Singapore scientists grow mini human brains

A midbrain organoid in a petri dish. The black pigment is neuromelanin, a hallmark of the human midbrain.

A midbrain organoid in a petri dish. The black pigment is neuromelanin, a hallmark of the human midbrain.

Mini midbrains provide next generation platforms to investigate human brain biology, diseases and therapeutics

Scientists in Singapore have made a big leap on research on the ‘mini-brain’. These advanced mini versions of the human midbrain will help researchers develop treatments and conduct other studies into Parkinson’s Disease[1] (PD) and ageing-related brain diseases.

These mini midbrain versions are three-dimensional miniature tissues that are grown in the laboratory and they have certain properties of specific parts of the human brains. This is the first time that the black pigment neuromelanin has been detected in an organoid model. The study also revealed functionally active dopaminergic neurons.

The human midbrain, which is the information superhighway, controls auditory, eye movements, vision and body movements. It contains special dopaminergic neurons that produce dopamine – which carries out significant roles in executive functions, motor control, motivation, reinforcement, and reward. High levels of dopamine elevate motor activity and impulsive behaviour, whereas low levels of dopamine lead to slowed reactions and disorders like PD, which is characterised by stiffness and difficulties in initiating movements.

Also causing PD is the dramatic reduction in neuromelanin production, leading to the degenerative condition of patients, which includes tremors and impaired motor skills. This creation is a key breakthrough for studies in PD, which affects an estimated seven to 10 million people worldwide. Furthermore, there are people who are affected by other causes of parkinsonism. Researchers now have access to the material that is affected in the disease itself, and different types of studies can be conducted in the laboratory instead of through simulations or on animals. Using stem cells, scientists have grown pieces of tissue, known as brain organoids, measuring about 2 to 3 mm long. These organoids contain the necessary hallmarks of the human midbrain, which are dopaminergic neurons and neuromelanin.

Jointly led by Prof Ng Huck Hui from A*STAR’s Genome Institute of Singapore (GIS) and Assistant Prof Shawn Je from Duke-NUS Medical School, this collaborative research between GIS, Duke-NUS, and the National Neuroscience Institute (NNI) is funded by the National Medical Research Council’s Translational Clinical Research (TCR) Programme In Parkinson’s disease (PD) and A*STAR. Other collaborators are from the Lieber Institute for Brain Development, the Johns Hopkins University School of Medicine, and the Nanyang Technological University.

Assistant Prof Shawn Je from Duke-NUS Medical School’s Neuroscience & Behavioural Disorders Programme said, “It is remarkable that our midbrain organoids mimic human midbrain development. The cells divide, cluster together in layers, and become electrically and chemically active in three-dimensional environment like our brain. Now we can really test how these mini brains react to existing or newly developed drugs before treating patients, which will be a game changer for drug development.”

Prof Tan Eng King, Research Director and Senior Consultant, Department of Neurology at NNI and Lead PI of the TCR Programme in PD, remarked, “The human brain is arguably the most complex organ and chronic brain diseases pose considerable challenges to doctors and patients. This achievement by our Singapore team represents an initial but momentous scientific landmark as we continue to strive for better therapies for our patients.”

GIS Executive Director Prof Ng Huck Hui said, “Considering one of the biggest challenges we face in PD research is the lack of accessibility to the human brains, we have achieved a significant step forward. The midbrain organoids display great potential in replacing animals’ brains which are currently used in research; we can now use these midbrains in culture instead to advance our understanding and future studies for the disease, and perhaps even other related diseases.”

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A patient’s budding cortex — in a dish?

Neurons and supporting cells in the spheroids form layers and organize themselves according to the architecture of the developing human brain and network with each other. Source: Sergiu Pasca, M.D., Stanford University

Neurons and supporting cells in the spheroids form layers and organize themselves according to the architecture of the developing human brain and network with each other. Source: Sergiu Pasca, M.D., Stanford University

Networking neurons thrive in 3-D human “organoid”

A patient tormented by suicidal thoughts gives his psychiatrist a few strands of his hair. She derives stem cells from them to grow budding brain tissue harboring the secrets of his unique illness in a petri dish. She uses the information to genetically engineer a personalized treatment to correct his brain circuit functioning. Just Sci-fi? Yes, but…

An evolving “disease-in-a-dish” technology, funded by the National Institutes of Health (NIH), is bringing closer the day when such a seemingly futuristic personalized medicine scenario might not seem so far-fetched. Scientists have perfected mini cultured 3-D structures that grow and function much like the outer mantle – the key working tissue, or cortex — of the brain of the person from whom they were derived. Strikingly, these “organoids” buzz with neuronal network activity. Cells talk with each other in circuits, much as they do in our brains.

