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Miracles in the Making

By Mary Daily

Published Jan 1, 2011 8:00 AM

Take a dynamic and inclusive leader. Add a visionary benefactor and a multidisciplinary team of dedicated, brilliant scientists. Mix well. What do you have? Potentially life-changing and eventually lifesaving science in the form of UCLA's Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, which in only a few short years can claim a long — and rapidly growing — string of breakthroughs.

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A single hESC (human embryonic stem cell), highly magnified. Image courtesy of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research.

 

Science went into high gear in 2005.

Breakthroughs were made in cell signaling, the study of how the earth was formed, plant science, brain wiring and many other areas.

"The most earthlike planet yet found outside the solar system" was discovered, according to the National Science Foundation (NSF). A 10th planet also was found in our own solar system (but Pluto, alas, was demoted to just a very large rock).

So great was the pace of inquiry in 2005 that NSF declared it "another banner year for science research." But something else happened in science that year that promises — indeed, has already begun — to reap extraordinary dividends, and at a blistering pace.

In 2005, UCLA launched a stem cell program, now known as the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. Led by a scientist celebrated for his mentoring as well as his science, the all-star team of medical researchers who collectively comprise the Broad Center has accumulated an impressive — and growing — number of breakthroughs in the cutting-edge field of stem cell research in just a little more than half a decade.

If you or a loved one suffers from any of a host of fatal diseases, the Broad Center is where you may find a fighting chance for a normal life.

And just maybe, someday, a cure.

Run, Don't Walk

Stem cells are special because they can renew themselves, but only embryonic stem (ES) cells have the natural ability to develop into most cell types — and help fight a long list of diseases and afflictions. They are pluripotent. By contrast, adult stem cells are tissue-specific and can only duplicate themselves, so their usefulness in disease fighting is, at best, limited.

Scientists began to unleash the magic of this science in 1981, deriving stem cells from early mouse embryos. This led to the discovery, in 1998, of a way to derive stem cells from human embryos and grow them in the lab. The stage was set to move regenerative medicine into the 21st century.

UCLA's stem cell research program hit the ground running in 2005 with the launch of what was originally called the Institute for Stem Cell Biology and Medicine.

A collaboration between the David Geffen School of Medicine at UCLA, the Jonsson Cancer Center, the UCLA Henry Samueli School of Engineering and Applied Science, and the UCLA College of Letters and Science, the new institute was backed with a $20-million commitment from the university over five years. The money would fund the pursuit of federal and state grants, including resources created by the passage of Proposition 71 as well as private funding, recruitment of a dozen new faculty positions, salaries, expansion of highly sophisticated laboratory space, infrastructure and advanced technologies.

To lead the new entity, the university named Dr. Owen Witte, UCLA professor of microbiology, immunology and molecular genetics, Howard Hughes Medical Institute investigator and a renowned scientist — whose laboratory research laid the groundwork for development of the targeted leukemia therapy Gleevec — as founding director.

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Image provided by the Broad Stem Cell Research Center.

Witte wasted no time, quickly building a community of scholars, scientists and researchers in fields as diverse as engineering and molecular biology, who collaborate to attack problems none of them could solve alone.

Then, in 2007, a scientist's dream came true: Los Angeles philanthropists Edythe and Eli Broad donated another $20 million to the center, not for bricks and mortar but for research, and the institute was renamed the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. The gift "has given us a tremendous amount of flexible resource to try out ideas without wading through the torturous cycle of research grants," Witte says.

In its short but fast-paced life, the Broad Stem Cell Research Center has become a major player in advancing stem cell science. UCLA has received grants to study HIV, neural repair, immune response, melanoma, blood development, cancer, stroke, sickle cell disease and age-related macular degeneration, among others.

