Religion on Politics on Science: The Rough Ride for Stem Cells Continues
On August 23, 2010, U.S. District Judge Royce Lamberth turned the recently revitalized world of stem-cell research on its unsuspecting ear. The decision centered on the Dickey-Wicker amendment, which bans federal financing of any research involving the destruction or endangerment of human embryos. According to Lamberth, the government violated that law when it acted upon President Obama’s 2009 executive order expanding support for research on human embryonic stem cells (hESC). Dickey-Wicker first passed in 1996 and has been reattached to congressional spending bills every year since.
Sherley v. Sebelius was initiated by various claimants, including a number of Christian groups who were later dismissed for lack of standing. The remaining plaintiffs, adult stem-cell (ASC) researchers James Sherley and Theresa Deisher, were recruited to the suit and continue to claim standing based on alleged harm to their careers resulting from increased competition for federal cash.
Lamberth’s preliminary injunction on funding had an immediate and major impact on the science community. The National Institutes of Health (NIH) was forced to abandon its review of fifty new grant applications. It also halted second-level review of twelve applications worth fifteen to twenty million dollars.
Although funding was restored on September 9 when the appeals court temporarily stayed Lamberth’s injunction, many experts warn that mounting uncertainty has already caused irreparable damage and say American postdoctoral researchers are rethinking entry into the field. They also tell us that foreign graduates are more reluctant to consider positions in the United States.
The appeals court heard oral arguments on December 6 and was expected to rule sometime in January. The outcome is anything but certain, and many legal experts expect the case to reach the U.S. Supreme Court. Regardless, the legal fracas serves more constructively to highlight weightier and even more contentious questions.
First, the science: Just how important is continued research on hESC, and to what extent do recent advances in ASC and induced pluripotent stem-cell (iPSC) technologies alter that discussion?
Nothing obscures or distorts science quite like politics inspired by religion. According to celebrated skeptic Susan Jacoby (2011), “The problem with the good news that embryonic stem cell research will now go forward is that the public relations campaign against right-wing religious restrictions . . . [has] oversold the possibility of immediate practical results to conquer such diseases as Alzheimer’s and Parkinson’s.”
Indeed, only three clinical trials involving hESC had received U.S. government approval as of this writing, and all were the product of privately funded research. In January 2009, Geron obtained permission to begin stem-cell therapy on patients with spinal-cord injuries. Then, in November 2010 and January 2011, respectively, Advanced Cell Technology got the Food and Drug Administration’s go-ahead to work on juveniles with Stargardt’s macular degeneration and adults with age-related macular degeneration. None of these trials, however, has produced any reportable results.
Research on ASC, by contrast, has already paid sumptuous dividends—including bona fide cures for certain blood diseases. Although ASC by themselves lack pluripotency, a barrage of recent headlines has flaunted this field’s undeniable vitality.
In 2009, for example, Dr. Tracy Grikscheit from Children’s Hospital Los Angeles opened up a pig and constructed a small intestine-like structure inside using nothing more than the animal’s intestinal stem cells and a biodegradable cylinder-shaped scaffolding, thus demonstrating that ASC somehow “know” what to do when seeded onto a familiar structure (Sala et al. 2009). Preliminary tests suggest that Grikscheit’s artificial bowel will function naturally in pigs.
A similar technique has improved the life of a human child. Again combining a synthetic scaffolding with stem cells harvested from his young spina bifida-inflicted patient, Dr. Anthony Atala, director of the Wake Forest Institute for Regenerative Medicine, created a new bladder that, once attached to the old paralyzed organ, attracted its own nerve and blood supplies. Now, several years after surgery, the twenty-year-old patient’s bladder performs normally.
But in recent months, iPSC have received more attention and generated more excitement among scientists than any other stem-cell technology. Back in 2006, Shinya Yamanaka was the first to successfully reprogram adult fibroblasts back to a pluripotent, embryonic-like state through the forced expression of four transcription factors (SOX2, KLF4, MYC, and OCT4). Just a few years later, staggering progress has been made in differentiating human iPSC into neurons and heart, liver, pancreas, and eye tissues. Now, say many experts, it appears that iPSC are “poised to have a major impact in biology and medicine” through applications in “disease modeling, drug screening, and, perhaps, cell-based therapies” (Sadelain 2010).
