by Kenneth W. Krause.
Kenneth W. Krause is a contributing editor and “Science Watch” columnist for the Skeptical Inquirer. Formerly a contributing editor and books columnist for the Humanist, Kenneth contributes regularly to Skeptic as well. He may be contacted at firstname.lastname@example.org.
During their recent campaigns, both governor-elect Scott Walker and senator-elect Ron Johnson were asked about their positions on stem cell research. Both acknowledged that the University of Wisconsin—Madison has led not just our nation, but indeed the entire world, in this important bio-medical discipline.
Both stated rather baldly that they didn’t support federal funding for research on human embryos because only other stem cell technologies had proven worthwhile. But because neither Walker nor Johnson ever offered any explanation for that belief, Wisconsinites need to confront them with the legal, religious, and, of course, scientific realities of stem cell research.
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 banning federal financing of any research involving the destruction or endangerment of human embryos. The government violated that law, according to Lamberth, when it acted upon president Obama’s 2009 executive order expanding support for research on human embryonic stem cells (hESCs). 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 was forced to abandon its review of 50 new grant applications. It also halted second-level review of twelve applications worth $15 to $20 million and its planned September review of another 22 applications valued at $54 million.
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. American postdocs are rethinking entry into the field, they say, and foreign graduates are more reluctant to consider positions in the U.S.
The appeals court heard oral arguments on December 6, and is expected to rule sometime in January. The outcome is anything but certain, but, either way, 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 hESCs, and to what extent do recent advances in ASC and induced pluripotent stem cell (iPSC) technologies alter that discussion?
As we know, nothing obscures or even distorts science quite like politics inspired one way or the other by religion. According to celebrated skeptic, Susan Jacoby, “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.”[i]
Indeed, only two clinical trials involving hESCs had received U.S. government approval as of this writing, and both 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, Advanced Cell Technology got the FDA go-ahead to work on patients with Stargardt’s Macular Degeneration. Neither trial, however, has produced any reportable results.
Research on ASCs, by contrast, has already paid sumptuous dividends—including bona fide cures for certain blood diseases. Although ASCs by themselves lack pluripotency, a barrage of recent headlines has flaunted this field’s undeniable vitality.
Last year, for example, Dr. Tracy Grikscheit from the 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 ASCs somehow “know” what to do when seeded onto a familiar structure.[ii] 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 20-year-old patient’s bladder performs normally.
But in recent months, iPSCs 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 iPSCs into neurons and heart, liver, pancreas, and eye tissues. Now, say many experts, it appears that iPSCs are “poised to have a major impact in biology and medicine” through applications in “disease modeling, drug screening, and, perhaps, cell-based therapies.”[iii]
Indeed, on December 12, 2010, researchers from the Cincinnati Children’s Hospital Medical Center in Ohio reported success in coaxing human iPSCs (and separately cultured hESCs) 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.[iv] Scientists have also used iPSCs to cure diabetes in mice.[v]
Nevertheless, iPSCs 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 1000 cells treated. Indeed, one study released last February reported that iPSCs were thousands of times less likely to proliferate and suffered greatly increased rates of early senescence (aging) and apoptosis (cell death) when compared to their embryonic counterparts.[vi]
Emerging evidence also indicates that iPSCs 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 iPSCs reprogrammed through the Yamanaka method to ESCs generated via somatic cell nuclear transfer.[vii] Disappointingly, they discovered that the iPSCs 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.
In 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,” 100 times more efficiently (a two percent success rate) than with viral methods and in roughly half the time (two weeks).[viii] 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.[ix] 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.[x] 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, 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 that hESCs “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 [iPSCs].” 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 hESCs 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 iPSCs “do not obviate the need for [hESCs]” may have been equally effective. He noted too the stubborn limitations of even the most successful ASC treatments involving the transplantation of hematopoietic cells. Despite 50 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 [hESCs] are critical to a multifaceted portfolio of NIH stem cell research.”
Senate subcommittees are notorious, of course, 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 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.”[xi]
Once 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 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 last 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 president Obama in 2009. State governors should support them in any way possible.
And we shouldn’t forget that the stem cell question is part of 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?
[i] Susan Jacoby, Never Say Die: The Myth and Marketing of the New Old Age. NY: Pantheon Books, 2011. 92-93.
[ii] Sala, F.G., et. al. 2009. Tissue-engineered small intestine and stomach form from autologous tissue in a preclinical large animal model. J. Surg. Res. 156(2), 205-12.
[iii] Sadelain, M., 2010. The need for genetically engineered therapeutic pluripotent stem cells (Editorial). Molecular Therapy 18(2), 2039.
[iv] Spence, J.R., et. al. 2010. Direct differentiation of human induced pluripotent stem cells into intestinal tissue in vitro. Nature advance online publication doi:10.1038/nature09691.
[v] Also on December 12, researchers at the Georgetown University Medical Center presented findings at the 50th annual meeting of the American Society of Cell Biology that insulin-secreting beta islet cells can be produced from human spermatogonial adult stem cells without the use of extra genes. They hope that continued progress in this area will lead to a novel solution to juvenile onset (type 1) diabetes.
[vi] Feng, Q., et. al. 2010. Hemangioblastic derivatives from human induced pluripotent stem cells exhibit limited expansion and early senescence. Stem Cells 28, 704-712.
[vii] Kim, K., et. al. 2010. Epigenetic memory in induced pluripotent stem cells. Nature 467, 285-290.
[viii] Warren, L., et. al. 2010. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7(5), 618-630.
[ix] Zhu, S., et. al. 2010. Reprogramming of human primary somatic cells by OCT4 and chemical compounds. Cell Stem Cell 7(6), 651-655.
[x] Szabo, E., et. al. 2010. Direct Conversion of human fibroblasts to multilineage blood progenitors. Nature advance online publication doi:10.1038/nature09591.
[xi] Jacoby, 98.