Biological computation: hearts and flytraps

The original computers were people using algorithms to get mathematical results such as rocket trajectories. After the invention of the digital computer, brains have been widely understood through analogies with computers and now artificial neural networks, which have strengths and drawbacks. We define and examine a new kind of computation better adapted to biological systems, called biological computation, a natural adaptation of mechanistic physical computation. Nervous systems are of course biological computers, and we focus on some edge cases of biological computing, hearts and flytraps. The heart has about the computing power of a slug, and much of its computing happens outside of its forty thousand neurons. The flytrap has about the computing power of a lobster ganglion. This account advances fundamental debates in neuroscience by illustrating ways that classical computability theory can miss complexities of biology. By this reframing of computation, we make way for resolving the disconnect between human and machine learning.

     

Applications of genetically-encoded biosensors for the construction and control of biosynthetic pathways

Cells are filled with biosensors, molecular systems that measure the state of the cell and respond by regulating host processes. In much the same way that an engineer would monitor a chemical reactor, the cell uses these sensors to monitor changing intracellular environments and produce consistent behavior despite the variable environment. While natural systems derive a clear benefit from pathway regulation, past research efforts in engineering cellular metabolism have focused on introducing new pathways and removing existing pathway regulation. Synthetic biology is a rapidly growing field that focuses on the development of new tools that support the design, construction, and optimization of biological systems. Recent advances have been made in the design of genetically-encoded biosensors and the application of this class of molecular tools for optimizing and regulating heterologous pathways. Biosensors to cellular metabolites can be taken directly from natural systems, engineered from natural sensors, or constructed entirely in vitro. When linked to reporters, such as antibiotic resistance markers, these metabolite sensors can be used to report on pathway productivity, allowing high-throughput screening for pathway optimization. Future directions will focus on the application of biosensors to introduce feedback control into metabolic pathways, providing dynamic control strategies to increase the efficient use of cellular resources and pathway reliability.     

Implementing re-configurable biological computation with distributed multicellular consortia

The use of synthetic biological circuits to deal with numerous biological challenges has been proposed in several studies, but its implementation is still remote. A major problem encountered is the complexity of the cellular engineering needed to achieve complex biological circuits and the lack of general-purpose biological systems. The generation of re-programmable circuits can increase circuit flexibility and the scalability of complex cell-based computing devices. Here we present a new architecture to produce reprogrammable biological circuits that allow the development of a variety of different functions with minimal cell engineering. We demonstrate the feasibility of creating several circuits using only a small set of engineered cells, which can be externally reprogrammed to implement simple logics in response to specific inputs. In this regard, depending on the computation needs, a device composed of a number of defined cells can generate a variety of circuits without the need of further cell engineering or rearrangements. In addition, the inclusion of a memory module in the circuits strongly improved the digital response of the devices. The reprogrammability of biological circuits is an intrinsic capacity that is not provided in electronics and it may be used as a tool to solve complex biological problems.     

Synthetic cells and organelles: compartmentalization strategies

The recent development of RNA replicating protocells and capsules that enclose complex biosynthetic cascade reactions are encouraging signs that we are gradually getting better at mastering the complexity of biological systems. The road to truly cellular compartments is still very long, but concrete progress is being made. Compartmentalization is a crucial natural methodology to enable control over biological processes occurring within the living cell. In fact, compartmentalization has been considered by some theories to be instrumental in the creation of life. With the advancement of chemical biology, artificial compartments that can mimic the cell as a whole, or that can be regarded as cell organelles, have recently received much attention. The membrane between the inner and outer environment of the compartment has to meet specific requirements, such as semi‐permeability, to allow communication and molecular transport over the border. The membrane can either be built from natural constituents or from synthetic polymers, introducing robustness to the capsule.     

Seeing tissue as a 'phase of matter': exploring statistical mechanics for the cell

The field of tissue engineering aims to produce living, biological constructs which possess the appropriate spatial ordering of cells and their extra cellular matrix products. The complexity of a single cell and its interactions in a large collective have made development of useful models to assist in tissue culture difficult, and consequentially most tissue culture endeavors are limited to trial and error approaches. Some cell types display a natural tendency to spontaneously self-assemble into large domains of parallel-oriented cells. In this work, we show that these cell culture systems can be studied in the context of continuous disorder-order phase transformations. We suggest that collective ordering of the cells is controlled by the amount of noise in the walk of the individual cells (directional persistence) because undifferentiated mesenchymal stem cells display a seven-times higher directional persistence than mature fibroblasts and have a 24-times larger final-oriented domain size, an observation that corresponds with collective ordering in self-propelled particle systems. The study of cell culture systems using analogies derived from statistical mechanics yields simple, practical models offering insight into how a long-range order can be obtained in tissue-engineered constructs, providing a new paradigm for managing operations with large collectives of living cells.     

