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Decision-making in artificial cells

Prof. Roy Bar-Ziv and his research team explore artificial gene expression systems in vitro that could ultimately mimic nature’s gene networks in controlling biochemical and structural functions. Using cell-free transcription/translation reactions, they continue to fine-tune the components of their artificial cells. Their latest feat: increasing the artificial cells’ efficiency in decision-making.

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.

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Understanding bio-materials to fight illness

Understanding materials in the living context crosses the traditional disciplines of biology, chemistry, and physics. Prof. Michael Elbaum and his group study enigmatic bio-materials and their properties, searching for basic physical principles underlying complex behavior. They also develop new tools for imaging and analysis of cells and biomolecules.

Coronaviruses such as SARS-CoV-2 are particularly prone to heat damage. Therefore, thermal inactivation is an important mechanism for decontamination of these viral pathogens.

Prof. Elbaum worked with Dr. Shahaf Armon, an intern in his lab and a past recipient of the Curwen-Lowy Postdoctoral Fellowship, to elucidate the thermodynamics underlying safe protocols for decontamination of shared instruments and personal protective equipment using heat treatments. They were able to create a model to predict thermal inactivation of the virus. Their predicted inactivation times could be useful for combatting the coronavirus pandemic in several ways, including predicting the period in which moderate fever is effective against the virus. This study was published in the Biophysical Journal in March 2021.

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Finding order in turbulence

Prof. Gregory Falkovich has focused his career on understanding turbulent systems, or cases involving irregular fluctuations within a system. For example, in calm ocean waters, a sudden freak wave can occur seemingly out of nowhere. In a recent study, published in Physical Review Letters (2020), he and his PhD student Michal Shavit worked out a way to discern a degree of order in these systems

Applying mathematical tools belonging to information theory to turbulent systems, they demonstrated that even when turbulence is weak – for example, when the wind produces low waves or even light ripples that interact weakly among themselves – these waves or ripples can be highly correlated and carry significant information about one another. Over time, measuring waves of a particular length can provide information about unmeasured waves on unexpected scales. The scientists’ finding is significant for turbulence modeling, because it means that existing data can actually help fill in the blanks about the parts of the system for which information has been missing. Furthermore, the applicability of these findings extends beyond turbulence to a variety of topics in fields ranging from civil engineering to experimental physics.

When building waterfronts, for example, it is vital to know as much as possible about the strength of waves in the area, including the probability of exceptionally strong waves resulting from interactions among weaker ones. Their new study may also have implications for the development of advanced communications along fiber-optic cables, which simultaneously convey multiple waves carrying information: As the density of this information increases, it will become ever more crucial to understand how these waves might interact with each other, including possible disturbances that could emerge. Yet another potential area of application is plasma research, in which it is important to know how ionized gas interacts with the various electromagnetic waves needed to create plasma.

The formulas derived by Michal and Prof. Falkovich use information theory to determine how many bits of information about a third wave can be obtained using its interactions with two other waves whose parameters are known. This research relates to the simplest possible case of making predictions within a turbulent system. The scientists’ formulas will need to be developed further in order to make predictions about real-life systems, which may involve interactions among dozens or even hundreds of waves. Still, these formulas provide the basis for a new approach to turbulence: finding order within a turbulent system by measuring the information shared within its parts.

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Geometrical structures

While idealized point particles, which have zero spatial extension, may often self-assemble to form ordered crystalline structures, those that attempt to self-assemble in one or more dimensions may not fit well next to one another - resulting in frustration. Such frustration may be the culprit for undesired filamentation, or anomalous growth, in protein assemblies, which occurs in a variety of conditions like sickle-cell disease and Alzheimer’s disease.

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.

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The physics of ants

The structure of ant nests is one of the most impressive of any animal dwellings in nature. What makes this even more exciting is that these nests are constructed without any architect, blueprint, or even work manager. Rather, they come to be by the concerted actions of a large number of ants each digging independently. Understanding the structure of an ants nest will teach us not only about the biology of ants but about the intricacy of biological wholes in relation to the complexity of the units which construct them.  

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.

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Mechanical instabilities in solids and fluids

The Clore Center for Biological Physics supported the Weizmann Institute’s participation a conference on the “Mechanical Instabilities in Solids and Fluids” held at the Hebrew University of Jerusalem and jointly sponsored by the Weizmann Institute and Harvard. The conference, held October 16-19 2017, was a tribute to the highly influential scientific work of Prof. Jay Fineberg, on the occasion of his 60th birthday. Prof. Fineberg made key contributions to a number of areas in nonlinear physics, condensed-matter physics and complex-systems physics. Instabilities play an essential role in shaping the world around us and have enormous influence on a broad range of scientific disciplines.

Down syndrome and maternal age

Down syndrome is the most abundant nonlethal chromosomal abnormality in humans, in which all or part of chromosome 21 appears in three copies instead of two (trisomy). Since 90 % of children with Down syndrome receive their extra chromosome from their mother, the incidence of Down syndrome in humans increases dramatically with maternal age. This is mainly the result of increased errors in cell division (meiosis), but factors such as differences in the rate of miscarriage may play a role as well.  Because the meiotic error rate increases almost exponentially after a certain age, its contribution to the overall incidence of Down syndrome may mask the contribution of other processes.

