A confocal image of human embryonic stem cells stained with antibodies specific to the embryonic antigen Tra1-60. Image © Chad A. Cowan



"Reprogramming Adult Stem Cells"

by
Kathy Wren

August 22, 2005 (AAAS ) -- Researchers in the August 26, 2005 issue of the journal Science have fused an adult skin cell with an embryonic stem cell and shown that the cell was reprogrammed to its embryonic state. If future experiments indicate that this reprogrammed state is retained after removing the embryonic stem cell DNA - currently a formidable technical hurdle -the hybrid cells could theoretically be used to produce embryonic stem cell lines that are tailored to individual patients without the need to create and destroy human embryos.

Chad A. Cowan and colleagues merged human embryonic stem cells with human skin cells called fibroblasts, producing hybrid cells that contained both the fibroblast and stem-cell chromosomes. The hybrid cells had the appearance, growth rate, and several key genetic characteristics of human embryonic cells. They also behaved like embryonic cells, differentiating into cells from each of the three main tissue types that form in a developing embryo. The authors conclude that human embryonic cells have the ability to reprogram adult-cell chromosomes following cell fusion.

"Stem Cell Breakthrough Is Reported by Scientists"


August 22, 2005; Washington, D.C. (AP and LA Times) –- Harvard scientists say they have fused an adult skin cell with an embryonic stem cell, a development that could lead to the creation of useful stem cells without involving human embryos. Preliminary results of the groundbreaking research were disclosed Sunday evening on the Science magazine website.

The Harvard researchers said they were able to show that the fused cell "was reprogrammed to its embryonic state." "If future experiments indicate that this reprogrammed state is retained after removing the embryonic stem-cell DNA -- currently a formidable technical hurdle –- the hybrid cells could theoretically be used to produce embryonic stem cell lines that are tailored to individual patients without the need to create and destroy human embryos," said a summary of the research reported on the Science website.

That could lead to creation of stem cells without having to use human eggs or make new human embryos in the process, thereby sidestepping much of the controversy over stem cell research. The Harvard researchers used laboratory-grown human embryonic stem cells - such as the ones that President Bush has already approved for use by Federally-funded researchers -- to essentially convert a skin cell into an embryonic stem cell. If hurdles can be overcome, the technique "may circumvent some of the logistical and societal concerns" that have held up much of the research in this country, Chad A. Cowan, Kevin Eggan and colleagues from the Harvard Stem Cell Institute report in the Science article.

"Harvard Researchers Report Potential Stem-Cell Breakthrough"

by
Randolph E. Schmid, Science Writer

August 22, 2005; Washington, D.C. (AP and Boston Globe) -- Harvard scientists announced they've discovered a way to fuse adult skin cells with embryonic stem cells, a promising breakthrough that could lead to the creation of useful stem cells without first having to create and destroy human embryos. The scientists said they were able to show in their early research that the fused cell "was reprogrammed to its embryonic state." Such a breakthrough could have the effect of taming a biting national debate about the ethics of stem-cell research, but not any time soon.

"If future experiments indicate that this reprogrammed state is retained after removing the embryonic stem-cell DNA -- currently a formidable technical hurdle -- the hybrid cells could theoretically be used to produce embryonic stem cells lines that are tailored to individual patients without the need to create and destroy human embryos," said a summary of the research reported on the Science journal site.

Researcher Kevin Eggan stressed, however, that the technology is preliminary. "I can't stress enough that this technology is not ready for prime time right now," Eggan said at a briefing Monday. "It is not a replacement for those techniques that we already have for derivation of embryonic stem cells." "This is the first step down a long and uncertain road," said Eggan, noting that it comes with its own set of limitations. It could easily be ten years before the process is usable in people, he said. Eggan said, "There are still fundamental biological hurdles that have to be overcome." The goal is to make stem cells that carry a patient's genes, and only the patients genes, he said. The cells created in this process carry too much DNA, both that of the stem cell and that from the embryonic stem cell used in the process.

The new process still involves use of an embryonic stem cell, but the researchers hope it will tell them how an adult cell can be reprogrammed into an embryonic stem cell without use of embryonic cells to begin with. "There are groups of people in the U.S. and elsewhere who feel it's fundamentally wrong to destroy early state (stem cells)," he said. Learning how the adult cell is changed might lead to a way around that concern, Eggan said.

