How Big Pharma can save a 450 million year old species

Latest update May 10, 2018 Started on May 10, 2018

Horseshoe crabs have roamed the oceans since the age of the dinosaurs. They are unique in shape – their shells look like a Samurai Helmet, and they are known for their distinctive blue blood. Since the 1990s, Horseshoe Crab populations around Delaware Bay have collapsed due to demand for the blue blood of Horseshoe Crabs from pharmaceutical companies to assess the safety of medical products. However, new technologies have been able to produce a synthetic alternative to Horseshoe Blood (using Army Worm blood). This NatGeo expedition is to track the progress of adoption of this synthetic alternative and bring an end to the bleeding of Horseshoe Crabs for their blue blood.

May 10, 2018
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In The Field

Meetings on the side of the World Economic Forum at Davos, Switzerland, with major pharmaceutical companies on the adoption of the rFC synthetic alternative to Horseshoe Crab blood.

Issues discussed at the World Economic Forum's Ocean Day, held for the first time at Davos this year.

Here’s everything you need to know about Davos 2019

Who's coming and what they'll be talking about. Read more:

Posted by World Economic Forum on Friday, January 18, 2019


On May 10 2018 in Cape May, New Jersey, Revive & Restore joined with First Lady Tammy Murphy, New Jersey Audubon, and Eli Lilly and Company to announce new research that dispels many perceived barriers to the adoption of a safe synthetic alternative to horseshoe crab blood for biomedical testing.

This was a strategy based on 4 pillars:

  1. Publish a peer reviewed study to demonstrate the rFC synthetic alternative is more effective than Horseshoe Crab Blood.
  2. Ensure regulators (U.S. Pharmacopeia) reinforce FDA guidance on the effectiveness of rFC over Horseshoe Crab blood.
  3. Encourage multiple manufacturers to produce rFC to ensure a competitive industry.
  4. Encourage Big Pharma to adopt rFC as the approved method for endotoxin testing over Horseshoe Crab blood.

This strategy was highlighted in several articles:

The key priority now is to ensure the widespread adoption of rFC by Big Pharma companies as part of their endotoxin testing.

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Creating an Incentive for the Adoption of a Synthetic Substitute

Until 2013, the manufacturing and patents for rFC were licensed to Lonza, one of four LAL manufacturers in the United States and one of three rFC manufacturers in the world. With the expiration of patent protection in the U.S., there is now an economic incentive for additional suppliers to begin producing rFC. In turn, the addition of new rFC manufacturers will end an important barrier to adoption for the pharmaceutical industry, which has been hesitant to transition to the synthetic alternative without a robust number of suppliers.

Lingering doubt on the efficacy of rFC has also been an important barrier to adoption of rFC. Although there is now abundant evidence that the efficacy of the synthetic alternative is equivalent to or better than LAL, adoption of new technology is difficult and change has come slow to the industry.

Since the development of the rFC test, numerous studies have been conducted to evaluate its efficacy and comparability to the LAL test for a wide variety of potential applications.

California-based NGO, Revive & Restore, synthesized these studies to demonstrate that all available scientific evidence suggests that commercially-available rFC tests detect endotoxins with equivalent or better efficacy than the LAL test. In fact, rFC signals fewer false positives, which can be costly when they occur in the manufacturing process.

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In 1997, two scientists at the University of Singapore, Professor Ling Ding Jeak, and her husband, Professor Bow Ho, developed a synthetic alternative to the product derived from Horseshoe Crab Blood (LAL). This synthetic alternative uses the blood of Army Worm blood, called recombinant factor C (rFC). The rFC alternative test does not require any Horseshoe Crab blood, and has the same level of effectiveness as Horseshoe Crab blood. Army Worms are a fast-growing, invasive species, destroying crops across the Americas and Africa (

One company soon acquired the exclusive U.S. patent for this new test.

However, this new test did not achieve sufficient market penetration to reduce demand for Horseshoe Crab. One of the main reasons for this was that the pharmaceutical industry required multiple providers in order to switch suppliers, and were also not fully aware of the effectiveness of the synthetic alternative test (rFC).

