 
|
|||||||||||||||||||||||||||||||||
              
|
Visiting the doctor in 2010
Sunday, July 09, 2000 By Byron Spice, Science Editor, Post-Gazette
It is the morning of July 9, 2010. Gloria wakes up with a sore throat. John feels a stabbing pain in his chest as he climbs the stairs to his office. Harold dresses for an appointment with his cancer specialist.
Genetic technology is expensive now, but that may change
Pharmacogenomics: One day, it may allow doctors to tailor drugs to individuals
Using genes to spy on infections
On this future Friday in Pittsburgh, all three will be making medical decisions with the help of their doctors, just as they might today. But they also will be guided by information gleaned from their own genes, if predictions made by scientists in the Human Genome Project become reality.
At lunch, Gloria phones her doctor. Analysis of the cells from the swab, she tells Gloria, shows a pattern of gene activation typical of how the body responds to a viral infection. No antibiotics will be needed, she assures Gloria, but tells her to drink plenty of fluids. The infection should run its course in a few days.
By the time John ends up in a cardiologist's office, a genetic analysis shows that he has several genetic mutations that predispose him to high cholesterol. The doctor advises John to start a walking program, but decides not to order a strict, low-fat diet. Given John's genetic makeup, a diet won't have much effect on his cholesterol levels, so he prescribes a cholesterol-lowering drug instead.
The doctor has encouraging news. When DNA from his tumor was tested on the patented Lymphochip, which checks thousands of genes typically active in the immune system's B cells, the active genes in Harold's tumor fit a profile known as the "GC B-like" subtype of B-cell lymphoma.
The distinction is lost on Harold, but he takes some comfort in his doctor's assurance that this subtype can be successfully treated with anthracycline-based chemotherapy. His odds of survival would have been much worse if he had the "activated B-like" subtype.
Making predictions about technology is full of pitfalls. How else to explain why we're not yet cruising in rocket cars and vacationing on Mars? But now that scientists have figured out more than 90 percent of the sequence, or spelling, of the human genetic code, it's natural to ponder how this new knowledge will change our lives.
One problem is that the people who know the most about these breakthroughs -- geneticists -- have their own biases.
"If you ask a shoe repairman if you need soles and a shine, what's the answer likely to be?" asked Dr. Ronald Bachman, chief of genetics at Oakland Kaiser Hospital in California.
Genetic profiling
Simply knowing most of the spelling of the full set of human genes, called the genome -- a feat announced by the international Human Genome Project and Celera Genomics two weeks ago -- doesn't mean you can read it and make sense of it. Researchers will labor for decades to understand the 3.1 billion letters in the human genome and to figure out the multiple functions of the thousands of genes spelled out in our DNA.
When experts try to guess what the practical effects of this genome knowledge will be, most put little emphasis on the technology that until now has hogged the genetic headlines -- gene therapy. Over the past decade, as more genes have been linked to specific diseases, people have speculated about curing those diseases by replacing the defective genes or adding beneficial ones to individual cells. But despite hundreds of clinical trials, gene therapy has had few successes.
"I bristle a bit when people think only about gene therapy," said Dr. Reed Pyeritz, past president of the American College of Medical Genetics. Even if the kinks get worked out, gene therapy probably will be used in only a select number of patients whose condition makes its expense and risks worthwhile.
The technology that will affect most patients in the near term, Pyeritz said, is the one that already is widespread: genetic tests.
Most people probably think of genetic tests as a way of confirming rare, devastating diseases like cystic fibrosis or muscular dystrophy. But increasingly, these tests will be used to add precision to cancer diagnoses and to understand how heart disease, diabetes, arthritis, Alzheimer's disease and other chronic ailments are likely to affect an individual.
"Likely" is the key word here, because these chronic diseases are affected by tens or even hundreds of genes; by environmental factors such as diet, occupational hazards and lifestyle; and, of course, by time. A bad genetic profile for a cancer or other chronic disease might increase someone's risk, but it's no guarantee that the person will develop the disease.
