No place like home: competition, dispersal and complex adaptation.

In many groups of organisms the location of settling is determined by competition, and fitter individuals tend to settle closer to their natal territory than less fit ones. In this work we study the implications of this phenomenon to the problem of adaptation and speciation on a rugged adaptive landscape. One consequence of fitness-associated dispersal (FAD) is that individuals with high fitness are more likely to experience inbreeding, especially with other fit individuals. Another consequence is that when dispersal is costly, the less fit individuals are more likely to pay the cost. When a rare and advantageous allelic combination appears, FAD may increase its chances to spread in the population. In a two-locus two-alleles model with negative epistasis, we find that FAD significantly shortens the waiting time for an adaptive peak shift in comparison with random dispersal.

Partnership.

Individuals are called partners when it is in their best interest to help each other, if by doing so they increase the probability of being together in the future when, for similar reasons, they will continue to help each other. Kinsmen or individuals who often face (hedonic) situations in which helping is the dominating strategy are committed to help each other. Partnership may develop among them since the loss of the other means the loss of a guaranteed helper. Thus, they may be willing to take additional risks to help each other. Partnership may occur among unrelated individuals and with no hedonic situations. Partnership creates bonds between partners which may be much stronger than those between kinsmen; an individual may take more risks for his partner than he will ever take for a kin. Partnership may evolve without the sophistication and memory required for reciprocation altruism. Although kin selection, partnership and reciprocation are likely to appear fused as the causes for altruism, we argue that it may be possible to distinguish between them in some situations. We show that as the partners get older partnership may become less important to them. We also show that like cooperation, and for analogous reasons, malice may evolve among partners so that each will be willing to take additional risks in order to eliminate the other.

Multiple asymmetry and concord resolutions of a conflict.

A model for a population-game with multiple asymmetry is studied, in which the participants are assumed to be different from one another both in size and in status as owners or non-owners of a territory. Only owners can reproduce, hence natural selection is assumed to operate in favor of the increase of ownership-time. Conditions for the evolutionary stability of the Bourgeois Principle of owner-priority, despite difference in body size, are characterized. It is shown that ownership-priority tends to be at least partially replaced by strength-priority as the availability of habitats, the expected longevity of potential intruders and the harm inflicted on the loser of an aggressive confrontation decrease, and as the expected longevity of the owner increases. It is further established that the combined effect of all these parameters can be characterized by a single parameter, referred to as the concord coefficient of the population. Finally, when this parameter reaches a certain critical level, only strength-priority can prevail. If the concord coefficient decreases below this critical level, no priority-rule can remain stable in the population, in which case aggressive confrontations cannot be avoided, at least in certain situations. In this case, it is shown that aggression emerges first among low-rank individuals.

Canalization, genetic assimilation and preadaptation. A quantitative genetic model.

We propose a mathematical model to analyze the evolution of canalization for a trait under stabilizing selection, where each individual in the population is randomly exposed to different environmental conditions, independently of its genotype. Without canalization, our trait (primary phenotype) is affected by both genetic variation and environmental perturbations (morphogenic environment). Selection of the trait depends on individually varying environmental conditions (selecting environment). Assuming no plasticity initially, morphogenic effects are not correlated with the direction of selection in individual environments. Under quite plausible assumptions we show that natural selection favors a system of canalization that tends to repress deviations from the phenotype that is optimal in the most common selecting environment. However, many experimental results, dating back to Waddington and others, indicate that natural canalization systems may fail under extreme environments. While this can be explained as an impossibility of the system to cope with extreme morphogenic pressure, we show that a canalization system that tends to be inactivated in extreme environments is even more advantageous than rigid canalization. Moreover, once this adaptive canalization is established, the resulting evolution of primary phenotype enables substantial preadaptation to permanent environmental changes resembling extreme niches of the previous environment.

Continuous stability and evolutionary convergence.

