We interview genes about cell processes

Biologist and Spinoza Prize recipient Thijn Brummelkamp introduced innovative methods for silencing genes in human cells. ‘I love complex puzzles and use fundamental insights to interrogate cells about why they do or do not do something.’ ‘You will surely be familiar with those lab posters covered in biochemical reactions. For a great many processes in the cell, we know how the biochemistry and metabolic networks fit together, but about genetic regulation we still know very little. It is my ambition to map that out. Humans have tens of thousands of genes, so it is an enormous challenge – and the search alone already yields many surprises and applications. Because it often turns out that something is regulated genetically in a quite different way from what we would expect on the basis of DNA information’, says biologist Thijn Brummelkamp (1975). The scientific director of the Netherlands Cancer Institute (NKI) and professor of experimental genetics in Utrecht will receive a Spinoza Prize of one and a half million euros on 14 October for his ‘outstanding, groundbreaking and inspiring’ research.

  Tinkering ‘As a secondary school pupil I had no interest in studying; I preferred tinkering. My father was a GP in Haarlem, so that was not what I wanted to be. I ended up – not entirely consciously – studying biology at Vrije Universiteit Amsterdam. There, during plant practicals, I became truly captivated by genetics. The idea that you could tinker with DNA fascinated me and that was what I wanted to do. I was also full of ambition, so I asked around for the best place to do an internship. That turned out to be the NKI, and through my PhD there I gradually moved further into human genetics research’, Brummelkamp recounts. His career has been defined by a search for the engine driving cell division, for the vulnerabilities of cancer cells, and for the factors that enable viruses to hijack human cells. ‘I love complex puzzles and use fundamental insights to interrogate cells about why they do or do not do something’, Brummelkamp summarises. ‘The run-up was quite long and I spent a great many hours and evenings in the lab. The acceleration in my career I owe to the development of genetic research systems that biomedical scientists had been genuinely waiting for.’

  Silencing Still during his PhD at the NKI, Brummelkamp developed, together with Reuven Agami and his supervisor René Bernards, RNA interference systems that make it possible to silence virtually any gene and to study molecular networks more effectively (Science, 2002 & Nature, 2004). ‘RNA interference was already known from research on plants and nematodes, but we made it accessible on a large scale in medical research into cancer and infectious diseases’, Brummelkamp explains. ‘Later we ran into the problem that such interference is not always complete, or that off-target effects occur. Knocking out human genes with mutations was also not an option at the time, because in diploid human cells you are by definition dealing with two chromosomes. If you silence a gene on one chromosome, there is always the complementary gene on the other chromosome. That is why we devised a completely different approach: a model system using haploid human cells.’ Research he carried out as a group leader at the Whitehead Institute for Biomedical Research in the United States (Science, 2009).

Interrogating ‘A haploid cell line is not a natural system, but it does make it possible to interview genes one by one and examine what role they play in cell processes. When you find something interesting, you test it in diploid cells to show what that gene normally does. It is a reductionist way of gaining greater insight into the regulation of cell processes and of observing the effects of mutations’, says Brummelkamp. This approach has already led to many surprising discoveries: for example, it has been elucidated how Ebola and Marburg viruses use a cholesterol transporter protein to enter human cells (Nature, 2011), and an alternative biosynthetic route for triglycerine in humans has been discovered (Nature, 2023).

‘Equally unexpected is the discovery that cancer cells sometimes die differently from what we had assumed. Every textbook states that cell death in response to excessive DNA damage is the result of activation of the protein p53, the most studied gene. But we discovered that cancer cells also possess a transfer RNase and a kinase that can block ribosomes and thereby trigger apoptosis. This offers a possible explanation for why not all tumours are equally sensitive to chemotherapy’, Brummelkamp explains. Research that illustrates how fundamental science can lead to applications in cancer research. ‘My heart lies with fundamental research, but the beauty of the combination of the Netherlands Cancer Institute (NKI) and the Antoni van Leeuwenhoek hospital is that we have 56 groups covering the entire spectrum from fundamental and translational to clinical research. And every day when I walk in here I see around me that we are doing this for a reason.’

  Almost all research is currently conducted in humans and mice, but Brummelkamp also sees prospects for genetic analyses in very different animal groups. ‘Elephants, for instance, because they are so large and consist of so many cells that they must have ingenious systems for keeping cell division errors in check. In a few years’ time I hope to have more to tell you about that.’