OUT FOR BLOOD BioWhittaker Inc. has found a life-saving use for the lowly horseshoe crab

THE BALTIMORE SUN

Chincoteague, Va. -- Leon Rose's grin splits the darkness and he says: "Watch this." The nets on the Susan Dawn groan and a glistening bounty of horseshoe crabs spills onto the deck of his old wooden workboat. Under a full moon, the bellies of these prehistoric creatures shine like polished mahogany and their legs wriggle madly to escape.

No wonder. Leon Rose is out for blood -- an ounce to be exact.

But the crabs will return to the Atlantic in less than 24 hours, shortly after making a donation.

Once the homely horseshoe was thought to be nearly useless to man -- good only for feeding hogs and baiting eel pots. Today, BioWhittaker Inc. of Walkersville uses the blood to help ensure that the drugs people are injected with are safe -- free of endotoxin, a bacterial product that can kill if it gets into a person's bloodstream.

Biotechnology companies across the country are turning the most obscure creatures -- from horseshoe crabs to algae to poison dart frogs -- into drugs and other products.

Test for septic shock

For BioWhittaker, which makes a drug-testing product from the horseshoe crab's blood, the creatures represent about 18 percent of company revenues -- and the hope for much more. On the horizon: a test for septic shock, a bacterial infection that kills 100,000 people a year in the United States. That prize product would significantly expand the $40 million- to $50 million-a-year market BioWhittaker now shares with several other companies.

BioWhittaker, a 40-year-old biotechnology company that spun off Whittaker Corp. in November, wants to grow. The company had revenues of $41 million last year on sales of its cell culture products and clinical diagnostic testing systems.

But is there enough blood out there for all these products -- and profits? There are no definitive studies tracking the crabs' death rate after blood is drawn, but biotech companies say crabs regenerate their blood in a couple months. And they say the crab population is still strong -- and likely to be protected by the competition among companies. After all, no crabs, no profits.

For BioWhittaker, product development begins on Leon Rose's boat in the Atlantic, far enough from the coast that Assateague Island's lighthouse is just a blink in the distance.

From spring to fall, Mr. Rose and his crew go out five days a week, often at sunset when the crabs emerge from their cool hiding place in the Atlantic's muddy bottom. For several hours, the Susan Dawn crew sets out and hauls back large nets bulging with crabs. Their motto "To Bleed" is tacked just above the door to the cabin.

When they head back, 600 or 700 crabs will be piled on the decks, some escaping boxes to lumber around like turtles. They are transferred to BioWhittaker's bleeding facility on Chincoteague, a place not unlike a Red Cross bloodmobile.

Horseshoe crabs have survived virtually unchanged for 200 million years, outlasting dinosaurs and ice ages. A relative of the land spider, the crab has a tough shell and adaptable nature that allows it to live for months out of the water without food or to adjust to arctic or tropical temperatures. Its eggs have even survived for a full year on beaches, waiting to be fertilized, said Carl N. Shuster Jr., a marine biologist who has studied the horseshoe for decades.

Blue blood

For BioWhittaker the one attribute that really counts is the crab's amebocytes. These white cells contain a coagulant, which protects the crab from invading bacteria by surrounding them with a blood clot.

At the BioWhittaker facility, the crabs are fit into benches that hold them in place. Gowned laboratory technicians gently slide a 2-inch needle into a muscle between the hard shell joint at the base of the crab's tail. A cloudy blue-colored blood shoots into a bottle.

In sterile conditions, blood cells are opened to get a lycate, a cellular material that is taken in large bottles to Walkersville, near Frederick, where it is turned into a line of products. Each one can be used to help drug manufacturers test their injectable drugs or medical devices -- such as an artificial hip -- for safety, said William McCormick, director of manufacturing for a portion of the company's biotechnology products.

Most often the products test the water used to manufacture the drugs. For example, one BioWhittaker product will turn the water to gel if it is impure.

The research that triggered the use of crab blood began more than 20 years ago. A Johns Hopkins University professor, Dr. Frederik Bang, discovered the extraordinary secrets of the horseshoe while studying how marine life fights infection at a Woods Hole, Mass., laboratory.

Since then a handful of companies, including BioWhittaker, have competed to provide the marketplace with a test for drug purity.

The Maryland company is the second-largest supplier, said Dr. McCormick, largely because its corporate predecessor stumbled in the mid-1980s after it bought Mallinkrodt, a company that had one superior product.

Many of Mallinkrodt's former employees left the company and the product's quality fell.

"It wasn't working," Dr. McCormick said. "We began losing business like crazy." Meanwhile, competitors such as Cape May Associates grew.

Since then BioWhittaker has gained back business by adding two new products to its line and achieving consistent quality, he said.

There is plenty of room for growth.

Many new drugs are not tested using the horseshoe crab blood but by the traditional method of injecting rabbits with the drug. If they develop a fever, the drug is impure.

But a recent change in U.S. law requiring drug manufacturers to use products like BioWhittaker's for testing certain drugs has made revenues grow. "We are seeing customers in places like Singapore, Argentina and Brazil," said Thomas R. Winkler, vice president and general manager of biotechnology products.

More dramatic growth may be seen as early as 1994, when BioWhittaker would like to begin selling a new test for septic shock.

Difficult entry

If the crab blood can detect the presence of endotoxin in a drug, company researchers have asked, then why not use it to test whether a person is also infected with the same bacteria? Since patients with that infection -- called septic shock -- can die within hours, a new, quick test is needed to tell doctors how and when to treat the disease.

Development of the life-saving test may be only several years off, Mr. Winkler said.

While there is no reason another company could not come along to capture BioWhittaker's place, gaining entry into the market is difficult. The Food and Drug Administration tightly regulates the small industry, scrutinizing the manufacturing process and testing a sample from every batch of the products the company produces to sell.

And what about the crabs? Can they handle the onslaught of science? Few studies have been done to find out what percentage of crabs may die because of the bleeding process or what the long-term effects might be on the crab population. One study found that 10 percent of the population that was bled died, Dr. Shuster said.

But preliminary results from a more recent study that tagged 12,000 horseshoe crabs -- half of which had been bled -- showed little difference in mortality, said Benjie Swan, head of Limuli Laboratories. The tiny New Jersey company extracts crab blood and sells it to other companies for processing.

And the horseshoe crab population along the East Coast is believed to be on the rise since commercial harvesting has been curtailed, Dr. Shuster said.

Despite the millions of crabs out there, Ms. Swan and Dr. McCormick are increasingly protective of their separate populations of crabs in Delaware Bay and Chincoteague. And they're growing more critical of those who haul truckloads of egg-filled female crabs from the beaches during mating season, quarter them and then sell them to fishermen for bait.

"Tens of thousands of crabs can be carried out every day," said Dr. McCormick, whose company contracts through a supplier who pays Leon Rose for the crabs.

"I discourage the use for eel baiting," he said. "I don't want my people involved."

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