TIME medicine

Stem Cells Allow Nearly Blind Patients to See

Stem cells could lead to new treatments for eye disorders Photography by Peter A. Kemmer—Getty Images/Flickr RF

Embryonic stem cells can be turned into a therapy to help the sight of the nearly blind

In a report published in the journal Lancet, scientists led by Dr. Robert Lanza, chief scientific officer at Advanced Cell Technology, provide the first evidence that stem cells from human embryos can be a safe and effective source of therapies for two types of eye diseases—age-related macular degeneration, the most common cause of vision loss in people over age 60, and Stargardt’s macular dystrophy, a rarer, inherited condition that can leave patients legally blind and only able to sense hand motions.

In the study, 18 patients with either disorder received transplants of retinal epithelial cells (RPE) made from stem cells that came from human embryos. The embryos were from IVF procedures and donated for research. Lanza and his team devised a process of treating the stem cells so they could turn into the RPE cells. In patients with macular degeneration, these are the cells responsible for their vision loss; normally they help to keep the nerve cells that sense light in the retina healthy and functioning properly, but in those with macular degeneration or Stargardt’s, they start to deteriorate. Without RPE cells, the nerves then start to die, leading to gradual vision loss.

MORE: Stem Cell Miracle? New Therapies May Cure Chronic Conditions Like Alzheimer’s

The transplants of RPE cells were injected directly into the space in front of the retina of each patient’s most damaged eye. The new RPE cells can’t force the formation of new nerve cells, but they can help the ones that are still there to keep functioning and doing their job to process light and help the patient to see. “Only one RPE can maintain the health of a thousand photoreceptors,” says Lanza.

The trial is the only one approved by the Food and Drug Administration involving human embryonic stem cells as a treatment. (Another, the first to gain the agency’s approval, involved using human embryonic stem cells to treat spinal cord injury, but was stopped by the company.) Because the stem cells come from unrelated donors, and because they can grow into any of the body’s many cells types, experts have been concerned about their risks, including the possibility of tumors and immune rejection.

MORE: Early Success in a Human Embryonic Stem Cell Trial to Treat Blindness

But Lanza says the retinal space in the eye is the ideal place to test such cells, since the body’s immune cells don’t enter this space. Even so, just to be safe, the patients were all given drugs to suppress their immune system for one week before the transplant and for 12 weeks following the surgery.

While the trial was only supposed to evaluate the safety of the therapy, it also provided valuable information about the technology’s potential effectiveness. The patients have been followed for more than three years, and half of the 18 were able to read three more lines on the eye chart. That translated to critical improvements in their daily lives as well—some were able to read their watch and use computers again.

“Our goal was to prevent further progression of the disease, not reverse it and see visual improvement,” says Lanza. “But seeing the improvement in vision was frosting on the cake.”

TIME diabetes

Type 1 Diabetes Treatment Gets Boost from Stem Cells

Human stem cell derived beta cells
Insulin-making cells grown from stem cells glow green two weeks after they are transplanted into mice (c) Douglas Melton 2014

Scientists started with stem cells and created the first insulin-making cells that respond to changes in glucose

Scientists are closer to a potential stem cell treatment for type 1 diabetes.

In a new article in the journal Cell, Douglas Melton, co-director of the Harvard Stem Cell Institute (and one of the 2009 TIME 100) and his colleagues describe how they made the first set of pancreatic cells that can sense and respond to changing levels of sugar in the blood and churn out the proper amounts of insulin.

It’s a critical first step toward a more permanent therapy for type 1 diabetics, who currently have to rely on insulin pumps that infuse insulin when needed or repeated injections of the hormone in order to keep their blood sugar levels under control. Because these patients have pancreatic beta cells that don’t make enough insulin, they need outside sources of the hormone to break down the sugars they eat.

MORE: Stem-Cell Research: The Quest Resumes

Melton started with two types of stem cells: those that come from excess embryos from IVF procedures, and those that can be made from skin or other cells of adults. The latter cells, known as iPS cells, have to be manipulated to erase their developmental history and returned back to an embryonic state. They then can turn into any cell in the body, including the pancreatic beta cells that produce insulin. While the embryonic stem cells from IVF don’t require this step, they aren’t genetically matched to patients, so any beta cells made from them may cause immune reactions when they are transplanted into diabetic patients.

Both techniques, however, produced similar amounts of insulin-making beta cells—something that would have surprised Melton a few years ago. But advances in stem cell technology have made even the iPS cells pretty amenable to reprogramming into beta cells. Melton’s group tested more than 150 different combinations of more than 70 different compounds, including growth factors, hormones and other signaling proteins that direct cells to develop into specific cell types, and narrowed the field down to 11 factors that efficiently turned the stem cells into functioning beta cells.

