Two teams of scientists reported Tuesday [20/11/2007] that they had turned human
skin cells into what appear to be embryonic stem cells without having
to make or destroy an embryo - a feat that could quell the ethical
debate troubling the field.
All they had to do, the scientists said, was add four genes. The
genes reprogrammed the chromosomes of the skin cells, making the cells
into blank slates that should be able to turn into any of the 220 cell
types of the human body, be it heart, brain, blood or bone. Until now,
the only way to get such human universal cells was to pluck them from a
human embryo several days after fertilization, destroying the embryo in
the process.
The reprogrammed skin cells may yet prove to have subtle differences
from embryonic stem cells that come directly from human embryos, and
the new method includes potentially risky steps, like introducing a
cancer gene. But stem cell researchers say they are confident that it
will not take long to perfect the method and that today's drawbacks
will prove to be temporary.
Researchers and ethicists not involved in the findings say the work
should reshape the stem cell field. At some time in the near future,
they said, the current debate over whether it is morally acceptable to
create and destroy human embryos to obtain stem cells should be moot.
"Everyone was waiting for this day to come," said the Reverend
Tadeusz Pacholczyk, director of education at the National Catholic
Bioethics Center.
"You should have a solution here that will address the moral objections that have been percolating for years," he added.
The two independent teams, from Japan and Wisconsin, note that their
method also creates stem cells that genetically match the donor without
having to resort to the controversial step of cloning. If stem cells
are used to make replacement cells and tissues for patients, it would
be invaluable to have genetically matched cells because they would not
be rejected by the immune system. Even more important, scientists say,
is that genetically matched cells from patients will enable them to
study complex diseases, like Alzheimer's, in the lab.
Until now, the only way to get embryonic stem cells that genetically
matched an individual would be to create embryos that were clones of
that person and extract their stem cells. Just last week, scientists in
Oregon reported that they did this with monkeys, but the prospect of
doing such experiments in humans has been ethically fraught.
But with the new method, human cloning for stem cell research, like
the creation of human embryos to extract stem cells, may be unnecessary.
"It really is amazing," said Dr. Leonard Zon, director of the stem
cell program at Harvard Medical School's Children's Hospital. And, said
Douglas Melton, co-director of the Stem Cell Institute at Harvard
University, it is "ethically uncomplicated."
For all the hopes invested in it over the past decade, embryonic
stem cell research has not yet produced any cures or major therapeutic
discoveries. Stem cells are so malleable that they may pose risk of
cancer, and the new method of obtaining stem cells includes steps that
raise their own safety concerns.
Still, the new work could allow the field to vault significant
problems, including the shortage of human embryonic stem cells and
restrictions on federal funding for such research.
The new discovery was published online Tuesday in Cell, in a paper
by Shinya Yamanaka of Kyoto University and the Gladstone Institute for
Cardiovascular Disease in San Francisco, and in Science, in a paper by
James Thomson and his colleagues at the University of Wisconsin-Madison.
While both groups used just four genes to reprogram human skin
cells, two of the four genes used by the Japanese scientists were
different from two of the four used by the American group. All the
genes in question, though, act in a similar way - they are master
regulator genes whose role is to turn other genes on or off.
The reprogrammed cells, the scientists report, appear to behave exactly like human embryonic stem cells.
Thomson and Yamanaka caution, though, that they still must confirm
that the reprogrammed human skin cells really are the same as stem
cells they get from embryos. And while those studies are under way,
Thomson and others say, it would be premature to abandon research with
stem cells taken from human embryos.
Another caveat is that, so far, scientists use a type of virus, a
retrovirus, to insert the genes into the cells' chromosomes.
Retroviruses slip genes into chromosomes at random, sometimes causing
mutations that can make normal cells turn into cancers.
In addition, one of the genes that the Japanese scientists insert is actually a cancer gene.
The cancer risk means that the resulting stem cells would not be
suitable for replacement cells or tissues for patients with diseases,
like diabetes, in which their own cells die. They would, though, be
ideal for the sort of studies that many researchers say are the real
promise of this endeavor - studying the causes and treatments of
complex diseases.
