Shinya Yamanaka of Kyoto University made one of the most important stem cell breakthroughs: giving adult cells many of the same characteristics of embryonic stem cells thus avoiding many of the negative issues that surround stem cells such as harvesting them from aborted fetuses. The new cells, known as induced pluipotent stem (iPS) cells, live a long time while retaining the ability to form all of the different tissues in the body and have the potential of replacing cells, tissues or organs damaged or lost to disease.

Yamanaka screened 24 candidate proteins and found four that were able to reprogram adult cells, reverting them to their embryonic state, by imbedding them into the skin cells of a newborn infant. He first used mouse cells and then showed that these factors are also effective in human cells. The mechanism that led to the creation of the iPS cells is still not well understood.

iPSCs may be used in regenerative medicine to produce different types of cells for various tissues and organs, such as nerves, heart and liver. If the iPSCs are put into practice, their applications are expected to be conducive to advancing regenerative medicine, for instance, by transplanting nerve cells necessary to treat spinal cord damage, the analysts said.Hopes are also high that iPSC technology will make it possible to test the effectiveness of new drugs and their toxicity prior to clinical tests, they said.

A team at Kyoto University, including Yamanaka, plans to create iPS cells from the cells of Japanese patients suffering from incurable diseases, including muscular dystrophy, juvenile diabetes, nerve-degenerating diseases, and watch them mature and ideally discover the point in which the cells change and become diseased.

Ian Wilmut — the man who cloned Dolly the sheep’said he is interested in working with Yamanaka on projects using iPS cells. Wilmut is doing his own research with iPS cells. He equated Yamanaka’s discovery of iPS cells withe discovery of the double-helix structure of DNA. “I certainly think Yamanaka will have the Nobel Prize,” he said.

Although Japanese researchers pioneering iPS technology Japan is falling behind the United States in finding applications for the technology in treating things like Alzheimer’s disease and spinal chord injuries.

In February 2011, a patent for the iPS technology was given to Kyoto University.

Discovery of iPS Cells

Yamanaka announced his discovery with mice iPS cells in December 2005; and with human cells in November 2007. Kyoto University received a patent for the method to create the iPS in September 2008, giving the university exclusive rights to create iPS cells of all type of animals, including humans. The discovery of iPS cells has made the production of embryonic stem cells by placing the nucleus of a human somatic cell into an ova obsolete.

In the mid 2000s Yamanaka formed a team researchers at Kyoto University’s Institute for Frontier medical Sciences motivated by Yamanaka’s theory that if special genes were inserted into skin cells iPScells could be created. The researchers often hashed out ideas while sitting around eating meat at a yakuniku restaurant. Certain candidate genes were selected and tried in experiments with genetically-modified mice. Among the most skilled researchers was Kazutoshi Takahashi, then a 31-year-old researcher at Kyoto University. He was known for putting in long hours and quickly and skillfully conducting many experiments.

The first iPs cells were created in the summer of 2005 by Takahashi. He told the Daily Yomiuri that when the moment of discovery came he told his professor, Shinya Yamanaka, “We’ve done it!” Yamanal replied, “No way!” But there in a 10-centimeter petri dish was a cluster of cells in a bowl shape”the first ips cells.

Shinya Yamanaka, iPS Stem Cell Pioneer

Eryn Brown wrote in the Los Angeles Times: “Perhaps no scientist has had a greater impact on stem cell research than Dr. Shinya Yamanaka. While most of his colleagues were looking for ways to grow human embryonic stem cells into replacement tissues for treating patients, the Japanese researcher took the opposite approach and figured out how to rewind mature body cells to a flexible state in which they could again become many types of cells. His 2006 discovery of induced pluripotent stem cells, or iPS cells, paves the way for pursuing regenerative medicine therapies without the need to destroy embryos.” [Source: Eryn Brown, Los Angeles Times, November 27, 2010]

Yamanaka is from Osaka and a graduate of Kobe University. His primary lab is at Kyoto University in Japan, but he spends part of the year at UC San Francisco's Gladstone Institute of Cardiovascular Disease, where he was a postdoctoral fellow in the 1990s.

