Research at Shriners Hospital for Children Northern California

To make treatment safer, Sacramento scientist studies stem cells' dark side
By Carrie Peyton Dahlberg - cpeytondahlberg@sacbee.com

Stem cell researcher Paul Knoepfler, center, observes as Natasha Varcakhanova manipulates stem cells at Shriners hospital in Sacramento. Knoepfler, a UC Davis Medical School professor, has been granted $2 million to study what could go wrong in eventual stem cell treatments. RENÉE C. BYER rbyer@sacbee.com Renee C. Byer / rbyer@sacbee.com


In a gleaming lab high within Shriners Hospitals for Children Northern California, Paul Knoepfler is waging a different kind of fight against cancer.

His target is a gene that causes tumors – and that can transform adult skin cells into versatile stem cells similar to those in embryos.

Doctors who are hoping to use stem cells to one day cure paralysis and wipe out devastating diseases don't want to give their patients cancer along with the cure.

Knoepfler, who just received a $2 million grant from the California Institute for Regenerative Medicine, is trying in his Sacramento lab to make eventual stem cell treatment safer.

"I'm very optimistic," he said. "I don't think the hurdles we're facing are insurmountable."

The prospects for stem cells, which can grow into every kind of tissue, are dazzling. But while cadres of researchers worldwide are focusing on spinal cord damage, diabetes, heart disease and countless other ills that stem cells might repair, Knoepfler and others are busy looking at what could go wrong.

Stem cells could trigger immune system attacks. They could cause benign tumors in dangerous places. They could cause cancer.

"I think the public thinks you can just inject cells and have the patient feel better," said Dr. Joseph Wu, a Stanford University Medical School professor who is studying stem cells' potential to repair damaged hearts.

He, too, is interested in how stem cell treatments might go wrong.

Wu is one of the authors of a study published online Monday by the Proceedings of the National Academy of Sciences that looks at how the immune system might stamp out stem cells before they can work.

"It's just a reality check," he said of the study in mice, which found that healthy immune systems quickly wiped out transplanted embryonic stem cells.

When the mice were given drugs to suppress their immune response, the stem cells lasted longer. But suppressing the immune system in people increases the risk of dangerous infections, so ideally, doctors would want to find another way to make stem cell treatments stick.

"I don't think it's impossible," Wu said. "It just will take us time to figure things out."

Wu worked with human embryonic stem cells, which have long transfixed researchers because they can grow into everything that makes up a human body – bone, blood, nerves, lungs.

If scientists can figure out how to nudge those cells safely toward becoming whatever a patient needs to have repaired, the hope is that the cells will be a powerful medical tool.

Knoepfler, a professor at UC Davis Medical School, is interested in both embryonic stem cells and a promising alternative that can be grown from adults, most commonly from skin cells.

Those cells generally wouldn't be vulnerable to immune system attack, since doctors likely would create them from a patient's own body.

Instead, different problems emerge. Researchers turn adult tissue into these stem cells, called induced pluripotent stem cells, by activating four key genes to change a mature cell's normal behavior.

One of those genes has been linked to cancer for decades.

That's why Knoepfler originally got interested in studying the gene called Myc. He wanted to make headway against tumors, to understand what role Myc plays in creating them, as well as what it does in healthy bodies.

He thinks the gene probably is involved in both helping stem cells divide and helping them remain stem cells before they start down the path of differentiating into blood cells, neurons or anything else.

Given that theory, it's not surprising that the first researchers to reprogram skin cells into stem cells chose Myc as one of their genetic midwives.

"In light of this new technology, Myc has really come into the spotlight. … It's a really hot field," said Meri Firpo, a professor at the University of Minnesota's Stem Cell Institute who has been following Knoepfler's work.

"His expertise suddenly becomes extremely important," she said. She's interested in what Knoepfler learns because of implications for her own research into ways stem cells might combat diabetes.

California's voter-funded stem cell agency is interested, too. Last week the California Institute for Regenerative Medicine, or CRIM, granted Knoepfler's lab $2 million over the next five years to study the gene.

"The CRIM award is like a booster rocket," said Knoepfler, and will come close to doubling his lab's budget.

The new money will let him hire more scientists, so ideas can be tested more quickly, and will support the costly, exacting process of growing stem cells.

Knoepfler hopes both to learn more about exactly how the critical Myc gene works, and to search for something better – another gene that could help create stem cells without as much cancer risk. "A goal we have is to find a safe substitute for Myc," he said – and ideally, to have it ready for testing in the next few years.

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