Impact of the Merrifield solid phase method on the design and synthesis of selective agonists and antagonists of oxytocin and vasopressin: a historical perspective

This tribute to Bruce Merrifield traces the author's fortuitous path in 1964 from Vincent du Vigneaud's laboratory to the laboratory of D. W. Woolley to learn the solid phase method and then to his first faculty position in the Department of Biochemistry, McGill University, Montreal in 1965. It recalls the key roles played from early 1966 to July 1967 by Bruce Merrifield, John Stewart, Arnold Marglin, Herb Takashima, and Vincent du Vigneaud in providing key advice to the author's efforts to use the solid phase method to synthesize oxytocin; while simultaneously the du Vigneaud and Merrifield laboratories were collaborating on the solid phase synthesis of deamino-oxytocin. Both syntheses were published in the same issue of the Journal of American Chemical Society in 1968. Also described is how this breakthrough impacted the author's scientific career: by leading to highly productive collaborative studies, initially with Wilbur H. Sawyer and subsequently with others, on the design and synthesis of selective agonists, antagonists, and radioiodinated ligands for oxytocin and vasopressin receptors. These syntheses were greatly facilitated by the contributions of highly talented graduate students, research technicians, and visiting peptide chemists from Hungary, England, Poland, Bulgaria, and China. Many of these peptides have become very valuable pharmacological tools in studies on the peripheral and central effects of oxytocin and vasopressin: further attesting to the profound impact of the solid phase method as the cornerstone for all the discoveries, which he and his collaborators and coworkers have made over the past 40 years.     

An interview with Dr. Frank Slack on his highly cited paper published in Cell Cycle

Frank Slack received his B.Sc from the University of Cape Town in South Africa, before completing his Ph.D in molecular biology at Tufts University School of Medicine. He started work on microRNAs as a postdoctoral fellow in Gary Ruvkun’s laboratory at Harvard Medical School, where he co-discovered the second known microRNA, let-7. He is currently an Associate Professor in the Department of Molecular, Cellular and Developmental Biology at Yale University. The Slack laboratory studies the roles of microRNAs and their targets in development, disease and aging.     

Neurotransmitter enzyme and receptor regulation: A look back

1. This report is a tribute to Dr. Julius Axelrod, in whose laboratory the author worked as a research associate from 1971-1974. 2. Work on the regulation of dopamine beta-hydroxylase and phenylethanolamine N-methyl transferase is reviewed, particularly studies showing how transynaptic and hormonal factors regulate enzyme synthesis and degradation respectively. 3. Work taking place in the author's laboratory is reviewed with respect to the influence Dr. Axelrod had on the author and his subsequent work.     

Photosynthesis Research in Canada from 1945 to the early 1970s

This history traces the development of photosynthesis research in Canada from 1945 to 1975, starting with the work of Gleb(1) Krotkov and his students, Paul Vittorio, Tony(1) Bidwell, Don(1) Nelson, Jim(1) Craigie, Bruce Tregunna, Andreas Hauschild, Geoff Lister and others in the Department of Biology at Queen's University, Kingston, Ontario. They focused on the influence of taxonomy and light quality on the path of carbon into early products, photorespiration and photosynthesis in young trees. During the same period, Ken(1) Clendenning and one of the authors (PRG) at the National Research Council of Canada (NRCC) laboratory in Ottawa began studies of chloroplast photoreduction and leaf carboxylases. They were joined by Don(1) Mortimer, who showed that the path of carbon varies with species of plant and by Morris Kates, who studied phospholipid enzymology in chloroplasts and leaves. Stan(1) Holt researched the chemistry and distribution of chlorophylls in different taxa. In 1952, Ralph Lewin joined NRCC's new Atlantic Regional Laboratory in Halifax, Nova Scotia, followed by Jim Craigie, Jack McLachlan and Tony Bidwell who mainly investigated the products of photosynthesis in marine algae. Tony Bidwell continued these studies in 1959 at the Department of Botany, University of Toronto. Dave(1) Canvin joined the staff at Queen's in 1965 and became involved in solving the mystery of photorespiration. Tony Bidwell returned to Queen's in 1969 and studied photosynthesis of algal chloroplasts using an 'artificial leaf.' In 1965, Don Nelson established a group at Simon Fraser University in Burnaby, British Columbia that included his former student, Geoff Lister who produced the first photosynthetic action spectra for trees, and Bill(1) Vidaver, who showed the useful relation between chlorophyll fluorescence and photosynthetic activity. In 1970, Mário Fragata headed a group at the Université du Québec à Trois Rivières, Québec, that began with studies of Photosystem II in chloroplasts and particles.     

