IEEE COMMUNICATIONS SURVEYS & TUTORIALS 1 A Survey of Biological Building Blocks for Synthetic Molecular Communication Systems Christian A. Soldner,¨ Eileen Socher, Vahid Jamali, Wayan Wicke, Arman Ahmadzadeh, Hans-Georg Breitinger, Andreas Burkovski, Kathrin Castiglione, Robert Schober, and Heinrich Sticht Abstract—Synthetic molecular communication (MC) is a new experimental evaluation of MCSs. One of the main advantages of communication engineering paradigm which is expected to enable employing proteins for signal emission and detection is that they revolutionary applications such as smart drug delivery and can be modified with tools from synthetic biology and be tailored real-time health monitoring. The design and implementation to a wide range of application needs. We discuss the properties, of synthetic MC systems (MCSs) at nano- and microscale is limitations, and applications of the proposed biological building very challenging. This is particularly true for synthetic MCSs blocks for synthetic MCSs in detail. Furthermore, we outline new employing biological components as transmitters and receivers research directions for the implementation and the theoretical or as interfaces with natural biological MCSs. Nevertheless, design and analysis of the proposed transmitter and receiver since such biological components have been optimized by nature architectures. over billions of years, using them in synthetic MCSs is highly promising. This paper provides a survey of biological components Index Terms—Molecular communications, transmitter and that can potentially serve as the main building blocks, i.e., receiver architecture, signaling particles, synthetic biology, and transmitter, receiver, and signaling particles, for the design test-bed implementation. and implementation of synthetic MCSs. Nature uses a large variety of signaling particles of different sizes and with vastly different properties for communication among biological entities. I. INTRODUCTION Here, we focus on three important classes of signaling particles: The development of nanomachines for medical applications cations (specifically protons and calcium ions), neurotransmit- such as real-time health monitoring and targeted drug delivery ters (specifically acetylcholine, dopamine, and serotonin), and phosphopeptides. These three classes have unique and distinct is a focus area of current nanotechnology research [1]–[3]. features such as their large diffusion coefficients, their specificity, In order to realize the full potential of such applications, and/or their uniqueness of signaling that make them suitable it is necessary that the nanomachines be able to efficiently candidates for signaling particles in synthetic MCSs. For each communicate with each other [4]–[7]. In particular, it is of these candidate signaling particles, we present several specific envisioned that a network of communicating nanomachines transmitter and receiver structures mainly built upon proteins that are capable of performing the distinct physiological func- can help realize the concept of the Internet of Bio-NanoThings tionalities required from the transmitters and receivers of MCSs. which is expected to enable nanomachines to perform complex Moreover, we present options for both microscale implementation tasks [8], [9]. For instance, a group of nanomachines may of MCSs as well as the micro-to-macroscale interfaces needed for detect a metabolic condition and communicate this obser- vation to another nanomachine which is then responsible This work was supported in part by the German Research Foundation under for triggering the release of a drug into the body. Since Projects SCHO 831/7-1 and SCHO 831/9-1, in part by the Friedrich-Alexander conventional communication techniques are not well suited for University Erlangen-Nurnberg¨ under the Emerging Fields Initiative, and in part by the STAEDTLER Foundation. communication at nano- and microscale, especially in liquid Christian A. Soldner¨ and Heinrich Sticht are with the Division of media, molecular communication (MC), where molecules are arXiv:1901.02221v3 [cs.ET] 9 Jul 2020 Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universitat¨ used as information carriers, has been proposed as a promising Erlangen-Nurnberg¨ (FAU), Fahrstr. 17, 91054 Erlangen, Germany. (email: fchristian.soeldner, [email protected]) bio-inspired mechanism for enabling communication among Eileen Socher is with the Institute of Biochemistry and the Institute of nanomachines [4], [5]. Anatomy, Friedrich-Alexander-Universitat¨ Erlangen-Nurnberg¨ (FAU), 91054 The general structure of a (synthetic) MC system (MCS) Erlangen, Germany. (email: [email protected]) Vahid Jamali, Wayan Wicke, Arman Ahmadzadeh, and Robert Schober is depicted in Fig. 1. In response to a certain input signal, are with the Institute for Digital Communications, Department of Elec- which may be artificial (e.g. a light impulse or an electrical trical, Electronics, and Communication Engineering (EEI), Friedrich- stimulation) or biological (e.g. a nerve signal), the transmitter Alexander-Universitat¨ Erlangen-Nurnberg¨ (FAU), Cauerstr. 