Continuous culture techniques as simulators for standard cells: Jacques Monod's, Aron Novick's and Leo Szilard's quantitative approach to microbiology.

Continuous culture techniques were developed in the early twentieth century to replace cumbersome studies of cell growth in batch cultures. In contrast to batch cultures, they constituted an open concept, as cells are forced to proliferate by adding new medium while cell suspension is constantly removed. During the 1940s and 1950s new devices have been designed-called "automatic syringe mechanism," "turbidostat," "chemostat," "bactogen," and "microbial auxanometer"-which allowed increasingly accurate quantitative measurements of bacterial growth. With these devices cell growth came under the external control of the experimenters and thus accessible for developing a mathematical theory of growth kinetics-developed mainly by Jacques Monod, Aron Novick and Leo Szilard in the early 1950s and still in use today. The paper explores the development of continuous culture devices and claims that these devices are simulators for standard cells following specific requirements, in particular involving mathematical constraints in the design and setting of the devices as well as experiments. These requirements have led to contemporary designs of continuous culture techniques realizing a specific event-based flow algorithm able to simulate directed evolution and produce artificial cells and microorganisms. This current development is seen as an alternative approach to today's synthetic biology.

Approaches and species in the history of vertebrate embryology.

Recent debates about model organisms echo far into the past; taking a longer view adds perspective to present concerns. The major approaches in the history of research on vertebrate embryos have tended to exploit different species, though there are long-term continuities too. Early nineteenth-century embryologists worked on surrogates for humans and began to explore the range of vertebrate embryogenesis; late nineteenth-century Darwinists hunted exotic ontogenies; around 1900 experimentalists favored living embryos in which they could easily intervene; reproductive scientists tackled farm animals and human beings; after World War II developmental biologists increasingly engineered species for laboratory life; and proponents of evo-devo have recently challenged the resulting dominance of a few models. Decisions about species have depended on research questions, biological properties, supply lines, and, not least, on methods. Nor are species simply chosen; embryology has transformed them even as they have profoundly shaped the science.

Small is beautiful but smaller is the aim: review of a life of research.

Background and origins of research of Adam Curtis. One persisting theme has been the pursuit of different landscapes at different scales to discover the routes to explain how the body is built. His research life fell in a fortunate period during which techniques and concepts for investigating structure have improved year by year. His most fortunate encounter was with Michael Abercrombie and his views on the social behaviour of cells, aims for quantitation, and statistical testing. Adam worked in various environments--in turn Geology as an undergraduate, Biophysics Ph.D. in a Genetics department and various departments in turn from anatomy via zoology to Cell Biology. Adam started his Ph.D. work in cell adhesion, studying cell movement, trapping and reaggregation phenomena, having an early start from the physico-chemical viewpoint. He made quantitative measurements of cell adhesion by kinetic methods. Interference reflection microscopy (IRM) and related optical interference techniques were brought into the field of biology by him. In turn this led with Chris Wilkinson, a long term colleague, to the use of micro- and nanofabrication for biological research. Polscope and photoelastic measurements were introduced to biology recently in his laboratory. One long term theme has been to map the adhesion of cells to substrates to discover contact areas. Early data came from IRM and then TIRF (Total Internal Reflection Fluorescence Microscopy) and then from Forster Resonance Energy Microscopy (FRET). Another important theme was the time scale that needed to be measured--very short indeed in suspension. This was very difficult and has only become possible very recently but hydrodynamic calculation shows it must be very short. The attractions of the Derjagin-Landau-Verwey-Overbeek theory (DLVO theory) are that they explain many features of biological adhesion. The main test of this theory depends upon the energy of the adhesion at various different separation distances between cell and cell or cell and substrate. Problems with cell adhesion molecules are discussed. Contact guidance of cells by oriented structures and Paul Weiss--Tests with grating replicas suggested that topographic rather than biochemical explanations were applicable. It became clearer later that this was an area of research waiting for microfabrication. Albert Harris influenced me considerably to start thinking about mechanical forces produced by cells. Pulling at cells showed effects on the cytoskeleton and on cell cycle time. Such thoughts led to a microfabricated device for tendon repair. Recent photoelastic measurements with the Polscope have allowed much more detailed analysis of the forces between cells. The interesting results on microfabricated devices led to work on nanostructures. Results led the Glasgow group to consider dimensions of structures and how cells could sense such small objects and questions about why order and size may be important. Differential protein adsorption onto surfaces seems to provide defective explanations of the effects. The results will be discussed in terms of very recent theories of cell interaction and cell signals and possible future developments will be outlined.

Chemically defined media and the culture of mammalian preimplantation embryos: historical perspective and current issues.