MORE: Woman Receives First Stem Cell Therapy Using Her Own Skin Cells

The two populations of stem cells churned out hundreds of millions of insulin-making cells, which is the volume of cells that a patient with type 1 diabetes would need to cure them and free them from their dependence on insulin. An average patient, says Melton, would need one or two “large coffee cups” worth of cells’, each containing about 300 million cells. Melton and his team then conducted a series of tests in a lab dish to confirm that the cells were functioning just like normal beta cells by producing more insulin when they were doused with glucose, and less when glucose levels dropped. That was a huge advance over previous efforts to make beta cells from stem cells—those cells could produce insulin, but they didn’t respond to changing levels of glucose and continuously pumped out insulin at will.

Next, the scientists transplanted about five million of the stem cell derived beta cells into healthy mice, and two weeks later, gave them an injection of glucose. About 73% of the mice produced enough insulin to successfully break down the sugar. What’s more, that was similar to the proportion of mice responding to glucose after getting a transplant of beta cells from human cadavers. That was especially encouraging since some type 1 diabetics currently receive such transplants to keep their diabetes under control. “We’ve now shown that we can produce an inexhaustible source of beta cells without having to do to cadavers,” he says.

MORE: First Stem Cells Cloned From Diabetes Patient, Thanks to Egg Donors

Taking the tests even further, the group showed that even mice that were already diabetic showed improved blood sugar levels after receiving a transplant of the stem cell beta cells—in other words, the transplanted cells effectively cured their diabetes. “We showed you can give three sequential challenges of glucose—similar to breakfast, lunch and dinner—and the cells responded properly,” says Melton.

But he acknowledges that as exciting as the advance is, it only solves half the problem for those with type 1 diabetes. The reason their beta cells aren’t able to make enough insulin may be due to the fact that they are attacked by the body’s own immune system for reasons that scientists still don’t understand. So the next step in turning these findings into a potential therapy is to find ways to protect the beta cells from destruction, either by encapsulating them in a mesh-like device similar to a molecular tea bag, or finding ways to genetically modify them to carry ‘don’t attack me’ proteins, the same way that fetal cells do so that an expectant mother’s immune cells don’t attack the growing baby.

MORE: Stem Cell Miracle? New Therapies May Cure Chronic Conditions like Alzheimer’s

“It’s taken me 10 to 15 years to get to this point, and I consider this a major step forward,” says Melton, who began researching ways to treat type 1 diabetes when first his son, then his daughter were diagnosed with the condition more than two decades ago. “But the longer term plan includes finding ways to protect these cells, and we haven’t solved that problem yet.”

TIME medicine

Woman Receives First Stem Cell Therapy Using Her Own Skin Cells

A Japanese woman is the first to receive retinal cells made from her own skin cells

Researchers at the RIKEN Center for Developmental Biology in Japan surgically transplanted a sheet of retinal pigment cells into the eye of a 70-year old woman on Friday.

The cells are the first induced pluripotent stem cells, or iPS cells, given to a human patient. They were made by Masayo Takahashi, who grew them from the patient’s own skin cells, which were treated with four genetic factors to revert back to an embryonic-like state. Takahashi then soaked the cells with the appropriate growth factors and other compounds so they developed into retinal pigment cells.

The patient was losing her sight due to macular degeneration, because her retinal pigment endothelial cells were damaged by an overgrowth of blood vessels. Replacing them with a new population of cells can restore her sight.

MORE: Stem-Cell Research: The Quest Resumes

Stem cell scientists are starting to test their treatments in eye-related diseases, because parts of the eye are protected from the body’s immune system, which could recognize the introduced cells as foreign and destroy them. That’s not a problem with the iPS cells, since they are made from the patient’s own skin cells, but it’s an added safety net to ensure that the therapy is safe and hopefully effective.

Because iPS cells are genetically treated to erase their skin cell development and revert them back to an embryonic-like state when they can become any type of cell, there are still concerns about their safety when transplanted into patients. The U.S. Food and Drug Administration has not yet approved a trial involving iPS cells – so far, only stem cells made from excess IVF embryos have been approved for treating macular degeneration. A 19-member committee of the Japanese ministry of health approved the experimental procedure four days ago, according to Nature, after Takahashi made her case, with the help of Dr. Shinya Yamanaka of Kyoto University, who shared the 2012 Nobel Prize for discovering iPS cells.

