Are you Smarter than a Mini-Brain Grown in a Dish?
By: Marissa Sumathipala
Scrolling through the latest headlines in biomedical research will probably reveal promising breakthroughs in understanding cancer, heart disease, or diabetes. Maybe there’s a new gene therapy for leukemia, or a new early biomarker for heart disease. Though there’s hope on the horizon for effective treatments and early intervention for these maladies, you’ll be hard-pressed to find similar research milestones for diseases like schizophrenia and autism. Why is so little is known about psychiatric and brain illnesses?
Our understanding of the brain is incredibly limited. We know far more about how the heart or liver works than we do about the brain works. After all, how do we study an organ as advanced and distinct as the human brain? At a molecular level, what makes humans so vastly different from, say, a mouse or a zebrafish, are the biochemical and electrical signals zipping around our brains. While the distinctive complexity of the human brain is what gives us our unique cognitive and emotional capacities, it also makes accurately modeling the organ in the lab an extremely daunting task. Differences in the complexity and organization of human brains compared to the brains of the rest of the animal explain why scientists cannot easily use common model organisms such as mice to tackle this question.
A complete molecular and cellular understanding of the brain could transform how we treat neurological and psychiatric diseases. An accurate experimental model of the human brain is necessary not only to unlock insights into neurological illness, but also to answer fundamental questions in neuroscience. These questions range in scale from how memories are stored in entire brain structures to how single neurons communicate with each other. Though human brain tissue samples from surgeries or postmortem samples can be used as simple models, this approach has two major limitations: The tissue degrades very rapidly, and the cells cannot be sustained or manipulated to conduct long-term experiments.
Recent advances in stem cell biology present a solution to these problems. Scientists can take skin cells and dedifferentiate them back into stem cells using combinations of proteins called transcription factors. These stem cells can then be redifferentiated into different types of brain cells, allowing scientists to probe how an individual’s unique genetic makeup affects the development of his or her brain cells. Studying isolated cells, however, is limited by the constant chatter between the many interconnected cells in the brain.
Paola Arlotta’s lab at Harvard University is developing methods to grow individual stem cells into clusters of cells that more closely capture the complexity of brain tissue. These cell clusters, each only a few millimeters in diameter, are called organoids. Previous studies have successfully used organoids to investigate the effect of the Zika virus on very early brain development[1]. While these experiments used organoids to study neurological development up to about two weeks, many complex human diseases manifest later in human development. To understand the progression of these ailments, Arlotta created a method to grow organoids for over 9 months, the oldest organoids to date[2].
A major hindrance to creating long-term organoids is hypoxia. Without a network of blood vessels to replenish oxygen levels, the cells become deprived of oxygen and die. Arlotta overcame this issue by seeding the organoids with fewer stem cells than usual and adding a protein called BDNF (brain-derived neurotrophic factor) to the organoids’ growth media. In normal brain function, BDNF expression is triggered by oxygen deprivation and helps to protect the brain from hypoxia-induced damage.
Arlotta’s studies not only increased the organoids’ lifespans, but also improved their quality and reproducibility. A longstanding question in the field of organoid research is whether or not organoids can capture the remarkable cellular diversity of actual brain tissue. In contrast to other tissues like muscle or bone, which contain only a few major cell types, brain tissue contains a large diversity of cell types. Each cell type varies greatly in their shape and structure, patterns of electrical firing, and gene expression signatures. Even two cells that look identical under a microscope can have different molecular make-ups, determined by patterns of DNA modifications that alter which genes are expressed at certain times [3].
To approach the question of cellular diversity, Arlotta teamed up with Steven McCarroll, a geneticist at Harvard Medical School. McCarroll’s lab developed Drop-seq, a method to measure the patterns of gene expression in individual cells.4 With Drop-seq, each cell in the organoid is separated into a microdroplet containing a bead with a DNA “barcode”. Then, the expression level of each gene in the cell is measured, yielding a unique gene signature for every individual cell. When organoid Drop-seq signatures were compared to those from actual brain tissue, Arlotta found that the organoid cell types matched up with subtypes of brain cells, including retinal rods and cones, interneurons, and glia. Moreover, as the organoids aged, the number and complexity of cell types increased, a hallmark sign of normal brain development. Similar to the human brain, the organoid’s neurons became more mature over time, forming specialized junctions of communication with other neurons called synapses.
