Eggs & Blood: Gifts & Commodities Primer
In Stem Cells Across the Curriculum (http://stemcellcurriculum.org) Update July 2017
TABLE OF CONTENTS
Front Matter: Permissions and Citations
List of Video and Media
List of Figures
I. How are Female Bodies Involved in Stem Cell Research and Regenerative Medicine?
II. What Is An Oocyte?
III. How Are Oocytes Used In Assisted Reproductive Technologies?
IV. How Are Oocytes Used for Stem Cell Research? What is a stem cell? What is SCNT?
Stem Cell Potency
Adult Stem Cells Associated with the Female Body
Induced Pluripotent Stem Cells and Sex Cells
Somatic Cell Nuclear Transfer: SCNT
V. How Do Researchers and Physicians Obtain Oocytes?
VI. What Are the Risks of Providing Oocytes?
VII. How Do We Reduce the Risk of Providing Oocytes?
Biological Alternatives: Cybrids, Menstrual Blood, Ovarian, Fetal, and Fat Cells
Treating Oocyte Providers as Research Subjects
VIII. What Policies Are in Place for Regulating Oocytes and ART?
United Kingdom: HFEA
India and Israel United States: ASRM, SART, & NOTA
X. What Policies Are in Place for Regulating Oocytes for SCR?
United Kingdom: HFEA
Korea: Hwang Scandal
United States: Dickey Wicker, Executive Orders, and Lawsuits
States Initiatives: California, New York & ESCROs
XI. What Are Some of the Feminist Responses to Oocyte Provision and Payment for SCR?
Science, Gendered Stereotypes, and the Value of Bodily Goods
Payment, Agency, Autonomy, and Protections
ARTs: Nonnormative Use and Disability Justice
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1. Video: March 9, 2009. Rep DeGette on MSNBC’s Hardball with Chris Matthews (11:34 min) Link
2. Video: Nature. 2009. Method of the Year. (5:25min) Link
3. Animation: Bennett & Johnson. 2007. Stem cell differentiation: A chromosome view. Howard Hughes Medical Institution Animation Department of Molecular and Cellular Biology. Harvard University. Link
4. Animation: Vidali, A. April 2011. IVF Procedure. A Simple Explanation of An In Vitro Fertilization Cycle. (3:19 min) Link
5. Video: Monks, K. & Bresnahan, S. June 16, 2014. Time-lapse video reveals secret of an embryo, helps women conceive. CNN.com. (7:38 min) Link
6. Animation: Melton, D. 2006. Potent Biology: Stem Cells, Cloning and Regeneration, Lecture 1 Understanding Embryonic Stem Cells, Part 9 Animation: Germ Layers and cell fate. Howard Hughes Medical Institute. Link
7. Interactive Animation: University of Michigan. 2013. Stem Cells Explained Tutorial. Link
8. Video: Australian Stem Cell Centre. Nov 14, 2010.How Can They Be Used: Cord Blood: Banking and Uses. Stem Cell Channel.(7:09 min) Link
9. Video: Australian Stem Cell Centre. Nov 14, 2010. Banking Cord Blood. Stem Cells Australia. Stem Cell Channel/YouTube. (3:46 min) Link
10. Animation: LifeCellFemme. 2011. LifeCell International. (5:59 min) Link
11. Video: Briganti, C. 2010. Mademoicell Design Process Video. Link
12. Animation: Bruce Conklin. 2011. Video1: iPSC to Direct Reprogramming, Video 2: CM-RBC and Video 3: M-chamberNBC,ed iPS-CV. The Gladstone Institutes. Educational use and non-commercial use only. Link
13. Video: Hardie, A. & Blackburn, C. 2012. Stem Cells The Future: An Introduction to iPS cells. Eurostemcell. (16:42 min) Link
14. Animation: Cellular Reprogramming Animation. World Stem Cell Summit 2010. Genetics Policy Institute.(2:46 min) Link
15. Video: 2009. Interview with John Gurdon and Shinya Yamanaka. Lasker Foundation. (7:57 min) Link
16. Animation: Melton, D. 2006. Potent Biology: Stem Cells, Cloning and Regeneration, Lecture 3 Coaxing Embryonic Stem Cells, Part 10 Animation: Cloning by somatic cell nuclear transfer. Howard Hughes Medical Institute Link
17. Video: Lahl, J. 2009. Inefficiency of Human Cloning and the Exploitation of Women. In Lines That Divide. (first video in right hand column). (1:23 min) Link
18. Animation: Sadava, et al., Life: The Science of Biology, Ninth Edition, Ovarian and Uterine Cycles. Sumanas. Sinauer Associates. Link
19. Video: Paikin, S. Nov 4, 2011. Alison Motluk: A Primer on Assisted Reproductive Technology. TVOkids.com. YouTube. (9:34 min) Link
20. Video: Daleiden, D. July 17, 2015. Planned Parenthood Uses Partial-Birth Abortions to Sell Baby Parts. In Three-part Series “Human Capital” by the Center for Medical Progress. YouTube. (8:51 min). Link Note: This is propaganda by pro-life groups and has been found to be falsified due to splicing and lack of context
21. Video: BBC. Cybrids. YouTube. (5:54 min) Link
22. Animation: Adistem. Link
23. Video: Rodriguez, R. 2010. Stem Cells From Your Own Fat. New Frontier of Plastic Surgery. Vimeo.(3:28 min) Link
24. Video: Dolgin, E. (Director).Feb 26, 2012. Stem cell discovery puts women’s reproduction on fertile ground. NatureVideo. Spoonful of Medicine. Produced by Erin Olsen, narrated by Rebecca Hersher, and animation and artwork by Katherine Vacari. MacMillan Publishers. (4:28 min) Link
25. Podcast: Science Podcast. May 24, 2013. Lacetera Interview Regarding Payments for Blood Stem Cells Link
26. Video: Schmitz, A. and Naggiar, S. March 15, 2013. Man Starts Organization to Compensate Bone Marrow Donors. Rock Center with Brian Williams. NBC.com. (1:39 min) Link Note: Scroll down to second video on page
27. Slide Show: BET July is African-American Bone Marrow Awareness Month. Bet.com. Link
28. Video: Schmitz, A. and Naggiar, S. March 15, 2013. Mom of Girl in Need of Transplants Wins Fight to Compensate Bone Marrow Donors. Rock Center with Brian Williams. NBC.com. Rockcenter.com. (7:56 min) Link
29. Video: Rosaryfilms. 2009 (Nightlight Adoptions). Stem Cell Research Policy of President Bush/ Adult versus Embryonic Stem Cells. President Bush’s speech in 2005 Veto of the Castle DeGette Stem Cell Research Enhancement Act. (15:24 min) Link
30. Video: Hannah’s Story: The First Snowflake Baby.Youtube. (3:36). Link
31.Video: C-SPAN. Aug 7, 2001. Human Reproductive Cloning. National Academy of Sciences. Link
32. Podcast: Radiolab: Set 23, 2016. Primitive Streak.(31 min)Link
33.Video: Democracy Now. March 12, 2010.Study: Median Wealth for Single Black Women: $100, Single Hispanic Women: $120, Single White Women: $41,000. (33 min) Link
34. Video: Benjamin, R. Feb 5, 2015. From park bench to lab bench. What kind of future are we designing? TEDxBaltimore. Youtube.(21:25 min) Link
35. Video: CBS News on Logo. Gay Couples Receive Breast Milk From Surrogate. Youtube. Link
36. Video: Chang & Singh. 2011. New Moms Sell Excess Breast Milk for Cash on Internet (4:51min) AND Breast Milk Banking (5:22 min). Good Morning America. ABCnews.com. Link
37.Video: Center for Bioethics and Culture Network. Calla Papademas’ Story. Vimeo. (13:51min) Link
38. Video: Thirteen/Education Broadcasting Corporation (Producer.) April 2, 2010. Religion and Ethics Weekly: Embryonic Stem Cell Controversy. (7 min) Link
39. Video: Morrissey, T. 2015. Ovary Action: Is it Worth Your Time and Money to Freeze Your Eggs? Broadly. Vice.com. (27 min) Link
Figure 1. Telomerase Activity in Embryos, Stem Cell Niches and Cancer Cells
Figure 2. Stem Cell Niche: Maintenance, Expansion, and Differentiation
Figure 3. Ovarian Hormone Stimulation and Procurement
Figure 4. Oocyte Ovarian Hyperstimulation
Figure 5. Oocyte Signaling
Figure 6. Chimera Cybrid Differences
In 2009, New York State became a pioneer in policies regarding human embryonic stem cell research (hESCR) by adopting a resolution to use public funds to support human egg provision (Empire State Stem Cell Board, 2009). The decision to cap the compensation at $10,000 was based on the going rate of compensation for egg providers in the private sector within the context of in vitro fertilization (IVF) where compensation ranges from $5,000 and $10,000. This New York state policy is unique in the United States (US). For example, both California and Massachusetts prohibit payment for egg provision for hESCR because socially conservative groups oppose embryo destruction, and pro-choice groups express concerns about potential health risks incurred by the egg provider (Santos, 2008). New York’s policy also stands in contrast to guidelines issued in 2005 by the National Academy of Sciences (NAS) (Hynes, et al., 2005). The NAS is a non-profit organization comprised of the nation’s leading researchers who provide advice on science policy at the federal level. Furthermore, the policy is in contrast to The United Kingdom, South Korea, Canada, Australia, France, Germany, and Israel where federal policies prohibit incentivization in the form of payment beyond reimbursement for medical expenses (Rao, 2006).
Egg providers are treated neither as human research subjects nor patients and, thus, weighing the benefits and risks involved with egg procurement in the context of hESCR proves challenging (Magnus & Cho, 2005). This poses a problem for stem cell researchers since few individuals donate eggs for stem cell research (SCR) altruistically, and little is known about the health effects of the process on young fertile individuals (Reproductive Health Technologies Project, 2016). As such, human eggs are perceived as scarce commodities.
Many scholars and activists refer to this emerging market, as “eggonomics” or “embryonic economies,” suggesting that researchers “eggsagerate” the therapeutic potential of stem cells at the cost of “eggsploiting” young women (Benjamin, 2013; Benjamin, 2013b p82; Franklin, 2006; Lovell-Badge 2012; Lahl, 2010).
What lessons can be learned as egg compensation policies for research purposes continue to be deliberated? Can we challenge normative assumptions regarding female bodies and biomedical research to support more just and informed participation? What roles can stakeholders with diverse interests play in shaping the policies that relate to SCR in ways that promote scientific innovation and socially just practices?
This primer serves to address these questions through a biological overview of reproductive biology in the context of SCR, consideration of contemporary international and domestic policies and practices surrounding the fertility industry and the SCR enterprise, and a review of varied feminist responses to eggs used for SCR.
Section I explores how the stem cell arena and the reproductive technology sector became intertwined, the ways in which female bodies are implicated as sites of unique biological resource for SCR, and the policies that regulate how human eggs and embryos are used in biomedical research.
Section II explains how eggs, or oocytes, are generated during human development, and the role that DNA nuclear reprogramming plays in reproduction and immortality.
Section III describes how oocytes and embryos are manipulated outside of the body in assisted reproductive technologies (ARTs). This section explains fertilization, human development, and the IVF procedure, as well as preimplantation genetic diagnosis (PGD), which leads to a surplus of embryos not immediately used for reproduction.
Section IV reviews the roles of oocytes in an array of stem cell technologies and outlines stem cell biology and vocabulary for the novice including stem cell potency, adult stem cell niches, induced pluripotent stem cells, and techniques such as somatic cell nuclear transfer (SCNT).
Section V describes the protocol used to mature eggs inside the body and retrieve multiple egg-containing follicles for both research and reproduction.
Section VI examines seminal reports and literature on the risks of the controlled ovarian stimulation protocols.
Section VII looks at some of the biological and juridical ways to reduce the risks associated with providing oocytes. This section includes a review of cybrids, as well as adult sources of stem cells including menstrual blood, breast milk, and fat cells as well as policies to treat oocyte providers as research subjects.
Section VIII provides insight on the ways that social and political movements have addressed health advocacy, human rights, and reproduction.
Section IX compares oocytes to other biomaterial using the example of bone marrow in the court case Flynn v. Holder, and illustrates the ways in which advances in SCR create a need for harmonization of scientific and clinical protocols and policies regarding human biospecimens.
Section X explores the varying international landscape regarding SCR and oocytes in the UK, Korea, and US including both California and New York. This section compares the different systems, stakeholders, and regulations involved to safeguard oocyte providers.
Section XI briefly reviews the diversity of feminist responses to ART and oocyte provision for SCR. This section includes literature on the historical understanding of female biology and the relationship between egg and sperm, an analysis of queering and challenging normative assumptions concerning ARTs and the ways in which this produces more bioresources for SCR, and an overview of different feminist stances on the exchange of money for oocyte procurement, evoking concepts such as undue inducement and exploitation. For the novice, concepts such as reproductive justice, disability rights, choice, just participant selection, autonomy, and protections are introduced.
This primer will use the phrase “people with ovaries”because not all individuals with ovaries identify as female. That said, the terms “woman” and “women” are also used because those terms are used universally in the research in this area. Of course, LGBTQ and gender non-conforming individuals undergo ovarian stimulation and egg retrieval and are most likely among the hundreds of thousands of research subjects in the studies discussed here, although they were not specifically mentioned in the literature. To our knowledge, no data exist yet about long-term health risks to transgender men who stop testosterone hormonal therapy in order to undergo ovarian stimulation and egg retrieval.
On Dec 16, 1999, the journal Science declared stem cell research (SCR) “Breakthrough of the Year,” following the isolation of human embryonic stem cells (hESCs) in 1998 and adult stem cells (ASCs) in 1999 (Vogel, 1999). Two research teams at separate institutions conducted this groundbreaking work on the isolation of hESCs. The Gearhart team removed cells from fetal tissue that would eventually develop into either spermatogonia or oogonia, otherwise known as sex cells. These fetal primordial germ cells (PGCs) were acquired from fetal tissue associated with pregnancy terminations that were performed to reduce medical health risks to the mother (Shamblott et al., 1998). The Thomson team at the University of Wisconsin removed stem cells from extranumerary embryos, or those that were created through In Vitro Fertilization (IVF), but were not used to achieve pregnancy (Thomson et al., 1998).
Both Thomson and Gearhart used funding from the private sector to conduct the research because the United States (US) the Dickey-Wicker appropriations rider prohibits the use of federal funds for the creation and/or destruction of embryos for research purposes (Degette & Paisner, 2008). The policy of prohibiting federal funding for human ESC research (hESCR) that involves the destruction of an embryo is grounded in the belief that an embryo is a potential life, and could be adopted as “snowflake babies.” However, some policy makers, such as Diana DeGette the Colorado Representative, has repeatedly presented a bill that will allow federal funding those embryos created through IVF, that have been donated for stem cell research. Though termination of embryonic development to procure hESCs is considered immoral by some members of society, there are others who support hESCR because of its potential to advance the field of regenerative medicine and to treat degenerative disease.
