Sensor

existsynthetic biologyof all developmental areas of (synthetic biology),Microbial therapy(microbiome therapy) is a part of rapid technological progress and high-profile. With the scientific unraveling of the close relationship between microbial ecology and human health, the microorganism is regarded as a “second genome” other than the human genome, which widely affects gastrointestinal health, chronic diseases, cancer, and mental diseases. and so on. The clinical application of microorganisms has therefore become more and more common. Whether it is used for disease treatment, diagnosis and prevention, or as a carrier for the delivery of therapeutic molecules, clinical trials are being carried out, and even derivative medicinal products have been approved for marketing. This feature article is titled “Microbial Therapy”. The following will introduce in-depth technical principles, clinical applications, and future development trends.

Innovative Manufacturing in the Contemporary Biotechnology Industry: Synthetic Biology (Geneline Online International Edition)

From natural to synthetic microbial therapy

From birth to death, the impact of microorganisms on human health is quite far-reaching. For example, the immunity of infants and young children is regulated by the microbial phase, the daily diet affects the composition of intestinal microbes, and microbial imbalance increases the risk of developing specific diseases. The importance of microorganisms in relation to human health has aroused the attention of various medical fields, and has become a therapeutic intervention strategy. For example, the faecal microbiota transplant (FMT) treatment method that has appeared in recent years, by transferring the microorganisms and antibacterial substances in the feces of healthy donors to the patient, achieves the effect of restoring the balance of intestinal bacteria and treating diseases.

The clinical application of natural microorganisms has already begun, and synthetic biology technology has further promoted microbial therapy. Through the purposeful gene editing and transformation of natural microorganisms, engineered microbes can target specific diseases and specific organ structures. It can also be used for real-time disease monitoring and has a wide range of clinical uses. However, at present, such technologies involve the safety of genetic modification and the risk of microbial infection, which is the cause of doubts hindering development.

Schematic diagram of the principle of the microbial therapeutic pathway (Image source / International Journal of Molecular Sciences)

Synthetic biology expands clinical use of microorganisms

The basic introduction of the principle of synthetic biology technology for microbial therapy is as follows. First, researchers screen out functional target genes and synthesize a large number of gene circuits related to the target genes, and then select the genes. to microbial genes, such as E. coli (E. Coli) plastids can generate microorganisms with the ability to generate therapeutic molecules or biomarkers that can detect specific diseases. Technology platforms such as organoids and biochips can be used to test the efficacy and safety of such treatments.

(Image credit/International Journal of Molecular Sciences)

The three main uses of synthetic biology combined with microbial therapy are introduced as follows: computer modeling to establish microbial flora, genetically modified microorganisms to synthesize therapeutic molecules, and biosensors for disease diagnosis.

Computer model helps reconstruct ‘natural’ microbial flora

In the study of microbial transplantation methods, different from directly isolating and analyzing potentially pathogenic microorganisms from living organisms, the bottom-top research method is to directly cultivate the host in a sterile environment, and then use it with the general culture conditions. Individual comparisons to confirm the role of gut microbes. The challenge with this research approach, however, is that microbial flora subcultured in the laboratory do not necessarily grow under natural conditions.

When faced with the above research limitations, the introduction of computer models to simulate and predict the growth pattern of microbial flora can be said to be a major contribution of synthetic biology to the application of microorganisms. Because the interaction between microorganisms and hosts, or even the metabolite interactions between different microorganisms cannot be fully observed under individual culture or laboratory culture conditions, these conditions further complicate the growth environment of microorganisms. With the help of computer model analysis, the growth environment of microbial flora can be deeply analyzed. The concept of “engineering” can be used to allow different microorganisms in the flora to distribute their respective metabolic functions through gene transfer, and to maintain the stable growth of microbial ecology in a group regulation manner. .

Genetically modified microorganisms to synthesize therapeutic molecules such as antibodies and cytokines

Oral administration of general antibody and protein drugs may face the problem of unstable activity of drug molecules in vivo. However, through microorganisms capable of synthesizing therapeutic molecules, as long as a small number of microorganisms survive in the host, they can re-proliferate, synthesize therapeutic molecules, and directly deliver them to the target organ structure. In addition, if the microorganism is from a native species in the host, it is not easy to trigger the immune inflammatory response of the host. For ulcerative colitis, new microbial-based drug delivery systems have emerged, such as the use of engineered Bacteroides (Bacteroides ovatus) to synthesize TGF-β1 molecules, lactic acid bacteria (Lactococcus lactis) Synthesize the cytokine IL-10 to relieve the symptoms of intestinal inflammation.

For some intractable diseases such as AIDS and cancer, microbial therapy also brings new medical opportunities. For example, Escherichia coli is engineered to secrete peptides that inhibit HIV fusion infection of mucosal cells. Since most HIV infections occur in gastrointestinal and vaginal mucosal cells, the mucosal surface itself gathers a variety of non-pathogenic symbiotic bacteria. Naturally occurring bacteria are an emerging therapeutic pipeline. In terms of cancer, there are colonized Escherichia coli, Salmonella (Salmonella typhimurium) to secrete tumor growth inhibitory proteins. These new treatment modalities are in the early stages of animal testing.

Biosensors detect disease progression

In the process of producing therapeutic molecules in the host, microorganisms may cause hidden side effects in the human body due to the associated production of metabolites.In order to reduce the risk in this regard, technology is now available to make microorganisms withbiosensor(biosensor) function, the sensor can monitor the progress of the disease by detecting biomarkers for specific diseases, and then coloring with fluorescent signals.

Common biomarkers include detection of blood matrix (heme) molecules associated with gastrointestinal bleeding and detection of nitric oxide (NO) molecules associated with inflammation or diabetes with Escherichia coli. The future direction of improvement is to increase the sensitivity of the sensor, so that it can detect target molecules in the low concentration range and improve the ability to specifically bind to target molecules.

final goal!Modular regulation of microbial functions like electronic circuits

The importance of the microbiome in the human body has gradually become the focus of pharmaceutical research and development. From probiotics, FMT to microbial treatment methods modified and regulated by synthetic biology, it has gradually accumulated clinical progress in various disease fields, biotechnology and pharmaceutical innovations and major manufacturers. It has also successively injected resources to integrate multiple technologies such as AI, automated culture, and gene selection to expand the application level of microbial therapy.

The core concept of microbial therapy assisted by synthetic biology is to replace the operating principle of electronic circuits with genetic engineering. With microorganisms as carriers, the gene circuits formed by the combination of various genetic elements of microorganisms can be modularized. It operates to achieve the desired regulation of disease states and therapeutic effects.

In order to achieve that goal, researchers are currently working on a more realistic simulation of the environment for culturing microorganisms in vitro, such as strengthening the development of test platforms such as vascular soft tissue, immune system, and matrix. In addition, some researchers continue to explore the relationship between the operation of the microbial flora in the host and environmental signals, and continue to improve the stability and safety of microbial treatment methods, whether from regulating the release rate of therapeutic molecules, establishing microbial ecological symbiosis, and long-term evaluation. Gene transfer risk and other directions. The combination of microbiology and engineering is expected to continue to broaden the boundaries of medical technology.

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References:
1. International Journal of Molecular Sciences,2020; https://pubmed.ncbi.nlm.nih.gov/33228099/
2. Nature, 2020; https://www.nature.com/articles/d41586-020-00201-6
3. Front. Bioeng. Biotechnol, 2019; https://www.frontiersin.org/articles/10.3389/fbioe.2019.00175/full

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