Artificial cell
An artificial cell, synthetic cell or minimal cell is an engineered particle that mimics one or many functions of a biological cell. Often, artificial cells are biological or polymeric membranes which enclose biologically active materials. As such, liposomes, polymersomes, nanoparticles, microcapsules and a number of other particles can qualify as artificial cells.
The terms "artificial cell" and "synthetic cell" are used in a variety of different fields and can have different meanings. Some stricter definitions are based on the assumption that the term "cell" directly relates to biological cells and that these structures therefore have to be alive and, further, that the term "artificial" implies that these structures are artificially built from the bottom-up, i.e. from basic components. As such, in the area of synthetic biology, an artificial cell can be understood as a completely synthetically made cell that can capture energy, maintain ion gradients, contain macromolecules as well as store information and have the ability to replicate. This kind of artificial cell has not yet been made.
Alternatively, the term "artificial" does not imply that the entire structure is man-made, but instead, it can refer to the idea that certain functions or structures of biological cells can be modified, simplified, replaced or supplemented with a synthetic entity.
In other fields, the term "artificial cell" can refer to any compartment that somewhat resembles a biological cell in size or structure, but is synthetically made, or even fully made from non-biological components. The term "artificial cell" is also used for structures with direct applications such as compartments for drug delivery. Micro-encapsulation allows for metabolism within the membrane, exchange of small molecules and prevention of passage of large substances across it. The main advantages of encapsulation include improved mimicry in the body, increased solubility of the cargo and decreased immune responses. Artificial cells have been clinically successful in hemoperfusion.
Bottom-up engineering of living artificial cells
German pathologist Rudolf Virchow proposed that not only does life arise from cells, but every cell comes from another cell; "Omnis cellula e cellula". Until now, most attempts to create an artificial cell have engineered modules that can mimic certain functions of living cells. Advances in cell-free transcription and translation reactions allow the expression of many genes as well as interdependent genetic and metabolic networks, but these efforts are still far from producing a fully operational cell.A bottom-up approach to build an artificial cell would involve creating a protocell de novo, entirely from non-living materials. As the term "cell" implies, one prerequisite is the generation of some sort of compartment that defines an individual, cellular unit. Phospholipid membranes are an obvious choice as compartmentalizing boundaries, as they act as selective barriers in all living biological cells. Scientists can encapsulate biomolecules in cell-sized phospholipid vesicles and by doing so, observe these molecules to act similarly as in biological cells and thereby recreate certain cell functions. In a similar way, functional biological building blocks can be encapsulated in these lipid compartments to achieve the synthesis of artificial cells.
Researchers have proposed creating a phospholipid bilayer vesicle with DNA capable of self-reproducing using synthetic genetic information. The three primary elements of such artificial cells are the formation of a lipid membrane, DNA and RNA replication through a template process and the harvesting of chemical energy for active transport across the membrane. The main hurdles foreseen and encountered with this proposed protocell are the creation of a minimal synthetic DNA that holds all sufficient information for life, and the reproduction of non-genetic components that are integral in cell development such as molecular self-organization. However, it is hoped that this kind of bottom-up approach would provide insight into the fundamental questions of organizations at the cellular level and the origins of biological life. So far, no completely artificial cell capable of self-reproduction has been synthesized using the molecules of life, and this objective is still in a distant future although various groups are currently working towards this goal.
Another method proposed to create a protocell more closely resembles the conditions believed to have been present during evolution known as the primordial soup. Various RNA polymers could be encapsulated in vesicles and in such small boundary conditions, chemical reactions would be tested for.
Ethics and controversy
Protocell research has created controversy and opposing opinions, including critics of the vague definition of "artificial life". The creation of a basic unit of life is the most pressing ethical concern. Synthetic organisms could escape and cause damage to human health and ecosystems, or the technology could be used to make a biological weapon. Cells with certain non-standard biochemistries, such as mirror life, could also have a competitive advantage over natural organisms. Although according to Ting Zhu, "the creation of a mirror-image organism lies well beyond the reach of present-day science".International research community
In the mid-2010s the research community started recognising the need to unify the field of synthetic cell research, acknowledging that the task of constructing an entire living organism from non-living components was beyond the resources of a single country.In 2017 the NSF-funded international Build-a-Cell large-scale research collaboration for the construction of synthetic living cell was started,. Build-a-Cell has conducted nine interdisciplinary workshopping events, open to all interested, to discuss and guide the future of the synthetic cell community. Build-a-Cell was followed by national synthetic cell organizations in several other countries. Those national organizations include FabriCell, MaxSynBio and BaSyC. The European synthetic cell efforts were unified in 2019 as SynCellEU initiative.
Top-down approach to create a minimal living cell
Members from the J. Craig Venter Institute have used a top-down computational approach to knock out genes in a living organism to a minimum set of genes. In 2010, the team succeeded in creating a replicating strain of Mycoplasma mycoides using synthetically created DNA deemed to be the minimum requirement for life which was inserted into a genomically empty bacterium. Proponents suggest that the process of top-down biosynthesis will enable the insertion of new genes that would perform beneficial functions such as generation of hydrogen for fuel or capturing excess carbon dioxide in the atmosphere. The myriad regulatory, metabolic, and signaling networks are not completely characterized. These top-down approaches have limitations for the understanding of fundamental molecular regulation, since the host organisms have a complex and incompletely defined molecular composition. In 2019 a complete computational model of all pathways in Mycoplasma Syn3.0 cell was published, representing the first complete in silico model for a living minimal organism.Heavy investing in biology has been done by large companies such as ExxonMobil, who has partnered with Synthetic Genomics Inc; Craig Venter's own biosynthetics company in the development of fuel from algae.
As of 2016, Mycoplasma genitalium is the only organism used as a starting point for engineering a minimal cell, since it has the smallest known genome that can be cultivated under laboratory conditions; the wild-type variety has 482, and removing exactly 100 genes deemed non-essential resulted in a viable strain with improved growth rates. Reduced-genome Escherichia coli is considered more useful, and viable strains have been developed with 15% of the genome removed.
A variation of an artificial cell has been created in which a completely synthetic genome was introduced to genomically emptied host cells. Although not completely artificial because the cytoplasmic components as well as the membrane from the host cell are kept, the engineered cell is under control of a synthetic genome and is able to replicate.
Artificial cells for medical applications
History
In the 1960s Thomas Chang developed microcapsules which he would later call "artificial cells", as they were cell-sized compartments made from artificial materials. These cells consisted of ultrathin membranes of nylon, collodion or crosslinked protein whose semipermeable properties allowed diffusion of small molecules in and out of the cell. These cells were micron-sized and contained cells, enzymes, hemoglobin, magnetic materials, adsorbents and proteins.Later artificial cells have ranged from hundred-micrometer to nanometer dimensions and can carry microorganisms, vaccines, genes, drugs, hormones and peptides. The first clinical use of artificial cells was in hemoperfusion by the encapsulation of activated charcoal.
In the 1970s, researchers were able to introduce enzymes, proteins and hormones to biodegradable microcapsules, later leading to clinical use in diseases such as Lesch–Nyhan syndrome. Although Chang's initial research focused on artificial red blood cells, only in the mid-1990s were biodegradable artificial red blood cells developed. Artificial cells in biological cell encapsulation were first used in the clinic in 1994 for treatment in a diabetic patient and since then other types of cells such as hepatocytes, adult stem cells and genetically engineered cells have been encapsulated and are under study for use in tissue regeneration.