arXiv subjects

Robert A. Gatenby

Publications and source records attributed to Robert A. Gatenby.

11 recordsLinked to original sources

arXiv2026

Adaptive High-Level Tight Control of Prostate Cancer: A Path from From Terminal Disease to Chronic Condition

Metastatic prostate cancer is one of the leading causes of cancer-related morbidity and mortality worldwide. It is characterized by a high mortality rate and a poor prognosis. In this work, we explore how a clinical oncologist can apply a Stackelberg game-theoretic framework to prolong metastatic prostate cancer survival, or even make it chronic in duration. We utilize a Bayesian optimization approach to identify the optimal adaptive chemotherapeutic treatment policy for a single drug (Abiraterone) to maximize the time before the patient begins to show symptoms. We show that, with precise adaptive optimization of drug delivery, it is possible to significantly prolong the cancer suppression period, potentially converting metastatic prostate cancer from a terminal disease to a chronic disease for most patients, as supported by clinical and analytical evidence. We suggest that clinicians might explore the possibility of implementing a high-level tight control (HLTC) treatment, in which the trigger signals (i.e. biomarker levels) for drug administration and cessation are both high and close together, typically yield the best outcomes, as demonstrated through both computation and theoretical analysis. This simple insight could serve as a valuable guide for improving current adaptive chemotherapy treatments in other hormone-sensitive cancers.

q-bio.QM↗

arXiv2024

Modeling non-genetic information dynamics in cells using reservoir computing

Virtually all cells use energy and ion-specific membrane pumps to maintain large transmembrane gradients of Na$^+$, K$^+$, Cl$^-$, Mg$^{++}$, and Ca$^{++}$. Although they consume up to 1/3 of a cell's energy budget, the corresponding evolutionary benefit of transmembrane ion gradients remain unclear. Here, we propose that ion gradients enable a dynamic and versatile biological system that acquires, analyzes, and responds to environmental information. We hypothesize environmental signals are transmitted into the cell by ion fluxes along pre-existing gradients through gated ion-specific membrane channels. The consequent changes of cytoplasmic ion concentration can generate a local response and orchestrate global or regional responses through wire-like ion fluxes along pre-existing and self-assembling cytoskeleton to engage the endoplasmic reticulum, mitochondria, and nucleus. Here, we frame our hypothesis through a quasi-physical (Cell-Reservoir) model that treats intra-cellular ion-based information dynamics as a sub-cellular process permitting spatiotemporally resolved cellular response that is also capable of learning complex nonlinear dynamical cellular behavior. We demonstrate the proposed ion dynamics permits rapid dissemination of response to information extrinsic perturbations that is consistent with experimental observations.

q-bio.CB↗

arXiv2021

Super-Linear Growth Reveals the Allee Effect in Tumors

Integrating experimental data into ecological models plays a central role in understanding biological mechanisms that drive tumor progression where such knowledge can be used to develop new therapeutic strategies. While the current studies emphasize the role of competition among tumor cells, they fail to explain recently observed super-linear growth dynamics across human tumors. Here we study tumor growth dynamics by developing a model that incorporates evolutionary dynamics inside tumors with tumor-microenvironment interactions. Our results reveal that tumor cells' ability to manipulate the environment and induce angiogenesis drives super-linear growth -- a process compatible with the Allee effect. In light of this understanding, our model suggests that for high-risk tumors that have a higher growth rate, suppressing angiogenesis can be the appropriate therapeutic intervention.

physics.bio-ph↗

arXiv2020

A comparative study between discrete and continuum models for the evolution of competing phenotype-structured cell populations in dynamical environments

Deterministic continuum models formulated in terms of non-local partial differential equations for the evolutionary dynamics of populations structured by phenotypic traits have been used recently to address open questions concerning the adaptation of asexual species to periodically fluctuating environmental conditions. These deterministic continuum models are usually defined on the basis of population-scale phenomenological assumptions and cannot capture adaptive phenomena that are driven by stochastic variability in the evolutionary paths of single individuals. In this paper, we develop a stochastic individual-based model for the coevolution between two competing phenotype-structured cell populations that are exposed to time-varying nutrient levels and undergo spontaneous, heritable phenotypic variations with different probabilities. The evolution of every cell is described by a set of rules that result in a discrete-time branching random walk on the space of phenotypic states. We formally show that the deterministic continuum counterpart of this model comprises a system of non-local partial differential equations for the cell population density functions coupled with an ordinary differential equation for the nutrient concentration. We compare the individual-based model and its continuum analogue, focussing on scenarios whereby the predictions of the two models differ. Our results clarify the conditions under which significant differences between the two models can emerge due to stochastic effects associated with small population levels. These differences arise in the presence of low probabilities of phenotypic variation, and become more apparent when the two populations are characterised by less fit initial mean phenotypes and smaller initial levels of phenotypic heterogeneity.

