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[Editor’s note: Today is a holiday; so I decided to take it (somewhat) easy and update a post from my not-so-secret other blog for today. If you don’t read that blog, it’s new to you. If you do, I changed the post up a bit so that it’s not entirely the same. Enjoy!]

I was trying to decide what to write about today and finding it rather difficult. Part of it might be because, in the States at least, it’s a long holiday weekend. Another part of the reason is that so many of the potential topics are so obvious, given the torrent of disinformation that last week brought about vaccines, COVID-19, and so many other medical topics. That being said, if there’s one thing I like to do, it’s to take on topics that no one else notices, which brings me to antivaxxers and horseshoe crabs.

Yes, horseshoe crabs.

Over at what I’ve long liked to refer to (along with The Huffington Post) as that “wretched hive of scum and antivaccine villainy”, Age of Autism (even though several other wretched hives of scum and antivaccine quackery have surpassed its wretchedness over the years), I came across this remarkable post urging vegans to be wary of any potential COVID-19 vaccine because of horseshoe crabs in a post entitled “Will Vegans Reject Covid Vaccine that Drains Horseshoe Crabs of Their Blood?“:

Note: Can you be a Vegan, a true Vegan who does not consume animal products, and take a COVID vaccine that calls for the ex-sanguination [sic] of horseshoe crabs? What’s the difference between the cruel existence of veal, and hooking horsehoe [sic] crabs to a machine that drains their 30% of their blood, if when they are returned “home,” many die? Is taking any product that knowingly harms animals hypocritical? If you have never seen horseshoe crabs in the wild, you should. We used to see them often on Cape Cod. They are mesmerizing, ancient creatures.

This isn’t a new tactic, either. Back in April, Sherri Tenpenny’s antivaccine website Vaxxter published an article with the title, “The Chilling Image Behind Every Vaccine“:

The image is startling. The sight of crabs being forced in clamps and bled out in what appears much like a lab from Blade Runner. The horseshoe crab is 300 million years old and that’s what haunts the image before you. That’s 200 million years older than dinosaurs. But even this sea creature isn’t likely to survive pharma’s wrath.

Horseshoe crabs are known for their unique blue blood. That blood will clot in the presence of specific bacterias, [sic] so pharma loves to use them to test out new medications, including vaccines.

Accompanying the article is an image similar to this one:

Horseshoe crabs bled

The reason the crabs’ blood is blue is because it uses copper in a protein called haemocyanin instead of iron in hemoglobin to bind oxygen. So there really is a precedent for calling Vulcans “blue-blooded”!

Elsewhere, more recently other alternative medicine and antivaccine sites have been taking up the cry, attempting to demonize any new COVID-19 vaccine (and, of course, vaccines in general) with the cry being taken up by blogs and websites such as The Vaccine Reaction and The Alternative Daily.

A regular reader might be wondering here: Why do pharmaceutical companies harvest the blood of horseshoe crabs to use for vaccines? In fact, I wondered that very thing and was rather amazed that I didn’t know about this particular practice, even after having written about vaccine safety issues for over 20 years. So this was a great learning opportunity for me to fill in a gap in my knowledge that I didn’t know that I had – and, hopefully, to fill in a gap that many SBM readers didn’t know they had either.

Here’s the explanation. There is a substance in the blood of horseshoe crabs, limulus amebocyte lysate, that can be used to detect endotoxin, a toxin that is a component of the bacterial wall of gram-negative bacteria. (Gram-negative or gram-positive refers to the ability of a species of bacteria to be stained with Gram stain.) Endotoxin is a lipopolysaccharide (LPS) consisting of lipid A and something called the O-polysaccharide, which allows bacteria to adhere to certain tissues and contributes to resistance to being engulfed by certain immune cells. The lipid A portion of LPS is the cause of the molecule’s endotoxin activity, as immune cells in humans and animals recognize it as an indicator of the presence of bacteria and activate an immune response to it, no previous exposure to endotoxin required. Thus, endotoxin can cause a robust inflammatory reaction and is the most potent contributor to septic shock in patients with gram-negative sepsis.

Which brings us to the reason why this extract from horseshoe crab blood is so important:

Due to the severe consequences of an infection, an injectable healthcare product such as a vaccine or intravenous solution must be sterile or free of live bacteria, but the manufacturing process to kill any bacteria can result in release of LPS or endotoxin into the product. Just as with a bacterial infection or sepsis, if sufficient endotoxin gets into our blood stream or spinal fluid we can develop fever, shock, and organ failure. In extreme cases, it can even result in death.

Therefore, injectables or implantables, products that come in contact with the blood stream or spinal fluid, are tested for sterility (the absence of live bacteria) as well as endotoxin. Testing for endotoxin helps assure product quality and safety.

