A reflection of the lasting contributions from Dr. Robert Bittman to sterol trafficking,sphingolipid and phospholipid research

With the passing of Dr. Robert Bittman from pancreatic cancer on the 1st October 2014, the lipid research field lost one of the most influential and significant personalities. Robert Bittman's genius was in chemical design and his contribution to the lipid research field was truly immense. The reagents and chemicals he designed and synthesised allowed interrogation of the role of lipids in constituting complex biophysical membranes, sterol transfer and in cellular communication networks. Here we provide a review of these works which serve as a lasting memory to his life.     

On the legacy of W.S. McCulloch

In this paper, we review McCulloch's legacy, from his early work in neurophysiology, and its relationship to his philosophical quest for an 'experimental epistemology' to his role in the cybernetics movement during the 1940s and 1950s and his contributions to the development of computer science and communication theory. There are three parts in chronological sequence. First, the period up to his work at Yale University with Dusser de Barenne, where he concentrated on the experimental study of the functional organization of sensory cortex. Second, the time of his Psychiatric Chair at the University of Chicago and the organization of the Macy Foundation Conferences. To this period corresponds the genesis and publication of the most influential and quoted work by McCulloch and Pitts: A Logical Calculus of the Ideas Immanent in Neurons Activity. Third, the period of his research activity at the Massachussetts Institute of Technology where he, Lettvin, Maturana and Pitts produced epochmaking papers on epistemological neurophysiology, the modelling of the reticular formation and other work with da Fonseca and Moreno-Díaz. We finally refer to the International Conference that took place in McCulloch's memory at the 25th anniversary of his death. Our main conclusion is that McCulloch's writings are still a source of inspiration from neurophysiology to artificial intelligence and robotics.     

Le dossier Vavilov

Vavilov’s dossier. Gould revived the memory of N.I. Vavilov, a victim of the Stalinian system and misjudged among occidental evolutionists. His contribution is impressive in applied research (phytogeography, his list of world-wide plant resources, a unique collection of germplasms intact and always available) as well as in theoretical research work on artificial selection, immunitary relationships between parasite and plant, the bases of his Law of homologous series in hereditary variations, and centers of origin of cultivated plants. Darwinian concept of natural selection were essential for him, but he considered that the evolutionary changes were not only produced by random variations, but by preset channels, recognising the internal constraints of heredity. His heritage has always been maintained in his Institutes. His Evolutionary theories are now confirmed by molecular genetics and systematics. S.J. Gould was the first to revive Vavilov’s memory and scientific importance. During his studies on the gastropod Cerion Gould recognised the balance between external and internal constraints in Evolution. To cite this article: M. Debrenne, F. Debrenne, C. R. Palevol 2 (2003).     

A rendezvous with the queen of ion channels: Three decades of ion channel research by David T Yue and his Calcium Signals Laboratory

David T. Yue was a renowned biophysicist who dedicated his life to the study of Ca²⁺ signaling in cells. In the wake of his passing, we are left not only with a feeling of great loss, but with a tremendous and impactful body of work contributed by a remarkable man. David's research spanned the spectrum from atomic structure to organ systems, with a quantitative rigor aimed at understanding the fundamental mechanisms underlying biological function. Along the way he developed new tools and approaches, enabling not only his own research but that of his contemporaries and those who will come after him. While we cannot hope to replicate the eloquence and style we are accustomed to in David's writing, we nonetheless undertake a review of David's chosen field of study with a focus on many of his contributions to the calcium channel field.     

Uneven distributions of naïve and memory T cells in the CD4 and CD8 T-cell populations derived from a single stem cell in an atomic bomb survivor: implications for the origins of the memory T-cell pools in adulthood