q-bio.PE↗

arXiv2019

Spontaneous Formation of Universes from Vacuum via Information-induced Holograms

All spontaneous emergence of quantum particles from false vacuums can occur via usual energy-based Lagrangians; or, as we show, via a variational principle of minimum loss of Fisher information. By this principle all material existence in the multiverse, including its life forms, are physical manifestations of Fisher information. The information principle serially formed our universe, and all others, in the multiverse. The resulting expansionary (Big bang) eras of time t and/or space-time x_i, i = x,y,z,t (c=1) for the universes are found to obey probability densities p(t) and p(x_i) of usual exponential forms. The existence of the multiverse allows preservation of invariant values of the 26 physical constants via their relay from one universe to another by successive Lorentzian wormholes. At each relay the emerging constants are represented by the intensities of an input hologram. The information principle was previously used to derive nearly all textbook physics and much cell biology, e.g. the Hodgkin-Huxley (H-H) equations governing ions emerging into biological cells. The equations we derive governing p(t) and p(x_i) for universes coincide with the H-H equations governing ions entering these biological cells. Thus, the information concept holds over a vast range of scale sizes.

physics.gen-ph↗

arXiv2019

Evolutionary dynamics of competing phenotype-structured populations in periodically fluctuating environments

Living species, ranging from bacteria to animals, exist in environmental conditions that exhibit spatial and temporal heterogeneity which requires them to adapt. Risk-spreading through spontaneous phenotypic variations is a known concept in ecology, which is used to explain how species may survive when faced with the evolutionary risks associated with temporally varying environments. In order to support a deeper understanding of the adaptive role of spontaneous phenotypic variations in fluctuating environments, we consider a system of non-local partial differential equations modelling the evolutionary dynamics of two competing phenotype-structured populations in the presence of periodically oscillating nutrient levels. The two populations undergo spontaneous phenotypic variations at different rates. The phenotypic state of each individual is represented by a continuous variable, and the phenotypic landscape of the populations evolves in time due to variations in the nutrient level. Exploiting the analytical tractability of our model, we study the long-time behaviour of the solutions to obtain a detailed mathematical depiction of evolutionary dynamics. The results suggest that when nutrient levels undergo small and slow oscillations, it is evolutionarily more convenient to rarely undergo spontaneous phenotypic variations. Conversely, under relatively large and fast periodic oscillations in the nutrient levels, which bring about alternating cycles of starvation and nutrient abundance, higher rates of spontaneous phenotypic variations confer a competitive advantage. We discuss the implications of our results in the context of cancer metabolism.

q-bio.PE↗

arXiv2017

Evolutionary advantage of directional symmetry breaking in self-replicating polymers

Due to the asymmetric nature of the nucleotides, the extant informational biomolecule, DNA, is constrained to replicate unidirectionally on a template. As a product of molecular evolution that sought to maximize replicative potential, DNA's unidirectional replication poses a mystery since symmetric bidirectional self-replicators obviously would replicate faster than unidirectional self-replicators and hence would have been evolutionarily more successful. Here we carefully examine the physico-chemical requirements for evolutionarily successful primordial self-replicators and theoretically show that at low monomer concentrations that possibly prevailed in the primordial oceans, asymmetric unidirectional self-replicators would have an evolutionary advantage over bidirectional self-replicators. The competing requirements of low and high kinetic barriers for formation and long lifetime of inter-strand bonds respectively are simultaneously satisfied through asymmetric kinetic influence of inter-strand bonds, resulting in evolutionarily successful unidirectional self-replicators.

q-bio.BM↗

arXiv2017

Evolutionary advantage of a broken symmetry in autocatalytic polymers explains fundamental properties of DNA

