Daniel Jarosz, Ph.D
Dan Jarosz is an Assistant Professor of Chemical and Systems Biology and of Developmental Biology at Stanford University. Dr. Jarosz received his B.S. in Chemistry from the University of Washington, where he also minored in Physics as part of the Early Entrance Program. He then moved to MIT to obtain a PhD in Biochemistry, where his thesis work established the function of a low-fidelity DNA polymerase with roles in cancer and infectious disease, and identified means through which its activity is regulated in normal biology and disease states.
Following his graduation in 2007, Dr. Jarosz pursued postdoctoral training in genetics and cell biology as a Damon Runyon Fellow at the Whitehead Institute for Biomedical Research. Here his work centered on the molecular chaperone Hsp90 – the so called ‘cancer chaperone’ – and its relationship to the capacity of genetic variation to produce new phenotypes. He also pioneered high throughput screening methods to investigate the physiological consequences of prion-like protein aggregation.
In 2013, Dr. Jarosz joined the Stanford faculty where the long-term goal of his research program is to understand how some biological systems can remain unaltered for long periods, whereas others that are genetically identical undergo rapid diversification. This paradox lies at the heart of how neurons can be killed by improper expression of a single aggregation-prone protein, how cancer cells can tolerate extraordinary mutation burden, and how disease-associated mutations have devastating consequences in some individuals, but no effect in others. Dr. Jarosz’s work employs multidisciplinary approaches ranging from chemical biology to systems-level quantitative genetics and uses models as diverse as baker’s yeast and the African turquoise killifish. He has been named an NIH New Innovator and has received a CAREER Award from the National Science Foundation as well as fellowships from the Searle, Glenn, Packard, Kimmel, and Vallee Foundations.
Quality control and aggregation in an aging vertebrate proteome
Age is the greatest risk factor for many neurodegenerative pathologies caused by protein aggregation. Yet because vertebrate model organisms have very long lifespans, examining the intersection of genetic risk factors with age has been extremely challenging. In particular, there are no proteomic experiments in complex model systems that permit the study of different organs and systemic cross-talk in a whole organism. To fill in these fundamental gaps in knowledge, we took advantage of the African turquoise killifish Nothobranchius furzeri, the shortest-lived vertebrate that can be bred in captivity. Over its 4-6 month lifespan this fish manifests age-dependent phenotypes and pathologies such as cognitive decline, loss of fertility, sarcopenia, and cancerous lesions. We established a robust protocol for isolating protein aggregates from fish tissues and performed a proteomic analysis of total protein and protein-aggregates in young and old fish alike. These experiments established tissue-specific patterns of proteostasis decline during aging. They also identified many vertebrate-specific proteins that have an increased propensity to aggregate with age, often in a tissue-specific manner. These changes in proteostasis and protein aggregation were accelerated in telomerase mutant animals with premature aging phenotypes. Many proteins that aggregated in an age-dependent manner harbor intrinsically disordered, prion-like domains and are linked to age-related degenerative diseases. Biochemical studies revealed that some of these proteins adopt an infectious, prion-like conformation in old tissues (e.g. the brain), but not in matched tissues from young animals. Taking advantage of the genetic and biochemical tractability of this model organism, across all life stages, we are now examining whether age-related decline in proteostasis and the aggregation of these intrinsically disordered proteins act as a driving forces in aging.