Yamanaka has received a number awards and prizes including the $700,000 Blazan Prize in biology, the Albert Lasker Basic Medical Research Award, the Shaw Prize and the Robert Koch Prize. In May 2011 he shared Israel’s $100,000 Wolf Prize for medicine with MIT researcher Rudolf Jaenisch. In November 2010 he received the $610,000 Kyoto Prize, which recognizes "significant contributions to the betterment of humankind," for his stem cell work. On his success Yamanaka told the Los Angeles Times, “When our group succeeded in generating iPS cells, I never imagined so many researchers would begin working on this new technology — or that the research would advance at such a rapid pace.”

Yamanaka’s Work with iPS Cells

Yamanaka told the Los Angeles Times, “In 2000, I became interested in how embryonic stem cells maintain their ability to develop into different kinds of cells. At the time, many laboratories were trying to turn embryonic stem cells into various functional cells. I thought the field was highly competitive, so I decided to go the opposite direction — [turning body cells] back to the embryonic state.” [Source: Eryn Brown, Los Angeles Times, November 27, 2010]

On the advantages of iPS cells, Yamanaka told the Los Angeles Times, “IPS cells can circumvent two obstacles faced by embryonic stem cells. One is the ethical controversy — we have to destroy embryos to isolate embryonic stem cells. The other is the risk of immune rejection when cells derived from embryonic stem cells are transplanted into a patient's body.” On their disadvantages he said, “The safety of the cells. They are made by using retroviruses to introduce genes into mature cells, but the process can cause iPS cells to grow tumors if the retrovirus is inserted in the wrong part of the genome.”

On the long-term potential of iPS cells, Yamanaka told the Los Angeles Times: “IPS cells can become an effective research tool for modeling drugs, screening drug compounds and testing for side effect or toxicity. In the future, when the safety and other issues are solved, iPS cell-derived functional cells may become sources for cell transplantation therapies.” On the primary scientific hurdles that remain with iPS cells he said, “Scientists need to find out the methods to generate safer iPS cells, how to turn those cells into functional cells, and how to transplant resultant cells into a body. We also need to figure out how to use the cells to study diseases in the lab.”

iPS Stem Cell Research

iPS cells created by Kyoto University Prof. Shinya Yamanaka and his colleagues were announced in 2006. Just like fertilized eggs, iPS cells taken from human skin cells or other somatic cells can transform into any kind of organ or tissue and can reproduce indefinitely. Embryonic stem cells can transform into any cell of the body. Scientists are hoping to harness embryonic stem cells to create a variety of replacement tissues for transplant, but their use has been controversial because human embryos have to be destroyed to harvest the cells. Embryonic stem cells are harvested from inside a blastocyst, which develops from a mammalian egg cell about a week after it is fertilized. [Source: AP, Yomiuri Shimbun]

“Valerie Ross wrote in Discover: When biologist James Thomson at the University of Wisconsin cultivated the first line of human embryonic stem cells in 1998, the work suggested an impending medical revolution. The cells, which could develop into any other type of cell in the body, promised tailor-made replacements for damaged or diseased organs and tissues. But isolating the cells required destroying human embryos, embroiling the research in religious controversy. Transplanted embryonic stem cells are ethically cleaner, but they have a genetic makeup different from the patient’s own, so they could be violently rejected by the immune system.

“In 2006, Japanese biologist Shinya Yamanaka found a solution: He reprogrammed skin cells from a mouse, turning them back into embryo-like cells, with the potential to grow into any tissue, simply by adding four genes. The next year, both Yamanaka and Thomson made these cells”called induced pluripotent stem cells, or IPS cells”from human skin. The new technique seemed to avoid the political pitfalls, and also to evade the perils of rejection since the cells were the patient’s own. [Source: Valerie Ross, Discover, January-February 2012]

“The Yomiuri Shimbun reported: “Cells, such as cardiac muscle that is produced from iPS cells, have already been utilized in tests to confirm the safety of newly produced medicines. Research to identify the causes of rare diseases and develop medicines to combat these illnesses has been carried out by producing nerve and bone cells from the iPS cells produced from patients who have rare diseases. [Source: Yomiuri Shimbun, May 13, 2011]

Setbacks in iPS Stem Cell Research

Scientists had high hopes iPS reprogrammed stem cells, which could be derived from a patient's own tissue and grown into any type of cell in the body. But studies in 2011 highlighted major issues with reprogrammed cells. Valerie Ross wrote in Discover magazine:Will we ever see the long- promised medical benefits of stem-cell therapy? Last year that question loomed larger than ever, as some of the most promising lines of research hit daunting roadblocks. [Source: Valerie Ross, Discover, January-February 2012]

