Stem cell news — differences and ethics

Two releases from yesterday on stem cells. Number one is on the found differences between reprogrammed skin cells and embryonic stem cells. Second is a call for stem cell debates by bioethicists before the science gets too far ahead of ethical considerations.

The first release:

UCLA scientists find molecular differences between embryonic stem cells and reprogrammed skin cells

UCLA researchers have found that embryonic stem cells and skin cells reprogrammed into embryonic-like cells have inherent molecular differences, demonstrating for the first time that the two cell types are clearly distinguishable from one another.

The data from the study suggest that embryonic stem cells and the reprogrammed cells, known as induced pluripotent stem (iPS) cells, have overlapping but still distinct gene expression signatures. The differing signatures were evident regardless of where the cell lines were generated, the methods by which they were derived or the species from which they were isolated, said Bill Lowry, a researcher with the Broad Stem Cell Research Center and a study author.

“We need to keep in mind that iPS cells are not perfectly similar to embryonic stem cells,” said Lowry, an assistant professor of molecular, cell and developmental biology. “We’re not sure what this means with regard to the biology of pluripotent stem cells. At this point our analyses comprise just an observation. It could be biologically irrelevant, or it could be manifested as an advantage or a disadvantage.”

The study appears in the July 2, 2009 issue of the journal Cell Stem Cell.

The iPS cells, like embryonic stem cells, have the potential to become all of the tissues in the body. However, iPS cells don’t require the destruction of an embryo.

The study was a collaboration between the labs of Lowry and UCLA researcher Kathrin Plath, who were among the first scientists and the first in California to reprogram human skin cells into iPS cells. The researchers performed microarray gene expression profiles on embryonic stem cells and iPS cells to measure the expression of thousands of genes at once, creating a global picture of cellular function.

Lowry and Plath noted that, when the molecular signatures were compared, it was clear that certain genes were expressed differently in embryonic stem cells than they were in iPS cells. They then compared their data to that stored on a National Institutes of Health data base, submitted by laboratories worldwide. They analyzed that data to see if the genetic profiling conducted in other labs validated their findings, and again they found overlapping but distinct differences in gene expression, Lowry said.

“This suggested to us that there could be something biologically relevant causing the distinct differences to arise in multiple labs in different experiments,” Lowry said. “That answered our first question: Would the same observation be made with cell lines created and maintained in other laboratories?”

Next, UCLA researchers wanted to confirm their findings in iPS cell lines created using the latest derivation methods. The cells from the UCLA labs were derived using an older method that used integrative viruses to insert four genes into the genome of the skin cells, including some genes known to cause cancer. They analyzed cell lines derived with newer methods that do not require integration of the reprogramming factors. Their analysis again showed different molecular signatures between iPS cells and their embryo-derived counterparts, and these signatures showed a significant degree of overlap with those generated with integrative methods.

To determine if this was a phenomenon limited to human embryonic stem cells, Lowry and Plath analyzed mouse embryonic stem cells and iPS lines derived from mouse skin cells and again validated their findings. They also analyzed iPS cell lines made from mouse blood cells with the same result

“We can’t explain this, but it appears something is different about iPS cells and embryonic stem cells,” Lowry said. “And the differences are there, no matter whose lab the cells come from, whether they’re human or mouse cells or the method used to derive the iPS cells. Perhaps most importantly, many of these differences are shared amongst lines made in various ways.”

Going forward, UCLA researchers will conduct more sophisticated analyses on the genes being expressed differently in the two cell types and try to understand what is causing that differential expression. They also plan to differentiate the iPS cells into various lineages to determine if the molecular signature is carried through to the mature cells. In their current study, Lowry and Plath did not look at differentiated cells, only the iPS and embryonic stem cells themselves.

Further study is crucial, said Mark Chin, a postdoctoral fellow and first author of the study.

“It will be important to further examine these cells lines in a careful and systematic manner, as has been done with other stem cell lines, if we are to understand the role they can play in clinical therapies and what effect the observed differences have on these cells,” he said.

 

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The stem cell center was launched in 2005 with a UCLA commitment of $20 million over five years. A $20 million gift from the Eli and Edythe Broad Foundation in 2007 resulted in the renaming of the center. With more than 150 members, the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research is committed to a multi-disciplinary, integrated collaboration of scientific, academic and medical disciplines for the purpose of understanding adult and human embryonic stem cells. The center supports innovation, excellence and the highest ethical standards focused on stem cell research with the intent of facilitating basic scientific inquiry directed towards future clinical applications to treat disease. The center is a collaboration of the David Geffen School of Medicine, UCLA’s Jonsson Cancer Center, the Henry Samueli School of Engineering and Applied Science and the UCLA College of Letters and Science. To learn more about the center, visit our web site at http://www.stemcell.ucla.edu.

