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Why does one cell in our body respond to a treatment, while another does not? The answer to this question could offer a breakthrough in the treatment of pathological, deregulated cells, as in the case of tumours. Pernette Verschure, professor of Functional Dynamics of the Epigenome, devotes her research to this important topic.

Although a tumour often consists of different cell types, even tumour cells of the same cell type can differ from each other. This results in small groups of tumour cells with an altered function. We call this a tumour-cell clone. In many cases, one cell clone of a tumour responds to treatment while another does not.

‘Why is that?’ Verschure wondered. With her research group, she focuses specifically on this cell-to-cell variability and the contribution of dynamics in epigenetic control mechanisms.

But what is epigenetics? Every human being receives one copy of the genome of the father and one of the mother, and carries this package of genetic information in every cell of its body from birth. However, during embryonic development, cells mature into unique cell types each with their own function, such as a liver cell or a brain cell, despite the same DNA information. Epigenetic regulatory proteins ensure that each cell is programmed to turn a part of the genes of the genome ‘on’ while another part is maintained ‘off’. In the field of epigenetics, researchers are interested in the processes that can interfere with epigenetic programming, e.g. external factors such as stress or nutrition.

‘At the molecular level, epigenetic processes are time and spatially-resolved,’ says Verschure. ‘Every gene in the genome that is programmed to be “on”, is not active all the time, but displays a certain rhythm. Moreover, although the epigenetic layer is stably maintained during life to maintain cell identity, it is also reversible. It is precisely this dynamic flexibility that I find so interesting. We want to understand how the epigenetic programme directs the dynamic rhythm of gene activity, and if we can exploit this as a read-out of susceptibility to changes in epigenetic programming. Eventually, such insights can be used to predict deregulated cell behavior.’

Insensitive to treatment

This understanding is essential for the treatment of cancer patients. Due to the differences between tumour cells, it is often noted that only part of the tumour cells are treated effectively.

As the coordinator and initiator of an international consortium, the EpiPredict project funded by the European research programme Horizon2020, Verschure has studied the contribution of epigenetics to the development of non-responsiveness to hormone therapy of breast cancer cells. ‘In order to understand the causal relationship between dynamics in the epigenetic layer and variability in the response of breast cancer cells, we have invested in the further development of quantitative, highly sensitive “single molecule” measurements in individual cells.’

In her lab, Verschure uses a combination of quantitative experimental measurements and computer analyses, machine learning and bioinformatics to predict the system behaviour of the epigenome. ‘We have identified classes of genes with defined dynamic gene activity and have started to unravel their epigenetic composition. Such deregulated epigenetics may be involved in the process of preventing patients from long-term responsiveness to hormonal treatment. By reprogramming the epigenetic composition of these genes in a targeted manner (“epigenetic editing”), we might be able to adjust the non-responsiveness to treatment responsiveness.’

Dialogue with patients

Verschure’s research team is also very active in the communicating of research findings to patients and the general public. ‘I think it is important to reach a broad audience and to conduct a dialogue with various stakeholders, such as patient groups and policymakers.

In the context of the EpiPredict project, we have actively reached out to involved stakeholders with blogs, videos and Science Cafés. We have organised a Science Café in London, where we interviewed patients, former patients and their representatives. That was a very valuable experience. It allows you to find out what's really going on with a patient, for example, how they feel about a particular treatment.’

Responsiveness to long-term epigenetic editing

Verschure will soon be launching a major interdisciplinary research programme on the responsiveness of genes to long-term epigenetic reprogramming. Several research universities, two applied universities, the Rathenau Institute (a parliamentary technology assessment institute) and a wide spectrum of companies are involved in this research, which is funded by the Dutch Research Council.

‘We can reset epigenetic programmes and gene functioning by targeting epigenetic regulatory proteins to specific genes using a variation of the CRISPR/Cas platform. This is known as epigenetic editing,’ says Verschure. ‘However, long-term gene activity reprogramming by epigenetic editing is difficult to achieve because not all genes respond in the same way. We are developing the rules and tools for long-term epigenetic editing as a new key technology to address major societal challenges, such as age-related diseases and global demand for food.’

Epigenetic reprogramming offers a unique opportunity for the research team to adjust deregulated cells. ‘We will focus not only on the responsiveness of breast cancer cells, but also on cells of the immune system and on skin cells that have been altered by ageing and, from a biotechnological perspective, on the creation of plants with new properties that will allow them to survive for example climate changes.’

Responsible innovation

Genome engineering is a sensitive area. Prof. Verschure is aware that this is a serious matter. We will engage with various stakeholders at an early stage. ‘We want to enable social debate on this subject. How does the public feel about epigenetic reprogramming? Do people understand the pros and cons? Together with the Rathenau Institute, we are going to make an inventory of the public perception of epigenetic editing, such that we can responsibly innovate this technology and eventually maximize its applications.’

Annual review Faculty of Science 2021

This interview was also published in the annual review of the University of Amsterdam Faculty of Science. Read our annual review for news and background on teaching and research at the Faculty of Science in 2021, including interviews with lecturers, researchers and students, facts and figures on enrolment and staff news about organisation developments and our valorisation activities.