Nikodem J. Poplawski

3D multi-cell simulation of tumor growth and angiogenesis.

We present a 3D multi-cell simulation of a generic simplification of vascular tumor growth which can be easily extended and adapted to describe more specific vascular tumor types and host tissues. Initially, tumor cells proliferate as they take up the oxygen which the pre-existing vasculature supplies. The tumor grows exponentially. When the oxygen level drops below a threshold, the tumor cells become hypoxic and start secreting pro-angiogenic factors. At this stage, the tumor reaches a maximum diameter characteristic of an avascular tumor spheroid. The endothelial cells in the pre-existing vasculature respond to the pro-angiogenic factors both by chemotaxing towards higher concentrations of pro-angiogenic factors and by forming new blood vessels via angiogenesis. The tumor-induced vasculature increases the growth rate of the resulting vascularized solid tumor compared to an avascular tumor, allowing the tumor to grow beyond the spheroid in these linear-growth phases. First, in the linear-spherical phase of growth, the tumor remains spherical while its volume increases. Second, in the linear-cylindrical phase of growth the tumor elongates into a cylinder. Finally, in the linear-sheet phase of growth, tumor growth accelerates as the tumor changes from cylindrical to paddle-shaped. Substantial periods during which the tumor grows slowly or not at all separate the exponential from the linear-spherical and the linear-spherical from the linear-cylindrical growth phases. In contrast to other simulations in which avascular tumors remain spherical, our simulated avascular tumors form cylinders following the blood vessels, leading to a different distribution of hypoxic cells within the tumor. Our simulations cover time periods which are long enough to produce a range of biologically reasonable complex morphologies, allowing us to study how tumor-induced angiogenesis affects the growth rate, size and morphology of simulated tumors.

Magnetization to Morphogenesis: A Brief History of the Glazier-Graner-Hogeweg Model

This chapter discusses the history and development of what we propose to rename the Glazier-Graner-Hogeweg model (GGH model), starting with its ancestors, simple models of magnetism, and concluding with its current state as a powerful, cell-oriented method for simulating biological development and tissue physiology. We will discuss some of the choices and accidents of this development and some of the positive and negative consequences of the model’s pedigree.

Nonsingular, big-bounce cosmology from spinor-torsion coupling

The Einstein-Cartan-Sciama-Kibble theory of gravity removes the constraint of general relativity that the affine connection be symmetric by regarding its antisymmetric part, the torsion tensor, as a dynamical variable. The minimal coupling between the torsion tensor and Dirac spinors generates a spin-spin interaction which is significant in fermionic matter at extremely high densities. We show that such an interaction averts the unphysical big-bang singularity, replacing it with a cusp-like bounce at a finite minimum scale factor, before which the Universe was contracting. This scenario also explains why the present Universe at largest scales appears spatially flat, homogeneous and isotropic.

Radial motion into an Einstein-Rosen bridge

We consider the radial geodesic motion of a massive particle into a black hole in isotropic coordinates, which represents the exterior region of an Einstein–Rosen bridge (wormhole). The particle enters the interior region, which is regular and physically equivalent to the asymptotically flat exterior of a white hole, and the particle’s proper time extends to infinity. Since the radial motion into a wormhole after passing the event horizon is physically different from the motion into a Schwarzschild black hole, Einstein–Rosen and Schwarzschild black holes are different, physical realizations of general relativity. Yet for distant observers, both solutions are indistinguishable. We show that timelike geodesics in the field of a wormhole are complete because the expansion scalar in the Raychaudhuri equation has a discontinuity at the horizon, and because the Einstein–Rosen bridge is represented by the Kruskal diagram with Rindler’s elliptic identification of the two antipodal future event horizons. These results suggest that observed astrophysical black holes may be Einstein–Rosen bridges, each with a new universe inside that formed simultaneously with the black hole. Accordingly, our own Universe may be the interior of a black

Adhesion between cells, diffusion of growth factors, and elasticity of the AER produce the paddle shape of the chick limb.

A central question in developmental biology is how cells interact to organize into tissues? In this paper, we study the role of mesenchyme-ectoderm interaction in the growing chick limb bud using Glazier and Graners cellular Potts model, a grid-based stochastic framework designed to simulate cell interactions and movement. We simulate cellular mechanisms including cell adhesion, growth, and division and diffusion of morphogens, to show that differential adhesion between the cells, diffusion of growth factors through the extracellular matrix, and the elastic properties of the apical ectodermal ridge together can produce the proper shape of the limb bud.

