Boyan Yordanov

• Researcher at Microsoft

We present a framework called the Reasoning Engine, which implements Satisfiability Modulo Theories (SMT)-based methods within a unified computational environment to address diverse biological analysis problems. The Reasoning Engine was used to reproduce results from key scientific studies, as well as supporting new research in stem cell biology. T...

We present a framework called the Reasoning Engine, which implements Satisfiability Modulo Theories (SMT) based methods within a unified computational environment to address diverse biological analysis problems. The reasoning engine was used to reproduce results from key scientific studies, as well as supporting new research in stem cell biology. T...

Targeted high-throughput DNA sequencing is a primary approach for genomics and molecular diagnostics, and more recently as a readout for DNA information storage. Oligonucleotide probes used to enrich gene loci of interest have different hybridization kinetics, resulting in non-uniform coverage that increases sequencing costs and decreases sequencin...

The prediction of DNA secondary structures from DNA sequences using thermodynamic models is imperfect for many biological sequences, both due to insufficient experimental data for training and to the kinetics of folding that lead to metastable structures. Here, we developed low-yield bisulfite sequencing (LYB-seq) to query the secondary structure s...

Targeted high-throughput DNA sequencing is a primary approach for genomics and molecular diagnostics, and more recently as a readout for DNA information storage. Oligonucleotide probes used to enriching gene loci of interest have different hybridization kinetics, resulting in non-uniform coverage that increases sequencing costs and decreases sequen...

Computational modelling of metabolic processes has proven to be a useful approach to formulate our knowledge and improve our understanding of core biochemical systems that are crucial to maintaining cellular functions. Towards understanding the broader role of metabolism on cellular decision-making in health and disease conditions, it is important...

A recurring set of small sub-networks have been identified as the building blocks of biological networks across diverse organisms. These network motifs are associated with certain dynamical behaviors and define key modules that are important for understanding complex biological programs. Besides studying the properties of motifs in isolation, curre...

Chemical reaction networks (CRNs) have been applied successfully to model a wide range of phenomena and are commonly used for designing molecular computation circuits. Often, CRNs with specific properties (oscillations, Turing patterns, multistability) are sought, which entails searching an exponentially large space of CRNs for those that satisfy a...

Cellular decision-making arises as the output of biochemical information processing, as complex cascades of molecular interactions are triggered by input stimuli. Deciphering critical interactions and how they are organised into biological programs is a huge challenge, compounded by the difficulty of manually navigating alternative hypotheses consi...

Both experimental and computational biology is becoming increasingly automated. Laboratory experiments are now performed automatically on high-throughput machinery, while computational models are synthesized or inferred automatically from data. However, integration between automated tasks in the process of biological discovery is still lacking, lar...

Methods from stochastic dynamical systems theory have been instrumental in understanding the behaviours of chemical reaction networks (CRNs) arising in natural systems. However, considerably less attention has been given to the inverse problem of synthesizing CRNs with a specified behaviour, which is important for the forward engineering of biologi...

A recurring set of small sub-networks have been identified as the building blocks of biological networks across diverse organisms. These network motifs have been associated with certain dynamical behaviors and define key modules that are important for understanding complex biological programs. Besides studying the properties of motifs in isolation,...

Hybridization is a key molecular process in biology and biotechnology, but so far there is no predictive model for accurately determining hybridization rate constants based on sequence information. Here, we report a weighted neighbour voting (WNV) prediction algorithm, in which the hybridization rate constant of an unknown sequence is predicted bas...

Hybridization is a key molecular process in biology and biotechnology, but to date there is no predictive model for accurately determining hybridization rate constants based on sequence information. To approach this problem systematically, we first performed 210 fluorescence kinetics experiments to observe the hybridization kinetics of 100 differen...

In this chapter, we develop a procedure that attempts to find the largest set of initial states from which an autonomous PWA system satisfies an LTL formula over the set labeling the polytopes in its definition. We formulate the problem for the general case of autonomous PWA systems with uncertain parameters, and we show that more efficient solutio...

In this chapter, we introduce the syntax and semantics of Linear Temporal Logic (LTL) and of one of its fragments, called syntactically co-safe LTL (scLTL), and we illustrate them through several examples.We also define the automata that will be later used for system analysis and control from such specifications.

In this chapter, we focus on verification and control of switched linear systems. We show that a finite bisimulation quotient of a stable switched linear system exists and can be constructed by performing a finite number of basic polyhedral operations. To construct the quotient system, we use a polyhedral Lyapunov function. The existence of such a...

In this chapter, we introduce the two classes of discrete-time dynamical systems that we will focus on in the rest of the book: piecewise affine control systems with polytopic parameter uncertainties and switched linear systems. As particular instantiations of the first class, we define autonomous systems, fixed parameter systems, and combinations...

