The holy grail of synthetic biology involves the manufacture of biomimetic artificial life that subsists on a vastly reduced genome compared to its native counterpart. In the present study, researchers successfully develop a minimalized synthetic cell that can divide and replicate uniformly providing tantalizing incites into the ingredients of life.

The desired outcome of the burgeoning field of synthetic biology involves the construction of artificial biological cells and systems that mirror their native counterparts in every way. These synthetic cells would do everything their natural counterparts can do yet operate with a fraction of the DNA code in a process known as minimalization. This process involves the identification of specific genes and their functions. Subsequently, any genes that are not crucial to the desired function or programming of the cell are ‘weeded’ out. Theoretically, this could lead to the creation of new autonomous lifeforms that have been streamlined down to their bare genetic components.

Once the minimalization of artificial cells and systems has been mastered researchers hope to program synthetic cells to perform a range of desired applications. These could include tiny computers that act as nanoscale drug factories or health sensors detecting and treating disease while inside the body. However, learning what each gene codes for is a laborious task involving the removal and addition of specific genes to create a synthetic genome that behaves normally. So far, this feat has never been achieved.

A synthetic cell that can divide and replicate uniformly

Now, a study from researchers led by NIST engineers a cell with a minimized synthetic genome that grows and divides normally. The team states they identified the nominal number of genes required for their cell to divide uniformly, in a step toward understanding the very basis of evolutionary biology. The study is published in the journal Cell.

Remarkably, in 2010 the lab constructed the first known cell with a synthetic genome. They accomplished this by stripping a bacteria called a mycoplasma of its DNA and replacing it with an artificial genome which they dubbed JCVI-syn1.0. This was the world’s first organism to have an entirely synthetic genome. Since then, the very same team has been working to minimalize the genome of their exobiologic down even further.

Five years ago, they achieved this by creating a single-celled synthetic organism that, with only 473 genes, was the most fundamental living cell at that time. However, this artificial cell, dubbed JCVI-syn3.0, behaved strangely when growing and dividing, producing aberrant cells of different shapes and sizes. The scientists, therefore, needed to rectify this deviation by establishing the key genes crucial for cell division. The current study identifies 19 genes that needed to be reintroduced into their artificial cell. The genes included the seven essential for normal cell division, creating a new variant dubbed JCVI-syn3A. 

A new technique to image ‘live’ artificial cells dividing

The present trial saw the group engineering dozens of different genomic versions of their artificial cell. They accomplished this by methodically adding and removing genes to provide a variant that divided normally. They were able to observe the diversified variants via a microfluidic chemostat, a liquid culturing and imaging system similar to an aquarium. It is in this way the cells were kept alive under a light microscope which videoed each variant division after a certain gene had either been added or subtracted.

In short, the new imaging technique allowed the scientists to video and observe how their genetic manipulations affected cell growth and division. Thus, if removing a gene disrupted the normal process, they’d replace it and remove another one. Accordingly, countless videos were produced showing how the resultant artificial strains grow and divide each time a gene is painstakingly added or subtracted. To illustrate, one set of videos recorded the variant cells created five years ago, JCVI-syn3.0, dividing aberrantly. As a result, these videos evidenced the synthetic cells forming filaments whilst others did not fully separate, forming a string of conjoined cells.

Consequently, there were many different configurations of cell division caught on video despite the fact the cells were all genetically identical. That was until 19 genes were selected to produce the variant JCVI-syn3A which sired cells that divided uniformly. The genes were not previously retained in the JCVI-syn3.0 variant.

Mapping the building blocks of life itself

Using this microfluidic chemostat the group plan to map the action that every gene codes for to build a step-by-step instruction manual of how a native cell works. However, there is a long way to go before this meticulous task is accomplished. As an illustration, only two of the seven genes reinstated back into this artificial organism for normal cell division have been identified. At this time, the roles that the other five play in cell division are still unknown.

The team surmises they have engineered an artificial cell that grows and divides uniformly while retaining a minimalized genome. For the future, the researchers state that synthetic cells using the most efficient configuration of their genome offer a platform to clarify genes underlying core physiological processes, proffering the ingredients of evolution itself.

Source: National Institute of Standards and Technology (NIST) 

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