December 2008 Archives

This Germ Could Save your Life ... 
       Or at Least Keep Your Teeth Cavity Free

Copyright Jessica Snyder Sachs, first published in Popular Science Photo of Strep. mutans courtesy Jeffrey Hillman 

It's a drizzly morning on New York's Upper East Side, and Rockefeller University microbiologist David Thaler is sipping a double espresso amid the retro-hippie pillows and dangling paper stars of Java Girl, a favorite haunt of the neighborhood's brainiac Nobel laureates, aging poets and famous entertainers. Thaler somehow manages to embody all three-a long, graying ponytail curling down the middle of his back, wire-frame glasses askew over expansive brown eyes, and a schnozz to rival an Einstein, Ginsberg or Allen. Thaler is one of the leading cheerleaders for a new field of biotechnology aimed at engineering the bacteria inside us to deliver drugs, destroy tumors, actively fight infection, and even vaccinate against their disease-causing kin.

Our ancestors, Thaler explains, emerged from the Stone Age by genetically engineering plants and animals through selective breeding, transforming the wolves that preyed on their flocks into the domestic dogs that would guard them. "Except for wild-caught fish, virtually everything we eat today has been engineered," he says. "Meanwhile, we're walking through this ocean of bacteria and only looking at them as something that can make us sick, rather than something to cultivate." He believes that it's time to move humanity from being microbe exterminators to microbe farmers.

Thaler thinks we need what he calls a "second Neolithic revolution." Although his day job as a microbiologist at Rockefeller revolves around such abstract research as testing life's speed limit (current record for replication: eight minutes), he sees himself as an idea man, someone who might help advance an entirely different mind-set in medical microbiology: Instead of using antibiotics to kill harmful bacteria in our bodies and our environment, why not coax bacteria to do our bidding?

"The technology to harness these bacteria exists," Thaler says. Biotechnology firms already use bacteria like E. coli as tiny factories. Just slip the DNA instructions for, say, a new protein-based drug into E. coli and, in its endless quest to replicate itself, the bacterium will replicate the drug as well.

But it's one thing to employ genetically engineered bacteria to produce pharmaceuticals inside a sealed vat. It's quite another to deploy what some call "Frankenbugs" inside a patient. The same characteristics that make bacteria so amenable to genetic engineering-their malleability, their incredible replication speed, their genetic promiscuity-allow their newly acquired DNA to spread to other microbes, including potentially dangerous ones.

Such concerns have largely kept the first generation of engineered superbugs confined to biohazard-containment labs. But the few microbes that have made it into limited human trials-a cavity stopper, a tumor destroyer, a bowel soother-have been enticingly successful. And so the first standoff over body-ready bugs is taking place before the review boards of medical centers and government regulatory agencies, the people who will decide if the world is ready for engineered superbugs.

"I honestly think people are more comfortable with the idea of nano-robots scurrying through their bodies than they are of deploying bacteria," Thaler muses. "But when you think about it, you cultivate your lawn. You'd probably like to cultivate your internal landscape."

THE CAVITY KILLER

Jeffrey Hillman, an oral biologist for-merly of the University of Florida, is a poster child for the kind of biotherapeutic future that Thaler envisions. Hillman has spent a decade lobbying the FDA to let him test a transgenic tooth bug in volunteers. "Fortunately, we had no idea what was ahead," says Hillman of the gantlet of regulatory requirements he has had to tackle since 1996. That was the year Hillman founded Oragenics, a biotech firm dedicated to commercializing his patented cavity-preventing Streptococcus mutans, a genetically modified organism (GMO) that's the product of nearly 30 years of research.

Inside the mouth of most every person on the planet, colonies of S. mutans bacteria thrive on leftover sugars. The by-product of their digestion is the acid that eats away at tooth enamel and causes cavities. But there are many different strains of S. mutans, and some cause more trouble than others. In the summer of 1976, Hillman was trying to replace cavity-prone strains with those that secrete less enamel-eroding acid. Unfortunately, it seemed almost impossible to permanently eradicate a person's "native" S. mutans once his or her teeth became colonized in early childhood.

"We were trying all sorts of crazy things," Hillman recalls. "One time, we were painting volunteers' teeth with iodine. Then we tried fitting their teeth with trays filled with antibiotics." Yet no matter how thoroughly Hillman banished his volunteers' native S. mutans or how quickly he re-colonized their teeth with a benign strain, the switch-out never stuck. "Slowly but surely, a person's indigenous strain always came back," Hillman says.

In 1982 Hillman hit on the idea of first finding a strain aggressive enough to elbow out a person's native tooth tenants and then knocking out its genes for acid production. He conducted the microbial equivalent of cockfights, setting various strains of S. mutans against each other in crowded petri dishes. He knew he had found his ideal candidate when he saw that one "pinprick" colony had cleared a perfect circle in the lawn of other bacteria around it. When Hillman and two of his labmates introduced the strain into their own mouths, it quickly took over, banishing their native S. mutans in the process.

Next, Hillman deleted the microbe's gene for acid production, but the superbugs didn't survive the genetic tinkering. Most strains of S. mutans, including this one, use lactic acid to dispose of metabolic waste. Without acid excretion, the waste builds to toxic levels, killing the microbe.

Hillman solved the problem by making his bug produce alcohol instead of acid. To do so, he borrowed a gene for alcohol production from Zymomonas mobilis, which is used to make pulque, or Mexican beer. The resulting bug didn't produce enough alcohol to make its host at all tipsy. But in studies with lab rats, it replaced the animals' existing S. mutans and kept the rats mostly cavity-free on a high-sugar diet that would normally destroy their teeth.