For example, researchers want to make embryonic stem cells from a
person with a disease like Alzheimer's and turn the stem cells into
nerve cells in a petri dish. Then, scientists hope, they may be able to
understand what goes awry in Alzheimer's patients when their brain
cells die and how to prevent or treat the disease.
But even the retrovirus drawback may be temporary, scientists say.
Yamanaka and several other researchers are trying to get the same
effect by adding chemicals or using more-benign viruses to get the
genes into cells. They say they are starting to see success.
It is only a matter of time until retroviruses are not needed, Melton predicted.
"Anyone who is going to suggest that this is just a side show and that it won't work is wrong," Melton said.
The new discovery was preceded by work in mice. Last year, Yamanaka
published a paper showing that he could add four genes to mouse cells
and turn them into mouse embryonic stem cells.
He even completed the ultimate test to show that the resulting stem
cells could become any type of mouse cell. He used them to create new
mice, whose every cell came from one of those stem cells. Twenty
percent of those mice, though, developed cancer, illustrating the risk
of using retroviruses and a cancer gene to make cells for replacement
parts.
Scientists were electrified by the reprogramming discovery, Melton said.
"Once it worked, I hit my forehead and said, 'It's so obvious,' " he said. "But it's not obvious until it's done."
Some were skeptical about Yamanaka's work and questioned whether such an approach would ever work in humans.
"They said: 'That's very good with mice. But let's see if you can do it with a human,' " Zon recalled.
But others set off in what became an international race to repeat the work with human cells.
"Dozens, if not hundreds, of labs have been attempting to do this,"
said Dr. George Daley, associate director of the stem cell program at
Children's Hospital.
Few expected that Yamanaka would succeed so soon. Nor did they expect that the same four genes would reprogram human cells.
"This shows it's not an esoteric thing that happened in the mouse,"
said Rudolf Jaenisch, a stem cell researcher at the Massachusetts
Institute of Technology.
Ever since the birth of Dolly the sheep, scientists knew that adult
cells could, in theory, turn into embryonic stem cells. But they had no
idea how to do it without cloning, the way Dolly was created.
With cloning, researchers put an adult cell's chromosomes into an
unfertilized egg whose genetic material was removed. The egg, by some
mysterious process, then does all the work. It reprograms the adult
cell's chromosomes, bringing them back to the state they were in just
after the egg was fertilized.
Those reprogrammed genes then direct the development of an embryo. A
few days later, a ball of stem cells emerges in the embryo. Since the
embryo's chromosomes came from the adult cell, every cell of the
embryo, including its stem cells, are exact genetic matches of the
adult.
The abiding questions, though, were: How did the egg reprogram the
adult cell's chromosomes? Would it be possible to reprogram an adult
cell without using an egg?
About four years ago, Yamanaka and Thomson independently hit upon
the same idea. They would search for genes that are being used in an
embryonic stem cell that are not being used in an adult cell. Then they
would see whether those genes would reprogram an adult cell.
Yamanaka worked with mouse cells and Thomson worked with human cells from foreskins.
The researchers found more than 1,000 candidate genes. So both
groups took educated guesses, trying to whittle down the genes to the
few dozen they thought might be the crucial ones and then asking
whether any combinations of those genes could turn a skin cell into a
stem cell.
It was laborious work, with no guarantee of a payoff.
"The number of factors could have been one or 10 or 100 or more," Yamanaka said in a telephone interview from his lab in Japan.
If many genes were required, the experiments would have failed,
Thomson said, because it would be impossible to test all the gene
combinations.
The mouse work went more quickly than Thomson's work with human
cells. As soon as Yamanaka saw that the mouse experiments succeeded, he
began trying the same brute force method in human skin cells that he
ordered from a commercial laboratory. Some were face cells from a
36-year-old white woman and others were connective tissue cells from
joints of a 69-year-old white man.
Yamanaka said he thought it would take a few years to find the right
genes and the right conditions to make the human experiments work.
Feeling the hot breath of competitors on his neck, he was in his lab
every day for 12 to 14 hours a day, he said.
A few months later, he succeeded.
"We did work very hard," Yamanaka said. "But we were very surprised."
