From natural to synthetic, microbial therapy leverages synthetic biology to open up fields of clinical application! | Gene News Online

Of all the advances in synthetic biology, microbiome therapy is the most rapidly developing and highly anticipated area of ​​technology. With the scientific revelation of the close relationship between microbial ecology and human health, the microorganism is considered a “second genome” other than the human genome, which widely affects gastrointestinal health, chronic diseases, cancer, and mental diseases etc. The clinical application of microorganisms has therefore become more and more common. Whether it is used for the treatment, diagnosis and prevention of diseases, or as a carrier for the delivery of therapeutic molecules, clinical trials are being carried out. , and even derivative medicinal products have been maintained. approved for marketing. This feature article is titled “Microbial Therapy” The following will present detailed 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 effect 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 an imbalance microbial increases the risk of developing certain diseases. The importance of microorganisms in relation to human health has attracted 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 treat diseases.

The clinical application of natural microorganisms has already begun, and synthetic biology technology has further advanced microbial therapy. By editing specific genes and transforming 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 are concerned with the safety of genetic modification and the risk of microbial infection, which is the cause of doubts that hinder development.

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

Synthetic biology is expanding the clinical use of microorganisms

The basic introduction of the principle of synthetic biology technology for microbial therapy is as follows.First, researchers screen 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. Coley) plastids can produce microorganisms with the ability to produce 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 together with microbial therapy are presented as follows: computer modeling to establish microbial flora, genetically modified microorganisms to synthesize therapeutic molecules, and biosensors for disease diagnosis.

Computer model helps recreate ‘natural’ microbial flora

In the study of microbial transplantation methods, unlike the isolation and analysis of potential pathogenic microorganisms directly from living organisms, the bottom-up research method is to directly culture 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 method, however, is that microbial flora subcultured in the laboratory do not necessarily grow under natural conditions.

When facing the research limitations above, it can be said that the introduction of computer models to simulate and predict the growth pattern of microbial flora is 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 single culture or laboratory culture conditions, these conditions complicate the growth environment of microorganisms further. 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 regulatory manner. .

Microorganisms genetically modified to synthesize therapeutic molecules such as antibodies and cytokines

Oral administration of antibody and general protein drugs may face the problem of unstable activity of drug molecules in vivo. However, through microorganisms that can synthesize therapeutic molecules, as long as a small number of microorganisms survive in the host, they can re-multiply, synthesize therapeutic molecules, and deliver them directly into the structure of the target organs. In addition, if the microorganism is from a native species in the host, it is not easy to trigger the host’s immune inflammatory response. 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 has been engineered to secrete peptides that prevent HIV fusion infection of mucosal cells. Since most HIV infections occur in gastrointestinal and sheath mucosal cells, the mucosal surface itself collects a variety of non-pathogenic symbiotic bacteria. an emerging therapeutic pipeline. In terms of cancer, Escherichia coli, Salmonella (Salmonella typhimurium) to secrete tumor growth inhibitory proteins. These new treatments are in the early stages of animal testing.

Biosensors detect disease progression

In the process of producing therapeutic molecules in the host, microorganisms can cause hidden side effects in the human body due to the associated production of metabolites. In order to reduce the risk in this respect, there are existing technologies that make microorganisms with the function of a biosensor. The sensor can detect disease-specific biomarkers (biomarkers), and then color them with fluorescent signals, in order perform the function of monitoring the progression of diseases.

Common biomarkers include the detection of blood matrix (heme) molecules associated with gastrointestinal bleeding and the detection of nitric oxide (NO) molecules associated with inflammation or diabetes with Escherichia coli. A 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 as 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 fields disease, biotechnology and pharmaceutical innovations and large manufacturers It has also successively injected resources to integrate multiple technologies such as AI, automated culture, and gene selection to expand the level of application of microbial therapy.

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

To achieve that goal, researchers are currently working on a more realistic simulation of the environment for cultivating 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 functioning of the microbial flora in the host and environmental signals, and continue to improve the stability and safety of microbial treatment methods, whether by regulating the release rate of therapeutic molecules, establishing an ecological microbial symbiosis, and long-term evaluation Risk of gene transfer and other instructions. The combination of microbiology and engineering is expected to continue to expand the frontiers of medical technology.

Further reading: exclusive topic on psychedelic drugs on the gene line

1. International Journal of Molecular Sciences, 2020;
2. Nature, 2020;
3. Front. Bioeng. Biotechnology, 2019;

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