Sharrer, G. Terry, The World and I
Innovative microscale analyses and novel techniques for gene repair offer the unprecedented opportunity to detect and correct genetic defects that are specific to individual patients.
Color, rubor, dolor, tumor (heat, redness, pain, and swelling)--the cardinal signs of inflammation that Aulus Cornelius Celsus taught in the first century a.d.--provided a focus for medicine that continued through the next two millennia. Over time, physicians sorted out diseases, developed diagnostics, and found effective remedies, but proficiency in healing was largely related to overcoming symptoms. Medicine's future, however, holds a new dimension, one dealing with the origins of disease--more precisely, specific versions of particular disorders, which may vary from individual to individual.
The energizer for this new approach has been the Human Genome Project's attempts to discover not only all the genes of our species but even the "single-nucleotide polymorphisms" (SNPs) that distinguish one person's genome from another's. With the discovery that many diseases arise from genetic defects, public attention has converged on the associated genes. But SNPs have drawn less notice, partly because their role in illnesses is not entirely clear.
SNPs are variations in the individual units (nucleotides) of the overall DNA structure. They occur about once in every 1,000 nucleotides of sequence, which means that there are conceivably 3 million SNPs in the human genome. Not even identical twins have identical SNPs. Most of these variations are in "noncoding regions," where the DNA sequence carries no instructions for protein synthesis. But some appear to be distantly linked to functional genes, and others are located within functional genes, where they may or may not exert a detectable influence. An example of an SNP with functional consequence would be a point mutation in a gene that leads to a disease.
One disease, various mutations
The genetics of colon cancer illustrates this specificity. About 95 percent of colon cancer patients have an adenocarcinoma (a type of tumor) in the colon, and nearly all of them have mutated genes on at least chromosomes 3, 5, 12, 17, and 18. These mutations began accumulating in a single cell that started the abnormal growth. Within each of those genes, however, hundreds of different point mutations are possible, causing functional changes. Each patient's repertoire of point mutations is distinct if not unique, leading to the inference that there may be nearly as many forms of colon cancer as there are people with that disease.
For diseases such as cystic fibrosis (CF), where the disorder is linked to a single defective gene, there is a mutation in the same nucleotide in many cases, but not in others. As a result, there is considerable diversity among those who ail from the same CF symptoms. Furthermore, SNPs have been implicated in such areas as susceptibility to infections, reaction to drugs, and even daily nutritional requirements.
It's ambitious to assume that all diseases can be subdivided into small groups, down to even individual expressions. In the nineteenth century, germ theory did something similar: It classified pyrexias (fevers) according to different causative pathogens. But will a medical approach that repairs genes ever be customized for individual patients? So far, expectations have outpaced results.
The surge in expectations is buttressed by remarkable innovations in diagnostics. Researchers have already developed microarray machines in which thousands of discrete DNA sequences are attached to glass chips [see "Genes on a Chip," The World & I, September 1997, p. 189]. In the foreseeable future, the entire human genome might be represented on a single chip. The strategy is that DNA fragments would be isolated from an individual, tagged with a fluorescent label, and tested for specific binding (hybridization) to complementary sequences on the chips. …