Studying microscopic motors in the stomach

These pumps – in fact proteins, each measuring only about five millionths of a millimetre – are produced in special cells in the lining of the stomach.

And their job is well defined: they pump acid – hydrochloric acid – into the stomach. But how hard do the pumps really have to work to do their job – and how do they actually function? It is a question that is significant to providing us with an even more detailed understanding of the digestive system, and it is one that has occupied scientists worldwide for the past 40 years. Only now have they managed to obtain an answer, which has just been published in the form of a research article in the scientific journal e-Life.

The study of the workload and detailed operation of the tiny pumps has been funded by the Lundbeck Foundation, amongst others. The research was carried out by Associate Professor Himanshu Khandelia of the Department of Physics, Chemistry and Pharmacy at the University of Southern Denmark (SDU), in collaboration with a number of Japanese colleagues.

To try to explain how the pumps work, in layman’s terms, you could start by thinking about how acidic the stomach contents are in humans, says Himanshu Khandelia:

“The pH value of our stomachs is about one, while in the rest of the body it is on average around seven. That’s a very big difference – it means that the acid concentration in the stomach is about a million times greater than in the rest of the body.”

And those tiny pumps – which are also some of the world’s smallest motors – have to work so hard to constantly pump enough acid into the stomach that you could compare them with world-class mountaineers, explains Himanshu Khandelia:

“A trained mountaineer can climb to the peak of certain not too steep mountains while for example carrying two small bags with the necessary equipment. But if we’re talking about Mount Everest and other mountains in that category, then only the very best mountaineers can reach the top, and only with very limited loads to carry.”

The task that the small pumps in our stomachs carry out could be compared to reaching the summit of Mount Everest, continues Himanshu Khandelia, “because it represents one of the most demanding forms of ion transport through membranes that take place in mammalian tissues.”

Crystals revealed the truth
But what use is this new knowledge? And how do you map a protein structure that measures just five millionths of a millimetre?

“It is important in itself to understand biological mechanisms,” says Himanshu Khandelia, “but when you look at the more practical applications of our discovery, it also has medical potential in the long run, because new knowledge about how the small pumps work could be applied in the development of new medicines for diseases that affect the digestive processes.”

To this we can add the motor analogy – that is, the idea of viewing the acid-pumping proteins as some of the world’s smallest engines.

“That analogy holds,” says Himanshu Khandelia. “We’re dealing with nanomotors here, of the kind that are being worked on in a number of research environments around the world. So our discovery could also prove relevant in that area.”

The mapping of the protein structure was carried out by Himanshu Khandelia’s Japanese partners, who were able to use crystallography to create pictures of the atomic structure of the acid-pumping proteins.

On the basis of these pictures and biochemical experiments, also conducted in Japan, Himanshu Khandelia was able to determine, via computer simulations, how the small acid-pumping proteins actually work.

The simulations, performed by Himanshu Khandelia using two supercomputers – one at SDU and one in Switzerland – showed amongst other things that the pumps can only transport one acid molecule into the stomach at a time, he says:

“Just as a world-class mountaineer can only carry one bag, and not two, right up to the top of Mount Everest.”