The trouble was that Hillman now had a true transgenic-an organism that expressed the genes of two different species. The prospect of tests in humans meant that he had to go to the FDA for approval. The FDA eventually referred his case to the National Institutes of Health's Recombinant DNA Advisory Committee, created in 1974 in response to public concern over the safety of interspecies gene transfer. The committee, which includes ethicists and patients as well as scientists and physicians, reviews any application for a transgenic intended to be used outside a sealed laboratory.

In 2004, the committee gave Hillman the green light. Usually, this is enough for full FDA approval. But not this time. FDA regulators asked Hillman to cripple his bug to guarantee that it could be removed should it ever cause problems. "When we asked them what kind of problems, they had no idea," he recalls. "I guess we were setting a precedent."

The regulators saw a genetically modified bacteria that was robust enough to take over any person's mouth, and they were worried about its unchecked spread. Their decision reflected a common criticism of GMO biotherapeutics. "The main problem . . . is that [GMOs] are usually poorly contained," argues geneticist Joe Cummins. Recently retired from the University of Western Ontario, Cummins is a leading spokesman for the London-based Institute for Science in Society, an anti-GMO lobbying group. "They're bound to escape and to pollute the systems of people who don't require therapy."

So Hillman knocked out more genes, this time rendering his microbe unable to survive without an amino acid that test subjects would need to supply, twice daily, by rinsing with a specially formulated mouthwash. In addition, the agency required that Hillman test on patients wearing full dentures that could be dropped into bleach at the end of a week. The volunteers could not have children in their homes, and their spouses had to wear full dentures as well. And both the volunteers and their spouses had to be robustly healthy and under age 55. "We screened more than 1,000 potential volunteers," Hillman says, "and we found two."

The miniature, two-person trial proceeded without a hitch at the end of 2006, with no adverse side effects and complete elimination of the organism at the end of seven days. Last November, past the 10th anniversary of his original FDA application, Hillman received approval to use his crippled transgenic in a larger clinical trial. "Real people with real teeth!" he exults. For safety, the volunteers will spend the weeklong trial in a biocontainment ward.

Should his superbug prove as harmless as it appears, Hillman hopes the FDA will eventually allow him to skip the step where he renders it a nutritional cripple. Users could then dispense with the daily amino-acid mouthwash.

Might the bug then begin spreading from one person's mouth to the next? It's unlikely, Hillman says. When he and his labmates colonized their teeth with their GMO's ancestor, it did not spread to wives and girlfriends, even while remaining in their own mouths for decades.

Proponents like Thaler ask whether such an "uncontrolled release," if it were to occur, would be a bad thing. "What would it be like for us to have benign versions of Typhoid Mary walking around," he asks, "spreading their health-enhancing germs?" In some cases, though, uncontrolled release of genetically modified bacteria could lead to disaster, even if the intended effects were nothing but beneficial.

ATTACKING CROHN'S

On day three of the study at the Academic Medical Centre in Amsterdam, the 43-year-old Dutch farmer felt so good that he was packing his bags to leave the hospital. The nurses caught him just as he was headed out the door of the center's new biocontainment ward for gene therapy. Its rooms are kept under negative pressure so that even if a window breaks, bacteria-laden air will flow in, not out. The man had been spending his days confined to little more than a glorified hospital room, with doctors and nurses coming and going in head-to-toe surgical garb. The bug that was healing his body had to remain isolated, by government order. "We had to explain to him that he was not free to leave, no matter how wonderful he felt," recalls study leader Maikel Peppelenbosch.

Over the previous eight months, Peppelenbosch had managed to win government approval for a clinical trial that deployed a genetically modified cheese-making bacterium, Lactococcus lactis-Thy12, to relieve Crohn's disease [launch the gallery

here, to see how it works]. This excruciating bowel disorder is caused by the immune system mistakenly attacking the intestines' normal complement of digestive microbes. The result is a vicious cycle of painful inflammation and gaping ulcers that can progress to life-threatening perforations of the colon.

Dutch approval of the trial-and the willingness of patients to cycle through 11 days of biological isolation-was a testament to both the seriousness of the disease and the lack of reliable cures, Peppelenbosch says. "These were patients for whom taking out the bowels was their last remaining option." Funding for the study came from the U.S., by way of a private research grant from billionaires Eli and Edythe Broad, whose son suffers from Crohn's.

The way to treat the disease is to turn off the immune system's attack on the intestines' native bacteria. Researchers have long known that lab animals whose bodies fail to produce the immune-calming molecule interleukin-10 develop severe inflammatory bowel disorders similar to Crohn's. But efforts to administer IL-10 are fraught with problems. Stomach acid destroys the protein, so it can't be taken by mouth. And introducing it into the bloodstream risks paralyzing a patient's immune system.

Any solution must deliver the immune-calming molecule exactly where it's needed-inside the intestinal tract-but nowhere else. That's where Lothar Steidler's creation comes in. In 1999 Steidler was pursuing postdoctoral studies into Crohn's-disease treatments at Ghent University in Belgium. In an impressive molecular sleight of hand, Steidler took the gene for IL-10 and slipped it into L. lactis.

But he didn't stick it just anywhere in the cheese bug's genome. Steidler understood how important it was to prevent his bug from escaping into, say, the sewer system, where any number of nasty, disease-causing bacteria might pick up the IL-10 gene. The result could be pandemic disaster: a pathogen out in the wild with the ability to cripple the body's disease-fighting response.