“It turns out that IPS cells — just like embryonic stem cells — are fraught with problems of their own. In one study, geneticist Joseph Ecker at the Salk Institute in California took various stem cell lines reprogrammed from skin, fat, and other tissues and examined each line’s genome for dna methylation, chemical marks that alter how genes are expressed. “Global levels of DNA methylation in IPS cells look amazingly similar to embryonic stem cells,” Ecker says, “but there are distinct regions that do not get reprogrammed properly.” In those regions, methylation of the reprogrammed cells’ genomes still resembled the tissues they came from, suggesting that the cells had not been fully set back to the embryonic stage. If so, they would not take on their desired therapeutic roles.

“In an independent study, immunologist Yang Xu at the University of California, San Diego, set out to test the presumption that IPS cells would elude rejection. When he injected mice with embryonic stem cells genetically identical to the mice’s own tissues, the new cells thrived, growing into a large clump of adult tissues. But when he injected the mice with genetically identical reprogrammed stem cells, their immune systems attacked, destroying the cells. “The immune system is good at picking out even tiny things that aren’t normal,” Xu says.

“The ongoing challenge is creating IPS cells that function as much like embryonic stem cells as possible. “Now that we’ve found these problems,” Ecker says optimistically, “we can try to correct them.” Until that happens, though, reprogrammed cells are far from ready for the clinic.

Advances in iPS Cell Research in Japan

The first iPS cells were produced by infecting human and mouse skin cell with retroviruses embedded with three or four genes. This methods is believed to increase the risk of cancer due to chromosome damage inflicted by the viruses. In October 2008. Yamanaka’s team announced they had produced iPS cells in mice without using viruses, a breakthrough that has made the making of iPS cells considerably safer. Instead of using viruses the scientists used plasmids, circular DNA cells, that are absorbed by skin over a couple days and don’t cause chromosome damage

In November 2008, scientist at the RIKEN Center for Developmental Biology said they created brain tissue from iPS cells, a breakthrough that could help produce treatments to treat Alzheimer’s disease.

In February 2009, a team at Keio University succeeded in improving damaged spinal chords of mice by transplanting iPS cells into them. In the experiments mice researchers paralyzed the hind legs of the mice by injuring their spinal chords and inserted iPS cells int the spinal chords while the mice’s immune system was repressed. Four weeks later the mice were able to walk using their hind legs.

In March 2009, scientists at Tokyo University announced they had created mouse kidneys using iPS cells. The same month scientists, at the University of Edinburgh, including Japanese researcher Keisuke Kaji, said they had created iPS cells with viruses — thus reducing the risk of cancer — using the technique and increased the production efficiency. The technique involves combining four types of virus-inducing genes into one group, sandwiching them with a specific DNA configuration and injecting them into human skin cells with a specific enzyme.

Kyoto University Team Finds Gene to Cut iPS Cell Cancer Risk

In June 2011, a research team led by Yamanaka announced that it had developed a more efficient technique to produce induced pluripotent stem (iPS) cells that is expected to minimize the risk of tumor development in medical applications of the cells. An article on the the breakthrough was published in the British science journal Nature. [Source: Yomiuri Shimbun, June 10, 2011]

The Yomiuri Shimbun reported: “A major advantage of the technique is that it does not require the use of an oncogene, whose expression can lead to development of cancer, the article said. The four genes usually inserted into adult somatic cells to produce iPS cells include one oncogene, which is used to increase the efficiency of the process. Another advantage of the new technique, which so far the team has used only on mice, is that it minimizes the risk of iPS cells developing incompletely, according to team member Momoko Maekawa, an assistant professor at the university. Incompletely developed iPS cells can also lead to cancer.”

“Generally, iPS cells are produced by introducing four types of genes into skin and other somatic cells. Not using the oncogene decreases the success rate of producing iPS cells to "0.01 percent, or less," according to the group. This inefficiency was the main obstacle to practical application of producing iPS cells without the oncogene, the group said. According to the article, the new technique almost completely eliminates the loss in efficiency caused by not using the oncogene.”