MORE: Stem Cell Miracle? New Therapies May Cure Chronic Conditions like Alzheimer’s

Japan’s stem cell scientists are hoping the surgery is a success; the field has been struggling since a well-publicized paper about a new way to make iPS cells was retracted amid allegations of fraud.

It’s not known whether the cells will continue to grow and form abnormal tumors, or whether they will migrate to other parts of the body. But now that the first patient has received them, those questions – and more, about the effectiveness of stem cell therapy – might be answered soon.

TIME Japan

Science Scandal Triggers Suicide, Soul-Searching in Japan

Sasai, deputy director of the Riken's Center for Developmental Biology, poses for a photo with Haruko Obokata in front of a screen showing STAP cells, in Kobe
Yoshiki Sasai, right, deputy director of the Riken's Center for Developmental Biology, poses for a photo with Haruko Obokata on Jan. 28, 2014. Kyodo/Reuters

Yoshiki Sasai’s death has generated mixed emotions among Japan's scientific community

It was a success story that Japan sorely needed: a young, talented and beautiful researcher developed a cheap and simple way to grow versatile stem cells.

The discovery promised to usher in a new age of regenerative medicine, validated Japan as a leader in scientific research and demonstrated that even in a male-dominated society, women could excel when given a chance.

Alas, it may have been too good to be true.

Intrigued by researcher Haruko Obokata’s breakthrough, other scientists tried but failed to replicate her results. Peer-review websites accused her of falsifying data and doctoring images, and supervisors were accused of lax management. Obokata, 30, was forced to retract her scientific papers, and the government-sponsored research center where she worked launched a formal investigation.

The matter took a darker turn this week when Obokata’s supervisor and mentor, Yoshiki Sasai, a noted scientist in his own right, was found hanging from a stairway railing at his office.

In farewell letters found at his desk, Sasai reportedly apologized for the turmoil, but urged Obokata to continue her work and to prove her detractors wrong.

Sasai’s death cast a pall over the controversy. But in a nation where suicide does not carry the same stigma as in some Western countries, there has been a certain degree of sympathy — if not outright approval.

“This is seen in some respects as an honorable way out of a shameful and devastating turn of events: ‘A highflyer brought low by an underling’s mistakes, seeking to atone for and expunge the shame,’” says Jeffrey Kingston, a professor of Asian studies at Tokyo’s Temple University-Japan. “This touches a chord of sympathy and understanding in Japan.”

Sasai was a noted stem-cell scientist and deputy director of the RIKEN Center for Developmental Biology, in Kobe — part of a national research system that receives roughly $1 billion a year in government support and is part of an ambitious effort to boost scientific research throughout Japan.

The 52-year-old was not directly involved in Obokata’s research, but had helped recruit her and supervised the research papers that were published in the British journal Nature in January.

But whether Sasai’s death generates sympathy for Obokata or the rest of Japan’s scientific community remains to be seen.

Obokata burst onto the scene in late January with the publication of the Nature papers, of which she was the lead author. Those studies claimed to have found a new way of creating stem cells, dubbed stimulus-triggered acquisition of pluripotency, or STAP. Such cells could be used to create new tissue, with potential for treating illnesses like Alzheimer’s, heart disease and stroke.

Poised and photogenic, Obokata was an instant hit with Japan’s frenetic media —mainstream and social, alike. Here, after all, was a different kind of scientist. Even in the lab, Obokata flashed stylish clothes, false eyelashes and fashionable hairstyles. She eschewed the usual white lab coat in favor of a traditional housewife’s kappogi (a gift from her grandmother, she explained) and had the walls of her lab painted pink and yellow and decorated with cartoon characters.

Even Prime Minister Shinzo Abe, who has made “womenomics” a key plinth of his economic revival package, noticed. He commended Obokata’s apparent achievement from the floor of Japan’s Parliament and vowed to build “a country where the women are the brightest in the world.”

But it didn’t take long for doubts to surface. Peer-review websites noticed oddities and discrepancies in Obokata’s research. Attempts to replicate her findings failed.

By mid-February, RIKEN had launched an internal investigation. In April, officials charged Obokata with fabricating data, doctoring images and borrowing descriptions from other research papers.

Meanwhile, discrepancies were found in the research of other leading scientists, though none with the public profile of Obokata.

In an excruciating, four-hour press conference televised live by many of Japan’s major networks, a tearful Obokata struggled to maintain her composure. She admitted errors in her research papers, but maintained they were innocent mistakes that did not affect the final results. STAP cells were real, she insisted.