The ethical controversy over the moral status of the embryo as it relates to SCR was gradual because the pace of technological and scientific development of assisted reproductive technologies (ARTs) was slow to start. In 1972, the first experiments utilizing recombinant DNA technology and the outcry against unethical use of human research subjects in the Tuskegee Syphilis Trial led to discussions concerning the value of life and potential regulations in manipulating it. In 1973, Roe v. Wade made abortion illegal in the US and led to a series of hearings to discuss biomedical ethics specifically with embryos and fetuses. LeRoy Walters, a bioethicist, was asked at one of these hearings to determine the cut off point for embryo research. Walters declared 14 days, because many early pregnancies are naturally terminated before this time in the womb, twinning can still occur (suggesting that the embryo is not yet a unique being), and the primitive nervous system (the primitive streak) begins to form at 14 days (Radiolab, 2016).
With the birth of the first “test-tube baby” in 1978, public anxiety escalated. There were concerns about the creation of “designer babies,” the disruption of traditional life cycles, and the social experience of “natural” children and their economic well being. Media regarding these concerns eclipsed debates about the moral status of the embryo, giving weight to the threat of a dystopian “brave new world.” Governments concerned with the health and “mistakes” associated with new technologies assembled national committees that became essential catalysts in framing the topics, relevant information, and arguments — including the rhetoric — concerning the ethical controversy of infertility technologies and biomedical research.
In the US, the Ethics Advisory Board was formed in 1977 to address the scientific, ethical, legal, and social issues surrounding IVF and embryo transfer in general, as well as addressing human health. Though guidelines are issued, they are voluntary as ARTs are not regulated by the Food and Drug Administration (FDA). The only requirements that fertility centers must abide by are overseen by the Centers for Disease Control (CDC), which requires each center to publish pregnancy rates. There are no requirements to specifically test any of the drugs, procedures, or instruments designed for ARTs, nor a regulatory body to assess ethical implications (CDC, 2013; Levine, 2010).
In the United Kingdom (UK), the Warnock Committee was founded in response to public outcry as media coverage suggested that industrialized embryo farming could accompany freezing technologies. In 1984, The Wornack Committee issued a report supporting IVF as an infertility treatment, opposing surrogate motherhood and supporting the creation of embryos for research. Additionally, the Committee recommended the establishment of a regulatory body to oversee human embryo research and ARTs, and in 1991, the Human Fertilisation and Embryo Authority (HFEA) was established. Mary Warnock’s intent was to produce a structure that would allow for maximum scientific innovation with strong regulatory control (Banchoff, 2011). This approach is similar to that of the Vannevar Bush report in 1945 titled “Science: The Endless Frontier,” however, it differed because though it supported transparency, Bush proposed a self-regulatory scheme to achieve cutting edge scientific exploration (Bush, 1945).
In Canada, there are federal laws to regulate oocyte provision, but like the US, some policy is being debated province by province (Paiken, 2011). With respect to health outcomes, the Canadian Public Health Agency conducted a study and proposed that eight different downstream outcomes related to ARTs be systematically studied, including the long-term health of egg providers and psychosocial effects, but no such study or registry is in place (Deonandan, 2010).
In Germany, the Benda Commission was assembled to address ethical concerns of IVF, genetic therapy, and genome research with the intention to produce research guidelines (Banchoff, 2011). The Commission was heavily influenced by the 1949 constitution’s value of human dignity, the shadow of Nazi eugenics, and the economic loss incurred when genetically modified rapeseed crops led to herbicide resistance in weeds. The Benda Commission banned all cloning, chimeras,and genetic modifications, but supported IVF as an infertility treatment. The Commission established that the embryo as deserving legal protection from arbitrary manipulation and, thus, embryos can not be created and destroyed for research (Banchoff, 2011). In 1983, the National Consultative Ethics Committee (CCNE) was formed in France to respond to the ethical issues surrounding IVF and embryo research, as well as organ donation, and genetic testing (Banchoff, 2011). The CCNE December “opinion” of 1986 banned the creation of embryos solely for research, yet permitted research on frozen surplus IVF embryos for reproductive medicine, and issued a three-year moratorium on the genetic diagnosis of embryos to discourage eugenics (Banchoff, 2011). The cut-off for research was set at seven days post-fertilization and the committee made a distinction between embryos with and without a “parental project.” Only embryos of the latter category could be utilized for research due to their lesser moral status, as there would no longer be any parents desiring these embryos (Banchoff, 2011).
Each of these countries quickly assembled committees to address the moral status of the embryo and the health of future children conceived through ARTs, but few recognized early on that IVF would create a vital resource for hESCR raising other ethical concerns such as the creation of savior siblings, payment for eggs and sperm, and the health of egg providers. To maintain their competitive edge in the fields of regenerative medicine and stem cell sciences, some countries revisited their policy positions, while others felt it was important to maintain consistency with their national values. For instance, France maintained restrictions on the human embryo, requiring researchers to demonstrate both scientific and medical value of the research as well as uphold ethical principles of conduct (Pain, 2013).
The HFEA has remained a leader attempting to identify consensus between liberal and conservative views. Additionally, HFEA through its Horizon Scanning process of identifying legal, ethical, social and regulatory implications mandates that fertility centers communicate the nature and potential health risks to children conceived via IVF including developmental and birth defects (HFEA, 2009).
At the federal level, the US has had a revolving door of ethics committee and commissions that change with each presidential administration. These bodies serve an advisory role to address bioethics, science, and technology, yet it is not always clear what their charge should be. In some cases it appears that consensus is not the goal, but rather to make transparent the diverse range of views on emerging technologies (Davis, 2010). In addition to these president appointed bodies, the US has the National Academy of Sciences, a prestigious professional organization of scientists that publishes reports to advise government. Beyond federal considerations, some states have set up specific ethics committee to address public funding of science that can have crosstalk with ART practices (Sulmasy, 2009).
With respect to health outcomes, The US National ART Surveillance System (NASS) collects limited health outcomes (birth weight, gestational age and infant sex) on children conceived through ART and is monitored by the CDC. In 2001 the CDC launched a feasibility study through States Monitoring Assisted Reproductive Technology (SMART) to use birth certificate data in pilot multi-state initiative in an effort to expand data collection on health outcomes of children conceived by ART, but, here, too, the variables are limited and do not capture long-term health outcomes for children (Pearson, 2006; Kissin et al., 2014).
As the field of SCR continues to tap early stage embryos created through IVF as biological resources, discoveries regarding this technology and its effect on DNA reprogramming and potentially health outcomes for children are being made. For instance, the percent of oxygen in embryo culture in IVF centers (20%) versus the womb (5%) varies, and it is known that oxygen levels can impact early DNA reprogramming events in cell differentiation and development (Halpert, 2012). Other studies, conducted on mice, have investigated the effect of in vitro culture on early stage embryos and fetal development with respect to genes involved in metabolism, and found aberrant DNA reprogramming events leading to increased risk of metabolic disorders later in life. More recently a literature search reviewing all studies conducted on the fetal development of ART created embryos in mammals reveals that there is a consistent shift in fetal and placenta growth curves that could have detrimental effects on metabolic activity later in life (Bloise et al., 2014).
Because hESCR can broaden our understanding of how the human body develops and may lead to the development of stem cell technologies for treating diseases or preventing their onset, this work has had the effect of creating a market where eggs (oocytes) are a commodity. Embryos are the result of fertilization, which requires fusion of oocyte and sperm, and thus, hESCR requires large numbers of human oocytes and sperm. Unlike sperm, there are a finite number of oocytes produced through gametogenesis in the body, resulting in an ovarian reserve that depletes during adulthood. Medical interventions to mature multiple eggs in the body and procedures to extract these eggs have moved from the reproductive sector to the research sector. Though pregnancy rates using ARTs hover at about 30%, the success of cloning using human oocytes is substantially less efficient, suggesting that large numbers of human oocytes will be required to optimize cloning protocols.
As the demand for oocytes increases in both the reproductive and SCR sectors, the language surrounding protocols of oocyte procurement is shifting. The term “donation” has been questioned because oocytes can be “shared, given, and sold” (Lancet, 2003; Shanley, 2002).
In the case of egg sharing, oocytes are either “shared” with another party for a lower cost of IVF, or “shared” with a researcher, again to lower the cost of IVF cycles (Choudary et al., 2012; Roberts & Throsby, 2008). In other situations, financial transactions for the procurement of oocytes is limited to medical reimbursement as the process continues to be viewed as a donation, while in other instances, those that provide oocytes receive monetary compensation for the time and inconvenience associated with the hormone administration and oocyte extraction.
Thus, the term “egg donation” does not fully encompass the range of activities involved in moving oocytes from the body to the fertility clinic and biotechnology sector. For this reason, those that provide oocytes for reproduction or SCR are referred to as “egg providers.”
Because deriving stem cells from embryos is ethically contentious due to the moral status of the embryo and concerns about the future health of oocyte providers, research on adult stem cells (ASCs) has gained more attention and funding.
In most countries federal funding is permitted for research on stem cells that reside in various niches in the adult body. These niches offer an autologous (donor and recipient are the same person) stem cell source that meets the immunocompatibility challenges associated with cell transplant therapy and do not require destruction of an embryo. However, to determine the “stemmyness” of ASCs their regenerative and cell differentiation potentials must be compared to ESCs. In this sense, ESCs are the “gold standard,” or the most capable of regenerating infinitely and differentiating into all cell types of the body. In this respect, ASCs as compared to ESCs have a reduced ability to regenerate in laboratory conditions, have a more limited range of cell differentiation potential, and represent a small proportion of the cells in a particular adult tissue or organ making isolation of these cells a challenge. As an example, cells collected during menstruation are recognized to have excellent regenerative power, but require specific isolation protocols and have not shown the full range of specialized cell functions that can be achieved with ESCs (Rowland, 2009; Lin et al., 2011).
Similarly, cells from cord blood, the placenta, breast milk, and fat, show great value for SCR, but the cells appear to have a limited range of differentiation potential, though new techniques may enhance their ability to differentiate into a more diverse range cell types.
Induced pluripotent stem cells (iPSCs) involve the manipulation of differentiated adult cells in the body (somatic cells) so they behave more like ESCs. The ablity to apply this reprogramming technique to adult human cells was accomplished in 2009, but studies reveal that iPSCs have a different characteristic profile compared to ESCs. That is to say, that though iPSCs are flecixible in their cell fate or differentiation potential, their gene expression profiles differ from those ESCs. Thus, researchers are continuing to work on all three types of stem cells: ESCs, ASCs, and iPSCS.
An oocyte, more commonly called an egg, possesses unique biological characteristics necessary for an embryo to develop into all the specialized cells of the adult organism.
This ability to establish any cell fate is dependent on DNA reprogramming factors, which have proven important for ESCR (Noggle et al., 2011). Understanding how these factors influence cell fate allows stem cell researchers to manipulate cells in culture so that they adopt a variety of cell fates; this may help replace aging or damaged tissues, and contribute to a better understanding of how our social and built environments can reprogram our DNA (Nobel Prize, 2012; Kubicek, 2011).
An oocyte is a cell with half the genetic content for the human genome as well as proteins and other molecules necessary for sexual reproduction. Humans have evolved to have 46 chromosomes (cellular structures that organize and compact DNA) in their genome, though some in the population carry one extra chromosome or are missing one chromosome. As the human genome is 6 billion bases, chromosomes allow cells to carry genetic information from generation to generation in compact form, with genomic DNA tightly wound around proteins. In each human, half of the genome (23 chromosomes) is provided by the mother and half (23 chromosomes) from the father, and the complete genome provides the genetic information used to develop various structures and characteristics such as brain, liver, and eye color. However, before there is ever a brain, liver or eyes to color, this DNA is used to create the non-descript clonal population of stem cells of the early embryo. To achieve this feat, the oocyte and the sperm DNA must revert to an undifferentiated, or non-specific, state. The oocyte works in concert with the sperm to produce a viable embryo, each cell complementing the other, providing necessary, yet distinct, genetic contributions to the process of sexual reproduction. Upon fusion, both oocyte and sperm contribute different DNA and molecules responsible for this vital process called nuclear DNA reprogramming (Holding, 2004; Gurdon, 2009). Nuclear DNA reprogramming involves a physical and chemical remodeling of the genome of the newly formed organism, such that the genes essential for embryonic development are activated and inactivated in a sequential manner.
The cells of the early embryo are described as totipotent, referring to having “total” potential to become any cell type including those of the supporting tissues of the embryo. Cells in an embryo that has reached day 5 in embryogenesis are referred to as pluripotent, referring to many (pluri) possible cell fates. The specific combination of genes that can be activated and inactivated during nuclear reprogramming determines whether cells become differentiated and follow a specific cell developmental path, remain partially differentiated and serving as precursor cells late in life, or remain undifferentiated.
There are other characteristics of oocytes that are important for scientists when conducting SCR. For example, an enzyme active in the egg called telomerase plays an important role in regeneration and cell differentiation. Telomerase maintains the lengths of the chromosomes by adding a cap of “non-coding” DNA (telomere) to the ends of all chromosomes during DNA replication. Without this enzyme, the chromosomes become shorter with every round of cell division due to the nature of the DNA replication system, eventually resulting in loss of important genetic information and eventually cell death (Zimmermann et al., 2003; Gammaitoni et al., 2004).
Most adult cells have programmed their DNA to keep telomerase inactive, so as we age the chromosomes shorten and, thus, most adult somatic cells can divide about 50 times. This limited number of divisions is referred to as the Hayflick Limit (Wadman, 2013, Azvolinsky, 2015). When cells reach this limit, they cannot function properly, leading to tissue dysfunction. This phenomena is important in cloning research, as DNA obtained from adult bodies is used to perform such experiments and therefore chromosomes should be shorter due to telomeric DNA loss. Interestingly, cloning in different animals has shown inconsistency in telomere length, with some animal clones possessing longer telomeres than the original DNA donor, and other animal clones possessing shorter telomeres (Lanza et al., 2000; Vogel, 2000).
In embryos, telomerase is active in ESCs because the embryo must undergo rapid and frequent cell division without losing vital genetic information thus, in the generation of sperm and egg, telomeres are restored. When a baby is born, the telomerase gene will be reprogrammed to be inactive in all cells of the body except those that will develop into egg and sperm cells and those that remain in the adult stem cell niches, such as mammalian neural precursor cells that differentiate into those of the olfactory bulb (Caporaso et al., 2003). The ASCs in these niches are a small unique population of cells capable of self-renewal and are most commonly found in sex cells and tissues that confront the environment, face cellular damage, and require replenishment.
These ASCs selectively activate telomerase in a controlled fashion to maintain a pool of healthy stem cells (e.g. in the gonads, skin, gut, hair follicle, liver, and bone marrow.) Later in life, an adult may develop cancer, which can be the result of ASCs obtaining genetic mutations or somatic cells acquiring genetic mutations that reactivate a variety of genes including the telomerase gene. In addition to chromosome maintenance and cell immortality, researchers have identified micro environments that can induce alternative splice variants of the telomerase gene product. These variants do not affect cell division but, rather, cell specialization, or lineage-specific differentiation (Radan et al., 2014). Though we know telomerase function is essential for the high regenerative power of stem cells, it appears that the enzyme may also be important for the switch from non-descript rapidly dividing cells to those that are no longer dividing, and instead developing specialized structures and functions to maintain proper organ and tissue specificity.
Assisted Reproductive Technologies (ARTs) include an array of techniques that help to achieve pregnancy. One of the most familiar of these technologies is In Vitro Fertilization (IVF): a process in which oocytes are removed from the body and manipulated to create an embryo that is later transferred to a uterus. In vitro refers to the historic nature of cell culture using glass test tubes (‘vitre’ is glass in Latin). A three-minute animation of the IVF process narrated by reproductive endocrinologist Dr. Andrea Vidali is available online and provides an overview of this process.
