Cells are the basic functional units of life. Their structures support growth, division, communication, and molecular transport. Human-made cell models that replicate one or more components and functions of natural cells are known as artificial cells.
The term artificial (or synthetic) cell has been used broadly in the literature, sometimes inconsistently, describing systems from a cell-sized compartment to a genetically engineered living cell. This is mainly due to the existence of two different methods used to create artificial cells: the top-down and the bottom-up approaches.
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Top-down versus bottom-up synthetic biology
The top-down approach uses natural cells as the starting material. This approach simplifies the complexity of natural cells by removing all cellular components that are not essential for cell survival. Scientists can also add back in desired functions.
The top-down approach has the advantage of using the host cell (termed the chassis) and its co-factors, metabolites, and transcription pathways. However, this method has a potential drawback: the risk of crosstalk between the host's endogenous systems and the introduced synthetic systems.
Some scientists are intrigued by the challenge of creating life from scratch or want to explore the origin of life. But the potential of artificial cells extends far beyond this.
The bottom-up approach to constructing artificial cells starts with nonliving materials. Functionality is achieved by reconstituting modules from natural or artificial molecular building blocks, gradually increasing complexity by adding more components step-by-step. This method can be broken down into three basic steps:
1. Design and test genetic circuits: this step involves designing and testing genetic circuits, including gene promoters and transcription factors, through iterative cycles between in vivo and in vitro systems.
2. Test in cell-free systems: the constructed circuits are then tested in cell-free systems to assess how artificial chemical environments affect their functions.
3. Encapsulate within membranes: finally, the cell-free systems are encapsulated within membranes.
The bottom-up approach helps to reveal principles of how cells are built and function. It may also eventually lead to the creation of the first truly synthetic living cell without biological ancestry.
Why do we need artificial cells?
Some scientists are intrigued by the challenge of creating life from scratch or want to explore the origin of life. But the potential of artificial cells extends far beyond this. Synthetic versions of living cells allow scientists to study each cellular component in a simplified environment where variables can be controlled without interference from a living and responsive cell.
Moreover, there are specific functions and tasks that natural cells cannot perform efficiently or at all. Scientists can design artificial cells to fill these gaps. Artificial cells can, for example, synthesize non-natural compounds, operate in extreme environments, or interface with electronic devices.
The versatility of artificial cells as a platform has transformed them into engineering tools with potential in applied biotechnology, particularly in healthcare, sensing, and environmental remediation.
Artificial cells as biosensors
Cell-based and cell-free biosensors can detect molecular signals ranging from chemical contaminants to disease markers.
Cell-based biosensors use living cells that have been genetically engineered to detect specific biological, chemical, or physical signals. These engineered cells respond to target stimuli by producing a detectable output, such as fluorescence or a change in metabolic activity. For instance, Escherichia coli cells engineered with a genetic circuit that fluoresces in the presence of arsenic were used to detect this toxic heavy metal in water samples.1
On the other hand, cell-free sensors employ biological components like proteins, nucleic acids, and synthetic genetic circuits in a non-living system to detect target stimuli.
Cell-free systems are particularly valuable for rapid diagnostics. For example, scientists at the Wyss Institute developed a cell-free system that changes color in the presence of Zika virus RNA in blood samples.2 Biosensors embedded in paper discs can detect 24 different RNA sequences found in the Zika viral genome. All the cellular components necessary for this process, including proteins, nucleic acids, and ribosomes, are extracted from living cells and freeze-dried onto the paper. The paper discs can be stored at room temperature, making them easy to ship to any location. Once rehydrated, all the components function just as they would inside a living cell.
Artificial cells for drug delivery and therapeutics
Artificial cell design aims to address two existing challenges in drug delivery systems:
1. The degradation of bio-sensitive molecules during circulation and
2. Unavoidable off-target interaction.
Artificial cells for drug delivery and therapeutics are constructed with a biocompatible and stable membrane that can encapsulate enzymes, drugs, or even active cells. This outer membrane protects the internal compounds from the host's immune defenses, such as leukocytes, antibodies, and enzymes found in the digestive system, ensuring safer transport of drugs to the desired location and maintaining the activity of the encapsulated components for an extended period.
One example of an approved medicine that uses the bottom-up approach to artificial cell design for drug delivery is Doxil, a chemotherapy medication.3 Doxil uses liposomes as its drug delivery system. These liposomes form biocompatible lipid bilayers that encapsulate molecules of doxorubicin, the pharmaceutically active compound. This approach allows the drug to act directly on the tumor site, enhancing its efficacy while reducing systemic toxicity.
