Stem Cell Biology and Its Complications
By GINA KOLATA
Published: August 24, 2010
The renewed debate over embryonic stem cells highlights the advances and complications that have arisen in the field since its controversial beginnings.
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The cells are a sort of blank slate, plucked from human embryos just a few days after fertilization. They tantalize scientists because they could in theory turn into any of the body’s 200 mature cell types, from blood to brain to liver to heart. They could be used to study and treat diseases and to study the basic biology of what determines a cell’s destiny — why a heart cell becomes a heart cell, for example, instead of a brain cell.
The problem is their origin — human embryos. In order to get stem cells, embryos must be destroyed. It is this fact that led to the court ruling on Monday blocking most federal financing for embryonic stem cell research.
The scientist who isolated human embryonic stem cells in 1998 struggled with this dilemma, consulting ethicists before proceeding. But in the end, the scientist, Dr. James Thomson of the University of Wisconsin, decided to go ahead because the embryos were from fertility clinics and were going to be destroyed anyway. And, he reasoned, the work could greatly benefit humanity.
Yet despite the high hopes for embryonic stem cells, progress has been slow — so far there are no treatments with the cells. The Food and Drug Administration just approved the first clinical study, a dose and safety test, of human embryonic stem cells to treat spinal cord injuries.
All along, though, scientists wondered if they could sidestep the ethical debate by creating embryonic stem cells without the embryos. Every cell has the same DNA. A heart cell is different from a liver cell because it uses different genes. But all the genes to make a liver cell, or any other cell, are there in the cell. The liver genes are masked in a heart cell and vice versa. Why can’t scientists find a way to unmask all of a cell’s genes and turn it directly into a stem cell without using an embryo?
A few years ago, two groups of researchers — one led by Dr. Thomson — did just that. They discovered that all they had to do was add four genes and a cell would reprogram itself back to its original state when it was a stem cell in an embryo. Like an embryonic stem cell, that reprogrammed cell seemed to be able to then turn into the many kinds of specialized cells in the body, an ability called pluripotent.
What has happened since that discovery, scientists say, is that stem cell biology turned out to be more complicated than they anticipated. Besides the stem cells from embryos, there are so-called adult stem cells found in all tissues but with limited potential because they can only turn into cells from their tissue of origin. And there are these newer cells made by reprogramming mature cells.
Now researchers are trying to figure out whether stem cells made by this reprogramming process really are the same as ones taken from embryos. Some say they found subtle differences between these cells, known as induced pluripotent stem cells, or I.P.S.C.’s, and embryonic stem cells. Others are not so sure.
They say they need embryonic stem cells as a basis of comparison, a gold standard to see if the newer reprogrammed cells are as good.
“We are not at the stage where you will find many investigators saying, ‘We don’t need embryonic stem cells because I.P. cells are the same,” said Dr. Timothy Kamp, a stem cell researcher and professor of medicine at the University of Wisconsin School of Medicine and Public Health. “We don’t know that yet.”
One complication is that different labs use different methods to obtain the reprogrammed cells and to study them, Dr. Kamp said. As a result, he said, “not all I.P. cells are the same.”
John Gearhart, director of the Institute for Regenerative Medicine at the University of Pennsylvania, and one of the first to isolate human embryonic stem cells, said some investigators ended up with reprogrammed cells “that will have little utility.” They are only partly reprogrammed, he explains.
“One worries about how safe and effective they are going to be” if they are ever used in therapies, Dr. Gearhart said.
Dr. George Q. Daley, a stem cell researcher at Children’s Hospital in Boston, saw subtle differences in a recent study. When he just compared the two types of cells side by side with molecular tests, they looked identical. Then he tried turning them into various types of mature cells and comparing the results.
Dr. Daley published a paper in March, in Nature Biotechnology, reporting that mouse I.P.S.C.’s from different tissues remembered, in a sense, where they came from. He has a similar paper under review showing the same effect with human induced pluripotent stem cells.
In the mouse study, it was harder to get pluripotent mouse cells derived from a skin cell, for example, to turn into blood cells than it was to get pluripotent stem cells made from blood cells to turn into blood cells.
“They tended to remember their tissue of origin,” Dr. Daley said.
Researchers need to find ways to make the cells forget where they came from, he said.
Rudolf Jaenisch, a stem cell researcher and biology professor at M.I.T., said he was not certain there were meaningful differences between human embryonic stem cells and human induced pluripotent cells.
But to answer that question will require the use of embryonic stem cells for comparisons, Dr. Jaenisch said.
“Things are very much in flux,” he said. “We will probably need human embryonic stem cells for a while. And then we probably will not need them anymore.”
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