Wednesday, July 16, 2008 | If artificial human embryonic stem cells prove as valuable as real ones, research into therapies for incurable diseases that has lagged because of short supplies of stem cells and the storm of controversy that surrounds them could be reinvigorated.
But it’s still a very big if.
“If this works, and that’s a very important clause, then this research will truly change the game,” said bioethicist Mike Kalichman, the director of the Research Ethics Program at the University of California, San Diego.
Researchers have found that a specific combination of four genes and a handful of chemicals unloaded onto adult human skin cells can induce — or reprogram — them to look and act like embryonic stem cells. It’s a tricky process because the gene combination is injected into the stem cells through a virus, which could be problematic. But it’s promising because many experts believe embryonic stem cells, also called ancestral cells, are the only type of cells with the potential to become any of the 220 cells with special functions in the human body.
Embryonic stem cells, and adult stem cells that can be induced to behave like them, are believed to be able to morph into any cell in the human body, such as the insulin-producing cells of the pancreas or the beating cells of the heart muscle. In theory, scientists could transform embryonic stem cells into healthy pancreas cells that could cure Type I diabetes by allowing doctors to replace a patient’s malfunctioning cells that give rise to the disease, for example. One scientist referred to the embryonic stem cells as the “Swiss army knife of tools” in a human toolbox.
The use of embryonic stem cells, however, is hotly debated because creating the cells in a laboratory requires destroying days-old embryos. On the other hand, the use of the reprogrammed adult skin cells — called “induced pluripotent cells” — has been deemed “morally acceptable” by the Roman Catholic Church because the technology doesn’t use and destroy embryos, which the church considers to be human life.
The technique using adult skin stem cells has been hailed by scientists worldwide for advancing the science while avoiding the major ethical controversy and quieting the most vocal opponents of embryonic stem cell research. In San Diego, researchers are increasingly developing alternatives to natural embryonic stem cells, such as using stem cells derived from unfertilized human egg cells. Other researchers are avoiding the controversy all together and harvesting adult stem cells found in fatty tissue to reconstruct body parts.
Along with easing ethical concerns, the artificial cells wouldn’t be as hard to come by as real embryonic cells, which have to be obtained from embryos left over from in vitro fertilization procedures and slated for disposal. The process usually requires the informed consent of the parents and is extremely expensive because the government has allowed only very limited federal funding for the work, leaving researchers reliant on hard-to-come-by venture capitalist or philanthropic funds.
Also, because the artificial cells are exact genetic copies of the skin cells, in theory, the reprogramming technique would allow tissue made from the cells to be transplanted into a person to replace cells damaged by disease without fear of rejection.
“It’s truly matched to the individual completely,” Kalichman said.
But as is the case with much promising research, there are some key hurdles researchers and ethicists still have to overcome, meaning the new technique isn’t expected to offer any medical benefits for patients in the immediate future.
Technically speaking, scientists need to find a virus-free way to infuse the adult skin stem cells with the gene and chemical combination that reprograms the skin cells to act like natural embryonic ones. Also, artificial embryonic stem cells have to be tested against natural ones to confirm initial findings about their behavior and ensure that they don’t mutate and become harmful in the long-term.
And despite the therapy’s embryo-free method, other ethical questions surrounding access and the testing process will have to be grappled with as the research moves closer to human treatments, Kalichman said.
“It could be 10, 20, 50 or 100 years” before a therapy is available, he said. “We don’t know.”
Researchers use viruses to ferry the genes into the skin cells, which could create problems because the viruses could also insert diseases or other contaminants into other chromosomes, said Ed Baetge, the chief scientist at Novocell, Inc., a San Diego-based stem cell engineering company. That wouldn’t matter if the cell lines are used to test experimental drugs on human cells, but it would block them from being tested as therapies in human patients.
Baetge’s company has learned how to use embryonic stem cells to create new insulin-producing pancreatic cells in a petri dish, a development Baetge believes could lead to a cure for Type I diabetes, a progressive disease in which the body’s immune system attacks the pancreas, rendering it unable to secrete insulin and regulate blood sugar. Baetge hopes to be in clinical trials with humans within the next several years.
Although he’s not using artificial, also called act-alike or human-induced, embryonic stem cells, he’s supportive of the emerging science because he knows first-hand how difficult it is to obtain embryos from in vitro fertilization clinics for research.
“They’ve got to find a way to coax those cells to change without using a virus to do it,” Baetge said. “If they do it, it will be revolutionary.”
The challenge now, Baetge said, is to find a way to induce the changes in the skin stem cells without using viruses that can be wily and difficult to control once they enter a body or cell. Scientists will have to find a drug or chemical, which are more predictable, to ferry the genes into the skin cells.
Also, while initial studies show that the artificial embryonic stem cells appear to behave like the real ones, many more years of research will be necessary to determine how the reprogrammed cells will function long-term in the human body.
A spokesman for the California Institute for Regenerative Medicine, which will distribute $3 billion in stem cell research grants over the next decade, said the agency will continue to fund research using cells created by many different methods, including reprogramming adult stem cells and the growing of natural embryonic stem cells in labs.
Kalichman, the bioethicist, agreed that all avenues of research should be pursued, but said it’s important that people scrutinize the process and ask the crucial questions when ethical and moral evaluations become necessary. For instance, he said, there needs to be a balance between the concerns of medical science and the eagerness of terminally ill patients to get new treatments as soon as possible will have to be negotiated.
“We can’t skip steps,” Kalichman said. Controlled animal studies have to be evaluated so doctors can understand any potential negative side effects. “We have to ensure that potential benefits outweigh potential harm if we’re going to help people get better.”
Another ethical concern is ensuring that the poor have access to treatments, particularly in states such as California where public funds are spent on research.
Spurred by the controversy and the difficulty of getting embryos, some biotechnology companies and academics in San Diego have been trying alternative techniques for producing stem cells.
At the La Jolla-based Burnham Institute for Medical Research, scientists are exploring the strategy of using stem cells as factories to make hormones or proteins the body is not making. A team led by Evan Snyder has shown in mice that stem cells may be able to supply missing enzymes to babies with Tay-Sachs disease n a genetic disorder in which harmful quantities of a fatty substance build up in tissues and nerve cells in the brain. A human trial could begin as soon as next year.
In Oceanside, International Stem Cell Corp. has produced an alternative to natural embryonic stem cells through the production of stem cells that act like embryonic ones but are derived from unfertilized, rather than fertilized, human egg cells which can’t become a complete human.
At least two emerging therapies avoid embryonic stem cells altogether.
Scientists at the Scripps Research Institute have found blood and bone marrow stem cells that help repair damaged vessels in the eye. San Diego-based Cytori Therapeutics has created a device, which is already commercially available in Europe, to locate stem cells in fat that could be used in breast reconstruction after lumpectomy. If successful, the harvested fat-derived stem cells could potentially be used to heal many body parts.