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Seminars

January 14, 2020 [Note Special Time: 2PM]: Harry McNamara, Harvard University
Synthetic Electrophysiology: Pattern formation and phase transitions in bioelectric tissues.
Host: E. Siggia
Electrical signaling in biology is typically associated with action potentials, transient spikes in membrane voltage that return to baseline. More generally, electrical tissues are reaction-diffusion systems which could support patterns which are structured in space but stationary in time. It is possible that electrical signaling could coordinate biological processes on timescales which are slower than action potentials – for example, during embryonic development. Constraints on electrophysiological measurement in vivo have made it challenging to assess these hypotheses quantitatively.
Here we present a new strategy to study biological pattern formation by building synthetic bioelectrical tissues from the bottom-up. We engineer electrically inert mammalian cells to express ion channels, optogenetic actuators, and fluorescent voltage indicators in tandem. By combining patterned illumination and all-optical electrophysiology, we study these synthetic bioelectric tissues as excitable media and compare their dynamics rigorously to mathematical predictions.
In one demonstration, we engineer bioelectrical circuits of spiking cells capable of simple information processing and memory(1) We also show that dynamical transitions between stable and arrhythmic spiking patterns in these tissues depends sensitively on tissue geometry and dimensionality(2). Finally, we show that synthetic tissues of electrically bistable cells can form spatially structured but time-stationary electrical domains which polarize via nucleation-and-growth phase transitions(3). Observation of electrical domains in a stem cell model of myogenesis suggest that bioelectrical phase transitions may play a physiological role during embryonic development.

  1. McNamara, H.M., Zhang, H., Werley, C.A. and Cohen, A.E., 2016. Optically controlled oscillators in an engineered bioelectric tissue. Physical Review X, 6(3), p.031001.
  2. McNamara, H.M., Dodson, S., Huang, Y.L., Miller, E.W., Sandstede, B. and Cohen, A.E., 2018. Geometry-dependent arrhythmias in electrically excitable tissues. Cell Systems, 7(4), pp.359-370.
  3. McNamara, H.M., Salegame, R., Al Tanoury, Z., Xu, H., Begum, S., Ortiz, G., Pourquie, O. and Cohen, A.E., 2019. Bioelectrical signaling via domain wall migration. bioRxiv, p.570440. (in press, Nature Physics).

 

