Robert Earle Buchanan: an unappreciated scientist

Robert Earle Buchanan (1883-1973), 19th President of the Society of American Bacteriologists (later American Society for Microbiology), was one of the more important 20th century microbiologists. He was a dominant force in creating the field of bacterial systematics and made significant contributions to microbial physiology. He also numbered a number of influential textbooks. A reasonable conclusion is that Buchanan was a major cultivator of modern microbiology. To justify that assertion, I have four major objectives in this essay: i) a brief biographical review of Buchanan's early life; ii) a brief review of his scientific contributions, many of which go beyond his recognized contributions to bacterial systematics; iii) Buchanan was an important academic administrator who created the microbiology program and fostered a strong graduate education program at Iowa State, iv)finally, I close the essay with a focus on Buchanan's "moral character."     

Fisher's contributions to genetics and heredity, with special emphasis on the Gregor Mendel controversy

R. A. Fisher is widely respected for his contributions to both statistics and genetics. For instance, his 1930 text on The Genetical Theory of Natural Selection remains a watershed contribution in that area. Fisher's subsequent research led him to study the work of (Johann) Gregor Mendel, the 19th century monk who first developed the basic principles of heredity with experiments on garden peas. In examining Mendel's original 1865 article, Fisher noted that the conformity between Mendel's reported and proposed (theoretical) ratios of segregating individuals was unusually good, "too good" perhaps. The resulting controversy as to whether Mendel "cooked" his data for presentation has continued to the current day. This review highlights Fisher's most salient points as regards Mendel's "too good" fit, within the context of Fisher's extensive contributions to the development of genetical and evolutionary theory.     

Stephen Angus Hutchinson, 1914–2005: an appreciation

Stephen A. Hutchinson (1914–2005), who spent most of his academic career at the University of Glasgow, served as President of the British Mycological Society in 1970, as Honorary Treasurer from 1961–85, and as a Trustee from 1967–99. A synopsis of his academic contributions and other activities is presented, along with a complete list of his publications.     

Prediction of C-to-U RNA editing sites in plant mitochondria using both biochemical and evolutionary information

Although cytidine-to-uridine conversions in plant mitochondria were discovered 18 years ago, it was still an enigmatic process. Since the sequencing projects of plant mitochondrial genomes are providing more and more available sequences, the requirements of computationally identifying C-to-U RNA editing sites are also increasing. By incorporating both evolutionary and biochemical information, we developed a novel algorithm for predicting C-to-U RNA editing sites in plant mitochondria. The algorithm has been implemented as an online service called CURE (Cytidine-to-Uridine Recognizing Editor). CURE performs better than other methods that are based on only biochemical or only evolutionary information. CURE also provides the ability of predicting C-to-U RNA editing sites in non-coding regions and the synonymous C-to-U RNA editing sites in coding regions that are impossible for other methods. Furthermore, CURE can carry out prediction directly on the entire mitochondria genome sequence. The prediction results of CURE suggest the functional importance of synonymous RNA editing sites, which was neglected before. The CURE service can be accessed at http://bioinfo.au.tsinghua.edu.cn/cure.     

Poetry, physiology, and puerperal fever: understanding the young Oliver Wendell Holmes

The 19th-century American physician Oliver Wendell Holmes (1809-1894) is known, internationally, more for his literary output than for his contributions to medical science. Yet a single paper he wrote in 1843--"The Contagiousness of Puerperal Fever"--has made him a hero in the eyes of many (especially in the United States) of the struggle against that scourge. Why that one article, written when Holmes was still in his thirties, should--even in its expanded 1855 version--so routinely be referred to as a "classic of medical literature", and why its author should have been raised on such a high pedestal that some grant him a position beside Ignác Semmelweis, are complicated questions. This present paper is an attempt to begin assessing what it is that makes someone a medical hero by looking at three different aspects of Holmes's early career. He was even as a young man a poet and a physiologist/anatomist as well as the author of this important essay. Whether and how those three features of Holmes's many-sides public persona are connected is discussed as a prelude to considering whether his work on puerperal fever legitimates his status as a medical hero.     

