The diagram on yesterday's Science page misidentified the layers of the skin's epidermis. The basal layer is the bottommost layer of cells depicted. The granular layer is the darker-shaded layer at the upper boundary of the prickle cell layer. (Published 7/17/90)
For most of medical history, a wart has been viewed as a harmless nuisance -- an unsightly bump that seems to sprout for no reason. It has provoked the healers of various eras to fight back with weapons as diverse as magic spells and lasers.
But the reality of what goes on inside a wart would make a fitting plot for a spy thriller. A wart is the product of a seemingly ingenious coup engineered deep within a skin cell by a virus that can recognize exactly the right moment to seize control.
The secret agents responsible for this diabolical takeover are the papilloma viruses, a family of sabotage artists so specialized that some cause warts only on the sole of the foot while others home in only on the vocal cords, the mouth or the genital tract. Papilloma viruses produce warts in many species of animals -- from human beings to elephants, giraffes and parrots. They also cause more than half a million sexually transmitted human cancers worldwide each year.
Over thousands of years of evolution, these miniature saboteurs have perfected a strategy that takes expert advantage of the complicated life cycle of epithelial cells -- the cells that form the skin and that line the mouth, the respiratory tree, the genital tract and other body surfaces.
The plot opens when an area of skin or epithelial tissue vulnerable to the virus suffers a minor injury. That gives the papilloma virus -- a tiny protein capsule containing fewer than a dozen genes -- the chance to gain entry to a basal cell. Basal cells make up the deepest layer of the skin.
Once inside, the virus hides in the basal cell's nucleus, and some of its genes issue signals encouraging the cell to divide. Subverting Genetic Program
Normally, a basal cell divides only once, forming two "daughter" cells, One becomes a new basal cell that stays on the bottom cell layer of the skin and another goes through a series of changes as it travels upward through successive cell layers. By the time it reaches the surface, it is a mature skin cell, destined to die and be shed after a few days.
But the papilloma virus subverts that program. Under its influence, the infected cell continues to divide, creating a "clone" of cells, each containing a copy of the virus. It is this clone, the progeny of a single infected cell, that becomes the wart.
The virus's goal is to take over the machinery of each infected cell and use it to manufacture new virus particles. But it must strike at the right moment, waiting quietly in the nucleus while the cell matures and moves toward the skin surface.
"The normal life cycle of the virus is intimately tied to the normal life cycle of the cell," said Peter Howley of the National Cancer Institute's Laboratory of Tumor Virus Biology.
When the cell reaches a level of the skin called the granular layer, changes in its activity somehow alert the virus that it is nearing the surface and that the moment to act has come. Several viral genes spring into action, sending commands that force the cell to make multiple copies of the virus's genetic blueprint and to wrap up each copy in a protein package.
By the time the cell reaches the surface and dies, a host of new viral invaders is ready to burst forth, each one able to mastermind the creation of a new wart -- either on the skin of the original victim, or on that of another person.
Warts are not cancers. The body eventually clears the viral infection, and most warts disappear on their own, usually within about two years. Normally, the papilloma virus keeps its subversive signals under tight rein. Viral genes encourage the infected cell to divide, but they do not make it immortal -- the first step in the development of cancer.
Sometimes, however, papilloma viruses cause cancer. Two human papilloma viruses, HPV 16 and HPV 18, have been implicated in both cervical cancer and cancer of the penis. Since these viruses are spread by sexual intercourse, both tumors show epidemiological patterns identical to that of a venereal disease. For instance, the more sexual partners a woman has, the greater her risk of cervical cancer.
Howley said the reason a papilloma virus infection occasionally leads to a cancer instead of a wart appears to be a cellular accident that relaxes the virus's strict control of its own genes. Normally, the virus's genes are carried on their own small circle of deoxyribonucleic acid or DNA. A normal viral gene called E2 seems to direct the overall operation, keeping the signals from other viral genes carefully in check.
But in rare instances, the virus's DNA accidentally becomes joined to one of the cell's chromosomes in a way that breaks apart the E2 gene. When that happens, the master gene's braking action is blocked, and other genes within the virus are free to become much more active. Uncontrolled Growth
When they do, the genes can subvert the action of two cellular proteins called p53 and RB, which normally act as regulators over the cell's growth, preventing it from becoming cancerous.
Studies by Howley and his research group suggest that when two viral genes called E6 and E7 bind to these p53 and RB safeguard molecules, they can unleash the cell's capacity for uncontrolled growth and start it down the path to becoming a cancer cell.
The cell becomes "immortal." Instead of maturing and dying after a limited lifespan, it lives on and continues to divide. Eventually, such a cell may accumulate additional genetic changes that transform it into a full-fledged cancer cell, able to invade other tissues, break through blood vessel walls and travel through the bloodstream to lymph nodes and distant organs.
For the virus, cancer is an accidental byproduct. Its sabotage program is merely designed to produce a wart. Nevertheless, widespread use of the Pap smear, a routine test to examine cells of a woman's cervix, has dramatically reduced cervical cancer deaths in the last few decades by allowing doctors to identify women with precancerous changes produced by papilloma viruses.
When tests pinpoint an area of abnormal cells, gynecologists use surgery, freezing or lasers to remove or destroy the cells before they become cancerous. "We have the benefit of 25 years of having treated a whole population with this nonspecific therapy and seeing a drop in cervical cancer," said Howley. "That's without knowing that we were treating a viral infection."