A stochastic process of long-term evolution due to mutation and selection is defined over an asexually reproducing population, with selection according to a population game with a one-dimensional continuity of pure strategies. Limiting the analysis to mutations of small effect, it is shown that long-term dynamic stability in such a process is equivalent to continuous stability in the relevant population game. In the case of a one-dimensional strategy set (but not necessarily if the strategy set is multi-dimensional), this result is virtually independent of the distribution of mutations.

On the changing concept of evolutionary population stability as a reflection of a changing point of view in the quantitative theory of evolution.

Eighteen different terms, currently employed to define various concepts of evolutionary stability in population dynamics are mentioned in this paper. Most of these terms are used in different connotations and even different meanings by different authors. On the other hand, different terms are often employed by different authors to define quite the same concept. Twenty-five years ago there was only one, well-defined, concept of stability, universally recognized in the field. In this paper I will try to relate the recent confusion, concerning concepts of population stability, with a more serious, though not that well-recognized, confusion in the modern analytic approach to population dynamics and quantitative evolution. Concepts of population stability will be examined in relation to each other on the one hand and, on the other hand, in relation to two dichotomies regarding the dynamic processes to which they correspond: Short-term versus long-term processes and processes concerning phenotypic changes versus process concerning genotypic changes. A hopefully more consistent use of the current terminology is suggested.

Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium. III. Growth conditions of human thymic epithelial cells and immunomodulatory activities in their culture supernatant.

We report here on a new approach to the cultivation of human thymic epithelial (HTE) cells, which apparently allows more faithful preservation of cell function. This approach, previously developed by us for mouse thymic epithelial (MTE) cells, is based on the use of culture plates coated with extracellular matrix (ECM), and on the use of serum-free, growth factor-supplemented medium. The nutritional requirements of HTE and MTE are somewhat different. Although both are critically dependent on ECM and insulin, they differ in their dependency on other growth factors: selenium and transferrin are much more important for HTE cells, whereas epidermal growth factor and hydrocortisone play a more essential role in MTE cultures. The epithelial nature of the cultured cells is indicated by positive staining with anti-keratin antibodies and by the presence of desmosomes and tonofilaments. The ultrastructural appearance of the cells further suggests high metabolic and secretory activities, not usually found in corresponding cell lines. The culture supernatant (CS) of HTE cells exhibited a strong enhancing effect on thymocyte response to Con A stimulation, as measured by cell proliferation and lymphokine production. The effect was observed on both human and mouse thymocytes, but was much stronger in the homologous combination. Thymic factors tested in parallel did not have such a differential effect. The dose-effect relationships were in the form of a bell-shaped curve, with fivefold enhancement of response at the peak and a measurable effect even with 1:1000 dilution, when human thymocytes were used. The responding thymocytes were those which do not bind peanut agglutinin and are resistant to hydrocortisone. The culture system described here may have advantages for the in vitro study of thymic stromal cell function.

Two-locus autosomal sex determination: on the evolutionary genetic stability of the even sex ratio.

In two-locus models of sex determination, there are two kinds of interior (polymorphic) equilibria. One class has the even sex ratio, and the other has equal allele frequencies in the two sexes. Equilibria of the second class may exhibit linkage disequilibrium. The condition for external stability of these second-class equilibria to invasion by a new allele is that the appropriately averaged sex ratio near the equilibrium be moved closer to the even sex ratio than the average among the resident genotypes. However, invasion by a new chromosome depends on the recombination fraction in a way that appears to preclude general results about the evolutionary genetic stability of the even sex ratio in this situation.

Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium. I. Growth conditions and morphology of murine thymic epithelial and mesenchymal cells.