Towards computing with proteins

Can proteins be used as computational devices to address difficult computational problems? In recent years there has been much interest in biological computing, that is, building a general purpose computer from biological molecules. Most of the current efforts are based on DNA because of its ability to self‐hybridize. The exquisite selectivity and specificity of complex protein‐based networks motivated us to suggest that similar principles can be used to devise biological systems that will be able to directly implement any logical circuit as a parallel asynchronous computation. Such devices, powered by ATP molecules, would be able to perform, for medical applications, digital computation with natural interface to biological input conditions. We discuss how to design protein molecules that would serve as the basic computational element by functioning as a NAND logical gate, utilizing DNA tags for recognition, and phosphorylation and exonuclease reactions for information processing. A solution of these elements could carry out effective computation. Finally, the model and its robustness to errors were tested in a computer simulation. Proteins 2006. © 2006 Wiley‐Liss, Inc.     

Decellularized adipose matrix provides an inductive microenvironment for stem cells in tissue regeneration

Stem cells play a key role in tissue regeneration due to their self-renewal and multidirectional differentiation, which are continuously regulated by signals from the extracellular matrix (ECM) microenvironment. Therefore, the unique biological and physical characteristics of the ECM are important determinants of stem cell behavior. Although the acellular ECM of specific tissues and organs (such as the skin, heart, cartilage, and lung) can mimic the natural microenvironment required for stem cell differentiation, the lack of donor sources restricts their development. With the rapid development of adipose tissue engineering, decellularized adipose matrix (DAM) has attracted much attention due to its wide range of sources and good regeneration capacity. Protocols for DAM preparation involve various physical, chemical, and biological methods. Different combinations of these methods may have different impacts on the structure and composition of DAM, which in turn interfere with the growth and differentiation of stem cells. This is a narrative review about DAM. We summarize the methods for decellularizing and sterilizing adipose tissue, and the impact of these methods on the biological and physical properties of DAM. In addition, we also analyze the application of different forms of DAM with or without stem cells in tissue regeneration (such as adipose tissue), repair (such as wounds, cartilage, bone, and nerves), in vitro bionic systems, clinical trials, and other disease research.     

Protein-based tissue engineering in bone and cartilage repair

Bioactive proteins signal host or transplanted cells to form the desired tissue type. Matrix systems are utilized to locally deliver the proteins and to maintain effective protein concentrations. For some indications, a matrix is required to define the physical form of the regenerated tissue. Substantial progress has been made in bone tissue engineering in recent years, based on the results of controlled clinical studies using bone morphogenetic proteins. Ongoing research in this area centers on the design of additional delivery matrices to expand the clinical indications, using synthetic delivery systems that mimic biological qualities of the natural materials currently in use. Although a similar rationale exists for the regeneration of articular cartilage with bioactive factors, advancement in this area has not been as substantial.     

Engineering scalable biological systems

Synthetic biology is focused on engineering biological organisms to study natural systems and to provide new solutions for pressing medical, industrial and environmental problems. At the core of engineered organisms are synthetic biological circuits that execute the tasks of sensing inputs, processing logic and performing output functions. In the last decade, significant progress has been made in developing basic designs for a wide range of biological circuits in bacteria, yeast and mammalian systems. However, significant challenges in the construction, probing, modulation and debugging of synthetic biological systems must be addressed in order to achieve scalable higher-complexity biological circuits. Furthermore, concomitant efforts to evaluate the safety and biocontainment of engineered organisms and address public and regulatory concerns will be necessary to ensure that technological advances are translated into real-world solutions.     

Proteomic tools for biomedicine

Proteomic tools measure gene expression, protein activity and interactions of biological events at the protein level. Proteins are the major catalysts of biological functions and contain several dimensions of information that collectively indicate the actual rather than the potential functional state as indicated by mRNA analysis. Measurements can be made in terms of protein quantity, location, and time-point. For the future we see a further integration of existing and new technologies for proteomics from a wide range of areas of biochemistry, chemistry, physics, computing science and molecular biology. This will further advance our knowledge of how biological systems are built up and what mechanisms control these systems. However, the potential of proteomics to comprehensively answer all biological questions is limited as only protein activity is measured. A unification of genomics, proteomics, and other technologies is needed if we are to start to understand the complexity of biological function in the context of disease and health.     

Biochemical engineering of natural product biosynthesis pathways

Metabolic engineering of natural products is a science that has been built on the goals of traditional strain improvement with the availability of modern molecular biological technologies. In the past 15 years, the state of the art in metabolic engineering of natural products has advanced from the first proof-of-principle experiment based on minimal known genetics to a commonplace event using highly specific and sophisticated gene manipulation methods. With the availability of genes, host organisms, vector systems, and standard molecular biological tools, it is expected that metabolic engineering will be translated into industrial reality.     

Toward scalable parts families for predictable design of biological circuits

Our current ability to engineer biological circuits is hindered by design cycles that are costly in terms of time and money, with constructs failing to operate as desired, or evolving away from the desired function once deployed. Synthetic biologists seek to understand biological design principles and use them to create technologies that increase the efficiency of the genetic engineering design cycle. Central to the approach is the creation of biological parts--encapsulated functions that can be composited together to create new pathways with predictable behaviors. We define five desirable characteristics of biological parts--independence, reliability, tunability, orthogonality and composability, and review studies of small natural and synthetic biological circuits that provide insights into each of these characteristics. We propose that the creation of appropriate sets of families of parts with these properties is a prerequisite for efficient, predictable engineering of new function in cells and will enable a large increase in the sophistication of genetic engineering applications.     

