Does Effective and Ethical Stem Cell Therapy Exist?
For folks of a certain age, the championing of stem cell therapy research is inextricably tied to cultural icons like Marty McFly or Superman—or, as they are known in real life, Michael J. Fox and Christopher Reeve. Both of these men are famous for more than just the beloved characters they brought to life, having made impassioned pleas over the years for the continuation of research on stem cell therapy—specifically, embryonic stem cell therapy. But despite the insistence of Fox, Reeve, and others in the late 1990s and early 2000s that embryonic stem cells would pave the way for an untold number of cures (if only we would keep religion out of it), today, adult stem cell therapy research leads the way, both in terms of the sheer volume of research conducted and in promising results for stem cell-based therapeutics. However, as we will discuss, even ostensibly ethical adult stem cell therapy research faces moral conundrums. But, as we will also see, one organization has been working tirelessly over the past two decades to develop new methods of conducting stem cell research that are free from the morally problematic use of abortion-derived cell lines plaguing all other forms of stem cell research—both embryonic and adult.
The Failed Promise of Embryonic Stem Cells
Christopher Reeve suffered from a traumatic equestrian accident that left him paralyzed from the shoulders down until he died in 2004 at the age of 52. For the past 30 years, 61-year-old Michael J. Fox has suffered from Parkinson’s disease. Both men established eponymous foundations to advocate for and fund research on embryonic stem cells, which are cells taken from (and thus requiring the destruction of) human embryos, prized for their ability to replicate and proliferate quickly and for their pluripotency. (Pluripotency, or the ability to differentiate into all of the various types of cells that give rise to our bodily tissues, had long been considered the sole purview of embryonic stem cells; this is no longer the case, as we will discuss in more detail later.) The great differences between Reeve’s and Fox’s conditions (one an injury, the other an autoimmune disease) gives one an idea of the breadth and span of the long-promised curative potential of embryonic stem cells.
Of course, controversy has swirled around embryonic stem cells ever since their promise became widely known and championed, most notably during the Bush Administration of the early 2000s. Often conducted on stem cells harvested from the “leftover” embryos created by the in vitro fertilization (IVF) process, embryonic stem cell research has long been criticized as highly unethical by Christians and other religious conservatives (since it requires the destruction of unique, embryonic human lives), yet has been championed by its proponents as a hidden wellspring of remedies for nearly every malady imaginable.
For decades the religious conservative view has been vilified as unnecessarily hamstringing scientific progress. “Keep religion out of stem cell research, Reeve urges medical school audience,” reads a 2003 article by the Yale School of Medicine, detailing a speech Reeve gave to Yale medical students.1 The article summarizes Reeve’s talk, identifying the enemy of such research and the stakes: “Social and religious conservatives have robbed American scientists of their chance to play a leading role in the promising field of stem cell research. ‘We’re giving away our pre-eminence in science and medicine,’ he said.”
Because people are going to use the increasingly socially acceptable option of IVF to build their families, so the logic goes, and because IVF necessitates the creation of multiple embryos that will go “unused” (i.e., unimplanted into a womb), why not use those embryos for good? And so it is that many “excess” IVF embryos end up “donated to science.” For those IVF patients who see no moral value in their embryos, or who desire “closure” from the IVF process and are eager to be done with the costly fees of keeping the embryos on ice, the offer of furthering the science of embryonic stem cell research— and all its therapeutic promises—encourages them to donate. And biobanks and researchers are only too eager to persuade would-be parents to do so. In this view, it’s a win-win situation for IVF patients—and for “science.”
