Alfred Gierer

A theory of biological pattern formation.

One of the elementary processes in morphogenesis is the formation of a spatial pattern of tissue structures, starting from almost homogeneous tissue. It will be shown that relatively simple molecular mechanisms based on auto- and cross catalysis can account for a primary pattern of morphogens to determine pattern formation of the tissue. The theory is based on short range activation, long range inhibition, and a distinction between activator and inhibitor concentrations on one hand, and the densities of their sources on the other. While source density is expected to change slowly, e.g. as an effect of cell differentiation, the concentration of activators and inhibitors can change rapidly to establish the primary pattern; this results from auto- and cross catalytic effects on the sources, spreading by diffusion or other mechanisms, and degradation.Employing an approximative equation, a criterium is derived for models, which lead to a striking pattern, starting from an even distribution of morphogens, and assuming a shallow source gradient. The polarity of the pattern depends on the direction of the source gradient, but can be rather independent of other features of source distribution. Models are proposed which explain size regulation (constant proportion of the parts of the pattern irrespective of total size). Depending on the choice of constants, aperiodic patterns, implying a one-to-one correlation between morphogen concentration and position in the tissue, or nearly periodic patterns can be obtained. The theory can be applied not only to multicellular tissues, but also to intracellular differentiation, e.g. of polar cells.The theory permits various molecular interpretations. One of the simplest models involves bimolecular activation and monomolecular inhibition. Source gradients may be substituted by, or added to, sink gradients, e.g. of degrading enzymes. Inhibitors can be substituted by substances required for, and depleted by activation.Sources may be either synthesizing systems or particulate structures releasing activators and inhibitors.Calculations by computer are presented to exemplify the main features of the theory proposed. The theory is applied to quantitative data on hydra — a suitable one-dimensional model for pattern formation — and is shown to account for activation and inhibition of secondary head formation.

Pattern formation by local self-activation and lateral inhibition.

In 1972, we proposed a theory of biological pattern formation in which concentration maxima of pattern forming substances are generated through local self-enhancement in conjunction with long range inhibition. Since then, much evidence in various developmental systems has confirmed the importance of autocatalytic feedback loops combined with inhibitory interaction. Examples are found in the formation of embryonal organizing regions, in segmentation, in the polarization of individual cells, and in gene activation. By computer simulations, we have shown that the theory accounts for much of the regulatory phenomena observed, including signalling to regenerate removed parts. These self-regulatory features contribute to making development robust and error-tolerant. Furthermore, the resulting pattern is, to a large extent, independent of the details provided by initial conditions and inducing signals.

Function of aggregated reticulocyte ribosomes in protein synthesis

The ribosome fraction of rabbit reticulocytes contains ribosomal units with a sedimentation coefficient of 80 s and some smaller components. In addition there is a spectrum of at least five more rapidly sedimenting fractions, comprising of the order of 30% or more of the material. The fast fractions are considered to be aggregates of ribosomes consisting of up to six ribosomal units. They disintegrate into the 80 s ribosomal units upon incubation with RNase. The fast fractions, separated from the slow fraction by sucrose gradient centrifugation, are shown to be more active both in whole cell and in cell-free incorporation of radioactive amino acids. Incorporation of [ 14 C]phenylalanine is stimulated by the addition of polyuridylic acid as messenger RNA. The stimulation of activity is maximum for unaggregated ribosomes. Part of the active products of stimulation appear to be aggregates. The results indicate that many of the aggregated ribosomes contain messenger RNA, but are not receptive to added messenger RNA; whereas many of the unaggregated ribosomes do not contain messenger RNA, but are receptive to added messenger RNA molecules. The simplest interpretation is that the linkage of the ribosomes into aggregates is due to the messenger RNA itself. The findings support a theory of protein synthesis whereby several ribosomes can operate simultaneously on one molecule of messenger RNA.

Quantitative Analysis of Cell Types during Growth and Morphogenesis in Hydra

SummaryTissue maceration was used to determine the absolute number and the distribution of cell types in Hydra. It was shown that the total number of cells per animal as well as the distribution of cells vary depending on temperature, feeding conditions, and state of growth. During head and foot regeneration and during budding the first detectable change in the cell distribution is an increase in the number of nerve cells at the site of morphogenesis. These results and the finding that nerve cells are most concentrated in the head region, diminishing in density down the body column, are discussed in relation to tissue polarity.

Molekulare Theorie der Mikroreibung

Clemens Schaefer zum 75. Geburtstag gewidmet Die Flüssigkeitsschichten, die um ein sich bewegendes Molekül herumfließen, haben infolge der endlichen Abmessungen der Flüssigkeitsmolekeln eine endliche Dicke. Die Berücksichtigung dieses Umstandes führt zu einer Modifikation der Stokesschen Gesetze der Kontinuumstheorie für den Zusammenhang zwischen Reibung und Viskosität. Es ergibt sich die richtige Größenordnung und ungefähr die richtige Radienabhängigkeit der beobachteten Mikroreibung.