So you can see why testing to make sure that endotoxin is eliminated from a vaccine, a medical device, or any injectable product is so important. How is this product used? An article from 2014 published in The Atlantic describes how. After waxing poetic about how horseshoe crab blood is blue, not red, the article goes on to describe how the blood is used to detect endotoxin:

The marvelous thing about horseshoe crab blood, though, isn’t the color. It’s a chemical found only in the amoebocytes of its blood cells that can detect mere traces of bacterial presence and trap them in inescapable clots.

To take advantage of this biological idiosyncrasy, pharmaceutical companies burst the cells that contain the chemical, called coagulogen. Then, they can use the coagulogen to detect contamination in any solution that might come into contact with blood. If there are dangerous bacterial endotoxins in the liquid—even at a concentration of one part per trillion—the horseshoe crab blood extract will go to work, turning the solution into what scientist Fred Bang, who co-discovered the substance, called a “gel.”

“This gel immobilized the bacteria but did not kill them,” Bang wrote in the 1956 paper announcing the substance. “The gel or clot was stable and tough and remained so for several weeks at room temperature.”

If there is no bacterial contamination, then the coagulation does not occur, and the solution can be considered free of bacteria. It’s a simple, nearly instantaneous test that goes by the name of the LAL, or Limulus amebocyte lysate, test (after the species name of the crab, Limulus polyphemus).

But why, you ask, did evolution endow the horseshoe crab with the ability to make coagulogen? The best guess is this. Horseshoe crabs live in a bacteria-rich environment near the shoreline, and their circulatory systems made the evolution of such a system advantageous. In 1956, a researcher named Fred Bang noted that when horseshoe crab blood comes into contact with endotoxin, cells called amebocytes clot and form a solid mass:

And that bacteria-rich habitat is why, Bang speculated, the crabs evolved their marvelous chemical defense. Their circulatory systems work more like a spider’s than like ours. If we inhale something bad, that thing has to find its way through our bodies and into our bloodstreams, fighting its way through our white blood cells along the way. But if bacteria find their way under a horseshoe crab’s exoskeleton, they can roam free to do damage.

“Large sinuses exist that allow blood direct contact with tissues,” the Woods Hole Marine Biological Laboratory’s history of the crab explains. “There are many wide open spaces and bacteria entering a crack in the shell of a horseshoe crab have easy access to large internal areas of the crab, a potentially deadly scenario.”

The coagulogen changes the wide-open terrain of the horseshoe crab’s circulatory system. When the crab blood cells sense invaders, they release granules of the chemical, which becomes a gooey physical barrier to the movement of the bacteria, preventing the spread of infection. The best metaphor might be the superpower of the X-Men’s Iceman, but instead of using cold to encase enemies, the horseshoe crab instead uses its remarkable chemistry.

A description of how Bang discovered limulus can be found here. In brief:

Bang was studying the circulation of blood using horseshoe crabs when he found that one of his crabs died as a result of a Vibrio bacterial infection. The infection caused a strange disease in which almost the entire blood volume of the crab clotted into a semi-solid mass. Other bacteria had not produced this sort of reaction at all. Bang began to investigate further and found that only gram-negative bacteria produced this reaction. Furthermore, heat-treated bacteria (dead bacteria) continued to produce the reaction so it wasn’t a pathological disease but something different.

Isn’t science cool? Isn’t evolution awesome? Imagine a chemical made by an organism that can react with another molecule at such low concentrations and basically immobilize it. Evolution’s done that for the humble horseshoe crab! And scientists figured out what the chemical is and how to use it to keep injectable medications and implantable devices safe.

Of course, like most antivaccine propaganda, there is a grain of a reasonable point buried in the spin and exaggeration, the main question being: Why do we still use horseshoe crab blood to obtain the necessary molecule? Why haven’t we been able to come up with a substitute or figure out a way to synthesize the chemical without bleeding millions of horseshoe crabs, resulting in the deaths of a not-insignificant number of them? After all, horseshoe crab blood is one of the most expensive resources in the world, costing around $60,000 per gallon (around $15,581 per liter, for the rest of the world). Worse, around 10-30% of the crabs don’t survive after bleeding, as the bleeding appears to make the bled animals more lethargic, slower, and less likely to follow the tides the way that their untouched counterparts do.

It turns out that there is a substitute. In 2016, a synthetic alternative to the use of horseshoe crab blood, recombinant factor C (rFC), was approved in Europe, and a handful of US drug companies also began using it, as was described in National Geographic in July in an article about how horseshoe crab blood will be critical to making a COVID-19 vaccine. The article also noted:

But on June 1, 2020, the American Pharmacopeia, which sets the scientific standards for drugs and other products in the U.S., declined to place rFC on equal footing with crab lysate, claiming that its safety is still unproven.

