The Continuing Mystery of Life’s Building Blocks

GARRISON, NEW YORK – Imagine for a moment that you have come across a trove of marvelous devices left by an ancient civilization. These mysterious instruments vary widely in size and complexity, but they all share a few wondrous capabilities.

If you want to understand how they work, it makes sense to start with the simplest and smallest device, then systematically carve off pieces until it stops working. Eventually, everything that is inessential will be gone, and you will be left with only the components necessary for it to perform its basic functions. And then, once you figure out what each of those pieces does, you will have your answer.

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This is roughly the journey of discovery that the American biotechnologist J. Craig Venter and his colleagues have been taking for the past two decades – only their marvelous devices are not archeological remains, but living organisms. And the pieces they are trying to understand are the genes that we share with all other forms of autonomous, reproductive life.

In a recent paper in the journal Science, Venter and his colleagues announced that they had created the smallest living and reproducing organism. Their creation – called JCVI-syn3.0 – is a simple cell, with only the genes that are essential for life; it has a smaller genome than any autonomously replicating organism found in nature, larger only than those found in viruses and other entities that rely on hosts for essential functions.

Venter and his team created their organism through a process of trial and error. They began by using their knowledge of biology to deduce the minimum set of genes that would be required for life. That approach failed.

So, instead, they took an existing organism and began to whittle it down. They started with the genome of Mycoplasma mycoides, a parasitic bacteria that infects cattle and goats, and also a close relative of Mycoplasma genitalium, which has the fewest genes – just 525 – known among free-living bacteria.

The team broke the M.mycoides genome into eight fragments and began deleting genes one by one. If the reconstructed organism failed to thrive, the gene was left in. If it did not appear to matter, it stayed out. In the end, 473 genes were required for the organism to thrive. (Humans, by comparison, have roughly 20,000 genes.)

The most important result of the Venter team’s work was to reveal how little we know about the basic biology of life. Most of the 473 genes take care of housekeeping: They make proteins, keep DNA in good repair, and are responsible for the cell’s membrane and cytoplasm. But there are 149 genes whose function is unknown. In other words, the purpose of nearly one-third of the genes needed to keep the organism alive, well, and reproducing remains a mystery.

Of the 149 genes with unknown functions, 70 have a structure that at least hints at their role in the cell. But we know nothing about the other 79, except that in these organisms, in this environment, life is impossible without them. Moreover, as Venter and his colleagues acknowledge, if the team began with a different microbe, or grew it in a different environment, the set of necessary genes would be different. So their genome is a minimal genome, not the minimal genome.

All of this implies many exciting discoveries ahead. And yet, when it comes to practical, commercial objectives, the news is considerably more sobering.

One of the primary goals of synthetic biology has been to create a platform, or chassis, to use as a foundation for building organisms designed for specific tasks. Just as Volkswagen uses its A5 platform to build 19 different vehicles, from luxury Audi A3s to small SUVs and budget models, a biological chassis would be a minimal microbial platform onto which could be bolted genetic instructions to make drugs, biofuels, cosmetics, or whatever one desires.

With the publication of the Science paper, two challenges become evident. The first is that biology is complicated. As Venter’s work shows, we do not yet have a sufficient grasp of the essentials of basic biology to design and build a cell. Genes do not function like fenders or brakes; they cannot be mounted on a chassis to perform a function independently of other components. Genes interact – amplifying, dampening, or even silencing one another. And those effects, in turn, influence still other genes.

Genomes, it turns out, function less like machines than like ecosystems with multitudinous relationships and complex feedback loops. Adding genomic parts to a synthetic organism in order to achieve a predictable result may be far more difficult than proponents of the chassis model have assumed.

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The second challenge regards the competition. When Venter and his team began their effort, genetic engineers had tools that were powerful but, by modern standards, crude. In recent years, scientists have found ways to edit genes with far greater precision. The most prominent, known as CRISPR Cas9, cuts DNA with remarkable (though not perfect) accuracy. As a result, gene editing has emerged as an alternative strategy to the chassis model for tailoring microbes to make useful products.

It is impossible to know whether synthetic organisms like Venter’s JCVI-syn 3.0 or gene-editing techniques will prove to be commercially dominant in biotechnology – or indeed whether some other method will supplant both. We can be confident, however, that our knowledge of basic biology will deepen, and that our growing ability to manipulate living organisms will confront us with increasingly serious ethical considerations.