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FEATURE

DISEASE-CAUSING MICROBES, ONCE CONSIDERED NEAR EXTINCTION, ARE RETURNING WITH A FURY -- AND SCIENTISTS ARE FIGHTING BACK.

NATURAL BORN KILLERS
WRITTEN BY DAVID PETECHUK AND MARK COLLINS
Every news headline about bacteria and viruses uses the same mix of militaristic lexicon and abbreviations: "The Battle Against AIDS," "The War on TB," "Attacking HIV." We've come to think of our bodies as war-weary battleships: our immune system always on full nuclear alert, always prepared for the next onslaught, and aided (when necessary) by multiple antibiotic warheads. We hear talk of "magic bullet" vaccines and "killer" T cells, the latest weapons from our immunologic Pentagon.

And we're used to success. We're the country (actually, the very university) that brought the world the Salk vaccine against polio. Our drug researchers have developed a wondrous array of antibiotics to cure diseases. Our insistence on pre-school immunizations and the availability of penicillin and other "miracle" drugs mean we never have to wait until a disease "runs its course." We can stop it -- blammo! -- right in its tracks.

But recently, the dispatches from the front lines have been mixed. As you read this, drug companies are delivering a chickenpox vaccine to pediatriciansÍ offices, the final chapter in conquering one of the last childhood diseases. At the same time, however, new and worrisome reports pour in. Newspapers now chart the spread of "flesh-eating bacteria," a particularly vicious form of streptococcus-A found most recently in England and North America. The New England Journal of Medicine notes the disturbing increase in whooping cough cases among children in Cincinnati -- despite the fact that most of them were inoculated against pertussis as infants. Add to this the continuing worries about deer ticks carrying Lyme disease, the spread of Hepatitis B, and a host of other marauding microbes, and suddenly our "victory" looks more like a stalemate. Where modern medicine was once looking to eradicate ancient diseases like tuberculosis, it's now trying desperately to keep pace with the latest ambushes from highly resistant strains of the contagion. And new infectious diseases -- new at least to humans -- are threatening to hoodwink not only our body's immune system but our entire armory of antibiotics and vaccines.

Perhaps, though, part of the solution might come from our verbal framework, not from our antibiotic arsenal. Instead of personifying microbes as malicious science fiction creatures bent on destruction, think of them as tight wound bags of genetic material -- no soul, no mind, all body. Bacteria are nothing more than one-celled clusters of DNA (dioxyribonucleic acid, the building blocks of life), with just enough additional biochemistry to make themselves functional. And viruses are even simpler. Technically not even organisms, viruses are nothing more than thimble-like capsules of genetic scraps. Bacteria and viruses are agents built for the most basic of operations: surviving and reproducing. (If they sound laughably plain, remember that we humans emerged from similar stock in the primordial soup.) Microbes don't exist to cause high fevers or to kill their host -- that's an unwitting side effect, nothing personal. Microbes don't "prey" on the old and the weak. The frail and the elderly are simply inviting places to set up shop. And no microbe has the wherewithal to outwit an antibiotic or a vaccine. This is merely a happy accident -- happy, at least, for the microbe.

So bacteria and viruses aren't evil enemies plotting their next move around our medical Maginot Line. Instead, they're more like tiny Forrest Gumps: pure, guileless, irrepressible survivors.

BUT OUR UNDERSTANDING of this microfortitude is recent. Just a few short years ago, there was talk of "the extinction of disease." Smallpox was one of the first to go; the rest would soon follow. Drug manufacturers stopped making certain types of antibiotics because there seemed to be no need. In 1969, US Surgeon General William Stewart confidently told Congress it was time to "close the book on infectious diseases."

At the time of Stewart's address, Edward Wing, now chief of the division of infectious diseases at Pitt's School of Medicine, was a med student at Harvard. "People tried to discourage me from going into the field," he recalls. "They told me there was no money in it, that there was nothing to it, that infectious diseases were too easy to treat."

Later, when Wing was a fellow at Stanford in the 1970s, two unusual outbreaks caused him and his colleagues to take another look. What appeared to be an outbreak of the flu among American Legion veterans attending a conference in Philadelphia turned out to be a previously unidentified disease caused by Legionnella pneumophila, a microbe that flourishes in water. "If you go ten feet out and ten feet down in the Monongahela River," says Wing, nodding toward the Mon from his ninth-floor office in Montefiore University Hospital, "you'll find the bacterium that causes Legionnaire's disease." This "new" microbe has been around for millenia, but identification of this potentially fatal bacterium reminded researchers that undetected, undiscovered microbes could still lurk around the next corner.

