A challenge in biomedical research is determining what will happen when a human is exposed to a new disease without conducting unnecessary experiments on humans. Lab-grown organs could be the answer.
Traditionally, researchers have studied laboratory organisms including bacteria, yeast, microscopic worms, fruit flies, frogs, fish and mice, as well as cells in Petri dishes. More than a century of intensive research has led to an extraordinarily detailed understanding of many biological processes, such as how DNA controls the behavior of roughly 200 different cell types in vertebrate animals.
This work has recently led to the development of an extraordinary new tool: miniature lab-grown organs, called organoids. These lab-grown organs can be derived from human cells, and are providing incredible insight into how healthy organs function, and how diseases such as cancer and infections progress. They also provide a safe and relatively inexpensive way to identify effective drugs for general use, or for individual patients.
What Are Organoids?
An organoid is a 3D cluster of cells—typically less than a centimeter wide—in which the cells have been coaxed to organize as a group and develop into many of the cell types that are present in a mature organ. Thus far, scientists have successfully grown miniature brains, retinas, lungs, blood vessels, mammary glands, livers, kidneys, pancreases, stomachs, intestines, fallopian tubes, bladders and prostates, according to Nature Reviews Molecular Cell Biology. Hundreds or thousands of organoids can be produced at one time for large-scale studies.
The process starts with stem cells, which have the potential to grow into many or all of the different cell types in the body. In 1998, the first human stem cells were generated from 5-day-old human embryos, which raised significant ethical concerns. These issues were largely circumvented in 2007 when techniques were developed to produce stem cells from adult skin cells. Skin cells from any human donor—such as a patient in need of specialized therapy—can be collected and forced to revert to an embryonic state. This can be achieved through the expression of just four specific genes, as an article in Nature explains. It’s the equivalent of restoring a smartphone to factory settings. Biopsies from specific organs can also collect naturally occurring stem cells that can develop into a small number of cell types for that organ (e.g. lung, liver, stomach, intestine). By definition, all stem cells can divide indefinitely without losing their potential and can be frozen for future research.
Decades of research into embryonic development, genetics and cell biology are providing the tools that scientists need to coax these stem cells to become miniature lab-grown organs. For each organ type, researchers need to find the right combination of signaling molecules and growth conditions—delivered at the right time and in the right order—to get the necessary cell types in the proper proportions and appropriate positions. This is arduous work, but it is aided by the natural inclination of cell groups to self-organize as they develop. Once a successful strategy is developed, that new organoid can be added to the scientific toolkit.
What Are Organoids Useful For?
Mice have been extraordinarily useful as laboratory organisms, but they do have significant limitations:
- Their brains are not as complex as human brains.
- They don’t suffer from the same infectious diseases as humans.
- They are too expensive for large-scale experiments.
Researchers are using organoids to help fill these gaps. For example, the virus that causes COVID-19 does not infect mice, but it does infect human organoids. A news feature published by Nature describes how the appropriate organoids were used to understand how COVID-19 affects the lungs, liver, kidneys and brain. The safety and efficacy of COVID vaccines were also evaluated in organoids. In another example, after testing ~1000 drugs on mini colons and mini lungs infected with COVID-19, scientists were able to select seven drugs for further study.
Brain organoids were used to better understand Zika virus, which can cause microcephaly (an unusually small head) in babies born from infected mothers. Brain organoids were used to understand how the virus increases cell death in developing neurons and to identify chemical compounds that could reduce that effect. Brain organoids are also being used to better understand neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease.
Cystic fibrosis is a genetic disease that is caused by mutations in the gene for a chloride channel, which is required for healthy lung function. Nearly 2,000 different mutations have been reported for cystic fibrosis. Different drugs have been developed, which work in different ways. Lung organoids can be used to test the effectiveness of each drug for each mutation.
Organoids have already made significant contributions to biomedical research and are quickly becoming a highly effective tool.
Scientists are working to make these miniature lab-grown organs even more similar to regular organs. They need to find a way to effectively incorporate immune cells and blood vessels, provide structural support with an extracellular matrix and connect different organoids (e.g. pancreas and intestines, or multiple brain regions) in a way that is functionally relevant.
Research in mice has already shown that liver organoids can work as functional livers when transplanted into mutant mice. This research may eventually contribute to lab-grown organs for human transplant patients. The possibilities seem endless.
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