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# 18.26 Synthetic Biology

It's natural to wonder about the role of chance or contingency in biology itself. Rather than serendipitous, it’s more accurate to say that life on Earth has been very selective. It depends on only two dozen of the elements in the periodic table, works with only one of the two possible orientations ("handedness") of building block molecules, and it uses a single type molecule to code genetic information. It employs only 20 amino acids from among thousands available and ten thousand proteins from among an essentially infinite number that are possible. Are these selections inevitable? Could they have been made differently? How do we begin to examine the sufficient and necessary conditions for life?

One way to answer these questions is through the study of synthetic biology. Steve Benner, a biochemist at the University of Florida, has been thinking about "weird" life for fifteen years. In 1988, as a young researcher, he attempted to organize a conference in Switzerland he called “Redesigning Life.” Senior scientists objected, convinced that the title would lead to riots if people interpreted the title as scientists tampering with nature.The storm abated and the conference proceeded; currently, synthetic biology is a rapidly-advancing field. Benner has made a career of asking deep questions about the nature of life on Earth. He wants to know what aspects of biology are optimal solutions within the constraints of physics and chemistry. He wants to know if our biochemistry contains any relics of experiments much earlier in the history of life. And he wants to know which of life’s features are accidents, where the initial conditions might easily have led to a different outcome.

Scientists like Benner have developed a growing toolbox that allows them to re-engineer microbes. The year after the Swiss conference, he persuaded cellular enzymes to accept an unnatural base pair into their DNA. More recently, Peter Schultz at the Scripps Institute created a molecule called 3-fluorobenzene which forms a base pair with itself rather than needing a partner. Snuck like a Trojan rung into the ladder of DNA, it was readily replicated by polymerases in the cell. These experiments add eight new letters to the alphabet of life. For the first time in four billion years, the syntax of life, which consists of A-T and C-G pairings, has new linguistic possibilities. Tinkering with mechanisms inside a cell is a wide-open landscape with unknown and untamed possibilities. Schultz has figured out how to add nearly 100 unconventional amino acids to the proteins in bacteria. Proteins are the workhorses inside a cell and new proteins will have different functions. A protein is expressed when an enzyme reads the DNA base sequence and transcribes it into RNA. Protein specificity comes from the fact that the transfer RNA recognizes codons (the 64 possible sequences of three base pairs) and the codons map to specific amino acids. Each time Schultz inserted a new amino acid, the protein that was expressed behaved differently.

This research has enormous practical importance. Bacteria can be tweaked to sniff out explosives or neutralize nerve gas. They can be modified to make insulin, or the anti-malarial drug artemisinin, so rare in nature that it’s very expensive to produce. As cells turn into tiny drug factories, it may become possible to treat diseases by fixing defective cell function or promoting the growth of cells that attack intruders.

Tweaking fundamental biochemistry that has been in place for four billion years is radical. An even more audacious approach involves inventing entirely novel tools for the toolbox, or building life from the ground up. In 2000, scientists inserted two devices into the innocuous bacterium E. coli, a bacterium which lives in the human gut. A group at Princeton put together three interacting genes in a way that made the bacteria emit light blink regularly, like Christmas tree lights. Meanwhile, a group in Boston set up two genes to interfere with each other function. In doing so, they created the equivalent of a toggle switch and endowed E. coli with a rudimentary digital memory. Essentially they used a biochemical means to control a set of on-off states as opposed to a semiconductor where the same thing is done with a flow of electrons. It took years to develop these tricks, but MIT biologist Drew Endy foresees a time when manmade biological mechanisms may far outnumber the products of eons of natural selection. Endy is the inventor of BioBricks. They don’t look that impressive—the dozens of vials on Endy’s desk seem to contain only clear, viscous liquid—but they represent a revolution in the making. Each BioBrick is a chunk of DNA that, when inserted into a cell, causes a protein to do something useful. They’re standardized so that they send and receive the same biochemical signals and interact well with each other. Endy and his colleague Thomas Knight have created a registry of 400 different BioBricks, and they make them freely available to other researcher.

Making components for “squishy” computers that work millions of times slower than the silicon kind doesn’t seem very promising, but the eventual goal is to engineer functions into living organisms. The researchers encounter the problem of persistence. Their tiny devices have to work in the busy and messy world of a cell, not in a sterile vial on a lab bench. In the world of the cell, they tend to mutate and break. How far can we take the idea of building life? Eckard Wimmer stunned the world in 2002 when he announced that he and his team had built a live poliovirus from mail-order segments of DNA and a genome map that’s freely available on the Internet. The implications for bioterrorism are obvious — what if someone could synthesize Ebola, smallpox, or anthrax? Even worse, what if synthesized germs could be endowed with resistance to antibiotics? The rate of progress is dizzying. Genome icon Craig Venter put together a virus that infects bacteria. It only took him three weeks to do what had taken Wimmer three years. It’s simply a matter of time before we see bacteria synthesized in the lab.