en

Marileen Dogterom

‘Building a cell from the bottom up’

Bio

Bio

Marileen Dogterom was trained as a theoretical physicist at the University of Groningen. After finishing her thesis in Paris and Princeton, and a post doc position at Bell Labs, she became head of department at the FOM Institute AMOLF in Amsterdam. In 2000 she took up a professorship at Leiden University. She has been professor at TU Delft and Chair of the Department of Bionanoscience since 2014.

POSITION AT:

TU Delft: Bionanoscience
Leiden University: Physics

Putting proteins in a droplet

“What we are researching is how the structures develop that make cell division possible. How the threads form that arrange the chromosomes in the cell nucleus and then pull them to two sides within the cell, enabling the cells to divide. We are attempting to bring together the proteins that form these threads and control this process, to see if we can initiate the process ourselves. We do it in a micro-droplet of water, floating in oil. In that  we bring the proteins together, one by one. It then turns out that with an amazingly small number of proteins, you can build something like a ‘cellular division machine’. The addition of more proteins will rapidly intensify the complexity of the system, making it increasingly realistic.”

Towards a realistic synthetic cell

“Another way of studying cell division is to take a normal cell and ‘unclothe it’, by repeatedly removing one gene (and therefore one protein) from the DNA and then seeing if the cell can still divide. This is more like Craig Venter’s approach, who recently said in a paper that he had been able to trace the DNA of a bacterium back to several hundred genes. It would appear that this number is sufficient to enable the entire cell, including cell division, to function. But these include many genes whose function we do not fully understand. What is so great about this approach is that you build the system from the bottom up, which helps you to understand what the role of each individual protein is.”

“Currently, we are working with around ten proteins, but I think that this will need ultimately to increase by another factor of ten in order to be able to recreate an entire cell. Craig Venter is now working with several hundred genes. I think that, in five or ten years’ time, we will be able to build a realistic synthetic cell, with over a hundred genes, which can divide and maintain itself for several generations.”

A close-knit community

“Our research is part of a major international initiative. Here in Delft we are working with physicists and biochemists. We also collaborate with Groningen, AMOLF and VU University Amsterdam, Nijmegen and Wageningen. In Groningen, they are conducting research into cell metabolism; AMOLF and VU are exploring gene expression; Nijmegen’s focus is on the thermodynamics of the system and Wageningen is looking at genome engineering. As for real cells, we are working closely with Anna Akhmanova’s group in Utrecht; they are manipulating the same proteins in living cells that we are adding to our micro-droplets. We are also collaborating closely in this field with Leiden and Rotterdam, and within Medical Delta we have a complete close-knit single molecule and cellular biophysics research community, with Thomas Schmidt in Leiden and Claire Wyman in Rotterdam.”

The route, not the destination

“Both of these research lines, synthetic cells and cellular biophysics research, will increasingly grow closer together in the years ahead. It is difficult to predict what impact this will have, but it will definitely result in a much more fundamental understanding of the cell – which is already of significant interest for the medical community. With the synthetic cell, we will soon have a testing system (which I like to compare with a flight simulator), in which we can add or manipulate all kinds of proteins in order to measure their effect. But you need to realise that achieving that ‘thing’ is not really the main aim. On the route towards that, we are learning to understand living systems at a much deeper level. That fundamental understanding can teach us so much.”