As a young medical student three decades ago, Mark Magnuson learned the basic facts of human development. Among those supposed facts was this one: Adult cells can't change what they are. A heart cell is always a heart cell, a skin cell is always a skin cell.
That's not the case with embryos, whose cells eventually create the entire human body. As embryonic cells divide, they develop distinct identities, becoming heart cells and brain cells and blood cells and every other kind of cell.
It's a process called differentiation. And once it happens, there is no going back. "When I was a medical student, I was taught that a differentiated cell was a differentiated cell," said Magnuson, a professor of medicine and director of the Vanderbilt Center for Stem Cell Biology in Nashville. "That was the end of the line."
Then along came the induced pluripotent stem cell (iPS cell), and everything changed. Over the past eight years, a quiet revolution has taken place in stem cell biology as researchers have discovered that they can actually teach old cells new tricks.
They have learned how to reprogram adult cells so that they can do many things an embryonic cell can do. No human embryos are destroyed in the process. Along the way, embryonic stem cells—just a decade ago hailed as the future of medicine—have largely been bypassed. Some researchers still use them, but for now, the future belongs to adult stem cells and iPS cells, which are adult cells genetically reprogrammed to express specific genes.
Every year for the past 10 years, the National Institutes of Health (NIH) has funded more adult stem cell research compared with embryonic research. For 2012, NIH grants totaled $146.5 million for embryonic stem cell research, but $504 million for adult stem cell research—a difference of $357.5 million. And the belief that adult stem cells are more promising than embryonic stem cells for therapies is now largely mainstream.
Turning Lead to Gold
iPS cells are the brainchild of Shinya Yamanaka, director of the Center for iPS Cell Research at Kyoto University, Japan, and a professor of anatomy at the University of California, San Francisco.
Yamanaka received the Nobel Prize in 2012 for his work undertaking the biological equivalent of turning lead to gold, transforming ordinary skin cells into stem cells. His inspiration for creating iPS cells came while visiting a friend's fertility clinic.
Looking at an embryo under a microscope, the father of two had a revelation. "When I saw the embryo, I suddenly realized there was such a small difference between it and my daughters," Yamanaka told The New York Times in 2007. "I thought, We can't keep destroying embryos for our research. There must be another way."
Yamanaka began trying to reprogram adult cells using a virus to introduce new genes into first mouse cells and then human cells. By 2007, he had successfully reprogrammed the cells to what's known as a pluripotent state—the ability to become other kinds of cells. He found that by making changes to four genes, those cells essentially went back in time and acted like embryonic cells.
That discovery democratized the field of stem cell research, said Maureen Condic, a stem cell researcher and associate professor of neurobiology and anatomy at the University of Utah's School of Medicine. She is a long-standing critic of embryonic stem cell research.
Before iPS cells came along, researchers either had to use embryonic stem cells collected by the NIH or create their own using embryos left over from fertility treatments. But donated embryos were rare and difficult to obtain. "You really had to have a close relationship with a fertility doctor to get access," she said.
Yamanaka changed that. "Using iPS cells is easier, cheaper, faster, and better," said Condic. "They have none of the ethical troubles of embryonic stem cells."
Her comment echoes the stance of the Christian Medical Association. Its CEO, David Stevens, said in 2010, "Compared to the speculative, controversial, and dangerous embryonic stem cell research that the [Obama] administration insists on funding illegally, iPS cell and adult stem cell research is a cheaper, faster, safer, more efficient and quicker path to the cures we need."
But miracle cures are not on the horizon—yet. Lost in the hype over the promise of adult stem cells is the reality that they are quite deadly. Stem cells excel at creating tumors.
"How many stem cells does it take to kill a mouse?" Condic said. "The answer is, only about two." In other words, implant two stem cells in a mouse, and those cells will crank out enough tumors to kill it.
Transferring either iPS cells or embryonic stem cells into a patient will not cure diseases, said Condic. Researchers want to get those stem cells to produce other kinds of cells, such as fully developed heart, skin, and brain cells.
That process has not been perfected. "It's very easy to make cells that look like heart cells," said Condic. "But transplant them into a mouse, and they die."
Until recently, it took about a month to reprogram adult cells into iPS cells. And only a few of the adult cells would actually become iPS cells. The process was inefficient. But scientists in Israel recently discovered how to create iPS cells in about a week, with most of the cells being reprogrammed, according to Nature journal.
Reprogramming Cells
For researchers, the biggest practical benefit of the iPS cells is the so-called "disease in a dish" approach. Scientists take a skin cell, reprogram it into an iPS cell, and then use that cell to recreate human tissue in a petri dish. The idea is to study how a disease progresses in the body's cells.
That's not been possible before, said Magnuson. "There's no way that a doctor could say, 'Can I have a piece of your heart so I can study it in the laboratory?'" That's essentially what medical researchers can do with iPS cells. "These things are almost a fantasy. We are doing something beyond the next step beyond."
