GENOMICS: REVOLUTIONIZING MEDICINE

New Challenges, New Technologies

We shall not cease from exploration — And the end of all our exploring — Will be to arrive where we started — And know the place for the first time.
- T.S. Eliot, 1942

To scientists investigating infectious disease and the workings of the immune system, the new millennium offers myriad new challenges. Ongoing research in molecular biology and genomics, made possible by new technologies, has opened up entirely new ways of looking at age-old phenomena. These discoveries suggest new avenues in the treatment and prevention of infectious disease just as new challenges are emerging — drug-resistant pathogens, rapidly changing environmental conditions that might favor pathogens over people, and newly emerging viruses such as Machupo virus or HIV.

"Rational" drug design for foiling flu
The 1918 influenza pandemic, though long past, remains as a vivid specter of what can occur. In fact, new strains of influenza are constantly emerging and are now responsible for about 20,000 deaths a year in the United States. As the structures and functions of pathogens and proteins become better known, rational drug design may become more feasible. These drugs are designed at the molecular level to disrupt or thwart pathogens in highly targeted ways. To combat flu, for example, researchers are trying to develop "plug drugs" — which they hope will plug active sites of enzymes that are known to be essential to viruses.

Strategic blocking. This diagram shows how a new plug drug — now being developed — might work by blocking the active site of an essential enzyme. The drug is specifically designed to inhibit neuraminidase — an enzyme that is essential for the release of viral progeny from a cell. If successful, the drug may prove effective against most known strains of flu.

Influenza virus.

Designing an AIDS drug from the inside out
AIDS — caused by the HIV virus — was first defined as an infectious disease in the 1980s. A dependable cure or prevention has proved elusive, and the disease is now pandemic. The development of a new generation of drugs, now underway, represents a dramatic change from the trial-by-error process of Ehrlich's day.

HIV — sequence showing a virus attacking and entering a T cell.

To develop effective drugs against infectious disease, scientists first determine which enzymes or pathways are critical to a given pathogen. They then create a specific chemical profile of a drug that would inhibit a key protein in the process. Next, they seek a drug that most closely fits the profile — through computer searches of known drugs — and modify it as necessary. One such custom-designed AIDS drug is currently in clinical trials. It is a protease inhibitor.

A new AIDS drug. Peptide-like drugs that block the protease enzyme of HIV can all be rendered ineffectual if resistance develops to one of them. Using rational drug design to search for a new class of inhibitors, researchers analyzed the protease (Figure 1) and its active site (Figure 2). They found that warfarin (Figure 3), a drug that stops a patient's blood from clotting and also kills rats, fit into and inhibited the enzyme's active site. Modifying warfarin with the aid of computers, investigators ultimately produced a new drug (Figure 4) 50,000 times more potent than warfarin. This drug is now in clinical trials.

Cutting-Edge Technology —
Plucking Genomic Information from Thin Air

The machine in front of you was initially developed as a tool to combat biological terrorism. Known as an Advanced Nucleic Acid Analyzer, it is a remarkable device. It analyzes samples filtered from air or taken from surfaces, and very quickly determines if biological agents are present and, if so, which ones. This portable device stands in stark contrast to the scenes of centuries past, when disease was caused by unseeable, unknowable, and largely unsuspected pathogens.

SmartCycler Lite, Portable Advanced Nucleic Acid Analyzer. The analyzer starts with infinitesimally small samples of pathogens and copies portions of their genomes — using an existing technique known as polymerase chain reaction (PCR) — until there is a sufficient amount to analyze. When compared with known databases, the genomic sequences may be used to identify which pathogens are present, and even their particular strains.

Pathogen catcher. More than 300 years ago, Leeuwenhoek "caught" the inhabitants of an invisible world with his lenses and made them visible. New technologies are now, similarly, making the largely invisible genomic world visible — though the process is less direct, and the technologies are chemical rather than optical.

Lower Right: Sample digital printout. The horizontal (x) axis indicates the number of amplification cycles, and the vertical (y) axis indicates the amount of signal detected. The absence of a signal after a sufficient number of cycles would indicate that the template reagent failed to match the genome of a suspected pathogen and that the genome, therefore, is not present.