Toward a systems level view of the ECM and related proteins: a framework for the systematic definition and analysis of biological systems

Advances in high throughput 'omic technologies are starting to provide unprecedented insights into how components of biological systems are organized and interact. Key to exploiting these datasets is the definition of the components that comprise the system of interest. Although a variety of knowledge bases exist that capture such information, a major challenge is determining how these resources may be best utilized. Here we present a systematic curation strategy to define a systems-level view of the human extracellular matrix (ECM)--a three-dimensional meshwork of proteins and polysaccharides that impart structure and mechanical stability to tissues. Employing our curation strategy we define a set of 357 proteins that represent core components of the ECM, together with an additional 524 genes that mediate related functional roles, and construct a map of their physical interactions. Topological properties help identify modules of functionally related proteins, including those involved in cell adhesion, bone formation and blood clotting. Because of its major role in cell adhesion, proliferation and morphogenesis, defects in the ECM have been implicated in cancer, atherosclerosis, asthma, fibrosis, and arthritis. We use MeSH annotations to identify modules enriched for specific disease terms that aid to strengthen existing as well as predict novel gene-disease associations. Mapping expression and conservation data onto the network reveal modules evolved in parallel to convey tissue-specific functionality on otherwise broadly expressed units. In addition to demonstrating an effective workflow for defining biological systems, this study crystallizes our current knowledge surrounding the organization of the ECM.     

Cell biology, chemogenomics and chemoproteomics

The scientific techniques used in molecular biological research and drug discovery have changed dramatically over the past 10 years due to the influence of genomics, proteomics and bioinformatics. Furthermore, genomics and functional genomics are now merging into a new scientific approach called chemogenomics. Advancements in the study of molecular cell biology are dependent upon "omics" researchers realizing the importance of and using the experimental tools currently available to cell biologists. For example, novel microscopic techniques utilizing advanced computer imaging allow for the examination of live specimens in a fourth dimension, viz., time. Yet, molecular biologists have not taken full advantage of these and other traditional and novel cell biology techniques for the further advancement of genomic and proteomic-oriented research. The application of traditional and novel cellular biological techniques will enhance the science of genomics. The authors hypothesize that a stronger interdisciplinary approach must be taken between cell biology (and its closely related fields) and genomics, proteomics and bio-chemoinformatics. Since there is a lot of confusion regarding many of the "omics" definitions, this article also clarifies some of the basic terminology used in genomics, and related fields. It also reviews the current status and future potential of chemogenomics and its relationship to cell biology. The authors also discuss and expand upon the differences between chemogenomics and the relatively new term--chemoproteomics. We conclude that the advances in cell biology methods and approaches and their adoption by "omics" researchers will allow scientists to maximize our knowledge about life.     

On the Limitations of Biological Knowledge

Scientific knowledge is grounded in a particular epistemology and, owing to the requirements of that epistemology, possesses limitations. Some limitations are intrinsic, in the sense that they depend inherently on the nature of scientific knowledge; others are contingent, depending on the present state of knowledge, including technology. Understanding limitations facilitates scientific research because one can then recognize when one is confronted by a limitation, as opposed to simply being unable to solve a problem within the existing bounds of possibility. In the hope that the role of limiting factors can be brought more clearly into focus and discussed, we consider several sources of limitation as they apply to biological knowledge: mathematical complexity, experimental constraints, validation, knowledge discovery, and human intellectual capacity.     

Touch,act and go: landing and operating on nucleosomes

Chromatin‐associated enzymes are responsible for the installation, removal and reading of precise post‐translation modifications on DNA and histone proteins. They are specifically recruited to the target gene by associated factors, and as a result of their activity, they contribute in modulating cell identity and differentiation. Structural and biophysical approaches are broadening our knowledge on these processes, demonstrating that DNA, histone tails and histone surfaces can each function as distinct yet functionally interconnected anchoring points promoting nucleosome binding and modification. The mechanisms underlying nucleosome recognition have been described for many histone modifiers and related readers. Here, we review the recent literature on the structural organization of these nucleosome‐associated proteins, the binding properties that drive nucleosome modification and the methodological advances in their analysis. The overarching conclusion is that besides acting on the same substrate (the nucleosome), each system functions through characteristic modes of action, which bring about specific biological functions in gene expression regulation.     

Translational Science: Epistemology and the Investigative Process

The term “translational science” has recently become very popular with its usage appearing to be almost exclusively related to medicine, in particular, the “translation” of biological knowledge into medical practice. Taking the perspective that translational science is somehow different than science and that sound science is grounded in an epistemology developed over millennia, it seems imperative that the meaning of translational science be carefully examined, especially how the scientific epistemology manifests itself in translational science. This paper examines epistemological issues relating mainly to modeling in translational science, with a focus on optimal operator synthesis. It goes on to discuss the implications of epistemology on the nature of collaborations conducive to the translational investigative process. The philosophical concepts are illustrated by considering intervention in gene regulatory networks.     

