This page highlights what specific researchers in the Olivera lab are currently working on.
Growing up in the Philippines, Baldomero "Toto" Olivera recalls that cone snails were sold by the kilo in local seafood markets. As a child, however, Olivera was blissfully unaware of the impact that the predatory cone snail, Conus magus, would have on his life's work. Nor could he have imagined that the creatures would even enable his lab to develop a drug to bring relief to people in chronic pain.
Now a distinguished professor of biology and neuroscientist at the University of Utah in Salt Lake City, Olivera was nicknamed Toto by a cousin who could not pronounce Totoy, a pet name sometimes given to Filipino boys. As an HHMI professor, he plans to take the story of the cone snail back to the children of the Philippines and the nearby Pacific islands the snails inhabit. "These snails have so much potential, and the children don't know anything about their biology," he explained.
Olivera will teach children and undergraduates from the Philippines, Hawaii, and U.S. territories in the Pacific about the richness of their surroundings through a project he calls the Biodiversity-Biomedical Links Initiative. "My idea is to concentrate on the biodiversity that's at their feet," he said. His goal is to interest young students by educating them about scientific principles that can be observed in organisms that they see every day.
And Olivera is well aware now that the fish-hunting cone snail, with its intriguing eating habits, is a good place to start. The snail harpoons fish with a radular tooth, a hypodermic needle-like structure that injects a paralyzing venom made up of 100 different components. Once the fish is harpooned and paralyzed, the snail reels it in and eats it.
By studying the complex neurotoxic venom made by the snails, Olivera and members of his lab have identified several drug candidates, as well as gained a better understanding of how ion channels work. Michael McIntosh, now a fellow researcher in psychiatry at the University of Utah, was an undergraduate in Olivera's lab when he discovered a cone snail toxin whose synthetic form is now used to treat pain effectively in patients who have become tolerant to morphine.
Olivera believes that the future of neuroscience depends on collaboration across disciplines. So he also plans to work to increase the number of students fluent in neuroscience by implementing an Interdisciplinary Undergraduate Neuroscience Program at the University of Utah. Students whose majors range from math to electrical engineering will be offered the opportunity to minor in neuroscience. "If we are to accelerate the pace of scientific progress, we need people looking at the same problems from different intellectual viewpoints," he said.See an impressive list of Dr. Olivera's publications.
Work in our laboratory focuses on the study of normal and abnormal brain functioning. Physiological, biochemical and genetic techniques are used to develop new approaches to studying the central nervous system. Part of our effort involves the isolation and characterization of natural products which can be used for pharmaceutical development to treat disorders of the nervous system. One of the current problems with medications is their lack of receptor specificity. In addition to targeting the therapeutically relevant receptor or ion channel, current medications often act on other targets, producing multiple side effects. The compounds we study are of particular interest due to their ability to act at a single target. Thus, we isolate and characterize these compounds to be able to better study the nervous system and to learn how to produce better medicines. Students are welcome in the lab and historically have made major contributions to this work.
If you'd like to learn more about Dr. McIntosh's work you can visit here.
My major research interest is understanding the ways that the nervous system functions. Cells in the nervous system communicate by electrical and chemical signals. These signals are activated or deactivated by specific ion channels in our body. We can change the activity of specific ion channel to understand nervous system function. We are developing tools which target specific ion channel complexes of nerve cells. A rich natural source of those molecular tools come from the venoms of carnivorous marine cone snails (Conus). They have evolved a wide variety of venom compounds to affect ion channels in their prey. The venom of a single Conus species contains more that 100 different biologically active substances, (“conopeptides”): each of these substances may act on a specific channel. There are estimates of about 700 species of Conus so we expect there to be over 50,000 different conopeptides. We characterize the toxins by determining the amino acid sequence (what each substance is made of and in what order). Once we know what the sequence is we can modify the amino acids to learn more about each amino acid’s function and importance. We also investigate the evolutionary relationship among the cone snails.
In addition, after the toxin peptides are synthesized on ribosomes, certain amino acids in these peptides are modified by enzymes in a process known as posttranslational modification. The modifications are important for the specific interaction of these peptides. We investigate the activity of these enzymes- in particular what determines which peptide is modified and the specific amino acid modified.
Our research is focused on discovery and development of neuroactive peptides for the treatment of neurological disorders. There are two main research directions: application of various peptide engineering techniques to improve bioavailability of neuropeptides, and discovery of novel conopeptides with a therapeutic potential. Our current projects include: (1) engineering anticonvulsant neuropeptides to improve their properties as drugs, (2) discovery and chemical modification of subtype selective sodium channel peptide antagonists produced by cone snails, conotoxins, and (3) engineering of conotoxins to modify bioavailability. An underlying theme in all three projects is that the neurotoxins and endogenous neuropeptides being investigated target ion channels and receptors with high potency and selectivity, thus they possess some unique characteristics desirable for a design of safe therapeutics. Our long-term goal is to develop a technology platform that would facilitate the transformation of neuroactive peptides into drugs.
If you'd like to learn more out Dr. Bulaj's work you can visit his website here.
My work in the McIntosh/Olivera lab involves studying α-conotoxins that act on receptors in the brain know as nicotinic acetylcholine receptors-the same receptors that nicotine from cigarette smoking acts on. These receptors are involved in many functions, including learning, memory and nicotine addiction. These receptors also die off in such disorders as Alzheimer’s and Parkinson’s disease. Therefore, finding drugs that can specifically act on these receptors may be medicinally beneficial. This is where the importance of α-conotoxins comes in. Besides testing the α-conotoxins that are made in the snail, I also test modified α-conotoxins on nicotinic receptors. What this means is that the amino acids that the original α-conotoxin is made of are switched to different amino acids. The advantage to doing this is that sometimes the modified α-conotoxin is actually a better blocker of a particular nicotinic receptor that the original α-conotoxin. Another of my projects involves figuring out which amino acids on the receptor bind to the α-conotoxin, either the original α-conotoxin that came from the snail or a modified one. This way, I can figure out which amino acids in the receptor have favorable interactions with which amino acids in the α-conotoxin. This will guide “smarter” modification of α-conotoxins that have even better activity on nicotinic receptors.
My research is focused on the cloning and sequencing of genes from venomous marine snails. While a genome (all the genes in a species) codes for all aspects of their life, I am focused on the genes that code for toxins. I study the toxins from cone snails as well as other similar venomous snails, or molluscs. I also study how these snails are related and how they differ from each other. I can study their relatedness, or speciation, by using the toxins and phylogenetic markers. A phylogenetic marker is a stable gene segment that evolves very slowly over time, whereas many other segments in the genome show more rapid variation. Understanding which cone snails are related and learning more about the specific toxin sequences can help us better target cone snail venoms for pharmaceutical purposes.
My research interests examine the pharmacology of receptors and ion channels, particularly those of the nicotinic acetylcholine receptor family. We use peptides isolated from cone snails to develop novel compounds that can be used to identify individual members of the nicotinic receptor family. Specifically, we conjugate contopeptides with fluorescent probes that can then be used to label receptors when used in conjunction with fluorescence microscopy. One of these receptors, the alpha7 nicotinic acetylcholine receptor, is involved in learning and memory and has been implicated in neurodegenerative diseases such as Alzheimers. Recent efforts in our lab have focused on developing a fluorescent conopeptide that can selectively label alpha7 receptors.