In memoriam: Lauri Saxén (1927-2005)

Dr. Lauri "Tupu" Saxen died last October (2005) at the age of 78. He was a physician, a scientist, a photographer, a naturalist, a great story-teller and a man who enjoyed science enormously. His name has become synonymous with the Finnish school of Developmental Biology, a school that focuses on reciprocal inductive interactions during vertebrate organogenesis. But many biologists probably don't know the full extent of his importance to the field. A few years ago, I had the occasion to outline some of his contributions which are so varied and important that it is difficult to believe that they are the work of one person, and I have included them in this brief eulogy. One could divide his scientific contributions into five categories: (1) the threshold hypothesis of amphibian metamorphosis; (2) the double-gradient hypothesis of primary embryonic induction; (3) the analysis of reciprocal induction during kidney development; (4) the integration of developmental biology with epidemiology and (5) the maintenance of a national infrastructure for science.     

A clustering-based preprocessing method for the elimination of unwanted residuals in metabolomic data

Introduction

The metabolome of a biological system is affected by multiple factors including factor of interest (e.g. metabolic perturbation due to disease) and unwanted factors or factors which are not primarily the focus of the study (e.g. batch effect, gender, and level of physical activity). Removal of these unwanted data variations is advantageous, as the unwanted variations may complicate biological interpretation of the data.

Objectives

We aim to develop a new unwanted variations elimination (UVE) method called clustering-based unwanted residuals elimination (CURE) to reduce metabolic variation caused by unwanted/hidden factors in metabolomic data.

Methods

A mean-centered metabolomic dataset can be viewed as a combination of a studied factor matrix and a residual matrix. The CURE method assumes that the residual should be normally distributed if it only contains inter-individual variation. However, if the residual forms multiple clusters in feature subspace of principal components analysis or partial least squares discriminant analysis, the residual may contain variation due to unwanted factors. This unwanted variation is removed by doing K-means data clustering and removal of means for each cluster from the residuals. The process is iterated until the residual no longer forms multiple clusters in feature subspace.

Results

Three simulated datasets and a human metabolomic dataset were used to demonstrate the performance of the proposed CURE method. CURE was found able to remove most of the variations caused by unwanted factors, while preserving inter-individual variation between samples.

Conclusion

The CURE method can effectively remove unwanted data variation, and can serve as an alternative UVE method for metabolomic data.

     

Known by the society he keeps: an interview with Robert Ruffolo

By his own admission, Robert R. Ruffolo, Head of Research and Development at Wyeth-Ayerst, is a bit of a nerd. Opting to spend seven nights per week with his textbooks at the expense of all else, he earned his pharmacy degree summa cum laude, and his PhD in pharmacology in just over three years. He speaks with unabashed enthusiasm for the pharmaceutical industry, for biomedicine, and particularly for the future of pharmacology. Even if you don't know Ruffolo, you've probably seen him-if not at a science symposium, then surely as the lead "actor" in televised promotions that ran throughout 1999 on behalf of the Pharmaceutical Research and Manufacturers of America (PhRMA; scenes reproduced here, with permission). "Actor" belongs in quotation marks, because if there is such a thing as type casting, then Ruffolo is certainly an example in the PhRMA ads: passionate about good drugs and the people who need them; proud of his profession and his contributions; dedicated to science as well as to his colleagues; and grateful for the opportunities he has had to contribute. The commercial's requisite happy ending, where three generations of a coronary-prone farm family ride off into the sunset, reflects Ruffolo's own success story in helping to bring carvedilol to market. In all of this, however, Ruffolo's sincerity transcends the hokey as well as the nerdy. His devotion to science includes a mission to help others, and he would argue that in this and most ways, he is not so different from his academic colleagues.     

Roy Walford and the immunologic theory of aging

Roy Walford died on April 27, 2004, at the age of 79. His contributions to gerontological research in such diverse areas as caloric restriction, genetics of lifespan, immunosenescence, DNA repair and replicative senescence were truly remarkable in their depth and innovation. Significantly, most of the areas that he pioneered during his illustrious research career remain the "hot" areas of current gerontological research. In this sense, he has achieved the most important type of immortality. His death was a major personal and professional loss to numerous scientists within the gerontological community. In launching this new journal on Immunity and Ageing, it is highly fitting, therefore, to remember him on the anniversary of his death by briefly reviewing the contributions of Roy Walford to this important facet of gerontology. Indeed, it was Roy who actually first coined the commonly used term "immunosenescence".     