Still, genetic tests should enable doctors to prescribe lifestyle changes and perhaps drugs that will prevent or delay the onset of a disease and, when treating an illness, to select medications that are the most effective and least likely to have serious side effects.
"I see that emerging for virtually every common disease," said Pyeritz, a medical geneticist at Allegheny General Hospital.
Information explosion
In one sense, the use of genetics in medical care is nothing new.
When Ashkenazi Jews who are prospective parents are tested to see if they are carriers of Tay-Sachs disease, that's genetics. When newborns are screened for phenylketonuria, or PKU, that's genetics. When a doctor records a patient's family history, taking note of relatives with heart disease or high blood pressure or diabetes, that's genetics, too.
And while gene therapy evokes the idea of microscopes and laboratories, some treatments already amount to gene therapy. A liver transplant, for instance, can overcome genetic abnormalities in the patient's original liver; the late Gov. Bob Casey's 1993 liver transplant cured him of familial amyloidosis, for instance.
Even worries about the danger of tampering with our genetic makeup already have some common counterparts today. In one sense, whenever a doctor warns a pregnant woman not to take certain drugs, he is trying to prevent genetic mutations that can harm her fetus.
What will change is the sheer amount of genetic information available to doctors and patients.
Dr. Joseph Scherger, chairman of family medicine at the University of California, Irvine and editor of "Hippocrates," a magazine for physicians, said genetic profiles will become as ubiquitous in most medical practices as comprehensive blood tests are today.
"If there is information out there, we want to get it," he said.
Individuals someday may have their entire genomes sequenced, perhaps at birth, but Dr. Karoly Mirnics of the University of Pittsburgh neurobiology department expects it will be another 20 years before the technology for this is available.
By 2010, however, it may be possible to scan a person's genome for 100,000 "single nucleotide polymorphisms," or SNPs -- single-letter variations in DNA spelling that could be used to predict someone's susceptibility to certain diseases, or select the best medications for them.
How biochips work
It's already possible, using new technologies called DNA microarrays or biochips, to test for thousands of genes at once. At Pitt, Mirnics has set up a facility for producing and using DNA microarrays, which can simultaneously test a genetic sample against up to 10,000 different bits of DNA arranged on a glass microscope slide.
Researchers use these microarrays to determine which of a cell's genes are actively producing proteins.
It works like this: Messenger RNA, a molecule that carries the code of a gene so a protein can be made, is extracted from the cell and labeled with fluorescent tags. A mixture of RNA from a variety of active genes is then placed on the microarray slide, which is covered with tiny bits of genes. Each gene type has a designated spot on the slide.
The fluorescently tagged RNA binds to the DNA fragments with genetic coding that is complementary to that of the RNA -- RNA from gene A binds with the DNA fragments of gene A, RNA from gene B binds with DNA fragments from gene B, and so forth. The slide can then be scanned to determine the brightness of each spot. In this way, the researcher can determine not only which genes are not active in the cell, but get a rough idea of how much protein is being produced by each of the genes that is active.
A similar technology, developed by Affymetrix of Santa Clara, Calif., synthesizes bits of genetic sequences on a silicon chip in a method similar to that used to produce computer chips. This biochip also relies on fluorescence to determine which genes are active.
These technologies are beginning to change genetic research, allowing investigators to sort through thousands of genes to find the handful that might be associated with a particular disease. So many scientists are seeking federal grants for these biochip-aided fishing expeditions that grant reviewers at the National Institute on Aging have come up with a name for them: Fish and Chips.
One hope is that this technology will change the way cancers are detected, said William Bigbee, leader of the molecular biomarkers group at the University of Pittsburgh Cancer Institute.
Until now, most cancer researchers have studied one gene at a time, or even a single SNP or other genetic marker. The result, he noted, has been scientific journals packed with study after study of promising markers that might be used for early detection of cancers. But individually, most aren't very powerful, and there hasn't been a good way to determine which combination of markers might work best.
