxiety and depression - and cover nearly half a century to examine how the portrayal of patients changed over that time period with respect to sex. We sampled ads for products treating anxiety, depression, and anxiety/depression published in the Journal of the American Medical Association between 1946 and 1990. Our findings confirm other studies showing a marked preponderance of female patient representation during the 1960s in psychotropic drug advertising. However, we also show that from the mid-1970s to the mid-1980s, the proportion of ads for drugs featuring depression and/or anxiety indications depicted male patients significantly more than prior years in which females predominated, demonstrating advertisers' reaction to the critique of gender stereotyping.

Downsizing obesity: On Ancel Keys, the origins of BMI, and the neglect of excess weight as a health hazard in the United States from the 1950s to 1970s.

In 1972 Body Mass Index, BMI was put forth by physiologist Ancel Keys in his analysis of Seven Countries Study heart disease epidemiological data as the best available measure of obesity. This work culminated more than 20 years of effort by Keys to discredit the accepted measure of obesity, weight relative to height, along with a major public health campaign in the United States to fight heart disease through weight control. Here, I retrace his campaign to replace weight as a measure of obesity and analyze its methodology and relationship to the broader research field of heart disease epidemiology. I also explore why the epidemiological community accepted BMI despite Keys's failure to demonstrate that either it or adiposity (body fat content), were superior as predictors of heart disease-one of the Seven Countries Study's central aims.

Group Weight Loss and Multiple Screening: A Tale of Two Heart Disease Programs in Postwar American Public Health.

In the late 1940s, amid elevated concern about heart disease and new funding to fight it, multiple screening emerged alongside group psychotherapy for weight loss as two innovative responses of the American public health community. I describe the early trajectory and fate in the 1950s of both programs as shaped by the ongoing political controversy about national health insurance. Group weight loss became the main de facto American response to a perceived obesity-driven heart disease crisis. The episode casts light on the larger picture of how postwar American public health gravitated toward interventions centered on individual behavior and may offer lessons for obesity interventions today.

History full circle: 'Novel' sympathomimetics in supplements.

Since the banning of ephedrine in over-the-counter nutritional supplements a decade ago, a plethora of untested and/or unsafe sympathomimetic stimulants have taken its place. This paper argues that these 'novel' stimulants in supplements recapitulate the work of synthetic chemists at commercial pharmaceutical firms during the 1930s and 1940s, all seeking substitutes for recently successful products based on ephedrine and amphetamine. Copyright © 2015 John Wiley & Sons, Ltd.

Amphetamine-Type Stimulants: The Early History of Their Medical and Non-Medical Uses.

Amphetamine was discovered as a drug in the late 1920s, and its pharmacological effects on attention and cognition, emotions, and appetite were explored thoroughly in the 1930s and 1940s. By the late 1940s, it had achieved medical and market success as an antidepressant and was quickly gaining such success as a diet medication. In contrast, both careful testing and extensive military experience had left the impression that the drugs' benefits for attention and cognition were more subjective than real and that any objective benefits were explained mainly by the drug's mood-elevating effects. Because of its unpatentable status, methamphetamine had been introduced for all the same uses by drug firms competing with the holder of the amphetamine patent. The drugs were being widely used nonmedically and their abuse potential was becoming recognized by medicine, eventually leading to their strict control internationally around 1970.

Stigma and the addiction paradigm for obesity: lessons from 1950s America.

AIMS: To discuss an historical episode in which obesity was conceptualized as an addictive disorder and declared to be a major epidemic in the early postwar United States. This history illuminates past consequences of framing obesity as an addiction in ways that may inform constructive policy responses today. METHODS: Review of secondary and primary sources, including archival documents, relating to obesity in biomedical and popular thought of the 1940s and 1950s. RESULTS: In the United States in the late 1940s and 1950s, new medical thinking about obesity reinterpreted overweight and obesity as chiefly the consequence of addiction (understood in the then dominant psychodynamic theory as a psychological defect, oral fixation). This new conception was rapidly taken up in popular discourse and clinical practice, with adverse effects through amplification of weight stigma. Further, in the conservative political context, the addiction concept contributed to an ineffective policy response to the alarming new epidemiological evidence about obesity's consequences. Despite a lack of evidence for efficacy of the intervention, public health efforts focused on correcting individual eating behaviour among obese people by encouraging self-help in lay groups modelled, in part, on Alcoholics Anonymous. Population-level intervention was neglected. CONCLUSIONS: Current public health policy initiatives must be mindful of the risks of reframing obesity as an addiction. These include inadvertently reinforcing stigma, narrowing responses to those aiming to modify individual behaviour and biology and neglecting population policies aiming to reduce the consumption of energy-dense foods, as all occurred in the 1950s United States.

On slicing an obvious salami thinly: science, patent case law, and the fate of the early biotech sector in the making of EPO.

This essay reconstructs in previously unavailable detail the 1980s race to clone and market what would be biotechnology's most important product to date, erythropoietin or EPO. The scientific contest continued into the U.S. courts, which were charged with deciding competing patent claims to the natural substance as a drug. Through case law in the new domain of recombinant DNA, the courts imposed a de facto policy that shaped the business and scientific environment of small biotechnology firms so as to narrow research efforts and assimilate the sector to the established pharmaceutical industry. However, alternative dispensations in patent law were possible at the time, and the public's interest might have been better served.

Weight stigma, addiction, science, and the medication of fatness in mid-twentieth century America.

