Download PDF Summer Bridge on Advanced Biomanufacturing for Medicines June 16, 2025 Volume 55 Issue 2 This issue of The Bridge features cutting-edge perspectives on the rapid progress and innovation in advanced biomanufacturing for medicines. Synthetic Biology's Impact on Biopharmaceutical Manufacturing Friday, June 13, 2025 Author: Mruthula Rammohan, Akash Vaidya, Spencer Grissom, Rachel Silvestri, Christopher Pirner, Kevin Solomon, and Mark Blenner There is great potential for synthetic biology to improve biopharmaceutical manufacturing, but fully unleashing it requires technical innovation and solutions that address ethical, legal, security, and societal implications. Synthetic biology has already shown its usefulness in biopharmaceutical manufacturing. Yet there is much more synthetic biology can do to improve the way we manufacture biopharmaceuticals and the very nature of the therapeutics available to prevent and treat disease. Synthetic biology can create medicines that combine specificity for two or more targets to improve patient outcomes and reduce side effects. It can also make the manufacturing process cheaper, faster, and more consistent. This makes medicine more accessible to more people, and it enables quicker response time to emerging pathogens. The production of biopharmaceuticals using simpler, more robust expression systems could increase global access, improve pandemic preparedness, and reduce manufacturing costs. This article begins with a brief description of what synthetic biology means in the context of biopharmaceutical manufacturing. We then break down the current and future contributions of synthetic biology to biopharmaceutical manufacturing according to technology maturity and modality, starting with applications related to mature biopharmaceuticals (e.g., monoclonal antibodies, bispecific antibodies, and cell therapies) and concluding with emerging modalities (e.g., living therapeutics, phage therapeutics, and expansions to gene therapy and cell therapies). The article closes with a call to action discussing where synthetic biology needs to be focused, and how we can apply lessons from past ethical, legal, and societal implications to accelerate the safe implementation of synthetic biology in the future. What is Synthetic Biology? While there is little consensus on the precise definition of synthetic biology, it is distinguished from its predecessor, genetic engineering, by its use of an iterative Design-Build-Test-Learn engineering framework that refines constructed systems based on collected knowledge (Freemont 2019). Unlike classical genetic engineering in which manipulated DNA sequences are imperfectly defined, resulting in the transfer of poorly understood extraneous flanking sequences that alter performance unexpectedly in a context-dependent manner, iterations of Design-Build-Test-Learn allow synthetic biology to engineer biomolecular, cellular, and/or tissue behavior with increasing levels of precision via the creation of gene circuits (figure 1). Analogous to electrical circuits made up of reliable parts like resistors, capacitors, and wires, gene circuits are built from DNA-encoded promoters, transcriptional terminators, protein encoding sequences and other biological parts. The design and development of ever more sophisticated biological behaviors is dramatically accelerated by advances in related disciplines. Molecular biology has given rise to tools such as CRISPR-Cas, the subject of the 2020 Nobel Prize in Chemistry, that reprogram a number of species with exquisite precision and ease by editing and introducing novel genetic sequences (Fernholm 2020). Rapid prototyping of genetic circuits is enabled with DNA synthesis and automated DNA assembly that have approached exponential, Moore’s Law-like growth rates in manufacturing capacity for DNA sequencing and DNA synthesis. What once took months to build at the close of the last century can now be completed in days with fewer than eight man-hours of work for less than a hundredth of the cost (Carlson 2022). Finally, next-generation sequencing and artificial intelligence (AI) quickly analyze and model the performance of natural and engineered systems for fractions of a penny per DNA base pair, enabling precise and inexpensive design of new biological systems. More importantly, the systematic framework of synthetic biology reduces development cost and accelerates biosystem design by enabling reuse and extensibility of established solutions to new biopharmaceutical challenges. How is Synthetic Biology Impacting Mature Biopharmaceuticals? Synthetic biology has already made and continues to make a big impact on mature biopharmaceuticals, the biologically made drugs already in the clinic, which include monoclonal antibodies, hormones like insulin, and proteins used in vaccines. Its use in the discovery and improvement of hormones, monoclonal antibodies, bispecific antibodies, gene therapies, and cell therapies to make cell line and bioprocess development more efficient through new genetic engineering tools and advanced cell lines is accelerating (figure 2). Discovery and Engineering of the Therapeutic Among mature biopharmaceuticals, synthetic biology has mainly played a role in the discovery and engineering of therapeutics. The biopharmaceutical industry was born alongside the early advances