Scientists already know that the venom of cone snails, which prowl the ocean floor for a fish dinner, contains compounds that can be adapted as pharmaceuticals to treat chronic pain, diabetes and other human maladies. But the cone snails’ venom has more secrets yet to be revealed. In a new study published in Science Advances, researchers report that a group of cone snails produces a venom compound similar to the hormone somatostatin.

While they continue to learn more about this venom compound and its possible pharmaceutical applications, the results show the wide variety of drug leads that venomous animals produce,  designed and refined over millions of years.

“We have to broaden the scope of what we expect that these venomous animals make, assuming that they could really be making anything,” says Helena Safavi-Hemami, an adjunct assistant professor at the University of Utah and associate professor at the University of Copenhagen.  “We should look very broadly and keep an open eye for completely new compounds.”

“Cone snail venom is like a natural library of compounds,” adds Iris Bea Ramiro of the University of Copenhagen. “It is just a matter of finding what is in that library.”

Find the full study here. This research was funded by the U.S. Department of Defense, a Villum Young Investigator Grant, the Department of Science and Technology—Philippine Council for Health Research and Development, USAID and the Benning Society.

Beginning in Bohol

The story begins in the Philippines, on the island of Bohol where Ramiro grew up. Although she and most Boholanos didn’t encounter cone snails often except for finding shells on the beach, fishermen knew how to find and catch the venomous snails, which are often sold to shell collectors and are sometimes eaten. One fisherman told Ramiro that his parents warned him to avoid eating a bean-like organ in the snail.

“The bean-like structure is actually a bulb that is connected to the gland where venom is produced,” Ramiro says.

Some cone snails are fish hunters. Some of those use a “taser-and-tether” hunting strategy, shooting a barbed hook into a fish and delivering a jolt of venom that chemically electrocutes and paralyzes the fish. Others use a net hunting strategy, releasing a cloud of venom into the water with compounds that leave the fish sensory-deprived and disoriented.

Of the estimated eight groups of fish hunting cone snails, though, only half have been extensively studied. Among the least-studied lineages are the Asprella cone snails. They’re not shallow-water snails, like some others. They like deeper waters, at depths of 200-800 feet (60-250 m), and have been less accessible to scientists.

As a graduate student at the University of the Philippines, Ramiro began studying Conus rolani, a species of Asprella snail. “No one in our lab was working on it at that time,” she says. “I was just looking to identify any small peptide (chain of amino acids) from the venom of C. rolani that had unusual or interesting activity in mice.”

She found one. A small peptide from the venom caused mice to act sluggishly or unresponsive. But it was slow-acting, hardly the expected effect since other cone snails produced venoms that acted almost immediately. It had a few similarities to the hormone somatostatin (more on that later) but not enough to say conclusively that the venom peptide and the human hormone were functionally related.

While exploring how and why the venom worked, Ramiro made a visit to the University of Utah, a hub of cone snail research.

Cone snails at the U

Far from the glittering waters of the Pacific, U researchers have been studying cone snails and their venom since 1970, when Baldomero “Toto” Olivera arrived in Salt Lake City, bringing the cone snail research he’d begun in his native Philippines.

Decades of study have provided an abundance of information about how venom compounds interact with the bodies of prey fish, including how the venoms interact with receptors in the body and overwhelm natural biochemical processes. Olivera and his colleagues investigated whether those effects could be employed as pharmaceuticals in humans. One effort yielded a pain medication, Prialt. Another, in which Safavi played a leading role at the U as an assistant professor, investigated how insulin analogs produced by cone snails might be adapted as a fast-acting insulin for people with diabetes.

“Somehow cone snails take some of their hormones and turn them into weapons,” Safavi says. So she and other researchers helped Ramiro compare the peptide she’d found, now called Consomatin Ro1, to known human proteins.

Frank Whitby, a research associate professor in the Department of Biochemistry, used X-ray crystallography to determine the structure of Consomatin Ro1. “This was an important contribution because it showed that Consomatin Ro1 does not resemble somatostatin but rather resembles a drug analog of somatostatin called octreotide,” says Christopher Hill, distinguished professor of biochemistry.

Meanwhile the research team also worked with local fishermen off Cebu, an island near Bohol, to bring Asprella specimens to the lab to observe their behavior and learn more about their biochemistry.

