Just under 3 years ago, scientists published the first complete maps of the human genome, the paired strands of deoxyribonucleic acid (DNA) that direct the development of every human cell. With these maps, scientists have already begun tightly focused investigations to pinpoint how each of the genome's 30,000 individual genes and its products—proteins or lipids—influence health and disease. NIDA is actively pursuing investigations in the emerging fields of genomics, proteomics, and lipidomics, which promise to reveal the molecular bases of drug responses and thereby open a new era of targeted, potentially individualized approaches to treating drug abuse and addiction.
Genomics
NIDA has initiated a public-private partnership through which drug abuse researchers will search the genome for gene variations that may affect vulnerability to nicotine addiction. The researchers will begin by studying associations between gene variations called single nucleotide polymorphisms (SNPs), smoking, and responses to nicotine. SNPs can be thought of as single-letter substitutions in the 3-billion-letter instructions of the human genome; for example, the sequence "CCAGTCA" may be changed to "TCAGTCA." More than 99 percent of such SNPs appear to make no significant biological difference, but others may alter cell functions in ways that influence a person's susceptibility to addictive drugs.
To begin, NIDA-supported researchers at Washington University in St. Louis will use a library of 1.5 million SNPs, developed by Perlegen Sciences, Inc., of Mountain View, California, to analyze genetic samples from 500 people with nicotine addiction and 500 who have smoked but have not become addicted. The researchers expect that their first sweep through Perlegen's library will yield 40,000 SNPs that appear in the genome of addicted smokers but not unaddicted smokers. Further screening will narrow the search to a few hundred, and, among these, the investigators hope to identify specific gene variations that contribute to nicotine addiction.
Proteomics
Identifying addiction-related sites on the genome is a daunting analytical task, but it is only a first step. The instructions encoded in a gene guide the assembly of amino acids that, in turn, combine in large complex molecules called proteins. While the genome remains unchanged throughout life, the proteome—the complete inventory of proteins in all cells in the —is dynamic, constantly changing as proteins are assembled or broken down in chemical interactions that are the molecular mechanisms of health and disease.
NIDA has initiated a research effort that will use proteomics, the exploration of the structure and function of proteins, to help reveal step-by-step molecular activities that enhance or inhibit the effects of addictive drugs. Under an initiative launched in 2004, investigators at Yale University and the University of Illinois will inventory and examine proteins in the brain. This effort will identify which proteins are present and active, but it will be far more than a mere catalog of neuroproteins: It will reveal how the proteins—such as those that act as receptors and transporters for chemical messengers like dopamine or serotonin—and their interactions change over time in healthy brains and in those affected by addictive drugs. This knowledge, in turn, will help us develop treatments that might prevent, reduce, or reverse the impacts of addictive drugs.
Lipidomics
More fully understanding the actions of proteins will require intensified study of still other biological compounds—the 1,000 or more chemical molecules called lipids, which include fatty acids that store energy, sterols such as testosterone and estrogen, and amides, which serve as chemical messengers. NIDA-supported researchers were among the first to study the role of lipids, in investigations that identified anandamide, a lipid that occurs naturally in the human and plays a role in obesity, pain, and immune response. Increasing interest in these versatile molecules has led to the emergence of a research discipline called lipidomics.
NIDA has nurtured lipidomics with direct support for researchers and by convening symposia to summarize progress and generate goals and strategies for the next research phase. In 2004, NIDA sponsored the first international lipidomics conference (see "NIDA-Sponsored Conference Highlights Intensive Research Focus on Lipids," NIDA NOTES, Vol. 19, No. 5). NIDA also organized lipidomics symposia at the meetings of the College on Problems of Drug Dependence and the International Cannabinoid Research Society. NIDA's direct contributions, including specific research support of lipidomics in its neuroproteomics research applications, will help elucidate the role of lipids in regulating the intricate biological processes that control the effects of addictive drugs.