We report here the successful selective cultivation of murine thymic mesenchymal reticular cells (MTMC) and murine thymic epithelial cells (MTEC) grown on extracellular matrix in the presence of defined medium. The selective growth of these two cell types was based on 1) conditions of tissue disruption and 2) differential growth requirements. Both cell types were dependent on transferrin, high density lipoproteins, insulin, hydrocortisone, and epidermal growth factor, whereas MTMC was dependent also on selenium and 3,5,3'-triiodothyronine. The elimination of single factors or extracellular matrix resulted in specific and different changes in the growth pattern of each cell subpopulation. Cells of both types exhibited the ultrastructural features of high metabolic activity. The epithelial nature of MTEC cultures was defined by bundles of tonofilaments and desmosomes and by positive staining to keratins and negative to vimentin. In addition MTEC were positively stained with mAb to thymic medullary epithelial cells and by Ulex europeus agglutinin, and were able to form Hassall's corpuscles, suggesting their medullary origin. MTEC were also H-2 and Ia positive. In contrast MTMC were positive for vimentin and periodic acid-Schiff, low positive for H-2, and negative for keratin and Ia. Both cells did not contain nonspecific esterase, nor did they phagocytize latex beads. With the use of all these criteria we classified MTEC as epithelial cells from the medullary compartment of the thymus and MTMC as reticular cells of mesenchymal origin.

Analysis of thymic stromal cell subpopulations grown in vitro on extracellular matrix in defined medium. II. Cytokine activities in murine thymic epithelial and mesenchymal cell culture supernatants.

Two morphologically distinct primary cultures of murine thymic stroma were established and found to be of epithelial (MTEC) and mesenchymal (MTMC) origin. These cultures were generated by selective conditions of tissue disruption and were maintained on extracellular matrix in defined medium. Culture supernatants (CS) from these cultures (EC-CS and MC-CS respectively), were tested for cytokine production and for effects on thymocyte maturation. Both supernatants displayed the activities of IL-3 and of granulocyte/macrophage-CSF and not of IL-1, -2, -4, or IFN. In addition they were found to be mitogenic to murine thymocytes in a "spontaneous" [3H]TdR incorporation assay. The two supernatants differed, however, in their effect on Con A stimulation. EC-CS had a strong enhancing effect, both when used for preincubation (18 h) before Con A stimulation or when present simultaneously with it. MC-CS had a small inconsistent effect under these conditions. Also EC-CS enhanced IL-2 and IL-3 production by thymocytes. The responsive thymocyte subpopulation was the one that does not bind peanut agglutinin. CS of an established thymic epithelial cell line displayed only part of these activities at a considerably lower level. CS from primary kidney cell culture was completely devoid of activity. The results suggest that primary thymic stromal cell cultures, cultivated under the defined conditions described here, may better preserve physiologic secretory activities, and probably also other cell functions, compared with established cell lines. Furthermore, the results are compatible with the hypothesis that the soluble factors, secreted by thymic stromal cells, are active on either very early or late stages of thymic differentiation, whereas the main intrathymic stages of differentiation are conceivable dependent primarily on direct contact with stromal cells.

Modulation of immune response and tumor development in tumor-bearing mice treated by the thymic factor thymostimulin.

Thymostimulin (TS), a partially purified thymic factor, has a significant impact on tumor development in C57B1/6 mice inoculated with Lewis lung carcinoma (3LL) cells, as judged by its effect on time of tumor appearance after tumor cell transplantation. In a previous study, we determined the conditions under which survival rate of the tumor-bearing mice can be significantly increased by TS treatment. In the study communicated here we analyzed host defense mechanisms that are modified by TS treatment in the tumor-bearing mice. In general, immune parameters that were increased or stimulated by the presence of the tumor were further increased in the TS-treated animals (number of lymphoid spleen cells, their response in mixed lymphocyte tumor cultures, their natural killer cell activity, and their ability to produce colony-stimulating factor), or reached earlier maximum levels (spontaneous [3H]thymidine incorporation, a reflection of in vivo spleen cell activation). Responses which reflect tumor-induced immunosuppression (proliferative response induced by phytohemagglutinin or concanavalin A stimulation) were restored to normal level by TS. Specific tumor-related reactions (specific cell-mediated cytotoxicity) were preserved in the TS-treated animals. The wide spectrum of TS effects had, nevertheless, certain elements of selectivity; e.g. colony-stimulating factor, but no interferon production is enhanced by TS in the tumor-bearing mice in diametric contrast to TS effect in Mengo virus-infected mice. The spectrum of TS effects was also dependent on the type of tumor cell used. The results indicate that the significant effect of TS on 3LL tumor development in mice is associated with a strong, multifaceted effect of TS on the immune system.

