Gene-targeting research in mice can help geneticists create therapies for human disease, Mario Capecchi, a Nobel Laureate in medicine and professor at the University of Utah School of Medicine, said during an event Wednesday evening.

Hosted by the Italian Research Institute, an organization created to promote the ideas of Italian scholars involved in the fields of science, technology and art, “Applications of Gene Targeting Technology in Therapies” addressed Capecchi’s research.

Edward Healton, the executive vice president for health sciences and executive dean at the Georgetown University School of Medicine, moderated the discussion.

Capecchi’s research on gene targeting, a technique to modify genes for a specific purpose, in mice has allowed scientists to understand how to create mutations in the DNA sequence. Recently, this research has been applied to understand disease and DNA sequences in humans.

Capecchi’s research has changed the way many labs around the country approach the topic, including the Pagan Lab at Georgetown, according to Healton. Capecchi’s character and determination is just as incredible as his cutting-edge research, Healton said.

“This man truly epitomizes what it means to follow your dreams,” Healton said.

Born in Italy in 1937, Capecchi lived on the streets alone as a 4-year-old before travelling to the United States at age 9. In the United States, he received a Doctor of Philosophy from Harvard University. In 2007, he won the Nobel Prize in Physiology or Medicine for discovering a technique for removing genes in mice.

Cappechi said that most projects are based on past research but also include a degree of spontaneity.

“You can start a project either on purpose or serendipitously, and I think scientists do both,” Capecchi said.

This spontaneity is what happened at a lab at the University of Utah, when Capecchi and his team observed what happened when the Hox8 gene, which helps regulate the embryonic growth of an animal, is removed from mice. At first, Capecchi’s team was unable to identify any significant outward differences between the mutant and normal mice. After a few weeks of study, Capecchi noted that the group of mice that underwent the mutation began grooming themselves.

The mutant mice spent almost twice as long grooming themselves than the normal mice did. This grooming time, which cut into the mice’s sleep schedules, initially appeared to be devoted solely to cleansing. Soon, however, Capecchi said the behavior was ingrained in their brains.

“This grooming behavior was pathological, in which the mice remove the body hair by grooming,” Capecchi said.

This behavior in mice can be apparent in humans, specifically when exploring Obsessive Compulsive Disorder in humans, Capecchi said. The behavior of the mice is very similar to a form of OCD called trichotillomania, a compulsion to remove one’s hair that affects approximately 3 percent of the population.

Using the research from the mutations in mice, Capecchi began to explore whether he could  identify the cells affected by the mutation in the mice and use this to create a possible treatment plan for humans who have OCD.

Capecchi and his team began to search for the differences between the mutant microglia —  an immune cell of the brain — and normal microglia, a task that drew doubt from other scientists.

“The big advantage is that you don’t know which questions not to ask,” Capecchi said. “The disadvantage here is that people are generally skeptical and you must work hard to prove yourself.”

Capecchi and his team used fluorescent imaging on the mice brains and discovered that the Hox8 gene likely plays a role in pathological behaviors and OCD. Capecchi said he believes this finding has broader implications than for OCD, however.

“Having told you that microglia are responsible for trichotillomania, I don’t believe it,” Capecchi said. “This system was set up to study one particular disease, now what are we really looking at?”

All the genes found link to neuropsychiatric disorders and at least half of them relate to the immune system, Capecchi said.

Yet Capecchi believes researchers should think more broadly about the implications of gene targeting.

“In science we see what we’re looking for,” Capecchi said. “We can’t see things we aren’t looking for, so what we’re looking at might be in a much bigger area than anxiety.”

These broader implications are only discoverable through continuous questioning, Capecchi said, quoting his mentor, James Watson, who discovered the structure of DNA.

“The same amount of effort goes into answering big questions as into answering little ones, so why not answer the big ones?” Capecchi said.

 

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