Recent News 32 : Bacteriophage Symphony: Engineering Phages as Live Biocomputers to Reprogram Microbial Communities

Bacteriophage Symphony: Engineering Phages as Live Biocomputers to Reprogram Microbial Communities

Harvard Undergraduate Microbiology Society

Looking at the micro-world under the magnifying lens, bacteriophages (specialized viruses that hunt bacteria) act like microbial grim reapers. But now, a new mindset in synthetic biology is reimaging their potential: why not use phages as living biocomputers, in addition to their role as precise, targeted snipers against germs, capable of hacking the genetic code of entire bacterial populations?

Well, beyond killing harmful bugs, “programmable” phages might convert disease-causing bacteria to beneficial bacteria or even direct whole microbiomes, like an orchestra conductor.

That precision turns traditional phage therapy upside-down. Phages have long been considered a last resort in fighting antibiotic-resistant infections, but now, researchers are creating specialized tools to reprogram bacteria rather than just destroy them.

Genetic circuits–essentially biological programs–function like lines of code, instructing microbes to carry out new behaviors at the molecular level. A phage that identifies its bacterial host and then inoculates it with a well-designed cassette (a small DNA package containing the genetic instructions) re-engineers the microbe to secrete anti-inflammatory chemicals, tune down nasty poisons, or cure genetic errors within the microbiome (Adler et al., 2022; Lopatina et al., 2023).

The health payout is huge. Beneficially, these smart phages can be employed in the human intestine to reset the microbiome of patients with chronic disorders such as inflammatory bowel disease and autism-spectrum disorders — which are caused by microbial imbalances — or metabolic syndromes. As opposed to general antibiotics that target the whole microbial ecosystem, programmable phages have the opportunity to only eliminate the troublemakers, leaving the beneficial bacteria intact, and in some cases, increasing their population (Kotomska et al., 2024; Hoshika et al., 2024).

In the agricultural sphere, programmable phages would be able to reverse antibiotic resistance by controlling the so-called antibiotic-resistant bacteria in livestock or soil effectively, essentially “restarting” the efficiency of the antibiotics we have already. Phages could target foul biofilms in wastewater and nudge the bacterial community to labor more and digest rotten sludge quicker. Out at sea, we can also install phages to collaborate with bacteria that consume plastics and accelerate the degradation of microplastics — an apt solution to mitigating a pressing global threat (Ando et al., 2022; Hoshika et al., 2024).

Rather than acting as simple bacterial killers, these engineered phages now function as precise tools for rewriting the genetic code of entire microbial communities. Researchers have already demonstrated proof-of-concept experiments in which phages either customized bacterial behavior, disrupted quorum sensing, or replaced genes that confer antibiotic resistance (Adler et al., 2022; Lopatina et al., 2023).

However, a competition between bacteria and phage might trigger resistance and an unconsidered release might transfer unwanted genes around or destabilize entire ecosystems. Rules and ethical prescriptions on how programmable phages can be used are yet to be developed. Even so, the potential benefit is massive: accuracy in microbiome engineering with a potential to transform medicine, agriculture and environmental management.

Phages are already used by nature as merciless bacterial killers. Now, with some synthetic-bio twist, they may even become the ultimate designers of microbial communities. By precisely reprogramming phages to edit or control specific bacteria, we can not only eliminate harmful microbes but also convert them into beneficial ones, unlocking a totally new level of control over the microscopic world with unprecedented precision.

Phages, once feared as microbial assassins, may now compose the symphony of health and sustainability.

References:

1. Adler, Benjamin A., et al. “CRISPR-based engineering of phages for in situ bacterial base editing.” Proceedings of the National Academy of Sciences, vol. 119, no. 45, 2022, pp. e2206744119. DOI: https://doi.org/10.1073/pnas.2206744119.
2. Ando, Hiroshi, et al. “Synthetic engineering and biological containment of bacteriophages.” Proceedings of the National Academy of Sciences, vol. 119, no. 47, 2022, pp. e2206739119. DOI: https://doi.org/10.1073/pnas.2206739119.
3. Kotomska, Aleksandra, et al. “In situ targeted base editing of bacteria in the mouse gut.” Nature, vol. 631, 2024, pp. 419–425. DOI: https://doi.org/10.1038/s41586-024-07559-7.
4. Hoshika, Yuki, et al. “Precise microbiome engineering using natural and synthetic bacteriophages for selective bacterial knockdown.” Frontiers in Microbiology, vol. 15, 2024, article 1403903. DOI: https://doi.org/10.3389/fmicb.2024.1403903.
5. Lopatina, Anna, et al. “Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice.” Nature Biotechnology, vol. 41, no. 5, 2023, pp. 1482–1501. DOI: https://doi.org/10.1038/s41587-023-01759-y.
6. Zheng, Tianpei, et al. “Engineering intercellular communication using M13 phagemid and CRISPR interference for distributed biocomputing.” Nature Communications, vol. 16, 2025, article 1374. DOI: https://doi.org/10.1038/s41467-025-58760-z.
7. https://medium.com/@harvardmicrosociety/bacteriophage-symphony-engineering-phages-as-live-biocomputers-to-reprogram-microbial-communities-663cd21a8991