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See also: Biological therapy for inflammatory bowel disease and Biologics for immunosuppression
Genetically engineered probiotics as living medicines to treat intestinal inflammation. a Genetically engineered E. coli Nissle 1917 (EcN) with csg (curli) operon deletion (PBP8 strain) containing plasmids encoding a synthetic curli operon capable of producing chimeric CsgA proteins (yellow chevrons with appended bright green domains), which are secreted and self-assembled extracellularly into therapeutic curli hybrid fibers. b CsgA (yellow), the main proteinaceous component of the E. coli biofilm matrix, was genetically fused to a therapeutic domain—in this case, TFF3 (PDB ID: 19ET, bright green), which is a cytokine secreted by mucus-producing cells. The flexible linker (black) includes a 6xHis tag for detection purposes. c Engineered bacteria are produced in bulk before delivery to the GI tract. A site of colonic inflammation is highlighted in red. d Interaction of E. coli and the colonic mucosa. Inflammatory lesions in IBD result in loss of colonic crypt structure, damage to epithelial tissue, and compromised barrier integrity (left panel, (−) E. coli). The resulting invasion of luminal contents and recruitment of immune cells to the site exacerbates the local inflammation. The application of E. coli (right panel, (+) E. coli) reinforces barrier function, promotes epithelial restitution, and dampens inflammatory signaling to ameliorate IBD activity.[1]

A living medicine is a type of biologic that consists of a living organism that is used to treat a disease. This usually takes the form of a cell (animal, bacterial, or fungal) or a virus that has been genetically engineered to possess therapeutic properties that is injected into a patient.[2][3] Perhaps the oldest use of a living medicine is the use of leeches for bloodletting, though living medicines have advanced tremendously since this time.

Examples of living medicines include cellular therapeutics (including immunotherapeutics), phage therapeutics, and bacterial therapeutics, a subset of the latter being probiotics.

Development of living medicines

a Several aspects require consideration during the design of an engineered bacterial therapeutic. The selection of a chassis organism can be guided by the desired site of activity and pharmacokinetic properties of the chassis, as well as manufacturing feasibility. The design of genetic circuits may also be influenced by the circuit’s effectors, pragmatic concerns regarding inducer compounds, and the genetic stability of regulatory circuits. Critically, the design of an engineered bacterial drug may also be constrained by considerations for the needs of patients. b Optimal strain design often requires a balance between strain suitability for function in the target microenvironment and concerns for feasibility of manufacturing and clinical development.[4]
Schematic representation of a workflow for developing clinical candidate-quality engineered strains. The development workflow should incorporate technologies for optimizing strain potency, as well as predictive in vitro and in vivo assays, as well quantitative pharmacology models, to maximize translational potential for patient populations.[5]

Development of living medicines is an extremely active research area in the fields of synthetic biology and microbiology.[6][7][8][9][10][11] Currently, there is a large focus on: 1) identifying microbes that naturally produce therapeutic effects (for example, probiotic bacteria), and 2) genetically programming organisms to produce therapeutic effects.[12][13]

Applications

Cancer therapy

Schematic of therapeutic bacteria strategies against hypoxic tumors
After systemic administration, bacteria localize to the tumor microenvironment. The interactions between bacteria, cancer cells, and the surrounding microenvironment cause various alterations in tumor-infiltrating immune cells, cytokines, and chemokines, which further facilitate tumor regression. ① Bacterial toxins from S. Typhimurium, Listeria, and Clostridium can kill tumor cells directly by inducing apoptosis or autophagy. Toxins delivered via Salmonella can upregulate Connexin 43 (Cx43), leading to bacteria-induced gap junctions between the tumor and dendritic cells (DCs), which allow cross-presentation of tumor antigens to the DCs. ② Upon exposure to tumor antigens and interaction with bacterial components, DCs secrete robust amounts of the proinflammatory cytokine IL-1β, which subsequently activates CD8+ T cells. ③ The antitumor response of the activated CD8+ T cells is further enhanced by bacterial flagellin (a protein subunit of the bacterial flagellum) via TLR5 activation. The perforin and granzyme proteins secreted by activated CD8+ T cells efficiently kill tumor cells in primary and metastatic tumors. ④ Flagellin and TLR5 signaling also decreases the abundance of CD4+ CD25+ regulatory T (Treg) cells, which subsequently improves the antitumor response of the activated CD8+ T cells. ⑤ S. Typhimurium flagellin stimulates NK cells to produce interferon-γ (IFN-γ), an important cytokine for both innate and adaptive immunity. ⑥ Listeria-infected MDSCs shift into an immune-stimulating phenotype characterized by increased IL-12 production, which further enhances the CD8+ T and NK cell responses. ⑦ Both S. Typhimurium and Clostridium infection can stimulate significant neutrophil accumulation. Elevated secretion of TNF-α and TNF-related apoptosis-inducing ligand (TRAIL) by neutrophils enhances the immune response and kills tumor cells by inducing apoptosis. ⑧ The macrophage inflammasome is activated through contact with bacterial components (LPS and flagellin) and Salmonella-damaged cancer cells, leading to elevated secretion of IL-1β and TNF-α into the tumor microenvironment. NK cell: natural killer cell. Treg cell: regulatory T cell. MDSCs: myeloid-derived suppressor cells. P2X7 receptor: purinoceptor 7-extracellular ATP receptor. LPS: lipopolysaccharide[14]
Bacteria involved in causing and treating cancers

