Zhao Zhang’s Jumping Genes

Zhao ZhangBy Karl Leif Bates

Zhao Zhang – ZZ to just about everyone – is a bit of a scientific outlier.

While most of his bioscience colleagues around the world are studying the 23,000 protein-coding genes that make us human, the Duke assistant professor of pharmacology and cancer biology is looking at the other part of the genome and asking what it does.

His lab’s tagline is “finding treasure in junk DNA.”

Specifically, Zhang’s group is looking at the half of our genome that is made up of long, repetitive sequences of DNA called transposons, or ‘jumping genes,’ the subject of Barbara McClintock’s 1983 Nobel Prize.

As the name implies, transposons jump around in the genome making changes and enabling innovation and evolution -- but also illnesses, including cancer.

“The transposon is like a virus, an endogenous virus,” Zhang explains. “They were viruses millions of years ago and they invaded our ancestors. But we’ve turned them into part of ourselves.”

He’s asking how and why that happened and whether transposons might be used as tools against diseases. “Transposons are so important, how come nobody is looking at them?”

Zhang was one of the first new faculty recruited to Duke with assistance from a special fund created by the Duke Endowment to advance faculty hiring in the sciences.

His dissertation work at the University of Massachusetts Medical School had focused on the activity of transposons in the germ cells – sperm and eggs. To avoid disastrous editing mistakes after conception, the germ cells have developed a system to control transposons, called the piRNA. Zhang thought piRNA could be used as a tool to investigate transposon biology in germ cells, work he did for five years with fruit flies at the Carnegie Institution for Science in Baltimore before coming to Duke last year.

He has continued that work, but also branched out to other fields, especially immunity. As relics of old infections, transposons play a role in educating the immune system about threats. He has also begun thinking about bits of circular DNA that are found in cancer cells that hardly anyone is studying. To get up to speed on immunology last year, the youthful-looking 36-year-old sat in on an introductory course at Duke and then an advanced course with only six students. One of the immunology professors was impressed enough to ask him if he was looking for a lab position.

Illustration of jumping geneJumping genes can produce virus-like particles and subsequently make new copies of themselves in our DNA. Courtesy of Zhao Zhang.

In a recent study, ZZ’s team found that a carefully controlled transposon called Gypsy is key to fruit fly viral immunity. As the fly metamorphosizes from a grub to a fly, essentially replacing all of its tissues with new structures, Gypsy is activated to prime the adult fly’s immune system for fighting viral infections. Flies with Gypsy silenced quickly succumb to viral challenges.

It’s a promising first step, but he’s hoping the transposons will help him get a handle on why cancer immunotherapy fails for up to 80 percent of patients.

“I still consider myself a basic scientist,” he says. “Of course, I would love to cure cancer tomorrow too!”

Zhang says his unusual childhood probably has something to do with his pursuit of off-beat scientific questions.

“I was born a criminal,” he says, as a second child in China, a country that had a one-child rule. For the first six years of his life he hid out in a small village with his grandmother to avoid detection. But to start school, he had to return to the larger town his parents lived in.

“I still remember every time somebody knocked on the door, I needed to hide in the closet. That made me feel life is not easy. And it also gave me a different view. I like to think about doing something a bit different than other people.”

He was eventually detected and his father lost his job and paid a significant fine. But Zhang survived and thrived and did well enough at university to come to the U.S. for graduate studies at the University of Massachusetts Medical School in 2008.

Zhang then skipped the step of having a post-doctoral fellowship. After he interviewed for a postdoc at Carnegie, they thought his ideas were so good they offered him a faculty job instead.

The boxes full of custom-made fruit flies from Baltimore have all been unpacked and his new equipment is in place and ZZ has hired three graduate students, three postdocs and two lab techs. He’s quite proud that three of his trainees at Carnegie and Duke so far have already gone on to become principal investigators themselves.

“Duke is unique at two things,” Zhang said. “One, the most important, is this collaborative environment. It’s relaxed and productive, but not super-competitive. The other is that this area provides a really nice quality of life for my family. With two little ones, I’d like to have a yard.”

Zhang and his wife, a research scientist at UNC, have just purchased their first home in Chapel Hill so that their two sons can attend Glenwood Elementary, which teaches in both Mandarin and English. The goal, he says, is that the boys will be able to talk to their grandparents back in China.

 

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