Anyone who gets a flu or Covid shot, childhood immunization, heart stent or hip replacement — and that’s almost everyone — is protected from exposure to potentially lethal contaminants known as endotoxins by a test that uses what might seem like an odd ingredient: the blue blood of the horseshoe crab.
Endotoxins are a worry in medicine. They exist in the cell walls of certain bacteria and can be released when the bacteria break down or die. These toxins can send a patient into a tailspin of fever, chills, septic shock and death.
To keep patients safe, pharmaceutical companies run roughly 70 million tests a year on injectable medicines and implants for the presence of these toxins with a substance called limulus amebocyte lysate. It is an extract of cells from horseshoe crab blood and can identify even infinitesimal amounts of the toxin by reacting with it. No other natural substance is known to work as well.
The problem is that horseshoe crabs are in trouble. Their numbers are declining — “a finite source with potentially infinite demand,” as one pharmaceutical executive told Agence France-Presse last year, “and those two things are mutually exclusive.”
A cloned alternative to using horseshoe crab blood, known as rFC, for recombinant factor C — the endotoxin-sensitive enzyme in the blood — came on the market in 2003 with one supplier. A second manufacturer began producing it in 2013. But nearly 10 years later, no standards have been set for the use of rFC by U.S. Pharmacopeia, the nonprofit scientific organization that sets the legally recognized standards for the strength, purity and quality of medicines manufactured and distributed in the United States. It’s been a bumpy road.
U.S.P. has proposed two sets of standards for rFC since 2019. The first was withdrawn. A second proposal was released in 2020 and was under review by an expert committee assembled by U.S.P. But last September U.S.P. dismissed that committee. In explaining the decision, U.S.P. cited “fundamental issues with the dynamic of this group that resulted in an inability to work collaboratively and productively, impeding the standards-setting process.”
U.S.P. has just convened a new expert committee, which is meeting for the first time this week. Hopefully, the committee will set standards for rFC so drug makers will be able to use the synthetic test without facing the possibility of what they say can be protracted and expensive testing to win approval by the Food and Drug Administration in the absence of U.S.P. standards. U.S.P.’s chief science officer, Jaap Venema, said, “We have made it very clear it is a top priority.” He added that the new committee would “weigh the available scientific evidence and stakeholder input to determine the appropriate way to include L.A.L. alternatives in our standards.”
Horseshoe crabs have survived five mass extinctions over 475 million years, but today they are gravely threatened worldwide by human exploitation.
In Asia, where horseshoe crabs are killed for food and for their blood, they face extinction from “relentless and unremitting” threats from humans, according to the International Union for the Conservation of Nature, which tracks trends in wildlife populations worldwide. Horseshoe crab numbers have plummeted in large swaths of China and are declining rapidly in Vietnam, leaving American horseshoe crabs, also diminished in numbers, to fill the growing gap.
In the United States, fishermen take some 1.4 million each year, killing almost half for use as bait. Pharmaceutical companies capture and extract blood from the other 700,000 to make the endotoxin test before releasing them to the sea. Up to 30 percent may die as a result. Many others never make it to shore to lay their eggs.
The International Union for the Conservation of Nature considers horseshoe crabs in the United States vulnerable to extinction along much of the East Coast and endangered in New England. Over 20 years of regulation of the horseshoe crab fishery by coastal states has failed to restore these ancient animals to their former abundance.
Their decline also poses a threat to migratory shorebirds like red knots, which depend on the energy-rich horseshoe crab eggs they consume on beaches in South Carolina and along the Delaware Bay during their spring refueling stops as they head north from Tierra del Fuego, at South America’s southernmost tip, to the Arctic.
To protect these creatures and the birds that depend on them, coastal states should prohibit these crabs from being harvested for bait, as the South Carolina Legislature did in 1991 and the New Jersey Legislature did in 2008.
And U.S.P. must fulfill its role and set standards for using rFC. As progress at U.S.P. has stalled, its counterpart in Europe has already given rFC the green light, and regulators in Japan have published guidance for using rFC.
At the drug maker Eli Lilly, the biologist Jay Bolden, a longtime birder concerned about the futures of both the horseshoe crab and the transcontinental red knot, began leading the company through an F.D.A. process to use rFC in 2013. Lilly — along with the drug makers Sanofi Pasteur, Pfizer and Roche-Genentech — has compiled voluminous data demonstrating that rFC is equivalent to or better than limulus amebocyte lysate and more reliable. Today, Lilly uses rFC in eight of its manufacturing facilities and for all its new injectable drugs.
Sanofi Pasteur, Pfizer and Roche-Genentech, sharing Lilly’s concerns about the depletion of horseshoe crabs, are also making the long transition to using rFC. A green light from U.S.P. would save drug makers “weeks of laboratory validation tests and documentation for every new product and subsequent F.D.A. regulatory review and approval,” according to Ned Mozier, a vice president at Pfizer.
Which is why many other pharmaceutical companies are waiting for U.S.P. to act.
Christopher Earl, a retired biopharmaceutical venture capitalist, told me that U.S.P.’s failure to determine that rFC can be used interchangeably with the test using horseshoe crab blood, without additional testing and validation, “is the single most important factor limiting further conversion” to the synthetic test.
“We know that multiple biopharmaceutical and biotechnology companies are eager to test rFC with the goal of replacing” the current test, he said, but U.S.P. needs to act.
And that’s where things stand today, as the spring spawning season for horseshoe crabs is about to begin. The animals will gather in large numbers to lay their eggs on beaches along the East Coast, where fishermen taking the crabs for bait and blood will scrape them from the seafloor with trawls or pull them from the beaches as they come in to lay their eggs.
Evelyn Der, a microbiologist overseeing work on the synthetic rFC test at Roche-Genentech, one of the world’s largest drug companies, wrote me, saying that “relying on the ancient horseshoe crab” for endotoxin testing “is not sustainable.” She added that “rFC adoption for endotoxin testing is imperative to spare the lives of horseshoe crabs and other dependent species.”
As the work of U.S.P.’s new expert committee gets underway, horseshoe crabs continue to face serious threats along much of the Eastern Seaboard.
In South Carolina, fishermen taking them for bleeding have been emptying horseshoe crabs from beaches designated to protect wildlife. On Long Island, scientists monitoring horseshoe crabs last spring and summer counted the fewest spawning horseshoe crabs on the fewest beaches in 20 years. Delaware Bay beaches are no longer suffused with horseshoe crab eggs.
After millions of horseshoe crabs were removed from the Eastern Seaboard in the 1990s, the population of migrating red knots crashed, resulting in the U.S. Fish and Wildlife Service listing the bird as threatened. Crab egg densities in New Jersey have yet to recover, the number of knots is still depleted, and populations of other shorebirds relying on the eggs are also tanking, some by at least 85 percent since 1980.
To protect the public health, pharmaceutical companies need an unlimited source for endotoxin tests that doesn’t depend on a wild animal. The world has only so many horseshoe crabs. It’s time for us to let them be.
Deborah Cramer is the author of “The Narrow Edge: A Tiny Bird, an Ancient Crab, and an Epic Journey.”
The Times is committed to publishing a diversity of letters to the editor. We’d like to hear what you think about this or any of our articles. Here are some tips. And here’s our email: [email protected].
Follow The New York Times Opinion section on Facebook, Twitter (@NYTopinion) and Instagram.
Source: Read Full Article