Artificial cells
Building an airplane without a blueprint
Door Rob van der Wal
By Rob van der Wal
Rob van der Wal
Decades. That’s how long it will probably take before the first truly man-made cell will be created. ‘I won’t be working anymore when that happens’, sighs biochemistry professor Bert Poolman (64), who’s been working on this holy grail for decades himself.
Creating a living cell out of nothing but dead molecules isn’t a simple task; it’s one of the greatest challenges in the field of cell biology. ‘Imagine having to build a plane, but you don’t have any blueprints’, he says.
Trying to create a structure consisting of hundreds of different molecules without detailed instructions is difficult enough without other factors complicating things. An airplane is a lifeless object while a cell is alive, which means everything inside it moves. Molecules are constantly entering the cell, crashing into each other. Reactions occur while other substances leave the cell.
All those things have to be replicated in artificial cells, as well. ‘A plane can’t decide to suddenly detach a motor or throw other parts away. A cell can’, says Poolman. Besides, living cells also possess recovery mechanisms, which means they can repair themselves. That’s not easy to replicate.
Molecules or living cell
Scientists trying to create artificial cells do this roughly one of two ways. Poolman and his colleagues utilise a bottom-up approach: they’re using molecules to build a cell. ‘We’re trying to build an entire reaction network, just like in real cells.’
Existing cells are based on years of evolution
Other researchers start with a living cell. ‘They then remove molecules to see if the cell can continue to work.’ It’s like removing more and more parts of a plane and seeing if it still flies.
In 2016, this research led to an artificial bacterial cell consisting of approximately five hundred genes. Any fewer, and the entire system stops working. The genes are sort of like the instruction manuals for the cell, on the basis of which the cell elements are created. Scientists have discovered the function of 350 of those cells. They’re still looking to find out what the other 150 do. They’re obviously essential; they just don’t know why yet.
Unnecessary components
The cell Poolman and his colleagues are trying to create would need a minimum of 250 genes – much fewer than the other researchers’. The idea behind this is that his cell will be more efficient.
‘We only look at the function a cell should have’, he says. ‘Existing cells are based on years of evolution.’ That means they contain components that are no longer essential, but for instance attached to elements that do have a specific function. Each of those elements has its own gene or genes.
Even though Poolman’s work is based on dead molecules, he keeps a close eye on his colleagues working on the living cell. Each year, they determine more of the genes’ functions. ‘Anything we think might be useful to us we incorporate into our cell’s design.’
Multiple groups
He hasn’t succeeded yet; his perfect artificial cell currently only exists on paper. Together with colleagues at other universities, he’s simultaneously working on several separate elements, either inspired by or even copied from existing cells. ‘This isn’t the kind of project you work on with just one group or just one lab.’
This isn’t the kind of project you work on with just one group or just one lab
Poolman and his group focus on the cell’s energy manufacturers. They provide all of the cell’s other processes, such as growth and division, with fuel. In the meantime, the TU Delft is taking on the mechanism that determines a cell’s shape, while groups at the Vrije Universiteit Amsterdam and Radboud University are focused on making RNA. These molecules play a role in translating information from the genes to other parts in the cell.
Together, they form research consortium BaSyC. The researchers involved in the consortium have together brought in millions in prestigious grants, such as ERC Grants, a Gravitation grant, and a VICI grant from the Dutch Research Council (NWO). On May 24, the consortium was awarded another 40 million in follow-up funding from the NWO, given to researchers ‘at the absolute top or close to it’. ‘It will allow a lot of follow-up research for the next ten years’, says Poolman.
On the edge
Already, the BaSyC researchers occasionally try to put their elements together to form a functional cell, although it’s tricky. ‘These elements didn’t evolve together like in a natural cell. They’ve never met each other before. We’re essentially making a cell without evolution.’
The beauty of it is that’s we’re unable to predict what’s going to happen
That means that things occasionally go wrong, says Poolman. Biochemical reactions, which in and of themselves can be predicted, can suddenly behave entirely differently in a lab-built cell. ‘But that’s the beauty of it. The fact that you can’t predict what’s going to happen means you’re working on the edge of life and death.’
Whether Poolman and his colleagues will actually be able to create life remains to be seen. ‘If you ask me, life is defined as a system that can maintain itself, something that can grow and divide’, he says. ‘We’ll probably make that work, but that’s just one characteristic of life. If you ask a theologian or a philosopher, there’s so much more to it, like interactions between people.’
It will take researchers decades before they’ve genuinely created a working artificial cell. But even now, they’re having breakthroughs, says Poolman. ‘We’re learning so much from biology and how molecules collaborate. We’re now trying to extrapolate that to what happens in real living cells.’
Useful applications
The knowledge they’ve gained comes in useful when living cells go off the rails, for instance when it turns into a cancer cell, when someone gets Alzheimer’s, or there’s an immune response. Using the knowledge from their research into artificial cells, Poolman’s colleagues might just be able to prevent disease on a cellular level.
The cells can also have a myriad of other useful applications. Many chemical processes that are bad for the environment will have to be replaced by green chemistry over the next few years. Cells will play an important role in this process, acting as ‘factories’ that can make certain substances, such as medication, as well bulk materials for industrial purposes, such as alcohol.
Knowing how to design a cell in such a way that it makes the substance you need is an important concomitant of the search for a working artificial cell.
That’s a good thing, says Poolman. ‘If our final goal was the only thing that would make us happy, we’d just be limiting ourselves.’