Why Horseshoe Crab Blood Is So Valuable

Horseshoe crabs often called living fossils represent one of oldest creatures on planet having remained nearly unchanged since first appearing on Earth over 450 million years ago due to exceptionally effective adaptations and genes coding for remarkable molecules allowing survival unchanged for so long.

Horseshoe crab blood made blue from copper-based oxygen carrying molecule so valuable it forms basis for multi-million dollar pharmaceutical industry where single liter goes for around sixteen thousand dollars making it one of most valuable liquids on Earth.

Horseshoe crab blood so valuable it forms basis for multi-million dollar pharmaceutical industry where single liter goes for around sixteen thousand dollars making it one of most valuable liquids on Earth creating reliance on animals putting immense pressure on fragile ecosystem.

American horseshoe crab represents ancient aquatic arthropod belonging to own class called Merostomata where they are not actually crabs but more closely related to scorpions with predecessors diverging from arachnid cousins around 480 million years ago with some studies even suggesting they are arachnids.

Modern horseshoe crab technically only been around for 20 million years but some early relatives like Limulus darwini existed around 150 million years ago and look nearly indistinguishable from today’s horseshoe crabs demonstrating remarkable morphological stability across geological time.

Pangaea supercontinent formed 335 million years ago and broke apart 175 million years ago while non-avian dinosaurs emerged 245 million years ago and died 66 million years ago where Earth experienced two different ice ages since horseshoe crabs came about demonstrating world has changed dramatically while horseshoe crabs crawled along sea floor unchanged.

Horseshoe crab hard shell called carapace represents exoskeleton so strong only sharks or turtles can penetrate it while guiding them through ocean depths are nine eyes including two compound eyes acting like our eyes five secondary simple eyes on shell top detecting UV light and two ventral eyes on underside helping with orientation.

In 1968 two researchers at Marine Biological Laboratory in Massachusetts observed that blood cells from horseshoe crabs vigorously clot in presence of bacterial endotoxin and when they published paper had no idea what they found would revolutionize drug safety testing forever.

Exotoxins like botulism neurotoxic protein are released from live bacteria into surrounding environment during infection whereas bacteria do not have to release exotoxins or even be alive to be dangerous as endotoxins are lipid portions of lipopolysaccharides in outer membrane released when bacteria die and cell wall breaks apart.

Many invertebrates including horseshoe crabs do not have adaptive immune systems that vertebrates possess but instead have innate immune system which attacks based on identification of general threat rather than strategic mounting of defense against specific invaders with immune memory.

Basis for horseshoe crab immune response are cells called granular amoebocytes where when bacteria contact horseshoe crab blood they trigger enzyme cascade mediated by amoebocytes causing blood in immediate area of infection to clot into gel surrounding and isolating infection from rest of crab neutralizing pathogens.

Historically pharmaceutical companies used huge colonies of rabbits for rabbit pyrogen test where to see if product or drug contaminated with endotoxin three unlucky rabbits would be injected with small amount of drug and monitored for four hours where rabbits have similar pyrogen tolerance as humans so fever indicates contamination.

In vitro test called LAL test meaning Limulus Amoebocyte Lysate from Limulus polyphemus American horseshoe crab has become worldwide standard for screening bacterial contamination capable of detecting endotoxin at significantly lower levels than rabbit pyrogen test where today every FDA-certified drug must be tested using LAL as do surgical implants like pacemakers and prosthetic devices.

After horseshoe crabs brought to lab tissue around their heart is pierced with needle and up to 30 percent of blood drained where amoebocytes in blood then extracted for LAL test with crabs released in new location so they do not accidentally get caught second time ensuring chance to recover with blood volume rebounding in about week.

In theory extracting blood from horseshoe crabs does not kill them being sort like non-consensual blood donation where LAL industry states no long-term ill effects measuring mortality rates less than three percent but conservationists tell different story with between 10 and 30 percent of bled animals actually dying according to various estimates equating to losses in hundreds of thousands.

Horseshoe crab population decline not just bad for the crabs but for entire ecosystem in which they live where many other species of animals rely on horseshoe crab eggs for food like shorebirds and turtles creating broader ecological consequences from pharmaceutical harvesting.

In 1995 scientists from National University of Singapore finally able to identify and isolate gene responsible for endotoxin-sensitive protein called Factor C most important component in LAL test and produce it in yeast where several years later they created rapid endotoxin test based on recombinant protein.

Despite synthetic test advances these alternatives still not widely available having been adopted extremely slowly due to regulatory and safety concerns where Europe did not recognize synthetic protein as alternate endotoxin detection until 2015 and FDA did not approve first drug using synthetic protein test until 2018 while American Pharmacopoeia declined to place synthetic protein on equal footing with crab lysate in 2020 claiming safety still unproven.

Horseshoe crab ancestors have faced and survived all five mass extinctions where these extinction events defined as loss of at least 75 percent of species happening in geological blink of eye from volcanoes erupting oceans warming ice sheets forming or oceans acidifying where great die-offs result from perfect storm of multiple calamities yet horseshoe crab ancestors were one of few creatures to survive.