underlying synthetic biology. Recombinant DNA technology developed in the 1970s led directly to the first biopharmaceuticals developed in the 1980s and 1990s, including insulin (recombinantly produced in Escherichia coli and Saccharomyces cerevisiae), orthoclone OKT3 (produced in a fusion of a B-cell and a myeloma cell), and rituximab (recombinantly produced in Chinese Hamster Ovary, or CHO cells). Another example of synthetic biology-based discovery and engineering is the use of phage display, a method of directed evolution where mutants are displayed on the surface of bacteriophages and selected for stronger binding to a ligand, which was instrumental in the production of adalimumab (humira). More recently, synthetic biology has led to the development of bispecific antibodies that can have higher specificity and potency. As of mid-2024, there are 12 FDA-approved bispecific antibodies, which combine antibody binding domains from two monoclonal antibodies (Schofield 2024). Synthetic biology is being used to improve the correct pairing of bispecific antibody fragments through engineered charge-charge interactions called knobs-and-holes (Ridgway et al. 1996). Improving Gene and Cell Therapies As of mid-2025, there are 10 FDA-approved gene therapies, many of which modify and hijack viruses to deliver functional genes to diseased cells. Gene therapies require engineering of the cargo to address a particular disease. They might also have tissue-specific promoters to limit expression to target cell types. Viral vector tropism is also being engineered through synthetic biology. Advances in synthetic biology technology can enable adenovirus-associated virus vectored gene therapies to achieve the precise control required in complex tissue-targeted therapeutic applications (Wang et al. 2024). Recombinant adenovirus-associated viruses are currently widely used in gene therapy; however, their natural tropism results in a somewhat broad distribution in tissues. Therefore, the resulting risks from off-target effects, limited payload size, and potential for inflammation make them unsafe for applications in certain organs such as the brain, heart, and retina. Engineering the viral capsids with tissue-targeting peptides or bioconjugating antibodies to the capsid enables preferential binding to specific cell types (Pham et al. 2024). Moreover, transcriptional controls can be improved by implementing tissue-specific promoters and incorporating miRNA binding sites to silence expression in off-target tissues. Cell therapies create chimeric antigen receptors (CAR) that target binding to immune cell activation. As of mid-2025, there are 21 FDA-approved cell therapies. The majority are CAR-T cell therapies, but similar CARs are now being introduced into other immune cells. Synthetic biology is increasing the safety profile of these therapies by enhancing the specificity of the response and including “kill switches” to mitigate the risk of immune overreaction and more complex gene circuits, making the activation of cell therapies more specific (Lu et al. 2024). Making Cell Lines and Process Development Improvements Synthetic biology has been applied in the biopharmaceutical space to optimize critical quality attributes (CQAs) at all levels of therapeutic protein production. CRISPR and RNA-based technologies have been used to selectively modulate the expression of native genes to improve cell growth, such as the knockout of pro-apoptotic proteins Bak and Casp3, hinder favorable protein quality attributes, such as glycosylation in the case of fucosyltransferases Fut8, or even reduce the accumulation of difficult-to-remove host cell proteins, such as the lipoprotein lipase Lpl, that can obstruct downstream purification (Chiu et al 2017; Glinšek et al. 2022; Xiong et al. 2019). The expression and stability of exogenous elements have also been fine-tuned using genetic circuits utilizing inducible and synthetic promoters and regulatory elements for conditional gene activation to provide modular and temporal control of gene expression (Chen et al. 2022; Teixeira and Fussenegger 2024). There has been a recent shift in cell line development (CLD) efforts away from random integration and towards site-specific integration of these therapeutic elements utilizing either transposons, a class of enzymes that “copy-and-paste” or “cut-and-paste” recombinant DNA into transcriptionally accessible regions of the genome, or inserting a landing pad to serve as a chassis for integration into safe-harbor regions characterized by long-term genetic stability and exceptional productivity (Chen et al 2020; Gaidukov et al. 2018; Hilliard and Lee 2023). These recent endeavors in synthetic biology serve to enhance the titer of high-quality therapeutics and reduce the burden necessary to find stable clones that display grams per liter titer. The production of biopharmaceuticals using simpler, more robust expression systems could increase global access, improve pandemic preparedness, and reduce manufacturing costs. Advanced Host Engineering Glycosylated protein therapeutics are still the fastest-growing class of compounds in the pharmaceutical industry. Mammalian cell culture is often the first choice of production host since they produce human-like glycans. Yeast offers a potentially less expensive, faster, and simpler production