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Saturday, November 24, 2007

Life After Embryonic Stem Cells

Twenty-five days. That's how long it took Dr. Shinya Yamanaka of Kyoto University to undo more than 30 years of exquisitely programmed biology packed into a woman's cheek cell — and just maybe change the world. In a procedure that some scientists thought could take decades to discover, Yamanaka tricked the cheek cell into acting like an embryonic stem cell — capable of dividing, developing and maturing into any of the body's more than 200 different cell types. And he wasn't alone: on the same day that he published his milestone in the journal Cell, James Thomson, a pioneering University of Wisconsin molecular biologist, reported similar success in Science.

Their papers cap a year of remarkable research, in which scientists have surged ahead of ethicists and politicians in finding ever more clever ways to generate stem cells. But where other breakthroughs relied on using cells from living embryos — tiny bits of inchoate life, fraught with ethical issues — the work by Yamanaka and Thomson sidesteps that abyss by nursing adult cells into a state in which their cellular destiny is yet to be fulfilled. No embryos, no eggs, no hand-wringing over where the cells come from and whether it is ethical to make them in the first place.

Stem cells generated by this method are ideal not just because they are free of political and moral baggage. They can also be coaxed into becoming any type of tissue, and then be transplanted back into the donor with little risk of rejection. Still, these cells are far from ready for medical use. The viruses used to ferry the genes that manipulate the cells can introduce genetic mutations and cancer. And with myriad ways to reprogram a cell, sorting out the best ones will take time — meaning that stem cells from embryos will remain useful (and controversial) for a while. Both Yamanaka and Thomson admit that we still know too little about how the process works to exploit the method's full potential. Nevertheless, their discovery has moved stem-cell research back to an embryonic state of its own — in which anything, it seems, is possible.

Stem Cell Basics
Research on stem cells is advancing knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. This promising area of science is also leading scientists to investigate the possibility of cell-based therapies to treat disease, which is often referred to as regenerative or reparative medicine.

Stem cells are one of the most fascinating areas of biology today. But like many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries.

The NIH developed this primer to help readers understand the answers to questions such as: What are stem cells? What different types of stem cells are there and where do they come from? What is the potential for new medical treatments using stem cells? What research is needed to make such treatments a reality?

Stem cells have two important characteristics that distinguish them from other types of cells. First, they are unspecialized cells that renew themselves for long periods through cell division. The second is that under certain physiologic or experimental conditions, they can be induced to become cells with special functions such as the beating cells of the heart muscle or the insulin-producing cells of the pancreas.

Scientists primarily work with two kinds of stem cells from animals and humans: embryonic stem cells and adult stem cells, which have different functions and characteristics that will be explained in this document. Scientists discovered ways to obtain or derive stem cells from early mouse embryos more than 20 years ago. Many years of detailed study of the biology of mouse stem cells led to the discovery, in 1998, of how to isolate stem cells from human embryos and grow the cells in the laboratory. These are called human embryonic stem cells. The embryos used in these studies were created for infertility purposes through in vitro fertilization procedures and when they were no longer needed for that purpose, they were donated for research with the informed consent of the donor.

Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a blastocyst, stem cells in developing tissues give rise to the multiple specialized cell types that make up the heart, lung, skin, and other tissues. In some adult tissues, such as bone marrow, muscle, and brain, discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, injury, or disease.

It has been hypothesized by scientists that stem cells may, at some point in the future, become the basis for treating diseases such as Parkinson's disease, diabetes, and heart disease.

Scientists want to study stem cells in the laboratory so they can learn about their essential properties and what makes them different from specialized cell types. As scientists learn more about stem cells, it may become possible to use the cells not just in cell-based therapies, but also for screening new drugs and toxins and understanding birth defects. However, as mentioned above, human embryonic stem cells have only been studied since 1998. Therefore, in order to develop such treatments scientists are intensively studying the fundamental properties of stem cells, which include:

1/determining precisely how stem cells remain unspecialized and self .renewing for many years; and
2/identifying the signals that cause stem cells to become specialized cells.

What are embryonic stem cells?
What stages of early embryonic development are important for generating embryonic stem cells?
Embryonic stem cells, as their name suggests, are derived from embryos. Specifically, embryonic stem cells are derived from embryos that develop from eggs that have been fertilized in vitro—in an in vitro fertilization clinic—and then donated for research purposes with informed consent of the donors. They are not derived from eggs fertilized in a woman's body. The embryos from which human embryonic stem cells are derived are typically four or five days old and are a hollow microscopic ball of cells called the blastocyst. The blastocyst includes three structures: the trophoblast, which is the layer of cells that surrounds the blastocyst; the blastocoel, which is the hollow cavity inside the blastocyst; and the inner cell mass, which is a group of approximately 30 cells at one end of the blastocoel.


