Ofer Feinerman

Variability and Robustness in T Cell Activation from Regulated Heterogeneity in Protein Levels

In T cells, the stochasticity of protein expression could contribute to the useful diversification of biological functions within a clonal population or interfere with accurate antigen discrimination. Combining computer modeling and single-cell measurements, we examined how endogenous variation in the expression levels of signaling proteins might affect antigen responsiveness during T cell activation. We found that the CD8 co-receptor fine-tunes activation thresholds, whereas the soluble hematopoietic phosphatase 1 (SHP-1) digitally regulates cell responsiveness. Stochastic variation in the expression of these proteins generates substantial diversity of activation within a clonal population of T cells, but co-regulation of CD8 and SHP-1 levels ultimately limits this very diversity. These findings reveal how eukaryotic cells can draw on regulated variation in gene expression to achieve phenotypic variability in a controlled manner.

Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response.

Understanding how the immune system decides between tolerance and activation by antigens requires addressing cytokine regulation as a highly dynamic process. We quantified the dynamics of interleukin‐2 (IL‐2) signaling in a population of T cells during an immune response by combining in silico modeling and single‐cell measurements in vitro. We demonstrate that IL‐2 receptor expression levels vary widely among T cells creating a large variability in the ability of the individual cells to consume, produce and participate in IL‐2 signaling within the population. Our model reveals that at the population level, these heterogeneous cells are engaged in a tug‐of‐war for IL‐2 between regulatory (Treg) and effector (Teff) T cells, whereby access to IL‐2 can either increase the survival of Teff cells or the suppressive capacity of Treg cells. This tug‐of‐war is the mechanism enforcing, at the systems level, a core function of Treg cells, namely the specific suppression of survival signals for weakly activated Teff cells but not for strongly activated cells. Our integrated model yields quantitative, experimentally validated predictions for the manipulation of Treg suppression.

Radio tagging reveals the roles of corpulence, experience and social information in ant decision making

Ant colonies are factories within fortresses (Oster and Wilson 1978). They run on resources foraged from an outside world fraught with danger. On what basis do individual ants decide to leave the safety of the nest? We investigated the relative roles of social information (returning nestmates), individual experience and physiology (lipid stores/corpulence) in predicting which ants leave the nest and when. We monitored Temnothorax albipennis workers individually using passive radio-frequency identification technology, a novel procedure as applied to ants. This method allowed the matching of individual corpulence measurements to activity patterns of large numbers of individuals over several days. Social information and physiology are both good predictors of when an ant leaves the nest. Positive feedback from social information causes bouts of activity at the colony level. When certain social information is removed from the system by preventing ants returning, physiology best predicts which ants leave the nest and when. Individual experience is strongly related to physiology. A small number of lean individuals are responsible for most external trips. An individual’s nutrient status could be a useful cue in division of labour, especially when public information from other ants is unavailable.

Automated long-term tracking and social behavioural phenotyping of animal colonies within a semi-natural environment

Social behaviour has a key role in animal survival across species, ranging from insects to primates and humans. However, the biological mechanisms driving natural interactions between multiple animals, over long-term periods, are poorly studied and remain elusive. Rigorous and objective quantification of behavioural parameters within a group poses a major challenge as it requires simultaneous monitoring of the positions of several individuals and comprehensive consideration of many complex factors. Automatic tracking and phenotyping of interacting animals could thus overcome the limitations of manual tracking methods. Here we report a broadly applicable system that automatically tracks the locations of multiple, uniquely identified animals, such as mice, within a semi-natural setting. The system combines video and radio frequency identified tracking data to obtain detailed behavioural profiles of both individuals and groups. We demonstrate the usefulness of these data in characterizing individual phenotypes, interactions between pairs and the collective social organization of groups.

Flexible task allocation and the organization of work in ants

Flexibility in task performance is essential for a robust system of division of labour. We investigated what factors determine which social insect workers respond to colony-level changes in task demand. We used radio-frequency identification technology to compare the roles of corpulence, age, spatial location and previous activity (intra-nest/extra-nest) in determining whether worker ants (Temnothorax albipennis) respond to an increase in demand for foraging or brood care. The less corpulent ants took on the extra foraging, irrespective of their age, previous activity or location in the nest, supporting a physiological threshold model. We found no relationship between ants that tended the extra brood and corpulence, age, spatial location or previous activity, but ants that transported the extra brood to the main brood pile were less corpulent and had high previous intra-nest activity. This supports spatial task-encounter and physiological threshold models for brood transport. Our data suggest a flexible task-allocation system allowing the colony to respond rapidly to changing needs, using a simple task-encounter system for generalized tasks, combined with physiologically based response thresholds for more specialized tasks. This could provide a social insect colony with a robust division of labour, flexibly allocating the workforce in response to current needs.