Richard Doll and Alice Stewart: reputation and the shaping of scientific "truth"

As the world watched the Fukushima reactors release radionuclides into the ocean and atmosphere, the warnings of Dr. Alice Stewart about radiation risk and the reassurances of Sir Richard Doll assumed renewed relevance. Doll and Stewart, pioneer cancer epidemiologists who made major contributions in the 1950s-he by demonstrating the link between lung cancer and smoking, she by discovering that fetal X-rays double the chance of a childhood cancer-were locked into opposition about low-dose radiation risk. When she went public with the discovery that radiation at a fraction of the dose "known" to be dangerous could kill a child, her reputation plummeted, whereas Doll, foremost among her detractors, was knighted and lauded as "the world's most distinguished medical epidemiologist" for his work. Their lives and careers, so closely intertwined, took contrary courses, he becoming "more of the establishment" (as he said), while she became more oppositional. When it was discovered, after his death, that he'd been taking large sums of money from industries whose chemicals he was clearing of cancer risk, his reputation remained unscathed; it is now enshrined in the "Authorized Biography" (2009) commissioned by the Wellcome Institute, along with Doll's denigration of Stewart as an "embittered" woman and biased scientist. Stewart lived long enough to see radiation science move her way, to see international committees affirm, in the 1990s, that there is no threshold beneath which radiation ceases to be dangerous; recent evidence from Chernobyl is bearing out her warnings. But a look at the making and breaking of these reputations reveals the power of status, position, and image to shape scientific "knowledge" and social policy.     

Extranodal natural killer/T-cell lymphoma involving the gastrointestinal tract: analysis of clinical features and outcomes from the Asia Lymphoma study group

Background

The gastrointestinal (GI) tract is one of the most common extranasal sites in extranodal NK/T-cell lymphoma (ENKTL). However, data regarding ENKTL involving the GI tract are relatively scarce. Thus, we performed a multicenter, multinational retrospective study to analyze clinical features and treatment outcomes of ENKTL involving the GI tract.

Patients and methods

Patients with ENKTL involving the GI tract diagnosed in twelve participating centers between 1991 and 2012 were retrospectively analyzed from five Asian countries.

Results

The analysis of 81 patients with ENKTL involving the GI tract revealed that more than 60% of patients presented as advanced disease with B symptoms. 55 patients (68%) had GI manifestations including abdominal pain (n = 26, 32%), GI tract bleeding (n = 17, 21%) and bowel perforation (n = 12, 15%). The most common GI site was the small intestine, including the jejunum and ileum (n = 57, 70.3%). There were 34 patients (42%) who received systemic chemotherapy while 33 patients (41%) underwent surgery plus chemotherapy. However, 35 patients (43%) died due to disease progression, and treatment-related mortality including sepsis occurred in 17 patients (21%). Thus, the median overall survival was 7.8 months (95% Confidence interval: 3.9 – 11.7 months). Patients who could undergo surgery plus chemotherapy showed a trend of better survival than those treated with chemotherapy alone.

Conclusion

Overall, the data indicated that ENKTL involving the GI tract has a dismal prognosis despite active treatment including chemotherapy and surgery. Thus, more effective treatment strategies are required for this disease entity.

     

Influence of sex hormones on the chick gastrointestinal transit and emptying

• 1.1. Gastrointestinal (GI) transit and emptying of male and female 15-day-old chickens treated with testosterone, estradiol and progesterone was measured by means of ¹⁴C-polyethylene glycol-4000.
• 2.2. All the administered sex hormones increased GI motility at the shortest time (0.5 and 1 hr) after the marker administration, but decreased GI motility at the longest times (2 and 4 hr). This motor pattern agrees with the known anabolic role of sex hormones.
• 3.3. We conclude that testosterone and estradiol increased GI motility and intestinal inhibitory reflexes. Thus, chicks' and mammals' GI motility were modified by testosterone and estradiol in a similar form.
• 4.4. The effect of progesterone on the chick GI motility was contrary to that observed in mammals. This may happen because of increased inhibitory GI motor reflexes or direct inhibition of visceral smooth muscle activity.
• 5.5. No statistical differences were observed between the sexes, which could be explained by the sexual immaturity of chicks.
• 6.6. Chicks constitute good biological material to study the influence of sex hormones on avian GI motility.