Stem cells created without embryos
Scientists have made a startling breakthrough that allows them to "reprogram" ordinary skin cells to act like embryonic stem cells.

Stem cells are considered the body's ultimate master cell, able to become almost any other kind of cell, such as heart or lung cells. They have thus been called "pluripotent," meaning they have the ability to differentiate into other cell types.

Until now, the best source of stem cells has been from cloning cells from discarded human embryos. But the use of embryos has been fraught with ethical questions. Now, two new studies suggest there may be an easier way.

On Tuesday, it was announced that laboratory teams working on two continents have both been able to publish landmark studies on the use of skin cells to create pluripotent stem cells that look and act like embryonic stem cells.

They call the cells "induced pluripotent stem cells," or iPS cells for short.

Dr. Janet Rossant, chief of research at Ottawa's Hospital for Sick Children, said the findings are a "very important step forward."

"You take the cell that has become quite specialized, making skin in this case, and by changing the genetic environment you can take the cell and make it think it's back in the embryo and it has the full potential to make every cell in the body," Rossant told CTV's Canada AM on Wednesday.

She said there are still major questions about the research and how it will effect treatment for serious diseases such as diabetes or Parkinson's, noting it needs to be clear the cells will not create tumours or disorganized tissue in patients.

Rossant said some cancer-related effects were detected in the testing, and the process still needs to be fine-tuned.

"On the other hand, this whole process already tells us we should be able to make cells we can study in a petri dish, cells from people who have serious disease, and be able to understand the biology of that diseases in a petri dish and develop new drugs and treatments right there in the dish that you could later test in people."

The findings may have political repercussions in the United States, where President George Bush rejected bills that would have funded embryonic stem cell research.

He had said that medical breakthroughs were possible without destroying embryos. Democrats had said that because of Bush's ideological beliefs he had blocked research that could have uncovered cures to diseases afflicting millions of people.

The authors of the study note that iPS cells are similar -- not identical -- to embryonic stem cells and differences have been noted. But more research is needed to determine what those differences mean.

The two studies are published in two journals: Science and Cell. The Cell paper is from a team led by Dr. Shinya Yamanaka of Kyoto University; the Science paper is from a team led by James Thomson and Junying Yu of the University of Wisconsin in Madison.

Both studies detail a "direct reprogramming" recipe that includes just four ingredients to transform ordinary skin cells, called fibroblasts, into iPS cells.

Yamanaka's team introduced the genes OCT3/4, SOX2, C-MYC, and KLF4 to get their iPS cells. The Thomson team used a slightly different cocktail: OCT4, NANOG, SOX2 and LIN28.

Yamanaka's team reports that they were able to use iPS cells to produce cardiac muscle cells. After 12 days of growth in laboratory dishes, the clumps of cardiac muscle cells actually started beating.

Technique far from perfect

But neither Yamanaka's nor Yu's recipe is perfect. The technique involves using a retrovirus to deliver the genes into the skin cells, which in turn disrupts the DNA of the skin cells. That creates the potential for developing cancer.

But the DNA disruption is just a byproduct of the technique, and experts say they believe it can be avoided.

Thomson, who also produced the first successful human embryonic stem cell lines in 1998, admits that a lot more research is needed on this new technique, "but these methods should be useful for developing disease models and for drug development," his team wrote.

Ian Wilmut of the Scottish Centre for Regenerative Medicine at the University of Edinburgh, who helped clone the first mammal in 1997, Dolly the sheep, said the findings are hugely significant.

"We can now envisage a time when a simple approach can be used to produce stem cells that are able to form any tissue from a small sample taken from any of us," Wilmut said in a statement.

"This will have enormous implications for research and perhaps one day for therapy."

The therapeutic implications of the research are likely years away. Besides overcoming the DNA disruption obstacle, scientists still have to answer basic questions about these cells.

In the short term, these cells would probably be used first for lab studies to create artificial human tissues to test potential drugs.

Scientists also say it's still important to pursue the strategy of using cloned cells from embryos.

The hope is that one day, scientists can use stem cells to treat a variety of diseases, including creating brain cells for Parkinson's disease, pancreatic cells for diabetes and nerve cells for spinal-cord injuries.

The new iPS techniques would likely qualify for federal research funding in the U.S., unlike projects that extract stem cells from human embryos for which funding has been strictly limited.

The iPS cell work would also likely win the approval of bioethicists and religious leaders.

R. Alta Charo, a University of Wisconsin-Madison professor of law and bioethics, says this research alters the debates surrounding both human embryonic stem cell research and human cloning.

"This is a method for creating a stem cell line without ever having to work through, at any stage, an entity that is a viable embryo," Charo says. "Therefore, you manage to avoid many of those debates with the right-to life community."

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