She has remained on the staff at RIKEN but has maintained a low profile, refusing interviews. In July, RIKEN officials announced that she would be allowed to take part in a five-month experiment designed to discover once and for all whether her initial findings were real. Other researchers and video cameras would monitor her work, officials said.

The RIKEN affair has been watched closely by Japan’s scientific community, which has produced its share of Nobel Prizes but is often viewed as insular and underperforming.

“One thing that should not be lost in all this is that Japan produces outstanding science,” says Jonathan Dorfan, a former director of the Stanford Linear Accelerator Center, at Stanford University, and now president of the Okinawa Institute of Science and Technology in Japan.

“People in the scientific community here are paying attention to this, and hopefully that will lead to the kind of training that will avoid an outcome like this happening again.”

TIME Stem Cells

Blockbuster Stem-Cell Studies Retracted Because of Fraud

Editors of Nature, which published two papers claiming to generate stem cells in a simplified way, are retracting both papers after data was “misrepresented.”

In an editorial published on Wednesday, editors at the scientific journal Nature announced their decision to retract two papers that received wide media attention, including by TIME, for apparently dramatically simplifying the process of creating stem cells. Genetically manipulating older, mature cells are the only confirmed methods for reprogramming them back to their embryonic state, but in the Nature papers, Japanese scientists claimed to have accomplished the feat by physical means, using an acidic bath or physical stress.

Several months after the papers were published, one of the co-authors, from the RIKEN Institute, called for their retraction, saying “I’m no longer sure that the articles are correct.” RIKEN’s own probe determined that the studies’ lead author, Haruko Obokata, was guilty of misconduct.

At the time, Nature launched its own investigation into concerns that some of the figures in the paper contained errors, and that parts of the text were plagiarized. The journal now says that “data that were an essential part of the authors’ claims have been misrepresented. Figures that were described as representing different cells and different embryos were in fact describing the same cells and the same embryos.”

MORE: Stem-Cell Scientist Guilty of Falsifying Data

While scientific journals have peer-review processes to check researchers’ work, they rely on the fact that the scientists are presenting their data in their entirety and without any biases—something that didn’t occur in this case.

Nature’s editors say they are reviewing their review process and intend to improve on the way they select articles to ensure that such mistakes are minimized.


First Stem Cells Cloned From Diabetes Patient, Thanks to Egg Donors

The feat could lead to new cell-based treatments for the disease, but it relies on the willingness of women to donate their eggs

Is donating eggs to scientists for a research study any different from donating eggs to a couple hoping to have a baby using in vitro fertilization (IVF)? That’s a question that stem cell researchers — and policy makers — have been wrestling with ever since it became possible to “clone” cells with a technique involving eggs and skin cells. The debate is bound to heat up again thanks to a breaking study published today in the journal Nature: for the first time, scientists have generated stem cells from a patient with a disease. And last week, researchers did the same with skin cells from two healthy men.

Nuclear transfer—the cloning process that created Dolly the sheep, the first mammal to be cloned—has more important implications for humans than creating mini-mes. The technique, which involves taking adult cells and inserting them into an egg stripped of its own DNA (so the donor genes can be erased and reprogrammed to develop into any type of cell in the human body) holds promise as a way to treat and even cure a host of diseases ranging from diabetes to Alzheimer’s. But for years, the barrier to perfecting the process using human cells has been the dearth of eggs available for study.

While women have been donating eggs for decades to help infertile couples conceive through in vitro fertilization (IVF) — and getting paid around $8,000 for their trouble — ethicists have flagged concerns about compensating women who want to donate eggs for research purposes, despite the fact that the procedure is medically identical. The lack of compensation has deterred women from enrolling in stem cell studies, for example, since the process requires two weeks of daily doctor visits, injections and tests, as well as a surgical procedure to remove the eggs. “When we surveyed women who donated to IVF cycles and were compensated, and said would you be wiling to do it without compensation, do you know what? They’re not. And why would they be?” says Dr. Mark Sauer, chief of reproductive endocrinology at Columbia University who has recruited egg donors for IVF cycles for decades.

In a research context, some ethicists have said, such payment, while not for the eggs themselves but for women’s time and effort, could be coercive, and therefore exploit women who may be economically less able to resist the offers. The concern has led some states, such as Massachusetts and California, to prohibit compensating women who donate eggs to research studies. And scientists can’t use federal dollars to pay women to donate eggs for research.

