Noah Whiteman, professor of evolutionary biology at UC Berkeley, writes about how toxins are repurposed into medicines for Issue 06. Whiteman’s recent book is called “Most Delicious Poison.”
Ella Watkins-Dulaney for Asimov Press.
When you hear the word "poison," perhaps you picture a Victorian-era cobalt bottle labeled "NOT TO BE TAKEN" or the iconic pictogram of a leering skull and crossbones. What probably does not come to mind, however, are the dried white beans in your kitchen pantry, the molluscs who once lived in cone shells in your bathroom jar, or the Botox injection that magically erased your facial lines. Yet, as an evolutionary biologist and geneticist who studies co-evolution between species, I think of these and more.
Now, don't worry. The way we typically prepare white beans completely deactivates the mild toxin that could otherwise cause food poisoning, the highly venomous cone snail that produced that shell was long gone by the time you picked it up, and Botox has been safe to inject by licensed healthcare professionals since FDA approval in 1991. All are examples of compounds we have not only learned to attenuate but actually use to our benefit.
The toxins they make fall into a class of biological molecules known as peptides or proteins. Both form from chains of amino acids — proteins often consist of more than 1,000 amino acids, while peptides typically contain fewer than 100. These amino acid chains have been used for eons by all cells for essential biological functions, such as transporting materials around the body or catalyzing chemical reactions. Additionally, many can be used as weapons by their bearers — either defensively or offensively — to cause pain, tissue damage, paralysis, emaciation, or even death. These abilities are precisely what make them promising as potential therapies, particularly as we find ways to enhance their safety profiles. Botulinum toxin (Botox) from bacteria is one such familiar example.
While small-molecule drugs continue to play a critical role in modern medicine, we are witnessing a shift toward the increasing development of amino acid-based therapeutics. Toxic peptides and proteins, particularly from the venoms of animals, are predicted to be a major source of next-generation peptide and protein-based drugs.
The prominence of these drugs has risen further still with the phenomenal success of semaglutide (sold as Wegovy and Ozempic). While these and other peptide-based drugs weren’t patterned directly on molecules from venoms, many rely on some of the natural mechanisms by which toxins operate. A closer look at these evolutionary templates reveals why inspiration from nature’s “poisonous proteins” will continue to drive drug development.
Peptide-Based Drugs
Sessile organisms, whether a sponge, coral, plant, or mushroom, are often quite literally between a rock and a hard place. They cannot jump, run, swim, or fly away from danger if a hungry animal wants to take a bite out of them. To counteract this vulnerability, evolution has driven these stationary creatures to produce myriad toxins that act as chemical defenses.
In plants, remarkably, a set of these toxins includes amino acids that mimic the normal amino acids needed by our cells to make proteins. When these non-proteinogenic amino acids are incorporated into proteins, they cause them to malfunction. For example, some legume plants make L-canavanine, which is a bitter and toxic molecular mimic of the amino acid L-arginine. Herbivorous animals that consume L-canavanine-bearing plants produce misfolded proteins by incorporating the mimic instead of L-arginine, rendering the resultant protein useless to the cell.
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