Collaborative search on the plane without communication

We use distributed computing tools to provide a new perspective on the behavior of cooperative biological ensembles. We introduce the Ants Nearby Treasure Search (ANTS) problem, a generalization of the classical cow-path problem [10, 20, 41, 42], which is relevant for collective foraging in animal groups. In the ANTS problem, k identical (probabilistic) agents, initially placed at some central location, collectively search for a treasure in the two-dimensional plane. The treasure is placed at a target location by an adversary and the goal is to find it as fast as possible as a function of both k and D, where D is the distance between the central location and the target. This is biologically motivated by cooperative, central place foraging, such as performed by ants around their nest. In this type of search there is a strong preference to locate nearby food sources before those that are further away. We focus on trying to find what can be achieved if communication is limited or altogether absent. Indeed, to avoid overlaps agents must be highly dispersed making communication difficult. Furthermore, if the agents do not commence the search in synchrony, then even initial communication is problematic. This holds, in particular, with respect to the question of whether the agents can communicate and conclude their total number, k. It turns out that the knowledge of k by the individual agents is crucial for performance. Indeed, it is a straightforward observation that the time required for finding the treasure is Ω(D + D2/k), and we show in this paper that this bound can be matched if the agents have knowledge of k up to some constant approximation. We present a tight bound for the competitive penalty that must be paid, in the running time, if the agents have no information about k. Specifically, this bound is slightly more than logarithmic in the number of agents. In addition, we give a lower bound for the setting in which the agents are given some estimation of k. Informally, our results imply that the agents can potentially perform well without any knowledge of their total number k, however, to further improve, they must use some information regarding k. Finally, we propose a uniform algorithm that is both efficient and extremely simple, suggesting its relevance for actual biological scenarios.

Ant groups optimally amplify the effect of transiently informed individuals

To cooperatively transport a large load, it is important that carriers conform in their efforts and align their forces. A downside of behavioural conformism is that it may decrease the groups responsiveness to external information. Combining experiment and theory, we show how ants optimize collective transport. On the single-ant scale, optimization stems from decision rules that balance individuality and compliance. Macroscopically, these rules poise the system at the transition between random walk and ballistic motion where the collective response to the steering of a single informed ant is maximized. We relate this peak in response to the divergence of susceptibility at a phase transition. Our theoretical models predict that the ant-load system can be transitioned through the critical point of this mesoscopic system by varying its size; we present experiments supporting these predictions. Our findings show that efficient group-level processes can arise from transient amplification of individual-based knowledge.

A picoliter 'fountain-pen' using co-axial dual pipettes.

A double pipette system for local, controlled drug infusion is presented. Two concentric pipettes can be manipulated separately and pressurized independently by a designated double holder. The inner pipette is loaded with the desirable solution (drug), and functions as a source, while the outer one is a sink. This gives a flow of the solution between the two pipettes that protrudes only a small distance into the surrounding fluid and does not diffuse away. Time resolution of the infusion is highly controllable, and oscillatory flow can be generated. Three implementations of the double pipette system are demonstrated. We show that local application of neurotransmitters in neuronal networks is an efficient way of stimulating activity in the network. We then present a wet micro lithography technique using topical application of proteins onto the substrate. Finally, we show that we can localize a given drug on a small targeted part of a cell.

Experience, corpulence and decision making in ant foraging

SUMMARY Social groups are structured by the decisions of their members. Social insects typically divide labour: some decide to stay in the nest while others forage for the colony. Two sources of information individuals may use when deciding whether to forage are their own experience of recent task performance and their own physiology, e.g. fat reserves (corpulence). The former is primarily personal information; the latter may give an indication of the food reserves of the whole colony. These factors are hard to separate because typically leaner individuals are also more experienced foragers. We designed an experiment to determine whether foraging specialisation is physiological or experience based (or both). We invented a system of automatic doors controlled by radio-tag information to manipulate task access and decouple these two sources of information. Our results show that when information from corpulence and recent experience conflict, ants behave only in accordance with their corpulence. However, among ants physiologically inclined to forage (less corpulent ants), recent experience of success positively influenced their propensity to forage again. Hence, foraging is organised via long-term physiological differences among individuals resulting in a relatively stable response threshold distribution, with fine-tuning provided by short-term learning processes. Through these simple rules, colonies can organise their foraging effort both robustly and flexibly.

Transport of Information along Unidimensional Layered Networks of Dissociated Hippocampal Neurons and Implications for Rate Coding

The ability of synchronous population activity in layered networks to transmit a rate code is a focus of recent debate. We investigate these issues using a patterned unidimensional hippocampal culture. The network exhibits population bursts that travel its full length, with the advantage that signals propagate along a clearly defined path. The amplitudes of activity are measured using calcium imaging, a good approximate of population rate code, and the distortion of the signal as it travels is analyzed. We demonstrate that propagation along the line is precisely described by information theory as a chain of Gaussian communication channels. The balance of excitatory and inhibitory synapses is crucial for this transmission. However, amplitude information carried along this layered neuronal structure fails within 3 mm, ∼10 mean axon lengths, and is limited by noise in the synaptic transmission. We conclude that rate codes cannot be reliably transmitted through long layered networks.