But in New York, policy makers who believed that donating eggs to research studies was equivalent on ethical grounds to donating for IVF purposes, passed a law in 2009 that allowed women to be compensated up to $10,000, as they would for donating to IVF cycles. That allowed Dieter Egli, a stem cell scientist at the New York Stem Cell Foundation, and his colleagues to finally achieve success in using the technique to create stem cells from a patient – in this case, a 32 year old woman with type I diabetes. He was able to use funds from a grant from New York State Stem Cell Science as well as private sources including the New York Stem Cell Foundation and the Russell Berrie Foundation Program in Cellular Therapies of Diabetes.

MORE: Scientists Report First Success in Cloning Human Stem Cells

Egli’s report — the one published in the journal Nature — could mean that diabetic patients may one day be able to make their own insulin-producing cells to replace their no longer functioning ones. Other patients needing to replace diseased or damaged cells may also benefit; those with Alzheimer’s could, for example, generate new neurons to replace ones involved in memory and cognition that have been lost to the neurodegenerative condition.

The feat was only possible, however, because 35 women agreed to donate 512 eggs for the study — and get compensated for their contribution. “It’s a lot of effort. To do it for no money, no compensation, would be really asking a lot, especially given the risks,” says Hannah, one of the women who agreed to donate her eggs for the study but requested a pseudonym to protect her privacy. Those risks include changes in hormone levels that can cause hot flashes, sleep disruptions, mood swings, as well as more severe but rare complications such as blood clots and kidney failure. Hannah, 32, has donated eggs to two IVF cycles as well as to this research. “The process is basically identical. So in terms of being compensated for the time and effort it took, from that perspective only, it deserves equal compensation,” she says.

MORE: Stem Cell Miracle? New Therapies May Cure Chronic Conditions like Alzheimer’s

Sauer, a co-author on the paper, was responsible for approaching women like Hannah who were recruited to donate for IVF cycles and ask them about whether they would be willing to donate their eggs to the stem cell study for the same compensation. Most agreed. He stresses that the compensation is not for “buying” the eggs but for the time and inconvenience of participating in the study. “To me, it always seemed insulting, to ask if they would be willing to [donate] for free to research when they could get $8,000 donating for IVF,” he says.

Could the fee be considered high enough that it’s coercive? Possibly, but if it’s not considered unethical in an IVF scenario, and the process is identical, why would it be any more suspect in a research setting? “The possibility that [my eggs] may become a living being is not more valid to me than if they become something that can help a person who is already alive,” says Hannah. And the procedure is time consuming and risky. All told, agreeing to become a donor involves weeks of disruptions, starting with the two weeks of daily appointments at the hospital for hormone injections or ultrasounds and culminating in the surgical procedure under general anesthesia to extract the eggs, which can take an entire day including the recovery. That’s followed by a few weeks of refraining from intercourse until the next menstrual period. “It’s about a month of changing your lifestyle,” says Hannah.

But thanks to donors like her, not only have Egli and his group created stem cells from the diabetic patient, they have also coaxed them to develop into insulin-producing cells that respond to glucose when transplanted into a mouse model for diabetes. He argues that the technology could potentially lead to life-saving treatments for patients, since the cells made from the process are the patient’s own, and won’t be rejected by their immune systems if transplanted. “In my opinion, we should learn to use a patient’s own cells,” Egli told reporters in a teleconference discussing the results. “I think that is going to become a reality.”

That is, as long as laws continue to allow women willing to donate eggs for research studies to be compensated just as women who donate eggs to IVF cycles. “It’s part of my body that is not being used,” says Hannah of her decision to participate in the research. “When I do hear things in the news about diseases like childhood diabetes, my ears perk up, and I wonder if at some point I’ll be hearing about the use of stem cells in developing some kind of prevention or treatment, and if my eggs contributed to that.”


Researchers Clone Cells From Two Adult Men

After years of failed attempts, researchers have successfully generated stem cells from adults. The process could provide a new way for scientists to generate healthy replacements for diseased or damaged cells in patients

After years of failed attempts, researchers have finally generated stem cells from adults using the same cloning technique that produced Dolly the sheep in 1996.

A previous claim that Korean investigators had succeeded in the feat turned out to be fraudulent. Then last year, a group at Oregon Health & Science University generated stem cells using the Dolly technique, but with cells from fetuses and infants.

MORE: Stem-Cell Research: The Quest Resumes

In this case, cells from a 35-year-old man and a 75-year-old man were used to generate two separate lines of stem cells. The process, known as nuclear transfer, involves taking the DNA from a donor and inserting it into an egg that has been stripped of its DNA. The resulting hybrid is stimulated to fuse and start dividing; after a few days the “embryo” creates a lining of stem cells that are destined to develop into all of the cells and tissues in the human body. Researchers extract these cells and grow them in the lab, where they are treated with the appropriate growth factors and other agents to develop into specific types of cells, like neurons, muscle, or insulin-producing cells.

