Excerpted from Pump: A Natural History of the Heart © 2021 by Bill Schutt. Reprinted by permission of Algonquin Books of Chapel Hill.
The story of the Atlantic horseshoe crab’s first turn toward medical relevance occurred in 1956. That’s when Fred Bang, a pathobiologist from Woods Hole, found that some bacteria made horseshoe crab blood clot into tight balls. He and his colleagues hypothesized that this was an ancient form of immune defense. Eventually, they determined that a type of blood cell called an amoebocyte was responsible for the clot formation. As the name suggests, amoebocytes look like amoebas, which are the splotchy single-celled protists that make pseudopods so popular and dysentery so unpopular.
Bang and people who studied after him thought that the amoebocyte’s ability to clot might have evolved because horseshoe crabs spend their whole lives digging through muck that is full of bacteria and pathogens. With their army of blood-borne amoebocytes, they can keep out foreign invaders by locking them up in prisons of gelatinous goo before they can spread their diseases.
Because of this, horseshoe crabs are not only resistant to disease but also very good at surviving severe physical damage. Even the most dangerous wounds quickly fill with clots made by amoebocytes, so hurt people can go about their lives as if they hadn’t just lost a fist-sized piece of shell to an outboard motor propeller. Horseshoe crabs have been around for almost 500 million years, making them one of the longest-living animals on Earth. They may have been able to survive five mass extinctions because of their unique defense and repair system.
We now know that the amoebocytes do their thing by detecting potentially lethal chemicals called endotoxins. They are linked to gram-negative bacteria, which includes pathogens like Escherichia coli (causes food poisoning), Salmonella (causes typhoid fever and food poisoning), Neisseria (causes meningitis and gonorrhea), Haemophilus influenzae (causes sepsis and meningitis), Bordetella pertussis (causes whooping cough), and Vibrio cholerae (causes cholera).
Oddly, the endotoxins are not themselves responsible for the myriad diseases associated with these bacteria. Nor are they protective products—released, for example, to combat the bacteria’s own enemies. Instead, these big molecules make up a lot of the cell membrane of bacteria, helping to build a wall between the cell and its surroundings. Endotoxins are also known as lipopolysaccharides, since they consist of a fat attached to a carbohydrate. Other living things can only be hurt by these molecules after the bacteria have been killed and lysed, which can happen when the immune system (or an antibiotic) is used to fight off an infection with gram-negative bacteria. At this point, the contents of the bacterial cell spill out, and the lipopolysaccharide parts of the membrane are let out into the environment.
Unfortunately, although the disease-causing bacteria may have been conquered, the sick host’s problems are not over. Endotoxins in the blood can make a fever come on quickly. Fever is one of the body’s defenses against a foreign invader. These things that raise body temperatures are called pyrogens, and if they do it for too long, they can cause serious problems like brain damage. The body’s dangerously overactive immune response can also cause more problems. This is something that doctors have had to deal with during the coronavirus pandemic. Endotoxic shock is a dangerous set of symptoms that can happen when someone is exposed to endotoxins. These include damage to the lining of the heart and blood vessels and dangerously low blood pressure.
Leslie and I went to the beach to look for horseshoe crab eggs. Afterward, Dan Gibson took us to the Woods Hole lab, where he prepared a microscope slide of fresh horseshoe crab blood. We were soon examining live horseshoe crab amoebocytes.
“They’re all full of granules,” I said, noting the sand-like particles that packed the cell interiors.
“Those are tiny packets of a protein called coagulogen,” Gibson said. As their name may suggest, coagulogens cause coagulation, or clotting. “As soon as the amoebocytes come into contact with even a small amount of endotoxin, they release their coagulogen packets. These quickly turn into a gel-like clot.” ”.
People can be seriously hurt by endotoxins, so in the 1940s the drug industry started checking its products for them. These substances can also be released accidentally during the drug-making process. One of the first methods developed was the rabbit pyrogen test, which became an industry standard. Here’s how it worked: the lab rabbits that were part of the test had their rectal temperatures taken at the start of the test, which sounds like a job for “the new guy.” Next, the lab technicians gave the rabbits injections of the drug batch that was being tested. Often, they did this through an ear vein that was easy to get to. They then recorded rectal temperatures every thirty minutes for the next three hours. If a fever developed, it would signal the potential presence of an endotoxin in that particular batch.
