Brain research we know that we hardly know anything volkswagenstiftung

June 2021 took place digitally.

Analysis and emotions – at its best, our brain can do both. For research, however, our thinking organ still holds many questions (Graphic: AdobeStock / peshkov).

Under the title"The human brain – explorations of a fascinating organ" languages Prof. Dr. Wolf Singer, Prof. Dr. Dr. Elisabeth Binder and Prof. Dr. Jurgen Knoblich with moderator Maria Grunwald. They gave u.a. Insight into the possibilities. Limitations of brain organoids.a. Insight into the possibilities. Limitations of brain organoids. Organoids are organ structures that are generated in vitro with the help of stem cells. Brain organoids represent one of the most important current research approaches to replicate parts of the human brain and thus to be able to study diseases about which science still knows too little to be able to treat them.

Brain research: methodological and intellectual challenges

The scientific kick-off was given by Prof. Dr. Wolf Singer, Professor emeritus at the Max Planck Institute for Brain Research in Frankfurt am Main and founding director of the Ernst Strungmann Institute for Neuroscience ibid. Under the title "The fascination of the human brain. What we know – consequences and challenges" he first gave an overview of findings that science considers to be certain about our brain. In addition to the evolution of the organ, this also includes, for example, which structures and areas are responsible for services such as vision, speech, motor skills, but also moral sensation, and how they interact with each other.

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He cited recording the activity of a very large number of nerve cells simultaneously and understanding their interaction as a major methodological and intellectual challenge. This requires complex mathematical methods. In addition, it is a matter of analyzing processes whose complexity and dynamics exceed our imagination. This is a major problem in hypothesis generation, he said. "We can't imagine what the brain can do."

Wolf Singer provided insight into the major gaps in knowledge that continue to plague research around the human brain by formulating three questions. The most important question for him is: What are the reasons for dysfunctions that lead to diseases, such as depression, schizophrenia, autism, personality disorders, or to degenerative diseases such as Parkinson's or Alzheimer's disease? He described the "mind-body problem" as the most difficult question that brain research will have to deal with for a long time to come. Behind this lies the question of how our individual sensations, emotions and decisions are produced by neuronal interaction. "We have no answer to this question", so Singer. He ended with the most burning question for him, calling it "the one that concerns me the most: How can it be that people lead normal, well-adjusted lives and at the same time are capable of planning and carrying out monstrous atrocities?? "The question is: Does brain research help us to at least mitigate this behavior?"

To record the activity of a very large number of nerve cells simultaneously and to understand their interaction is a methodological and intellectual challenge, Singer said. (Photo: Volkswagen Foundation)

Psychiatric Diagnoses: From Symptom to Mechanism

Taking the medical angle in the following lecture Prof. Dr. Dr. Elisabeth Binder, Executive Director of the Max Planck Institute for Psychiatry in Munich, a. She dealt with "Status and perspectives of the treatment of psychiatric diseases".

To start, Binder pointed out that psychiatric diseases are a worldwide problem. They are among the diseases that, in addition to the individual suffering of those affected, contribute to the greatest burden of disease on society, z.B. due to dropout from work or social life. In addition, these diseases are difficult to treat. As a result, half of patients remain in a state in which they do not return to the same level of functioning as before the disease.

Binder called it a dilemma that psychiatry still has only a very rudimentary understanding of disease processes. The diagnoses are purely symptom-based, there are no biomarkers, treatment takes place according to the trial and error principle. To illustrate this, she said that there are more than 3,000 approved clinical tests in internal medicine, ranging from blood-based examinations to ultrasound, ECG and blood prere monitors. "In psychiatry, on the other hand, we have a single approved diagnostic tool: that is the cataloging of symptoms, which are worked out in a dialogue between patient and therapist. All our diagnoses are based on symptoms only."

Binder described it as a dilemma that psychiatry still has only a very rudimentary understanding of disease processes. (Photo: Volkswagen Foundation)

But she also shared encouraging messages. She emphasized that there have been breakthroughs in several areas in recent years, including major advances in genetics, so-called optogenetic methods, and smart devices that measure patients' movement, stress levels, or sleep patterns in the natural environment.

All these possibilities and methods generate vast amounts of data that now need to be understood. "Advances in artificial intelligence are very important for this.", said the psychiatrist. "We need a mechanism-based diagnosis that allows us to understand psychiatric diseases from genes, to cells, to circuitry, to behavior." Then it would be possible to treat patients who at the moment still have the same diagnosis as z.B. This will help to differentiate between patients who have schizophrenia or depression but are ill for different reasons, and thus to be able to offer personalized interventions in the future.

