Nathaniel Heintz: 2011 Allen Institute for Brain Science Symposium

Nathaniel Heintz, The Rockefeller University; Howard Hughes Medical Institute Genetic dissection of the mouse brain: Toward a 21st century brain pharmacology

In the trek toward a 21st century brain pharmacology there are at least three major paradoxes, Dr. Heintz posited. The genetic paradox: why do mutations in nearly ubiquitously expressed genes that act in common biological pathways result in specific clinical phenotypes? The treatment paradox: how do drugs that act across a broad spectrum of neurotransmitter systems target specific clinical applications? And the hmC paradox: why do the genomes of neurons contain hydroxymethylcytosine, a sixth nucleotide? Is it relevant for neurological disease? After pointing out these dilemmas Dr. Heintz proceeded to lay out a plan of attack for identifying cell type-specific molecular profiles that may ultimately lead to more specific pharmacological disease treatments. He invented a method, dubbed TRAP (Translating Ribosome Affinity Purification), which leverages a ribosome tagging strategy in genetically engineered mice to help isolate the cell's protein production machinery. This technique captures the full spectrum of genetic messages being used to make proteins in specific cell types. Using the TRAP method, Dr. Heintz and colleagues can read out the molecular profile for specific cell types involved in certain behaviors, diseases or pharmacological responses. Because these mice reproduce endogenous expression, TRAP analysis of individual cell populations can reveal cell-specific molecular phenotypes that are not evident from analysis of whole tissue samples. The goal is to generate a pharmacology that targets specific cell types and specific molecules. The bottom line, Dr. Heintz said, is that by studying individual cell types you can understand at a molecular level whether they are different from other cells or uniform. He hopes to generate a pharmacology that will allow neuroscientists to get out of mice and into humans.