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Transformed: The stem cell breakthrough
Grownto order
The breakthrough in creating stem cells could be a step towards regenerating organs and limbs, as Peter Aldhous reports
A FACTORY worker has just lost three fingers, hopelessly mangled by a powerful industrial press. Right now, there is nothing much his surgeons can do, beyond stitching up the wound. If only the injured worker were more like a salamander, the severed digits would grow back all of their own accord. You’ll have heard about the idea of regenerating body parts before. Now, though, the dream might have some foundation. The remarkable discovery that it is possible to turn skin cells back to an embryonic state, when they have the potential to become any type of cell in the body, could open up a huge range of possibilities. For one thing, if a skin cell can be turned into a far more versatile embryonic cell, then maybe there’s a way to turn any specialised cell directly into another. There may be no need to wind back the clock of a cell’s development first. If so, then the idea of activating the mechanisms – dormant or blocked in our species – that give salamanders such formidable powers of recovery from injury suddenly doesn’t seem quite so farfetched. “Why shouldn’t we be able to regenerate body parts?” asks Doug Melton, a stem cell biologist at Harvard University. The reprogrammed skin cells that have led to this enthusiasm seem to have the same properties as the embryonic stem cells (ESCs) found in human embryos just a few days old. Like ESCs, they have the ability to develop into any of the body’s tissues. Such cells could be grown into new neurons for treating people who have suffered some form of brain damage, say, or into new heart muscle cells for people who have had heart attacks. The catch
G
40 | NewScientist | 3 May 2008
is that unless these cells are a perfect genetic match, the patient’s immune system is likely to reject them. Researchers used to think the only way to obtain genetically matched cells with the potential to develop into any tissue was by “therapeutic cloning”: taking the nucleus out of a cell from an adult patient, putting it into an egg cell stripped of its chromosomes and taking ESCs from the resulting cloned embryo. So stem cell research was dealt a severe blow when it emerged in 2005 that the one researcher who claimed to have created
“We may be on the brink of a new era of cellular alchemy” cloned lines of human ESCs, South Korea’s Woo Suk Hwang, had faked his results. To date, no one has achieved the feat. But there is now another way, thanks to Shinya Yamanaka, a stem cell biologist at Kyoto University in Japan. Yamanaka knew that during cloning, the adult nucleus must get reprogrammed by some factors present in the egg cell. Find out which genes are turned on by these factors and it should be possible to achieve the same effect without resorting to cloning. So Yamanaka started experimenting with 24 candidate genes. In June 2006, Yamanaka announced that he had succeeded. By adding extra copies of just four genes, he had reprogrammed mouse skin cells to a state where they could give rise
to any of the body’s cells and tissues. These so-called induced pluripotent stem (iPS) cells created a sensation. After this it took Yamanaka little more than a year to create the first human iPS cells, using the human versions of the four genes. A competing team, led by James Thomson of the University of Wisconsin-Madison, matched the feat by adding a slightly different set of four genes. Eager to get in on the action, many groups worldwide are now creating lines of iPS cells. Unlike cloning, which requires special skill in micromanipulation to get the nucleus into the egg cell, the genetic modification methods used by Yamanaka are standard laboratory fare. “It’s relatively easy,” says Konrad Hochedlinger, a stem cell biologist at the Massachusetts General Hospital in Boston. “Any lab that has some expertise with ESCs can do it.” For the first time, researchers who want to harness the versatility of embryonic cells have their hands on a type of cell that poses no ethical problems. Still, not everyone is convinced of their potential: “These, at best, are proxies for natural ESCs. They can never be used,” says Tom Okarma, president of Geron of Menlo Park, California, a biotech firm that has invested millions in developing ESC therapies. Biologists who have less of a vested interest in conventional ESCs, however, are impressed by how similar to them iPS cells seem to be. And there is already strong evidence that iPS cells could prove useful in treating disease. In April, researchers led by Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, announced that they had reduced the www.newscientist.com
WWW.MDI-DIGITAL.COM
www.newscientist.com
3 May 2008 | NewScientist | 41