Generation and regeneration of sequence of structures during morphogenesis

Abstract Models for the generation and repair of sequences of structures in space are proposed. One possibility consists of the mutual or sequential induction of locally exclusive states. The general properties of such an interaction are demonstrated by a system of two components which mutually activate each other: the partition of a field into two parts with good size regulation is possible. Symmetric double gradients or periodic patterns can be formed. In a two-dimensional field, this type of interaction permits the formation of “stripes” of high concentrations of the components. In an extension to more than two components, sequences of structures are formed which show intercalary or terminal regeneration. Relatively simple molecular interactions can lead to such patterns. In some biological cases, experimental evidence suggests that the first step in the formation of a sequence is the determination of one or both terminal elements, followed by sequential filling in of the missing structures. The latter process can be mediated by a general signal formed at the discontinuity. If some monotonically increasing physical parameter r (positional value) occurs in the natural sequence, a discontinuity in the r -concentration is formed at the location of the gap. This discontinuity can be converted into a local maximum and/or minimum, serving as a gap sensing signal and leading to the induction of the missing structures. The other extreme type of model posits that the determination consists solely of the response of cells to the local concentration of a morphogen. In such a positional information scheme, a sequence of structures can be elongated by marginal growth if a feedback of the achieved states of determination or to the morphogen gradient is assumed. This permits the successive increase of the maximum morphogen concentration during the outgrowth enabling the accretion of new structures. The similarities in and differences between such models are discussed. Intermediate forms of these “pure” types are presumably involved in the control of development and some examples are given. Possible application to the developmental control of insects are discussed, in particular to the phenomena of intercalary regeneration and the duplication of excessive parts, as well as to the promimo-distal organisation of the vertebrate limb. Computer simulations are provided which demonstrate the feasibility of the models proposed.

Generation of biological patterns and form: Some physical, mathematical, and logical aspects

While many different mechanisms contribute to the generation of spatial order in the development of an organism, the formation of morphogenetic fields within initially nearuniform cells and tissues which in turn direct cell responses giving rise to pattern and form are of major importance and an essential part of the biological generation cycle. The chemical nature of such fields is not yet known, but it is most likely that they represent spatial concentration patterns of substances (or states of substances) produced by molecular kinetics. Short-range autocatalytic activation in conjunction with longer range inhibition or depletion effects suffice to generate such patterns. These conditions are necessary for the simplest two-factor case and are likely to be fair approximations in multi-component systems in which activation and inhibition may be system parameters, subsuming the action of several agents. The conditions of autocatalysis and lateral inhibition can be shown to be closely related to the analytical results obtained by general stability analysis, although this correspondence is not trivial and not immediately obvious. Very different molecular mechanisms are consistent with the concept, but fairly simple mechanisms known in molecular biology, in suitable

ON THE GROWTH MECHANISM OF THE BACTERIAL CHROMOSOME.

Physical methods have been used to determine the number of growth points on the DNA of E. coli bacteria. The thymine analogue [14C]5-bromouracil was incorporated into DNA for varying short times. The labelled DNA was isolated with a molecular weight of 4 × 107. The density distribution of the radioactivity was investigated in CsCl gradients. As the size of the 5-bromouracil-labelled section of DNA increases relative to the size of the isolated piece of DNA (4 × 107 mol. wt.), the radioactivity shifts towards the density of a pure hybrid thymine—5-bromouracil double strand. From the density distribution of the radioactivity and the size of the isolated DNA one can calculate the size of the 5-bromouracil-labelled section. One calculates the same size for the total amount of radioactivity incorporated into DNA per nucleus. Thus the chromosome grows at only one point.

Self-renewal of stem cells and differentiation of nerve cells in the developing chick retina

Data on proliferation and self-renewal of stem cells in the developing chick retina were obtained on the basis of measurements of cells labeled by [3H]thymidine pulses in conjunction with the rate of increase in total cell number. Duration of S-phase was found to be about 4 h between stages 4 and 9 days. Self-renewal drops below the critical value of 50% (implying a transition from increase to depletion of absolute number of stem cells in the tissue) around day 7.6. The spatial order of cell proliferation was studied by measurements taken on subregions of retinas at various stages of development. Proliferating cells forming the ventricular layer increase in all regions of the retina up to day 7, though the proportion of proliferating cells is lowest in the center. From day 5 on it is higher in the nasal as compared to the temporal part of the tissue. After day 7 self-renewal of stem cells drops below 50%, stem cells become depleted and withdraw gradually from mitosis. The process is initiated in the center slightly temporal to the dorsal end of the optic fissure and then spreads rapidly towards the periphery, reaching the temporal margin first. The findings imply that while cells at the periphery are younger on the average, those cells which have become postmitotic at an early stage are not confined to a small central core of the fully developed retina, because the tissue continues to grow and produce postmitotic cells in all regions of the retina up to day 7.

Die Infektiosität der Nucleinsäure aus Tabakmosaikvirus

Die durch kurzzeitige Phenolbehandlung des Tabakmosaikvirus isolierte Ribonucleinsäure hat infektiöse Eigenschaften. Es wurde gezeigt, daß der Effekt nicht auf Beimengungen von intaktem Virus beruht oder von der Anwesenheit kleinerer Mengen von nativem Virusprotein abhängt. Somit erscheint die Ribonucleinsäure als diejenige Komponente des Virus, die den Reproduktionsvorgang bewirkt.