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Rewriting Life

Turning Stem Cells into Tissues

Scientists are learning how to control the two unique properties of stem cells.

The most eagerly anticipated therapeutic use for stem cells is regenerative medicine. Biologists dream of the day they can take a stem cell and create any of the body’s cell types, producing pancreas or liver tissue that doctors could use to aid a failing organ.

But to realize that dream, scientists must first understand the forces operating in stem cells – what makes some stem cells stay stem cells, while others grow into brain, liver, and skin cells?

“If we want to take stem cells and convert them into something useful – neurons to treat Parkinson’s disease, or insulin-producing cells to treat diabetes – we need to learn a lot about what makes a cell a neuron or a pancreatic cell,” says Rudolf Jaenisch, a stem cell expert at the Whitehead Institute for Biomedical Research in Cambridge, MA.

Scientists are now integrating genomics, proteomics, and other technologies in an effort to understand the two unique properties of stem cells: their ability to divide indefinitely to create more stem cells, and their ability to differentiate into any number of cell types. This approach – known as systems biology – aims to build a useful cellular model out of the masses of information generated by high-throughput analysis.

“The cell is a machine. Though we know the genes and proteins in a cell, we don’t know how the machine works,” says Paul Matsudaira, director of the MIT Computational and Systems Biology Initiative (CSBi). Systems biologists hope that by studying how ensembles of genes or proteins in a given cell react to changes in that cell, they can get a more comprehensive understanding of a cellular system than they would through the traditional method of looking at single genes or proteins.

“People have been doing…modeling [in biology] for a while, but it’s gotten a bad name, probably because there were so many unknown variables,” says Ihor Lemischka, a biologist at Princeton University. “But now with all the ‘omics data, there’s the sense that biologists are finally playing with a full deck of cards.”

Under normal physiological conditions, a stem cell begins to assume its chosen identity when the embryo is a few days old. That fate – whether the cell self-renews or becomes specialized – is governed by a complex regulatory network. The genes that push a stem cell down a particular developmental pathway are regulated at many different levels. At the most basic level, proteins known as transcription factors bind to DNA to turn on a gene. Genes are also regulated by how a cell’s DNA is packaged, which determines if a gene’s “on switch” is accessible enough to be activated. The entire regulatory process is mediated by the cell’s environment, which affects DNA, RNA, proteins, and other players in the system.

Scientists would ultimately like to create a complete wiring diagram of the stem cell’s regulatory circuit. To date, scientists from different labs have identified several of the top level control systems in the network. In a paper published in September, Rick Young, a biologist at Whitehead, and colleagues describe the use of microarray technology to identify a set of genes that are kept inactive in undifferentiated stem cells. Researchers theorize that when these genes are turned on, they produce transcription factors that spur the cell along different developmental paths. Young’s collaborator, David Gifford, a computer scientist at MIT, is studying the packaging of DNA in an effort to determine whether some of these genes have been activated in specific cell types. The research was presented at a conference at MIT last week titled “Systems Biology of the Stem Cell.”

Lemischka and colleagues at Princeton University have identified another set of genes that are kept inactive in undifferentiated stem cells. They are now examining how turning these genes on and off impacts different parts of the cell, such as its proteins, cDNAs, RNAs, and histone modifiers, the proteins that determine how DNA is packaged.

Scientists can also use array technologies to examine other characteristics of stem cells. Jaenisch and colleagues published a paper in the Proceedings of the National Academy of Sciences on January 16 showing that stem cells derived from cloned embryos are functionally identical to stem cells derived from fertilized embryos – the two cell types show no difference in gene expression patterns. Previous research has shown that a high percentage of animals created from cloned embryos develop abnormally, so scientists had been concerned that stem cells derived from cloned embryos carry genetic abnormalities that make them unsuitable for therapeutic purposes. However, according to the latest finding, this does not seem to be the case.

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