Organoids for Medicine
By David Prentice, PhD | March 08, 2018
by David Prentice, PhD
A recent innovation in creating model systems for studies of physiology and development has been the construction of organoids. These three-dimensional cellular structures resemble miniature organs in terms of functionality, and they can even be used to model development and differentiation and disease, as well as drug development. Besides providing superior models to study tissue organization and development, organoids can also serve as starting points for potential transplantation. Organoids are supplanting the typical in vitro cell and tissue culture two-dimensional monocultures of cells, which have been used for decades. Since native organs exist and function as three-dimensional arrangements of multiple cell types, with the architecture and interactions an essential component of function, organoids can approximate the in vivo relationship of cells within an organ. Organoid development and study has rapidly become a critical modeling science over the last few years, to the extent that organoids were chosen as the 2017 Method of the Year by Nature Methods.
Organoids are not organisms; what is constructed is not a rudimentary embryo or developing precursor that will grow into a complete, maturing embryo. The focus of organoids is development and study of only one organ system, not manufacture of a complete embryo, so the in vitro model systems avoid the ethical problems of laboratory techniques such as cloning (somatic cell nuclear transfer), three-parent embryos, creating embryos by tetraploid complementation or embryo formation via combining embryonic stem cells and trophoblast stem cells. Each of these techniques has as its goal the production of an embryo, an entire developing organism. However, there is still need for awareness of some ethical concerns in construction and use of organoids.
Organoids can be constructed in various ways in the lab. The simplest organoids can be constructed via aggregation of cells in suspension. One example is aggregation of hepatocytes into “mini-livers,” actually just 3-D monocultures in suspension that are small enough such that they survive by nutrient diffusion in the culture. These mini-livers can serve as laboratory models for liver function and as bio-artificial livers for toxicity testing, plus they may potentially be a starting platform for transplantation for liver regeneration. The laboratory of McGuckin and Forraz has shown that hepatocytes can be produced in culture from umbilical cord blood stem cells, a readily-available source of multipotent stem cells.
The source of the starting cell population is one point of ethical concern for organoids. The vast majority of current research uses induced pluripotent stem (iPS) cells or adult stem cells, but in the past there has been use of embryonic stem cells (which are derived by destruction of young human embryos.) But since iPS cells can functionally mirror embryonic stem cells, there is no need to use any ethically questionable sources. Moreover, the ability to create iPS cells from virtually any person or tissue makes it advantageous to use them for modeling, as they can be used to study a “disease in a dish” based on derivation from patients.
Under the proper conditions (sometimes by including an appropriate extracellular matrix for cell attachment and stimulation), the cells aggregate, interconnect and begin growth and development of miniature organ structures. Organoids have already shown that they can provide superior models for the study of normal as well as abnormal cell and organ physiology. The complexity of the constructs continues to improve and even amaze, as they demonstrate in vitro the functional abilities previously seen only in vivo.
Various organoid types have now been developed. As discussed in an earlier The Point Blog, some researchers have created an “artificial thymic organoid” or “thymus in a dish” that allows maturation and training of immature T-lymphocytes, preparing them to respond to specific antigens. The artificial thymic organoids could produce mature T cells starting from various blood and marrow stem cell sources.
Some scientists have developed an organoid model of the gut, while others have finessed the laboratory production of colon organoids. And making use of the flexibility inherent in organoid construction and starting cell sources, researchers have also constructed an organoid model for colorectal cancer.
Some of the most interesting organoid work has involved construction of brain organoids. Human brain organoids have been constructed that recapitulate normal early brain structure and model early brain development including differentiation of multiple cellular types and zonal cell layers for brain cortex, as well as model abnormal development including microcephaly. Such brain organoids have been extensively used to investigate Zika virus infection in the developing brain, decipher the mechanisms involved and also model potential treatments and preventative measures.
As organoid creation advances, ethical questions must be considered. Development of a liver organoid in culture seems uncomplicated, but development of a functioning brain in the laboratory does raise concerns. At some point in development, via increased size, complexity or interneural connections, does an organoid in the lab develop the potential to “think” or even develop some form of consciousness? What might be our ethical responsibilities toward such an entity? While pluripotent stem cells are not embryos, is there some point of cellular aggregation and re-organization that does require our consideration as to whether a created construct might be designated an organism from a biological and bioethical viewpoint? We need to proactively consider the bioethical implications of potential biological advances.
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