IVF can utilize eggs from the person undergoing embryo transfer or a third party oocyte provider. Eggs are obtained from the oocyte provider via controlled ovarian stimulation, which refers to the specific sequence of hormones that are injected into the oocyte provider to promote the maturation and release of multiple oocytes (Kiessling, 2007).
Although 100,000 IVF cycles take place in the US annually, the procedure is considered experimental, as there have been no clinical trials nor FDA approval. The federal government does not regulate the IVF industry. Instead, professional societies self-regulate by publishing guidelines based on research and experience (Spar, 2006; ASRM, 2013; SART, 2013). Because exogenous hormone exposure varies, it is recommended that the entire process be monitored to ensure the health of the oocyte provider and the production of viable oocytes. It should be noted that it is often difficult to predict which oocyte providers will produce the most oocytes, though age is significant factor. Some young oocyte providers produce large numbers of oocytes, and are referred to as Super Ovulators, and often provide oocytes multiple times during the course of their lives. The risks associated with this procedure are discussed in later sections of this primer, but it is important to note that there is little know regarding the short term and long-term risks associated with oocyte procurement protocols. Once a significant number of mature oocytes are collected, they must be fertilized to produce embryos suitable for uterine transfer.
In order to achieve fertilization, the egg secretes chemicals that act as chemoattractants for sperm moving up the fallopian tube, however, in IVF, oocytes are incubated with sperm in culture at a ratio of about 1 to 75,000, respectively, to promote fertilization and embryogenesis.
After roughly eighteen hours of incubation, over half the oocytes will have undergone fertilization. An internal cascade of events induces an electrochemical gradient, which serves as an internal cellular signal, stimulating oocyte and sperm DNA to fuse, resulting in a one-celled zygote. The process of embryogenesis begins once the zygote undergoes cell division via mitosis to expand the cell population.
The zygote produces a cluster of 6-8 genetically and morphologically identical cells called the blastomere. In the body, the blastomere continues to develop and move down the fallopian tube to the uterus. It is here that the early embryo is exposed to a maternal gradient of signaling factors secreted by uterine cells. These factors are referred to as morphogens and determine the patterning of tissues in the developing embryo such that it will have a front, back, top and bottom. Ultimately, these morphogens influence internal cellular factors in the embryonic cells that reprogram DNA to allow for differential expression of genes, thereby yielding different structures and functions arising in different layers of embryonic stem cells. (Lawrence & Stuhl, 1996).
During the first five days post-fertilization, the embryo undergoes many rounds of mitosis, doubling the number of cells such that by day five, the embryo is made up of 150 cells called the blastocyst. The blastocyst is a hollow ball with cells at the center called the inner cell mass (ICM) and an outer layer of cells called the trophoblast. Based on the morphology, cell number (0-8), symmetry, internal cytoplasmic streaming (A-D), and timing of the first three cell divisions, an embryologist may grade the quality of the embryos created via IVF using an Embryoscope, e.g 8AA.
This information is used to determine which embryos will be transferred to the uterus. Embryo grading reflects the probability that a blastocyst will develop into a full-term fetus. The grading is an indirect measure of proper DNA reprogramming events, cell differentiation, and organization of the primary germ layers (ectoderm, mesoderm, endoderm and germ cells) that emerge from the ICM, and which will ultimately make up the developing embryo.
The cells on the outer layer of the hollow ball, the trophoblast, will develop into the supporting tissues of the embryo, including the placenta, the umbilical cord, the amnion, and chorion. As the trophoblast responds to the uterine environment, it secretes enzymes that disaggregate the uterine cells in the lining of the uterus, allowing the trophoblast cells to infiltrate, thus, forming the placenta, which is a naturally occurring chimera. A chimera is defined as a tissue comprised of cells from two different organisms; here the placenta is comprised of cells of the mother, or gestational carrier, and the cells of the fetus. This kind of mixture differs from a cybrid, in which a single cell and all progeny of that cell would contain genetic material from two different organisms.
Because the pregnancy success rate via IVF is approximately 30%, multiple oocytes may be procured to ensure that more than one embryo develops in vitro, providing more opportunity to implant a viable embryo with the appropriate germ layer and trophoblast distribution and organization (Centers for Disease Control, 2013). Age can play an important role in the generation of mature oocytes, and is indirectly proportional to the number of oocytes released; people under the age of 30 are capable of releasing 8-30 oocytes with exogenous hormone hyperstimulation, and those over the age of 40 typically generate between 6-10 oocytes. These declining numbers reflect a phenomenon known as depletion of the ovarian reserve. In addition to age, other factors can reduce the number of oocytes retrieved upon hormone stimulation such as medical history, various environmental and genetic factors including severe endometriosis, pelvic inflammatory disease, ovarian surgery, various systemic illnesses, chemotherapy, and smoking. Depending on the number of mature oocytes retrieved via controlled ovarian hyperstimulation, IVF may result in the generation of multiple embryos capable of implantation.
Many countries try to limit the likelihood of multiple births at one time. To prevent this, some embryos may not be transferred to the uterus, and instead are frozen and stored for another cycle of transfer, or given to others seeking pregnancy through ART (Centers for Disease Control, 2013; Jungheim et al., 2010). If pregnancy is successful and there is no need for further embryo transfer, the recipient of IVF may be approached and asked to donate their extranumerary embryos to SCR.
This process is referred to as re-consent because the first procedure of informed consent details the experimental protocol of IVF for reproductive purposes, while the second asks the same person if they have been informed about the possibility of providing embryos for research purposes. Re-consent is needed if embryos generated via IVF are to be used for SCR. If re-consent is not obtained, it can influence whether stem cell lines created from embryos originating in fertility centers can be included in national registries and whether some researchers will be prohibited from accessing these lines depending on their stem cell funding source (Wadman, 2010).
PGD and PGS
Preimplantation Genetic Diagnosis (PGD) or Preimplantation Genetic Screening (PGS) is a two-step process involving both IVF and genetic screening of embryos prior to transfer to the recipients’ uterus.
After the IVF process and before transfer of embryos, a single cell of the blastomere or blastocyst is removed and analyzed for specific genetic characteristics (Verlinsky et al., 1998). PGD was first introduced as an option for families with a history of lethal genetic childhood diseases, and later PGD was adopted to screen embryos for biological sex via the presence of X and Y chromosomes (Handyside et al., 1990). More recently, PGD can be used to screen embryos for genetic variations that may influence risk for disease such as BRCA1, which confers elevated risk for breast and ovarian cancer (Paunova et al., 2009).
Presently, using PGD, it is possible to screen for over 100 gene variants that convey risk for disease or disability. These genetic variations are detected either as large chromosomal changes via fluorescence in situ hybridization (FISH) or through the use of polymerase chain reaction (PCR), which is capable of detecting single nucleotide polymorphisms (SNPs), or small DNA changes. More recently, PGD centers have incorporated array-comparative genomic hybridization (aCGH) and next generation sequencing (NGS) technology to screen for many genetic variations simultaneously.
All of these techniques involve manipulation of DNA collected from the embryo and analyzed using visual techniques, such as fluorescent tagging or staining of DNA sequences of interest. All of the techniques exploit the natural ability of DNA to be double stranded and complementary. The technique involves creating a single stranded DNA of known sequence as “bait” to fish out the complementary sequence in the embryo genome, or in some cases look for no match as a sign of no elevated disease risk. The bait is tagged in some way so that the resulting complementary binding and attachment to the embryo genome is visualized and recorded as a positive test.
FISH (Fluorescent In Situ Hybridization): can identify large chromosomal abnormalities, such as aneuploidy, polyploidy, and large chromosomal rearrangements of translocations. The method involves making a visible DNA probe (single stranded DNA that that is complementary to chromosomes or specific sequences. This method is not very specific, and is used commonly with individuals who have experienced repeated infertility or miscarriage, which may indicate some chromosomal segregation problems or lethal translocations during the creation of gametes (where chromosomes break and recombine in ways that can not lead to the development of the embryo).
PCR (Polymerase Chain Reaction): can identify large and small DNA genetic sequence variations, and also involves the creation of a single stranded piece of DNA that is complementary to the flanking regions of interest, and this DNA serves as a primer for the amplification of the region of interest so it can be further analyzed by gel electrophoresis, or restriction enzyme digestion and then gel electrophoresis. This technique is highly specific, requires prior knowledge of the family history and the specific genetic variant that may be inherited in the family. It is costly, precisely because it is customized to each case.
aCGH (Array-Comparative Genomic Hybridization): is essentially using DNA microarray technology, in which 20-70 different genetic variants known to contribute to disease risk are placed on a microchip as single stranded entities (acting as the probe, or the bait for the fishing expedition). In some cases the chip is representative of various locations representing all the chromosomes and the intensity of the signal that you get would indicate polyploidy or aneuploidy. The DNA from the embryo is collected, made to be single stranded and fluorescent and hybridized to this chip. Depending on the the fluorescence signal the pattern indicates whether the embryo harbors any known DNA sequences that might contribute to increased disease risk in the case of specific single gene disorders, or whether the embryo has an abnormal number of chromosomes in the case of repeated infertility or miscarriage history. The advantage of CGH is that it is very sensitive, and specific, and can screen for many variants all in one go, thus, more comprehensive, and also very fast. In comparison, PCR would require the synthesis of probes for each of the variants for each of the genes of interest, escalating costs and potentially missing those variants in the population for which there are not large numbers. aCGH has been used for some time now, and is considered common practice for many centers.
NGS (Next Generation Sequencing) involves the sequencing of many millions of small fragments of DNA in parallel.These sequence read outs are then analyzed using bioinformatics software that can then map the individual reads to the human reference genome. Each of the base in the human genome is sequenced multiple times, providing highly accurate data for even a single base pair difference. NGS can be used to sequence entire genomes or constrained to specific areas of interest, including all 22 000 coding genes (a whole exome) or small numbers of individual genes.
One important thing about all these tests which can be seen in the ZoomGraphic is that the tests are increasingly being applied to the blastocyst stage of embryogenesis, when the embryo has already segregated cells to the trophoblast (the outer layer of cells which will become the supporting tissue upon implantation, such as placenta) and the inner cell mass. The latter will further amplify and specialize to become all the cells of the developing fetus. There is work in other animals that suggest that some organisms have evolved to “throw off” chromosomally defunct cells to the trophoblast as it can tolerate mistakes more readily as a complex multicellular supportable tissue. This phenomenon preserves the more pristine cells for the inner cell mass, where a single cell will be responsible for the lineage of an entire set of bodily tissues performing many functions. What this means then for Preimplantation Genetic Screening (PGS), is that the cells being tested may not reflect the true nature of the DNA in the cells of the developing fetus. In other words, potentially many false positives for chromosomal abnormality would be detected.
Given the large number of people applying PGD/ PGS to embryos created in fertility centers, a number of extranumerary embryos are generated, as the potential parents have applied negative selection to these embryos with abnormal chromosome number, or that carry genetic variants associated with elevated risk of disease. A 60 Minutes episode titled: A Surplus of Embryos: What should happen with extra embryos?” aired on February 9, 2006, yet policies are not keeping up with the increased use of reproductive technologies leaving those who utilized IVF with a range of choices.
The Reproductive Genetics Institute (RGI) of Chicago, Illinois has one of the largest repositories of hESC cultures (cell lines) derived from donated embryos not selected for embryo transfer during the PGD process. These cell lines represent 70 different genetic disorders that can be studied in vitro. However, since RGI was one of the first clinics to offer the service, consent was obtained from some donors during the 1990s when hESCR was just beginning. Because the consent process did not include SCR as a specific option for biomedical research, the US has not included these cell lines in the national registry for federally funded SCR because the language in the informed consent is considered exculpatory, or too broad. Though RGI has attempted to acquire re-consent, this is a laborious and time consuming process as PGD is offered through RGI as a third-party service meaning that several hundred IVF centers would need to be involved in this re-consent process (RGI, 2013; Wadman, 2010). The consent process is not always clear, as it appears that some of the hESC lines in the US National Institutes of Health (NIH) registry were derived from embryos created with anonymous egg or sperm donations (Kaiser, 2013).
Stem Cell Research (SCR) is conducted and funded to expand knowledge on human reproduction, aging, and development. Scientists seek to understand the genetic and environmental contributions to neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, both of which show late onset and are poorly understood. By modeling disease in a Petri dish, researchers can track the development of cells before the cells adopt disease pathology. By changing the growth conditions, scientists can better understand what exacerbates the cell’s disease pathology and inform public health interventions through the screening of potential environmental toxins. Though SCR may result in the development of cell transplant therapies that ameliorate disease symptoms or disability, more likely, it will result in drugs or techniques that will help damaged organs repair themselves. Different types of stem cells are studied with respect to their potential to regenerate and repopulate tissues, their capacity to become or stimulate other cells to become specialized for specific tissue and organ function, and their potential to be accepted by hosts if transplanted into a person who is not the donor of the stem cell source.
In contrast to adult and fetal cells that are specialized and exhibit a finite life span, ESCs are biologically unique. ESCs are not specialized, remain undifferentiated, have the ability to regenerate infinitely, and can become a variety of cells in the body. Differentiated adult cells are specialized to perform a specific function for the duration of their life cycle (e.g. brain, liver, or muscle cells). However, in the adult body, stem cell niches exist; some examples are skin, hair, gut, bone marrow, ovaries, and menstrual blood. Within their niche, adult stem cells (ASCs) typically do not rapidly divide, but instead must be triggered by environmental cues, both to undergo cell division (mitosis) for regenerating the stem cell population and to differentiate and produce the specialized cells for their specific tissue (Powell, 2005). Typically, ASCs serve as a repair system for the body. For example, because our skin is under constant stress from UV light, skin is an expected location for stem cells that can be triggered to regenerate, differentiate, and replenish the tissue as it becomes damaged and sloughs off. In an attempt to categorize cells based on their ability to differentiate or adopt new cell fates, the term potency is used to describe the potential for cell differentiation, or specialization. Researchers also use the term “plasticity” in reference to the ability of a cell to be stimulated to differentiate into an alternative cell type.
Stem Cell Potency
Totipotency is a characteristic of cells created during the first few days of human embryonic development. The “total potentiality” refers to the ability of these cells to differentiate into those that will eventually make up the developing embryo, fetus, and adult, as well as those involved in the establishment of the supporting tissues of the embryo, including the placenta, the umbilical cord, the amnion, and chorion. These cells also have high regenerative power, such that each cell division results in the production of new stem cell, thereby maintaining the stem cell population. This phenomenon is described as “self renewal.”
After five days of embryonic development these totipotent ESCs differentiate into two types of cells, some in the center of the hollow ball of cells, and some on the periphery. The cells on the periphery are referred to as the trophoblast and later in embryogenesis develop into the supporting tissues essential for embryogenesis. The cells internal to the hollow ball are referred to as the ICM and will develop into the cells of the embryo. The ICM differentiates further into the cell types, or layers, made up of cells specific to the endoderm, mesoderm, and ectoderm. The ESCs of the ICM have high regenerative power but are more limited in their plasticity such that cells in one germ layer give rise to cells specific to that germ layer lineage. For instance, cells of the ectoderm can go on to differentiate into those of skin and the nervous system, but not blood and, thus, these ESCs are considered multipotent. Each layer serves as a source of precursor cells that will differentiate further into the specialized cells of various tissues located in the body. These ICM cells can regenerate an unlimited pool of undifferentiated cells in vitro, being of great use to stem cell researchers studying the mechanisms that contribute to this pluripotent state and the genetic switches that contribute to specific differentiation pathways.
