Unremarkable-looking or no, the colonies of cells I saw that day in Dravid’s lab hold incredible promise: the ability to morph into any tissue type in the body. With the right care and feeding, these cells could become muscle, liver, nerves or anything else. They could eventually replace damaged organs or calm the tremors of Parkinson’s disease. They might explain how cancer develops. Or reveal the mysteries of how a minuscule fertilized egg turns into a walking, talking human being.

All of this isn’t going to happen, of course, in Dravid’s lab. But he is part of an explosion of activity in regenerative medicine that, with the passage of Proposition 71, is epicentered in California. According to the California Stem Cell Report, some 50 established stem cell scientists relocated to the Golden State between January 2005 and August 2007. Dravid, formerly of Johns Hopkins University, is one of them.

USC is a powerful magnet in this westward migration. Childrens Hospital Los Angeles – often called USC’s “third campus” because of its long affiliation with the Keck School of Medicine of USC – is only a part of the equation. The university also is home to the Eli and Edythe Broad Center for Integrative Biology and Stem Cell Research, directed by Martin F. Pera, a recognized pioneer in the development of embryonic stem cells. (Pera, whose current research looks at chemical signals that keep stem cells from differentiating, is another relatively new transplant, coming to USC from Australia’s Monash University almost two years ago.) And over in the School of Dentistry’s Center for Craniofacial Molecular Biology, world-famous researcher Songtao Shi, formerly of the National Institutes of Health, is identifying regenerative cells in everything from baby teeth to adult tendons.

Not all the top USC stem cell researchers are newcomers. Dravid’s research is part of a program run by pediatric hematologist Gay Crooks, who investigates how best to culture and genetically manipulate human embryonic stem cells to combat diseases of the blood and immune system. On USC’s faculty since 1989, she is one of several investigators at Childrens Hospital’s Saban Research Institute who are zeroing in on the cellular miracles taking place inside bone marrow, cord blood, lung, liver and mesenchymal tissue and amniotic fluid.

One of her longtime colleagues is Donald Kohn, leader of the Gene, Immune and Stem Cell Therapy Program at the institute. Kohn, who joined USC in 1987, has created a new type of vector – a virus that can deliver new genes to cells. Kohn’s work has centered on the developing gene therapy for blood cell diseases by “fixing” the broken genes in blood-forming stem cells. He has performed clinical trials of stem cell gene therapy in so-called “bubble babies,” infants born lacking an immune system to protect them from life-threatening infections. He used stem cells from the umbilical cord blood of newborns in his first trial and is using the stem cells from bone marrow in an ongoing study.

And, back on USC’s Health Sciences campus, 20-year Keck School of Medicine veteran David Hinton explores the therapeutic potential of retinal pigment epithelial cell lines.

Together the Keck School and Childrens Hospital Los Angeles already have attracted $24 million in stem cell grants under Prop. 71. (All the physicians and scientists at Childrens Hospital Los Angeles are faculty members at the Keck School.)

To keep the momentum going, in November the university announced the creation of a major research consortium – the Southern California Stem Cell Scientific Collaboration, or SC3 – bringing together the stellar facilities, training programs and experts of USC and Childrens Hospital Los Angeles with those of Caltech, UC Santa Barbara, the City of Hope National Medical Center and the House Ear Institute.

“This collaborative effort now integrates six prestigious institutions to ensure that we are rapidly advancing the science while being good stewards of the resources awarded to us,” says new Keck School dean Carmen Puliafito.

The science isn’t as new as it may seem. Long before stem cells were making a regular appearance on the six o’clock news, they were saving lives. In the late 1950s, doctors started giving bone-marrow transplants to patients with leukemia after aggressive chemotherapy that wiped out the body’s immune system. Inside each dose of spongy-red bone marrow lie millions of “adult” stem cells capable of making a renewable supply of all the body’s different blood components: red blood cells that carry oxygen, white blood cells that fight bacterial and viral invaders, even platelets that stanch blood loss in an injury.

Replacing a person’s own faulty white blood cell supply with a supply renewed by the adult stem cells in bone marrow has successfully treated thousands of leukemia patients as well as a growing number of patients with other blood-related diseases.

Scientists found that bone marrow isn’t the only type of cell factory churning away in the body. Over the years, research has shown that almost every type of tissue contains at least a few adult stem cells. These cells can renew aging tissue that is constantly being sloughed off, such as the surface of the tongue and the lining of the intestines. Or they can take on the task of making brand-new tissue when the existing tissue gets damaged, such as torn skin or broken bones.

Like all stem cells, tissue stem cells have the power to divide indefinitely and the ability to develop into different cell types. But they have limitations. Under normal circumstances, skin stem cells can only make new skin; bone stem cells make only new bone.