Plastoquinone redox control of chloroplast thylakoid protein phosphorylation and distribution of excitation energy between photosystems: discovery,background, implications

Chloroplast thylakoid protein phosphorylation was discovered, and the most conspicuous phosphoproteins identified, by John Bennett at Warwick University. His initial findings were published in 1977. The phosphoproteins included apoproteins of chloroplast light harvesting complex II. Thylakoid protein phosphorylation was shown to influence distribution of excitation energy between Photosystems I and II in 1979, during a visit by Bennett to the laboratory of Charles J. Arntzen at the University of Illinois at Urbana-Champaign. That work was published by Bennett, Katherine E. Steinback and Arntzen in 1980. Control of both protein phosphorylation and excitation energy distribution by the redox state of the plastoquinone pool was first established in 1980 during the author's visit to Arntzen's laboratory. The experiments were prompted by the realization that coupling between redox state of an inter-photosystem electron carrier and excitation energy distribution provides a concrete mechanism for adaptations known as state transitions. This work was published by Allen, Bennett, Steinback, and Arntzen in 1981. This discovery and its background are discussed, together with some implications for photosynthesis and for research generally. This minireview is a personal account of the Urbana-Warwick and related collaborations in 1979–83: it includes impressions, conjectures, and acknowledgements for which the author is solely responsible. This revised version was published online in June 2006 with corrections to the Cover Date.     

Andrzej Krzysztof Tarkowski abroad, in photos and correspondence

An informal account records the remaining traces of Tarkowski's research visits to the United Kingdom and France. The account has many authors and it should not be regarded as an exact history. The early 1960s began with the dramatic production of chimaeras at the University of Bangor and the long term exchange of information with Anne McLaren's Edinburgh laboratory. The techniques of parthenogenesis and nuclear transfer became the obsession of the 1970's and Tarkowski pursued the problem in Oxford (U.K.), in France, and with his group in Warsaw (Poland). A variant of this theme emerged during the 1980's and this was attempts to produce interspecies hybrids in Oxford and Warsaw. During the 1990's, the Warsaw laboratory became sufficiently well funded to make his trips unnecessary and his pupils became a Polish Diaspora of Embryologists.     

Defining the limits of diving biochemistry in marine mammals

The field of marine mammal diving biochemistry was essentially untouched when Peter Hochachka turned his attention to it in the mid-1970s. Over the next 30 years, his work followed three main themes in this area: first, most biologists at that time supported the theory that diving mammals utilized enhanced metabolic pathways for hypoxic energy production (glycolysis to lactate) and reduced their metabolic rate while diving. Peter began his work on potential hypoxic adaptations in marine mammals by working out the details of how these pathways would be regulated. By the 1980s, he started to ask how diving mammals balanced the increased demands of exercise with the apparently conflicting demands to reduce aerobic metabolism while exercising underwater. By the 1990s, his work involved complex models of the interplay between the neural, hormonal, behavioral and evolutionary components of diving biochemistry and animal exercise. From a comparative approach, he excelled at bringing themes of hypoxic adaptation from many different types of animals to the field of diving mammal biochemistry. This review traces the history of Peter Hochachka's work on diving biochemistry from the perspective of those of us who spent time with him both inside the laboratory and outside in the field from Antarctica to Iceland.     

Robert Koch

This article traces the origins of bacteriological research, with particular attention to the role of Robert Koch, and his postulates, on infectious agents. By chronologically following Koch's work on anthrax, germ photography and tuberculosis, it shows how the visual representation of germs transformed laboratory research in medical science.     

