One of the great benefits of cell reprogramming–converting adult cells into stem cells–is the ability to capture an individual’s genetic diversity. Scientists are now using this technology, known as induced pluripotent stem (iPS) cell reprogramming, to create banks of stem cells from different people. The banks will be used to test the toxicity of different drugs using cells from people of different ethnicities, and could potentially supply cells for tissue replacement therapies. Researchers presented details of their efforts at the International Society for Stem Cell Research conference in San Francisco this week.
Shinya Yamanaka, a stem cell scientist at the Gladstone Institute, in San Francisco, and Kyoto University, in Japan, first created iPS cells in 2007 by adding just four genes to adult cells that are normally active only in embryos. (James Thomson and Junying Yu at the University of Wisconsin, in Madison, simultaneously published a similar approach.) The cells can reproduce themselves many times over, and they can develop into any cell type in the human body, the two defining characteristics of embryonic stem cells. Furthermore, because they are not made from human embryos, iPS cells bypass the ethical and technical challenges associated with embryonic stem cells.
Scientists have since created iPS cells from patients with different diseases, including amyotrophic lateral sclerosis (ALS) and Parkinson’s disease, and these cells are being used to study these diseases. A number of startups are developing ways to use the cells to screen drugs, both for toxicity in human cells and for their effectiveness in alleviating molecular signs of disease. Jeanne Loring, founding director of the Center for Regenerative Medicine at The Scripps Research Institute in La Jolla, CA, is developing a stem cell bank that will be used for toxicity testing, focusing initially on Africans and African Americans, groups known to have a high level of genetic diversity. Loring and collaborators are analyzing a number of genetic variants in the cells they collect, paying particular attention to variations in drug-metabolizing enzymes that can affect how patients respond to specific drugs, including antidepressants, pain medicines, and drugs for heart disease.
The longer-term goal for iPS cells is to use them to repair or replace damaged or diseased tissue. Just like organ transplants, stem cell transplants must be matched to the recipient. However, Yamanaka points out that creating personalized cells for everyone who needs them is likely to be too time-consuming and expensive to be practical. It can take two to six months to create a line of stem cells from an individual, and someone suffering from spinal cord damage, for example, would likely need a cell transplant within days of injury. (Stem cell treatments for spinal cord injury have not yet been approved by the U.S. Food and Drug Administration, though one company hopes to test embryonic stem cells for this purpose soon.)
Yamanaka’s team is instead working to create a bank of stem cell lines that would be appropriate for a large percentage of the Japanese population. Although the concept of such a stem cell bank was first proposed several years ago for embryonic stem cells, iPS cell technology has made it much easier to create.
To explore the feasibility of creating a bank of stem cells, Yamanaka’s team tested the tissue type of 107 Japanese volunteers. People vary highly in the genes that code for cell surface molecules called human leukocyte antigens (HLA), and the closer these antigens match between donor and recipient, the less likely the recipient’s immune system is to reject the transplanted tissue. The researchers discovered that two of the volunteers were homozygous–meaning they carried two matching copies–of each of three HLA genes. Because of this rare genotype, these people could serve as donors to anyone with those three antigens–nearly one-third of the volunteer group. According to a collaborator’s calculations, just 50 different HLA types could cover 90 percent of the Japanese population. The researchers have since made iPS cells from these individuals and shown that they behave normally and can be differentiated into numerous cell types.
Roger Pederson, a stem cell biologist at Cambridge University, in the U.K., warns that even this level of matching would require some immunosuppression because of slight HLA mismatches. “But it’s preferable to making lines for everyone who needs one,” says Pederson, who proposed the idea of a stem cell bank in 2005.
It’s not yet clear how difficult it would be to create a similar tissue-matched bank for more diverse populations. “The Japanese are a particularly homogeneous population, and I wonder if it would be possible to do a similar screen in the U.S.,” says Loring. Because Americans are ethnically heterogeneous, there are likely fewer homozygotes, she says.
In 2005, Pederson’s team analyzed HLA types for cadaver organ donors and for people on the organ donation waiting list in the U.K., calculating that 150 lines of stem cells would provide a beneficial match for about 85 percent of those on the list. Ten donors homozygous for common HLA types would provide a beneficial match for about 67 percent. The researchers aren’t yet creating such a bank, but they are analyzing the best way to create a clinically useful bank of cells.
Population-based stem cell banking is still in its early days. (Banks of newborns’ umbilical cord blood, often stored in private facilities by parents, represent a different kind of banking. The stem cells from this blood are useful for a limited set of rare diseases, and they cannot be expanded or differentiated the way iPS cells can.) While scientists are studying ways to use iPS cells as disease treatments, none have yet been tested in clinical trials. In addition, these cells aren’t yet suitable for human transplant; the way they are currently made may carry some risk of cancer. “We still haven’t determined which type of induction is best, but after solving the technical issues, creating this kind of bank would be feasible,” says Yamanaka.
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