Synthetic Symbiont Therapeutics: A New Frontier in Biomedicine

Synthetic symbiont therapeutics is an emerging field with the potential to revolutionize medicine. This approach involves engineering microorganisms to perform specific functions within the human body, harnessing the power of engineered microbes to restore balance and promote health¹. It leverages the natural symbiotic relationships between humans and their microbiome, which plays a crucial role in human health and disease¹. This article explores the key aspects of synthetic symbiont therapeutics, including its applications, technologies, ethical implications, and research pathways.

The growing interest in synthetic symbiont therapeutics is reflected in the record levels of investment in synthetic biology companies in 2020, with a total of $7.8 billion raised in private and public financing². This trend is expected to continue, with the global synthetic biology market projected to reach $80.17 billion by 2033, driven by factors such as the rising need for eco-friendly and sustainable processes, expanding applications in biotechnology and healthcare, and technological advancements in DNA synthesis³.

One fascinating example of the complex interactions between symbiotic bacteria and their hosts is the production of tetrodotoxin by certain bacteria found in symbiotic relationships with animals⁴. While not directly related to therapeutics, it highlights the diverse roles that symbiotic bacteria can play.

Applications of Synthetic Symbiont Therapeutics

Synthetic symbiont therapeutics has diverse applications across various medical fields. Some of the most promising areas include:

• Gastrointestinal Disorders: Engineered probiotics can be designed to address gastrointestinal disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD)⁵. These modified bacteria can produce therapeutic compounds, enhance gut functionality, or deliver anti-inflammatory effects⁵. For instance, engineered probiotics may synthesize therapeutic peptides or cytokines that can alleviate symptoms of IBS and IBD⁵. Studies have shown that modified probiotics can effectively alter the gut microbiota composition, restoring balance and improving patient outcomes⁵. Compared to traditional treatments, engineered probiotics offer the advantage of targeted delivery and reduced side effects¹.
• Cancer Treatment: Bacteria-based cancer therapies are a significant area of research in synthetic symbiont therapeutics⁶. These therapies utilize various strategies, including the production of therapeutic molecules like cytokines, enzymes, and antibodies, to influence the immune system and target cancer cells⁵.
• Metabolic Diseases: Synthetic microbiota may help treat metabolic diseases, including diabetes and obesity, by improving bile acid metabolism and short-chain fatty acid (SCFA) generation⁵. This could enhance glucose metabolism and decrease the buildup of fat⁵. A recent study has shown that gut microbes can utilize glucose excreted from the gut to produce SCFAs, highlighting a novel symbiotic relationship between the host and its microbiota⁸. This discovery opens up new avenues for modulating gut microbiota and their metabolites to treat metabolic diseases.
• Autoimmune Disorders: Engineered probiotics that alter immune responses have the potential to improve autoimmune disorders like rheumatoid arthritis and multiple sclerosis⁵.
• Infectious Diseases: Synthetic biology can be applied to construct probiotic strains that have been endowed with functionalities allowing them to identify, compete with, and in some cases kill microbial pathogens as well as stimulate host immunity⁹. This may have the greatest potential for use against pathogens that infect the gastrointestinal tract, such as Vibrio cholerae, Staphylococcus aureus, Clostridium perfringens, and Clostridioides difficile⁹. A recent study demonstrated the effectiveness of a synthetic microbiome therapy in mice for treating C. difficile infection¹⁰. This targeted treatment, which uses specific bacteria strains linked to C. difficile suppression, was as effective as human fecal transplants in mice and had fewer safety concerns¹⁰.

Technologies Used in Synthetic Symbiont Therapeutics

Synthetic symbiont therapeutics relies on a range of cutting-edge technologies to engineer microorganisms with desired functionalities. These include:

• CRISPR/Cas9 Gene Editing: This technology allows for precise and targeted modifications of bacterial genomes, enabling the insertion, deletion, or alteration of specific genes⁵. CRISPR/Cas9 has revolutionized microbial engineering, offering a powerful tool for developing synthetic symbiont therapeutics. It allows for the precise manipulation of bacterial genomes to introduce new functionalities or enhance existing ones.
• Metabolic Engineering: By modifying metabolic pathways, scientists can reprogram bacteria to produce therapeutic compounds or perform specific metabolic functions within the host⁵.
• Synthetic Oligonucleotide Synthesis: This technology enables the synthesis of custom-designed DNA sequences, which can be used to introduce new genes or modify existing ones in bacteria⁵. Enzymatic DNA synthesis plays a crucial role in this process, offering advantages such as high accuracy and efficiency¹¹.
• Genetic Circuits: Synthetic biologists can design and implement genetic circuits in bacteria, allowing them to sense and respond to specific environmental cues or disease states⁷.
• High-Throughput Screening: Researchers use high-throughput screening methods to identify and characterize bacterial strains with desired therapeutic properties¹².