A nonlinear ergodic theorem for discrete systems

A theorem concerning the asymptotic behavior of a general class of systems of difference equations is proven. This theorem guarantees the existence of a stable normalized distribution vector, and enables the constructing of a scalar limiting equation for an aggregate variable. This theory is illustrated using an example from population dynamics, a nonlinear size-structured model of competition for a dynamically modeled limiting resource.Supported in the Program in Applied Mathematics at the University of Arizona by the Applied Mathematics and Population Biology/Ecology Divisions of the National Science Foundation under grant No. DMS-8902508. Supported at Cornell University by the US Army Research Office through the Mathematical Sciences Institute, Contract DAAL03-91-C-0027, and by the National Science Foundation through the Biometrics Unit, grant No. DEB-9253570; This work comprises part of the author's dissertation at the University of Arizona, directed by J. M. Cushing     

Donald Richard Nelson: The Most Unforgettable Character I Ever Met

This volume is dedicated to the work, life and memory of Donald Richard Nelson. The present article is based primarily on the author's 38-year friendship and personal experience with the man. The text chronicles his life and times from budding naturalist to champion spearfisher through graduate school and on to becoming scientist, teacher and mentor to dozens of graduate students. The author perceives Nelson as a unique character, creative, introspective, kind, wise and gentle. His influence in the field of contemporary elasmobranch biology, especially ethology and sensory physiology was enormous.     

Homer Wheelon, M.D., physiologist, artist, and poet: origins of the tailpieces in journals of the American Physiological Society

Since 1953, illustrations have been inserted as "tailpieces" at the ends of articles in The American Journal of Physiology and The Journal of Applied Physiology. The drawings were made by Homer Wheelon, a member of the American Physiological Society from 1919 until his death in 1960. Forty-five years after his death, Wheelon is unknown, but he contributed 32 publications to the medical literature and trained J. Earl Thomas, an important 20th century gastrointestinal physiologist. Wheelon was born into poverty in 1883 to itinerant Methodist preachers, circumstances that guided his education and career choices. Throughout his life, Wheelon exhibited a fondness and talent for art and photography and an unusual breadth of intellectual interests and knowledge. Wheelon received a bachelor's degree from the University of Washington, then studied at the University of Oregon, Northwestern University, and St. Louis University. Earning his M.D. from St. Louis University and assuming a faculty position there, Wheelon and his graduate student, Thomas, conducted widely recognized gastrointestinal research. Returning to Seattle in 1921, Wheelon became a highly respected physician and hospital administrator, but he also found time to indulge his interest in visual art and poetry. In 1933, inspired by observing a rabbit being used in a pregnancy test, Wheelon began to write and illustrate an epic, 322-page poem, Rabbit No. 202, illustrations from which became the journals' tailpieces. The present study traces Wheelon's personal life and scientific career in an attempt to understand this complex man and the origins of his unusual poem and its drawings.     

The fine structure of muscle in a marine turbellarian

Summary The fine structure of the myofibers of Notoplana acticola as studied by electron microscopy indicates that they are composed of thick myofilaments about 200 Å wide with tapering ends and thin myofilaments about 50 Å wide, arranged alongside each other parallel to the long axis of the cell. There is no orderly transverse arrangement of filaments; instead they appear staggered in the fiber. In cross sections 6 to 10 thin filaments form an orbit around one thick filament with possible cross-linkage between the two types of filaments.Dense bodies are associated with the sarcolemma and with the sarcoplasmic reticulum, and appear to serve as attachments for the thin filaments. Dense bodies are compared to elements forming a fragmented Z-disc.Mitochondria, situated in the periphery or the center of fibers, are associated with granules interpreted as glycogen.The sarcoplasmic reticulum consists of: sacs or cisternae in close proximity to the sarcolemma, longitudinal tubular elements between and parallel to the myofilaments, and a tubular network around the filaments. There is no well-defined sarcolemmal-derived transverse tubule system as described in striated muscles. It is hypothesized that in these muscles, the functional equivalent of the T system may be the area of sarcolemma in contact with the cisternae of the sarcoplasmic reticulum.This work was supported by Grant No. GM 10292 from the U. S. Public Health Service to Professor Richard M. Eakin, Department of Zoology at the University of California, Berkeley, USA, where this investigation was conducted during the author's sabbatical leave of absence from the University of Illinois.I wish to thank Professor Eakin for valuable discussions and for his kind hospitality in extending the facilities of his laboratory and the use of the electron microscope to me, and the John Simon Guggenheim Memorial Foundation for the Fellowship which I held during 1964–65.     