It took a year, Ramiro says, to confirm that the peptide that she’d originally isolated from the C. rolanisnail activates two of the five human receptors for somatostatin “with unique selectivity,” she says.

“Then,” Safavi says, “we really wanted to understand what it’s doing and how it could be better than somatostatin.”

Snails and snakes 

Somatostatin is a hormone that, in humans and many other vertebrates, is generally an inhibitor—kind of a wet blanket. It’s the main inhibitor of growth hormone, and can be used to treat the excessive growth disorder acromegaly. It also inhibits hormones in the pancreas and signals of pain and inflammation.

“So it’s this hormone that has many, many different functions in the human body,” Safavi says, “But it’s always blocking something. And because of that, it had been an interesting hormone for drug development for some time.”

How can a hormone like somatostatin work as a weaponized venom, especially when it acts slowly? The best way to understand that, the researchers say, is to look to another predator with a slow-acting venom: the rattlesnake.

Rattlesnakes, vipers and cobras have developed a hunting strategy to protect themselves against dangerous prey that could possibly fight back. The snakes strike, injecting their venom, and then retreat. They then wait and follow their prey until the venom takes its full effect and the prey is dead or nearly dead and safe to approach and eat.

Observations of cone snails in tanks showed similarities to the rattlesnakes’ strike-and-release hunting strategy. After injecting venom, the snails would wait, sometimes up to three hours, before delivering a second injection and waiting again.

“And only when the prey is really incapacitated and unable to swim, they come and eat it,” Safavi says. “If you don’t catch the prey immediately, you have the advantage of just waiting until the prey can no longer move. That’s particularly important if the prey can fight back.”

How does a venom component that mimics somatostatin help with that strategy? It’s still unclear. The study showed that Consomatin Ro1 can block pain in mice with efficiency similar to morphine, and it may be used to block pain so that prey doesn’t know it’s been struck, Safavi says. Different species of fish hunters may use these toxins for different purposes.

Tiny drug designers

As a somatostatin analog, Safavi says, Consomatin Ro1 is structured “as if it was designed by drug makers.” The molecule is short, stable and efficient in the receptors it targets.

That’s likely a reflection of the process of evolution. Cone snails likely began using their own somatostatin in venom and then, through generations of trial and error, refined the compound for maximum effectiveness. That’s an advantage for us, since the biology of fish and humans is similar enough that a compound that’s highly effective in fish will likely be effective in humans.

It’s yet to be seen whether Consomatin Ro1 is more effective than somatostatin analog drugs already on the market that treat growth disorders or tumors.

“The advantage with the cone snails, though, is that there are so many species,” Safavi says. “And we know that many of these species make somatostatin, so the chances of finding the best analog might be pretty high.”

Future directions

Next, the research team wants to investigate the origin of Consomatin Ro1 in snails, as well as better understand the potential of the compound as an anti-inflammatory or pain reliever. They’ll also look to see if modifications to the compound could make it even more useful.

The results show how venomous animals can turn a hormone into a weapon and suggest that the range of biochemical tools in venom might be broader than previously thought.

“There’s evidence that viruses also turn hormones into weapons,” Safavi says. “We can spend a lot of time trying to design good hormone drugs, or we could try to look at nature more often. And I think if we did the latter, we might be more successful or we might be faster in our drug development efforts.” Safavi will continue this work when she returns to the U as an associate professor of biochemistry in summer 2022.

“This gives insight to the development of next-generation therapeutics,” says Hill. “More generally, this is a great example of how evolution in the natural world has already developed drug-like natural products that have great potential to improve human health.”

“Discovering new peptides from the cone snails is fun and exciting but it could be a long and difficult journey,” Ramiro says, adding that the integration of various disciplines including biology, biochemistry and pharmacology have made this study successful. “There is still so much we can find, discover and learn from the cone snails and their venom.”

Drs. Annemarie Dedek, Eve Tsai and Mike Hildebrand (left to right) have shown for the first time that neurons in the spinal cord process pain signals differently in women compared to men. CREDIT Justin Tang

A new study published in the journal BRAIN shows for the first time that neurons in the spinal cord process pain signals differently in women compared to men. The finding could lead to better and more personalized treatments for chronic pain, which are desperately needed, especially in light of the opioid epidemic.

