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Medicine's 'Genaissance'.

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.

Microscale diagnostics

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. Each person's DNA sequence would produce a characteristic binding pattern, detectable by an optical scanner.

Analysis of gene sequences would be followed by analysis of gene expression--that is, the production of specific types of RNA and proteins. It should then become possible to understand a patient's changing biochemistry in much finer detail than is possible today. Miniaturization of instruments used in biological analysis could bring the technology that's currently available only in major research hospitals to the local clinic or private doctor's office. And it is not far-fetched to imagine an annual "checkup" involving the comparison of a recent microarray analysis with an earlier evaluation recorded on a CD-ROM.

It now appears that an individual's SNPs may determine how much of a drug remains in his body over time, as well the extent of benefits and likely side effects of the drug. From that perspective, microscale diagnostics might lead to better medicines, new indications for older drugs, and a decline in the 100,000 annual deaths (in the United States) caused by adverse reactions.

Correcting genetic defects

The original concept of gene therapy--to replace a defective gene with a properly functioning one--has barely met with proof on the practical level. Since the beginnings of this therapy in September 1990, some 300 clinical trials involving about 6,000 patients have been conducted, but the results have been mostly disappointing. Nonetheless, if gene- replacement therapy is geared to the individual's genetic makeup, it may eventually become an adjuvant to chemotherapy and radiation, lessening their severity or enhancing their effectiveness.

Meanwhile, scientists at Kimeragen (in Newtown, Pennsylvania) have devised a newer strategy--known as chimeraplasty--to repair defective genes. [Kimeragen Inc. recently merged with the French company ValiGene to form ValiGen.] Whereas gene therapy mainly uses genetically engineered viruses to deliver a replacement gene, chimeraplasty relies on short, synthetically produced sequences of DNA/RNA hybrids (chimeraplasts) to interact with the faulty genetic material and to stimulate the cell's genetic repair mechanism to correct the defects.

The first clinical protocol, tested on rats, was designed to treat Crigler-Najjar syndrome--a genetic disease in which a defective liver enzyme fails to break down bilirubin, which at high levels can damage the central nervous system. The chimeraplasts were cleverly introduced into the nuclei of liver cells, where the chimeraplasts' sequence matched almost perfectly with a complementary sequence on a chromosome. But a mismatch of one nucleotide, at the point mutation linked to the disease, activated the cellular DNA repair enzymes to fix the defective gene. Widening the applications for this approach would mainly depend on finding the delivery systems for specific types of cells.

If this type of "gene medicine" delivers on its promise, the individual diagnosis and treatment of disease holds many startling eventualities. Intractable, chronic diseases--such as cancer, stroke, Alzheimer's, and diabetes--might be beaten down. This approach may extend life expectancy a little further, but more important, it would tremendously improve the quality of life for those who would otherwise suffer.

Of course, at present it is almost unimaginable that a drug company might someday customize its medicines to suit each patient, or that an insurance company would pay for that. But where there's a way, there may be a will. Diseases will never disappear from the human condition, but a genetically driven medical renaissance--or "genaissance," to borrow the name of one company working in this rising field--has already begun to advance our potential in health care.n

G. Terry Sharrer, Ph. D., is curator of health sciences at the Smithsonian Institution in Washington, D.C., and board chairman of the National Foundation for Cancer Research in Bethesda, Maryland.
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Author:Sharrer, G. Terry
Publication:World and I
Geographic Code:1USA
Date:May 1, 2000
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