If it were that simple, though, everyone would donate their excess embryos without a second thought, and there wouldn’t be hundreds of thousands (perhaps millions) of embryos frozen in limbo all over the United States. A 2016 NPR report on “leftover” embryos includes the following quote from Francine Lederer, a clinical psychologist in private practice in Los Angeles: “After successful IVF treatments, many couples come to view their embryos as human life, which makes it even harder for them to find closure” (emphasis mine). “Some,” says the report, “even have funeral ceremonies for the embryos.”2
But it’s not just the arguably natural feeling of value that many people attach to their embryos that has “hamstrung” the science of embryonic stem cell research. The science itself has been plagued with issues since its inception, including (and especially) the high potential for embryonic stem cells to become cancerous. They can cause teratomas, which are tumors that may contain hair, bone, or muscle cells, and may or may not be malignant.
In fact, it is precisely because of the fast replication rate and pluripotency for which they are so prized that embryonic stem cells are prone to these oncogenic effects. As Kögler et al. summarize it in a 2004 Journal of Experimental Medicine article: “Although embryonic stem cells have the broadest differentiation potential, their use for cellular therapeutics is excluded for several reasons: the uncontrollable development of teratomas in a syngeneic transplantation model, imprinting-related developmental abnormalities, and ethical issues.”3 Others have pointed to difficulties in precisely directing cellular differentiation, and the potential for these cells to be rejected (similar to organ rejection) in transplantees, as additional practical obstacles hindering the therapeutic use of embryonic stem cells.4
Adult Stem Cell Research
Eighteen years after his impassioned pleas and untimely death, Reeve would perhaps be surprised to learn the market for adult stem cells has far outstripped that of embryonic stem cells, for precisely the reasons outlined by Kögler et al. above. In an extensive overview of all U.S.-based stem cell clinical trials occurring from 1999-2014, Redfield et al. found that “the vast majority of stem cell clinical trials from 1999 to 2014 have been conducted with adult stem cells.”5 On the financial side, adult stem cells dominated the stem cell market in 2020, capturing 85.7 percent of the $9.38 billion market, according to a Grand View Research Market Analysis Report.6 The same report projects the market for stem cells to reach $18.41 billion by 2028.
Adult stem cell therapy uses adult somatic stem cells (ASCs), defined as “self-renewing groups of cells in tissues and organs that can produce specific lineages of precursor cells leading to differentiated cell progeny.”7 While ASCs lack the pluripotency of embryonic stem cells, they still have the ability to differentiate into other types of cells (a phenomenon known as multipotency).
ASCs have been successfully (and ethically) used to treat certain cancers of the blood and bone, through processes known as hematopoietic stem cell transplants. Procedures that fall under this umbrella include bone marrow transplants, peripheral blood stem cell transplants, and (umbilical) cord blood transplants. Transplantation of healthy stem cells usually follows the destruction of a patient’s cancer cells via chemotherapy or radiation therapy, which also kills the stem cells found in their bone marrow (where new blood cells are normally created). Transplantation can be allogeneic (meaning that the cells come from another individual) or autologous (where the cells come from the patient, previously harvested and preserved prior to cancer treatment). In this way, a patient’s immune system can be “rebuilt” from the cellular level on up, as the healthy transplanted stem cells take over for the now-destroyed, diseased cells.
The potential for using hematopoietic stem cell transplants to treat not only bone and blood cancers, but autoimmune diseases, HIV/AIDS, and other conditions is exciting, to say the least. However, the complete destruction of a patient’s existing stem cells poses an unrealistic treatment plan for those who do not already require chemotherapy or radiation therapy. While many challenges remain, some reports of success using adult stem cells have been particularly noteworthy. For example, a New York City woman now appears to be cured of HIV after receiving a transplant of stem cells from an adult relative. The stem cells, which contained a rare genetic mutation that prohibits HIV invasion, were in umbilical cord blood (which itself contains stem cells) from an unrelated (living) newborn child.8
Additionally, a particular type of ASC, known as a mesenchymal stem cell (MSC), has shown promise in animal models in the treatment of neurodegenerative disorders such as Multiple Sclerosis, Alzheimer’s Disease, Huntington’s Disease,9 amyotrophic lateral sclerosis, Parkinson’s Disease, stroke, spinal cord injury, and others, for both cellular replacement and neuroprotection. Notably, MSCs are currently in Phase II trials for the treatment of Parkinson’s Disease. Importantly—and ethically setting ASC-based therapies above embryonic stem cell based-therapies—these therapies do not require the ongoing destruction of embryonic human life, but rather the continued proliferation of human life.
