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Miniature brains made from stem cells. (Copyright: BIH/David Ausserhofer)


Miniature brains made from stem cells

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The brain organoids generated from human stem cells fit into a small petri dish. (Copyright: BIH/David Ausserhofer)
The brain organoids generated from human stem cells fit into a small petri dish. (Copyright: BIH/David Ausserhofer)
After approximately 30 to 40 days, the brain model has grown to a size of 4 to 5 millimetres. (Copyright: BIH/David Ausserhofer)
After approximately 30 to 40 days, the brain model has grown to a size of 4 to 5 millimetres. (Copyright: BIH/David Ausserhofer)

Scientists of the Charité and the Berlin Institute of Health (BIH) have established a brain model from human pluripotent stem cells. Ultimately, it is their goal to discover novel therapeutics that can prevent cell death in the event of a stroke. A welcome side effect is that this method may replace a large amount of animal testing.

One could say that strokes have been relatively well researched already. Within the last twenty to thirty years mouse models particularly have shed new scientific light on the pathophysiology of stroke. But for the large majority of patients an effective therapy is still wanting today. The dissolution of artery-clogging blood clots either through medication (lysis) or operatively (thrombectomy) is an option for only 10 to 15 percent of the patients.´Time is the greatest adversary in this field.

Roughly 270,000 people in Germany suffer from this serious event each year – about half of them suffer severe neurological long-term damage and about a quarter of them die as a result. The demand for new therapies is huge.

Focusing on cell death
Dr. Philipp Mergenthaler and Dr. Harald Stachelscheid from the Charité and the Berlin Institute of Health agree that there is a “problem” with strokes. The neurologist and the stem cell scientist have teamed up more than two years ago to research novel therapeutic advances. They have already detected a promising hint: a molecule that may under certain circumstances bring cell death to a halt in the event of a stroke.

This may be newsworthy in itself, but equally impressive is how they got there. To get a closer look at the mechanisms of cell death in the brain and at the effectiveness of the new molecule in particular, the scientists no longer rely on animal testing in mice as was the fashion, but on especially engineered miniature brains. The two researchers generate so-called organoids in the Charité laboratories with the aid of induced pluripotent stem cells, which were generated from cells of adult humans. In order to achieve this, a mature cell is taken from, say, the blood or the skin and then regressed by design in the laboratory to an embryonic-like state.

Brain-like tissue from humans, not mice
Harald Stachelscheid, who is the head of the core facility for pluripotent stem cells at the BIH, says “pluripotent stem cells are especially valuable, because they can differentiate into all cell types of the body.” Thus also into neurons, astrocytes, oligodendrocytes and microglia cells, which are the cells that make up the brain. These organoids – only measuring a few millimeters – possess cell types and to some extent the organizational structures of a brain.

“It is crucial that the brain-like tissue comes from humans,” emphasizes medical doctor and neuroscientist Philipp Mergenthaler, who is affiliated with the Charité Centre for Stroke Research Berlin among others and who is supported by the Charité-BIH Clinician Scientist Program. “Beyond that, we can study disease mechanisms closely tailored to the individual patient and potential therapeutics in a personalized medicine context.”

Is it therefore possible to study the effects of a stroke deeper and more realistically with brain organoids than with mice in animal testing? You could call this the aspiration of the endeavour, but the translation of results from basic research into clinical use is always complex. “Let’s be honest about this,” says Philipp Mergenthaler, “we do not know yet how well organoids may eventually represent human diseases.”

This circumstance makes the research on and the further development of the model the principal challenge for the two scientists. And also one which is neither financed nor receiving grants from third parties. But since the scientific world looks at human models as future models and since it is an established goal to reduce animal testing, the two researchers do this daunting task “on the side”, so to speak. But colleagues from other disciplines offer assistance.

