Researchers at the University of Washington (UW) School of Medicine in Seattle have developed an automated system that uses robots to produce human mini-organs, known as organoids, from stem cells.
The breakthrough will lead to greater use of organoids in research and drug discovery, according to research leader Benjamin Freedman, assistant professor of medicine, Division of Nephrology, at the UW School of Medicine:
This is a new ‘secret weapon’ in our fight against disease. The traditional way to grow cells for biomedical research is to culture them as flat, two-dimensional sheets, which are overly simplistic. In recent years, researchers have been increasingly successful in growing stem cells into more complex, three-dimensional structures called organoids.
These rudimentary organoids replicate the behaviour of normal human organs. A report published on Cell Stem Cell, and pithily titled ‘High-Throughput Screening Enhances Kidney Organoid Differentiation from Human Pluripotent Stem Cells and Enables Automated Multidimensional Phenotyping’, explains the motivation behind the research.
Human pluripotent (capable of giving rise to several different cell types) stem cells have huge potential for use in high-throughput screening (HTS) – a scientific method commonly used in drug discovery to automate and accelerate tests.
In the new research, robotics, data processing, liquid-handling devices, and sensitive detectors were combined so that researchers were able to conduct millions of tests far more quickly.
Freedman and his team used fully-automated liquid-handling robots to generate and analyse kidney organoids in microwell arrays over a period of 21 days. The robots introduced the stem cells into plates that contained up to 384 miniature wells, with each microwell containing ten or more organoids.
Speed, repetition, consistency
This production-line approach meant that thousands of kidney mini-organs could be produced in just three weeks, work that would take human lab-workers far longer to carry out by hand.
The report’s author Dr. Jennifer Harder and her team also used robotics to analyse the results, using a cutting-edge process known as single-cell RNA sequencing to identify the types of cells found in the organoids.
She shared her experience of using robotics:
Ordinarily, just setting up an experiment of this magnitude would take a researcher all day, while the robot can do it in 20 minutes. On top of that, the robot doesn’t get tired and make mistakes. There’s no question: for repetitive, tedious tasks like this, robots do a better job than humans.
By using automation, her team can make adjustments at any point and rapidly test the results of these changes. For example, the researchers were able to greatly increase the number of blood vessel cells in their organoids to make them more like real kidneys.
The team also searched for drugs that could affect diseased kidneys, producing polycystic kidney organoids and testing their reactions to different substances. They discovered that a factor called blebbistatin causes cysts to significantly increase by blocking the protein myosin.
“Myosin, which is better known for its role in muscle contraction, may allow kidney tubules to expand and contract. If it is not functioning properly it might lead to cysts,” Freedman explained. “It’s definitely a pathway we will be looking at.”
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Although similar approaches have been successful with adult stem cells, this is the first report of successfully automating the manufacture of organoids from pluripotent stem cells.
The ability of HTS to introduce, incubate, and analyse microwells automatically and rapidly is the lynchpin of this research’s success, accelerating the process, improving accuracy, controlling variables, and making the whole process more viable.
Existing HTS systems test in the region of 100,000 compounds per day. When you consider this alongside the proficiency of robotics when it comes to repetitive, accurate tasks, it’s clear that such systems are far superior to manual processing.
This is especially the case since a 2010 breakthrough, which enabled an HTS process to carry out screening 1,000 times faster, at one millionth of the cost of conventional techniques.
More recently, HTS drug-discovery has been used with intact living organisms, such as nematodes and zebrafish.