Breakthrough: The Killer Snail Chemist

This video is part of “Breakthrough: Portraits of Women in Science,” a short film anthology from Science Friday and Howard Hughes Medical Institute (HHMI) that follows women working at the forefront of their fields. Hear Ira speak with Mandë Holford (and see some cone snails in action) here, and make sure to check out the rest of the Breakthrough series.

mande holford looks at cone snail shells
Mandë Holford studies “killer” cone snails. Credit: Science Friday

She roamed across the Sahara and the Serengeti, spotting elephants. She traveled south to the Amazon, where the brilliant colors of the birds and reptiles left her dazzled. She dove into the ocean and marveled at the great blue whales. And then, promptly at 5:45pm, she’d head to the elephant near the Hall of African Mammals, where she’d meet her mother.

“As a kid growing up in New York, you have a couple of places that are really special, and the American Museum of Natural History is one of those for me,” says Mandë Holford, a biochemist at Hunter College and the American Museum of Natural History. “My parents would sometimes use it as a way of babysitting.”

A self-professed nerd, she spent a lot of time reading as a child. But the museum offered more than any one book could cover. “It’s just a place of wonder…Going to the museum is like bringing that reading alive,” she says. “It was like a walking book for me.”

Those afternoons spent wandering through the museum set a tone for Holford’s life. She roamed through the halls finding new adventures and new sets of biological wonders. “What I didn’t understand as a child was that that was science,” she says.

Bridging The Gap

Holford went on to study science, but she didn’t find what she was looking for in a single field. As an undergrad, she studied under a physical chemist. But they weren’t just studying the bacteria they were working with—they were growing it themselves.

“So he was doing a little bit of recombinant biology, as well as physical chemistry, and so that was the first time I learned about science being collaborative and integrated,” Holford says.  “And I just got completely blown away that this was a career, and this was a job.” She thought to herself, “I want to do this. I absolutely want to do this.”

[This polar bear researcher begins her day with a thrilling helicopter ride.]

While she pursued her Ph.D. at Rockefeller University, a very “human-centric” biomedical institute, the natural world was never far from sight—both literally and figuratively. The university was located on the east side of Central Park, and the American Museum of Natural History on the west. A bridge stretched across the park from one institution to the other, and as she crossed it, Holford thought, “This is what I would like to do. I’d like to bridge the medical training that I received at Rockefeller with the natural history and the wonder and excitement of studying what’s here in biodiversity. And figure out how to make science—how to do the kind of work that is both beneficial to society, but also exploring the wonder that’s here on our planet.”

But she needed to find an organism that encompassed that—one that had a human, biomedical application, but was also strongly grounded in the natural world.

New Pathways, Old Problems

Then, she saw a video of a snail eating a fish.

Baldomero “Toto” Olivera, whose research focuses on venomous marine snails, visited Rockefeller to give a talk on cone snails. Encased within their delicate and stunning shells, the cone snail’s proboscis is tipped with venom, and it uses it to harpoon and paralyze its prey before engulfing it entirely in its mouth. In its natural form, the venom could be lethal even to humans. But the snails’ venom is made up of many peptides, molecules composed of amino acids. And some of the individual peptides have potential medical applications—they could offer promising treatments for cancer, as well as opioid-free solutions for chronic pain. Here was the link to Holford’s biomedical work.

cone snail fish
Credit: Biopixel

“I was excited, because I saw an organism that had an evolutionary history that was exciting, that would have been of interest to someone working in a natural history museum,” she says. “And it had an application in that the venoms were a means to alleviate some of the issues and disorders that we have, the human disorders that are there.”

Holford went on to do a post-doc with the “Godfather of Snails,” as she christened Olivera, and continued her love affair with the killer cone snails.

“What’s wonderful is something that kills you can actually then potentially be something that cures you,” she says. “It’s like this strange twist of nature. You have this very, very [lethal] snail…And then, in a surprising twist, you can also extract some of the parts of this venom and use it to cure something, or to treat something that is causing pain.”

cone snail attacks fish
This fish falls victim of a violent death. The venom paralyzes the prey. Credit: courtesy of Dr. Jason Biggs, University of Guam

But Holford points out that looking to nature for answers is nothing new. For millions of years—from the Aztecs to ancient Asian cultures, to the Native Americans—we’ve been looking to our natural environment for cures to the things that ail us, she explains. Now, we’ve just gotten a bit more “strategic” about how we do it.

One of those strategic methods is venom research, which also lends itself to interdisciplinary studies. The venom itself is natural, but researchers extract it and learn about its components using analytical biochemical methods. And in the end, its applications are biological.

“What’s amazing about the peptides that we’re finding in the snail venom is not only are they giving us new drugs, but they’re also giving us new pathways for treating old problems,” says Holford.

The Deep End

Holford runs her own lab and is now at the forefront of biomedical research. But like anyone at the start of her career, she experienced a few growing pains.