Once a person is born, some stem cells in the body maintain the characteristic of regeneration, replenishing the supply of cells of a specific tissue. This is most commonly found in tissues that experience damage due to continuous environmental exposure to cellular threats. These ASCs are considered multipotent, because they are more limited in their scope of potential cell fates, have variable regeneration rates, and are a small minority population in the body. The ASCs are not uniform in their capacity to repair tissue. Some are in constant renewal such as those in the bone marrow, while other ASCs appear to require very specific chemical signals in order to enter the self renewal state. Because some tissues are capable of self repair, such as the liver, stem cell researchers are interested in understanding how to trigger ASCs in other tissues to adopt this regenerative state. Understanding how to induce regeneration and differentiation could aid in the development of stem cell related therapies to repair aging and degenerating tissues and replace cells lost due to injuries.
Adult Stem Cells Associated with Reproductive Tissues: Umbilical Cord, Menstrual Blood, Breast Milk, and iPSC Induced Oocytes
Cord and menstrual blood are interesting because they are expelled from the body requiring no invasive procedure, possess multipotent cells that regenerate rapidly, and support the early stages of human development. These cells also tend to have fewer specific proteins on their surface, which is important to lower the odds of graft versus host disease (GVHD) in which the body rejects transplanted cells that do not originate from the same body.
Although recent attention has also been given to the identification of placental stem cells, indigenous cultures have long heralded the placenta as a source of vitality, and cultural practices surrounding the placenta and cord blood reflect this knowledge (Delvin, 2014). However, given the placenta’s role in selectively passing chemicals and blood between fetus and mother, the placenta may harbor toxic chemicals and, thus, these cells will need to be monitored more carefully.
For this reason, many countries have systems in place to harvest and store umbilical cord stem cells in public banks due to their low immunogenicity (low GVHD) and ease of retrieval (Kurtzberg et al., 2005). In the US, LifeCord is an FDA-approved national system designed to educate and increase the number of cord blood donations to public stem cell banks (LifeCord.com). Australia also has a national system for collection and storage of these vital cells.
However, many individuals are not aware of the public option for cord blood banking due to the overwhelming nature of advertising for private cord blood banking. The private cord blood banking industry charges annual fees, leaving this option out of reach for many. In addition, over 97% of all placenta and cord blood are treated as human waste and discarded by hospitals. Given the loss of valuable material that could be used to treat cancer, degenerative diseases, and genetic blood disorders, some have proposed a system of incentives to increase donation and access to a more diverse cord blood bank. New technologies in stem cell biology have also led to methods by which a single cord blood sample can be amplified to supply enough stem cells to treat an average sized adult (Mohapatra, 2013).
In South Korea, hESCR is advanced through a nationalist agenda that places a heavy burden of responsibility on women through private cord blood banking systems. This agenda is tied to economic interests that go beyond the fees secured for procurement and banking, but to a future stem cell industry that is dependent on cord blood as a biological resource. Here the notion of “scientific motherhood” has been theorized as the practice of providing cord blood in hopes of advancing the national agenda while also protecting the health of one’s child (Jeong, 2014; Jeong, 2016). In this context, mothers are held responsible for providing a vital resource for stem cell research and should they refuse or neglect this duty, they would be viewed as unpatriotic.
Additionally, a growing market for cord blood has emerged with as much as 40% of all publicly banked cord blood units being traded across country borders. The biocapital being generated is not insignificant, with some units trading for as much as $30K per unit, resulting in a $30million industry (Sleeboom-Faulkner & Chang, 2016;Ballen, 2017; Dickenson, 2013). The high cost is the result of some communities possessing low genetic diversity, such that those of mixed ethnic background find it more difficult to find an immunological match in existing national banks. Thus, the public banks trade among themselves to address this gap and, in some cases, have developed an export business to provide products for particular minorities. This export business not only serves an underserved population with goods, it provides a steady income to support the expenses of maintaining a public cord bank more generally (Dickenson, 2013).
The high cost is the result of some communities possessing low genetic diversity, such that those of mixed ethnic background find it more difficult to find an immunological match in existing national banks. Thus, the public banks trade among themselves to address this gap and, in some cases, have developed an export business to provide products for particular minorities. This export business not only serves an underserved population with goods, it provides a steady income to support the expenses of maintaining a public cord bank more generally (Dickenson, 2013). The industry has been expanding at rapid speed, leading to a conference in 2014 and special issue of New Genetics and Society dedicated to the topic of “Private, Public, and the Hybrid in Umbilical Cord Blood Banking,” published in 2016.
Umbilical cord blood is not the only source of adult stem cells specific to the mother. Menstrual blood stem cells appear to have a greater differential potential and regenerative power as compared to many other adult stem cell sources. Given the discovery that menstrual blood stem cells, or endometrial regenerative cells (ERCs), have one of the fastest recorded regeneration times, doubling every 20 hours, and that they are present in high numbers, many companies have been developed to harvest and store these cells (Meng et al., 2009; Rowland, 2009; Anonymous, 2007). Limited examples of these cells addressing limb injury in humans or neural diseases in animals have only increased the economic interest (Anonymous, 2010; Anonymous, 2008). Most recently Medistem has filed a patent for their procedure and begun clinical trials using menstrual stem cells for treatment of heart disease related disorders (Khoury et al., 2014). Companies have capitalized on this accessible and potential source of stem cells by offering services to cryopreserve menstrual blood cells for private use by family members for fees ranging from $800 to $1,000, plus annual storage fees of approximately $100 (Cryo-Cell, 2013).
In response to this commercialization approach, designer Chelsea Briganti has designed a proof of concept project entitled Mademoicell. The project includes a device, similar to a Diva cup, that can collect menstrual blood, store it properly at cold temperatures, that allow them to be shipped safely to a bank. Her goal was to create a service at low cost using public stem cell banks that would be accessible to anyone in need of a cell transplant (Labarre, 2010; Ngo, 2010).
In most cases the cells vital for regenerative medicine from these blood sources (cord, menstrual, bone marrow) are the hematopoietic stem cells (HSCs) capable of giving rise to a wide range of blood cell types. In some cases, researchers have demonstrated more plasticity in these blood sources, showing that they can lead to differentiation of cells beyond the mesodermal lineage, inducing those common to the endoderm or ectoderm lineages. These findings have led some to believe that mesenchymal cells (MSCs) are present in these blood samples. MSCs secrete signaling proteins that, when released into tissue, can promote cell regeneration in that tissue. However, MSCs are very susceptible to freeze-thaw cycle damage and thus, their potency requires high maintenance. In response to this challenge, some researchers are exploring synthetic stem cells (synMSCs). These synthetic “cells” are simply the essential signaling molecules packaged into the membrane of the MSC, and can tolerate the harsh conditions of cryopreservation and lyophilization (freeze drying). The drawback of these “cells” is that they are not self replicating. Then again, the tissue regenerative results seen with injection of blood stem cells may be a result of the short lived effect of signaling factors being released by the donor MSCs, which quickly die out, yet reset the regenerative power of cells in the recipient tissue (Caplan, 2017a; Caplan, 2017b; deWindt et al., 2017). In this way, the synMSCs would be quite similar to the native MSCs, but provide researchers with more standardization and stability of storage and administration in the clinical setting (Kwon, 2017; Luo et al, 2017).
Another source of stem cells that does not require invasive procedures for retrieval is breast milk. Stem cells in breast milk appear to have both regenerative power and wide differentiation capabilities when exposed to three-dimensional scaffolding in an in vitro environment. Breast milk stem cells are not only useful for the study of regenerative medicine, but could serve as important models to understand how breast cancer develops and ultimately may be used in bioengineering applications for successful reconstruction of breast tissue (Hassiotou et al., 2012).
Induced Pluripotent Stem Cells and Sex Cells
Stem cell research utilizes ESCs and ASCs as well as another class of stem cells that are somewhere in between. Stem cell researchers are interested in manipulating cells of the adult body in the lab to expand their differentiation potential, creating a new class of stem cells. For example, blood stem cells in bone marrow can give rise to white blood cells and red blood cells, but do not become skin or neuron in the body. Thus, if stem cell researchers can manipulate bone marrow stem cells to transdifferentiate and adopt the characteristics of precursor neural cells or skin, they may be able to address neurodegenerative disease or burns either through cell transplant therapy or the development of drugs that trigger this phenomenon in the body. The ability to coax somatic cells to broaden their cell fate potential by returning to an embryonic state is an emerging field of stem cell research involving induced pluripotent cells (iPSCs).
Induced pluripotent stem cells (iPSCs) are adult cells in which the DNA has been reprogrammed developmentally to mimic the potency of ESCs. iPSCs are an interesting class of stem cells because they are derived from an individual’s somatic cells, or any cell in the body (the soma) that is not a sex cell. Since they are patient-specific, they would reduce GVHD should they be used in stem cell transplant therapy.
In 2012, researchers at Kyoto University successfully created primordial germ cells from mouse iPSCs, and then later used these cells in IVF, to produce in baby mice, suggesting that it may be possible in the future to create human eggs from human iPSCs. However, it is important to note that in this case the development of mature mouse oocytes required transplanting the oocyte precursor cells into live mouse ovaries. This in vivo environment of the body was essential for the development of the egg, suggesting that this work may not necessarily obviate the need for human bodies in creating human oocytes from human iPSCs (Normile, 2012; Hayashi, 2012, Cyranoski, 2016).
Somatic Cell Nuclear Transfer: SCNT
Though ESCs, have the most regenerative power and differentiation potential, they are limited in a therapeutic context in that the embryo would need to be related to putative stem cell transplant patient. By creating an “human clone” or early stage embryo from the patient, the resulting ESCs derived from this embryo would be immunologically matched. Having a steady pool of oocytes is particularly important for researchers who focus on hESCR and in particular human cloning. These researchers create “cloned” five-day embryos to retrieve the essential ESCs that have not yet adopted a specific cell fate and can be influenced to progress down a specific path of development. In this process, nuclear DNA from a patient or research subject is transferred into an anucleated human oocyte (one in which the nucleus was removed). The manipulated oocyte reprograms the DNA, and is subjected to a chemical gradient of calcium that mimics the electrical gradient created when sperm fuse with the oocyte during fertilization. Thus, the oocyte containing a full set of human DNA originating from a somatic cell taken from the patient is stimulated to undergo cell division as if it had been fertilized.
SCNT ESCs represent a genetic clone of the patient and are immunologically matched. However, because the efficiency of human cloning is demonstrably low, projections about the number of oocytes needed to achieve such medical goals have alarmed many.
The view regarding the enormous numbers of oocytes that might be necessary to achieve human therapeutic cloning was challenged in 2013, when stem cell researchers successfully achieved human cloning for research purposes with high efficiency, using only two egg donors and a total of twenty eggs (Cyranoski, 2013a; Tachibana et al., 2013; Pollack, 2013). The work drew attention because it suggests that, with an increased efficiency in human cloning techniques, the number of eggs needed to conduct preliminary work on cell plasticity may be far fewer than had been
predicted. As with other paradigm-shifting work, this notion has been challenged by developmental biologists. They claim that the egg is an essential component of cellular reprogramming, and that this human cloning achievement does not preclude the need for human eggs for understanding the intricate molecular processes at play in reprogramming (Cyranoski, 2013b).
Procedurally, oocytes are obtained similarly for IVF and SCR purposes. In both cases the goal of the intervention is to artificially mature as many oocytes in the body as possible without undue health risks to the egg provider. Many researchers have tried to mature eggs outside the body, and despite some purported success in 2012, this technique continues to be challenging, producing nonviable or low-quality eggs (Powell, 2012). Currently, all IVF and SCR efforts that result in the development of an embryo require maturation of human oocytes in the body. The ovarian hyperstimulation protocol is designed to reduce a person’s need to undergo repeated cycles of hormone injection by maximizing the number of oocytes obtained in one cycle. A hormone loop between the pituitary gland, the hypothalamus, and the ovaries is manipulated by introducing exogenous hormones via injection (Kiessling, 2007).
Without exogenous hormone intervention, the pituitary gland releases a hormone called FSH (follicle-stimulating hormone), which, in turn, increases the amount of estrogen in the ovaries, allowing a single oocyte to mature. Oocyte maturation results in the release of another hormone called LH (luteinizing hormone). To obtain multiple mature oocytes, endocrinologists mimic this process through the injection of hormones that interact with the body in the same manner as FSH or LH but at levels that result in 5 to 30 mature oocytes via the artificially induced process, as opposed to 1 oocyte as occurs in nature (Kiessling, 2007).
The protocol begins at home, with self-administered injection of gonadotropic hormones, called GnRH agonists that interrupt the body’s hormone cycle by blocking communication between the pituitary gland and the ovary. The goal of administering hormone agonists is to halt the maturation and release of an oocyte. The first step in the hormone injection protocol is akin to a “reset” button that clears the body of any FSH. Hence, the provider’s body is primed for a specific level of hormone stimulation (Kiessling, 2007). GnRH agonists reduce the amount of FSH and LH, which results in lower levels of estrogen, and ultimately prevents oocyte maturation. A common example of a GnRH agonist is Lupron, which is FDA approved for prostate cancer treatment but used “off-label” for oocyte procurement. Safer protocols have been developed to reduce the negative side-effects of Lupron, such as the use of an LH agonist with a shorter half-life and delivered at a lower dose (Batzer & Daar, 2011; Ellison & Meliker, 2011).
After about six to ten days of GnRH agonist injections, a different drug is administered to up-regulate the amount of FSH and LH that was just suppressed. The self-administered drug stimulates multiple follicle development of oocytes and is used for 7-10 days. Additionally another drug, usually another GnRH agonist, is prescribed to prevent spontaneous ovulation because spontaneous ovulation will result in eggs expelled from the body before a physician can collect them. Lastly, before the egg retrieval process can occur, a final drug, usually hCG, is injected to prepare for retrieval of the matured eggs (Kiessling, 2007).
A table of the sequence of hormone/drug administration is summarized in the Reproductive Health Technologies Project’s Policy Brief on Ovarian Stimulation and Egg Retrieval (RHTP, 2012).
The retrieval process takes place in a medical setting, and usually under anesthesia, and lasts about thirty minutes (Kiessling, 2007). A physician uses an ultrasound-guided needle to pierce the vaginal wall and the ovarian wall to aspirate the matured oocytes (Steinbrook, 2006; Kiessling, 2007). A typical retrieval yields between 6 to 20 eggs (Delvigne & Rozenberg, 2002). The eggs are used fresh or frozen and stored for future IVF. The American Society for Reproductive Medicine (ASRM) estimates that egg providers commit 56 hours to this process in a medical setting and that the process can take weeks due to menstrual cycle synching between provider and recipient (Steinbrook, 2006).
Over the last 20 years there have been over one million IVF cycles performed with one hundred thousand people undergoing this cycle.