Front Instabilities and Invasiveness of Simulated Avascular Tumors

We study the interface morphology of a 2D simulation of an avascular tumor composed of identical cells growing in an homogeneous healthy tissue matrix (TM), in order to understand the origin of the morphological changes often observed during real tumor growth. We use the Glazier–Graner–Hogeweg model, which treats tumor cells as extended, deformable objects, to study the effects of two parameters: a dimensionless diffusion-limitation parameter defined as the ratio of the tumor consumption rate to the substrate transport rate, and the tumor-TM surface tension. We model TM as a nondiffusing field, neglecting the TM pressure and haptotactic repulsion acting on a real growing tumor; thus, our model is appropriate for studying tumors with highly motile cells, e.g., gliomas. We show that the diffusion-limitation parameter determines whether the growing tumor develops a smooth (noninvasive) or fingered (invasive) interface, and that the sensitivity of tumor morphology to tumor-TM surface tension increases with the size of the dimensionless diffusion-limitation parameter. For large diffusion-limitation parameters, we find a transition (missed in previous work) between dendritic structures, produced when tumor-TM surface tension is high, and seaweed-like structures, produced when tumor-TM surface tension is low. This observation leads to a direct analogy between the mathematics and dynamics of tumors and those observed in nonbiological directional solidification. Our results are also consistent with the biological observation that hypoxia promotes invasive growth of tumor cells by inducing higher levels of receptors for scatter factors that weaken cell-cell adhesion and increase cell motility. These findings suggest that tumor morphology may have value in predicting the efficiency of antiangiogenic therapy in individual patients.

The Glazier-Graner-Hogeweg Model: Extensions, Future Directions, and Opportunities for Further Study

One of the reasons for the enormous success of the Glazier-Graner-HogewegGlazier-Graner-Hogeweg Model (GGH) model is that it is a framework for model building rather than a specific biological model. Thus new ideas constantly emerge for ways to extend it to describe new biological (and non-biological) phenomena. The GGH model automatically integrates extensions with the whole body of prior GGH work, a flexibility which makes it unusually simple and rewarding to work with. In this chapter we discuss some possible future directions to extend GGH modeling. We discuss off-lattice extensions to the GGH model, which can treat fluids and solids, new classes of model objects, approaches to increasing computational efficiency, parallelization, and new model-development platforms that will accelerate our ability to generate successful models. We also discuss a non-GGH, but GGH-inspired, model of plant development by Merks and collaborators, which uses the Hamiltonian and Monte-Carlo approaches of the GGH but solves them using Finite Element (FE) methods.

Interacting dark energy in f(R) gravity

The field equations in f(R) gravity derived from the Palatini variational principle and formulated in the Einstein conformal frame yield a cosmological term which varies with time. Moreover, they break the conservation of the energy-momentum tensor for matter, generating the interaction between matter and dark energy. Unlike phenomenological models of interacting dark energy, f(R) gravity derives such an interaction from a covariant Lagrangian which is a function of a relativistically invariant quantity (the curvature scalar R). We derive the expressions for the quantities describing this interaction in terms of an arbitrary function f(R), and examine how the simplest phenomenological models of a variable cosmological constant are related to f(R) gravity. Particularly, we show that {lambda}c{sup 2}=H{sup 2}(1-2q) for a flat, homogeneous and isotropic, pressureless universe. For the Lagrangian of form R-1/R, which is the simplest way of introducing current cosmic acceleration in f(R) gravity, the predicted matter-dark energy interaction rate changes significantly in time, and its current value is relatively weak (on the order of 1% of H{sub 0}), in agreement with astronomical observations.

Cosmological constant from quarks and torsion

We present a simple and natural way to derive the observed small, positive cosmological constant from the gravitational interaction of condensing fermions. In the Riemann-Cartan spacetime, torsion gives rise to the axial-axial four-fermion interaction term in the Dirac Lagrangian for spinor fields. We show that this nonlinear term acts like a cosmological constant if these fields have a nonzero vacuum expectation value. For quark fields in QCD, such a torsion-induced cosmological constant is positive and its energy scale is only about 8 times larger than the observed value. Adding leptons to this picture could lower this scale to the observed value.

The cosmic snap parameter in f(R) gravity

We derive the expression for the snap parameter in f(R) gravity. We use the Palatini variational principle to obtain the field equations and regard the Einstein conformal frame as physical. We predict the present-day value of the snap parameter for the particular case f(R) = R − const/R, which is the simplest f(R) model explaining the current acceleration of the universe.