Brains on demand: Scientists succeed in growing human brain tissue in 'test tubes'

The spinning bioreactor system used for growth of cerebral organoids. At right, a close-up showing the floating organoids within the bioreactor. Credit: Copyright: IMBA/Magdalena Renner

(Medical Xpress)—Complex human brain tissue has been successfully developed in a three-dimensional culture system established in an Austrian laboratory. The method described in the current issue of Nature allows pluripotent stem cells to develop into cerebral organoids - or "mini brains" - that consist of several discrete brain regions. Instead of using so-called patterning growth factors to achieve this, scientists at the renowned Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (OeAW) fine-tuned growth conditions and provided a conducive environment. As a result, intrinsic cues from the stem cells guided the development towards different interdependent brain tissues. Using the "mini brains", the scientists were also able to model the development of a human neuronal disorder and identify its origin - opening up routes to long hoped-for model systems of the human brain.

The development of the remains one of the greatest mysteries in biology. Derived from a simple tissue, it develops into the most complex natural structure known to man. Studies of the human brain's development and associated human disorders are extremely difficult, as no scientist has thus far successfully established a three-dimensional culture model of the developing brain as a whole. Now, a research group lead by Dr. Jürgen Knoblich at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) has changed just that.

Brain size matters

Starting with established lines and induced pluripotent stem (iPS) cells, the group identified growth conditions that aided the differentiation of the stem cells into several brain tissues. While using media for neuronal induction and differentiation, the group was able to avoid the use of patterning growth factor conditions, which are usually applied in order to generate specific cell identities from stem cells. Dr. Knoblich explains the new method: "We modified an established approach to generate so-called neuroectoderm, a cell layer from which the nervous system derives. Fragments of this tissue were then maintained in a 3D-culture and embedded in droplets of a specific gel that provided a scaffold for complex tissue growth. In order to enhance nutrient absorption, we later transferred the gel droplets to a spinning bioreactor. Within three to four weeks defined brain regions were formed."

A magnified image of a cerebral organoid showing cerebral tissue adjacent to developing retinal tissue (brown pigmented region). Credit: Copyright: IMBA/Madeline A. Lancaster

Already after 15 - 20 days, so-called "cerebral organoids" formed which consisted of continuous tissue (neuroepithelia) surrounding a fluid-filled cavity that was reminiscent of a cerebral ventricle. After 20 - 30 days, defined , including a cerebral cortex, retina, meninges as well as choroid plexus, developed. After two months, the mini brains reached a maximum size, but they could survive indefinitely (currently up to 10 months) in the spinning bioreactor. Further growth, however, was not achieved, most likely due to the lack of a circulation system and hence a lack of nutrients and oxygen at the core of the mini brains.

Microcephaly in mini brains

The new method also offers great potential for establishing model systems for human brain disorders. Such models are urgently needed, as the commonly used animal models are of considerably lower complexity, and often do not adequately recapitulate the human disease. Knoblich's group has now demonstrated that the mini brains offer great potential as a human model system by analysing the onset of microcephaly, a human genetic disorder in which brain size is significantly reduced. By generating iPS cells from skin tissue of a microcephaly patient, the scientists were able to grow mini brains affected by this disorder. As expected, the patient derived organoids grew to a lesser size. Further analysis led to a surprising finding: while the neuroepithilial tissue was smaller than in mini brains unaffected by the disorder, increased neuronal outgrowth could be observed. This lead to the hypothesis that, during brain development of patients with microcephaly, the neural differentiation happens prematurely at the expense of stem and progenitor cells which would otherwise contribute to a more pronounced growth in . Further experiments also revealed that a change in the direction in which the divide might be causal for the disorder.

"In addition to the potential for new insights into the development of human brain disorders, mini brains will also be of great interest to the pharmaceutical and chemical industry," explains Dr. Madeline A. Lancaster, team member and first author of the publication. "They allow for the testing of therapies against brain defects and other neuronal disorders. Furthermore, they will enable the analysis of the effects that specific chemicals have on development."

More information: M. A. Lancaster, M. Renner, C.-A. Martin, D. Wenzel, L. S. Bicknell, M. E. Hurles, T. Homfray, J. S. Penninger, A. P. Jackson & J. A. Knoblich. Cerebral organoids model human brain development and microcephaly. Nature, DOI: 10.1038/nature12517

Journal reference: Nature search and more info website

Provided by Institute of Molecular Biotechnology of the Austrian Academy of Sciences

4.8 /5 (13 votes)

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Jeddy_Mctedder
1 / 5 (10) Aug 28, 2013
this is straight out of science fiction. growing brains in a jar. i understand these experimental neuro setups' are not even really approximations of brains but they do show similar enough patterns to be considered useful for observation and experiment. the only concern is , are these 'models' so grossly distorted from the natural thing in ways we cannot understand? so much so that using them as subjects in experimental hyptothesis will prove at best useless and at worst highly misleading?
packrat
1.4 / 5 (9) Aug 28, 2013
What I'm wondering is how long will it be before one of these gets wired into a computer system to supply 'fuzzy logic' or some other capability to it.
Requiem
1 / 5 (6) Aug 29, 2013
It'd be really interesting to see what types of devices we could wire a brain up to if we could bring one to full term in an environment like this.

Provide interfaces to CCD arrays, microphones, sound synthesis engines, etc for it to grow into in the appropriate topological locations and see what it makes of the signals and feedback it receives. We already know that an adult monkey can learn to control a robotic arm with crude electrode implants.

I think it goes without saying that if you provided an analog signal of the appropriate strength from each pixel in a CCD it would easily gain sight. I wonder if it would be able to decode any data represented as a bit stream? If it could, wouldn't it be something if it figured out H264? It'd be cool(morality aside) to find out what the limits would be.

Taking the idea a bit further, what if we replaced pilots with these things in advanced fighter aircraft, directly wired into every sensor and weapons control system?
Requiem
1 / 5 (5) Aug 29, 2013
Cont...

Imagine the training regimes that would be presented to these purpose-grown brains. It'd probably take a good while(and many tries) to find regimes that didn't result in them going insane before their "warranty ran out". Obviously for every iteration of the physical interfaces, the input signals(and to a lesser degree the devices generating them), and the training regime, you'd need to grow a new brain and allow it to reach the desired level of maturity and training before making an evaluation.

Kind of chilling.
Grallen
not rated yet Aug 29, 2013
The mini brain was growing an eye... it's almost like cloning, but starting at a point where it (probably) can't work out.

It bugs me a little that the lab grown human neural tissue is organizing itself. Does it have activity? What does that mean since it's human tissue.

I love tricky questions.
semmsterr
not rated yet Aug 29, 2013
What I'm wondering is how long will it be before one of these gets wired into a computer system to supply 'fuzzy logic' or some other capability to it.


Sounds exciting!
antialias_physorg
5 / 5 (1) Aug 29, 2013
Google for 'neuron on a chip' and you'll see that that was already done (of course just with single neurons, but still...)

I'm a bit queasy about this type of research. Of course its invaluable for studying diseases of the brain.
But at some point it'll be awfully close to making a functional brain that we'll have to start considering ethical implications.

A brain that has matured beyond the stage where abortion would be legal might have a right to live (?)