New Frontiers in Stem Cell Research: Induced Pluripotent Stem (iPS) Cells
Despite the promise of ASCs (and their comparative lack of ethical concerns), the technology has limitations. Harvesting adult stem cells is invasive, and they lack the pluripotent and self-renewal capacities of embryonic stem cells, which limits their potential as therapeutics across a wider range of injuries, disorders, and diseases, especially depending on how advanced a disease is.
For example, human adult somatic stem cell therapy acts via paracrine effects, that is, the stem cells secrete bioactive molecules that bind to receptors on neighboring cells to protect and repair damaged tissue. While this mechanism may be helpful in the early stages of neurodegenerative diseases (for example, in early-stage Parkinson’s disease, where adult human somatic stem cell therapy could repair and protect dopaminergic cells from further damage), for late-stage neurodegenerative diseases, there may be no cells left to protect and repair. In these cases, embryonic stem cells are hypothetically favored for their ability to differentiate into specialized tissue, therapeutically acting by physically replacing damaged cells and tissues. As we’ve discussed, though, the use of embryonic stem cells is ethically problematic, and carries significant risks of teratoma formation—which is especially concerning when implantation of these cells is done in the brain. So, it is at this point that one might be wondering: Are there options for safely and ethically conducting research on stem cell-based therapeutics for things like late-stage neurodegenerative diseases? Encouragingly, the answer is “yes.” Enter induced pluripotent stem (iPS) cells.
In recent years, a growing segment of the stem cell market concerns what are known as induced pluripotent stem (iPS) cells, which are created from adult stem cells that have been “reprogrammed” to exhibit the same pluripotency and capability of self-renewal as embryonic stem cells. This exciting development may provide the bridge needed to further research the therapeutic potential of pluripotent stem cells, without requiring the destruction of human embryos. However, as we will discuss, the technology is not without its own practical complications and ethical conundrums—that is, until very recently.
History of iPS Cells
In 2006, Japanese researcher Shinya Yamanaka discovered that the adult, mature cells of mice could be reprogrammed back to a state of pluripotency; that they could, essentially, become stem cells with the introduction of various protein transcription factors (or genes), known now as “the Yamanaka factors.” As we’ve discussed above, pluripotency was once thought to be the exclusive purview of embryonic stem cells, which was the key reason behind the concerted push to make the controversial research mainstream. But Yamanaka’s research proved differently, and in 2012, he won the Nobel Prize in Physiology or Medicine “for the discovery that mature cells can be reprogrammed to become pluripotent,” alongside British scientist Sir John B. Gurdon, who first discovered in 1962 that the specialization of mature cells could be reversed.10
Today, a growing portion of the stem cell market centers on Yamanaka’s induced pluripotent stem (iPS) cells, which are adult somatic cells “that have been genetically reprogrammed to an embryonic stem (ES) cell-like state through the forced expression of genes and factors important for maintaining the defining properties of ES cells.11
Practical and Ethical Issues with iPS Cells
Early on in the development of iPS cell technology, Yamanaka and other researchers favored integrative viruses as the primary means for delivering the genes needed to “reprogram” adult somatic cells to a state of pluripotency, so they could be used in stem cell therapeutics research. An “integrative virus” is one which, upon infecting a cell, integrates its genome into the host cell’s chromosome, either incidentally or as part of the virus’s life cycle (as is the case with retroviruses).12 However, the use of integrative viruses in cellular reprogramming proved problematic, because it introduced oncogenic (cancer) risks as well as risks of viral contamination of the cells.
