First of several posts to commemorate
#RareDiseaseDay (Feb 28, 2015).
Evolution is a strange thing: sometimes it favors keeping a mutation in the gene pool, even when a double dose of it is harmful—even fatal. Why? Because a single copy of that mutation is protective in certain situations.
A classic example is the sickle-cell mutation: People carrying a single copy don’t develop sickle cell disease, but they make enough sickled red blood cells to keep the malaria parasite from getting a toe-hold. (Certain other genetic disorders affecting red blood cells have a similar effect.)
Or consider cystic fibrosis. Carriers of mutations in the CFTR gene—some 1 in 25 people of European ancestry—appear to be protected from typhoid fever, cholera and possibly tuberculosis. While the mechanism of TB protection isn’t clear, in typhoid CFTR mutations are thought to interfere with the entry of Salmonella typhi into cells, and to prevent excess fluid secretion (aka diarrhea) in people infected by Vibrio cholera.
It makes sense historically that mutations that help people survive widely circulating, often lethal infectious diseases, especially TB, have stayed in circulation. Less convincing is the controversial theory that mutations for rare metabolic disorders like Tay Sachs and Gaucher disease have persisted in Ashkenazi Jews because single copies enhanced intellectual ability when Jews were restricted to cognitively demanding occupations.
More recently, though, there’s been another fascinating example of the so-called “heterozygote advantage.” The causative gene for Niemann-Pick C1 (NPC1), a neurologic disorder sometimes called “childhood Alzheimer’s,” encodes a protein that transports cholesterol into cells—but also, oddly enough, serves as an entry portal for the Ebola virus. When the NPC1 protein is defective, Ebola cannot enter cells, and NPC1 carrier mice, when exposed to Ebola, were largely protected from infection.
As an excellent post by science writer Ricki Lewis nicely puts it, “Making sense of the intriguing pairings of genetic and infectious diseases can reveal ways to fight those infections.”
Some therapeutics derived from rare disease discoveries are already in development. For instance, CFTR inhibitors are now being proposed as treatments for cholera and diarrheal diseases; one product is now FDA-approved for diarrhea caused by anti-HIV retroviral drugs.
In the case of Ebola, parents of children with NPC1 disease are funding and gathering samples for a project to study cells from both NPC1 carriers and Ebola survivors. In January, a Montreal biotech company, H&P Labs, announced a partnership with Harvard University and Brigham and Women’s Hospital to develop new anti-Ebola compounds: one group would target NPC1 itself, and the other would block Ebola from getting into the cell compartment where NPC1 resides.
As genetic research turns toward discovering mutations that protect against disease, perhaps it will find that rare disease genes play more of a role than we thought.