In this chapter, we introduce model checking, which is the most basic analysis problem in formal verification. As the focus of the book is on LTL, we restrict our attention to LTL specifications. Since we focus on analysis, we consider transition systems with no inputs. Informally, the LTL model checking problem consists of determining whether the...

Unlike the systems we discussed in previous chapters, which evolved autonomously, in this chapter we consider PWA control systems, which can be affected externally by applying a control signal. Then, it is possible to guarantee the satisfaction of a specification by trajectories of a PWA control system if an appropriate control signal is applied. W...

In Chap. 9, we treated the temporal logic control problem for a PWA system.While being able to accommodate full LTL specifications, the method from Chap. 9 was conservative, mainly because the original (rough) partition of the state space was not refined if a control strategy was not found. In this chapter, we address this limitation. We restrict o...

In this chapter, we focus on synthesis of an optimal control strategy for a PWA system constrained to satisfy a temporal logic specification. The specification is a formula of syntactically co-safe Linear Temporal Logic (scLTL). The cost is a quadratic function that penalizes the distance from desired state and control trajectories, which are calle...

In this chapter, we define the syntax and semantics of transition systems, and provide several illustrative examples. In particular, we present different (deterministic, nondeterministic, finite, and infinite) transition system representations for discrete-time dynamical systems. We also introduce simulation and bisimulation relations, which are ce...

In this chapter, we focus on the problem of analyzing a finite transition system with the goal of partitioning its state space into satisfying and non-satisfying subsets of states. Since the focus is on analysis, we consider transition systems with no inputs.

In this chapter , we treat the general problem of controlling non-deterministic finite transition systems from specifications given as LTL formulas over their sets of observations. We show that, in general, this control problem can be mapped to a Rabin game. For the particular case when the LTL formula translates to a deterministic Büchi automaton,...

In this chapter, we we study autonomous PWA systems with uncertain parameters. The parameters of the system are allowed to vary in predefined polytopic ranges. In this chapter we assume that those ranges can be restricted further. In other words, we treat the parameter ranges not as an uncertainty inherent in the system, but rather as allowed range...

This book bridges fundamental gaps between control theory and formal methods. Although it focuses on discrete-time linear and piecewise affine systems, it also provides general frameworks for abstraction, analysis, and control of more general models. The book is self-contained, and while some mathematical knowledge is necessary, readers are not ex...

Predictive biology is elusive because rigorous, data-constrained, mechanistic models of complex biological systems are difficult to derive and validate. Current approaches tend to construct and examine static interaction network models, which are descriptively rich, but often lack explanatory and predictive power, or dynamic models that can be simu...

Studying the gene regulatory networks (GRNs) that govern how cells change into specific cell types with unique roles throughout development is an active area of experimental research. The fate specification process can be viewed as a program prescribing the system dynamics, governed by a network of genetic interactions. To investigate the possibili...

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Bidirectional intercellular signaling is an essential feature of multicellular organisms, and the engineering of complex biological systems will require multiple pathways for intercellular signaling with minimal crosstalk. Natural quorum-sensing systems provide components for cell communication, but their use is often constrained by signal crosstal...

Bidirectional intercellular signaling is an essential feature of multicellular organisms, and the engineering of complex biological systems will require multiple pathways for intercellular signaling with minimal crosstalk. Natural quorum-sensing systems provide components for cell communication, but their use is often constrained by signal crosstal...

This chapter provides an overview of a programming language for Genetic Engineering of Cells (GEC). A GEC program specifies a genetic circuit at a high level of abstraction through constraints on otherwise unspecified DNA parts. The GEC compiler then selects parts which satisfy the constraints from a given parts database. GEC further provides more...

A fundamental question in biology is how cells change into specific cell types with unique roles throughout development. This process can be viewed as a program prescribing the system dynamics, governed by a network of genetic interactions. Recent experimental evidence suggests that these networks are not fixed but rather change their topology as c...

We consider how to generate chemical reaction networks (CRNs) from functional specifications. We propose a two-stage approach that combines synthesis by satisfiability modulo theories and Markov chain Monte Carlo based optimisation. First, we identify candidate CRNs that have the possibility to produce correct computations for a given finite set of...

In this paper, we focus on discrete-time continuous-space Piecewise Affine (PWA) systems, and study properties of their trajectories expressed as temporal and logical statements over polyhedral regions. Specifically, given a PWA system and a Linear Temporal Logic (LTL) formula over linear predicates in its state variables, we attempt to find the la...

We present a novel technique to analyze the bounded reachability probability problem for large Markov chains. The essential idea is to incrementally search for sets of paths that lead to the goal region and to choose the sets in a way that allows us to easily determine the probability mass they represent. To effectively analyze the system dynamics...

