German physiologist Rudolph Virchow first hypothesized cellular pathology--disease at the cellular level--in the 1850s. Today, new treatments for many disorders are a direct result of understanding a disease process at the cellular level. Here, we take a look at how three abnormalities--in cell membranes, in peroxisomes, and in lysosomes--cause whole-body symptoms.
Cystic Fibrosis and the Cell Membrane
Cystic fibrosis (CF) was first described in medical journals in 1938 as a defect in the channels leading from certain glands, resulting in a variety of problems--chokingly thick mucus in the lungs and frequent infection there; a clogged pancreas, preventing digestive juices from reaching the intestines; and salty sweat. A child with CF is often small and sickly, and until the recent availability of biochemical tests, was often initially diagnosed simply as having failure to thrive.
Earlier descriptions of CF mentioned the characteristic of salty sweat. A seventeenth century English saying states, "A child that is salty to taste will die shortly after birth." But this symptom would be a telling clue in explaining how the genetic abnormality causes symptoms felt at a whole-body level.
Researchers identified the cellular defect behind cystic fibrosis in 1989 as abnormal channels in lung and pancreas cells that trap salt within cells. The salty cellular interiors draw moisture in from surrounding tissue, drying out the mucus until it is so sticky that it clogs organs. Several new treatments, including a healthy gene introduced into the lungs in a nasal spray, target the illness at the cellular source.
Adrenoleukodystrophy (ALD) and Peroxisomes
For young Lorenzo Odone, the first sign of adrenoleukodystrophy was disruptive behavior in school. When he became lethargic, weak, and dizzy, his teachers and parents realized that his problem was not just temper tantrums. His skin darkened, blood sugar levels plummeted, heart rhythm altered, and the levels of electrolytes in his body fluids became imbalanced. He lost control over his limbs as his nervous system continued to deteriorate. Lorenzo's parents took him to many doctors. Finally one of them tested for an enzyme normally manufactured in peroxisomes.
Lorenzo's peroxisomes lacked the second most abundant protein in the outer membrane of this organelle. Normally, the missing protein transports an enzyme into the peroxisome. The enzyme controls breakdown of a type of very long chain fatty acid. Without the enzyme, the fatty acid builds up in cells in the brain and spinal cord, eventually stripping these cells of their fatty sheaths, made of a substance called myelin, that are vital for nerve transmission. Death comes in a few years.
For Lorenzo and many other sufferers of ALD, eating a type of triglyceride from rapeseed oil slows buildup of the very long chain fatty acids for a few years, stalling symptoms. But the treatment eventually impairs blood clotting and other vital functions, and fails to halt the progression of the illness.
Tay-Sachs Disease and Lysosomes
Michael was a pleasant, happy infant who seemed to be developing normally until about six months of age. Able to roll over and sit for a few seconds, suddenly he seemed to lose those abilities. Soon, he no longer turned and smiled at his mother's voice, as he had before, and he did not seem as interested in his mobile as he once was. Concerned about Michael's reversals in development, his anxious parents took him to the doctor. It took exams by several specialists to diagnose Michael's Tay-Sachs disease, because, thanks to screening programs in the population groups known to have this inherited illness, fewer than ten new cases appear each year. Michael's parents were not among those ethnic groups and previously had no idea that they both were carriers of the gene that causes this very rare illness.
A neurologist clinched her suspicion of Tay-Sachs by looking into Michael's eyes, where she saw the telltale cherry red spot indicating the illness. A look at his cells provided further clues--the lysosomes, tiny enzyme-filled sacs, were swollen to huge proportions. Michael's lysosomes lacked one of the forty types of lysosomal enzymes, resulting in a lysosomal storage disease that built up fatty material on his nerve cells. His nervous system would continue to fail, and he would be paralyzed and unable to see or hear by the time he died, before the age of four.
The cellular and molecular signs of Tay-Sachs disease--the swollen lysosomes and missing enzyme--had been present long before Michael began to lag developmentally. The next time his parents expected a child, they had her tested before birth for the enzyme deficiency. They learned, happily, that she would be a carrier like themselves, but not ill.