Ingrid WIckelgren
Popular Science, March 1996
Maryland biologist RALPH COLLINS likes to drive across the country – not to see the sights, but to pick up the local dirt. Literally. On the road, Collins pulls over whenever he spies an interesting dirt patch, perhaps near a stream or under a construction site. Then, wielding high-tech tools (a spoon and a plastic sandwich bag), the scientist scoops some soil into the bag and drives on.
Whoever owns this dirt doesn’t seem to miss it, and the soil samples are precious to Collins. In these clumps of earth, the National Cancer Institute researcher hopes to find a treatment for AIDS or cancer. Collins is a bioprospector, someone who scours nature for compounds that fight disease or perform everyday jobs such as removing fabric stains and keeping bread fresh. While many bioprospectors probe plants and animals for novel substances, Collins taps nature’s smallest and most abundant servants-microorganisms such as fungi and bacteria.
Collins’ fascination with what lurks in the dirt is far from unusual. Large pharmaceutical companies as well as smaller biotech firms screen thousands of microbes a week for profitable potions. University and government scientists help in the hunt by collecting and identifying fungi and bacteria from a variety of environments. Even researchers’ friends and relatives join the pursuit by taking back microbial souvenirs from their favorite vacation spots.
Such soil-searching efforts have manifold benefits:
• On vacation in Norway, an employee at Sandoz Pharmaceuticals took home a mold that later produced a blockbuster anti-rejection drug known as cyclosporin. • In a corn field, a graduate student at the University of Wisconsin found a bacterial ice-forming protein that’s now used by hundreds of ski resorts to make artificial snow.
• In the soil of an Indonesian temple, a scientist dug up a microbial molecule that soft-drink suppliers now use to tum starch into sugar.
• On a golf course in Japan, a scientist picked up a clump of soil that harbored a cure for a parasitic infection that plagues livestock.
That’s just a start. Microbial spoils are sources of flavors and nutrients in foods and vitamins. They provide cheaper and more effective ways to make cheese, bleach paper, process juice, and stonewash jeans. And safe, biodegradable molecules from microbes can often replace toxic and otherwise polluting chemicals used in industrial processes.
What’s good for humankind is also good for the bottom line. At the Danish company Novo Nordisk, for example, sales of industrial chemicals derived from microbes reached $570 million in 1994.
Not that finding lucrative microorganisms is easy. For drugs especially, sifting through thousands of soil samples for a disease-fighting microbe is like looking for a needle in a haystack. On average, one marketable new drug is found for every 20,000 natural compounds tested. As a result, years may pass before a research group finds even one important new chemical.
But the wait is worth it, because nature’s novelty far surpasses human inventiveness. “The magic of natural compounds,” says Art Girarda, microbiologist at Pfizer, a major drug company “is that nature gives us things a chemist never dreamed of.”
lvermectin, sold by pharmaceutical giant Merck, is a case in point. A product of a soil bacterium, lvermectin fights parasitic worm infections in humans and animals better than any other known substance. Yet this wonder drug has a novel biochemical method of action that no one could have predicted. It paralyzes the worms by blocking the transmission of nerve signals.
We’ve barely begun to tap nature’s vast resources. Only a tiny fraction of all microbes have been identified. Finding the rest or what’s out there is a race against time, warns Cornell University ecologist Thomas Eisner. Given the rapid loss of biodiversity on Earth, he and other experts fear that beneficial species will become extinct before anyone even knows they exist.
To jump-start the collection process, the National Institutes of Health and the National Science Foundation last year established the Bioprospecting Opportunity Awards. These grants are designed to encourage scientists already conducting biodiversity research to add a bioprospecting component to their work. The National Cancer Institute also has expanded its program to screen natural sources for activity against cancers and the AIDS virus.
Those national efforts involve probing plants as well as microbes for valuable compounds. But most pharmaceutical and biotech companies have bet on the microbes. Collecting them is easy, and they can be grown in petri dishes, laboratory flasks, or fermentation tanks.
In fact, people have been raising microorganisms for thousands of years without knowing it. In ancient times, these tiny workhorses were used to make beer and wine. But no one recognized their contribution until 1837, when French and German scientists independently showed that yeast causes fermentation.
By the early 1900s, scientists began looking to microbes as sources of substances other than alcohol. One of the first chemicals to be mass produced from fungi was citric acid. now used to flavor soft drinks and acidified foods. The acid was originally extracted from citrus fruits such as lemons and limes. But in 1917, a Pfizer chemist named James Currie realized that it could be made more cheaply using fungi.
Even then, the world was blind to microbes as a source of medicines. The first clue that drugs might come from these microscopic organisms emerged in 1928, when a mold invaded a petri dish in Alexander Fleming’s London laboratory. It seemed to prevent bacteria in the dish from growing. To the astute Fleming, that could mean only one thing: The mold made a substance that killed bacteria. Fleming’s observation led to the production, in the early 1940s, of the first antibiotic, penicillin.
The discovery of penicillin launched the antibiotic era – a mad race to find microbial substances that could wipe out disease-causing bacteria. That race produced hundreds of life-saving antibiotics including tetracycline, streptomycin, and terramycin, In the last 20 years, the hunt has broadened beyond bacterial infections to include other medical problems such as heart disease and the rejection of transplanted organs. The success of these more recent efforts has depended not only on luck but also on a better understanding of the molecular causes of disease.
