Vaccines rely on horseshoe crabs

By Tim Prudente
The Baltimore Sun/TNS

BALTIMORE - Far from the medical labs and test tubes, a fisherman in old rubber boots walks across the docks of West Ocean City to inspect his catch.

He peers in a crate of spiny tails and grasping claws, hundreds of a common yet precious creature, among the oldest species on Earth: horseshoe crabs.

The scene on the docks is a glimpse into a strange and guarded Maryland fishery, one supporting a multimillion-dollar industry as surprising as the catch itself - a seemingly alien creature with 10 eyes, 12 legs and magical, milky blue blood.

It’s the blood that everyone’s after. About three tablespoons extracted from a live, wild horseshoe crab is refined and used to detect toxins in everyday medical products: saline drips, flu shots, heart stents. The crab blood has been the worldwide testing-standard for decades, saving countless lives from infection by screening everything from insulin shots to breast implants.

And now the coronavirus vaccine.

As the first doses reach Americans, pharmaceutical companies are relying on the blood of horseshoe crabs from the Maryland coast to ensure the shots are clean and safe.

News sites around the world are calling attention to this real-life science fiction. “Why are we ‘milking’ crabs for a coronavirus vaccine?” asks BBC News in London. Anti-vaccine activists seized on the crab blood to discourage vegans from the shots. Even as pharmaceutical companies step toward a synthetic alternative, blue-blood mythology grows.

The internet is rife with claims of horseshoe crab blood as gold: one quart worth $15,000, a gallon worth as much as a Lexus. The actual costs are proprietary and confidential. Still, the speculation’s enough to inspire bootleg bleeders. A horseshoes crab conservation group in Delaware gets offers of bottled blood from an Indonesian fisherman who wants payment through WhatsApp.

In Maryland, the few horseshoe crab fishermen have largely retreated from attention. State officials permit three fishing boats to catch the crabs for bleeding then release them back at sea. Crews dock in the harbor of West Ocean City, at Martin Fish Co.

The story of the horseshoe crab is a lesson in humility. For all of science and engineering, man still depends on mother nature. And his plan to beat the coronavirus relies on history’s trash fish.

Considered living fossils, horseshoe crabs trace back 445 million years, before the first animals crept onto land. Not a crab at all, but genetically closer to a spider, it’s a relic of the ocean insects that scuttled across prehistoric sea floors.

They survived the catastrophe that killed off the dinosaurs; they survived the Ice Age, and the coming of man. These creatures changed so little that an Ohio church set out a 68-foot fiberglass horseshoe crab as testament to divine creation over evolution.

The crabs live only on the east coasts of Asia and North America. The world’s largest population of American horseshoes winters off Maryland shores and spawns each spring in Delaware Bay. The latest trawl survey puts this population at more than 14 million mature crabs.

The American horseshoe is the biggest and the darkest, enough so to frighten children at the beach, but it’s literally toothless. Their spiny tails are no barbed defense, but a prop to right themselves in the waves. The crabs are harmless, just swimming Army helmets really.

Throughout history, they were practically worthless, too.

Researchers believe American Indians first plowed the horseshoe crabs into the soil for crops. Centuries later, farmers around Delaware Bay adopted the practice. Horseshoes were dried and ground, then spread over peach orchards or fed to hogs as mash. Historic photos show blankets of them drying in the sun, by the hundreds of thousands, obscuring the fields. Towns built factories to crush them into fertilizer. The smell was overwhelming.

By the 1960s, horseshoe crab populations plunged. Then chemical fertilizers arrived, and the factories closed. The crabs became bait, in smaller numbers, for eels and conch.

Meanwhile, a Johns Hopkins researcher studying the immune system of the crabs had made a surprising discovery. Dr. Frederik Bang found that an injection of seawater bacteria caused their strange blood to congeal. A blue jelly would encase and trap the bacteria. These crabs, after all, spent their lives slogging through a bacterial soup on the sea floor.

In the summer of 1963, another Hopkins researcher, Dr. Jack Levin, traveled to Cape Cod to study horseshoe crabs with Bang. Levin’s research would solve a problem that had confounded doctors since the invention of hypodermic needles: how to ensure injections are clean and safe.

Even trace amounts of certain bacterial toxins can prove deadly when delivered into the blood stream. Known as endotoxins, these contaminates caused the infamous “injection fever” of the 19th Century; septicemic blood poisoning from a tainted shot can still be fatal.

Medicine had long relied on laboratory rabbits to screen for this danger: a sick rabbit meant a bad dose. But Levin devised a better method with crab blood. He could mix an extract of blood cells into a solution and watch. If nothing happens, the solution’s clean; if the extract gels, it’s dirty.

Horseshoe crab blood could be medicine’s warning bell.

A multimillion-dollar industry grew on the Atlantic Coast. Workers with syringes drew the blood of horseshoe crabs at laboratories in the Lowcountry of South Carolina, near the Jersey Shore, on Cape Cod and Virginia’s Chincoteague Island. A Swiss company would bleed them in a Salisbury business park and truck the crabs back to Ocean City for release.

By the late 1990s, the number of horseshoes bled and returned to sea reached 260,000 a year, according to federal regulators. By the mid-2000s, the number climbed past 300,000 crabs. Researchers estimated by then the industry made $60 million a year.

The labs drew blood from nearly 640,000 horseshoe crabs in 2019, according to the Atlantic States Marine Fisheries Commission. For the first time in history, the horseshoe crab was worth more alive than dead.

Inside the labs, workers slide a needle through a hinge of the shell. They draw the blood from the crab’s slow-beating, tube-shaped heart. Then technicians spin the blood in a centrifuge to separate the cells. The product is refined and sold as endotoxin test kits to pharmaceutical companies. The companies test injections and medical implants. They may, for instance, bathe a dental implant in water and test the water.

