A helping hand for nature offers promising prospects for pharmaceuticals

Every spring, thousands of red knots land on the beaches of the Delaware Bay, a crucial stop on their epic migratory journey. One of the longest in the world, it starts at the Tierra del Fuego archipelago, at the southern tip of South America, up to the Canadian Arctic and back. Red knots fly up to 30,000 kilometers in one year, a record distance that requires a very special diet that includes horseshoe crab eggs. These eggs allow red knots to gain weight during their stop at the Delaware Bay before pursuing their long journey, going from 100 grams to up to 300 grams.

Recognizable by its helmet-like shell, the horseshoe crab appeared on earth around 200 million years before the dinosaurs. It is also a glue that holds coastal ecosystems together in parts of Southeast Asia and along the North American Atlantic coast, including the Delaware Bay. Its eggs provide local species of fish, terrapins and shorebirds with the resources they need to survive.

But as horseshoe crabs face rapid decline, the whole local ecosystem is threatened to collapse, taking not only the red knots with it, but also one of our most vital medical components.

Beyond local species, the horseshoe crab is also vital to us humans, due to a component found in its peculiar electric blue blood. It contains limulus amebocyte lysate (LAL), an extract used by the biomedical and pharmaceutical industries to detect toxins that may contaminate injectable drugs, including vaccines, and medical implants. Considered a revolution in endotoxin testing, LAL has replaced previous rabbit testing since the late 1970s, contributing, alongside fishing activities, to significant declines in global horseshoe crab populations, with the Asian species facing extinction.

According to Larry Niles, a wildlife biologist leading the Wildlife Research Partnership scientists’ group, there are now between 5- and 10-times fewer eggs on the beaches during spawning periods than there used to be thirty years go. “They are what is called a keystone species. If you take it out of an ecosystem, it essentially collapses” he says. This is the danger facing the Delaware Bay today, as the number of red knots observed on its beaches went from around 90,000 to as low as 7,000. According to him, the decline of horseshoe crabs has not only impacted the wildlife but also caused a ripple effect on the local economy, as rural towns along the bay shore have gradually lost major incomes generated by recreational fishing.

The decline of horseshoe crabs also causes a serious issue for the medical field, as the world’s supply of LAL could be threatened by any catastrophe that would substantially harm horseshoe crab populations. In the wake of the Covid 19 pandemic, a worrying question arises: will the pharmaceutical industry be able to meet the surge in demand for endotoxin tests when the next pandemic strikes?

Synthetic equivalents to LAL do exist, and are considered comparable, if not better, as they can theoretically be produced in unlimited quantities and, according to some practitioners, produce fewer false positives¹. Synthetics are accepted by regulatory authorities in Europe and the United States, and the US Pharmacopeia issued long-awaited new guidance on the use of synthetics last year. Better still, rFC, the oldest available alternative, has been off-patent since 2017. Although the need to switch from one to the other at an industrial scale seems obvious, it has yet to be widely implemented.

“From an industry perspective, the launch of the next game changing injectable product should not depend on how many horseshoe crabs are left in the bay.” says Adam Kanzer, Head of Stewardship Americas at BNP Paribas Asset Management (BNPP AM). Dedicated to monitor portfolio companies on questions of long-term risks and their impact on the environment and society, the BNPP AM Stewardship team brought the LAL issue to several pharmaceutical companies in Europe and the United States. “We laid out the business and scientific cases, backed with scientific studies, and asked them a whole series of questions about where they were in this process and what they could do about it.”

Rachel Crossley, Head of Stewardship Europe at BNPP AM, brought the issue to the Pharmaceutical Supply Chain Initiative (PSCI), a group of over 80 global pharmaceutical companies focused on sustainability issues in their supply chains. An industry working group was formed that published a position paper on best practices for use of horseshoe crabs in the sector. PSCI is now monitoring their members to see how they’re complying with those best practices.

“We’ve have had good responses from most of the companies we have engaged with since the paper came out”, says Rachel Crossley. “A few confirmed good progress with reducing their use of LAL, with others developing plans to phase it out. Very few haven’t responded or have indicated they are not taking action” says Rachel Crossley. “We will continue to urge them to join their industry peers and do so.”

As environmental issues are increasingly impacting the global economy, BNPP AM has also helped bring together a group of investors in Nature Action 100, a collaborative initiative engaging with 100 companies believed to be systemically important to the goal of reversing nature loss.

The ripple effect that started with a small initiative designed to understand the falling red knot populations on the beaches of the Delaware Bay is – with an enormous amount of work from a lot of dedicated people – leading to changes in practice across a large swathe of the pharmaceutical industry. This will not only benefit horseshoe crab populations and the ecosystems that depend on them, but the companies and investors alike, over the longer term. “Nature is clearly on the investor agenda now in a way that it never was before. There is much stronger recognition that investors require both a stable climate and stable ecosystems to continue to deliver returns to our clients over the long run.”

[1] Comparison of Limulus amebocyte lysate test methods for endotoxin measurement in protein solutions – ScienceDirect