December 23, 2022 PAO-12-022-NI-01
Synthetic biology (synbio) pertains to the design and engineering of synthetic biological systems for use in various applications, including the production of commercial products, such as pharmaceuticals, specialty chemicals, food and feed ingredients, fuels, and so on.1
Advances in gene-editing technologies and increased knowledge of biological systems and processes, combined with digital technologies, such as artificial intelligence and big data analytics and process automation and process analytical technologies (PAT), are rapidly widening the application opportunities for synthetic biology. Some predict that sectors ranging from biopharma and medical devices to electronics, beauty, textiles, and fashion, among others, could face real competition from cost-effective synbio-based alternatives within the next five years.1 These new products could offer novel solutions with innovative properties or improved performance over existing options. They could also impart greater supply chain resilience while reducing the carbon footprint of many manufacturing operations.
Synbio in practice includes the use of engineered cells or enzymes to produce chemicals used to produce various products as well as engineered cells (bacteria, chimeric antigen receptor (CAR)-T cells, genome-edited soy cells) used as therapeutics and in other applications. These cells and enzymes are developed using techniques such as metabolic engineering, directed evolution, automated strain engineering, metagenomic discovery, gene circuit design, and genome editing.2
Unlike protein and genetic engineering, synthetic biology leverages an iterative approach to the design of synthetic biological systems that exhibit specific properties and are responsive in a controlled manner.3 This features are established using gene circuit designs, such as toggle switches, oscillators, and logic gates. The result is the generation of specific outputs at a desired level based on certain inputs to the system. The outputs can be simple, such as increased production of a specific protein or metabolite, or complex, such as a controlled immune responses.
In the biopharmaceutical industry, synbio has already found applications in the improvement of vaccines and innovation in the field of molecular diagnostics and novel therapeutics, including those based on living cells and organisms.4 Engineered systems comprising cascades of enzymes enable more cost-effective and sustainable production of complex small molecule pharmaceutical intermediates. Many forms of synbio are also used in other aspects of drug manufacturing, as well as in drug discovery and development.5 Ready access to inexpensive synthetic DNA, genome sequencing technology, and CRISPR gene-editing tools is making design and test cycles shorter and shorter.
Indeed, synthetic biology is expected to significantly accelerate the rate of innovation in the biopharma industry, impacting target validation, assay development, hit finding, lead optimization, and chemical synthesis, among other aspects.6 One recent example demonstrating the value of synbio in drug development is Moderna’s COVID-19 vaccine, which rapidly advanced from concept to approval by leveraging many of the principles of synthetic biology.7
Currently, there are two ways in which synthetic biology is most impacting the biopharma sector.8 The first involves engineering of biosynthetic pathways, gene networks, proteins, and molecular switches that improve natural cellular processes for use in both in vitro and in vivo applications. The second consists of the engineering of natural cells/organisms to improve their functionality or the creation of novel synthetic cells or organisms with novel functionality.
For synbio applications in which engineered organisms are leveraged to produce specific products, to generate compound libraries, and so on, two types of organisms are largely used.6 These organisms are referred to as chassis organisms because they are well understood, with extensive knowledge about their genomes and biochemical pathways enabling the rapid creation of platform strains. They include the prokaryotic organism Escherichia coli and the eukaryote Saccharomyces cerevisiae. Another examples include Streptomyces coelicolor and Aspergillus oryzae.10
Within these chassis organisms and in other synbio applications, such as the engineering of cell therapies, synthetic circuits provide the precise control that differentiates synbio from genetic engineering.11 Each of these carefully designed artificial circuits generally consists of a sensor to collect internal and/or external inputs, a logic processor that responds to those inputs, and an actuator that generates the desired outputs. Specific elements include switches, oscillators, cascades, feedback loops, and Boolean (“AND,” “OR,” and “NOT”) logic gates, with each circuit modulating endogenous cellular networks through the control of the expression of DNA, RNA, and/or specific proteins. Circuits can be activated by the binding of drugs (e.g., kinases, promoters, activators, repressors) to a specific target.
However, care must be taken to avoid unwanted immune responses to synthetic circuits comprising artificial elements. One approach includes encapsulation with compatible biomaterials. It is also important to avoid off-target effects of genome-engineering using CRISPR-Cas9 through the development of highly precise circuits.
Synbio in its various forms can benefit all phases of the drug development cycle from discovery through manufacturing.
When combined with genome mining, synbio techniques can help identify gene clusters associated with biosynthetic pathways in plants that lead to the production of natural metabolites with potential therapeutic value.10 Some researchers are using such technology to build natural product libraries containing novel small molecules with unique biological activities.
Synthetic biology tools, most notably CRISPR-Cas gene editing, can also be applied to target validation through the creation of more disease-relevant cell lines.10
Meanwhile, directed evolution based on mutagenesis and selection can be used to optimize drug design for enhanced efficacy, as well as for optimization of cell lines for more efficient and productive expression during drug substance manufacturing at large scale.10 It can, for instance, improve hit identification and lead-generation efforts.6 Furthermore, synbio can enable completion of multiple complex transformations in one organisms, greatly simplifying the production of advanced drug substances.12 Fermentation using yeast or bacteria also eliminates the variability associated with agriculture-based sourcing of natural products and affords agility in manufacturing, greatly enhancing supply chain resiliency.
Tools such as automated DNA printers are facilitating cell and organism engineering to accelerate the drug discovery process and increase the ability of drug companies to cost-effectively produce personalized medicines.13 Continuously improving DNA sequencing and bioinformatics are similarly enabling rapid advances in drug discovery and development.
