‘Nice to see that my research helps people get better’

More than 20 years ago Klaas Poelstra, now Professor of Pharmacy and Vice Dean of the Faculty of Mathematics and Natural Sciences, made a discovery. It led to a patent that was sold to a small company, a company that pharmaceutical giant Pfizer is about to acquire for over half a billion euros. Poelstra and the University of Groningen do not stand to gain much from the takeover, ‘But we’ve learned a lot since then’, he says.

It sounds like a novel: at the end of 1993 the young Klaas Poelstra has just handed in his thesis manuscript and is pondering a question that has puzzled him for years. An answer starts to form, and while he cycles home on Friday afternoon, he suddenly sees an experiment that will give him the answer. So he turns round, cycles back to the pathology laboratory at the UMCG and performs the experiment. Eureka!

What Poelstra was trying to find out was what the enzyme alkaline phosphatase did. It is found in all sorts of cells in the body – and in almost every animal. But no one knew what it did there. ‘The enzyme only works at very high pH’, Poelstra explains. The pH scale runs from 1 to 14, with 1 being extremely acidic. Coke has a pH of 2.4 and normal water is neutral at pH 7. Above that is what we call ‘basic’ or alkaline.

Alkaline phosphatase only starts to work at pH 11. ‘But cells dissolve at this pH, so you don’t find it anywhere in the body’, is how Poelstra describes the problem. Why is there an enzyme in the body that can only be active in test tubes? His supervisor put him on the right track. ‘One characteristic of acids is their positive charge. Certain substances such as sugars have a strong negative charge, which is similar to an alkaline environment. So this enzyme could be active in the presence of compounds with a negative charge.’

By chance, Poelstra used endotoxin a lot in his research, a toxin that comes from certain types of bacteria. ‘I knew that endotoxins have a negative charge and when I took a better look at the structure I saw that there were also lots of phosphate groups on them.’ Poelstra also had a test that made the working of phosphates visible. What struck him on his bike was that he should expose cells to endotoxin to see if this was what the alkaline phosphatase responded to.

The experiment did not take long and the results were clear: alkaline phosphatase did indeed respond to endotoxin. ‘To be precise, it removes phosphate groups from the toxin at neutral pH, meaning the toxin is no longer toxic.’ It seems that the alkaline phosphatase is in our bodies to protect them from this toxin.

The enzyme thus has great medical potential – to treat blood poisoning (sepsis), for instance, or certain kidney disorders in which endotoxin has a role. Once the findings had been confirmed, the University of Groningen entered into a partnership with Technology Foundation STW. Together they applied for a patent for the use of alkaline phosphatase to treat sepsis and later other diseases.

The patent was sold to a doctor who set up a company together with a partner to bring the discovery to the market. The revenue went to STW, which used it to hire Poelstra. He decided not to work for the company. ‘I wanted to study new things. At a company like that you spend your time trying to raise funds and fiddling with the enzyme to make it suitable for treatment. That didn’t really appeal to me.’ Poelstra moved to the Department of Pharmacy soon after, where he focused on drug targeting .

The company still exists 20 years later and is now called (after a takeover) AM Pharma . It has since developed a treatment for acute kidney failure that appears to be most successful. ‘A few patients have been treated, and it seems to have helped them recover. It’s nice to see that my research helps people get better.’

The success attracted the attention of pharmaceutical giant Pfizer, which has put in a takeover bid for AM Pharma. If the first patient tests go well, Pfizer will pay 600 million dollars for the company. The University of Groningen may also stand to benefit somewhat from this. ‘The first patent expired just last year, but other patents were applied for later, so those are still valid. The lawyers need to discover if this will earn us anything.’

Patent application was uncharted territory in the 1990s. With his first application Poelstra was one of the biggest ‘patent applicants’ the University of Groningen had ever known. ‘We had to find out how it all worked.’ This is another reason why the alkaline phosphatase has not been a great money-spinner. Since then Poelstra has patented five further discoveries. ‘One led to nothing, but the other four are also used by small businesses.’

Poelstra thinks that they might just hit the jackpot if they find a way to deliver drugs at the right place in patients with cancer or liver disease. The University of Groningen would stand to earn much more then. ‘We have now learned a great deal.’ Nowadays the University of Groningen applies for a few dozen patents a year.

The story of alkaline phosphotase show how fundamental research can lead to useful applications, but that it also takes a long time, more than 20 years in this case. ‘And that is not particularly long for drugs research.’

Poelstra has put his research on the backburner since he was appointed Vice Dean of the Faculty of Mathematics and Natural Sciences a year ago. ‘I like new challenges, new lines of research, but a period in an administrative role will also deliver new insights and contacts.’