“There is enormous potential. It’s going to change biology and medicine” symptoms of Parkinson’s in mice by treating them with neurons derived from iPS cells. The team did this by first creating iPS cell lines from mouse skin cells. The iPS cells were then turned into dopamine-producing neurons and implanted into the brains of rats in which dopamine-producing cells had been killed, to mimic Parkinson’s. After four weeks, the treated rats showed significant improvement compared with controls. It’s an impressive proof of principle, and not the only one. Last December, Jaenisch announced that he had cured mice of sicklecell anaemia by creating iPS cells, correcting the faulty gene that causes the disease, deriving blood stem cells and implanting them. “There is enormous potential in Yamanaka’s findings,” says Melton. “It’s going to change biology and medicine.” It might not change things in the way that many imagine, though. In theory, just like therapeutic cloning, iPS cells could lead to personalised therapies. The logic is compelling: if you can treat people using tissues genetically identical to their own, there will be no problem with immune rejection. In practice, however, this remains a distant goal at odds with the harsh realities of healthcare economics. It is one thing to treat a few rats with Parkinson’s, quite another to produce personalised therapies for millions of deserving patients with a wide variety of debilitating conditions. It takes more than a month to create a single human iPS cell line at present, for instance, to which you would need to add weeks of culturing to derive the particular type of cells that each patient needs. Even if patients could afford to wait for their therapy, the intense effort involved means 42 | NewScientist | 3 May 2008
that the process is likely to cost hundreds of thousands of dollars. Then there’s the matter of convincing medical regulators that each new cell line is safe and stable. “It’s technically infeasible as well as ridiculously costly,” argues Okarma, whose company is instead developing therapies based on a small number of human ESCs. “You need cells that come in a vial and are delivered to the clinic,” agrees Alan Trounson, president of the California Institute for Regenerative Medicine in San Francisco. “Personalised stem cell therapy is really going to be a very rare kind of approach.”
Stem cell banks Biologists predict that iPS cells will make their most immediate mark as tools rather than treatments. Reprogramming makes it possible to derive cell lines from patients suffering from conditions with a genetic element. Studying these cells should tell us much about how specific genetic variations lead to a disease developing – and make it possible to test potentially useful drugs. Biologists haven’t given up on getting iPS cells into the clinic, though. Reprogrammed cells could be used to create custom stem cell banks to minimise problems with immune rejection – a kind of halfway house towards personalised therapies (see “Off-the-shelf cells”, opposite). Still, there is one big problem. Yamanaka’s technique uses retroviruses to get the extra genes into cells added this way. This a double cancer risk. Retroviruses integrate the extra gene copies into the cells’ chromosomes, and if they land in the wrong place they can trigger
cancer. Furthermore, genes added this way remain permanently switched on, which increases the risk of tumours because these genes have growth-related effects. Yamanaka has now managed to reprogram cells without adding a gene called c-Myc, thought to be the riskiest of the four he used initially. He has also shown that mouse cells taken from the liver or stomach are less prone to becoming cancerous after reprogramming than those created from skin. But what’s really needed is a way to reprogram cells without using retroviruses, and without leaving extra copies of the genes involved sitting around in the genome. Two main avenues are being explored. One is to insert the genes into cells in a way that means they don’t integrate into the genome. Already, a company called PrimeGen, of Irvine, California, claims to have generated iPS cells by adding carbon nanotubes coated with the reprogramming genes, but has yet to reveal its results. Alternatively, rather than add genes, you could introduce the proteins they encode directly into the cell, or find small molecules that have the same effect and are easier to get into cells. Sheng Ding of the Scripps Research Institute in La Jolla, California, is already busy screening promising candidates from his library of more than 100,000 small molecules. He claims he can create iPS cells using just one or two genes plus one or two drug-like molecules. While researchers work on ways to create safer iPS cells, some have been inspired by Yamanaka’s achievement to think about a broader range of possibilities. “If the goal is to turn one cell type into another,” says Melton, www.newscientist.com
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“why do you need to go back to the beginning?” Indeed, using similar methods to Yamanaka’s, Melton claims in unpublished work to have created insulin-producing pancreatic beta cells from another type of specialised adult cell – without having to wind back the clock to an embryonic state. Hold on, though. Haven’t we heard something like this before? A few years ago, several biologists documented impressive feats of “transdifferentiation”. There were claims to
_FI9;BB
have turned brain cells into blood cells, and bone marrow into just about everything else. Many of these experiments proved impossible to repeat, or turned out to be due to artefacts such as cells fusing with one another. Melton agrees that early claims of transdifferentiation were based on flawed experiments, but he argues that this time around the science is on a sounder footing. “Much of that stuff was done so poorly that the criticisms were valid,” he says.
