Genome Mining Technique Furthers Biologic Discovery

A newly developed method for microscopically extracting, or “mining,” data from genomes could represent a considerable boost in the search for new therapeutic drugs and improve the understanding of basic functions such as how cells communicate with one another.

Analyzing marine and terrestrial samples obtained from Alaska to San Diego’s La Jolla Cove, a research technique jointly created by scientists from the University of California San Diego (UCSD) Scripps Institution of Oceanography (La Jolla, USA) and Skaggs School of Pharmacy and Pharmaceutical Sciences at UCSD (CA, USA) and their colleagues taps powerful laboratory instruments to trace promising chemical compounds back to their genomic roots. The study’s findings were published the October 9, 2011, online publication of the journal Nature Chemical Biology.

Graduate student Roland Kersten developed a technique that utilizes mass spectrometry, a mass-analyzing application that decodes the composition and size of molecules, to reveal core structural features of genomes. “With only very small amounts of crude sample material, the mass spectrometer is able to fragment the unknown peptide into individual amino acid building blocks, so we can then map those to the genome level,” said Dr. Kersten, who works jointly in Dr. Pieter Dorrestein’s laboratory at the School of Pharmacy and Dr. Brad Moore’s lab at the Scripps Center for Marine Biotechnology and Biomedicine. “That provides us information about how to reassemble the molecule.”
Knowing such details through this genomic mining approach gives scientists a way to connect the natural chemicals generated by organisms back to the enzymes that construct them. These biosynthetic pathways are considered very valuable data in the search for new pharmaceuticals to treat diseases.

Using the new method, the scientists have already discovered two new classes of peptides, compounds comprised of amino acids that serve in functions ranging from communication to protection. “This represents a paradigm shift in the way that natural products are discovered and characterized, and it’s fundamentally different than what’s been practiced for the past decades in this field,” said Dr. Moore, a professor at Scripps and the Skaggs School of Pharmacy and Pharmaceutical Sciences at UCSD. “This has the capability of really changing the way natural products, or simply chemicals, are discovered in nature.”

The researchers are working on ways to automate the process to analyze biological samples faster. They believe the new technique will streamline the discovery of promising natural products. “We’re trying to bring up the speed of discovery in chemistry,” said Dr. Moore. “There’s a huge amount of information that’s out there and we are only scratching the surface-we’d like to dig a little deeper.”

“My UC San Diego colleague Bill Gerwick often states that natural products are a part of central dogma following DNA, RNA and proteins,” said Dr. Dorrestein. “I agree with Bill, natural products and related chemistries control biology yet these molecules are difficult to characterize. The tools for characterizing the molecules that control biology have not kept pace with modern science. The thought process introduced in this manuscript provides the foundation for finally bringing the fourth branch of central dogma into the realm of modern life sciences.”

Related Links:
Scripps Institution of Oceanography
Skaggs School of Pharmacy and Pharmaceutical Sciences