合成生物学伦理、法律与社会问题探讨

合成生物学是以基因组学、系统生物学知识和分子生物学技术为基础,综合了科学与工程的一门新兴交叉学科。它使生命科学和生物技术研发进入了以人工设计、合成自然界中原本不曾出现的人造生命体系,以及对这些人工体系进行体内、体外优化,或利用这些人造生命体系研究自然生命规律为目标的新时代。然而,合成生物学研究在迅速发展、表现出巨大潜力和应用前景的同时,也引发了社会各界对相关社会、伦理、安全,以及知识产权等问题的重视与讨论。就世界各国针对合成生命对传统意义上生命概念的挑战、合成生物学产品存在的潜在风险危害、合成生物学研究的风险评估与监管等问题进行回顾综述和相关探讨。     

Motifs,modules and games in bacteria

Global explorations of regulatory network dynamics, organization and evolution have become tractable thanks to high-throughput sequencing and molecular measurement of bacterial physiology. From these, a nascent conceptual framework is developing, that views the principles of regulation in term of motifs, modules and games. Motifs are small, repeated, and conserved biological units ranging from molecular domains to small reaction networks. They are arranged into functional modules, genetically dissectible cellular functions such as the cell cycle, or different stress responses. The dynamical functioning of modules defines the organism's strategy to survive in a game, pitting cell against cell, and cell against environment. Placing pathway structure and dynamics into an evolutionary context begins to allow discrimination between those physical and molecular features that particularize a species to its surroundings, and those that provide core physiological function. This approach promises to generate a higher level understanding of cellular design, pathway evolution and cellular bioengineering.     

Dynamical analysis of cellular networks based on the Green's function matrix

The complexity of cellular networks often limits human intuition in understanding functional regulations in a cell from static network diagrams. To this end, mathematical models of ordinary differential equations (ODEs) have commonly been used to simulate dynamical behavior of cellular networks, to which a quantitative model analysis can be applied in order to gain biological insights. In this paper, we introduce a dynamical analysis based on the use of Green's function matrix (GFM) as sensitivity coefficients with respect to initial concentrations. In contrast to the classical (parametric) sensitivity analysis, the GFM analysis gives a dynamical, molecule-by-molecule insight on how system behavior is accomplished and complementarily how (impulse) signal propagates through the network. The knowledge gained will have application from model reduction and validation to drug discovery research in identifying potential drug targets, studying drug efficacy and specificity, and optimizing drug dosing and timing. The efficacy of the method is demonstrated through applications to common network motifs and a Fas-induced programmed cell death model in Jurkat T cell line.     

Functional genomics and proteomics approaches to study the ERBB network in cancer

Substantial progress in functional genomic and proteomic technologies has opened new perspectives in biomedical research. The sequence of the human genome has been mostly determined and opened new visions on its complexity and regulation. New technologies, like RNAi and protein arrays, allow gathering knowledge beyond single gene analysis. Increasingly, biological processes are studied with systems biological approaches, where qualitative and quantitative data of the components are utilized to model the respective processes, to predict effects of perturbations, and to then refine these models after experimental testing. Here, we describe the potential of applying functional genomics and proteomics, taking the ERBB family of growth-factor receptors as an example to study the signaling network and its impact on cancer.     

Synthetic modular systems--reverse engineering of signal transduction

During the last decades, biology has decomposed cellular systems into genetic, functional and molecular networks. It has become evident that these networks consist of components with specific functions (e.g., proteins and genes). This has generated a considerable amount of knowledge and hypotheses concerning cellular organization. The idea discussed here is to test the extent of this knowledge by reconstructing, or reverse engineering, new synthetic biological systems from known components. We will discuss how integration of computational methods with proteomics and engineering concepts might lead us to a deeper and more abstract understanding of signal transduction systems. Designing and successfully introducing synthetic proteins into cellular pathways would provide us with a powerful research tool with many applications, such as development of biosensors, protein drugs and rewiring of biological pathways.     

Randomness in microtubule dynamics: an error that requires correction or an inherent plasticity required for normal cellular function?

Microtubules (MTs) play roles in regulating the mechanical structure and dynamics of cells. While MTs appear to be highly ordered structures, recent data suggest some randomness in their structure and dynamics. Part of this inherent randomness is attributed to errors and correction mechanisms are being investigated to overcome these ‘mistakes.’ However, this randomness may also be part of the normal intracellular function of MTs. It is possible that random events in MT structure and dynamics may contribute to their normal function and may even be part of an improved efficacy mechanism. An alternative view, wherein MT and kinetochore errors are part of required cell plasticity, is also discussed. These data may further support the concept of randomness in biological pathways as part of self‐organization or accurate and enhanced function.     

"Immunetworks", intersecting circuits and dynamics

This paper proposes a study of biological regulation networks based on a multi-level strategy. Given a network, the first structural level of this strategy consists in analysing the architecture of the network interactions in order to describe it. The second dynamical level consists in relating the patterns found in the architecture to the possible dynamical behaviours of the network. It is known that circuits are the patterns that play the most important part in the dynamics of a network in the sense that they are responsible for the diversity of its asymptotic behaviours. Here, we pursue further this idea and argue that beyond the influence of underlying circuits, intersections of circuits also impact significantly on the dynamics of a network and thus need to be payed special attention to. For some genetic regulation networks involved in the control of the immune system (“immunetworks”), we show that the small number of attractors can be explained by the presence, in the underlying structures of these networks, of intersecting circuits that “inter-lock”.     

