State of stem: prop. 71 funding spurs range of activity on cell frontier.

PACKED inside an incubator in a laboratory at Childrens Hospital Los Angeles are dozens of miniature petri dishes containing a reddish-orange liquid.

Suspended in the gel are millions of human embryonic stem cells--and with them, the promise of destroying fatal brain tumors, repairing damaged hearts and producing insulin in diabetics.

But for researcher Carolyn Lutzko, one of the few scientists in Los Angeles actually, growing the cells, any hopes for medical miracles remain far in the distance.

"With these things you are spending 50 to 70 percent of your time trying to keep them alive," said Lutzko, who is also an assistant professor of pediatrics at USC's Keck School of Medicine. "They are slower growing. They are less predictable, and they are more delicate."

Such is the reality of human embryonic stem cell research. While institutions in Los Angeles and elsewhere are gearing up for $3 billion in statewide grants for accelerated stem cell research, the field is still in its infancy. The work is very fundamental--more so than many voters may have realized when they passed Proposition 71 in November.

Just last week came another setback: the existing lines, including the ones in Lutzko's incubator, are contaminated with a mouse acid that will likely make them unsuitable for human therapies. This will require scientists to create new uncontaminated colonies, perhaps setting back cures for several years.

Even so, dozens of researchers in the Los Angeles area already performing research using other types of stem cells are clamoring to get a share of the money, which will largely be targeted for human embryonic stem cells--the ones that hold the most promise.

"I don't mean to sound like a Pollyana, but this is a silver bullet," said Dr. John Torday, a professor of pediatrics at Harbor UCLA Medical Center who expects to seek funding for stem cell research on treating chronic lung disease. "I think it's a major breakthrough. It's a technical tour de force."

Broad interest

At UCLA, researchers now working with stem cells from rats hope to one day fix damaged spinal cords and brains. Cedars-Sinai Medical Center researchers, using adult neural stem cells, are conquering brain tumors in mice, and researchers at the City of Hope are trying to grow human embryonic stem cells to produce human insulin.

They're all hoping to secure some grant money from the newly formed California Institute of Regenerative Medicine, an outgrowth of Proposition 71. If the government-funded effort works, it will jumpstart an industry, in California and could lead to dramatic advances in treatments borne out of stem cell research.

Scientists have actually used stem cell therapy for more than three decades, in the form of bone marrow transplants for leukemia and other blood diseases, although the nature of how the therapy worked was not always fully understood.

In fact, bone marrow contains "adult stem cells" that are able to produce red blood cells, white blood cells and the other components of the blood and immune system.

Adult stem cells, found throughout the body, can turn into the types of tissues where they are found, such as blood, muscle and bone. However, researchers have also learned to coax them into other types of cells.

Embryonic stem cells can turn into any type of tissue in the human body, such as blood. muscle, tissue, organs and the like.

Much research was focused on adult stem cells until 1998, when a University of Wisconsin researcher was able to isolate and culture stem cells from embryos. Because of their ability to differentiate into any and all cells, these are considered more valuable.

While there is much hype surrounding the potential of embryonic stem cells, Lutzko and other researchers working with them are still trying to better control their basic replication into new stem cells. This is the first step before other researchers can use them for more sophisticated applications.

"We are looking at the genes involved in keeping it a stem cell. The second side to that is that we obviously want to use these cells for clinical applications," said Lutzko, who has been growing the cells for three years after getting some of them from the original Wisconsin researchers. (Although the contaminated cells are unsuitable for human therapies, they are still usable for research.)

Growing the cells takes about a week under highly controlled conditions, including maintaining the air at temperatures and with carbon dioxide concentrations that mimic the human body.

Lutzko's knowledge has led other scientists around Los Angeles and elsewhere in the country to seek her out and ask her to teach them the process. Helping them takes at least two weeks, and it doesn't always work out.

"It's an art, and not every scientist can do it successfully," she said.

Lutzko's other research involves coaxing the stem cells to turn into blood cells. This is done by placing them in a dish with blood components, which signal the cells to begin differentiating.

The problem is that scientists only have a limited understanding of how that differentiation works. While Lutzko thinks that embryonic stem cells will one day be able to generate blood for transfusions, eliminating the reliance on donors, as of now she can only do it with limited success.

"The problem is it's so inefficient," she said.

High hopes

There are a few other researchers in Los Angeles already working with human embryonic stem cells. Dr. Chu-Chih Shih, a professor of hematology at the City of Hope in Duarte, recently received a batch from Wisconsin.

Shih believes he may be able to convert the stem cells into islet cells, which are found in the pancreas and produce insulin. They could then be transplanted into Type 1 diabetics whose islet cells no longer function.

But Shih is also at the starting gate. He just started growing his cells in the past month and is having trouble with them, though he believes that may be because they were only recently thawed. Still, it's sobering.

"We are just getting them to replicate." said. "We are going to follow the protocol word for word."

Most other researchers in Los Angeles are conducting experiments that use mouse, rat or human adult stem cells, although many believe the next logical step is moving to human embryonic stem cells.

Dr. Harley Komblum, an assistant professor of pediatrics and molecular and medical pharmacology at UCLA, is studying how brain stem cells derived from fetal rats repair brain lesions in mice. But the ultimate target of the research is humans.

"I am interested in how the cells might be used for repair," he said. "Completely restoring the complex circuitry of a spinal cord after an injury is probably not doable, but that does not mean that some function cannot be restored."

Kornblum has high hopes that adult neural stem cells, which differentiate into brain, spinal cord and other neural cells, might be the ultimate answer for humans. But he also plans to seek Proposition 71 funding to study if human embryonic cells might work better.

