Center Activities

For cells, as with people, making well-informed decisions can take time and energy. On a cellular level, decisions are made by a genetic regulatory network (GRN) that integrates information from the environment and then modulates RNA and protein production according to the response needed. The number of regulatory molecules in each cell can vary from between one to a few hundred. This difference can result in fluctuations in information processing – when more cells are involved in the regulatory processes, more inputs are involved in the average, and decision-making becomes more precise and deterministic. In contrast, when fewer regulatory molecules are present, there are less inputs to average in the gene expression decision. With fewer inputs, the process goes faster, but is less precise, resulting in fuzzy decision-making and fluctuations in outputs, in this case, gene expressions.

For this reason, finding a way to create efficient artificial cells with a few decision-making molecules has proven challenging. Postdoctoral fellow Dr. Ferdinand Greiss, Staff Scientist Dr. Shirley Shulman Daube, and Prof. Bar-Ziv, in collaboration with Prof. Vincent Noireaux from the University of Minnesota, decided to demonstrate the decision-making process in bistable gene networks (gene networks that have one of two outputs) in artificial cells with constant protein turnover. Their results were reported in Nature Communications (2020).

In their experiment, they created two systems – one with a greater number of molecules in the gene regulatory network, and one with fewer molecules or copies. In the system with more regulatory molecules, gene decision-making was slower but precise, while the network with fewer copies was rapid and fuzzy, or had fewer defined outputs. They also found more fluctuations or variability in gene decision-making when there were fewer regulatory molecules. Therefore, artificial cells with fewer gene molecules could be more susceptible to random outcomes as compared to cells with more gene molecules. However, in low-copy cells, gene regulation occurred despite lower DNA and protein concentrations than one would find in biological cells, indicating that other factors, such as co-expression localization – or the close proximity of the feedback protein to the gene regulating molecules in an artificial cell – might be enhancing the rate. Their findings could shed light on the tolerance of living cells for fuzzy, yet more timely decision-making, and help scientists weigh the tradeoffs (economic and functional) between speed and accuracy when constructing autonomous cells.

Dr. Efi Efrati, from the Department of Physics of Complex Systems, and his research team have been seeking to classify and quantify geometric frustration in the most general framework. Recently, they were successful in setting the proper conditions for two-dimensional liquid crystals, where the constituents’ geometry determined their relative orientation rather than position. The researchers mapped out all possible and impossible local geometries, and demonstrated strategies for optimal solutions for frustrated assemblies.

With a firm grasp on this geometry in two dimensions, Dr. Efrati and his team have begun exploring frustration in three dimensions—an understanding that is expected to be relevant to a myriad of self-assembling biological systems. One such biological structure is that of hemoglobin fibers that form in sickle-cell anemia. These structures form through the aggregation of the relatively large hemoglobin molecules, which are normally water soluble, into chiral fibers of a limited diameter and a high aspect ratio. This biological connection provides scientists with the motivation necessary to study frustrated assemblies, offering a naturally occurring path to elucidate a complex phenomenon.

While nest construction in ant colonies was studied before, these works always neglected the natural dynamics. In other words - previous works ignored the fact that ant nests gradually grow with the growth of the colony itself: starting off with a single individual (the queen) and eventually reaching thousands of workers. Dr. Ofer Feinerman and his lab members at the Department of Physics of Complex Systems have recently constructed a climate controlled room with the facilities to house and photograph 60 two-dimensional nests over long time scales. These are similar to the ant farms we all know, but with much bigger dimensions. Each nest is first occupied by a single mated queen and then documented over the course of a full year – recording nest growth, tunnel and chamber structure, population growth, occupancy of the different nest chambers etc. This will provide us with a first of kind look at the natural course in which an ant nest develops and, most interestingly, the bi-directional effects between the growing ant colony and its nest. Eventually, it will be interesting to compare these results to the development of the skeleton of a growing child.

Using mathematical and biophysical tools, Prof. Maya Schuldiner, from the Department of Molecular Genetics, partnered with Prof. Roee Ozeri, from the Department of Physics of Complex Systems, to understand just how cells make energy allocation decisions. Together, the two teams exposed simple yeast cells to a defined heat stress and performed hundreds of experiments spanning a broad range of temperatures and exposure times.

The researchers found that for a given exposure time, higher temperature did not necessarily indicate lower survival, and that increased viability at certain temperatures did not correlate with increased ability to resume proliferation. Rather, they saw that at certain activation levels, the stress responses themselves reduced the ability of cells to later proliferate. The teams genetically manipulated stress responses and witnessed how a “miscalculation” by a mutant strain could indeed translate locally to improved survival during stress—reiterating the tension between survival and competence.

This collaborative study provided new insights as to how cells gauge the levels of stress they endure and create a balance between short-term chances of survival and long-term future capacity to proliferate. This work could open the door to better understanding, and potentially treating, disease states that are induced through cellular stress such as diabetes, cancer, and neurodegeneration.