Cannabis-like synthetic drugs may inhibit pain and inflammation, but their development is hampered by insufficient knowledge about the cellular receptor in the human body that such drugs should activate. Marjolein Soethoudt focused her PhD research on this receptor. She developed better molecular tools to investigate it, and published a high-impact paper in Nature Communications. She graduated in April this year.
Order in attempts to develop cannabis-like medicines
The use of marijuana or cannabis - the dried leaves, flowers, stems, and seeds from the cannabis plant - has two distinct effects. Firstly, its psychoactive component tetrahydrocannabinol (THC) affects the brain in a way that makes you feel high. And secondly, it affects the immune system, inhibiting pain and inflammation. ‘The latter property makes cannabis attractive for medicinal use, and as from September 2003, such use is admitted in the Netherlands’, Marjolein Soethoudt says. ‘Still, the effect on the brain is a serious disadvantage.’
In theory at least it should be possible to design synthetic cannabis-like medicines with desirable properties only. Around 1990 it was discovered that the protein on the surface of brain cells to which THC binds – a so-called receptor – differs from the THC-receptor on cells elsewhere in the body. Brain cells have cannabinoid receptor 1 (CB1R), other cells have cannabinoid receptor 2 (CB2R). While the part of the protein to which THC binds is largely similar for both receptor types, pharmaceutical researchers hope to design drugs that only bind to CB2R and activate it. But until now, they have not been successful.
‘Before we can exploit the cannabinoid receptor 2 as a therapeutic target, we first have to thoroughly understand it’, Soethoudt says. ‘We need to know exactly on what cells it occurs, study its role in biological and disease processes, and unravel how it works on a molecular level. When activated, it modulates various processes in the cell, and we don’t know yet which of these are relevant for therapeutic purposes. To investigate these topics, we need the right tools: molecules that serve as chemical probes. These probes should have the right physiological and chemical properties, selectively bind to this receptor, activate it, and trigger relevant pathways.’
Several groups trying to develop synthetic cannabis-like drugs that target CB2R investigate the properties of the receptor. However, until now, they have employed different chemical probes and applied different methods and functional assays, dependent on their expertise. The result was chaos, Soethoudt states: ‘Across different labs, findings were not reproducible, not comparable and often even contradictory. As a consequence, no chemical probes that can be considered as golden standards are available yet, and CB2R still has not been properly validated as a therapeutic target.’
Soethoudt managed to create order in this chaos. In collaboration with 12 academic and industry labs, she profiled 18 molecules that are most widely used as probes for the characterisation of CB2R. With all assays that were available, the team tested these molecules for their activity and behaviour in cell cultures and in organisms, their selectivity for the CB2 receptor, and their influence on what happened in the cells after they bound to the receptor.
Soethoudt, who supervised the process, says: ‘It took us three years, but then we had selected three molecules of which we all agreed that they were the most suitable probes. The use of these tools will improve preclinical trials and reduce the need for animal experiments.’ The publication in Nature Communications was welcomed by the cannabis research community and is now seen as a reference paper. ‘It also captured quite some media attention, as cannabis-like drugs are seen as exciting.’
For Marjolein Soethoudt (1990), the bachelor programme Bio-Pharmaceutical Sciences at Leiden University was initially an alternative for studying Medicine. She had applied for Medicine, but didn’t get in. Fortunately, Bio-Pharmaceutical Sciences soon turned out to offer what she really liked, with organic chemistry as one of her favourite subjects of study. She never applied for Medicine again.
After completing her Master’s and an internship in New Zealand, which resulted in a first authorship of a paper on antioxidants, she completed a multidisciplinary PhD project on medicinal chemistry in Leiden. She is currently affiliated to Janssen Vaccines and Prevention (Leiden) as a Science and Business Fellow.