A Handbook of Bioethical Considerations Regarding Nascent Human Beings and Their Cells (Handbook II)

This is Issue 10 in CLI’s On Science Series. This handbook is a companion to “Handbook of Nascent Human Beings: A Visual Aid for Understanding the Science and Experimentation (Handbook I)“

Introduction

The purpose of this handbook is to provide a useful reference guide to understanding ethical and moral implications for scientific experimentation involving nascent human beings and cells derived from nascent human beings.  In particular, the attributes of nascent human beings and cells derived from them are presented in the context of their moral significance and bioethics considerations regarding the permissibility of their use in biomedical research.

I. Human Gametes (Egg and Sperm)

Moral Status:  Both oocytes and sperm are alive.  They take up chemical energy and turn it into the important cellular work of human reproduction.  However, they themselves are not human beings.  In the instant of their existence, their half-complement of human DNA is insufficient to achieve the constituents, properties, and activities that define single-celled nascent human beings.  In fact, independently, gamete cells do not even divide, which is an essential attribute of nascent human beings.  Therefore, there are no concerns regarding the intrinsic moral status of either natural or bioengineered human gametes themselves for use in experimentation.  However, important issues of moral status do arise if gametes are fused to conceive human beings (See Handbook of Nascent Human Beings: A Visual Aid for Understanding the Science and Experimentation. Available at https://lozierinstitute.org/handbook-of-nascent-human-beings/. Henceforth “Handbook I.”).

Bioethics Considerations:  Bioethics considerations for experimentation with natural gamete cells removed from human beings all relate to respect for and treatment of the donor human beings.  The same well-established bioethical guidelines, regulations, and laws for the removal and use of tissues, organs, and cells from human beings who are legally adults apply to the removal and use of their gametes.  Foundational bioethical principles are informed consent; noncoerced donation; no undue pain, injury, or death; and scientifically sound experimentation with the donor’s cells.  Because of documented health risks to women during ovarian stimulation and egg retrieval, recruitment of donors for the sole purpose of experimentation with their harvested eggs continues to be a significant issue of bioethics debate.

In the usual cases in which donors are not the legal age for consent, the same bioethical principles apply for their respect and protection, ensured by their parents or legal guardians.  Because of the sanctity of human life, bioethics considerations even apply to the removal and use of gamete cells from human beings who are deceased at the time of removal.  In the absence of living permissions from deceased human beings themselves, their parents, their legal guardians, or other authorized family members must grant permission for removal and use of gamete cells for purposes of assisted reproduction (e.g., in vitro fertilization) or experimentation.

II. Cells from Nascent Human Beings

Moral Status:  The intrinsic moral status of cells removed from a human being is only an issue at very early embryonic developmental ages of nascent human beings (See Handbook I, “Nascent Human Beings Conceived by Natural Processes”).  Similar to the natural origin of multiple births like twinning, one or more cells in a 2-4 cell stage embryo may be, or become, an actively developing human being after removal.  However, after a few sequential divisions of single-celled human beings, the cell differentiation process of human development begins forming functional human attributes.  Functional attributes across distinct cell types are the precursors for the formation of the different organs and tissues of the human body at more mature ages of development.  At later stages in the development and maturation of human beings, removed cells are not human beings, because, in the instant of their existence, they lack the constituents, properties, and activities that define single-celled nascent human beings.

Bioethics Considerations:  Bioethics considerations for experimentation with either natural cells removed from human beings or their cell derivatives all relate to respect for and treatment of the donor human beings.  There are well-established bioethical guidelines, regulations, and laws for the removal and use of tissues, organs, and cells from human beings who are legally adult human beings.  Foundational bioethical principles are informed consent; noncoerced donation; no undue pain, injury, or death; and scientifically sound experimentation with donated cells.  The same bioethical principles apply for the respect and protection of human being cell donors who are legally minors, ensured by their parents or legal guardians.  Because of the sanctity of human life, bioethics considerations even apply to the removal and use of cells from human beings who are deceased at the time of removal.  In the absence of living permissions from deceased human beings themselves, their parents, their legal guardians, or other authorized family members must grant permission for removal and use of their cells, tissues, or organs for medical applications or experimentation.

III.A. Zygotic Nascent Human Beings

Moral Status:  At the moment of their conception by fertilization, new human beings are zygotes, and they are alive.  They take up chemical energy from their environment and turn it into the unique cell work of life, self-duplication, which only living cells can do.  They have a full-complement human genome (DNA) activated by the unique cytoplasm of the egg for spontaneous and independent human development.  In the instant of their conception, their full-complement of human DNA is sufficient to achieve the constituents, properties, and activities that define single-celled nascent living human beings.