For this to happen, basic research, clinical research and patient care must be closely intertwined. Elisabeth Binder ended with the appeal: "We must take a broader view of people. This will lead to more targeted and more effective therapies."

Brain organoids: recapitulation of the human brain

The currently probably most promising method for a better understanding of the human brain presented Prof. Dr. Jurgen Knoblich, scientific director at the Institute for Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences in Vienna before. In 2013, his team succeeded in synthesizing a brain organoid that recapitulates the development of some parts of the human brain.

Under the title "Brain Organoids – An Approach to the Human Brain he first linked to Elisabeth Binder's statements about the large number of people with mental illnesses. She was faced with relatively few options for treating these disorders. In recent decades, there have been no new active principles, which has led most pharmaceutical companies to stop researching new drugs. The success rate in drug development for neurological. Psychiatric diseases, he said, are the lowest of all. "But", so Prof. Knoblich: "There is hope!"

"With the models we currently have, we think we can make a big contribution to the study of neurological and psychiatric diseases.", summarized Knoblich. (Photo: Volkswagen Foundation)

Researchers are able to turn induced pluripotent stem cells, known as iPS cells, into ties of various organs. Knoblich's team initially focused on research into microcephaly, a hereditary disease in which affected children are born with an unusually small head, which can lead to brain damage and developmental delays. When the ZIKA virus appeared in Brazil in 2016 and at the same time there was an enormous increase in newborns with microcephaly, experiments in organoids provided evidence that the ZIKA virus was causally responsible for these diseases.

According to Knoblich, brain organoids can also be used to create brain tumor models that can be used to test the efficacy of certain drugs. The latest "coup he presented the single cell analysis in cerebral organoids. "This allows us to predict which genes were active in a single cell. Recently, we succeeded in identifying the precursor cells of tuberous sclerosis."

In summary, Jurgen Knoblich stated that brain organoids already reflect human brain development very well. "With the models we currently have, we think we can make a major contribution to the study of neurological and psychiatric diseases", he summed up. In the future, it will also be possible to develop models for more common hereditary diseases and to use organoids for the automated search for drugs. The ensuing discussion focused primarily on ethical ies. Legal ies concerning the handling of brain organoids. Prof. Knoblich explained that organoids do not have blood vessels, among other things. One approach, he said, is to implant organoids into the brains of mice, whose blood vessels grow into the organoid and supply it.

There was a follow-up question from the audience: How can the acceptance of animal experiments be improved?? Prof. Singer pleaded for more education, more transparency, the laboratories must allow a direct view of the animals. He said, "I think we need to make it clear that scientific curiosity is a cultural activity. What makes us special is our ability to penetrate the world." At the same time, he described animal testing as the most ethically challenging aspect of brain research.

Moderator Maria Grunwald (l.u.) spoke with Prof. Dr. Wolf Singer (r.u.), Prof. Dr. Dr. Elisabeth Binder (r.o.)) and Prof. Dr. Jurgen Knoblich on the human brain. (Photo: Volkswagen Foundation)

Whether the experts saw further ethical concerns in organoid research, he was asked from the audience. Jurgen Knoblich answered that the scientific community is working intensively on ethical questions concerning human stem cells. "It is important for me to point out that this is what scientists from all over the world are discussing." There were people who compared the activities of brain organoids with those of human newborns. In his view, this is unjustified, even a "false reality". He ruled out that present-day brain organoids could have a consciousness. "Even a piece of brain operated out in tumors has no consciousness.", he said. "And that's much bigger than an organoid."

Moderator Grunwald wanted to know whether brain organoids needed to be protected and who actually owned them? Jurgen Knoblich answered that they do not need protection. If it were found that the organoid had a sense of pain, it would look different "but we are miles away from that". The organoids belong to the respective research institution, and that is also highly relevant, she said. He believed that it would be the end of this research if the donor of the iPS cells from which the organoid was created had to agree to every experiment. Then there would also be no reproducibility of scientific findings.

Organoids: "A great tool that can't explain everything"

Elisabeth Binder was asked what she thought should be in the statement on brain organoids that the Leopoldina working group is currently drafting. She said it was important to her to also point out the limitations for psychiatric research. "There will be many potentials, but there are also many other mechanisms or circuitry that we cannot represent. We are interested in complex behavior. Organoids will never be able to behave. It's a great and new tool, but it can't explain everything", according to the researcher. Wolf Singer agreed with this statement, pointing out that certain questions about psychiatric diseases can only be studied on the system itself, not on a surrogate such as organoids.

In response to the moderator's final question about which other profession they would like to slip into in order to advance brain research, all three researchers settled on the profession of educator. Prof. Binder noted that education always involves the question of how to create optimal conditions for brain development. Prof. Knoblich added that education is a particularly important social task.

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