“To find a gene that could effectively replace the oncogene in the process, the group inserted 1,437 genes, one by one, into mouse cells. It found that using a gene called Glis1 increased the success rate in producing iPS cells by as much as 100 times. All iPS cells developed completely when the Glis1 gene was inserted into somatic cells of mice, compared with the 80 percent of iPS cells that developed incompletely without the insertion of Glis1 genes, according to the group.”

“Incomplete cells can become cancerous after being transplanted into human bodies, a major obstacle to clinical application. The group found that iPS cells produced by inserting Glis1 genes did not produce malignancy in mice over a period of one year. In an experiment using human somatic cells, about 90 percent of the produced iPS cells developed imperfectly without Glis1 genes. However, only about 50 percent of iPS cells developed imperfectly with the use of Glis1 genes, the group said.”

IPS Cell Patent Granted to Kyoto University

Kyoto University has been granted a U.S. patent for the technology used in creating induced pluripotent stem cells (iPS cells). As the United States is by far the world's largest medical market, Kyoto University effectively has 80 percent of the global market in terms of patent acquisition of this high-value technology because it already has obtained patents in Japan and Europe.

The patent covers two basic methods of creating iPSCs--producing pluripotent cells similar to embryonic stem cells by injecting three kinds of genes into skin and other somatic cells, and by inserting two kinds of genes and proteins with cellular multiplication properties into somatic cells. The patent also covers a group of genes similar to those used for iPSC production, but not directly used in the two methods.

As the iPSC patent granted in Japan does not cover such genes, the U.S. patent has a much broader application, according to analysts. The patent approved in Europe in July for Yamanaka's breakthrough, however, is even wider in scope, covering substances to be created by genes employed in the technology, in addition to ones similar to them, they said.

After first receiving a patent in Japan in September 2008, the iPSC technology has so far been granted patents in more than 40 countries. Kyoto University filed an application for a patent with the U.S. patent office in June 2008. The patent it was granted is good through June 25, 2027, the university officials said.

To broaden the range of iPSC-related studies, Kyoto University will provide the technology to universities and other nonprofit research organizations free of charge, while offering it to other bodies at relatively low fees, the university officials noted. At a press conference Thursday, Yamanaka said: "For Kyoto University, a public entity, to acquire iPSC patents is of great importance in that researchers around the world will be able to carry out iPSC studies much more easily.

"We would like to see our endeavors in developing iPSCs prove truly useful by carrying out further studies in tandem with researchers around the world to advance regenerative medicine and develop new drugs."

Kyoto University Acquires iPS Cell Drug Patent in U.S.

“In May 2012, Kyodo, reported: “Kyoto University has obtained a research and development patent in the U.S. that covers new drugs incorporating variant cells and tissues made from induced pluripotent stem cells (iPS) , according to its Center for iPS Cell Research and Application. The patent given to the university, which also patented a method for creating iPS cells, will cover the use and sale of both cells and tissue produced from such cells, which are artificially derived from an adult cell, the officials said. [Source: Kyodo, May 13, 2012]

“The patent will require companies to pay licensing fees to Kyoto University when they sell products derived from iPS cells in the United States. However, as a public institution, the university intends to keep licensing fees low to encourage broader use of the patent, the officials said. It is the first time Kyoto University has taken out this kind of a patent in the United States, which represents the frontline in pharmaceutical development and regenerative medicine. The university has a similar domestic patent.

“The Yomiuri Shimbun reported: “By obtaining the patent, Kyoto University will have greater influence on U.S. research institutes and drugmakers. The United States is the world's largest medical and pharmaceutical market. The patent rights cover whole procedures of research and development involving iPS cells. This includes creating iPS cells by using four kinds of genes called "Yamanaka factors" or by putting three of the four genes into skin and other cells; changing the produced iPS cells into other kinds of cells; and conducting various types of research and development by using the transformed cells. [Source: Yomiuri Shimbun, May 14, 2012]

“This is the third time the university has obtained a U.S. patent for iPS cells, but the previous patents did not cover research and development using the transformed cells, including instances where researchers or companies that have no contract with the university developed new medicines by using cardiac muscle cells or other cells produced from iPS.From now on, companies will be required to obtain approval from the university if they want to use the transformed cells to create and sell new drugs. The patent will expire in December 2026. "We'd like to make efforts to obtain [a similar patent] in Europe and other countries as well," said Naoko Takasu, head of legal affairs at Kyoto University's Center for iPS Cell Research and Application.

