This may be life at its simplest: a bacterium that’s been designed and brought to life in the lab, containing a minimal genome with only the genes necessary for life.
And that’s just 473 genes.
The synthetic bacterium, dubbed Syn 3.0, has a smaller genome than that of any organism so far found in nature, and is described today in the journal Science by genome sequencing pioneer J. Craig Venter and his colleagues.
“We decided the only way to answer basic questions about life would be to get to a minimal genome. And that probably the only way to do that is by trying to synthesize a genome, and that started our 20-year quest to do this,” Venter, founder of J. Craig Venter Institute in San Diego, said in a press conference on Wednesday.
The sleek genome of Syn 3.0 could provide a platform for scientists to study the genes behind the basics of life, and investigate other genes by adding them back into the cell and watching the effects.
Humans have about 20,000 genes. The record for highest number of genes goes to water flea species Daphnia pulex, which has nearly 31,000 genes. Syn 3.0 now holds the record on the other end of the spectrum, beating previous low-record-holder Mycoplasma genitalium (525 genes), which is found in the urinary and genital tracts of humans.
Syn 3.0 is not the first synthetic life form born in the lab. In 2010, Venter and colleagues built Syn 1.0 by stitching together human-made nuclei bases (adenine, cytosine, guanine and thymine) and creating a synthetic genome resembling that of the bacterium Mycoplasma mycoides, a parasite that infects cows and other ruminants. Once the synthetic genome was inserted into an existing cell that was stripped off of its DNA, the cell booted up and started making proteins and dividing. Syn 1.0 was an almost exact copy of the natural M. mycoides genome, save for a few watermark sequences added in, which read quotes like Richard Feynmann's “What I cannot build, I cannot understand.”
But to understand what many of these genes actually do, the team decided to strip genes from Syn 1.0 one by one to find the simplest genome that could still sustain life. This trial-and-error process weeded out genes that had either nonessential or redundant functions, reducing Syn 1.0’s 901 genes to about half.
This small, streamlined genome is still full of mysteries—the function of one-third of these genes is still unknown.
“Knowing that we are missing a third of our fundamental knowledge is a key finding,” Venter said.
WHAT IS LIFE?
There isn’t a clean-cut, universally agreed-upon answer to this question. But some criteria for considering an organism alive include the ability to carry out homeostasis, metabolism, and self-replication.
Cells are basic units of life, operated by a genome, which contains instructions for functions common to all forms of life. But each genome also contains additional instructions specific to the species. For example, typical bacteria such as Bacillus subtilis and Escherichia coli carry between 4000 and 5000 genes. Many of these genes enable the bacteria to be highly adaptable and thrive in diverse environments.
But some bacteria are simpler. One idea for finding the code behind the universal core functions has been to sequence the genome of the simplest known cells. In 1995, Venter and his team sequenced the genome of M. genitalium. Even with the sequence in hand, deciphering the operating system of the cell was a daunting task, the researchers said.
Eventually, the team decided to make a genome from scratch, copying M. mycoides (which has more genes than M. genitalium but grows much faster) and ultimately Syn 1.0 was born.
Syn 1.0 had 901 genes—obviously many more than what a cell needed in order to simply live. The researchers divided the genome into eight segments, so they could eliminate chunks of DNA in each part and put it back into the genome to see if the cell still worked. A couple of hundreds of combinations later, Syn 3.0 was created.
The new genome is not the absolute minimum possible, because the researchers kept some genes that seemed necessary for fast growth. “It had to grow at a sufficient pace to be a good experimental model,” Venter said. “When we used to work with M. genitalium, a typical experiment took three months.”
Moreover, other variations of minimal gene sets are possible. “Every genome is context specific. It depends on the chemicals in the environment it has available to it,” Venter said. “There's no such thing as a true minimal genome without defining the context.”
LIFE OUTSIDE THE LAB
The minimal genome may provide insights to the earlier steps in evolution, when different components came together to form basic self-replicating cells. Moreover, cells with minimal genomes could show uncommon processes that might have been typical in early evolution.
In Syn 3.0’s genome, the genes are grouped based on the various biological functions they are involved in and the groups are reorganized, in the same way that files are defragmented on a hard disk. Those that repair DNA, for example, sit together in one group, and those that build cell membrane in another.
Hutchison et al. in Science
The most important task for scientists would be to find the function of those 149 genes that remain unknown.
In the past, researchers have tried to make a minimal genome by relying on previous knowledge about what genes do and putting those genes together. But this method didn't create a living cell. The likely explanation is that many genes that we don't know about (as Syn 3.0 highlights) were not included in the recipe, but were essential for the cell to function.
The success in creating a living cell in this study suggests that sometimes synthetic biology may be a more fruitful approach than hypothesis-based method, Steven Benner of the Foundation for Applied Molecular Evolution told mental_floss.
“Existing theory about what genes are essential for life was not adequate to get a viable cell. Thus, to get a viable cell, here the researchers turned to synthetic biology and made discoveries about many essential and semi-essential genes that we did not know about," Benner said.
Simply put: Don't start with a hypothesis. Just start tinkering with the genes and see what happens.
In theory, it’s possible to add more genes to the set and create more complex organisms with higher functions.
“Our long-term vision has been to design and build synthetic organisms on demand, where you can add in specific functions and predict what the outcome is going to be,” said study co-author Daniel Gibson, an associate professor at J. Craig Venter Institute.
Unlike its predecessor, Syn 3.0’s genome doesn’t include watermark sequences in form of Easter egg philosophical quotations. “For Syn1.0 it was essential to watermark those cells in order to distinguish them from naturally growing Mycoplasma mycoides,” Gibson told mental_floss. “It was less critical for Syn 3.0, because it’s so unique, and there is no single genome sequence like it.”