GENOMICS: REVOLUTIONIZING MEDICINE

A Massive Atlas of the Human Genome

In the mid-1980s, planning began for a research and compilation project — on a scale that was without precedent in the life sciences. The Human Genome Project has the ambitious goal of fully sequencing and mapping the 3 billion or so base pairs of the human genome — and mapping the locations of all known genes. The number of human genes is not yet known, but estimates generally range from 50,000 to as high as 140,000. When completed, the individual maps will collectively form a comprehensive "atlas" of the human genome. The Human Genome Project has become a worldwide effort that includes other national governments, agencies, and private companies. By the spring of 2000, a "first" or "rough" draft of a human genome atlas will likely be complete.

Chasing down "single nucleotide polymorphisms" — a.k.a. SNPs or "snips". How important is the change of a single nucleotide in the genome? In 1999, 10 pharmaceutical companies started a genome mapping consortium to identify single nucleotide variations in genomic sequences. These so-called single nucleotide polymorphisms originally were used as "landmarks" for different regions of the genome. But they may also be responsible for affecting inherited traits. Some SNPs may cause a disease while others may affect the rate at which a person metabolizes a drug. Thus, the identification of "snips" — when correlated with drug reactions — may eventually be a powerful tool for predicting which patients will react well to a drug.

Of mice and men — the Chediak-Higashi syndrome. The change in a single nucleotide can produce significant functional differences. The Chediak-Higashi syndrome is one example of an immune deficiency disease that can be caused by a single nucleotide polymorphism. The chart above shows a single base change at position 1103 that alters the structure of a key protein and results in the syndrome. More significant changes or deletions may also produce the same condition. A patient with this syndrome must contend with a devastating breakdown of the immune system's ability to defend itself against bacterial pathogens.

Mapping Viruses, Bacteria, and Other Organisms

Organisms — ranging from the simplest known to the most complex — are being sequenced and mapped around the clock and around the globe. Scientists post the results of their work on GenBank and other web sites. The sequencing of simpler organisms has an importance that goes beyond their complexity. The study of a tiny 470-gene organism, for example, might ultimately provide answers to the most basic of questions: what is the genetic threshold for life?

Mycloplasma genitalium. Out of the entire realm of known and fully functioning organisms, this microbe is believed to have the fewest genes. Researchers, trying to ascertain which of its 470 genes are essential for its survival, disabled them one by one — and then performed additional experiments to see what the results might imply. Viruses may have smaller genomes but are not self-sustaining.

Two organisms that thrive in hostile environments

The study of extremes — whether of structure or function — can help elucidate the norm. Helicobacter pylori is a pathogenic bacterium that colonizes in the human stomach. How does it survive in such extreme acidity? Thermotoga maritima, a non pathogenic marine bacterium, survives in extreme heat — usually the death knell for bacteria. How does it do that?

H. pylori, shown with a representation of its chromosome. Many proteins are acid-sensitive and once exposed can no longer function. This organism's tolerance for acidity seems to come from an ability to create an electrical barrier that keeps out hydrogen ions, which defines an acid. The discovery that H. pylori can cause stomach ulcers has softened the distinction between infectious and genetic diseases.

T. maritima genome, showing predicted coding regions and other features. Many proteins are sensitive to heat, which can temporarily or permanently destabilize their structures. The ability of this organism to survive in geothermal heated marine sediment is related to the heat-resistant characteristics of its proteins. These properties cannot yet be predicted by genomic sequences, suggesting, at this time, the need for more information.

Diagramming Metabolic Pathways

Physical maps of genomes, and genetic maps of chromosomes, represent the alignment of genes and traits on the chromosomes. Currently, a new type of diagram — one that deals in processes rather than exclusively in structures — is emerging. Representations of this type correlate genomic sequences of the A-T-C-G variety with the functions associated with the proteins encoded by the genetic information.

Solute transport and metabolic pathways of H. pylori. Bacterial cells and cells from higher organisms have complex mechanisms and pathways to regulate metabolism and the flow of materials in, out, and within the cell. This map traces some of those pathways.