Several years later, five healthy homosexual men in Los Angeles developed a deadly form of pneumonia usually found only in highly immunocompromised people, such as heart transplant patients. According to Wing, these cases were among the first manifestations of AIDS in the United States.

The discovery of AIDS punctured any complacency toward infectious diseases. "Some germs once found only in animals are no longer confined to isolated pockets in the environment and have begun to spill over into the human population," says Frederick Ruben, professor of medicine in the division of infectious diseases. "Lyme disease and, probably, AIDS are examples."

The human immunodeficiency virus (HIV), which causes AIDS, is perhaps just one example of a primate microbe crossing over to humans. But new diseases don't necessarily emanate from exotic places. As we alter our environment, we may unwittingly place ourselves in closer contact with infected animals. For example, the westward shift of agriculture resulted in reforestation of the East Coast and rapid increase in the deer population. As people moved further out from the city, their proximity to deer increased. Some deer carry ticks that may leave behind the Borrelia burgdorferi bacterium, which causes Lyme disease. The first case of Lyme disease was reported in 1969. In 1991, the Centers for Disease Control and Prevention recorded 9,344 cases.

"If you think this talk about new and deadly diseases is being overdone, you're crazy," says Ruben. "There are many unknown other diseases out there, and we'd be naive to think we've scratched the surface."

DESPITE RUBEN'S WARNing, William Pasculle, professor of medicine at Pitt and associate director of the University of Pittsburgh Medical Center's microbiology laboratory, is even more concerned about well-known infectious foes. "The fact is, most of the infectious diseases we're worried about have been around for a long time, but have come back in drug-resistant forms," says Pasculle.

For 50 years, drug therapy has been the treatment of choice against infectious diseases. The granddaddy of antibiotics, penicillin, came into mainstream use at the end of World War II. The success of penicillin as a "cure-all" for many previously untreatable bacterial infections spurred pharmaceutical companies to conduct massive antibiotic research. Today, close to one hundred different antibiotics are available.

Antibiotics, one of the crowning achievements of modern medicine, attack bacteria's metabolism without harming the human host. Some halt bacteria's ability to replicate through genetic copying or their ability to form the proteins needed for survival. Others inhibit enzymes that allow bacteria to reproduce or, like penicillin, destroy an enzyme that stabilizes the bacterial cell walls, causing the cell to collapse.

But resistance to antibiotics is nothing new; a resistant strain of staph emerged within three years of penicillin's introduction. In fact, the development of resistance is part of nature's course. Bacteria, like most simple life forms, are in a near-constant state of reproduction. Occasionally mistakes are made in the transference of DNA. These aberrations are usually inconsequential to the microbe. But sometimes -- quite by chance -- these mutations actually protect the bacteria against an antibiotic. Some bacteria, for instance, develop their own enzymes to stop the antibiotic. Others change their structure, leaving the antibiotics searching in vain for their targets. Needless to say, this new variant flourishes while the older strain may be quelled by drugs.

Pasculle is studying vancomycin-resistant enterococci, a version of strep first reported in 1988 that has quickly spread through hospitals coast-to-coast. "In graduate school, I was taught that it was genetically impossible for this enterococcus bacterium to become resistant to the antibiotic vancomycin," says Pasculle. "Unfortunately for us, bacteria don't read text books."

In his lab in Scaife Hall, Pasculle pulls out a stack of round plastic plates containing bright red- and green-colored cultures of infectious bacteria. Antibiotics have been placed in a circle in the cultures. It's easy to tell which antibiotics are effective: The bacteria surrounding them are clearly receding. In the case of vancomycin-resistant enterococcus, Pasculle and colleagues have found only one experimental antibiotic that remains effective.

"Bacteria have no brains and respond to only a few stimuli, including sugar, water, and nitrogen," he says. "They simply eat the same things we do. When they find enough of those things, they grow and multiply." Perhaps the only silver lining in this story, says Pasculle, is that the enterococcus bacterium isn't fatal.