The macromolecules that encode and translate information in living systems, DNA and RNA, exhibit distinctive structural asymmetries, including homochirality or mirror image asymmetry and $3' - 5'$ directionality, that are invariant across all life forms. The evolutionary advantages of these broken symmetries remain unknown. Here we utilize a very simple model of hypothetical self-replicating polymers to show that asymmetric autocatalytic polymers are more successful in self-replication compared to their symmetric counterparts in the Darwinian competition for space and common substrates. This broken-symmetry property, called asymmetric cooperativity, arises with the maximization of a replication potential, where the catalytic influence of inter-strand bonds on their left and right neighbors is unequal. Asymmetric cooperativity also leads to tentative, qualitative and simple evolution-based explanations for a number of other properties of DNA that include four nucleotide alphabet, three nucleotide codons, circular genomes, helicity, anti-parallel double-strand orientation, heteromolecular base-pairing, asymmetric base compositions, and palindromic instability, apart from the structural asymmetries mentioned above. Our model results and tentative explanations are consistent with multiple lines of experimental evidence, which include evidence for the presence of asymmetric cooperativity in DNA.

q-bio.BM↗

arXiv2014

Derivation of Principle of Extreme Physical Information

The unknown amplitude law q(x) defining an observed effect may be found using the principle of Extreme Physical Information. EPI is derived as follows. The observations follow an information flow J --> I, with J the information intrinsic to the source and I the Fisher information level in its data, obeying (i) I=4 Integral dx q' -squared. Here q'= dq/dx and p(x) = q(x)-squared is the probability. It was previously shown, using L. Hardy's 5 axioms defining physics, that I = max. Therefore, its variation (ii) delta I = 0. Note that I is generic, obeying (i) for all source effects, whereas J is specific to the particular effect. Hence, rather than having form (i), J obeys (iii) J = Integral dx j[q(x),s(x)] with j some function of its arguments and s(x) a known source, such as of mass, biological fitness, etc. Information I decreases under any irreversible operation such as measurement, so that I l.e. J or, equivalently, I = kJ where 0 l.e. k l.e. 1. Then the variation delta I = k delta J so that property (ii) gives (iv) delta J = 0 as well. Then combining (ii) and (iv), delta(I - J) = 0. Or, I - J = L = extremum. What kind of extremum? Eqs. (i) and (iii) give (v) L=4q'^2 - j[q(x),s(x)]. Differentiating (v), (d^2 L )/(dq'^2) = +8. Then by the Legendre condition the extremum is a minimum. The unknown source effect obeys (vi) I - J= minimum, EPI.

physics.data-an↗

arXiv2013

A Markov chain model of evolution in asexually reproducing populations: insight and analytical tractability in the evolutionary process

The evolutionary process has been modelled in many ways using both stochastic and deterministic models. We develop an algebraic model of evolution in a population of asexually reproducing organisms in which we represent a stochastic walk in phenotype space, constrained to the edges of an underlying graph representing the genotype, with a time-homogeneous Markov Chain. We show its equivalence to a more standard, explicit stochastic model and show the algebraic model's superiority in computational efficiency. Because of this increase in efficiency, we offer the ability to simulate the evolution of much larger populations in more realistic genotype spaces. Further, we show how the algebraic properties of the Markov Chain model can give insight into the evolutionary process and allow for analysis using familiar linear algebraic methods.

q-bio.PE↗

arXiv2005

Power laws of complex systems from Extreme physical information

Many complex systems obey allometric, or power, laws y=Yx^{a}. Here y is the measured value of some system attribute a, Y is a constant, and x is a stochastic variable. Remarkably, for many living systems the exponent a is limited to values +or- n/4, n=0,1,2... Here x is the mass of a randomly selected creature in the population. These quarter-power laws hold for many attributes, such as pulse rate (n=-1). Allometry has, in the past, been theoretically justified on a case-by-case basis. An ultimate goal is to find a common cause for allometry of all types and for both living and nonliving systems. The principle I - J = extrem. of Extreme physical information (EPI) is found to provide such a cause. It describes the flow of Fisher information J => I from an attribute value a on the cell level to its exterior observation y. Data y are formed via a system channel function y = f(x,a), with f(x,a) to be found. Extremizing the difference I - J through variation of f(x,a) results in a general allometric law f(x,a)= y = Yx^{a}. Darwinian evolution is presumed to cause a second extremization of I - J, now with respect to the choice of a. The solution is a=+or-n/4, n=0,1,2..., defining the particular powers of biological allometry. Under special circumstances, the model predicts that such biological systems are controlled by but two distinct intracellular information sources. These sources are conjectured to be cellular DNA and cellular transmembrane ion gradients

q-bio.CB↗