The researchers used laboratory grown human embryonic stem cells -- such as the ones that President Bush has already approved for use by federally funded researchers -- to essentially convert a skin cell into an embryonic stem cell itself. If a number of hurdles can be overcome in subsequent research, the new technique "may circumvent some of the logistical and societal concerns" that have hampered much of the research in this country, Chad A. Cowan,
Eggan and colleagues from the Harvard Stem Cell Institute reported in the Science article.

Those social concerns are reflected in the Senate's looming debate over a House-passed bill to force taxpayers to fund stem cell research that would destroy human embryos, legislation that Bush has promised to veto. Bush and many fellow conservatives believe it is immoral to create embryos only to destroy them, even in the name of scientific progress that could cure or treat diseases afflicting millions of people. Debate and a vote on the bill will proceed next month as planned, Senate Majority Leader Bill Frist's spokeswoman, Amy Call, said Monday. Frist earlier this month said he will vote for the bill, widely expected to pass even in the face of Bush's veto threat.

The hybrid cells created by the Harvard team "had the appearance, growth rate, and several key genetic characteristics of human embryonic cells," the summary of their work said. "They also behaved like embryonic cells, differentiating into cells from each of the three main tissue types that form in a developing embryo," it said. The authors conclude that human embryonic cells have the ability to reprogram adult cell chromosomes following cell fusion."


"Researchers Devise New Technique for Creating Human Stem Cells"

August 26, 2005; Researchers have developed a new technique for creating human embryonic stem cells by fusing adult somatic cells with embryonic stem cells. The fusion causes the adult cells to undergo genetic reprogramming, which results in cells that have the developmental characteristics of human embryonic stem cells. The new technique may permit scientists to derive new human embryonic stem cell lines without the need to use human embryos.

This approach could become an alternative to Somatic Cell Nuclear Transfer (SCNT), a method that is currently used to produce human stem cells. SCNT involves transferring the nuclei of adult cells, called somatic cells, into oocytes in which scientists have removed the nuclei.

“The long term goal for this experiment was to do cell fusion in a way that would allow the elimination
of the embryonic stem cell nucleus to create an embryonic stem cell from the somatic cell.”
-- Douglas A. Melton, Harvard University
The researchers said that -while the technique might one day be used along with SCNT, which involves the use of unfertilized human eggs - technical hurdles must be cleared before the new technique sees widespread use. It is more likely that the new technique will see immediate use in helping to accelerate understanding of how embryonic cells “reprogram” somatic cells to an embryonic state.

The researchers published their findings in the August 26, 2005, issue of the journal Science. Senior author Kevin Eggan and Howard Hughes Medical Institute investigator Douglas A. Melton, both at Harvard University, led the research team, which also included Harvard colleagues Chad Cowan and Jocelyn Atienza.

In theory, researchers can induce embryonic stem cells to mature into a variety of specialized cells. For that reason, many researchers believe stem cells offer promise for creating populations of specialized cells that can be used to rejuvenate organs, such as the pancreas or heart, that are damaged by disease or trauma. Stem cells also provide a model system in which researchers can study the causes of genetic disease and the basis of embryonic development.

Eggan, Melton and their colleagues decided to pursue their alternative route after other researchers had shown that genetic reprogramming can occur when mouse somatic cells are fused to mouse embryonic stem cells. The scientists knew that if their studies were successful, it would provide the research community with a new option for producing reprogrammed cells using embryonic stem cells, which are more plentiful and easier to obtain than unfertilized human eggs.

In the studies published in Science, the researchers combined human fibroblast cells with human embryonic stem cells in the presence of a detergent-like substance that caused the two cell types to fuse. The researchers demonstrated that they had achieved fusion of the two cell types by searching the fused cells for two distinctive genetic markers present in the somatic fibroblast and stem cells. The researchers were also able to further confirmed that fusion occurred by studying the chromosomal makeup of the fused cells. Their analyses showed that the hybrid cells were “tetraploid” - meaning they contained the combined chromosomes of both the somatic cells and the embryonic stem cells.

One of the key findings from the study was that the fusion cells have the characteristics of human embryonic stem cells. “ Our assays showed that the hybrid cells, unlike adult cells, showed the development potential of embryonic stem cells,” said Eggan. “We found they could be induced to mature into nerve cells, hair follicles, muscle cells and gut endoderm cells. And, since these cell types are derived from three different parts of the embryo, this really demonstrated the ability of these cells to give rise to a variety of different cell types.”

Furthermore, Eggan noted that genetic analyses of the fused cells revealed that the somatic cell genes characteristic of adult cells had all been switched off, while those characteristic of embryonic cells had been switched on. “ With the exception of a few genes one way or the other which is perhaps because these cells are now tetraploid the hybrid cells are indistinguishable from human embryonic stem cells,” he said.

