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Book Excerpt from Future Science: Essays From the Cutting Edge

In an essay entitled "Molecular Cut and Paste: The New Generation of Biological Tools," virologist William McEwan envisions a future where viruses are reprogrammed to become the workhorses of science and medicine.

By | October 1, 2011

VINTAGE, AUGUST 2011

This afternoon I received in the post a slim FedEx envelope containing four small vials of DNA. The DNA had been synthesized according to my instructions in under three weeks, at a cost of 39 U.S. cents per base pair (the rungs adenine-thymine or guanine-cytosine in the DNA ladder). The 10 micrograms I ordered are dried, flaky, and barely visible to the naked eye, yet once I have restored them in water and made an RNA copy of this template, they will encode a virus I have designed.

My virus will be self-replicating, but only in certain tissue-culture cells; it will cause any cell it infects to glow bright green and will serve as a research tool to help me answer questions concerning antiviral immunity. I have designed my virus out of parts—some standard and often used, some particular to this virus—using sequences that hail from bacteria, bacteriophages, jellyfish, and the common cold virus. By simply putting these parts together, I have infinitely increased their usefulness. What is extraordinary is that if I had done this experiment a mere eight years ago, it would have been a world first and unthinkable on a standard research grant. A combination of cheap DNA synthesis, freely accessible databases, and our ever-expanding knowledge of protein science is conspiring to permit a revolution in creating powerful molecular tools.

Nature is already an expert in splicing together her existing repertoire to generate proteins with new functions. Her unit of operation is the protein domain, an evolutionarily independent protein structure that specializes in a particular task, such as an enzymatic activity or recognition of other proteins. We can trace the evolutionary descent of the protein domains by examining their sequences and grouping them into family trees. We find that over the eons of evolutionary time the DNA that encodes protein domains has been duplicated and combined in countless ways through rare genetic events, and that such shuffling is one of the main drivers of protein evolution. The result is an array of single- and multidomain proteins that make up an organism’s proteome. We can now view the protein domain as a functional module, which can be cut and pasted into new multidomain contexts while remaining able to perform the same task. This modular capability immediately lends itself to engineering: we don’t have to go about finding or artificially evolving a protein that performs our chosen task; we merely combine components that together are greater than the sum of their parts.

I’m interested in the defense mechanisms within cells—mechanisms that specifically recognize and disable intracellular pathogens. This type of defense is considered separate from the two main branches of immunity that are more intensely studied: the evolutionarily ancient “innate” immune system and the vertebrate-specific “adaptive” immune system. Innate immunity is the recognition of conserved features of pathogens—for example, the detection by specialized cells, such as macrophages, of the sugary capsule that surrounds many bacteria. Adaptive immunity works by fielding a huge diversity of immune recognition molecules, such as antibodies, and then producing large quantities of those that recognize nonself, pathogen-derived targets. The newly discovered kind of immunity on which I work, sometimes termed “intrinsic immunity,” shares features with innate immunity but tends to be widely expressed, instead of residing just within “professional” immune cells, and is always “on.” In other words, every cell in an organism is primed and ready to disable an invading pathogen. The intrinsic immune system is at a strategic disadvantage, as its targets are often fast-evolving viruses that can rapidly mutate to evade recognition. Unlike the adaptive immune system, which can quickly generate a response to an almost infinite diversity of targets, the intrinsic immune system must rely on rare mutations and blind selection over evolutionary time to compete with its opponents. . . .

Reprinted from Future Science: Essays From the Cutting Edge, edited and with a preface by Max Brockman © 2011 by Max Brockman. Used with permission of the publisher, Vintage Books.

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