Training microbes to speak the molecular code of healing: Intracellular living therapeutics convert cellular signals into coordinated healing programs
Get small and look inside
I became a microbiologist because I was fascinated by the secret lives of microbes. Viruses and bacteria had an elegance I couldn’t ignore – tiny organisms that could hijack or reshape the biology of much larger hosts. When I specialized in virology, I was drawn to the question of how viruses moved through the body, how they entered cells, and hijacked cell biology for their own purposes. Some of my early work focused on mother-to-infant transmission of HIV. Because the genomes of viruses, such as HIV, are prone to mutation, we could use the patterns of genetic change to reconstruct the cellular pathways HIV traveled in transmission from infected mothers to their children(1-3). But as I squinted at fragments of genetic code on a page, I remember thinking: Wouldn’t it be so much easier if we could just watch this process unfold directly in the body?
Since developing such an imaging approach in humans would be challenging, and all of our medical imaging tools such as CT scans, MRI, PET, ultrasound seemed incapable of visualizing single cells or individual microbes, we had to look at alternatives. We reasoned that light could carry information at scales small enough to reveal cellular and molecular patterns, and if we could genetically tag the cells or pathogens we wanted to follow, we could watch their journeys and their biology inside living organisms from the outside in. That was the seed that grew into in vivo bioluminescence imaging (BLI)(4-7) – a technique that’s since become a cornerstone of biomedical research and a foundational tool in the field of molecular imaging(8,9). With bioluminescence, we can watch cell biology unfold in its natural habitat, relatively unperturbed and in real time; this imaging tool has helped guide the development of many therapies now used in the clinic.
That was my first real step into reimagining the relationships between tools and biology. Imaging taught me that once you can see a system clearly, you can begin to manipulate it. And today, the challenge we’ve taken up is even bigger: not just to observe biology, but to engineer it and guide it. Not to conquer nature, but to work with it, to partner with cells and microbes at the most intimate level – from the inside out(10-13).
In her biography, “A Feeling for the Organism” Barbara McClintock reportedly described her discovery of jumping genes as “going inside the cell” and observing its chromosomes closely(14). So following her guidance, envision a city so small that it fits inside a single cell, its streets winding through the cytoplasm like intricate highways, its inhabitants bustling with purpose. Every building, every signal, every conversation matters for the life of the city. Now imagine that in this microscopic metropolis, some of the workers are engineered microbial partners, tiny living devices trained to communicate in the language of the cell itself. They don’t merely coexist – they instruct, modulate, and sometimes even reprogram the city’s residents to perform remarkable feats of repair and restoration. Although highly metaphorical, this is not science fiction. This is an emerging frontier in biomedicine: training microbes to speak the molecular code of healing, such that we can engineer microbes to guide cells by delivering molecular instructions that restore tissue function.
For decades, medical interventions have been largely external. Drugs are delivered, surgeries performed, gene therapies introduced – but the cell itself remained largely an audience or a target, and not a participant. The new paradigm flips that idea entirely: rather than imposing healing from the outside, we are designing living therapeutics that work from within the cell as synthetic organelles, synthelles, that reprogram cells through intricate molecular conversations that guide healing functions. Synthelles are like synthetic mitochondria that can be engineered for a desired function.
The promise of intracellular therapies
The concept is deceptively simple, yet profoundly transformative. Cells are already capable of complex, coordinated behaviors: they repair tissue, respond to injury, mount immune defenses, and regulate growth. However, these processes can go awry, particularly in diseases like cancer, chronic inflammation, or degenerative disorders. Traditional therapies often aim to compensate for these failures, but they do not necessarily restore the cell’s own decision-making processes. That is where synthelles can come into play and act as engineered intracellular devices to redirect and reprogram cells at the sites of tissue damage.
Synthelles reside in the cytoplasm with the intent to remain outside the nucleus and not to alter the cell’s genome. From the cytoplasm, they deliver molecular instructions in the form of transcription factors, or other signaling molecules to the cell’s command center – the nucleus. Alternatively, they redirect the highways in the cytoplasm-molecular networks-essentially giving the cell a set of new instructions without rewriting its DNA. These tiny devices can sense the cellular environment, respond to molecular cues, and adjust their activity accordingly. In essence, they act as biological conductors, orchestrating the complex symphony of cellular processes.
In a recent study, our team demonstrated that synthelles could modulate macrophages – immune cells responsible for detecting and removing pathogens – enhancing their ability to clear malignant cancer cells in living animal models(10). The immune cells were not forcibly changed; instead, they were guided, responding to molecular signals delivered by the synthelles as cytoplasmic devices. It was, in effect, teaching intracellular bacteria to speak the molecular language of mammalian cells and direct the conversation and actions toward removing cancer cells.
Microbial partners as living messengers
The metaphor of language extends to the molecular communication of naturally occurring microbial endosymbionts. These living bacteria take up residence within cells and also send molecular signals to the host. Far from being passive passengers, they can cause disease through the molecular instructions that they communicate to their host cells. Evolution of intracellular bacteria has led to communication pathways mediated by proteins, RNA and small molecules. These pathways and communication schemes can teach engineers how to better design and build engineered endosymbionts.
Tissue regeneration is an ideal target for cellular reprogramming since a few reprogrammed cells can reconstitute a tissue, and as such this can compensate for anticipated poor efficacy of endosymbiont up take. For guided regeneration, microbial partners can be programmed to release growth factors only when local damage signals are detected. Similarly, in oncology, they can instruct immune cells to attack tumor tissue selectively, turning the very environment of the tumor against itself. Unlike classical drugs, these living therapeutics adapt to the local context, creating a feedback loop that is dynamic, precise, and remarkably efficient. Our lab’s work on bioluminescent imaging provides a vivid example of how these interactions can be observed in real time.