Nascent human beings conceived by artificial processes (e.g., in vitro fertilization, IVF) who are of zygotic age differ from naturally conceived human beings only in where and how their conception occurred.  In the case of IVF, fertilization occurs in vitro, i.e., outside of the womb, “in a test tube” or “in a petri dish.”  Scientists have also discovered that introduction of a nucleus – isolated from a human somatic cell with a full-complement of genomic DNA – into the cytoplasm of an unfertilized egg, whose own half-complement of DNA was removed, is biologically equivalent to fertilization.  Therefore, the nascent human beings conceived by such human “cloning” experimentation are morally equivalent to those conceived by natural fertilization or IVF.  This biological equivalency is the basis for grave concerns about moral trespasses against both natural and bioengineered zygotic nascent human beings when they are used for experimentation.

There are many scientists who advocate for therapeutic cloning and even germline genetic engineering (See Handbook I, “Therapeutic Cloning” and “Genetic Engineering,” respectively), if experimentation is limited to the purpose of prevention or treatment of genetic diseases.  However, scientists must carefully consider which genes are less valued, worth changing, and/or which human lives need to be “fixed” if such genes do or do not exist. In addition, few express comfort with germline genetic engineering experimentation that has the motivation of alteration or augmentation of human attributes not defined as disease or disorder (e.g., enhancement genes or “designer genes”).  The suggestion of human attribute experimentation and future cosmetic interventions provokes strong cautionary warnings and prohibitive responses.  The idea of pre-ordaining the biological make-up and character of human beings from their very conception is abhorrent to the moral and religious principles of many people regarding what is permissible for one human being to do to another.  Even germline genetic engineering experimentation with the stated goal of preventing disease is problematic or not allowable within some moral and religious ideologies.

Bioethics Considerations:  There are two main issues considered in discussions of the bioethics of experimentation with zygotic nascent human beings.  The first issue focuses on the potential for future harm to the children and adults who are the offspring of germline genetic engineering experiments.  Of course, this issue is predicated on the position that the experimentation is morally and ethically permissible.  There are known and well-acknowledged potential dangers of gene editing, whether somatic or germline.  A common concern is harmful “off-target effects.”  These are adverse side effects that can emerge because of unintended gene-editing events that occur at other places in a genetically-engineered cell’s DNA.  In addition to these well-appreciated potential harmful effects, there are likely to be other biological and technical problems that will only become apparent during the experimentation itself or later if new germline-editing procedures are approved for wider usage.  Many of these will be directly caused by the intended gene edit.

The second bioethics consideration for experimentation with zygotic nascent human beings focuses on the inherent suffering and ultimate death of the human being undergoing gene editing, a currently overlooked or disregarded issue by scientist groups that advocate for the experimentation.  Human subjects research with children and adults has well-developed bioethics principles and regulations.  Generally, throughout biomedical research, experimentation with child human beings and adult human beings is required by law or research institutions’ guidelines to meet the following requirements:

• Informed consent (by the research subject or their legal guardian in the case of child human beings or disabled human beings);
• No undue pain, suffering, injury (physical or mental), or death; and
• Scientifically sound experimentation

Although proponents of experimentation with zygotic nascent human beings argue that principles 1 and 3 are met, there can be no argument that principle 2 is not.  As a result, government, private, and industry institutions that conduct and promote experimentation with zygotic nascent human beings suspend or ignore principle 2 in their bioethics guidelines.

III.B. Embryonic Nascent Human Beings

Moral Status: The embryonic stage of a developing human being is from day 0 through 8 weeks after sperm-egg fusion (fertilization).  When embryonic human beings conceived by IVF are donated for research and supported with conditions for continued development in the laboratory, scientists do not call them embryos.  They call them “embryoid bodies.”  Similarly disguising terms are used for the cloned embryonic human beings conceived from clonal human embryonic stem cell (hESC) lines and induced pluripotent stem cell (iPSC) lines (See Handbook I, “Embryonic Stem Cells and Embryonic Stem Cell Lines,” and “Induced Pluripotent Stem Cells,” respectively).  They are now referred to as “induced blastoids (iBlastoids)” or “blastocyst-like structures” or “embryoids” or “synthetic embryos” or “embryo models” (See Handbook I, “Human Embryo Models [Blastoids]”).  The change in naming does not cause a change in the moral worth of embryonic human beings conceived by these bioengineering methods.  If single-celled zygotic nascent human beings on day 1 of sperm-egg fusion are living human beings, then embryonic human beings at any stage certainly are, too; and there is no question of their moral worth as human beings given that it is precisely this special character, and only this unique character, that motivates the scientists who seek to experiment on them.

