Making stem cells from adult humans

Two reports published in April 2014 showed for the first time how stem cells could be generated from embryos that were produced using adult skin cells. Shown here is a colony of an embryonic stem line derived from a patient with Type 1 diabetes.

Stem cells have the potential to become many different kinds of cells, and can renew themselves through cell division. Scientists view stem cells as a possible gateway to curing many medical conditions, from Parkinson's disease to diabetes. Stem cells are viewed on computer here at UConn Health Center in 2010.

A closeup of a microscope slide taken in 2000 at the Reproductive Genetics Institute's Chicago laboratory shows transplanted stem cells taken from the umbilical cord blood of a baby named Adam Nash. Adam's sister Molly has a genetic disease called Fanconi Anemia. Their parents wanted to have a child who could be a stem cell donor for Molly. Using in vitro fertilization, doctors created embryos and then tested them for the genetic disease. They chose one that did not have the disorder, which grew into baby Adam. Molly received a stem cell transplant from stem cells from Adam's umbilical cord. Both children are alive today.

In 1998, then-President Bill Clinton requested a National Bioethics Advisory Commission to study the question of stem cell research.

In 2000, The National Institutes of Health issued guidelines for the use of embryonic stem cells in research, specifying that scientists receiving federal funds could use only extra embryos that would otherwise be discarded. President Clinton approved federal funding for stem cell research but Congress did not fund it. Above, a Cell Expansion System which is used to grow cells is seen during the 2010 World Stem Cell Summit in Detroit.

In August 2001, then-President George W. Bush announced he would allow federal funding for about 60 existing stem cell lines created before this date. Above, a human stem cell colony, which is no more than 1mm wide and comprises thousands of individual stem cells, grows on mouse embryonic fibroblast in a research laboratory in September 2001.

In 2005, Connecticut and Illinois designated state funds to support stem cell research in their states. Above, a woman works on stem cells at the University of Connecticut's Stem Cell Institute at the UConn Health Center in August 2010 in Farmington, Connecticut.

In March 2009, President Barack Obama signed an executive order that removed restrictions on embryonic stem cell research. His action overturned an order approved by President George W. Bush in August 2001 that barred the National Institutes of Health from funding research on embryonic stem cells beyond using 60 cell lines that existed at that time. Above, Obama signs the order.

In November 2010, William Caldwell, CEO of Advanced Cell Technology, told CNN that the FDA had granted approval for his company to start a clinical trial using cells grown from human embryonic stem cells. The treatment would be for an inherited degenerative eye disease. Above, dozens of packages containing frozen embryonic stem cells remain in liquid nitrogen in a laboratory, at the University of Sao Paulo's human genome research center, in Sao Paulo, Brazil, in March 2008.

In May 2011, stem cell therapy in sports medicine was spotlighted after New York Yankee pitcher Bartolo Colon was revealed to have had fat and bone marrow stem cells injected into his injured elbow and shoulder while in the Dominican Republic. Above, Colon pitches against the Boston Red Sox on in May 2011.

In February 2012, early research published by scientists at Cedars-Sinai Medical Center and Johns Hopkins University showed that a patient's own stem cells can be used to regenerate heart tissue and help undo damage caused by a heart attack. It is the first instance of therapeutic regeneration. Above, fluid is removed from the knee of a patient to collect adult stem cells by at a clinic in Broomfield, Colorado.

In October 2012, Sir John Gurdon and Shinya Yamanaka were awarded the Nobel Prize for Physiology or Medicine for discovering how to make pluripotent stem cells. They both showed that cells could be reprogrammed after they had already specialized. This changed scientists' understanding of how cells and organisms develop. Above, Sir Gurdon speaks at a press conference after being awarded the Prize.

On May 16, 2013, scientists announced that they had, for the first time, produced embryos using skin cells, and then used the embryos to make stem cell lines. This technique resembles what was used in cloning Dolly the sheep, but the earlier technique could not have led to a fully-cloned human baby. Above, a photo provided by the Oregon Health & Science University shows a stem cell colony produced from human skin cells.