The majority are those who are seeking reproductive services for themselves versus third party donors (~10%), however, in recent years there has been a doubling in the number of people seeking oocytes from third-party donors (Scutti, 2013; Sunderam, 2015). The health risks associated with exogenous ovarian hyperstimulation vary for each person (Centers for Disease Control, 2013; Giudice et al., 2007). A young person undergoing the procurement process for SCR may have a very different risk profile than an older person experiencing infertility, simply due to differing levels of endogenous (produced by the body) hormones circulating in the body. The vast majority of knowledge on health risk has been collected from infertile women seeking assisted reproductive technology over the age of 30; additional risks may be connected to the age of the provider, history of familial disease, body mass index, and fertility status. Many have argued that the known risks associated with controlled ovarian stimulation for people using IVF technology for reproductive purposes where the donor and recipient are one in the same, do not transfer to third party oocyte providers (Ellison & Meliker, 2011; Batzer & Daar, 2011). That said, with the limited data on hand, the known health risks associated with oocyte provision fit into four major categories associated with different stages of the process: 1) hormone injection, 2) process of ovarian stimulation, 3) egg retrieval surgery, and 4) psychological risks.
Most of the literature that assesses risk due to hormone injection focuses on the risk of ovarian hyperstimulation syndrome (OHSS), which may occur after the final trigger shot of hCG because it is an overstimulation of the ovaries (Delvigne & Rozenberg, 2002). OHSS is caused by an increase of estrogen production that releases fluid in the abdomen (and sometimes lungs), resulting in swelling of the entire ovary. This can result in pain and difficulty breathing. OHSS is classified into three subgroups: mild, moderate, and severe, with the latter occurring 0.1 to 0.2% of the time, though renal failure can occur in 1.4% of those undergoing the procedure (Giudice et al., 2007). Risk for OHSS is largely unpredictable, however, it is clear that pregnancy (which triggers the body to increase estrogen production endogenously), lower body weight, younger age, history of polycystic ovarian syndrome, and number of oocytes retrieved, all increase risk. Reports of OHSS vary depending on which form (mild, moderate, or severe) qualifies for inclusion in the data sample and there is usually a global underreporting of mild cases of OHSS. Though rare, some individuals may have pre-existing conditions that present elevated risk of OHSS, and if not monitored carefully can result in exacerbated symptoms and ultimately death (Giudice et al., 2007; Aramwit et al., 2008; Delvigne & Rozenberg, 2002).
There are other risks associated with the hormone injection aside from OHSS, including the risk of an allergic reaction to the injections. Some providers, in anecdotal stories, have reported mood swings and irritability caused by the hormone injections. Hormone injections may also exacerbate preexisting conditions such as growth of benign tumors (Hamilton, 2000). Since many young women who serve as third party providers may be unaware of the existence of such tumors, this risk is challenging to mitigate, as there are currently no biomarker screening methods in existence to exclude this at risk population.
Moreover, the full range and intensity of long-term health consequences are unknown because few large-scale studies have been conducted to assess the risks of hormone-induced loss of fertility and hormone-dependent cancers such as breast, ovarian, uterine, and endometrial cancer. Participants in a workshop in 2006, conducted by the Committee on Assessing the Medical Risks of Human Oocyte Donation for Stem Cell Research funded by the US National Academy of Sciences (NAS), were hesitant to link hormone injections to endometrial cancer because of the small sample size and the conflation of third party egg providers for IVF with those undergoing hyperstimulation because they are seeking pregnancy. However, the published 2007 report links fertility drugs with an increased risk of uterine cancer (Giudice, et al. 2007). Of the few small-scale studies published to date, most focus on infertile individuals who are utilizing controlled ovarian hyperstimulation to achieve IVF-assisted pregnancies and data on third party oocyte providers is lacking (Asante et al., 2013; Calderon-Margalit et al., 2009). One large-scale study, involving 21,000 women, published in the journal, Fertility & Sterility, suggests that individuals below the age of 25 that undergo IVF to treat infertility are at elevated risk of breast cancer compared to those that treated their infertility through means other than IVF (Stewart, 2012). However, it should be noted that results even among those experiencing infertility are inconsistent across studies and that studies on third party oocyte providers is lacking.
In 2017, there were no large scale studies dedicated to the long term health of fertile individuals seeking hormone intervention for egg freezing and subsequent IVF, nor for young fertile third party egg providers. This information is particularly relevant as IVF, oocyte donation, and egg freezing become more mainstream. The recent decision to move “egg freezing” from an experimental to non-experimental protocol by the ASRM, the publication of the book Egg Donation: The Reasons and The Risks by journalist Kristi Lew targeting pre-teen women, and commercial websites that promote oocyte “donation” as a means to pay for college tuition do not adequately present the potential health risks associated with hormone stimulation at a young age (Alberta et al., 2014; Beeson, 2009; Lew, 2009). This lack of research has resulted in calls to action to perform such studies (Schnieder, et al. 2017).
Other health risks associated with oocyte procurement are often overshadowed by the possibility of OHSS, but additional risks exist. There are those who may experience adverse outcomes caused by retrieval surgery, such as infection, hemorrhaging due to trauma to blood vessels, and ovarian torsion, which increases with OHSS (Kiessling, 2007). There are also psychological risks involved in the oocyte provision. The NAS report divides psychological risk into issues associated with the screening process, the oocyte procurement procedure, and the post-provision adjustment of giving up one’s eggs. The screening for donation may reveal unwanted familial or disease risk information including risk factors for Alzheimer’s disease or cystic fibrosis. Lastly, there is the risk of adjusting to an unknown future. Psychological risk also varies depending on the purpose for undergoing the procedure (e.g., to “preserve” oocytes for one’s own future as a result of cancer treatment vs. to delay childbearing decisions; to provide for another’s infertility treatment; to provide for research), and complicated by different fertility practices such as egg sharing policies.
Egg sharing policies allow people providing eggs for their own reproductive purposes to share half of their oocytes with another party or to fertility/embryo research in exchange for a reduction of their individual cost of IVF. Egg sharing for reproductive purposes, originated in the UK in 1993. In 2009, the policy was expanded to include donations for fertility and embryo research and is also offered by commercial IVF centers supporting reproductive choice in the US (Blyth, 2002; HFEA, 1993; Lancet, 2003). The policy simultaneously places women in the positions of providers and recipients, which comes with added social and ethical consequences (Choudhary et al., 2012). This option may carry a psychological burden to oocyte providers because they could be compromising their most viable oocytes and the chance of pregnancy for a lower cost of IVF (Haimes, et al., 2012). In these cases, the oocyte provider must be prepared to accept that the oocytes exchanged for reduced cost of IVF, might have resulted in successful pregnancy in someone else, or may have been utilized in process of extracting ESCs for SCR (HFEA, 2009; Lancet, 2003; Plows, 2008; Roberts & Throsby, 2008; Jeong, 2013; Goedeke, et al., 2017). Although screening in egg sharing programs seeks to uncover any psychological vulnerabilities, the screening process cannot guarantee that the egg sharer will not have a negative psychological experience should they be unsuccessful in achieving a full term pregnancy (Blyth, 2002). More recently, HFEA regulators investigated reports that some IVF clinics were inducing egg donation in return or free or discounted IVF treatment. The investigation revealed that these clinics were selling the donated eggs, which is illegal, and were not in compliance with HFEA protocols for informed consent (Siddique, 2017).
Biological Alternatives: Cybrids, Menstrual Blood, Ovarian, Fetal, and Fat Cells
Those opposed to harvesting humans oocytes for the creation human embryos that will be terminated upon ESC extraction have suggested that other approaches be the focus of this field of research. Some potential biological alternatives to using human eggs for SCR that do not involve the morally contentious embryo sources include: animal eggs, human fat cells, menstrual blood, in cells, or ovarian stem cells.
Recently, bioethicist Alta Charo, highlighted the importance of fetal tissue research in an editorial for the New England Journal of Medicine, and reveals the inaccuracies and fabrications presented in the claims made by anti-abortion activists against Planned Parenthood in their role of providing fetal tissue for research purposes in exchange for reimbursement costs of storage and delivery (Charo, 2015).
That said, the use of tissue from aborted fetuses continues to raise questions regarding transparency and consent as described in the ethnographic work of Pfeffer and Kent regarding the movement of fetal tissue from the clinic to the stem cell research sector in the Britain (Pfeffer & Kent, 2007). Additionally with the media blitz regarding Planned Parenthood, the International Society for Stem Cell Research publicized this on their News Feed
In the United States, fetal tissue research has emerged as a political issue for the first time in decades. Not only is the U.S. Congress looking into the value of the research and the sources of fetal tissue but legislatures in at least 11 states (Alabama, Arizona, California, Georgia, Illinois, Michigan, New Hampshire, New Jersey, Ohio, South Dakota, and Wisconsin) are considering enacting bans of one type or another on the use of fetal tissue. (ISSCR Policy Brief, November 6, 2015).
Given the debates surrounding human fetal and embryonic tissue research, using animal eggs for SCR is one viable alternative to create humanesque embryos without the requirement of human eggs. The combination of animal eggs and human DNA for stem cell research is referred to as cybrid technology and is similar to technologies used to produce clones through somatic cell nuclear transfer (SCNT) (Tachibana et al., 2013; Cervera and Stojkovic, 2008) In cybrid technology, researchers remove the nucleus of the animal egg and replace it with a human nucleus (Baylis, 2008). The resulting cybrid contains animal cytoplasm, animal mitochondrial DNA, and human nuclear DNA. Exposing the cybrid to exogenous chemicals mimics the events of sperm and egg fusion and triggers the cybrid to undergo cell division as if it had been fertilized. The resulting five-day embryo is then used to collect ESCs from the inner cell mass for SCR. Because this embryo can not develop into a fetus, it could be reasoned that this is ethically more acceptable to use as compared to human fetal and embryonic tissue, which may have resulted in a live birth.
Though both cybrids and chimeras refer to biological fusions, the difference lies at the level of scale in that cybrids refer to mixtures of DNA within a single cell, and chimeras refer to mixtures of cells in a tissue. As a reminder, the placenta is a chimeric tissue made up of fetal cells and mother’s cells, each maintaining its own distinct cellular boundaries.
Chimeric organisms can also be comprised of cells from different organisms in which each cell is distinct with respect to its origin of species, such that a human cell containing human DNA can be identified and segregated from an animal cell containing animal DNA. A cybrid involves intracellular mixing, such that each cell is comprised of a mixture of animal and human DNA, with the two species no longer distinct at the cellular level. If a cybrid develops into an eight-cell embryo, each cell in this embryo would contain both animal mitochondrial DNA and human nuclear DNA. In 2008, the HFEA issued two separate licenses to institutions conducting research using cybrid technology in the UK.
This technique appears to reduce the need for human eggs. However, feminist scholar Francoise Baylis argues that this is simply a stepping stone to working out the technical difficulties associated with mammalian cloning and nuclear reprogramming. Baylis goes on to argue that once this is sorted out, there will again be an increased need to secure human eggs for continuing this kind of research (Baylis, 2008). Her concern is that cybrid technology does not support egg providers, but instead objectifies the egg providers more. She claims that by distracting the conversation to focus on present day cybrid research, we are furthering the invisibility of women in the stem cell debate and though the decision to move forward is cast as democractic, she and others are critical of the public consultation process (Baylis, 2009). Father Thomas Berg, a former NYSTEM Ethics Committee member who publicly denounced public funding of hESCR via oocyte compensation schemes, echoes this stance (Berg, 2007).
More recently, some have proposed SHEEFs (synthetic human entities with embryo like features) as way to remove the need for human eggs and to circumvent the 14-day rule. In the US, scientists working with federal funding are not permitted to conduct research on embryos after 14 days, the time at which the primitive streak forms (Radiolab, 2016). In 2014, Warmflash, Brivanlou, and others, were able to mix embryonic cells to create a “gastruloid” or “artificial” embryo, one that did not require fertilization (Zimmer, 2017). In 2017, George Church and others argued that SHEEFS require ethical consideration and new regulations should be put in place as technological advances will move these SHEEFs into the realm of more embryo like (Aach et al., 2017).
Another biological alternative to procuring oocytes for ESCR is to redirect efforts towards ASCs in the human body. Recently, researchers have identified stem cells in fat procured through liposuction that have remarkable plasticity, or a wide range of potential to become different types of cells. These cells are referred to as adipose derived stem cells (ADSCs).
While these have potential, they are small in number and require expansion in culture. Upon procuring the fat via suction, the material is spun down, creating a small stem cell pellet, which can be disaggregated, grown in culture, and expanded to create a variety of cell types (Bora & Majumdar, 2017; Zuk, 2002).
Though they are multipotent, exhibiting a more limited scope of differentiation than ESCs, they have been used to reconstruct the breast using a painting technique and some doctors are using these cells to treat knee injuries (Begley, 2010).
Another alternative, mentioned earlier, is menstrual blood, expelled when embryo implantation does not occur. Menstrual blood contains the endometrial lining of the uterus where stem cells named endometrial regenerative cells (ERCs) reside. There is some evidence that these cells may hold more promise than other ASCs in their capacity to regenerate and differentiate into a wide range of cell types in a shorter period of time, but others have argued that these cells are not very different from those of the bone marrow (Rowland, 2009).
As researchers redirect efforts toward ASC research, attention has returned to the egg as commodity. Researchers claim to have identified stem cells in adult ovaries and this work could change the landscape of both reproductive medicine and SCR. In 2004, researchers demonstrated that stem cells in mouse ovaries could give rise to new eggs. Later in 2010, researchers acquired human ovarian tissue from people undergoing sex reassignment surgery in Japan and identified and isolated putative ovarian stem cells from this tissue. Researchers purified and placed these isolated cells into biopsied human ovarian tissue and then transplanted that tissue into a live mouse, where they developed into mature eggs (White et al., 2012). This research suggests that an unlimited supply of human eggs could become available for SCR and assisted reproductive medicine.
The work surrounding adult ovarian stem cells is promising in that it would require only a small number of people with ovaries representing the diversity of the human population to provide ovarian tissue to generate eggs in the lab environment. Yet, the work is also intended to build a commercial industry (Ovascience) for those seeking reproductive choices and, thus, contributes to the commodification of bodily tissue. It is possible that scientists will also find this abundant source of human eggs useful for cloning research. Lastly, though the work is heralded as revolutionary, many in the field are not yet convinced that these cells are true stem cells (Lovell-Badge, 2012; Hanna & Hennebold, 2014; Couzin-Frankel, 2015).
Treating Oocyte Providers as Research Subjects
Currently, oocyte procurement practices sit in an unusual place with respect to ethical frameworks for biomedical research.
Typically, biomedical research using human subjects involves an informed consent process that allows research subjects to make decisions regarding participation through evaluation of risk and benefit (Magnus & Cho, 2005). In the US, informed consent involves oversight and regulation via Institutional Review Boards in compliance with the Code of Federal Regulations 45 (CFR45), which is in line with international guidelines.
Research protocols that do not provide direct benefit to the research participant must be evaluated to determine if individual and societal benefits outweigh the risks to participants. This approach is used in Phase I clinical trials in which drugs are tested on a small number of healthy human research subjects to determine drug safety, dosage, and adverse side effects. In these Phase I trials, healthy “volunteers” can be paid for their participation and their health is followed for the duration of the trial, which may span one to five years.
Paying healthy volunteers for their participation is commonplace and can take many forms, spanning reimbursement to cover expenses incurred during participation, compensation to address injuries sustained during participation, renumeration in which payment addresses the subjects’ time and inconvenience, and inducement, which is pay designed to provide incentives for participation (Czarny et al., 2010).
