MONUMENTAL ACHIEVEMENT
Stem-cell breakthrough uses human skin not embryos, opens new research pathways
By Mira Oberman, Agence France-Presse
CHICAGO
In a major breakthrough, scientists have generated stem cells from human skin that could help in the fight against major diseases and sidestep the battle over using embryonic cells. The discovery opens the door for promising research into using the blank-slate stem cells to test new drugs and study how diseases function without being forced to destroy embryos in the process, which has led to legal restrictions on research in the United States.
The researchers in Japan and the US have also eliminated a major hurdle to using stem cells therapeutically. The stem cells could eventually be generated with a specific patient's genetic code, eliminating the risk that the body would reject transplanted tissues or organs.
The new method is expected to rapidly advance research in the treatment of cancer, Alzheimer's and Parkinson's diseases, diabetes, arthritis, spinal-cord injuries, strokes, burns, and heart disease because scientists will have much greater access to stem cells.
"[The] work is monumental in its importance to the field of stem-cell science and its potential impact on our ability to accelerate the benefits of this technology to the bedside," said Deepak Srivastava, director of the Gladstone Institute of Cardiovascular Disease. "Not only does this discovery enable more research, it offers a new pathway to apply the benefits of stem cells to human disease."
Stem cells are seen as a possible magic bullet because they can be developed into any of the 220 types of cells in the human body. But research has been limited in the US because of ethical concerns, and very few labs have had the resources and technical expertise to work with embryonic stem cells.
The new method is fairly straightforward and can be repeated by standard labs with relative ease, said study author James Thomson of the University of Wisconsin at Madison. "My personal barometer of optimism has gone up a lot," Thomson said. "Funding is finally going to go up because this does remove the political debate. And as we engage more and more people in the United States things are going to accelerate."
The White House hailed the discovery as a means of solving medical problems "without compromising either the high aims of science or the sanctity of human life."
Two teams of researchers were simultaneously able to transform the skin cells by using a retrovirus to insert four different genes into the cells.
The Japanese team, led by Prof. Shinya Yamanaka of Kyoto University, managed to produce one stem-cell line out of every 5,000 cells. "This efficiency may sound very low, but it means that from one experiment, with a single ten centimeter dish, you can get multiple iPS (induced pluripotent stem) cell lines," he said, referring to a stem-cell type capable of creating any type of cell in the body except those of the placenta.
The US team, led by Thomson, reprogrammed one of every 10,000 cells but did so without the use of a gene that is known to cause cancer. Both techniques have the risk of mutation because the cells retained copies of the virus used to deliver the genes.
The crucial next step is to find a way to switch on the genes that cause the skin cells to regress into stem cells rather than relying on the retrovirus to insert the genes.
"It's almost inconceivable at the pace this science is moving that we won't find a way to do this," stem-cell researcher Douglas Melton of Harvard University told Science magazine.
The ability to design patient-specific and disease-specific stem cells ought to help push research forward even before the mutation risk is eliminated.
"These cells should be extremely useful in understanding disease mechanisms and screening effective and safe drugs," Yamanaka said. "If we can overcome safety issues, we may be able to use human iPS cells in cell transplantation therapies."
While the skin cells may eventually prove to be more useful than embryonic stem cells, Yamanaka cautioned that it would be premature to conclude that iPS cells can replace embryonic stem cells. "We are still a long way from finding cures or therapies from stem cells and we don't know what processes will be effective," he added.
Thomson cautioned it could be a couple years before researchers resolve all the problems with iPS cells and can confirm that they do not eventually act differently than embryonic stem cells.
Thomson's paper appears in Science magazine and Yamanaka's paper in Cell.
Japanese team goes one better
Ten days after announcing the breakthrough on November 20, the Japanese team announced a further advance, saying they had made good progress towards clearing a key safety hurdle in their work. In further research unveiled by Nature Biotechnology, Yamanaka's team reported that they can now produce iPS cells without having to resort to a cancer gene found to cause tumors in many of the lab mice in the earlier experiment. If confirmed, it will remove a significant safety hazard in using these cells in transplants one day.