Dealing with malaria in the last 60 years. A personal experience

Dealing with malaria in the last 60 years is seen by the author in the perspective of his own experience. His malaria work, which began in 1941, covered the study of the habits of the mosquitoes dwelling in the savanna country of Eastern Colombia and the effect on malaria transmission of the newly introduced DDT residual spraying. The success of the campaign he later directed in Sarawak and Brunei contributed to the launching by WHO of its global malaria eradication campaign. Further successful work in Uganda showed the possibility of effective control and even eradication in highland country but left unsolved the problem of how to interrupt transmission of holoendemic malaria in Africa. The author's work with WHO in the Middle East showed to what extent social and economic conditions could influence the course of a malaria campaign. This was also the experience in America, both in Colombia in the author's early work and later in Mexico during an evaluation of the national malaria programme. Development of insecticide resistance was also encountered in his career and the refractoriness of the European vectors was also observed in his work as a malariologist.     

The fine structure of photoreceptors in a marine flatworm

Summary The ocelli or eyes of the marine polyclad turbellarian Notoplana acticola are clustered on the paired dorsal nuchal tentacles and in two longitudinal bands lateral to the cerebral ganglion. The ocelli, studied by electron microscopy, were characterized as rhabdomeric and non-ciliary in origin. There are 60 to 80 ocelli per animal each enclosed in a fibrous capsule to which muscle fibers may attach. An ocellus consists of a pigmented eyecup into which 30 to 50 photoreceptor cells send dendritic processes through interruptions in or among pigment cell projections across the eyecup opening. The dendritic processes terminate in numerous long intertwined microvilli which fill the eyecup. The nucleated cell body of each photoreceptor cell lies outside the eyecup and projects an axonal process to the cerebral mass. Within the dendritic processes are observed mitochondria, ribosomes, neurotubules, multivesicular bodies, vesicles and vacuoles. The cell body contains smaller mitochondria, endoplasmic reticulum, ribosomes, vesicles and prominent Golgi complexes.After dark adaptation, there are some structural alterations in terms of swelling of microvilli, increased numbers of vacuoles associated with the microvilli and dendritic processes, and changes in the pigment cell projections.This work was supported by Grant No. GM 10292 from the U.S. Public Health Service to Professor Richard M. Eakin, Department of Zoology at the University of California, Berkeley, U.S.A., where this investigation was conducted during the author's sabbatical leave of absence from the University of Illinois, and by Grant No. 1 SO 1 FR 5369 from the U.S. Public Health Service to the University of Illinois at the Medical Center.I express appreciation to Professor Eakin for interesting discussions and generous hospitality to me as a guest in his laboratory, and to the John Simon Guggenheim Memorial Foundation for the Fellowship which I held during 1964–65. I thank Dr. John P. Marbarger, Director of the Aeromedical Laboratory for the electron microscope facilities used at the University of Illinois.     

