Systeembericht: Dutch centres for systems biology now open in eighteen months

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Dutch centres for systems biology now open eighteen months

Things are going well at the three Dutch centres for systems biology that

opened in late 2010. The management of the centres in Amsterdam, Groningen

and Nijmegen have informed us that all new vacancies for researchers

– 11 to 14 at each centre – have now been filled, a good start has been

made on the research, and a number of papers have even been published

in leading journals. The 13 million euros being invested in the centres for

five years is already bearing fruit, they assure us. And there is a lot more in

prospect: information which should lead to a better and more comprehensive

understanding of how cancer, ageing-associated diseases and disruptions

of the energy metabolism occur. These are the research themes on

which the three centres are focusing.

Cancer Systems Biology Center, Amsterdam

In Amsterdam, Lodewyk Wessels and Roderick Beijersbergen of the Cancer Systems

Biology Center (CSBC) at the Netherlands Cancer Institute proudly recall a paper

published in Nature in March 2012. It showed how cancer cells from the colon,

unlike melanoma cells, are able to circumvent the blocking effect of anti-tumour

drugs that target a particular protein in a signalling route. The two researchers

identified pathways that lead from a receptor on the cell surface to the triggering of

a growth signal in the cell that prompts tumour behaviour, and discovered how a

blockage in one route leads to the activation of another. ‘It’s a good example of our

approach’, says Beijersbergen. ‘We are trying to discover which genes and proteins

play a role in the development of tumours in certain types of breast cancer, and

how the different elements – around a hundred, it is estimated – are linked. Then

we will develop a computer model to find out what happens in that complex

network when certain steps are inhibited, blocked or stimulated.’

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The CSBC is focusing on a few signalling routes involved in the metabolism and the

survival of cells, and in cells’ response to growth hormones – the MAP-kinase and

PI3-kinase networks. The focus is on two types of breast cancer for which there is

currently no effective treatment – triple negative and invasive lobular tumours.

New drugs are often largely ineffective because tumour cells are able to

compensate for the blockages they cause, reopening pathways or using alternative

ones. The various research groups at the CSBC are working together to develop a

computer model based on observed changes in tumours. The goal is to identify the

dynamics of the various networks and, ultimately, to predict the effects of certain

clinical drug treatments. The researchers are working not only with computer

models and in vitro cultures of breast cancer cells, but also with mouse models for

breast cancer, and tumour material from patients.

‘The findings from the colon tumours are a by-product of our search for the

structure of the signalling networks that play a role in breast cancer’, explains

Wessels. ‘We are trying to make the best possible computer model of the networks

based on what we know from the literature and what we have found in our cell

lines. Then we will test our findings on other cell lines, in mouse models and on

patient material, and adjust the model accordingly. We are using mice, for

example, to study what the genes we have found in cell culture actually do in a

living organism. In tumour material from patients we are exploring whether our

findings are correct, whether there is evidence of new proteins that are involved in

the formation of tumours, and whether we can predict the effectiveness of certain

drug treatments.’

The new information on the regulation of the kinase network has now given rise

to a new combination therapy that overcomes colon tumours’ resistance to the

first drug. This will now be tested in a clinical study on patients with this specific

type of colon tumour.

Centre for Systems Biology and Bioenergetics, Nijmegen

Paediatrician and professor of mitochondrial medicine Jan Smeitink of the Centre

for Systems Biology and Bioenergetics (CSBB) at UMC St Radboud is also extremely

pleased with his group’s initial progress. As he explains, his group was not set up

specifically for this grant, but had already existed for some time. ‘From clinicians to

mathematicians, biochemists to bioinformaticists and cell biologists to

pharmacologists, they had been working on hereditary disorders of the energy

metabolism for years, often in varying combinations’, he explains. ‘The CSBB has

brought them together to focus on a single theme.’ For personal reasons, Smeitink

has devoted his career to the treatment and understanding of these often fatal

disorders, which now lie at the core of the CSBB’s work. The centre focuses

particularly on the energy metabolism in the mitochondria of muscle cells.

Smeitink’s goal is to have a model of a muscle cell within five years that can

predict what will happen if disruptions occur in the energy metabolism, and

provide a guide for interventions. ‘In the beginning we had a great deal of trouble

with definitions’, he recalls. ‘Even the mere concept of a “model’ meant something

different to each discipline. The mathematicians envisaged something entirely

different from the biologists. Eventually we will produce both a biological and a

mathematical model.’

Energy production in mitochondria revolves around the production of ATP in a

process known as oxidative phosphorylation, a complex chain of enzymatic

conversions involving several protein complexes. Complex-I, for example, includes

45 different proteins and a small change at a crucial location or an assembly error

can disrupt energy production. Smeitink has been working on complex-I since

1996. This is the most intricate complex, which is also involved in the majority of

hereditary mitochondrial disorders. ‘We do not want to risk overstretching

ourselves,’ explains Smeitink, ‘which is why we are focusing on complex-I in

particular, but in the slipstream of the research we will also look at other things.

We want to have the best possible understanding of what happens, but we will

still have to work to some extent with a black-box model.’ There are around a

thousand patients in the Netherlands with mitochondrial disorders in energyguzzling

cells in the brain, muscles and heart, 80% of whom will die before the age

of ten. Some 250 gene defects have now been identified.

The strength of the Nijmegen study lies in the combination of a huge amount of

clinical data from patients, new bioinformation methods for tracing genes,

imaging techniques that allow interactions between proteins in the cell or the

number and type of free radicals to be observed, and the input of mathematicians

in the development of models and of pharmacologists in developing suitable drugs

for interventions.

