Showing papers by "Ron Weiss published in 2007"

A universal RNAi-based logic evaluator that operates in mammalian cells

Abstract: Molecular automata1,2,3 that combine sensing4,5,6, computation7,8,9,10,11,12 and actuation13,14 enable programmable manipulation of biological systems. We use RNA interference (RNAi)15 in human kidney cells to construct a molecular computing core that implements general Boolean logic1,3,8,9,10,11,12,16 to make decisions based on endogenous molecular inputs. The state of an endogenous input is encoded by the presence or absence of 'mediator' small interfering RNAs (siRNAs). The encoding rules, combined with a specific arrangement of the siRNA targets in a synthetic gene network17, allow direct evaluation of any Boolean expression in standard forms using siRNAs and indirect evaluation using endogenous inputs. We demonstrate direct evaluation of expressions with up to five logic variables. Implementation of the encoding rules through sensory up- and down-regulatory links between the inputs and siRNA mediators will allow arbitrary Boolean decision-making using these inputs.

Engineered bidirectional communication mediates a consensus in a microbial biofilm consortium

Abstract: Microbial consortia form when multiple species colocalize and communally generate a function that none is capable of alone Consortia abound in nature, and their cooperative metabolic activities influence everything from biodiversity in the global food chain to human weight gain Here, we present an engineered consortium in which the microbial members communicate with each other and exhibit a “consensus” gene expression response Two colocalized populations of Escherichia coli converse bidirectionally by exchanging acyl-homoserine lactone signals The consortium generates the gene-expression response if and only if both populations are present at sufficient cell densities Because neither population can respond without the other's signal, this consensus function can be considered a logical AND gate in which the inputs are cell populations The microbial consensus consortium operates in diverse growth modes, including in a biofilm, where it sustains its response for several days

Thick film laser induced forward transfer for deposition of thermally and mechanically sensitive materials

Abstract: Laser forward transfer processes incorporating thin absorbing films can be used to deposit robust organic and inorganic materials but the deposition of more delicate materials has remained elusive due to contamination and stress induced during the transfer process. Here, we present the approach to high resolution patterning of sensitive materials by incorporating a thick film polymer absorbing layer that is able to dissipate shock energy through mechanical deformation. Multiple mechanisms for transfer as a function of incident laser energy are observed and we show viable and contamination-free deposition of living mammalian embryonic stem cells.

Robustness analysis and tuning of synthetic gene networks

Abstract: Motivation: The goal of synthetic biology is to design and construct biological systems that present a desired behavior. The construction of synthetic gene networks implementing simple functions has demonstrated the feasibility of this approach. However, the design of these networks is difficult, notably because existing techniques and tools are not adapted to deal with uncertainties on molecular concentrations and parameter values. Results: We propose an approach for the analysis of a class of uncertain piecewise-multiaffine differential equation models. This modeling framework is well adapted to the experimental data currently available. Moreover, these models present interesting mathematical properties that allow the development of efficient algorithms for solving robustness analyses and tuning problems. These algorithms are implemented in the tool RoVerGeNe, and their practical applicability and biological relevance are demonstrated on the analysis of the tuning of a synthetic transcriptional cascade built in Escherichia coli. Availability: RoVerGeNe and the transcriptional cascade model are available at http://iasi.bu.edu/%7Ebatt/rovergene/rovergene.htm Contact: gregory.batt@imag.fr

Model checking genetic regulatory networks with parameter uncertainty

Abstract: The lack of precise numerical information for the values of biological parameters severely limits the development and analysis of models of genetic regulatory networks. To deal with this problem, we propose a method for the analysis of genetic regulatory networks with parameter uncertainty. We consider models based on piecewise-multiaffine differential equations, dynamical properties expressed in temporal logic, and intervals for the values of uncertain parameters. The problem is then either to guarantee that the system satisfies the expected properties for every possible parameter value - the corresponding parameter set is then called valid - or to find valid subsets of a given parameter set. The proposed method uses discrete abstractions and model checking, and allows for efficient search of the parameter space. This approach has been implemented in a tool for robust verification of gene networks (RoVerGeNe) and applied to the tuning of a synthetic network build in E. coli.

Model checking liveness properties of genetic regulatory networks

Abstract: Recent studies have demonstrated the possibility to build genetic regulatory networks that confer a desired behavior to a living organism. However, the design of these networks is difficult, notably because of uncertainties on parameter values. In previous work, we proposed an approach to analyze genetic regulatory networks with parameter uncertainties. In this approach, the models are based on piecewise-multiaffine (PMA) differential equations, the specifications are expressed in temporal logic, and uncertain parameters are given by intervals. Abstractions are used to obtain finite discrete representations of the dynamics of the system, amenable to model checking. However, the abstraction process creates spurious behaviors along which time does not progress, called time-converging behaviors. Consequently, the verification of liveness properties, expressing that something will eventually happen, and implicitly assuming progress of time, often fails. In this work, we extend our previous approach to enforce progress of time. More precisely, we define transient regions as subsets of the state space left in finite time by every solution trajectory, show how they can be used to rule out time-converging behaviors, and provide sufficient conditions for their identification in PMA systems. This approach is implemented in RoVerGeNe and applied to the analysis of a network built in the bacterium E. coli.