January 16, 2020 [Note Special Time: 2PM]: Lishibanya Mohapatra, Brandeis University
How cells control the size of their organelles.
Host: E. Siggia
Cells contain a number of micron-scale structures, whose physiological functions are related to their size. Examples include cytoskeletal elements like mitotic spindle, cilia and actin cables. Each of these structures is characterized by a narrow size distribution and is composed of molecular building blocks (tubulin dimers and actin monomers) that diffuse in the cytoplasm. A key question is how the size of these structures is maintained in light of constant turnover of their molecular components. Using theory, simulations and experiments in various cell types, I will describe how we can aim to uncover design principles of size-control in biology.
January 21, 2020 [Note Special Time: 2PM]: Jennifer Crodelle, New York University
A model for the development of orientation preference maps in the visual cortex of mice.
Host: E. Siggia
The mammalian primary visual cortex (V1) contains neurons that respond preferentially to oriented visual stimuli (e.g., horizontal bars). In the mouse, these orientation-preferring neurons are scattered throughout V1 in what’s called a “salt and pepper” orientation-preference (OP) map. Despite the seemingly random distribution of OPs in the visual cortex of mice, it has been shown that radially-distributed clonally-related cells show similar stimulus feature selectivity, as well as preferential synaptic connectivity with fellow sister cells. Importantly, each of these characteristics relies on gap-junction coupling between sister cells during the first postnatal week. We construct an idealized model of the mouse visual cortex during the first two postnatal weeks of development and analyze the effect of gap-junction coupling on the formation of synaptic connections both into and within V1. In particular, we use this model to propose a role for gap-junction coupling between sister cells in facilitating the formation of the salt-and-pepper OP that is typical of the adult mouse visual cortex.
January 23, 2020 [Note Special Time: 2PM]: Liat Shenhav, University of California, Los Angeles
Spatiotemporal modeling of microbial communities.
Host: E. Siggia
Microbial communities can undergo rapid changes, that can both cause and indicate host disease, rendering longitudinal microbiome studies key for understanding microbiome-associated disorders. However, most standard statistical methods, based on random samples, are not applicable for addressing the methodological and statistical challenges associated with repeated, structured observations of a complex ecosystem. Therefore, to elucidate how and why our microbiome varies in time, and whether these trajectories are consistent across humans, we developed new methods for modeling the temporal and spatial dynamics of microbial communities.
We developed a method to identify ‘time-dependent’ microbes (Shenhav et al., PLoS Computational Biology 2019) and showed that their temporal patterns differentiate between the developing microbial communities of infants and those of adults. In a different project, we derived a new nonlinear system for microbial dynamics, termed “compositional” Lotka-Volterra (cLV), and addressed a longstanding challenge in the field by showing that relative abundance trajectories predicted by this new method are as accurate as trajectories predicted using the standard Lotka-Volterra model (Joseph, Shenhav et al., in review). We also developed models to deconvolute the dynamics of microbial community formation. Using these methods, we found significant differences between vaginally- and cesarean-delivered infants in terms of initial colonization and succession of their gut microbial community (Shenhav et al., Nature Methods 2019) as well as the trajectories of these communities in the first years of life (Martino*, Shenhav* et al., in prep.). These models, designed to identify and predict time-dependent patterns, would help us better understand the temporal nature of the human microbiome from the time of its formation at birth and throughout life.
February 4, 2020: Gabriel D. Victora, The Rockefeller University
Directing evolution: Can we choose what the immune system sees?
Host: E. Siggia
Not available
February 18, 2020: Adam Cohen, Harvard University
Optical electrophysiology for dissecting cortical microcircuits.
Host: E. Siggia
Combined optogenetic perturbation and voltage imaging enables high-resolution mapping of bioelectrical dynamics in intact tissues. I will describe application to Layer 1 of the mouse barrel cortex. We developed techniques to distinguish the separate contributions of excitatory and inhibitory synaptic inputs to membrane potential. Using these tools, we deciphered how the sensory-evoked responses emerged from local network dynamics.
February 25, 2020: Bojan Zagrovic, University of Vienna
RNA-protein interactions and the structure of the genetic code.
Host: A. Vaziri
The notion of physicochemical complementarity is one of the most powerful mechanistic paradigms in molecular biology. Recently, we have revealed a robust, statistically significant matching between the nucleobase-density profiles of mRNA coding sequences and the nucleobase-binding profiles of the protein sequences they encode. For example, purine-density profiles of mRNA sequences mirror the guanine-affinity profiles of their cognate protein sequences with quantitative accuracy (median Pearson correlation coefficient |R| = 0.80 across the entire human proteome). Overall, our results support as well as redefine the stereochemical hypothesis concerning the origin of the genetic code, the idea that the code evolved from direct interactions between amino acids and the appropriate bases. Moreover, our findings support the possibility of direct, complementary, co-aligned interactions between mRNAs and their cognate proteins even in present-day cells, especially if both are unstructured, with implications extending to different facets of nucleic-acid/protein biology. In this talk, I will focus on different lines of evidence regarding the complementarity hypothesis, with a particular focus on experimental UV-crosslinking and immunoprecipitation (CLIP) results.
March 3, 2020: Simon Tavare, Columbia University
Some statistical problems in cancer evolution.
Host: E. Siggia
This talk addresses some statistical and computational problems arising in the study of cancer evolution. The starting point comes from population genetics: how should we estimate evolutionarily relevant parameters from DNA sequence data taken from samples of individuals?
I will give a brief overview of what we learned, touching on Approximate Bayesian Computation as an inference method when likelihoods are intractable. To illustrate ABC I will give an example concerning inference about the number of distinct DNA sequences in a sample, given only information about the relative frequency of point mutations in the samples. This provides an introduction to inference from typical cancer sequencing data, in which individuals are replaced by cells and in which typically we do not know which mutations occur in which cells. I will discuss a stochastic model that exploits coalescent theory to study clonal sweeps, and describe new techniques for deconvolving clones from single cell sequencing data. Time permitting, I will describe some novel experimental methods we are developing to understand the 3D structure of tumors, paving the way for some challenging inferential problems that will require engagement from data scientists and others.
March 5, 2020: Konrad Kording, University of Pennsylvania
Tuning to many features.
Host: A. Vaziri
I will present a sequence of analyses of neural tuning properties where we ask how a set of dimensions affect tuning. In area V4, we analyzed tuning to natural and artificial stimuli asking how similar those tunings are. We find that they are hugely complex and are vastly different between artificial and natural conditions. In basal ganglia and M1 we tried to estimate the dimensionality of tuning and find that the dimensionality is very high. I will review theoretical insights of why such complex tuning may be a very efficient strategy for the brain.
March 10, 2020: Daniel Fletcher, University of California, Berkeley
Mind the gap: Size-based organization at cell-cell contacts.
Host: E. Siggia
Membrane interfaces formed at junctions between cells are often associated with characteristic patterns of protein organization, such as in epithelial tissues and between cells of the immune system. Size is emerging as a critical feature of cell surface proteins that can directly affect cell-cell interface formation and contribute to spatial arrangement of proteins at junctions, as well as their downstream signaling. This talk will present a new method for characterizing cell surface protein size that enables nanometer-scale height measurements, and I will describe the implications of protein height on macrophage phagocytosis, cell-cell fusion, and viral entry. Results from these studies support a model in which the topography of cell surfaces plays a key role in mediating cell-cell interaction and communication.
March 24, 2020: CANCELLEDAlex Mogilner, New York University
Feedbacks between mechanics and geometry ensures almost deterministic mitotic spindle assembly.
Host: J. Nirody
One of the most fundamental cell biological events is assembly of the mitotic spindle. Two existent models of the spindle assembly are 1) search-and-capture (SAC) and 2) acentrosomal microtubule assembly (AMA). SAC model is pleasingly simple: microtubules (MTs), organized into two asters focused at two centrosomes, grow and shrink randomly. As soon as a growing MT end bumps into a kinetochore (KT), the connection between the spindle pole and chromosome is established. This model predicts that KTs are captured at random times and that slow spindle assembly is plagued by errors. For decades, the SAC model seemed to work. Our recent data ruins the SAC model and suggests that a hybrid between SAC and AMA models could work. I will explain how we used 3D tracking of centrosomes and KTs in animal cells to develop a computational model, which explains the remarkable speed and precision of the almost deterministic process of the spindle assembly emerging from random and imprecise molecular events.
March 31, 2020: CANCELLED –  Mark Siegal, New York University
Mechanisms controlling variation in complex traits.
Host: A. Raju
Many cellular processes are robust (or “canalized”), producing stereotyped outcomes despite environmental and genetic perturbations. Other processes generate extensive heterogeneity even among genetically identical cells under constant and benign conditions, making some microbial infections and tumors very difficult to treat. We use high-throughput imaging of individual cells of the budding yeast, Saccharomyces cerevisiae, to understand how robustness and heterogeneity are achieved. I will present our work quantifying the extent to which the protein-folding chaperone Hsp90 buffers mutational effects. Hsp90 had been proposed to be an agent of canalization. However, by measuring cell-morphology traits of millions of cells from different strains and with different levels of functional Hsp90, we found that Hsp90 has very little effect on the extent of phenotypic variation caused by mutations and, if anything, tends to enhance their effects rather than buffer them. Our results support a model in which natural selection preferentially allows Hsp90-buffered mutations to persist in populations. I will also present our work on a form of nongenetic heterogeneity in yeast in which growth rate correlates positively with susceptibility to acute stress at the single-cell level. We have found that heterogeneity in intracellular cyclic AMP (cAMP) levels, acting through the protein kinase A pathway and its target transcription factors Msn2 and Msn4, underlies the heterogeneity of growth and stress susceptibility. Perturbations that cause or mimic high-cAMP conditions reduce the fraction of slower-growing cells and concomitantly reduce stress survival dramatically, suggesting that it is in principle possible to make cell populations respond more uniformly to treatment by specifically targeting their heterogeneity.
April 7, 2020: CANCELLED –  Gunter Wagner, Yale University
How to turn a crisis into a new identity?
The origin of a novel cell type through signaling network restructuring.
Host: E. Siggia
The number of traceable cell types varies massively among multicellular animals from somewhere between 5 and 30 in the anatomically most primitive animals (e.g. Trichoplax or sponges) to over 500 histologically distinguishable cell types in humans, the latter number likely an underestimate possibly by a factor of five or six. Hence, the evolutionary origin of novel cell types is a major mode of how body plan complexity evolves. While there is a good amount of research dedicated towards mapping the evolutionary history of cell type evolution and homology, driven by single cell technology, the mechanistic basis for the origin of novel cell types is entirely unknown. In my lab we are addressing this problem by examining the origin of a cell type, the decidual stromal cell (DSC), that only exists in placental [eutherian] mammals, and is thus “only” 100 to 65 Mio years old. The comparison of cell differentiation in an outgroup, the opossum, with that of human cells shows that a large part of the gene regulatory network underlying the differentiation of DSCs utilizes a network that in opossum regulates the cellular stress reaction, likely homologous to the fibroblast activation during wound healing. Fibroblast activation is a transient self-limiting process, and the origin of a novel cell type consists of modifications of the signaling network that allow the assumption of a sustainable gene regulatory state. In brief, the comparative data suggests that key steps in the origin of the DSC were 1) the permanent inhibition of Akt-pathway activity, releasing key transcription factors like FOXO1 from degradation, 2) a sustained activation of the PKA pathway by PGE2, 3) an alternative mechanism for inhibiting JNK dependent apoptosis, after Akt inhibition of JNK has been removed, and 4) the development of autocrine signals to replace the transient paracrine signals. On a general level these results suggest that a narrow gene regulatory network perspective is insufficient to understand the mechanisms of cell type origination.
April 14, 2020: CANCELLEDFelicity Muth, University of Texas, Austin
New insights into the cognitive ecology of pollination.
Host: J. Nirody
Perception, learning and memory in animals are often studied under fairly artificial lab conditions. However, like any other trait, cognition is shaped by natural selection and the animals’ ecological environment, meaning simplifications can often be misleading. Bees are an insect model system for understanding cognition, yet the majority of what we know about this topic has been carried out under artificial lab conditions, using nectar rewards (in the form of sucrose solution). Bees also collect pollen, their main source of protein and critical for colony survival. Here I present a series of experiments investigating bee learning from an ecological perspective. I will also discuss recent work on how neonicotinoid pesticides affect bee behavior and cognition.
April 21, 2020: CANCELLEDTimothy Linksvayer, University of Pennsylvania
To Come
Host: J. Nirody
To Come
April 28, 2020: CANCELLEDJianhua Xing, University of Pittsburgh
To Come
Host: J. Nirody
To Come
April 29, 2020: CANCELLEDJoshua S. Weitz, Georgia Institute of Technology
Microbes Get Sick Too: Phage Therapy and the Prospects for a Systems Approach for Treating Drug-Resistant Infections.
Host: J. Cohen
Multi-drug resistant bacterial pathogens constitute a critical public health threat. This threat has spurred a multidisciplinary response to develop antibiotic alternatives, including the use of bacteriophage to selectively target and eliminate bacterial pathogens. However, significant hurdlesremain to translate the lysis of pathogens by phage into an evolutionary robust therapeutic. In this talk, I present collaborative efforts to address this gap via a dynamicalsystems approach to phage therapy in an immune system context. In doing so, I highlight how the combined use of mathematical models, in vitro manipulation, and in vivo experiments may shed light on principles underlying curative treatment of acute infections.
May 5, 2020: CANCELLED – Martha Munoz, Yale University
To Come
Host: J. Nirody
To Come
May 12, 2020: CANCELLED –  David Labonte, Imperial College London
To Come
Host: J. Nirody
To Come
May 19, 2020: CANCELLED Sujit S. Datta, Princeton University
To Come
Host: J. Nirody
To Come
May 26, 2020: CANCELLED –  David Sivak, Simon Fraser University
To Come
Host: J. Nirody
To Come
May 28, 2020 [Peter H. Seller Lecture]: CANCELLEDDame Janet Thornton, EMBL-EBI
To Come
Host: S. Strickland and M. Magnasco
To Come

Past Seminars

Click here for past seminars from the Center for Studies in Physics and Biology.



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