Horseshoe Crab Blood Ensures the Safety of Drugs and Vaccines, But Supplies Are Dwindling

If you visit the beaches in the mid-Atlantic in the early spring, you will see thousands of horseshoe crabs come to shore to lay their eggs. For local birds, it’s an all-out feast. For pharmaceutical companies, it’s a vital resource that’s used to test the efficacy of various drugs and vaccines.

The horseshoe crab is the world’s only natural resource for limulus amebocyte lysate (LAL), a substance that detects a potentially fatal contaminant called endotoxin. It’s found in the creatures’ milky blue blood. Every year, pharmaceutical manufacturers collect around half a million crabs from the wild, strap them to steel shelves while they are still alive, and drain around one third of all their blood before releasing them back into nature. The blood has become so valuable in recent years, a liter now goes for around $15,000.

The immune cells in the crab blood coagulate around toxic bacteria, giving researchers a clear indication of contamination. This makes it incredibly effective at spotting signs of infection, but supplies are dwindling.

“All pharmaceutical companies around the world rely on these crabs. When you think about it, your mind is boggled by the reliance that we have on this primitive creature,” says Barbara Brummer, state director for The Nature Conservancy in New Jersey.

In 1990, there were around 1.24 million horseshoe crabs reported in Delaware Bay. By 2002, that number had dropped to just 333,500. In 2016, the International Union for Conservation of Nature listed them as “vulnerable” to extinction.

Environmentalists are pushing the medical industry to reduce its dependence on crab blood. Animal researchers say draining the crabs of their blood can harm the creatures and anywhere between 5% and 30% of them will die when released from captivity. Females also tend to become lethargic after being drained of their blood, which makes it hard for them to wade into shallow waters to lay their eggs.

The COVID-19 pandemic accelerated demand for horseshoe crab blood as drug companies began testing vaccines before bringing them to market. In 2020, the industry bled nearly 650,000 crabs in America, 36% more than in 2018.

The decline in the horseshoe crab population is also having a widespread effect on the natural environment. The birds that rely on the crab eggs for food are declining in numbers as well.

“What we’re fighting isn’t just a battle about horseshoe crabs. It’s about keeping ecosystems productive,” says Larry Niles, a biologist with the Conserve Wildlife Foundation of New Jersey, who has spent his career researching the environment and species of Delaware Bay.

Considering the impact on the natural ecosystem, the industry has been steadily shifting away from crab blood. In Europe, a synthetic alternative for LAL is quickly becoming the new medical standard.

A Swiss biotech company called Lonza was able to clone horseshoe crab DNA in 2003 to create recombinant Factor C (RFC), a sustainable LAL alternative. Jay Bolden, an avid birdwatcher and biologist, helped convince drug makers in the U.S. to consider making the switch. 

It was first used in America by Eli Lilly, a pharmaceutical company. In 2017, the company published a study that showed RFC detected endotoxins as well as LAL, if not better. The test also turned up fewer false positives and was significantly cheaper to produce compared to those that use real crab blood.

Eli Lilly says 80% of the company’s products are now tested with RFC instead of LAL.

But forgoing authentic horseshoe crab blood remains a challenge in the U.S. Regulators have been slow to approve the synthetic alternative in an abundance of caution.

In 2018, the FDA approved the first medicine tested with RFC. Six more of Eli Lilly’s products have since been authorized for use in the U.S.

RFC is now listed as an approved endotoxin-testing agent in Europe, China, and Japan, but the U.S. Pharmacopeia (USP), a non-profit that helps set medical quality standards on which the FDA relies, has been reluctant to add the synthetic substance to its list of authorized testing materials.

When asked why the agency has been slow to approve RFC, it said, “one adverse incident might not only set back the adoption of RFC but could damage overall trust in vaccines or other injectables, already plagued by misinformation.”

But the regulatory delay comes at a cost. The horseshoe crab population will continue to decline as demand for vaccines, injectables, and drugs increases.

“We are doing damage to an endangered population and not using an alternative that is equally effective and could be mass-produced” more cheaply, Brummer said.

Every creature plays a vital role in the local ecosystem. Coastlines in the mid-Atlantic region could see diminishing wildlife, tourism, and fishing revenue in the years to come unless the U.S. finds a way to stabilize the horseshoe crab population.

“The value of a natural resource,” Niles said, “doesn’t belong to companies that are exploiting it. It belongs to us.”