What's disturbing is that many doctors, by overprescribing antibiotics, have unwittingly increased the chances of a drug-resistant mutation. Confronted with a feverish child and worried parent, some physicians are understandably inclined to fight the infection with an aggressive antibiotic. "The average physician is not equipped to understand the differences in the dizzying array of antibiotics they have to choose from," says Pasculle. "In many parts of the world, antibiotics are available over the counter like cough drops." Improper prophylactic use of antibiotics, such as using broad-spectrum antiobiotics instead of more specific agents to prevent infections in surgical patients, compounds the problem. In addition, nearly half of US-manufactured antibiotics are used in livestock feed, nurturing the development of antibiotic-resistant strains of bacteria that could find their way into the human population, via mosquitoes, tainted water, or undercooked meat. "Some physicians use sledge hammers to kill fleas," Pasculle says. "The result is they splatter flea viscera all over the place." In our bodies, the result is to create new strains of bacteria resistant to the antibiotic sledge hammer. Antibiotics designed to fight specific infections also come in contact with other bacteria in the body. As a result, an antibiotic prescribed for an infection in the lungs may leave a resistant bacterium in the intestinal tract.

THE STRUGGLE AGAINST bacteria and viruses seems to strike at some innate fear in us„the sense of an unseen, impending predator. The current crop of resilient microbes fuels our anxiety. But perhaps some perspective is in order. Although we've learned how much we don't know about bacteria and viruses, we're light years ahead of where we were when, say, penicillin was introduced.

Take, for instance, the continuing fight against AIDS. On one hand, HIV has proven to be a frustrating and elusive foe for researchers. On the other hand, the intense scientific scrutiny has produced a quantum leap in our understanding of viruses and infection.

And a good portion of that new knowledge has come from the Pitt Men's Study, one of the oldest and largest federally funded AIDS research projects. Pitt's project -- part of the Multi-Center AIDS Cohort Study -- provides a decade-long snapshot of both healthy and infected men. This invaluable comparison helps to chart not only individual symptoms but the disease's long-term course within a research population.

"I don't mean to sound glib, but it's absolutely remarkable that AIDS came when it did," says Monto Ho, chair of the Graduate School of Public Health's Department of Infectious Diseases and veteran of ten years of AIDS clinical studies. With the advent of new technology and a wealth of cumulative knowledge (including Ho's own three-plus decades of research), researchers knew very soon after the first round of AIDS infections that the disease was probably viral. In fact, they could describe with some confidence the characteristics of the virus -- all this before the virus was even discovered. "Twenty years ago, we'd be in a fog about AIDS and many other diseases," Ho says.

By way of example, Ho points to how the use of monoclonal antibodies helped identify the disease process. This technique clones large quantities of antibodies, the substances produced by white blood cells to fight off infections. "Say you have the surface of cells that can stimulate a thousand different antibodies," says Ho. "This technique can isolate every single one of those possible antibodies." Without monoclonal antibodies, scientists could not have discovered that HIV destroys T cells, one of the body's chief defenders against infection.

Charles Rinaldo, director of the Pitt Men's Study, uses the technique of monoclonal antibodies to study dendritic cells found in the skin, mucous, and blood. These cells are the front line scavengers that first pick up viral invaders. Dendritic cells process viruses and excite T cells to turn and attack. If there's a defect in the dendritic cell, it may fail to activate the T cell properly. "These 'memory-killer' T cells could play a crucial role in inhibiting the replication of the HIV virus," says Rinaldo. "We believe that an effective AIDS vaccine would need to stimulate these cells."

Because a vaccine is still years away, prevention remains the key. According to Ho, the increase in sexually transmitted diseases in the '70s, coupled with the growth of intravenous drug use, laid the foundation for the firestorm of AIDS a decade later. And, as increased tourism and global travel make our world smaller, infectious diseases can now be carried throughout the world in a matter of hours.

WHAT WE'RE LEFT WITH, then, is a complicated, muddied picture of the often odd dance between microbes and medicine. The ever-mutable bacteria and viruses want nothing more than to be left alone, while scientists continue to probe the endlessly adaptable agents, trying to find and exploit their weaknesses. It's a strange struggle, conjuring up both respect for nature and awe at our own ability to comprehend nature's design. Each step by either side is countered by a parry and another thrust. And we -- civilians on the sidelines -- watch with nervous attention, realizing with each passing volley, with each passing news story, the exact manner of the odds at stake.


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