For example, if you’ve never hunted for cone snails in the wild, you may need to learn on the fly. Holford’s first snail collection trip was in Panama, and she went in “completely green.

“I didn’t study evolutionary biology, or taxonomy, or anything that,” she says. “So this was like really just jumping into the deep end, literally, and trying to figure out, how do you find snails?”

In books, the cone snails’ shells are polished and shiny, and their patterns are strikingly visible. It’s a different story when the organisms are buried in the sand. Researchers must look for trails in the sand, and then dig up the snails.

“One of the first things they teach you when you’re learning to dive is, if it’s too beautiful, don’t touch it, and if it’s too ugly, don’t touch it. Because everything can potentially kill you, and it’s usually the beautiful or the ugly things that are lethal.”

And the consequences for a wrong choice are no small matter: “One of the first things they teach you when you’re learning to dive is, if it’s too beautiful, don’t touch it, and if it’s too ugly, don’t touch it,” says Holford. “Because everything can potentially kill you, and it’s usually the beautiful or the ugly things that are lethal.”

But the trials Holford encountered while snail hunting only provided practice for a career as a scientist.

“As a scientist, you’re always learning to deal with failure, because experiments fail all the time,” she says. “So you have to sort of have this tough skin to pick up and start again, and being in Panama was one of the first times.”

The “Cheapest” Career

Since that first expedition to Panama, Holford’s work has taken her all over the world. On a trip to Papua New Guinea, she noticed something about the local students with whom they were working.

“I would notice that they were staring at me,” she says. “And you know, in your subconscious, you’re like, ‘What is it? Is it my hair? Do I have something in my teeth? What’s going on?’”

It had nothing to do with her teeth.

Holford estimates that there were scientists from roughly 30 different countries on the collection trip. She also believes that she was the only black American woman on the trip who was coming as a chief scientist.

[Three scientists share stories about India’s first interplanetary mission, MOM.]

“I was the only New Yorker and the only New Yorker that looked like I did, and I looked very similar to the native Papua New Guinean people,” she says. A colleague pointed out that it was rare for the people of Papua New Guinea to see someone in her position look so similar to them.

“And it was something I wasn’t prepared for, because I didn’t view myself as a role model,” Holford says. “And I wasn’t trying to be anybody’s role model. You’re just trying to do your thing…And it’s a huge responsibility to be seen in that role. But it was also empowering.”

The reason it was empowering, Holford says, is because she wanted to convey to the students that they too could do the work that she was doing.

“I like to say that science is one of the cheapest careers. It’s like soccer—all you need is a ball. In science, all you need is a brain, and all of us are born that way. So if you’re interested in science, you can certainly become a scientist.”

“I like to say that science is one of the cheapest careers. It’s like soccer—all you need is a ball. In science, all you need is a brain, and all of us are born that way. So if you’re interested in science, you can certainly become a scientist.”

And that’s exactly what happened to Holford. Her path to becoming a scientist  began in the halls of the American Museum of Natural History, and her days at the museum may still end around 5:45pm. But now, she doesn’t need her mom to take her home.

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Video Transcript

Download the transcript.

MANDE HOLFORD: Cone snails are fascinating because they’re so unexpected. It’s this gorgeous shell. And it’s this little tiny animal that actually moves very slow. Not at all. And can easily be overlooked. But they pack a powerful punch. And what’s wonderful is something that kills you can actually then potentially be something that cures you.

It’s just amazing, all the snails do. And also, the potential for what they can do for human disease and drug discovery. My name is Mande Holford. And I’m a venomous snail hunter. We work with these killer snails to investigate their venom and look for novel compounds that can be used to treat pain in cancer.

I grew up in Brooklyn. And I’m one of five kids. And my parents came from South America to New York. And decided that this is where they’re going to try to make their life. As a kid growing up in New York, you have a couple of places that are really special. And the American Museum of Natural History is one of those for me. We would go to the Museum of Natural History and go on our adventure roaming through the halls.

Each hall was like a new adventure. What I didn’t understand as a child then was that that was science. It has a special place in my heart to be a scientist.

Almost every Natural History Museum on the planet has a shell collection. You can learn about biodiversity. You can learn about family trees of the snails. And look at how venom has evolved over time.

The snails that we work with, are they’re not garden snails. These are marine snails. They’re found in tropical marine environments all over the world. In the whole family of the snails, there are upwards of I would say 20,000 species. Not all snails are venomous. But some of these species of these snails are fatal to humans. I affectionately like to call my snails killers snails because they’re very, very lethal. Deadly, actually.

Conus geographus, it’s been tagged the cigarette cone, because after you get envenomated you basically have time to smoke a cigarette. And then you’re going to drop dead.

My love for killer snails wasn’t there originally. As I was finishing my graduate program, there was a seminar from Toto Olivera – I call him the godfather of snails. He came and he gave a talk. And he showed a video of a snail eating a fish. And I was completely, like everyone in the audience, we were blown away. Like how is this possible?

