Natalia L. Komarova

Antibody neutralization and escape by HIV-1

Neutralizing antibodies (Nab) are a principal component of an effective human immune response to many pathogens, yet their role in HIV-1 infection is unclear. To gain a better understanding of this role, we examined plasma from patients with acute HIV infection. Here we report the detection of autologous Nab as early as 52 days after detection of HIV-specific antibodies. The viral inhibitory activity of Nab resulted in complete replacement of neutralization-sensitive virus by successive populations of resistant virus. Escape virus contained mutations in the env gene that were unexpectedly sparse, did not map generally to known neutralization epitopes, and involved primarily changes in N-linked glycosylation. This pattern of escape, and the exceptional density of HIV-1 envelope glycosylation generally, led us to postulate an evolving ‘glycan shield’ mechanism of neutralization escape whereby selected changes in glycan packing prevent Nab binding but not receptor binding. Direct support for this model was obtained by mutational substitution showing that Nab-selected alterations in glycosylation conferred escape from both autologous antibody and epitope-specific monoclonal antibodies. The evolving glycan shield thus represents a new mechanism contributing to HIV-1 persistence in the face of an evolving antibody repertoire.

The role of chromosomal instability in tumor initiation

Chromosomal instability (CIN) is a defining characteristic of most human cancers. Mutation of CIN genes increases the probability that whole chromosomes or large fractions of chromosomes are gained or lost during cell division. The consequence of CIN is an imbalance in the number of chromosomes per cell (aneuploidy) and an enhanced rate of loss of heterozygosity. A major question of cancer genetics is to what extent CIN, or any genetic instability, is an early event and consequently a driving force for tumor progression. In this article, we develop a mathematical framework for studying the effect of CIN on the somatic evolution of cancer. Specifically, we calculate the conditions for CIN to initiate the process of colorectal tumorigenesis before the inactivation of tumor suppressor genes.

Computational and evolutionary aspects of language

Language is our legacy. It is the main evolutionary contribution of humans, and perhaps the most interesting trait that has emerged in the past 500 million years. Understanding how darwinian evolution gives rise to human language requires the integration of formal language theory, learning theory and evolutionary dynamics. Formal language theory provides a mathematical description of language and grammar. Learning theory formalizes the task of language acquisition—it can be shown that no procedure can learn an unrestricted set of languages. Universal grammar specifies the restricted set of languages learnable by the human brain. Evolutionary dynamics can be formulated to describe the cultural evolution of language and the biological evolution of universal grammar.

Towards an evolutionary theory of language

Language is a biological trait that radically changed the performance of one species and the appearance of the planet. Understanding how human language came about is one of the most interesting tasks for evolutionary biology. Here we discuss how natural selection can guide the emergence of some basic features of human language, including arbitrary signs, words, syntactic communication and grammar. We show how natural selection can lead to the duality of patterning of human language: sequences of phonemes form words; sequences of words form sentences. Finally, we present a framework for the population dynamics of grammar acquisition, which allows us to study the cultural evolution of grammar and the biological evolution of universal grammar.

Evolutionary dynamics of feedback escape and the development of stem-cell–driven cancers

Cancers are thought to arise in tissue stem cells, and similar to healthy tissue, are thought to be maintained by a small population of tumor stem or initiating cells, whereas the majority of tumor cells are more differentiated with limited replicative potential. Healthy tissue homeostasis is achieved by feedback loops, and particular importance has been attached to signals secreted from differentiated cells that inhibit stem-cell division and stem-cell self-renewal, as documented in the olfactory epithelium and other tissues. Therefore, a key event in carcinogenesis must be escape from these feedback loops, which is studied here using evolutionary computational models. We find that out of all potential evolutionary pathways, only one unique sequence of phenotypic transitions can lead to complete escape in stem-cell–driven tumors, even though the required mutations for these transitions are certainly tissue specific. This insight, supported by data, facilitates the search for driver mutations and for therapeutic targets. Different growth patterns can result from feedback escape, which we call “inhibited,” “uninhibited,” and “sigmoidal,” and which are found in published data. The finding of inhibited growth patterns in data indicates that besides architecture, the regulatory mechanisms of healthy tissue continue to operate to a degree in tumors.

