| FEATURES & INNOVATIONS |


H


uck Hui Ng and his team were observing a plate of mini brains when they noticed something that made them think of the renowned French anatomist Felix Vicq d’Azyr.


In 1786, D’Azyr published a treatise of the human brain, in which he described for the first time the presence of “dark spots” buried deep in the brain stem, the brain’s control center. Huck Hui’s team was seeing the same


cloudy speckles materialize in their nursery of tiny midbrains1


. Since D’Azyr’s time, neurol-


ogists had discovered that the dark pigments, called neuromelanin, were produced by dopamine-secreting neurons, and that damage to these neurons causes Parkinson’s disease. “We were very excited,” says Huck Hui at


the A*STAR Genome Institute of Singapore. “It was the first time that neuromelanin had been detected in vitro.” The mottled bulbs, derived from stem cells, signaled to Huck Hui and his collaborators, Hyunsoo Shawn Je at Duke–NUS Medical School and Eng King Tan at Singa- pore’s National Neuroscience Institute, that they were on course to determine the biological basis for Parkinson’s. “It marked the start of a very exciting journey in trying to understand Parkinson’s disease.” The discovery also fueled increasing confidence in the use of stem cells to study complex diseases in the human brain. Neurodegenerative diseases such as Alzheim-


er’s and Parkinson’s are characterized by a progressive deterioration of the nervous system. These diseases can cause declines in mental capacity, a condition known as dementia, as well as reduced control over movement, resulting in the characteristic Parkinson’s tremors. Up to 10 million people globally have Parkinson’s disease and more than 45 million suffer from Alzheimer’s or some other form of dementia. With 8 million cases of dementia diagnosed every year, those numbers are expected to triple by 2050. And the cost of caring for these patients is no small burden — estimated at US$815 billion in 2015 alone. “We hope our work will have an impact on the lives of patients afflicted with these diseases,” says Huck Hui.


Black stuff Living models of human tissue made from stem cells try to copy what our bodies naturally do. For years, researchers rushed to create model cell lines for every occasion — neurons, heart muscle cells, red blood cells. These human cell


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cultures, they believed, could better mimic the progression of disease in the human body than any other organism, especially the popular laboratory mouse. But cells in the body do not exist in segre-


gated communities; they mix together to form complex organs. A new approach to stem cell derived models emerged around 2010, which tried instead to grow whole organs on three-di- mensional (3D) scaffolds. Scientists produced rudimentary intestines, eyes and pituitary glands, but the brain remained difficult to recreate. That is, until 2013, when a group of researchers in Europe contoured its outer folds. The publication inspired Huck Hui and his collaborators in Singapore to attempt a similar model for the midbrain — a critical region in the pathogenesis of Parkinson’s disease. They started with a batch of human embry-


onic stem cells, feeding and coaxing them into shape over several months. “We had to guide the differentiation in a very precise way, telling the embryonic cells what to do at every stage. It is a pretty lengthy and painful protocol,” says Huck Hui. The researchers made their first real


breakthrough in 2014: the cells formed tissue-like structures, two millimeters wide, resembling the midbrain. “We were excited, but the excitement was followed by a period of skepticism,” says Huck Hui. It was not enough just to have a blob of cells sitting in the laboratory, they needed to determine whether it was brain-like in function. They found that the neurons were definitely


living, firing electric pulses back and forth when stimulated. And the neurons were not just any samples — they produced dopamine. The real surprise came when the two-month-old minia- ture organs, or organoids, formed dark deposits of neuromelanin. “This proved to us that our organ system was very different from what others had done in the past,” says Huck Hui. The team is now trying to create mutant


versions of the organoids that replicate what happens in the motor systems of patients with Parkinson’s, which is characterized by a dramatic loss of dopamine-secreting neurons.


In a clump Similar work on stem cell models of the diseased brain is already underway in other A*STAR labs. Shi-Yan Ng at the A*STAR Institute of Molecular Cell Biology (IMCB)


A*STAR RESEARCH 33


© 2017 A*STAR Genome Institute of Singapore


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