The processes that lead to the establishment and maintenance of memory T-cell pools in humans are not well understood. In this study, we examined the emergence of na?ve and memory T cells in an adult male who was exposed to an atomic bomb radiation dose of approximately 2 Gy in 1945 at the age of 17. The analysis presented here was made possible by our earlier observation that this particular individual carries a hematopoietic stem cell mutation at the hypoxanthine phosphoribosyltransferase (HPRT) locus that is almost certainly a result of his exposure to A-bomb radiation. Our key finding is that we detected a very much higher HPRT mutant frequency in the naive (CD45RA(+)) cell component of this individual's CD4 and CD8 T-cell populations than in the memory (CD45RA(-)) cell component of his CD4 and CD8 T-cell populations. This stands in marked contrast to our finding that HPRT mutant frequencies are fairly similar in the na?ve CD45RA(+) and memory CD45RA(-) components of the CD4 and CD8 T-cell populations of three unexposed individuals examined concurrently. In addition we found that the HPRT mutant frequencies were about 30-fold higher in the na?ve (CD45RA(+)) CD4 T cells of the exposed individual than in his memory (CD45RA(-)) cell populations, but that the effect was a little less striking in his CD8 cell populations, where the HPRT mutant frequencies were only about 15-fold higher in his na?ve T-cell pools than in his memory T-cell pools. We further found that 100% of the HPRT mutant cells in both his CD4 and CD8 na?ve cell subsets appeared to have originated from repeated divisions of the initial HPRT mutant stem cell, whereas only 4 of 24 and 5 of 6 mutant cells in his CD4 and CD8 memory cell subsets appeared to have originated from that same stem cell. The most straightforward conclusion may be that the great majority of the T cells produced by this individual since he was 17 years old have remained as na?ve-type T cells, rather than having become memory-type T cells. Thus the T cells that have been produced from the hematopoietic stem cells of this particular A-bomb-exposed individual seldom seem to enter and/or to remain in the memory T-cell pool for long periods. We speculate that this constraint on entry into memory T-cell pools may also apply to unirradiated individuals, but in the absence of genetic markers to assist us in obtaining evidential support, we must await clarifying information from radically different experimental approaches.     

H.J. Muller's contributions to mutation research

H. J. Muller is best known for his Nobel Prize work on the induction of mutations by ionizing radiation. Geneticists are less familiar with his contributions to mutation and how he related the process of mutagenesis to the gene and distinguished gene mutations from other genetic and epigenetic events such as polyploidy, chromosome rearrangements, and position effects. The hallmark of Muller's contributions is his design of genetic stocks to solve genetic problems and allow experimentation to reveal new phenomena. In this review I relate Muller's personality to his teaching and research and present a history of Muller's ideas on mutation from his first days in Morgan's fly lab to his final thoughts on what became called “Muller's ratchet”, a term he did not get to enjoy because it was coined seven years after his death.     

Eric Kandel: the future of memory

Watching ice floes glide by on the Hudson River from Eric Kandel's office, one gets a sense of placid reflection tempered by constant action-an apt analogy for Kandel's ability to calmly manage several ongoing projects and commitments at once. In addition to his well-lauded, ongoing research at Columbia University Medical Center's New York State Psychiatric Institute, Kandel has written several books on neurobiology, behavior, and memory. In addition to being a Nobel Laureate Scientist, he is well-known as an editor of the seminal textbook Principles of Neural Science. He and his colleagues are in the midst of working on a new edition of Principles, and he is working on a scientific autobiography. MI sat down with Dr. Kandel and discussed with him a range of topics including childhood and early career influences, intramural research at the NIH, the HHMI, ethical considerations of altering memory and, of course, Aplysia.     

Epilogue: Luria's Psychological Symphony

A finely worked bronze dog has been standing on my desk for twenty years now. Aside from the books with their dedicatory signatures, it is the only material thing I have in memory of Aleksandr Romanovich Luria. A week after he died, Lana Pimenovna, his wife, asked if I could drop in to see her. I thought that the reason for her call—to ask me to enlarge, reproduce, and frame some photos she had made of Aleksandr Romanovich in various years during his lifetime—was only a pretext: the publisher's in-house photographer or any other photographer could have done this.     

