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How biological 'alchemy' can change a cell's destiny
18 June 2008
From New Scientist Print Edition.
Peter Aldhous, Philadelphia

Enlarge A new kind of stem cell?

Call it biological alchemy: specialist pancreatic cells that secrete digestive enzymes have been converted directly into insulin-producing beta cells. Meanwhile, epithelial cells from the back of the eye have been coaxed into becoming a versatile, new type of stem cell.

Both advances, reported last week in Philadelphia, Pennsylvania, at the annual meeting of the International Society for Stem Cell Research (ISSCR), may take us closer to a "regenerative" approach to repairing damaged tissue. And both are products of a wave of enthusiasm that has built since Shinya Yamanaka of Kyoto University in Japan showed that it is possible to "reprogram" adult cells back to an embryonic state. It's "Shinya-mania", jokes George Daley of the Children's Hospital Boston.

Yamanaka infected skin cells with retroviruses carrying the genes for four transcription factors - proteins that regulate the activity of other genes by binding to DNA. The viruses inserted themselves into the cells' chromosomes and started making the transcription factors, which in some cases were able to erase the cells' developmental history. Like embryonic stem cells, the resulting cells were "pluripotent", having the potential to turn into any other type of cell in the body.

If you can wind the developmental clock of an adult cell right back to the beginning, can you use similar methods to turn one type of specialised adult cell directly into another? Yes, says Doug Melton of Harvard University. His team has converted pancreatic exocrine cells, which secrete digestive enzymes, into beta cells, which control blood sugar levels by releasing insulin.

In type 1 diabetes, the beta cells are destroyed by the body's own immune system. In the hope of restoring some level of insulin production, Melton has been searching for ways to coax embryonic stem cells into becoming beta cells. Inspired by Yamanaka, he also wondered if it might be possible to make beta cells in a single step by reprogramming pancreatic exocrine cells, which make up 95 per cent of cells in the pancreas.

Starting with more than 1100 transcription factor genes, Melton's team looked for those active during the development of the pancreas, eventually settling on nine candidates that seemed critical in beta cell development. The researchers put each of these genes into different adenoviruses and injected them all into the pancreases of lab mice.

Although pancreatic exocrine cells arise through a different developmental pathway to beta cells, some seemed to turn into fully functional beta cells. Not only did they secrete insulin, their gene expression was also very similar to normal beta cells. "If we look at every gene we know to be important for beta cell function, we find it turned on," says Melton.

The researchers have since found that they can achieve the same reprogramming using viruses carrying the genes for just three transcription factors. The converted cells seemed to produce the transcription factors only briefly, but after eight months, the reprogrammed cells were still producing insulin. In mice whose original beta cells had been destroyed, the converted cells were also able to control blood sugar levels - although not quite as effectively as in normal mice.

Unfortunately, the method is unsuitable for treating people with diabetes. First, it might cause harmful inflammation of the pancreas. And while adenoviruses rarely insert into the genome - making them safer than Yamanaka's retroviruses - if they were to do so they could trigger cancer.

It might eventually be possible to find a combination of drugs that can reprogram pancreatic exocrine cells, removing the need to inject a potentially dangerous virus, but it won't be easy. "We'd love to mimic transcription factors with small molecules, but that has proven to be very difficult," says Daley.

Sheng Ding of The Scripps Research Institute in La Jolla, California, is already creating pluripotent cells using just two of Yamanaka's genes and one small-molecule drug (Cell Stem Cell, DOI: 10.1016/j.stem.2008.05.011). And for at least one type of cell, it seems possible to go much of the way towards pluripotency without using genes or viruses.

Sally Temple of the New York Neural Stem Cell Institute in Rensselaer says that her team has turned cells from the eye into something resembling human embryonic stem cells, just by altering the conditions in which they were grown in the lab. "It is, in a way, environmental reprogramming," she says.

Temple took cells from the retinal pigment epithelium (RPE), a layer of cells behind the retina (see Diagram). In amphibians, these cells can regenerate all the cell types in a damaged retina, so Temple wondered whether the human versions might have hidden regenerative powers. When she made them grow in small floating spheres under the conditions normally used to grow embryonic stem cells, they began making "marker" proteins typical of pluripotent cells.

Although Temple cautions that her team has not yet determined exactly what the altered cells are capable of, they do seem to be able to differentiate into a wide range of cells. "Whatever the answers, these are going to be very interesting cells," says Ron McKay, a stem cell biologist at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland.

Previous claims to have cultured similarly versatile stem cells have proved hard to repeat. But Temple has created the cultures many times, using cells taken from different human cadavers, and switched them back and forth between the two states, just by altering the culture conditions. They can also be taken from living people, raising the possibility that cells might be removed, reprogrammed and then transplanted back into the people they came from, avoiding immune rejection.

The RPE cells aren't identical to embryonic stem cells. A key indicator of pluripotent cells is that they form tumours called teratomas, consisting of a mishmash of different types of cell, when injected into immune-deficient mice. The RPE cells failed to do this. But there might be a way to reprogram Temple's cells to a fully pluripotent state, allowing Yamanaka's trick to be done without genes or viruses.

Expect Shinya-mania to continue, says Daley, who predicts an explosion of cellular reprogramming. "You're seeing the front edge of a wave of experiments," he says.

From issue 2661 of New Scientist magazine, 18 June 2008, page 8-9

Crackdown on 'miracle cures' Despite exciting lab results, the only stem-cell treatments that are ready for patients are those using bone-marrow stem cells to reconstitute the blood. But that hasn't stopped clinics advertising a range of other, speculative "therapies". Now the crackdown against such practices has begun. Worried by a rise in "stem cell tourism", driven by websites advertising unproven therapies, the International Society for Stem Cell Research (ISSCR) is drafting guidelines to help people identify treatments that are the modern equivalent of snake oil. The need for such guidelines is undeniable. Timothy Caulfield of the University of Alberta's Health Law Institute in Edmonton, Canada, and colleagues surveyed 32 websites, based all over the world, offering stem-cell-based treatments. Only one identified its treatment as experimental, while 26 presented theirs as being routine. Many sites claimed to be able to treat several diseases and also offered cosmetic procedures. While the scientific basis for their claims is shaky at best, the average cost of a treatment was just over $8000. Excluding cosmetic treatments, the figure was almost $24,000. But the biggest concern is that patients might be harmed. "These kinds of clinics do pose a real risk to public safety," warns Caulfield. The ISSCR guidelines will include standards for producing stem cells and the evidence from lab and animal studies that should be required before moving to trials in people. They will also criticise clinics offering unproven treatments. "We're working on a very strong statement," says Insoo Hyun, a bioethicist at Case Western Reserve University in Cleveland, Ohio, and co-chair of the team drafting the guidelines. The task force is also working on a list of frequently asked questions, and aims to work with patient groups to explain what the guidelines mean.

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