Reporting in the journal Cell Stem Cell, Dr. Robert Lanza, chief scientific officer at biotechnology company Advanced Cell Technology, and his colleagues found that tweaking the Oregon team’s process was the key to success with reprogramming the older cells. Like the earlier team, Lanza’s group used caffeine to prevent the fused egg from dividing prematurely. Rather than leaving the egg with its newly introduced DNA for 30 minutes before activating the dividing stage, they let the eggs rest for about two hours. This gave the DNA enough time to acclimate to its new environment and interact with the egg’s development factors, which erased each of the donor cell’s existing history and reprogrammed it to act like a brand new cell in an embryo.

VIDEO: Breakthrough in Cloning Human Stem Cells: Explainer

The team, which included an international group of stem cell scientists, used 77 eggs from four different donors. They tested their new method by waiting for 30 minutes before activating 38 of the resulting embryos, and waiting two hours before triggering 39 of them. None of the 38 developed into the next stage, while two of the embryos getting extended time did. “There is a massive molecular change occurring. You are taking a fully differentiated cell, and you need to have the egg do its magic,” says Lanza. “You need to extend the reprogramming time before you can force the cell to divide.”

While a 5% efficiency may not seem laudable, Lanza says that it’s not so bad given that the stem cells appear to have had their genetic history completely erased and returned to that of a blank slate. “This procedure works well, and works with adult cells,” says Lanza.

The results also teach stem cell scientists some important lessons. First, that the nuclear transfer method that the Oregon team used is valid, and that with some changes it can be replicated using older adult cells. “It looks like the protocols we described are real, they are universal, they work in different hands, in different labs and with different cells,” says Shoukhrat Mitalopov, director of the center for embryonic cell and gene therapy at Oregon Health & Science University, and lead investigator of that study.

MORE: Stem Cell Miracle? New Therapies May Cure Chronic Conditions like Alzheimer’s

Second, the findings confirm that the key factor in making nuclear transfer work with human cells is not the age of the donor cell, as some experts have argued, but the quality of the donor egg. “No matter how much you tweak the protocols or optimize them, it looks like the major player in efficiency is the individual egg quality,” says Mitalipov. He notes that all of his stem cell lines came from the same egg donor. The two cell lines described by Lanza’s group also came from one egg donor.

This latest success should reignite the debate over which reprogramming method generates the most reliable, and potentially useful, stem cells for eventually treating patients. The nuclear transfer method may join two other ways of making stem cells: one, developed by James Thomson in 1998, relied on extracting them from days-old embryos left over from IVF, and another, developed by Japanese scientist Shinya Yamanaka in 2006 (and for which he was awarded the Nobel Prize), bypassed the egg and embryo completely, allowing researchers to make stem cells by modifying an adult’s cells using a mixture of just four genes.

MORE: Stem Cell Researcher Calls for Retraction of His Own Work

Each method has it advantages and risks, however. IVF embryos are difficult to come by, since they require permission from couples to be used for stem cells research, and they may not be genetically matched to patients who might benefit from cells they generate.

While so-called induced pluripotent stem cells, or iPS cells, avoid the need for embryos and could be matched to patients, some studies suggest that the process may not completely reprogram cells, leaving populations of some partially reprogrammed ones in the mix. In addition, iPS cells aren’t useful for treating mitochondrial diseases, which result from mutations in the cell’s energy factories, which have their own DNA outside of the cell’s DNA in the nucleus. If a cell with a mitochondrial mutation is reprogrammed using the iPS technique, any mutations would be reprogrammed as well.

MORE: FDA Approves Second Trial of Stem-Cell Therapy

Nuclear transfer, however, could treat these disorders since it involves an egg that provides its own, healthy mitochondria. But the process requires a good supply of eggs, which have to be donated by healthy volunteers. That raises ethical concerns since the technique could produce human clones. That’s why research on nuclear transfer is not funded by the federal government, and scientists know less about these cells and their potential than they do about iPS cells. “They have become kind of like cursed cells,” says Mitalipov of the stem cells generated through nuclear transfer. “But we clearly need to understand more about them.”

For patients who might one day benefit from stem cell-based therapies, that understanding could mean the difference between life and death, which is why the latest findings are potentially significant. “We have another way to skin the cat,” Lanza says. “The hope is that iPS cells work out, but for the future application of stem cell therapies to treating disease, it’s good knowing there is another way to make stem cells should we need to.”