Hence, Horseshoe Crabs continued to be harvested for their blood, despite a more sustainable alternative existing.


Horseshoe crabs have been integral to the safe production of injectable vaccines, drugs, and certain medical devices. In the United States, hundreds of thousands of the American horseshoe crab (Limulus polyphemus) are captured and bled alive every year for this purpose. Compounds in horseshoe crab blood effectively and efficiently detect bacterial contamination; the reaction between these compounds and contaminants is the basis of the biomedical test, Limulus Amebocyte Lysate (LAL).

LAL became the industry standard for detecting bacterial contaminants, known as endotoxins, in the late 1970s. LAL replaced the pyrogen test, which used rabbits for detecting bacterial contamination. Every injectable medication approved by the U.S. Food & Drug Administration must be tested for the potential contamination by bacterial endotoxins. Because of population growth and innovations in the pharmaceutical field, global demand for this testing process is growing.

The bleeding of horseshoe crabs is a procedure that kills between 15 and 30 percent of bled crabs and poses unknown long-term risks to the species, as several new studies have shown:

The biomedical applications of horseshoe crab blood create a huge demand for the horseshoe crab; about half a million are bled annually in North America. But the pharmaceutical industry alone isn’t responsible for the over harvest of this species. Not only are the crabs captured and bled for biomedical applications, about 500,000 are also harvested as bait for the eel and conch fisheries. Compounding the threat of over harvesting are the effects of climate change; more intense storms and rising sea levels are diminishing the availability of suitable spawning habitat for the horseshoe crab.

The situation is more dire in Asia; in addition to the huge take of crabs for biomedical testing, food, and other uses – massive shoreline alterations on the continent are destroying estuary habitats for horseshoe crabs and migratory shorebirds at an unprecedented scale. All three 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 ancient animal. But the bleeding and over-harvest of the horseshoe crab is causing significant ecosystem-level impacts as well. Most notably, along the Atlantic Flyway of North America, six species of long-distance migrant shorebirds synchronize their northward migration to gorge on the eggs of spawning horseshoe crabs on their way to Arctic nesting grounds. A recent study has confirmed the highly-correlated relationship between the availability of horseshoe crab eggs and the survival of long distance migratory shorebirds. Whether a similar relationship exists between migratory shorebirds in the Asian Far Eastern flyway and horseshoe crabs is not known.

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This story begins in the 1940s, with the widespread use of animal testing of biomedical products, mainly rabbits. The Rabbit Pyrogen Test was adopted in the US.

In 1956, the clotting properties of Horseshoe Crabs were discovered by researchers at the Woods Hole Marine Biological Laboratory ( A decade later, scientists discover that endotoxins were the key factor in causing horseshoe crab blood to clot. In the 1970s, the Limulus Amebocyte Lysate (LAL) test was developed from Horseshoe Crab blood and piloted in clinical settings.

Horseshoe Crabs were not in demand at this stage. However, in 1977, 52 people die from a contaminated swine flu vaccine and the FDA allow the substitution of Horseshoe Crab Blood (LAL) for the Rabbit Pyrogen Test.

This led to growing demand for Horseshoe Crab blood for biomedical purposes.

Expedition Background

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.

There are three main locations around the world that Horseshoe Crabs are found – East Coast of the US on the shores of New Jersey and Delaware, China and Japan. Every year between the full moons of May and June, millions of Horseshoe Crabs come onshore from the warm Atlantic waters to spawn:

The species are not just endangered, but Delaware Bay is a hotspot of biodiversity. Birds like the Red Knot fly for two or three days non stop from South America, sleeping in the air at 20,000 feet, and land in Delaware Bay hoping to feast on the eggs of Horseshoe Crabs.

The Red Knot (Calidris canutus) depends upon Horseshoe Crab eggs for the last leg of its extraordinary spring migration from the tip of South America to the Canadian Arctic. There they gorge on eggs to double their body weight before continuing their journey to the Arctic.

As the numbers of horseshoe crabs decline, so too does the red knot population.

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