"I knew I had to build in some sort of suicidal mechanism," he explains. He also had to prevent gene swapping between his "good bug" and a potential bad guy. So Steidler made sure that the incoming IL-10 gene always replaces another gene needed to produce the nutrient thymidine. That way, his new bugs can't make thymidine, and so they die of nutrient starvation within a few days. That fleeting life span is enough to complete their mission but not long enough to survive in the waste that flushes down the toilet.

Even better, if the inserted gene jumps into another organism, it replaces that microbe's thymidine gene. So any bug that receives the gene likewise becomes a doomed nutritional cripple. "Fortunately, Lothar designed this bacterium very well," says Peppelenbosch, who collaborated with Steidler to usher the transgenic through regulatory approval in the Netherlands. Their proposal received no objections from either regulators or the public-an unexpected feat in rabidly anti-GMO Europe, he notes.

The team faced no lack of volunteers for the trial. The doctors at the Academic Medical Centre saw scores of patients with severe Crohn's that failed to respond to standard anti-inflammatory drugs. The researchers ushered 10 patients into their containment ward, one by one, for their seven-day treatment and 11-day isolation.

Eight of the 10 Crohn's patients experienced relief from pain and diarrhea, five dramatically so. One withdrew early for unrelated reasons, and none experienced any worsening of symptoms or problematic side effects. Most important for the prospect of larger studies, Steidler demonstrated that his transgenic microbe completely disappeared from the volunteers' stool within a day of swallowing their last capsules of live bacteria.

As expected, the patients' symptoms reappeared a few weeks after they returned home, and several came back to plead for continued treatment. "We couldn't, of course," Peppelenbosch says, because the trial was over. Steidler and Peppelenbosch are seeking Dutch approval for a larger, placebo-controlled trial, this time without the onerous restrictions of isolating patients on a biohazard ward. 

Built-in suicide mechanisms such as Steidler's may prove key to the widespread use of GMO biotherapeutics. "Now that the biocontainment issues are being fully recognized and achieved, I think it's all going to move very quickly," predicts North Carolina State University micro-biologist Todd Klaenhammer.

THE TUMOR BUGS

In January 2002, doctors at the Mary Crowley Medical Research Center in Dallas began injecting a genetically modified breed of salmonella into three cancer patients with large, inoperable tumors that had failed to respond to radiation or chemotherapy. For reasons still poorly understood, salmonella proliferates inside malignancies, perhaps because cancerous tumors tend to remain beyond the reach of the immune system. This salmonella was special, though. A Yale University team led by microbiologist David Bermudes inserted an E. coli gene into the bacteria. The gene produced an enzyme that activates a highly noxious, tissue-destroying drug. "The beauty is that neither the enzyme nor the drug that it activates does anything toxic except in places where they end up together," Bermudes explains. In other words, the system is engineered to be harmless outside a tumor but deadly inside it.

The 2002 pilot trial proved a success, in that the bioengineered salmonella delivered its enzyme payload, produced a modest shrinkage in tumor size, and did no harm to the three patients, but the trial was too small to make any claims of a cure. To move into larger, meaningful trials would require following in Hillman's footsteps through a battery of federal regulatory review boards. That costs money. Even if the researchers received approval to go ahead, they would need to come up with the many millions of dollars needed to usher any potential cancer treatment through large-scale patient trials.

That investment would most likely come from Vion Pharmaceuticals, the Connecticut biotech firm that currently holds Bermudes's patent on the tumor-busting salmonella. Vion has no plans to tackle the regulatory process in the near future, however, says Ivan King, Vion's vice president for research and development. "As a small company, we cannot move many things forward at any one time," he says. What's needed, he believes, is interest from a larger pharmaceutical company with much deeper pockets-just the kind of company that has yet to show interest in highly experimental bioengineered bacteria.

THE NATURAL WAY

Meanwhile, some researchers are focusing on unmodified microbes that could benefit the body. These "probiotics" are sold in grocery and health-food stores, yet few of the numerous available products have been rigorously tested. One of the exceptions is Lactobacillus GG, or "Culturelle," isolated in the 1980s by Sherwood Gorbach and Barry Goldin of Tufts University. Over the past two decades, Gorbach, Goldin and others have published 250 scientific papers on this strain's disease-fighting effects. Studies suggest that the bug has an immune-calming effect that may ease some food allergies. But its one clear and proven benefit is to reduce a person's risk of picking up one of the many nasty intestinal bugs that cause food poisoning, traveler's diarrhea and antibiotic-induced gastroenteritis, which results when antibiotics kill off a person's normal intestinal bacteria and a disease-causing invader moves in.

In Europe, where probiotics have long been popular, they have also been used to prevent chronic respiratory and ear infections. In the early 1990s, Swedish ear-nose-and-throat specialist Kristian Roos developed a throat spray containing a medley of throat bacteria that dramatically reduced the recurrence of chronic strep infections. A few years later, Roos developed a similar concoction that protected toddlers and preschoolers who were predisposed to ear infections.

Roos's probiotics demonstrated their worth in small clinical trials. But they also illustrate the challenge of developing a natural probiotic into a medical therapeutic. A small clinical trial may be enough to put a health claim on a nutritional supplement sold over the counter. But Roos wants to see such cures in the hands of doctors, who would judiciously prescribe them to patients. To do that, he must prove that his probiotics work in the same kind of large, multimillion-dollar trials that have stymied Bermudes's cancer-fighting GMO.