     

W. Montague Cobb (1904–1990): Physical Anthropologist, Anatomist, and Activist

William Montague Cobb's life and work reflect a profound integration of art, literature, social activism, and science. This article presents some of the highlights of his academic development and professional contributions. We have considered his early academic development within the contexts of the formative years of American physical anthropology, Howard University Medical School, and the social issues in American society that influenced Cobb. His approaches to teaching, anatomical and anthropological research, and medicine are unique, and yet are closely reasoned and creative reflections of the major currents of academe and the broader society with which he dealt. Imbued with a sense of social responsibility, Cobb's applied anthropology involved the accumulation of extensive data on the one hand, and the formation of organizations for social activism on the other. It was directed toward solving problems of health care and racism. His work thereby served to balance the widespread distortion and neglect of medical and racial problems facing A fro-America between 1930 and the present day. He was also a principal builder of black medical and scientific institutions, and he preserved the record of his coworkers' contributions through his many biographies. This work represents no more than a sketch of his rich and prolific career (during which he produced more than 1,100 publications); the emphasis of this biographical study has been to ascertain the circumstances and attitudes that helped mold the first Afro-American Ph.D. in physical anthropology.     

R.A. Fisher's contributions to genetical statistics

R. A. Fisher (1890-1962) was a professor of genetics, and many of his statistical innovations found expression in the development of methodology in statistical genetics. However, whereas his contributions in mathematical statistics are easily identified, in population genetics he shares his preeminence with Sewall Wright (1889-1988) and J. B. S. Haldane (1892-1965). This paper traces some of Fisher's major contributions to the foundations of statistical genetics, and his interactions with Wright and with Haldane which contributed to the development of the subject. With modern technology, both statistical methodology and genetic data are changing. Nonetheless much of Fisher's work remains relevant, and may even serve as a foundation for future research in the statistical analysis of DNA data. For Fisher's work reflects his view of the role of statistics in scientific inference, expressed in 1949: There is no wide or urgent demand for people who will define methods of proof in set theory in the name of improving mathematical statistics. There is a widespread and urgent demand for mathematicians who understand that branch of mathematics known as theoretical statistics, but who are capable also of recognising situations in the real world to which such mathematics is applicable. In recognising features of the real world to which his models and analyses should be applicable, Fisher laid a lasting foundation for statistical inference in genetic analyses.     

Common to both academia and industry: the challenge of discovery. An interview with Perry Molinoff

Perry Molinoff recognizes the distinctions between basic and applied science, between academic and industrial research, and between the preclinical and clinical realities of drug development. But he generally discusses these categories in fluid, practical terms, having throughout his career crossed the lines of distinction that have sometimes been rather heavily drawn among pharmacologists. As a third-year medical student at Harvard, he decided "to take a year off" to conduct laboratory research. After receiving his MD and pursuing further clinical and postdoctoral work, he enjoyed an academic career that included fourteen years as the A.N. Richards Professor and Chair of Pharmacology at the University of Pennsylvania School of Medicine. He has just completed six years as Vice President of Neuroscience and Genitourinary Drug Discovery for Bristol-Myers Squibb and will soon return to teaching, in the Departments of Psychiatry and Pharmacology at Yale University. Referring to himself as either pharmacologist or neuroscientist, depending on context, he has made fundamental discoveries in receptor biology, has overseen the discovery and development of drugs and their subsequent clinical trials, and has mentored a host of pharmacologists and neuroscientists who themselves have established careers in industry and academia. The pursuit of discovery as its own reward emerges as a theme that has marked his professional life (and is perhaps reflected also in the images displayed in his office of the Himalayan mountains, photographed by Molinoff himself from the Everest base camp last year).     

Rupert Riedl and the re-synthesis of evolutionary and developmental biology: body plans and evolvability

This paper reviews the scientific career of Rupert Riedl and his contributions to evolutionary biology. Rupert Riedl, a native of Vienna, Austria, began his career as a marine biologist who made important contributions to the systematics and anatomy of major invertebrate groups, as well as to marine ecology. When he assumed a professorship at the University of North Carolina in 1968, the predominant thinking in evolutionary biology focused on population genetics, to the virtual exclusion of most of the rest of biology. In this atmosphere Riedl developed his "systems theory" of evolution, which emphasizes the role of functional and developmental integration in limiting and enabling adaptive evolution by natural selection. The main objective of this theory is to account for the observed patterns of morphological evolution, such as the conservation of body plans. In contrast to other "alternative" theories of evolution, Riedl never denied the importance of natural selection as the driving force of evolution, but thought it necessary to contextualize natural selection with the organismal boundary conditions of adaptation. In Riedl's view development is the most important factor besides natural selection in shaping the pattern and processes of morphological evolution.     

