Stem cell frontiers

A look at the progress and potential pitfalls in California's $3 billion stem cell research program.

Four years after California residents captured worldwide attention by voting to spend $3 billion on stem cell research, many of the anticipated new therapies are at least 10 years away and numerous hurdles must be overcome.

Yet the optimism remains.

As research kicks into high gear, scientists point to areas that hold great promise, including:

Using stem cells to deliver missing enzymes or absorb toxins to help keep dying cells alive. This approach may be useful for people with Parkinson's or Alzheimer's diseases.

Transplanting stem cells to repair damage caused by macular degeneration.

Treating diabetics with insulin-producing cells the body will not reject.

Using stem cells to repair heart damage or spinal cord injuries.

Attacking cancer at its root by eliminating what some believe are cancer stem cells.

In many cases, however, before scientists can begin clinical trials, they face major stumbling blocks.

No one knows, for example, how to ensure that transplanted stem cells won't eventually form cancerous tumors.

Or how to guarantee that a stem cell meant to form heart muscle won't begin making an ear or a hair follicle.

Watchdog groups are concerned that women who donate eggs to make embryonic stem cells will not be adequately protected from the side effects of ovary stimulation drugs.

Others fear the new therapies will be too expensive for many Californians.

Money may be one of the biggest hurdles. The $3 billion taxpayer investment will not be nearly enough to take most therapies through the required trials and bring them to market.

"The drug industry computes that it needs $1 billion for every new drug, " said Alan Trounson, president of the state stem cell agency, known as the California Institute for Regenerative Medicine. "If that's the case, we're going to be handicapped severely here."

For that reason, Trounson and other stem cell leaders have begun to look at partnering with the biotech industry to ensure the work continues beyond the limits of the state program.

Despite such challenges, most scientists believe the technological and ethical hurdles will be overcome.

"I would say this is the most exciting time to be in science, ever, " said Dr. Arnold Kriegstein, director of the UC San Francisco Institute for Regeneration Medicine.

"I don't think there's ever been as many opportunities to actually alter the course of a disease as there is right now."

Building blocks

The ability of stem cells to self-renew has ignited scientists' imaginations. Many believe the cells can become a replacement kit for damaged or diseased muscles, nerves, skin and other organs.

Three major types of stem cells exist: adult, embryonic and a new form known as induced pluripotent stem cells.

Adult stem cells can be found in many major tissues and the umbilical cords of newborns. They are limited because they can only form more of their own tissue type. For decades, physicians have used such cells from bone marrow to treat leukemia, lymphoma and other blood disorders.

Embryonic stem cells hold the greatest promise. Appearing in embryos a few days old, they can form any of the more than 200 human cell types.

Last year, a discovery rocked the stem cell world. Dr. Shinya Yamanaka of Kyoto University and James Thomson of the University of Wisconsin revealed they had reverse engineered adult skin cells to take on properties similar to embryonic stem cells, including the ability to form many cell types. No embryos were needed to make these induced pluripotent stem cells.

This discovery added new dimensions to the emotional debate surrounding embryonic stem cells.

Critics argue that scientists should not be allowed to destroy embryos, which are typically left over from in-vitro fertilization, to obtain embryonic stem cells. The cells are placed in a Petri dish where they divide to create a stem cell line.

In 2001, President Bush agreed and banned using federal funds to create new embryonic stem cell lines. Researchers should use existing lines only, the president said. Scientists countered that such lines are too few in number and are of poor quality.

Persuaded that such restrictions could cause the United States to fall behind in an important scientific frontier, Californians set out on their own. In an unprecedented move, 59 percent of the state's voters agreed in 2004 to provide $3 billion over 10 years for stem cell science, including research banned from federal funding.

In recent months, the discovery of the reverse-engineered cells has led some to argue for discontinuing embryonic stem cell research. But because reverse-engineering the cells involves retroviruses, which can cause cancer, scientists in California are continuing to research all three stem cell types.

So where is this all headed?

The public has focused its attention on cell replacement therapy, which has the highest hurdles. But early progress may occur in areas that are equally important, if less dramatic.