On Tuesday, August 5, the world's first stem cell burger was cooked and eaten in London. The brainchild of Maastricht University's Mark Post, the burger was made of 20,000 small strands of meat grown from a cow's muscle cells and took three months to create and cost $330,000 to develop.

In September 2013, scientists announced they had created what they are calling "cerebral organoids" using stem cells. These pea-sized structures are made of human brain tissue, and they can help researchers explore important questions about brain development and disorders that occur during these first stages of life.

Researchers said in January 2014 they had developed a new method of making stem cells. Mouse cells were "stressed" in several ways, such as by being placed in an acidic environment. Researchers were then able to use those cells to generate various tissues in developing mice. This image shows a mouse fetus that has tissues that grew, in part, from the stem cells. However, other researchers have been unable to replicate the findings. Click through the gallery to learn more about stem cell research.

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• In two new studies, adult skin cells were used to make embryos


• Stem cells can grow into any kind of tissue


• Many future medical advances are hoped to arise from stem cells

(CNN) -- For the first time, cloning technologies have been used to generate stem cells that are genetically matched to adult patients.

Fear not: No legitimate scientist is in the business of cloning humans. But cloned embryos can be used as a source for stem cells that match a patient and can produce any cell type in that person.

Researchers in two studies published this month have created human embryos for this purpose. Usually an embryo forms when sperm fertilizes egg; in this case, scientists put the nucleus of an adult skin cell inside an egg, and that reconstructed egg went through the initial stages of embryonic development.

"This is a dream that we've had for 15 years or so in the stem cell field," said John Gearhart, director of the Institute for Regenerative Medicine at the University of Pennsylvania. Gearhart first proposed this approach for patient-specific stem cell generation in the 1990s but was not involved in the recent studies.

Stem cells have the potential to develop into any kind of tissue in the human body. From growing organs to treating diabetes, many future medical advances are hoped to arise from stem cells.

Scientists wrote in the journal Cell Stem Cell this month that they used skin cells from a man, 35, and another man, 75, to create stem cells from cloned embryos.

"We reaffirmed that it is possible to produce patient-specific stem cells using a nuclear transfer technology regardless of the patient's age," said co-lead author Young Gie Chung at the CHA Stem Cell Institute in Seoul, South Korea.

On Monday, an independent group led by scientists at the New York Stem Cell Foundation Research Institute published results in Nature using a similar approach. They used skin cells from a 32-year-old woman with Type 1 diabetes to generate stem cells matched to her.

Both new reports follow the groundbreaking research published last year by Shoukhrat Mitalipov and colleagues at Oregon Health & Science University in the journal Cell. In that study, researchers produced cloned embryos and stem cells using skin cells from a fetus and an 8-month-old baby.

"It's a remarkable process that gives us these master cells, these stems cells that are essentially the seeds for all of the tissues in our bodies," said George Daley, director of the Stem Cell Transplantation Program at Boston Children's Hospital, who was not involved in the recent studies. "That's why it's so important for medical research."

A brief history of stem cells

The first developments in the field of stem cell research used leftover embryos created by the union of sperm and egg from in vitro fertilization.

But embryonic stem cell research is controversial because to use the stem cells for developing medical treatments, the embryo is destroyed. Embryos have the potential to develop into a fully formed human, bringing up ethical questions.

Scientists later realized that it's not necessary to use embryos to obtain stem cells that match patients. Shinya Yamanaka won the 2012 Nobel Prize for Physiology or Medicine for discovering how to make "induced pluripotent stem cells," or IPS cells.

IPS cells are made by inserting genes to "turn back the clock" on mature cells that already have specific functions. It doesn't matter what the cell was before; it can now be reprogrammed as any kind of cell researchers want.

Why, then, would researchers bother to make stem cells using cloning, which requires human eggs and the creation of embryos?

"People have made patient-matched stem cells using IPS methods," said Dieter Egli, senior author on the Nature paper that could have implications for diabetes treatment and researcher at the New York Stem Cell Foundation. "But it is not clear in the U.S. at the very least, and also elsewhere, how and if these are going to be translated into people."