Chip technologies, however, allow researchers to isolate cancer cells and determine all of the genes that are turned on, or "expressed," inside them, Bigbee said. In this way, the cells will tell the researchers which genetic markers are important.
The National Cancer Institute last year launched a new initiative, called the Early Detection Research Network, to take advantage of these technologies and set up a collaborative network for clinically testing promising sets of cancer markers.
At Pitt, for instance, Robert Ferrell of the Graduate School of Public Health and Dr. Robert Edwards at Magee-Womens Hospital are looking for genetic markers for ovarian cancer, which is difficult to detect at an early, treatable stage. They are taking samples of ovarian tissue from women who have early- and late-stage ovarian cancers and from women without ovarian disease and noting differences in which genes are expressed and the degree of expression.
Their hope is to find a genetic profile for ovarian cancer that can be identified by a blood test or other screening test. Other Pitt researchers are looking for markers for lung, colorectal, and head and neck cancers.
Even after a cancer is detected, gene expression analysis can refine a cancer diagnosis. Last year, researchers at the Whitehead Institute/MIT Center for Genome Research first demonstrated that this was possible, showing that DNA microarrays could be used to distinguish between acute myeloid leukemia and acute lymphoblastic leukemia. In February, scientists at the National Cancer Institute and elsewhere used the same technology to detect previously unknown subtypes of B-cell lymphoma.
A doctor's question
Dr. Michael Haggerty doesn't do genetic research. But as a practicing cardiologist at St. Francis Medical Center, he grapples daily with genetic conundrums and he eagerly scans the scientific literature in search of answers.
Why, for instance, do some people seem to tolerate high blood pressure and others develop heart failure? Part of the answer would seem to be genetic, and a study published last fall by researchers at the Salk Institute in La Jolla, Calif., seems to offer an important clue.
The scientists engineered mice whose heart cells lacked a receptor necessary to use a protein made by the gp130 gene. The mice developed and functioned normally, but when experimenters induced high blood pressure, most of the gp130-deficient mice developed fatal cases of heart failure. Normal mice seemed to tolerate the high blood pressure.
Could the gp130 gene be important in predicting the outcome of human patients? Does it suggest a way of preventing heart failure in some patients? No one knows for sure yet, but Haggerty and his patients are looking for that sort of guidance.
"Why is it that we have people who smoke, have high blood pressure, have high cholesterol, are under the same stress, yet have different outcomes?"
Everyone knows or has heard tales of people who forsake exercise, smoke and eat bacon and eggs for breakfast every day, yet live into their 80s or 90s. Those stories, even if they are sometimes apocryphal, weaken suggestions by physicians that patients improve their diets or lifestyles.
"People are pretty smart," Haggerty said. "They ask about this stuff. And we don't know a lot."
That's why many authorities believe genetics will have its biggest impact on preventive medicine, identifying the patients who have the greatest risk for a particular disease.
But that leaves unanswered the question of whether people will pay attention to the information.
Heeding the warnings
"We all know how to live forever," Ferrell, a geneticist in Pitt's public health school, wryly observed. Yet most people fail to follow general diet, lifestyle and medical screening recommendations. The big question, as Ferrell sees it, is: "If I know I have a [genetic] predisposition, will I change my behavior?"
Ferrell, Haggerty and others bet that you will, though studies show that many people who are aware of their increased risk of disease may not be following advice that could prevent the disease or pick up early signs of it.
This spring, researchers at the University of Utah reported in the American Journal of Preventive Medicine that many people with a family history of colon cancer were not following the American Cancer Society's colorectal cancer screening recommendations. While 84 percent of the 95 people surveyed said they would be willing to take a genetic test, fewer than a third of those over 40 had tested their stool for blood within the previous year, and just 59 percent had their colons examined by colonoscopy or sigmoidoscopy in the previous five years.