“Embryonic” stem cells, on the other hand, are capable of making any human tissue. The ability to manipulate these cells in a lab setting – first accomplished in 1998 – has prompted many scientists to rethink the very idea of treating disease.

“Stem cells have led to a revolution in thinking about how we should approach disorders ranging from cancer to birth defects to problems that require replacement of dead or damaged tissue,” says Pera.

The almost-limitless potential of embryonic stem cells, however, comes with a catch. They’re found in just one place – growing inside a blastocyst, the hollow ball of cells formed four to five days after a woman’s egg is fertilized. The simplest way to harvest the 70 to 100 stem cells within the blastocyst is to destroy it. For people who believe an embryo is akin to any other human tissue used and discarded in research labs, there’s no ethical problem. For those who believe life begins at conception, harvesting stem cells borders precariously on taking a human life.

(In mid-November 2007, scientists in Japan and at the University of Wisconsin announced that they had come up with an alternative method of developing embryonic stem cells by reprogramming human skin cells. This is a breakthrough, but not yet a total solution. Since viruses are used to insert genes into the cells, some scientists fear unwelcome mutations could be created.)

To tackle the ethical questions raised by the use of embryonic stem cells, President George W. Bush announced a set of guidelines in 2001 limiting grants from the National Institutes of Health for research involving only groups of embryonic stem cells, or cell lines, that already had been cultured.

“I have concluded,” Bush said at the time, “that we should allow federal funds to be used for research on these existing stem cell lines, where the life-and-death decision has already been made.”

Yet those cells come with a host of problems. Grown using primitive (by today’s standard) methods requiring continuous direct contact with supporting mouse cells, all these pre-existing lines have been contaminated with mouse proteins and may contain disease-causing agents. And their numbers are dwindling. The more the cells grow and divide, the more health and genetic problems they accrue. 

By November 2004, it was clear only a fraction of the 60-odd cell lines approved for NIH-funded research were viable. For research institutions around the country, it was a time of dread. Would American stem cell scientists bolt to Europe or Asia, where no such restrictions hampered their efforts? In California, though, research universities were rejoicing: Prop. 71 had passed.

The ballot measure authorized the sale of $3 billion in state bonds over 10 years to fund stem cell research and to build new research facilities. Although this money could finance all kinds of stem cell research, Prop. 71 gave priority to research on human embryonic stem cells – assuring scientists in the Golden State the financial means to bypass NIH funding restrictions.

The ballot initiative established the California Institute for Regenerative Medicine (CIRM), an independent agency to review research proposals and award grants. Cancer researcher Brian Henderson, the Keck School’s dean at the time, joined CIRM’s board immediately. Soon after, the board recruited Keck neuroscientist Zach Hall as its first president. At the time, Hall was the medical school’s top academic recruiter and director of its Zilkha Neurogenetic Institute.

Inside USC, more subtle changes were under way. According to Rob Maxson, director of the Transgenic/Knockout Mouse Core Facility at the USC/Norris Comprehensive Cancer Center, USC had few “card-carrying” stem cell biologists at the time. But with $3 billion in CIRM funds on the table, researchers in closely related disciplines were ready and willing to retool.

“We have always had a good group of developmental biologists here, and by definition that involves stem cells,” says Maxson, a professor of biochemistry and molecular biology. The school set about redefining “the way we presented ourselves to the world.”

The only thing missing now was a leader – someone with the clout and connections to pull together USC’s disparate stem cell assets into a unified, world-class program. By organizing the first-ever CIRM conference in March 2005, Henderson and other senior leaders arranged for likely candidates to come to them. They invited the best minds in the field to USC for a two-day symposium. Researchers from around the globe gave talks, attended poster sessions and schmoozed at social mixers. Several months later, USC asked Martin Pera to lead its stem cell efforts.

The Australia-based scientist didn’t hesitate. “It was too attractive an opportunity to pass up,” recalls Pera. “I think California is going to be one of the world’s centers for this type of work because of the commitment of the state,” he predicted shortly after his appointment. “And USC’s commitment to stem cell research is certainly strong and impressive. This was the right time and the right place for me to take on this new challenge.”

Pera certainly has the clout and connections to make it so. Back in the 1990s, he was among the first to propose developing embryonic stem cells directly from unused in vitro fertilization human embryos. Originally a cancer researcher, Pera had discovered – a decade earlier at Oxford – stem cells in tissue taken from patients with testicular tumors. “Our whole concept of the embryonic stem cell came from a study of cancers in mice,” he explains.