The thought of growing organs in a lab sounds like something out of Frankenstein rather than a Nature paper. However, while Frankenstein’s ghoulish monster transformed lives for the worse, Arlotta’s brain organoids could transform lives for the better. Brain organoids can be used to study the molecular underpinnings of fundamental neurological functions like learning, plasticity, and memory without the need to use model organisms. And, in the context of disease, the applications of organoids are endless. Organoids can used to track disease development, identify gene targets for treatment, screen drugs, and find biomarkers for early diagnosis.
On a broader scale, advances such as Arlotta’s organoids could transform societal perceptions of disease. Patients with psychiatric diseases often bear more blame and stigma for their condition than patients with diseases like cancer that have known biological causes. Brain organoids are a step toward uncovering the biological roots of psychiatric diseases—a step toward creating a future with more empathy and understanding toward these diseases and the humans they impact.
References:
1. Garcez, P. P., Loiola, E. C., Costa, R. M. da, Higa, L. M., Trindade, P., Delvecchio, R., … Rehen, S. K. (2016). Zika virus impairs growth in human neurospheres and brain organoids. Science, 352(6287), 816–818. https://doi.org/10.1126/science.aaf6116
2. Quadrato, G., Nguyen, T., Macosko, E. Z., Sherwood, J. L., Yang, S. M., Berger, D., … Arlotta, P. (2017). Cell diversity and network dynamics in photosensitive human brain organoids. Nature, 545(7652), 48–53. https://doi.org/10.1038/nature22047
3. Lister, R., Mukamel, E. A., Nery, J. R., Urich, M., Puddifoot, C. A., Johnson, N. D., … Ecker, J. R. (2013). Global epigenomic reconfiguration during mammalian brain development. Science (New York, N.Y.), 341(6146), 1237905. https://doi.org/10.1126/science.1237905
4. Macosko, E. Z., Basu, A., Satija, R., Nemesh, J., Shekhar, K., Goldman, M., … McCarroll, S. A. (2015). Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell, 161(5), 1202–1214. https://doi.org/10.1016/j.cell.2015.05.002
Scrolling through the latest headlines in biomedical research will probably reveal promising breakthroughs in understanding cancer, heart disease, or diabetes. Maybe there’s a new gene therapy for leukemia, or a new early biomarker for heart disease. Though there’s hope on the horizon for effective treatments and early intervention for these maladies, you’ll be hard-pressed to find similar research milestones for diseases like schizophrenia and autism. Why is so little is known about psychiatric and brain illnesses?
Our understanding of the brain is incredibly limited. We know far more about how the heart or liver works than we do about the brain works. After all, how do we study an organ as advanced and distinct as the human brain? At a molecular level, what makes humans so vastly different from, say, a mouse or a zebrafish, are the biochemical and electrical signals zipping around our brains. While the distinctive complexity of the human brain is what gives us our unique cognitive and emotional capacities, it also makes accurately modeling the organ in the lab an extremely daunting task. Differences in the complexity and organization of human brains compared to the brains of the rest of the animal explain why scientists cannot easily use common model organisms such as mice to tackle this question.
A complete molecular and cellular understanding of the brain could transform how we treat neurological and psychiatric diseases. An accurate experimental model of the human brain is necessary not only to unlock insights into neurological illness, but also to answer fundamental questions in neuroscience. These questions range in scale from how memories are stored in entire brain structures to how single neurons communicate with each other. Though human brain tissue samples from surgeries or postmortem samples can be used as simple models, this approach has two major limitations: The tissue degrades very rapidly, and the cells cannot be sustained or manipulated to conduct long-term experiments.
Recent advances in stem cell biology present a solution to these problems. Scientists can take skin cells and dedifferentiate them back into stem cells using combinations of proteins called transcription factors. These stem cells can then be redifferentiated into different types of brain cells, allowing scientists to probe how an individual’s unique genetic makeup affects the development of his or her brain cells. Studying isolated cells, however, is limited by the constant chatter between the many interconnected cells in the brain.
