Organoids and the biomedical pursuit of human models in vitro

by Dr. Sara Bea - Project Alumna

“Inside every stem cell is an organ waiting to happen—biologists have known this for generations. But only recently have they learned how readily that potential can be unlocked in culture” – Eisenstein 2018, 19

Organoids are three-dimensional (3D) assemblages of stem cells that mimic the architecture and functionality of a human organ in vivo. These 3D cellular cultures can be grown in vitro and are used as model systems for human biology and medicine. In the past ten years, organoid research has increased exponentiality both in scope and hype; organoids were the method of the year in Nature in 2018 and were featured as special issues in Science in 2019 and Development in 2017.

The boom of organoids as cell-based biotechnology and powerful tools rests on their ability to provide human-specific models of disease and development. Human organoids are thus said to bridge the gap between animal models and human beings, as a matter of fact, organoids cast into high relief the many inadequacies of animal models: species differences and poor correspondence as well as ethical issues regarding animal experimentation. The message is that when it comes to the study of human disease and development, there is simply nothing like a human to act as a human model. Since organoids can be derived from human pluripotent stem cells (hPSC), both from induced pluripotent stem cells (iPSC) and adult stem cells (AdSC), the ethical controversies surrounding the use of embryonic stem cells (ESC) cease to apply and the privileges of personalised medicine are emphasised.

In contrast with two-dimensional (2D) cultures, cell lines often derived from patients’ biopsies, stem cell-based organoids offer higher levels of physiological complexity, dynamism and cell functionality and can be kept stable for longer. Living biobanks of patient-derived organoids stand as a great resource for biomedical research and the pharmaceutical research community.

These mini versions of human organs provide unprecedented human specificity and accuracy, and in some cases the visibility of biological process that were inaccessible and lay hidden otherwise. For example, real-time early development or embryogenesis in mammals unlike in egg-laying models was not directly observable, with organoids it is possible to study stem cells self-organising and recapitulating organogenic processes live. These insights are invaluable for basic science and so the claims brought about are profound: “we are digging deeper, little by little, into the molecular traits that make us unique, a long and challenging journey to reach the core of understanding about human evolution and human origins.” ¹ Organoids coupled with state-of-the-arts live imaging techniques render visible, for the first time, human development in real time – special attention has been given to the analysis of human brain development and how it differs from that of other animals. ²

Expanding the body of knowledge in basic science is in and of itself a legitimate application of organoids, nevertheless, their promissory value seems to lie in their capacity to translate basic science insights into actual clinical therapies. One powerful argument for channelling more resources to organoid research is that it enables a better understanding of human genetic diversity and associated influence on disease and drug response than animal models. Organoid research is widely applied for disease modelling and drug screening, as they enable a deeper understanding of human-specific diseases such as cancer, genetic disorders, and infectious diseases. About the latter, organoid-based research established a causal connection between zika virus and microcephaly in new-borns ³, and more recently organoids are also used to model human response to SARS-CoV2 and to test therapeutic compounds to block the entrance of the virus. ⁴

The manifold applications of hPSC-organoids materialise and intensify the longstanding promises of regenerative medicine – personalised medicine, precision diagnostics and tailor-made therapeutics – and manifest their potential to revolutionise the study of disease. It is with this grand endpoint in sight that the existing limitations of organoid biotechnologies are thoroughly scrutinised. Their size remains small and the maturity and functionality of cells insufficient, this means that the possibilities for scalability and standardisation require to address many technical challenges to do with the reliability and reproducibility of organoid cultures. If organoids are to stand as patient avatars and surrogate human organ systems capable of accelerating therapeutics, then the level of correspondence between in vitro organoid and in vivo tissue remains crucial.

Building better human models in vitro require organoids with a higher degree of cellular complexity and increased reproducibility; both ends can sometimes clash and reconciling them in the lab is a matter of delicate balance. To date, the organoids generated have succeeded in assembling a variety of cells that show a degree of morphological properties and functional differentiation representative of the in vivo organ in question. A major drawback of organoids is their lack of blood flow or vascularisation, without it the complexity of their architecture and functionality stalls. Achieving organ maturity is key and modulates the scope and extent of applications in disease modelling, toxicological screening, and regenerative therapeutics. Engrafting organoids onto a host animal provides in vivo vascularisation and has been shown to improve organoid function. However, the road ahead to build better human models is paved by advances in bioengineering and biomaterials that aim to provide an engineered vascular system with fluid flow: organoid growth and perfusion would be achieved with microfluidic platforms such as organs-on-a-chip and bioreactor technologies.

Organoid research is still in its infancy, organoids remain imperfect human models and the difficulty of in vivo-in vitro correspondence endures. For stem cells undoubtedly show their capacity for self-assembling and self-organising in culture as in nature, alas the processes that guide their development are yet to be fully understood. Robust protocols are required for key developmental processes that regulate human organ assembly. And the crux of the matter is that the existing knowledge about cellular differentiation and human developmental processes has been derived from animal models which as organoids throw into stark relief, are poorly equipped to grasp the specificity of the human. Getting closer to the human with models requires strengthening the basic science and deciphering human developmental biology. This is no mean feat considering that the contemporary biomedical landscape is inflected by an ethos of translatability and a culture of impact that prioritises end-products and biotechnologies with clinical applicability. This project tracks the biomedical pursuit of (more) human models and moving across human and animal domains attends to both in vitro innovations – organoid systems – and in vivo models – interspecies research. ⁵ The inquiry will shed light into how the ongoing shifts, additions, and disruptions alter the biomedical research infrastructure as we know it and elucidate the implications for the laboratory, the clinic, the animal, and the human body.

1. Wu and Belmonte, 2016. Stem Cells: A Renaissance in Human Biology Research. Cell, Vol. 165, Issue 7: 1572-1585→
2. TEDx Talks, Growing Mini Brains to Discover What Makes Us Human | Madeline Lancaster | TEDxCERN. [https://www.youtube.com/watch?v=EjiWRINEatQ]→
3. Qian et al., 2017, Using Brain Organoids to Understand Zika Virus-Induced Microcephaly.” Development, Vol. 144, Issue 6: 952-957.→
4. Monteil et al., 2020, Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2.” Cell, Vol. 181, Issue 4: 905-913.→
5. Hinterberger and Bea, 2021. Cells, animals, and human subjects: regulating interspecies biomedical research. In The Cambridge Handbook of Health Research Regulation. Cambridge: Cambridge University Press→