In medieval Italy, it was believed that anyone walking near a swamp risked falling ill from the “bad air” – mala aria. Victims suffered fever, headache, nausea, and chills, and sometimes the illness progressed to vomiting, jaundice, and death. Today we still call this condition malaria. For much of human history, it ravaged populations in the humid tropics and subtropics, killing countless numbers of people. In the 20th century, it was responsible for up to 5% of deaths worldwide; it still kills around 600,000 people each year.
What malaria was and how it infected humans was deeply mysterious until just 150 years ago. In 1880, French physician Charles Louis Alphonse Laveran examined a sample of a soldier’s blood through a crude microscope and discovered the true cause of the disease: not miasma, but a genus of shape-shifting single-celled protists called Plasmodium. Since then, scientists and doctors have accurately described the life cycle of parasites, their hosts and disease progression, and even the nuances of various phenomena. Plasmodium species, which present slightly different forms of the disease. But some crucial aspects remain a mystery.
For example, Plasmodium invades human red blood cells as part of its life cycle. To enter, the microbe creates a ring-shaped structure called a movable junction, which briefly creates a space in the cell membrane through which it can slip. The gap then disappears without a trace. It opens and closes so quickly, on such a small scale, that imaging technologies cannot capture it. The researchers had no idea what the portal structure actually looked like. “Because of that,” said Chi-Min Ho, a microbiologist and structural biologist at Columbia University, “we really didn’t know anything about how it worked.”
Now, Ho’s lab has photographed the junction in motion just as the invasion took place, in unprecedented detail. His team discovered that when the Plasmodium The parasite installs molecular joints in the host cell, radically remodeling the cell membrane to slip in without leaving a trace. This knowledge could help inform the next generation of malaria treatments and influence the drug discovery process for other parasitic diseases, such as cyclosporosis and toxoplasmosis.
“This is a totally mind-blowing paper,” said Jake Baum, a parasitologist at the University of New South Wales, who was not involved in the research. “At the end of the day, it’s not molecular biology. It’s biophysics.”
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The history of malaria research has paralleled advances in microscopy, from the development of simple optical microscopes like the one used by Laveran to the cutting-edge cryoelectronic techniques in Ho’s lab. Indeed, the cells invaded by microbes are extremely small, and the parasites are even smaller. Measuring approximately 8 micrometers in diameter, red blood cells are among the smallest cells in the human body, and all species of Plasmodium represent only a fraction of this size during the invasion phase.
Attempts to image breaking-in parasites began in the 1970s, when pioneering microbiologists first applied electron microscopy. These scientists observed a distinct thickening of the cell membrane near the parasite’s access point. Then the small, round Plasmodium seemed to simply merge with the cell, like a water droplet merging into a larger pool. It will be decades before techniques develop sufficiently to isolate the proteins that make this possible, let alone image them.
Gn Health