Scientists aspire to reprogram cells that are still inside a living organism. That's what scientists at the Spanish National Cancer Research Centre in Madrid did recently, according to Nature. Those scientists originally created iPS cells in the lab. This summer, they also created those cells inside mice. "This opens up new possibilities in regenerative medicine," researcher Manuel Serrano told Reuters.
Magnuson hopes to reprogram the cells in a human pancreas. What diabetes patients need are more beta cells, which create insulin. In type 1 diabetes, an immune response kills off the beta cells, meaning the patient no longer produces insulin in her system. In type 2 diabetes, the body becomes resistant to insulin.
The advances made with iPS and adult stem cells have surprised researchers like David Hess, chairman of the department of neurology at Georgia Regents University in Augusta, Georgia. Hess said that many researchers were troubled by the idea of using embryonic stem cells. In 2001, President George W. Bush restricted federal funding for embryonic stem cell research. In 2009, President Obama lifted those restrictions.
Hess is currently working with researchers at the University of Georgia who are trying to use pig iPS cells to create adult pig neurons. He is also an investigator in clinical trials of adult stem cells found in bone marrow. Known as mesenchymal stem cells, Hess said, those cells are used by the body to help repair itself.
But sometimes the body's immune system makes it difficult for those mesenchymal cells to work properly, especially after a traumatic event like a stroke. Researchers hope to develop a technique that will calm the immune system and give the mesenchymal cells time to help repair the brain after a stroke.
Hess said that the early 2000s brought fierce public debate over the ethics of destroying human embryos to acquire stem cells. Researchers and advocates for the use of embryonic cells promised that scientists would discover a miracle cure for Alzheimer's or Parkinson's. "There was a lot of magical thinking going on," Hess said.
Hess does see valid reason to hope that diabetes or other diseases might be cured using therapies derived from stem cells. But right now, he said, the most important thing is to learn more about diseases.
Customized Medicine
For the most part, the switch from human embryonic stem cells to iPS cells has gone without controversy. Many of the original skeptics have been won over.
The California Institute for Regenerative Medicine (CIRM)—a state agency set up exclusively to fund embryonic stem cell research—is now investing millions in iPS projects, funding more than 100 such projects to date.
"Researchers we fund are using them to explore potential new therapies for deadly diseases and disorders," said spokesman Kevin McCormack. "But the main use at the moment seems to be for drug screening, seeing which medications that are already available might be useful against a wide variety of medical conditions."
CIRM still regards embryonic stem cell research as "the gold standard," he said. "It's the cell type that we have the most knowledge about and experience using." But most of the new requests for funding come for projects involving iPS cells. Among recent CIRM grants was $6 million to the Human BioMolecular Research Institute in San Diego.
John Cashman, the institute's director, said that researchers there are using iPS cells to try to grow mature heart cells in the lab. It's part of an effort to fine-tune a drug used to treat a heart condition, using the "disease in a dish" approach. "It's one thing to make iPS cells—it's another thing to make fully mature cells," said Cashman. "We are not there yet."
Cashman said that those mature cells will be used to adjust a drug used to treat a specific heart condition."It's called drug rescue," he said. "You take an existing drug and retain the helpful qualities while removing anything harmful."
Researchers believe iPS cells could one day aid individualized medicine. A doctor could take a skin cell, turn it into an iPS cell, and then grow a patient's own tissue in the lab. That tissue could then be used to test specific medicines to see which is right for that particular patient.
Growing Promise
At least two scientists feel vindicated by the recent advances in stem cell research. James L. Sherley, director of the Adult Stem Cell Technology Center in Boston, and Theresa Deisher, founder of avm Biotechnology in Seattle, sued the Obama administration in 2009 to block the federal government from funding more embryonic stem cell research.
In August 2010, a federal judge in Washington, D.C., granted Sherley and Deisher an injunction that blocked federal funding. The injunction was overturned less than three weeks later, and the plaintiffs eventually lost. But their belief in the potential of adult stem cells has become conventional.
Both now work on projects designed to make adult stem cells and iPS cells easier to use. Deisher's company is creating a technique to make adult stem cell therapies more effective. She said that adult stem cells don't always stay in the organs they are supposed to be treating. Instead, they end up in the spleen or lymphatic system. Her team is trying to fix that.
Deisher said that about 65 diseases now can be treated using adult stem cells. About a decade ago, there was a great deal of pressure on researchers to use embryonic stem cells; those who opposed doing so were ostracized. That's no longer the case, she said, believing some credit should go to the 2009 lawsuit.
Sherley, a Memphis native who grew up Southern Baptist, is a former MIT researcher who later joined the Boston Biomedical Research Institute. That firm closed this past year. He's now trying to incorporate his Adult Stem Cell Technology Center as a nonprofit.
Scientists are still unlocking the secrets of how adult cells work. "If [you] start with a human liver stem cell—and you put it through differentiation—you will produce mature adult stem cells," Sherley said. "That is what you need for medication or a transplant." The goal is clear, but researchers admit that it is beyond their reach for the moment.
Still, evangelicals' fears about federally funded embryonic stem cell research have proven largely unfounded, as stem cell researchers find that solid science and solid ethics can go hand in hand.
Bob Smietana is a journalist based in Nashville.