The 2009 Lindau Nobel Laureate Meeting: Martin Chalfie,Chemistry 2008

American Biologist Martin Chalfie shared the 2008 Nobel Prize in Chemistry with Roger Tsien and Osamu Shimomura for their discovery and development of the Green Fluorescent Protein (GFP).Martin Chalfie was born in Chicago in 1947 and grew up in Skokie Illinois. Although he had an interest in science from a young age-- learning the names of the planets and reading books about dinosaurs-- his journey to a career in biological science was circuitous. In high school, Chalfie enjoyed his AP Chemistry course, but his other science courses did not make much of an impression on him, and he began his undergraduate studies at Harvard uncertain of what he wanted to study. Eventually he did choose to major in Biochemistry, and during the summer between his sophomore and junior years, he joined Klaus Weber''s lab and began his first real research project, studying the active site of the enzyme aspartate transcarbamylase. Unfortunately, none of the experiments he performed in Weber''s lab worked, and Chalfie came to the conclusion that research was not for him.Following graduation in 1969, he was hired as a teacher Hamden Hall Country Day School in Connecticut where he taught high school chemistry, algebra, and social sciences for 2 years. After his first year of teaching, he decided to give research another try. He took a summer job in Jose Zadunaisky''s lab at Yale, studying chloride transport in the frog retina. Chalfie enjoyed this experience a great deal, and having gained confidence in his own scientific abilities, he applied to graduate school at Harvard, where he joined the Physiology department in 1972 and studied norepinephrine synthesis and secretion under Bob Pearlman. His interest in working on C. elegans led him to post doc with Sydney Brenner, at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England. In 1982 he was offered position at Columbia University.When Chalfie first heard about GFP at a research seminar given by Paul Brehm in 1989, his lab was studying genes involved in the development and function of touch-sensitive cells in C. elegans. He immediately became very excited about the idea of expressing the fluorescent protein in the nematode, hoping to figure out where the genes were expressed in the live organism. At the time, all methods of examining localization, such as antibody staining or in situ hybridization, required fixation of the tissue or cells, revealing the location of proteins only at fixed points in time.In September 1992, after obtaining GFP DNA from Douglas Prasher, Chalfie asked his rotation student, Ghia Euskirchen to express GFP in E. coli, unaware that several other labs were also trying to express the protein, without success. Chalfie and Euskirchen used PCR to amplify only the coding sequence of GFP, which they placed in an expression vector and expressed in E.coli. Because of her engineering background, Euskirchen knew that the microscope in the Chalfie lab was not good enough to use for this type of experiment, so she captured images of green bacteria using the microscope from her former engineering lab. This work demonstrated that GFP fluorescence requires no component other than GFP itself. In fact, the difficulty that other labs had encountered stemmed from their use of restriction enzyme digestions for subcloning, which brought along an extra sequence that prevented GFP''s fluorescent expression. Following Euskirchen''s successful expression in E. coli, Chalfie''s technician Yuan Tu went on to express GFP in C. elegans, and Chalfie published the findings in Science in 1994.Through the study of C. elegans and GFP, Chalfie feels there is an important lesson to be learned about the importance basic research. Though there has been a recent push for clinically-relevant or patent-producing (translational) research, Chalfie warns that taking this approach alone is a mistake, given how "woefully little" we know about biology. He points out the vast expanse of the unknowns in biology, noting that important discoveries such as GFP are very frequently made through basic research using a diverse set of model organisms. Indeed, the study of GFP bioluminescence did not originally have a direct application to human health. Our understanding of it, however, has led to a wide array of clinically-relevant discoveries and developments. Chalfie believes we should not limit ourselves: "We should be a little freer and investigate things in different directions, and be a little bit awed by what we''re going to find."Download video file.^{(152M, mp4)}     

Spontaneous behavior of a rhesus monkey (Macaca mulatta) during memory tests suggests memory awareness

Humans can predict with some accuracy whether or not they know the correct answer to a question before responding. In some cases the capacity to make such predictions depends on memory awareness, the ability to introspectively discriminate between knowing and not knowing. In this unplanned retrospective analysis of video taped behavior we asked whether a rhesus monkey's apparent frustration predicted his accuracy in a matching-to-sample task on a trial-by-trial basis. The monkey was likely to aggressively strike the computer touchscreen when committing errors, whereas he generally touched the screen more gently when selecting the correct stimulus. This difference in behavior, which occurred before the monkey received feedback on the accuracy of his choice, suggests that he knew whether or not he remembered the correct response.     