Engineering microbes with synthetic biology frameworks

Typically, the outcome of biologically engineered unit operations cannot be controlled a priori due to the incorporation of ad hoc design into complex natural systems. To mitigate this problem, synthetic biology presents a systematic approach to standardizing biological components for the purpose of increasing their programmability and robustness when assembled with the aim to achieve novel biological functions. A complex engineered biological system using only standardized biological components is yet to exist. Nevertheless, current attempts to create and to implement modular, standardized biological components pave the way for the future creation of highly predictable artificial biological systems. Although synthetic biology frameworks can be applied to any biological engineering endeavor, this article will focus on providing a brief overview of advances in the field and its recent utilization for the engineering of microbes.     

Stem cells for osteoarticular and vascular tissue engineering

Tissue damages or loss of organs often result in structural and metabolic changes that can cause serious complications. The therapeutic objective of tissue engineering (TE) is to recreate, regenerate or restore function of damaged tissue. TE is based on the coalescence of three components: a scaffold or matrix from natural or synthetic origin biodegradable or not, reparative cells and signals (hypoxia, mechanical stress, morphogens…). Articular cartilage, bone and blood vessels are tissues for which TE has progressed significantly, from basic research to clinical trials. If biomaterials must exhibit different properties depending on the tissue to regenerate, the cellular component of TE is mostly represented by stem cells notably adult mesenchymal stem cells harvested from bone marrow or adipose tissue. In recent years, progress has been made in our understanding of the biological mechanisms that govern stem cell differentiation and in the development of materials with controlled physicochemical and biological properties. However, many technological barriers and regulations concerns have to be overcome before tissue engineering enters into the therapeutic arsenal of regenerative medicine. This review aims at highlighting the progress in the use of stem cells for engineering osteoarticular and vascular tissues.     

Biomimetic modelling

Biomimetics is seen as a path from biology to engineering. The only path from engineering to biology in current use is the application of engineering concepts and models to biological systems. However, there is another pathway: the verification of biological mechanisms by manufacture, leading to an iterative process between biology and engineering in which the new understanding that the engineering implementation of a biological system can bring is fed back into biology, allowing a more complete and certain understanding and the possibility of further revelations for application in engineering. This is a pathway as yet unformalized, and one that offers the possibility that engineers can also be scientists.     

Toward synthetic life: Biomimetic synthetic cell communication

Engineering synthetic minimal cells provide a controllable chassis for studying the biochemical principles of natural life, increasing our understanding of complex biological processes. Recently, synthetic cell engineering has enabled communication between both natural live cells and other synthetic cells.A system such as these enable studying interactions between populations of cells, both natural and artificial, and engineering small molecule cell communication protocols for a variety of basic research and practical applications. In this review, we summarize recent progress in engineering communication between synthetic and natural cells, and we speculate about the possible future directions of this work.     

Dentin regeneration based on tooth tissue engineering: A review

Missing or damaged teeth due to caries, genetic disorders, oral cancer, or infection may contribute to physical and mental impairment that reduces the quality of life. Despite major progress in dental tissue repair and those replacing missing teeth with prostheses, clinical treatments are not yet entirely satisfactory, as they do not regenerate tissues with natural teeth features. Therefore, much of the focus has centered on tissue engineering (TE) based on dental stem/progenitor cells to create bioengineered dental tissues. Many in vitro and in vivo studies have shown the use of cells in regenerating sections of a tooth or a whole tooth. Tooth tissue engineering (TTE), as a promising method for dental tissue regeneration, can form durable biological substitutes for soft and mineralized dental tissues. The cell-based TE approach, which directly seeds cells and bioactive components onto the biodegradable scaffolds, is currently the most potential method. Three essential components of this strategy are cells, scaffolds, and growth factors (GFs). This study investigates dentin regeneration after an injury such as caries using TE and stem/progenitor cell-based strategies. We begin by discussing about the biological structure of a dentin and dentinogenesis. The engineering of teeth requires knowledge of the processes that underlie the growth of an organ or tissue. Then, the three fundamental requirements for dentin regeneration, namely cell sources, GFs, and scaffolds are covered in the current study, which may ultimately lead to new insights in this field.     

Identifying quantitative operation principles in metabolic pathways: a systematic method for searching feasible enzyme activity patterns leading to cellular adaptive responses

Background  

Optimization methods allow designing changes in a system so that specific goals are attained. These techniques are fundamental for metabolic engineering. However, they are not directly applicable for investigating the evolution of metabolic adaptation to environmental changes. Although biological systems have evolved by natural selection and result in well-adapted systems, we can hardly expect that actual metabolic processes are at the theoretical optimum that could result from an optimization analysis. More likely, natural systems are to be found in a feasible region compatible with global physiological requirements.