Within weeks of moving from Australia, where he had spent the last 20 years at Monash University, to his new home in Los Angeles, Pera started the process of recruiting scientists to USC’s burgeoning stem cell center. To date, he has hired eight stem cell researchers, the most recent being Krzysztof Kobielak, who arrived in the fall of 2007 from Rockefeller University with a focus on the microenvironment that controls the stem cells of the hair and skin; and Gregor Adams, most recently of Harvard University, who studies the regulation of stem cells that produce red blood cells, white blood cells and platelets. Pera plans to recruit 10 more researchers in the near future.

With a world-class leader in place and a fast-growing roster of new researchers, USC lacked only the necessary facilities. Eli and Edythe Broad stepped up to the plate. Last year their philanthropic organization, the Los Angeles-based Broad Foundation, pledged $25 million to USC’s new stem cell program.

Along with a $7 million grant from the Keck Foundation and $2 million in university funds, USC had enough to begin planning an $83 million four-story, 80,000-square-foot structure to house its stem cell researchers. Construction of the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC is set to begin later this year on San Pablo Street, at the heart of the Health Sciences campus. Last summer, CIRM had awarded an additional $6.4 million to construct stem cell research labs in the Smith Research Tower of Childrens Hospital Los Angeles and in the new Harlyne J. Norris Cancer Research Tower of the Keck School.

While Pera was busy recruiting scientists and raising funds for the stem cell center’s infrastructure, Maxson was putting together a CIRM grant proposal for a series of classes – one preparing students and fellows to work with stem cells, a second covering the ethical considerations surrounding stem cell research. When the $3.16 million CIRM training grant was awarded, the Keck School tapped Cheng-Ming Chuong, a USC developmental biologist in the Department of Pathology, to implement the first class. A multi-campus effort delivered by Webcast, it featured instructors and students at the Keck School, Childrens Hospital Los Angeles and Caltech, with lectures originating from and delivered to all three campus locations.

“It was a unique opportunity to integrate all of us into one course,” says Chuong of the first course, which offers expertise in the fields of reproductive biology, tissue engineering and medicine. The ethics class, he adds, will be up and running later this year. 

As for USC’s stem cell researchers, old and new, they have been busier than ever doing what they do best. In the case of Gay Crooks, this means studying the blood-forming stem cells that treat patients with leukemia and other hematological and immune diseases. The Australian-born physician and scientist, whose career path brought her to Childrens Hospital Los Angeles 18 years ago, started out studying how best to transfer these stem cells from donors to patients. She soon found that the cells themselves made fascinating research subjects.

Over the years, Crooks’ research program has grown and changed. Now director of the Childrens Hospital Los Angeles Stem Cell Project, her focus lies in two different areas. The first involves adult stem cells that have already headed down the one-way developmental path to becoming immune cells.

Though these cells can be lifesavers when transplanted into patients with leukemia and other disorders, there remains much room for improvement. Before the cells can engraft, or permanently settle into their new hosts, doctors must wipe out a patient’s native bone marrow and immune system, Crooks says. For weeks or months after a bone marrow transplant, the new cells must slowly divide and rebuild the immune system. The transition can leave an already-weakened patient unable to rally against deadly infections.

In a recent experiment, Crooks and Donald Kohn collected immune-forming stem cells and inserted a gene that has the power to make cells divide significantly faster. The gene can toggle on and off. Early results show that when the gene is turned on, the cells multiply much faster than cells in which the gene is turned off.

“Immune reconstitution is a major problem we’re facing with this type of stem cell transplant,” says Crooks. “This study suggests that there are ways to manipulate stem cells to get them to help patients faster.” Eventually, inserting the gene into stem cells destined for transplants could fix the problem of immune reconstitution.

In a second project, Crooks is working with Gautam Dravid, the Childrens Hospital postdoctoral fellow who let me peek at embryonic stem cells under his microscope. Dravid and Crooks hope to mold embryonic stem cells into the more-targeted stem cells that make blood. Other researchers have successfully coaxed embryonic stem cells to make blood, but “no one has been able to prove that you can make an adult stem cell from an embryonic stem cell,” says Crooks. The scientists are using the blood-making system as a model to learn how to guide embryonic cells down the pathway to more-targeted stem cell types.

Team members are using several of the NIH-approved lines of pre-existing cells right now. But after receiving a $2.5 million grant from CIRM earlier this year, they plan to expand their work to new lines of embryonic stem cells.

A CIRM grant also is making a difference in the work of Keck School molecular biologist Peter Laird. An expert in epigenetics – or gene silencing – Laird landed part of a $3.4 million grant last year for his cancer-related stem cell research. Based at the USC/Norris Comprehensive Cancer Center since 1996, Laird got his scientific training in the Netherlands and later at the Whitehead Institute in Cambridge, Mass. Early in his career, he became interested in how changes to a cell’s DNA might spur it to become cancerous. He and other researchers eventually showed that methyl groups – chemical groups that clip onto strings of DNA like charms on a bracelet – seem to bind to particular common genes in cancerous cells. Once a methyl group binds to a gene, the gene is usually permanently switched off – or silenced.