The construction of a scientific model: Otto Warburg and the building block strategy

In the years 1919 to 1923, Otto Warburg published four papers that were to revolutionise the field of photosynthesis. In these articles, he introduced a number of new techniques to measure the rate of photosynthesis, put forward a new model of the mechanism and added a completely new perspective to the topic by attempting to establish the process’s efficiency in terms of the light quantum requirement. In this paper I trace the roots of Warburg’s series of contributions to photosynthesis research by exploring three different contexts of inspiration: Warburg’s own research into cell respiration, his father’s work on the quantum yield of photochemical reactions in general and the photosynthesis work carried out by Richard Willstätter and Arthur Stoll. When these influences are considered together, it becomes clear that Warburg implemented a Building Block Strategy in his research: rather than inventing his photosynthesis model from scratch, he availed himself of fragments from other contexts, which he then recombined in a new and innovative way. This way of working is considered to be standard practice in scientific research.     

Still going strong: Leeuwenhoek at eighty

At age 80, Antony van Leeuwenhoek was a world-famous scientist who came from a prosperous Delft family with a heritage of public service. He continued that tradition by serving in paid municipal offices. Self-taught, he began his scientific career in his 40s, when he began making hundreds of tiny single-lens microscopes. Pioneering the use of now-common microscopic techniques, he was the first human to see microbes and microscopic structures in animals, plants, and minerals. Over 50 years, he wrote only letters, more than 300 of them, and published half of them himself. More than a hundred were published in translation in the Royal Society’s Philosophical Transactions. Today, Leeuwenhoek is considered in the lesser rank of scientists and is not well known outside of his homeland. Recent archival research in Delft has contributed new information about his life that helps to contextualize his science, but much remains to be learned.     

Darwin and palaeontology: a re-evaluation of his interpretation of the fossil record

Charles Darwin's empirical research in palaeontology, especially on fossil invertebrates, has been relatively neglected as a source of insight into his thinking, other than to note that he viewed the fossil record as very incomplete. During the Beagle voyage, Darwin gained extensive experience with a wide diversity of fossil taxa, and he thought deeply about the nature of the fossil record. That record was, for him, a major source of evidence for large-scale transmutation, but much less so for natural selection or single lineages. Darwin's interpretation of the fossil record has been criticised for its focus on incompleteness, but the record as he knew it was extremely incomplete. He was compelled to address this in arguing for descent with modification, which was likely his primary goal. Darwin's gradualism has been both misrepresented and exaggerated, and has distracted us from the importance of the fossil record in his thinking, which should be viewed in the context of the multiple, sometimes competing demands of the multifaceted argument he presented in the Origin of Species.     

Postcolonial Ecologies of Parasite and Host: Making Parasitism Cosmopolitan

The interest of F. Macfarlane Burnet in host–parasite interactions grew through the 1920s and 1930s, culminating in his book, Biological Aspects of Infectious Disease (1940), often regarded as the founding text of disease ecology. Our knowledge of the influences on Burnet’s ecological thinking is still incomplete. Burnet later attributed much of his conceptual development to his reading of British theoretical biology, especially the work of Julian Huxley and Charles Elton, and regretted he did not study Theobald Smith’s Parasitism and Disease (1934) until after he had formulated his ideas. Scholars also have adduced Burnet’s fascination with natural history and the clinical and public health demands on his research effort, among other influences. I want to consider here additional contributions to Burnet’s ecological thinking, focusing on his intellectual milieu, placing his research in a settler society with exceptional expertise in environmental studies and pest management. In part, an ‘‘ecological turn’’ in Australian science in the 1930s, derived to a degree from British colonial scientific investments, shaped Burnet’s conceptual development. This raises the question of whether we might characterize, in postcolonial fashion, disease ecology, and other studies of parasitism, as successful settler colonial or dominion science.     

