How Venom Achieves its Dramatic Feats

'22 Whitman Fellow Mandë Holford of City University of New York (CUNY): Hunter College studies how animal venoms evolved and act. Credit: Nora Bradford

Though venom is mainly used by animals to paralyze or kill prey, scientists have other uses for venom’s unique ability to manipulate cellular physiology.

Mandë Holford, associate professor at CUNY Hunter College and E.E. Just Fellow in the MBL Whitman Center, wants to know how exactly venom achieves its dramatic and deadly feats. She studies the compounds found in the arsenal of venomous snails and has recently started to examine cephalopod venoms.

While it may be surprising to hear that venomous snails and cephalopods exist, research shows that 15-30% of animal biodiversity is venomous.

Venoms are complex mixtures of small molecules, proteins, and peptides (which are made up of the same material as proteins but are smaller). Though venom is widely used in the animal kingdom, the mixtures of peptides involved are species-specific.

Holford hopes that her research will unlock new avenues for understanding how venom evolved, specifically, how venom genes were weaponized. She hopes to translate the selectivity of venom’s ability to manipulate blood, brains, and cellular membranes to identify new therapeutic applications for pain and cancer. Individual peptides from venoms have been used in therapies for various diseases and disorders in the past, and Holford plans to share the specific strengths of the toxins she studies to expand the field.

The Evolution of Venom

Holford uses proteomics to investigate what proteins are being expressed in an animal’s venom, analyzes the genome and RNA transcripts (genomics and transcriptomics) in venom to see the potential for what could be expressed, and tests the activity of bioactive peptides in the venom using bioinformatics and functional assays.

“You can milk a snake and get tons of venom, but you can’t really milk a snail so it’s harder to get large quantities of venom,” says Holford. “With the advent of these -omics techniques, we can look at very rare, very small, very hard-to-collect animals.” This allows scientists like her to do comparative biology to investigate how venom has evolved in different animals.

Snail tank in Mande Holford Lab. Credit Nora Bradford
A snail tank in the Holford lab in the Whitman Center. Credit: Nora Bradford

Each venom peptide is expressed by a single gene. So to fully understand how the genes involved in producing venoms got weaponized for that purpose over the course of evolution, researchers need a system for manipulating those building blocks. That’s where organoids come into play.

Organoids are small tissue cultures that recapitulate the function of an organ in a petri dish. Holford hoped to use this technique to create a stockpile of venom gland organoids in her lab, in order to genetically manipulate how the genes in the venom glands work.

But never before has a marine invertebrate organoid been made. Over the course of the summer at MBL, Holford and her team made headway in growing a small number of glands and keeping them for a short amount of time. While she continues to hone this technique, she decided to explore another route for studying venom: cephalopods.

Carrie Albertin, an MBL Hibbitt Fellow who studies cephalopod genomics, had indicated that squid ink sacs can continue functioning outside of the animal. This led Holford to think that MBL’s cultured cephalopods may be the model organisms venom researchers seek to unravel how venom genes evolved and are regulated to produce such exquisite toxins.

After her experience at MBL, Holford is excited to begin studying cephalopods as “a way to go beyond the chemical interactions of peptides and bioactive toxins, and use laboratory organisms to  study toxin gene expression and gene evolution.This approach can shed light on the molecular processes that drive venom’s phenotypic diversity.”

“Without guiding principles for how venoms and venom glands develop in vivo, we and other venom researchers  have just scratched the surface,” she says. “We need lab models that can be manipulated in a controlled environment to revolutionize how we study venoms and venom gland biology, so that we can radically transform how we generate, modify, and utilize venom arsenals. Deciphering how complex traits like venoms occur in nature is a wide-open question.”

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Two species of venomous cone snail, Conus striatus and Conus bullatus. Credit Mande Holford, MBL Whitman Fellow