Hakkennes Speeds Chemo Breakthrough, Cuts Side Effects

In mice and zebrafish embryos, it already works: chemotherapy that attacks only the tumour and not healthy tissue. The drug is given, then doctors wait for it to reach the tumour, and finally they shine laser light onto the tumour.

Active in one place and switched on by light

Scaling this up for use in humans is still a long way off, theoretical chemist Matthijs Hakkennes explains. 'You do not just need a working molecule that becomes active when light shines on it. It also has to reach the right places in the body, target tumour cells and be completely safe.'

When a chemist comes up with a potentially suitable molecule on the drawing board, it can easily take two or three years before that molecule can actually be made in the lab. Testing it can then take another year. 'Quite often it does not work as well as hoped, and by then your four years of PhD research are over.'

'There is an infinite soup of possible molecules. My computational models help to determine the right direction.'

Not a fish, but a fishing rod

Instead of catching a fish that researchers have to throw back after four years, Hakkennes worked on building a fishing rod. He developed computer models that predict which molecules are likely to be suitable. 'That way, in the endless soup of molecules you could imagine, you can move in a direction that has a better chance of success.'

Models that design molecules and predict their properties have existed for some time. But not for organic molecules that contain a metal component, which is needed for chemotherapy. 'Those metals all have unusual properties, which means existing models do not work. That is what I worked on.'

Fitting like a key in a lock

The researcher developed, among other things, the programme MetalDock, which predicts how metal-based medicines bind to proteins. 'You can think of that binding as a key fitting into a lock. Our molecules have a metal centre, with organic side groups around it. One of those side groups has to break off under the influence of light. The part that remains then has to fit the protein in the cancer cell like a key.'

One of MetalDock's clever features is that it saves computing power. 'It takes a lot of processing power to calculate how one possible molecule behaves. So, the programme first performs a relatively simple calculation on many molecules to make an initial selection.'

Other simulation methods can then carry out increasingly complex, but more accurate, calculations to make the selection process stricter. After several rounds of selection, a manageable number of potentially effective molecules remains. 'That is where we can invest the large amount of computing power needed to make a 3D film of how they behave.'

Appreciation for the new tools

Hakkennes himself also turned out to be the right key for the right lock during his research. Chemistry professor Sylvestre Bonnet writes: 'His ability to communicate with others really stood out to me. As a theorist, he worked very well with experimental chemists. Together, they could determine which models were needed and how his calculations could be compared with experiments. The cum laude distinction is therefore fully deserved.'

Chemotherapy with a light switch is not available yet, but the results of Hakkennes's research do bring the technology closer to being used in practice. Researchers outside this field are also pleased with his results.

'I received many emails from people in places such as Bangladesh and China thanking me for developing MetalDock. They work on other metal-organic molecules and now have a tool that helps them predict how those molecules bind to others.'

Thesis and defence

Matthijs Hakkennes defended his PhD thesis, Computational Tools and Protocols for the Development of Photoactivated Metallodrugs, on 17 April. His supervisors were Professor Sylvestre Bonnet and Dr Francesco Buda.