In a study titled "Transmission of trisomy decreases with maternal age in mouse models of Down syndrome, mirroring a phenomenon in human Down syndrome mothers", that was published in BioMed Central Genomics, Prof. Elisha Moses and his team used some of the tools of biological physics to investigate the factors involved. They showed, in mouse models and human data, that — while the rate of trisomy increases with maternal age — older females have significantly lower probability to transmit the trisomy to the offspring. While Down syndrome occurs in humans and not in rodents, several mouse models for Down syndrome have been developed for studying this disorder. They compared the ratio of trisomic to non-trisomic offspring in two of these models. Their findings suggest that the decreased supportive environment of the older uterus negatively selects the less fit trisomic embryos. These results concur with findings in human studies as well and may help explain the apparent contradiction. 

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Spring school for advanced imaging in biological research

The “Spring School for Advanced Imaging in Biological Research” helped Weizmann students and scientists to become acquainted with leading edge research projects using advanced imaging methods. It also offered an opportunity for interaction with international and national leading scientists in the field.

The two day conference, held March 15 and 16, 2017, presented a lineup of information-packed presentations on a wide array of imaging technologies and research. The technologies spanned a wide range, from standard optical microscopy to advanced multiphoton and light sheet imaging, and from magnetic resonance imaging (MRI) to matrix-assisted laser desorption ionization (MALDI).

Pioneering cell free biology

Prof. Roy Bar-Ziv of the Department of Materials and Interfaces is a pioneer in a new area of science, called “cell-free biology.” The field is dedicated to recreating some of the basic processes of living cells outside of the normal cellular structure. Prof. Bar-Ziv was the first to create “DNA on a chip” that enables scientists to isolate, observe, and control the genetics of basic cellular processes in new ways. Cell-free systems like DNA on a chip, that can replicate biochemical pathways, have been critical for helping scientists unravel the inner workings of the cell.

Working with cell-free protein synthesis and other biological processes on silicon surfaces and in small, controllable compartments allows scientists to replicate, outside the living cell, some of the biochemical machines and processes that run the daily business of the cell. Prof. Bar-Ziv and his lab have taken some of the first steps to recreate conditions where the synthesis of parts of these essential biological processes could lead to the assembly of functional biomolecular “machines” such as programmable protein-making factories. This is a long road, but they have made significant progress in developing a whole new toolbox for reconstituting machine assembly outside the living cell.

The importance of this effort is twofold. First, by taking biological machinery apart and successfully reconstituting it, scientists can learn about biological design principles. Secondly, by learning how to build biological machines outside the cell they can potentially learn how to target the regulatory machinery in the living cell.

In a recent article about building biological systems in the journal Cell Systems, Prof. Bar-Ziv argues that there is more to building a cell than knowing the genes. We need to understand the chemical and spatial organization of macromolecules in the cell, and how the cell optimizes the conditions for basic functions, such as machine assembly and self-replication.

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NetSci-X 2017 international conference

The NetSci-X annual conference is part of the International School on Network Science. The conference brings together leading researchers and innovators to connect, meet, and establish interdisciplinary channels for collaboration on biological, environmental, social, technological, and economic networks.

The 2017 NetSci-X conference took place in Tel Aviv. Organized by Tel Aviv University and Bar-Ilan University, the conference enjoys the sponsorship of the Clore Center and Weizmann’s Department of Physics of Complex Systems. Prof. Elisha Moses is an invited speaker at the conference, and Prof. Uri Alon of the Department of Molecular Cell Biology will be one of the keynote speakers.

Coping with temperature

Living organisms thrive at a set point in which external and internal conditions optimally support well-being, function, and reproduction. Stress can therefore be defined as any deviation from that optimal point. During stress, cells need to optimize their resource allocation to match the ongoing task of protecting themselves against accumulated damage. If cells miscalculate such energy allotment, they can earmark too little and then die from lack of preservation, or too much, and then die from over-exhaustion of resources. Determining exactly how much energy goes into fighting stress has direct consequences on longevity and disease states.

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.

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A closer look at neurons

Thanks to the availability of highly sensitive molecular tools, combined with more sophisticated imaging technologies, scientists are able to analyze the formation and operations of neuronal networks in ways previously unimaginable. Prof. Menachem Segal, from the Department of Neurobiology, and his team have been able to examine central neurons living on glass plates - tracing minute changes in the structure and function of the connections among them, and observing their spontaneous activity and ability to undergo plastic changes under controlled conditions.

In their quest to understand neuronal network operations, the scientists delved into a less explored mode of regulation of intracellular calcium, as calcium ions play a pivotal role in the function of a neuron. Using culture neurons of the hippocampus, they studied the possible role of this mode—called calcium-store-operated entry channel (SOCE)—in the formation and behavior of dendritic spines, or the protrusions from neurons that typically receive inputs from axons.

In calcium store-depleted neurons, a transient elevation of extracellular calcium concentration caused a rise in calcium ions that was mediated by activation of the SOCE. The store depletion resulted in an increase in the calcium sensor’s association with the ion channel in dendritic spines. Ultimately, the researchers discovered that an influx of calcium through ion channels could facilitate the maturation of dendritic spines and the formation of functional synapses in central neurons. These novel findings could provide a potential link between malfunction of the SOCE system and neurodegenerative disease, opening a new avenue for the analysis and possible future development of novel therapies for Alzheimer’s disease.

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