A pioneering accomplishment in the field of genetic research could help scientists gain new insights into the very definition of life. The new research, published Thursday in the journal Science, describes the synthetic creation of a “minimal genome” — a cell containing only the genes absolutely required to keep itself alive.
With just 473 genes, it’s the smallest genome of any living, dividing cell found in nature and may provide important insights into the fundamental genetic requirements for life.
The idea of designing and studying a “minimal genome” is a concept that’s fascinated scientists for decades. In fact, unlocking the secrets of the genome has been a preoccupation of genetic researchers since the first genome sequencing was performed on a bacterium in 1995 — the event that ultimately led to this week’s breakthrough, according to the new study’s authors.
“This is a study that had its origins a little over 20 years ago in 1995, when this institute sequenced the very first genome in history, Haemophilus influenzae,” said the new paper’s senior author J. Craig Venter, founder of the J. Craig Venter Institute, which specializes in genomic research, during a Wednesday teleconference.
Later that same year, the institute also sequenced the genome of a second type of bacteria, Mycoplasma genitalium. These breakthroughs allowed for the first genomic comparisons between two different species, Venter said.
Venter is most famous for his role as a leader of the team that first sequenced the human genome in 2000.
“[My colleagues] and myself were discussing the philosophy of these differences in the genomes and decided the only way to answer basic questions about life would be to get to a minimal genome, and probably the only way to do that would be by trying to synthesize a genome,” Venter said.
“And that started our 20-year quest to do this.”
The reason that researchers must synthesize, or essentially design their own, minimal genome is because just about every living organism we know of contains more genes than are actually necessary for its basic survival. Even the simplest bacteria contain extra, nonessential genes that are related to its growth, development and ability to react to its environment, but that aren’t technically required to keep the cell alive.
So in order to get down to a truly minimal genome, scientists must take an existing genetic sequence and pare it down themselves, cutting away all the nonessential genes until they end up with only the ones that are absolutely essential.
They do this by creating synthetic genomes — genomes that are designed and chemically built from the ground up using our existing knowledge of an organism’s genetic information.
Along the way, scientists can add or delete genetic information as they see fit. It’s the same basic principle that’s used in genetic engineering research. But in the case of a minimal genome, the goal is to slice off as much unnecessary genetic information as possible without changing or adding anything else to the organism’s genome.
And that’s just what Venter and his colleagues set out to do.
They started with the genome of a type of bacteria known as Mycoplasma mycoides, a parasite normally found in cows and goats. In 2010, the group succeeded in building the complete M. mycoides genome from scratch and transplanting it into another cell.
This time around, they used a variety of methods to whittle the genome down before transplanting it.
To start, the researchers divided the bacterium’s genome into eight different segments that could be individually altered and tested — just to make the experiments a little more manageable. They then applied a handful of techniques to peel away the nonessential genes.
They call this their “design-build-test” approach.
First, they applied their basic knowledge of genetics and biochemistry to infer which genes might be safe to remove — but this technique did not produce viable cells.
The researchers then conducted a series of experiments in which they inserted bits of foreign genetic information — called transposons — into the genome in order to disrupt the functions of certain genes and figure out which ones the cell could do without. This process helped them whittle down the genome until no more genes could be removed.
Along the way, the researchers were able to divide the bacterium’s genes into three major categories: essential, nonessential and quasi-essential, meaning they weren’t absolutely required for life but were necessary to help the cell grow at a healthy pace.
It allowed them to discover how much we don’t know, even about the core sections of the genome
Venter and his colleagues also discovered that the genome contained a number of redundant genes — pairs of genes that performed the same function in the cell. These genes made the whittling process a little confusing at first — if one of the redundant genes was removed (but not the other), the cell would continue functioning, tricking the researchers into believing it was a nonessential gene.
A great deal of trial and error was required in order for the researchers to classify all the genes.
Finally, though, they reached a point where no more genes could be removed without killing the cell.
The result is the smallest genome ever recorded in a self-replicating — that means alive and able to divide — cell. It contains just 473 genes, all of which are either directly required to keep the cell alive or to enable it to grow and divide fast enough to be practical for the researchers’ experiments.
Interestingly, about a third of the resulting genome consists of genes with unknown biological functions. Most of the known essential genes perform functions related to expressing genes, passing down genetic information from one generation to the next, or performing essential functions in the cell’s membrane and cytosol, so the scientists predict that the unknown genes will have similar jobs — we just don’t know what yet.
“One of the great findings but also the great caveats of this work is that it allowed them to discover how much we don’t know, even about the core sections of the genome,” said Adam Arkin, director of the Synthetic Biology Institute at the University of California Berkeley, in a statement.
That said, Venter also noted that the concept of a minimal cell is context-dependent.
The specific genes that an organism requires to survive — even an organism as simple as a bacterial cell — depend on what kind of environment the cell is living in and what kinds of nutrients are available to it.
And, of course, one species’ minimal genome would likely differ significantly from that of another species.
With that in mind, exploring different forms of minimal genomes could have important industrial applications, said Daniel Gibson, another of the study’s authors and another scientist at the J. Craig Venter Institute, during the same teleconference.
Because these cells are so simple, devote all their energy to essential functions and are subject to very few genetic mutations, they are “straightforward to engineer” and could provide helpful insights into more complex types of biosynthesis in the future, he said.
Still, there’s plenty of work left to be done before the study of minimal genomes may yield practical applications.
“The major limitation is that this is the beginning of a very long road,” said Sriram Kosuri, an assistant professor of biochemistry at UCLA, in a statement.
“It's not as if this new minimal genome will automatically lead to either fundamental insights or industrial applications immediately. That said, they've created a self-replicating biological organism that might be a better starting point for such scientific and engineering goals than continuing to study natural systems."