For that kind of money, Roos admits, investors are right to expect an ironclad patent to protect their investment. But that's difficult to do with bacteria that occur naturally on and in the human body. "Even though we can patent our particular mixture of organisms, it would be easy for someone else to come along and put together something slightly different from the hundreds of protective strains found in people's throats," he explains. Without the assurance of some meaningful patent protection on his product, he has been unable to attract financial investors, and his treatments languish in a storage freezer.

THE GOOD-MOOD BUG

Microbiologist John Stanford of University College London and his wife, Cynthia, discovered Mycobacterium vaccae while searching for a tuberculosis vaccine booster in Uganda in the early 1970s. Experts had long proposed that the widely variable efficacy of the TB vaccine stemmed from bacteria in a region's soil that provided a natural booster effect. The Stanfords, crisscrossing the African nation in search of this bacterium, isolated M. vaccae, a benign genetic cousin of Mycobacterium tuberculosis, from the muddy shores of Lake Kyoga, an area where the TB vaccine proved unusually effective against both tuberculosis and leprosy. The Stanfords hoped that injections of M. vaccae would help prevent or cure TB, but at best their vaccine proved only mildly beneficial. More curious were anecdotal reports of unexpected benefits-regressions of allergies, asthma and even cancer.

In 1992 John Stanford and his colleague Graham Rook went on to form a publicly traded company, SR Pharma, to test these immune-boosting benefits in clinical trials with late-stage lung-cancer patients. But in 2001, under a spotlight of media attention, the trial failed to appreciably increase patients' survival time. SR Pharma's stock crashed, and following a dispute over the company's future focus, the company removed Rook and Stanford from its board of directors.

Yet the trial did produce one bona fide benefit: a significant increase in "quality of life" among patients who got M. vaccae injections versus those who received a placebo. That dovetails with the work of University of Colorado neuroscientist Christopher Lowry, who last May published a study where he used M. vaccae in psychotropic experiments with rats. Lowry discovered that the bug increased brain levels of the mood-enhancing hormone serotonin and decreased depressive behavior. Even more promising, Lowry showed that M. vaccae appeared to be more discriminating than antidepressant drugs in the kinds of brain neurons it activates. It switches on the serotonin neurons associated with enhancing mood, without stimulating those that increase hyperalertness-that is, anxiety and sleeplessness. "Prozac without the side effects," he calls it. In addition, recent studies have shown that M. vaccae may be effective against TB-the Stanfords' original studies didn't supply enough doses-and may increase the survival times of some late-stage cancer patients.

It's just this sort of surprising potential that inspires researchers. "We're always saying things like, 'I feel lousy today. I must have caught a bug,' " Thaler says. "We never say, 'I feel great. I must have picked up an endorphin-producing one.' What would it mean to cultivate yourself to be contagiously healthy?"

 Jessica Snyder Sachs is a contributing editor at Popular Science. Her most recent book is Good Germs, Bad Germs: Health and Survival in a Bacterial World.

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A fragile linkage exists between the nation's water supplies, the wild places where they come from, and the life that the two support together

copyright Jessica Snyder Sachs, as first appeared in National Wildlife

FOR TENS OF MILLIONS of years, a corps of natural hydrologists ensured the continuous cleansing of our continent's water supplies. In woodlands across North America, some 200 million beavers slowed rivers and streams to a silt-dropping crawl with their semiporous dams. Moreover their relentless logging created an elaborate network of wetland meadows that absorbed and cleansed surface runoff.

Beyond the forests, tens of millions of bison and elk worked in tandem with wildfires to sustain the short-grass and tallgrass prairies that soaked up the torrential downpours of seasonal thunderstorms. Beneath these same grasslands, hundreds of thousands of prairie dogs dug vast networks of tunnels that channeled groundwater deeper, to feed and refresh underground rivers that, in turn, continually recharged the continent's lakes and above-ground streams.

In these ways, a network of keystone species helped maintain a clean supply of the continent's most vital, life-sustaining substance. For while many forms of life can survive without oxygen, none can do so without water. Indeed, 60 to 80 percent of every living cell consists of water, and all vital biological processes begin or end with this simple molecule.

So far as science can discern, life on this planet began in a watery cradle. And when astronomers scan other planets for the potential to support life, they look first for signs of the molecule H20.

As seen from space, the sparkling blue ball that is Earth reveals itself to be a paradise of wetness. Above the oceans and lakes that cover more than 70 percent of the planet's surface drifts an ever-shifting lace of water-vapor clouds. Water pours from our skies, courses down our mountains and flows across every continent, back to the seas where the warming sun sends it skyward again. In this manner, our planet continually recycles an estimated 370 quintillion gallons (18 zeros), most of it older than the oldest fossils.

As life in North America and elsewhere evolved around water's unique properties, elaborate ecosystems developed to ensure continual recycling and purification. In Water: A Natural History, environmental engineer Alice Outwater describes the consequences of disrupting these ecosystems, particularly the large-scale decimation of North America's pre-Columbian populations of beaver, bison, elk and prairie dogs. "By tampering with and in some cases eliminating the ecological niches where water cleans itself," she says, "we have simplified the pathways that water takes through the American landscape, and we have ended up with dirty water."