Dynamics of genetic instability in sporadic and familial colorectal cancer

Genetic instability is a defining feature of human cancer. In colorectal cancer, two specific types of genetic instabilities have been identified: microsatellite instability (MIN) leads to a 1000-fold increase in the rate of subtle DNA changes, whereas chromosomal instability (CIN) enhances the rate at which gross chromosomal changes occur during cell division. In this paper, we develop a mathematical model for the dynamics of colon cancer initiation. We outline the processes and rate constants that determine the fraction of colon cancers where MIN or CIN mutations precede the inactivation of the first tumor suppressor gene. For a wide range of parameter values, we find support for the radical hypothesis that genetic instability initiates colonic tumorigenesis. We compare sporadic and hereditary forms of colorectal cancer.

Nonlinear dynamics of sand banks and sand waves

Sand banks and sand waves are two types of sand structures that are commonly observed on an off-shore sea bed. We describe the formation of these features using the equations of the fluid motion coupled with the mass conservation law for the sediment transport. The bottom features are a result of an instability due to tide–bottom interactions. There are at least two mechanisms responsible for the growth of sand banks and sand waves. One is linear instability, and the other is nonlinear coupling between long sand banks and short sand waves. One novel feature of this work is the suggestion that the latter is more important for the generation of sand banks. We derive nonlinear amplitude equations governing the coupled dynamics of sand waves and sand banks. Based on these equations, we estimate characteristic features for sand banks and find that the estimates are consistent with measurements.

A theoretical framework for specificity in cell signaling

Different cellular signal transduction pathways are often interconnected, so that the potential for undesirable crosstalk between pathways exists. Nevertheless, signaling networks have evolved that maintain specificity from signal to cellular response. Here, we develop a framework for the analysis of networks containing two or more interconnected signaling pathways. We define two properties, specificity and fidelity, that all pathways in a network must possess in order to avoid paradoxical situations where one pathway activates another pathways output, or responds to another pathways input, more than its own. In unembellished networks that share components, it is impossible for all pathways to have both mutual specificity and mutual fidelity. However, inclusion of either of two related insulating mechanisms—compartmentalization or the action of a scaffold protein—allows both properties to be achieved, provided deactivation rates are fast compared to exchange rates.

Linear instability mechanisms for sand wave formation

A height- and flow-dependent model for turbulent viscosity is employed to explain the generation of sand waves in tidal seas. This new model resolves the problem of excitation of very long waves in sand wave formation, because it leads to damping of the long waves and gives a finite separation between the most excited mode and the zero mode. For parameters within their physically realistic ranges, a linear analysis of the resulting system yields a first excited mode whose wavelength is similar to the characteristic wavelength of sand waves observed in nature. The physical mechanism of sand wave formation as predicted by the new model is explained in detail. The dispersion relation obtained can be the starting point for a weakly nonlinear analysis of the system.

Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer

Resistance to cytotoxic chemotherapy is a major cause of mortality in colorectal cancer (CRC) patients. Chemoresistance has been linked primarily to a subset of cancer cells undergoing epithelial-mesenchymal transition (EMT). Curcumin, a botanical with antitumorigenic properties, has been shown to enhance sensitivity of cancer cells to chemotherapeutic drugs, but the molecular mechanisms underlying this phenomenon remain unclear. Effects of curcumin and 5-fluorouracil (5FU) individually, and in combination, were examined in parental and 5FU resistant (5FUR) cell lines. We performed a series of growth proliferation and apoptosis assays in 2D and 3D cell cultures. Furthermore, we identified and analyzed the expression pattern of a subset of putative EMT-suppressive microRNAs (miRNAs) and their downstream target genes regulated by curcumin. Chemosensitizing effects of curcumin were validated in a xenograft mouse model. Combined treatment with curcumin and 5FU enhanced cellular apoptosis and inhibited proliferation in both parental and 5FUR cells, whereas 5FU alone was ineffective in 5FUR cells. A group of EMT-suppressive miRNAs were upregulated by curcumin treatment in 5FUR cells. Curcumin suppressed EMT in 5FUR cells by downregulating BMI1, SUZ12 and EZH2 transcripts, key mediators of cancer stemness-related polycomb repressive complex subunits. Using a xenograft and mathematical models, we further demonstrated that curcumin sensitized 5FU to suppress tumor growth. We provide novel mechanistic evidence for curcumin-mediated sensitization to 5FU-related chemoresistance through suppression of EMT in 5FUR cells via upregulation of EMT-suppressive miRNAs. This study highlights the potential therapeutic usefulness of curcumin as an adjunct in patients with chemoresistant advanced CRC.