Histochemistry and cell biology: what’s in a name?

Histochemistry represents an integrative discipline aiming at the in situ detection, localization and functional characterization of cellular and extracellular components in single cells and complex organs. Therefore, the development of new methods and improvement of existing ones continues to be important. This, however, is with the declared intent for their application in the various fields of developmental and cell biology as well as pathology in order to contribute to the solution of open problems. This review summarizes recent advancements in these fields. Accepted: 8 November 1999     

Quantitative modeling in cell biology: what is it good for?

Recently, there has been a surge in the number of pioneering studies combining experiments with quantitative modeling to explain both relatively simple modules of molecular machinery of the cell and to achieve system-level understanding of cellular networks. Here we discuss the utility and methods of modeling and review several current models of cell signaling, cytoskeletal self-organization, nuclear transport, and the cell cycle. We discuss successes of and barriers to modeling in cell biology and its future directions, and we argue, using the field of bacterial chemotaxis as an example, that the closer the complete systematic understanding of cell behavior is, the more important modeling becomes and the more experiment and theory merge.     

Cancer and stem cell biology: how tightly intertwined?

Ever since the discovery of cancer stem cells in leukemia and, more recently, in solid tumors, enormous attention has been paid to the apparent stem cell nature of cancer. These concepts were the focus of the "Stem Cells and Cancer" symposium held recently at the University of California, San Francisco, and the inspiration for this overview of current research and important questions emerging in this area.     

Cancer immunotherapy: simply cell biology?

There is a clear need for improved cancer therapy and survival rates. Effective immunotherapy would be the treatment modality of choice from several viewpoints, and dendritic cell (DC)-based immunotherapy is emerging as the most promising approach to cancer immunotherapy. However, the plethora of approaches to DC-based cancer therapy now threatens to impede the development of an effective immunotherapy regime, as competing egos and commercial interests masquerade as scientific rigour. Here, I argue that the current controversies regarding the numerous approaches reflect the paucity of our immunological understanding, and present a simple cell biological analysis that defines the rationale for the development of effective cancer immunotherapy.     

Single-molecule biology: what is it and how does it work?

Biochemistry and structural biology are undergoing a dramatic revolution. Until now, we have tried to study subtle and complex biological processes by crude in vitro techniques, looking at average behaviors of vast numbers of molecules under conditions usually remote from those existing in the cell. Researchers have realized the limitations of this approach, but none other has been available. Now, we can not only observe the nuances of the behaviors of individual molecules but prod and probe them as well. Perhaps most important is the emerging ability to carry out such observations and manipulations within the living cell. The long-awaited leap to an in vivo biochemistry is at last underway.     

Phage-exclusion enzymes: a bonanza of biochemical and cell biology reagents?

Many parasitic DNA elements including prophages and plasmids synthesize proteins that kill the cell after infection by other phages, thereby blocking the multiplication of the infecting phages and their spread to other nearby cells. The only known function of these proteins is to exclude the infecting phage, and therefore to protect their hosts, and thereby the DNA elements themselves, against phage contagion. Many of these exclusions have been studied extensively and some have long been used in molecular genetics, but their molecular basis was unknown. The most famous of the phage exclusions are those caused by the Rex proteins of λ prophage. The Rex exclusions are still not completely understood, but recent evidence has begun to lead to more specific models for their action. One of the Rex proteins, RexA, may be activated by a DNA-protein complex, perhaps a recombination or replication intermediate, produced after phage infection. In the activated state, RexA may activate RexB, which has been proposed to be a membrane ion channel that allows the passage of monovalent cations, destroying the cellular membrane potential, and killing the cell. We now understand two other phage exclusions at the molecular level which use strategies that are remarkably similar to each other. The parasitic DNA elements responsible for the exclusions both constitutively synthesize enzymes that are inactive as synthesized by the DNA element but are activated after phage infection by a short peptide determinant encoded by the infecting phage. In the activated state, the enzymes cleave evolutionarily conserved components of the translation apparatus, in one case EF-Tu, and in the other case tRNA^Lys. Translation is blocked and development of the phage is arrested. A myriad of different phage-exclusion systems are known to exist and many of these may also be specific for highly conserved cellular components, furnishing generally useful enzymes for biochemical and biomedical research.     

Modifying modifiers: what happens when interspecific interactions interact?

