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Confronting a contagion
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They haven’t yet had the time, but the scientists at Kartik Chandran’s New York laboratory (www.chandranlab.org) are planning an outing to see the medical thriller Contagion. After all, their real-life pursuits overlap somewhat with Hollywood’s latest attempt to scare us with those tiny, nasty pieces of life we call viruses.
As in the movie, Chandran (37) investigates a virus that originates in bats and spreads through animal hosts to humans. As in the movie, the virus that Chandran of the Albert Einstein College of Medicine and collaborators Sean Whelan of Harvard Medical School and Thijn Brummelkamp of the Whitehead Institute investigate is one of the most virulent pathogens known to man, with a fatality rate reaching 90%.
There are differences thereon. The fictional paramyxovirus created for the movie is airborne, the medical equivalent of nuclear doomsday. The virus that Chandran has investigated for eight years is the Ebola, which is less of a threat than its fictional cousin only because it spreads through human contact.
Now, Chandran, Whelan and Brummelkamp have found in the Ebola virus a key weakness that could one day help create a drug to treat the deadly fevers it activates. In a paper published in the journal Nature last month, the scientists explained how a protein known as Niemann-Pick C1 (NPC1) stops the Ebola virus (and its cousin, the Marburg) from carrying out its destructive work inside human blood cells.
Also Read | Samar Halarnkar’s previous columns
“One remarkable thing about NPC1 is its indispensable role in infection by the Ebola and Marburg virus (and only these viruses)," Chandran, a Bangalore boy who lost his mother to malaria, told me. “Cells that don’t have NPC1 cannot be infected at all, which is pretty amazing."
Why is it amazing? As with all viruses, Ebola does its deadly work by using the genetic material inside a human cell to replicate itself. It is particularly fecund, making more than a million versions of itself in 1 millimetre. Low levels of NPC1 blunts Ebola’s virulence. “It is rare to have such a dramatic reduction, which told us right away that NPC1 was special," said Chandran.
Chandran and his colleagues have successfully shown that mice bred with low levels of the protein NPC1 are unaffected by the Ebola virus, which destroys the immune system, stops the coagulation of blood and cause ruptures in cells that line blood vessels. This is why Ebola victims bleed frighteningly from the eyes, ears and mouth.
Ebola fever was first detected in 1976 in villages along the Ebola river in the Congo. There have been at least two dozen Ebola outbreaks in Africa, and with no vaccines or drugs to fight it, or even a clear idea of how it spreads. Scientists were particularly limited in their understanding of how the Ebola virus enters its host cell.
Taking educated guesses and riding on “a measure of luck", Chandran and his colleagues in 2005 first probed a critical step in the invasion process; it results in the delivery of Ebola’s payload through the cell wall into the cytoplasm, where all the goodies for viral multiplication are located.
In their latest work, they succeeded in fooling Ebola to reveal its secrets. They used a harmless virus coated with the Ebola’s glycoprotein, a biochemical compound, in the manner of a sheep in wolf’s clothing. Put another way, they asked the virus itself to reveal cellular genes it could not infect. The NPC1 gene emerged the strongest candidate (there are others the researchers are studying).
Breakthroughs in science are often a result of expecting the unexpected in expected places. NPC1 is a protein that has been extensively studied, primarily in human metabolic disorders and the metabolism of cholesterol.
Blocking NPC1 to create a drug against Ebola may be unknown scientific territory, but the adverse effect of its absence is well documented. The protein lends its name to the Niemann-Pick disease, the collective term for a group of hereditary afflictions in which the deficiency of NPC1 causes cholesterol to accumulate in the spleen, liver and brain. Affecting mostly children, it is a neurological disease that begins with a swollen belly, a red spot in the eye and ends in a loss of motor skills, blindness, deafness and death. The disease ends lives early— many victims are as young as two years—and there is no effective treatment for most forms of the disease.
“In one sense, we virologists and the folks that work on Niemann-Pick disease are trying to accomplish exactly the opposite," said Chandran. “We want to kill this protein and they want to restore it."
The irony apart, understanding the role of NPC1 will help other studies on the protein, the ecology of Ebola (which species can it infect? Which ones are resistant?) and Neimann-Pick disease. It’s hard to say exactly how at the moment, Chandran said.
“But that," he added, “is the beauty of basic science—it can lead you in unexpected directions."
Samar Halarnkar is editor-at-large, the Hindustan Times and Mint. This is a fortnightly column that explores the cutting edge of science and technology. Comments are welcome at frontiermail@livemint.com
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