Today, the center is the state's second-highest recipient of California Institute of Regenerative Medicine (CIRM) research grants in the field. Most recently, in October and November, California's state stem cell agency awarded $12 million to five Broad Center researchers to explore new and more effective therapies to regenerate bone, target deadly brain cancers, treat patients with spinal cord injury, and treat corneal disorders that result in blindness. The center also leads the state in funding for training predoctoral, postdoctoral and clinical fellows in stem cell science.

Four Genes Equal One Breakthrough

The most hopeful expectations lie in regenerative medicine — the creation of healthy cells to replace damaged or destroyed ones.

"It's the ability to remake what is damaged and replace what is lost," Witte explains, calling regenerative medicine "a game changer ... We're pushing the envelope because we know we can make a difference."

He cites Alzheimer's, Parkinson's and heart diseases as among those that lend themselves to this type of therapy.

But politics has roiled the lab for as long as there has been stem cell science. The use of human ES cells remains a political flashpoint, with controversy constantly impinging on the science and limiting researchers' access to human ES cells (most recently in August, when a federal judge blocked President Barack Obama's 2009 executive order expanding human ES cell research). So it has long been clear that a viable alternative was needed to keep the science moving.

The answer began to emerge in 2006, when a researcher in Kyoto, Japan, inserted into the genome of adult mouse skin cells four genes that are typically highly expressed in embryonic stem cells. The result was induced pluripotent stem cells, or iPS cells, which are highly similar to ES cells. Here was the viable alternative — and here again, UCLA would play a pivotal role.

At about the same time as the Japanese researchers were making their discovery, biochemist Kathrin Plath and molecular and cellular biologist Bill Lowry joined Witte's team.

Plath, who grew up in Germany, attended Harvard Medical School and, following postdocs at MIT and UC San Francisco, joined the faculty of UCLA's medical school.

Lowry, from Seattle, attended the University of Washington and the Weill Cornell Graduate School of Medical Sciences in New York, where he studied how cells communicate with one another, called cell signaling. At Rockefeller University, his postdoctoral studies focused on how stem cells translate signals from their environment into a coherent response. Now, on UCLA's life sciences faculty in the College of Letters & Science, Lowry teaches undergraduates in addition to running his lab.

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Image provided the Broad Stem Cell Research Center.

Building on the Japanese discovery, Plath and Lowry — through several attempts — made a huge breakthrough: By using the same four genes, they produced iPS cells from an adult human skin cell. It was a seminal leap in regenerative medicine.

"If we can take a skin cell back into an embryonic state," Plath explains, "we can override what was set up in development."

Plath and Lowry were the first in California to make the discovery, and it would not have been possible without first knowing how to successfully grow human ES cells in the lab.

The team has now created about 50 iPS lines for future use.

All Together Now

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Image provided by the Broad Stem Cell Research Center.

In the Biomedical Sciences Research Building, Lowry's lab is one floor above Plath's, and the two scientists talk by phone several times a day, while the postdocs, students and technicians in their labs run up and down the stairs consulting one another.

"For the initial reprogramming experiments, Kathrin and I were side by side at the bench," Lowry says, "but since then it's been more like they'll generate one piece of the puzzle and give it to us and we do the next step and then hand it over to someone else. We work together to mutual benefit."

Steven Peckman, the center's associate director for administration and planning, underscores that it also helps that the Broad scientists work "in a university environment, where collaboration is highly sought and encouraged."

Indeed, the researchers regularly turn to other colleagues with different expertise. "If we have questions, they help us immediately," Plath notes.

And these collaborations extend to engineering, medicine, life sciences, law and the CNSI (California NanoSystems Institute), which houses the most powerful microscope on campus.

The result is exactly what Witte envisioned. From the start, he knew the team would need chemists, physicists, engineers, philosophers and lawyers. "The entire campus was the fuel to build the center," he says.

And, noting the entire university's collective history in advancing medical knowledge in the field, Witte adds, "The number of things [UCLA] has taken from concept into clinical trials is remarkable for the short time we've been doing it."

That movement of discoveries into clinical evaluation — closer to actually helping patients — is the center's overarching goal.