Another promising application of artificial cells in therapeutics is the generation of artificial pancreatic beta cells.4 These cells have a pH-sensitive glucose-metabolism machinery that senses glucose levels and releases insulin accordingly. In vitro experiments showed that this glucose-responsive design functions similarly to natural beta cells, releasing insulin only when glucose concentration is high. This method can offer more robust and consistent insulin secretion than traditional insulin injections or pumps, which often struggle to accurately mimic the body's natural insulin regulation.
Artificial cells for bioproduction, remediation, and pollution control
Currently, the commercial value of environmental biotechnology is significantly lower compared to its biomedical counterparts. However, the increasing urgency to combat climate change, manage waste, and sustain natural resources drives significant interest and innovation in this field.
The versatility of artificial cells as a platform has transformed them into engineering tools with potential in applied biotechnology, particularly in healthcare, sensing, and environmental remediation.
In bioproduction, artificial cells can be engineered to produce valuable materials. For instance, microorganisms have been successfully modified to produce polyhydroxyalkanoates (PHA),5 a family of biopolyesters used in environmentally friendly packaging, medical applications, and smart materials. Despite a significant number of studies on PHA and increasing market demand, a major restriction to their wide commercialization and industrialization is the high cost of production—between two and five times higher than the cost of synthetic plastic production. To make PHAs more cost-effective, extensive research has focused on the possibility of using industrial waste streams for microbial fermentation processes.6 These waste streams include plant oils, molasses from the sugar industry, lignocellulosic materials, oil palm shell, pressed fruit fiber, biodiesel waste, and waste animal oil.
Additionally, synthetic cells help to control pollution. For example, synthetic cells designed for photosynthesis can convert carbon dioxide into biofuels,7 providing a renewable energy source while simultaneously reducing greenhouse gas emissions. This approach addresses the problem of industrial CO2 emissions and offers a sustainable alternative to fossil fuels.
Future directions
The field of synthetic cellular systems is still in a nascent stage and faces technical and ethical challenges.
Precision in the design and fabrication of artificial cells, especially at a molecular level, is difficult to achieve. Ensuring the stability, durability, and biocompatibility of artificial cells is crucial, as they must function effectively under various environmental conditions without triggering an immune response or causing toxicity. Additionally, integrating multiple functions into a single artificial cell without interference between different processes is a significant hurdle.
Advances in nanotechnology, synthetic biology, material science, and computational biology hold promise for overcoming these challenges. Nanotechnology enables more precise construction, while synthetic biology innovations can provide better control over functions. Breakthroughs in material science could lead to more stable and biocompatible materials, and computational tools and artificial intelligence can optimize the design and functionality of artificial cells.
Developing comprehensive guidelines and regulatory frameworks through transparent dialogue with stakeholders will ensure the safe and effective application of artificial cells. Ethical considerations, including the potential impact on natural ecosystems and the long-term effects of introducing synthetic organisms into the environment, must also be carefully evaluated.
The synthetic cell community is still far from creating a fully autonomous, living cell from scratch. However, the field is making great progress. In the meantime, we can expect to see very exciting practical applications of artificial cells that may help us address everyday challenges in health, climate, and the environment.
References:
1. Li, Pengsong et al. “Development of a whole-sensor biosensor based on an ArsR-Pars regulatory circuit from Geobacter sulfurreducens”. Environmental Science and Ecotechnologly. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9488089/. Published 7 April 2021.
2. Karlikow, Margot et al. “Field validation of the performance of paper-based tests for the detection of the Zika and chikungunya viruses in serum samples”. Nature Biomedical Engineering. https://www.nature.com/articles/s41551-022-00850-0. Published 7 March 2022.
3. Barenholz, Yechezkel. “Doxil ®--the first FDA-approved nano-drug: lessons learned”. Journal of Controlled Release. https://pubmed.ncbi.nlm.nih.gov/22484195/. Published 10 June 2012.
4. Liu, Jian et al. “Genetically encoded synthetic beta cells for insulin biosynthesis and release under hyperglycemic conditions”. Advanced Functional Material. https://onlinelibrary.wiley.com/doi/full/10.1002/adfm.202111271. Published 20 January 2022.
5. Drakonaki, Athina et al. "Production of polyhydroxybutyrate by genetically modified pseudomonas sp. phDV1: a comparative study of utilizing wine industry waste as a carbon source". Microorganisms. https://doi.org/10.3390/microorganisms11061592. Published 15 June 2023.
6. Surendran, Arthy et al. “Can polyhydroxyalkanoates be produced efficiently from waste plant and animal oils?” Frontiers in bioengineering and biotechnology. https://doi.org/10.3389/fbioe.2020.00169. Published 16 March 2020.
7. Singh, Varsha K. et al. “Cyanobacteria as a Biocatalyst for Sustainable Production of Biofuels and Chemicals”. Energies. https://www.mdpi.com/1996-1073/17/2/408. Published 14 January 2024.