Off-the-shelf cells The immune system is one of the biggest obstacles to repairing or replacing damaged tissues or organs. Unless the cells used match a patient’s own, there is a high chance they will be rejected. But deriving matching cells from each patient is likely to be extremely expensive. Instead, an “off-theshelf” therapy is needed. In a few parts of the body, such as the eye, studies show that nonmatching cells might just escape the immune system’s attention. Advanced Cell Technology, a stem cell company based in Los Angeles, is hoping to use off-the-shelf cells to treat certain diseases that lead to blindness. In other parts of the body, however, non-matching cells will somehow have to be protected from the immune system. The simplest approach is the one used for organ
www.newscientist.com
transplants, where tissue-typing based on a diverse group of genes known as HLA is used to obtain a reasonable match between donor and recipient, and drugs are given to suppress any immune reaction. In 2005, stem cell biologist Roger Pedersen and immunologist Andrew Bradley of the University of Cambridge calculated that a bank of just 150 randomly selected lines of human embryonic stem cells (ESCs) would guarantee an HLA match for about 85 per cent of the UK population, to a standard as high as that required for kidney transplants. Rare donor cell lines in which both copies of common HLA genes are identical are especially useful: with these, just 10 carefully selected cell lines would be needed. This is now a viable prospect: a large population could be screened for desired HLA types and
reprogramming used to turn adult cells from the superdonors into induced pluripotent stem (iPS) cells. Reprogrammed cells might also help provide an alternative to the immunosuppressive drugs needed to prevent rejection even with a superdonor cell bank. Work on dendritic cells, which regulate immune activity, at the University of Oxford by a team led by Paul Fairchild has shown that dendritic cells derived from ESCs can induce immune “tolerance” to the HLA type they contain. The idea, then, is to derive both dendritic cells and the cells needed for therapy from the same ESC line, and implant the two cell types together to avoid immune rejection. If dendritic cells can also be grown from iPS cells, the same method should work for iPS-derived cells as well.
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“But it would be wrong to conclude that it couldn’t happen.” The wider possibilities of altering a cell’s fate aren’t lost on Ding, who with other leading stem cell biologists has formed a company called Fate Therapeutics, based in Seattle. As well as commercialising Ding’s efforts to create safer iPS cells, the company aims to develop drugs to move cells backwards and forwards along particular developmental pathways. One idea is to create personalised bloodforming stem cells for people with certain kinds of cancers, by winding back the developmental clock of some of their white blood cells. That could remove the need for bone-marrow transplants, which can have serious complications. Fate Therapeutics also wants to develop drugs to stimulate adult stem cells in the body to regenerate tissues damaged by disease or injury. That sounds a lot like making people more like salamanders – an eventual goal acknowledged on the company’s website, which states: “The regeneration of appendages and limbs can be enhanced in models of traumatic injury and amputation.” If Melton and the founders of Fate Therapeutics are on the right track, then we may be on the brink of a new era of cellular alchemy, in which biologists learn how to turn base cells into therapeutic gold. What started with some humble cultures of mouse skin cells in a little-known Japanese laboratory might yet end with doctors gaining the power to unleash our inner salamander. Fast-forward to the emergency room of the future: “Lost your fingers? No problem. We’ll soon have them growing back.” G 3 May 2008 | NewScientist | 43
The breakthrough in creating stem cells could be a step towards regenerating organs and limbs, as Peter Aldhous reports
A FACTORY worker has just lost three fingers, hopelessly mangled by a powerful industrial press. Right now, there is nothing much his surgeons can do, beyond stitching up the wound. If only the injured worker were more like a salamander, the severed digits would grow back all of their own accord. You’ll have heard about the idea of regenerating body parts before. Now, though, the dream might have some foundation. The remarkable discovery that it is possible to turn skin cells back to an embryonic state, when they have the potential to become any type of cell in the body, could open up a huge range of possibilities. For one thing, if a skin cell can be turned into a far more versatile embryonic cell, then maybe there’s a way to turn any specialised cell directly into