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ScienceWeek
THEORETICAL BIOLOGY: ON THE DEMISE OF THEORETICAL EMBRYOLOGY
The following points are made by Peter Lawrence (Current Biology 2004 14:R7):
1) Once upon a time, about thirty years ago, there were two species of developmental biologists. The first of these were the experimentalists. These had been around for more than a hundred years and had descended from predecessors such as Boveri, Morgan and Spemann. In attempting to understand the awesome complexity and reliability of development, they developed explanations verging on vitalism. They built concepts such as epigenesis (the hypothesis that development is essentially a process of elaboration from a simpler start), regulation (the notion that embryos are often able to correct damage done to them either by the environment or by the experimentalists) and fields (the idea that specific domains of embryos are to some extent self organizing). These concepts were rather abstract and took little account of either cells or genes. Their experiments, which consisted mainly of transplanting or excising parts of embryos, were published in journals such as Journal of Experimental Zoology and Developmental Biology, and they built their careers as scientists always have. As ever, their fields of investigation evolved through a process of natural selection that was fuelled by fashion.
2) But, around 30 years ago, there was also a growing number of theoretical embryologists, a more recently evolved species, and these usually came from a physics or mathematical background. Perversely, they denied themselves the pleasure of studying embryos and instead took a mix of equations and simulation and tried to model developmental processes. They published their results in special journals such as the Journal of Theoretical Biology. They needed the experimentalists largely to describe phenomena for analysis. But the experimentalists didn't need the theoreticians and usually ignored them, mostly because they could not understand their maths or their language. The theoreticians were powered by the conviction that they were cleverer than the biologists (they were) and that thinking and argument and analysis alone can solve biological problems (they cannot).
3) During the past 30 years we have seen the gradual disappearance and near-extinction of those theoreticians who had attempted to model developmental processes. Some of their journals died out and their impact on biology faded -- they were killed off partly by the sheer unpredictability and illogicality of biological mechanism. And also because molecular biology as well as genetics gave the experimentalists new and powerful tools to solve problems. For example, one could spend years making mathematical models of how to form the stripes of a segmentation gene in the embryo of Drosophila, but one experimental result on the gene itself could destroy all of them.
4) It is remarkable that almost an entire species of scientist can arise and die out in such a short period, but it has happened before -- fashion influences young people too much when they choose their careers so that, at any time and in any one field, there are either too many, or too few scientists. Of course there are still theoreticians working in developmental biology, but they are few in number. Now there seems to be a new wave of theorists arriving, and most are recruits from physics, mathematics and computing. The author hopes they won't mind being warned that they would be wise not to try to answer the problems of animal development with their heads alone. They must use their hands as well.
Current Biology http://www.current-biology.com
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THEORETICAL BIOLOGY: CONTROLLING CELL CYCLE DYNAMICS
During the past few decades, studies of the *cell division cycle have revealed many of the genes and proteins that drive and regulate cell division, and methods for the artificial control of the cell cycle have become apparent. Such manipulations are typically achieved by introducing mutations into the genes that regulate the cycle. These mutations, however, usually result in uncontrolled cell division, or complete suppression of cell division, or cause the cell to commit fatal errors during the cell cycle.
The following points are made by T.S. Gardner et al (Proc. Nat. Acad. Sci. 1998 95:14190):
1) Using mathematical modeling of cell division cycle dynamics, the authors report a potential mechanism for the precise control of the frequency of cell division and regulation of the size of the dividing cell. The work of the authors involves the application of a specific biochemical constraint to two already existing mathematical models of cell cycle dynamics (models by A. Goldbeter; B. Novak and J.J. Tyson). The authors report that control of the cell cycle in their application is achieved by artificially expressing a protein that reversibly binds and inactivates any one of the cell division cycle proteins.
2) In the simplest case (the Goldbeter model), the frequency of cell division cycle oscillations can be increased or decreased by regulating the rate of synthesis, the binding rate, or the equilibrium constant of the binding protein. In a more complex model of cell division (the Novak-Tyson model), the authors report that the same reversible binding reaction can alter the mean cell mass in a continuously dividing cell.
