Imaging Interactions between Genes and the Environment

When people talk about “nature versus nurture” and how each can shape an individual’s character or behavior, they are really weighing the respective influences of genetics and environment, and ultimately the interactions between the two. Teasing out these interactions has often seemed a difficult if not impossible task. But with the introduction of the breakthrough PET radiotracer [11C] Martinostat, the Center’s Jacob Hooker and colleagues showed that it can be done.

“There’s really been no way to understand the relationship between the genome and the environment at the whole-organ scale, especially as it relates to brain function and changes resulting from the environment,” says Hooker, director of Radiochemistry at the Center and head of the Hooker Research Group. “The idea with Martinostat was to develop an imaging tool that could point us in the direction of that information, or at least answer the question of whether getting there was possible.” Interactions between the genome and the environment and how they manifest in the occurrence of disease and the development of personality traits, for instance, are known as epigenetic activity. Such interactions can take place in utero or during early childhood, or later in life as a result of malnutrition, drug abuse or any number of other external factors. Enzymes called histone deacetylases (HDACs) are part of the epigenetic machinery in the body and change the way genetic information is read. Martinostat works by targeting and thus enabling imaging of these enzymes.

Hooker and colleagues introduced the imaging probe with a pair of papers in late 2014. Here, lead authors Changning Wang and Frederick “Al” Schroeder, respectively, described the radiotracer and how it can be used to image HDAC. Next, in a 2016 paper in the journal Science Translational Medicine, a team including co-lead authors Hsiao-Ying (Monica) Wey and Tonya Gilbert demonstrated the utility of Martinostat in healthy human subjects, thus opening the door to further application.

Since publication of the Science Translational Medicine paper, the researchers have applied the probe in studies of several neurologic or psychiatric disorders. They have demonstrated HDAC dysregulation in schizophrenia, bipolar disorder and Alzheimer’s disease, for example, and are beginning to look at the relationship between the HDAC signal and autism.

At the same time, Hooker and colleagues are helping other institutions get off the ground in adopting the probe themselves. With assistance from the Martinos group, including background information and technical knowhow, researchers at McGill University in Montreal and University of California, San Francisco are now using the probe, while two university medical centers in Asia are either using it or will be soon.