Synlogic, a leading company in the field, utilizes a comprehensive process for designing Synthetic Biotics¹³. This process involves several key steps:

1. Assess the Problem: This step involves identifying and validating the target, using predictive modeling, and employing bioinformatics to understand the underlying mechanism or metabolic dysfunction causing the disease¹³.
2. Design Solutions: This step involves using cutting-edge DNA assembly to target candidate pathways, employing mathematical models to predict pathway efficiency, utilizing proprietary switches and parts to control and tune engineered circuits, and selecting an optimal microbial "chassis" or foundational microbe for the therapeutic¹³.
3. Build the Synthetic Biotic: This step involves inserting the fine-tuned parts into the genome of the microbe using proprietary integration systems, conducting unique functional assays, and performing in-house process development research and optimization¹³.

Ethical and Societal Implications

The development of synthetic symbiont therapeutics raises important ethical and societal considerations. These include:

• Biosafety and Biocontainment: Ensuring the safety of engineered microbes and preventing their unintended release into the environment is crucial⁵. This requires robust biocontainment strategies and risk assessment protocols to minimize potential harm to human health and the environment.
• Genetic Stability: Maintaining the genetic stability of engineered microbes over time is essential to prevent unintended consequences⁵. This involves careful selection of microbial chassis and genetic engineering techniques to ensure long-term stability and minimize the risk of mutations or horizontal gene transfer.
• Ethical Considerations: Ethical concerns revolve around the creation of synthetic organisms and the potential for unintended genetic changes, emphasizing the need for strong regulatory frameworks to ensure safe application⁵. These frameworks should address issues such as informed consent, equitable access to therapies, and potential long-term effects on human health and the environment.
• Public Perception and Acceptance: Engaging the public in discussions about the potential benefits and risks of synthetic symbiont therapeutics is crucial to foster trust and acceptance¹⁴. This requires transparent communication, public education initiatives, and open dialogue to address concerns and promote responsible innovation.

Research Pathways in Synthetic Symbiont Therapeutics

Research in synthetic symbiont therapeutics is rapidly advancing, with scientists exploring various pathways to develop novel treatments. These include:

• Engineering Probiotics: Researchers are engineering probiotics to produce therapeutic compounds, enhance gut functionality, or deliver anti-inflammatory effects¹.
• Developing Synthetic Microbial Consortia: Scientists are designing synthetic microbial communities that can be introduced into the gut to restore balance and treat diseases¹. A successful model community should resemble the target ecological community, be representative, and meet the following criteria: accessibility, manageability, tractability, and stability¹⁵. These criteria evaluate the suitability of a synthetic microbial community for therapeutic applications.
• Creating Microbial Biosensors: Researchers are developing microbial biosensors that can detect disease states and trigger therapeutic responses⁷.
• Improving Delivery Systems: Scientists are exploring novel delivery systems to enhance the survival and efficacy of engineered microbes in the gut¹.

One promising research pathway is the Synthetic Symbiosis project (SynSym), which aims to transfer nitrogen fixation to bacteria associated with cereal crops¹⁶. This project has the potential to revolutionize agriculture by reducing the need for nitrogen fertilizers and promoting sustainable farming practices.

The iGEM (International Genetically Engineered Machine) competition is another important initiative that fosters research and innovation in synthetic biology¹⁷. This competition brings together student teams from around the world to design and build biological systems with novel functions, contributing to the advancement of the field.

Funding and Investment in Synthetic Symbiont Therapeutics

The field of synthetic symbiont therapeutics has attracted significant funding from both government and private sources. This investment is crucial for supporting research and development, clinical trials, and the commercialization of new therapies.

• Government Funding: In the United States, federal agencies such as the Biomedical Advanced Research and Development Authority (BARDA) and the National Institutes of Health (NIH) have provided substantial funding for synthetic biology research, including projects related to vaccine development and therapeutic applications³.
• Private Investment: Venture capital firms and private investors have also played a key role in funding synthetic biology companies¹⁸. For example, Symbiotic Capital, a life science credit firm, has raised over $600 million to provide loans to biotechs and other life sciences businesses¹⁸.

The increasing investment in synthetic symbiont therapeutics reflects the growing recognition of its potential to address unmet medical needs and revolutionize healthcare.

Companies and Research Groups Involved

Several companies and research groups are actively involved in the development of synthetic symbiont therapeutics. These include:

Conclusion

Synthetic symbiont therapeutics represents a new frontier in biomedicine, offering the potential to develop targeted and effective treatments for a wide range of diseases. By harnessing the power of engineered microbes, scientists aim to restore balance within the human microbiome and promote health. While ethical and societal considerations need to be carefully addressed, the ongoing research and development in this field hold immense promise for revolutionizing medicine and improving human health.

The future of synthetic symbiont therapeutics is bright, with ongoing research paving the way for potential breakthroughs in various areas. These include the development of personalized probiotics tailored to individual patient needs, the creation of more complex and sophisticated synthetic microbial consortia, and the engineering of microbes with enhanced therapeutic capabilities. However, challenges remain, such as ensuring the long-term stability and safety of engineered microbes, addressing ethical concerns, and gaining public acceptance. Overcoming these challenges will require continued innovation, collaboration, and responsible development of this promising technology. The long-term implications of synthetic symbiont therapeutics extend beyond medicine, with potential applications in agriculture, environmental science, and other fields. As this technology matures, it has the potential to reshape our understanding of human health and disease, offering new solutions to global challenges and improving the quality of life for people around the world.

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