another. There may be no need to wind back the clock of a cell’s development first. If so, then the idea of activating the mechanisms – dormant or blocked in our species – that give salamanders such formidable powers of recovery from injury suddenly doesn’t seem quite so farfetched. “Why shouldn’t we be able to regenerate body parts?” asks Doug Melton, a stem cell biologist at Harvard University. The reprogrammed skin cells that have led to this enthusiasm seem to have the same properties as the embryonic stem cells (ESCs) found in human embryos just a few days old. Like ESCs, they have the ability to develop into any of the body’s tissues. Such cells could be grown into new neurons for treating people who have suffered some form of brain damage, say, or into new heart muscle cells for people who have had heart attacks. The catch
G
40 | NewScientist | 3 May 2008
is that unless these cells are a perfect genetic match, the patient’s immune system is likely to reject them. Researchers used to think the only way to obtain genetically matched cells with the potential to develop into any tissue was by “therapeutic cloning”: taking the nucleus out of a cell from an adult patient, putting it into an egg cell stripped of its chromosomes and taking ESCs from the resulting cloned embryo. So stem cell research was dealt a severe blow when it emerged in 2005 that the one researcher who claimed to have created
“We may be on the brink of a new era of cellular alchemy” cloned lines of human ESCs, South Korea’s Woo Suk Hwang, had faked his results. To date, no one has achieved the feat. But there is now another way, thanks to Shinya Yamanaka, a stem cell biologist at Kyoto University in Japan. Yamanaka knew that during cloning, the adult nucleus must get reprogrammed by some factors present in the egg cell. Find out which genes are turned on by these factors and it should be possible to achieve the same effect without resorting to cloning. So Yamanaka started experimenting with 24 candidate genes. In June 2006, Yamanaka announced that he had succeeded. By adding extra copies of just four genes, he had reprogrammed mouse skin cells to a state where they could give rise
to any of the body’s cells and tissues. These so-called induced pluripotent stem (iPS) cells created a sensation. After this it took Yamanaka little more than a year to create the first human iPS cells, using the human versions of the four genes. A competing team, led by James Thomson of the University of Wisconsin-Madison, matched the feat by adding a slightly different set of four genes. Eager to get in on the action, many groups worldwide are now creating lines of iPS cells. Unlike cloning, which requires special skill in micromanipulation to get the nucleus into the egg cell, the genetic modification methods used by Yamanaka are standard laboratory fare. “It’s relatively easy,” says Konrad Hochedlinger, a stem cell biologist at the Massachusetts General Hospital in Boston. “Any lab that has some expertise with ESCs can do it.” For the first time, researchers who want to harness the versatility of embryonic cells have their hands on a type of cell that poses no ethical problems. Still, not everyone is convinced of their potential: “These, at best, are proxies for natural ESCs. They can never be used,” says Tom Okarma, president of Geron of Menlo Park, California, a biotech firm that has invested millions in developing ESC therapies. Biologists who have less of a vested interest in conventional ESCs, however, are impressed by how similar to them iPS cells seem to be. And there is already strong evidence that iPS cells could prove useful in treating disease. In April, researchers led by Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, announced that they had reduced the www.newscientist.com
WWW.MDI-DIGITAL.COM
www.newscientist.com
3 May 2008 | NewScientist | 41
“There is enormous potential. It’s going to change biology and medicine” symptoms of Parkinson’s in mice by treating them with neurons derived from iPS cells. The team did this by first creating iPS cell lines from mouse skin cells. The iPS cells were then turned into dopamine-producing neurons and implanted into the brains of rats in which dopamine-producing cells had been killed, to mimic Parkinson’s. After four weeks, the treated rats showed significant improvement compared with controls. It’s an impressive proof of principle, and not the only one. Last December, Jaenisch announced that he had cured mice of sicklecell anaemia by creating iPS cells, correcting the faulty gene that causes the disease, deriving blood stem cells and implanting them. “There is enormous potential in Yamanaka’s findings,” says Melton. “It’s going to change biology and medicine.” It might not change things in the way that many imagine, though. In theory, just like therapeutic cloning, iPS cells could lead to personalised therapies. The logic is compelling: