Cell biology: Developmental predisposition to cancer.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
Martin A Nowak
Publications and source records attributed to Martin A Nowak.
Local regulation of homeostasis favors chromosomal instability.
Tissues of long-lived multicellular organisms have to maintain a constant number of functioning cells for many years. This process is called homeostasis. Homeostasis breaks down when cells emerge with mutations in tumor suppressor genes or oncogenes. Such mutated cells can have increased net rates of proliferation, which is increased somatic fitness. We show that the best protection against such mutations is achieved when homeostasis is regulated locally via small compartments. Small compartments, on the other hand, allow the accumulation of cells with reduced somatic fitness. Cells with mutations conferring genetic instability normally have a reduced somatic fitness because they have an increased probability of producing deleterious mutations or triggering apoptosis. Thus, small compartments protect against mutations in tumor suppressor genes or oncogenes but promote the emergence of genetic instability.
Cell Transformation, Neoplastic↗
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.
Amino Acid Sequence↗
Competitive exclusion and coexistence of universal grammars.
Universal grammar (UG) is a list of innate constraints that specify the set of grammars that can be learned by the child during primary language acquisition. UG of the human brain has been shaped by evolution. Evolution requires variation. Hence, we have to postulate and study variation of UG. We investigate evolutionary dynamics and language acquisition in the context of multiple UGs. We provide examples for competitive exclusion and stable coexistence of different UGs. More specific UGs admit fewer candidate grammars, and less specific UGs admit more candidate grammars. We will analyze conditions for more specific UGs to outcompete less specific UGs and vice versa. An interesting finding is that less specific UGs can resist invasion by more specific UGs if learning is more accurate. In other words, accurate learning stabilizes UGs that admit large numbers of candidate grammars.
Biological Evolution↗
The significance of unstable chromosomes in colorectal cancer.
A very large fraction of cancers have an abnormal genetic content, called aneuploidy, which is characterized by changes in chromosome structure and number. One explanation for this aneuploidy is chromosomal instability, in which cancer cells gain or lose whole chromosomes or large fractions of chromosomes at a greatly increased rate compared with normal cells. Here, we explore experimental and theoretical evidence for the initiation of chromosomal instability in very early colorectal cancers, and reflect on the role that chromosomal instability could have in colorectal tumorigenesis.
Cell Transformation, Neoplastic↗
Patterns of cell division and the risk of cancer.
Epidermal and intestinal tissues divide throughout life to replace lost surface cells. These renewing tissues have long-lived basal stem cell lineages that divide many times, each division producing one stem cell and one transit cell. The transit cell divides a limited number of times, producing cells that move up from the basal layer and eventually slough off from the surface. If mutation rates are the same in stem and transit divisions, we show that minimal cancer risk is obtained by using the fewest possible stem divisions subject to the constraints imposed by the need to renew the tissue. In this case, stem cells are a necessary risk imposed by the constraints of tissue architecture. Cairns suggested that stem cells may have lower mutation rates than transit cells do. We develop a mathematical model to study the consequences of different stem and transit mutation rates. Our model shows that stem cell mutation rates two or three orders of magnitude less than transit mutation rates may favor relatively more stem divisions and fewer transit divisions, perhaps explaining how renewing tissues allocate cell divisions between long stem and short transit lineages.
Cell Division↗
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.
Animals↗
Unifying evolutionary dynamics.
Darwinian evolution is based on three fundamental principles, reproduction, mutation and selection, which describe how populations change over time and how new forms evolve out of old ones. There are numerous mathematical descriptions of the resulting evolutionary dynamics. In this paper, we show that apparently very different formulations are part of a single unified framework. At the center of this framework is the equivalence between the replicator-mutator equation and the Price equation. From these equations, we obtain as special cases adaptive dynamics, evolutionary game dynamics, the Lotka-Volterra equation of ecology and the quasispecies equation of molecular evolution.
Animals↗
Evolution: the good, the bad and the lonely.
Explore the source record for details and available documents.
Altruism↗
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.
Biological Evolution↗
The different effects of apoptosis and DNA repair on tumorigenesis.
Complex multicellular organisms have evolved mechanisms to ensure that individual cells follow their proper developmental and somatic programs. Tumorigenesis, or uncontrolled cellular proliferation, is caused by somatic mutations to those genetic constraints that normally operate within a tissue. Genes involved in DNA repair and apoptosis are particularly instrumental in safeguarding cells against tumorigenesis. In this paper, we introduce a stochastic framework to analyse the somatic evolution of cancer initiation. Within this model, we study how apoptosis and DNA repair can maintain the transient stability of somatic cells and delay the onset of cancer. Focusing on individual cell lineages, we calculate the waiting time before tumorigenesis in the presence of varying degrees of apoptosis and DNA repair. We find that the loss of DNA repair or the loss of apoptosis both hasten tumorigenesis, but in characteristically different ways.
Animals↗
Mathematical models of HIV pathogenesis and treatment.
We review mathematical models of HIV dynamics, disease progression, and therapy. We start by introducing a basic model of virus infection and demonstrate how it was used to study HIV dynamics and to measure crucial parameters that lead to a new understanding of the disease process. We discuss the diversity threshold model as an example of the general principle that virus evolution can drive disease progression and the destruction of the immune system. Finally, we show how mathematical models can be used to understand correlates of long-term immunological control of HIV, and to design therapy regimes that convert a progressing patient into a state of long-term non-progression.
Algorithms↗
Empathy leads to fairness.
In the Ultimatum Game, two players are asked to split a prize. The first player, the proposer, makes an offer of how to split the prize. The second player, the responder, either accepts the offer, in which case the prize is split as agreed, or rejects it, in which case neither player receives anything. The rational strategy suggested by classical game theory is for the proposer to offer the smallest possible positive share and for the responder to accept. Humans do not play this way, however, and instead tend to offer 50% of the prize and to reject offers below 20%. Here we study the Ultimatum Game in an evolutionary context and show that empathy can lead to the evolution of fairness. Empathy means that individuals make offers which they themselves would be prepared to accept.
Biological Evolution↗
The economics of fair play.
Explore the source record for details and available documents.
Journal Article↗
Compromised influenza virus-specific CD8(+)-T-cell memory in CD4(+)-T-cell-deficient mice.
The primary influenza A virus-specific CD8(+)-T-cell responses measured by tetramer staining of spleen, lymph node, and bronchoalveolar lavage (BAL) lymphocyte populations were similar in magnitude for conventional I-A(b+/+) and CD4(+)-T-cell-deficient I-A(b-/-) mice. Comparable levels of virus-specific cytotoxic-T-lymphocyte activity were detected in the inflammatory exudate recovered by BAL following challenge. However, both the size of the memory T-cell pool and the magnitude of the recall response in the lymphoid tissues (but not the BAL specimens) were significantly diminished in mice lacking the CD4(+) subset. Also, the rate of virus elimination from the infected respiratory tract slowed at low virus loads following challenge of naïve and previously immunized I-A(b-/-) mice. Thus, though the capacity to mediate the CD8(+)-T-cell effector function is broadly preserved in the absence of concurrent CD4(+)-T-cell help, both the maintenance and recall of memory are compromised and the clearance of residual virus is delayed. These findings are consistent with mathematical models that predict virus-host dynamics in this, and other, models of infection.
Animals↗
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.
Adenomatous Polyposis Coli↗