Turing on Super-Turing and adaptivity

Biological processes are often compared to computation and modeled on the Universal Turing Machine. While many systems or aspects of systems can be well described in this manner, Turing computation can only compute what it has been programmed for. It has no ability to learn or adapt to new situations. Yet, adaptation, choice and learning are all hallmarks of living organisms. This suggests that there must be a different form of computation capable of this sort of calculation. It also suggests that there are current computational models of biological systems that may be fundamentally incorrect. We argue that the Super-Turing model is both capable of modeling adaptive computation, and furthermore, a possible answer to the computational model searched for by Turing himself.     

Probability in biology: Overview of a comprehensive theory of probability in living systems

Probability is closely related to biological organization and adaptation to the environment. Living systems need to maintain their organizational order by producing specific internal events non-randomly, and must cope with the uncertain environments. These processes involve increases in the probability of favorable events for these systems by reducing the degree of uncertainty of events. Systems with this ability will survive and reproduce more than those that have less of this ability. Probabilistic phenomena have been deeply explored using the mathematical theory of probability since Kolmogorov's axiomatization provided mathematical consistency for the theory. However, the interpretation of the concept of probability remains both unresolved and controversial, which creates problems when the mathematical theory is applied to problems in real systems. In this article, recent advances in the study of the foundations of probability from a biological viewpoint are reviewed, and a new perspective is discussed toward a comprehensive theory of probability for understanding the organization and adaptation of living systems.     

Molecular imaging of hydrogen peroxide produced for cell signaling

Hydrogen peroxide (H2O2) is emerging as a newly recognized messenger in cellular signal transduction. However, a substantial challenge in elucidating its diverse roles in complex biological environments is the lack of methods for probing this reactive oxygen metabolite in living systems with molecular specificity. Here we report the synthesis and application of Peroxy Green 1 (PG1) and Peroxy Crimson 1 (PC1), two new fluorescent probes that show high selectivity for H2O2 and are capable of visualizing endogenous H2O2 produced in living cells by growth factor stimulation, including the first direct imaging of peroxide produced for brain cell signaling. The combined features of reactive oxygen species selectivity, sensitivity to signaling levels of H2O2, and live-cell compatibility presage many new opportunities for PG1, PC1 and related synthetic reagents for exploring the physiological roles of H2O2 in living systems with molecular imaging.     

Pressure and life: some biological strategies

All biological processes of life on Earth experience varying degrees of pressure. Aquatic organisms living in the deep-sea, as well as chondrocytic cells of articular cartilage are exposed to hydrostatic pressures that rise up to several hundred times that of atmospheric pressure. In the case of marine larvae that disperse through the oceanic water column, pressure changes might be responsible for stress conditions during development, limiting colonisation capabilities. In a number of biological systems, life strategies may be significantly influenced by pressure. In this review, we will focus on the consequences of pressure changes on various biological processes, and more specifically on animals living in the deep-sea. Revisiting general principles of pressure effects on biological systems, we present recent data illustrating the diversity of effects pressure may have at different levels in biological systems, with particular attention to effects on gene expression. After a review of the main pressure equipments available today for studying species living naturally at high pressure, we summarise what is known concerning pressure impact during animal development.     

Designing de novo: interdisciplinary debates in synthetic biology

Synthetic biology is often presented as a promissory field that ambitions to produce novelty by design. The ultimate promise is the production of living systems that will perform new and desired functions in predictable ways. Nevertheless, realizing promises of novelty has not proven to be a straightforward endeavour. This paper provides an overview of, and explores the existing debates on, the possibility of designing living systems de novo as they appear in interdisciplinary talks between engineering and biological views within the field of synthetic biology. To broaden such interdisciplinary debates, we include the views from the social sciences and the humanities and we point to some fundamental sources of disagreement within the field. Different views co-exist, sometimes as controversial tensions, but sometimes also pointing to integration in the form of intermediate positions. As the field is emerging, multiple choices are possible. They will inform alternative trajectories in synthetic biology and will certainly shape its future. What direction is best is to be decided in reflexive and socially robust ways.     