Egli points out that there have been some reports that IPS cells may have shortcomings when converted into specific cell types, and that stem cells produced by cloning may be better.

But which stem cell type is better and safer -- the IPS cells or cells from cloned embryos? That is still an open question. To settle it, there would need to be a comparison of the two stem cell types generated using the DNA of the same person.

Gearhart doesn't see the cloning method replacing the use of IPS cells, which are not controversial and don't require that women donate their eggs.

"As we learn more about the reprogramming process that normally occurs in the egg following fertilization, we can use that information to produce better IPS cells," Gearhart said.

The process of extracting eggs is complex and expensive; having enough supply is a "serious concern," Daley said.

"The more we learn about reprogramming, the more I think IPS will be the one of choice," Gearhart said.

Making stem cells by cloning

An embryo, the earliest stage of human development, is a cluster of cells smaller than the period at the end of this sentence.

To make a cloned embryo, scientists use equipment analogous to "like a half-million-dollar video game," Daley said.

Researchers perform surgery on eggs with needles that are the 10th of the size of a human hair. They use joysticks to manipulate the tiny equipment, spearing the egg, removing its DNA and then transferring the nucleus of a skin cell into the egg.

"That process, which is called nuclear transfer, sets in motion this remarkable process of early human development," Daley said. "We trick this reconstructed egg into thinking it's been fertilized."

Chung's group -- which led the Cell Stem Cell study -- used this cloning method that Mitalipov had pioneered to get two stem cell lines out of 77 eggs. "It seems that the quality of oocyte (egg) plays a pivotal role," Chung said.

Egli and colleagues had their own spin on the cloning process, amending it so that it happens in a more controlled way. Their study in Nature used electricity in combination with chemicals, and manipulating the calcium concentration, to improve the procedure. They generated stem cells specific to the diabetic patient who had donated skin cells; the eggs came from donors.

This group got four cell lines from 71 eggs, said research assistant Lydia Mailander. The average egg donation is 14 to 15 oocytes. Researchers estimate it would take two such donations to get one stem cell line.

In mice, Egli and colleagues showed in a separate study that the cloned stem cells from the diabetic patient mature into glucose-responsive beta cells, which secrete insulin into the bloodstream of the animals.

Further considerations

It's not clear that there are enough eggs in supply to support a large-scale production of stem cells this way, experts said.

For the near-term research purposes, there seem to be enough eggs available for stem cell cloning: About 10,000 egg donor cycles occur annually in the United States, Egli said.

But egg donation for research is generally low, Gearhart said. According to the American Diabetes Association, about 1 million Americans have Type 1 diabetes, the target population for a potential stem cell therapy.

The cloning method takes a few weeks, and is not significantly faster than generating IPS cells, Egli said.

Including compensation to the woman, an egg donation cycle costs about $14,000, Egli said.

"It may not at all be more expensive (than IPS) if the cells that we make are actually better," he said. "That's why it's important to do these comparisons."

Such a comparison would be interesting, said Daley, but the advantages would have to be considerable to beat out IPS, which is "much more efficient and less ethically contentious that Yamanaka (the Nobel winner) taught us."

Still, from a research perspective, the cloning method could help scientists interested in understanding how an egg reprograms the cell, Daley said. It could help answer: "How does an egg reset the whole identity of an adult cell back to an embryonic state?"

Stem cell cloning research might, in this way, teach scientists how to make stem cells more efficiently, he said, and optimize them for medical applications.

How about making a clone?

Mitalipov told CNN in 2013 that the embryos created in his study, from skin cells and eggs, would not grow babies. That would have required additional technology, and it wasn't part of the study.

But the same basic "nuclear transfer" principle used in Mitalipov's, Chung's and Egli's studies was used create Dolly the sheep, the first mammal clone.

In Dolly's case, an embryo created by nuclear transfer was transplanted to a ewe, which gave birth to a sheep.

In the case of human embryos generated in these stem cell experiments, "it would be dangerous and unethical to attempt to transfer them into a uterus," Daley said.