The 25,000-Gene Question

A single drop of saliva contains a great deal of genetic information, more than enough to fill a book. Collect that saliva with a quick swab of your cheek and for a fee someone will read that book and interpret its information for you.

But instead of a tome of genetic information what you’re likely to get in return might be akin to the Cliffs Notes of your genetic makeup, critics of direct-to-consumer genetic testing say.

Last November, Time magazine declared the retail DNA test the invention of the year, saying, “We are at the beginning of a personal-genomics revolution that will transform not only how we take care of ourselves but also what we mean by personal information.”

But the hype has been tempered by concerns in the medical and scientific community, where personal genomic testing is seen as having potential but it is still far from being clinically useful. As experts point out, genes are only part of the story. So when it comes to personalized tests, they say, it pays to be skeptical.

Dr. Maynard Olson, a University of Washington professor of genome sciences and medicine, and one of the main architects of the Human Genome Project, said he would not recommend retail DNA tests to his family.

“They have no value in their present form,” said Olson, who fears that many of the people who are likely to get tested could fall into the “worried well,” those who think they are at an increased risk of a particular disease but who don’t have the practical knowledge to take any action.

A 25,000-piece puzzle

Since the Human Genome Project was completed in 2003, dozens of personal genome testing companies have sprouted throughout the United States, with several offering consumers a quick assessment of their genetic susceptibility to many disorders, including cancer, diabetes and Alzheimer’s disease.

Some of these companies, the Federal Trade Commission has warned, claim people can protect themselves against diseases by consuming special foods and supplements, and offer for sale expensive customized dietary supplements. The FTC also warns consumers that there’s no valid scientific studies showing that genetic tests can be used safely or effectively to recommend nutritional choices. And consumers should be wary about any tests that claim to assess a person’s ability to withstand environmental exposures, such as cigarette smoke.

Why such warnings? Researchers point to the incredible complexity of the human body. Simply unraveling the human genome doesn’t mean we have learned how it works. And just because a certain gene may test positive for a certain disease, That doesn’t mean a person with the gene will develop it.

Genes are coded instructions for making a living thing—each gene a recipe for building proteins, the most complicated and important chemicals in the body. Proteins build, regulate and maintain the body, from growing healthy bones to keeping a heart beating and controlling digestion.

Human beings have about 25,000 genes. And just as easily as genes affect the color of someone’s eyes, hair and skin, they also influence a person’s risk of disease and response to drugs.

Researchers already have identified genes that are associated with several human disorders, including cystic fibrosis, sickle cell anemia, Huntington’s disease and some rare, inherited types of cancer. But these are diseases caused by mutations in a single gene.

The genetic puzzle becomes inherently more complex with most common diseases, such as cancer, heart disease and diabetes. Researchers have found that multiple genes interact to determine the risk of getting most diseases. Lifestyle and environmental factors also affect how genes behave.

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Unwelcome side effects

As Time touted the invention of retail DNA tests, Drs. Amy McGuire and Wylie Burke published a paper in The Journal of the American Medical Association, “An Unwelcome Side Effect of Direct-To-Consumer Personal Genome Testing.”

The “clinical value, if any, of most direct-to-consumer personal genome tests remain unproven,” they wrote. Simply because a test shows a “statistically significant association between a particular genomic variant and a disease does not necessarily mean that the presence of that variant in a given individual is clinically meaningful.”

The bioethics and public policy researchers are concerned that people who undergo genetic testing may overwhelm the medical system by seeking medical advice based on their results, straining already limited health care resources. Also, many doctors are not adequately prepared to answer questions based on a genomic test. At best, some experts have advised the medical community to give general statements about their limited predictive value.

Burke, professor and chair of the Department of Medical History and Ethics at the University of Washington and a researcher at the Hutchinson Center, said direct-to-consumer genetic testing should be regulated.

Under certain conditions, she is not against these tests. Pregnancy tests, for example, are useful tools, giving women convenience and privacy. But other tests, especially those that have not proven themselves reliable and predictive, are not valuable to the public, she said.

“It may not be up to someone like me to say consumers can’t have it,” she said about such genetic testing. But such tests could become a drain on society’s resources. Patients who send away for results will likely bring them to their own doctor and ask for treatment or advice—even though there may be none to give.

“I think there will be a shakeout in 10 to 20 years, and we will have grappled with the TMI (too much information) problem,” Burke said.

Dr. Lee Hartwell, president and director of the Hutchinson Center, said there are two major problems in offering genetic testing to the public at the present stage of development.

The first is that some of the information is derived from small groups of people or from specific populations and may not apply to the person getting the information. A more general problem, even for information that is reliable, is that the risk factors are nearly all quite small—usually less than a 50 percent increase in risk. Many people don’t understand statistics and will only hear that they are at increased risk, he said.