In the original research, Yamanaka used a retrovirus to deliver four genes, including the cancer gene c-Myc, into skin cells. The gene delivery in essence "reprogrammed" these cells so that they lost their specialized adult functions and become primitive and versatile, functioning like embryonic stem cells.
This time, the team used only three genes, leaving out c-Myc, in a bid to find whether this would still induce the reprogramming yet also reduce the cancer risk. The main test involved mice that had been engineered to have specialized cells that were derived from the iPS cells.
At a 100-day deadline in the experiment, none of the 26 mice with iPS cells that had been derived without c-Myc died of tumors. But among mice that had iPS cells derived with c-Myc, six of the 37 animals died of tumors.
Yamanaka's team also created human iPS cells from a skin sample taken from a 36-year-old adult. The cells were of high quality, but without c-Myc, the efficiency of iPS-cell generation "decreased substantially," they wrote. "In approximately half the experiments, we were not able to obtain human iPS cells when transduction with the Myc retrovirus was omitted," they said.
The next step is to find a way of increasing generation of iPS cells by using a safe substitute for c-Myc.
One of the big pluses from Yamanaka's work is that it could one day allow doctors to create stem cells that bear the patient's genetic code, thus eliminating the risk that if these cells are transplanted they will be at-tacked as alien by the body's immune system.
But Yamanaka cautioned it would take time to put the research to practical use. "The goal is far off in the distance," he said, adding that embryonic stem cells, despite the controversies surrounding them, would still have to be used for a while.
End to ethical dilemma
The breakthrough was hailed as a means of ending the ethical dilemma that has hounded stem-cell research.
US President George W. Bush, who has blocked federal funding of research using new embryonic stem cells, applauded the discovery. "The President believes medical problems can be solved without compromising either the high aims of science or the sanctity of human life," the White House said in a statement.
"We will continue to encourage scientists to expand the frontiers of stem cell research and continue to advance the understanding of human biology in an ethically responsible way."
The US Conference of Catholic Bishops said the new discovery "reminds us once again that medical progress and respect for human life are not in conflict; they can and should support and enrich one another for the good of all."
The Vatican said the creation of stem cells from skin should not pose the "ethical problems" associated with the use of embryos. "The new research taking shape should not pose ethical problems," Monsignor Elio Sgreccia, head of the Pontifical Academy for Life, told the religious news agency I-Media. "As of now we consider this process legitimate, pending further verification."
The Catholic Church "is not concerned about technical processes. It reacts only if a process threatens human dignity," Sgreccia said. It is this principle that has prompted the Church to reject human cloning and "fight the destruction of embryonic stem cells," he said, adding: "You cannot save the life of one person by killing another. It's ethical Machiavellianism."
Sgreccia said Yamanaka "took part last year in the work of the Academy for Life here at the Vatican."
Pope John Paul II set up the academy in 1994 to support medical and legal research "relative to the promotion and defense of life, above all in the direct relation that they have with Christian morality" and Church directives.
Australian researcher Prof. Alan Trounson, who was recently named head of the world's biggest research project into stem-cell research, said the development was a breakthrough in genetic research. "This is a very important development because you could take cells from patients with severe diseases like motor neuron disease or Parkinson's or diabetes and start to analyze the cause of the disease," he told national radio.
"But it also means that in the fullness of time we could probably take cells from the person and judge how they are going to respond to different drugs. And eventually, one hopes, with modification it will produce this technology to make cells for cell therapy for patients."
Trounson, currently at Monash University in Melbourne but soon to move to head the California Institute for Regenerative Medicine which has a research budget of US$3 billion, said the technique demonstrated the trend away from controversial therapeutic cloning.
"I think this takes the edge off that particular issue because we appear to have a way in which we can change cells into the cell type we need to study in the laboratory without using human eggs and without forming an embryo of any kind," he told the Australian Broadcasting Corporation.
Asked whether this trend could lead to the bypassing of the ethical cloning debate, he said: "I think that's correct."
