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Reawakening a ‘Sleeping Beauty’ of a Gene

illustration of DNA

Illustration courtesy of South Carolina Sea Grant Consortium

A special gene that stopped functioning millions of years ago in ancestors of the salmon family is now awake. Minnesota Sea Grant scientists have converted this fish gene into a new DNA delivery system that promises to revolutionize the cutting-edge science of human gene therapy.

This gene, called a transposon, is a stretch of DNA that can hop in and out of chromosomes. It provides a new tool that could be used to transport normal genes into genetically-damaged cells that cause such illnesses as hemophilia or cancer.

The discovery was based on Sea Grant-funded research to genetically engineer faster-growing fish for aquaculture purposes by Perry Hackett, professor in the University of Minnesota’s Department of Genetics and Cell Biology. Like other researchers, he had a difficult time moving engineered genes into the chromosomes of the fish’s cells.

In an attempt to develop a better DNA delivery system, Hackett and his colleagues, Zsuzsanna Izvák and Zoltán Ivics (who now work for the Netherlands Cancer Institute), began studying transposons. Despite an intense search, they could not find an active transposon gene in modern fish. But their research indicated that two inactive genes from Atlantic salmon (Salmo salar) and a single element from rainbow trout (Oncorhynchus mykiss) had transposons that stopped functioning more than 10 million years ago due to mutations.

They resurrected the transposon through a painstaking genetic process, working their way back through time, removing the mutations and rebuilding it as it once was millions of years ago.

“The partial genes were in very bad shape with deletions and so on,” said Hackett. “It took nearly three years.”

Perry Hackett

Perry Hackett

Their reconstructed transposon worked. In laboratory culture dishes, it carried new gene sequences past natural barriers into the nucleus of human, zebrafish (Danio rerio), and mouse cells and inserted them into the DNA. Izsvák named this unique transposon system Sleeping Beauty.

Hackett sees it as a tool that could be used for many purposes. “The uses to which you can put a new tool are limited only by the amount of time and imagination you have.”

So far, most attempts to develop human gene therapy have relied on viruses to deliver the new genes to cells. The viruses have been modified to become harmless while retaining their ability to insert their genetic code into the human chromosome targets. Some researchers fear that different inactive viruses might combine to recreate a dangerous hybrid.

Gene therapy researchers consider Hackett’s development promising. They hope it will match the chromosome insertion efficiency of viruses without presenting the potential hazards.

Sleeping Beauty has also awakened corporate interest. Tony Strauss, with the University Office of Patents and Technology Marketing, said the University is in the initial stages of forming a company to develop the technology. “It’s certainly an exciting discovery,” Strauss said. “A large number of companies have contacted us and expressed interest. We’re moving forward rapidly in this exploratory stage.” Companies are interested in buying rights to use the process in such fields as agriculture, pharmaceuticals, and biotherapy.

Hackett and his team’s work was published in the November 14, 1997, issue of the journal Cell (Vol. 91, pp. 1-20). For more information on his research, contact Hackett at 612.624.6736.

Sources: Tom Majeski, St. Paul Pioneer Press, 11/14/97; Jim Dawson, Minneapolis Star-Tribune, 11/14/97; Jonathan Knight, New Scientist, 11/22/97.

The National Sea Grant College Program has awarded Minnesota Sea Grant Researcher Perry Hackett $154,213 for a two-year biotechnology project, entitled Development of Vectors to Inactivate Gene Expression in Fish. The objective is to improve aquaculture of economically important fish, such as salmon, northern pike, trout, and catfish.

Hackett’s was one of 24 projects funded through Sea Grant’s Marine Biotechnology National Strategic Investment.

By Marie Zhuikov
March 1998

Return to March 1998 Seiche

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