From Synthetic Genomes to Designer Vaccines
Guest post by Markus Schmidt
In 2010 scientists from the J. Craig Venter Institute (JCVI) announced the creation of the first bacterial cell controlled by a chemically synthesized genome (1). The so-called “synthetic” cell was basically Mycoplasma mycoides, a bacterium with an exceptionally small genome of about 1 million base pairs and without a cell wall. Carole Lartigue, one of the co-authors of that landmark paper, later returned to the National Research Institute for Agriculture (INRA) in Bordeaux, France, to continue working on Mycoplasma. In fact Mycoplasma is not just a beautiful model organism for synthetic genomics. Their small genomes make them also a great model for systems biology, a work that was spearheaded by Luis Serrano at Centre for Genomics Regulation (CRG) in Barcelona, (2, 3, 4) who characterized Mycoplasma in a quantitative manner to apply this knowledge to do a rational engineering for novel applications. Some mycoplasma, however, are also pathogens affecting humans and a variety of farm animals (Table 1). The mycoplasma infections not only cause animal suffering and death, but also lead to epidemics, resulting in production delays, lower food-conversion rates and an overall decreasing efficiency and profit for farmers.
Table 1: Main mycoplasma infections of farm animals
|Animal||Mycoplasma species||Disease||Existing vaccines|
|Cattle||M. bovis||Mastitis, Pneumonia, Arthritis||Inactivated (not effective)|
|M. mycoides subsp mycoides||Contagious bovine pleuropneumonia (CBPP)||attenuated|
|Pig||M. hyopneumoniae||Respiratory disease||Inactivated|
|Poultry||M. gallisepticum||Chronic respiratory disease (CRD), sinusitis||Inactivated|
|M. synoviae||Arthritis, respiratory disease||Inactivated|
|Sheep/goat||M. agalactiae||Contagious agalactiae, mastitis, pneumonia, arthritis||none|
|M. ovipneumoniae||Atypical pneumonia||none|
|M. capricolum (subsp. capripneumoniae)||Contagious caprine pleuropneumonia (CCPP)||none|
Animal Mycoplasma species Disease Existing vaccines Cattle M. bovis Mastitis, Pneumonia, Arthritis Inactivated (not effective) M. mycoides subsp mycoides Contagious bovine pleuropneumonia (CBPP) attenuated Pig M. hyopneumoniae Respiratory disease Inactivated Poultry M. gallisepticum Chronic respiratory disease (CRD), sinusitis Inactivated M. synoviae Arthritis, respiratory disease Inactivated Sheep/goat M. agalactiae Contagious agalactiae, mastitis, pneumonia, arthritis none M. ovipneumoniae Atypical pneumonia none M. capricolum (subsp. capripneumoniae) Contagious caprine pleuropneumonia (CCPP) none
In the European H2020 funded project MycoSynVac (2015-2020), CRG together with INRA, the global healthcare leader MSD Animal Health, and other partners across Europe, are now working on the first synthetic biology-derived animal vaccine. Traditionally, bacterial vaccines are made from simply inactivated or attenuated pathogens, which are deployed to ‘train’ the immune system of the host. In many Mycoplasma species, however, these vaccines don’t work really well, because the inactivated pathogens don’t attach, for example, to the host epithelial cells, thus failing to trigger an appropriate immune reaction. The goal of MycoSynVac is not just a mere attenuated pathogen, but a reprogrammed organism that has to be, so to say, ‘semi-infectious.’ In other words, the reprogrammed microbe should be able to ‘inhabit’ the host, to attach for example to host epithelial cells in the respiratory tract, but then refrain from causing cell damage and inflammatory response because the virulence factors had been removed (5).
Re-programming this behaviour requires not only a deep understanding of the pathogenic life cycle and its cause on a genetic level (6), but also reliable bioinformatics models (7), precise gene editing tools for Mycoplasma (8, 9).
Mycosynvac is also developing extra layers of safety (10) with newly developed biosafety control circuits built into the vaccine. These and other challenges don’t exactly make this vaccine a low hanging fruit, but when considering the impact and scope of a successful product, it immediately seems worthwhile. The reasons are manifold: (A) The market for animal products and animal vaccines is huge, with M. hyopneumoniae vaccines alone currently topping $150 million annually. (B) For many pathogens there is either no vaccine available or they don’t work very well, so new applications are in high demand. (C) The designed vaccines will be based on a standardized “chassis” that can hold several different types of pathogenic epitopes (the surface molecules necessary for the protective immune responses), so development of the next vaccine(s) should be much easier and faster. (D) Making it easier to engineer novel vaccines will also allow for a systematic replacement of antibiotics in agriculture. Antibiotics in farming industry is already a serious concern in the surge of antimicrobial resistance (AMR) and so-called ‘superbugs’ (multi-resistant pathogens) affecting animals and humans alike. Vaccines as tools to reduce AMR have historically been under-recognized in these discussions, even though their effectiveness in reducing disease and AMR is well documented (11). (E) Last but not least, once approved for farm animals, the next goal will be synthetic biology vaccines for human infections with an even bigger market and impact.
If you want another short summary of MycoSynVac check out the music video below:
Dr. Markus Schmidt is founder and team leader of BIOFACTION KG, a research, technology assessment and art-science company in Vienna, Austria. With an educational background in electronic engineering, biology and environmental risk assessment he has carried out environmental risk assessment and safety and public perception studies in a number of science and technology fields such as GM-crops, gene therapy, nanotechnology, converging technologies, and synthetic biology. He worked in several research projects at the interface of biotechnology and society, published over 30 peer review papers, 2 books, worked as a high level policy advisory and enables the collaboration of art and science through festivals, exhibitions and residency programs.
1. Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome
2. Transcriptome Complexity in a Genome-Reduced Bacterium
3. Proteome Organization in a Genome-Reduced Bacterium
4. Impact of Genome Reduction on Bacterial Metabolism and Its Regulation
5. Comparative “-omics” in Mycoplasma pneumoniae Clinical Isolates Reveals Key Virulence Factors
6. Complete Genome Sequence of Mycoplasma mycoides subsp. mycoides T1/44, a Vaccine Strain against Contagious Bovine Pleuropneumonia
7. Persistence of Functional Protein Domains in Mycoplasma Species and their Role in Host Specificity and Synthetic Minimal Life
8. In-Yeast Engineering of a Bacterial Genome Using CRISPR/Cas9
9. Cloning, Stability, and Modification of Mycoplasma hominis Genome in Yeast
10. Synthetic bugs on the loose: containment options for deeply engineered (micro)organisms
11. The role of vaccines in preventing bacterial antimicrobial resistance