host but requires engineering of the glycosylation pathway to produce human-like complex glycans and not make its natural high-mannose glycans. A combination of gene deletions and insertions has modified Pichia pastoris to be able to produce human-like glycoproteins (Potgieter et al. 2009), such as interferon, growth factors, and monoclonal antibodies; however, the health and somewhat low productivity of these highly engineered cells has rendered the original attempts at host alternatives unable to compete with mammalian hosts. Recent advances in synthetic biology have breathed new life into these efforts. Escherichia coli is the most studied and one of the fastest-growing microbes; however, its inability to readily form disulfide bonds and other post-translational modifications (PTMs) has hindered its use to produce biopharmaceuticals like monoclonal antibodies (mAbs). These shortcomings have been overcome through extensive protein and E. coli strain engineering. Recently, E. coli has been engineered to produce full-length antibodies that are produced and disulfide-bonded in the cytoplasm by using the E. coli strain that has reducing enzymes knocked out and a disulfide bond isomerase integrated, SHuffle (Lobstein et al. 2012). Additionally, the effector region of the heavy chain maintains functionality of the product without the need for PTMs (Rashid 2022; Robinson et al. 2015). How is Synthetic Biology Enabling Emerging Biopharmaceuticals? In addition to advancing existing modalities in biopharmaceuticals, synthetic biology is also enabling entirely new modalities and technologies, such as RNA therapeutics, living medicines, phage therapies, and non-canonical amino acids (figure 3). RNA Therapeutics RNA-based therapeutics can transform from unstable, broad-acting macromolecules to programmable, conditionally active medicines with the help of synthetic biology (Pfeifer et al. 2023). Despite the prominence of mRNA vaccines during the COVID-19 pandemic, their broad applications are limited by their low translation efficiency, rapid degradation, and the lack of control over the time and location of protein production. Specifically, spatiotemporal control over mRNA translation and protein expression is crucial in cancer treatment, chronic disease management, and regenerative medicine applications. Synthetic biology offers solutions to resolve these issues. Researchers are enhancing the stability along with translation efficiency by designing improved sequences with optimized secondary structures, untranslated regions, modified nucleotides, and codon usage. Therapeutics containing synthetic RNA devices, such as logic gates and riboswitches, enable conditional translation. For instance, protein translation from mRNA can be regulated by the presence of a specific microRNA signature or a disease-related metabolite, thus reducing off-target effects and enabling more precise treatment. Additionally, synthetic biology has led to the development of two new RNA formats: self-amplifying RNA and circular RNA, which can reduce dosing requirements and extend expression times (Chen et al. 2023; Bloom et al. 2021).Together, these tools enable RNA to transition from a fragile treatment into a programmable platform with enhanced control capabilities and improved durability and specificity. Living Medicines In addition to CAR T-cells, bacterial and mammalian cells are being engineered as theranostics, or “smart” systems, that can sense environmental triggers and execute therapeutic responses (Zhao et al. 2023). Targeted delivery is the holy grail for cancer therapy, which traditionally suffers from systemic toxicity and severe side effects. The discovery that some bacterial species, such as Salmonella typhimurium and E. coli Nissle 1917, selectively colonize tumors but have poor anticancer potential. Synthetic biology can augment the limited anticancer properties of bacteria by enabling remodeling of the immunosuppressive tumor microenvironment, which critically supports cancer survival and growth. Some notable progress in this area includes engineering bacteria to produce pro-inflammatory interleukins or other cytokines, replenish immune-limiting metabolites such as arginine, or secrete signaling proteins like development endothelial locus-1 to recruit inflammatory macrophages to the tumor. Phage Therapy Although the therapeutic potential of bacteriophages was revealed over a century ago, it has been largely ignored since the advent of penicillin in 1928. However, a serendipitous discovery in ex-Soviet Georgia, involving successful bacteriophage therapy against drug-resistant Staphylococcus aureus infections, motivated the country to continue phage research and treatment (Parfitt 2005). The arms race against multidrug-resistant microbes is now catalyzing a resurgence of synthetic biology-assisted phage therapy. Several creative strategies are being investigated to overcome the susceptibility to resistance, low efficacy, and narrow target range of natural phages (Meile et al. 2022). Lytic and non-lytic phages have been armed with biofilm-degrading enzymes, membrane permeabilizers, and various agents disrupting bacterial genomes, RNA transcription, and protein translation in the so-called ESKAPE multi-drug-resistant pathogens. Engineered CRISPR-armed phages are being used as antimicrobial