But the new discovery will make it harder to fight opponents of stem-cell research, warned Alta Charo, a professor of law and bioethics at the University of Wisconsin at Madison.
Bush has twice vetoed attempts to grant federal funding to new embryonic-stem-cell research and Republicans have also tried to ban the research completely.
"It's going to fuel those who call for preferential federal funding only for non-embryonic-stem-cell research and it will certainly complicate any efforts to expand funding for embryonic-stem-cell research at the federal level," said Charo, who sits on the advisory board of the International Society for Stem Cell Research. "No matter how well this new technique can be used ... calls for criminalization or wholesale de-funding of embryonic-stem-cell and cloning research are not warranted," she said.
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Turning lead into gold
Breakthrough opens door to organ transplants grown in lab
Mira Oberman and Kyoko Hasegawa, Agence France-Presse
CHICAGO
Transplantable hearts grown in petri dishes and the regeneration of amputated limbs were once the things of science fiction. But a major breakthrough brought those dreams closer to reality after researchers announced they were able to turn the clock back on skin cells and transform them into stem cells, the mutable building blocks of organs and tissues.
"This is truly the Holy Grail: To be able to take a few cells from a patient-say a cheek swab or few skin cells-and turn them into stem cells in the laboratory," Robert Lanza of Advanced Cell Technology said. "It's bit like learning how to turn lead into gold."
While the research is still in its infancy, the potential benefits are "tremendous" said Lanza, who has already found ways to cut the death rate following heart attacks in half, restore blood to limbs which would otherwise have to be amputated and construct a functioning kidney using stem cells.
The new technique, while far from perfected, is so promising that the man who managed to clone the world's first sheep, Dolly, is giving up his work cloning embryos to focus on stem cells derived from skin cells.
"The fact that [the] introduction of a small number of proteins into adult human cells could produce cells that are equivalent to embryo stem cells takes us into an entirely new era of stem-cell biology," said Ian Wilmut, the Scottish researcher who first created a viable clone by transferring a cell nucleus into a new embryo. "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."
One of the greatest advantages of the new technique is its simplicity: it takes just four genes to turn the skin cell back into a stem cell. This, unlike the complex and expensive process developed by Wilmut, can be done in a standard biological lab. And skin cells are much easier to harvest than embryos.
The main hurdle to overcome is finding a safe way to transform the skin cells.
"It's an explosion of resources," said Konrad Hochedlinger, of the Harvard Stem Cell Institute. "You can take skin cells from a diabetic, turn them into pancreatic cells, and figure out what happens," he said.
These stems cells could allow researchers to map the genetic structure of diseased cells, a process which could unlock a cure. They could also allow researchers to do chemical screens to identify drugs that may cure or treat the disease, a process that could significantly speed up the process of bringing life-saving drugs to the market.
Just the beginning
While it is incredibly promising, the new technique should not be seen as a reason to abandon controversial embryonic-stem-cell research, scientists cautioned.
"This new research is just the beginning-we hardly understand how these cells work," said James Thomson of the University of Wisconsin at Madison, who led one of the two teams that made the simultaneous discoveries. "It is not the time to abandon stem-cell research," Thomson said, adding that embryonic stem cells will remain the "gold standard" by which other research is measured.
The lack of sufficient funding has already set the field back by four to five years while the political controversy and "strong stigma" have prevented many young scientists from entering the field, Thomson added.
The discovery shows that more, not less, embryonic-stem-cell research is needed said Robert Klein, chair of the California Institute for Regenerative Medicine, which funds embryonic-stem-cell research.
"With as brilliant of a discovery as this is, it will be three or four years before we really understand the stability of these lines," he said. "It would be an absolute tragedy if this nation made a second strategic mistake and bet the entire future of the nation's research on research that has no history."
"It was a breakthrough. It allowed us to see a goal. But the goal is far off in the distance," Shinya Yamanaka, the leader of the Kyoto University research team, said in an interview. But he cautioned it would still take a long time before researchers could treat stem cells from skin like those from embryos.