Gravitational biology within the German Space Program: goals, achievements, and perspectives

Summary. Gravity plays an important role for the evolution, orientation and development of organisms. Most of us, however, tend to overlook its importance because – due to its constant presence from the beginning of evolution some 4 billion years ago – this environmental parameter is almost hardwired into our interpretation of reality. This negligence of gravity is the more surprising as we all have our strong fights with this factor, especially during the very early and again during the late phases of our lives. On the other hand, scientists have been fascinated to observe the effects of gravity especially on plants and microorganisms for more than a hundred years, since Darwin and Sachs demonstrated the role of the root cap for downward growing plants. Different experimental approaches are nowadays available in order to change the influence of gravity and to study the corresponding influences on the physiology of biological systems. With the advent of spaceflight, a long-term nearly nullification of gravity is possible. Utilisation of this so-called “microgravity” condition for research in life sciences thus became an important asset in the space programs of various space agencies around the world. The German Space Life Sciences Program is managed – like all other space programs and activities in Germany – by the German Aerospace Center (DLR) in its role as space agency for Germany. Within the current space program, approved by the German government in May 2001, the overall goal for its life sciences part was defined as to gain scientific knowledge and to disclose new application potential by research under space conditions, especially by utilising the microgravity environment of the International Space Station. Three main scientific fields have been identified in collaboration with the scientific community: integrative human physiology, biotechnological applications of the microgravity environment, and fundamental biology of gravity and radiation responses (i.e., gravitational and radiation biology). In the present contribution, specific goals as well as achievements and perspectives of research in gravitational biology are given. In addition, some information is provided on spaceflight opportunities available. Correspondence and reprints: German Aerospace Center (DLR), Space Agency, P.O. Box 300364, 53183 Bonn, Federal Republic of Germany.     

Biology coming full circle: Joining the whole and the parts

The new cover of Experimental Biology and Medicine features the hermeneutic circle of biology, a concept we have adapted from the hermeneutic principle that one understands the whole only in terms of each part and the parts only in terms of the whole. Our hermeneutic circle summarizes the course of experimental biology through 2500 years of the achievements of reductionist research (understanding the parts), which culminates in our ability to rapidly sequence the genome. Rather than returning along the same path in a constructionist approach that simply builds upon this knowledge, but in reverse, an alternative is to close the circle with synthetic constructions that seek to integrate the full complexity of biological and physiological systems (understanding the whole), of which organs-on-chips are one example. This closing of the circle cannot be a comprehensively accurate representation of biology, but it can be a synthetic one that effectively defines particular biological subsystems. The illustration of the hermeneutic circle of biology is also intended to suggest both the multiple cycles that may be required to reach such a synthesis and the expansion of the circle in an outward spiral as knowledge increases. Our commentary explains the symbolism of the new cover in a philosophical and scientific discussion.     

Fleck and the social constitution of scientific objectivity

Ludwik Fleck’s theory of thought-styles has been hailed as a pioneer of constructivist science studies and sociology of scientific knowledge. But this consensus ignores an important feature of Fleck’s epistemology. At the core of his account is the ideal of ‘objective truth, clarity, and accuracy’. I begin with Fleck’s account of modern natural science, locating the ideal of scientific objectivity within his general social epistemology. I then draw on Fleck’s view of scientific objectivity to improve upon reflexive accounts of the origin and development of the theory of thought-styles, and reply to objections that Fleck’s epistemological stance is self-undermining or inconsistent. Explicating the role of scientific objectivity in Fleck’s epistemology reveals his view to be an internally consistent alternative to recent social accounts of scientific objectivity by Harding, Daston and Galison. I use these contrasts to indicate the strengths and weaknesses of Fleck’s innovative social epistemology, and propose modifications to address the latter. The result is a renewed version of Fleck’s social epistemology, which reconciles commitment to scientific objectivity with integrated sociology, history and philosophy of science.     

Modeling the topological organization of cellular processes

The cell as a dynamical system presents the characteristics of having a dynamical structure. That is, the exact phase space of the system cannot be fixed before the evolution and integrative cell models must state the evolution of the structure jointly with the evolution of the cell state. This kind of dynamical systems is very challenging to model and simulate. New programming concepts must be developed to ease their modeling and simulation. In this context, the goal of the MGS project is to develop an experimental programming language dedicated to the simulation of this kind of systems. MGS proposes a unified view on several computational mechanisms (CHAM, Lindenmayer systems, Paun systems, cellular automata) enabling the specification of spatially localized computations on heterogeneous entities. The evolution of a dynamical structure is handled through the concept of transformation which relies on the topological organization of the system components. An example based on the modeling of spatially distributed biochemical networks is used to illustrate how these notions can be used to model the spatial and temporal organization of intracellular processes.