Every few seconds, your lungs inflate and deflate without your conscious thought. This rhythmic action occurs in millions of tiny air sacs, where oxygen enters your bloodstream and where invading bacteria attempt to establish a presence. Replicating that movement in a laboratory has been almost unattainable—until now.
Scientists at the Francis Crick Institute along with biotechnology firm AlveoliX have developed the first human lung-on-chip model utilizing cells from a single individual. The device does not merely remain stationary under a microscope. Specialized machinery pulls and stretches a thin silicone membrane in three dimensions, simulating the expansion and contraction associated with actual breathing. This mechanical flexing encourages the cells to develop tiny hair-like structures known as microvilli, which enhance the surface area for gas exchange. Consequently, a vivid, microscopic representation of air sac tissue emerges, resembling and behaving like the deepest regions of a human lung.
What distinguishes this from previous lung chips is its genetic consistency. Earlier models were assembled from cells donated by various individuals or sourced from commercial cell lines—genetic mixtures that failed to represent how a particular body might react to diseases. In this instance, scientists produced every element from the stem cells of a single donor: the epithelial cells lining the air sacs, the endothelial cells forming the walls of blood vessels, and the macrophages monitoring for pathogens.
Tuberculosis Breaks Through in Five Days
To evaluate if this breathing chip could uncover hidden disease mechanisms, the research team introduced Mycobacterium tuberculosis, the pathogen responsible for TB. Tuberculosis progresses maddeningly slowly in humans, taking months before symptoms become apparent. By the time healthcare providers observe signs of infection, the initial confrontation has already occurred.
Within the chip, that confrontation became observable. Macrophages congregated around the bacteria and formed dense clusters. Inside those clusters, necrotic cores emerged—areas of dead immune cells encircled by living ones, emblematic of early TB pathology. Within five days, both the epithelial barrier defending the air sacs and the endothelial lining of blood vessels entirely collapsed. The bacteria did not multiply rapidly, but the immune response alone destroyed the lung’s structure.
The researchers subsequently engineered a variant of the chip featuring a specific genetic defect. They deleted ATG14, a gene associated with autophagy, a cellular waste disposal process. Upon infecting this modified chip with TB, the immune cells perished more rapidly, even though bacterial levels remained unchanged. The damage to the blood vessel lining was more severe. The gene, it turns out, does not directly eliminate bacteria—it helps preserve our own cells during the struggle.
“Composed entirely of genetically identical cells, the chips could be developed from stem cells of individuals with particular genetic mutations. This would enable us to understand how infections like TB impact specific individuals and assess the effectiveness of treatments such as antibiotics,” explains Maximiliano G. Gutierrez, principal group leader at the Crick.
Why a Single Genetic Source Matters
Utilizing cells from one donor significantly alters what these chips can demonstrate. Physicians could potentially obtain a patient’s stem cells, cultivate their lung on a chip, and evaluate which antibiotics are most effective for that individual’s genetic profile before prescribing any treatment. For diseases like TB that take months to show results in patients, this level of precision could be life-saving.
The breathing motion itself proved vital. Without the rhythmic stretch, the cells do not develop microvilli or create proper barriers. It is insufficient to cultivate lung cells in a dish—they require the physical forces they would encounter within a chest cavity to function correctly.
The team is not halting with tuberculosis. They’re modifying the system to investigate influenza, COVID-19, and lung cancer. By incorporating additional cell types into the setup, they aim to construct even more comprehensive miniature lungs that could replace animal testing in preliminary drug development. As non-animal technologies become increasingly important in research, these chips provide a method to study human lung biology directly rather than relying on extrapolations from mice or other animals with divergent immune systems and lung architectures.
This advancement is both mechanical and biological: a chip that breathes, constructed from a single person’s genetic framework, unveiling disease processes that have remained hidden for as long as we have examined respiratory infections.
[Science Advances: 10.1126/sciadv.aea9874](https://doi.org/10.1126/sciadv.aea9874)
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