Alison feature

It has long been a goal of the scientific community to understand the mysteries of how the human brain develops from just a few cells into an organ capable of coordinating conscious thought. Slowly but surely, scientists are illuminating this black box of biology, both through studies of human brain cells and of living brains in laboratory animals like mice. These approaches have their limitations: cell cultures can’t recapitulate all the complex behavior of a brain, and mouse brains are not nearly as complicated as human brains in structure or intellectual capacity. Such research approaches have been necessary alternatives to studying live human brains, which, for ethical reasons, can only be observed in a minimally invasive experimental context. But the latest breakthrough in the field of brain development bypasses some of these caveats by successfully growing human brain-like structures from progenitor stem cells in the laboratory [1]. The research team, led by Dr. Juergen A. Knoblich of the Austrian Academy of Science in Vienna, created “cerebral organoids,” so named for their similarity to a developing human brain. These organoids may prove to be valuable tools for understanding healthy brain growth as well as developmental disorders. They may also raise some interesting ethical questions about how far scientists can take the lab-grown cerebral tissue as a model for the human brain.

Stem Cells: Is there anything they can’t do?

The cells that make up the different organs in our bodies are all highly specialized for their particular tissues. For example, muscle cells look and behave very differently from blood cells or brain cells. But they all originate from stem cells, which have the ability to become many different types of specialized cells. Embryonic stem cells are some of the first cells that form after the fertilization of an egg, and they have the ability to become every type of cell found in the body.

Scientists can also take adult cells that have already become specialized and “reprogram” them to return to a stem cell state [2]. These reprogrammed cells are called “induced pluripotent stem cells,” or iPSCs, and they can be induced to re-specialize into different types of tissues. Previously, scientists have been able to successfully create beating heart tissue as well as other organoids from stem cells [3,4], but growing an organ as complex as the brain had not yet been accomplished.

Dr. Knoblich’s team created the cerebral organoids by taking either human embryonic stem cells or iPSCs and culturing them in the presence of specific nutrients and growth factors. Their culturing technique mimicked what happens during natural brain development, and so it signaled the stem cells to specialize into different types of brain cells. Once the cells started to specialize, the team transferred them to a gel matrix scaffold, giving them a structural base for growing and spreading into different, spatially-separated layers of brain tissue (for more on scaffolds and how they are used to grow organs, see [3]).

Just how cerebral are these organoids?

Various news outlets have referred to the cerebral organoids as “mini-brains” [5], calling to mind the classic science fiction image of a brain in a jar. But, calling them “mini-brains” is an oversimplification of what they actually are. For instance, the cerebral organoids are a model of the embryonic brain, not the adult brain (see Figure 1). The stem cells were able to form multiple layers of specialized brain tissue, but not all regions of the brain developed, and the organoids only grew to have a diameter of about 4 mm (approximately the length of an uncooked grain of rice). While they appear to be able to survive indefinitely at this size, without connection to a functional circulatory system they are unlikely to get much bigger [1]. Indeed, experts are quick to dispel the perception that cerebral organoids can be thought of as miniature adult brains. One likened this notion to “inventing the first abacus and saying you can use it to run the latest version of Microsoft Windows” [6].

Figure 1. Key differences between (a) cerebral organoids [1], (b) the embryonic brain [11], and (c) the adult brain (images not to scale) [12].

Despite the limitations of the organoids, they still have a great deal of potential as a tool to enhance our understanding of brain development. Knoblich’s team carefully examined the cerebral organoids to see which specialized regions of brain tissue were able to develop. They found that the organoids’ development reflected real-life brain development, forming structural partitions of the forebrain, midbrain, and hindbrain regions as they grew. Importantly, the organoids developed specialized layers of tissue that are only found in human brains. As mentioned above, a great deal of brain research is done in mice and other model organisms whose brains develop to a lower level of complexity than the human brain. Knoblich’s team showed that the cerebral organoids developed key brain regions and cell types that do not develop in the brains of other animals, which means that they have the potential to be used to study the development of these regions in depth [1].

Modeling microcephaly

The fact that particular brain regions only develop in humans means that some human neurological disorders can’t be studied using model organisms like mice. Microcephaly, a condition characterized by abnormal development of an infant’s brain, resulting in significantly smaller brain and head size, is one such disorder [7]. Knoblich’s team first demonstrated that the organoids could be used to model and study this disease by making iPSCs from the skin cells of a patient with microcephaly. When they used the same culturing system described above, they found that the cerebral organoids that grew were smaller than organoids grown from iPSCs from healthy patients. Furthermore, the microcephalic organoids showed a different pattern of specialization into different layers of brain tissue, which points to improper specialization as an important factor in the development of this disease. This gave scientists hope that, with further study, the cerebral organoid model could lead to better understanding of how and why microcephaly occurs [1].

