Designing self-replicating cells one gene at a time and solving the mystery of the origins of life

Meet JCVI-syn3A, the world’s first self-reproducing synthetic organism.  This tiny little microbe was designed by trial and error in a lab and is capable of both maintaining its own internal structure and creating copies of itself, just like a real cell.  The implications for medicine and our understanding of ourselves are, needless to say, enormous.

Scientists at the Cellular Engineering Group at the National Institute of Standards and Technology announced a major breakthrough in our ability to literally design life itself last week:  They’ve created the world’s first perfectly replicating synthetic cell, that is a designer organism that both manages its own internal metabolism and can replicate itself.  The tiny bacterium goes by the rather technical name, JCVI-syn3A, and is an “upgrade” (for lack of a better term) to another designer organism created in 2016, JCVI-syn3.0.

The new bacterium’s “ancestor,” again for lack of a better word, was able to manage its metabolism and build proteins, plus replicate its own DNA, but creating copies of itself were beyond its meager capabilities.  When it would attempt to do, the copies would take a wide variety of shapes and sizes.  The new version solves that problem by adding more genes to the synthetic cell.

Our attempts to design a life form actually begin back in 1995, when a team led by genomics entrepreneur J. Craig Venter started working on a sexually transmitted microbe, Mycoplasma gentalium which has the smallest genome of any living organism, 470.  By comparison, the common E. coli bacteria has 4,000 and our own cells have between 20,000 and 25,000.  At the time, the technology didn’t exist to construct genes from scratch.  Instead, the team pursued a trial and error process.  First, they mapped all 470 genes, then they started deactivating them one-by-one to determine which are critical to the functioning microbe.  They identified 375 genes as essential, literally adding a watermark to the others indicating they were not required.

From there, they set out to build these genes from scratch, rather than just turn off existing ones.  The technology at the time didn’t exist and it wasn’t until 2008 that they were able to move ahead.  Then, they further refined this process, even switching out the underlying bacterium for a faster growing and replicating variety, and ultimately unveiled the JCVI-syn1.0 cell in 2010, hailing it as the dawn of synthetic life.  The news was so controversial that then-President Barack Obama launched a bioethics review and even the Catholic Church got involved, questioning the claim that man had created life.

The 1.0 organism still had a copied genome rather than an actually designed one, and the genome itself had grown to 1,000,000 DNA base pairs, far more than what was considered a minimally viable number.  The team continued its efforts until finally unveiling 3.0 in 2016.  The number of base pairs in 3.0 was almost cut in half to 531,000 and the 473 genes were all that were required.

Amazingly, even then there remained 149 genes with an unknown purpose, some of which are shared in other organisms — including humans.  Venter said “We don’t know about a third of essential life, and we’re trying to sort that out now.”  Another colleague, Martin Fussenegar with the Swiss Institute of Technology remarked, “We’ve sequenced everything on this planet, and we still don’t know 149 genes that are most essential for life!  This is the coolest thing I want to know.”

The newly upgraded synthetic cell capable of reproduction also begins its life as a sexually transmitted bacteria.  The scientists can now remove the existing organism’s DNA and replace it with designer code, this time with 491 genes, meaning the difference between the two man-made cells is only a total of 19 genes, 7 of which are required for replication.

While the scientists believe these seven genes likely act on the cell membrane itself, ensuring it is flexible enough to divide properly or by generating forces against the membrane that cause it to split, the team has yet to discover the specific mechanisms involved.  “Our study was not designed to figure out the mechanisms inside of the cell associated with each of these genes of unknown function,” explained Elizabeth Strychalski, the leader of the current research team. “That’s going to have to be a future study.”

That these breakthroughs are largely still the result of trial and error, and we’ve not yet reached the point where you can type the gene you want into a computer and some biological version of Google Translate creates the organism, shouldn’t detract from the amazing feat the team achieved.  “There’s just so many ways in which this coming century of biology could potentially change our daily lives for the better,” said Strychalski.

