Olivera Lab Members
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.
I study ligand-gated ion channels that are involved in pain, inflammation, and addiction. The channels I am most interested in are the nicotinic acetycholine receptors. These receptors are found in the brain, spinal cord, peripheral nerves, muscles, lymphocytes, macrophages, mast cells and other granular immune cells, skin cells and lungs. There are many different types of nicotinic acetylcholine receptors. Some nicotinic receptors that are expressed in peripheral nerves, immune cells and spinal cord may be involved with neuropathic pain. Other nicotinic receptors expressed in the lung, skin as well as immune cells may be involved in inflammation. There are nicotinic receptors in brain that are responsible for the addicting effects of nicotine. Nicotine is a drug that binds to nicotinic receptors. I study nicotinic receptors using conopeptides. Conopeptides are small peptides that are produced by venomous sea snails called cone snails. Some conopeptides bind selectively to specific subtypes of nicotinic receptors blocking the function of the receptors. By blocking receptor function, I can tell what the receptors are doing. I also use nicotinic receptor knockout mice to study nicotinic receptors.
I am also interested in neurotensin receptors and their involvement in pain, epilepsy and psychosis. These are G-protein coupled receptors found in the nervous system. Neurotensin receptors bind neurotensin which is a peptide hormone produced in the body. I use conopeptides and neurotensin receptor knockout mice to study neurotensin receptors.
I am currently working on the evolution of the genus Conus, both looking at the species diversity and at the toxin-coding genes in this group (i.e. conotoxins). The first part of my work consists in collecting several specimens that might belong to several species. In some cases, it is difficult to guess which specimens belong to the same species and which ones belong to a different species. In cases that are too difficult to tell from looking at the shell alone, I find out the DNA sequences. Specimens that belong to the same species should have very similar DNA sequences. I am also interested in determining the relationships between these species, using phylogenetic approaches.
The second part of my work concerns the evolution of the conotoxins within Conus. These genes are grouped in mutli-genic families (i.e. groups of genes that are structurally and functionally related). They are supposed to be created by gene duplication. Typically when one gene is duplicated, one copy keeps the original function while the other copy can evolve into another function. My work consists in looking for the processes at the origin of the apparition and the evolution of new genes.
I am studying a group of conotoxins called the conantokins. Conanantokins are a unique group of toxins that block a receptor in the brain called the NMDA receptor. By blocking NMDA receptors, it may be possible to treat a number of neurological disorders, including chronic pain, epilepsy, stroke, and perhaps even drug addiction and Parkinson’s disease. However, there are many different kinds of NMDA receptors in the brain–blocking only the ones that malfunction could be a very effective treatment in each of these disorders, but blocking too many different types of receptors at once can result in side effects. I use a method called electrophyisiology to study the effects of conantokins on many different kinds of NMDA receptors. By understanding how conantokins interact with each type of receptor, our goal is to develop drugs that safely and effectively treat each of these neurological disorders.
Pharmacologically active peptides from venom ducts of predatory cone snails (genus Conus) have potential therapeutic effects towards neurological disorders. Conantokins are one type of peptide found in Conus venom ducts that are functionally characterized to be N-methyl-D-aspartate (NMDA) receptor antagonists. NMDA receptors are a class of ionotropic glutamate receptors located in the brain and play a role in learning, memory, development, pain, and long term potentiation. Conantokins have been promising therapies for pain, epilepsy, and stroke. The NMDA receptor is a heterotetramer consisting of two NR1 subunits and two NR2 subunits. There are four different NR2 subunits (NR2A, NR2B, NR2C, and NR2D) each encoded by different genes, but only one gene encodes the NR1 subunit. The main factor limiting the use of NMDA receptor antagonists as therapies is the lack of selectivity for specific subunit combinations.
Our aim is to discover conantokins that are specific and can be used as therapeutics. To achieve this selectivity we have characterized novel conantokins from Conus bocki using two-electrode voltage clamp recordings. Our results show that conantokins-Bk2, -Bk4, and -Bk6 from Conus bocki are NMDA receptor antagonists that display a unique selectivity for the NR2D subunit. The NR2D subunit is located primarily in the striatum which is the major input station of the basal ganglia and functions in planning and modulation of motor pathways. Selective NR2D receptor antagonists like the conantokins found in Conus bocki could potentially be used as therapeutics and neuroprotection for pathologies such as Parkinson’s disease linked to the dysfunction of the striatum.
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.
Snails have venom to protect themselves from predators and also to prey. There are around 100 active components (toxins) in venom of one snail. Toxins have many targets. For example, Conus geographus venom consists of toxins that target different sites along muscles and nerves.
In the laboratory, we study targets of toxins and also find how strongly toxins bind to their targets. First, we have channels (pores) of different organisms that sit on cell membrane and let the molecules go through. They can be opened or closed. Special cells (neurons) in the body use this transport of molecules to talk to each other and to muscles. Second, we measure the flux of charged molecules through these channels in the presence and absence of toxin. If the toxin blocks a particular channel than the flux decreases in the presence of toxin. We can conclude that the toxin is effective on this channel. We can also measure how long it takes for the toxin to block a channel or be washed away. Third, we compare different toxins from different snails.
I am working with α-conotoxin from the fish hunting cone snail Conus Bullatus. We found that it effectively blocks nicotinic acetylcholine receptors. We are interested which site on the toxin binds to which site of a receptor (receptors are the channels that open only when particular molecule binds at particular site). We change one amino acid (building block of all proteins and peptides) in the toxin and several amino acids at receptor and then look at how it affects the toxin’s binding. From these studies, we will be able to tell how toxin interacts with its target.
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.