Experimentation with embryonic human beings presents formidable moral and philosophical questions about the nature of humanness.  It is forcing thinkers in religion, legal theory, social science, theology, philosophy, ethics, and biomedical science to confront the prospect of human-made creatures previously only imagined in the old mythologies of the world, including human-animal chimeras.  Concerns about human-animal chimera experiments with embryonic human beings were first raised during attempts to conceive cloned embryonic humans as sources for production of hESC lines.  Human cloning required that women donate eggs.  A significant public backlash was met because of the evident potential for exploitation of women egg donors and risks of significant acute and long-term injury to them.  So, scientists tried using the eggs of animals, like cows, to clone chimeric embryos using human cell nuclei.

The incompatibility between two different species (human and animal) prevented the successful conception of cloned human-animal chimeric embryos.  However, now with the achievement of successful manipulated conceptions of both cloned embryonic animals (e.g., mice, monkeys) and cloned embryonic human beings, human-animal chimera experimentation has re-appeared in reputable scientific journals.  Although human-animal zygotes proved defective for development, scientists have found that human iPSCs will integrate and develop within the embryos of mice and monkeys.  Scientists propose to pursue this human-monkey chimeric research to learn if they can grow human organs for transplantation medicine in monkeys, despite advancements and ethical alternatives using tissue engineering and regenerative medicine.  Imagined macabre futures could become realities when pursuing human-animal chimeras.  While many might be willing to accept a life-saving human kidney or liver grown in a monkey, none would seem to ever need or want a brain of the same origin or the disturbing possibility of human-animal chimeras producing offspring.  The troubling existential question is, “How will human beings treat monkeys born with human brains…and how will they treat us?”

Bioethics Considerations:  The bioethics considerations for experimentation with embryonic human beings may feel daunting because of their often-argued entwinement with IVF and assisted reproduction.  However, the characterization of “entwinement” serves proponents of the experimentation who wish to obscure the essential bioethics trespass.  They attempt to justify the experimentation by the argument that using donated unwanted embryonic human beings, conceived by IVF, for research turns the moral trespass of their death and destruction into a public good by potentially leading to new medical breakthroughs.  This argument, which is made and accepted by many people, would never be acceptable if the experimental subjects were child human beings.  Though current bioethics practice does not extend this impermissibility to embryonic human beings, there is no moral basis for humanity that can reasonably justify such a dereliction of respectfulness and humility.

Proponents of experimentation with embryonic human beings authorized by their parents make the argument that using them for research is better than discarding them.  This utilitarian bioethics view is in conflict with the moral principle of respectful regard for human life.  Instead of discarding embryonic human beings, some IVF clinics transfer them to their families who have burial ceremonies for them after they are thawed and expire. Some couples choose a life-saving option and donate their “extra” embryos to another family for adoption (also known as “snowflake babies”).  The moral principles do not focus on what might be gained by society, but instead on what is lost by society when a process is permitted that has the purpose of gaining benefits from the deaths of weaker human beings.

The renaming of embryonic human beings with scientific terms like embryoid body, iBlastoid, blastocyst-like structures, embryoid, synthetic embryo or embryo model is a well-known form of dehumanization.  This is a common method of evading bioethics scrutiny.  In the bioethics of human subjects research, humanness is the essential quality of focus.  The renaming gives non-scientists the impression that no human subjects are involved in or adversely affected by the experimentation.  It also lulls many practicing scientists into a false conviction of ethically responsible science, when in fact tens of thousands of living human beings are being killed and discarded without ceremony in their research.  In the case of the new science of cloned “blastoid” experimentation, which avoids donation of embryonic human beings conceived by IVF, scientists can now create an endless number of human beings for the specific purpose of human exploitation, manipulation, and destruction.