Paola Arlotta’s lab at Harvard University is developing methods to grow individual stem cells into clusters of cells that more closely capture the complexity of brain tissue. These cell clusters, each only a few millimeters in diameter, are called organoids. Previous studies have successfully used organoids to investigate the effect of the Zika virus on very early brain development[1]. While these experiments used organoids to study neurological development up to about two weeks, many complex human diseases manifest later in human development. To understand the progression of these ailments, Arlotta created a method to grow organoids for over 9 months, the oldest organoids to date[2].
A major hindrance to creating long-term organoids is hypoxia. Without a network of blood vessels to replenish oxygen levels, the cells become deprived of oxygen and die. Arlotta overcame this issue by seeding the organoids with fewer stem cells than usual and adding a protein called BDNF (brain-derived neurotrophic factor) to the organoids’ growth media. In normal brain function, BDNF expression is triggered by oxygen deprivation and helps to protect the brain from hypoxia-induced damage.
Arlotta’s studies not only increased the organoids’ lifespans, but also improved their quality and reproducibility. A longstanding question in the field of organoid research is whether or not organoids can capture the remarkable cellular diversity of actual brain tissue. In contrast to other tissues like muscle or bone, which contain only a few major cell types, brain tissue contains a large diversity of cell types. Each cell type varies greatly in their shape and structure, patterns of electrical firing, and gene expression signatures. Even two cells that look identical under a microscope can have different molecular make-ups, determined by patterns of DNA modifications that alter which genes are expressed at certain times [3].
To approach the question of cellular diversity, Arlotta teamed up with Steven McCarroll, a geneticist at Harvard Medical School. McCarroll’s lab developed Drop-seq, a method to measure the patterns of gene expression in individual cells.4 With Drop-seq, each cell in the organoid is separated into a microdroplet containing a bead with a DNA “barcode”. Then, the expression level of each gene in the cell is measured, yielding a unique gene signature for every individual cell. When organoid Drop-seq signatures were compared to those from actual brain tissue, Arlotta found that the organoid cell types matched up with subtypes of brain cells, including retinal rods and cones, interneurons, and glia. Moreover, as the organoids aged, the number and complexity of cell types increased, a hallmark sign of normal brain development. Similar to the human brain, the organoid’s neurons became more mature over time, forming specialized junctions of communication with other neurons called synapses.
The thought of growing organs in a lab sounds like something out of Frankenstein rather than a Nature paper. However, while Frankenstein’s ghoulish monster transformed lives for the worse, Arlotta’s brain organoids could transform lives for the better. Brain organoids can be used to study the molecular underpinnings of fundamental neurological functions like learning, plasticity, and memory without the need to use model organisms. And, in the context of disease, the applications of organoids are endless. Organoids can used to track disease development, identify gene targets for treatment, screen drugs, and find biomarkers for early diagnosis.
On a broader scale, advances such as Arlotta’s organoids could transform societal perceptions of disease. Patients with psychiatric diseases often bear more blame and stigma for their condition than patients with diseases like cancer that have known biological causes. Brain organoids are a step toward uncovering the biological roots of psychiatric diseases—a step toward creating a future with more empathy and understanding toward these diseases and the humans they impact.
References:
1. Garcez, P. P., Loiola, E. C., Costa, R. M. da, Higa, L. M., Trindade, P., Delvecchio, R., … Rehen, S. K. (2016). Zika virus impairs growth in human neurospheres and brain organoids. Science, 352(6287), 816–818. https://doi.org/10.1126/science.aaf6116
2. Quadrato, G., Nguyen, T., Macosko, E. Z., Sherwood, J. L., Yang, S. M., Berger, D., … Arlotta, P. (2017). Cell diversity and network dynamics in photosensitive human brain organoids. Nature, 545(7652), 48–53. https://doi.org/10.1038/nature22047
3. Lister, R., Mukamel, E. A., Nery, J. R., Urich, M., Puddifoot, C. A., Johnson, N. D., … Ecker, J. R. (2013). Global epigenomic reconfiguration during mammalian brain development. Science (New York, N.Y.), 341(6146), 1237905. https://doi.org/10.1126/science.1237905
4. Macosko, E. Z., Basu, A., Satija, R., Nemesh, J., Shekhar, K., Goldman, M., … McCarroll, S. A. (2015). Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell, 161(5), 1202–1214. https://doi.org/10.1016/j.cell.2015.05.002
