Stem Cell 'Master Gene' Found Ability to Manipulate It May Aid Therapy By Rick Weiss Washington Post Staff Writer Friday, May 30, 2003; Page A01
Scientists yesterday said they have discovered a long-sought "master gene" in embryonic stem cells that is largely responsible for giving those cells their unique regenerative and therapeutic potential.
The discovery of the gene brings scientists closer to a holy grail of biology: the ability to turn ordinary cells into those that possess all the biomedical potency of human embryonic stem cells, eliminating the need to destroy embryos to get them.
Researchers cautioned that the new work -- details of which were published in today's issue of the journal Cell -- will not bring a quick end to the political controversy over human embryo research. Some said research involving human embryos will be more important than ever for at least a while, as scientists turn their attention to the master gene and how it works in its natural, embryonic environment.
But experts said the work -- conducted mostly on mouse embryo cells but also on human equivalents -- is already revealing more about the mysterious capacity of embryonic stem cells to retain indefinitely their youthful potential to become any kind of cell the body might need. That phenomenon is known as pluripotency.
In recognition of that power, the researchers have named the gene "nanog," a reference to the mythological Celtic land of Tir Nan Og, whose fairy-like residents are said to stay forever young.
"Until now, pluripotency and stem cells have been a black box, really," said Austin Smith, the University of Edinburgh researcher who led one of the two teams announcing their results today. "If we want to use these cells in the clinic someday, we have to understand how they are controlled. But there's been at least one major piece missing to even begin to understand that, which was nanog."
For years, researchers have tried to crack the secret of embryonic stem cells. The cells appear to have the potential to cure a wide variety of degenerative diseases but have stirred intense political controversy because embryos must be destroyed to retrieve them.
The cells can multiply for years in laboratory dishes, suspended in timeless youthfulness, and still retain their potential to turn into liver, muscle, brain or any other tissue they may be called upon to become. By contrast, ordinary cells grow visibly older with every day spent in a laboratory dish, and they cannot help but turn into one kind of tissue or another after a few days of life.
Working independently, Smith's team and one led by Shinya Yamanaka of Japan's Nara Institute of Science and Technology conducted a series of experiments on the gene they would later agree to call nanog -- a gene that caught their attention because it is active only in embryonic stem cells.
All genes are stretches of DNA code that direct cells to make proteins needed for life. This particular gene, the researchers found, belonged to a special class of genes whose proteins attach themselves to specific regions of a cell's DNA strand.
In doing so, the proteins precisely turn "on" and "off" other genes in that stretch of DNA, affecting the production of other proteins that affect the activity of other genes. As a result, a regulator such as nanog can almost single-handedly control the activity of a whole collection of genes.
In nanog's case, the resulting pattern of gene activity is typically seen in human cells only around the fourth or fifth day of embryo development -- when, from a cell's point of view, everything is possible but nothing has been decided.
Most of the work described in today's papers in Cell involved the mouse version of nanog in mouse stem cells, where it was easiest to study the gene's role. But some of it involved the human version of nanog, identifiable by its structural similarity to mouse nanog.
In one crucial experiment, Smith's team inserted copies of the human nanog gene into mouse embryonic stem cells, and subjected those cells to laboratory conditions that normally force such cells to mature and become one kind of tissue. The human nanog gene prevented that process.
That suggests that if scientists were to reawaken the dormant nanog gene in adult human cells -- something the Japanese group and others would like to try soon -- they might "reprogram" the gene activity patterns in those adult cells and turn them into cells that, for all practical purposes, are embryonic stem cells.
"As we know more and more about pluripotency, it probably will be possible to reprogram cells to make stem cells out of any cell in the body," said James Thomson, the University of Wisconsin scientist who first isolated human embryonic stem cells in 1998. "This is an important step in that direction."
Thomson and others warned that it would not be easy. "No other previously identified important genes can match nanog in the ability to maintain pluripotency," Yamanaka said in an e-mail exchange, adding that nanog's discovery puts scientists "close to the summit" of understanding the essence of stem cells. However, he said, "We do not know at this moment how nanog is regulated."
In other words, scientists have yet to identify the signal that tells nanog to turn on early in an embryo's existence. So they are hampered in their effort to make a drug or chemical cocktail that could switch on nanog in an older cell and transform it into a stem cell. (In the current experiments, nanog activity was turned up or blocked with genetic techniques that so altered the cells as to make them unacceptable for use in humans.)
"When we solve this question, we will probably be on the top of the ladder," Yamanaka said.
To get there, scientists said, will require studies of more human embryos. Opponents of embryo research said yesterday that is unacceptable, despite the researchers' laudable goals.
"If the reason you want to transcend embryo research is that it's wrong, then it's wrong to work on them in order to get past them as well," said Richard Doerflinger of the U.S. Conference of Catholic Bishops. Like other opponents, Doerflinger advocates research on other kinds of stem cells that can be retrieved from adults but that some scientists believe have lesser biomedical potential.
Besides, Doerflinger said, history shows that scientists' interest in embryos has been a one-way street. Promises to restrict research to embryos being discarded from fertility clinics were quickly superceded by requests to make new embryos from scratch and, most recently, to make cloned human embryos, he said.
"The one thing that's true of embryo research," Doerflinger said, "is that once people have done a little of it, they want to do more."