‘In the ‘80s we at DSM felt that antibiotics should be synthesised differently. Although at that time, we did not produce those medicines ourselves.’ Says Alle Bruggink, former Nijmegen professor, former head of DSM Chemfern Research, and member of the Dutch EL&I Ministry’s Scientific and Technological Committee on the biobased economy.
Biocatalysis
‘Antibiotics form a group of complex substances. They need many organic chemical steps for their synthesis, and then, production costs were too high. Third world countries which first bought antibiotics in Europe, started to produce them themselves, and did so at lower cost. There was a solution, biocatalysis, which allows many reactions to take place along a shorter pathway, using enzymes. Antibiotics are peptides, consisting of coupled amino acids. The protease enzyme separates peptides, and we thought it might be possible to reverse that reaction in order to remove the side chain from the penicillin ring, and mount another. Gist-brocades in Delft started research along these lines and had its first successful lab tests around 1990. They did not merely process the side chain, but also the ring. They succeeded in changing the penicillin ring containing five atoms, into a cephalosporin skeleton containing six atoms. In organic chemistry you would need wizardry to do that. Enzymatically, that is much simpler, provided you have the correct enzyme at hand. The ring structure in the antibiotic molecule defines the way it works, the side chain defines the speed at which the molecule is absorbed. They really performed top science in Delft.’
All knowledge concentrated
In the early 1990s, three companies were reputed for their biocatalytic knowledge: Danish NOVO, and Dutch Gist-brocades and DSM (which later merged). DSM had a working relationship with NOVO, which produced not merely penicillins but also insulin. Then, NOVO judged the contamination risk of their insulin production with penicillins to be too high; insulin being much more important to them, they sold their penicillin knowledge to DSM. Just about then, Chemfern was formed, a joint venture of DSM and Gist-brocades, and DSM contributed this knowledge to the new business, as a kind of dowry. In other words: around 1995 all knowledge in the world about catalytic production of penicillins and their relatives, cephalosporins, was concentrated in Chemfern. Although this in itself was not enough for success, for that would also need production and marketing capabilities.’
‘Dutch government took up an interest, and we presented a plan to develop this production capability, in close cooperation with a major part of Dutch universities’ chemical departments. Four Dutch universities cooperated in the research, all of them with several professors and PhD students in chemistry and biochemistry. In total we had some twenty sub projects. Participants were Wageningen, Nijmegen and Groningen universities; Delft Technical University even participated twice. DSM and Gist-brocades participated with their full knowledge. It was a unique project for universities and businesses; it was the first in its kind in size, and it has never been done again at this scale in the Netherlands.’
A match between businesses’ and universities’ contrbutions
Alle Bruggink’s philosophy in this matter is as follows: ‘I hold the opinion that there should be a match in number between business researchers and university researchers. And I feel that there should be both respect and competition between university and corporate researchers. This would seem to be a matter of course, but it is not. And: there should be complete openness among all who are involved, among universities as well. In fact, the confidence we had in them was never betrayed. We cooperated with 30 to 40 researchers in universities and had a similar amount in-house. We did research in seven locations in total. The project leader should have talks with all researchers, both at universities and in corporate laboratories, in order to keep track of advances and to keep up spirits. It would seem a matter of course, but it is not. I gathered them once a year in Vaalsbroek, our Limburg castle, for a joint conference.’
The ‘Green Pathways’ project was a success and the results were alike. ‘We could change the ring and add and remove side chains, in fact we could produce anything.’ DSM started to produce Green Cephalexine in Barcelona and obtained a product which was superior to organic synthetic products, not merely in production costs but also in every other respect. It did not taste bitterly, it had no bad smell, shelf life increased appreciably, and there was much less contamination (and hence less toxicity). In short, the product was much better. Official figures testify to this: 66% reduction in energy use, 75% reduction in feedstock use, 90% less waste production, 50% less air pollution, and 50% less water pollution. All sustainability scores were much better. Thanks to enzymatic catalysis. It was the first big commercial success for bio production.
The lead
Ten years afterwards, DSM still has this lead, even though ever more countries produce such medicines by means of biocatalytic technology, often in joint ventures with DSM, like in China and India. The knowledge did not stay confined to the Netherlands. Alle: ‘It would not have been feasible.’ But patents are still in Dutch hands, which lend the Netherlands (and DSM) a unique position in the world.
Courtesy NOM, development agency for the Northern Dutch provinces