7, 91058 Er- 1 langen, Germany. (email: fvahid.jamali, wayan.wicke, arman.ahmadzadeh, releases a pattern of signaling particles , which represents the [email protected]) information to be conveyed. Depending on how sophisticated Hans-Georg Breitinger is with the Department of Biochemistry, Faculty of the transmitter is, it may also apply advanced encoding and Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo 11835, Egypt. (email: [email protected]) modulation techniques for efficient representation of the data Andreas Burkovski is with the Division of Microbiology, Department of before releasing the corresponding signaling particles into Biology, Friedrich-Alexander-Universitat¨ Erlangen-Nurnberg¨ (FAU), Staudtstr. the channel. The signaling particles propagate through the 5, 91058 Erlangen, Germany. (email: [email protected]) Kathrin Castiglione is with the Institute of Bioprocess Engineering, De- channel, e.g. via free diffusion where the propagation may be partment of Chemical and Bioengineering, Friedrich-Alexander-Universitat¨ Erlangen-Nurnberg¨ (FAU), Paul-Gordanstr. 3, 91052 Erlangen, Germany. 1Throughout this paper we use the terms molecules and particles interchange- (email: [email protected]) ably, although the latter term is broader as not all particles are molecules. IEEE COMMUNICATIONS SURVEYS & TUTORIALS 2 Focus of This Survey Transmitter Information Source Control/Computing Unit Physical Channel Natural/Synthetic Encoding, Release Stimulus, ... Modulation, ... Mechanism Signaling Receiver Particles Information Sink Control/Computing Unit New Action, Detection, Reception Readout, ... Decoding, ... Mechanism Fig. 1. General block diagram of an MCS. This paper surveys suitable biological building blocks for implementation of the release and reception mechanisms for several classes of signaling particles. The color code used to represent transmitter, channel, and receiver will be applied throughout the paper. further accelerated by advection [10]. The receiver observes the is the development of communication-theoretical models signaling particles and recovers the data by applying suitable for the release, propagation, and reception of the signaling demodulation and decoding techniques. Thereby, the data may particles that account for the features and constraints of either be read out using an artificial mechanism (e.g. via a the adopted biological building blocks [12]–[17]. Based light emission or an electrical current) or trigger a biological on these models, the basic functionalities of MCSs such as process (e.g. a nerve signal). channel coding [18], [19], modulation [20], [21], detection [21]–[23], decoding [19], [24], synchronization [25], [26], A. Motivation and Scope and estimation [27], [28] can be developed and their Although synthetic MC has received considerable interest performance can be analyzed. from the research community over the past decade, the research • Stage 3 – Control and Computing Modules: The area is still in its infancy. In particular, the design, analysis, implementation of the communication-theoretical concepts and implementation of microscale biological MCSs require developed in Stage 2 depends on where the correspond- inherently a multidisciplinary approach with contributions ing operations are to be performed. For instance, for from different engineering disciplines, including electrical, health monitoring applications where the observations biological, and chemical engineering, and different branches of can be collected and accessed from outside the MC science, including biology, chemistry, physics, and medicine. environment, a personal computer may be responsible Particularly, the field of synthetic biology is expected to play a for part of the processing. For other applications, such as crucial role in the fabrication and implementation of the main targeted drug delivery, sophisticated nano-transmitters and components of future synthetic MCSs, i.e., the transmitter, nano-receivers may have to process the data themselves. receiver, and signaling particles. Various options have been proposed for realizing con- In this paper, we review biological components suitable trol/computing units at nano- and microscale for biological for implementation of MCSs. In order to define the scope transmitters/receivers including molecular circuits (i.e., of this survey paper