On the evolution of an inner conflict.

A simple two-locus genetic model is suggested, in which a "conflict" between alleles located at different loci leads to the establishment under certain conditions of fixation of a double mutant type which is different from the wild type only in the fact that a smaller fraction of its offspring, either males or females, survive to maturity. The double mutant is characterized by conflicting features determined by the different loci. The results are obtained by an analysis of an exact genetic model, though they are partly interpreted in terms of locus-dependent kin selection.

On the survival probability of a slightly advantageous mutant gene in a multitype population: a multidimensional branching process model.

The estimated survival probability of a slightly supercritical Galton-Watson process is generalized to a multitype branching process. The result is used to estimate the probability of initial success of a mutant gene whose effect on the individual carrier depends on the carrier's sex, class, etc. The probability of initial success is also estimated in a case where the effect of the mutation is manifested in terms of the distribution of types within one's progeny, e.g. in a case of a change in the sex ratio.

Thymic hormonal activity on human peripheral blood lymphocytes, in vitro. IV. Proliferative response to allogeneic tumor cells in healthy adults and cancer patients.

A mixed lymphocyte tumor culture (MLTC) assay was used in order to assess thymic hormonal activity on human T-lymphocyte function. Peripheral blood mononuclear cells (PBMC) from 55 healthy subjects and 54 immunodeficient cancer patients were incubated with the thymic extract TP-1, cultured with allogeneic tumor cells (Raji lymphoma or IgR3 melanoma cells) under limiting stimulation conditions and their proliferative response measured by 3H-thymidine incorporation. Mean proliferative response in the cancer group was lower than in the healthy group. TP-1 caused a significant enhancement of mean proliferative response, comparable in the healthy and cancer groups, under all the conditions tested. Analysis of response in the individual cases disclosed a wide scatter of TP-1 effects, including some cases of TP-1 induced suppression. A significant negative correlation between TP-1 effect and level of proliferative response in control was found: enhancement of proliferative response by TP-1 became progressively greater as control proliferative response became progressively lower. A similar pattern was noticed in the cases of TP-1 induced suppression. The negative correlation was similar for the healthy and cancer groups. These results cannot be interpreted in terms of restoration of deficient immune functions, but are compatible with an indirect, regulatory effect of TP-1 on proliferative response, exerted to a comparable degree in the healthy and immunodeficient situations. The possibility that thymic factors regulate normal immune functions, not merely restore deficient functions to normal, may have interesting clinical implications.

Assortment of encounters and evolution of cooperativeness.

The method of evolutionary stable strategies (ESS), in its current form, is confronted with a difficulty when it tries to explain how some social behaviors initiate their evolution. We show that this difficulty may be removed by changing the assumption made tacitly in game theory (and in ESS) of randomness of meetings or encounters. In reality, such randomness seems to be rare in nature. Family, population and social structure, customs, and habits impose various types of deviation from randomness. Introducing nonrandomness of meeting in a way formally similar to assortative mating, we show that the bar to initial increase of inherited cooperative or altruistic behaviors can be removed, provided there is sufficient assortment of meetings. Family structure may cause contacts predominantly between certain types of relatives, and one can reconstruct some results of classical kin selection in terms of evolutionary stable strategy with assortative meetings. Neighbor effects and group selection might be similarly treated. Assortment need not be a passive consequence of population and social structure, but it can also be actively pursued. Behaviors favoring the choice of cooperative companions will have the effect of favoring the evolution of cooperativeness. It can be shown that discrimination in the choice of companions, especially if combined with assortment, can favor the development of cooperativeness, making initial increase of cooperative behavior possible even at levels of assortment passively imposed which would not be adequate, per se, to guarantee the increase of cooperativeness. It is possible that, in some cases, cooperativeness and behavior favoring some type of assortment are coselected.