Considerable advances in media development for the culture of preimplantation mammalian embryos have been made since mouse embryos were first cultured and successfully transferred to foster mothers. The purpose of this review is to detail the history of the development of chemically defined media for the culture of preimplantation embryos. Two approaches have been used to determine the composition of chemically defined media: the 'back-to-nature' approach and 'let the embryo choose' or empirical optimization approach. Recent developments, including the supplementation of media with amino acids and the use of sequential media for the extended culture of preimplantation embryos, are critically assessed. Importantly, it is recognized that even the best media currently used are not optimal and inevitably cause imbalances and stress to the embryos. Consequently, preimplantation embryos must adapt to the culture environment in order to survive. The adaptations to stress that occur when embryos are placed in a chemically defined environment are reviewed. The implications of these various stresses on the patterns of gene expression in the early embryo and their potential long-term effects are also emphasized. The scientific and ethical issues raised by the commercialization of human embryo culture media are briefly addressed.

[From wound healing to modern tissue engineering of the skin. A historical review on early techniques of cell and tissue culture]. / Von der Wundheilung zum modernen Tissue Engineering der Haut Ein historischer Rückblick auf frühe Verfahren der Zell- und Gewebekultur.

The early precursors of modern techniques of keratinocyte transplantation and tissue engineering of the skin are reviewed, starting with histological research into the processes of wound healing and of skin transplantation in the 19th century and continuing with the introduction of cell and tissue culture techniques in early 20th century medicine. The later experimental and clinical application of this research in dermatology and plastic surgery is also explored.

The golden age of retinal cell culture.

In the late 1950s, the study of retinal cells in vitro was in its infancy. Today, retinal cell and tissue culture is routinely used for studies of cell growth, differentiation, cytotoxicity, gene expression, and cell death. This review discusses the major classifications of retinal cell and tissue culture, including primary cell/explant models, retinoblastoma cell lines, and genetically engineered cell lines. These topics are addressed in an historical perspective, coupled with present-day applications for this continually-developing technology.

Egg culture: the foundation.

Ralph Brinster began his classic work on egg culture more than 35 years ago. His interest in mammalian egg culture had developed, in part, as a consequence of his experiences with animal breeding and reproduction that he gained while growing up on a farm. Ralph decided early in his career that an in vitro approach to culturing eggs would provide a powerful tool with which to study the development of these cells. Beginning at the close of the 19th century, a number of investigators had performed in vitro studies on egg culture and the related area of egg transfer; however, the ability to recover and transplant eggs had reached a much higher level of perfection than had culture. Eggs of many species could be successfully transferred, but there was no reliable technique for egg culture. In 1963, Ralph reported a method for culturing eggs in microdrops of medium under oil (Brinster, 1963), which has become universally used. Two years later, he identified pyruvate as the central and essential energy source for early stages of mouse eggs (Brinster, 1965b). These two developments revolutionized in vitro studies of mammalian eggs and issued in an era of intense research activity concerning egg culture and egg manipulation. Effective formulations of culture media could now be developed to allow routine in vitro maintenance of eggs, and important parameters for these recipes were soon determined. It was quickly established that the requirement for pyruvate as an energy source exists at ovulation in many species and is already present in germ cells of the mouse fetus. The metabolic activity of the fertilized mouse egg was shown to be low and comparable to bone; however, four days later, at the blastocyst stage of development, the metabolic activity was comparable to brain. Thus, a foundation of understanding about the biology of early mammalian eggs was established between 1960 and 1970, and subsequent studies have broadened this understanding. However, the greatest impact of a simple, reliable egg culture method has been to provide the ability to perform complicated manipulative procedures on preimplantation stages of mammalian embryos. In no area has this been more important than in development of transgenic animals. All methods for generating germ line genetic modifications rely on the ability to maintain and manipulate eggs and early developmental stages in vitro without loss of developmental competence. The importance of efficient egg culture to manipulation and transgenesis is fundamental and enabling.

The African polio vaccine-acquired immune deficiency syndrome connection.

Seroepidemiological, clinical and molecular findings suggest that the acquired immune deficiency syndrome virus human immunodeficiency virus-1 was introduced into the human species at the time (late 1950s) and in the geographic area (Zaire) in which millions of Africans were vaccinated with attenuated poliomyelitis virus strains that were produced in kidney tissue obtained from monkeys. Since monkeys not only harbor viruses that are remarkably similar to and genetically related to human immunodeficiency virus-1, but also served as tissue donors for the African polio vaccine, it is reasonable to suspect that a then non-detectable monkey virus with human-1-like properties was unknowingly co-cultured with the attenuated poliovirus virus and subsequently administered to the vaccinees. The possibility of such a polio vaccine-acquired immune deficiency syndrome connection is a reminder of the unpredictable danger of artifically crossing natural species-barriers in biomedical laboratories.