“But an increased risk of 20 percent is not worth thinking about. Smoking increases the risk of lung cancer by at least 2,000 percent—now there is something worth thinking about,” Hartwell said.

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Charting a responsible approach

The nascent gene testing industry has attracted the concern of policymakers. Last year, the states of New York and California questioned the legality of selling mail-order genetic tests without the involvement of physicians. And the federal government has been under pressure to regulate these companies, more so after a federal advisory committee found significant gaps in the oversight of genetic tests. Some of these companies now say they’re prepared to accept federal oversight and industrywide standards.

Against this background, former President Bush last May signed into law the Genetic Information Nondiscrimination Act. The law, debated in Congress for more than 13 years, protects people against discrimination based on their genetic information with respect to health insurance and employment.

Two of the most prominent direct-to-consumer genetic testing companies in the United States are Navigenics and 23andMe, Time’s recipient of the invention of the year.

In its mission statement, Navigenics says it’s committed to using the latest genetic science to “illuminate the future of your health and arm you with the knowledge to change it for the better.”

Dr. David Agus, Navigenics co-founder, is aware of the criticism against the growing genetic-testing industry, but some patients can’t wait for the comprehensive research that will prove the value of certain markers, he said. Patients may choose, individually, to act on information that is incomplete, he said.

Agus, a prostate cancer specialist who directs the Spielberg Family Center for Applied Proteomics at Cedars-Sinai Medical Center in Los Angeles, disagrees that the tests will create a “worried well,” as others have pointed out.

The results of commercial testing, he said, should be considered as just one factor that a patient should put in context with others. However, he agreed consumers need what he called “risk education” to interpret what some of their results might mean.

But is simply looking at genes the best way to go? Hartwell and other researchers said genetic testing has promise, but there are many other avenues worth exploring now, including continued research on proteins. Ultimately, trace proteins may be better biomarkers, signaling the presence of disease early enough to cure it.

Whereas genes may show that someone might get sick in the indefinite future, proteins reflect what’s really going on now, revealing a person’s dynamic, real-time state of health, Hartwell said.

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Meaningful genetic testing

This is not to say the study of genes isn’t helping advance medicine. In some specific areas, there is sufficient research on genetic risk.

The medical community has made positive strides in breast, colon and ovarian cancers. Increasingly, doctors are working with other specialists to unveil a complex overview of risk to patients in a medical setting.

Consider breast and ovarian cancers. Thousands of women carry one of two genes identified with breast and ovarian cancer, BRCA1 and BRCA2. But by themselves, these markers are not enough to be predictive of disease. At the Seattle Cancer Care Alliance, Dr. Elizabeth Swisher leads a special clinic to help women understand their risk, based on family history and on genetic testing—if they choose to have it.

As director of the SCCA’s Breast and Ovarian Cancer Prevention Program, Swisher’s goal is to help prevent cancer for some women or help find it earlier when it is more treatable. Women at high risk can choose preventive surgery, such as removal of their breast tissue or ovaries, or they can choose to get more frequent mammograms or other exams.

However, giving women their risk information is a rigorous process and every patient is educated carefully about her own choices, Swisher said.

Direct-to-consumer sales of genetic information can be dangerous, she said, because they don’t involve the patient in a medical community that can help interpret the information.

The SCCA also is helping identify and educate patients at high risk of colon and other gastrointestinal cancers due to genetic factors. A key part of the program clearly explains what the genetic factors mean to the patient and for their children, and helps them deal with the information constructively. Armed with this information, patients may choose to make changes in their diet or get more intense surveillance, such as more frequent colonoscopies.

Dr. Cornelia M. Ulrich, formerly of the Hutchinson Center, has been studying how different people respond to a class of drugs known as non-steroidal anti inflammatory drugs (NSAIDs). Genetic differences in how people process these drugs could be crucial to whether doctors prescribe aspirin and ibuprofen, for example, for prevention of inflammation. Many cancers arise after a patient has an inflammatory condition, such as hepatitis B or chronic gastritis from the Helicobacter pylori bacterium. Some believe that NSAIDs might be helpful in preventing some cancers.

“In the future, physicians may consider not only a person’s family history of cancer and current medications and diseases, but also what is known about their genetically determined capacity to process NSAIDs,” Ulrich wrote in an article she co-authored for Discovery Medicine. In the meantime, the biomedical community has by no means closed the door on genetic testing.

“Of course, the hope is that as knowledge increases, some genomic information will prove clinically useful,” McGuire and Burke wrote in the JAMA paper. Both called for more research to evaluate the predictive value of genomic tests and their potential to improve the use of clinically effective interventions.

“(Genetic) test manufacturers should be eager to disclose robust evidence that supports health benefits from test use,” they wrote. “As the evidence accumulates, formal health technology assessment will be worth pursuing as a first step toward evidence-based use of personal genomics in health care.”