Dr. John Yu, co-director of the Comprehensive Brain Tumor Program at Cedars-Sinai Medical Center, is taking another approach. He is injecting human adult neural stem cells into mice who have glioblastomas, which are highly aggressive brain tumors that generally are fatal in 12 months.

The neural stem cells are genetically augmented to contain "killer" genes that boost the immune response to the tumor. They also somehow know to home in on the tumor. The result: Mice are surviving the tumors, giving hope that a similar approach might work with humans, using either adult or embryonic stem cells.

"You load them with agents that can kill tumor cells and they can act like heat-seeking missiles," said Yu, who also expects to apply for Proposition 71 funds. "It appears that cancer is really a stem cell disease."

Still, scientists acknowledge that cures for cancer, diabetes, Parkinson's and other major diseases are years, possibly decades, away.

While they can use the existing stem cell lines that are contaminated with mouse acid for animal research, few believe that any human therapies can be derived from them.

That's because the mouse acid would be expected to cause a sort of allergic reaction if the cells were injected into a person. Dr. Ajit Varki, the San Diego researcher who conclusively proved the contamination, thinks new stem cell lines are likely the best solution, although it will not be easy to grow them.

"It's like starting over to make an orchid grow in a different soil and a different fertilizer," said Varki, a professor of medicine at the University of California at San Diego. "It's a technical wake-up call."

Nearly all embryonic stem cell lines, and all the ones approved for federal funding, are grown in what is basically a mush of crushed mouse embryos that provide an assortment of nutrients and growth factors that are able to keep human embryonic stem cells from differentiating.

The problem is scientists are not exactly sure how the process works and are only now experimenting with non-mouse media, including tissue from the foreskin of circumcised infants.

Scientists in Singapore report they have been able to successfully grow human embryonic stem cells in a non-animal, human-derived culture, but Varki said it's unclear how good the lines are.

Still, researchers say that stem cells present the possibilities for some of the most important medical and biological breakthroughs in years.

"What you are talking about is unlocking this wonderful mystery, which is what makes cells grow, develop, change and die," said Dr. Michael Friedman, president of" the City of Hope. "And this is the fundamental secret of life."

RELATED ARTICLE: Local endeavors.

Sampling of stem cell research being conducted in L.A. area.

UCLA: More than 50 labs doing research on cancer, heart disease and other maladies. Much of the work involves adult stem cells, while mouse cells also are being employed.

USC: Relationship with Childrens Hospital Los Angeles, where studies are being done on the role adult stem cells play in immune-compromised children, blood cancer, liver disease, diabetes and other childhood diseases. Researchers are also growing human embryonic stem cells.

City of Hope: Ongoing experiments using adult neural stem cells to deliver brain tumor therapies.

Caltech: Handful of researchers pursuing various lines of inquiry, including the role that neural crest cells may play in birth defects and cancer

Cedars-Sinai Medical Center: Researchers are focusing on treating brain tumors with stem cells, and repairing heart muscles damaged after myocardial infarctions, among other lines of inquiry

Harbor-UCLA Medical Center: Researchers doing work on erectile dysfunction and chronic lung diseases believe they are good targets for stem cell therapy

--Laurence Darmiento

RELATED ARTICLE: The race is on.

THE fact that there will be $3 billion available for stem cell research over the next decade has set off a scramble among institutions around Los Angeles to position themselves for funding grants.

UCLA is already considering setting up a stem cell research center, while institutions ranging from USC to the City of Hope are planning to recruit new faculty members who have an interest in the research.

In addition, top administrators at UCLA, USC, the City of Hope, Cedars-Sinai Medical Center and Caltech secured positions on the board of the California Institute for Regenerative Medicine, the body formed by Proposition 71 to dole out the research funding.

"We are going to be aggressive," said Dr. Leonard Rome, senior associate dean for research at UCLA's Geffen School of Medicine.

Until now, most human stem cell research has been done on adult stem cells. But since voters passed Proposition 71 as a response to federal limits on funding embryonic stem cell research, scientists expect most of the state's money to go toward embryonic stem cells.

UCLA's plan for a stem cell institute is only in the discussion stage, but it gained currency when the university surveyed its faculty and found dozens either already involved in stem cell research or interested in pursuing it. This included both human embryonic and adult, along with mouse stem cell work.

Similarly, USC has formed an advisory committee to direct the school's funding effort. The proposition also prompted USC to move forward with its stalled biotech park.

The park has been held up for years over difficulties assembling the land, but now the university plans to build a building that could house stem cell researchers or a company doing stem cell work.

"When we started to organize this, we found a lot of people who were not involved who had a lot of interest in stem cell research," said Dr. Frank Markland, an associate dean for scientific affairs at the Keck School of Medicine.

All the institutions also report an interest in recruiting new researchers interested in stem cell work, but no one is talking publicly about lobbying for the funding--especially since critics have noted that the Institute board includes representatives of institutions likely to receive funding.

The board has taken steps to blunt this criticism by establishing an objective process for reviewing grant proposals that will include outside researchers sitting on the committee that makes the decisions.

"It will be experts from outside the state of California," said board member Dr. Michael Friedman, president of the City of Hope.

Rome said UCLA did not push for a seat on the board to directly influence grant making, but to ensure that the board was composed of top medical and scientific minds that would ensure grant applications would be scientifically evaluated--creating a playing field that is good for the school.

"I thought it was really important for the committee to get started with what I would call top values," he said.

--Laurence Darmiento