IPS Cells Created from 110-year-old People

In November 2011, the Yomiuri Shimbun reported: “Aiming to discover the key to longevity, a team of Keio University researchers has succeeded in creating induced pluripotent stem cells (iPS) from the blood of people aged 110 or older. There are more than 47,000 people aged 100 or older in the country, but only about 60 have what is called superlongevity, i.e. are aged 110 or older. Led by university lecturers Nobuyoshi Hirose and Shinsuke Yuasa, the Keio team took blood from 13 men and women with superlongevity, and made iPS cells from the samples of four of them, the team said. The remaining samples were preserved by freezing. [Source: Yomiuri Shimbun, November 27, 2011]

“It has been learned that people with superlongevity are less susceptible to such problems as hardening of the arteries and the development of cancer. Their cells may have a stronger defense mechanism against illness than those of ordinary people, but the details have yet to be clarified. On the strength of its achievement making iPS cells from people with superlongevity, the Keio University team plans to create cells of such organs and tissues as veins, cardiac muscle and nerves. It will examine the cells' proliferation capabilities, ability to recover from injuries, tolerance for stress and the speed at which they age, and compare the data with that for ordinary people.

“The team also plans to analyze the genome of the people with superlongevity, in an attempt to clarify the secret of a long life, the researchers said.The researchers said their study of the iPS cells could make it possible to observe cells of various organs and tissues before they begin to differentiate, which could reveal the characteristics of the cells of people with superlongevity at the time of their birth. "If we can discover the key to longevity, the knowledge may help prevent hardening of the arteries and cancer, as well as promote the development of new medicine," Hirose said. "Analysis of the genome of the people with superlongevity may help clarify the genetic factors behind a long life.”

Stem Cells May Help Blind People See

Alicia Chang of AP wrote: “Two legally blind women appeared to gain some vision after receiving an experimental treatment using embryonic stem cells, scientists have reported. "This study provides reason for encouragement, but plans to now get such a treatment would be premature," said stem cell expert Paul Knoepfler of the University of California, who had no role in the research. While embryonic stem cells were first isolated more than a decade ago, most of the research has been done in lab animals. The new results come from the first tests in humans for a vision problem. Researchers caution the work is still very preliminary. [Source: Alicia Chang, AP, January 24, 2012]

“In 2011, each patient was injected in one eye with cells derived from embryonic stem cells at the University of California, Los Angeles. One patient had the "dry" form of age-related macular degeneration, the most common cause of blindness. The other had a rare disorder known as Stargardt disease that causes serious vision loss. There's no cure for either eye problem.After four months, both showed some improvement in reading progressively smaller letters on an eye chart. The Stargardt patient, a graphic artist in Los Angeles, went from seeing no letters at all to being able to read five of the largest letters.However, experts said the improvement of the macular degeneration patient might be mostly psychological, because the vision in her untreated eye appeared to get better too.

“Both patients remain legally blind despite their improvements, said experts not connected with the study. "One must be very careful not to over-interpret the visual benefit," said Vanderbilt University retina specialist Dr Paul Sternberg, who is also the president-elect of the American Academy of Ophthalmology. The findings were published online by the journal Lancet. This early test was meant to study whether the stem cell therapy was safe in people and not whether it would improve vision Scientists at UCLA and Advanced Cell Technology (ACT), which funded the work, said they were pleased that there have been no signs of rejection or abnormal growth months after the procedure.

Stem Cells Reduce Parkinson's Symptoms in Monkeys

In February 2012, the Yomiuri Shimbun reported: “Japanese researchers have been able to improve the symptoms of Parkinson's disease in monkeys by transplanting nerve cells derived from embryonic stem cells into their brains, the team has announced. The finding is the world's first reported success of its kind with a primate, according to the research team led by Associate Prof. Jun Takahashi of Kyoto University's Institute for Frontier Medical Sciences. It has been released in the online edition of U.S. journal Stem Cells. [Source: Yomiuri Shimbun, February 23, 2012]

“Parkinson's disease is a neurological illness believed to be caused by a deficit of the neurotransmitter dopamine in the brain. After the transplant, the monkeys, which had been almost unable to move, showed improvements in their symptoms to the point where they became able to walk on their own, the team said. Takahashi's research team used the embryonic stem cells to cultivate a cell mass in which 35 percent of the cells were dopamine-producing neurons.These neurons then were transplanted into the four crab-eating monkeys, whose conditions were observed over a one-year period.