if you can treat people using tissues genetically identical to their own, there will be no problem with immune rejection. In practice, however, this remains a distant goal at odds with the harsh realities of healthcare economics. It is one thing to treat a few rats with Parkinson’s, quite another to produce personalised therapies for millions of deserving patients with a wide variety of debilitating conditions. It takes more than a month to create a single human iPS cell line at present, for instance, to which you would need to add weeks of culturing to derive the particular type of cells that each patient needs. Even if patients could afford to wait for their therapy, the intense effort involved means 42 | NewScientist | 3 May 2008
that the process is likely to cost hundreds of thousands of dollars. Then there’s the matter of convincing medical regulators that each new cell line is safe and stable. “It’s technically infeasible as well as ridiculously costly,” argues Okarma, whose company is instead developing therapies based on a small number of human ESCs. “You need cells that come in a vial and are delivered to the clinic,” agrees Alan Trounson, president of the California Institute for Regenerative Medicine in San Francisco. “Personalised stem cell therapy is really going to be a very rare kind of approach.”
Stem cell banks Biologists predict that iPS cells will make their most immediate mark as tools rather than treatments. Reprogramming makes it possible to derive cell lines from patients suffering from conditions with a genetic element. Studying these cells should tell us much about how specific genetic variations lead to a disease developing – and make it possible to test potentially useful drugs. Biologists haven’t given up on getting iPS cells into the clinic, though. Reprogrammed cells could be used to create custom stem cell banks to minimise problems with immune rejection – a kind of halfway house towards personalised therapies (see “Off-the-shelf cells”, opposite). Still, there is one big problem. Yamanaka’s technique uses retroviruses to get the extra genes into cells added this way. This a double cancer risk. Retroviruses integrate the extra gene copies into the cells’ chromosomes, and if they land in the wrong place they can trigger
cancer. Furthermore, genes added this way remain permanently switched on, which increases the risk of tumours because these genes have growth-related effects. Yamanaka has now managed to reprogram cells without adding a gene called c-Myc, thought to be the riskiest of the four he used initially. He has also shown that mouse cells taken from the liver or stomach are less prone to becoming cancerous after reprogramming than those created from skin. But what’s really needed is a way to reprogram cells without using retroviruses, and without leaving extra copies of the genes involved sitting around in the genome. Two main avenues are being explored. One is to insert the genes into cells in a way that means they don’t integrate into the genome. Already, a company called PrimeGen, of Irvine, California, claims to have generated iPS cells by adding carbon nanotubes coated with the reprogramming genes, but has yet to reveal its results. Alternatively, rather than add genes, you could introduce the proteins they encode directly into the cell, or find small molecules that have the same effect and are easier to get into cells. Sheng Ding of the Scripps Research Institute in La Jolla, California, is already busy screening promising candidates from his library of more than 100,000 small molecules. He claims he can create iPS cells using just one or two genes plus one or two drug-like molecules. While researchers work on ways to create safer iPS cells, some have been inspired by Yamanaka’s achievement to think about a broader range of possibilities. “If the goal is to turn one cell type into another,” says Melton, www.newscientist.com
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“why do you need to go back to the beginning?” Indeed, using similar methods to Yamanaka’s, Melton claims in unpublished work to have created insulin-producing pancreatic beta cells from another type of specialised adult cell – without having to wind back the clock to an embryonic state. Hold on, though. Haven’t we heard something like this before? A few years ago, several biologists documented impressive feats of “transdifferentiation”. There were claims to
_FI9;BB
have turned brain cells into blood cells, and bone marrow into just about everything else. Many of these experiments proved impossible to repeat, or turned out to be due to artefacts such as cells fusing with one another. Melton agrees that early claims of transdifferentiation were based on flawed experiments, but he argues that this time around the science is on a sounder footing. “Much of that stuff was done so poorly that the criticisms were valid,” he says.