This is, of course, a valid issue from an environmental and ethical perspective. If the recombinant rFC is good enough for Europe, whose drug and medical device regulation is as stringent as that in the US, why isn’t it good enough for the US? In June, the Smithsonian reported:

Now, an influential United States group has abandoned plans to list a synthetic alternative, called recombinant Factor C (rFC), alongside the tried and true blue fluid, reports John Miller for Reuters. The move by medical standards group U.S. Pharmacopeia (USP) would have given rFC equal standing with crab blood, which has long been the industry standard for testing, per Reuters.

The gist of the USP’s rationale is that rFC requires more testing, and that the current crab-derived test has a 30-year track record of safe and effective use, reports the [New York] Times. Many expected the alternative test to be approved for widespread use as it was in Europe by the European Pharmacopeia, per the Times.

For drug makers in the U.S., using the synthetic alternative will require a kind of application designed to demonstrate that the non-standard test is up to snuff—a hurdle that makes companies less likely to abandon the animal-based test, reports Caroline Delbert for Popular Mechanics.

Certainly, it must be far less expensive and labor-intensive to manufacture the necessary component to detect endotoxin using recombinant methods than it is to bleed over a half million horseshoe crabs a year and then isolate the compound from the blood. Worse, as several articles noted, a combination of overharvesting and the bleeding is resulting in a decline in horseshoe crab populations, which are a vital food source for migratory birds and critical to the ocean ecosystem. It is a legitimate question to ask why we’re still isolating this vital compound in such a barbaric manner, but that’s not really what antivaxxers are about here. What they’re about here is spreading fear, uncertainty, and doubt about any potential new COVID-19 vaccine that uses the LAL test to verify that it is free of bacteria and endotoxin. It’s about demonization, not education.

Hopefully, Delbert was correct in speculating at the end of her Popular Mechanics article:

Eli Lilly is a huge company with deep pockets, but it’s said outright that the extra and different regulations on rFC are discouraging other companies, per the Guardian. The USP decision is a further obstacle, but the USP has approved alternative testing regimens in the past, like the sterility testing that also affects injectable and biological drugs. If its complaint is a lack of data, then the more people who adopt the synthetic regimen, the more data will accumulate on their side.

And the sooner, the better.

This co-optation of the story of how horseshoe crab blood is used to make a test that can detect minute traces of endotoxin in injectable drugs and using that story to try to convince vegans not to vaccinate is just a variation on a theme of a technique that antivaxxers have been using since long before I started paying attention to these issues. They take a belief system and then find an ingredient or something about vaccines that they can use to try to convince those with that belief system that vaccines are against what they believe. Examples abound, mostly with religious beliefs. For example, antivaxxers have long tried to convince Muslims and Jews that the gelatin derived from pigs that is used in some vaccines makes vaccines irredeemably against their religions, even though Rabbis and Islamic scholars have long pointed out that there is a reasonable exception for vaccines. Indeed, Rabbis and Jewish medical experts actively encourage Jews to be vaccinated, and Islamic legal scholars have rejected the claim that the use of gelatin from “impure animals” is against Islam. Another example of how antivaxxers try to weaponize beliefs against vaccines is their persistent drumbeat of criticism of the use of cell lines derived from human fetuses in the 1960s to grow up stocks of virus to be used in the manufacture of vaccines in order to turn those with religious beliefs against abortion against vaccines, a phenomenon I’ve written about more times than I can remember. It doesn’t matter that vaccines made using these cell lines have saved millions of lives and prevented billions of cases of infectious disease, or that the Catholic Church itself has stated that their use is acceptable. Every year, it seems, antivaxxers find new and more ridiculous ways to try to weaponize antiabortion beliefs against vaccines.

The bottom line is that most antivaxxers are not vegan and that these antivaxxers don’t give a rodent’s posterior about horseshoe crabs. One also wonders whether they know or care about the implications of what they are saying. After all, it’s not just a COVID-19 vaccine that would use the LAL test to check for endotoxin that vegans would have to eschew if they accepted the “logic” of this antivaccine post by the wandering band of scientifically illiterate cranks at AoA. They would have to eschew nearly all IV fluids, injectable medications, implantable devices, and, yes, vaccines, given how widely the LAL test is used. They would, in fact, have to give up a large percentage of modern medicine.

On second thought, maybe antivaxxers do realize the implication of their arguments. Maybe that’s what they want. Or maybe there’s no “maybe” about it.

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Posted by David Gorski

Dr. Gorski's full information can be found here, along with information for patients. David H. Gorski, MD, PhD, FACS is a surgical oncologist at the Barbara Ann Karmanos Cancer Institute specializing in breast cancer surgery, where he also serves as the American College of Surgeons Committee on Cancer Liaison Physician as well as an Associate Professor of Surgery and member of the faculty of the Graduate Program in Cancer Biology at Wayne State University. If you are a potential patient and found this page through a Google search, please check out Dr. Gorski's biographical information, disclaimers regarding his writings, and notice to patients here.