Doctors also may have problems carrying out the preventive side of medicine.
A survey by Dr. Randall Stafford of Harvard Medical School of 10,942 doctor visits by people with diagnosed heart disease found that doctors had prescribed daily aspirin to only a quarter of the patients, despite the fact that aspirin has been shown to reduce the risk of second heart attacks and other cardiovascular problems.
"We don't necessarily do a good job of using effective technology that we already have," Stafford said, which suggests that the health system may be ill-prepared to take full advantage of genetic breakthroughs. "Part of it may be an issue of physician awareness and training. But it's also a reflection of a medical system that's still heavily oriented toward acute care" -- treating people after problems have occurred.
Preventive medicine gets short shrift, Stafford said, although some health systems have developed electronic systems to help identify patients who can benefit from preventive therapies.
He said the health care system also is driven too much by high-powered drug marketing that is aimed at doctors and, increasingly, at the general public. Existing, cheaper medications like aspirin and lifestyle and diet changes seldom get the same promotional push, said Stafford, senior scientist at Partners/Massachusetts General Hospital Institute for Health Policy.
Unanswered questions
In one way, the shift of most private health plans to managed care should bolster the use of genetic testing for prevention of disease. Michael Weinstein, a spokesman for Highmark Blue Cross Blue Shield, noted that insurance historically never covered the costs of screening tests for healthy people, but managed care covers many more of those tests and thus may be more compatible with the new age of genetic medicine.
But Weinstein also emphasized that genetic testing raises issues that health insurers have barely begun to address. Should plans pay to screen patients for disorders that can't be treated? What level of care is suitable for a patient with a genetic susceptibility to a disease, but no symptoms? And how much is all of this going to cost anyway?
"There are multiple issues that are just starting to be discussed because this is just in its infancy," Weinstein said.
Kaiser Permanente, the granddaddy of HMOs, thus far has embraced genetic testing. At its hospital in Oakland, Calif., genetic testing is steadily being integrated into patient care.
Each year, 32,000 pregnant women are served by Kaiser in northern California and each fills out a one-page questionnaire designed to detect people at risk for genetic disorders and to offer counseling. Each patient also fills out a half-page "ethnic screen," which identifies racial or ethnic groups that can benefit from testing for sickle cell anemia or various forms of the blood disorder called thalassemia.
Pregnant women 35 and older are automatically referred to genetic counseling, and about two-thirds accept the service, said Bachman, the hospital's chief of genetics. In California, every woman must be offered the "triple marker" blood test, which detects various congenital abnormalities, such as spina bifida. Almost every prenatal patient undergoes ultrasound, which can identify problems such as cleft lip and heart defects.
In the last six months, Kaiser began a new program to test prenatally for cystic fibrosis, a genetic disease that results in the production of thick mucus. That's been controversial, Bachman admitted, because it's not clear whether detecting the disease in the unborn results in better survival. The fear is that it might cause some parents to abort an affected fetus.
"We're not on a search-and-destroy mission," Bachman maintained, explaining that the cystic fibrosis and other tests aren't intended just to find problems, but to help the family prepare for children who will have special needs. Without cystic fibrosis testing, affected babies often are mistakenly treated for asthma, which can cause years of delay before the correct diagnosis is determined.
Genetics is well established in obstetric and pediatric practices, but Bachman said it has been difficult to get internal medicine physicians interested in the genetics of adults. It is hard to get internists to consider such genetic conditions as the iron-overload susceptibility known as hemochromatosis, which can be an underlying cause for diseases such as diabetes, cirrhosis and arthritis.
Most physicians around the nation aren't spending much time preparing for the genetic revolution, added the University of California's Scherger. Until the new technology is in their hands, many time-harried doctors simply won't think about it.
"The tendency in medicine is not to anticipate change," Scherger said. "Physicians have a tendency to run looking at the ground."
|
||||||||||||||||||||||||||||||||
Sunday, July 16: