ICTS

How much we do understand regarding how information contained in DNA is stored and expressed? Genomes consists of genes and regulatory elements that control their expression. But these constitute of only a fraction of the genome. Most of the genome remains unexplored in
terms of functional elements. A large amount of data in the form of genomic sequences and epigenome features have been accumulated using approaches like Next Generation Sequencing (NGS), sequencing using chromatin immunoprecipitation (ChIP-seq), high-throughput
sequencing to capture chromosome conformation (HiC), etc. However, there is substantial gap in analysis and in making sense of this huge information content. New tools, approaches and theoretical perspectives/models may help us understand how genetic information is stored,
contained and used by living forms.

Epithelial cells line various organ systems in metazoan animals. Their plasma membrane is specialized to form a protective sheath that communicates with the outside environment in order to absorb nutrients. The epithelial cell plasma membrane is organized into 3 domains. The apical domain contains microvilli that help absorb nutrients. The lateral domain functions in adhesion between adjacent cells. The basal membrane attaches to the extracellular matrix. These domains show the presence of distinct phospholipid and protein
composition that enable the execution of various functions. Epithelial cells are cylindrical in shape where the cross section of the plasma membrane is organized as a polygonal array. The adherens junction complex is present in the apical part
of the lateral domain of epithelial cells. It contains the highly conserved junctional transmembrane protein E-cadherin. The extracellular domains of E-cadherin molecules belonging to adjacent cells interact with each other to stabilize edges in epithelial cells. E-
cadherin molecules are concentrated in an electron dense belt at the apical region and are present in a sparse manner throughout the rest of the lateral membrane. E-cadherin molecules interact with the actin and tubulin cytoskeleton via their cytoplasmic domains.
The epithelial plasma membrane contains other polarity complexes such as the apical Bazooka complex and the lateral Dlg-Lgl-Scrib complex in addition to the adherens junction complex.

The polygonal array of epithelial cells across various tissues has hexagon dominance with fewer pentagons and heptagons. Changes in molecular architecture of lateral membrane lead to changes in this polygon distribution. A recent study shows that the lateral
membrane of epithelial cells in bent tissues has intercalations across several cells to form a structure called scutoid. Both the hexagon dominance and scutoid structure has been calculated to occur as a strategy to achieve surface energy minimization.
Epithelial cell shapes exhibit plasticity and remodel by changing the relative balance of distribution and dynamics of adhesion and contractility in their membranes. This enables a transition of planar epithelial cells to form tubes or germ layers during organism
development. Increased contractility and decreased adhesion correlates with decrease in adhesion and enables an epithelial cell to change shape and acquire migratory ability. The goal of the talk at the meeting on Thirsting for Theoretical Biology at ICTS 2019 will be
to highlight molecular and geometric principles that regulate polygonal epithelial architecture formation and maintenance using various examples from metazoan embryogenesis.

This talk will attempt to highlight the following:

1. Molecular architecture changes when formation of polygonal epithelial cells in mature tissues and during embryogenesis. 
2. Geometric considerations at the lateral membrane of epithelial cells that give rise to the unique polygonal architecture of epithelial cells.
3. Principle of conservation of volume when epithelial shape changes occur during different processes of cell elongation such as in gastrulation.

In Saccharomyces cerevisiae , enzymes required for glucose utilisation are constitutively expressed. In contrast, the genes encoding enzymes (GAL/MEL genes/regulon) required for the galactose utilisation (Lelior pathway of galactose catabolism) are induced only in presence of galactose, provided glucose is absent. The GAL/MEL genes are separately transcribed, but are controlled by the same genetic regulatory apparatus, which is commonly referred to as GAL genetic switch. Thus, galactose is an inducer while glucose is a repressor of the GAL genetic switch. Accordingly, Saccharomyces cerevisiae shows a classical diauxic growth when grown in presence of equimolar concentrations of glucose and galactose. However, a diauxic growth is NOT observed when Saccharomyces cerevisiae is grown on melibiose, a disaccharide consisting of glucose and galactose. Free melibiose cannot be taken up by the cell. It has to be hydrolysed to glucose and galactose outside the cell by -galactosidase, a member of the GAL/MEL regulon. -galactosidase
has a basal expression and generates equimolar concentrations of glucose and galactose. Because -galactosidase is a member of the GAL/MEL regulon, its expression is also under the control of GAL genetic switch. That is, expression of -galactosidase is induced by galactose and repressed by glucose. The question therefore, is, (a) what is the underlying regulatory feature that confers diauxic growth when cells are challenged with a mixture of glucose and galactose (b) why diauxic growth is
NOT observed when cells are challenged with melibiose (C) how do individual members of a population growing in a mixture of glucose and galactose respond as compared to the response of individual members to melibiose.

I will cover some published work (from our group), as well as unpublished work. Here, i'll mainly emphasize the biology, but also introduce a fair bit of modeling that was done (in collaboration with Sandeep Krishna).

The story of Rama, exiled prince of Ayodhya, god incarnate, has been told in every Indian language for the last two centuries. It has become the bedrock of Hindu culture within the sub-continent and beyond, providing us with a cultural vocabulary that is reflected in our everyday speech, in music and dance, in painting and sculpture. The first English translation of the Sanskrit Ramayana by Ralph Griffiths was published in the second half of the 19^th century and we continue to translate it today with the same dedication and fervour as that of early Indologists and scholars who first brought it to a wider audience.