NAD(P)H Quinone-Oxydoreductase 1 Protects Eukaryotic Translation Initiation Factor 4GI from Degradation by the Proteasome

The eukaryotic translation initiation factor 4GI (eIF4GI) serves as a central adapter in cap-binding complex assembly. Although eIF4GI has been shown to be sensitive to proteasomal degradation, how the eIF4GI steady-state level is controlled remains unknown. Here, we show that eIF4GI exists in a complex with NAD(P)H quinone-oxydoreductase 1 (NQO1) in cell extracts. Treatment of cells with dicumarol (dicoumarol), a pharmacological inhibitor of NQO1 known to preclude NQO1 binding to its protein partners, provokes eIF4GI degradation by the proteasome. Consistently, the eIF4GI steady-state level also diminishes upon the silencing of NQO1 (by transfection with small interfering RNA), while eIF4GI accumulates upon the overexpression of NQO1 (by transfection with cDNA). We further reveal that treatment of cells with dicumarol frees eIF4GI from mRNA translation initiation complexes due to strong activation of its natural competitor, the translational repressor 4E-BP1. As a consequence of cap-binding complex dissociation and eIF4GI degradation, protein synthesis is dramatically inhibited. Finally, we show that the regulation of eIF4GI stability by the proteasome may be prominent under oxidative stress. Our findings assign NQO1 an original role in the regulation of mRNA translation via the control of eIF4GI stability by the proteasome.In eukaryotes, eukaryotic translation initiation factor 4G (eIF4G) plays a central role in the recruitment of ribosomes to the mRNA 5′ end and is therefore critical for the regulation of protein synthesis (14). Two homologues of eIF4G, eIF4GI and eIF4GII, have been cloned (15). Although they differ in various respects, both homologues clearly function in translation initiation. The most thoroughly studied of these is eIF4GI, which serves as a scaffolding protein for the assembly of eIF4F, a protein complex composed of eIF4E (the mRNA cap-binding factor) and eIF4A (an ATP-dependent RNA helicase). Thus, via its association with the mRNA cap-binding protein eIF4E and with another translation initiation factor (eIF3) which is bound to the 40S ribosomal subunit, eIF4GI creates a physical link between the mRNA cap structure and the ribosome, thus facilitating cap-dependent translation initiation (25). eIF4GI functions also in cap-independent, internal ribosome entry site (IRES)-mediated translation initiation. For instance, upon picornavirus infection, eIF4G is rapidly attacked by viral proteases. The resulting eIF4GI cleavage products serve to reprogram the cell''s translational machinery, as the N-terminal cleavage product inhibits cap-dependent translation of host cell mRNAs by sequestering eIF4E while the C-terminal cleavage product stimulates IRES-mediated translation of viral mRNAs (23). Similarly, apoptotic caspases cleave eIF4G into an N-terminal fragment that blocks cap-dependent translation and a C-terminal fragment that is utilized for IRES-mediated translation of mRNAs encoding proapoptotic proteins (22).The regulation of eIF4GI cleavage by viral proteases or apoptotic caspases has been extensively studied. Little is known, however, about the regulation of eIF4GI steady-state levels. Yet the eIF4GI amount that exists at a given moment results from the sum of the effects of de novo synthesis and ongoing degradation. Many cellular proteins are physiologically degraded by the proteasome. This has been shown to be true for eIF4GI, as the factor can be degraded by the proteasome in vitro (5) and in living cells (6). However, how eIF4GI targeting for or protection from destruction by the proteasome is regulated remains unknown.There are two major routes to degradation by the proteasome. In the more conventional route, polyubiquitinated proteins are targeted to the 26S proteasome. Alternatively, a few proteins can be degraded by the 20S proteasome (and sometimes by the 26S proteasome) in a ubiquitin-independent manner (16). Interestingly, it has been shown recently that a few of these proteins (1, 2, 13) can be protected from degradation by the 20S proteasome by binding to the NAD(P)H quinone-oxydoreductase 1 (NQO1). It has been proposed that NQO1 may interact with the 20S proteasome and may consequently block access of target proteins to the 20S degradation core. Because eIF4GI can be degraded in vitro by the 20S proteasome (5) and since it appears that proteasomes can degrade eIF4GI in living cells independently of ubiquitination (6), we asked whether NQO1 could protect eIF4GI from degradation by the proteasome.