There is tremendous interest in using bacteria as a therapy to treat tumors. In particular, tumor-homing bacteria that thrive in hypoxic environments are particularly attractive for this purpose, as they will tend to migrate to, invade (through the leaky vasculature in the tumor microenvironment) and colonize tumors. This property tends to increase their residence time in the tumor, giving them longer to exert their therapeutic effects, in contrast to other bacteria that would be quickly cleared by the immune system.[15][16][17]

References

  1. ^  This article incorporates text by Pichet Praveschotinunt, Anna M. Duraj-Thatte, Ilia Gelfat, Franziska Bahl, David B. Chou & Neel S. Joshi available under the CC BY 4.0 license.
  2. ^ editor, Ian Sample Science (16 January 2019). "'Living medicine' helps make toxic ammonia breakthrough". The Guardian. Retrieved 5 April 2020. {{cite news}}: |last1= has generic name (help)
  3. ^ "Engineering Living Medicines for Chronic Diseases | SBE | Society for Biological Engineering". www.aiche.org.
  4. ^  This article incorporates text by Mark R. Charbonneau, Vincent M. Isabella, Ning Li & Caroline B. Kurtz available under the CC BY 4.0 license.
  5. ^  This article incorporates text by Mark R. Charbonneau, Vincent M. Isabella, Ning Li & Caroline B. Kurtz available under the CC BY 4.0 license.
  6. ^ McCarty, Niko (18 December 2018). "Why 2018 Was the Year of 'Living' Medicine". Medium. Medium. Retrieved 5 April 2020.
  7. ^ Kelly, Jason (12 June 2019). "The Era of Living Medicines". Ginkgo Bioworks. Retrieved 5 April 2020.
  8. ^ ServiceFeb. 18, Robert F. (18 February 2020). "From 'living' cement to medicine-delivering biofilms, biologists remake the material world". AAAS. Retrieved 5 April 2020.{{cite news}}: CS1 maint: numeric names: authors list (link)
  9. ^ Kurtz, Caroline B.; Millet, Yves A.; Puurunen, Marja K.; Perreault, Mylène; Charbonneau, Mark R.; Isabella, Vincent M.; Kotula, Jonathan W.; Antipov, Eugene; Dagon, Yossi; Denney, William S.; Wagner, David A. (2019-01-16). "An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans". Science Translational Medicine. 11 (475): eaau7975. doi:10.1126/scitranslmed.aau7975. ISSN 1946-6234.
  10. ^ Charbonneau, Mark R.; Isabella, Vincent M.; Li, Ning; Kurtz, Caroline B. (2020-04-08). "Developing a new class of engineered live bacterial therapeutics to treat human diseases". Nature Communications. 11 (1): 1–11. doi:10.1038/s41467-020-15508-1. ISSN 2041-1723.
  11. ^ "Gene Circuits Empower Next-Generation Cell and Gene Therapies". GEN - Genetic Engineering and Biotechnology News. 1 February 2020. Retrieved 5 April 2020.
  12. ^ "Why now is the time for programmable living medicines: insights from Jim Collins, Aoife Brennan, and Jason Kelly". SynBioBeta. SynBioBeta. 2 April 2019. Retrieved 5 April 2020.
  13. ^ Costa, Kevin (20 February 2019). "Living medicines: Ginkgo's machine to disrupt the pharma industry". SynBioBeta. SynBioBeta. Retrieved 5 April 2020.
  14. ^  This article incorporates text by Mai Thi-Quynh Duong, Yeshan Qin, Sung-Hwan You & Jung-Joon Min available under the CC BY 4.0 license.
  15. ^ Duong, Mai Thi-Quynh; Qin, Yeshan; You, Sung-Hwan; Min, Jung-Joon (2019-12-11). "Bacteria-cancer interactions: bacteria-based cancer therapy". Experimental & Molecular Medicine. 51 (12): 1–15. doi:10.1038/s12276-019-0297-0. ISSN 2092-6413. PMC 6906302. PMID 31827064.
  16. ^ Sedighi, Mansour; Zahedi Bialvaei, Abed; Hamblin, Michael R.; Ohadi, Elnaz; Asadi, Arezoo; Halajzadeh, Masoumeh; Lohrasbi, Vahid; Mohammadzadeh, Nima; Amiriani, Taghi; Krutova, Marcela; Amini, Abolfazl (2019-04-05). "Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities". Cancer Medicine: cam4.2148. doi:10.1002/cam4.2148. ISSN 2045-7634. PMC 6558487. PMID 30950210.
  17. ^ Song, Shiyu; Vuai, Miza S.; Zhong, Mintao (2018-03-15). "The role of bacteria in cancer therapy – enemies in the past, but allies at present". Infectious Agents and Cancer. 13 (1): 9. doi:10.1186/s13027-018-0180-y. ISSN 1750-9378. PMC 5856380. PMID 29568324.{{cite journal}}: CS1 maint: unflagged free DOI (link)
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