The death and life of the resurrection drug.

Abstract

In his own words, it was the most dramatic moment of his scientific career. At the back of an auditorium in Nairobi, Kenya, Cyrus Bacchi met Simon Van Nieuwenhove. Bacchi, at the time, was essentially a biochemist whose interest was the African trypanosome. Van Nieuwenhove was a clinician who had worked for many years in the field in Africa. The topic of their conversation was eflornithine—a small and simple compound that would eventually make a big impact. Bacchi had shown that the compound had an effect on the parasite that causes Human African Trypanosomiasis. Van Nieuwenhove was dosing patients with it. The story of eflornithine did not start with eflornithine.It started because no one knew how to purify an enzyme. Bacchi was working on his thesis, which centred on the α-glycerophosphate shuttle in hemoflagellates. The shuttle acts as a way to transport reducing equivalents from the cytosol to the mitochondrion. α-glycerophosphate dehydrogenase was the enzyme he spent much of his time trying to purify. The reason he could not purify it was it was hidden within another compartment of the trypanosome. It would not be until several years later, and published in 1977, that Fred Opperdoes discovered the glycosome [1]: the organelle that encapsulates glycolysis in trypanosomes, and the organelle that was hiding the enzyme. At every step of the purification process Bacchi lost activity in his enzyme extracts. Magnesium chloride, surprisingly, managed to boost activity. Bacchi looked into other nonmetallic compounds that would act as cations and eventually chose the polyamines: naturally occurring, nitrogen-containing cations whose concentration is closely controlled by the cell. Spermidine and spermine were found to be the best replacements for magnesium, yielding higher activities. With evidence that the enzyme he was trying to purify was most likely locked within the glycosome, Bacchi moved his attention to how the polyamines were made within the trypanosome. This was an area that had amassed a lot of knowledge everywhere apart from in trypanosomes. It was in 1677 that Anton van Leeuwenhoek first observed spermatozoa in humans, dogs, and a host of other organisms, and he later discovered crystals of spermine phosphate in human semen. Modern research had identified the biologically active polyamines—spermidine and spermine—in plants and many types of mammalian cells. The biochemical pathways that make and degrade the polyamines, along with some of their enzymes, had also been identified. At the time, nothing was known about polyamines in protozoa, and in trypanosomes in particular. Did these parasites contain polyamines? Could polyamine metabolism be a useful chemotherapeutic target?