The COVID-19 pandemic brought global attention to genetic vaccine technologies. Synthetic biology approaches are further advancing nucleic acid–based vaccines such against the SARS-CoV-2 virus and many other harmful and highly infectious pathogens. One synbio technique with great applicability for improving vaccines is genomic codon deoptimization/optimization. It can be used for virus attenuation, as well as engineering of plasmid-free DNA vaccines with increased immunogenicity and mRNA vaccines with increased intracellular stability.3
There are many ways in which synthetic biology is being used for the creation of novel therapeutics. As described above, cell line optimization is enabling more productive fermentation of important drug substances. Similarly, directed evolution has been widely used to optimize antibody-based therapeutics.
In the cell therapy field, synthetic biology tools are used to engineer precise control of the functionality of these advanced medicines.3 CAR T-cell therapies are a prime example.3 For these advanced medicines, synbio tools are being used to introduce, for instance, kill switches that turn the cells off in the event the patient suffers from cytokine release syndrome.6 Others include AND-gate logic circuits that cause the expression of a second CAR receptor for a second antigen to increase specificity. Other cellular therapies are being developed using synthetic biology circuits that respond in a controlled manner to specific disease biomarkers.14
Synbio is also being employed in the development of treatments for cancer and other diseases based on engineered bacterial systems.6,15 Human peptides may be able to convert certain bacteria into tumor-killing machines.
Polypharmacology is yet another area where synbio is playing an important role. The goal is to develop drugs that act on multiple targets and/or disease pathways simultaneously to simplify treatment while reducing side effects and increasing efficacy.16 Such drugs would help in the fight against diseases with many different contributing causes, including cardiovascular disease, diabetes, Alzheimer’s disease, and many mental illnesses.
Most futuristic of all synbio-based systems are xenobots, which are created using the embryonic skin, muscle, and cardiac cells of the African clawed frog Xenopus laevis based on designs proposed using artificial intelligence (AI) algorithms that allow computer-simulated robios to evolve bodies and minds in hundreds of thousands of different simulated environments.17–22 Structures are identified that perform certain functions well, then the structures are created by hand using the frog cells.
The first structures comprising skin cells only “walked.”17 Second-generation versions moved faster, had a longer life span, navigated more diverse environments, exhibited recordable memories, and were able to heal thenselves.18,19 More recent versions with approximately 3,000 cells organized in very specific “Pac-Man” shape suggested by the ever-evolving computer program “swam” and collected individual cells in a petri dish, assembling “baby” xenobots that could move.20 This kinematic replication is known to occur at the level of molecules but had never before been reported at the cell or organism level.
Many different xenobots have since be created, with a wide range of shapes and functionalities.18 These “living robots” could have many different potential uses, such as in microrobotic drug delivery systems and the cleanup of radioactive and other environmental contaminants. They can also be used to evaluate novel dosage forms, and their ability to self-repair might have applications in the treatment of neurodegenerative disorders and cancer.20 Xenobots are also providing scientists with information on how individual cells communicate with one another and ultimately create larger organisms.19
The attraction of synbio for the pharmaceutical industry lies in its ability to provide novel solutions with heightened control of biological and biochemical pathways. Synthetic cells can be carefully designed with specific features and functionalities that enable production of complex chemical and biological compounds or that can serve as therapeutic agents that interfere with disease mechanisms. They also have the added advantage of having simpler frameworks that are easier to manipulate and target against specific cells, tissues, and pathogens than cells isolated from very sick patients.3
For these reasons, synbio presents tremendous new opportunities for generating truly personalized medicines tailored to match individual DNA and disease profiles for a vast array of diseases, including those with numerous contributing factors.3 In addition, with synthetic biology tools, it may be possible to cost-effectively produce custom drugs on demand.
Of course, regulatory considerations must be factored into any discussion of the future biopharma applications for synbio.3 The advantages and benefits of synthetic cells and organism-like systems and how they outweigh potential risks must be clearly demonstrated to regulators.
Going forward, continued engineering of protein- and antibody-based therapeutics using AI, biology, fermentation, chemistry, and robotic systems and technologies will continue to accelerate drug discovery and development for this important class of therapeutics, for which synbio tools have already been recognized as having a tremendous positive impact.2 Increasing numbers of engineered cellular therapies will advance through the clinic. The same will be true for live biotherapeutics based on bacteria –– some on individual species and others formulated with consortia. Eventually, organism-like systems will play important roles in not just biopharmaceuticals but many other fields.
Ongoing innovation in the synbio field, will, however, require greater investment, clear overarching strategies and goals, standards mechanisms for assessing risk, and means for training future researchers in not only synbio tools and techniques but how to consider ethics when moving into the next generation of synbio solutions.23
It is generally thought that measurable investment in synthetic biology will occur over the next 5–10 years, but it will take time for the conservative biopharma industry to fully embrace widespread application of synthetic biology.6 Once early adopters show how synbio approaches can dramatically accelerate drug discovery, development, and manufacturing and early clinical data confirm the advantages of synbio-based therapeutics, the race will be on. By that time, further advances in AI, bioinformatics, gene-editing technologies, understanding of biological pathways and disease mechanisms, and other crucial components of synbio will make these approaches irresistible.
List of Selected Players in the Biopharma Synthetic Biology Space
Dr. Challener is an established industry editor and technical writing expert in the areas of chemistry and pharmaceuticals. She writes for various corporations and associations, as well as marketing agencies and research organizations, including That’s Nice and Nice Insight.