Last night, I headed down to the beautiful Bell House in the Gowanus section of Brooklyn for this month's Secret Science Club lecture, featuring Biochemist Mandë Holford, of the City University Graduate Center and the American Museum of Natural History.
Dr Holford began her lecture with a quick recap of her curriculum vitae, first identifying herself as a Brooklyn native, and noting that she was pleased to be giving a lecture in the borough of her birth. In her CV recap, Dr Holford joked about how she studied cone snails at the University of Utah, far from any ocean, under Dr Baldomero Olivera, the "Godfather of Snails". She characterized her work as studying biological organisms from a chemical perspective- the protein synthesis that she studies is dynamic in nature but static in the lab. She specifically studies venomous snails that prey on other organisms, notably fish:
As an aside, there's something disconcerting about watching an invertebrate killing an eating a vertebrate. Sure, it happens all the time, but I feel a bit of "chordate solidarity" when I watch it.
Dr Holford quipped that cone snails are not your garden variety of snail. These snails are highly venomous, and her specialty is studying the ecology of these venomous animals in order to discover new medical treatments.
The Conoideans prey on fish, utilizing toxins which paralyze their prey. The venoms employed by conoids have anywhere from fifty to two hundred neuropeptides which shut down the nervous systems of prey. Because the snails are slow, they have to neutralize their prey quickly. The venoms are fast and potent, just like an "ideal" drug. The peptides in the snail venoms shut down several parts of the nervous system- Dr Holford likened the effect to a cluster bomb.
The various neuropeptides in the snail venom block the neural pathways, acting as chemical blocks and interfering with electrical processes- various components of the venoms effect sodium channels, calcium channels and interfering with neurons' action potential. Analgesic compounds in the snail venom block pain signals in the snails' prey.
Dr Holford then went into a digression about the development of analgesics, using the term "venomics" to describe her field of study. She noted that the organisms she studies have evolved their venoms over millions of years, and the key for a "molluscs to medicine" effort is figuring out what compounds are involved in these evolutionarily honed venoms. In order to gain this understanding of venomics, a "family tree" of venomous snails has to be parsed out- which snails are interesting from a venomic standpoint? Which venoms can be the basis of analgesics? Which snails can be worked with? Besides the Conidae, Dr Holford also studies the venomous Terebridae, and Turridae. She joked that her laboratory is the tropical beaches of the world.
Dr Holford described fieldwork that she conducted in the vicinity of New Ireland's Kavieng peninsula. Specimen collection was accomplished through diving, snorkeling, and dredging. Much of the diving took place at night, as cone snails are nocturnal. The purpose of the collection was to determine species diversity and to discover new toxins.
Cone shells deliver their venoms with barbed "harpoons" that tether their poisoned prey. The harpoons are modified radulae and are connected to a venom sac by a venom duct. The taxonomy of the conoidea has yet to be fully sorted out, because a lot of diverse species were lumped together into a "junk" clade. The classification of cone shells involves a correlation of anatomical and molecular analysis- this figure represents the evolving understanding of Conoidea cladistics. It is generally accepted that the cone snails are derived from the terebrids.
The lecture then shifted to the pharmacological studies of the venomous snails. The amino acid sequences of the neuropeptides need to be figured out in order to allow the synthesis of them to occur. Because of the number of neuropeptides produced by the snails, a "kitchen sink" approach has to be used- which peptides operate on sodium channels, which on potassium channels, which on calcium channels? Additionally, the therapeutic goals need to be clarified- which diseases are to be worked on?
If the snail venoms were to be obtained from the snails, tons of snails would have to be collected- sequencing the neuropeptides bypasses the need for collection. The peptides are "fragmented" and analyzed using mass spectrometry.
Synthesized peptides are lineral, while the peptides produced naturally by the snails are "folded". In order to be used pharmaceutically, the peptides must be folded by cysteine and sulfide bonds.
One particularly promising snail peptide, known as Tv1 was found to not only kill cancerous cells, but to "distinguish" between cancerous and normal cells. Other peptides promise to be effective pain relievers that are not addicting like opiates. "Vampire snails" also produce antigoagulants as well as anaesthetics. Since different peptides target different analgesic pathways, a plethora of drugs can potentially be synthesizd, including drugs to treat epilepsy and myocardial infarcion. Since snail toxins affect the central nervous system, targeting is a problem- specificity has to be developed, the site of action and the delivery method have to be refined to target the peripheral nervous system. These toxins are much more complex than morphine. One promising delivery technique would be to use a "trojan horse" approach, coating a peptide in a "scaffold" of other proteins so the peptide can "do what it needs to do".
Dr Holford indicated that there's a lot more work to do in this field before the venoms can be used therapeutically. In the Q&A session after the lecture, some bastard in the audience asked her if the snail toxins were produced by symbionts (you'll recall that that is similar to the bastard's question last month- that bastard seems to be obsessed with symbiosis!). She answered that the snails synthesize their venom on their own.
Once again, the Secret Science Club has delivered a great lecture. Dr Holford's lecture hit that "secret science sweet spot"- a little bit of an adventure narrative and a whole lot of information about the biology of the cone snails and their relatives, and about the process of peptide analysis and development of pharmaceuticals. She knocked it out of the park!
Here's a short video of Dr Holford discussing the medicinal potential of snail venom. Pour yourself a vodka and grapefruit juice with a splash of Campari (the drink of the night, which was delicious) and soak in that Secret Science ambiance:
Here's a link to The Venom Cure, a PBS presentation that covered the same ground as Dr Holford's lecture.