1. The strength of the trophic link between any given pair of species in a food web is likely to depend on the presence and/or densities of other species in the community. How these trophic interaction modifications (TIMs) interact with one another to produce a net modifying effect is an important but under-explored issue. 2. We review several specific types of TIMs that are well understood to address whether the magnitude of the net modification changes with the number of modifiers, and whether modifiers usually increase or decrease each other's effects. 3. Modifications of interactions are generally not independent. It is likely that TIMs interact antagonistically in the majority of cases; the magnitudes of TIMs decrease as more modifiers are added, or new TIMs reduce the magnitudes of modifications that are already present. 4. Individual modifications are likely to have a smaller effect in many-species systems than expected from independent combination of modifications measured in systems with relatively few species. Thus, models that lack explicit TIMs may in some cases yield adequate predictions for species-level perturbations, provided that the net effects of TIMs are implicitly included in measured interaction strengths. 5. Many types of TIMs share structural similarities. Nevertheless, a complete understanding of their effects may require theory that distinguishes different 'functional groups' of modifiers and addresses how these are structured according to trophic relationships.     

So what if parasites vary?

The British Society for Parasitology Autumn Symposium was held on 14 September 2001 at the Linnean Society of London, UK, only a few yards from the room in which Darwin and Wallace presented their joint papers on organic variation. Fittingly, the symposium--Parasite variation: immunological and ecological significance--considered the consequences of parasite variation.     

Coordinating cell polarity and cell cycle progression: what can we learn from flies and worms?

Spatio-temporal coordination of events during cell division is crucial for animal development. In recent years, emerging data have strengthened the notion that tight coupling of cell cycle progression and cell polarity in dividing cells is crucial for asymmetric cell division and ultimately for metazoan development. Although it is acknowledged that such coupling exists, the molecular mechanisms linking the cell cycle and cell polarity machineries are still under investigation. Key cell cycle regulators control cell polarity, and thus influence cell fate determination and/or differentiation, whereas some factors involved in cell polarity regulate cell cycle timing and proliferation potential. The scope of this review is to discuss the data linking cell polarity and cell cycle progression, and the importance of such coupling for asymmetric cell division. Because studies in model organisms such as Caenorhabditis elegans and Drosophila melanogaster have started to reveal the molecular mechanisms of this coordination, we will concentrate on these two systems. We review examples of molecular mechanisms suggesting a coupling between cell polarity and cell cycle progression.     

Community dynamics: what happens when we rerun the tape?

The role of historical events, such as disturbances, in producing alternative developmental outcomes in forest structure has long been debated. Diversity in the assemblages of coexisting species is one measure of alternative outcomes of succession. The intermediate disturbance hypothesis proposes that a moderate disturbance level produces the highest levels of species diversity. Here, we use an agent-based model of forest development under a gradient of lightning strike frequency to analyse long-term dynamics of species coexistence in a multi-species forest. The configurations of species that result from disturbance dynamics reflect the interactions between life-history characteristics of the species and disturbance characteristics. Model results suggest that low levels of disturbance lead to highly ordered landscapes which exclude fire and are captured by late successional species. High levels of disturbance lead to oscillation between domination by early successional species and large disturbances. At intermediate levels of disturbance, the forest displays the broadest array of developmental pathways, highest entropy as measured by Shannon's index of diversity, and critical slowing near steady states. Long transients at intermediate regimes may reflect the working out of closely balanced constraints of competition between species with varying strategic adaptations to disturbance. Intermediate disturbance levels also result in the greatest number of alternative diversity configurations as outcomes of succession, reflecting an unpredictable and nonequilibrium forest dynamic.     

TGFβ in T cell biology and tumor immunity: Angel or devil?

The evolutionally conserved transforming growth factor β (TGFβ) affects multiple cell types in the immune system by either stimulating or inhibiting their differentiation and function. Studies using transgenic mice with ablation of TGFβ or its receptor have revealed the biological significance of TGFβ signaling in the control of T cells. However, it is now clear that TGFβ is more than an immunosuppressive cytokine. Disruption of TGFβ signaling pathway also leads to impaired generation of certain T cell populations. Therefore, in the normal physiological state, TGFβ actively maintains T cell homeostasis and regulates T cell function. However, in the tumor microenvironment, TGFβ creates an immunosuppressive milieu that inhibits antitumor immunity. Here, we review recent advances in our understanding of the roles of TGFβ in the regulation of T cells and tumor immunity.