Although it has long been known that women and men experience pain differently, most pain research uses male rodents. The new study is unique because it used female and male spinal cord tissue from both rats and humans (generously donated by deceased individuals and their families).

By examining the spinal cord tissue in the laboratory, the researchers were able to show that a neuronal growth factor called BDNF plays a major role in amplifying spinal cord pain signalling in male humans and male rats, but not in female humans or female rats. When female rats had their ovaries removed, the difference disappeared, pointing to a hormonal connection.

“Developing new pain drugs requires a detailed understanding of how pain is processed at the biological level,” said Dr. Annemarie Dedek, lead author of the study and now a MITACS- and Eli Lilly-funded industrial research fellow at Carleton University and The Ottawa Hospital. “This new discovery lays the foundation for the development of new treatments to help those suffering from chronic pain.”

If you have eaten a chili pepper, you have likely felt how your body reacts to the spicy hot sensation. New research published by biologists at the University of Oklahoma shows that the brain categorizes taste, temperature and pain-related sensations in a common region of the brain. The researchers suggest the brain also groups these sensations together as either pleasant or aversive, potentially offering new insights into how scientists might better understand the body’s response to and treatment of pain.

“The spicy hot sensation you get from a chili pepper is actually a pain sensation…this follows activation of pain-related fibers that innervate the tongue and are heat sensitive,” said Christian H. Lemon, Ph.D., an associate professor in the Department of Biology in the Dodge Family College of Arts and Sciences at OU. “What happens is a chemical in chili peppers, called capsaicin, causes activation of pain fibers and ‘tricks’ the neurons to react like there is a heat stimulus in your mouth, so you’ll notice when you eat spicy foods, your body will react to try to remove the heat ­– your blood vessels can dilate and you can start to sweat because your body ‘thinks’ it’s overheating.”

Lemon, who is also a member of the OU Institute for Biomedical Engineering, Science and Technology, and researchers in his lab, Jinrong Li, Ph.D., and Md Sams Sazzad Ali, Ph.D., published an article in The Journal of Neuroscience that examines how taste, temperature and pain-related sensations interact in the brain. Their article was also selected for the journal’s Featured Research section.

“Neural messages associated with pain are partly carried by neural circuits involved with sensing temperature,” Lemon said. “This would explain, for example, why when you touch a hot stove, it’s a burning pain. There are intimate ties between temperature and pain, and there are intimate ties between temperature and taste…just about everything we eat is either warmed or cooled, and that’s known to have a fairly robust effect on the way we perceive certain tastes.”

The research team wanted to better understand how temperature and pain intersect with taste neurologically. Building on their previous research that had shown that temperature and taste signals come together in a particular section of the midbrain, Lemon’s research group used mouse models under anesthesia to artificially stimulate temperature and pain-related fibers, combined with a physiological method to monitor the actions occurring in the brain to determine the connection between these senses.

“It’s been known that temperature and taste can activate some of the same cells in the brain, but this was rarely systematically studied,” he said. “We wanted to know if the temperature responses that we were seeing in this part of the brain were actually attributable to activation of thermal and pain-related fibers that innervate the head, face and mouth. To do this we used a modern genetic technology where we could insert a protein into these ‘temperature/pain’ cells that allowed us to control these cells with blue light – we could turn the cells on with a light, like a light switch.”

“What we found is that these neurons that scientists have studied for a long time as taste neurons actually respond to artificial stimulation of these temperature/pain cells,” he added. “This is significant because most scientists that have looked at taste, they’re usually only studying neural circuits from the perspective of taste. Pain scientists are usually only looking at pain-related responses, but they actually come together in this part of the midbrain, and not only do they come together, they do so in a very systematic way where preferred tastes and preferred temperatures are separated from adverse taste and temperatures in terms of the way that the responses are happening in this part of the brain.”

The researchers categorize preferred or pleasurable tastes as something sweet, like sugar, whereas adverse tastes are bitter – which can signify that something may be toxic or harmful. Similarly, people, and mice, have preferred temperatures, like a comfortably warmed or cooled environment as compared to an extreme cold or extreme heat stimulus.

