By Lalarukh Haris Shaikh, Palantir Technologies, Twitter: @LalarukhHaris
This is a short, but powerful, almost always forgotten, but not to be missed story of the horseshoe crab and its discreet role in medicine.
Horseshoe crabs are one of the most remarkable ancient creatures that have changed the landscape of drug intervention and testing due to their physiology. Most current and notable is their role in the race to discover a successful COVID-19 vaccine.
Horseshoe crabs have survived, and remain unchanged, for almost 450 million years, since before dinosaurs existed. Humans and medicine owe a great deal to these crabs that look rather undesirable to the naked eye – a brown hard shell that resembles a helmet, with a soft inner belly hidden underneath. With a short, razor-sharp tail and ten lobster-like legs, they run to find the perfect partner during the annual mating season. The result: an average of four thousand eggs laid per female.
The United States pharmaceutical industry has an average net revenue of $50 million a year just from harvesting roughly 600,000 crabs for their unique properties. So, what exactly makes these crabs so special?
Around their organs and tissues circulates bright blue blood, made up of hemocyanin, a metalloprotein which contains copper and is used to carry oxygen about their bodies. Hemacyanin is similar to hemoglobin in our blood, which contains iron and gives our blood its deep red colour.
This blood is the creature’s primitive defense system: it carries around amebocytes in its hemolymph, or blood. Amebocytes are amoeba-like cells that defends the crab against bacterial endotoxins. The amebocytes react to the lipopolysaccharides (LPS) in the wall of gram-negative bacteria, resulting in coagulation (or clumping together of blood).
Since the 1970’s, Limulus amebocyte lysate (LAL) has been crucial to the detection and quantification of bacterial endotoxins. This process is used to understand bacterial contamination in injecting anything and everything into humans. Before this time the pharmaceutical industry relied on the physiology of rabbits to detect endotoxins in drugs and vaccines, usually resulting in the euthanization of these animals.
Using horseshoe crabs by contrast results in the sea creatures being bled out a bit, but then freed back into their environment. Today, by FDA regulations, every invasive medication including vaccines, as well as most equipment that enters the human body, during surgery or permanently, has to be rigorously tested for the detection of bacterial contamination using LAL.
This testing has become a gold standard around the world, using LAL’s reaction to a pathogen, and the subsequent coagulation that takes place, as a way of quantifying the presence and amount of endotoxins in a sample.
To date, the COVID-19 pandemic, caused by multiple evolving variants of the virus, has led to the death of over 2.8 million people worldwide, with more lives lost each day. This ever-changing disease requires the continuous need to develop, test and roll out vaccines that protect against the disease. Each vaccine in the race is being meticulously tested before the roll out, and the world is relying heavily on the oversensitive response and defense mechanism of the horseshoe crabs to carry out sterility tests on the vaccines.
The rush to save humanity in such a short time means that the crab population is in danger. Before the pandemic, approximately 15-30% of the crabs would die as a result of the pharmaceutical industry’s harvesting, along with the creatures being used as fish bait. Over the last couple of years, their population has declined significantly, with the UN reporting a 30% loss since the 1970’s. And now, the International Union of Conservation of Nature has listed some species of the crab as being near threatened status.
In the 1990’s, scientists from the University of Singapore created a synthetic equivalent to LAL, using Limulus clotting factor C-protein that isn’t derived from the horseshoe crab, yet still acts as using the same clotting pathway. Even though the new technology has been made available commercially for over a decade, old pharmaceutical regulations and red tape has resulted in a slow uptake.
The introduction of synthetic LAL might have meant that humans may once and for all leave the powerful sea creature alone. However, on 1 June 2020, the United States of Pharmacopeia (the official entity that publishes quality standards of medicine) announced that the surrogate test and technology required significant research.
The European equivalent, by contrast, has approved widespread use. On 20 June, just a few weeks later, horseshoe crab conservationists celebrated a bittersweet International Horseshoe Crab Day all over the world with activities and public outreach dedicated to protecting the animal.