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Computational Biology
28.07.2016

Monitoring cell fates

An international team of researchers led by scientists of Helmholtz Zentrum München and ETH Zurich has been studying the factors influencing the development of different blood cells. Their research shows that certain molecular mechanisms are not as relevant as previously assumed. This finding helps to improve our understanding of diseases such as leukaemia and anaemia. The study is published in ‘Nature’.

Red and white blood cells move along a vessel

Stem cells can give rise to all types of specialised blood cells. Source: Fotolia/psdesign1

In biological terms, a cell is the smallest functional entity of living organisms. The human body contains an enormous number of cells: somewhere in the region of 10 to 100 trillion, depending on a person’s size and weight. Most of these cells perform specific functions in the body and are called differentiated cells. Stem cells, on the other hand, are able to continuously divide to produce more stem cells and differentiated cells, thereby providing an endless supply of differentiated cells. Certain cells in the body have a relatively short life span. For example, many white blood cells (leucocytes) and blood platelets (thrombocytes) die within a few hours to a couple of days, while red blood cells (erythrocytes) survive around four months.

Stem cell regeneration

Stem cells in the bone marrow thus produce millions of new blood cells every second. These stem cells are multipotent, which means they can generate all types of specialised blood cell with different functions: red blood cells, responsible for oxygen transport, white blood cells that are part of the body’s immune defence system, and blood platelets which play a key role in blood-clotting. Exactly how stem cells develop into different cell types is still only partly understood. The process of differentiation – in other words, the decision as to which type of cell will be produced – depends on a number of different external and internal factors.

Timm Schroeder, Professor at the ETH Zurich Department of Biosystems Science and Engineering based in Basel, and his colleagues are studying the factors that play a role in the development of the individual blood cells. “The regulation of stem cell differentiation plays a vital role in maintining the normal process of blood formation”, explains Professor Schroeder. “If this system starts to malfunction, it can lead to life-threatening diseases such as anaemia and leukaemia. We therefore need to have a better understanding of the molecular mechanism involved in this regulation”, the former Helmholtz scientist said.

Observation at the molecular level

The cell biologist and his team are analysing how stem cells differentiate into the different types of blood cell and how molecules in the cell nucleus (transcription factors) control this complex process. Working with Prof. Dr. Dr. Fabian Theis, Direcor of the Institute of Computational Biology at the Helmholtz Zentrum Munich, they have developed an innovative microscopy technique for observing cells – cutting-edge equipment that is only found in very few of the world’s stem cell research laboratories.

The two proteins GATA1 and PU.1 have been a particular focus of the researcher’s attention. They play an important role in the differentiation of blood cells, explains Timm Schroeder. “They are transcription factors capable of activating or disabling comprehensive genetic programs with many target genes. This makes them powerful regulators of cell fates.”

Promising potential

Using time-lapse microscopy, the researchers could observe living blood stem cells with unprecedented precision as they differentiated, while also quantifying the two proteins GATA1 and PU.1. “For decades it was thought that these two transcription factors were responsible for making the lineage decisions for stem cells. Now we are able to show that this is not the case, but that other mechanisms must be responsible for these decisions”, explains Schroeder. Research now needs to concentrate on other molecular mechanisms in order to understand the extremely complex process of blood stem cell differentiation.

Blood diseases such as leukaemia are severe disorders of the blood system. To improve our understanding of such diseases in future and to come up with effective treatments, we need to know exactly how the individual blood cells are created. A foundation stone for this research has now been laid.

Further information

Original publication
Hoppe SP et al.: Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios. Nature 2016, 535: 299-302, doi: 10.1038/nature18320

The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.

The Institute of Computational Biology (ICB) develops and applies methods for the model-based description of biological systems, using a data-driven approach by integrating information on multiple scales ranging from single-cell time series to large-scale omics. Given the fast technological advances in molecular biology, the aim is to provide and collaboratively apply innovative tools with experimental groups in order to jointly advance the understanding and treatment of common human diseases. 

Freedom and individual responsibility, entrepreneurial spirit and open-mindedness: ETH Zurich stands on a bedrock of true Swiss values. Our university for science and technology dates back to the year 1855, when the founders of modern-day Switzerland created it as a centre of innovation and knowledge. At ETH Zurich, students discover an ideal environment for independent thinking, researchers a climate which inspires top performance. Situated in the heart of Europe, yet forging connections all over the world, ETH Zurich is pioneering effective solutions to the global challenges of today and tomorrow. Some 500 professors teach around 20,000 students – including 4,000 doctoral students – from over 120 countries. Their collective research embraces many disciplines: natural sciences and engineering sciences, architecture, mathematics, system-oriented natural sciences, as well as management and social sciences. The results and innovations produced by ETH researchers are channelled into some of Switzerland’s most high-tech sectors: from computer science through to micro- and nanotechnology and cutting-edge medicine. Every year ETH registers around 90 patents and 200 inventions on average. Since 1996, the university has produced a total of 330 commercial spin-offs. ETH also has an excellent reputation in scientific circles: 21 Nobel laureates have studied, taught or researched here, and in international league tables ETH Zurich regularly ranks as one of the world’s top universities.

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