Fred Bang’s colleague, hematologist Jack Levin, found that horseshoe crab blood would clot when it was exposed to endotoxins. In the late 1960s, Levin created an assay, a chemical test that would replace the time-consuming and controversial rabbit pyrogen test. Levin and his colleagues basically cut open horseshoe crab amoebocytes to get the part that makes clots. They called it Limulus amoebocyte lysate (LAL). LAL could check for endotoxins in pharmaceuticals and vaccines, and researchers eventually found that it also worked on medical instruments like catheters and syringes. Sterilization might kill bacteria on these instruments, but it could also introduce endotoxins into patients who are getting medical care.
The rabbit community probably felt relieved when this discovery was made, but horseshoe crabs and their fans were not as happy. This was especially true when another Woods Hole researcher quickly started a biomedical company that started taking horseshoe crab blood on a large scale. Soon, three more companies like this popped up along the Atlantic coast. This made making LAL a multimillion-dollar business. Because of this, every year about 500,000 horseshoe crabs are taken out of the water, and a lot of them do it during spawning season. The vast majority are taken to large-scale labs not in tanks of cold salt water, but in the backs of open pickup trucks. Workers in masks and gowns greet the crabs when they get there. They scrub them with disinfectant, bend their hinged shells in half (this is called “the abdominal flexure position”), and strap them to long metal tables in an assembly line fashion. Large-gauge syringes are then inserted directly into the horseshoe crabs’ hearts. The blood, blue-tinted and with the consistency of milk, drips down into glass collecting bottles. And in a move that would make Count Dracula proud, the blood is collected until it stops flowing, which is usually around 30% of the way through.
Horseshoe crabs should live through their ordeal, at least in theory. Once they’ve been bled, they have to be returned to the area where they were caught by law. Chris Chabot, a neurobiologist at Plymouth State University, says that about 20 to 30 percent of the crabs die in the 72 hours between being caught and bleeding to return.
Chabot told Leslie and me, “It’s important that the gill-breathing crabs stay out of the water the whole time.” We went to the University of New Hampshire’s Jackson Estuarine Laboratory to see the scientist and his coworker, zoologist Win Watson.
Chabot also said that the fact that no one knows if specimens that have been bled have any short- or long-term effects when they are put back into the water—or even if they survive—could be important. The Atlantic States Marine Fisheries Commission (ASMFC) has been officially in charge of horseshoe crab populations since 1998. However, different rules have made it hard for the ASMFC to get death rate data for horseshoe crabs caught for biomedical companies. In light of this, Chabot and his research group have been looking into what happens to horseshoe crabs after they are caught and then put back into the water. To do this, he and his students took a small group of specimens and put them through conditions that were similar to what crabs go through when they come into contact with the biomedical industry.
The subjects that Chabot and his students studied seemed bored and lost. They thought that this might be because the crab’s body can’t deliver as much oxygen as it needs after bleeding. “It takes weeks to replenish the amoebocytes and the hemocyanin they’ve lost,” he told us.
Chabot also said that many of the horseshoe crabs’ protective amoebocytes were being broken down in a test tube. This meant that they would not be able to do things like heal wounds or go back to places that are full of gram-negative bacteria. This made things look pretty bad for the horseshoe crabs going home after a long day on the assembly line.
Watson confirmed that horseshoe crabs can die after being out of the water for three days in hot weather and losing a lot of blood. Additionally, he said that because crabs are usually caught during mating season and sometimes before mating, any death rate could affect the size of future generations, especially since the bigger female crabs are chosen during collection. And because crabs take a long time to grow up, researchers and everyone else may not realize how bad the problems are for ten years. The American Spiny Lobster Commission (ASMC) says that the number of horseshoe crabs in New York and New England is already starting to go down.
Watson and Chabot both said that some easy steps could be taken to lower the number of deaths, which would help horseshoe crab populations stay healthy without hurting the LAL industry. The first step would be to delay the harvesting of horseshoe crabs until after the mating season. They also said that specimens should be brought to and from biotech labs in cool water tanks instead of being stacked on boat decks and in the backs of trucks, where they would get dry and hot. They said that this would not only keep the horseshoe crabs from getting heat stress, but it would also keep the thin, membranous “pages” of their book gills from drying out.
After talking to Watson and Chabot, it’s clear that they know how important LAL is to the medical field and to the patients whose lives it saves. These researchers are just trying to make things better for a species that has been facing threats to its survival for a long time, even before people came along and added pollution, habitat loss, and overfishing to the list of things that hurt horseshoe crabs.