"Scientists have to continue embryonic stem cell research as it would take some time for us-at least a year, I would say-to prove its safety in research on monkey cells," followed by tests on human cells, he said.
Research involving embryonic stem cells-which can develop into various organs or nerves-is seen as having the potential to save lives by helping find cures for diseases such as cancer and diabetes. But the studies have provoked a furore among religious conservatives, who argue that such research destroys a human life, albeit one at its earliest stage of development.
US President George Bush has banned all federal funding for research on new human stem cells, battling with Congress, although money is still available for research on embryos gathered before the ban.
Japan, the largest spender on scientific research after the US, has fewer taboos about embryonic research. However, all projects in Japan need approval from a government panel on bioethics, which has restrictions including a prohibition on attempts at human cloning. Many women are also hesitant to donate eggs.
"Before our success in the human skin research, we had to do research on animals because it is extremely hard to obtain human embryonic stem cells for research purposes," Yamanaka said.
Yamanaka's team generated versatile iPS (induced pluripotent stem) cells, which, like embryonic stem cells, can develop into various organs and tissues. This alternative way of developing stem cells, however, holds the risk of causing cancer because it uses a retrovirus-seen as having a carcinogenic quality-to make the skin cell function as a stem cell. The new cells will have to be studied to see if the tissues will break down over time or if they cause other mutations or cancer.
"We have to test the safety of the alternative stem cells first, including the risk of cancer," said Yamanaka. "But honestly, I can't predict at all how long it may take for us to solve the challenges," he said. "We were able to adapt our mice experiment to human skin a year later, but it could have taken years. The same can be said for our future research."
Other challenges include trying to verify that the iPS cells function in exactly the same way as embryonic stem cells using human eggs. Theoretically, iPS cells could also develop into human eggs and sperm. "Further research must be done in order to avoid the misuse of reproductive cells," Yamanaka said.
Another set of Japanese researchers in March said they had succeeded in cloning mouse embryos from unfertilized eggs, believing it was less controversial than using fertilized eggs.
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MIGHTY MICE
Scientists engineer rats that can run 20 meters per minute, eat 60-percent more than wild mice, and live longer
WASHINGTON
US researchers have engineered a line of "mighty mice" whose human equivalent would have similar abilities to the bicycling champion Lance Armstrong. The breed of mice can run six kilometers at a speed of 20 meters (yards) per minute for up to six hours without stopping, according to Richard Hanson, a biochemistry professor at Case Western Reserve University in Cleveland, Ohio.
"They are metabolically similar to Lance Armstrong biking up the Pyrenees; they utilize mainly fatty acids for energy and produce very little lactic acid," said Hanson, the senior author of the article which was published in the Journal of Biological Chemistry.
The genetically engineered mice can eat 60 percent more than wild mice in a control group but remain slim and fit. The "mighty mice" live longer, and some females were able to reproduce much later in life than other mice.
The researchers said some "have had offspring at 2.5 years of age, an amazing feat considering most mice do not reproduce after they are one year old." Hanson said the strength of the mice was made possible by the fact that they produce very little lactic acid, which forms during intense exercise.
Scientists bred 500 of the mice, which also showed more aggression than other mice, over the past five years as part of a project aimed at unlocking the metabolic and physiological function of phosphoeno-lypyruvate carboxykinases (PEPCK-C) in muscles and tissues.
The key to their unusual traits is the over-expression of the gene that influence production of the enzyme PEPCK-C (phosphoenolypyruvate carboxykinases), said Hanson.
The transgenic mice are descended from six "founder lines" that "contain a chimeric gene in which a copy of the cDNA for PEPCK-C was linked to the skeletal actin gene promoter," the research said. The resulting mice showed different levels of PEPCK-C in their muscles, but one particularly active group had levels of PEPCK-C activity of nine units per gram of skeletal muscle, compared to just 0.08 units per gram in the muscles of control mice.
"From a very early age, the PEPCK-C mice ran continuously in their cages," said Parvin Hakimi, a researcher in the Hanson lab.
