ORLANDO, Fla.—The genome project sequenced all three billion base pairs of human DNA, revealing the instructions cells need to build all the proteins in the body. But that was just a warm-up, according to Thomas C. Spelsberg, PhD, of the Mayo Clinic in Rochester, Minn.
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March 2010“Medical genomics is evolving into individualized medicine,” Dr. Spelsberg said at a guest lecture at the Triological Society’s Combined Sections Meeting held here Feb. 4-7. “You can start looking at disease biomarkers, new targeted drugs, disease subcategories, predispositions to diseases and even pharmacogenomics, which is individualized drug metabolism. This is the future, folks.”
Dr. Spelsberg, the George M. Eisenberg Professor in the department of biochemistry and molecular biology at the Mayo Graduate School of Medicine, explained that medical genomics has given way to transcriptonomics, the study of all the mRNAs (messenger RNAs) that code for proteins. Other areas medical genomics has evolved into include preoteomics, the study of all the proteins in cells or organisms, and metabolomics, the study of the activity of cell proteins and enzymes.
Dr. Spelsberg said the knowledge produced by these emerging fields will enable physicians to customize diagnosis and treatment based on each patient’s genetic endowment. Already, researchers have identified about 10 “obesogenes” involved in the maintenance of body weight. Dr. Spelsberg displayed a photo of two rats side by side. One appeared normal, while the other was enormously fat. The fat mouse, he explained, lacked the gene for leptin, the hormone that triggers a feeling of satiety.
Polymorphisms
But the genes themselves are only part of the story. Genes also mutate or “morph” into polymorphisms that can leave the body more susceptible to dysfunction. Some polymorphisms are inherited, some develop over time. “Identical twins are born with the exact same DNA, but they develop polymorphisms with age and start to look different,” Dr. Spelsberg said. “They grow apart.”
The environment plays a role in developing polymorphisms. “People who live in cities get more polymorphisms,” Dr. Spelsberg said. “They say for every 15 cigarettes you smoke you develop a new polymorphism. Smokers have a lot more polymorphisms compared to nonsmokers. And people who get lots of sun have more polymorphisms in their skin. What they’re finding is that the more polymorphisms you get, the shorter your lifespan will be.”
Even though humans are 99.9 percent identical genetically, that remaining 0.1 percent amounts to three million polymorphisms. Most polymorphisms are nonfunctional, but some—about one in 30—alter the structure of the proteins produced by the cell, producing observable changes. A deeper understanding of how polymorphisms interact reveals subclasses of diseases.
“We can get a pretty good idea not only what diseases you’re predisposed to, but also what subtype of disease,” Dr. Spelsberg said.
Computer analysis of DNA samples has increased the speed of discovery exponentially. “It used to take months to analyze one gene,” Dr. Spelsberg said. “Then it went to days. Now in one afternoon we can assay 10,000 genes. We can tell what genes are different in people with a particular disease. Computer programs can tell you exactly what pathways are involved. All this can be done in a week.”
Someday humans will be given a little flash drive at birth that will tell everything about them at the genetic level.—Thomas C. Spelsberg, PhD
Personalized Medicine
Dr. Spelsberg indulged in speculation about what the future will bring. “There will be newborn and prenatal analysis for polymorphisms in major disease-related genes,” he said. “There will be lifetime preventive measures that people can take. There will be focused checkups as you age, looking for disease susceptibility. There will be improved disease detection and accurate subclassification of diseases for individualized treatment. Someday humans will be given a little flash drive at birth that will tell everything about them at the genetic level.”
And while all that may sound like science fiction, some of it is starting to happen.
“Individualized medicine programs have been ongoing at Mayo,” Dr. Spelsberg said. “There were 83 new genomic-based tests introduced at Mayo in 2008. They conducted 775,000 genomic tests. I’m not talking about the future here. These things are happening now, and much more is on the way.” ENTtoday
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