Many of these genes appear to play a direct role in why cells turn malignant. For example, genes that can protect a cell from cancer are frequently tagged by methyl groups. Laird’s work has revealed that genes that seem to have no relation to cancer are also commonly methylated. For example, a gene called MYOD1, which determines whether a cell becomes muscle during early development, frequently carries a methyl mark in colon cancer cells.

A paper recently published by old colleagues from the Whitehead Institute proved inspirational to Laird for solving this conundrum. It suggested that proteins called “polycombs” are responsible for keeping some genes in stem cells poised for action, ready to permanently turn on or off at any time. Stem cells that eventually become muscle, for example, gradually and permanently turn on genes that make muscle proteins and turn off genes that make proteins for nerves, bone and other tissues. 

Laird had an inkling that these polycomb proteins might relate to the unusual methyl patterns in the DNA of cancer cells. When he examined which genes are affected by polycomb proteins, he found they’re often the same ones that carry methyl tags in malignant cells. His theory, published earlier this year, is that the important developmental genes affected by polycomb proteins are unusually susceptible to picking up methyl tags even after cells reach a mature stage.

While turning off particular genes in development might be a boon, it could later become a liability. “This cell becomes a rogue cell, a ticking time bomb,” says Laird. “It’s in a perpetual state of renewal and can’t grow up. We think these are the cells predisposed to becoming cancer.”

Laird plans to keep investigating the similarities between stem and cancer cells in the years to come. Last October, his efforts, and those of other USC researchers, got a significant boost when the Kenneth T. and Eileen L. Norris Foundation earmarked a $10 million gift for the creation of the USC Epigenome Center.

While many USC-based projects are still far from reaching patients, David Hinton’s work is inching closer. A professor of pathology, neurosurgery and ophthalmology at the Keck School, Hinton studies how embryonic stem cells might be used to treat macular degeneration. A CIRM grant awarded in February 2007 supports his current research.

The most common cause of blindness in Americans over 60, advanced macular degeneration afflicts an estimated 1.75 million people in this country. As part of the retina needed for sharp, central vision deteriorates, the patient gradually loses the ability to drive, read or recognize faces easily.

One form of the disease is associated with growth of blood vessels under the retina; treatments for this form have improved patients’ vision. However, no effective treatment exists for the more common, dry form of macular degeneration. Hinton is hoping that embryonic stem cells might change that.

Previous research has shown that before the macula degenerates, cells that support the retina – called retinal pigment epithelium, or RPE, cells – die off. If clinicians could replace these cells, Hinton hypothesizes, a patient’s vision might be saved.

He is currently searching for the right conditions to grow embryonic stem cells that can create large numbers of pure RPE cells. He and his team, including co-investigator Rajat Agrawal, an assistant professor of ophthalmology research, and Danhong Zhu, a postdoctoral fellow, have had some success in growing the cells. The researchers now are working to optimize their method. Eventually, Hinton says, he and his colleagues plan to implant the cells in blinded rats and rabbits to see if they can affect vision. Human trials may not be far behind.

Other winners from the last round of CIRM grant awards include new hires Qi-Long Ying (from the University of Edinburgh) and Wange Lu (from the lab of Caltech Nobelist David Baltimore), both of whom study the mechanisms of embryonic stem cell proliferation and differentiation.

And the ranks of promising USC stem cell scientists just keep swelling. There’s Michael Kahn, an  interdisciplinary senior scientist who holds the newly created title of Provost’s Professor of Medicine and Pharmacy. Recently recruited from the University of Washington, Kahn is a leader in the emerging field of chemical genomics. He uses small molecules to probe cell regulatory networks, resulting in compounds that can direct stem cell differentiation. There is also Songtao Shi PhD ’96, a brilliant NIH scientist who was recruited back to his alma mater last year after winning acclaim in 2003 for discovering a new source of adult stem cells in children’s primary teeth. Now on the faculty at the School of Dentistry’s Center for Craniofacial Molecular Biology, Shi broke new ground again last fall identifying unique cells within adult tendons that have stem-cell characteristics – including the ability to proliferate and self-renew. The findings hold tremendous promise for the treatment of tendon injuries caused by overuse and trauma.

When the last round of CIRM awards was announced in mid-December, no one was terribly surprised to see Shi’s name on the list. His $3.25 million grant focuses on a stem cell-based repair for major orofacial defects.

Christen Brownlee is a science writer based in Baltimore. This is her first story for USC Trojan Family Magazine.

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