“I would venture to say that bacteria and archaea use everything that you can imagine for the purpose of defence — and then, some that you cannot,” said Eugene Koonin, an evolutionary biologist at the National Library of Medicine in Bethesda, Md. It highlights how impressive proven microbial immune systems are; they have not only reduced the essence of survival strategies of nearly all prokaryotes to subcellular agents, but they have also transformed biotechnology. From the discovery of restriction enzymes in the 1970s to transformative CRISPR-Cas systems in the 2010s, microbial immunity has burgeoned into an incredible toolbox for genetic engineering, diagnostics and therapeutics.
This innovation is a byproduct of an ancient and ongoing war: bacteria and archaea versus bacteriophages. Those viruses, whose numbers far exceed those of the bacteria that they infect, are in an evolutionary arms race with their microbial hosts. Bacteria have many kinds of immune systems, such as enzymes that cleave DNA, or self-sacrificial strategies that spare the lives of kin. Bacteriophages strike back, evolve countermeasures, and so the cycle of adaptation continues. Though this complexity is only beginning to be appreciated by microbiologists, it is already transforming the landscape of molecular biology.
Among the most transformative discoveries in the field of immunity is that adaptive immunity is conferred to bacteria by the CRISPR-Cas system. When the immune system reads these snippets of genetic information, they become short strands of RNA that stick to any corresponding viral DNA should there be a second infiltration, and their attachment creates the destruction of the matching sequence a kind of molecular memory. Its precision and flexibility turned it into a mainstay of genome editing technologies, and won its discoverers the 2020 Nobel Prize in Chemistry. But CRISPR is just the start.
Over the last decade, novel systems of microbial immunity with possible future applications were found because of novel capabilities in computational biology and genomic sequencing. CBASS researched by Philip Kranzusch of Harvard Medical School and Rotem Sorek of the Weizmann Institute of Science in one instance convinces human immune pathways to join forces with STING-signaling molecules in a hypothetical war of peoples in the wake of viral attacks. Similarly, bacterial gasdermins and viperins show great similarity to eukaryotic immune proteins; these both form pores in the membrane and block viral transcription. Cumulate such discoveries are the embodiment of the strand of evolutionary conservation of similarity between the m and h mini-immunity, or b vectors that can be back traced from this to the origins of immune systems, and hence therein the potential target thereof for derivation of therapeutic avenues for the amelioration of disease.
Each new tool in evolution, like the Argonaute system, which employs small RNA guides to seek out and cause degradation of viral RNA or in some instances DNA. They are thought to be easier to manufacture and are expected to be more flexible, with a lack of a need for a PAM sequence as characterize Argonaute systems as in CRISPR-Cas. (Such as a system called SPARTA that emits fluorescence when it detects a specific DNA sequence.) Researchers such as Daan Swarts at Wageningen University are investigating Argonaute’s potential as a diagnostic device. Swarts noted, “Basically, any type of sequence can be detected with these Argonautes,” says Swarts. “We’ve not run into any limitations yet.”
Even lesser-known mechanisms, such as retrons, are standing up and taking notice. Many viral reverse-transcribing elements produce intracellular DNA by reverse transcription and have been co-opted for genome engineering. Retron-mediated stable, high-throughput genetic engineering, followed by continuous evolution of the selected synthetic genomes, is a significant recent addition to the precision biology toolkit. They provide particular advantages over other technologies for the capture of cell states and the creation of targeted genotype-phenotype connections since they enable the in situ generation of DNA signal.
Diverse innovations in diagnostics and therapeutics are inspired by microbial immune systems outside of gene editing. CRISPR-based diagnostics have demonstrated remarkable sensitivity and also collateral cleavage activities that lead to multiplexing capabilities due to amplified signals, thus using systems such as Cas12 or Cas13. This is even used in feedback circuits, which can amplify signals in a way similar to the exponential chain reactions that occur in polymerase chain reaction (PCR), achieving sensitivity gains of over a thousand times. Box 1 Moving Towards Amplification-Free and Rapid Low-Cost Accessible Diagnostic Platforms
Therapeutically, though, phage therapies have re-emerged, for the better, thanks to lessons gleaned from research on microbial immunity. This case is prompting researchers and clinicians to work on the development of bacteriophages, phage therapy for the development of personalized treatment, engineered phages for greater specificity, and personalized medicine targeting resistant bacteria due to the necessity to work against antibiotic resistant bacteria. UNA virus therapy promises to surpass the hurdles of resistance and regulatory approval, while innovations in phage libraries and delivery systems have made it an attractive alternative to antibiotics in recent comprehensive review.
But while exciting, the future does have challenges. Furthermore, regulatory frameworks need to be modified for the unique characteristics of microbial based therapies and the ethical consequences of deploying genetically engineered systems must be dealt with. And because microbial immunity is so multifaceted, scientists are hungry for data that might explain how it works and how to tap into it.
The secrets of microbial immune systems are set to keep opening up, and their hold over biotechnology can only grow. From precision genome editing to next-generation diagnostics and therapeutic strategies, these ancient defense mechanisms symbolize more than a testament to the innovation of nature they are an inlet to transformational innovations that could advance the state of medicine and science for generations.