Miniature brains emit electric signals
A group of neurophysiologists with Prof. Dr. Jörg Geiger of the Charité assist in measuring the functions of nerve cells and their electric activity – and in fact the tiny three-dimensional nerve clusters do show some spontaneous neuronal activity. The computer models of the experimental research of Charité neurologist Prof. Dr. Petra Ritter will also be instrumental. These models are informed by large amounts of data from clinical studies and clinical imaging thus simulating neuronal brain activity in a life-like manner. This will enable the researchers to compare the simulations with the measurements done on the organoids. Mergenthaler explains, that it is “from these elements and from what we can gather from microscopy and metabolic activity that we can create a comprehensive picture of how close our organoids actually are to reality.”

But much more help is needed in the form of artificial intelligence, since there is a plethora of data coming in – with enhanced microscopy alone creating hundreds of thousands of images. Harald Stachelscheid emphasizes that “it is only with the aid of tools like deep learning that we can even process these images in a way that computers can draw useful information from them." Philipp Mergenthaler adds that “we do develop the relevant software ourselves, but it also shows that such a project can only succeed with the help of very many partners.”

Organoid platform being distinguished by the state of Berlin
There is a large amount of human and artificial intelligence present in the newly developed model platform. Since this approach has the potential to replace animal testing in stroke research, Mergenthaler and Stachelscheid already in 2017 were rewarded the prize of the state of Berlin “for the promotion of research into replacement and complementary methods for animal testing in research and lecture.”

The decisive edge in this is that one plate of cell cultures features 100 to 400 organoids at the same time. The plates themselves are no larger than a CD. Thousands of miniature brains can thus “live” together in a constricted space for research purposes. It would be unthinkable to keep a comparable number of mice this way. Quantitatively speaking, the human models are far superior to animal testing as a much larger number of tests on medical agents can be conducted within a short period of time. “This aspect is paramount in the reduction of animal testing” says Mergenthaler. “We do believe that organoids can substantially improve the validity and reproducibility of test results in stroke research – and this helps to reduce animal testing on a large scale.”

Blood vessels still to come
The human models do carry one disadvantage: organoids have no blood vessels and therefore no circulation. Scientists all over the world and also at the BIH are busy working on a solution, but blood vessels remain a tender spot. Stachelscheid even calls them the “Holy Grail” in the world of organoids. But scientists say that this deficit can be pretty well compensated with the validation techniques named above. Apart from that, every model needs to be validated according to its purpose, there is no “one-fits-all” in this. Stachelscheid says that “we hope, anyway, that we do evaluate some aspects better than the mouse model.”

It is for further experiments to show whether this hope is justified. We will only know how applicable the approach from Mergenthaler’s and Stachelscheid’s laboratories really is when their results can be validated on humans.

The molecule still has a long way to go
So there is no telling whether the molecule will make its long way into the pharmacies of the world. Research with human model systems is only one step in the development of new drugs that lasts for years. But we should cross our fingers for its success. If it all works out, the new agent could protect brain neurons from dying and thus prevent some of the neurological consequences of a stroke. “We may not be able to save the core areas of the stroke, because they are prone to die within minutes,” explains Mergenthaler. “But the larger area around the core area that also suffers from deficient circulation and that is at high risk in the hours and days after the stroke may be protected from further damage.”

The molecule that the Berlin neuroscientist has developed in cooperation with the University of Toronto would be the first specific drug to prevent cell death in the event of a stroke. And one of the first that substantially owes its existence to organoids. Wouldn’t it be wonderful if it could diminish suffering for both stroke patients and mice?

(Author: Beatrice Hamberger)


Dr. med. Philipp Mergenthaler
Klinik für Neurologie mit Experimenteller Neurologie
Centrum für Schlafanfallforschung Berlin
Charité - Universitätsmedizin Berlin
Charitéplatz 1
10117 Berlin

Dr. rer. nat. Harald Stachelscheid
Berliner Institut für Gesundheitsforschung
Core Unit Stammzellen
Augustenburger Platz 1
13353 Berlin     

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