Department of Biosciences and Bioengineering, IIT Guwahati







Non-genetic heterogeneity

Molecular Network of Human Cripto-1

Recombinant Therapeutics

Theoretical studies of signaling networks

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Cellular heterogeneity in expression of human Cripto-1

It is commonly assumed that a population of genetically identical cells will be homogenous and all the cells in that population would behave similarly. However, that is not true. Like many other cellular processes, expression of a gene is stochastic. Such stochasticity leads to non-genetic cellular heterogeneity in gene expression. The extent of heterogeneity depends upon the structure and dynamics of transcriptional circuit. Data generated from single cell experiments gives us the measure and pattern of heterogeneity in gene expression. The pattern and extent of such heterogeneity can be used to identify the structure of a gene expression network. Recently, we have investigated the heterogeneity in expression of human Cripto-1. Cripto-1 is involved in development and progression of various types of cancer. It is believed that heterogeneity in expression Cripto-1 may play critical role in diversification of tumor cells. We have shown that Cripto-1 has a bimodal expression, with a sub-population having higher expression and another having lower expression of Cripto-1 [PMID: 25658584]. We have established that such heterogeneity originates from a positive feedback circuit that controls expression of Cripto-1. This observation reaffirms with the general principle that positive feedback, in a transcriptional circuit, amplifies noise in gene expression and often triggers emergence of two subpopulations.


Understanding complexities of molecular network of human Cripto-1:

Molecular signaling networks are extensively investigated in several biological systems, including human. Conventionally, such investigations focus on identifying components of a particular network. However, we are interested to learn the logic of design of such networks. As a model system, we have focused on the molecular signaling pathways of human Cripto-1 (CR-1). CR-1 is expressed in developing embryo and is involved in several processes required for correct embryonic development. Though absent in adult, CR-1 is produced in several types of cancer cells.  It is now well established that CR-1 can induce many process linked with development of cancer, including excessive cell proliferation. This molecule can activate multiple molecular pathways required for control of cell proliferation. We are trying to understand the integration of these pathways, and the controls that fine tune the dynamics of CR-1 signaling.

Contrary to the well known pro-proliferating effect of Human CR-1, we have shown that CR-1 can also reduce cell proliferation in particular cellular system [PMID: 22182448]. We have shown that CR-1 can activate two opposing molecular pathways thereby creating a network motif similar to incoherent feedforward (see the figure given bellow). Such motif can act as pulse generator and suitable for signal adaptation.


A possible Incoherent Feed-forward Loop of Cripto-1




Recombinant Ligand for Targeted Therapy:

Recombinant molecules are now widely used as therapeutic agents. Recombinant antibodies are frequently developed for targeted delivery of drugs. Most of the targets for antibody-based therapy are cell surface receptors which are overexpressed in diseased state. Natural ligands for these receptors can also be used for similar purposes. We are developing recombinant proteins based on such ligands. One such molecule is Diphtheria toxin (DT), a bacterial toxin. It binds specifically to a cell surface molecule called HB-EGF. HB-EGF is overexpressed in many types of cancers and induces oncogenic signals. We have created recombinant receptor-binding domain of DT that binds HB-EGF on cell surface. This molecule can be used to home drugs to cells expressing HB-EGF or to block HB-EGF signaling. We have established that it can bind, carry and deliver Curcumin to cells expressing HB-EGF and increases potency of this potential chemotherapeutic agent [PMID: 24224661].

Old Molecule, New Tricks: Recombinant Receptor-binding Domain of DT for Therapy


Theoretical studies of signaling networks:

We have broad interest in theoretical studies on cell signaling; particularly on those facets of cell signaling that can not be investigated directly using experimental tools. Currently we are studying receptor mediated receptor cross-linking on cell surface. Receptor cross-linking can modulate cellular signaling and is known to be involved in various crucial cellular processes like immune response.  We are also interested in architecture of molecular networks and cellular heterogeneity in gene expression. We investigate these problems by creating simplified mathematical models based on our current understanding of these biological systems. Subsequently these models are used to answer specific questions.




systems biology, cell signaling, heterogeneity, stochasticity, network, computational biology