Indeed, on December 12, 2010, researchers from the Cincinnati Children’s Hospital Medical Center in Ohio reported success in coaxing human iPSC (and separately cultured hESC) to form a three-dimensional organ resembling an intestine and to recapitulate smooth-muscle tissue, nutrient-absorbing cells, and mucous-, hormone-, and enzyme-secreting cells (Spence et al. 2010). Scientists have also used iPSC to cure diabetes in mice.1
Nevertheless, iPSC have presented their own problems. First, the insertion of external genes into reprogrammed cells can cause any number of expression anomalies. Second, one of Yamanaka’s transcription factors is known to cause tumors. Third, the reprogramming process can be inefficient, resulting in only one success for every 1,000 cells treated. Indeed, one 2010 study reported that iPSC were thousands of times less likely to proliferate and suffered greatly increased rates of early senescence (aging) and apoptosis (cell death) when compared with their embryonic counterparts (Feng et al. 2010).
Emerging evidence also indicates that iPSC tend to retain traits from their tissue of origin—striking residual DNA methylation signatures that could seriously compromise their suitability for use in the fields of genetic engineering and regenerative medicine. In one of three new studies describing this phenomenon, now dubbed epigenetic memory, researchers compared iPSC reprogrammed through the Yamanaka method with mouse ESC generated via somatic-cell nuclear transfer (Kim et al. 2010). Disappointingly, they discovered that the iPSC were less likely to achieve “ground state pluripotency” and that they tended to differentiate into their original cell types.
Then again, scientists have addressed—and in some cases, overcome—these obstacles almost as quickly as journalists can write about them. Some labs now use viruses that don’t invade the cell’s genome, while others employ tiny rings of DNA called episomes that don’t replicate when the cell divides.
This past September, Derrick Rossi of the Harvard Medical School used synthetic RNA molecules corresponding to the standard Yamanaka factors to produce RNA-induced pluripotent stem cells, or “RiPS,” one hundred times more efficiently (a two percent success rate) than with viral methods and in roughly half the time (two weeks) (Warren et al. 2010). And because RNA disintegrates rapidly, RiPS are genetically identical to their source cells. Unfortunately, Rossi’s process is exceptionally expensive and time consuming.
Even more recently, Sheng Ding, a chemist at the Scripps Research Institute in San Diego, effectively reprogrammed human skin cells by treating them with drugs and only one virus-delivered gene, OCT4 (Zhu et al. 2010). And because that gene, too, has been replaced in experiments on mice, says Ding, a human protocol entirely free of foreign genes may not be far off.
The direct conversion of ordinary body cells has lately gained momentum as well. On November 7, Mickie Bhatia at McMaster University reported the first-ever conversion of human skin cells into red, white, and platelet blood cells using an OCT4-infused virus and a brew of immune-system stimulating proteins called cytokines (Szabo et al. 2010). Because these cells never pass through an embryonic-like state, the risk of tumor formation is averted. On the downside, converted cells will not easily multiply in the lab.
Regardless, America’s most prominent and accomplished researchers continue to insist that neither ASC nor iPSC technologies have advanced far enough to render aggressive hESC research superfluous, let alone obsolete. During a well-publicized hearing on stem-cell research held on September 16, 2010, a Senate appropriations subcommittee took testimony from Francis Collins, director of the NIH, and George Daley, director of the Stem Cell Transplantation Program at the Children’s Hospital Boston.
A vocal evangelical Christian as well, Collins made it plain during the hearing that hESC “remain the gold standard for pluripotency” and that “to prohibit work on [them] will thus do severe collateral damage to the new and exciting research on [iPSC].” He then reminded the senators that the NIH spends nearly three times as much on ASC research as it does on hESC research every year.
But Collins’s most poignant testimony divulged how hESC are currently “providing key tools to help us study the origins of many devastating diseases that afflict babies and young children,” including fragile X and Rett syndromes, developmental disorders of the brain. Americans “must persevere and move this research forward in a strong and consistent manner,” he urged. The politics of delay and uncertainty, he warned, were tantamount to “pouring sand into the engine of discovery.”