Sergiu Pasca, M.D. External Web Site Policy, of Stanford University, Palo Alto, CA, and colleagues, debut what they call “human cortical spheroids,” May 25, 2015 online in the journal Nature Methods.

“There’s been amazing progress in this field over the past few years,” said Thomas R. Insel, M.D., Director of the NIH’s National Institute of Mental Health, which provided most of the funding for the study. “The cortex spheroids grow to a state in which they express functional connectivity, allowing for modeling and understanding of mental illnesses. They do not even begin to approach the complexity of a whole human brain. But that is not exactly what we need to study disorders of brain circuitry. As we seek advances that promise enormous potential benefits to patients, we are ever mindful of the ethical issues they present.”

Prior to the new study, scientists had developed a way to study neurons differentiated from stem cells derived from patients’ skin cells — using a technology called induced pluripotent stem cells (iPSCs). They had even produced primitive organoids by coaxing neurons and support cells to organize themselves, mimicking the brain’s own architecture. But these lacked the complex circuitry required to even begin to mimic the workings of our brains.

Based on an improved, streamlined method for producing iPSCs, Pasca’s team’s cortex-like spheroids harbor healthier neurons supported by a more naturalistic network of supporting glial cells, resulting in more functional neural connections and circuitry. Like the developing brain, the neurons form layers and talk with each other via neural networks. The spheroid technology is more consistent than earlier organoids in generating the same kinds of cortex-like structures in repeated experiments.

The budding cortex also lends itself to analysis using conventional brain slice methods. So, in a sci-fi future, it might potentially reveal what circuits went awry in the developing cortex of a particular individual with a brain disorder.

“While the technology is still maturing, there is great potential for using these assays to more accurately develop, test safety and effectiveness of new treatments before they are used in individuals with a mental illness,” said David Panchision, Ph.D., NIMH program director for stem cell research.

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3-D ‘organoids’ grown from patient tumors could personalize drug screening

3-D organoid cultures derived from healthy and tumor tissue from colorectal cancer patients are used for a high throughput drug screen to identify genedrug associations that may facilitate personalized therapy. CREDIT van de Wetering et al./Cell 2015

3-D organoid cultures derived from healthy and tumor tissue from colorectal cancer patients are used for a high throughput drug screen to identify genedrug associations that may facilitate personalized therapy.
CREDIT
van de Wetering et al./Cell 2015

Three-dimensional cultures (or “organoids”) derived from the tumors of cancer patients closely replicate key properties of the original tumors, reveals a study published May 7 in Cell. These “organoid” cultures are amenable to large-scale drug screens for the detection of genetic changes associated with drug sensitivity and pave the way for personalized treatment approaches that could optimize clinical outcomes in cancer patients.

“This is the first time that a collection of cancer organoids, or a living biobank, has been derived from patient tumors,” says senior study author Mathew Garnett, a geneticist at the Wellcome Trust Sanger Institute. “We believe that these organoids are an important new tool in the arsenal of cancer biologists and may ultimately improve our ability to develop more effective cancer treatments.”

To study the causes of cancer and develop new cancer treatments, many laboratories use experimental model systems such as cells grown from patient tumors. However, currently available cell lines have been derived under suboptimal conditions and therefore fail to reflect important features of tumor cells. As a result, it has been challenging to predict the drug sensitivity of individual patients based on their unique spectrum of genetic mutations.

In recent years, scientists have developed organoid cell culture systems as an alternative approach to grow normal and diseased tissue in a dish. In contrast to cell lines, organoids display the hallmarks of the original tissue in terms of its 3D architecture, the cell types present, and their self-renewal properties. Given the advantages of organoids, Garnett and Hans Clevers of the Hubrecht Institute set out to test whether these cultures could potentially bridge the gap between cancer genetics and patient outcomes.

In the new study, the researchers grew 22 organoids derived from tumor tissue from 20 patients with colorectal cancer and then sequenced genomic DNA isolated from these cultures. The genetic mutations in the organoid cultures closely matched those in the corresponding tumor biopsies and agreed well with previous large-scale analyses of colorectal cancer mutations. These findings confirm that the cultures faithfully capture the genomic features of the tumors from which they are derived as well as much of the genomic diversity associated with colorectal cancer.

To link drug sensitivity to genetic changes, the researchers next screened the responses of the organoids to 83 experimental and approved cancer drugs. Given their diverse genetic profiles, the organoids displayed a range of sensitivities to the drugs. In validation of the approach, the researchers identified previously reported associations between specific mutations and resistance to particular drugs. The organoids also revealed a novel gene-drug association, indicating that the subset of cancer patients with RNF43 mutations would strongly benefit from a drug that inhibits a protein called porcupine. “At some point in the future, this approach may be suitable for modeling individual patient response to cancer therapies to inform clinical treatment,” Garnett says.

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