“According to the study, the monkeys exhibited reduced shaking of their limbs half a year later. They had remained nearly motionless inside their cages all day long before the transplant, but the improvement of their symptoms eventually enabled them to occasionally walk around the cages. The research team confirmed that normal nerve cells had been created in their brains. The finding could mark a major breakthrough for applying embryonic stem cells in clinical settings, experts said. The Health, Labor and Welfare Ministry has been encouraging researchers to study the clinical applications of not only stem cells, but also induced pluripotent stem cells, which also can grow into many kinds of human cells.Takahashi's team has already performed experiments to transplant iPS cells into monkeys' brains."We'll make further efforts to enhance the safety of these cell transplants," Takahashi said. "And we hope to start clinical application studies as early as three years from now.”

iPS Cells Already Used to Develop New Medicines

In October 2012, the Yomiuri Shimbun reported: “Regenerative medicine is expected to advance significantly thanks to iPS cells because they can be transformed into the cells of many organs and tissues. They may even be used to recover bodily functions and tissues lost because of illness and accidents. Unlike embryonic stem cells (ES cells), which are produced by extracting certain elements of a fertilized egg, thereby "killing" it, iPS cells can be produced from a patient's own cells. Therefore, organs created by iPS cells are less likely to be rejected by a person's immune system. [Source: Yomiuri Shimbun, October 10, 2012]

A project team led by Masayo Takahashi, of the Laboratory for Retinal Regeneration at the Riken national research institute, plans to study the transplantation of retinal pigment epithelial cells made from iPS cells. The study, which may begin as early as next year, is aimed at patients suffering from age-related maculopathy, the weakening of the eyesight caused by the deterioration of retinal cells. Prof. Hideyuki Okano at Keio University will start a clinical study on patients with spinal cord injuries in about five years. In an experiment, he found that marmosets paralyzed in all four limbs were able to walk about six weeks after he transplanted nerve cells created from iPS cells.

Some medical technologies using iPS cells are already in practical use in the development of new drugs. Japanese and U.S. firms sell cardiac muscle, nerve and hepatic cells made from iPS cells that are used in experiments to determine the side effects of new medicines before they are administered to patients. Side effects are a major problem in the development of new medicines, as humans could exhibit side effects, even when no side effects were detected in animal experiments. By examining the reactions of organ cells cultivated from iPS cells, researchers can more accurately determine the toxicity and the effectiveness of new medicines. Using iPS cells produced from the cells of patients will help researchers understand the mechanism of an illness and develop new medicines to fight it.

A team led by Keio University Prof. Norihiro Suzuki has produced iPS cells from cells taken from Alzheimer's patients. After they transformed iPS cells into nerve cells, they succeeded in re-creating the characteristics of the illness, such as cells producing twice as many highly toxic proteins. The team is attempting to find a cure by using these nerve cells. "iPS cells were first produced in a mouse experiment in 2006, and clinical applications have already been planned," said Okano, who is conducting joint research with Nobel laureate Shinya Yamanaka. "His idea is brilliant, and the technology [of producing iPS cells] took the world by storm. No wonder he received the prize.”

Researchers Make Killer T Cells from iPS Cells

In January 2012, Jiji Press reported: “Japanese researchers said they have succeeded in efficiently using induced pluripotent stem cells to efficiently produce T cells capable of destroying melanoma, an achievement that could make cell-based anticancer therapy more powerful. Current cancer immunotherapy tries to stimulate patients' immune systems to increase T cells, a type of lymphocyte, in their bodies. But its effects are limited; the number of T cells does not increase dramatically. [Source: Jiji Press, January 5, 2012]

The researchers headed by Hiroshi Kawamoto of the national research institute Riken said their new method using iPS cells is efficient enough to mass-produce T cells with specific functions. T cells have millions of variants with unique receptors, depending on their genetic configurations. T cells react to other cells by using their receptors on the surface. One type, cytotoxic T lymphocyte, is known to attack viruses and cancer cells.

