Dirk Slotboom studies how cells eat
Solving the protein puzzle
He apparently had it at the ready, because before our interview has even properly started, Dirk Slotboom has grabbed pen and paper. He draws two curved, parallel lines: the walls of a cell. The lines are interrupted by a cluster of geometric shapes. It’s a transport protein, a large molecule that can pick a specific substance, like a nutrient or a hormone, from its surroundings and take it to the cell.
‘But this is just a cartoon’, says the biochemistry professor. ‘This is what transporters look like in the textbooks, but these nano machines actually consist of large, complex proteins. We haven’t been able to actually see them transport anything through the cell wall with our own eyes. Yet.’
It’s a mystery that we’re slowly but surely unravelling with the help of microscopes that keep getting better, as well as clever experiments. The more we know about cells, the more we’ll understand life. We might even be able to create our own.
It’s one of the most important scientific goals today: to recreate a living cell. Creating a synthetic cell means putting together a complex system by combining various molecules. Together, they should show certain behaviour and characteristics that the separate components do not, like a series of useless parts that, when put together properly, suddenly form a functional bicycle. Except it’s much more complicated and much, much smaller.
Watching a transport protein in real life would be the ultimate eureka moment
‘Making an artificial cell is an enormous challenge and has been teaching me a lot of fundamental things, for example about the origins of life’, says Slotboom. The entire research group is working on the topic. ‘Especially my office neighbour, Bert Poolman, is focused on it. I’m indirectly involved. A synthetic cell needs transport proteins to survive too, after all.’
Slotboom thinks it will be years before we create a living synthetic cell. ‘But the past has taught me that I might be too sceptical. Ten years ago, for example, I never would have thought we’d have electron microscopes with this high a resolution in 2020.’
He hopes that the new microscopy technologies advance in such a way that he will be able to witness a transport protein with his own eyes. ‘I would be discovering an essential bit of life, since I’d be watching it happen in real time. It would be the ultimate eureka moment. I want to know how living organisms work. How they function and how they stay alive.’
Slotboom has been focusing on transport proteins since he started his PhD research. ‘Life has several essential characteristics, like the fact that it’s compartmentalised. But a single, closed off compartment isn’t enough. In order to survive, you have to be able to absorb and deliver substances from and to your surroundings. That’s where the transport proteins come in.’
His research group has been working on refining those cartoonesque drawings in textbooks. What do transport proteins look like? What happens when the transporter grabs a substance, changes shape, and releases the substance on the other side of the cell wall? And why does molecule A fit the binding site perfectly, while molecules B and C pass it by?
‘Most transporters are really picky, they only transport one specific substance’, says Slotboom. ‘This does mean that even the smallest concentration of molecules can be picked up. People have approximately eight hundred different transporters.’
In 2013, Slotboom discovered the movements of a single transport protein. He published an article in Nature about this in 2016. In 2016, he found out that a certain protein eats vitamins by catching them with two ‘arms’ and closing them in. He published about those findings in Nature Communications.
Slotboom prefers being at the very start of fundamental research. ‘That’s not true for every researcher’, he says. ‘Many PhD students and post-docs are looking for ways to apply their results. Stephan Rempel, a PhD student in my group, was working on some amazing fundamental questions, but he realised that nobody was quoting his articles. He went looking for a suitable subject where he could combine fundamental questions with potential applications.’
He succeeded and found something very special. Rempel studied the transport of vitamin B12 in Mycobacterium tubercucolosis, the bacterium that causes the infectious disease tuberculosis. ‘We knew that the tuberculosis bacteria can absorb vitamin B12’, Slotboom explains, ‘but we didn’t know how, or why, since the bacteria can make the vitamin itself. It looks like there’s a relationship between vitamin B12 and how Mycobacterium tuberculosis develops during infection.’
We were surprised by the protein that transports vitamin B12 to the tuberculosis bacterium
The researchers wanted to find out how the one-celled organism absorbs vitamin B12 and what the transporters who transport it look like. Slotboom: ‘We studied the transport protein using an electron microscope. The images we got were slightly different from what we expected.’ Slotboom can’t tell us what they found exactly, since this research will soon be published in one of the biggest scientific journals in the world.
Can he give us a hint?
Again, Slotboom reaches for his pen and paper. Again, he draws a cell wall and a transport protein. But this protein is different; it looks more like a ship’s lock. ‘A fish who happens to swim in a lock when the doors are open is trapped when those doors close. When the doors on the other side of the lock open, the fish will swim out on the other side. Without realising it was caught, the fish has ended up on the other side of the lock.’
What’s the point of this lock-like transporter? ‘We can only speculate what its specific use for an organism is. Maybe the bacterium is using the transporter to ‘sample’ what’s available on the outside’, Slotboom explains. ‘The organism can absorb substances that are new to it. If the substance is useful, it could lead to later generations of the bacterium developing a transporter that’s specific to that substance.’
The drawback to this is that these could also let through substances that are dangerous. Slotboom: ‘We can make use of that, for instance by developing a new antibiotic that is particularly tasty to that transporter. Once that antibiotic is picked up, it can destroy the tuberculosis bacterium. This possible application would also mean that Stephan would get the attention he deserves’, Slotboom laughs.
We need young people, the established order isn’t enough
His studies do sometimes lead to potential applications, but Slotboom remains a fundamental researcher. ‘But in the current landscape, with the focus increasingly on short-term projects, it’s becoming more difficult to keep up long-term research.’
Therefore, Slotboom was very pleased to receive a 780 thousand euro TOP grant from research financier NWO, at the end of 2018. ‘Science can’t survive without fundamental research’, he says. ‘If you want to continue to discover new things, you need to give people the freedom to do so. If you limit that freedom, you start inhibiting scientific endeavours. We also need young, creative people to come up with good new ideas. The established order, the people who’ve been studying things for years, isn’t enough anymore.’
He laughs. ‘Unfortunately, I’m slowly becoming part of the established order myself.’