The heparanome--the enigma of encoding and decoding heparan sulfate sulfation

Heparan sulfate (HS) is a cell surface carbohydrate polymer modified with sulfate moieties whose highly ordered composition is central to directing specific cell signaling events. The ability of the cell to generate these information rich glycans with such specificity has opened up a new field of "heparanomics" which seeks to understand the systems involved in generating these cell type and developmental stage specific HS sulfation patterns. Unlike other instances where biological information is encrypted as linear sequences in molecules such as DNA, HS sulfation patterns are generated through a non-template driven process. Thus, deciphering the sulfation code and the dynamic nature of its generation has posed a new challenge to system biologists. The recent discovery of two sulfatases, Sulf1 and Sulf2, with the unique ability to edit sulfation patterns at the cell surface, has opened up a new dimension as to how we understand the regulation of HS sulfation patterning and pattern-dependent cell signaling events. This review will focus on the functional relationship between HS sulfation patterning and biological processes. Special attention will be given to Sulf1 and Sulf2 and how these key editing enzymes might act in concert with the HS biosynthetic enzymes to generate and regulate specific HS sulfation patterns in vivo. We will further explore the use of knock out mice as biological models for understanding the dynamic systems involved in generating HS sulfation patterns and their biological relevance. A brief overview of new technologies and innovations summarizes advances in the systems biology field for understanding non-template molecular networks and their influence on the "heparanome".     

The impacts of climate change in coastal marine systems

Anthropogenically induced global climate change has profound implications for marine ecosystems and the economic and social systems that depend upon them. The relationship between temperature and individual performance is reasonably well understood, and much climate-related research has focused on potential shifts in distribution and abundance driven directly by temperature. However, recent work has revealed that both abiotic changes and biological responses in the ocean will be substantially more complex. For example, changes in ocean chemistry may be more important than changes in temperature for the performance and survival of many organisms. Ocean circulation, which drives larval transport, will also change, with important consequences for population dynamics. Furthermore, climatic impacts on one or a few 'leverage species' may result in sweeping community-level changes. Finally, synergistic effects between climate and other anthropogenic variables, particularly fishing pressure, will likely exacerbate climate-induced changes. Efforts to manage and conserve living marine systems in the face of climate change will require improvements to the existing predictive framework. Key directions for future research include identifying key demographic transitions that influence population dynamics, predicting changes in the community-level impacts of ecologically dominant species, incorporating populations' ability to evolve (adapt), and understanding the scales over which climate will change and living systems will respond.     

Assessing the impacts of genetically modified microorganisms

The progression towards greater industrial sustainability involves the analysis of biotechnology as a means of achieving clean or cleaner products and processes. Because living systems manage their chemistry more efficiently than man-made factories, and their wastes tend to be recyclable and biodegradable, they can be expected to be more environmentally clean. Industry has begun to use enzymes instead of traditional catalysts in many industrial production processes. The future holds obstacles as well as opportunities for biotechnological applications. A greater ability to manipulate biological materials and processes will have significant impact on manufacturing industries. A growing proportion of biotechnologyderived processes and products is based on the use of genetically modified microorganisms. This extends the analysis from the aspect of cleanliness to the aspect of safety.     

Oxidative stress and its effects during dehydration

Water is usually thought to be required for the living state, but several organisms are capable of surviving complete dehydration (anhydrobiotes). Elucidation of the mechanisms of tolerance against dehydration may lead to development of new methods for preserving biological materials that do not normally support drying, which is of enormous practical importance in industry, in clinical medicine as well as in agriculture. One of the molecular mechanisms of damage leading to death in desiccation-sensitive cells upon drying is free-radical attack to phospholipids, DNA and proteins. This review aims to summarize the strategies used by anhydrobiotes to cope with the danger of oxygen toxicity and to present our recent results about the importance of some antioxidant defense systems in the dehydration tolerance of Saccharomyces cerevisiae, a usual model in the study of stress response.     

Are attractors 'strange', or is life more complicated than the simple laws of physics?

Interesting and intriguing questions involve complex systems whose properties cannot be explained fully by reductionist approaches. Last century was dominated by physics, and applying the simple laws of physics to biology appeared to be a practical solution to understand living organisms. However, although some attributes of living organisms involve physico-chemical properties, the genetic program and evolutionary history of complex biological systems make them unique and unpredictable. Furthermore, there are and will be 'unobservable' phenomena in biology which have to be accounted for.     

Chemogenomics approaches to novel target discovery

Chemogenomics involves the combination of a compound's effect on biological targets together with modern genomics technologies. The merger of these two methodologies is creating a new way to screen for compound-target interactions, as well as map chemical and biological space in a parallel fashion. The challenge associated with mining complex databases has initiated the development of many novel in silico tools to profile and analyze data in a systematic way. The ability to analyze the combinatorial effects of chemical libraries on biological systems will aid the discovery of new therapeutic entities. Chemogenomics provides a tool for the rapid validation of novel targeted therapeutics, where a specific molecular target is modulated by a small molecule. Along with targeted therapies comes the ability to discovery pathway nodes where a single molecular target might be an essential component of more than one disease. Several disease areas will benefit directly from the chemogenomics approach, the most advanced being cancer. A genetic loss-of-function screen can be modulated in the presence of a compound to search for genes or pathways involved in the compound's activity. Several recent papers highlight how chemogenomics is changing with RNA interference-based screening and shaping the discovery of new targeted therapies. Together, chemical and RNA interference-based screens open the door for a new way to discovery disease-associated genes and novel targeted therapies.     