Two models for an effective undergraduate research experience in physiology and other natural sciences

68A realistic research experience is beneficial to undergraduate students, but it is often difficult for liberal arts colleges to offer this opportunity. We describe two approaches for developing and maintaining an interdisciplinary research program at small colleges. An active and continuing involvement of an individual with extensive research experience is an essential element in both. One model was developed by the faculty of Taylor University, Upland, IN and a research scientist who had retired from a major university to join the Taylor faculty as their first Research Professor. The school's Science Research Training Program was initially funded by a modest endowment provided by interested alumni and by extramural grants awarded to the Research Professor and to the institution; the program now enjoys significant funding from diverse sources. Taylor is not located near any large research university and consequently supplies all resources required for the experiments and stipends for students pursuing projects full-time during the summer. The second model was developed by the faculty at Asbury College in Wilmore, KY, working with a scientist having a full-time appointment at the University of Kentucky and a part-time appointment at the college. In this approach, Asbury faculty may place their students for a period of training, often during the summer, in a laboratory of a cooperating host faculty at the University of Kentucky or other institution. The host faculty funds the research and pays a stipend to those students who work full-time during the summer. Relationships established between faculty at the College and at the University of Kentucky have been mutually beneficial. The success of both programs is evidenced by the students' presenting their data at state and national scientific meetings, by their publishing their results in national journals, and by the undergraduate school faculty developing independent research programs.     

Uptake of ferritin by the cephalopod optic gland

Summary Horse spleen ferritin, injected into the blood of the octopus, leaves the capillaries via pericyte junctions and windows. One hour after the administration, ferritin has entered the optic gland main cells; three hours later, it is accumulated in dense-bodies. The evidence for resorption supports earlier papers reporting that the ultrastructure of the organ is unusual for an endocrine gland.We thank Professor R. Martin for his help and for permission to work in his laboratory at the Ulm University (Germany) and the Swiss Government for financial support     

Shigeru Nakano – An Uncommon Japanese Fish Ecologist

On 27 March 2000 Shigeru Nakano was lost in the Sea of Cortez off Bahia de Los Angeles in Baja California, when the research vessel that he and eight others were using to return from nearby islands capsized in an unexpected storm. Shigeru Nakano, Takuya Abe, and Masahiko Higashi, all faculty of the Center for Ecological Research (CER) at Kyoto University in Japan were visiting island research sites where Gary Polis of the University of California-Davis was studying food webs, and were accompanied by five other researchers and students. Nakano and his two Japanese colleagues, Polis, and Michael Rose, a postgraduate researcher, drowned. Survivors reported that Shigeru Nakano repeatedly pulled others back to the capsized boat when they were washed away by the raging sea, and strapped his own life jacket onto one of his colleagues who could not swim, literally giving his own life to save the lives of others. Nakano was a superb diver and field biologist, the best I have ever known, but I know from personal experiences during grueling field work in the mountains of Japan and Montana that he would never have left his friends to swim to the nearest island more than a kilometer away and save himself. Nakano's body was not recovered despite an extensive search effort. He was 37 years old and is survived by his wife and three children, and his parents and brother.     

Cornelis den hartog: An outstanding aquatic ecologist

A survey is given of the work and life of Cornelis den Hartog up to the date in 1996 at which he retired from his position as a professor at the University of Nijmegen. Cornelis (Kees) den Hartog made important contributions to aquatic ecology in the widest sense,e.g. on brackish water typology, meiofauna (microturbellaria), macroinvertebrates, littoral algae, seagrasses and aquatic macrophytes. He favoured the ecosystem approach in aquatic ecology by studying structure and functioning in an integrated way. He lead 31 students to their doctor's degree (PhD).     

An interview with Dr. Heiko Hermeking on his highly cited paper published in Cell Cycle

Heiko Hermeking holds a professorship for Experimental and Molecular Pathology at the Pathology Institute of the Ludwig-Maximilians University Munich in Germany. He also received his Ph.D. from this university, working in Dirk Eick’s laboratory, where he discovered that p53 mediates c-MYC-induced apoptosis. He then carried out four years of postdoctoral studies in Bert Vogelstein and Ken Kinzler’s laboratory at the Johns Hopkins Medical School in Baltimore, MD, where he used the SAGE technique, which had just been developed in this laboratory, to identify important p53 (14-3-3 ) and c-MYC (CDK4) target genes. Then he was an independent group leader at the Max-Planck-Institute of Biochemistry in Martinsried near Munich. His current work focuses on the analysis of genes, microRNAs and pathways that are regulated by c-MYC or p53.