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  • Writer's pictureKirk Hartley

21 Republicans (and 1 Democrat – Dan Lipinski) Seek to Downgrade and Slow Research on Embryoni

Amazing how some of our elected representatives think their religious abstractions are an excuse to seek to take us backwards in science. Thus, this year once again sees a host of Republicans (21) – and Democrat Dan Lipinksi of Chicago – sponsor a bill that would downgrade and slow funding for research using embryonic stem cells. The current bill is here; a Hill article is here, a current announcement from the Republican "leader" is here, and here is a prior statement from Rep. Lipinski’s office. Hat tip to Paul Knoepfler, a stem cell scientist who blogs, here is the main page for his blog, and here is the relevant post.

It’s a shame these purported leaders fail to read – or respect – science. Time and again, researchers have shown that induced stem cells have problems that are not found in embryonic stem cells. (Induced stem cells (iPS cells) are the supposedly "ethical" alternative to embryonic stem cells.) Thus, for example, this past spring, the leading science journal known as Nature published a major article detailing genomic flaws in iPS cells. The flaws include alterations in genes associated with cancer. Does this mean iPS cells can never work? No, but it means more steps and research are needed, and answers and outcomes arrive more slowly. Delay may seem ok to legislators wrapped up in their own beliefs and busy pandering to right wingers, but it’s not ok for people who are suffering or dying today.

The ScienceDaily summary of the research is here; key excerpts are set out below:

"A new study — published in the March 3 issue of the journal Nature and led by scientists at the University of California, San Diego in collaboration with other leading stem cell research groups — finds that the genetic material of reprogrammed cells may in fact be compromised, and suggests that extensive genetic screening of hiPSCs become standard practice before these stem cells are used clinically.

A national team of researchers, co-directed by Kun Zhang, PhD, an assistant professor of bioengineering in the UC San Diego Jacobs School of Engineering, examined 22 different hiPSC lines obtained from seven research groups that employed different methods to reprogram skin cells into pluripotent stem cells. In all of these cell lines, the researchers found protein-coding point mutations, an estimated six mutations per exome. The exome is the part of the genome that contains the genetic instructions for making proteins and other gene products.

"Every single stem cell line we looked at had mutations. Based on our best knowledge, we expected to see 10 times fewer mutations than we actually observed," said Zhang, a faculty member of the Institute for Genomic Medicine and the Institute of Engineering in Medicine, both at UC San Diego.

The findings help answer the question of whether reprogramming adult mammalian cells into hiPSCs affects the overall genome at the fundamental level of single nucleotides. They do. Zhang called the mutations "permanent genome scars."

The scientists said while some of the mutations appeared to be silent, the majority did change specific protein functions, including those in genes associated with causative effects in cancers. (emphasis added).

"Reprogrammed stem cells provide an important new tool in the fight against human disease, but to use these cells directly in the clinic, we must ensure that they are safe and that we are able to define their structure and behavior in the most precise terms," said Lawrence S.B. Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine at the UCSD School of Medicine and co-director of the study with Zhang. Goldstein is also director of the UC San Diego Stem Cell Program.

More after the jump ….

The full article is here in Nature. The article abstract closes with a warning that using iPS cells means there is a need for "extensiv genetic screening" before using human iPS cells. Thus, the abstract states:

"Defined transcription factors can induce epigenetic reprogramming of adult mammalian cells into induced pluripotent stem cells. Although DNA factors are integrated during some reprogramming methods, it is unknown whether the genome remains unchanged at the single nucleotide level. Here we show that 22 human induced pluripotent stem (hiPS) cell lines reprogrammed using five different methods each contained an average of five protein-coding point mutations in the regions sampled (an estimated six protein-coding point mutations per exome). The majority of these mutations were non-synonymous, nonsense or splice variants, and were enriched in genes mutated or having causative effects in cancers. At least half of these reprogramming-associated mutations pre-existed in fibroblast progenitors at low frequencies, whereas the rest occurred during or after reprogramming. Thus, hiPS cells acquire genetic modifications in addition to epigenetic modifications. Extensive genetic screening should become a standard procedure to ensure hiPS cell safety before clinical use." (emphasis added).

The article quoted above is only one of many articles publishing research findings which prove that iPS cells are NOT equivalent to or as good as as embryonic stem cells. Instead, the induced cells are in fact different, and those differences are additional variables which inevitably slow research. If we lived in a world of 100% funding and all research were occurring at once, that would not be an issue. But instead we live in a world of diminishing science budgets, and so further delays and costs will inevitably create more suffering and deaths that might otherwise be avoided if embryonic cell research pushed ahead as quickly as possible. Set out below are other papers detailing why iPS cells are NOT equivalent and suffer from variables not found in embryonic stem cells.

For example, a 2009 study published in Nature Genetics describes the reality that iPS cells are not the same as embryonic stem cells, as is detailed in this article from Science Daily. Thus, [as explained by an MD, PhD, George Q.] "Daley, director of the Stem Cell Transplantation Program at HHMI/Children’s Hospital in Boston, "Our data also point to differences between iPS cells and embryonic stem (ES) cells, which everyone has felt were similar if not identical. Such differences may prove important in the behavior of iPS cells in studies on tissue formation and may complicate therapies based on iPS cells. We need to develop ways of generating iPS cells that are a closer match to ES cells in their methylation patterns. Only then will we be confident that iPS cells are a safe replacement for ES cells in research and therapy."

Why the concern? Because the iPS cells show changes in the methylation of DNA, which means that usual DNA functions are altered by chemical changes. The ScienceDaily summary put it this way:

"The study, done jointly with George Q. Daley, M.D., Ph.D., and colleagues from Harvard University, was published Nov. 1 in the advanced online edition of Nature Genetics. The researchers suggest in the study that certain sites throughout the genome appear to be generally involved in distinguishing DNA methylation among different cell types and cancers, and these same sites are involved in reprogramming fibroblasts back into stem cells. (emphasis added).

The scientists used the CHARM method (comprehensive high-throughput arrays for relative methylation) to survey where, across the genomes of nine human iPS cell lines, genes had been silenced, or turned off, and then compared these DNA methylation sites with those of the fibroblasts the iPS cells were derived from.

"This type of research gets to the fabric of the fundamental differences between stem cells and their parental cells," says Akiko Doi, a doctoral candidate in the graduate program in Cellular and Molecular Medicine at Johns Hopkins. "Clearly, that fabric involves these DMRs, which are essential to our understanding the nature of these potentially therapeutic iPS cells."

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