Representing and analysing molecular and cellular function using the computer

Determining the biological function of a myriad of genes, and understanding how they interact to yield a living cell, is the major challenge of the post genome-sequencing era. The complexity of biological systems is such that this cannot be envisaged without the help of powerful computer systems capable of representing and analysing the intricate networks of physical and functional interactions between the different cellular components. In this review we try to provide the reader with an appreciation of where we stand in this regard. We discuss some of the inherent problems in describing the different facets of biological function, give an overview of how information on function is currently represented in the major biological databases, and describe different systems for organising and categorising the functions of gene products. In a second part, we present a new general data model, currently under development, which describes information on molecular function and cellular processes in a rigorous manner. The model is capable of representing a large variety of biochemical processes, including metabolic pathways, regulation of gene expression and signal transduction. It also incorporates taxonomies for categorising molecular entities, interactions and processes, and it offers means of viewing the information at different levels of resolution, and dealing with incomplete knowledge. The data model has been implemented in the database on protein function and cellular processes 'aMAZE' (http://www.ebi.ac.uk/research/pfbp/), which presently covers metabolic pathways and their regulation. Several tools for querying, displaying, and performing analyses on such pathways are briefly described in order to illustrate the practical applications enabled by the model.     

Synthetic biology in biofilms: Tools,challenges, and opportunities

The field of synthetic biology seeks to program living cells to perform novel functions with applications ranging from environmental biosensing to smart cell-based therapeutics. Bacteria are an especially attractive chassis organism due to their rapid growth, ease of genetic manipulation, and ability to persist across many environmental niches. Despite significant progress in bacterial synthetic biology, programming bacteria to perform novel functions outside the well-controlled laboratory context remains challenging. In contrast to planktonic laboratory growth, bacteria in nature predominately reside in the context of densely packed communities known as biofilms. While biofilms have historically been considered environmental and biomedical hazards, their physiology and emergent behaviors could be leveraged for synthetic biology to engineer more capable and robust bacteria. Specifically, bacteria within biofilms participate in complex emergent behaviors such as collective organization, cell-to-cell signaling, and division of labor. Understanding and utilizing these properties can enable the effective deployment of engineered bacteria into natural target environments. Toward this goal, this review summarizes the current state of synthetic biology in biofilms by highlighting new molecular tools and remaining biological challenges. Looking to future opportunities, advancing synthetic biology in biofilms will enable the next generation of smart cell-based technologies for use in medicine, biomanufacturing, and environmental remediation.     

Detection of Atomic Scale Changes in the Free Volume Void Size of Three-Dimensional Colorectal Cancer Cell Culture Using Positron Annihilation Lifetime Spectroscopy

Positron annihilation lifetime spectroscopy (PALS) provides a direct measurement of the free volume void sizes in polymers and biological systems. This free volume is critical in explaining and understanding physical and mechanical properties of polymers. Moreover, PALS has been recently proposed as a potential tool in detecting cancer at early stages, probing the differences in the subnanometer scale free volume voids between cancerous/healthy skin samples of the same patient. Despite several investigations on free volume in complex cancerous tissues, no positron annihilation studies of living cancer cell cultures have been reported. We demonstrate that PALS can be applied to the study in human living 3D cell cultures. The technique is also capable to detect atomic scale changes in the size of the free volume voids due to the biological responses to TGF-β. PALS may be developed to characterize the effect of different culture conditions in the free volume voids of cells grown in vitro.     

Atomic force microscopy comes of age

AFM (atomic force microscopy) analysis, both of fixed cells, and live cells in physiological environments, is set to offer a step change in the research of cellular function. With the ability to map cell topography and morphology, provide structural details of surface proteins and their expression patterns and to detect pico‐Newton force interactions, AFM represents an exciting addition to the arsenal of the cell biologist. With the explosion of new applications, and the advent of combined instrumentation such as AFM—confocal systems, the biological application of AFM has come of age. The use of AFM in the area of biomedical research has been proposed for some time, and is one where a significant impact could be made. Fixed cell analysis provides qualitative and quantitative subcellular and surface data capable of revealing new biomarkers in medical pathologies. Image height and contrast, surface roughness, fractal, volume and force analysis provide a platform for the multiparameter analysis of cell and protein functions. Here, we review the current status of AFM in the field and discuss the important contribution AFM is poised to make in the understanding of biological systems.