Cell death, neurodegenerative disease and mitochondrial quality control: One of our goals is to understand the genetic and molecular mechanisms that regulate cell death, neurodegeneration, and cancer. Much of our work on neurodegeneration, particularly as it relates to defects in mitochondrial function, Alzheimer's disease and Parkinsons disease, occurs in collaboration with the lab of Ming Guo, MD, PhD, a practicing Neurologist and researcher at UCLA. Expression from the mitochondrial genome (mtDNA) is required in almost all cells for respiration. Mutant mtDNA accumulates during adulthood and contributes to many diseases of aging, including Alzheimer's, Parkinsons, diabetes and muscle wasting. We are particularly interested in devising methods for selectively removing damaged mtDNA. We have developed a model of mtDNA mutation accumulation in muscle and are using this system to identify molecules that can promote the selective removal of mutant mtDNA, a form of quality control. In short, our goal is to engineer mtDNA "housecleaning" during adulthood. Recent results indicate that we can promote the removal of ~80% of mutant mtDNA in Drosophila muscle. We are, naturally, interested in expanding this work into human systems, and drug screens.
Controlling the composition and fate of wild populations: A second goal addresses three questions in applied evolutionary population biology. 1) Can we bring about reproductive isolation (speciation) between populations of plants or animals that otherwise freely interbreed? Answers to this question have application to the growing number of situations in which plants and animals are engineered to show specific pharmaceutical or agricultural traits. In brief, we would like to be able to limit gene flow between engineered organisms and their wild counterparts. 2) Can we engineer the genetics of populations so that they drive themselves to local extinction? For example, invasive non-native plants and animals cause substantial economic losses and sometimes function as vectors of disease. A number also cause substantial environmental damage, leading in many cases to extensive range reduction and/or extinction of unique, endemic species. Our goal is to develop genetic tricks that drive local extinction of invasive species and disease vectors. 3) Can we drive genes into wild populations (population replacement) such that all individuals express a trait of interest? With regard to this last aim, we are also interested in developing transgenic mosquitoes that lack the ability to transmit pathogens such as malaria, dengue fever and chikungunya. We are also working with the citrus industry to develop population replacement-based strategies to prevent the citrus psyllid, an invasive insect, from transmitting Candidatus Liberobacter, the causative agent of the citrus disease HLB.
Lifetime, single shot contraception: In a third project we are working to develop single shot, lifetime (but reversible) contraceptives for a variety of mammalian species. In brief, there remains a need for very long-term or permanent, non-surgical methods of male and female contraception for humans that can be implemented in resource-poor settings in which access to health care may be sporadic. There is also a desire for non-lethal, humane, methods of population control for captive and free roaming animals. We have developed a technology, vectored contraception (VC), which can contribute to these goals. In VC an intramuscular injection is used to bring about transgene-mediated expression of a monoclonal antibody or other protein able to inhibit fertility through action on a specific target. In proof-of-principal experiments we recently showed that a single intramuscular injection of a replication defective, recombinant adeno-associated virus (rAAV) designed to express an antibody that binds gonadotropin releasing hormone (GnRH), a master regulator of reproduction in all vertebrates, results in long-term infertility in male and female mice. Female mice are also rendered infertile through rAAV-dependent expression of an antibody that binds the mouse zona pellucida (ZP), a glycoprotein matrix that surrounds the egg and serves as a critical sperm-binding site. Many proteins known or suspected to be important for reproduction can be targeted using VC, providing a new class of strategies for bringing about long-term inhibition of fertility in many species. We are working to implement several of these, along with strategies for bringing about reversal on demand.
Interactive learning and Community Science Academy. For the last three years I have been pioneering use of the SKIES learning system to enhance student participation in class, to provide new forums for asking questions, and to encourage students to add their own content to my lectures, in the form of links to scientific articles, in-class clarifications, in-depth explanations, and flashcards. More recently, a number of other Professors have begun using this system. An important goal going forward is to create links between classes so as to create a more general web of knowledge that students and others can use to explore.
In a second, related activity, I hosted the beginnings of The Community Science Academy at Caltech (CSA@Caltech). The goal of CSA, initiated by two Caltech alumni, James Maloney and Julius Su, is to develop curriculum and instrumentation to support low cost but high quality science relevant to community needs CSA is currently hosted by the Caltech Center for Teaching, Learning and Outreach. I also serve as PI on a grant from the Camille and Henry Dreyfus Foundation, Special Grant Program in the Chemical Sciences, 2014-2015. The goal of this grant is to foster High School community science and the design of portable custom molecular sensors.
- Li, J., Olvera, A.I., Akbari, O.S., Moradian, A., Sweredoski, M.J.,Hess, S., and Hay, B.A. (2015). Vectored antibody gene delivery mediates long-term contraception. Current Biol.