Having co-authored Rossi’s ground-breaking RiPS paper, Daley’s adamant avowal that iPSC “do not obviate the need for [hESC]” may have been equally effective. He also noted the stubborn limitations of even the most successful ASC treatments involving the transplantation of hematopoietic cells. Despite fifty years of this research and practice, Daley said, “patients still die or become severely disabled because the transplant regimens are so toxic.”
Clearly irritated by the current legal intrusion into scientific matters, Daley likened the political debate concerning different classes of stem cells to a contest between entertainers on American Idol. These arguments, he scolded, “are not based on sound scientific evidence, but rather ideologically driven attempts” to control science and distort sober medical realities. Urging new legislation to encourage American research, Daley was “convinced that [hESC] are critical to a multifaceted portfolio of NIH stem cell research.”
Senate subcommittees are notorious for choosing witnesses certain to confirm member predilections. But these researchers’ credentials, and those of their many professional supporters, cannot be denied. In the end, Jacoby (2011, 98) concurs: “That treatments may be a generation or two . . . away is not an argument against basic scientific research. The difficulty of the science makes it more, not less, important for researchers to move full speed ahead now in all areas that offer promise for the alleviation of the most serious age related diseases.”
After the judiciary imposes itself, however, it quickly loses the option to bow out gracefully. Dickey-Wicker was a legal accident waiting to happen. But from the wreckage we must now address the next unavoidable question: How should Americans dispose of the stem-cell quandary—through the courts or through Congress?
In the courts, the defense will argue that Dickey-Wicker preceded and thus could not have been intended to control modern hESC research. It will contend that mere research on stem cells previously derived from embryos does not constitute harming those embryos, which is apparently the reasoning Congress relied upon during the past two presidential administrations.
But even the best-case judicial solution would be inadequate. With polls showing continued and increasing popular support for hESC research, all science-friendly members of Congress should promptly push for clear and comprehensive legislation that would override Dickey-Wicker and codify many of the research guidelines announced by Obama in 2009.
And we shouldn’t forget that the stem-cell question is part of a larger issue looming on the cultural horizon. America stands at a crossroads. Will it remain a nation committed to scientific innovation and economic progress? Or will ideology finally tear down those long-partnered academic and entrepreneurial edifices that generations of supremely talented, energetic, forward-thinking, and, yes, conscientious persons have worked so hard to erect?
- Also on December 12, researchers at Georgetown University Medical Center presented findings at the fiftieth annual meeting of the American Society of Cell Biology that insulin-secreting beta islet cells, normally found in the pancreas, can be produced from human spermatogonial ASC without the use of extra genes. These researchers hope that continued progress in this area will lead to a novel solution to juvenile-onset (type 1) diabetes. ↑
Feng, Q., S. Lu, I. Klimanskaya, et al. 2010. Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence. Stem Cells 28: 704–12.
Jacoby, S. 2011. Never Say Die: The Myth and Marketing of the New Old Age. New York: Pantheon Books.
Kim, K., A. Doi, B. Wen, et al. 2010. Epigenetic memory in induced pluripotent stem cells. Nature 467(7313): 285–90.
Sadelain, M. 2010. The need for genetically engineered therapeutic pluripotent stem cells (Editorial). Molecular Therapy 18(2): 2039.
Sala, F.G., S.M. Kunisaki, E.R. Ochoa, et al. 2009. Tissue-engineered small intestine and stomach form from autologous tissue in a preclinical large animal model. Journal of Surgical Research 156(2): 205–12.
Spence, J.R., C.N. Mayhew, S.A. Rankin, et al. 2010. Direct differentiation of human induced pluripotent stem cells into intestinal tissue in vitro. Nature (advance online publication). doi: 10.1038/nature09691.
Szabo, E., S. Rampalli, R.M. Risueño, et al. 2010. Direct conversion of human fibroblasts to multilineage blood progenitors. Nature (advance online publication). doi: 10.1038/ nature09591.
Warren, L., P.D. Manos, T. Ahfeldt, et al. 2010. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7(5): 618–30.
Zhu, S., W. Li, H. Zhou, et al. 2010. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 7(6), 651–55.