Asymmetric Cell Division

The ability to reproduce is one of the most fundamental traits of all living organisms. Cells - the basic building blocks of each and every living organism - reproduce by cell division, a process in which a parent cell splits into two daughter cells. In general, the two daughter cells are identical. However, sometimes cells divide asymmetrically, that is, into two cells which differ in size, shape or potential. Asymmetric cell division is especially important in stem cells, the most important characteristic of which is that they can produce further stem cells as well as specialised cells which do not divide again and serve to replace dead cells in the body. Jürgen Knoblich`s work has shed light on asymmetric cell division in the Drosophila melanogaster fruit fly, broken the process down into clearly defined steps and identified the mechanisms which control each individual step. In particular, Knoblich and his team have succeeded in explaining how stem cells deliberately pass on certain factors to only one of the two daughter cells, and how those factors change a daughter cell in such a way that it develops differently from the parent cell. For this purpose, Knoblich broke the process of asymmetric cell division down into three steps: First, the parent cell has to define an axis along which asymmetric cell division takes place. This axis has to be coordinated with the surrounding cells so that the two different daughter cells each end up in the right place. During cell division, certain factors - known as "Numb" and "Brat" in flies - are transported along this axis so that they are concentrated at one end of the cell. At the same time, the division plane is oriented in such a way that only one of the two daughter cells inherits the concentrated material. For all of these processes, Knoblich discovered the decisive genes and identified the mechanisms by which their interaction leads to successful asymmetric cell division. These genes are also found in humans, and the latest findings from Knoblich`s laboratory have shown that they work in a surprisingly similar manner in mice. This discovery is especially significant because Knoblich`s research team has also found that defects in asymmetric cell division can trigger brain tumours, at least in flies. As it is becoming increasingly clear that stem cells play an important role in the formation of tumours in humans, Knoblich`s work bears particular significance for the field of tumour biology. Knoblich`s efforts could someday make it possible to manipulate asymmetric cell division processes, thus directing stem cells to generate either more stem cells or more specialised cells. Such a breakthrough would eliminate a major obstacle faced by stem cell therapy as well as tumour biology.

The human brain undoubtedly is the most complex but also the most fascinating structure that nature has generated. It contains 86 billion neurons that have to be born at the right time, migrate to the right position and wire up in the correct way, in order to allow us to perform the cognitive processes we are capable of. The funds provided by this research grant have enabled us to make important progress towards understanding how this fascinating structure is formed in a developing embryo. We have analyzed brain development in simple animal models like insects and have obtained valuable information on how the neural stem cells in those animals generate the various types of neurons present in those simple brains. Specifically, we have asked how defects in the regulatory processes can lead to the formation of brain tumors. In doing so, we have established valuable connections between energy metabolism and brain tumors but also identified and characterized new tumor inducing genes and pathways.In the end, however, we want to understand the human brain. For this, our research group has developed a three-dimensional cell culture method that allows us to examine the development of the human brain in the laboratory. Using stem cells that can be generated from any human individual, we are able to grow cultures that resemble the brain of a three- month old human embryo. The similarity of our cultures with an actual human embryonic brain is striking: Both the three-dimensional organization, the different types of cells and their relative three-dimensional arrangement can all be recapitulated in our culture system. The nerve cells we are able to grow are electrically active, communicate with each other and extend long cable-like processes called axons to reach nerve cells far away in the cultures. Most importantly, we can grow our cultures from human patients who suffer from diseases that affect brain development. We have worked with a patient who carries a mutation causing microcephaly, a devastating brain disorder resulting in unnaturally small brains and major cognitive impairment. We could recapitulate the disease in our cultures and use them to find out why those defects arise. Most importantly, our work has opened the path for characterizing more common neuropsychiatric disorders like epilepsy or autism. As our cultures can be grown in large numbers, they open the possibility of testing potential drugs to see whether they can cure the defects. This is not only an alternative to animal experiments but also allows for the development of more specific drugs that are individually tailored to individual patients and their specific sub-forms of the disease.The work that led us to develop the brain culture system marked a major change in our research direction. Without the generous funds provided under this grant, this would certainly not have been possible.