“ The long term goal for this experiment was to do cell fusion in a way that would allow the elimination of the embryonic stem cell nucleus to create an embryonic stem cell from the somatic cell,” said Melton. “This paper reports only the first step toward that goal, because we end up with a tetraploid cell. So, while this does not obviate the need for human oocytes, it demonstrates that this general approach of cell fusion is an interesting one that should be further explored.”

The researchers also performed fusion experiments using pelvic bone cells as the somatic cells and a different human embryonic cell line, to demonstrate that their technique was not restricted to one adult-cell type or embryonic cell line.

In both cases, the researchers observed extensive reprogramming of the somatic cells. “We were surprised at how complete the reprogramming was,” said Eggan. “I think we were expecting that there would be more 'memory' of the adult state than the embryonic in the hybrid cells. It was quite clear that when we looked at these hybrid cells, they had completely reverted to an embryonic state.”

Melton said that the remaining technical hurdle is figuring out a way to eliminate the embryonic stem-cell nucleus in the hybrid cell, causing it to have a normal number of chromosomes. One problem, said Melton, is that the nucleus in stem cells is large, occupying nearly the entire cell. Thus, it is not practical to physically extract the nucleus, as is currently done with oocytes, which have a relatively small nucleus. An alternative approach of destroying the embryonic stem-cell nucleus with chemicals or radiation would induce the cell's suicide program, called apoptosis, he said.

Melton emphasized that “at this stage in our understanding, the hard fact is that the only way
to create an embryonic stem cell from a somatic cell is by nuclear transfer into oocytes. Taking advantage of this current capability -- such as colleagues in South Korea and other countries are doing -- is critical if we are to maintain the progress necessary to realize the extraordinary clinical potential of this technology.”

Eggan added that the most realistic current promise of the fusion technique is in studying the machinery of genetic reprogramming of somatic cells by embryonic cells. “It is extremely difficult to study the reprogramming process using eggs, because in the case of humans it is very difficult to obtain eggs in any quantity and difficult or impossible to genetically manipulate them,” he said. “But embryonic stem cells can be grown in large quantities. We can isolate the components of the reprogramming machinery, and we can genetically manipulate the cells to analyze the reprogramming process.”

"Harvard Researchers Report: Stem- Cell Breakthrough"

August 22, 2005; Washington, D.C. (AP and WSJ) -- Harvard scientists announced they have discovered a way to fuse adult skin cells with embryonic stem cells, a promising breakthrough that could lead to the creation of useful stem cells without first having to create and destroy human embryos. The scientists said they were able to show in their early research that the fused cell "was reprogrammed to its embryonic state." Such a breakthrough could have the effect of taming a biting national debate about the ethics of stem-cell research.

Researcher Kevin Eggan stressed, however, that the technology is preliminary. "I can't stress enough that this technology is not ready for prime time right now," he said at a briefing Monday. "It is not a replacement for those techniques that we already have for derivation of embryonic stem cells. … This is the first step down a long and uncertain road," said Dr. Eggan, noting that it comes with its own set of limitations. “If future experiments indicate that this reprogrammed state is retained after removing the embryonic stem-cell DNA -- currently a formidable technical hurdle - the hybrid cells could theoretically be used to produce embryonic stem-cells lines that are tailored to individual patients without the need to create and destroy human embryos," said a summary of the research reported on the Science journal site. It could easily be ten years before the process is usable in people, he said. "There are still fundamental biological hurdles that have to be overcome."

The goal is to make stem cells that carry a patient's genes, and only the patients genes, he said. The cells created in this process carry too much DNA, both that of the stem cell and that from the embryonic stem cell used in the process. The new process still involves use of an embryonic stem cell, but the researchers hope it will tell them how an adult cell can be reprogrammed into an embryonic stem cell without use of embryonic cells to begin with.

"There are groups of people in the U.S. and elsewhere who feel it's fundamentally wrong to destroy early state [stem cells]," he said. Learning how the adult cell is changed might lead to a way around that concern, Dr. Eggan said.

The researchers used laboratory-grown human embryonic stem cells -- such as the ones that President Bush has already approved for use by federally funded researchers -- to essentially convert a skin cell into an embryonic stem cell itself. If a number of hurdles can be overcome in subsequent research, the new technique "may circumvent some of the logistical and societal concerns" that have hampered much of the research in this country, Chad A. Cowan, Dr. Eggan and colleagues from the Harvard Stem Cell Institute reported in the Science article.

