Rapidly developing technologies for genome and epigenome editing (see sidebar) offer new tools to help environmental health researchers answer questions about exposures and health. The National Academies of Science, Engineering, and Medicine (NASEM) invited a group of experts to a Jan. 10-11 workshop, where they expressed enthusiasm about this promising field.

Woychik leads the NIEHS Mammalian Genome Group, which studies epigenomic regulation of transcription as the body responds to environmental exposures. (Photo courtesy of Steve McCaw)

NIEHS Deputy Director Rick Woychik, Ph.D., spoke early in the day-and-a-half-long program. He said researchers need faster ways to determine which gene variants predispose a person to different responses to the environment, and he issued a charge to the assembled experts.

“You’ll have to help [NIEHS] understand how genome editing tools can be brought to bear on some of these complex and important questions in genome biology and environmental health sciences,” he said.

“We have a great opportunity to make a difference for public health,” observed Reza Rasoulpour, Ph.D., from Dow AgroSciences. Rasoulpour is a member of Emerging Science for Environmental Health Decisions, the NASEM committee that sponsored the workshop.

Organizers were mindful of the complex ethical issues associated with gene editing. “The National Academies recently released a report specifically about these issues,” said planning committee member Lesa Aylward, Ph.D., from Summit Toxicology. “We want to acknowledge [ethical concerns] but recognize that they are outside the scope of this limited workshop.” The present workshop was just one of many NASEM activities related to gene editing, she explained.

Mechanisms of exposure effects

“The genomics era has brought a more mechanistic focus to environmental health sciences, as researchers use new tools to uncover which genes and which pathways are implicated in an individual’s response to an exposure,” observed Woychik.

Fyodor Urnov, Ph.D., from the University of California at Berkeley, underscored the point. “Editing has the potential to give us a level of insight into biological systems that we never really had before,” he said. For example, engineering transcription factors to edit the epigenome can help uncover the molecular pathways affected by exposures, Urnov explained.

Engineering to reduce off-target effects

When the editing system targets an amino acid sequence close, but not identical, to the sequence of interest, off-target effects can occur. Vikram Pattanayak, M.D., Ph.D., from Massachusetts General Hospital, engineered a CRISPR-Cas9 system that increases specificity to the point of no detectible off-targets.

Current systems are specific enough for most research applications, and computational prediction tools can point researchers to the editing technology with the greatest specificity for their project, Pattanayak explained. He added that therapeutic applications would likely call for greater specificity.

Identify pathways to prevent or reverse effects

Several speakers specifically addressed toxicology and environmental health studies.

“The epigenome is dynamic and potentially modifiable, so it’s hopeful,” said NIEHS grantee Dana Dolinoy, Ph.D., from the University of Michigan. Her lab uses a class of small noncoding RNA called piRNA to make epigenetic changes in mice. Dolinoy expressed hope that nutritional or pharmacological approaches may be developed to counteract the epigenomic effects of environmental exposures.

NIEHS grantee Rebecca Fry, Ph.D., from the University of North Carolina at Chapel Hill, described potential uses of genome editing in environmental health science.

• To confirm the functional role of genes and proteins within biological pathways as mediators of disease.
• To establish key mechanistic relationships necessary for adverse outcome pathway development, which is key to risk assessment.
• To prevent contaminant-induced disease by blocking pathways.

According to several representatives of regulatory agencies, editing tools may lead to better regulatory decisions, as scientists uncover the events that lead to observed effects in the body. At the same time, new challenges are arising in products that are being submitted for approval, such as use of gene editing in new organisms that function as biological pesticide products.