Monaural Speech Separation using Source-Adapted Models

Abstract: We propose a model-based source separation system for use on single channel speech mixtures where the precise source characteristics are not known a priori. We do this by representing the space of source variation with a parametric signal model based on the eigenvoice technique for rapid speaker adaptation. We present an algorithm to infer the characteristics of the sources present in a mixture, allowing for significantly improved separation performance over that obtained using unadapted source models. The algorithm is evaluated on the task defined in the 2006 Speech Separation Challenge [1] and compared with separation using source-dependent models.

Synthetic biology: from bacteria to stem cells

Abstract: Synthetic biology is revolutionizing how we conceptualize and approach the engineering of biological systems. Recent advances in the field are allowing us to expand beyond the construction and analysis of small gene networks towards the implementation of complex multicellular systems with a variety of applications. We have developed an integrated computational/experimental approach to engineering complex behavior in living systems ranging from bacteria to stem cells. In our research, we appropriate useful design principles from electrical engineering and other well established fields. These principles include abstraction, standardization, modularity, and computer aided design. But we also spend considerable effort towards understanding what makes synthetic biology different from all other existing engineering disciplines and discovering new design and construction rules that are effective for this unique discipline.

Engineered cellular pathways for programmed autoregulation of differentiation

Abstract: The present invention provides compositions and methods for programming mammalian cells to perform desired functions. In particular, the present invention provides compositions and methods for programming stem cells to differentiate into a desired cell type. A quorum sensing systems that regulates the expression of cell fate regulators is introduced into mammalian host cells, such as stem cells. The quorum sensing systems generally comprises vectors that express the components of a bacterial quorum sensing pathway, including proteins which catalyze the synthesis of an autoinducer and a gene encoding a regulatory partner of the autoinducer, and vectors in which genes encoding cell fate regulators are operably linked to a promoter induced by the autoinducer/regulatory partner complex. The system can also comprise vectors in which genes encoding additional cell fate regulators are operably linked to a promoter that is induced by a factor synthesized in response to a first stage of differentiation, so that a second stage of differentiation is triggered.

Enabling the new biology of the 21st century

Abstract: Systems biology is an integrative science that aims to bridge the individual behavior of biological components with a collective behavior of the system Synthetic biology, a technological counterpart, borrows key hierarchical and modular concepts from systems biology Novel pathways, cell-like systems and multi-cell communities are constructed from a library of standardized biological parts The shared goals of systems biology and synthetic biology are to gain a fundamental understanding of cellular processes and create new cell circuits using a combination of experimental, theoretical and computational methods To meet the growing need of scientific community, a new journal Systems and Synthetic Biology has been launched The journal will provide an open access, peer reviewed, scientific and scholarly digital content covering theoretical, experimental and technological aspects of these disciplines A cell is an evolvable and self-replicating molecular machine From a hydrogen atom to the level of a cell and then an entire organism, biology manages information over many magnitudes in size and number of components The topological complexity of biological systems is far greater than that of rationally designed artificial systems Furthermore, complexity introduced by weighted networks, feedback loops, reversibility of reactions, transient networks and cooperative interaction demands novel ways of data acquisition, analysis, integration and hypothesis generation The grand challenge in systems biology is to build a complete and high-resolution description of molecular topography and connect molecular interactions with physiological responses (Nurse 2003; Dhar et al 2004; Westerhoff and Palsson 2004) Systems biology will realize its fullest potential once individual contributions of components are tied to variations in the system level behavior Synthetic biology combines knowledge from various disciplines including molecular biology, engineering, mathematics, and physics to design and implement new cellular behaviors The new behaviors are achieved through a variety of bioengineering efforts that include the construction of novel proteins, genetic circuits, signaling cascades, and metabolic networks Through the de novo construction of elements and circuits, the goal of synthetic biology is both to improve our quantitative understanding of natural phenomenon as well as to foster an engineering discipline for obtaining new complex cell behaviors in a predictable and reliable fashion Recent achievements include the development of sophisticated non-native behaviors such as bi-stability, oscillations, customizable biosensing proteins, metabolic networks optimized for drug synthesis, and coordinated behavior of cell populations (Gardner et al 2000; Elowitz and Leibler 2000; Basu et al 2005) Future advancements in this field will require a variety of improvements in many areas such as DNA synthesis, mathematical modeling tools, standards and abstractions for the construction of complex circuits, and the ability to manipulate different aspects of the complex biochemical machinery of cells Systems and Synthetic Biology will publish research articles that either advance this field as an engineering discipline or use synthetic biology to improve our scientific knowledge of existing phenomenon The journal aims to publish original research articles in experimental and theoretical aspects of systems and synthetic biology, methodological developments, reviews and commentaries The aim is to disseminate information and stimulate the development of these disciplines Both systems biology and synthetic biology have been recently recognized as specialized disciplines and require a dedicated platform to bring together publications that currently find destinations in diverse journals The journal will provide a unique home for experimental systems biologists and synthetic biologists while providing adequate coverage for theoretical work Systems and Synthetic Biology has a distinguished board of scientists from experimental, theoretical, computational, mathematical, engineering fields Over the last several years, the open access philosophy (Varmus et al 2000; Wadman 2004; Gannon 2004) has practically rewritten the first principles of electronic publishing Springer offers a unique Open Choice model that offers an option of choosing the traditional publishing model or open access In the Open access option authors would retain the copyright to their work and are free to place a copy of their article on their individual or institutional website All the articles will be peer-reviewed and available in both print and electronic versions via SpringerLink In addition, every article will be registered in CrossRef and included in the appropriate Abstracting and Indexing services Authors may also want to incorporate additional non-text files such as sound or video in the electronic edition All submitted papers will be subjected to rigorous peer review, which will be closed and strictly confidential