Through this artificial stimulation of temperature/pain cells and the corresponding taste neurons, they discovered the brain segregated preferable tastes and temperatures from adverse tastes and temperatures. This finding offers new insights into how these senses interact, which could have implications for how scientists understand the brain’s responses to stimuli that cause pain.

“What our results show is that in a midbrain circuit there’s a very orderly representation of taste and temperature hedonics – whether or not something is pleasurable or aversive – dependent on input from these temperature/pain cells,” Lemon said. “These findings suggest that the brain is actually using common cells to represent information from different senses where there are relationships between the senses. Since pain has ties to temperature sensing, these results might provide clues as to how temperature or pain signals might interact with other senses, which could be important for developing novel therapeutic strategies for pain management.”

From left: Dr. Ted Price BS’97, doctoral student Ishwarya Sankaranarayanan, and research scientists Stephanie Shiers PhD’19, Dr. Diana Tavares-Ferreira and Dr. Pradipta Ray are part of a UT Dallas team exploring the origins of chronic pain and the potential for better treatments. CREDIT University of Texas at Dallas

An investigation into how human nerve cells differ from animal cells has provided researchers from The University of Texas at Dallas’ Center for Advanced Pain Studies (CAPS) with important clues in the pursuit of more effective treatments for chronic pain.

Dr. Ted Price BS’97, Ashbel Smith Professor of neuroscience in the School of Behavioral and Brain Sciences (BBS) and CAPS director, leads a team that is analyzing the origins of how pain is generated by nociceptors — pain-sensing nerve cells — in human dorsal root ganglia (DRG) neurons. Price is co-corresponding author of a study, featured on the cover of the Feb. 16 issue of Science Translational Medicine, that charts the full range of messenger RNA (mRNA) strands — a grouping called the transcriptome — produced in these cells.

Because mRNA is a single-stranded copy of a gene that can be translated into protein, the findings provide neuroscientists with a much better understanding of which genes are expressed in DRG neurons. The study also reinforces the value of studying human tissue — as opposed to animal cells — in the search for pain treatments.

DRG neurons are specialized nerve cells clustered near the base of the spine. Very little work has been done previously with these cells from humans due to the scarcity of their availability for research.

“We’re one of the few groups in the country with access to human donor DRG tissue acquired specifically for research,” said Stephanie Shiers PhD’19, neuroscience research scientist and a joint first author of the paper.

Shiers’ prior research made the case in broad terms that significant differences exist between the nociceptors in mice and humans. That work explained why proposed pain treatments that succeed in mice fail in humans.

“This paper is the next step, clearly demonstrating the profound scale of those differences,” Price said. “An entire set of nociceptors that many people study in mice just aren’t found in humans. There are subtypes in humans that don’t exist even in nonhuman primates.

“It’s not that we should abandon all existing nonhuman models of pain. But some are really good, while others aren’t, depending on what you want to study. When it comes to this aspect of pain, our work shows which is which.”

To profile all the gene activity in a DRG tissue sample, the research team used an advanced technique called spatial transcriptomics, which has enhanced capabilities compared with single-cell RNA sequencing.

“It’s rare to have access to both the human tissue we used and to the technology,” said Dr. Diana Tavares-Ferreira, also a co-first and co-corresponding author of the study and a CAPS fellow. “Spatial transcriptomics allows us to overcome the large size of these neurons and to see with a degree of certainty where and how a gene is expressed in human nociceptors.

“Our main goal was to fully characterize the whole transcriptome of human DRG neurons because so much of the work that’s been done to find new pain therapeutic targets has been in mice. Our results help clarify why those efforts struggle to produce results.”

By describing the neuron types present in human DRG and detailing their gene expression, the team has a much better picture of what the physiological functions are for each gene, Price said.

“With that knowledge, not only can anybody use our data to seek drug targets that they couldn’t have sought before, but in some cases we also don’t need to use the mice at all now. We can use the human information,” he said.

Price called removing that reliance on animal models “a fundamental change,” because it allows scientists to explore how any cell type might interact with any neuron in the human peripheral nervous system.

“We’re now able to approach developing pain therapeutics in a more specific way and to think about how chronic pain happens in people in a different way,” Price said. “My hope is that our findings can change the way people do research in our field. It’s a road map that we will use, and others are welcome to follow.”