Organoids could put an end to animal testing – 09/03/2023 – Science

A new technology for testing drugs and conducting health-related research could lead to the end of laboratory animal testing.

These are the so-called organs on chips and organoids, created in the last 15 years and which have revolutionized health research.

The methodology recreates tissues and organs in small three-dimensional models that simulate human systems, thus allowing us to observe the effects on our own organisms more effectively.

With the growing concern surrounding the ethical issues of using animal models in medicine and also the difficulty in predicting with 100% accuracy the effects based only on non-human animals —clinical research often fails precisely in moving from animal testing to or people—the new models can lessen errors and break down the barriers to moving away from experimentation.

Unlike the culture of cells in plates, used for more than a century, the new models simulate tissues, organs or parts of organs including the interactions between the different types of cells in three-dimensional structures or in interconnected chips.

The organs on chips are connected to a system, for example the vascular one, while the cells are arranged as they would be in the real organ. It is as if it were a network of connections, similar to what happens in cell phone electronic chips, but where the communication paths are formed by groups of cells that interact — for example, the path of a secreted protein in the cell to another tissue.

The patent was created by Donald Ingber, then director of the Wyss Institute at Harvard University, in 2010, with a successful lung-on-chip model. Since then, several researches have advanced to create other organs and systems and have helped to understand the molecular pathways of fluid exchange and biochemical interactions between cells.

Organoids are three-dimensional models of living cells that have characteristics observed in parts of human organs or tissues. Unlike cells grown in plates, which have only a thin, flat layer (in slides analyzed under a microscope), organoids are like a “slice of cake”, showing height, depth and width. They help to preserve functions present in the tissues of origin, such as the different layers (dermis, vessels, muscles, etc.) of the organs.

This makes it possible, for example, to “turn on and off” protein expressions on cell surfaces and see how they interact with other systems.

There are several applications of organoids currently in medical research, such as the growth and treatment of tumors, embryogenesis (formation of embryonic tissues) and cell development, regeneration and immunotherapeutic studies.

For Stevens Rehen, neuroscientist and professor at the Institute of Biology at UFRJ (Federal University of Rio de Janeiro), organoids have revolutionized medical research due to their ability to express more complex phenomena between organs.

“In our laboratory, we cultivate human brain organoids from cells taken from skin biopsies or collected from the urine of volunteers and they are often used to study complex phenomena that emerge from the interaction between cells”, he says.

Rehen and his team use, in their studies at Idor (Instituto D’Or de Pesquisa e Ensino), brain organoids to assess the effects of viruses such as Zika and Sars-CoV-2 on human brain tissue and the medical potential of psychedelics .

In addition to organoids generated from reprogrammed patient cells, Rehen points out that there are also so-called PDOs (patient-derived organoids), which are grown from samples and help to understand the biology of tumors or diseases. specific.

In a publication at the beginning of February in the specialized journal Cell Stem Cell, researchers from the Department of Neurosurgery at the University of Pennsylvania (USA) demonstrated that brain organoids, when implanted in rats in the laboratory, responded successfully to light stimuli, opening a new path for the study of therapies that can recover damaged areas of the brain in humans.

Other applications of brain organoids are for research into brain damage involved in degenerative diseases such as Alzheimer’s.

The application of the new models can also be combined to unite the cellular three-dimensional model, provided by the organoids, with the communication system by channels and circuits of the chips.

In a more recent study, researchers at Massachusetts General Hospital and Brigham Women’s Hospital, in partnership with the Wyss Institute, combined an organ chip with an organoid to simulate a type of condition common in children, autosomal recessive polycystic kidney disease. (APRKD, its acronym in English). Mortality from this disease reaches 30% in early childhood.

The initial model created to analyze the expression of the mutated PKHD1 gene, related to the disease, was not successful because it was difficult to imitate the biophysical conditions of the kidneys in the organoid – the gene is only expressed when the urinary flow passes through the cells. The researchers then inserted the cells modified with the PKHD1 mutation into a chip and stimulated the cells with a simulated urine stream.

The result was the visualization of two molecules involved in the expression of the mutagenic gene on the cell surface and which may serve as targets for new therapies.

In Brazil, Rehen’s team recently published a study to understand the biological and chemical conditions involved in the process of cellular degeneration in Alzheimer’s. According to the study, the accumulation of beta-amyloid and tau proteins, already associated in the past with the early development of Alzheimer’s, could be studied in organoids derived from patients with the condition.

“This will make it possible to test the effect of new substances on the accumulation of these proteins, which can help in the development of new treatments”, he points out, noting that research of this type is still in its initial stages and the results need to be confirmed with other studies.