It has been debated that with increasing socioeconomic inequality, financial inducements to increase volunteer participation could create pressure for people to participate in research despite medical risks. This concern has been discussed at length and most recently reviewed in a policy forum article published in the journal Science, titled “Economic Rewards to Motivate Blood Donations.” It could be argued that in the case of donations to blood banks and bone marrow stem cell banks, the benefit to society outweighs the potential health risks associated with retrieval as both can be easily procured by tapping the peripheral blood supply of the donor (Mohapatra, 2013). But even in these cases, most countries shy away from providing direct financial inducement to increase participation based on the historical view that doing so could constitute undue inducement and compromise the quality of the donation, though new studies suggest that this view may not be founded on evidence (Lacetera et al., 2013; Klein, 2013).
Oocyte providers sit in between these two very different examples of payment for participation in biomedical research and practice, yet some scholars believe that paying oocyte providers should be considered in the context of research ethics paying careful attention to undue inducement (Ballantyne & de Lacey, 2008; Hyun, 2006). However, unlike healthy volunteers in clinical trial studies, the bodies of the oocyte providers are not being studied despite being administered exogenous hormones and undergoing invasive surgery. In the US reproductive sector data on oocyte providers’ experiences and their health following oocyte provision is not systematically collected, analyzed, or used to inform health practices and policies. Similarly, in states that have moved forward with payment for oocyte provision in the SCR sector, data on oocyte providers is not gathered or used in a research context. Conversely, oocyte provision is more akin to blood donation in that the donor’s participation is viewed as a service for society with no further research conducted on the actual donor. But unlike blood donation, the process is considered more invasive and time consuming, with oocyte providers being paid up to $10,000 in the research sector (Roxland, 2010).
Professional societies and various advocacy groups question the placement of oocyte providers in an exceptional position outside of normative practices regarding ethical conduct as applied to human research subjects or patients (Magnus & Cho, 2005). The Ethics Committee of the ASRM, the self-regulatory arm of this professional society of reproductive specialists, has issued guidelines concerning the health of the oocyte provider, “ … oocyte donors become patients owed the same duties present in the ordinary physician-patient relationship. Programs should ensure that every donor has a physician whose primary responsibility is caring for the donor” (Alberta et al., 2014) Yet, most oocyte providers are not followed after oocytes are retrieved, prompting several advocacy groups to call for a national egg donor registry to monitor the health of providers (Stein, 2011). They reason that without data on health risks, oocyte providers cannot adequately weigh benefits, be they financial or otherwise, against health risks, compromising the informed consent process. A database of this nature would acknowledge the experimental nature of the process and view the oocyte providers as research subjects, much like those in a clinical trial.
Many have tried to raise awareness about the lack of research, and proper risk communication with informed consent. A grass roots effort to create a database and to treat and follow oocyte providers who have themselves experienced infertility, or provided in the context of IVF, is in place, but no such similar effort has been mounted for oocyte providers for SCR (Bamford, 2011; Infertility Family Research Registry; We Are Egg Donors). We Are Egg Donors provides community support and responses to recent events via their blog. In 2017, Sonja O’Hara an egg donor, wrote, directed, and acted in her fictional film “Ovum” to raise awareness of the issues using satire. Sonja used her compensation as an egg provider to finance 70% of her film (We Are Egg Donors Blog). Other donors used the We are Egg Donors Blog to comment on the film (We Are Donors Blog).
Lisa Ikemoto, bioethicist, lawyer, and a director of the Reproductive Health Technologies Project, argues that the ART industry and the SCR field are dependent on one another (Ikemoto, 2009). Ikemoto traces the effects of a neoliberal economy on these two evolving fields, each of which requires eggs and embryos resulting in inextricably linked practices that require continued investment in technology innovation. Like Ikemoto, developmental biologist John Gearhart believes that these two fields led to groundbreaking discoveries because researchers and clinicians saw the techniques as having cross purpose. In commemoration of the Nobel Prize for IVF, Gearhart co-authored an essay to highlight the development of IVF as instrumental to expanding our understanding of human embryogenesis, DNA reprogramming, and stem cell biology (Gearhart & Coutifaris, 2011). A useful method, perhaps, to distill the policy initiatives that bind these two industries is to review the history of each of these research areas.
Although many forms of reproductive assistance have been in play for centuries, the practice of IVF was not popularized until 1978 with the birth of Louise Brown, the first successful IVF baby born in the UK. Subsequently, with the assistance of fertility specialist Howard Jones, the first IVF baby was born in 1981 in the US, and soon thereafter other countries followed suit (Gates, 2006). It is noteworthy that ART emerged within the backdrop of acceptance for social policy regarding reproductive choice, after the landmark US Supreme Court decision of Roe v. Wade in 1973 (Lawnix, 2008). In addition, IVF as a reproductive choice has moved beyond those experiencing infertility to mature into an industry offering reproductive choices to homosexuals, single people, and those interested in screening out some genetic susceptibility to disease using IVF in combination with Preimplantation Genetic Diagnosis (PGD).
The birth of SCR can be traced to 1886 when William Sedgwick described the regenerative properties of plants and later in 1951 with the advent of human tissue culture techniques. However, it can be said that regenerative medicine reemerged as a field with the success of cloning Dolly the sheep in 1996 and the isolation of human embryonic stem cells in 1998.
Internationally, both the ART and SCR sectors grew exponentially over the last 40 years, yet few global policies were put in place. This has led to a patchwork of policies with some countries developing robust structures and processes that regulate what is permissible and what is not, and others using a more laissez faire approach, allowing markets to dictate practices.
At the forefront of reproductive and cloning innovation, the UK has taken the lead in establishing regulatory frameworks for both ART and SCR practices and, through its national healthcare system, provides one cycle of IVF for those diagnosed with infertility. In 1987, an interdisciplinary committee met to craft a proposal titled “The Human Fertilisation and Embryology Authority: A Framework for Legislation,” and three years later, the Human Fertilisation and Embryology Authority (HFEA) was established to oversee ART and embryo research. The HFEA mission is “dedicated to licensing and monitoring UK fertility clinics and all UK research involving human embryos, and providing impartial and authoritative information to the public.”
Along with issuing information to the public, the HFEA website lists several documents regarding egg sharing arrangements, which allow people providing eggs for their own reproductive purposes to share their eggs with another party to reduce their individual cost of IVF. Additionally, the HFEA issued a new policy in 2004 mandating identity release for people conceived by egg/sperm donors once they turn eighteen. While IVF is a regulated practice in the UK, this is not the case in the rest of Europe or the rest of the world. Therefore, some people cross national borders in order to satisfy their unique reproductive needs, a phenomena referred to as “reproductive tourism.”
In 2007, The Parliamentary Joint Committee on the Human Tissue and Embryos (Draft) Bill was convened to review the Public Bodies Bill, to determine whether HFEA could be merged with the Human Tissue Authority (HTA). The unanimous response by the committee and almost all medical organizations was that a merger would set back what is considered the world leader in policy and regulation regarding embryo and reproductive research (Deech, 2010).
In 2010 there was, again, movement to dismantle HFEA and distribute its roles among several existing health and safety bodies, such as the Care Quality Commission (CQC) and The Health Research Authority, to address the economic crisis and reduce operating costs. In September 2012, the open comment and response about this proposal was posted and due to the negative feedback and impending new technologies involving “three parent” embryos it was decided that HFEA should remain as an entity as it provides a necessary level of expertise and specialization (Ahmad, 2012; GOV.UK, 2013; Gallagher, 2015).
While practices in the UK may have paved the way for IVF, the oocyte global economy is part of a larger ART industry that includes gestational surrogacy. Surrogacy falls under the umbrella of ART because someone else is laboring the pregnancy, and in many cases the pregnancy is the result of a third-party oocyte provider as well (Scutti, 2013). Due to lower prices outside the US, some Americans outsource their surrogacy to other countries. This emerging market has unfortunately led to oocyte provision related deaths in India, resulting in regulatory changes regarding medical tourism and their $500 million fertility industry (Lal, 2012). The Assisted Reproductive Technologies Bill 2010 was a broad attempt to begin regulating the practice of reproductive services and prohibits Indian women from selling or receiving compensation for oocytes used outside the country for reproductive purposes. Additionally, neither compensation nor payment for gametes or embryos for SCR is permitted; these cells can only be used in research if donated by fertility clinics and with informed consent of the donor. In 2008, a Draft Assisted Reproductive Technology Bill was drafted, and over the years has gone through a number of revisions based on recommendations and suggestions made by different ministries and departments of the central government. In 2016 the bill, which proposes a national registry and regulatory board split the two issues, creating two bills one for ART and one for Surrogacy (Cussins, 2012; Malik, 2017).
Though India is considered the surrogacy capital of the world, Israel may be called the IVF capital. Israel claims to have more IVF clinics per capita than any other city in the world, invests heavily in research involving reproductive technologies, and provides federal assistance to subsidize the cost of IVF. Despite having the infrastructure to conduct all procedures related to IVF within the country, Israel has laws in place that prohibit oocyte provision that cross religious lines as part of a national campaign to strengthen and expand the Jewish State. Additionally, Israel felt that oocyte provision should not involve unnecessary health risks, thus, third-party oocyte provision could only occur via the egg sharing model.
However, in 2000, a scandal, dubbed the “eggs affair,” resulted in a “crisis of trust” for those seeking IVF. This scandal involved a personal injury action put forth by several egg sharers who claimed that a fertility doctor had subjected them to excessive ovarian hyperstimulation to create excess ova for others without their informed consent. The case was settled out of court, but it is believed that the doctor secured over 238 ova from a single woman (Shalev & Werner-Felmayer, 2012). The fall out of this scandal was a shortage of ova resulting in the search for oocytes outside of the country.
In 2005, the Health Ministry approved six foreign clinics working in conjunction with Israeli hospitals and centers to provide egg donation services. Three of these clinics are in Ukraine, two in the Czech Republic, and one in New Jersey (Klein, 2015). Sociologist Michal Nahman has examined how this confluence of permissive and restrictive policies has tapped the European egg market. She writes in “Reverse Traffic: Intersecting Inequalities in Egg Donation” about how IVF practice in Israel maintains a hierarchy of power and inequality with oocyte providers in Romania, where the history of oppression of women’s reproduction leads to a willingness to undergo invasive procedures repeatedly for little compensation (Nahman, 2011).
In 2010, Israel in an effort to address the oocyte shortage, enacted the The Eggs Donation Law. Under this law oocyte provision is highly regulated, placing restrictions on age of provider, relationship with IVF recipient, and caps on the quantity to be used for SCR (20%) versus reproduction (80%) (Shalev & Werner-Felmayer, 2012). Furthermore, only three cycles of egg retrieval may be done with a gap of 180 days between each cycle. Despite efforts to expand egg donation, Israel continues to experience a shortage partly due to a lack of participation by the 25 IVF clinics in the country. A Ministry study involving survey responses revealed that only two of the clinics offered donor services. In response the Ministry announced that they would revoke licenses from those not participating and double the payment to egg donors. The government is now looking into the establishment of a national donor egg bank (Atias & Yulzari, 2014).
The bill in India is one of the first initiatives towards regulating the ART field internationally, and the trend is spreading. Though there are no federal laws in the US regarding reproductive technologies and practices and no national healthcare coverage for infertility, some states have initiated bills that promote stratified reproduction. A system of stratified reproduction reinforces social inequality along race, class, sexuality, and ability lines. In this situation, those of economic means can purchase reproductive choice, while those of lower socioeconomic class are excluded from these choices and/or carry the burden of health risk associated with ART. One example of such practices is Louisiana Senate Bill 162, which legalizes surrogacy through financial contracts between surrogates and potential parents, yet bars LGBQT individuals from participating in surrogacy and only applies if the heterosexual couple is married and can demonstrate medical need (McGaughy, 2013). Along the same lines, states have taken different stances on payment for oocyte procurement for SCR with many tying access to oocytes and embryos to fertility clinics. Thus, stem cell researchers often work in conjunction with a fertility center, but given the high cost associated with IVF, stem cell lines procured form these extranumerary embryos will be limited by the characteristics of those who can afford such reproductive practice.
Unlike the UK, there are no federal regulatory bodies or policies in place for ART. Instead, the US relies on professional societies such as the American Society of Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technologies (SART) to self-regulate and issue guidelines for fertility clinics to follow. These guidelines include the number of times a person should be allowed to provide eggs (six) and caps on compensation associated with the process ($8,000 to $10,000). However, research shows that these regulations often are not followed by fertility clinics (Klitzman & Sauer, 2009; Levine, 2010; Fiore & Hinsch 2011; Luk & Petrozza, 2008; Keehn et al., 2012). Moreover, in some cases, exclusionary practices are exercised as described in Johnson’s study regarding lesbian access to IVF clinics (Johnson, 2012;ASRM, 2015).
Some have argued that a self-regulated industry will promote policies and practices that result in increased profit without adequate attention to health consequences. From an economic standpoint, one might argue that providers can not negotiate for adequate payment or compensation if there is no knowledge of common levels of payment, financial caps, or the financial fall out associated with unknown health risks.
Yet, the landscape does appear to be shifting, as can be seen in the case of Kamakahi v. ASRM. Lindsay Kamakahi is a third party egg provider for reproductive purposes who brought a class action complaint against ASRM for price fixing, claiming that ASRM violated the Sherman Act and prohibited egg providers from receiving fair compensation. Legal scholars have argued that the implementation of egg provider advocates may reduce coercion, explain protocols and clinical procedures, and provide education about policies, practices, payment models, potential health risks, and recommended guidelines. (Jones, 2015; Krawiec, 2014)
Rather than wait for infertility industries to adopt different practices, governments to institute regulations, or for scientists to conduct long-term studies on oocyte provider health, some health advocates have taken action to solve the problem directly creating registries, community support groups, and exchanging information regarding their personal experiences. Lupron Victims Hub, We are Egg Donors, and the Infertility Family Research Registry all seek to address the data gap and advocate on behalf of donors/providers. Their aim is to collect enough data to promote formal action by governments to systematically address these issues.
ASRM’s decision to remove the “experimental” label on egg freezing is perhaps one such example of the need for egg provider advocates. Though Facebook, Apple, and Intel embraced this news offering employees financial support for egg freezing, news coverage muddied the message (Motluk, 2011). Egg freezing, for the past twenty years, has been used for women as an option to medically treat infertility that is a result of cancer chemotherapy or prophylactic surgery. However, by removing the “experimental” label, some reporters believed that ASRM was now encouraging “social” egg freezing, or the practice of freezing one’s eggs for future cycles of IVF without medical need. But a close look at the ASRM guidelines states quite the opposite. In fact, ASRM strongly recommends that individuals avoid social egg freezing, that is egg freezing without a medical need (ASRM, 2013). When these announcements were made, many in the fertility industry pivoted to provide services for this growing sector of clients, such as the session hosted by ASRM titled “Fertility Preservation Patients: How to Re-engineer your Practice to Accommodate Them” (Tsigoinos, 2014).
However, with many hailing social egg freezing as a smart alternative for young, career-driven individuals wishing to delay childbearing decisions, the number of extranumerary embryos that could result from the downstream fertilization could provide the SCR sector with a necessary biological resource in high numbers.
As people begin social freezing at earlier age, the number of mature oocytes procured can be up to 70 per person after two cycles of hormone treatment (Stein, 2012). Again, an egg provider advocate, or an IVF advocate, would be in a position to explain the intersection of IVF and SCR in ways that would hopefully permit the egg provider to arrive at an informed decision regarding the extranumerary ova and/or extranumerary embryos created via IVF and what it might mean to donate them or share them with the SCR sector.