Without wetlands and prairie grasslands to absorb rainfall, water slaloms across the landscape, picking up and dumping sediment into streams and lakes. Without beaver dams to brake their flow, streams frequently deepen into brown-water gulleys, continually eating away at their own banks. In an even more dramatic manner, development that clears natural vegetation speeds sediment-laden runoff during rainstorms, while adding a potentially toxic load of pesticides and other chemicals. The U.S. Geological Survey's recently completed ten-year assessment of the nation's water resources found multiple pesticides and unnaturally elevated levels of phosphorus and nitrogen in virtually all streams and groundwater sampled outside undeveloped wilderness. The majority of these streams contained pesticides at levels that exceeded--and often far exceeded--federal guidelines for the protection of aquatic life. These same chemicals can likewise endanger humans if they enter the drinking water supply.

"Scientific studies have repeatedly shown that our ability to protect our water sources from pollutants--and there are many of them--relates closely to our ability to safeguard our own health, especially that of our children, with their growing bodies," observes Monty Fischer, National Wildlife Federation policy director of water resources. "As conservationists, we're also keenly aware of the crucial role an untainted and abundant water supply plays in sustaining wildlife."

Certainly, Fischer points out, part of the solution is increased water efficiency--from turning off the faucet when we brush our teeth to making sure that our municipalities repair leaky water mains and otherwise invest in efficient water-delivery systems. But more important, he says, "is a public understanding of the linkage between the water flowing out of your tap and the wild places where it comes from, both in terms of the quantity and quality of that water, and the commitment it takes to protect those water sources."

Outwater agrees, adding: "An undeniable symbiosis exists between our country's water, the land from which it springs and the life that the two support together. Safeguarding that symbiosis is a responsibility all of us must share."

New Jersey journalist Jessica Snyder Sachs wrote about the effects of pesticides on endangered species in the December/January issue.

SIDEBAR:

H₂O: The Incredible Molecule

What is it that makes H₂O the liquid of life itself?

In chemical structure, the water molecule could hardly be simpler: two hydrogen atoms stuck like Mickey Mouse ears onto a single atom of oxygen. But in that simplicity can be found water's unique properties.

In essence, every water molecule is a tiny magnet, and its strong polar nature gives it the ability to dissolve an unparalleled range of substances, including a wide range of salts. In addition to the familiar sodium-chloride molecule we know as table salt, these include scores of biologically important substances such as potassium chloride, magnesium chloride and calcium sulfate. Indeed, all living beings--from plants to humans--depend on water to release the life-sustaining minerals contained in these salts.

Water's remarkable solvent powers provide the perfect medium for virtually every biological reaction that occurs inside a living cell--from energy-storing photosynthesis to energy-consuming respiration. And water has the remarkable ability to dissolve gases--most importantly, oxygen and carbon dioxide. It is water's oxygen-carrying capacity that sustains aquatic animal life.

A water molecule's mini-magnet configuration generates a host of other queer qualities, as well. Given its simple structure and small size, it should fly apart into gaseous form at extremely low temperatures. But water molecules cluster into tight groups, with each molecule's negatively charged oxygen atom lining up with the positively charged hydrogen on its neighbors. The considerable amount of energy needed to break these "hydrogen bonds" gives water the unusually high boiling point of 212 degrees F (100 degrees C). As a result, the planet's surface water never completely evaporates under the beating sun. Instead, oceans and lakes act as impressive energy sinks for storing and slowly releasing solar energy to temper seasons, and smooth out temperature differences between day and night.

As temperatures drop toward freezing, the hydrogen bonds between water molecules perform another impressive trick. They preassemble into the open-lattice structure that gives snowflakes their beautiful patterns and makes ice lighter than water. This bizarre quality of water being lighter as a solid than as a liquid has a huge consequence: It is the reason that lakes and oceans don't freeze from the bottom up, solidifying into a global ice block that even the hottest summer would never melt.--Jessica Snyder Sachs

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Copyright Jessica Snyder Sachs, as first appeared in National Wildlife

THE EARLY MORNING SUN glints off the amber, "swamp tea" waters of Okefenokee National Wildlife Refuge, as an eager group of Sunday birders clamber up its wetland observation tower. For the last half mile of boardwalk, they've heard the croak of sandhill cranes above the rustling sound of the sawgrass blocking their view. "They'll be lifting off any day now," says refuge ranger Maggie O'Connell of the swamp's winter population of several thousand greater sandhill cranes. Though only mid-February, winter is already loosening its halfhearted grip on southern Georgia's Great Okefenokee, one of the largest intact freshwater ecosystems in the world.

Atop the 50-foot tower, O'Connell surveys her domain. "Seventeen miles to the horizon without a stitch of solid ground," she marvels. Indeed, the dense vegetation of this landscape grows atop floating peat-bog islands, the largest crowned by bald cypress draped in ghostly green Spanish moss. For good reason, the Creek Indians dubbed this Oguafenogua, the "land of the trembling earth." Stomp hard enough and even the trees shake.

Like the majority of the 539 units in America's National Wildlife Refuge System, the Okefenokee was protected to serve as sanctuary for migratory waterfowl such as the cranes, teals, mergansers, herons and egrets seen feeding across its open, wet "prairie." But the Georgia reserve has evolved far beyond its "duck factory" genesis.

This refuge's expanded purpose becomes clear as the sun rises high enough to banish the morning chill, and boaters begin paddling and motoring up the swamp's 120 miles of canals and slow-moving streams. Blinking back at them from the shore or half-submerged in the shimmering blackwater are the sleek American alligators that are among the Okefenokee's star attractions. Many of the visitors will linger after returning to dock--lunching on the refuge's grassy picnic grounds, touring its new million-dollar environmental education exhibit, and shopping for souvenirs in the gift shop. Some will spend the night, either in the state park easement on the refuge's west side or deep in the swamp, on one of seven overnight canoeing platforms.