A prime indication of the powerful effect that dehumanization can wreak on responsible ethical conduct is now very apparent.  With the reports of successful production of cloned embryonic human beings (i.e., blastoids), some scientists have called to rescind earlier regulations that previously prohibited scientists from allowing embryonic human beings to develop beyond a “14-day” limit.  The new techniques improve the ability to experimentally manipulate cloned embryonic human beings and can produce unlimited numbers of them.  With these significant advances in technology, scientists now want to allow the embryonic human beings conceived by their experimentation to develop past the previous 14-day limit (See Heipel, E, “ISSCR’s Reversal of the 14-Day Rule.” June 2021. Available at https://lozierinstitute.org/isscrs-reversal-of-the-14-day-rule/).

The ensuing controversy will certainly see proponents continue to focus the debate on the false dichotomy that whatever new stopping time they extort from the public, it is better than going even further.  The same strategy resulted in the previous 14-day limit, when in fact both morally and by current bioethics principles of human subject research, only a 0-day restriction should be permissible (For more information, see Sherley, JL, “Closing the Slippery Slope from a 14-Day Rule to an N-Day Rule.” Nov 2021. Available at https://lozierinstitute.org/closing-the-slippery-slope-from-a-14-day-rule-to-an-n-day-rule/).

IV. Human Embryonic Stem Cells (hESCs)

Moral Status:  The moral trespass of experimentation with hESCs occurs in the instant of their production.  Embryonic nascent human beings of blastula age (3-5 days post-fertilization) are living human beings, who merit the same respect and care as human beings at later ages of their development and lives.

Certainly, tetraploid complementation with hESCs (See Handbook I, “Embryonic Stem Cell [hESC] Research.”) is a clear moral trespass.  The procedure brings about the conception of an embryonic nascent human being, whose creation continues a chain of human destruction and exploitation.  The source of the required complementing tetraploid embryo is another sacrificed zygotic nascent human being.  As such, even if the justification given were assisted reproduction, it would have a morally repugnant foundation.

Bioethics Considerations:  Thus far, scientists have not developed a procedure for removing the cells required to make hESCs from embryonic nascent human beings without causing their death.  To address the moral trespass of hESC production, some scientists suggested producing hESCs with very early cells removed after only two divisions of newly-conceived embryonic nascent human beings.  In most cases, the embryonic nascent human beings losing the cell could continue with successful development and life.  However, the cells extracted at this age of development proved not to be very effective for producing hESCs.  So, this strategy was abandoned.  This approach also did not address the violation of the fundamental requirement of informed consent for the responsible ethical conduct of human subjects research.

Human ESCs have been the subject of major public sociopolitical, religious, and research bioethics debates on the moral and ethical permissibility of producing them and using them.  Despite efforts to protect embryonic nascent human beings from death in the hESC research industry, currently, private institutions are generally free to conduct this form of human experimentation; and many government-funded research institutions have developed guidelines and regulations for their continued production and usage of hESCs.

Tetraploid complementation with human pluripotent stem cells has been discussed in the scientific and bioethics literature, but it has not gained much traction as a focus of human experimentation.  The reasons for this state of progress are likely to be both societal and scientific.  In the first case, religious and social objections could be expected given the Frankensteinian character of tetraploid complementation experiments.  However, it is more likely that scientific interest has been dampened because of the requirement of uterine implantation for effective fetal development.

The muted history and experience of human tetraploid complementation contrasts the current excitement over the newest technologies for producing cloned embryonic nascent human beings (i.e., blastoids).  Human beings produced by tetraploid complementation would also be human clones.  The newer scientific techniques have another feature, the ability to genetically-engineer the different parts of assembled cloned embryonic nascent human beings.  This scientific manipulation capability is a major motivation of scientific agencies that have introduced new bioethics guidelines that extend the age of experimentation with embryonic nascent human beings.  The new guidelines insidiously revive interest in human tetraploid complementation experimentation as well (For more information, see https://lozierinstitute.org/isscrs-reversal-of-the-14-day-rule/ and https://lozierinstitute.org/closing-the-slippery-slope-from-a-14-day-rule-to-an-n-day-rule/.)

V. Human Induced Pluripotent Stem Cells (hiPSCs)

Moral Status:  Nobel Laureate Professor Shinya Yamanaka describes his desire to find genes that could produce pluripotent cells for research without requiring the destruction of embryonic nascent human beings as the motivation for his work.  He achieved his purpose.  Human iPSCs are derived from the mature somatic cells from informed consenting adult human beings or from child human beings with the consent of their parents or legal guardians.  Therefore, their production presents no moral concerns.  So, the current use of the same cells, hiPSCs, to produce cloned embryonic nascent human beings, who are conceived and sacrificed for human experimentation, is an appalling irony that reveals the base motivation of scientists to persistently pursue such illicit human subjects research.  Like hESCs, hiPSCs have also been discussed in the context of the moral trespass of using them for tetraploid complementation.

