About six years ago, scientists succeeded in mapping out the complete human genetic code. One of the more striking revelations to come out of this massive study of human DNA — the hereditary material in all organisms — is that while we share 99.8 percent of our genes with other humans, the differences in the remaining 0.2 percent determine our proclivity to develop illnesses — heart disease, for example — as well as our response to treatments. So people who suffer from a particular disease will be able to have their DNA screened so that doctors can prescribe the drug that will precisely target their condition and, perhaps equally important, exclude the drugs that won’t work.
The Human Genome
The genome is the complete DNA sequence of an organism. The human genome contains about three billion base pairs. The base pairs are arranged in 23 pairs of separate DNA segments called chromosomes. Scientists have recorded the sequence of base pairs in each of these chromosomes, in effect creating a map of the DNA contained in each cell. The human genome contains between 20,000 and 25,000 genes, which appear in clusters along chromosomal DNA strands. One active area of research is identifying the normal functions of these genes — scientists so far have been able to identify roles for about half of them. Another field of research focuses on genetic variations, particularly those that may impact a person’s susceptibility to disease.
Actually, even before the human genome map was completed, scientists had already identified certain large genetic abnormalities associated with specific illnesses. For example, it’s long been known that Down’s Syndrome is caused by an extra copy of chromosome 21, an abnormality that’s fairly easy to spot with a microscope.
Scientists have also been able to identify “simple” genetic disorders caused by mutations of a single gene. For example, sickle cell anemia is caused by a variant of the hemoglobin, beta (HBB) gene located on chromosome 11. Mutation of this gene causes abnormalities in the protein the gene produces, which in turn causes biological dysfunction or illness.
Scientists around the world are currently studying, one by one, differences in these genes (“variants”) between healthy people and those with diseases. These variants and the products of the genome — RNA (ribonucleic acid) and proteins — produce so-called “molecular signatures” that can be associated with specific clinical characteristics or diseases. Already, scientists have determined the molecular signatures for many types of cancers, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and cardiovascular disease.
One of the largest genome-wide studies done so far examined about 16,000 individuals for clues to seven common complex diseases, including high blood pressure, rheumatoid arthritis, and diabetes. The researchers identified 24 independent associations between the various disorders and specific variants. Additional studies are beginning to confirm some of these links and even find new ones.
How Genomic Information Is Used
Fighting disease with precision-guided medicine, often tailored to the individual (“designer medicine”), is one outcome of these research studies. “We are taking the groundbreaking position that the genome will dramatically enhance our ability to give individualized care to both patients and healthy people,” says Geoffrey S. Ginsburg, MD, PhD, director of the Center for Genomic Medicine at Duke University in North Carolina.
This information enables physicians to make more informed treatment choices. “There are an amazing number of excellent drugs on the market, but most are only effective in 20 to 50 percent of patients. We want to use genomic information to better define who is most likely to benefit from a specific drug and to avoid giving drugs to people who will receive no benefit,” says Dr. Ginsburg.
Equally important, molecular signatures can be used to determine which patients will not respond to a particular drug. The results can be lifesaving, since patients with these signatures can be given other drugs that are more effective for them. Genomic medicine has already begun to reveal its potential. FDA-approved genetic tests now enable physicians to target highly effective therapies to patients most likely to benefit. These include Herceptin for patients with HER 2-positive breast cancer, Gleevic for patients with Philadelphia chromosome-positive chronic myeloid leukemia, and Tarceva for patients with human epidermal growth factor receptor 1 (HER1/EGFR) non-small-cell lung cancer.
Genomic Testing
Genomic tests are also being used now to determine the optimal dosage of certain risky drugs such as warfarin, and some antipsychotic and antidepressant medications. Eight genetic variants tell cardiologists which patients at risk of sudden death from long QT syndrome (a disorder that can cause fast, sudden heart rates) will respond better to one class of medications than another.
Genetic and genomic tests can predict the risk of developing a disease such as breast cancer in some families, or type 2 diabetes, or be used in place of tissue biopsy to monitor rejection in heart transplant patients.
Indeed, personalized medicine made possible by genomic tests may:
• Help predict who is at risk — and who is not at risk for a disease.
• Provide more accurate diagnostic and prognostic information for a disease.
• Help select optimal treatments and reduce trial-and-error.
• Reduce adverse drug reactions.
• Increase patient compliance.
• Reduce the time, cost, and failure rate of clinical trials.
• Revive drugs that have failed clinical trials and that might be useful for specific individuals, rather than for the general population.
• Avoid withdrawal of marketed drugs.
• Increase overall effectiveness of health care.
• Reduce the overall health care costs.
The Larger Picture
Personalized, genomic-guided care is beginning to transform health care, but before it can become routine, its many implications must be understood. There is also a need for integrating the genome sciences and clinical practice with related issues involving privacy, confidentiality, economics, ethics, law, policy, social acceptance, and more.
Some private companies in the United States are already providing DNA analysis to the public, offering to assess your disease risk based on the variations contained in your genome. A few even offer genetic counseling and disease prevention and screening advice. But experts caution that current tests aren’t able yet to identify all the genetic variants that combine to produce vulnerability or resistance to a disease. It’s likely that many more genetic variations will need to be identified before a fully accurate risk assessment can be developed. Indeed, much more research needs to be done before a complete picture of a person’s genetic profile can be obtained. More importantly, a person’s genetic architecture often is only one piece of the puzzle when it comes to disease, interacting as it does with environmental exposures and lifestyle habits.
As for patients already diagnosed with a disease, Dr. Ginsburg feels the more they know about genomics and health, the more likely they are to take advantage of the benefits of personalized medicine. “It’s okay to ask your physician about genomic testing and work together to use it to take care of you today — as an individual — in ways that just were not possible yesterday,” he says.
Many scientists believe that genomic medicine is the future of medicine and that we are now seeing the dawn of this dramatic development in medical science and practice. As we celebrate Medicine Week, it is exciting to think that the future is here and now.