In addition to playing host to more than 400,000 visitors a year, the staff of this national wildlife refuge have launched an ambitious long-term project to restore and expand the area's upland stands of rare longleaf pine and wiregrass habitat--home to endangered red-cockaded woodpeckers and threatened gopher tortoises, indigo snakes and Florida black bears. To this end, nearly half the refuge staff work on the fire crews that conduct prescribed burns to beat back the saw palmetto and slash pine that once were kept in check by seasonal wildfires. "We figure it'll take about 300 years of active management to restore the area," says O'Connell.

Now, as it prepares to celebrate its centennial year beginning in March, the National Wildlife Refuge System as a whole is experiencing an equally radical deepening and expansion of its purpose. Administered by the U.S. Fish and Wildlife Service, it is the world's only national network of public lands set aside specifically for wildlife. And for years, it struggled without any sense of unifying mission. Beginning with President Theodore Roosevelt's founding of the first refuge--Florida's Pelican Island in 1903--one unit after another has flickered into being with its own narrowly defined mission. Before Roosevelt left office in 1909, these included 56 big game preserves and bird reservations such as Idaho's Mindoka refuge for ducks and geese, Oklahoma's Wichita Mountains for bison and elk, and Alaska's Fire Island for moose.

In addition to playing host to more than 400,000 visitors a year, the staff of this national wildlife refuge have launched an ambitious long-term project to restore and expand the area's upland stands of rare longleaf pine and wiregrass habitat--home to endangered red-cockaded woodpeckers and threatened gopher tortoises, indigo snakes and Florida black bears. To this end, nearly half the refuge staff work on the fire crews that conduct prescribed burns to beat back the saw palmetto and slash pine that once were kept in check by seasonal wildfires. "We figure it'll take about 300 years of active management to restore the area," says O'Connell.

Now, as it prepares to celebrate its centennial year beginning in March, the National Wildlife Refuge System as a whole is experiencing an equally radical deepening and expansion of its purpose. Administered by the U.S. Fish and Wildlife Service, it is the world's only national network of public lands set aside specifically for wildlife. And for years, it struggled without any sense of unifying mission. Beginning with President Theodore Roosevelt's founding of the first refuge--Florida's Pelican Island in 1903--one unit after another has flickered into being with its own narrowly defined mission. Before Roosevelt left office in 1909, these included 56 big game preserves and bird reservations such as Idaho's Mindoka refuge for ducks and geese, Oklahoma's Wichita Mountains for bison and elk, and Alaska's Fire Island for moose.

Since 1934, the Migratory Bird Hunting and Conservation Stamp Act has funded the acquisition of millions of acres of additional waterfowl habitat, concentrated up and down North America's four major migratory flyways. Among the first, Montana's Red Rock Lakes refuge became the last-chance sanctuary for the highly endangered trumpeter swan in 1935.

In 1966, Congress passed the National Wildlife Refuge Administration Act, enlarging the refuge system further with several thousand small prairie pothole wetlands designated as "Waterfowl Production Areas." And in 1980, the Alaska National Interest Lands Conservation Act nearly tripled the refuge system's holdings with some 54 million acres of pristine arctic and subarctic habitat.

By the time the 500th refuge--West Virginia's Canaan Valley--was established in 1994, the system encompassed more units than the National Forest Service and more land (90 million acres) than the National Park Service's holdings. Yet much of the refuge system continued to be managed under a mishmash of policies and regulations that left its lands vulnerable to such strangely incompatible uses as jet skiing, dune-buggy racing, livestock grazing, oil drilling, even military war games and bombing runs. Refuge managers opposing such uses stood on shaky legal ground unless they could show that the activities directly threatened the specific purpose for which their refuges had been established.

A case in point: In 1990, the manager of Aransas National Wildlife Refuge on the Texas Gulf Coast tried to remove privately owned cattle from the preserve's wildlife-rich Matagorda Island. Biologists had determined that overgrazing had already degraded the island's otherwise pristine habitat, including nesting sites for endangered sea turtles and underbrush vital to wintering songbirds. The problem was that Congress had established the refuge in 1937 specifically as a sanctuary for the world's last wild population of whooping cranes.

"We could show that the cattle were definitely degrading the overall ecosystem of Matagorda Island," explains National Wildlife Refuge System Director Dan Ashe. "But technically, in order to deny the grazing permit, we had to show that it was incompatible with the refuge's original purpose." In the end, federal administrators stood behind the refuge manager's claim that cattle grazing constituted an incompatible use. "But a lot of people, including our own attorneys, thought we were stretching things," admits Ashe.

Such legalistic hand-tying came to an end in 1996, with an executive order by President Clinton, followed the next year by the bipartisan passage of the National Wildlife Refuge System Improvement Act. These two legal directives set forth "conservation" as the refuge system's singular and all-encompassing purpose--a purpose against which any proposed use had to be judged. The groundbreaking Improvement Act also required the staff at every refuge to create a 15-year comprehensive conservation plan--guided, in large part, by public input. Indeed, by placing an emphasis on "wildlife-compatible" uses such as observation, photography and limited hunting, the law acknowledged that refuges are for people too.

Specifically, some 2 million hunters and 6 million anglers visit the refuge system each year. Twice that number--some 16 million visitors--come solely to watch wildlife or soak in the beauty and serenity of the nation's wildest places. Add busloads of students and tour groups taking advantage of environmental education programs and the tally swells to at least 35 million visitors a year. The importance of their input in setting the system's agenda for its second century can hardly be underestimated, says Jamie Rappaport Clark, former director of the U.S. Fish and Wildlife Service during the Clinton administration and now NWF senior vice president for conservation programs. "The pressures on the refuge system have grown tremendously in recent years," she explains. "We have more threatened and endangered species, more demands for human activity on the landscape, and more development and encroachment from the outside. As a result, the job of safeguarding these wild places and passing them on to new generations demands a high level of public engagement."