Differentiation of neuroblastoma cells by chick gizzard extract

Cholinergic neuroblastoma NS20Y cells were differentiated by the chicken gizzard extract. They were first inoculated into a glass culture bottle and the aggregated cells which grew in the suspension culture were collected. The aggregated cells (round and immature neuroblastoma cells) were seeded on a polyornithinecoated plastic dish, and the effect of various agents on the differentiation of the neuroblastoma was investigated. When gizzard extract from chicken was added to the culture, many flat cells with neurites emerged around the cell aggregates within 24 h. The flat cells could evoke action potentials with high frequency (in 70% cells). Cyclic GMP levels in the treated cultures were much lower than that in the control culture, and remained continuously lower during 2 days culture. The factor responsible for the differentiation of neuroblastoma cells was rich in the chick gizzard among extracts or conditioned media from various tissues tested. A similar effect was observed by the addition of dibutyryl cyclic AMP or prostaglandin E₁ plus theophylline over a slower time course. The factor in gizzard extract was trypsin-sensitive and heat-labile. The molecular size was estimated to be about 12 s.     

Between Biochemists and Embryologists – The Biochemical Study of Embryonic Induction in the 1930s

The discovery by Hans Spemann of the “organizer” tissue and its ability to induce the formation of the amphibian embryo’s neural tube inspired leading embryologists to attempt to elucidate embryonic inductions’ underlying mechanism. Joseph Needham, who during the 1930s conducted research in biochemical embryology, proposed that embryonic induction is mediated by a specific chemical entity embedded in the inducing tissue, surmising that chemical to be a hormone of sterol-like structure. Along with embryologist Conrad H. Waddington, they conducted research aimed at the isolation and functional characterization of the underlying agent. As historians clearly pointed out, embryologists came to question Needham’s biochemical approach; he failed to locate the hormone he sought and eventually abandoned his quest. Yet, this study finds that the difficulties he ran into resulted primarily from the limited conditions for conducting his experiments at his institute. In addition, Needham’s research reflected the interests of leading biochemists in hormone and cancer research, because it offered novel theoretical models and experimental methods for engaging with the function of the hormones and carcinogens they isolated. Needham and Waddington were deterred neither by the mounting challenges nor by the limited experimental infrastructure. Like their colleagues in hormone and cancer research, they anticipated difficulties in attempting to establish causal links between complex biological phenomena and simple chemical triggering.     

Ferdinand Vandeveer Hayden as Naturalist

SYNOPSIS. Like most American naturalists born during the firsthalf of the nineteenth century, Ferdinand Vandeveer Hayden (1829–1887)was fascinated with all living creatures from boyhood, and,like many others, he enriched his early proclivities by studyingmedicine. He worked in Cleveland under J. P. Kirtland and thenin Albany, where he came under the tutelage of James Hall, ofthe Geological Survey of New York. Hall sent him on his firstcollecting trip in the summer of 1853. Showing the independencefor which he became famous, Hayden broke with Hall, however,and with the encouragement of S. F. Baird, and partial sponsorshipfrom the Smithsonian Institution, he spent the remainder ofthe 1850s on a series of exploring and collecting expeditionsto the Upper Missouri River. During the 1860s and 1870s he gainedrenown as a geologist, in particular as director of the Surveyof the Territories, but he never lost his broader interestsin natural history. Both his writings and the unique collectionshe himself made illustrate his catholic curiosity. More importantto natural history were the voluminous publications he sponsoredthrough his Survey, which stimulated specialized research onan encyclopedic range of subjects.     

The costs of being a restless intellect: Julian Huxley’s popular and scientific career in the 1920s

Julian Huxley’s (1887–1975) contribution to twentieth-century biology and science popularisation is well documented. What has not been appreciated so far is that despite Huxley’s eminence as a public scientific figure and the part that he played in the rise of experimental zoology in Britain in the 1920s, his own research was often heavily criticised in this period by his colleagues. This resulted in numerous difficulties in getting his scientific research published in the early 1920s. At this time, Huxley started his popular science career. Huxley’s friends criticised him for engaging in this actively and attributed the publication difficulties to the time that he allocated to popular science. The cause might also have its roots in his self-professed inability to delve deeply into the particularities of research. This affected Huxley’s standing in the scientific community and seems to have contributed to the fact that Huxley failed twice in the late 1920s to be elected to the Royal Society. This picture undermines to some extent Peter J. Bowler’s recent portrayal of Huxley as a science populariser.