By tagging synthelles, microbial endosymbionts and/or the host cells with bioluminescent markers, we can watch the molecular dialogue unfold within living tissue, tracking how engineered microbes sense, respond, and guide cellular behavior. The cells are alive with conversation, responding to cues as participants of a meticulously choreographed molecular dance.
Rewriting healing without rewriting the genome
When using living therapeutics that are capable of replication and reside in the interior of the cell, safety is a significant concern. By operating in the cytoplasm rather than in the nucleus where DNA damage can occur, synthelles minimize the risk of unintended genetic consequences for the target cells. By sparing the DNA, cells retain their inherent identity, while gaining the ability to perform new functions or correct aberrant behaviors. It is precision medicine in its most literal sense: delivering therapeutic instructions where they are needed, when they are needed, and with minimal collateral damage and no genomic damage.
This strategy contrasts sharply with gene-editing approaches that permanently modify DNA. While powerful, those methods carry risks of off-target effects, unpredictable mutations, or long-term consequences that are difficult to anticipate. With intracellular living devices, the therapy is modular, reversible, and tunable, akin to adding software to a biological operating system rather than rewriting the hardware. That being said, software can go awry.
Challenges and ethical considerations
Certainly, no discussion of living therapeutics would be complete without acknowledging the challenges. Designing organisms that can live safely within human cells, respond predictably, and be eliminated when necessary requires extensive knowledge of cell biology, advanced bioengineering skill and effective containment strategies. Moreover, the ethical implications of programming living organisms for therapeutic purposes must be carefully considered, particularly when it comes to off target cells being reprogrammed, long-term effects of mistargeted reprogramming, ecological impact, and patient consent.
Nonetheless, the field is advancing rapidly. With rigorous research, meticulous design, and thoughtful ethical frameworks, these living devices may one day move from experimental models to routine clinical applications.
A symphony of molecular signals
If we continue with the city metaphor, synthelles act as both teachers and messengers, conveying instructions to cells that, in turn, respond with precise action. They modulate signaling pathways, adjust gene expression indirectly, and coordinate cell behavior across tissues. In the process, they turn static, passive cells into active participants in tissue repair.
Consider chronic inflammation, which underlies a wide range of diseases, from inflammatory bowel disease to cardiovascular disorders. Here, synthelles can be designed to detect inflammatory signals and instruct immune cells to restore balance. The molecular conversation is nuanced: some signals encourage cell proliferation and repair, while others dampen overactive immune responses that cause tissue damage. In this context, the synthelles are not just passive tools; they are living translators of the molecular code, converting complex biochemical information into actionable guidance.
From concept to clinic
Of course, translating these ideas from the laboratory to the clinic is a significant challenge. Ensuring the safety, stability, and specificity of living intracellular devices requires meticulous design, rigorous testing, and regulatory oversight. Yet the potential rewards are enormous. In regenerative medicine, we could imagine a future where a patient’s cells are guided to rebuild damaged organs or tissues with minimal intervention. In oncology, living therapeutics could selectively reprogram tumor microenvironments, enhancing immune surveillance and improving treatment outcomes.
There is also a profound conceptual shift. Traditionally, medicine has treated cells as targets – something to act upon. With intracellular living devices, cells become partners, capable of receiving, interpreting, and responding to therapeutic signals. The act of healing becomes a conversation, with molecular words, sentences, and instructions encoded in proteins, signaling molecules, and metabolic cues.
The language of life
The metaphor of language is not just poetic – it is literal in a sense. Synthelles operate by interacting with the biochemical language of the cell through encoded instructions integrated into their design. It is teaching biology to guide itself, and in doing so, unlocking possibilities that were previously unimaginable. As research progresses, the vocabulary of this molecular language will expand. Engineers and biologists are exploring ways to create modular devices that can carry multiple instructions, respond to multiple cues, and even communicate with one another. Imagine a network of microbial partners conversing with host cells, coordinating repair processes with the precision of a conductor leading a symphony; the potential is staggering.
A vision for the future
The promise of training microbes to speak the molecular code of healing is more than a technical advance; it is a conceptual leap. It shifts medicine from a paradigm of intervention to one of collaboration – where humans, cells, and engineered synthelles participate in a shared project of repair and restoration. Each microscopic conversation, each molecular instruction, contributes to a system that is adaptive, responsive, and intelligent.
Imagine a patient recovering from injury, their own cells guided by trained synthelle partners to rebuild tissue, suppress harmful inflammation, and restore function. Or a cancer patient whose tumor microenvironment is quietly reprogrammed, instructing immune cells to act with precision and restraint. The possibilities extend to degenerative diseases, autoimmune disorders, and beyond. The potential applications are only limited by our imagination – and by our ability to teach cells and microbes to speak the language of healing fluently and safely.
Conclusion
Medicine is entering an era where the tools of therapy are living, intelligent, and intracellular. By training microbes live inside mammalian cells and speak the molecular code of healing, we are not just designing treatments; we are orchestrating cellular symphonies, guiding biology to repair, restore, and regenerate itself. The cells are no longer passive targets – they are active participants in their own recovery, and the recovery of their neighboring cells. And as we learn to communicate in this molecular language, the boundaries of what medicine can achieve will expand in ways that were once the realm of science fiction.
In the microscopic cities inside our bodies, a quiet revolution is underway. Messages are being delivered, instructions are being followed, and life itself is learning to heal. Training microbes to speak the molecular code of healing is not merely a scientific advance – it is a glimpse into a future where biology and medicine converse fluently, and where healing begins from the inside out.