In fact, the most serious threats to refuge wildlife and habitat--urban sprawl, water depletion, pollution and invasive species--originate outside refuge borders and, therefore beyond the system's authority. Consequently, progress depends on activism on the part of local citizens and allied conservation organizations.

In recent years, for example, the Okefenokee National Wildlife Refuge has depended on a large coalition of conservation groups, including NWF and its affiliate, the Georgia Wildlife Federation, to stave off plans by the chemical giant DuPont to excavate a 30-mile-long, 50-foot-deep titanium strip mine a few feet from the refuge's eastern border. The proposed mining operations would generate a 24-hour-a-day onslaught of dust, smoke, exhaust, noise and light directly alongside the refuge's main wildlife observation drive. Worse, scientific studies indicate the mine could irrevocably alter the Okefenokee's delicate hydrology and ecology. With no authority to stop operations off refuge grounds, refuge managers continue to rely on sustained and vocal public opposition to keep DuPont's plans at bay.

Public opposition has, at least for the time being, helped play an even larger role in confronting what many people view as the greatest single threat to the refuge system in its 100-year history: the proposed opening of the coastal plain section of Alaska's 19.6 million-acre Arctic National Wildlife Refuge to oil drilling--a plan that the U.S. Senate voted down last year. Scientific studies by government wildlife biologists had confirmed that petroleum operations on the Arctic refuge would disrupt its vast caribou calving grounds and irreparably harm the region's delicate tundra ecosystem. More importantly, says Clark, "opening Arctic to drilling would totally blow apart the purpose of the entire refuge system. For if there's the will to violate a refuge as spectacular and ecologically unique as Arctic, what would stop the same from happening at the system's 75 million other acres?"

At the least, adds Clark, the 1997 Refuge Improvement Act makes doing so extremely difficult. "As there's no possible way to open up the heart of this refuge to drilling and call it 'compatible' with conservation," she says, "it would require Congressional legislation to literally set the Refuge Improvement Act aside."

More insidious threats to the system include a widening budget shortfall for staffing and maintenance, says Evan Hirsche, president of the National Wildlife Refuge Association, the umbrella organization for more than 200 local refuge volunteer "friends" groups. "Wildlife refuges have long been the black sheep of federal land holdings in terms of monetary support," he says. Specifically, the system must manage more than 94 million acres--and the welfare of more than 200 threatened or endangered species--with an annual budget of $370 million, or less than $4 an acre.

"As a result," says Hirsche, "a great deal of conservation objectives are not being met." Primary among these has been the refuge system's losing battle with invasive species such as the Australian pine and Brazilian pepper trees supplanting native habitat at Florida's Pelican Island National Wildlife Refuge; the zebra mussels and purple loosestrife crowding out native mollusks and wetland plant species in the Upper Mississippi National Fish and Wildlife Refuge; and nutria, a beaver-like Central American rodent, tearing up tidal marshes in Maryland's Blackwater National Wildlife Refuge. Also showing the strain of underfunding is the refuge system's aging infrastructure of access roads, buildings, water-management facilities and other assets.

The severe underfunding for maintenance and staff has also slowed the system's opening of new refuges, despite the annual influx of "Duck Stamp" money for land acquisition. "Before we acquire new areas, we have to ask ourselves whether we'll have the funds to manage them," explains Ashe. "Too often, I hear the argument, 'You don't have to do anything, just buy the land and protect it.' But 'protect' is an active verb."

Indeed, though much of the refuge system consists of wilderness where humans seldom tread, at a minimum, these places must be posted and patrolled. "In this day and age, even our most remote areas are no longer insulated from such illegal activities as drug trafficking, poaching and garbage dumping," says Ashe. "If we just left these places alone, I don't think anyone would be happy with what we'd find when we came back five years later." Moreover, a large percentage of the refuge system requires intensive management such as controlled burning to maintain ecosystem balance and active farming to provide grain for migratory waterfowl. "We need more maintenance workers, more equipment operators, more law-enforcement officers," says Ashe.

In particular, Ashe and conservation activists agree, the system needs more wildlife biologists. "The lack of biological expertise undermines any effort at strategic planning and wise management," says Clark. "Many of our refuges need extensive habitat restoration that can't be carried out because of this lack of biological expertise." At the very least, she explains, the system needs enough biologists to conduct wildlife surveys, monitor wildlife threats and prioritize spending at individual refuges.

For all these reasons, a coalition of 20 conservation groups, including the National Wildlife Federation, recently called on President Bush and Congress to nearly double the refuge system's budget. "Because of their strategic locations and acreage, our refuges provide safe havens for hundreds of threatened and endangered species, provide migratory stopover for millions of birds, while at the same time provide terrific areas for solace and enjoyment for people who want to experience nature," argues Clark. "But it's a system that desperately requires increased funding if it's going to address the needs of both wildlife and people."

The good news is that authorities in Washington, D.C., are finally getting the message. "We've seen sustained budget increases over recent years, including Secretary of the Interior Gale Norton's endorsement of a nearly $57 million increase for maintenance and operations in 2003," says Ashe, who credits conservation groups for their persistent lobbying on behalf of the refuge system. "Constituent organizations like the National Wildlife Federation have in the past five to six years rallied to our defense. It's in large part thanks to them that government leaders have been able to set aside political differences and support us."