One of the first fruits of California's program may be new diagnostic and genetic tests to reveal abnormal development, said Renee Reijo Pera, director of the Center for Human Embryonic Stem Cell Research and Education at Stanford University.

Watching stem cells differentiate will deepen scientists' understanding of normal development. Having the ability to tailor-make stem cells with particular disease characteristics should further that understanding.

"You can ask the question: When do you see the first signs of muscular degeneration when you make a stem cell line (from) somebody with muscular dystrophy?" Pera said. "When do you see the first signs of neural degeneration in a Parkinson's patient?"

Companies will use stem cells with disease characteristics to test drugs and speed them to the market quicker.

Scientists are also keenly interested in using stem cells to deliver missing enzymes or to absorb toxic substances to help keep cells alive.

Some think this approach could work with Alzheimer's disease, which is considered an unlikely candidate for cell replacement therapy because of the complexity of the human brain and questions about whether replacing dead neurons would alter personality.

In Alzheimer's disease, scientists believe neurons die because of beta-amyloid, a toxic substance the disease produces. Scientists can design stem cells to absorb and hold beta-amyloid, Kriegstein said.

If these stem cells are delivered to a patient's brain, "they might act as little sponges, soaking up the beta-amyloid as it's produced, " he said. Lowering the toxic level could slow down or perhaps arrest the disease by preventing neurons from dying.

Such treatments appear to be at least several years away.

Great promise

Despite the excitement generated by such approaches, it was the possibility of cell replacement therapy that ignited the outpouring of support for California's stem cell initiative.

One condition believed to hold great promise for such therapy is age-related macular degeneration, the leading cause of blindness in the elderly.

"There is a strong view that that might be a very early application of embryonic stem cells because it's easy to produce pigmented retinal epithelial cells and the eye is a contained area, " Trounson said. That makes it easier to monitor the cells.

But before clinical trials can begin, scientists will need to make sure the immune system does not reject the transplanted cells, said Dr. David Hinton, professor of pathology, neurosurgery and ophthalmology at the Keck School of Medicine at the University of Southern California.

Other scientists have zeroed in on diabetes, a condition in which the body fails to produce enough insulin. Today, scientists sometimes treat diabetics by transplanting insulin-producing islet cells from another person. But the patient must then take drugs to suppress the immune system to avoid rejecting the cells, which increases the risk of contracting other diseases.

The goal is to design insulin-producing cells the patient's body can tolerate.

"Many laboratories, including our own here at UCSF, are trying to do that, and significant progress has been made, " Kriegstein said.

Parkinson's disease also has generated a great deal of attention because it involves one cell type that dies, which makes it an easier target for cell replacement than more complex diseases.

In Parkinson's, tremors and other symptoms appear when dopamine-producing neurons degenerate. If stem cells could be made to produce dopamine, scientists believe they could treat or cure the disease.

Others are working on using stem cells to repair heart damage. Scientists have transformed embryonic stem cells into beating heart cells, said Dr. Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease in San Francisco. Yet many challenges remain.

The technical hurdle is "how best to introduce them into the heart and have them integrate with existing cells and communicate properly collectively, because you can't have a heart beating and cells you introduce beating independently, " Srivastava said.

One of the hottest areas of study is the possibility that the body has cancer stem cells. The theory is that chemotherapy and radiation kill tumors without touching cancer stem cells, which are thought to be radiation-resistant.

If scientists prove that cancer stem cells exist, they can develop methods to attack the root cause of cancer.

Caution needed

Such pursuits represent only the beginning. Throughout California and around the world, scientists are exploring how to use stem cells to repair spinal cord injuries, create blood products, treat Lou Gehrig's, Huntington's and Crohn's diseases, form cartilage, bone and muscle tissue for reconstructive surgery, and attack numerous other conditions.

None of this will be in widespread use soon. Nearly 50 human trials involving stem cells are under way, but most use adult stem cells from blood or bone marrow.