Few outsiders are allowed into the blood labs. The photos online capture a futuristic scene: technicians in white lab coats, rows of horseshoe crabs strapped to stainless-steel counters, the creatures dripping a blue milk into glass bottles.

“These things are being produced in clean rooms that look like the stuff they make microchips in,” said Glenn Gauvry, who runs a horseshoe crab conservation group in Delaware.

His conservation work receives funding from the labs. Though some wildlife groups consider the money compromising, Gauvry says he can influence the industry more from the inside. He sees himself an honest broker to the question that shadows the industry. How many crabs die?

The Swiss company Lonza bleeds crabs in Salisbury and finds 5 percent of them die. Some academic researchers believe more crabs die undersea; they put the death rate as high as 30 percent. The Atlantic States Marine Fisheries Commission, which regulates the industry, settles in the middle.

“They go with 15 percent because they don’t know whether it’s 30 percent or whether it’s 5 percent,” Gauvry said. “In terms of what dies out there, of what gets released, it’s difficult to measure.”

A 5 percent death rate would mean nearly 32,000 crabs died last year; 15 percent would mean 95,000 dead crabs. Both estimates fall well below the half-a-million crabs or more killed annually to bait eel and whelk pots. The fisheries commission finds the population of American horseshoe crabs holding steady.

Still, the Sci-Fi photos of the bloodletting provoke sharp criticism from U.S. wildlife groups. Horseshoe crabs in Delaware Bay feed a beloved little bird on its migration from South America to the Arctic. The Red Knots, an environmentally threatened species, land in Delaware each spring and gorge on an abundance of horseshoe crab eggs to sustain their 9,000-mile journey. Without the crabs, the birds wouldn’t make it.

All this causes some hard feelings between communities of bird watchers and horseshoe crab fishermen. Wildlife conservation groups have urged U.S. pharmaceutical companies to quit testing with crab blood.

Meanwhile, researchers in Singapore cloned the blood of horseshoe crabs and developed a synthetic test for endotoxins. In Europe last summer, authorities announced they will accept the synthetic test as equal to crab blood.

Wildlife groups and pharmaceutical companies expected the same decision from the U.S. Pharmacopeia, which sets the national standards for medicine. The approval didn’t come, though the U.S. Pharmacopeia left open the door for companies that want to use the synthetic and are willing to demonstrate that it’s safe and effective.

The decision frustrated Ryan Phelan, director of Revive & Restore, a California wildlife conservation group that lobbied for the synthetic. Phelan says the blood labs sowed doubt about the synthetic test.

“You’ve got a very large, biomedical bleeding industry with a vested interest in keeping those horseshoes crabs coming in and basically protecting this monopoly,” she said.

Still, signs show the industry coming around. Indianapolis drug maker Eli Lilly and Company decided to test all its new medications with the synthetic. The Swiss company Lonza sells a synthetic test in addition to its crab-blood test. In Delaware, Gauvry believes the shift is inevitable.

For now, the industry says it has plenty of horseshoe crab blood to screen coronavirus vaccines. Pharmaceutical companies test a sample from a batch of vaccines, not every dose. And that sample size, say three vials, doesn’t change whether the batch contains 100,000 doses or 1 million, says Allen Burgenson of Lonza.

In fact, Burgenson says, the industry produces enough tests in one day to screen 5 billion doses of coronavirus vaccine.

Back in West Ocean City, one of the few remaining work boats motors in past sundown. The trawler sits low in the water, its deck laden with hundreds of horseshoe crabs.

No one takes notice on this November evening. There’s no clue the catch might help inoculate America.

Once, the fishing harbor had dozens and dozens of these working boats. The old names hang on the wall at Martin Fish Co. like ghosts: L.D. Lynch, Gulf Rambler, Atlantic Girl. A faded red life ring reads “Suzanne.” Each year, it’s harder to make a living on the sea.

Three boats hold permits in Maryland to catch horseshoes for the labs. Two boats sell to Lonza, with its lab in Salisbury; one to a Japanese chemical company, with a lab on the Virginia Eastern Shore. A third company bleeds horseshoes in South Carolina and a fourth in Cape Cod - but that’s all.

To the handful of Maryland fishermen, the biomedical contract offers steady work. Some summer nights, they fill their nets within an hour. One tow might deliver a mound of crabs chest-high; a crew may catch 1,200 horseshoes in a night. The work’s good enough to keep the boats running.

Their nightly catch is loaded on refrigerated trucks, temperature set to match seawater, and hauled to the Salisbury lab. By day, the crabs are washed and pricked; they bleed freely until they clot. The shells are notched so lab workers don’t bleed the same crab twice. Then drivers return the crabs to the docks.

By evening, the boats head out with the previous night’s catch. Crews don’t dump these crabs overboard, but slide them in the sea. As one fisherman likes to say, “We treat these crabs like babies.”

The coronavirus epidemic brings a flood of attention to their little fishery, and the men are wary of outsiders. But as the world strives against the virus, they are quietly proud of their contribution. “Blue bloods save lives,” one fisherman’s son told his school for the 3rd Grade science fair.

On the docks now, a fisherman inspects the big crates: nearly 800 live crabs. Like wet, black wood they glisten. They smell of brine. Their legs curl and uncurl reflexively.

The fisherman cradles a big one on its back. With his fingertips, he brushes its spider mouth. The inky legs close around his hand.

More than ever, the futures of these crabs and of people are bound together.

Horseshoe crabs, the plentiful, strange and ancient life form crawling beneath the Chesapeake waters, carry within them a highly-prized, copper-based, blue-colored blood that's used worldwide for testing vaccines and medical devices for toxins.