Admittedly, recent federal funding increases fall far short of the refuge system's staggering maintenance backlog--currently estimated at more than $526 million, with another $700 million needed for high-priority projects such as restoring degraded habitats and promoting the recovery of endangered species.

Increasingly, refuges have come to rely on volunteers to pick up the slack. Every year some 30,000 volunteers donate more than a million hours of their time to driving heavy equipment, conducting habitat surveys, building boardwalks, running bookstores and nature programs, and lobbying for increased local, state and federal support. "That translates to about $13 million worth of services a year," notes Hirsche.

The need for volunteer support will only increase in the refuge system's second century. "These precious places are mere islands in the landscape, and we can't hope to ever acquire all the land we need," he explains. "As a result, the success of the system's conservation mission will depend on local volunteers becoming envoys to neighboring landowners and local governments, and in this way extending each refuge's wildlife objectives beyond its borders."

In the future that Hirsche envisions, "refuges will become shining examples for private landowners, state land managers and other federal land agencies of how they can all develop management policies consistent with species conservation."

New Jersey-based journalist Jessica Snyder Sachs visited the Okefenokee and Pelican Island National Wildlife Refuges while reporting for this article.

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Copyright Jessica Snyder Sachs, as first appeared in National Wildlife

FROM A DISTANCE, the oddly stunted mangrove trees of Florida's Pelican Island look dusted in snow. Approach closer, however, and the snowfall turns out to be hundreds of nesting egrets, herons, ibises, wood storks and downy young pelicans. The mangrove's dwarfed greenery likewise results from the birds, whose continual pruning for nesting material has produced an island-wide bonsai effect. Scientists estimate that this tiny islet, a stone's throw from the East Florida mainland on one side and barrier islands on the other, has provided the birds and their nestlings safe haven from predators for thousands of years.

Yet in the closing years of the 19th century, this ancient rookery came within a hair's breadth of extirpation. First came the winter tourists, shooting clouds of island birds for idle entertainment. Plume hunters followed, systematically raking the island for both nestlings and adults to feed the insatiable demand for fashionable feathered hats. Naturalists and scientists only added to the massacre in the late 1800s with their wholesale collection of eggs and specimens for display.

Watching it all from the mainland, boat builder Paul Kroegel cursed the mindless slaughter. In 1881, Kroegel established his boat shop across from Pelican Island in order to enjoy the sight of reeling birds. But by 1898, the herons, egrets, roseate spoonbills and white ibises were gone, the pelicans severely reduced. Over the next five years, Kroegel and pioneering wildlife conservationists William Dutcher and Theodore Palmer lobbied officials in Washington, D.C., for protection. In 1903, they finally convinced President Theodore Roosevelt to declare Pelican Island a wildlife sanctuary--the country's first national wildlife refuge.

Hired as the sanctuary's first manager, Kroegel earned $1 a month to keep his eye on the island rookery. He kept a ten-gauge shotgun in his dockside skiff to help persuade trespassers to move on. The mild-mannered conservationist started the island on its slow recovery.

A century later, refuge manager Paul Tritaik continues the fight to protect Pelican Island and its spectacular diversity of nesting birds. Instead of a gun, Tritaik faces the island's modern-day threats with an impressive array of bureaucratic wrangling and artfully harnessed public activism. "I try every angle I can," says Tritaik of his ten years managing a refuge that until recently didn't so much as provide him with his own budget, let alone a wildlife biologist or other full-time help.

When he arrived at the refuge in 1993, Tritaik realized that Pelican Island was literally disappearing. "I noticed it when I was looking at old aerial photos of the island," he explains. "The shape of the island was dramatically different than it is today." A survey confirmed Tritaik's worst fears: Over the course of the 20th century, the island had eroded from a 5.5-acre triangle to a 2.2-acre comma.

Part of the problem, Tritaik realized, was the island's location--dead center in Florida's busy Intracoastal Waterway. The wakes generated by the heavy boat traffic had been pounding on the fragile islet for decades. "At some point, I knew the island would simply be too small to support a viable rookery," he says. But Tritaik remained powerless to stop or even slow the traffic.

Though the refuge had acquired some 4,700 acres of surrounding water from the state of Florida in 1963, the additional territory came with the precondition that no restrictions be placed on fishing or boating. Tritaik first turned to volunteer labor to try to stabilize the islet's battered shore. When that made little headway, he finagled Pelican Island's designation as a National Historic Landmark into getting money for hiring a helicopter to dump 250 tons of oyster shell.

Similarly, Tritaik has wrangled Environmental Protection Agency funds to help clean and restore the surrounding Indian River Lagoon, even as he gleaned other restoration money based on its status as a National Wilderness Area. Most importantly, perhaps, Tritaik continues to network with Pelican Island's many passionate local supporters, who stand ready to wield their lobbying clout as well as their physical labor.

A sea change in government support arrived in 1999, says Tritaik, when U.S. Fish and Wildlife Service Director Jamie Rappaport Clark committed her agency to transforming this, the nation's first wildlife refuge, into a showcase for the system's upcoming centennial. Within three years, the refuge had acquired more than 150 acres of neighboring barrier island. The newly acquired acreage will allow the refuge to welcome the public for the first time with hiking trails, boardwalk, rookery observation tower and visitors' center. "Pelican Island today," says Tritaik, "stands as a monument to the National Wildlife Refuge System that it spawned."

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