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Los Angeles Times – Health

3:22 PM, May 29, 2009

Triple Helix: Designing a New Molecule of Life

From the December 2008 Scientific American Magazine

Peptide nucleic acid, a synthetic hybrid of protein and DNA, could form the basis of a new class of drugs—and of artificial life unlike anything found in nature

By Peter E. Nielsen

Key Concepts

• A synthetic molecule called peptide nucleic acid (PNA) combines the information-storage properties of DNA with the chemical stability of a proteinlike backbone.
• Drugs based on PNA would achieve therapeutic effects by binding to specific base sequences of DNA or RNA, repressing or promoting the corresponding gene.
• Some researchers working to construct artificial life-forms out of mixtures of chemicals are also considering PNA as a useful ingredient for their designs.
• PNA-like molecules may have served as primordial genetic material at the origin of life.

For all the magnificent diversity of life on this planet, ranging from tiny bacteria to majestic blue whales, from sunshine-harv­­est­­ing plants to mineral-digesting endoliths miles underground, only one kind of “life as we know it” exists. All these organisms are based on nucleic acids—DNA and RNA—and proteins, working together more or less as described by the so-called central dogma of molecular biology: DNA stores information that is transcribed into RNA, which then serves as a template for producing a protein. The proteins, in turn, serve as important structural elements in tissues and, as enzymes, are the cell’s workhorses.

Yet scientists dream of synthesizing life that is utterly alien to this world—both to better understand the minimum components required for life (as part of the quest to uncover the essence of life and how life originated on earth) and, frankly, to see if they can do it. That is, they hope to put together a novel combination of molecules that can self-organize, metabolize (make use of an energy source), grow, reproduce and evolve.

A molecule that some researchers study in pursuit of this vision is peptide nucleic acid (PNA), which mimics the information-storing features of DNA and RNA but is built on a proteinlike backbone that is simpler and sturdier than their sugar-phosphate backbones. My group developed PNA more than 15 years ago in the course of a project with a rather more immediately useful goal than the creation of unprecedented life-forms. We sought to design drugs that would work by acting on the DNA composing specific genes, to either block or enhance the gene’s expression (the production of the protein it encodes). Such drugs would be conceptually similar to “antisense” compounds, such as short DNA or RNA strands that bind to a specific RNA sequence to interfere with the production of disease-related proteins [see “Hitting the Genetic Off Switch,” by Gary Stix; Scientific American, October 2004].

PNA’s unique properties potentially give it several advantages over antisense DNAs and RNAs, including more versatility in binding to DNA as well as RNA, stronger binding to its target and greater chemical stability in the enzyme-laden cellular environment. Many studies have demonstrated PNA’s suitability for modifying gene expression, mostly in molecular test-tube experiments and in cell cultures. Studies in animals have begun, as has research on ways to transform PNA into drugs that can readily enter a person’s cells from the bloodstream.

In addition to fomenting exciting medical research, these amazing molecules have inspired speculations relating to the origin of life on earth. Some scientists have suggested that PNAs or a very similar molecule may have formed the basis of an early kind of life at a time before proteins, DNA and RNA had evolved. Perhaps rather than creating novel life, artificial-life researchers will be re-creating our earliest ancestors.

Into the Groove
The story of PNA’s discovery begins in the early 1990s. To generate drugs with broader capabilities than antisense RNA, my colleagues Michael Egholm, Rolf H. Berg, and Ole Buchardt and I wanted to develop small molecules able to recognize double-stranded, or duplex, DNA having specific sequences of bases—no easy task. The difficulty has to do with the structure of the familiar DNA double helix.

It is the bases—thymine (T), adenine (A), cytosine (C) and guanine (G)—that store information in DNA. (In RNA, thymine is replaced by the very similar molecule uracil, or U.) Pairs of these bases joined by hydrogen bonds form the “rungs” of the familiar DNA “ladder.” C binds with G, and A binds with T, in what is called Watson-Crick base-pairing. A compound that binds with a stretch of double-helical DNA having a characteristic base sequence would therefore be one that acts on any gene containing that particular sequence of bases on one of its strands.

DNAWellnessInfo.com Resource:  http://www.scientificamerican.com/article.cfm?id=triple-helix-designing-a-new-molecule&ec=su_triplehelix