Head below the fold for the second release on a call for an ethics debate on stem cells.

Release number two:

Bioethicists lead call for public debates on future uses of stem cells

Science is running ahead of public debate and guidelines to grapple with use of stem cell-derived eggs and sperm

More than 40 scientists, bioethicists, lawyers and science journal editors are calling on their colleagues, policy makers and the public to begin developing guidelines for the research and reproductive use of stem cell-derived eggs and sperm, even though such use may be a decade or more away.

“Science has always moved faster than social debate or society’s ability to grapple with these issues,” says Debra Mathews, Ph.D., lead author of a paper published in the July issue of Cell Stem Cell and assistant director of science programs at the Johns Hopkins Berman Institute of Bioethics. The paper calls for all parties to begin engaging in open discussion and debates, and describes the need for informed social policy well in advance of the eventual use of eggs and sperm derived from pluripotent stem cells.

Mathews said stem cell researchers need to be better prepared to address public questions about uses of so-called pluripotent stem cell-derived gametes — regardless of how realistic or soon those uses may be. Such uses would potentially include reproductive uses such as the creation of sperm and eggs for in vitro fertilization, embryo selection based on genetic profile, and the creation of embryos from the tissues of fetuses, children and the deceased.

The issues are too complex, and the stakes are too high, the authors suggest, for the public to be caught unaware by some new capability for using stem cell-derived gametes, and the research already is moving rapidly toward generation of sperm and eggs capable of making human embryos and potentially children.

“Because derived-gamete research will require the creation and destruction of human embryos, this line of research will be morally objectionable to those who imbue human embryos with full moral status, and those objections must be addressed,” the authors state.

In their paper, the Johns Hopkins-led team described an analysis of the current state of pluripotent stem cell science and suggested a framework for the debates that need to take place.

There was consensus by the authors that policymakers should not restrict scientific inquiry solely because ethical or moral disagreement exists about the use of these cells. Instead, they offered recommendations for guidelines that would be the focus of social debate. Among them were that restrictions should be specific to those aspects of the technology that are deemed morally unacceptable in a given nation or state, and that specific consent should be required of tissue donors whose cells will be used to derive gametes for use in reproduction. This approach would rule out using for reproduction any tissue from fetuses, minors and the deceased. Consent, they said, need not be required in situations involving laboratory studies that produce no embryos.

The authors emphasized that significant oversight rules must be in place before any reproductive uses of gametes even begins, and early attempts to use gametes for these purposes should take place only as part of clinical research that follows the highest ethical standards.

Assuming that reproductive use of stem cell-derived gametes does occur, the health of women carrying the resulting fetuses, and of children born to them, should be monitored rigorously and tracked in long-term studies.

Pluripotent stem cell-derived gamete research brings together several of today’s most contentious ethical issues, including the use of embryonic stem cells, the increasing ability to identify and understand risks associated with particular parts of the human genome, advanced reproductive technologies to treat infertility and interest in “human enhancement.”

Mathews noted that pluripotent stem cell-derived gamete research already is producing significant advances in basic understanding of how eggs and sperm develop from germ cells, infertility, genetic diseases and some cancers.

Mathews said the most difficult scientific issue the study team faced was predicting how long it would take to get from a human stem cell to a set of gametes capable of successful test-tube fertilization, and how long, if ever, it would be until such gametes are used in clinical care. The group believes it will take at least a decade to develop derived human gametes and that clinical applications likely won’t be available for several years beyond that.

Whatever the time frame, she said determining whether pluripotent stem cell-derived gametes can function reliably and normally is critical for both nonreproductive and reproductive purposes.

Scientists and the public also must prepare, Mathews noted, for the potential production of large numbers of human gametes that facilitate multigenerational laboratory studies of human genetics and disease.

“Although many welcome the prospects for disease prevention and health promotion that such research should facilitate, many others will find the treatment of human embryos in such blatantly manipulative ways to be ethically unacceptable,” the authors said in their paper.

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 Other authors of the paper are Peter J. Donovan of the University of California, Irvine; John Harris of the University of Manchester; Robin Lovell-Badge of the MRC National Institute for Medical Research; Julian Savulescu of the University of Oxford; and Ruth Faden, director of the Johns Hopkins Berman Institute of Bioethics in Baltimore.