Both my HHMI Professor outreach project and my research program focus on an unusual group of marine animals, the venomous cone snails. The HHMI Professor project led to the development of a module primarily aimed at second and third graders to do experiments that span the gamut from the physical sciences (in particular chemistry) to biodiversity. The experimental work on biodiversity focuses on the cone snails; the module is designed to cover three class periods. College undergraduates are recruited to serve as mentors for the second and third graders as they perform the experiments. The module, called From Chemistry to Biodiversity, has been widely applied in a broad variety of different cultural settings, from fishing villages in the rural Philippines to sophisticated Salt Lake City schools in the most affluent neighborhoods, where parents are highly educated. In most cases, only relatively minor adjustments are necessary to make the modules effective.
When teachers for higher grade levels learn about the experiments, they frequently request that it be adapted for their classes, so we have both a middle school and high school version of the Chemistry to Biodiversity module. This module will be incorporated widely into the curriculum of schools in the Philippines, since there has been a government mandate to increase the number of grades by two (to twelve), so science educators are looking for material to incorporate. In at least four large provinces in the Philippines (with a population of 6 million people) our modules will essentially be disseminated through incorporation into the standard K -12 curriculum. However, a trial into cultural minorities in the Philippines had only mixed success; the module as presented really seemed to be out of context, and to be effective for truly isolated cultural minorities, more work will be necessary to increase the efficacy of the presentations.
Research in the Olivera Lab
The focus of the research program of my laboratory has been on the individual molecular components present in cone snail venoms, which are mostly relatively small, highly structured peptides (“conopeptides as conotoxins”). These have broad biomedical implications, since individual venom peptides, which have been evolved by the cone snails, are generally highly selective ligands for receptors and ion channels. Over the years, these have been widely used by the neuroscience community, and have proven diagnostic and therapeutic applications. One conopeptide has become a commercial drug (approved by the US Food and Drug Administration and also used in the European community). It is a 25 amino acid peptide found in the venom of Conus magus, also known as the magician’s cone. The drug, used to alleviate severe, intractable pain, is sold in the United States under the trade name Prialt.
More recently, we have tried to combine multiple Conus venom peptides to develop a new platform, which we call Constellation Pharmacology. For neuroscience, this can be applied in two different ways. In essence, because they are so selectively targeted to ion channels and receptors, conopeptides can be used as diagnostic pharmacological tools to determine if their specific ion channel target is expressed in an individual neuronal subclass. The approach that we are using is to systematically analyze an anatomical locus in the nervous system (e.g., a particular region in the brain) by dissociating the cells, and applying a series of pharmacological challenges. We monitor the response of the cells by standard calcium imaging; we have found that with the right combination of peptides from cone snail venoms, it is possible to distinguish the different neuronal subclasses present. Thus, this becomes an effective way to identify the cell types in the brain. Furthermore, this method does not require that the work be done in a model organism, and changes in the diverse cell types present in an anatomical locus can be assessed as a function of development, disease progression, or change in physiology (for example, to evaluate molecular/cellular changes as a consequence of a specific learning or conditioning paradigm).
Once an anatomical region has been analyzed to the point where different neuronal subclasses can be distinguished from each other, a much more refined analysis can continue until the complement of receptors and ion channels that are present on each neuronal subclass are defined by all available pharmacological agents. The other major application of the technology however is that a heterogeneous mixture of cells whose constellation of ion channels and receptors have been characterized becomes in effect, a high-content assay for discovery. It becomes feasible to evaluate unexplored Conus venoms for components that have novel targeting specificity for particular isoforms of ion channels and receptors. Every isoform of an ion channel and receptor that is expressed in one of the neuronal subclasses present in a heterogeneous cell culture can in principle be assayed.
What we feel are the most significant class of ion channels that are largely unexplored are the enormously diverse heteromeric K channels. There are ~70 genes that encode different monomeric subunits of K channels, and since a functional channel is tetrameric, the potential combinations comprise a vast diversity that has essentially been undefined and unexplored. We are finding that our technological platform, Constellation Pharmacology, is able to identify cone snail venom components that specifically target a particular K channel isoform, and that the diversity of K channels in different types of neurons allows a much more refined definition of the different neuronal subtypes. In this way, we hope to use a pharmacological approach to bridge the widening gap between molecular and systems/behavioral neuroscience, the two most rapidly developing sectors of modern neuroscience. Thus, cone snails are both the basis of my HHMI Professor’s outreach activities, and potentially an important contributor to integrated progress in the neurosciences.
As of May 2014