DNA, in essence, is the code of life. It contains the genes that determine the behavior of our cells, which together form an individual. Each cell in our bodies contains the entire genetic code. This DNA is several meters long, while a cell is merely a few micrometers in diameter. ‘These simple numbers sketch the momentous task of folding these long DNA threads so that they fit inside tiny cells,’ says chromosome biologist Benjamin Rowland, who leads a research group at the Netherlands Cancer Institute. ‘This feat becomes even more challenging if we consider that within this confined space, the DNA must be spatially organized in such a manner that the cell can perform its many vital roles.’
Benjamin Rowland embarked on his career out of sheer curiosity. ‘I have always wanted to know how stuff works’, he says. As a little kid, he had one of those old-fashioned mechanical alarm clocks in his bedroom which he could not resist opening up to figure out how it worked. ‘That clock had a beautiful mechanism with cog-wheels and springs that made it tick. For a couple of years I dreamt of becoming a watch builder. In the end I became a scientist, but I have not changed that much, really. I still want to figure out how stuff works. But now I am studying the most beautiful mechanism of all: the secret of life itself.’
Genes are carefully controlled by regulatory elements that also lie on the DNA, but they are often a long distance away from the gene. How can they regulate a gene from such a distance? This is possible because the DNA is folded into loops, so that distant parts of the DNA are brought close together. These loops are built by cohesin, which is an advanced molecular machine. ‘But how on earth does all of that work?’, Rowland cannot stop wondering. And as soon as he has found an answer to one question, a new one tends to pop up.
His lab at the Netherlands Cancer Institute investigates the mechanisms by which this tiny ring-shaped protein complex is regulated and in turn regulates our DNA. When these mechanisms work well, this allows life to manifest itself in all its beauty, as Benjamin Rowland has learned over the years. But when these mechanisms are defective, this will lead to severe diseases. ‘We have already learned a great deal about how cohesin shapes DNA,’ Rowland says. ‘By providing structure to DNA, cohesin for example determines which genes can be switched on and off, which in turn determines the very behavior of the cells inside our body. When this process goes wrong, it will lead to devastating developmental disorders. But cohesin also enables cells to repair DNA when this is broken. This repair is essential to prevent cells from becoming cancer cells, while it also plays an important role in determining whether cancer cells can be killed with specific anti-cancer drugs.’
In recent years, the cohesin ring has revealed itself to be a central player within the cell that controls some of the most important aspects of human health, ranging from embryonic development, to cancer, to the immune system. Rowland: ‘What is also fascinating, is that cohesin, along with a few very similar ring-shaped molecular machines, has been conserved throughout evolution. These complexes therefore presumably shape the DNA of all life on earth. When they were discovered, some twenty-five years ago, we knew that they were important, but it is only over the last few years that we've come to understand just how important.'
Very recent work has revealed that cohesin, by building loops in the DNA, also enables the formation of antibodies, which is essential for protecting the body against, for example, viruses. ‘Who would have predicted that cohesin also plays an important role in our defense against, say, corona or influenza viruses?’ Rowland says. ‘Now that we have reached the point that we know that cohesin controls all these major cellular processes, this brings us to the next question: How does cohesin know to do what, and when? If cohesin controls all these basic processes, what makes it control the right process at the right moment? I personally believe this is one of the most exciting open questions in biology today. Ours is an extremely exciting time to be operating in this field of research.’
Rowland considers it the responsibility of scientists to keep asking the type of questions that when answered have the potential to substantially change our understanding of ourselves, the world, or beyond. ‘One should then not be dogmatic in terms of methodologies for how one goes about to answer such questions. Our group, for example, collaborates with people all over the world. People who are specialized in all kinds of very different but complementary techniques.’
This type of discovery research has, somewhat loftily, been described as an intergenerational gift. Rowland: ‘But I can certainly subscribe to that notion. We as a research community are pushing the boundaries of knowledge. What we are discovering today will form the basis for future generations to ask new questions and to develop applications that will make the world a better place. If we can reach a level of understanding for what makes life work, then we can also fix things when stuff goes wrong.’
A bit like the job of a watchmaker? Rowland smiles and looks at the watch on his wrist. ‘Very much so, really. Did you know that the movement of my own body provides the energy for my watch to tick? Isn’t that incredible? I guess I just love any truly beautiful mechanism.’