According to the Riken-led team's article published in the U.S. journal Cell Stem Cell, the group established iPS cells, which are immature cells that can develop into any type of tissue, from mature cytotoxic T cells specific to the melanoma epitope. They then differentiated the iPS cells into cells with a T-cell receptor specific to the epitope. After stimulating the differentiated cells with an immunosuppressive antibody, the team saw a large number of cells specific for the original epitope generated.

Similar results can be expected in research projects involving other types of cancer, it said. A different team led by Hiromitsu Nakauchi, a professor at the University of Tokyo, also reported in the same journal that it had reprogrammed clonally expanded T cells from an AIDS patient into iPS cells and regenerated HIV-killing cells from the pluripotent cells.

iPS Fraud

In early October 2012, around the time it was announced that Yamanaka had won the Nobel Prize, the Yomiuri Shimbun reported on its front page that iPS cells were apparently transplanted into six human patients at Harvard early in 2012 as a heart disease treatment. According to the article “a Japanese clinical researcher named Hisashi Moriguchi working at Harvard University transplanted iPSC-derived heart muscle cells in a world first. The pace of clinical development is moving unexpectedly quickly. The first case was 8 months ago, and that patient is already out of the hospital. The patient was a man in his thirties who had received a liver transplant, and subsequently required treatment for ischemic cardiomyopathy. The study received interim approval from the Harvard IRB The autologous iPSCs were generated from cells obtained by biopsy, using a different reprogramming method than the original Yamanaka method. Safety testing was done in pigs in advance. Moriguchi stated there were no adverse events in the six cases. [Source: Knoepfler Lab Stem Cell Blog, October 10, 2012]

It turned out the whole thing was a big fraud. David Cyranoski wrote in Nature: “From the beginning, it seemed too good to be true. Days after Kyoto University biologist Shinya Yamanaka won a Nobel prize for his 2006 discovery of induced pluripotent stem (iPS) cells, Hisashi Moriguchi — a visiting researcher at the University of Tokyo — claimed to have modified that technology to treat a person with terminal heart failure. But after being alerted to the story by Nature, Harvard Medical School and Massachusetts General Hospital (MGH), where Moriguchi claimed to have done the work, denied that the procedure had taken place. “No clinical trials related to Dr Moriguchi's work have been approved by institutional review boards at either Harvard University or MGH,” wrote David Cameron, a spokesman for Harvard Medical School in Boston, Massachusetts. “The work he is reporting was not done at MGH,” says Ryan Donovan, a public-affairs official at MGH, also in Boston. [Source: David Cyranoski, Nature, October 12, 2012]

A video clip posted online by the Nippon News Network — and subsequently removed — showed Moriguchi presenting his research at the New York Stem Cell Foundation meeting. If true, Moriguchi’s feat would have catapulted iPS cells into use in a wide range of clinical situations, years ahead of most specialists' predictions. But there were reasons to be suspicious. Moriguchi said he had invented a method to reprogram cells using just two chemicals: microRNA-145 inhibitor and TGF- ligand1. But Hiromitsu Nakauchi, a stem-cell researcher at the University of Tokyo, says that he has “never heard of success with that method”. He adds that he had also never heard of Moriguchi before this week. Moriguchi also said that the cells could be differentiated into cardiac cells using a ‘supercooling' method that he had invented. “That’s another weird thing,” says Nakauchi.

The article in which Moriguchi presented his two-chemical method, published in a book1 describing advances in stem-cell research, includes paragraphs copied almost verbatim from other papers. The section headed “2.3 Western blotting”, for example, is identical to a passage from a 2007 paper by Yamanaka2. Section 2.1.1, in which Moriguchi describes human liver biopsies, matches the number of patients and timing of specimen extractions described in an earlier article3, although the name of the institution has been changed.

When contacted by Nature, Moriguchi stood by his publication. “We are all doing similar things so it makes sense that we’d use similar words,” he says. He did admit to using other papers “as reference’. To support his supercooling technique, Moriguchi cited a paper of his own in Scientific Reports4 (a Nature Publishing Group journal). When Nature pointed out that that paper describes supercooling of human ovaries for preservation and not, as he asserted, for the differentiation of iPS cells into cardiac cells, Moriguchi said that a referee had recommended that he leave the latter experiment out of the paper “because it’s basically the same technology’. Moriguchi says that he did most of the contentious work himself, including safety research in pigs, the initial surgery and some of a further five similar procedures in other patients that took place from August onwards. Other researchers were involved in some of the procedures, he says, but he would not provide any names.

