The Horseshoe Crab

The four species of horseshoe crabs are an ancient (~450 million years old) and important species that support the ecological function of estuaries and the survival of migratory shorebirds. The current over-exploitation of horseshoe crabs is sadly not dissimilar to other mismanaged species that were driven to extinction.

The Problem

The Harvesting of Horseshoe Crabs for the Pharmaceutical Industry

In the United States, one species of horseshoe crab (Limulus polyphemus) is harvested annually in huge numbers by the pharmaceutical industry and bled alive, its blood used to create the biomedical test, Limulus Amebocyte Lysate (LAL). LAL is the gold standard for endotoxin testing in vaccines and injectable biomedical devices (human and pets). Every drug certified by the U.S. Food & Drug Administration must be tested using LAL. Global demand for this testing process is very high and growing. In the U.S., estuaries like Delaware Bay – where Horseshoe crabs go to spawn each spring – currently support only one third the population that habitat models predict they should.

A synthetic alternative, known as recombinant factor C (rFC), was developed approximately 15 years ago but has not achieved sufficient market penetration to supplant the bleeding of horseshoe crabs by any significant amount. Understanding exactly why that is the case remains a mystery that Revive & Restore is trying to solve.

While the biomedical applications of Horseshoe crab blood create a huge demand for the crab, the pharmaceutical industry alone isn’t responsible for the over harvest of this species. Not only are the crabs caputured and bled for biomedical applications, they are also harvested as bait for the eel and conch fisheries. Compounding the threat of over harvesting are the effects of climate change and rising sea levels, which are diminishing the availability of suitable beach spawning habitat.

The situation is more dire in Asia – where, in addition to the huge take of crabs for biomedical testing, food, and other uses, massive shoreline alterations on the continent are destroying habitats for migratory shorebirds at an unprecedented scale. All three of the Asian horseshoe crab species have been modeled to go functionally extinct in seven years under current harvest rates.

All of these issues warrant concern and immediate conservation action solely to protect this crab. But the over harvest of the Horseshoe crab is causing significant ecosystem-level impacts as well. Most notably, a suite of long distance migrant shorebirds synchronize their northward migration in the Atlantic flyway to gorge on the eggs of spawning horseshoe crabs on their way to the Arctic nesting grounds. A recent study (still in review) has confirmed a highly-correlated relationship between the availability of horseshoe crab eggs and the survival of long distance migratory shorebirds. The existence of similar functions for migratory shorebirds in the Asian Far Eastern flyway are not known. However, a potential domino effect is predicted when the dwindling population of the Asian horseshoe crabs threatens the survival of migrant birds in that region.

Learn more about the synthetic substitute to Horseshoe Crab blood here.

The Red Knot (Calidris canutus) depends upon Horseshoe Crab eggs for its survival during its spring migration from South America to the Canadian Arctic. As the numbers of Horseshoe Crab dwindle, so too does the Red Knot population. For any meaningful recovery of this bird, Horseshoe Crabs must return to spawn on the beaches of Delaware Bay in greater in numbers.

The Solution

Creating an Incentive for the Adoption of a Synthetic Substitute

Recombinant Factor C (rFC) – a synthetic substitute for LAL – was developed by Dr. Ling Ding and Bow Ho of the National University of Singapore. Her process was subsequently licensed by Lonza, and their patent for rFC will remain in effect through May 2018. The upcoming expiration of patent protection in the U.S. provides an economic incentive for the widespread adoption by the pharmaceutical industry of the synthetic substitute to Horseshoe Crab blood. Currently, the only pharmaceutical company to use rFC in place of LAL in the manufacturing process of vaccines and injectable medical devices is Eli Lilly, which has replaced LAL in all but the final testing of selected products.

Dr. Ding’s research shows that the efficacy for rFC is in many ways better than that of LAL. As she explained to Revive & Restore Executive Director Ryan Phelan, when LAL is used, every component of the full cascade needs to be fully functional in order to allow the signal of an endotoxin to be successfully detected. The cascade constitutes the Factor C, Factor B, Proclotting enzyme, and Coagulogen. LAL suffers from batch-to-batch and seasonal variations in the efficacy of each element of the cascade. Furthermore, the presence of Factor G in LAL (if not deactivated or completely removed in LAL processing) can give rise to false positive detection of endotoxin. The problems with LAL have been well-documented in scientific journals and reports over the last 40 to 50 years.

But the manufacture and use of LAL is a huge industry. In 2016, it was estimated that approximately 70 million tests are performed annually for endotoxins using LAL. One of the critical factors limiting the adoption of rFC stems from the industry-wide reliance on LAL as the standard test for endotoxin detection for nearly 50 years. The pharmaceutical industry continues to see LAL testing as the gold standard for endotoxin detection despite several recent studies proving the efficacy of rFC is equal if not better than LAL. Because of the industry as a whole still doubts the efficacy of the synthetic substitute, it has been a challenge for rFC to gain significant market share.

Those study results suggest there should be growing interest in and conversion to a substitute that is off-patent, easy to manufacture, and that provides a consistent and more effective performance. However, the economic incentives to switch to the synthetic alternative have not been quantified, and any modeling will need to take into consideration the cost to drug manufacturers to “convert” from LAL to rFC. Since only Eli Lilly has done so, data on this approach has been difficult to acquire.

In keeping with our mission to protect endangered species using genomic technologies, Revive & Restore is focused on increasing the number of pharmaceutical companies that agree to transition from LAL to the synthetic alternative as a means of endotoxin testing. To do so we are examining the economics of rFC adoption and how the release of patent protections next year might affect the manufacturing costs for pharmaceutical companies that switch to rFC. We have heard that rFC is not hard or costly to produce. If more suppliers start manufacturing the substitute, its price should drop. We are also working with a law firm to explore the regulatory framework that has contributed to the slow and limited adoption of rFC.