Obesity and overweight are today recognised as subject to harmful stigma. Through an analysis of discussions of obesity in major American newspapers, the medical literature, and pharmaceutical advertising in the 1930s, 1940s and 1950s, I document a significant shift in medical thinking about overweight and obesity based in psychiatry, and explore the relationship of that shift to changes in popular understandings of fatness after the Second World War. I argue that the psychiatrically-oriented postwar medical thinking about obesity was more stigmatising as compared with the endocrinologically-oriented thinking of the interwar period, in that the newer biomedical theory linked fatness to the already stigmatised condition of addiction and authorised attribution of moral blame to the fat. I further argue that the pharmaceutical industry cannot be assigned the lead role in medicalisation in this period that some authors attributed to it. These events cast doubt on the received view of fatness as subject to decreasing stigma and increasing medicalisation over the course of the twentieth century, and call for exploration of the social factors influencing specific forms of medicalisation.

Medical science and the military: the Allies' use of amphetamine during World War II.

Although amphetamine was thoroughly tested by leading scientists for its effects in boosting or maintaining physical and mental performance in fatigued subjects, the results never provided solid grounds for approving the drug's use, and, in any case, came too late to be decisive. The grounds on which amphetamine was actually adopted by both British and American militaries had less to do with the science of fatigue than with the drug's mood-altering effects, as judged by military men. It increased confidence and aggression, and elevated "morale."

Association of trial registration with the results and conclusions of published trials of new oncology drugs.

BACKGROUND: Registration of clinical trials has been introduced largely to reduce bias toward statistically significant results in the trial literature. Doubts remain about whether advance registration alone is an adequate measure to reduce selective publication, selective outcome reporting, and biased design. One of the first areas of medicine in which registration was widely adopted was oncology, although the bulk of registered oncology trials remain unpublished. The net influence of registration on the literature remains untested. This study compares the prevalence of favorable results and conclusions among published reports of registered and unregistered randomized controlled trials of new oncology drugs. METHODS: We conducted a cross-sectional study of published original research articles reporting clinical trials evaluating the efficacy of drugs newly approved for antimalignancy indications by the United States Food and Drug Administration (FDA) from 2000 through 2005. Drugs receiving first-time approval for indications in oncology were identified using the FDA web site and Thomson Centerwatch. Relevant trial reports were identified using PubMed and the Cochrane Library. Evidence of advance trial registration was obtained by a search of clinicaltrials.gov, WHO, ISRCTN, NCI-PDQ trial databases and corporate trial registries, as well as articles themselves. Data on blinding, results for primary outcomes, and author conclusions were extracted independently by two coders. Univariate and multivariate logistic regression identified associations between favorable results and conclusions and independent variables including advance registration, study design characteristics, and industry sponsorship. RESULTS: Of 137 original research reports from 115 distinct randomized trials assessing 25 newly approved drugs for treating cancer, the 54 publications describing data from trials registered prior to publication were as likely to report statistically significant efficacy results and reach conclusions favoring the test drug (for results, OR = 1.77; 95% CI = 0.87 to 3.61) as reports of trials not registered in advance. In multivariate analysis, reports of prior registered trials were again as likely to favor the test drug (OR = 1.29; 95% CI = 0.54 to 3.08); large sample sizes and surrogate outcome measures were statistically significant predictors of favorable efficacy results at p < 0.05. Subgroup analysis of the main reports from each trial (n = 115) similarly indicated that registered trials were as likely to report results favoring the test drug as trials not registered in advance (OR = 1.11; 95% CI = 0.44 to 2.80), and also that large trials and trials with nonstringent blinding were significantly more likely to report results favoring the test drug. CONCLUSIONS: Trial registration alone, without a requirement for full reporting of research results, does not appear to reduce a bias toward results and conclusions favoring new drugs in the clinical trials literature. Our findings support the inclusion of full results reporting in trial registers, as well as protocols to allow assessment of whether results have been completely reported.

America's first amphetamine epidemic 1929-1971: a quantitative and qualitative retrospective with implications for the present.

Using historical research that draws on new primary sources, I review the causes and course of the first, mainly iatrogenic amphetamine epidemic in the United States from the 1940s through the 1960s. Retrospective epidemiology indicates that the absolute prevalence of both nonmedical stimulant use and stimulant dependence or abuse have reached nearly the same levels today as at the epidemic's peak around 1969. Further parallels between epidemics past and present, including evidence that consumption of prescribed amphetamines has also reached the same absolute levels today as at the original epidemic's peak, suggest that stricter limits on pharmaceutical stimulants must be considered in any efforts to reduce amphetamine abuse today.

The drug industry and clinical research in interwar America: three types of physician collaborator.

This essay describes collaborations between American pharmaceutical companies and clinical investigators, mainly in academic medical centers and other research institutions, during the interwar period. I argue that efforts on the part of early twentieth-century "scientific medicine" reformers to impose higher standards on the testing and promotion of pharmaceuticals led both to the intended disciplining of the drug industry and also, as a reciprocal but unintended consequence, to a deep involvement with industry among medical scientists. Three basic patterns of collaboration between clinical trialists and sponsoring drugs firms are described. These patterns may help illuminate the mutual accommodation between ethical drug firms and academic clinical researchers (and institutions) that still prevails today.

The moral economy of the drug company-medical scientist collaboration in interwar America.

This paper explores the exchange relationships underlying collaborations between pharmaceutical companies and preclinical (laboratory-based) researchers, in universities and similar contexts, during the interwar period. It also examines the arguments advanced to justify such collaborations in particular contexts as a way of investigating the perceived costs and benefits, especially among the academic parties in these collaborations, and the way these collaborations were regarded in the US biomedical research community.