cocktails against a broad range of entero-pathogenic strains of E. coli and K. pneumoniae (Andrews et al. 2021). Another variation on phage therapy was recently demonstrated by engineering T4 bacteriophage to persistently co-opt commensal gut bacteria to produce therapeutics, such as a pro-inflammatory enzyme with increased activity in ulcerative colitis (Baker et al. 2025). Fully unleashing the potential for synthetic biology in biopharmaceutical manufacturing requires not only technical innovation but also solutions that address the ethical, legal, security, and societal implications of the field. Non-Canonical Amino Acids Synthetic biology is no longer restricted to the natural protein building blocks. Recent decades have seen tremendous strides in genetic code expansion, enabling the incorporation of non-canonical amino acids (NCAAs) into full-length proteins. Genetic code expansion has already been widely explored with NCAAs containing bio-orthogonally reactive functional handles such as azides and alkynes. These groups can undergo “click” conjugation for facile, site-selective protein modifications. Many of the mature and emerging biopharmaceutical technologies described above, including antibodies and viral vectors, have already benefited from NCAA-mediated bio-orthogonal functionalization with fluorescent markers, stabilizing polymers, targeting motifs, and therapeutic payloads (Yan et al. 2023). Emerging applications include the production of natural peptides with enhanced antimicrobial efficacy and bispecific antibody assembly via simple chemical conjugation without genetic fusion. Efforts to make NCAAs without expensive precursors through in vivo biosynthesis are already in progress (Jones et al. 2023). Last, NCAAs are being used to elicit a more potent immune response with the promise of making difficult-to-immunize targets more immunogenic (Butler and Kunjapur 2023). Ethical, Legal, Security, and Societal Implications Fully unleashing the potential for synthetic biology in biopharmaceutical manufacturing requires not only technical innovation but also solutions that address the ethical, legal, security, and societal implications of the field. Ethical In 2010, the Presidential Commission on the Study of Bioethical Issues released a report titled New Directions: The Ethics of Synthetic Biology and Emerging Technologies (Gutmann and Wagner 2010). The report laid out five guiding principles for evaluating ethical implications of synthetic biology. Public beneficence requires us to act to maximize public benefits and minimize public harm, considering the individuals, community, institution/company, and public. Responsible stewardship considers the benefits and risks extending to current and future generations, nonhuman life, and the environment. Intellectual freedom and responsibility supports unambiguous protection of scientific intellectual freedom while providing only as much oversight as is truly necessary to ensure justice, fairness, security, and safety. Democratic deliberation requires active participation by citizens and decision-making inclusive of opposing views. Last, justice and fairness, which seeks to avoid unjust distributions of the benefits and risks on specific groups of people or geographies. Legal Supporting the rapid pace of development in biopharmaceuticals by synthetic biology is significant knowledge generation via billions in public and private investments. This investment is motivated by the creation of intellectual property (IP) that provides certain protections to earn a return and foster future innovation. However, the current IP landscape can also restrict development. For example, the protracted patent dispute on the application of CRISPR-Cas technology to eukaryotic cells caused a “wait-and-see” approach to licensing, and the established industry is still mostly hesitant to entangle their products with this uncertain IP to this day (Schwaiger 2024; WIPO 2024). Companies with resources have sought to avoid existing IP licensing by developing their own similar but independent technology. For example, companies have developed their own versions of transposase and integrase technologies rather than license existing effective technologies. Such activities are legal but ultimately result in duplicated efforts. Security Access to life-saving medicine was recently identified by the National Security Commission on Emerging Biotechnology as a persistent national security risk (Young and Rozo 2025). With China outpacing the US in biotechnology innovation—particularly in manufacturing—they could be in a position to use access to biopharmaceuticals for geopolitical leverage. Other security concerns include so-called “dual-use” technologies that could be readily weaponized to cause harm. With the growing ease and capacity to synthesize small pieces of DNA and do synthetic biology, there is growing concern about so-called “sequences of concern” that could be leveraged by a nefarious or careless actor to, for example, synthesize or enhance, then release, pathogens or toxins. US government agencies have developed a framework to incentivize DNA-provider screening of sequences they sell by requiring federal funds to purchase nucleic acids only from providers that comply with the framework (Mackelprang et al. 2025). There are ongoing discussions around