Additionally, the advocate could provide information on short term and potential long-term health risks associated with ovarian hyperstimulation. Given that there are few studies to date on the effects of hormone stimulation at young age and one study that suggests there may be a link between this kind of treatment and the development of breast cancer, the new reproductive choice of social egg freezing may in fact place women in a dire health situation later in life (Stewart, 2012).
That said, if there is a population willing to undertake the risks associated with social egg freezing and a surplus of unused eggs in the future, egg sharing practices may emerge between IVF clinics and SCR centers. That said, the ASRM has clearly stated that there should be no financial compensation for “dead embryos.” The ASRM has also countered HFEA’s egg sharing model for SCR claiming that it could be seen as undue inducement for those who are financially unable to seek IVF services. Most likely, ASRM will approach egg sharing schemes with social egg freezers using the same caution. However, other models as outlined in the study on the Monetary Payments for the Procurement of Oocytes for Stem Cell Research: In Search of Ethical and Political Consistency may be applicable in these contexts (Isasi and Knoppers, 2007).
Citizens United v. Federal Election Commission), it is paradoxical that the US federal government allows for the barter and sale of gametes (egg and sperm) for reproductive purposes, yet, does not support the compensation of bone marrow donations designed to diversify existing bone marrow stem cell banks (Flynn v. Holder). The National Organ Transplant Act of 1984 (NOTA) “prohibits the transfer of any human organ for valuable consideration for use in a human transplantation if the transfer affects interstate commerce.” However, this act does not prohibit the sale of bodily reproductive tissue such as eggs and sperm, which is left to the private sector and market-driven economy.
Given a capitalist culture where everything can be commodified and corporations can act as individuals (
In 2009, the US Attorney General, Eric Holder was sued for prohibiting payment for bone marrow stem cell donations by plaintiffs represented by the Arlington-based libertarian nonprofit Institute for Justice (Kramer, 2010). The plaintiffs included California nonprofit MoreMarrowDonors.org (MMD), parents of children living with disease, and a physician. At the state court level, the case was decided in favor of the government based on the policies associated with NOTA. The plaintiffs took the decision to the US 9th Circuit Court of Appeals, where the decision was reversed in favor of the plaintiffs on December 1, 2011. The decision in Flynn v. Holder permits compensation for bone marrow donations via apheresis (peripheral blood draw) in the form of scholarships, housing allowances, and charitable donations, but not direct cash payment. Patients can now also ask their insurance providers to cover the costs of such compensation (Barnes, 2012)
The stakeholders in this groundbreaking case were all interested in diversifying the bone marrow stem cell supply, but their approaches and philosophies differ. MMD is a nonprofit that seeks to broaden the diversity of existing hematopoietic stem cells (HSC), which are collected from bone marrow to treat a variety of blood and genetic disorders and reestablish blood cells following cancer. Because individuals from mixed-race populations are more genetically diverse, and the number of donors in the registry from mixed-race backgrounds is low, immunological matching proves challenging for non-Caucasian recipients (Brown, 1996; NMDP). Though the US National Marrow Donor Program (NMDP) is one of the most ethnically diverse in the world with over 11 million donors registered, it estimates that less than 3% of donors self identify as mixed race.
Currently, those of mixed heritage can identify a bone marrow match about 25% of the time as compared to Caucasians who match 66% of the time.
The matches consider the presence of over 600 million possible combinations of HLA surface proteins on haemopoeitic blood stem cells (Brown, 1996; NMDP). For those regions with a scarcity of bone marrow donations from diverse backgrounds, MMD has proposed a pilot program to pay immunologically matched donors up to $3,000 in non-cash payments to promote donors of mixed-race backgrounds to provide bone marrow stem cells (Shay, 2010).
Though all plaintiffs sought to broaden the diversity of the pool of bone marrow stem cells as the current national registry only contains donations from 2% of the population, the involvement of the MMD and their proposed compensation program speaks to the larger notion of “just participant selection” and community based approaches designed to address health inequities in the US. With this proposed program, the donor and recipient both belong to the community of underrepresented minorities that lack representation in bone marrow stem cell banks. However, the $3000 compensation scheme could present opportunities for exploitation, which is a concern of the NMDP. That the program would provide donors with educational scholarships, housing allowances, or contributions to a charity of their choice also raises ethical concerns regarding paternalism in that particular things are being held at value by one group but perhaps not by the provider or the community that they represent.
The idea of paying donors who possess HLA combinations that are not well represented in the current registry has also been deliberated by economists who use mathematical models to determine the probability of matches across races and countries. They argue that altruism alone may not be sufficient in addressing those populations in greatest need, which they argue would be African Americans given the wide range of HLA genetic diversity within this racial group. Though their models are based on generalizations, they conclude that to meet the demands of the African American population, the US would need to increase donations from this group by tenfold. Bergstrom et al. are careful to point out that all races would benefit from increased participation in the registry, but that payment for donation should only apply for those populations in greatest need (Bergstrom et al., 2008).
Doreen Flynn, another plaintiff in the case, and mother of three daughters living with Fanconi Anemia (FA) believes that payment to all donors regardless of race is in order. Flynn is in a unique position as a mother, as she gave birth to one daughter with FA, but then conceived two more using IVF and PGD in hopes of birthing children without FA. Due to errors in her PGD diagnosis, both siblings also live with FA, but she has not had success in matching donors in the NDMP for her children. Flynn argues that because blood stem cells can be expanded in vivo through the administration of granulocyte-stimulating factor five days prior to donation, that payments to those with unique HLA profiles can save the lives of her children.
Due to the stimulation, an increased number of HSCs in marrow results in a larger number of stem cells migrating to the peripheral blood supply (PBSC) where they can be collected without the painful procedure of bone marrow aspiration (Cohen, 2012). Because 70% of bone marrow donations are currently collected from the peripheral blood supply, the plaintiffs argued that the prohibition of payment under NOTA violated the constitutional Equal Protection Clause, because donors could regenerate their own supply of bone marrow stem cells and would experience little harm through a procedure not dissimilar to sperm and blood donation (Barnes, 2012).
The NMDP and the Justice Department both expressed concern regarding exploitation of the impoverished and the vulnerable. The 9th District Court panel deliberated on the notion of “blood for money” exchanges in which very ill patients might be financially depleted in trying to secure a bone marrow stem cell match, but ultimately decided in favor of the plaintiffs (Williams, 2012). The decision in the case is in line with a trend in which economic rewards are used to motivate donations of bodily tissues (Lacetera et al., 2013; Klein & Crespi, 2013). There are also several studies that suggest compensation increases the rate of provision for sperm, eggs, and blood (Ikemoto, 2009; Klitzman & Sauer, 2009; Egli et al., 2011). These policies are careful to avoid language that would indicate the purchase of a biological product and, rather, express a desire to recognize the efforts associated with providing a product or service. Though some argue that these policies place society on an ethical slippery slope, others present evidence for proposals that would move towards the payment for bodily goods, as appeared in a New England Journal of Medicine editorial titled “Made-To-Order Embryos for Sale – A Brave New World?” (Cohen & Adashi, 2013).
The international landscape regarding the regulation of SCR is extremely varied, and can be separated into categories such as permissive, mixed, and restrictive with respect to four major areas: creation of embryos for research purposes, termination of embryos for research purposes, human cloning, and the creation of chimeras or cybrids for research. All of these applications require the procurement of human eggs. Thus, the regulation of these four research avenues is explored individually in the following section.
One definition of a permissive policy is a state, body, or country that allows the creation of embryos solely for research purposes. This approach is taken in China, India, and the UK (Daar, 2004). Mixed-policy countries allow public funding for research on extranumerary embryos from IVF clinics but will not allot government funding to create and destroy embryos for this purpose, leaving the creation of the embryos specifically for research to be funded by the private sector. Mixed-policy countries include Mexico, Canada, France, and the US. Finally, restrictive policies exist in countries such as South Africa, Germany, and Italy. The German government passed a law in April 2002 that only allows SCR to be conducted on lines created prior to January 2002 and imported across national borders for research purposes (Waldby, 2006). Therefore, in Germany no embryos can be created in any context (reproductive or otherwise) from which hESCs could be derived.
Without an international consensus, the UK is one of the first to develop legislation that offers strict guidelines for SCR in 2001. An amendment to the 1990 HFEA Act was passed, which permits the creation of human embryos via IVF technology for the purposes of research (Reuters, 2001). This act was later expanded in 2003 to include human embryos cloned via SCNT. making the UK the first nation to support and promote hESCR.
In 2008, the UK also became the first nation to support the creation of cybrids (Ahmad, 2012; Baylis, 2008). HFEA continues to maintain a licensing system for all stem cell lines generated in the UK. HFEA is thought to have the largest database of such lines in the world.
In 2004, a research team at Seoul National University in South Korea headed by veterinarian Woo Suk Hwang and gynecologist Shin Yong Moon published a falsified report in Science Express. They claimed to have established pluripotent hESC lines from cloned human blastocysts that were capable of differentiating into three primary germ layers, using 427 human eggs via altruistic donation (Hwang et al., 2004). In reality, Hwang’s research used almost five times as many eggs, and many were obtained by paying women for oocyte provision and encouraging junior lab workers to provide oocytes. In response to this scandal, Korean Womenlink, founded in 1987 to promote gender equality and a participatory democratic society, is one of 35 women’s organizations suing Dr. Hwang (Johnston, 2006; Widdows, 2009; Anonymous, 2009). The potential destruction of the blastocyst, the unethical practice of oocyte provider recruitment in the Hwang case, and the possibility of reproductive cloning became focal points in the political debates surrounding stem cell technologies and research. The backlash in South Korea resulted in a no-payment model for oocyte provision. Similar to Israel’s response to scandal involving oocyte provision, South Korea devised egg sharing models, as a means to secure oocytes and human embryos for SCR via the reproductive sector (Jeong, 2013; Shalev & Werner-Felmayer, 2012).
The work in South Korea was leveraged by George W. Bush’s stance regarding hESCR. The former President defended his decision by executive order to restrict federal funding for hESCR to those human cell lines created before August 9, 2001 by vetoing two Congressional bills in 2005 and in 2007. Congress was just one vote shy of overruling the veto in 2007. The bills proposed that extranumerary embryos created through IVF be used for SCR, but stopped short of proposing the creation of embryos specifically for research, thus, gaining bipartisan support. In his televised speech pertaining to the veto, President Bush appeared with “snowflake children” commenting that to harvest tissues and organs from embryos that could be adopted, was immoral and not in line with American values.
The President was also quite vocal about his support for the international ban on human cloning of any kind, stimulating a great deal of media coverage centered on the intersection of the scientific, political, ethical and even economic perspectives of SCR. This coverage combined with a growing number of state-sponsored initiatives and private sector organizations dedicated to hESCR prompted the public to grapple with the complexities of this field, and more specifically to deliberate about the fate of unused frozen excess embryos stored in fertility biobanks (Lewin, 2015;Bell, 2011).
In an attempt to inform the public about cloning as a technique used for SCR, the US National Academy of Sciences hosted an open forum on reproductive and therapeutic cloning, which was aired on C-SPAN.
Unfortunately, this conflation proved problematic, causing many in the general public to misunderstand in what ways the methods and practices associated with these two types of cloning are similar and where they differ. Though the two types of cloning (therapeutic and reproductive) have a shared provenance, the goals and outcomes are quite different. With reproductive cloning one seeks to give birth to a full-fledged child, while therapeutic cloning seeks to create five-day old embryos that would be terminated when the ESCs are removed. About one hour into the symposium on “Human Reproductive Cloning” Rudolf Jaenisch, a leader in the field of DNA reprogramming, raises a critical eye on cloning for reproductive purposes, stating the science is still preliminary and to try to reproduce using this technique is unethical and not scientifically sound. To further the divide between scientists seeking to understand stem cells and human development from those seeking new reproductive technologies, some scientists suggested new nomenclature. The word “cloning” holds different meanings for the lay public versus scientists, and it is precisely this language that leads the public into believing that humans are being cloned to harvest body parts (Vogelstein et al., 2002; O’ Mathuna 2002). Still, language aside, the intentional creation and subsequent termination of the five-day old human embryo prove ethically challenging for many. In the Hardball video many arguments are brought to bear on both sides of the debate regarding the moral status of the embryo.
In 2009, President Obama via executive order, lifted the restriction on federal support for research on existing hESC lines established after 2001. This executive order allows researchers to use federal funding to support hESCR using cell lines established from extranumerary embryos obtained from fertility clinics. However, President Obama also signed the annual Dickey-Wicker appropriations rider that prohibits federal funding for the destruction and creation of human embryos for research purposes.
This rider leaves the establishment or derivation of new hESC lines from the ICM of embryos in the private sector, which places the regulation of oocyte provision in this sector as well. In 2005, the US NAS recommended that no payments should be provided for donating eggs, sperm, or blastocysts (Hynes et al., 2005). The public restrictions on hESCR have led to many private institutions and non-profit organizations such as The New York Stem Cell Foundation, The Michael J. Fox Foundation, the Juvenile Diabetes Foundation, and The Brooke Ellison Project to secure and provide funding for human cloning for the purposes hESCR and regenerative medicine (Tachibana et al., 2013). Part of their desire to do so arose from the loss of scientific talent and expertise to other nations with more lenient policies (Scott & McCormick, 2006).
The fight over research dollars for SCR came to a head in 2011 when adult stem cell researchers who claimed that the presidential administration incorrectly interpreted the Dickey-Wicker appropriations rider brought a lawsuit against the NIH. Though the lawsuit was dismissed, the legal action alongside a patchwork of state laws regarding hESCR, has left many stem cell researchers wondering how stable this area of research will be without legislation at the national level (Barr, 2011). To that end, in 2011, House Representative and Democrat Diane DeGette of Colorado reintroduced the H.R. 2376 Stem Cell Research Advancement Act to support federal funding of SCR using extranumerary embryos from the reproductive sector.
This bill was proposed in an effort to stabilize policies for hESCR and assuage ethical concerns surrounding expanded egg procurement and compensation outside the reproductive sector. Though the bill has been proposed and amended several times, the bill has not yet gone to deliberation in the House Energy and Commerce Committee (Open Congress, 2011). To determine if such an approach is scientifically feasible, researchers investigated embryos deemed unusable for embryo transfer to achieve pregnancy. These embryos are referred to as “dead,” or non-viable, due to mitotic arrest, and contain a low percentage of viable cells for SCR (Gavrilov et al., 2009).
With President Donald Trump in office, the Obama executive order will most likely be reversed, with prohibitions on federal funding using extranumerary embryos from IVF clinics. The President claimed to reverse every executive order issued by Obama, and upon taking office, dismantled many scientific and environmental policies through executive action (Servick, 2016). Moreover, his administration carries a strong pro-life stance with both the Secretary of Health and Human Services (HHS), Tom Price, and Vice President Pence vocally opposed to hESCR. In addition, the President’s decision to remove federal funding for health services provided by Planned Parenthood sends a strong message that religious values will override scientific research. That said President Trump is keen on economic investments and may see support for hESCR as part of a plan to “Make America Great Again” by keeping stem cell researchers at home and providing ample federal support for their work. His decision to reappoint Francis Collins as Director of the National Institutes of Health (NIH) allows him to placate both sides, as Collins is an advocate of scientific innovation and someone who is has reaffirmed his religious values. This appointment is appealing to those Republican leaders who would like to see the US remain a leader in SCR respectful of their constituents’ concerns regarding the value of life (Reed, 2017). However, the appointment was opposed by 40 Republicans in the House who see this move as one that places scientific innovation above the moral status of the embryo (Ertlet, 2017).