The "mighty mice" primarily relied on "fatty acids as a source of energy during exercise, while the control animals rapidly switched from fatty acid metabolism to using muscle glycogen (carbohydrates) as a fuel; this dramatically raised the blood lactate levels," the research said.
The PEPCK-C enzyme was first discovered at the medical school of Case Western Reserve University in 1955, the study authors said.
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CLONING BREAKTHROUGH
Scientists create first cloned embryo from primate using somatic-cell nuclear transfer
Richard Ingham, Agence France-Presse
PARIS
Scientists have created the world's first cloned embryo from a monkey, in work that could spur cloning of human cells for use in medical research. In a paper published by Nature, a team in the United States said they had created cloned embryos of rhesus macaques, using the same method that famously led to Dolly the Sheep and other genetically duplicated animals.
It is the first time that this technique has been successfully used to create cloned primate embryos. The group generated two lines of embryonic stem cells from the embryos, according to the research headed by Shoukhrat Mitalipov of the Oregon Health and Science University in Beaverton, Oregon.
Dolly, the world's first cloned animal, was created in 1996, by using so-called somatic-cell nuclear transfer (SCNT) in which the genetic core of an egg is removed and replaced with the nucleus of an adult cell. The egg is then stimulated with chemicals or a jolt of electricity to prompt its division.
The list of other cloned creatures using SCNT includes mice, pigs, cats, cows, and dogs. Until now, though, there has been no cloned primate, for researchers have encountered obstacles that cause cell development to be catastrophically flawed.
Work on primate cloning has also stirred controversy among ethicists, who say it could open the door to cloning human beings, not just cells. In an exceptional move, Nature said it moved forward the release of the paper because of "continuing speculation."
Researchers distinguish between "reproductive cloning" of humans-in which a putative cloned baby would be born-and "therapeutic cloning," in which only cloned cells would be used for medical reasons and no baby would result.
Helen Wallace of Genewatch UK, a British group that monitors cloning and other activities in biotechnology, said the breakthrough would cause "a real worry" in some quarters that it would tempt a renegade scientist to create a cloned baby.
"The clear risk of an experiment [in human reproductive cloning] is of a deformed baby and maternal suffering," she said. "In Britain, we don't think that the technology is going to go that far because there are laws against reproductive cloning. However, in most countries around the world, there are no legal safeguards.
Stem cells are immature cells that develop into the specific tissues of the body. Embryonic stem cells have the highest capability of all, because they can differentiate into any tissue. Scientists hope to be able to coax these cells into one day becoming replacement tissue for organs that are damaged or diseased.
Transplanted cells from a donor, though, run the risk of being attacked as intruders by the patient's immune system. By creating stem cells programmed with the patient's own DNA the risk of rejection would be skirted.
Mitalipov's team said they collected 304 eggs, also known as oocytes, from 14 female rhesus macaques. The donor nucleus came from skin cells taken from an adult male monkey housed at the Oregon National Primate Research Center.
The claim that the stem cells were an exact DNA copy of the donor monkey's genetic code was validated independently by a team led by David Cram of Monash University in Melbourne, Australia. That confirmation comes on the heels of a scandal surrounding earlier claims on cloning. In 2004, South Korean scientist Hwang Woo-suk announced he had created 30 cloned human embryos from which he derived stem cells, but his data turned out to be fake.
In a commentary published in Nature, British scientist Ian Wilmut-Dolly's "father"-and colleague Jane Taylor of the Center for Regenerative Medicine in Edinburgh, Scotland, said the new advance's brightest benefits may lie not in creating replacement tissue from stem cells but in unlocking basic knowledge about inherited disorders.
By making patient-specific cells, doctors could obtain cells whose genome would provide a telltale of a disease. These cells could be compared with healthy counterparts to see what is wrong, and a library of drugs could then be screened to see if a treatment is available.
"Ultimately, this approach might lead to treatments for neurodegenerative diseases, some cancers and psychiatric disorders," the two said.
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