Most recently, the non-integrative Sendai virus has been favored by researchers for gene delivery in the creation of iPS cells, although Sendai still poses a cancer risk through a different mechanism. Furthermore, as a virus, Sendai also carries risks of viral contamination. In addition, ethical concerns accompany the use of the Sendai virus, as it must be grown and incubated within human cells. Most commonly, this is done via the immortalized, abortion-derived human embryonic kidney (HEK) 293 cell line (which, incidentally, is the same cell line that has been historically used for the development of several different vaccines, including for Covid-19, as well as drugs and medicines for various diseases).13
In more recent years, non-viral methods of gene delivery, including the messenger RNA (mRNA) and episomal methods, have become increasingly appealing alternative, non-integrative approaches for the delivery of the genes needed to create iPS cells. Yet these methods also carry practical challenges and ethical concerns. The mRNA method, while non-integrative, has several shortcomings: Notably, it is an expensive and time-intensive process for creating iPS cells, it does not work for every type of cell, and it requires the use of cancer genes (which likewise means it poses a cancer risk). The use of episomes, which are defined as “extrachromosomal, closed circular DNA molecules of a plasmid or a viral genome origin, that are replicated autonomously in the host cell,” which therefore gives them “significant vector potential for the transfer of nucleic acids into cells,” has become an increasingly attractive option for iPS cell creation, because it is both quick and free of viruses.14 However, like the mRNA method, the episomal method also carries oncogenic risks due to its use of cancer genes.
Towards the Development of Ethical iPS Cells
In an exciting new development, Cellular Engineering Technologies (CET), a biotechnology company owned by American pulmonary physicianscientist Dr. Alan Moy, was recently issued a U.S. patent for its method of producing iPS cells without the use of viruses or cancer genes, eliminating viral contamination risk and substantially reducing the cancer risk associated with other methods of iPS cell creation. Furthermore, the cell line is ethical in origin, coming from a rare cord blood stem cell, and placental-derived mesenchymal stem cell, eliminating concerns of the destruction of human life associated with embryonic stem cells.
In 2017 and 2018, in collaboration with the John Paul II Medical Research Institute (JP2MRI), CET published the first report of efficiently produced iPS cells via CET’s novel, cancer gene-free episomal method, and received their patent this year, in 2022. Moreover, the National Institutes of Health awarded a grant to CET to develop commercial methods to scale-up production of iPS cells for therapy, without the use of abortion-derived cells (including the immortalized HEK-293 cell line). This means that, for the first time ever, iPS cells can be developed more quickly, cheaply, and ethically than both embryonic stem cells and iPS cells produced by other means.
Implications for the Ethical Production of Vaccines, Medicines, and Other Therapeutics
Truly, with recent advancements in adult stem cell therapy, and with the development of Dr. Moy’s improvements to iPS technology, the need for using embryonic stem cells in research has been eliminated (if it ever existed in the first place). Equally exciting, the technology developed by CET and JP2MRI has implications beyond stem cell therapy. In developing the technology to transform adult stem cells from cord blood and placenta tissue into immortalized human stem cell lines, JP2MRI has also eliminated the need for using aborted fetal cell lines, including the commonly used HEK-293 line, for the bio-production of vaccines, medicines, diagnostics, and research reagents.
The work of CET and JP2MRI vindicates those who have long insisted that the healing of born bodies need not be done at the expense of unborn human lives. A far cry from Christopher Reeve’s lament to Yale medical students that “social and religious conservatives have robbed American scientists of their chance to play a leading role in the promising field of stem cell research,” Dr. Moy’s work rather affirms the exciting potential for ethical stem therapy to outperform the waning, destructive approach of embryonic stem cell research. It also provides another powerful refutation of the various claims throughout human history that the youngest, weakest, and most vulnerable among us must be sacrificed to preserve the lives of the stronger and more powerful.
NOTES
1. Yale School of Medicine. 2003. “Keep religion out of stem cell research, Reeve urges medical school audience.” [online] Available at: <https://medicine.yale.edu/news/yale-medicine-magazine/ article/keep-religion-out-of-stem-cell-research-reeve/#:~:text=He%20called%20stem%20cell%20 research,make%20it%20happen%20here%2C%E2%80%9D%20but> [Accessed 6 September 2022].