The steps Watson and Chabot suggested would help save a lot of horseshoe crabs, but there is still another risk that comes with harvesting them. This one comes from the fact that a ganglion, a small group of neurons just above the heart, starts and controls each horseshoe crab’s heartbeat. Due to tiny electrical pulses, its job is to make sure that each part of the heart contracts in the right order.
These neurogenic hearts are found in crustaceans like shrimp as well as segmented worms like earthworms and leeches. These hearts are very different from the myogenic hearts found in humans and other vertebrates. These hearts beat without being stimulated by nerves or ganglia. Instead, the signal for myogenic contraction comes from cardiac pacemakers, which are small areas of specialized muscle tissue inside the heart.
Neurogenic hearts don’t have these pacemakers, which may help explain why Aztec art never shows priests holding the still-beating hearts of lobsters or horseshoe crabs that have just been sacrificed. This is because their neurogenic hearts would have stopped beating as soon as they were cut off from the ganglia that controlled them.
Meanwhile, thanks to pacemaker cells, human hearts have the ability to generate a continuous sequence of electrical signals. These start in the sinoatrial (SA) node in the right atrium and quickly move through the heart along very specific paths called conduction pathways. The signals move from the right atrium to the left atrium, which are both in the upper “base” of the heart. They move like water ripples after a pebble hits it. As the ripple moves down toward the ventricles, the atrioventricular (AV) node, a different group of pacemaker cells, slows down the signal. This gives the ventricles a little extra time to fill with blood. The electrical signal from the AV node continues down toward the pointy apex of the heart. As it does, the muscles making up each ventricle are stimulated to contract in turn.
Yet, even though our myogenic heart starts its own beat, a pair of nerves decide how fast and how hard it contracts. These are the vagus nerve, which slows down the heartbeat, and the cardiac accelerator nerve, which . well, you know. These nerves are part of the autonomic nervous system (ANS), which does a lot of work without your permission or input.
There are two divisions of the ANS. One, called the sympathetic division, gets your body ready for real or imagined threats by raising your blood pressure and heart rate. This is often referred to as the “fight-or-flight response. “When your heart rate goes up, your ANS also makes more blood flow to your brain and leg muscles.” This occurs as blood vessels supplying those areas receive a signal to start vasodilation (i. e. , widening of their inner diameters). At the same time, the digestive tract and kidneys don’t get as much blood because the small blood vessels that normally bring blood to them narrow. It is thought that breaking down Cheerios and peeing become less important when you are suddenly faced with a grizzly bear or the thought of speaking in front of a crowd. Instead, the extra blood heads to the leg muscles through their wide-open capillaries—preparing you for a sprint. Also, the brain gets more blood, which should help you figure out what to do if running away doesn’t work.
The second division of the autonomic nervous system is the parasympathetic division, which takes over during normal (a. k. a. grizzly bear- and public-speaking-free) conditions. This is the “rest-and-repose” alternative of the ANS. It lowers the heart rate and sends blood to organs that have been hurt by the fight-or-flight response, like those that digest food and make urine.
It’s interesting that the heart doesn’t stop beating, which would be quickly fatal, if the nerves that control the ANS are hurt or their impulses are blocked (attention fugu fans). In its place, the SA node controls the heart rate and keeps it at a steady 104 beats per minute.
It’s not good for a horseshoe crab to get the hypodermic Dracula treatment because its heart can’t pace itself. Its heartbeat is solely governed by the ganglion situated above it.
Watson said that the ganglion turns on motor neurons, which send a chemical called glutamate to the heart muscle to talk to it. This chemical messenger fits like a key into neurotransmitter-specific locks found on the surface of the heart. The locks on these cells are called receptors, and the key-and-lock arrangement tells the muscle cells to contract. *.
Watson said, “The problem is that if you stick a needle into a horseshoe crab to drain its blood and hit the cardiac ganglion by accident, you’ll probably kill the animal.” ”.
“So, when workers in these biomedical facilities put needles into specimens that are bleeding, they have to think about where the cardiac ganglion is located, right?”
Horseshoe crabs are ancient arthropods that have been around for hundreds of millions of years. Despite their prehistoric appearance, these marine creatures play an important role in modern medicine. A unique compound in horseshoe crab blood has proven invaluable to the pharmaceutical industry and has saved countless human lives.
