If you’ve ever had a vaccine or received intravenous medication and didn’t develop a potentially life-threatening fever, you can thank horseshoe crabs (horseshoe crab).
How could those animals often called living fossilsWhy are they so important in modern medicine because they have barely changed over millions of years?Limulus blood is used to produce a substance called Limulus amoeba lysate (LAL), which scientists use to test Toxic substances called endotoxins Inject medications intravenously.
These bacterial toxins are ubiquitous in the environment and cannot be removed simply through sterilization. They may cause what is historically known as “injection heat”. Excessive concentrations can cause shock or even death.
The identification of LAL as a highly sensitive endotoxin detector was a 20th century medical safety breakthrough. Now, however, critics are questioning the environmental impact and the process of reviewing and approving synthetic alternatives to horseshoe crab blood.
we learn Science & Technology and public policyand recently published white paper Examine the social, political and economic issues associated with the use of Limulus limulus for the production of limulus reagents. We view this issue as a test case for a complex issue that spans multiple institutions and requires attention to both natural and human health.
marine solutions
The doctor began to inject various solutions into the patient mid 1800sbut it was not until the 1920s that biochemists discovered Florence Seibert The exothermic reaction was found to be due to contamination of the water in these solutions. She created a method to detect and remove the substance causing this reaction, which became the medical standard in the 1940s.
is called Rabbit Pyrogen Test, which requires scientists to inject rabbits with intravenous drugs and then monitor the animals. If a rabbit has a fever, it means that a batch of medicines has been contaminated.
The LAL method was discovered by accident.Working with horseshoe crabs Marine Biological Laboratory In the 1950s and 1960s, in Woods Hole, Massachusetts, Pathobiologist Frederik Bang and medical researcher Jack Levin Notice the animals noble Solidified in a strange way. Through a series of experiments, they isolated endotoxin as a coagulant and designed a method to extract limulus imine from blood. This compound gels or clots almost immediately when fever-causing toxins are present.
Academic researchers, biomedical companies, and the U.S. Food and Drug Administration improved the production of LAL reagent and measured it in rabbit tests.By the 1990s, LAL had become FDA Approved Methods Rabbits have largely been used to detect endotoxins in drugs.
Producing LAL requires catching horseshoe crabs from the ocean and beaches, Drains up to 30% of blood Live crabs are released into the ocean in a laboratory.It is controversial How many crabs died in the process – Estimates range from a few percent to 30 percent or more – and the possible harmful effects on survivors.
There are currently five FDA-approved drugs horseshoe crab producer Along the East Coast of the United States. The quantity of LAL they produce and their sales value are proprietary.
Bait and Biotechnology
As the production of biomedical Limulus reagents increased in the 1990s, so did the harvesting of horseshoe crabs for use as bait for other species, particularly eels and conch for foreign seafood markets. Over the past 25 years, hundreds of thousands of horseshoe crabs have been harvested annually for this purpose, with millions of horseshoe crabs harvested in earlier years.Two fisheries combine to kill over half a million There are horseshoe crabs every year.
No agreed upon total population estimate Limulusbut the most recent Federal Assessment of Limulus Fisheries The population was found to be neither growing strongly nor declining.
It’s not just crabs that environmentalists are worried about.millions of shorebirds Migrating along the Atlantic coast, many stop by in the spring, when horseshoe crabs lay their eggs on mid-Atlantic beaches and feed on crab eggs.especially for red knot This species can migrate up to 9,000 miles between the tip of South America and the Canadian Arctic, gorging on horseshoe crab eggs to provide them with vital energy for their arduous journey.
red knot is classified as threatened The Endangered Species Act was enacted in 2015 largely because horseshoe crab fishing threatened this important food source.As biomedical crab harvest reaches same or More than bait harvestedAfterwards, conservation groups began calling on the LAL industry to find new sources.
biomedical alternatives
Many important drugs are derived from living organisms.Penicillin was the first important antibiotic Originally produced using molds.Other sources of medications currently in use include Cows, pigs, chickens and fish.ocean is a promising sources for such products.
If possible, synthesize these substances in a laboratory – especially widely used drugs, e.g. insulin – Offers many benefits.It is often cheaper, more efficient, avoids putting species at risk, and solves Some patients’ concerns About the use of animal-based medical products.
In the 1990s, researchers at the National University of Singapore Invent and patent First process to create synthetic endotoxin detection compounds using horseshoe crab DNA recombinant DNA technology. The result, termed recombinant factor C (rFC), mimics the first step in the three-part cascade that occurs when LAL is exposed to endotoxin.
Subsequently, many biomedical companies Made my own version rFC and compounds called recombinant cascade reagents (rCR) reproduce the entire LAL reaction without the use of horseshoe crab blood. However, to this day, lysate remains the dominant technology for detecting endotoxins in medicine.
The main reason is United States PharmacopeiaQuasi-regulatory organizations that set safety standards for medical products consider rFC and rCR to be “alternative” methods for detecting endotoxins, so they require case-by-case validation before they can be used, which can be a lengthy and expensive process. The FDA generally follows the United States Pharmacopeia.
Some deep-pocketed big pharma companies have pledged Switching from LAL to rFC. But most drug manufacturers stick to proven methods.
Conservation group hopes U.S.P. Fully certified rFC No additional testing or validation is required for use in industry. In their view, LAL manufacturers are delaying rFC and rCR approval to protect their interests. Endotoxin testing market.USP and LAL manufacturers counter that they are conducting due diligence protect public health.
Change is coming
Change may be coming.All major LAL manufacturers now have their own reconstituted products – a tacit admission that the market and regulations are moving towards Limulus-Free way to detect endotoxins.
Atlantic fisheries regulators are currently considering New fishing limits for horseshoe crabsthe United States Pharmacopeia is Weighing instructions Regarding LAL’s recombinant replacement. Public comment will be sought in the winter of 2024, followed by review by the United States Pharmacopeia and FDA.
Even if rFC and rCR are not immediately approved, we believe in gathering more complete data on horseshoe crab populations and demanding more transparency from the LAL industry How it handles crabs will represent progress. So does directing medical companies to use recombinant products for testing during the manufacturing process while retaining LAL reagents only for final product testing.
Developing policy on complex scientific issues across different agencies is no easy task. But we believe incremental action to protect human health and the environment could be an important step forward.
Christopher Whitneyassociate professor of science, technology and society, Rochester Institute of Technology and Julie ClunellMaster of Science, Technology and Public Policy student, Rochester Institute of Technology
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