3) The authors suggest that because their control scheme is general and requires only the expression of a single protein, it provides a practical means for tuning the characteristics of the cell cycle in vivo.
Proc. Nat. Acad. Sci. http://www.pnas.org
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Notes:
cell division cycle: (cell cycle) Prior to each cell division, a cell passes through a series of preparatory stages that are collectively known as the "cell cycle". The cycle is considered to begin when two new cells are formed by the division of a single parent cell, and it ends when one of these new cells in turn divides to form two more cells. The paramount process is the transfer of a complete set of genetic instructions to each new cell. The periodicity of the cycle varies from one type of cell to another, and within a single type, the periodicity can also vary in response to ambient conditions. Laboratory methods are now available to not only control the periodicity of the cell cycle, but also to synchronize the periodicities of a population of cultured cells. The obvious oscillatory behavior of biological cells has for many decades been the focus of much research involving mathematical modeling.
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DEVELOPMENTAL BIOLOGY: VOLVOX EMBRYOLOGY
The following points are made by Roediger Schmitt and Manfred Sumper (Nature 2003 424:499):
1) Something quite remarkable happens to embryos of the multicellular green alga Volvox carteri: they turn completely inside out to establish the adult body plan. This inversion process closely resembles the initial stages of the more complex gastrulation that occurs in animal embryos -- so Volvox could arguably be considered a simple model for analyzing the principles that direct such changes in shape.
2) In the embryos of most multicellular animals, sheets of cells invaginate during gastrulation, neurulation, and organ formation. Gastrulation is the central process in early animal development, and occurs during the blastula stage -- when the embryo consists simply of a hollow ball of cells. It involves complex movements that carry those cells whose descendants will form the future internal organs from their superficial position on the blastula to their definitive positions inside the embryo. Similarly, neurulation in vertebrates involves a complicated curling of a cellular sheet to form the neural tube, which in turn develops into the central nervous system.
3) Gastrulation has fascinated developmental biologists ever since it was recognized in 1874. Nearly 100 years ago, the Italian embryologist Angelo Ruffini (1864-1929) first described the appearance of elongated cells -- known as bottle or flask cells -- at the onset of the process in amphibians. Then, in his classic papers on amphibian gastrulation, Johannes Holtfreter (1901-1992) claimed that the ability to invaginate is an innate property of flask cells. Modern investigations confirm that the number and arrangement of the flask cells are critical factors for proper initiation of invagination. But, as pointed out by Keller (1996), what flask cells do -- and how, in a biomechanical sense, they do it -- remains to be elucidated. Volvox carteri, a much simpler organism, might be the Rosetta Stone that enables researchers to unlock the problem.
4) Volvox is a multicellular green alga that exhibits the simplest kind of differentiation -- the division of labor between just two types of cell. The adult organism consists of about 2,000 mortal somatic cells, which make up the surface of a hollow sphere, and 16 larger, potentially immortal reproductive cells just below the surface. The development of Volvox starts with a single reproductive cell, which undergoes a patterned sequence of 11 cell divisions. The first five divisions are symmetrical, resulting in an embryo consisting of 32 cells of similar sizes. But the sixth division of the 16 most anterior cells is asymmetric, and results in the production of 16 cell pairs of unequal size. The larger cells will become the new reproductive cells.
5) As a result of geometrical constraints, at the end of the 11 cell divisions the embryo is inside out with respect to the adult configuration: the large reproductive cells protrude from the surface, and the bases of the developing flagella of all the somatic cells point to the interior of the hollow sphere. So cell division is followed by inversion, in which the curvature of the embryo is reversed to establish the adult configuration. Development of Volvox therefore resembles that of classic models of animal development, such as sea urchins and nematode worms, in that an important differentiating cell division is visibly asymmetric, and the adult configuration is attained by a gastrulation-like event.
Nature http://www.nature.com/nature
ScienceWeek http://scienceweek.com
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