research summary

 

Biological systems can remain unaltered for long periods. Yet to survive in fluctuating environments they must also undergo rapid diversification. However, mechanisms that safeguard the fidelity of replication often limit the source of such novelty to relatively modest changes in DNA sequence. My laboratory’s primary focus is to achieve a molecular understanding of this paradox, which offers the potential to thwart human pathologies ranging from cancer to neurodegeneration. It also has broad implications for our understanding of evolution and development.

Whether environmental stimuli can fuel evolutionary innovation has long been controversial. We have begun to achieve mechanistic insight by recognizing that the fundamental physical properties of biomolecules exert a strong influence on adaptive landscapes. Proteins, the molecules that drive virtually every phenotype in an organism, are made as long linear polymers that must properly fold into intricate three-dimensional conformations to function. Most mutations destabilize the proteins in which they occur. Organisms cope with this challenge by employing a cohort of molecular chaperones: proteins that help other proteins to fold properly. This ancient stress-regulated response also impacts the folding and function of mutated proteins. Through quantitative analysis of the map between genotype and phenotype we have found that one such chaperone, Hsp90, creates an interface that allows environmental stimuli to alter the consequences of genetic variation. Indeed, different levels of Hsp90 function may provide an explanation for why the same mutations that cause devastating consequences in some individuals can have no effects in others. We are using systems level approaches to probe the design principles that govern the function of Hsp90 and other such ‘genetic capacitors.’

Although the heritable variation that encodes new forms and functions is generally ascribed to mutations in DNA, genetically identical organisms can nonetheless express different heritable traits. A second area of research in my laboratory involves how protein misfolding drives a novel mode of transgenerational epigenetic inheritance. Prions, the self-templating protein conformations best known for causing mad cow disease, also provide a means through which environmental stimuli can directly induce heritable phenotypic diversity in populations of genetically identical individuals. We previously discovered that this mechanism of inheritance is common in nature, and that it frequently produces beneficial phenotypes. We have recently identified a large new class of such protein-based molecular memories. These protein-based genes regulate the decoding of genetic information, metabolism, and even cross-kingdom social interactions and are thus ideally poised to promote phenotypic diversification. To investigate how this paradigm-shifting mechanism of inheritance influences adaptation, disease, and development we are using multidisciplinary approaches including biochemistry, high-throughput screening, live cell imaging, and quantitative genetics. Ultimately we seek not only to understand mechanisms that link environmental stress to the acquisition of biological novelty, but also to identify means of manipulating them for therapeutic benefit and of harnessing their power to engineer synthetic signaling networks.