How far can they go?

Cerebral organoids are promising models that could be used to study normal brain development as well as other developmental disorders. However, there are ethical limits to the growth of brain-like structures in the laboratory, and scientists will have to consider this as technology advances beyond these small organoids in the future. There is precedent for limiting just how much of a human brain can be created experimentally. For example, in the effort to study human-specific disorders, researchers have developed techniques to “humanize” organs of laboratory animals. “Humanized” animals have some part of their bodies made up of human cells and tissues. For example, mice that have elements of human bone marrow and other tissues can be used to model the human immune system, allowing researchers to study infectious diseases without using human patients [10]. Humanized animals have helped us learn a great deal, but ethical concerns were raised when scientists turned to humanizing animal brains.

In 2005, a committee of ethicists and scientists put together a set of guidelines concerning the ethics of studies in which human brain cells and/or stem cells would be injected into the brains of animals, including primates. Such studies were being proposed as way to study neurodegenerative disorders like Parkinson’s disease. The committee raised concerns that human brain cells, if provided in a large enough number and in the right brain regions, could potentially make the animals “too human” in terms of their capacity for thought and emotion. This concern was especially important for the studies that proposed putting human brain cells into monkeys and apes, as they are humankind’s closest relatives on the evolutionary tree. The committee recommended limiting the percentage of non-human brains that could be made up of human brain cells, along with other guidelines for avoiding any ethical grey areas [8,9].

Perhaps a new set of guidelines will now have to emerge to govern just how developed human brain-like organoids can become. As one scientist put it, we could never grow a fully functional human brain in the lab because it “would be conscious, have hopes, dreams, feel pain, and would ask questions about what we were doing to it!” [6]. For now, these possibilities are technically far off, and there is still much that scientists can learn about the human brain just from studying these tiny cerebral organoids.

Alison Hill is a graduate student in the Harvard Virology Program.

References:

[1] Lancaster, M.A., et al., Cerebral organoids model human brain development and microcephaly. Nature, 2013. 501: p.373-379.

[2] Wai, Stephanie. “Giving Ordinary Cells the Superpowers of Stem Cells.” SITN Flash, 2007. Web, accessed 15 September 2013. http://sitn.hms.harvard.edu/uncategorized/2007/issue32/

[3] Kelsey, Ilana. “Custom-Made Body Parts: Advances in Tissue Engineering.” SITN Flash, 2012. Web, accessed 15 September 2013. http://sitn.hms.harvard.edu/flash/2012/issue129b/

[4] “Stem Cells Grow Beating Heart. Discovery News, 2013. Web, accessed 15 September 2013. http://news.discovery.com/tech/biotechnology/stem-cells-grow-beating-heart-130814.htm

[5] Landau, Elizabeth. “Scientists grow mini brains from stem cells.” CNN.com, 2013. Web, accessed 15 September 2013. http://www.cnn.com/2013/08/28/health/stem-cell-brain/index.html

[6] “Expert reaction to brain organoids.” Science Media Centre, 2013. Web, accessed 15 September 2013. http://www.sciencemediacentre.org/expert-reaction-to-brain-organoids/

[7] Staff, Mayo Clinic. “Microcephaly.” MayoClinic.com, 2012. Web, accessed 15 September 2013. http://www.mayoclinic.com/health/microcephaly/DS01169

[8] Weiss, Rick. “Human Brain Cells are Grown in Mice.” Washington Post, 2005. Web, accessed 15 September 2013. http://www.washingtonpost.com/wp-dyn/content/article/2005/12/12/AR2005121201388.html

[9] “Ethical Guidelines Suggested for Research That Would Put Human Stem Cells in Primates.” Stanford School of Medicine Press Release, 2005. Web, accessed 15 September 2013. http://med.stanford.edu/news_releases/2005/july/greely.htm

[10] “Mouse with human immune system may revolutionize HIV vaccine research. ” Massachusetts General Hospital press release, 2012. Web, accessed 28 September 2013. http://www.massgeneral.org/about/pressrelease.aspx?id=1484

[11] “Development of the human embryonic brain.” Animation by Howard Hughes Medical Institute Biointeractive Resources. Web, accessed 30 September 2013. http://www.hhmi.org/biointeractive/development-human-embryonic-brain

[12] Hankem, File: Human Brain Sketch with Eyes and Cerebellum.svg. Web, accessed 30 September 2013. https://commons.wikimedia.org/wiki/File:Myelinisation.svg#

Also of interest:

For a breakdown of different types of stem cells, see the California Institute for Regenerative Medicine’s website: http://www.cirm.ca.gov/our-progress/stem-cell-definitions

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