Anthrobots as Self-Constructing Biobots from Human Lung Epithelium

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The exploration of the latent space of functional morphologies achievable with wild-type genomes has become a focal point in various scientific disciplines, including evolutionary biology, developmental biology, cell biology, and synthetic biology. This quest has led to the emergence of an exciting field known as biobots, which seeks to engineer living structures for a myriad of applications, ranging from regenerative medicine to robotics and space exploration.

A Decade of Advancements

Over the past decade, interest in developing biological structures from scratch has witnessed a surge. Within this realm, biobots have garnered significant attention as a subset of functional biogenic assemblies, combining biological cells with inert materials. These early biobots utilized a range of living cells, from bacteria to mammalian tissues, embedded within carefully designed 3D scaffolds to amplify biological functionality.

The Birth of Xenobots

A significant breakthrough in this field was the creation of Xenobots, the first fully-biological biobots. These structures were sculpted from amphibian embryonic cells, showcasing spontaneous locomotion without external guidance. This prompted questions about the generalizability of this phenomenon to other organisms, particularly mammals, and the scalability of the technology.

Enter Anthrobots

To address these questions, researchers introduced Anthrobots, fully biological, self-constructing motile living structures created from human lung epithelium. Leveraging normal human bronchial epithelial (NHBE) cells’ native tissue plasticity, Anthrobots are produced through a scalable method that requires no external form-giving machinery or manual sculpting. The cilia-driven propulsion mechanism enables them to exhibit movement for 45–60 days.

Anthrobots’ Unique Properties

Anthrobots exhibit a remarkable ability to move across scratches in human neuronal monolayers, inducing gap closures. This unexpected behavior opens the door to numerous in vitro and in vivo applications, especially considering their potential use with patient-specific cells.

Comparison with Other Methods

The development of Anthrobots follows distinct methodologies from other recent advances in creating airway organoids. While similar to the Boecking & Walentek method in initial proliferation within a gel-based matrix, Anthrobots differentiate by achieving cilia localization in low-adhesive environments. This novel approach is faster, less laborious, and potentially higher-throughput compared to existing protocols.

Convergence of Technologies

The Anthrobot method, along with three other protocols, constitutes convergent yet distinct technical approaches to producing cilia-out spheroids derived from human airway epithelium. These protocols explore the morphogenetic potential of non-embryonic wild-type cells, marking significant strides in understanding the plasticity landscape of human airway epithelium.

Discussion

Biorobotics and bioengineering have ushered in a new era with two significant impacts: the creation of useful living machines and the exploration of unconventional configurations for living materials. This dual impact has broad implications, not only in the realm of regenerative medicine but also in understanding the macro-scale rules governing self-assembly of form and function. Our study focuses on the creation of Anthrobots, self-constructing living structures derived from human lung epithelium, and delves into the morphological and functional capabilities of these adult mammalian cells.

Comparative Analysis with Xenobots

The initial motivation for this research stems from the need to understand whether the unique properties of Xenobots, self-motile biobots created from frog cells, are specific to amphibian genomes and embryonic states. Despite the vast differences in genomes and evolutionary history, Anthrobots exhibit morphological and functional similarities with Xenobots, challenging the notion that such plasticity is confined to amphibian tissues and embryonic states.

Morphological and Behavioral Correlations

Anthrobots display distinct movement and morphological classes, each significantly correlated. This correlation has profound implications for the future control of higher-order behaviors, suggesting that manipulating Anthrobot morphology through synthetic morphogenesis can influence real-time physiological signaling. Machine learning classifiers may further enhance our ability to predict movement types without the need for immunostaining, contributing to cracking the morphogenetic code.

Bilateral Symmetry and Self-Assembly in Anthrobots

The ability of Anthrobots to establish bilateral symmetry is a noteworthy aspect of self-assembly in a symmetrical environment. This observation opens avenues for studying how multicellular amniote embryos bisect themselves to establish a single midplane for their bodyplan, providing insights into the poorly-understood process of symmetry establishment in complex biological systems.

Anthrobots as Agents of Repair

An intriguing finding is the Anthrobots’ capacity to traverse neural tissues and induce efficient healing of defects in live human neural monolayers in vitro. This unexpected ability raises questions about the underlying mechanisms and biochemical aspects driving neural repair. The controlled fusion of Anthrobots for different-sized collectives introduces the possibility of tailored repair strategies, presenting a novel avenue for therapeutic applications.

Personalization and In Vivo Deployment

Given that Anthrobots are derived from adult human tissue, the prospect of personalization for each patient emerges. This paves the way for safe in-vivo deployment without triggering an immune response. Potential applications include plaque removal in arteries, mucus clearance in airways, and targeted drug delivery. The ability to modulate Anthrobot size further enhances their versatility in addressing specific patient needs.

Future Directions and Unanswered Questions

The study opens numerous avenues for future exploration. Questions about the generality of Anthrobot creation from various cell types, their behaviors in diverse environments, and their potential impact on different tissue types remain unanswered. The ability to read out transcriptional or physiological signatures in living Anthrobots offers opportunities to understand their past and immediate interactions, potentially uncovering preferences or primitive learning capacities.

Contributions to Evolutionary Developmental Biology

In a broader context, the study contributes to evolutionary developmental biology by revealing additional morphogenetic competencies of cells. The implications of a single genome producing diverse forms in different environments raise questions about the evolutionary factors influencing anatomical and functional features.

Synthetic Biological Systems and Predictive Control

Anthrobots serve as a valuable model system in the study of synthetic biological systems, offering insights into the adjacent possible in morphological and behavioral spaces. Additionally, their predictable and controllable properties make them an essential tool for understanding the system-level properties of multiscale complex systems.

Conclusion

In conclusion, this study unveils the morphogenetic and behavioral capacities of Anthrobots, providing a foundation for further research. Anthrobots, derived from adult human cells, showcase unexpected capabilities, raising new questions and offering exciting prospects for applications in regenerative medicine, drug screening, and beyond. As we navigate this uncharted territory, Anthrobots stand as a testament to the untapped potential of living constructs and their ability to bridge the gap between biological and technological frontiers.


reference link : https://onlinelibrary.wiley.com/doi/10.1002/advs.202303575

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