The cholesterol-lowering drug Mevacor is a good example. In the 1970s, Merck scientists began looking for a natural compound that would lower cholesterol levels in people. The researchers approached their search rationally: They first studied how the body synthesizes cholesterol and identified a key chemical step where a drug might interfere. Then they designed a test for a substance that would block this step. After running thousands of natural chemicals through this test, they hit pay dirt in the early 1980s with a chemical in a soil sample from Spain. In 1987, Mevacor reached the market.
Another molecular test spotted a winner in a clump of soil taken from the foot of Mount Tsukuba outside Tokyo. Scientists at the Japanese drug company Fujisawa had been looking for a medicine that could suppress the immune system. Such drugs are given to recipients of organ transplants to prevent them from rejecting their new organs. Fujisawa scientists had developed a test for a compound that would suppress key molecular events that trigger the destructive immune response. In the mid-1980s, a compound from the mountain soil passed” this test. In 1994, Prograf was finally approved by the U.S. Food and Drug Administration for use in liver transplants.
Meanwhile, industry’s use of microbes has extended far beyond alcohol and citric acid. Several companies are now profiting from protein molecules, called enzymes, made by microbes. These proteins catalyze chemical reactions that make it possible for microbes to break down their “food,” but the same proteins can also aid chemical processes useful to people. In detergents, microbial enzymes break down fat, starch, and protein stains. Other enzymes go a step further. Carezyme, an enzyme used in the detergents Tide and Cheer, makes cotton fabrics look new by snipping off the fuzz created by frequent washings.
Later this year, Novo Nordisk will introduce a new enzyme, derived from a soil fungus, that will make separating white and colored laundry unnecessary. The enzyme breaks up any dye floating in solution, thus preventing dye that washes out of one piece of clothing from spreading to another. Bachelors everywhere will be freed from the curse of pink underwear.
In the food industry, microbial enzymes can improve the yield and quality of tropical juices by breaking down unwanted molecules in fruits. And a starch-degrading enzyme helps bread retain moisture, keeping it fresh longer.
Many microbial enzymes not only work better than synthetic counterparts but also benefit the environment. For example, toxic bleaching compounds such as chlorine are usually required to produce high-quality paper. However, a new Novo enzyme called Pulpzyme helps make paper more susceptible to bleaching so that less chlorine is needed. Enzymes can also reduce the amount of polluting sulfides needed to treat leather and can replace hexane, an explosive and poisonous solvent, in the extraction of oil from vegetables.
Although microbial products abound, each one marks the end of a long road from collection to market. Gaining government approval for a new drug, for example, typically takes 14 years after researchers find a “hit” -a chemical that shows promise in a lab test. Not surprisingly, pharmaceutical companies have developed an elaborate process for moving potential drugs through the steps to approval.
At Pfizer headquarters in Croton, Connecticut, the process starts in the lab of Liang Huang, curator of the company’s 50,000-piece microbial culture collection. Huang’s research team is responsible not only for preserving precious fungi and bacteria, but also for collecting them, growing them, and coaxing them to produce their unique cocktails of chemicals.
After Huang finishes his work, the chemicals from the microbes fall into the hands of Robin Spencer, assistant director of exploratory medicinals, and his robots. One of those robots uses toothpick-thin retractable tubes to suck up liquids from an array of plastic compartments the size of pencil erasers. The robot’s metallic arm slides over to another array of plastic wells, and the tubes spit the fluids into the correct receptacles for tests. Directed by a portable computer on a nearby stool, the robot works around the clock measuring out samples, a task that would drive a person crazy.
A second robot tests as many as 7,200 compounds a night for their activity against diseases. The robot adds a “target” chemical to each of the plastic wells filled by the first robot, setting off thousands of different chemical reactions. In the morning, Spencer and his team can see, -often, by a color change – whether any of the chemicals show promise.
Such automation, known in the industry as “high throughput screening,” has completely transformed the way Spencer’s lab works. “Nine years ago, it would have been heroic to do 1,000 [tests] in a year,” quips the energetic biochemist. “Now, we do 300,000 in six months. The ability to screen lots of compounds quickly is essential, given the slim chance that any one will show promise as a drug. Yet faster screening doesn’t necessarily speed up the rate at which drugs enter the marketplace. That’s because would-be drugs must leap additional hurdles, including the difficulties of mass production and several lengthy rounds of clinical trials, before they are sold.
While promising substances make their way toward the corner drugstore, Huang and other bioprospectors are recruiting new microbial potential. Moving beyond garden variety dirt, scientists are increasingly searching for microbes in exotic locales such as bat caves, hot springs, undersea volcanoes, fossils, and even mummies. Unusual environments breed unusual microbes. For example, within Yellowstone’s hot springs live microbes that produce heat-stable enzymes, which are useful in food processing and other industries.
Indeed, wherever weird microbes are said to live, bioprospectors prowl. A society of giant bacteria was discovered 1,000 feet underground at the government’s Savannah River nuclear plant in South Carolina a few years ago. Researchers are flocking to Antarctica to search for microbes that love the cold. And Cornell University chemist John Clardy and his co-workers are picking apart plants to isolate members of a recently discovered breed of fungi that live inside leaves and stems. “The name of the game is to find something different,” says Clardy. There is a niche for everyone. One University of Iowa prospector studies animal dung for resident fungi. “It’s a fertile area,” Clardy observes.
But plenty of microbial treasures are waiting to be discovered on playgrounds, golf courses, and in backyards. Of all sources, soil is the richest in microbes-which explains why some researchers carry a spoon and a box of sandwich bags wherever they go. “Inevitably; says Huang, “we always go back to dirt.”