Off-the-shelf cells The immune system is one of the biggest obstacles to repairing or replacing damaged tissues or organs. Unless the cells used match a patient’s own, there is a high chance they will be rejected. But deriving matching cells from each patient is likely to be extremely expensive. Instead, an “off-theshelf” therapy is needed. In a few parts of the body, such as the eye, studies show that nonmatching cells might just escape the immune system’s attention. Advanced Cell Technology, a stem cell company based in Los Angeles, is hoping to use off-the-shelf cells to treat certain diseases that lead to blindness. In other parts of the body, however, non-matching cells will somehow have to be protected from the immune system. The simplest approach is the one used for organ
www.newscientist.com
transplants, where tissue-typing based on a diverse group of genes known as HLA is used to obtain a reasonable match between donor and recipient, and drugs are given to suppress any immune reaction. In 2005, stem cell biologist Roger Pedersen and immunologist Andrew Bradley of the University of Cambridge calculated that a bank of just 150 randomly selected lines of human embryonic stem cells (ESCs) would guarantee an HLA match for about 85 per cent of the UK population, to a standard as high as that required for kidney transplants. Rare donor cell lines in which both copies of common HLA genes are identical are especially useful: with these, just 10 carefully selected cell lines would be needed. This is now a viable prospect: a large population could be screened for desired HLA types and
reprogramming used to turn adult cells from the superdonors into induced pluripotent stem (iPS) cells. Reprogrammed cells might also help provide an alternative to the immunosuppressive drugs needed to prevent rejection even with a superdonor cell bank. Work on dendritic cells, which regulate immune activity, at the University of Oxford by a team led by Paul Fairchild has shown that dendritic cells derived from ESCs can induce immune “tolerance” to the HLA type they contain. The idea, then, is to derive both dendritic cells and the cells needed for therapy from the same ESC line, and implant the two cell types together to avoid immune rejection. If dendritic cells can also be grown from iPS cells, the same method should work for iPS-derived cells as well.
D;KHED
_FI9;BB
“But it would be wrong to conclude that it couldn’t happen.” The wider possibilities of altering a cell’s fate aren’t lost on Ding, who with other leading stem cell biologists has formed a company called Fate Therapeutics, based in Seattle. As well as commercialising Ding’s efforts to create safer iPS cells, the company aims to develop drugs to move cells backwards and forwards along particular developmental pathways. One idea is to create personalised bloodforming stem cells for people with certain kinds of cancers, by winding back the developmental clock of some of their white blood cells. That could remove the need for bone-marrow transplants, which can have serious complications. Fate Therapeutics also wants to develop drugs to stimulate adult stem cells in the body to regenerate tissues damaged by disease or injury. That sounds a lot like making people more like salamanders – an eventual goal acknowledged on the company’s website, which states: “The regeneration of appendages and limbs can be enhanced in models of traumatic injury and amputation.” If Melton and the founders of Fate Therapeutics are on the right track, then we may be on the brink of a new era of cellular alchemy, in which biologists learn how to turn base cells into therapeutic gold. What started with some humble cultures of mouse skin cells in a little-known Japanese laboratory might yet end with doctors gaining the power to unleash our inner salamander. Fast-forward to the emergency room of the future: “Lost your fingers? No problem. We’ll soon have them growing back.” G 3 May 2008 | NewScientist | 43