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NIGMS Hosts Workshop on Basic Biology of Stem Cells

By Alison Davis

In many ways, the most pressing problem facing the field of stem cell research is the same question biologists have been asking for years. What basic properties inside cells make them behave the way they do?

True, stem cells are unique in having the ability to choose between making exact copies of themselves or developing into any type of cell in the body. However, they possess much of the same molecular machinery as do cells that have "decided" what tissue type to become.

"All problems in stem cell biology are problems of basic biology," said Dr. Margaret Goodell of Baylor College of Medicine, who studies adult stem cells in muscle and blood, and who spoke at a recent NIGMS-sponsored workshop on the basic biology of mammalian stem cells. The June 9-10 meeting, organized by Dr. Judith Greenberg, acting director of NIGMS, was intended to stimulate thought and discussion between basic scientists and stem cell biologists and identify areas in need of further research.

Endless Questions

Greenberg kicked off the meeting by posing a few seemingly simple, but still unanswered, questions about stem cells. Among them:

"What mechanisms keep stem cells in an undifferentiated state? Is there a unique complement of genes expressed in embryonic stem cells? Do all embryonic stem cell lines have the same properties? How do embryonic stem cells differ from adult stem cells?"

"The questions are endless," Greenberg said, "but the answers are essential if we are to rationally manipulate embryonic and adult stem cells for therapeutic uses."

"The questions are endless," said Dr. Judith Greenberg, acting director of NIGMS.

Greenberg, who is also director of the NIGMS Division of Genetics and Developmental Biology, conceived the idea to hold a meeting to bring together stem cell biologists and basic biologists, including scientists working with model organisms such as roundworms and fruit flies. The workshop, and the discussion that followed, brought one important message to the fore: Scientists working in many disciplines need to get together to move the promising field of stem cell biology forward. Anticipated benefits include improved experimental systems for fundamental biological studies about health, potential tools for drug discovery and testing, and potential sources for transplantation therapies.

"It's an incredibly multidisciplinary area," said Dr. James Thomson of the Wisconsin Regional Primate Research Center of the University of Wisconsin, encouraging biologists and other biomedical researchers to think together about research problems. A pioneer in studies of embryonic stem cells and one of the workshop's co-chairs, he gave the first keynote address, updating the audience on the field of stem cell research.

Culture Shock

Hard work from all sorts of biologists, chemists, and even engineers, physicists and computer scientists is especially needed for one particular task that has not been easy to accomplish: figuring out how to get finicky stem cells to grow well in the lab. Scientists have had great difficulty culturing stem cells efficiently and reliably, and this has caused a bottleneck in the field.

What's especially challenging, veteran stem cell researchers say, is getting stem cells not to change, or differentiate, into other cell types.

"It takes someone who is trying to think like these cells," said NIGMS grantee Dr. Marc Kirschner. (Photo: Stu Rosner)

In a half-day discussion session that followed the meeting, Harvard University cell biologist Dr. Marc Kirschner said that taking steps to learn how to culture stem cells systematically has great potential to make stem cells an attractive model system for probing basic biology. "Low-tech" research is what's needed, he said, referring to the labor-intensive process of determining workable culture conditions in which stem cells can thrive while staying undifferentiated, or pluripotent. Doing so requires getting well-trained senior scientists to work out those difficult issues.

"It takes someone who's trying to think like these cells," said Kirschner.

He delivered a second keynote talk on some of the ways basic biology underlies stem cell research. According to Kirschner, by focusing on the characteristics unique to multi-celled organisms (metazoans), scientists may be able to unveil some of the secrets of stem cells, such as how cells make choices to become different, forming biological compartments such as tissues, and how and why some tissue types (like skin) can regenerate, whereas others (like the brain) cannot.

Back to Basics

"We need to better understand the molecular logic of developmental plasticity," said Dr. Kenneth Zaret of Fox Chase Cancer Center, who also co-chaired the workshop. His research examines cellular communication events that lead to development of the liver and pancreas. Advances in stem cell biology can enhance basic science, Zaret said, by leading to better experimental systems.

Cells' molecular logic drives many important cellular processes: the cell cycle, transcription, genomic imprinting, and chromosome structure and function, to name just a few. Dr. Richard Young of the Whitehead Institute for Biomedical Research spoke about his efforts to understand transcriptional regulatory networks — a dynamic form of measuring gene activity — in living cells.

He discussed his recent studies aimed at understanding how cell-wide control of gene activity can weave together the many different functions in cells. That's especially important because scientists are becoming increasingly aware that cellular processes do not take place independently of each other. A major challenge to understanding cell behavior — for stem cells or any cells — rests with piecing together data obtained from separate processes into a meaningful context.

According to Young, an important step in meeting such challenges will be to train a new generation of scientists who can attack biological problems using computer-based methods.

"It's extraordinarily valuable to co-mentor students in computer science and biology," he said, "so they can feel comfortable in both environments."

Several workshop speakers discussed ongoing fundamental research aimed at understanding how chromatin, the complicated packaging system that keeps DNA wound inside chromosomes, plays important roles in regulating gene activity. Some of this control, said Dr. Timothy Bestor of Columbia University, may have a major impact on stem cell-related research. For example, he hypothesized, the poor success rates and severe growth abnormalities observed in cloned animals may be caused by incorrect "marking" of DNA in chromatin at early stages of development.

Future Therapies?

Other speakers discussed more applied aspects of stem cell biology. Dr. Pamela Gehron Robey of NIDCR presented experiments in which she has identified skeletal stem cells, some of which have the ability to make bone, circulating in blood. She described the extreme plasticity of these adult stem cells with regard to their ability to change back and forth between bone and fat tissue.

Dr. Ron McKay of NINDS addressed the promise of pluripotent stem cell research to advance knowledge in diseases of the nervous system, such as Parkinson's disease. He presented results showing that midbrain stem cells can generate functional, dopamine-producing neurons.

Dr. James Thomson encouraged biomedical researchers to work collaboratively in the area of stem cell research. (Photo: Jeff Miller)

One prediction echoed by many workshop speakers, including McKay, is that studying stem cells will have a profound future influence on medicine. Indeed, embryonic stem cells have the ability not only to make identical copies of themselves, but also to become anything in the body. These properties make them tantalizing as possible therapies to treat many ravaging human diseases.

But Thomson stressed that such therapies may not arrive soon, citing "astronomical" costs in obtaining sufficient numbers of cells required for patient-specific therapy, as well as weighty challenges in evaluating the benefits and risks of treating diseases, especially chronic disorders such as diabetes.

It seems that for the foreseeable future, embryonic and adult stem cells hold great promise in serving as increasingly important model systems to study fundamental biological problems. According to Thomson, since stem cells are so-called "primary" cultures, they offer an advantage over using cell lines, which by nature have altered growth properties or problems with their chromosomes. Also, Thomson added, access to primary tissue isn't always the best option for studying normal human biology, with cultures often being derived from diseased or damaged human tissues.

Another exciting use for stem cells may be as an important model system for drug discovery and testing. Thomson and others predicted that this particular use of stem cells may partially obviate the need to use research animals in drug toxicity studies.

For summaries of all the speakers' talks and general discussion topics from the meeting, visit http://www.nigms.nih.gov/stemcellworkshop/.


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