 

‘We now have a model that relates data from a patient’s skin cells, like the level of disruption in the calcium metabolism and the quantity of free radicals, with the

severity of the disorder’, Smeitink says. ‘By using high-content microscopy, we

have also been able to reduce the length of time it takes to analyse patient

material from several weeks to just a few days. We can now see how the number

of free radicals in a cell changes under the influence of drugs, for example. There

are quite a few drug treatments – like cholesterol-lowering medications, antiinflammatories,

classic antibiotics and anti-epileptics – that affect the energy

metabolism of mitochondria, causing tiredness. We have worked out how certain

drugs do this, and discovered a substance that curbs this interaction in mice. This is

one of the most recent results of our collaboration at the CSBB, alongside a major

review paper in The New England Journal of Medicine last March.’

 

Systems Biology Center for Energy Metabolism and Aging, Groningen

The Groningen centre for systems biology also focuses on the energy metabolism,

but there the emphasis is on ageing. What happens to the energy metabolism

when cells grow older, and how does the energy metabolism influence ageing?

These are the two key questions exercising the minds of staff at the Systems

Biology Center for Energy Metabolism and Aging (SBC-EMA). The centre is a

collaborative venture involving the University of Groningen’s Faculty of

Mathematics and Science and its UMC. Matthias Heinemann and Barbara Bakker

coordinate the research on yeast cells and mice. ‘Yeast cells die after three days,

but we have little idea what kills them and what happens as they age’, says

Heinemann, who specialises in yeast. ‘Ageing is a very broad phenomenon. We

know at any rate that the energy metabolism changes as yeast cells grow older.

But we don’t know the cause and effect.’

Heinemann’s group conducted a major experiment in which they spent three days

taking samples from a growing and dividing population of yeast cells. The

researchers hope that the continuous monitoring of a range of properties in the

yeast cells will help them understand what happens during ageing, such as the

presence of certain proteins, and the activity of genes. ‘We are using various

statistical modelling methods to try and establish what happens first, and what

follows, and to describe it in a quantitative model’, says Heinemann. ‘We are

looking not only at a population of ageing yeast cells, but also at the ageing of an

individual cell.’

This is not easy, because during the three days of the mother cell’s life, she and her

daughters divide 30 to 40 times. How do you find the mother among her tens of

billions of descendants? Heinemann and his colleagues have developed a

technique that keeps the mother cell in position. ‘It’s one of our centre’s first

publications,’ he says, ‘a very technical paper, but essential to our research on the

ageing of individual cells.’ Ageing can be manipulated, by caloric restriction, for

example – a very low-energy diet, in other words. This works not only in various

groups of animals, but also in yeast cells. It would seem that the genes involved in

the glucose metabolism play a role in this.

Bakker focuses mainly on mice. They are much more complex than yeast cells,

because the various types of tissue and cell behave differently, and influence each

other. Besides the fact that caloric restriction curbs ageing in both yeast and mice,

similar genes also appear to play a role in ageing in both organisms to a certain

extent. As with yeast, the researchers are therefore beginning with a detailed

characterisation of the ageing process in mice under various conditions, such as a

high- or low-fat diet, large or small amounts of food, and large or small amounts of

exercise on a treadmill in the cage. ‘But this experiment will take two years rather

than three days’, says Bakker. ‘That is why we have thoroughly tested our method

on old mice left over from another study. Since mice are more complex than yeast

cells, we are forced to restrict ourselves mainly to the sugar and fat metabolism in

their liver, skeletal muscle and heart. The mice are subjected to all kinds of

measurements in each age group, and when they have been killed other research

groups, such as stem cell researchers, can use their material.’

The mice researchers, like those working on yeast, are working towards computer

models that can help explain the ageing process. ‘We now have a well-validated

computer model of the oxidation of fatty acids, and we are now linking it to the

sugar metabolism’, says Bakker, who points out that her group is still focused

mainly on technical preparations for the experiment, such as fine-tuning the

operations that will need to be performed on the animals, and learning the right

way of inserting cannulas. ‘Our model is currently based on data from young

animals. During the course of the experiment we think we should be able to

expand this to include animals of various ages and histories. In paediatrics we have

been focusing on the metabolisation of fatty acids and sugar. So there are clear

similarities with the Nijmegen study.

Systems biology is an approach to biological processes

that combines experiments and computer modelling.

In systems biology research, information from various

disciplines – such as biology, mathematics, medicine

and engineering – are combined to enable us to understand

life as a system. The increase in knowledge

achieved by this approach will have a huge impact,

both social and economic, in a range of sectors. In

the medical and pharmaceutical sector, it offers the

prospect of ‘personalised medicine’, the development

of new drug treatments and alternatives to animal

testing.

NWO and ZonMw opened a call for systems biology research

in 2009. This led to the establishment of three

research centres. The results of their work will help

in the development of better treatments for breast

cancer and specific metabolic disorders, and improve

our understanding of how people can enjoy an active

and healthy old age.

Programmes for systems biology research are funded

by ZonMw, the Netherlands Organisation for Scientific

Research (NWO), the European Commission and the

Dutch Ministry of Health, Welfare and Sport. ZonMw’s

main commissioning organisations are the Ministry

and NWO.

For further information, go to:

www.zonmw.nl/erasysbio

www.zonmw.nnl/mkmd

ww.nwo.nl/systeembiologie

Contact

Rob  Diemel Theo Saat

T +31 70 349 52 52 T + 31 70 344 07 91

E [email protected] E [email protected]

ZonMw supports health research and healthcare

innovation.

NWO enhances scientific quality and innovation by

selecting and funding the best research.