In the middle of the night, in a University of Cambridge laboratory, then graduate student Sin Urban was studying a fruit fly gene identified 30 years earlier, whose function had long eluded scientists. He found that the gene encodes an unusual sort of enzyme. This discovery began a scientific journey that would take Urban across disciplines—from embryology to enzymology to parasitology.
Urban was studying the function of a gene called Rhomboid-1 in embryos of the fruit fly Drosophila melanogaster. Scientists knew that embryos need the protein encoded by Rhomboid-1 to develop properly. In particular, they knew the protein helped cells in the embryo communicate with one another with chemical signals. But they didn't know exactly how this communication got underway.
In his Cambridge lab, Urban discovered that Rhomboid-1 and other members of the rhomboid family initiate this cellular discourse by snipping away proteins embedded in the cell membrane, freeing them to “talk” to other cells. Urban determined that rhomboids belong to a group of enzymes known as proteases, which break down proteins. But unlike most proteases, which exist inside the cell, rhomboids are unique in that they reside in the cell membrane.
Proteases need water to cleave their targets, but rhomboids function in the water-free membrane, a feat that has fascinated scientists ever since Urban’s discovery. “As soon as you put a protease in a membrane it becomes a completely different enzyme,” he says. “In some respects studying rhomboids is essentially a new frontier in enzymology, a new chapter in biochemistry.”
And just as unusual as rhomboids’ location is their prevalence. “This is one of those rare cases where an enzyme seems to fulfill a fundamental function for most forms of life,” he says. “Essentially there is no branch of the tree of life that does not have these enzymes.” Their presence in such varied life forms suggests that they are ancient structures that evolved before the emergence of multicellular organisms. Yet despite their ubiquity, the role of rhomboids in most species remains a mystery. “The only thing more surprising than how common this enzyme is, is how little we still know about it,” Urban says.
Urban, who is now at the Johns Hopkins University, has started to uncover several facets of rhomboids’ function in different organisms, including several that cause human disease. He showed, for example, that a rhomboid enzyme helps the malaria parasite—of the genus Plasmodium—invade red blood cells, causing fever, anemia, and sometimes death.
To invade human cells, these parasites first grab hold of cells using “sticky” proteins on their surface. Once attached, the parasites start to push into the cells, but they need to cut off their sticky proteins before they can move completely inside—and the rhomboid acts as the scissor. Interfering with rhomboid activity could prevent the malaria parasite from infecting blood cells and causing damage. “This is their Achilles’ heel,” Urban says. “Malaria parasites can’t live outside the cell, so if you can interfere with their ability to invade a cell, you can cure the disease.”
Urban discovered that other microbes use rhomboids to cause disease as well. This finding is encouraging, says Urban, because “if we can turn off a rhomboid in malaria, maybe we can turn off a rhomboid in pathogenic bacteria like E. coli, for example. So maybe you could treat a whole range of infectious diseases with one drug,” he explains.
It is still too early to know whether that strategy would work. One problem is that no one yet knows how human rhomboids function, and there is concern that shutting off those enzymes could lead unwanted side effects. “At this point, we have no idea whether we would be able to turn a malaria rhomboid off while keeping a human rhomboid on,” Urban says.
But regardless of whether his research eventually leads to treatments for infectious disease, Urban continues to be excited by his scientific journey. “Enzymes carry out the core chemical reactions that make life possible, and they also regulate nearly every aspect of cell behavior. Our work is adding new dimensions to a really rich body of enzyme study that’s been going on for over a century,” he says.