Moriguchi agreed that he was claiming “quite a variety of expertise’ for this array of procedures. To Nature, he said that he had learned the necessary surgical techniques while earning a medical degree at the Tokyo Medical and Dental University, but today he changed his story, saying that he has a nursing degree from the institution, not a medical degree. The University of Tokyo did confirm that Moriguchi held a position there from 2006 to 2009, during which he studied “medical economics’ and “evaluation of clinical technologies’. He is currently a visiting researcher at the university, working in the laboratory of Makoto Mihara in the university hospital's cosmetic-surgery section, where he “comes in once or twice a week’, says a secretary. Mihara was in a meeting concerning the case and could not be reached for comment.

Moriguchi also claims to have a laboratory at MGH and Harvard Medical School. The institutions confirmed that Moriguchi was a visiting fellow at MGH in 1999-2000, but he has not been associated with the hospital or the medical school since then. When questioned about who had funded his iPS cell procedures, where the procedures had been carried out, where his ethical review had taken place and which good manufacturing practice (GMP) facility had produced the necessary clinical-grade cells, Moriguchi referred again to MGH and Harvard Medical School. He could not, however, name the head of the ethical review board or any contacts at the GMP facility. Jerome Ritz, co-director of the Connell O'Reilly Cell Manipulation Core Facility at Harvard Medical School, told Nature, “We have not produced any iPS cells for any patients in our facility. I can't imagine what other facility might have produced these cells.”

Moriguchi Admits Reports of iPS Transplants Were Lies

In mid October 2012, the Yomiuri Shimbun reported: “Hisashi Moriguchi, who falsely announced that he transplanted cardiac muscle cells derived from induced pluripotent stem cells to heart disease patients, has admitted five of the six transplants he claimed to have performed were lies. During a New York press conference Saturday morning, however, he admitted five of them were false, saying the operations are "scheduled for the future." He apologized, saying, "I am responsible [for causing trouble] and I am very sorry for that." [Source: Yomiuri Shimbun, October 16, 2012]

The remaining transplant--which he previously claimed to have performed in February this year--was performed in June last year, he said. He previously stated the transplant was performed at Massachusetts General Hospital in Boston, which is affiliated with Harvard University, but retracted this statement Saturday. "I got the approval of the institutional review board of the hospital, but the operation itself was performed at another hospital in Boston," Moriguchi said. However, the hospital said it gave no such approval.

In late October 2012, the Yomiuri Shimbun reported: “The Yomiuri Shimbun has concluded six of the seven articles that reported on studies conducted by Hisashi Moriguchi were false. Moriguchi fabricated research in which he claimed he successfully transplanted cardiac muscle cells made from induced pluripotent stem (iPS) cells into humans. Among the six false articles, a series of articles related to the "iPS cardiac muscle cell transplantation" were carried in the newspaper's morning edition on Oct. 11, 2012[Source: Yomiuri Shimbun, October 27, 2012]

Reporters failed to verify Moriguchi's title and the true nature of his studies in the six false articles, The Yomiuri Shimbun said. The reporter in charge of the Oct. 11 articles had believed Moriguchi was a doctor. In actuality, Moriguchi did not have a national license certifying him to practice medicine. Four of the five articles, which were carried in the period from September 2009 to May 2010, reported on Moriguchi's "studies" regarding methods to create iPS cells and others. Moriguchi gave a number of dubious explanations in the four articles, including one in which he claimed he conducted all four studies by himself "during a 21-month stay in the United States beginning in late 2008." Multiple experts have said it would be "impossible" for Moriguchi to conduct the studies in such a short period all by himself.

One false article was carried in July 2012 reported that a group of researchers, including Moriguchi, had successfully enabled a former cancer patient to become pregnant by using a part of her ovary that had been removed and frozen before receiving cancer treatment. Multiple experts said such a method is "unthinkable," and Moriguchi said he did not attend the "surgery.”

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Text Sources: New York Times, Washington Post, Los Angeles Times, Times of London, Yomiuri Shimbun, Daily Yomiuri, Japan Times, Mainichi Shimbun, The Guardian, National Geographic, The New Yorker, Time, Newsweek, Reuters, AP, Lonely Planet Guides, Compton’s Encyclopedia and various books and other publications.

Last updated January 2013

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