What are we doing when we translate Ramayana, a text from a time and a place that is far away? What meaning do we ‘carry over’ and what, apart from meaning, do we leave behind? How do persuade our readers that a story that was first told two thousand five hundred years ago can still speak to us, can provide us with a way think about our own lives? What are our responsibilities when we translate a text that has become central to a religion, especially when that religion is not ours?

These are some of the questions that a translator of the Sanskrit Ramayana, or any other classical text, must ask of her/himself. But, as a translator negotiates the two languages and cultures that are in conversation with each other through the act of translation, s/he must also be aware of her/his own voice and its relationship to the voice of the original writer. No translation can be perfectly neutral or objective. What it can be, and must be, is transparent. Such transparency can be achieved only when the translator locates her/himself within the text and the context of the work and acknowledges the enormous distance between the time and place of the text and her/his own time and place. 

It is a translator’s job to make a text from another language accessible to a new audience. This means that s/he must seek out the universals in the story – the emotions and motivations for action, the compelling power of central events, the inevitability of the end as it is. As translators and readers, we can only respond to the characters in the text if we believe that all great stories, from any culture and any time, speak, ultimately, to the human condition. Different cultures might provide different answers but the fundamental questions we ask – who am I, why am I here, what does it mean to be good, what will happen to me after I die -- remain the same.

My talk will deal with the rapid blood stem cell response to a dynamic micro-environment and consequent changes in cell state. Cell and molecular biology studies, combined with biophysical analyses, provide useful and elegant models of organelle dynamics and signalling. But they do so in a limited context and over short time frames. What we lack is a temporal map of vesicular traffic and organelle organization, and how it connects to and integrates with cell fate and tissue properties in vivo. A map of organelle dynamics could be used to generate and test computed models. Comparison between invertebrate and vertebrate models may reveal fundamental cellular mechanisms that regulate this process.

Blood stem cells can self-renew as well as reconstitute the entire blood system. Little is known about how individual stem cells or groups respond to rapidly changing environmental cues and make cell fate choices. Seemingly homogeneous groups display a range of responses to maintenance or differentiation cues. Transcript or protein profiles can help identify stem cell state and predict fate. Whether and how variation in organelle organization affects cell fate and phenotype in a sensitive and dynamic environment such as during haematopoiesis, is under explored and to date not known.

References:
OCIAD1 controls electron transport chain complex I activity to regulate energy metabolism in human pluripotent stem cells. Shetty D, Kalamkar K and Inamdar MS*. (2018) Stem Cell Reports 11(1), P128-141
Sinha A, Khadilkar RJ, Vinay KS, Roychowdhury Sinha A, Inamdar MS. Conserved regulation of the Jak/STAT pathway by the endosomal protein asrij maintains stem cell potency. Cell Rep. 2013 Aug 29;4(4):649-58.
Norregaard K, Metzler R, Ritter CM, Berg-Sørensen K, Oddershede LB. Manipulation and Motion of Organelles and Single Molecules in Living Cells. Chem. Rev., 2017, 117 (5), pp 4342–4375
Zajac AL, Goldman YE, Holzbaur EL, Ostap EM. Local cytoskeletal and organelle interactions impact molecular-motor- driven early endosomal trafficking. Curr Biol. 2013 Jul 8;23(13):1173-80.

Blood stem cells can self-renew as well as reconstitute the entire blood system. Little is known about how individual stem cells or groups respond to rapidly changing environmental cues and make cell fate choices. Seemingly homogeneous groups display a range of responses to maintenance or differentiation cues. Transcript or protein profiles can help identify stem cell state and predict fate. Whether and how variation in organelle organization affects cell fate and phenotype in a sensitive and dynamic environment such as during haematopoiesis, is under explored and to date not known.

The tissues that make up our bodies are multicellular assemblies that are organized in a tightly regulated manner to ensure their stereotypical shape and architecture that is also essential for their function. This order is most boldly and beautifully manifest in the spots and stripes that decorate the coats, skin and wings of animals, birds, fish and flies. These ordered patterns depend both on gene regulatory networks that generate spatial and temporal patterns of cell proliferation and differentiation, and on cell (re) organization that is driven by dynamic cell shape changes, cell rearrangements, cell movement and cell interactions. We examine the origins of spatial order during the formation (morphogenesis) of tissues in the developing fruit fly (Drosophila) embryo. We are particularly interested in understanding how much of this order is imposed by a genetic pre-pattern (top-down control), how much emerges as a consequence of dynamic cellular interactions (bottom-up control), and whether and how the two control mechanisms influence each other. In particular, we are interested in understanding how, and how much, bottom-up control (that is dependent on the modulation of cell behaviour by the modulation of physical interactions between cells) influences the spatial ordering of tissues. I will discuss insights obtained from our explorations on the origins of ordered tissue patterns (stripes, seams, rosettes and placodes) and highlight the importance of “emergent” changes in the physical properties of cellular interfaces (adhesion and contractility). I will also attempt to address how spatial order at subcellular or molecular scales (nodes, asters and patches) influences order at cellular and tissue scales.

In this would like to cover topics such as: separating genomes, constricting membranes, spatial organisation of sub-cellular components and shaping cylindrical cells. While these are universal processes, I would focus on the biology of these aspects in prokaryotes which involve minimal components and on the past and recent efforts to reconstitute them outside of the cell.