Bioethics Considerations:  Until the reports of their use to conceive cloned embryonic nascent human beings (i.e., blastoids), there were no bioethics concerns for the use of iPSCs.  They are derived from the mature somatic cells of adult human beings or child human beings with their informed consent or that of their legal guardians, respectively.  However, their ironic use for producing cloned embryonic nascent human beings, and the future potential for their use in tetraploid complementation research, moves them right into the main arena of the now emerging bioethics debate over the permissibility of human embryo experimentation with basically zero limits on how far they may be allowed to mature for laboratory experiments.

VI. Human Metakaryote Stem Cells

Moral Status:  Like other tissue stem cells (See VII below.), metakaryote stem cells are not living human beings; and they do not have the pluripotent properties of embryonic stem cells (See Handbook I, “Metakaryote Stem Cells.”).  Experimentation with them does not present moral issues.  The only moral issues that might arise is in how they are sourced and used.  Thus far, scientists involved in this early research have not sourced them from electively aborted fetal human beings.  Instead, their experimental analyses were performed with mouse embryos, metakaryote stem cells found in cultures of human cancer cell lines, and human tissues from spontaneous fetal miscarriages donated for biomedical research with informed consent.

Bioethics Considerations:  As for other tissue stem cells, the bioethics considerations for human metakaryote stem cell experimentation are the aforementioned principles for the responsible ethics in the conduct of research with human subjects.  The principles are not relevant to the cells themselves, because they are not living human beings.  However, they do apply to the respectful and humane treatment of the human beings who donate them.

VII. Human Tissue Stem Cells

Moral Status:  Tissue stem cells (e.g., adult stem cells) are not living human beings.  As such, experimentation with them does not present moral issues.  The only moral issues that might arise are in how they are sourced and used.  Thus far, scientists have not bent them into a moral irony as they have with iPSCs, whose founding vision was as a moral alternative to hESCs.

Bioethics Considerations:  The bioethics considerations for human tissue stem cell experimentation are the aforementioned principles for the responsible ethics in the conduct of research with human subjects.  The principles are not relevant to the cells themselves, because they are not living human beings.  However, they do apply to the respectful and humane treatment of the human beings who donate them.

VIII. Human Organoids

Moral Status:  Organoids are not living human beings; and, therefore, most human organoid experimentation does not provoke moral concerns unless their cell source includes hESCs.  However, human cerebral organoids continue to give pause for grave concern.  They evoke a future vision of experimentation with engineered, highly developed human cerebral cortices, the organs of human cognition and personality expression.  If the accepted essence of humanness assigned to human beings is cerebral cortices and their extended supporting anatomical body, whether or not developed, then the essential moral question at issue is whether such human cortices are members of our humanity.

The biological properties of recently described gastruloids, human embryos grown to the gastrula stage of human development (See Handbook I, “Human Embryo Models [Blastoids].”), are not yet fully known.  They may be essentially embryonic nascent human beings conceived in laboratory tubes by scientists similar to iBlastoids.  If this turns out to be their biological nature, then human gastruloid experimentation will trespass against the same moral tenets that require human respect for other embryonic nascent human beings and their exception from human experimentation.

Bioethics Considerations:  For the most part, for experimentation with human organoids that were not developed with hESCs, the only bioethics considerations are responsible sourcing of human cells and tissues with informed consent and ethical treatment of donors.  Donors include those who donate their tissues for direct organoid formation or those whose donated cells were used to make iPSCs for organoid formation.

In the case of human cerebral cortex organoids and gastruloids, issues of the bioethics of responsible experimentation will develop in parallel with the discussion and debate of the moral implications of this research.  To the extent that these entities are agreed to be non-human, the bioethics discussion of experimentation with them will fade accordingly.  However, as continues to be true for embryonic nascent human beings, as long as their humanness and the moral status that pertains to it holds, there will be a need for scrutiny of the bioethics guidelines developed by scientists to justify their subjection to experimentation.

James L. Sherley, M.D., Ph.D. is an associate scholar with the Charlotte Lozier Institute. Tara Sander Lee, Ph.D. is Senior Fellow and Director of Life Sciences at the Charlotte Lozier Institute.