Cellular Calls

By putting up the money to advance stem cell research, Proposition 71 also puts the scientific scrutiny of the world on California.

by Lori Oliwenstein

Ever since the first human stem cells were grown in a lab dish in 1997, researchers have heralded them as a potential source of replacement cells to treat diseases such as Parkinson’s, Alzheimer’s and diabetes.

But hamstrung by federal regulations limiting the scope of stem cell research, scientists working with these controversial cells became isolated in under-funded laboratories or gave up promising research efforts.

Believing in the potential of stem cell research, California’s voters went to the polls last November and made history. With the passage of Proposition 71, they created the first-ever state-funded institute to regulate and support stem cell research: the California Institute for Regenerative Medicine.

Now, researchers who have grown accustomed to working in relative obscurity are beginning to step back into the limelight as private and public entities from universities to biotechnology start-ups vie for a piece of the $3 billion Prop 71 pie.

Scientists at the Keck School of Medicine of USC are certainly well poised to take in some of that limelight and make good use of these funds. There are a number of researchers on both the USC Health Sciences and University Park campuses—as well as at USC-affiliated Childrens Hospital Los Angeles—who have continued their scientific pursuit of stem cell technology through the darker years in the field.

Keck School leaders are also in positions of importance in the state’s stem cell efforts. Brian E. Henderson, M.D., dean of the Keck School of Medicine, is one of Governor Arnold Schwarzenegger’s five appointees to the 29-member Independent Citizens’ Oversight Committee, which will govern the California Institute for Regenerative Medicine and the way in which it disburses the stem cell funds.

“This is an important initiative not only to California, but to the world,” Henderson says. “And it is significant that the Keck School of Medicine is an integral part of this process.” In fact, in February the Oversight Committee held its first full public meeting at the Keck School of Medicine.

In addition to Henderson, the Keck School sacrificed one of its own for the good of the cause: In March, former Zilkha Neurogenetic Institute director and Keck School senior associate dean for academic development Zach Hall, Ph.D., was voted in as interim president of the California Institute for Regenerative Medicine.

Stem cell celebration

In order to make up for lost time, key faculty at the Keck School gathered together for daylong stem cell discussions, research sessions and presentations. The following are brief synopses of the science that may reveal the promise of stem cells for Parkinson’s disease, lung injury, degenerative diseases of the retina and liver injury.

Parkinson’s disease: At the Keck School Department of Neurology, Michael Jakowec, Ph.D., assistant professor, is collaborating on a study to determine just which neurotransmitters, and hence which neurological stem cells, are critical for the treatment of Parkinson’s disease.

“The simplistic view of Parkinson’s is that it is a disease with continuous cell death, leading to progressive dopamine depletion,” Jakowec says. “Therefore, blocking cell death or replacing dopamine neurotransmission should cure this disorder.”

Unfortunately, he notes, this simplistic view is not entirely correct. Research he has done with Department of Neurology assistant professor Giselle Petzinger, M.D., and Department of Neurosurgery assistant professor Mark Liker, M.D., indicates that Parkinson’s involves other types of neurotransmitters—any of which might be “just as important of a target for therapeutic treatment” as is the dopamine system. “This may indicate that dopamine replacement as a sole strategy may be too simplistic and inaccurate and must be kept in consideration for potentially successful stem cell applications,” Jakowec says.

Lung injury: Zea Borok, M.D., associate professor of medicine at the Keck School and co-chief of the division of pulmonary and critical care medicine, and her colleagues are attempting to determine the human stem cells that can regenerate and recreate healthy epithelial cells and tissues in diseased lungs.

In studies of immune-deficient mice, Borok says, they have found that human cord blood cells make their way to the lungs within a month of full-body irradiation. In addition, they have begun to look into the chemicals that can be used to draw those possible stem cells into the lungs more readily, in order to ultimately enhance the recovery of damaged lungs.

Retinal degeneration: A study led by Doheny Retina Institute researcher SriniVas Sadda, M.D., assistant professor of ophthalmology at the Keck School, showed that cells called retinal progenitor cells (or RPCs) can be prompted to differentiate into specific retinal neurons and potentially improve visual function in rat models of degenerative eye diseases.

“There are a number of mechanisms by which RPCs may have a beneficial effect on retinal degenerative diseases, including both photoreceptor rescue and direct neuronal replacement,” Sadda says. “Continued efforts to further understand the biology of these cells will be critical for realizing their full potential.”

Liver injury: Laurie DeLeve, M.D., Ph.D., associate professor of medicine at the Keck School, and her colleagues found that rats who had been irradiated—a process that kills stem cells in bone marrow—were much less able to repair injury to liver cells called sinusoidal endothelial cells (SECs) than rats who were not irradiated.

DeLeve explains that if the liver is to recover after injury, the damaged SECs need to be replaced. Based on a finding that bone marrow stem cells can apparently work to enhance the repair of injuries to the liver, she and her colleagues are investigating bone marrow stem cells as a new potential avenue for the treatment of at least a subset of liver injuries.

