A proposal released this week by an obscure U.S. pharmaceutical organization could help end a decadeslong practice of bleeding horseshoe crabs caught along the U.S. East Coast for a protein used to test drug safety.
On 22 August, the U.S. Pharmacopoeia (USP)—a nongovernmental organization that helps set industry testing standards—published draft guidelines on using synthetic alternatives to horseshoe crab blood. The move could help reduce the need to harvest blood from hundreds of thousands of crabs each year, a practice that kills up to 30% of the captured animals. That has put at risk U.S. populations of the 445-million-year-old arthropods, as well as the migratory shorebirds that feed on horseshoe crab eggs, conservationists say.
The draft guidelines are a “first and important step” toward changing how companies test for dangerous bacterial contamination in their products, says Jaap Venema, chief science officer at USP.
Conservationists welcomed the proposal. The lack of an industry standard for replacing the horseshoe blood protein has been “the biggest impediment to [pharmaceutical companies] transitioning,” says ecologist David Mizrahi, vice president of research and monitoring at New Jersey Audubon and co-founder of the Horseshoe Crab Recovery Coalition.
The discovery in the 1970s that a horseshoe crab’s blue-tinged blood coagulates in the presence of endotoxins—a dangerous bacterial byproduct—was a breakthrough moment for pharmaceuticals. The coagulating enzyme, limulus amoebocyte lysate (LAL), soon became the global standard for endotoxin testing, used to check everything from pacemakers to chemotherapy drugs and COVID-19 vaccines.
But this lifesaving test comes at a high cost. Because horseshoe crabs cannot be raised in captivity, companies in North America harvest blood from Atlantic coast animals captured as they migrate inshore each spring to breed.
Demand for the animals’ blood is growing. In 2016, an estimated 400,000 horseshoe crabs were captured for their blood. That number has since shot up to about 600,000 crabs a year.
Bleeding the crabs doesn’t necessarily kill them—70% to 95% survive and are put back in the ocean, according to conservation and industry estimates. But some released animals later skip breeding or die from blood loss and stress, Mizrahi says. Although Atlantic horseshoe crab numbers are recovering from a population crash in the 1990s—partly caused by overfishing of the animals for use as bait—they remain below historic levels.
Not just horseshoe crabs are at risk, Mizrahi says. Their breeding coincides with the spring migration of shorebirds, such as the endangered red knot, that feed on the crabs’ eggs before continuing north. This refueling is so critical that some states have banned harvesting female horseshoe crabs.
Conservation groups have for years pushed for pharmaceutical companies to switch to synthetic alternatives. One substitute, a protein called recombinant factor C (rFC), has existed since the 1990s. The European Pharmacopeia has endorsed the use of rFC since 2019.
But much of the industry has been slow to use rFC because it’s not endorsed by USP, which sets standards for drug manufacturing in 150 countries. Companies currently have to prove to regulators that synthetic alternatives are as effective for LAL for each product—a process that takes time and money.
USP’s microbiology committee has previously made proposals to replace LAL. But after public comment, the organization rejected them, citing a lack of data. Infighting has also hampered these efforts: The last panel tasked with creating the standard was dismissed by Venema in September 2022 because of “fundamental issues with the dynamic of this group,” according to a USP press release.
The proposal is stronger this time because a large body of data now supports the use of synthetic alternatives, Venema says. The standards will be open for public comment in November and December and could be finalized in 2024.
Not everyone is ready to abandon the horseshoe crab protein. “We’re pleased to see that the USP is considering the proposal,” says Nora Blair, a senior manager at Charles Rivers Laboratories, a leading source of LAL. However, these alternatives “may not be suitable for all products produced by the biopharmaceutical industry.”
Still, Mizrahi expects that the USP proposal will meet with limited backlash. The next stage will be convincing companies to take up the alternative tests. “That said, this is definitely a step in the right direction,” he says.