The design of synthetic circuits for controlling molecular-scale processes is an important goal of synthetic biology, with potential applications in future in vitro and in vivo biotechnology. In this paper, we present a computational approach for designing feedback control circuits constructed from nucleic acids. Our approach relies on an existing...

Deciphering the developmental program of an embryo is a fundamental question in biology. Landmark papers [9,10] have recently shown how computational models of gene regulatory networks provide system-level causal understanding of the developmental processes of the sea urchin, and enable powerful predictive capabilities. A crucial aspect of the work...

Predicting stem cell renewal or differentiation Predicting complex mammalian cell behavior is extremely challenging. Dunn et al. developed a computational model that predicts when embryonic stem cells will self-renew or differentiate. The model revealed an essential program governing pluripotency and identifies a minimal set of components and inter...

The ability to design and construct synthetic biological systems with predictable behavior could enable significant advances in medical treatment, agricultural sustainability, and bioenergy production. However, to reach a stage where such systems can be reliably designed from biological components, integrated experimental and computational techniqu...

We present a method for the analysis of functional properties of large-scale DNA strand displacement (DSD) circuits based on Satisfiability Modulo Theories that enables us to prove the functional correctness of DNA circuit designs for arbitrary inputs, and provides significantly improved scalability and expressivity over existing methods. We implem...

Synthetic biology focuses on the re-engineering of living organisms for useful purposes while DNA computing targets the construction of therapeutics and computational circuits directly from DNA strands. The complexity of biological systems is a major engineering challenge and their modeling relies on a number of diverse formalisms. Moreover, many a...

We present a computational framework for automatic synthesis of a feedback control strategy for a discrete-time piece-wise affine (PWA) system from a specification given as a linear temporal logic (LTL) formula over an arbitrary set of linear predicates in the system's state variables. Our approach consists of two main steps. First, by defining app...

We present a framework that allows us to construct and formally analyze the behavior of synthetic gene circuits from specifications in a high level language used in describing electronic circuits. Our back-end synthesis tool automatically generates genetic-regulatory network (GRN) topology realizing the specifications with assigned biological “part...

The design of genetic networks with specific functions is one of the major goals of synthetic biology. However, constructing biological devices that work "as required" remains challenging, while the cost of uncovering flawed designs experimentally is large. To address this issue, we propose a fully automated framework that allows the correctness of...

We present a computational framework for automatic synthesis of a feedback control strategy for a piecewise affine (PWA) system from a specification given as a Linear Temporal Logic (LTL) formula over an arbitrary set of linear predicates in its state variables. First, by defining partitions for its state and input spaces, we construct a finite abs...

We present a computational framework for identifying a set of initial states from which all trajectories of a piecewise affine (PWA) system satisfy a Linear Temporal Logic (LTL) formula over a set of linear predicates in its state variables. Our approach is based on the construction and refinement of finite abstractions of infinite systems. We deri...

In this technical note, we study temporal logic properties of trajectories of discrete-time piecewise affine (PWA) systems. Specifically, given a PWA system and a linear temporal logic formula over regions in its state space, we attempt to find the largest region of initial states from which all trajectories of the system satisfy the formula. Our m...

We consider the problem of controlling a discrete-time piecewise affine (PWA) system from a specification given as a Linear Temporal Logic (LTL) formula over linear predicates in its state variables. We present a computational framework for finding initial states and feedback control strategies guaranteeing the satisfaction of such a specification...

In this paper, we consider discrete-time continuous-space Piecewise Affine (PWA) systems with parameter uncertainties, and study temporal logic properties of their trajectories. Specifically, given a PWA system with polytopal parameter uncertainties, and a Linear Temporal Logic (LTL) formula over linear predicates in the states of the system, we at...

In this paper, we consider discrete-time continuous-space piecewise affine (PWA) systems with uncertain parameters, and study temporal logic properties of their trajectories. Specifically, given a PWA system with polyhedral parameter uncertainties and a linear temporal logic (LTL) formula over linear predicates in its state variables, we attempt to...

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...

Human transthyretin (TTR) is an amyloidogenic protein whose aggregation is associated with several types of amyloid diseases. The following mechanism of TTR amyloid formation has been proposed. TTR tetramer at first dissociates into native monomers, which is the rate-limiting step in fibril formation. The monomeric species then partially unfold to...

Transthyretin (TTR) is one of the known 20 or so human proteins that form fibrils in vivo, which is a hallmark of amyloid diseases. Recently, molecular dynamics simulations using ENCAD force field have revealed that under low pH conditions, the peptide planes of several amyloidogenic proteins can flip in one direction to form an alpha-pleated struc...