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Posted: Jul 18, 2013

Time to investigate the whole human genome

(Nanowerk News) How to cure malignant brain tumour? Why two cells from the same organism, in spite of having identical gene set up, have different shape and functions? How small variations in human genes determine changes in the way we think, feel and behave? Answers to such questions are sought by scientists from the new Laboratory of Molecular Neurobiology of the Nencki Institute.
Watching individuals is not enough to predict the reactions of a crowd of people. The same is true in genetics: we can study individual genes in the cell, but to understand the functioning of the whole cell in a given tissue, one must find out how the entire genome works in a particular setting. The study of genomes and deciphering the information they carry about human brain cells is the main research objective of a new core facility at the Nencki Institute of Experimental Biology in Warsaw, called The Laboratory of Molecular Neurobiology and established under the Neurobiology Center. This lab replaced a former unit and is about to start research activity – as one of five new core facilities of the Neurobiology Center established under the project entitled Centre for Preclinical Research and Technology CePT.
Many research groups in the world focus their scientific endeavours on the functions of one or several genes or the proteins they code. But each human cell consists of over 20 thousand genes! Moreover, different genes are active in different types of cells. This phenomenon is related to the fact that even though each cell from the same organism has an identical set of genes, protein coding genome occupy no more than 2% of the human DNA. It is estimated that approximately 80% of the DNA – in the past considered useless and called “junk DNA” – contains sequences regulating the expression of genes. It also turns out that a set of regulatory sequences differs in cells of different types and under various conditions. Therefore without the knowledge about how the whole genome is read out in a given type of cell, one cannot understand its functioning.
“Our lab focuses on large scale genome research as we try to analyse at the same time the level of regulation for all genes present in the genome. We are one of the first research groups in the world to soon conduct such analyses on specialised brain tissue cells”, explains Prof. Bozena Kaminska (Nencki Institute). In the next five years the lab will sequence 150 human genomes.
Nencki researchers are interested in cells’ pathology, especially brain tumor transformation. Tumours are caused by gene mutations but epigenetic effects, arising from reversible modifications of protein-DNA complexes inside the tumour cell and in its vicinity, are also important. These changes can influence the reading of genetic information.
The current strategy of fighting tumours consists of attempts to inhibit the functions of molecules encoded by the altered genes and find ways to kill the tumour cells or stop their proliferation. This is a difficult task, because many tumour mutations increase the life span and prevent cell death. As opposed to gene mutations, which are irreversible and impossible to correct, epigenetic changes may be reversed. A new approach has therefore surfaced in fighting tumours, focused on investigating epigenetic mechanisms both inside the tumour as well as in its microenvironment.
“We want to understand the chemical and biological processes, which occur within tumour vicinity and facilitate tumour progression. Why? A tumour cell shapes its microenvironment to support its growth, actively inhibiting the immune system. Instead of attacking the tumour cell directly, we can try to restore the original features to its environment, which could limit the development of the tumour or even eliminate it”, states Prof. Kaminska.
It is especially important that research conducted in the Laboratory of Molecular Neurobiology of the Nencki Institute focuses on deciphering the whole genome information not only in laboratory cell lines but also in cells from human brain tumours. It is possible due to cooperation with the Institute of Psychiatry and Neurology in Warsaw and Children’s Memorial Health Institute, which supply samples of tumours removed from patients for research. From those tumours different types of cells are isolated, including glioma initiating cells, which are important for tumour recurrence.
“The obvious application area for our research is medicine, especially with respect to investigating the mechanisms in brain tumour pathology. But not only. Epigenetic changes and dysfunctions in reading genetic information may also cause disorders accompanying mental illness such as schizophrenia. In cooperation with psychologist Prof. Janusz Rybakowski from Poznan and an expert in bioinformatics Prof. Jan Komorowski from the Uppsala University we plan to create brain specific ‘maps of regulatory areas’ to search them for genetic changes associated with schizophrenia”, says Prof. Kaminska.
The new lab at the Nencki Institute has at its disposal an excellent set of cutting edge research equipment. Previously used devices, which enable investigating the expression of one to several genes, have been supplemented with microarray scanner, which makes it possible to investigate at the same time the expression of virtually every human gene. Another valuable purchase is a device for laser microdissection. It enables researchers to precisely cut out tissue fragments of interest or even individual cells from the tissue. The equipment installed in the lab is very accurate: no more than 150 cells are needed to isolate the RNA and investigate the expression profile of all genes.
Complexity of such research requires specialised IT support provided by a team of IT experts, who not only process the data gathered using these special methods but also create their own algorithms for analysis, which help predict, among other, the effect of a drug on individual cells. Since the information recorded about individual genome or a full description of cell reactions may occupy even half a terabyte, works are under way to equip the lab with a large server, which would be able to effectively process huge amount of data.
The Centre for Preclinical Research and Technology CePT, of which the Nencki Institute is a partner, is the largest biomedical and biotechnological undertaking in Central and Eastern Europe. The budget of this project amounts to over 388 million PLN, of which 85% comes from the European Fund for Regional Development. Under CePT a network of related core facility labs is being established, integrating research and implementation activities of various scientific institutions of the Ochota Research Centre. These labs allow conducting basic and preclinical research at the highest European level in the area of protein structural and functional analysis, physics, chemistry and nanotechnology of biomaterials, molecular biotechnology, instrumental support for medical technologies, pathophysiology and physiology, oncology, genomics, neurobiology and ageing-related diseases.
The Nencki Institute of Experimental Biology of the Polish Academy of Sciences has been established in 1918 and is the largest non-university centre for biological research in Poland. Priority fields for the Institute include neurobiology, neurophysiology, cellular biology and biochemistry and molecular biology – at the level of complexity from tissue organisms through cellular organelles to proteins and genes. There are 31 labs at the Institute, among them modern Laboratory of Confocal Microscopy, Laboratory of Cytometry, Laboratory of Electron Microscopy, Behavioural and Electrophysiological Tests. The Institute is equipped with state-of-the-art research equipment and modernized animal house, where lab animals are bred, also transgenic animals, in accordance with the highest standards. Quality of experiments, publications and close ties with the international science community, place the Institute among the leading biological research centres in Europe.
Source: Nencki Institute of Experimental Biology
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