Some states have chosen to restrict or ban hESCR, including Arizona and South Dakota (NYSCF). Other states, like California and Massachusetts, have policies in place that support hESCR, though they do not provide public funding for payment or compensation for oocyte providers that contribute to SCR beyond medical costs (Fossett, 2007; Santos, 2008). Conversely, New York is going against the grain with The New York State Stem Cell Science (NYSTEM), a publically funded program. NYSTEM supports SCR by providing $600 million of state funding for adult and embryonic stem cell research, with 2 to 3% directed towards the ethical, legal, and social dimensions of this research, including education initiatives and review of the oocyte provider informed consent process (Roxland, 2010; Roxland, 2012). In this capacity in 2009, the Empire State Stem Cell Board (ESSCB) decided that payment of up to $10,000 to egg providers for SCR purposes is allowable under contracts issued to institutions through NYSTEM, through which an Embryonic Stem Cell Research Oversight Committee (ESCRO) oversees the oocyte provider informed consent process (Chapman, 2008; ESSCB, 2009; Roxland, 2010).). This decision was not connected to legislation and, thus, public deliberation was absent from this process.
However, the policy has been debated in the American Journal of Bioethics with with scholars and practitioners debating the nature of policies and structures to promote the sale of bodily tissues (Ellison & Meliker, 2011). Elison and Meliker argue that paying people to provide oocytes despite unknown health risks is not different from current practices of employment in which agricultural workers and miners are exposed to toxic materials. But in the same journal issue, many feminist scholars provided evidence based counterarguments to such rationale (See Section XI).
Bioethicist and NYSTEM Ethics Committee member Robert Klitzman has argued that compensation for participation in oocyte provision for SCR is socially just, in that under-represented minorities or those living with disease or disability who are not typically recruited by privately run IVF clinics, now have the opportunity to receive the going rate of $10,000 should they choose to provide oocytes for state-funded SCR (Klitzman & Sauer, 2009). Board president and founder of the Women’s Bioethics Project, Kathryn Hinsch agrees with this approach and believes that to ask women to volunteer would be exploitive (Fiore & Hinsch 2011). Charis Thompson, feminist scholar who examines stem cell research in society, builds a three tiered argument for compensation (Thompson, 2007). She believes that by paying young health oocyte providers we can relieve pressure to donate on those living with disease and disability and seeking SCR-based therapies, as they may have increased risks associated with hormone treatment. Like Klitzman and Hinsch, Thompson supports equitable payment and uses the reproductive sector as a reference point. She cautions that without such policy in place, a black or grey market could emerge (Thompson, 2007).
The economic equity argument presented by these scholars is based on studies that reveal that recruitment and payment of oocyte providers for reproductive purposes targets primarily Caucasian and Asian individuals with a college education, desirable physical traits, and absence of disease, disability, or alternative lifestyle choices (Pollack, 2003; Levine, 2010; Keehn, 2012). The characteristics associated with oocyte providers in the SCR sector differ from that of the reproductive sector in that those living with disease or disability and those that represent a wider range of biological diversity due to population genetics associated with various ethnic groups are being sought. That economic inequity is stratified racially in the US means that individuals from under represented minorities may seek this payment scheme despite unknown long-term health risks. A report issued by The Insight Center for Community Economic Development found that nearly half of black and Hispanic women have zero to negative wealth, meaning that their debt exceeds their assets. The disparity is not insignificant: the median wealth for single black women is $100; for a single Hispanic women $120; and for a single Caucasian women $41,000 (Chang, 2010).
That said, it could be argued that these ethnically diverse stem cells will serve a wider segment of the population due to immunological matching (Mosher et al. 2010). Procuring ESCs from embryos that possess genetic variants known to increase the risk of disease and disability permit researchers to study disease progression in cell culture, and potentially develop therapies to treat those diseases that disproportionately affect communities of color, such as diabetes. This biomedical approach to health disparity continues to be challenged by social justice scholars who claim that the benefits of the research may never reach these communities, and that $10K will do little to bridge the economic gap, but may increase health disparity due to increased health risks associated with the provision protocol (Benjamin, 2014).
The financial cap of $10,000 was based on evidence from a qualitative research study focusing on 230 women who were engaged in providing eggs for reproductive purposes and compensated $8,000 to do so. Interviews revealed that most subjects in this attitudinal study felt that $10,000 is an appropriate amount for compensation, and that few, if any, would provide eggs for SCR without payment on the order of that provided for reproductive purposes (Klitzman & Sauer, 2009). The New York stance is also informed by research showing that altruistic donation of oocytes for SCR is untenable (Egli et al., 2011). Other arguments regarding oocyte compensation involve analysis of gender equity, autonomy, and agency and are presented in later sections of this primer.
Though these arguments address economic equity across the reproductive and SCR sectors, they may not adequately balance benefit and risk, given that the process in the reproductive sector differs from that in the research sector. Because fertility research has led to reduced levels of hormone administration to achieve successful pregnancy, oocyte provision in the reproductive sector may present less hormone-related health risks to egg sharers as compared to those who provide oocytes for SCR sector exclusively. However, for those that are third-party providers in the reproductive sector, the synchronizing of menstrual cycles between provider and recipient requires additional hormone administration to the provider over a ten day period, thereby increasing risks associated with hormones (Mertes & Pennings, 2011). While oocyte providers will be monitored carefully in the SCR sector, it could be argued that the low efficiency associated with SCNT cloning techniques requires more oocytes per provider to achieve the desired level of genetic and biological diversity. Thus, oocyte providers in the SCR sector may be subject to hormone hyperstimulation, and health risk associated with these procedures is not currently a robust area of biomedical research. Concerns regarding undue inducement, commodification of the body, and possible health risk to oocyte providers has led to different responses to the current state initiatives (Santos, 2008).
In New York, a lawsuit against the state was brought forward by the Feminists Choosing Life NY (FCLNY) Coalition for inappropriate use of state funds that they claimed placed women at risk unnecessarily given the lack of data on hormone effects on increasingly young oocyte providers and their desire to uphold the moral status of the embryo (Crowley, 2009; Zacher, 2011) www.FeminstChoosingLife.org) The case was dismissed in 2012 on grounds that the state was not in violation of any regulations.
In 2013, California State Assemblyperson Susan Bonilla introduced a bill (AB926) to provide compensation to oocyte providers for SCR in an attempt to reverse the current state laws that prohibit payment beyond that for medical expenses as instituted by the California Institute for Regenerative Medicine (CIRM). Though the bill received bipartisan support, Governor Gerry Brown vetoed the bill, saying that “Not everything in life is for sale, nor should it be (Lifscher, 2013).” The result is that researchers funded by CIRM are bound by payment restrictions and cannot utilize hESC lines that were derived from embryos created with oocytes in which the oocyte provider was paid for services. The derivation and use of hESCs from cloned five-day blastocysts is but one example in SCR of the complicated network of policies that stem cell researchers must navigate (Tachibana et al., 2013; Pollack, 2013). Because the techniques involved in stem cell science are not located within one entity, cells move across state lines and from fertility center to lab, presenting challenges for ethical oversight (Kahn & Mastroianni, 2004). Although Shoukhrat Mitalipov’s research team, the first to successfully clone human embryos for SCR, is eager to share their hESC lines with other researchers, many will not be permitted to use them because some funding sources prohibit the use of cell lines created through oocyte compensation schemes. Because of California’s state law that bans compensation for oocyte provision, researchers funded by CIRM cannot use Mitalipov’s cell lines (Cyranoski, 2013). Because these lines are off limits to some with state and federal funding, the divide between privately and publicly funded research will only continue to grow. Perhaps more problematic, is that these hESCs lines can not be part of the US National Institutes of Health (NIH) stem cell registry because of the payments made to the oocyte providers. Given that many of the 200 hESCs cell lines in this registry fail to meet the informed consent regulations might mean that many of these lines were created using biomaterials from providers who received compensation as third party actors at fertility centers, creating a lack of consistency in regulatory oversight (Kaiser, 2013).
Interested in moving SCR in California forward, Bonilla argued that it is common practice and law to compensate medical research volunteers for their time, trouble, inconvenience, and potential health risk, an approach that has been discussed by feminist and social justice scholars (Benjamin, 2013a; Ballantyne & de Lacey, 2008). The ASRM legislative advocate lobbied for the California bill. Their interest in this bill was based on claims that prohibiting compensation to oocyte providers in the SCR sector hinders infertility research that could benefit women who, as a consequence of cancer prevention and treatment practices, are currently in need of assisted reproductive technologies (Gutierrez, 2013; Reuter, 2013).
The claim that egg providers for SCR are similar to medical research volunteers is a stretch, as egg provision in SCR seeks to create embryos not only for reproductive purposes, but for the study of basic science related to human development and regenerative medicine. Furthermore, unlike medical research subjects participating in clinical trials, the health of the oocyte provider in this context is not monitored once the eggs are obtained.
Furthermore, to argue that families living with cancer, or cancer risk, could benefit from such a bill, potentially places these very individuals at increased risk of cancer. According to ASRM, cancer survivors could benefit from advances in ART technology as a result of investment in SCR, as chemotherapy and prophylactic surgery can leave them infertile. However, most ARTs involve hormone stimulation that could increase their cancer risk. These concerns are supported by a handful of studies demonstrating a correlation between exogenous hormone administration for infertility at young age and increased cancer risk (Stewart, 2012; Stein, 2011). Though these studies are based on women with a history of infertility, the lack of data on fertile providers leaves cancer risk an open question, especially in light of the fact that providers are not systematically screened for cancer risk.
Some of the opposition to the standing New York policy and the proposed California Bonilla Bill for compensation for oocyte provision for research centers on the informed consent process and the ways in which it may minimize, exclude, or provide unclear language about potential harm. However, in New York, the informed consent forms underwent several rounds of revision by the members of the Empire State Stem Cell Ethics Committee before being approved (NYSTEM, 2012). The resulting model for informed consent is seen by some as a step in the right direction because it highlights the lack of data and lists both physical and psychological risks. The lack of data mentioned in these forms highlights the need for long-term studies on oocyte provider health. Unlike the UK, which has opted to track oocyte providers and provide modest payment and egg sharing schemes, the US has no national registry of providers, nor plans to establish a federally funded database on long-term effects of hormone administration. Despite this lack of data, the International Society for Stem Cell Research published a position statement in Cell Stem Cell in support of modest compensation for oocyte provision where undue inducement can be avoided (Haimes, et al., 2013)
This lack of federal oversight on oocyte provider health has resulted in grassroots efforts and lobbying for regulation and oversight of the ovarian stimulation protocol and compensation policies at both the federal and state level. In New York, a bill that would require pharmacists to distribute Lupron, an ovarian stimulation protocol drug, with the following warning label: “Caution: This drug could cause adverse reactions including, but not limited to heart attacks, diabetes, convulsions, excessive bleeding, and could lead to death” has been deliberated by both the NY Senate consumer protections and affairs committee and the higher education committee, with a decision still pending as of January 2012 (Open Legislation, 2012).
Though bone marrow and oocyte compensation policies may respond to community need by promoting diverse and equitable representation of participants and stem cell products, it can be argued that these policies propagate injustice. Opponents of payment for tissues for SCR claim that the compensation schemes described here may reaffirm the very disparity they seek to minimize. They argue that by providing compensation for human tissues in a society with an inequitable distribution of resources, we remove the option of “choice” and create scenarios where the disadvantaged must sell their bodily tissues and cells to gain the same privileges of those who seek these disenfranchised bodies as sources of biological goods (Chamany, 2011; Hyun, 2006; Ikemoto, 2009;Roberts, 2009; Park, 2012; Haimes, 2012). These scholars and activists are concerned that disproportionate health risk is being outsourced to marginalized populations for the benefit of those with privilege (Anonymous, 2012). This is particularly problematic in the case of New York, where public funding is supporting the advancement of SCR without a simultaneous investment in oocyte provider health research.
Furthermore, it is unlikely that the drugs or therapies associated with this research will be immediately accessible to the mainstream public given laws like that of the Bayh-Dole Act. This law and others permit the use of public funding for research that results in the commercialization of products of that research through the issuance of patents on new technologies, protocols, and products. Before Bayh-Dole, all federally funded research and discoveries belonged to the public sector, but since its enactment, many companies seek to fund basic research using public funding through academic collaborations as they also receive tax incentives to do so (Ikemoto, 2009).
It should be of note that with public funding (NIH) and advances in stem cell research and design, a three dimensional model of a female reproductive system has been created on a chip. Evatar consists of 3-D models of five reproductive organs: ovaries, fallopian tubes, the uterus, cervix and vagina, in addition to liver. The model is designed to address the influence of substances, including hormones, drugs, and environmental exposures on the body (NIH, 2017).
Science, Gendered Stereotypes, and the Value of Bodily Goods
Feminist responses to egg provision for SCR critically evaluate how historically marginalized bodies are limited in their ability to participate in, access, and direct biomedical and scientific research. The view of women in science and society is reflected in the value placed on tissues and cells that are sourced from female bodies, and the limits placed on women’s agency and autonomy as it pertains to bodily labor. The gender inequity in science, biomedical research, and labor elicits a range of responses designed to bridge the gap. Most importantly, there is no singular feminist response. The following section represents a range of different perspectives on oocyte provision and, more broadly, the value of bodily tissue and the ways in which gender influences value.
In 1983, scientists Schatten and Schatten published an essay, “The Energetic Egg” that details molecular research and attitudes regarding the oocyte’s role in fertilization. Scientific discussion as far back at the 1800s recognized the importance of the egg in reproduction, however, in the public eye it was described as unimportant, subordinate, passive, and inferior (Gross, 1998). Gradually discourse shifted to descriptions of eggs as extremely important, exceptional, and special. Schatten and Schatten reject portrayals of the egg as an expression of the passive female body. In their essay, they highlight how the egg is actively involved in the process of embryogenesis, from the secretion of chemical signals to attract sperm, to the production of factors essential for the DNA reprogramming essential for pluripotency, and ultimately the generation of energy required for rapid cell division in early embryogenesis through mitochondrial contribution (Schatten & Schatten, 1983; Gurdon, 2009). Gerald Schatten who continued to investigate the powerful role of oocyte reprogramming factors in human cloning and embryogenesis cautioned restraint in the use of reproductive technologies. He called for a “ARTsilomar,” harkening back to the conference of 1975 when scientists convened and decided to place a one-year moratorium on recombinant DNA technology until more was known about health and environmental risks (Lenzen-Schulte, 2003).
While Schatten and Schatten criticized those that describe the egg as “passive” and “welcoming,” feminist scholarship extended this criticism. Emily Martin, a feminist anthropologist, analyzed medical and biology textbooks and found numerous portrayals of gendered stereotypes. She contends that because science is a male-dominated field, men are the creators and perpetrators of patriarchal stereotypes about women and men, and subsequently, the egg and sperm (Martin, 1991). Despite the redress that Schatten and Schatten claim was accepted by the scientific community, many textbooks continue to describe fertilization as a male-dominated process with the sperm all-important and the egg a welcoming recipient, thereby reifying the gender stereotypes common to much of science (Beldecos, 1988). In addition, depictions of processes associated with the female body continue to present females as the weaker and more passive sex. This is particularly true in describing female reproductive biology:
“By extolling the female cycle as a productive enterprise, menstruation must necessarily be viewed as failure. Medical texts describe menstruation as ‘debris’ of the uteri