Alcino J. Silva

Biography

Silva was born in Portugal in 1961, but spent his early years in Luanda, Angola. He left Africa when he was only 12 and in Portugal he went through the Carnation Revolution of 1974. He arrived in the United States in 1978, attended Rutgers University, where he studied biology and philosophy and worked in the Drosophila laboratory of William Sofer. After that he pursued graduate studies in Human Genetics at the University of Utah. There, he worked with Raymond White, one of the pioneers of modern Human Genetics. His graduate work showed that epigenetic patterns of DNA methylation can be polymorphic and that they are inherited in a Mendelian fashion.[4] During his graduate studies he became intrigued by the inner processes of science, and organized yearly graduate symposia where leading scientists shared their insights on this subject. It was in Utah that he realized that he could combine his passion for biology with his interest in epistemology.[5] It was also in Utah, while working with Mario Capecchi, that he had the idea of bringing the newly developed mouse gene targetingapproaches [6] to studies of memory. Capecchi shared the Nobel prize with Martin Evans and Oliver Smithies for the development of gene targeting strategies in mice

Research Interest

Weidong Li and Steven Kushner led a team in the Silva lab that developed a treatment for the cognitive deficits associated with an animal model of Neurofibromatosis type I(NF1).[26] They discovered that Lovastatin, a statin that crosses the blood-brain barrier, at a dose that does not affect control mice, rescues the Ras/MAPK signaling, synaptic plasticity and behavioral deficits of mice with a NF1 mutation.[27] Statins decrease the levels of isoprenyls, lipid groups that are required for the isoprenylation and activity of Ras,[28] a signaling molecule normally regulated by the protein encoded by the NF1 gene. The work in the Silva lab showed that the NF1 mutation leads to increases in the levels of active Ras in the brain, and that statins reverse this increase without affecting Ras signaling in controls. These results have led to a number of small promising, but inconclusive, clinical trials,[29][30][31] and to two large on going clinical studies in the USA and Europe.[32][33] A team led by Dan Ehninger in the Silva lab also showed that rapamycin, an FDA approved inhibitor of mTOR, can reverse the late-LTP deficits and learning impairments they discovered in an animal model of Tuberous Sclerosis (Tsc2 heterozygous mice).[34] Interestingly, TSC is highly associated with autism, but the Tsc2 heterozygous mice did not show any autism-like behavioral abnormalities, such as social interaction deficits. Artificially activating the immune system of pregnant mice, however, does reveal social interaction deficits in Tsc2 heterozygous progeny, suggesting that the autism-like symptoms in TSC require not only Tsc mutations, but also another factor, such as immune activation during pregnancy.[35] Importantly, analyses of human TSC data suggested a similar interaction between the TSC mutation and immuno-activation during pregnancy.[35] Recently, Miou Zhou and colleagues at the Silva lab found that rapamycin is also capable of both preventing and reversing behavioral deficits caused by mutation of a schizophrenia-causing gene (DISC 1) in neurons that are born and develop in adult mice (i.e., adult neurogenesis).[36]Surprisingly, rapamycin reverses behavioral deficits despite its inability to reverse structural deficits discovered in neurons with Disc 1 knock down. All together, these findings make a compelling case that adult treatments may be effective at reversing behavioral cognitive and psychiatric symptoms associated with neurodevelopmental disorders such as NF1, TSC and Schizophrenia.[37]