A Marine Marvel
Horseshoe crabs have survived and thrived through the ages, with fossils dating back 445 million years. They pre-date the dinosaurs by over 200 million years. Four species exist today, found along the east coast of North America and Asia. With their protective helmet-shaped shells and spike-like tails, horseshoe crabs resemble remnants of the past.
These intriguing animals spend most of their lives submerged in shallow coastal waters and wetlands. As spring approaches, horseshoe crabs migrate to sandy beaches to spawn. The females lay thousands of eggs in nests along the shoreline. Their eggs provide nourishment for migratory shorebirds and help sustain coastal ecosystems.
Miracle Blood
Beneath its prehistoric facade, the horseshoe crab possesses a remarkable defense mechanism within its blood. Horseshoe crab blood contains amebocytes, which are cells that recognize and coagulate around dangerous endotoxins. When the crab blood cells detect a threat, they create clots to isolate and neutralize the harmful bacteria before it can spread.
This instantaneous reaction to toxins makes horseshoe crab blood invaluable for biomedical testing A clotting agent called Limulus Amebocyte Lysate (LAL) is derived from crab blood cells to detect bacterial endotoxins in vaccines, injectable drugs, and medical implants Even minuscule amounts of endotoxins can be catastrophic if injected into the human body. LAL tests ensure these potentially lethal toxins are not present, enabling safe pharmaceuticals for human use.
Saving Human Lives
Before LAL testing existed, many pharmaceutical products contained undetected endotoxins that caused illness or death in patients. The creation of the LAL test revolutionized medical safety in the 1970s. Regulations now mandate that all injectable drugs and medical devices be screened with LAL.
This vital crab blood derivative has played a critical role in the development of insulin, flu vaccines, cancer medications, IV fluids, prosthetic joints, pacemakers, and many more lifesaving medical innovations. By detecting even infinitesimal traces of toxins, LAL has prevented millions of people from exposure to deadly bacteria. The global LAL market was valued at $596 million in 2019 and is projected to expand as demand for injectable pharmaceuticals increases.
A Delicate Balance
Currently, LAL is predominantly produced from wild horseshoe crab blood cells Some conservationists are concerned about potential impacts to horseshoe crab populations However, the biomedical industry follows strict regulations to ensure bleeding procedures do not harm the crabs. Most collected crabs are returned alive to their habitats. Monitoring programs are in place to study population trends and manage harvesting sustainably.
Synthetic alternatives to LAL are also being developed to reduce reliance on horseshoe crabs. Scientists have engineered a recombinant protein that mimics crab blood cells in detecting toxins. As innovative new technologies emerge, the biomedical field can continue benefitting from horseshoe crab biology while still preserving their ecological role along the shores.
For over 40 years, the marvelous blood of horseshoe crabs has been an indispensable resource for the healthcare industry. This unsung hero of modern medicine has protected humanity from invisible threats and enabled remarkable medical breakthroughs that saved countless lives. While we search for more sustainable practices, the miraculous blue blood of the horseshoe crab will remain an invaluable gift from nature.
Why Horseshoe Crab Blood Is So Valuable
FAQ
What is so special about horseshoe crab blood?
Why horseshoe crab blood is so expensive so expensive?
Is horseshoe crab blood worth more than gold?
Is it illegal to harvest horseshoe crab blood?
What is horseshoe crab blood?
Horseshoe crab blood is a bright shade of blue, as well as having remarkable antibacterial properties that have proved invaluable to the medical industry. Image via Business Insider. What is horseshoe crab blood used for? Horseshoe crab blood is bright blue. It contains important immune cells that are exceptionally sensitive to toxic bacteria.
Why is horseshoe crab blood so expensive?
The price of horseshoe crab blood is also unbelievably high, at $15,000 per quart, making it an expensive resource. But the over-harvesting of horseshoe crabs has made the species increasingly vulnerable to extinction, which could spell danger for humankind.
Why do horseshoe crabs have a special color?
When the copper in their blood is exposed to oxygen, the result is an unusual color. In addition to the color of the blood of horseshoe crabs, it is also special due to the animal’s prehistoric traits. As the sea creature has been around for so many years, their blood still contains a type of prehistoric blood cell, amebocytes.
Why do we have horseshoe crabs?
Nature plays a huge part in the medicines we rely on every day. And when it comes to vaccines, we have horseshoe crabs and their blood to thank for keeping us safe. Horseshoe crabs are older than the dinosaurs. They’ve been around for 450 million years, which means they watched the rise and fall of millions of other species, and survived ice ages.