Nowhere is the bench-to-bedside connection more seamless than in the work of Arnold Chin, a urological surgeon in his second year of medical practice and another of Witte's wunderkinds.

Chin, who is studying how to modify the immune system to fight bladder cancer, believes he can selectively identify the cell populations in individual cancer patients and test them for sensitivities to chemotherapies before the drugs are administered to the body. This would decrease damage to healthy cells and save valuable treatment time.

In caring for patients, Chin literally touches the desperate need for regenerative medicine and the urgency to find solutions. "We see the suffering and how treatments don't always work and delays occur," he says. "That points us to the problems."

From his surgeries, he has access, with patients' consent, to clinical material for study. Information flows both ways.

A huge UCLA advantage is that "the hospital's right next door," says Chin, sitting in scrubs in his office in the MacDonald Medical Research Laboratory Building and looking much younger than his 37 years. "This morning I made rounds, saw a patient in the clinic, met with people working on a research project and am headed into surgery — all before noon."

Chin joined the medical school faculty last year after earning a UCLA M.D./Ph.D. in 2003. Raised in Palo Alto, he volunteered in a hospital as a teenager and earned his undergraduate degree at Princeton. When he interviewed for medical school at UCLA, Witte was the first person he talked to.

In Chin's Ph.D. program, Witte served on his doctoral committee, and he has remained supportive. "I think he wanted me to have this opportunity to interact with more senior scientists," Chin says of his work with the center.

All the young scientists praise Witte as a leader and mentor. "He takes input, and lots of decisions are made together, but things get done," notes Lowry, who came to UCLA in part because "there wasn't just a collection of people who wanted to do stem cell research; there was an infrastructure and a system. Most of that is a credit to Owen."

Building a Better Future

"Embryonic stem cells remain the gold standard by which we test everything," Peckman says, and the derivation of human ES cells is an important area of research at UCLA. Yet the ability to produce human iPS cells has thrown open the doors to the future and heightened excitement among the center scientists — many of whom, not surprisingly, are also gourmet cooks, wizards in the kitchen who love to experiment.

In the lab, they study iPS cells in a dish and, by varying the recipe of the media in the dish, coax the cells into any desired cell type. In the dish, they also watch the development of disease and test the cells' response to pharmaceuticals. These patient-specific, disease-specific cells provide very fertile ground for further work.

No one is more thrilled about this than assistant professor and Broad team member Amander Clark, who studies the causes of infertility. She has converted iPS cells into the precursors to eggs and sperm, where the cells' relationship to the donor is an enormous advantage.

A soft-spoken Australian, Clark completed her Ph.D. at the University of Melbourne before postdocs at Baylor College of Medicine and UC San Francisco. Witte's vision drew her to UCLA because it aligned closely to her hopes for her own career. And it didn't hurt that Los Angeles reminded her of Melbourne. Like Lowry, she teaches undergraduates in the College of Letters & Science.

Clark and her colleagues have generated six ES lines, from which they are learning "the very first steps in how pluripotent stem cell lines are created," she explains.

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Image provided by the Broad Stem Cell Research Center.

A major milestone for the center was the acceptance of three of the ES lines into the National Institutes of Health (NIH) Human Embryonic Stem Cell Registry, allowing them to be used in federally funded research projects and increasing the diversity of cell lines available for study. UCLA's ES lines, along with 13 iPS lines created by Plath and Lowry's team, are in storage on campus, available for research to faculty who meet specific ethics and review standards.

No one can predict precisely what else these intrepid medical scientists will achieve in the future, of course, but given the speed with which they work and the advances they have already made, they may soon be able to offer even the sickest patients a fighting chance.

New planets and plant science may have dominated the science headlines in 2005. But tomorrow, it may very well be Broad Stem Cell Research Center breakthroughs that grab the headlines — and offer hope and help for those who suffer from the deadliest diseases.

As Bill Lowry says: "I can't think of anything that's out of the realm of possibility."

Or more important.