Those social concerns are reflected in the Senate's looming debate over a House-passed bill to force taxpayers to fund stem-cell research that would destroy human embryos, legislation that Mr. Bush has promised to veto. The president and many fellow conservatives believe it is immoral to create embryos only to destroy them, even in the name of scientific progress that could cure or treat diseases afflicting millions of people. Debate and a vote on the bill will proceed next month as planned. Senate Majority Leader Bill Frist said earlier this month that he will vote for the Bill, widely expected to pass even in the face of Mr. Bush's veto threat.

The hybrid cells created by the Harvard team "had the appearance, growth rate, and several key genetic characteristics of human embryonic cells," the summary of their work said. "They also behaved like embryonic cells, differentiating into cells from each of the three main tissue types that form in a developing embryo," it said. The authors conclude that human embryonic cells have the ability to reprogram adult cell chromosomes following cell fusion."

"Skin Cells ‘Reprogrammed’ to Stem Cells:

Scientists’ Work Could Clear Moral Hurdle to Embryonic
Research"

by
Rick Weiss

August 22, 2005 (The Washington Post) -- Scientists for the first time have turned ordinary skin cells into what appear to be embryonic stem cells without having to use human eggs or make new human embryos in the process, as has always been required in the past, a Harvard research team announced yesterday. The technique uses laboratory-grown human embryonic stem cells - such as the ones that President Bush has already approved for use by Federally-funded researchers to "reprogram" the genes in a person's skin cell, turning that skin cell into an embryonic stem cell itself. The approach -- details of which are to be published this week in the journal Science but were made public on the journal's website yesterday -- is still in an early stage of development. But if further studies confirm its usefulness, it could offer an end run around the heated social and religious debate that has for years overshadowed the field of human embryonic stem cell research.

Since the new stem cells in this technique are essentially rejuvenated versions of a person's own skin cells, the DNA in those new stem cells matches the DNA of the person who provided the skin cells. In theory at least, that means that any tissues grown from those newly minted stem cells could be transplanted into the person to treat a disease without much risk that they would be rejected, because they would constitute an exact genetic match.

Fate of Embryos at Heart of Debate

 Until now, the only way to turn a person's ordinary cell into a "personalized" stem cell such as this was to turn that ordinary cell into an embryo first and later destroy the embryo to retrieve the new stem cells growing inside – a process widely known as "therapeutic cloning." That prospect, like others in the promising arena of human embryonic stem cell research, has stirred strong emotions among those who believe that days-old human embryos should not be intentionally destroyed.

Embryonic stem cells are capable of becoming virtually any kind of cell or tissue and are being intensely studied around the world as the core of a newly emerging field of regenerative medicine, in which researchers hope to grow new tissues to revitalize ailing organs. Although human embryonic stem cells have never been tested in humans, some researchers expect human clinical trials to begin within a year or so. Researchers caution, however, that like many other nascent therapies that initially seemed promising, stem cells may never live up to their promise.

If some lingering, and potentially daunting, uncertainties can be dealt with successfully, the new technique "may circumvent some of the logistical and societal concerns" that have hampered much of the research in this country, Chad A. Cowan, Kevin Eggan and colleagues from the Harvard Stem Cell Institute report in the Science article.

More immediately, the new work could have an impact on Capitol Hill, where the Senate is poised to vote on legislation already passed by the House -that would loosen Bush's restrictions on human embryonic research. Last month, Senate Majority Leader Bill Frist (R-TN) surprised many of his colleagues by announcing he would break with the president and support the Senate Bill, which Bush has promised to veto.

Discovery Could Be a Game-Changer

Some opponents of relaxing the current restrictions have argued that new techniques will soon eliminate the need to use human eggs or embryos to make cells that are, for all intents and purposes, human embryonic stem cells. They and others have for some months predicted that if such new findings were to emerge, they could shift the balance of votes in the Senate.

The researchers emphasize in their report that the technique is still far from finding an application in medicine. Most important, they note: Because it involves the fusion of a stem cell and a person's ordinary skin cell, the process leads to the creation of a hybrid cell. While that cell has all the characteristics of a new embryonic stem cell, it contains the DNA of the person who donated the skin cell and also the DNA that was in the initial embryonic stem cell.

At some point before these hybrid cells are coaxed to grow into replacement parts to be transplanted into a person, that extra DNA must be extracted, the researchers write. The team describes this task as a "substantial technical barrier" to the clinical use of stem cells made by the new technique. They do not mention that several teams, including ones in Illinois and Australia, [who?] have said in recent interviews that they are making progress removing stem cell DNA from such hybrid cells. None of those teams has published details of their results. But several leading researchers have said they believe it will be feasible to remove the extra DNA.