The Food and Drug Administration has yet to approve implanting cells derived from embryonic stem cells in humans. Many questions remain about safety and technological issues.

Scientists are discovering how to drive stem cells to form a particular type of organ or tissue. But they need ways to monitor transplanted cells and to remove them if a problem emerges.

One concern is that a few overlooked stem cells might develop differently and later form bone or tooth cells in the heart, for example.

Or they could create a cancerous tumor. "It only takes a few bad apples to cause trouble, " Srivastava said.

Researchers are exploring how to design stem cells to self-destruct if they turn cancerous. "So the cell is programmed to commit suicide if it goes awry, " he said.

Such problems are solvable, scientists say, but they stress the need for caution.

Because of these concerns, the FDA may decide to follow a small number of patients in clinical safety trials for five to 10 years before allowing larger trials.

To speed development, some researchers believe the FDA should allow what are known as Phase I and Phase II trials to be conducted concurrently. "Otherwise, it just puts such a long gap in it, " Trounson said.

Phase III trials involving hundreds of patients would come next before a new therapy is approved for the market. The process can take 20 years or longer.

Keeping options open

Despite the excitement about reverse-engineered cells, many scientists believe it is important not to abandon embryonic stem cells.

To custom-make such cells, scientists at UCSF, Stanford and elsewhere are attempting a procedure not yet performed successfully with human cells known as therapeutic cloning, or "somatic cell nuclear transfer." South Korean researchers claimed to have done this, but that turned out to be fraudulent.

The procedure involves removing the nucleus of a woman's egg, replacing it with the nucleus of an adult cell and stimulating the egg into dividing. Scientists would then remove stem cells. Oregon researchers have accomplished this with monkey embryos.

Scientists say this technique, which is banned from federal funding, holds great promise because it would enable them to tailor-make stem cell lines using a nucleus from someone with a particular ailment such as Lou Gehrig's disease. This would produce cells for testing drugs and therapies.

The technique could also be used to create stem cells with a patient's own DNA. Since the stem cells are genetically matched, they would not be rejected by the patient's immune system.

This approach, however, worries watchdogs because of the large number of women's eggs that may be required.

Women donors might not be fully informed of the risks of drugs used to stimulate ovulation, say Marcy Darnovsky and Jesse Reynolds of the Center for Genetics and Society in Oakland. Employees at fertility clinics, where the eggs will be extracted, may have ties to stem cell researchers and may not have a woman's best interests at heart, Reynolds said.

Some fear low-income women could be coerced into becoming donors. To help prevent this, California's stem cell initiative banned the use of state funds to pay for eggs. Darnovsky and Reynolds helped campaign for a 2006 law that also prohibits payment for eggs in privately funded stem cell research.

"We were concerned about a lack of a firewall between researchers and the fertility doctor, " Darnovsky said. "There's a lot of people who take really good care of these women and a lot who don't."

Scientists in California and elsewhere, meanwhile, continue to explore the reverse-engineered stem cells made without embryos. A major goal is to find ways to produce them without using cancer-causing retroviruses.

It is important to continue exploring both methods, scientists say, because the gene profiles of the reverse-engineered cells are not identical to embryonic stem cells.

"Whether that's significant or not, whether that means something, is something we don't know yet, " Kriegstein said.

Despite the hurdles, California researchers hope to show significant progress within the 10 years of the state program.

But because of financial constraints, Trounson said, the biotech and pharmaceutical industries will need to play key roles in moving therapies forward. That may generate questions. Trounson wonders what will happen if scientists develop a therapy that cures a disease like diabetes with one shot of stem cells. How will companies recoup enough money to offset their investment and make the treatment affordable to most people? These are among the tough issues that stem cell leaders and the public will face.

Few people expect stem cell research to extend life spans significantly. But many scientists believe it will improve the quality of life.

"At the end of the day, " Pera said, "I don't know anybody in the stem cell field who doesn't hope that we will learn kind of the rule book of human life - how cell decisions are made, what genes are turned on to make a hair cell, what genes are turned on to make a neuron."

Reach Sandy Kleffman at 925-943-8249 or