An autonomous molecular computer for logical control of gene expression

Early biomolecular computer research focused on laboratory-scale, human-operated computers for complex computational problems. Recently, simple molecular-scale autonomous programmable computers were demonstrated allowing both input and output information to be in molecular form. Such computers, using biological molecules as input data and biologically active molecules as outputs, could produce a system for 'logical' control of biological processes. Here we describe an autonomous biomolecular computer that, at least in vitro, logically analyses the levels of messenger RNA species, and in response produces a molecule capable of affecting levels of gene expression. The computer operates at a concentration of close to a trillion computers per microlitre and consists of three programmable modules: a computation module, that is, a stochastic molecular automaton; an input module, by which specific mRNA levels or point mutations regulate software molecule concentrations, and hence automaton transition probabilities; and an output module, capable of controlled release of a short single-stranded DNA molecule. This approach might be applied in vivo to biochemical sensing, genetic engineering and even medical diagnosis and treatment. As a proof of principle we programmed the computer to identify and analyse mRNA of disease-related genes associated with models of small-cell lung cancer and prostate cancer, and to produce a single-stranded DNA molecule modelled after an anticancer drug.     

Francis Galton’s regression towards mediocrity and the stability of types

A prevalent narrative locates the discovery of the statistical phenomenon of regression to the mean in the work of Francis Galton. It is claimed that after 1885, Galton came to explain the fact that offspring deviated less from the mean value of the population than their parents did as a population-level statistical phenomenon and not as the result of the processes of inheritance. Arguing against this claim, we show that Galton did not explain regression towards mediocrity statistically, and did not give up on his ideas regarding an inheritance process that caused offspring to revert to the mean. While the common narrative focuses almost exclusively on Galton’s statistics, our arguments emphasize the anthropological and biological questions that Galton addressed. Galton used regression towards mediocrity to support the claim that some biological types were more stable than others and hence were resistant to evolutionary change. This view had implications concerning both natural selection and eugenics. The statistical explanation attributed to Galton appeared later, during the biometrician-mutationist debate in the early 1900s. It was in the context of this debate and specifically by the biometricians, that the development of the statistical explanation was originally attributed to Galton.     

The twisted ion-permeation pathway of a resting voltage-sensing domain

Proteins containing voltage-sensing domains (VSDs) translate changes in membrane potential into changes in ion permeability or enzymatic activity. In channels, voltage change triggers a switch in conformation of the VSD, which drives gating in a separate pore domain, or, in channels lacking a pore domain, directly gates an ion pathway within the VSD. Neither mechanism is well understood. In the Shaker potassium channel, mutation of the first arginine residue of the S4 helix to a smaller uncharged residue makes the VSD permeable to ions ('omega current') in the resting conformation ('S4 down'). Here we perform a structure-guided perturbation analysis of the omega conductance to map its VSD permeation pathway. We find that there are four omega pores per channel, which is consistent with one conduction path per VSD. Permeating ions from the extracellular medium enter the VSD at its peripheral junction with the pore domain, and then plunge into the core of the VSD in a curved conduction pathway. Our results provide a model of the resting conformation of the VSD.     

Detectable radio flares following gravitational waves from mergers of binary neutron stars

Mergers of neutron-star/neutron-star binaries are strong sources of gravitational waves. They can also launch subrelativistic and mildly relativistic outflows and are often assumed to be the sources of short γ-ray bursts. An electromagnetic signature that persisted for weeks to months after the event would strengthen any future claim of a detection of gravitational waves. Here we present results of calculations showing that the interaction of mildly relativistic outflows with the surrounding medium produces radio flares with peak emission at 1.4 gigahertz that persist at detectable (submillijansky) levels for weeks, out to a redshift of 0.1. Slower subrelativistic outflows produce flares detectable for years at 150 megahertz, as well as at 1.4 gigahertz, from slightly shorter distances. The radio transient RT 19870422 (ref. 11) has the properties predicted by our model, and its most probable origin is the merger of a compact neutron-star/neutron-star binary. The lack of radio detections usually associated with short γ-ray bursts does not constrain the radio transients that we discuss here (from mildly relativistic and subrelativistic outflows) because short γ-ray burst redshifts are typically >0.1 and the appropriate timescales (longer than weeks) have not been sampled.     

Analysis of a RanGTP-regulated gradient in mitotic somatic cells

The RanGTPase cycle provides directionality to nucleocytoplasmic transport, regulating interactions between cargoes and nuclear transport receptors of the importin-beta family. The Ran-importin-beta system also functions in mitotic spindle assembly and nuclear pore and nuclear envelope formation. The common principle underlying these diverse functions throughout the cell cycle is thought to be anisotropy of the distribution of RanGTP (the RanGTP gradient), driven by the chromatin-associated guanine nucleotide exchange factor RCC1 (refs 1, 4, 5). However, the existence and function of a RanGTP gradient during mitosis in cells is unclear. Here we examine the Ran-importin-beta system in cells by conventional and fluorescence lifetime microscopy using a biosensor, termed Rango, that increases its fluorescence resonance energy transfer signal when released from importin-beta by RanGTP. Rango is predominantly free in mitotic cells, but is further liberated around mitotic chromatin. In vitro experiments and modelling show that this localized increase of free cargoes corresponds to changes in RanGTP concentration sufficient to stabilize microtubules in extracts. In cells, the Ran-importin-beta-cargo gradient kinetically promotes spindle formation but is largely dispensable once the spindle has been established. Consistent with previous reports, we observe that the Ran system also affects spindle pole formation and chromosome congression in vivo. Our results demonstrate that conserved Ran-regulated pathways are involved in multiple, parallel processes required for spindle function, but that their relative contribution differs in chromatin- versus centrosome/kinetochore-driven spindle assembly systems.     

Richard Lewontin and the “complications of linkage”

During the 1960s and 1970s population geneticists pushed beyond models of single genes to grapple with the effect on evolution of multiple genes associated by linkage. The resulting models of multiple interacting loci suggested that blocks of genes, maybe even entire chromosomes or the genome itself, should be treated as a unit. In this context, Richard Lewontin wrote his famous 1974 book The Genetic Basis of Evolutionary Change, which concludes with an argument for considering the entire genome as the unit of selection as a result of linkage. Why did Lewontin and others devote so much intellectual energy to the “complications of linkage” in the 1960s and 1970s? We argue that this attention to linkage should be understood in the context of research on chromosomal inversions and co-adapted gene complexes that occupied mid-century evolutionary genetics. For Lewontin, the complications of linkage were an extension of this chromosomal focus expressed in the new language of models for linkage disequilibrium.     

Processing of wild cereal grains in the Upper Palaeolithic revealed by starch grain analysis

Barley (Hordeum vulgare L.) and wheat (Triticum monococcum L. and Triticum turgidum L.) were among the principal 'founder crops' of southwest Asian agriculture. Two issues that were central to the cultural transition from foraging to food production are poorly understood. They are the dates at which human groups began to routinely exploit wild varieties of wheat and barley, and when foragers first utilized technologies to pound and grind the hard, fibrous seeds of these and other plants to turn them into easily digestible foodstuffs. Here we report the earliest direct evidence for human processing of grass seeds, including barley and possibly wheat, in the form of starch grains recovered from a ground stone artefact from the Upper Palaeolithic site of Ohalo II in Israel. Associated evidence for an oven-like hearth was also found at this site, suggesting that dough made from grain flour was baked. Our data indicate that routine processing of a selected group of wild cereals, combined with effective methods of cooking ground seeds, were practiced at least 12,000 years before their domestication in southwest Asia.