‘We're Just Not There Yet’

Some even suspect that the new technique for making personalized stem cells would still work even if the "starter" stem cells' DNA were removed before those cells were fused to the skin cells. It is not clear whether the genetic reprogramming imposed upon the skin cells by the fused stem cells requires the initial presence of the stem cells' DNA, or whether fluids in the initial stem cells can do the job themselves. "Their data are certainly very good ... and quite significant," said Prof. John Gearhart, M.D., Ph.D., a stem-cell researcher at Johns Hopkins Medical Institutions. But the extra DNA "is problematic." "I think we have to keep our eye on the ball here," Gearhart said. "If this stuff proves to work, that's wonderful. But we're just not there yet, and it's going to take a long time to demonstrate that. Meanwhile, other techniques already work well. So let's get on with it." Still, it is fascinating, Gearhart said, to see such good evidence that something in embryonic stem cells is able to turn an ordinary skin cell into the equivalent of an embryonic stem cell a genetic alchemy apparently accomplished by turning key genes in the skin cell either "on" or "off." Even if the work does not lead directly to clinical applications, he and the Harvard researchers said, it is likely to boost the amount and quality of research into what stem cells really are and how they work.

“Researchers Report Potential Stem Cell Breakthrough"


August 22, 2005; Washington, D.C. (AP and CNN) -- Harvard scientists announced they've discovered a way to fuse adult skin cells with embryonic stem cells, a promising breakthrough that could lead to the creation of useful stem cells without first having to create and destroy human embryos. The scientists said they were able to show in their early research that the fused cell "was reprogrammed to its embryonic state." Such a breakthrough could have the effect of taming a biting national debate about the ethics of stem-cell research, but not any time soon.

"If future experiments indicate that this reprogrammed state is retained after removing the embryonic stem cell DNA -- currently a formidable technical hurdle -- the hybrid cells could theoretically be used to produce embryonic stem cells lines that are tailored to individual patients without the need to create and destroy human embryos," said a summary of the research reported on the Science journal site.

Researcher Kevin Eggan stressed, however, that the technology is preliminary. "I can't stress enough that this technology is not ready for prime time right now," Eggan said at a briefing Monday. "It is not a replacement for those techniques that we already have for derivation of embryonic stem cells." "This is the first step down a long and uncertain road," said Eggan, noting that it comes with its own set of limitations. It could easily be ten years before the process is usable in people, he said. Eggan said, "There are still fundamental biological hurdles that have to be overcome." The goal is to make stem cells that carry a patient's genes, and only the patients genes, he said. The cells created in this process carry too much DNA, both that of the stem cell and that from the embryonic stem cell used in the process.

The new process still involves use of an embryonic stem cell, but the researchers hope it will tell them how an adult cell can be reprogrammed into an embryonic stem cell without use of embryonic cells to begin with. "There are groups of people in the U.S. and elsewhere who feel it's fundamentally wrong to destroy early state (stem cells)," he said. Learning how the adult cell is changed might lead to a way around that concern, Eggan said.

The researchers used laboratory grown human embryonic stem cells -- such as the ones that President Bush has already approved for use by federally funded researchers -- to essentially convert a skin cell into an embryonic stem cell itself.

If a number of hurdles can be overcome in subsequent research, the new technique "may circumvent some of the logistical and societal concerns" that have hampered much of the research in this country, Chad A. Cowan, Eggan and colleagues from the Harvard Stem Cell Institute reported in the Science article.

Those social concerns are reflected in the Senate's looming debate over a House-passed Bill to force taxpayers to fund stem cell research that would destroy human embryos, legislation that Bush has promised to veto. Bush and many fellow conservatives believe it is immoral to create embryos only to destroy them, even in the name of scientific progress that could cure or treat diseases afflicting millions of people. Debate and a vote on the Bill will proceed next month as planned, Senate Majority Leader Bill Frist's spokeswoman, Amy Call, said Monday. Frist earlier this month said he will vote for the Bill, widely expected to pass even in the face of Bush's veto threat.

The hybrid cells created by the Harvard team "had the appearance, growth rate, and several key genetic characteristics of human embryonic cells," the summary of their work said. "They also behaved like embryonic cells, differentiating into cells from each of the three main tissue types that form in a developing embryo," it said. The authors conclude that human embryonic cells have the ability to reprogram adult cell chromosomes following cell fusion."