Introduction: Synthetic Biology

Published as part of Chemical Reviews special issue “Synthetic Biology”. The 21st century is undeniably the century of biology, with scientific advancements accelerating at an unprecedented pace due to our growing ability to manipulate, reprogram, and engineer biological systems. At the heart of many groundbreaking discoveries in biotechnology over the past 25 years are chemists─driven by a deep-rooted desire to understand molecules and design new ones. Chemists are, by nature, builders. Whether synthesizing complex natural products, constructing entire proteins and nucleic acids, or assembling novel biomolecular systems, we learn by creating and refining the very molecules that shape life. In this spirit, synthetic biology─a field dedicated to harnessing and engineering biological systems─has become a natural extension of chemical biology, offering vast opportunities for innovation. This special issue, Synthetic Biology, highlights recent contributions by chemists in engineering biological systems to develop tools and technologies that deepen our understanding of nature while enabling new applications in both basic research and medicine. The selected works span multiple scales, from small molecules to biological macromolecules to entire organisms, illustrating how synthetic biology serves both as a means to answer fundamental biological questions and as a platform for groundbreaking biotechnological and therapeutic advancements. Collectively, this collection reflects the fearless, inventive spirit of chemists as they continue to push the boundaries of what is possible in synthetic biology. Starting with small molecule discovery, synthetic biology has revolutionized natural product research in the postgenomics era, enabling the discovery, characterization, and engineering of bioactive compounds with unprecedented precision. Tang and colleagues review key advancements in the field of natural products research from a synthetic biology perspective, focusing on three major aspects. First, they explore the integration of bioinformatics and analytical tools in identifying natural products through biosynthetic gene clusters (BGCs), enhancing the efficiency of natural product discovery. Second, they examine the heterologous expression of natural product biosynthetic pathways across various host organisms, such as bacteria, fungi, and plants, allowing researchers to bypass native-host limitations. Finally, they discuss strategies for modifying and diversifying natural product structures, including innovations in megasynthase engineering, precursor-directed synthesis, and combinatorial biosynthesis. These developments are expanding the chemical diversity of bioactive molecules, driving applications in drug discovery, biotechnology, and metabolic engineering. Moving from small molecules to fundamental cell biology, this collection features two reviews on using synthetic biology approaches to understand lipids. Lipid biology plays a fundamental role in cellular function, influencing everything from membrane structure to intracellular signaling. Cells contain thousands of different lipids, which participate in rapid metabolic processes, interact with other biomolecules, and self-assemble into supramolecular structures like membranes. Baskin and colleagues review the emerging field of “synthetic lipid biology”, which they define, which is aimed at applying synthetic biology principles to better understand and manipulate lipids and biomembranes. Key advancements include the de novo synthesis of lipids and membranes, precise membrane editing via optogenetics and protein engineering, bioorthogonal chemical tools for tracking lipid metabolism and transport, and novel techniques for studying lipid–protein interactions and membrane dynamics. By combining these diverse strategies, synthetic lipid biology seeks to uncover fundamental principles of lipid behavior and function, ultimately advancing our ability to engineer and exploit lipid-based systems for biomedical and biotechnological applications. In addition to their role as barriers and signaling molecules, lipids are also used to modify and regulate proteins. Wang and colleagues review the biosynthesis of protein lipidation, a crucial post-translational modification that regulates protein structure and function though the attachment of lipid groups to proteins. They examine the natural enzymatic pathways responsible for protein lipidation in mammalian cells, synthetic approaches for engineering protein lipidation, and strategies for site-specific lipidation. Synthetic biology tools that control the lipid membrane composition, signaling, and biomolecule modification state will continue to open new opportunities for cellular engineering and biotechnology applications. This collection features two reviews on emerging ways to control protein function using synthetic biology approaches. First, Dassama and colleagues review the use of biologics─proteins, peptides, and nucleic acids─as targeting moieties in targeted protein degradation technologies. Targeted protein degradation is an emerging field with the potential to transform biomedicine by selectively degrading disease-related proteins. Current targeted protein degradation approaches rely on small molecule ligands, limiting their applicability to proteins with well-defined binding sites. This review highlights the successes, challenges, and opportunities of using protein- and peptide-based binders as components of degrader technologies, highlighting that biologics-based degraders are both valuable research tools and promising therapeutic agents. Second, Wang and colleagues review synthetic biology for sensing and perturbing cell surface receptor activity. Cell-surface receptors regulate essential cellular processes, and their dysfunction is linked to various diseases. This review discusses molecular tools to study receptor biology and signaling pathways, enabling visualization of receptor localization, real-time and permanent sensing of receptor activation, and targeted perturbation or mimicry of receptor functions. Together, these two reviews highlight how synthetic biology approaches involving engineering protein binder-based biotechnologies can create powerful research tools with exciting clinical potential. Finally, moving from proteins to whole organisms, Peng and colleagues review the use of engineered phages as antibiotics. With the rise of antibiotic-resistant infections, phages offer a promising alternative for combating multidrug-resistant bacteria. Unlike conventional antibiotics, phages provide host specificity, self-amplification, and biofilm degradation. This review explores how phage engineering─through chemical and genetic modifications─can expand host specificity, enhance efficacy, and introduce new functionalities into the viruses. The review also highlights the use of engineered phages in bacterial detection and elimination, integrating synthetic biology and nanotechnology. All the reviews in this collection present a vision for the future in each of these important research areas. Chemists are poised to continue to lead in both fundamental and applied research at the intersection of biology and medicine, fueled by the mindset of a molecular builder. We hope that this collection of reviews inspires more chemists to enter the world of synthetic biology. B.C.D. thanks the NIH (GM 119840, EB 035016) for support. Bryan C. Dickinson is a Professor of Chemistry at the University of Chicago. He earned his B.S. in Biochemistry from the University of Maryland, earned his Ph.D. in Chemistry from the University of California at Berkeley with Christopher Chang and was a Jane Coffin Childs Memorial postdoctoral fellow at Harvard with Professor David Liu. He joined the faculty at the University of Chicago in the Department of Chemistry in the Summer of 2014 and was promoted to Associate Professor in 2019 and to Professor in 2023. The Dickinson Group employs synthetic organic chemistry, molecular evolution, and protein design to develop molecular technologies to study and control chemistry in living systems. The group’s current primary research interests include: 1) developing new evolution technologies to reprogram and control biomolecular interactions, 2) engineering RNA-targeting biotechnologies as new therapeutic platforms, and 3) developing novel proximity-labeling chemistries to study biomolecular interactions. This article has not yet been cited by other publications.