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From ancient blood come modern cures, or, How Horseshoe Crabs and Medicine Intertwined

Gorman, R. (2020). Atlantic Horseshoe Crabs and Endotoxin Testing: Perspectives on Alternatives, Sustainable Methods, and the 3Rs (Replacement, Reduction, and Refinement). Frontiers in Marine Science. Retrieved from https://www.frontiersin.org/article/10.3389/fmars.2020.582132

Sometimes it’s not just “snake oil”

Figure 1: “Limulus polyphemus – Atlantic horseshoe crab in Florida, USA”  by James St. John, December 2012. www.flickr.com/

It’s true, there are many “remedies” out there that do nothing—like wearing copper bracelets to help with arthritis or taking elixirs made from mineral oils and not much else, but other times nature provides us with substances that are infinitely more useful. In the midst of the COVID-19 pandemic, some of you may have seen news about squalene (an oil found in shark liver) and how it is used in vaccine production. As much as this has conservationists worried about shark populations, another marine organism has been supplying humans with a key extract for testing vaccines for contamination since the 1970s: horseshoe crabs. In this case, we’re not using oil; rather, we’re after their blood and a very specific cell extract within it. Not only is horseshoe crab blood needed for testing vaccines, but also for making sure every IV drip, implanted port, or injected medicine is free of toxic bacterial remains.

Horseshoe crabs are therefore harvested on a regular basis from wild populations and bled in specialized facilities before being released back into the ocean. As more vaccines and medicines are produced globally, we are now collecting over 500,000 horseshoe crabs each year to keep up with the pharmaceutical demand. Combine this with changing habitat conditions, and that ~8-30% collected horseshoe crabs die after being returned from these periodic blood drives, scientists are concerned these creatures may be dwindling in numbers.

As more discussions about the sustainability of collecting these animals happen, social science is entering the picture to get a better idea of what stances different industries are taking. In a new series of interviews, Dr. Richard Gorman has tried gauging what a small number of people within the pharmaceutical and conservation fields think about approaching the issue from the “3R” perspective. The 3Rs stand for “the ambition to replace, reduce, and refine the use of animals in science” – something that does not seem to have been considered when it comes to horseshoe crabs, but could be incredibly helpful in taking some pressure off their wild populations.

Figure 2: “Blue blood” by Sue Gerhart, 2004. www.flickr.com/ The hemocyanin in the blood gives it a distinctly blue hue when compared to our red, hemoglobin-rich blood.

Can we reduce?

When compared to previous harvests of crabs (e.g. for fertilizer in the late 1800s), the yearly haul of horseshoe crabs is much smaller. That doesn’t mean it can’t be reduced further. The majority of those interviewed in pharmaceutical, biotech, and conservation fields recognized reducing the number of crabs collected as the ideal option, even if it is a difficult goal. It’s been suggested that raising a stock of horseshoe crabs solely for scheduled bleeding would be the best solution since conditions and the health of the animals can always be controlled. Unfortunately, horseshoe crabs are not always easy to keep and breed in captivity. What’s more helpful, though, is getting creative with the biomedical technology since using smaller amounts of cellular extract would directly translate to fewer crabs being collected. Either way, it’s a long road ahead on the reduction front.

Can we replace?

Replacement here means substituting the blood extract with something else from a non-animal source. Prior to using horseshoe crab blood in the 1970s, scientists had relied on testing medicine batches on rabbits and waiting to see if the small mammals displayed symptoms. We don’t want to repeat that pattern. The good news? A synthetic form of the horseshoe crab’s protein was developed in 2001! The bad news? It hasn’t been as well received or embraced by the pharmaceutical industry, mainly because of concerns over how to mass-produce it, and questions on if the synthetic version works equally well. Positive steps were taken in 2019, though, with the European Pharmacopoeia recognizing the synthetic test as equally sensitive to the one made from the horseshoe crab’s protein. The larger issue at hand now is bringing the biotechnologists and conservationists closer together to recognize there are ways to strike a compromised balance that meets some of the goals of each industry. It will all have to be monitored carefully since there are a lot of separate pressures facing these crabs.

Can we refine?

If we aren’t able to reduce or replace horseshoe crab blood yet, is it possible to make the process less of an ordeal for them? Some researchers gave suggestions ranging from limiting the volume of blood drawn (and maybe removing the cells we need before reinjecting the rest of the blood back to the animal) to exploring breeding a “lab strain” of horseshoe crabs meant exclusively for regular sampling. To date though, efforts for refinement aren’t openly discussed due to the confidential or secret nature of many biomedical companies.

Figure 3: “Horseshoe crab pile” pixabay.com/ Horseshoe crabs depicted here ensuring the next generation will be born! Breeding late in spring ends up supporting many other species—especially the migratory birds that use the Atlantic Flyway that feed on the thousands of baby horseshoe crabs that hatch out a month later. We’re not the only ones benefiting from this ancient species!

And in the end?

While Dr. Gorman’s interviews are only the tip of the iceberg (or horseshoe crab pile as it were), it’s good to know the welfare and use of these creatures is being discussed. It will likely take mixing approaches, and each step of the industrial chain will need to step up and participate if we want to make progress to lessen the stress on the wild populations. The responsibility can’t only lie with the companies extracting the blood—we all benefit from these organisms, so let’s make it a combined effort to change their future!


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