The Secret Life of Stem Cells

By Eric Sauter

Jeanne Loring, the new director of the Center for Regenerative Medicine at The Scripps Research Institute, spent Christmas in Antarctica, a place she had dreamed of going for a long time, and a place far away from the world of embryonic stem cells and research on how they might be used as therapies for disease.

She is energetic and straight-to-the-point, talking in whole paragraphs punctuated by the occasional colloquialism.

"Ever since I was a grad student I believed that scientists have to be responsible to the public.  I wanted my research to have an impact on human disease," she said. "That's why I jumped to biotech early in my career."

Loring, who joined Scripps Research last year, has had a broad career in science. With a degree in molecular biology and a Ph.D. in developmental neurobiology, she was on the faculty of the University of California, Davis, and has held research and management positions at biotechnology companies including Hana Biologics, GenPharm International, and Incyte Genomics. She also serves as director of  a National Institutes of Health (NIH) Human Embryonic Stem Cell Training Course.

Loring's drive to make a difference in human disease helps explain why she has immersed herself in the field of embryonic stem cells. There are certain things that have a huge impact in science and medicine—the development of penicillin, the polio vaccine, the human genome project… The next wave, Loring believes, is the rise of embryonic stem cells. For Loring, it's nothing less than the beginning of a new era.

"I think we are at the end of the beginning of stem cell research as a scientific discipline," she said, trying to put the relatively new science into a historical context. "We have a critical mass now. In 2001, when the NIH was looking around for people who were working on human embryonic stem cells, there were just a handful of us, and we didn't know each other.  Just seven years later, the research has become mainstream, and both the NIH and [the State of] California have invested in the future of stem cell research."

Hidden Changes

Loring's own research has been focused on epigenetics—hidden changes in genes not involving a change in the basic DNA sequence itself.

As the BBC recently described it in a report provocatively entitled The Ghost in Your Genes: "At the heart of this new field is a simple but contentious idea—that genes have a 'memory'… Epigenetics adds a whole new layer to genes beyond the DNA. It proposes a control system of 'switches' that turn genes on or off—and suggests that things people experience, like nutrition and stress, can control these switches and cause heritable effects in humans."

Loring calls epigenetics "the secret life of stem cells" and is determined to unlock those secrets: "I want to understand what makes stem cells tick, to figure out why they are different from other cells and what that means."

Loring has her eye on one area in particular.

"We all know that DNA contains genes that code for proteins. But DNA codes for other molecules, like microRNAs, which don't code for proteins. These tiny bits of RNA are powerful. A microRNA can be like a conductor of an orchestra, coordinating the activities of a suite of different genes all at once."

Loring has found unique complements of microRNAs in human embryonic stem cells and believes that they may be key to the pluripotent state—the ability of stem cells to become all of the cell types in the human body.

"We think that a balance of several elements, each with the power to regulate some aspect of a cell's biological machinery, keeps stem cells pluripotent. Imagine that pluripotent cells are balls in a pinball machine, being kept in play by multiple flippers, bouncing in and out of the slots. MicroRNAs and other epigenetic influences are the flippers—when one fails, another compensates, so the cells remain pluripotent. Cells lose pluripotence when the regulatory balance fails, and what they become—nerve cells, muscle cells, blood cells—depends on the direction in which they fall out of the balance, which way they were last 'flipped.'"

In her laboratory, Loring leans towards using a combination of epigenetic factors—DNA methylation, DNA-binding molecules, and microRNA to control the development of embryonic stems cells. She believes that a shift in the balance of these factors in embryonic stem cells can drive them to become the cell type that she wants them to become. This rebalancing approach is also the basis for her work toward turning skin cells into pluripotent cells that can then be turned into any cell type in the body. "This is going to work", she says. "The question of success is no longer 'if,' but 'when'."

"I think in another decade we will see the medical applications of the basic research now being done with stem cells," she said. "But I don't think we should think of stem cells as some sort of miracle drug. Stem cells will be like any other drug or therapy—with successes and failures."

Patent Rights

The other side of Loring's desire to make a difference has been her public battle with the Wisconsin Alumni Research Foundation (WARF) over three patents that grew out of studies conducted at the University of Wisconsin in the 1990s, patents that gave the foundation a virtual lock on human embryonic stem cell lines.

Driven by a desire to promote future research, Loring joined with Dan Ravicher, an attorney who founded the Public Patent Foundation in New York and John Simpson of the Foundation for Taxpayer and Consumer Rights in Santa Monica, California. Together, in July 2006, they formally challenged WARF's patents, asking that they be re-examined. 

In 2007 the patent office finished that re-examination and rejected the three patents. WARF appealed the ruling and, in a decision last week, two of the three patents were upheld in a final determination. The third patent was also upheld, but can be appealed.

"We do need patents to protect inventions, but we have to make sure the patent system doesn't actually interfere with our mission," she said. "For a scientist, challenging a patent is like grassroots politics—thinking globally, acting locally. If I can get people interested in making changes in the patent system then I feel I've accomplished something."

While mounting the challenge took a year of work, Loring has no regrets. "The confrontation energized me," Loring said. "Besides, in my scientific career, I spend a lot of time forging collaborations and reading the scientific literature. Patents have become another source of valuable scientific information for me and I read them along with the usual scientific literature. I talk to patent attorneys and ethicists about patent policy, just as I discuss research direction with my scientific colleagues. It's part of the same package for me."

The Future Is Now

Part of that package for Loring has also been helping to shape public policy on stem cells. Last year she flew to Washington to give a personal lesson in stem cell biology to key members of the US legislature. She's hosted California Governor Arnold Schwarzenegger in her laboratory and shown him embryonic stem cells through her microscope. Last summer, Loring chaired an NIH workshop that focused on the development of a blueprint for the use of embryonic stem cells. "Our goal is to see whether we can integrate stem cells into conventional medicine," she said. "We no longer feel trapped by the idea that stem cells are only good for transplantation. For example, we are exploring the use of stem cells as delivery vehicles—as a way to deliver growth factors to the brain."

Loring has another workshop coming early in May to discuss how to use embryonic stem cells in the NIH Roadmap—a program of overlapping research programs that the NIH wants to prioritize.

Loring is ahead of the curve thinking about these questions, and that, she notes, is what brought her to Scripps Research.

"The best thing about stem cell research for me is that it brings a fresh perspective to many different areas of research," she said. "Scripps has superb research programs, such as those in medicinal chemistry and high throughput screening. Because Scripps Research has a tradition of being on the cutting edge of research, the institute's scientists are always ready to explore the next big thing. And, I believe that the next big thing is stem cells."

Send comments to: mikaono[at]scripps.edu

"I wanted my research to have an impact on human disease," says Professor Jeanne Loring.