The snail is hidden under the sand. They have a siphon that sticks up. The siphon is kind of like a nose. It can smell. If there is prey in the water, then the proboscis comes out. And it’s kind of like a tongue. And on the tip of the tongue is a harpoon, which is filled with venom. And then when they harpoon the prey with the venom, their venom has things in them that will shut down everything basically in the prey. Blood sugar, locomotion. The prey then instantly becomes paralyzed. Its mouth, or rostrum, opens really wide. And it will then engulf a fish or a worm completely whole. So the venom arsenal that nature has developed has worked wonderfully for millions and millions and millions of years. It’s kind of been perfected.

Learning from nature is actually something we’ve been doing for a long time. All cultures. Ancient cultures have traditionally used their natural environment to look for cures to things that ailed them. And so what we’ve done now is we’ve gotten a little bit more strategic in how we learn from nature.

You have to be very careful when you collect the snails. Usually we have scuba gloves on. And then you sometimes can use salad tongues. Very high tech. To pick them up, drop them in the bucket, drop them in a bag, and bring them back up to the surface.

After we’ve collected the snails, we will dissect out the venom gland to then figure out what are the components inside of the venom. Venom is actually a cocktail. I like to call it nature’s deadliest cocktail. The venom of the snails that we work with is mostly proteins with peptides.

Peptides are small proteins. Each snail and produce upwards of 200 different peptides in their venom arsenal. But each peptide is very targeted. They come in and they can block specific function of the prey. Since the peptides found in venoms are very specific, very potent, those are sort of the ideal for the drug discovery world. But they’re also giving us new pathways for treating old problems. And what we have to do is figure out how they work and where they work in the cell.

Once we have identified which peptide we want to work on, we create it in the lab. The goal then is to identify the molecular target of the channel inside of the cell that they’re working on. For example, in the instance of chronic pain there’s this constant signal from one neuron to another. Peptides will block the channel that’s helping to perpetuate that signal.

Cancer cells, like normal cells, they have these different channels on them that the peptides could target. In cancer, tumor cells or proliferating and there’s this signal that’s sort of gone crazy. With the group here at Hunter College, we got very excited because we found a peptide. It’s called TV1. TV1 was hitting tumor cells at a higher degree than it was hitting normal cells. And so we’re trying to identify which channel in the liver tumor cells are being inhibited with TV1.

The first drug from the snails, these killer snails, was ziconotide. The commercial name is Prialt. It’s found from Conus magus. Similar to how the venom peptides will target a tumor cell to shut down proliferation, it works in stopping chronic pain signal.

Currently, the way that most drug companies are dealing with pain is through the opioid receptor. And the big major side effect is addiction. With Prialt, you don’t have the side effect of addiction. So the snails showed us not only a new drug. But they showed us a new model for how to treat pain.

Prialt is wonderful, but it doesn’t cross the blood brain barrier. You have to take a spinal tap, which is a very painful and invasive way of doing it. So we’re looking for ways in which we can deliver the Prialt drug without delivering it through a spinal tap. We have what we call a Trojan horse strategy, in which we are encapsulating the peptide inside of a nano container. And trying to shuttle it across the blood brain barrier. And then releasing it.

What we’re trying to do is learn from how the cells are giving us new drugs, but also giving us new pathways and new models for looking at diseases and disorders, particularly around pain and cancer. Cells are really fascinating because it’s always like the little package with the big surprise.

And the more you learn about nature, you find out that there are lots of twists. And some of them are good. And some of them are not so good. But this a really, really surprising twist of nature that’s possible when you study the venom.

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A film by Science Friday
Article written by Johanna Mayer
Produced in collaboration with the Howard Hughes Medical Institute
Produced by Emily V. Driscoll and Luke Groskin
Directed and Edited by  Emily V. Driscoll
Filmed by  Christian Baker and Dusty Hulet
Animations by M. Gail Rudakewich and Luke Groskin
Music by Audio Network
Additional Photos and Video by
Olivera Lab, Shutterstock, Pond5, NatureFootage, BioPixel, iBiology, Mandë Holford, Gregory S. Herbert
Guillaume van den Bossche, The National Library of Medicine
Project Advisors:
Laura A. Helft, Laura Bonetta, Dennis W.C. Liu and Sean B. Carroll – Howard Hughes Medical Institute
Special Thanks to
American Museum of Natural History, Hunter College, Olivera Lab at the University of Utah
Baldomero “Toto” Olivera, Talia Amador, Devin Callahan, Sean Christensen, Mandë Halford,
Gregory S. Herbert, My Huynh, Terry Merritt, Aubrey Miller, Kendra Snyder, Danielle Dana,
Chistian Skotte, Ariel Zych and Jennifer Fenwick
Science Friday/HHMI © 2017

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Emily Driscoll is a science documentary producer in New York, New York. Her production company is BonSci Films.

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Luke Groskin is Science Friday’s video producer. He’s on a mission to make you love spiders and other odd creatures.

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