2. Fraga, J., 2016. “After IVF, Some Struggle With What To Do With Leftover Embryos.” [online] NPR.org. Available at: <https://www.npr.org/sections/health-shots/2016/08/20/489232868/after-ivfsome-struggle-with-what-to-do-with-leftover-embryos> [Accessed 6 September 2022].
3. Kögler, Gesine et al., A New Human Somatic Stem Cell from Placental Cord Blood with Intrinsic Pluripotent Differentiation Potential, Journal of Experimental Medicine, Vol. 200, No. 2 (July 19, 2004), p. 123.
4. USCCB. n.d. Practical Problems with Embryonic Stem Cells. [online] Available at: <https://www. usccb.org/issues-and-action/human-life-and-dignity/stem-cell-research/practical-problems-withembryonic-stem-cells> [Accessed 6 September 2022].
5. Redfield, E., Luciano, E., Sewell, M., Mitzel, L., Sanford, I., Schmidt, A., Flickinger, T., Salmonowicz, J. and Doroski, D., 2021. Types of Stem Cells Used in US-Based Clinical Trials between 1999 and 2014. Catholic Social Science Review, 26, pp.169-191.
6. Grandviewresearch.com. 2022. Stem Cells Market Size, Share & Trends Report, 2021-2028. [online] Available at: <https://www.grandviewresearch.com/industry-analysis/stem-cells-market> [Accessed 6 September 2022].
7. Tweedell, K., 2017. The Adaptability of Somatic Stem Cells: A Review. Journal of Stem Cells and Regenerative Medicine, 13(1), pp.3-13.
8. McKay, B., 2022. Woman Appears Cured of HIV After Umbilical-Cord Blood Transplant. [online] The Wall Street Journal. Available at: <https://www.wsj.com/articles/woman-appears-cured-of-hivafter-umbilical-cord-blood-transplant-11644945720> [Accessed 6 September 2022].
9. Lake, D., 2021. First in the nation, FDA-approved Phase II mesenchymal stem cell therapy for Parkinson’s disease begins UTHealth News UTHealth. [online] UTHealth Houston News. Available at: <https://www.uth.edu/news/story.htm?id=39f08ac0-b3d0-476d-9ac4-e9c3527f1c94> [Accessed 6 September 2022].
10. NobelPrize.org. 2012. The Nobel Prize in Physiology or Medicine 2012. [online] Available at: <https://www.nobelprize.org/prizes/medicine/2012/press-release/> [Accessed 6 September 2022].
11. Ye, L., Swingen, C. and Zhang, J., 2013. Induced Pluripotent Stem Cells and Their Potential for Basic and Clinical Sciences. Current Cardiology Reviews, 9(1), pp.63-72.
12. Desfarges S, Ciuffi A. Viral Integration and Consequences on Host Gene Expression. Viruses: Essential Agents of Life. 2012;147-175. Published 2012 Sep 25. doi:10.1007/978-94-007-4899-6_7
13. Wadman, M., 2020. Abortion opponents protest COVID-19 vaccines’ use of fetal cells. [online] Science.org. Available at: <https://www.science.org/content/article/abortion-opponents-protest-covid19-vaccines-use-fetal-cells> [Accessed 6 September 2022].
14. Stavrou, E.F., Simantirakis, E., Verras, M. et al. Episomal vectors based on S/MAR and the β-globin Replicator, encoding a synthetic transcriptional activator, mediate efficient γ-globin activation in haematopoietic cells. Scientific Reports. 9, 19765 (2019). https://doi.org/10.1038/s41598-019-56056-z
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Original Bio:
Grace Emily Stark is the editor of Natural Womanhood (www.naturalwomanhood.org) and a Ramsey fellow at the Center for Bioethics and Culture. In 2019, she completed a Robert Novak Journalism Fellowship on the side effects of birth control.
