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STEM CELL RESEARCH

Genetic Errors in Human Stem Cells: Should We be Worried?

Stem Cells in Bottle SOURCE: AP Photo/Damian Dovarganes University of California, Irvine, researcher Hans Keirstead holds a special bottle with human embryonic stem cells.

Human pluripotent stem cells are expected to significantly improve medicine by helping researchers understand human development and disease, making drug development more efficient, and aiding in repair of degenerated tissues.

In the last year, scientists all over the world have been closely examining the DNA of many different preparations of human pluripotent stem cells, and they all have come to a similar conclusion: they have mistakes in their DNA sequences (publications are listed below). This is not surprising, because every time a cell divides, there’s a chance that the DNA sequence doesn’t get copied perfectly. This happens every day in our own bodies as our cells renew themselves; our cells can tolerate a lot of little changes without causing problems. DNA mistakes are a normal part of life.

However, not all errors in DNA are benign. Cancers involve changes in the DNA that make cells grow wildly out of control, but these changes are unusual—such as the breaking of chromosomes, inactivating genes that suppress tumor formation or hyper-activating genes that enhance growth. Even these changes don’t usually cause problems because our immune systems recognize these grossly abnormal cells and wipe them out.

Why do pluripotent stem cells have errors in their DNA? The techniques we use require that the cells be expanded from a single cell to a million cells before we can examine their DNA. This means that they have to double at least 20 times, which makes 20 chances for mistakes to be made in copying the DNA sequence. Some errors give the cells a growth advantage—think of evolution and survival of the fittest. If a cell grows just a little faster than its neighbors, eventually, over many cell doublings, it will become the dominant cell type in the culture. This dominant cell type is the one that we detect by sophisticated DNA analysis methods.

So, there are errors in DNA in cancers and there are errors in both human embryonic stem cells, which are derived from embryos, and induced pluripotent stem cells, which are derived from adult tissue. Should we be worried? I think we should be careful, but there are several reasons why we shouldn’t be worried, yet.

First, by far the greatest uses of pluripotent stem cells will not involve transplanting them to humans. Cultures of these cells will be valuable for understanding human disease. They will be very helpful for drug development, where they can be used to improve the testing of drugs in culture dishes before they are tested in people. DNA abnormalities are not important in cultured cells, unless they affect some critical function that is necessary for the assays and experiments that researchers use.

Second, the recent reports of DNA abnormalities in these cells will encourage other scientists in both basic and clinical research to look more closely at the DNA of the cells they are using. This is an important step forward that will improve the quality of stem cell research everywhere.

Last, these new reports strongly argue that when cells are destined to be transplanted to people, they must be checked for abnormalities that are related to cancer. We have not yet determined whether any of the aberrations we have seen in stem cells actually increase the chances that they become cancerous. Small mistakes in DNA are normal, as pointed out earlier. They do not harm us. We are working to identify what, if any, DNA changes reported in the recent scientific papers are dangerous. After we do this, we will know what to worry about.

Jeanne F. Loring is Professor and Director Center for Regenerative Medicine in the Department of Chemical Physiology at The Scripps Research Institute.

References

Gore, A., Li, Z., Fung, H.L., Young, J.E., Agarwal, S., Antosiewicz-Bourget, J., Canto, I., Giorgetti, A., Israel, M.A., Kiskinis, E., Lee, J.H., Loh, Y.H., Manos, P.D., Montserrat, N., Panopoulos, A.D., Ruiz, S., Wilbert, M.L., Yu, J., Kirkness, E.F., Izpisua Belmonte, J.C., Rossi, D.J., Thomson, J.A., Eggan, K., Daley, G.Q., Goldstein, L.S., Zhang, K., 2011. Somatic coding mutations in human induced pluripotent stem cells. Nature 471, 63-67.

Hussein, S.M., Batada, N.N., Vuoristo, S., Ching, R.W., Autio, R., Narva, E., Ng, S., Sourour, M., Hamalainen, R., Olsson, C., Lundin, K., Mikkola, M., Trokovic, R., Peitz, M., Brustle, O., Bazett-Jones, D.P., Alitalo, K., Lahesmaa, R., Nagy, A., Otonkoski, T., 2011. Copy number variation and selection during reprogramming to pluripotency. Nature 471, 58-62.

Laurent, L.C., Ulitsky, I., Slavin, I., Tran, H., Schork, A., Morey, R., Lynch, C., Harness, J.V., Lee, S., Barrero, M.J., Ku, S., Martynova, M., Semechkin, R., Galat, V., Gottesfeld, J., Izpisua Belmonte, J.C., Murry, C., Keirstead, H.S., Park, H.S., Schmidt, U., Laslett, A.L., Muller, F.J., Nievergelt, C.M., Shamir, R., Loring, J.F., 2011. Dynamic changes in the copy number of pluripotency and cell proliferation genes in human ESCs and iPSCs during reprogramming and time in culture. Cell Stem Cell 8, 106-118.

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