TIME Stem Cells

Stem-Cell Scientist Guilty of Falsifying Data

Researchers Find Way To Create Pluripotent Cells With Fewer Drawbacks
Japanese biologist Haruko Obokata in her laboratory at the Riken Center for Developmental Biology in Kobe, Japan, on Jan. 28, 2014 The Asahi Shimbun/Getty Images

A committee has found Haruko Obokata, a scientist based in Kobe, Japan, guilty of misconduct for falsifying research data that would have rocked the scientific community if proved to be true

Haruko Obokata, a stem-cell scientist at the Riken Center for Developmental Biology in Kobe, Japan, has been found guilty of misconduct by a committee of investigators led by her own government-funded institute after other researchers questioned the findings.

In January, Obokata, with colleagues both in Japan and in the U.S., published two papers claiming to describe a surprising new way to generate stem cells from already developed cells. The process involved simply stressing the mouse cells, either with an acidic solution or with physical force, to turn back the clock on their development and revert back to an earlier stem-cell stage in which these cells could then be made into any of the body’s hundreds of cell types.

After other researchers could not replicate the results, however, one of the senior scientists on the paper, Teruhiko Wakayama, called for the two papers, which appeared in the journal Nature, to be retracted. Wakayama said he was only able to repeat the experiment successfully with Obokata’s help, but wasn’t able to do so on his own.

More skepticism arose as scientists pointed out discrepancies and irregularities in the images of the stem cells published in the papers, and the Riken committee concluded that some of the images were enhanced or falsified to improve the results.

The committee did not determine whether the actual technique, known as stimulus-triggered activation of pluripotency (STAP), is valid or not. A scientist at the Chinese University of Hong Kong reported on ResearchGate that he had partially repeated Obokata’s experiment, but that claim hasn’t been verified. Officials at Nature are also investigating the study.

This isn’t the first time that falsified data has plagued the stem-cell field. In 2006, South Korean veterinary scientist Hwang Woo-suk claimed to have successfully used the cloning technique on human cells to generate patient-specific stem cells, but it later emerged that the stem cells came from already existing embryos.

In a statement in Japanese translated by the journal Science, Obokata said she would appeal the judgment. “I am filled with feelings of indignation and surprise,” she wrote. “At this stage, considering the STAP cell discovery itself to be fabricated is a misunderstanding; I cannot possibly accept this.” Riken scientists will attempt to replicate her research, along with outside experts in the stem-cell field. The institute plans to set up a new committee to determine Obokata’s punishment.



Stem Cell Researcher Calls for Retraction of His Own Work

Japanese co-author says “I’m no longer sure that the articles are correct.”

Teruhiko Wakayama, a respected stem cell scientist from Japan’s RIKEN Institute, said he is not certain about the methods used in two studies he co-authored with lead investigator Haruko Obokata.

In the ground-breaking work, heralded by some in the field as a game-changer in the way stem cells are made, Obokata and her team, which included researchers from Harvard University and other international institutes, detailed how they were able to coax already developed cells to revert back to an embryonic-like state to become stem cells by simply exposing them to chemical solutions (mostly acidic) or physical stress. Stem cells can be manipulated to develop into any of the body’s tissues to repair or replace diseased cells.

The controversy erupted when Obokata and her team published a tips sheet for other researchers to follow to replicate their work. But inconsistencies between the newly released methods and the original protocol in the papers, as well as questions about images in the published work, led some to wonder about the validity of the results. Wakayama himself said he was able to repeat the study only once, with Obokata’s assistance, but not on his own.

MORE: The Rise and Fall of the Cloning King

In a press conference in Japan last month, Wakayama, who is best known for using stem cell techniques to clone mice, said he asked all of the scientists involved to retract the papers, which were published in the journal Nature in January, and to have the data and results reviewed by other scientists. RIKEN is investigating the work, as is Nature.

The development adds another black eye to the field of stem cell science, which is ripe with possibility but has struggled to establish its credibility. In 2006, Korean researcher Woo Suk Hwang claimed he had become the first to successfully “clone” human cells, generating patient-specific lines of stem cells from a person’s skin cell. The work turned out to be fraudulent, and the stem cells derived from an already established technique of extracting them from existing embryos.

Since then, both policy makers and those in the field have been more skeptical of milestone claims – for good reason, as the latest study shows.

