In the Search for the Essentials of a Minimal Life-form - Learn about the obstacles Venter, Smith and Hutchison faced when they set out to examine what those essential components of life are.

There has always been a small portion of humanity that sought to divest of the clutter and accoutrement of daily life…to reduce their dependence on the vulgar wants and desires of civilized people and live a frugal and minimal life. Monasteries and hermits have been promoting that life strategy for hundreds, if not thousands, of years. In the mid-1800s, Henry David Thoreau certainly argued for such a need in his great work “Walden.” And in our own, more modern world, we can see a similar enticement, or at least vicarious amusement, in the nearly two decades of reality show after reality show in which contestants simulate that very notion of throwing off the vestiges of “stuff” and existing in a bare minimal state for a while.

So what are the barest essentials that you need to survive? I imagine that the answer to that question may have changed considerably over the last 40-50 years. We have grown to depend and “exist” on so many technical wonders and achievements; it’s difficult for many of us now to even conceive of our existence without the devices or tools that seem to be permanently attached to us day in and day out.

Of course, the answer depends greatly on what “life” we’re talking about. Any grade school child will rattle off the requisite “food, water and shelter” line that has been taught for generations. But are those the only essential things needed to live?

hen we think about these questions, we take for granted the building blocks of our bodies; our muscles and bones that let us forage for that ‘food and drink’. We forget about the cells that make up those organs, each one running tirelessly for the duration of our lives; replicating, protecting and building us into who we are. We forget about the DNA that is the building block of all those cells; constantly replicating, editing and self-correcting in order to ensure that we remain who we started out to be.

Then there is the fact that all things fail eventually. We know that viruses invade our DNA and change them, altering the genome into something different, for good or for bad. We know that cells can mutate into cancers or can die off unexpectedly due to illness or disease. Either or both of those things can cause our muscles and bones can become damaged. And without some kind of cellular or genetic treatment, the “essentials” of our lives become very different from what our children are taught in school.

More than twenty years ago, a group of scientists led by Craig Venter, Hamilton Smith and Clyde Hutchison, set out to examine what those essential components of life are and to attempt to create such a minimal life form. And not just for any sort of Frankenstein, monstrous amusement, but in order to solve a problem. The problem is that when we attempt to use cells to help us achieve solutions to problems, in the medical field and so on, those cells come with genetic baggage. We don’t know what that baggage does or whether it will adversely affect our goals. So the baggage has to go. Only, we also don’t know what part of a cell’s genome is baggage and what part is essential. At long last, Venter’s group finally did it, and the science news world literally erupted over their success as reported in the journal Science.

In 1996, Mushegian and Koonin estimated that the “minimum set of necessary genes” for a bacterial cell was close to 260 genes by cross-comparing the miniscule genome of the bacteria, Mycoplasma genitalium (which has only 525 genes) to Haemophilus influenza (which has 1703 genes). Working with that estimate, Venter’s group began to experiment with Mycoplasma mycoides, a bacterium that, while larger than M. genitalium, also replicates faster which makes it easier to research. The idea was to build a bacterial cell that had only the barest essential genes required in order to survive, reproduce and thrive.Certainly, they did not think that it would be as difficult as it turned out to be.

They quickly ran into two key problems: First, there are a LOT of genes which we still do not fully comprehend or even know whether they are essential. How many? Well, it ends up that after all was said and done, we still don’t know what 1/3 of the essential genes that Venter’s final M. mycoides (named syn 3.0) needed.That’s 149 essential genes that we have no idea at all about! Second, life has a habit of enjoying a duplication of effort in order to ensure survival. So if one vital gene gets mutated or truncated, there is a backup to make sure that life goes on. But when screening for essential or nonessential genes, that gives rise to a number of false positives.

If you delete a gene, and the cell continues to survive, you assume that the gene was nonessential. But if you then delete the BACKUP gene, the cell might suddenly die.So which gene was the essential one; the first, the second or both?All of that redundancy took an enormous amount of time to sift through, using a variety of cutting edge Tn5 mutagenesis and DNA synthesis. And there are also the quasi-essential genes. These are genes that aren’t absolutely necessary to survive, but for whatever reason are very necessary if the goal is to grow or reproduce efficiently.

There is also the trade-off between genome size and growth rate.It took the team several rough years to reduce the genome to 516 genes (only nine fewer than the original M. genitalium) and several more to finally reduce the genome to the Syn3.0’s “working approximation of a minimal cell” at 473 genes. So Syn3.0 actually only becomes the compromise between small size and researchable growth rate.

So what makes all of these genes essential? We’re still not sure. To be clear, this isn’t an absolute result. Being essential means different things depending on the environment in which something lives. Certainly, Native Americans in the Amazon jungle have different essential requirements than the Inuit do in the Polar circle. So is the case for bacteria. Free living bacteria require a wider range of redundant and novel genes to cover a wide variety of unknown circumstances. That’s just life. But bacteria such as M. genitalium live in an isolated and closed environment, allowing them to lose genes over time that are no longer necessary to their existence. Put those bacteria into a harsher existence and you’ll probably find that they’re no longer able to adequately cope.

As a species, humanity enjoys priding itself on its adaptability and tenacity under stress. Certainly we have developed ways to survive, and even thrive, under even most of the harshest conditions that we have found on our planet. But at the core of that, we must remember that we do not do it alone. We adapt and thrive based on the DNA, the cells and even the bacteria within us that together allow us to conquer an ever widening arc of unknown circumstances; further proving that “what is essential” is just as elusive an idea as “what is independent”.

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