June 7, 2000 Princeton scientists have outlined the molecular genetics behind a great mystery of biology: how blood cells replenish themselves. The results - a database of more than 2,000 genes - give biologists their first comprehensive picture of the workings of blood stem cells, the master component of bone marrow that gives rise to all cellular constituents of blood, from red and white cells to platelets.
The data, published in the June 2 issue of Science, offer biologists a powerful tool for understanding diseases of the blood such as leukemias , and also how blood stem cells may better be used therapeutically in transplantation and eventual gene therapy scenarios. The research also may yield insights into other types of stem cells throughout the body, such as those responsible for the production of skin, intestinal cells, and liver tissue.
Biologists have been fascinated with stem cells, particularly those of the blood, for many years, but had made relatively little progress in mapping out the molecular interactions that give the cells their unique properties. The general hallmark of all stem cells is their balancing act between maintaining their own numbers and spawning progeny that go on to become the many types of mature specialized cells of different tissues and organs.
"Very little is known, in any mammalian stem cell system, about how the underlying molecular biology allows these cells to make choices about their fates," said Ihor Lemischka, professor of molecular biology and senior author of the paper.
Lemischka and colleagues, working in collaboration with scientists at the University of Pennsylvania led by G. Christian Overton, created a "library" of gene fragments from blood stem cells of mice. They also created a library of genes from a sample of mature blood cells that had been depleted of stem cells. They then "subtracted" the two libraries, removing the majority of commonly expressed "housekeeping" genes while enriching for those that are preferentially expressed in the immature stem cells. By analyzing the DNA sequences in the "subtracted" library using sophisticated computational techniques and comparing them to the sequences of many other genes and proteins, the researchers have so far identified more than 2,000 genes that are likely to be active in stem cells.
The approach is far more comprehensive than previous techniques, which typically involve finding an animal that has a stem cell disorder and looking for the gene mutation that causes it, or which focus on small numbers of genes previously identified in other systems. "Traditionally, it had been a largely serendipitous process - no one had really asked the question: Can we look at everything that's there at once? Nor were the proper tools available," said Lemischka.
This big-picture approach could answer a host of critical questions, says Lemischka. What, for example, prevents the proliferation process from getting out of hand, as it does in the leukemia blood cancers, or how are the correct proportions of mature blood cells produced on a daily basis throughout life?
In addition to yielding a wealth of new genetic information, the research demonstrates an innovative approach to collecting, analyzing and presenting the data. The paper in Science is accompanied by a website, the Stem Cell Database, that gives access to the database of genes and outlines many aspects of stem cell biology. (http://stemcell.princeton.edu) Mostly through the work of postdoctoral researcher Robert Phillips, the database is extensively annotated and includes comparisons to information from other major sources.
Phillip Sharp, professor of biology at MIT, noted that the database is a unique contribution to the literature. "They had to create an almost entirely new method of publishing that allowed them to communicate the essence of the work and make the details available to others," observed Sharp. "That's quite remarkable."
The researchers plan eventually to open an identical database to contributions from other scientists. "We hope that the database will become a major and continuously evolving resource for the entire stem cell research community and that it will facilitate the kinds of large-scale and multi-laboratory interactions that are necessary to address complex biological questions," says Lemischka. In addition, "As the Genome Project and other databases grow and approach completion, integration of new data into the existing Stem Cell Database will increase its power and usefulness to biologists," says Phillips.
The project also represents a constructive model of interactions between the private biotechnology sector and academia. "While the funding for the large-scale acquisition of gene sequences was provided by ImClone Systems Incorporated, a New York-based biotechnology company, we all agreed from the beginning that both the actual sequence data as well as the complete results of the bioinformatic analyses and annotation would be freely available to the public; this is how it should be," says Lemischka.
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