Re-creation

The modern cell took 3.8 billion years to evolve. Now, scientists are tantalisingly close to recreating the entire process in a test tube. By synthesising and adding different parts of a cell to a basic artificial template, they can be moulded to perform novel functions, potentially revolutionising areas such as medicine, the fuel industry and the environment.

The goal is to create a fully functioning, self-replicating synthetic cell from artificial DNA. It is believed that just 151 genes are required to form the basic template of a self‐replicating cell. Using this basic code, artificially created gene sequences could be added to give rise to a foreign structure - gifting the cell with a novel function.

The first artificial cell was actually created in 1957. The source: the student lodgings-come-lab of an undergraduate called Thomas Chang – then studying at McGill University. It was essentially a small permeable plastic sack, consisting of polymersomes – a synthetic replica of the cell membrane. Importantly, it behaved in much the same way as a natural red blood cell; it could retain haemoglobin - the protein responsible for carrying oxygen. For the last 30 years, scientists have been using gene therapy to modify single genes in existing cells. Using gene therapy to create cells capable of producing novel functions, such as producing oil, would be like trying to modify another artist’s masterpiece; it may interfere with the existing cellular functions. It would be much easier to start from scratch, using an accepted basic cellular structure (a fresh canvas) to which genes coding for different enzymes or proteins (paint) can be added. It would be more flexible and efficient than having to worry whether the cell is compatible.

By producing simple cellular structures and organelles from scratch, scientists have begun to realise how it might be possible to alter cellular function. A significant step towards a self‐sufficient artificial cell was made in 2009 with the creation of an artificial ribosome. The ribosome is where the RNA of a cell is converted into proteins. The ribosome is one of the most conserved and complex cell organelles. The researchers disassembled a ribosome taken from an E.coli bacterium into its constituent molecular parts. From these molecular parts, it was possible to work out a DNA sequence coding for the ribosome. This DNA sequence was then added to a test tube containing the RNA code for luciferase – the enzyme responsible for fireflies’ distinctive glow. The experimenters’ glowing test tube meant that the ribosome must have self‐assembled and then carried out its usual function: converting the RNA message into the luciferase enzyme protein, which was responsible for the glow.
The next step is to find the basic cellular template. This involves stripping cells of any characteristics that may define a particular cell type to give a uniform cell that is still capable of replicating. Even artificial replication maybe a step closer now that researchers at the University of Edinburgh have shown how synthetic heterochromatin – a cellular structure that contains DNA – can be used to initiate the formation of an active centromere, which is required for moving the chromosomes during cell division.

Attempts are already being made at creating the first fully artificial bacterial cell and in essence, synthetic life. A team at the J. Craig Venter Institute have managed to combine, through a series of controlled enzymatic reactions, the four separate DNA bases – A, T, G and C - to create an entire synthetic genome. The genome contains the code for the bacterium Mycoplasma genitalium: a resident of the human genital tract that has one of the simplest genomes. The next step will be to introduce the synthetic genome into a cell, creating a fully artificial bacterial cell.
To get a better understanding of the origin of cellular life, artificial protocells – the precursor to the cell  - are being used to replicate what might have happened. The emergence of a capsular structure, like a protocell, would have allowed molecules to form organised groups for the first time. Scientists hope to use these artificial protocells to simulate the chance processes that resulted in the right combination of molecules coming together and to allow for the extraction of nutrients from the environment and their conversion to energy. It is thought that the evolution of the cell began when several types of these protocells started to compete for limited resources, resulting in the survival of the more metabolically efficient protocells. The accumulation and diversification of cell functions over millions of years gave rise cells that were able to reproduce – the basic requirement for the evolution of the cell. Being able to replicate would have enabled the more successful cells to survive and, over billions of years, produce the variety of cells that we see today.

As genome sequencing projects uncover more and more gene sequences (see the Next Generation Sequencing Focus articles in EUSci Issue 4), the number of artificial sequences and artificial cells that could be created will increase exponentially, providing myriad potential applications for artificial cells. Having a basic core structure of a cell to which new components can be added might enable the creation of cells that could produce large quantities of fuel. By stripping the cell of any unwanted metabolic pathways cells could be designed to produce a particular product without any by-products. By inserting a gene sequence that codes for enzymes that produce biofuels, artificial cells could help alleviate the growing pressure on our fuel reserves. Scientists are already working on synthetic bacteria that can convert crops into fuels such as diesel.
Cells could be used to produce other products too. The Bill & Melinda Gates Foundation have backed a team of scientists at the University of California who are trying to create a cellular anti-malarial drug factory. By combining yeast, E.coli bacteria and synthetic wormwood genes, they may be able to produce large quantities of a potent anti-malarial drug called artemisinin (see page 26).

As well as producing drugs, artificial cells could be useful in drug delivery. Scientists at Nottingham University have created synthetic capsules that mimic the natural cell membrane. Interestingly, these capsules were seen to interact with natural bacterial cells and transfer molecules. By targeting the capsules to carry drug molecules to specific bacteria cells, they could be used as a means of fighting bacterial infections. This way the disease causing bacteria present in the body could be destroyed, whilst leaving normal bacterial flora unaffected. Artificial cells similar to white blood cells have been made that can bind to particular molecular signals present on the surface of cells. Once the cells have bound to their target cell, they release their contents. An exciting possibility for these cells is that they could be used to transport a drug designed to target a specific cell type, such as a tumour cell.

During the 3.8 billion years since the birth of the cell it has developed into an enormous diversity of types with an equally astonishing variety of shared and unique functions; from brain cells to bacteria, each cell is the product of selective pressures refining it to suit its particular environment. Uncovering the genetic code for a basic cellular structure is allowing scientists to synthesise the fundamental requirements for life, which can then be harnessed and extended to perform novel functions. The diversity of cell functions and the possibility of creating new ones, means that the potential benefits of the artificial cell are limited only by our imagination - ironically, the product of another useful set of cells: the human brain.