#5. Making the Midbrain

In our final Research Story of 2016, we shift our attention to neuroscience and ask Associate Professor Wang Hongyan, Interim Director of the Neuroscience and Behavioural Disorders Programme at Duke-NUS, for what she thinks is the biggest research story of 2016 to impact neuroscience research. Her pick, a home-grown story literally, is that of the midbrain organoid developed in Singapore by a team from Duke-NUS, A*STAR’s Genome Institute of Singapore and the National Neuroscience Institute.

Making Mini-brains

How does your brain interface so seamlessly with the world? …retain memories? …learn? …determine your personality? And, where does it all go so wrong with neuropsychological disorders? Due to the complexities of the brain and difficulties in accessing human brain tissue for research, these questions have eluded scientists for a long time. Now, researchers are a step closer to answering these questions, by growing brain organoids in the lab. Brain organoids are essentially mini-brains grown in a petri dish, and show remarkable similarity to human brains with the same neural cell populations, 3D architecture and connectivity.

Starting out with a mere human skin cell, scientists are able to generate induced pluripotent stem cells (IPSCs), which can potentially develop into any cell type in humans. By adding specific transcription and growth factors, IPSCs can be coaxed into mimicking neurodevelopment and grow into a brain organoid. Using this method, laboratories around the world have successfully grown foetal cerebral organoids and cerebellum organoids. In this story, Singapore lays claim to developing the world’s first midbrain organoid.

The Midbrain

The midbrain lies in the middle of the brainstem and is comprised of dopamine producing (aka dopaminergic) neurons. As the main interface between the fore- and hind-brain, the midbrain relays sensory information from the forebrain to the hindbrain to dictate body movements and adjustments. Beyond motor function, the midbrain has roles in the motivation, reinforcement and reward systems.

Within the midbrain lies the substantia nigra (SN), a structure involved with movement and reward. Neuromelanin, a dark pigment linked to neuroprotection in aging, is a hallmark of the SN in humans and other primates. Parkinson’s disease (PD), probably the most well-known neurological disorder associated with the midbrain, is linked to a loss of SN dopaminergic neurons, and a reduction of neuromelanin levels in the SN.

The Mini-midbrain

The mini-midbrains generated in Singapore mimic human midbrain development, with cells forming a 3D structure that became electrically and chemically active, just like the human midbrain. Then, an amazing thing happened. Dark spots started forming in the midbrain organoid revealing the production of neuromelanin, which is typically observed in the human midbrain only after the third year of life. A first for midbrain organoids!

What does this mean for neuroscience research?

Using mini-midbrains, scientists are now able to better model neurological diseases. All it takes is a single skin cell to generate midbrain organoids, providing researchers access to previously limited brain tissue for manipulation and experimentation. In particular, because of the presence of neuromelanin, we may use the midbrain organoids generated to model neurological disorders that occur later in life, such as PD. Hopefully, we would gain better understanding of the pathophysiology of PD, and identify drugs that would be effective in treating PD. We can expand our knowledge of neuropsychological disorders, while accelerating drug screening and discovery for these often-debilitating diseases.

Being able to quickly and accurately generate human midbrain organoids also lessens our reliance on drug screens in animal models, which are less than accurate representations of human development and function. With such overwhelming differences between the brain and behaviour of humans and rodents, it is not surprising that so many seemingly promising drug candidates for neuropsychological disorders tested in animal models have failed in humans.

What is next?

While mini-brains bear striking similarities to human brains and neurodevelopment, they still differ in some pertinent ways and work is underway to overcome these differences. Moreover, current organoids are for specific brain sub-regions; an organoid modelling interconnected sub-regions of the brain is not yet a reality. The generation of such a complete mini-brain may require multiple body patterning cues, which are absent when brain organoids grow in petri dishes. In addition to producing a better and more complete brain organoid, research at Duke-NUS are also working on developing a brain organoid with its own vasculature.

As scientists continue to tweak, improve and innovate, we expect to see more consistent and accurate representations of the brain. We look forward to the day when scientists are able to grow customised mini-midbrains for anyone to diagnose and treat neurological diseases!