what exactly constitutes a sequence of concern and how to identify them in the small synthetic DNA purchases. Societal Implications Finally, despite the benefit of many of these technologies, there is a persistent question of negative public perception and thus whether public resources should be marshalled to support their development and provide access to the community. Nowhere is this more apparent than in the ongoing backlash against mRNA vaccines, driven in part by the vaccine mandates of the COVID-19 epidemic, the perceived lack of appropriate safety controls in their rapid development, and the politicization of science (Bardosh et al. 2022). With trust in science at its lowest in decades, failure to properly socialize synthetic biology and gain public acceptance jeopardizes the expected gains our society could reap. A Call to Action for Scientists, Engineers, and Policymakers Focus on Synthetic Biology to Enable Continuous Manufacturing For all its complexity, biomanufacturing lags behind other forms of advanced manufacturing. While the industry has made good progress to intensify processes, there are few approved biopharmaceuticals made with continuous manufacturing. Barriers to continuous manufacturing are numerous, but one critical limitation stands out. The cells are subject to a low rate of mutation over time, which can lead to loss of productivity and product quality changes. Similarly, epigenetic effects can also result in productivity and quality changes over time. In addition to point mutations, mobile genetic elements are another source of instability. A better understanding of the drivers of phenotypic variation and synthetic circuits that control instability, allowing instability during clone selection to achieve high productivity, and turning off instability once a clone is selected. Genome reduction that removes potential sources of instability will be needed to allow continuous cultivation. A reduced genome E. coli strain has already been engineered by removing 15% of the genome, including nonessential genes, recombinogenic and mobile DNA, and cryptic virulence genes, resulting in improved growth, greater stability, and higher productivity (Pósfai et al. 2006). Genome reductions are becoming easier with novel genome editing tools and bottom-up genome synthesis. A regulatory shift that moves the focus to the product rather than the process will also be needed to facilitate the adoption of continuous manufacturing. Focus on Making Synthetic Biology Reliably Predictable While the analogy of synthetic biology to electronics components is common, the complexity and unpredictability (or rather, our poor predictive understanding) of biological systems typically prevents generalization across systems. Thus, we cannot take full advantage of the work we’ve already done. The application of AI to make synthetic biology more predictable is widely touted as the expected “ChatGPT moment” for synthetic biology. Large data sets will need to be generated and used to train AI models to predict gene circuit and cellular behavior across modalities, cell lines, and scales. However, data is extremely valuable in the current IP framework we operate under and gives companies their competitive advantage. Without a change in the IP landscape, public support will be needed to generate these data sets. Getting the industry to adopt an open access standard common in software engineering, where code (“DNA”) is freely available in a public repository or “commons” to be leveraged and built upon by others, will not work under the current IP model, where competitive advantage would be lost for sharing these innovations and data. The semiconductor industry is a similar knowledge-generating industry with rapid growth that seems unsuitable for conventional IP protections (Hoeren 2016). That may serve as a useful model for biopharma. Trade secrets did not facilitate knowledge sharing and innovation, copyright was insufficient to protect implementations of ideas, and traditional implementations of patents were too restrictive. A robust patent ecosystem with extensive cross-licensing agreements at a fair price was established, and all players benefit by relatively free access to information through patent disclosures, the certainty of favorable licensing terms for leveraged patents, and stable revenue generation through cross-licensing royalties of their own IP. Similar models could be adopted by biopharma, although it will require strong incentives to facilitate the development of this culture of openness and fair pricing. 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National Security Commission on Emerging Biotechnology. Zhao N, Song Y, Xie X, Zhu Z, Duan C, Nong C, Wang H, Bao R. 2023. Synthetic biology-inspired cell engineering in diagnosis, treatment, and drug development. Signal Transduct Target Ther 8(1):112. About the Author:Mruthula Rammohan‡, Akash Vaidya‡, Spencer Grissom‡, Rachel Silvestri, and Christopher Pirner are doctoral candidates in the Department of Chemical and Biomolecular Engineering at the University of Delaware. Kevin Solomon* and Mark Blenner* are Thomas and Kipp Gutshall Career Development Associate Professors in the Department of Chemical and Biomolecular Engineering at the University of Delaware. ‡Equal contribution; *Equal contribution, corresponding authors