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Genetics in the News…
A growing band of researchers are trying to redefine how diseases are classified by no longer looking at symptoms and physiological measurements, but at the genetic roots themselves. It seems that similar sets of genes are active in relatively uncommonly related diseases.
Duchenne muscular dystrophy may not seem to have much in common with a heart attack. One is a rare inherited disease that primarily strikes boys. The other is a common cause of death in both men and women. Genetics show they are surprisingly similar.
Marc Vidal, a biologist at Harvard, and Albert-Laszlo Barabasi, now a physicist at Northeastern University, created a map of what they called the “diseasome” that was published last year in The Proceedings of the National Academy of Sciences.
Nosology (the field of disease classification) is used to track and lump dissimilar diseases together. What were thought to be single diseases are being split into separate ailments. Just as they mapped the human genome, scientists are trying to the map the “diseasome.” This will mean they will collect all the diseases and the genes that are associated and see where the information leads.
The research will doubtless lead to improve the problems diseases create. Scientists are finding that two tumors that arise in the same part of the body and look the same on a pathologist’s slide might be quite different in terms of what is occurring at the gene and protein level. Certain breast cancers are already being treated differently from others because of genetic markers like estrogen receptor and Her2, and also more complicated patterns of genetic activity. In the future, science will think about diseases based on the “molecular pathways” that are aberrant, rather than the anatomical origin of a tumor.
The reclassification of diseases with their seemingly unlikely associations (as in the example of Duchenne dystrophy and heart attacks) may also help find drugs. Forty drugs are available to treat heart attacks, but none to treat muscular dystrophy, If the diseases are similar in some molecular way, perhaps the heart attack drugs should be tested on muscular dystrophy.
Scientists at the Broad Institute have developed a “Connectivity Map,” which profiles drugs by the genes they activate as a way to find new uses for existing drugs. The research will also improve understanding of the causes of disease and of the functions of particular genes. For instance, two genes have recently been found to influence the risk of both diabetes and prostate cancer.
“I’m shaking my head with disbelief that two genes would pop up in these two diseases that have absolutely nothing in common,” said Dr. Francis S. Collins, the director of the National Human Genome Research Institute. He said another gene, cyclin-dependent kinase inhibitor 2A, seemed to be involved in cancer, diabetes and heart disease.
A consistent way to classify diseases is also essential for tracking public health and detecting epidemics. The World Health Organization takes pains to periodically revise its International Classification of Diseases, which is used, among other ways, to database and report causes of death throughout the world. The classification is also the basis of the ICD-9 codes used for medical billing in the United States.
The first international classification, in the 1850s, had about 140 categories of disease. The 10th edition, in 1993, had 12,000 categories. The next version is due in 2015 and will have expanded remarkably. The increase stems mainly from better knowledge and diagnostic techniques that allow diseases to be distinguished from one another. For most of human history, diseases were named and classified by symptoms, the most observable process of diseases.
Linnaeus, the 18th-century Swedish scientist known for categorizing creatures into genus and species, also developed a taxonomy of disease. He had 11 classes — painful disease, motor diseases, blemishes and so on — that were further broken down into orders and species. But not knowing about viruses, for instance, he classified rabies as a mental disease.
In the 19th century, a big shift occurred. Doctors began learning how to peer inside the body. And diseases began to be classified by their anatomic or physiological features. The stethoscope let doctors realize that what had been thought of as 17 conditions — like coughing up blood and shortness of breath — could all be different symptoms of the same disease, tuberculosis.
The shift from symptoms to anatomical measurements had big implications for patients. Until the 18th century, you were expected to feel sick to be sick. However, now “sick” can be based on measurements like high blood pressure with a person not feeling ill at all.
Some of the earliest work has until now been with inherited diseases caused by mutations in a single gene. Diseases have been subdivided by the type of mutation. Hemophilia was divided into hemophilia A and B, caused by mutations in different genes for different clotting factors. And what was once considered a mild form of hemophilia was later identified as a variant of a different clotting disorder, von Willebrand disease, caused by mutations in a different gene and requiring a different clotting factor as treatment.
Diseases are being lumped, as well as split. Researchers at Johns Hopkins reported in the April issue of Nature Genetics that two rare syndromes with different symptoms might represent a continuum of one disease. One syndrome, Meckel-Gruber, is tied to neural defects and death in babies. The other, Bardet-Biedl, is marked by vision loss, obesity, diabetes and extra fingers and toes.
The techniques are being applied to diseases for which the genetic cause is not as clearly known and which might be a result of multiple genes.
One area that might benefit from genetic disease classification is psychiatry. Because of the difficulty of measuring the brain, psychiatric diagnoses are still mainly based on symptoms. The Diagnostic and Statistical Manual of Mental Disorders (DSM) contains descriptions of conditions as diverse as acute stress disorder and voyeurism.
Scientists have found that certain genes appear to be associated with both schizophrenia and bipolar disorder. Those links, and the fact that some drugs work for both diseases, have prompted a debate over whether they are truly distinct disorders. “The way we categorize these into two separate entities is almost certainly not correct,” said Dr. Wade H. Berrettini, a professor of psychiatry at the University of Pennsylvania.
Experts agree that it is extremely naïve to think that psychiatric illnesses will collapse into categories defined by a gene since each gene at most has a quite modest effect on the illness. That may well hold true for other diseases, as well. Attempts at classification could bring its own ambiguities. For instance, newborns are now often screened for cystic fibrosis with the idea that they can be treated early to help avoid complications. But some infants with a mutation in the gene responsible for the disease are unlikely ever to have symptoms. Do they have the disease? The scientists point out that they do not know what to call these infants since they don’t have a language for it yet. Evolving?
The fact is that nosology based on genes might one day make today’s disease classifications look as quaint as ones from 100 years ago look now. One category in the 1909 listing of the causes of death, for instance, was “visitation of God.” So 100 (or fewer) years from now, the codes we establish might indeed be laughable as well.
Coders and transcriptionists should make note of these relatively new terms, nosology, diseasome, and the testing that will surely become a reality.