“USC has a lot of expertise and good research going on,” DeLeve says. “However, that will not be enough to be a major power in the field. We will need to collaborate, so that local expertise can be shared. We need to think about what facilities we will need to be competitive.”

What the Keck School has in its favor, notes Frank Markland Jr., Ph.D., associate dean for scientific affairs at the Keck School and professor of biochemistry and molecular biology, is strong faculty members, a strong recruitment program, and the strong support of the dean.

Stem cell illumination

Perhaps nowhere is the Keck School of Medicine so well represented in stem cell research than at Childrens Hospital Los Angeles (CHLA), where there are several groups of physicians and scientists focusing on embryonic stem cell research at the Saban Research Institute.

Keck School associate professor of pediatrics Gay Crooks, M.D., who heads up the CHLA Saban Stem Cell Project, has been focused for a dozen years on identifying and characterizing human stem cells in bone marrow and cord blood, and pinning down how these cells grow in different culture conditions in the laboratory.

In addition, she has been working on ways to visualize these stem cells as they travel into the body, settle in the marrow of bones, and put down reproductive roots. She does this through bioluminescence imaging, a technique that tags human stem cells transplanted into a mouse model with the same gene that fireflies carry, creating a glow that can be detected by high-tech imaging instruments. This work was published by the journal Blood in November 2003.

“Our work was the first to show how imaging techniques can be used to track normal stem cells after they engraft and grow in the bone marrow after transplantation,” Crooks says. “We can image how the human cells are engrafting and growing over time, and gain a very clear idea of the dynamics of how stem cells engraft.

“The technique allows us to ask new questions about how bone marrow stem cells behave,” she adds, “and discover how we can perform bone marrow transplants better in humans.”

Among CHLA’s most noted stem cell biologists is Donald Kohn, M.D., chair of the Keck School’s newly formed Stem Cell Steering Committee and professor of pediatrics. The Steering Committee is responsible for assisting in the recruitment of key stem cell scientists both at the USC Health Sciences Campus and CHLA, and with organizing the Keck School’s response to the California Institute for Regenerative Medicine’s recent call for the first round of grant applications.

Kohn notes that human embryonic stem cells can be prompted to differentiate into any of an almost unlimited number of types of cells. But the difficulty is getting them to become precisely the type you want, especially in the laboratory. That is why Kohn and his group are working to find the most efficient ways to tweak a stem cell’s genes in order to both make them do what they want them to do, and to get a better look at their biological properties in the process. Of course, as with any form of gene-tweaking, this will require an effective transport mechanism, or vector, to get those tweaked genes into the embryonic stem cells. And that is where Kohn and his colleagues are now focusing.

Still, says Kohn, there is a long road ahead.

“We’re at the beginning, with science’s first baby steps of trying to manipulate stem cells and genes,” he says. “Just as we now have medicines that make penicillin seem like a weak antibiotic, we’ll look back in 10 to 20 years and be able to do things with stem cells that we’re just beginning to think about now.”

Stem cell expectations

Even though the starter’s gun has only just gone off in the stem cell arena, there are already those reminding all parties involved that it is slow and steady that wins the race.

“No one wants results to come back faster than I do,” cautions Independent Citizens’ Oversight Committee member Joan Samuelson, the founder and president of the Parkinson’s Action Network, who herself has Parkinson’s disease. “But some of these questions and issues are complicated. Some of the answers may take a while.”

Ultimately, only time will tell if the search for stem-cell-based cures is going to bear fruit for the scientists who are working tirelessly toward that end. And looking over the researchers’ shoulders, waiting for the answer, will not only be the California-state taxpayers who are providing the money for these critical studies, but the millions of people around the globe who suffer from the diseases that stem cell research may someday make obsolete.

 

STEM CELL POTENTIAL

A stem cell is any cell in the body that has held on to the ability to divide and develop into a variety of cell types; it is a cell that has not completely and irrevocably transformed itself into one specific type. In the blood, for instance, the so-called hematopoetic stem cells are the source of every red and white cell created by the body. This kind of stem cell is known as a multipotent stem cell.

An embryonic stem cell is one that retains the ability to differentiate into virtually any kind of cell. Such cells are considered to be pluripotent—to have retained almost their full potential to become whatever they need to be. Pluripotent cells are more valuable in stem cell research because of this ability.

Embryonic stem cells are cultivated from cells removed from human embryos when they are just three or four days post-fertilization. The cells are then grown in a laboratory dish to be used for research purposes.

The excitement over stem cells comes from their promise to provide insight into the way human cells develop normally, and what happens when they go awry, such as in cancer. In addition, stem cells have the potential to be able to replace diseased or dead tissues in humans, thereby slowing, halting or even reversing any one of a dizzying array of medical conditions, from stroke to Parkinson’s disease.