TIME Stem Cells

Growing Your Own Tissue: Just Add Stress and Stir

Stem cells division, computer artwork Getty Images / Brand X

Researchers report on an exciting new way to reprogram cells so patients might one day grown their own cells to replace diseased ones

It took seven days for Haruko Obokata and her team to learn that they might have rewritten the rules of biology. Working with a bunch of blood cells obtained from newborn mouse spleens, the group found that physical stress —in the form of acidic conditions, or the tight squeeze through a pipette—could turn developed cells back to their embryonic state.

In recent years, such embryonic stem cells, which have the capacity to morph into any of the body’s cells, have become a hot area of research. If doctors can find a reliable way of generating them, they could potentially recreate any tissues, or organs, for that matter, that need replacing if they become diseased. Dead heart tissue starved of oxygen after a heart attack could be replaced, and ailing pancreas cells that no longer produce enough insulin might help diabetic patients.

So far, however, there are only two ways to obtain embryonic stem cells—both of which involve introducing new genetic material to cells. In one, a cloning method known as nuclear transfer, DNA from a mature, developed cell, is inserted into an empty egg cell and electrically and chemically coddled until it starts dividing and producing stem cells. In 2006, Japanese researcher Shinya Yamanaka improved on this method by mixing adult mouse cells with certain genetic factors that produced the same result—embryonic-like stem cells that had erased their developmental history and were reprogrammed back to the time when they could become any cell in the body (he repeated the procedure with human cells the following year and earned the Nobel Prize in 2012).

MORE: Stem Cells Could Lead to Better Breasts After Reconstructive Surgery

But Obokata and her team eliminated the need for any genetic manipulation at all. In their experiment, reported in the journal Nature, all it took was a bath of acidic, low pH solution to turn back the clock on the mouse blood cells. “It was really surprising to see such a remarkable transformation triggered simply by stimuli from outside the cell,” Obokata said during a press briefing.

Plant cells can do it, as a survival mechanism; during periods of drought, for example, carrot cells can reprogram themselves to generate entirely new plants when conditions improved. But Obokata is the first to demonstrate the process in animals.

MORE: Stem-Cell Research: The Quest Resumes

To prove that the cells were indeed reprogrammed, and not simply already embryonic, the scientists measured levels of marker proteins that signal pluripotency, or a cell’s ability to turn into a multitude of different cell types. None of the blood cells expressed these markers before they were exposed to the acidic medium. And to show that the reprogrammed cells were indeed able to generate any of the body’s cells, they injected them into early embryos and found that the resulting mice were chimeric, meaning they possessed a mixture of their original and the reprogrammed cells.

“It’s remarkable that something so simple could do this,” says Austin Smith, director of the Wellcome Trust-MRC Stem Cell Institute at the University of Cambridge. “But it seems a bit dangerous.”

Why, for example, did the low pH not prompt the cells to form tumors instead? And why doesn’t this reprogramming occur in the body, when similar conditions are met—such as, for example, in the stomach, which is highly acidic? “I guess our tissues have some inhibitory mechanism to inhibit reprogramming,” Obokata said. “But to prove that we need further studies.”

MORE: Scientists Report First Success in Cloning Human Stem Cells

First among them would be tests of human cells, to see if what occurred in the mice is also possible in humans. That could open the door to considering this process as a way to generate cells that patients might eventually use to treat diseases such as Alzheimer’s, heart conditions and spinal cord injuries. Already, the first trials of using embryonic stem cells, made from the nuclear transfer technique, are underway in the U.S. to treat macular degeneration.

There are limitations to the technology. Obokata says the efficiency of producing them from acidic conditions is relatively low, at 6% to 7%. And it’s not clear that the cells, which Obokata dubbed STAP cells, for stimulus-triggered acquisition of pluripotency, can be produced by every tissue in the body. She and her team tested brain, skin, muscle, fat, bone marrow, lung and liver tissues from mice and all produced STAP cells, although Smith points out that these represent only three different cell types.

MORE: Early Success in a Human Embryonic Stem Cell Trial to Treat Blindness

She and her group also used cells from week-old mice, meaning they were still relatively young, despite being fully developed into blood cells. Obokata has done preliminary work with some older mouse cells, and said that “the reprogramming efficiency decreases along with age.” But she is hoping to modify and improve on the technology to make STAP cells as efficient to make from older cells as they are from younger ones.

More follow up research on the fate of the cells is also critical, to see if they tend to generate tumors later. But it’s an exciting step that could lay the foundation for a new age in regenerative medicine, when scientists might have their pick of several reprogramming techniques that could help them to match the best method to the right patients to treat their disease.

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