Stanford gene therapists land a big one

Fishing for tools to improve human gene therapy, two Stanford scientists may have found a remarkably effective genetic hook hidden in the trout genome.

Tom Abate, Chronicle Staff Writer

In the current issue of Nature Biotechnology, Stanford geneticist Mark Kay and researcher Stephen Yant show how they used a section of trout DNA called a transposon to splice therapeutic genes into chromosomes.

As Kay explains it, gene therapy is all about delivering a needed gene to cells that are missing it. Hemophiliacs, for instance, lack one of two genes critical to blood clotting.

To get missing genes into cells, scientists often used viruses as delivery vehicles. Viruses are good at breaking into cells. They make us sick because once they get in, they often unload genetic cargo that can disrupt the cell.

But gene therapists scoop the troublesome innards out of their delivery viruses and install therapeutic genes instead. So when an altered virus breaks into a cell, it delivers a gene that would, in Kay’s experiments, make blood- clotting proteins.

But after a decade of experiments, scientists have learned that viral delivery vehicles almost always drop off their therapeutic cargo short of the ideal goal — the chromosomes. Only when a missing gene gets into a chromosome does it become part of the person’s genetic makeup — and permanently cure the deficiency.

"What we’ve found is that the integration frequency of the (gene) into the chromosomes is very, very low," often less than a fraction of a percent, Kay said.

In their current paper, Kay and Yant boosted the integration of genes into the chromosomes of mice by borrowing a transposon from a trout.

Transposons are genetic sequences that can splice themselves into chromosomes. In nature they’re a nuisance because they can splice themselves into the middle of a useful gene and muck it up. Therefore, most organisms inactivate transposons — in the same way our cells try to repel viruses.

The transposon used in the Stanford experiment has its own tale. It was awakened after millions of years by University of Minnesota scientist Perry Hackett. In 1997, Hackett used genetic engineering to reactivate this transposon — dubbed "Sleeping Beauty" — on the theory that it could help splice gene therapies directly into chromosomes much more effectively than viruses.

Kay and Yant used Sleeping Beauty as the middle component of a three-tiered gene therapy. They used an adenovirus, the bug that causes colds, as the basic delivery vehicle. Inside the neutered adenovirus, they placed Sleeping Beauty, and inside the transposon, they placed the blood-clotting gene.

When they delivered this triple-decker therapy into the liver cells of mice,

they found it was more than 100 times more effective than current adenoviral systems.

But even so, only 5 percent of the genes wound up in chromosomes, indicating that much still needs to be done to improve integration.

Transposon gene therapy is a hot area. Hackett and some University of Minnesota colleagues have formed a company, Discovery Genomics Inc., to expand on their work with Sleeping Beauty.

James Merritt, chief medical officer of the Texas gene therapy firm Introgen, called the transposon work "an exciting development" for the entire field.

FDA UPDATE: Capitol Hill sources say the Bush administration plans to appoint former Stanford medical economist Mark McClellan to the long-vacant post of commissioner of the U.S. Food and Drug Administration.

But the appointment has been delayed because McClellan, who serves on Bush’s Council of Economic Advisers, has been a prime architect of the administration’s Medicare drug policy, and the White House hasn’t wanted to weaken that effort by moving him now.

If McClellan can wrap up his Medicare work soon, Capitol insiders expect he would prove acceptable to Sen. Edward Kennedy, D-Mass., whose objection had nixed prior potential nominees.

Kennedy has privately insisted that the new FDA commissioner not be tied to industry and have a medical background. McClellan, 39, clears those hurdles and more.

His resume is an overachiever’s dream. He has a master’s in public health from Harvard, an M.D. from Harvard and MIT, and a doctorate in economics from MIT. He has held a variety of think tank and academic posts with a medical policy bent. He also served briefly in the Clinton administration Treasury Department.

The current administration likes the fact that McClellan is a Texas boy with the right political pedigree. His mother, Carole Keeton Rylander, is a former Austin mayor who now serves as the state’s elected comptroller. When Bush appointed McClellan to his current post, Sen. Phil Gramm, R-Texas, expressed his delight, saying "Mark’s mama is one of my closest political allies."

But tea leaf readers on Capitol Hill think McClellan’s FDA appointment may be weeks away.

If Bush does tap McClellan for the FDA job, his first task may be reining in two deputies who have exercised considerable clout during the 19 month-plus interregnum. Deputy FDA commissioner Lester Crawford, who was reportedly Health and Human Services Secretary Tommy Thompson’s choice for the top job, has been large and in charge recently. And FDA general counsel Daniel Troy has been nudging the FDA in a deregulatory direction.

Industry people looking for clues about McClellan’s thinking might peruse the professor’s curriculum vitae, which lists several articles with titles like "The marginal cost-effectiveness of medical technology," indicating that the potential FDA commish might balance economics and therapeutics in evaluating novel technologies.

SUPER SUNFLOWER: An Ohio State University ecologist has shown that pesticidal genes bioengineered into sunflower plants can jump to wild relatives, and furthermore, that when they do make the leap, these genes give the affected wild plants an evolutionary edge over other unaffected sunflowers.

Researchers such as UC Berkeley ecologist Ignacio Chapela, who did his studies on corn, have already argued that genetic drift from bioengineered to ordinary plants can occur.

But the recent work by Ohio State Professor Allison Snow extends the genetic drift debate by asserting that a genetically engineered trait that crosses over to wild plants can enable them to thrive at the expense of their ordinary rivals.

Snow made a preliminary presentation of her findings at the August meeting of the Ecological Society of America. She studied sunflowers that had been bioengineered with a gene from the pest-killing bacterium Bacillus thuringiensis (Bt).

She found that the Bt gene jumped through cross-pollination to wild sunflowers and helped them to outperform unaffected wild cousins. She did her work in special plots where she set up the conditions for this gene flow and did not observe the results on actual farms. The Bt sunflower she studied is not yet in commercial use.

Snow, who has submitted her work to scientific journals, is reluctant to discuss the results until they have been reviewed and vetted by her scientific peers.

But in a brief phone interview, she said her work, if OKd by other scientists, would show for the first time that genetic drift could affect populations of wild plants of the same species.

Snow said she doesn’t want her findings to be blown out of proportion, given the highly charged debate over genetically engineered foods. She said the genetic drift she described could only take place between plants of the same species, so that a GE sunflower could not pass its pest-resistant gene to a dandelion, for instance.

Nevertheless, should her work gain credence in scientific journals, it would bolster the case of biotech critics who warn that GE crops that do have wild cousins could pass traits into the wild and affect the development of their species.

Corn and soy, the two most widely planted biotech crops, don’t raise these concerns because they don’t have wild cousins, Snow said. But bioengineered canola, rice, squash and wheat, all crops that are either already in the field or are being readied for commercial introduction, do have wild relatives and could potentially raise the same issues as the sunflowers, she said.

Snow’s work was funded by the U.S. Department of Agriculture, as part of its oversight mission to study the interplay of bioengineered and wild plants.

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