The ability for scientists to engineer what are essentially microscopic, self-reproducing robots has almost limitless potential, from healthcare to the environment.  Up next for the team is to turn these simple cells into living sensors that can take measurements from their environment. “One vision is that when the cell senses a disease state, then it can make that therapeutic, and when a disease state is longer there, they could stop making that therapeutic,” Strychalski said.  Peeking even farther into the future, the cells could be used to produce food and fuel, or even perform computations at a molecular scale.  While these advances are likely years away, the building blocks are now coming into place:  Designer cells, self-replicating organisms, and a continuing mastery of the genetic code.

The implications for our continued understanding of evolution in action are also pretty astounding.  Though we do not yet know the exact mechanisms supported by the seven additional genes, the relatively small number that separate a self-replicating entity from a non-self replicating one are a startling finding on their own.  Simply put, there isn’t a lot of “code” in a handful of genes, meaning we’re once again witnessing how relatively small changes in DNA have huge effects.

In this case, the literal difference between life and death.  The origin of the original replicator has long been one of evolution’s greatest mysteries; research such as the minimal amount of DNA required to sustain both metabolism and replication can allow us to peer even further back into the past.  Recently, we’ve learned that scientists have rediscovered the work of a Hungarian biologist, Tibor Gánti, who proposed a model for the origin of life in 1971.  He called the simplest form of life a chemoton, positing that it contains only “genes, metabolism, and membrane,” and doesn’t require the complex enzymes that facilitate more sophisticated chemical pathways.

The question becomes:  How close is our synthetic cell to a potential chemoton?

Unfortunately, I was unable to determine a precise answer, though I suspect we must be tantalizingly close.  First, the cells are using DNA, which obviously arose later much later than any hypothetical chemoton, and it’s unclear what it would take to get something like this to work with an RNA gene-model or even something simpler.  Also, it’s unclear from the publicly available reporting whether or not the genes currently used encode for any enzymes.  Though the genes don’t support any truly complex behaviors like hunting and eating, and are mostly devoted to building the basic proteins and copying DNA, we still don’t know what almost 200 genes do and anything is possible.

At the same time, is there any doubt we will be able to answer this question very soon?

The scientific world is rapidly converging on breakthroughs unimagined just a couple of decades ago.  Between mRNA technology that allows us to insert instruction sets into our own cells and the creation of synthetic self-reproducing cells, both powered by the explosion of computing power, it seems clear we are poised to learn more about the origins of life than anyone thought possible.

This knowledge could extend far deeper than you think.  Although these organisms and the mRNA are synthetic, they can both use real genes.  These real genes must’ve arisen naturally through evolution, however long ago.  For example, if a gene in the original Mycoplasma gentalium is shared with humans it is likely it arose longer than 2.7 billion years ago, when the prokaryotic cells that survive today as bacteria (and other microbes) split from the more complicated eukaryotic cells that make up all plants and animals. 

You might find it doubtful that we can make any assumptions about what might or might not have happened eons in the past, but genes are like computer code:  They work or they don’t.  They work when the sequence of information that assembles the proteins and other molecules that build and manage our bodies is preserved over time.  This means that many of the basic building blocks of life are unchanged from generation to generation, however far you go back into the past.

Otherwise, these genes would have to have evolved separately in the exact same way across multiple lineages.  Mathematically this is possible, but it rarely happens because the odds are incredibly low.  Even if this particular gene happened to have arisen separately, there will be others that didn’t.  The key is to find them and map them.  The combination of trial and error and synthetic genes is a critical breakthrough in this process:  Scientists can determine whether or not a gene is essential to basic processes like replication, and then look for that gene in the real world.

When they find it, they can compare it across a wide variety of organisms, from simple bacteria to our own bodies.  The more widely the gene is shared, the older it is.  The more genes we find, the more likely we will be able to look further and further back in time.  Therefore, it’s only a matter of time before we build a true chemoton, and understand exactly what it takes to support a minimally viable form of self-replicating life.

To call this a breakthrough would be the understatement at the century.  Darwin first proposed his theory of evolution in 1859.  At the time, they didn’t even know what genes were or how hereditary information was transmitted from generation to generation.  This would not become known until Watson and Crick identified the structure of DNA in 1953. Less than 70 years later, we are close to unlocking the fundamental mysteries of life.

One thing is for sure: This little microbe, JCVI-syn3A, needs a much better name. Does anyone have any ideas?

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