Mechanistic Explanations and Models in Molecular Systems Biology

Mechanistic models in molecular systems biology are generally mathematical models of the action of networks of biochemical reactions, involving metabolism, signal transduction, and/or gene expression. They can be either simulated numerically or analyzed analytically. Systems biology integrates quantitative molecular data acquisition with mathematical models to design new experiments, discriminate between alternative mechanisms and explain the molecular basis of cellular properties. At the heart of this approach are mechanistic models of molecular networks. We focus on the articulation and development of mechanistic models, identifying five constraints which guide the articulation of models in molecular systems biology. These constraints are not independent of one another, with the result that modeling becomes an iterative process. We illustrate the use of these constraints in the modeling of the mechanism for bistability in the lac operon.     

Systematic identification of genomic markers of drug sensitivity in cancer cells

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.     

Teaching in tandem-running ants

The ant Temnothorax albipennis uses a technique known as tandem running to lead another ant from the nest to food--with signals between the two ants controlling both the speed and course of the run. Here we analyse the results of this communication and show that tandem running is an example of teaching, to our knowledge the first in a non-human animal, that involves bidirectional feedback between teacher and pupil. This behaviour indicates that it could be the value of information, rather than the constraint of brain size, that has influenced the evolution of teaching.     

An experiment to evaluate methods for estimating fossil fuel resources

Estimates of petroleum and natural gas resources vary substantially, both over time and across estimation methods. This paper develops a simulation model of global oil resources to evaluate different resource estimation techniques. Protocols for the Hubbert life cycle and USGS geological analogy methods are developed and applied to synthetic data generated by the model. It is shown that the Hubbert method can generate an accurate estimate as early as twenty years before the peak of global production, but the geological analogy approach overestimates the true resource base over the life cycle of the resource. The results show the applicability of simulation and the synthetic data approach to the problem of evaluating forecasting methods.     

Examination of the potential mutagenicity of hair dye constituents using the micronucleus test

Summary 12 compounds which are constitutents of hair dyes or chemically related aromatic amines, aminophenols, their nitroderivatives and aromatic hydroxyderivatives were examined for evidence of mutagenic potential by means of the micronucleus test. None of the compounds tested caused an increase in the incidence of micronucleated erythrocytes after oral dosing.Acknowledgment. These investigations were conducted on behalf and with the assistance of Elida-Gibbs GmbH, Hamburg, Goldwell GmbH, Darmstadt, Thera-Chemie GmbH, Dusseldorf, L'Oreal-Haarkosm, und Parf. GmbH, Karlsruhe, Kadus-Werk K.G., Lenzkirch, Hans Schwarzkopf GmbH, Hamburg, Wella AG, Darmstadt.     

100-metre-diameter moonlets in Saturn's A ring from observations of 'propeller' structures

Saturn's main rings are composed predominantly of water-ice particles ranging between about 1 centimetre and 10 metres in radius. Above this size range, the number of particles drops sharply, according to the interpretation of spacecraft and stellar occultations. Other than the gap moons Pan and Daphnis (the provisional name of S/2005 S1), which have sizes of several kilometres, no individual bodies in the rings have been directly observed, and the population of ring particles larger than ten metres has been essentially unknown. Here we report the observation of four longitudinal double-streaks in an otherwise bland part of the mid-A ring. We infer that these 'propeller'-shaped perturbations arise from the effects of embedded moonlets approximately 40 to 120 m in diameter. Direct observation of this phenomenon validates models of proto-planetary disks in which similar processes are posited. A population of moonlets, as implied by the size distribution that we find, could help explain gaps in the more tenuous regions of the Cassini division and the C ring. The existence of such large embedded moonlets is most naturally compatible with a ring originating in the break-up of a larger body, but accretion from a circumplanetary disk is also plausible if subsequent growth onto large particles occurs after the primary accretion phase has concluded.     

A topographically forced asymmetry in the martian circulation and climate

Large seasonal and hemispheric asymmetries in the martian climate system are generally ascribed to variations in solar heating associated with orbital eccentricity. As the orbital elements slowly change (over a period of >104 years), characteristics of the climate such as dustiness and the vigour of atmospheric circulation are thought to vary, as should asymmetries in the climate (for example, the deposition of water ice at the northern versus the southern pole). Such orbitally driven climate change might be responsible for the observed layering in Mars' polar deposits by modulating deposition of dust and water ice. Most current theories assume that climate asymmetries completely reverse as the angular distance between equinox and perihelion changes by 180 degrees. Here we describe a major climate mechanism that will not precess in this way. We show that Mars' global north-south elevation difference forces a dominant southern summer Hadley circulation that is independent of perihelion timing. The Hadley circulation, a tropical overturning cell responsible for trade winds, largely controls interhemispheric transport of water and the bulk dustiness of the atmosphere. The topography therefore imprints a strong handedness on climate, with water ice and the active formation of polar layered deposits more likely in the north.