The bioethical challenge of organoids


Article from the Alphonsian Academy Blog

One of the most promising innovations in the field of biomedical research is the so-called organoids[1]. An organoid is a three-dimensional biological structure derived from pluripotent stem cells or differentiated cells that self-organise through cell-cell and cell-substrate/matrix interactions to recreate aspects of the architecture and function of a given organ in vitro. As early as the 1990s, the possibility of moving from classical single-layer cell cultures to structures with three-dimensional architecture was reported, but the development of this field of research has become tumultuous in the last decade due to an improvement in our ability to manipulate stem cells, a deeper understanding of the mechanisms of cell differentiation, and the introduction of innovative biomedical techniques such as 3-D printing. Starting cells can be stem cells derived from blastocyst disruption (ESCs) or stem cells taken from an adult body or induced pluripotent stem cells (iPSCs) according to the somatic cell reprogramming method first proposed by Takahashi and Yamanaka. In addition to stem cells, it is an established fact that organoids can also originate from differentiated cells, such as, for example, cholangiocytes, cells of the liver’s biliary tract. In the current state of research, organoids appear as cell aggregates of only a few centimetres in size that do not have the complex structure of natural organs, lacking among other things blood supply and innervation, but whose histological, anatomical and functional characteristics are similar to those of the corresponding organs. Today, there are different types of organoids such as the kidneys, intestines, pancreas, liver, heart, ovary, testis, retina and even the brain.

The applications of organoids are manifold.

One application that has already come into use is in the field of pharmacological and oncological research: drugs or chemotherapeutics can be tested on the organoid, limiting both the use of animal models and the use of human subjects, and although the environment of an organoid cannot be compared to that of a living organism, the organoid is closer to the situation in a living organism than classical two-dimensional cell cultures. The preparation of organoids from the cells of a certain patient could facilitate the personalisation of treatments and therapies that would be tried out on structures that can be brought back to the patient himself. Finally, organoids have been developed to study particular human diseases and to test experimental therapies on them.

A second area of application for organoids – still in its infancy – is in the field of transplant medicine and regenerative medicine in general. Organoids are considered a source of potential tissues for transplantation. Liver organoids, for example, could be used to restore liver function in patients diagnosed with metabolic liver disease. In view of the slow progress of xenotransplantation research and the difficulties arising from cadaveric donor transplants, both because of the scarcity of available organs and the debates surrounding the ascertainment of death, lately due to the too short asystole times in some countries, organoids promise to be a viable and relatively easy alternative. Remaining in the realm of the futuristic, the combination of organoid technology with gene therapy technologies could produce healthy organoids suitable for transplantation from organs of patients with genetic defects and treated with appropriate editing.

Organoids are expected to revolutionise biomedical research and therapy, but several ethical issues are already looming[2].

The question arises, first of all, as to how to regulate the relationship with cell donors participating in organoid research in relation to issues concerning ownership, patenting, commercialisation, and the storage of organoids in biobanks. Some propose resorting to the practice of anonymisation: under this practice, when a tissue is completely de-identified, it is thought to have sufficiently guaranteed donor privacy. This practice, however, may prove to be an obstacle to adequately exploiting the potential of organoids, which must be able to be linked with the personal and biological data of donors, especially when donor tissues have mutations and/or rare diseases, such as cystic fibrosis. The other model, that of informed consent, also presents difficulties because it is not easy to foresee the possible future uses of donated samples in relation to innovative technological possibilities, such as cloning, transplantation and human enhancement, and the commercial spin-offs of organoids might not be appreciated by donors who might be willing to accept their use only for research purposes and to improve their own and others’ health. Studies on gonadal and cerebral organoids raise particular problems – but we will go into them in more detail in a later intervention – because of the close relationship they maintain with the personality of the donors and the possible admixture with animal organs.

An ethical issue that is certainly not new concerns the production of pluripotent stem cells from embryonic blastocysts. Personalist morality is convinced that every human existence, from conception onwards, deserves the unconditional respect due to the person and, for this reason, does not accept that a human embryo, even an early one, can be destroyed for any purpose. On the other hand, stem cells suitable for the production of organoids can be obtained today by different and entirely legitimate routes.

Another problem is that of gastruloids. These are special organoids that do not mimic individual organs, but the developmental processes of the embryo. Gastruloids are similar to human embryos in that they contain cells from each of the three germ layers, recapitulating aspects of in vitro embryogenesis and, in particular, the process of gastrulation, a process that moves an embryo from a one-dimensional state to a multidimensional, multi-layered structure. Research on gastrulation could provide valuable information on the early development of the human embryo and the disorders associated with early pregnancy and miscarriage in the first trimester. There are, however, ethical concerns about the moral status of gastruloids and the developmental stage at which gastruloids can be allowed to mature[3]. According to some, if we deactivate the genes necessary for gastruloids to progress to more advanced stages of development, these defective gastruloids could not be qualified as embryos, but would be mere biological artefacts. In the absence of an agreed ethical qualification of the human embryo, especially the early stage embryo, it becomes difficult to answer the question of whether or not gastruloids should be classified as embryos. A similar question was addressed in Dignitas personae 30 with regard to ANT and OAR techniques as well as so-called partenotes, embryos resulting from parthenogenesis.

In discussions about the degree of maturation that human gastruloids should be allowed to reach, reference is often made to the 14-day rule, which was approved by the Warnock committee in Great Britain in 1982 and is now widely accepted internationally. Since it takes 14 days from fertilisation for the primitive stria to appear, an event of dramatic significance in the development of the embryo, in vitro cultivation of human embryos is only permitted up to that date. We cannot go into the biological and ontological aspects of the issue here, but if, on the basis of the similarities between gastruloids and human embryos, some researchers tend to apply the 14-day rule to the culture of human gastruloids in vitro, for the same reason, precisely because of the doubt as to their precise nature, we believe that human gastruloids should not be formed and that they should, in any case, receive the respect due to any form of life that is even doubtfully human[4]. Regardless of the issue of defective gastruloids, the underlying question about these studies is which project we are moving towards. It is worth recalling the reflections that seemed to sound apocalyptic and are turning out, instead, to be prophetic by Francesco Ognibene at the news of the creation of artificial embryos (‘blastoids’) of mice in the Netherlands in 2018. “It is not difficult to imagine that, once sufficient safety has been acquired on animal models, we will move on to tests on human embryos, with the foreseeable result of setting in motion a biological mechanism whose possible outcome is unknown (…) The hypothesis of the ‘blastoid’ evolving into a ‘humanoid’ is by no means remote, and reveals the ambition with which every possible ethical question is being raised: to obtain living beings created in the laboratory from beginning to end, life forms that are the integral birth of science, its works set in motion to be observed under the microscope but which cannot leave one entirely certain that one does not want to see them, sooner or later, also in the real world, arrived at the conclusion of a pregnancy and brought to life, whatever they may be.”[5]

p. Maurizio Pietro Faggioni, ofm

(free translation by Scala News, see the full original text in Italian and with footnotes on the site of the Alphonsian Academy Blog)