The emergence of molecular medicine and diagnostics is bringing sweeping changes to the delivery of health care. Practitioners will begin to see patients in a completely new way. For clinicians who don’t know what they don’t know, change will be a challenge.
Abstract
Biotechnology is changing how doctors ‘see’ patients and disease processes. Optical probes and computer-assisted genetic screening tools let researchers peer into the structure and functions of cellular proteins on a molecular level. Soon, this clearer vision of individual patients will be available in the clinic, making drug and biologic treatments safer. These new lenses will push medicine toward risk prediction and away from acute intervention.
Genetics is transforming the way clinicians see patients and predict their susceptibilities, predispositions, and prognoses. Learning to see genetically is gradual and complex, and will influence every aspect of medicine. If medical practice can be thought of as comprising five steps — examination, history, and diagnosis; classification of disease; prognosis; treatment; and follow-up — then molecular diagnostics is changing the linear model these steps have represented into a more fluid, continuous cycle of testing, prevention, treatment, and more testing. This cycle, informed by a patient’s unique genetic profile, will be marked by targeted therapeutic interventions, a shift in focus that has come to be known as personalized medicine.
“Personalized medicine is not just for the future,” says Edward Abrahams, executive director of the Personalized Medicine Coalition, a not-for-profit advocacy group in Washington. “It’s here and now. But are practitioners ready? We need to educate the medical and other communities about the system-wide paradigm shift that personalized medicine represents. We also need to accelerate its advance by addressing some of the public policy issues that exist around regulation and reimbursement.”
WHAT’S “ENOUGH”?
How much do healthcare practitioners need to know about genetics? After all, practitioners use tests having mechanics or principles that they do not always understand completely. They do not need to comprehend the intricacies of how a test works, as long as they are able to interpret and apply its results. Some physicians will want to know a great deal about underlying genetics, but most probably won’t.
While all diseases have a genetic component, specific knowledge needed to make treatment decisions is not yet fully available. “At some level, genetics underlies virtually all cases of morbidity and mortality around the world — not merely single-gene disorders,” according to Joseph McInerney, director of the National Coalition for Health Professional Education in Genetics (NCHPEG), in Lutherville, Md. “The question is not whether a certain disease, such as diabetes or a particular type of mental illness, is genetic. A better question is, ‘What role do genes play in a patient and his or her relatives at this particular time, with this particular onset and expression of disease?’”
“Personalized medicine is here and now,” says Edward Abrahams, executive director of the Personalized Medicine Coalition, whose members include drug and device manufacturers, information technology companies, and universities. The coalition works to build consensus on public policy issues related to personalized medicine.
PHOTOGRAPH BY ROB CRANDALL
Practicing physicians want practical solutions, McInerney says. “They want to know how genetics will change their practice tomorrow. We haven’t done a good job of telling physicians how genetics is relevant. The obvious and immediate relevance is about risks and predictions — red flags in a family history that can indicate a more significant genetic contribution to disease.”
To practice medicine responsibly in a genetics age, practitioners will need to master an agreed-upon knowledge base and set of skills. NCHPEG, founded in 1996 jointly by the National Human Genome Research Institute, the American Medical Association, and the American Nurses Association, seeks to educate healthcare professionals on the effects of genetics and genomics on healthcare. The group has created a list of core competencies in genetics for healthcare professionals, some of which accompany this article. NCHPEG’s Web site «www.nchpeg.org» contains other practitioner tools, including monographs on the genetics of common disorders.*
With the advent of individualized molecular medicine, the questions a patient asks in the examination room will change, McInerney predicts. “Today’s patient asks, ‘Doc, what’s wrong with me?’ And tomorrow, the question will be, ‘Doc, what’s going to be wrong with me in 10 or 20 years?’”
Being able to answer that second question could come with a catch. A physician perhaps will be able to tell a patient, with a high degree of certainty, what will go wrong down the road, but might not be able to do anything about it. There may be a diagnosis but not a tolerable treatment, aside from the usual preventive measures — diet and exercise — or “watchful waiting.”
Because diseases cross specialty lines, the genetics factor is likely to force a more integrated team model of medicine, as opposed to the handoff of patients from family practitioner to specialist.
According to McInerney, confusion already exists in ordering and interpreting genetic tests. “One such example is a carrier test for cystic fibrosis,” he says. “A doctor might not know how to interpret the test results or provide the appropriate advice to the patient.” If single-gene disorders such as cystic fibrosis or sickle cell disease present a challenge to the average provider, more complex diseases, including most chronic diseases in humans, are even more problematic.
“Genes are segregated in Mendelian patterns,” McInerney says, “but if you look at the family history of complex disease, the phenotypes do not follow classic patterns of single-gene disorders; this makes it more difficult and nuanced to recognize the genes, assess their contribution, and communicate the risk.”
FROM BENCH TO BEDSIDE
As genomics becomes integrated into medicine, the gap between clinical practice and clinical research will continue to narrow, predicts Matthew Hude, national managing partner for biotechnology in the San Francisco office of Deloitte, the consulting firm. “Genomic medicine will make the practicing physician more aware of clinical research and vice versa.” Hude, who has a background in clinical research, also notes a tug-of-war over the size of clinical studies. Consumer advocacy groups seek larger trials for better safety oversight to predict adverse events, while molecular medicine will demand smaller trials based on a population with a particular genetic makeup. More postmarketing studies may offer a compromise.
Classification of cancers already has made strides in the genomic era because of gene-probing techniques, such as microarrays or biochips, which are used for monitoring and measuring changes in gene expression for each gene represented on the chip. Another innovation in categorizing disease is immunohistochemistry, which is a method of detecting the presence of specific protein markers in cells or tissues.
In detecting and determining how to treat cancer, “the question to answer is: ‘Which pathways drove the tumor?’” says Ken Bloom, MD, medical director of Clarient, in Irvine, Calif. “When we know that, we can attack the tumor. We think about genomics, proteomics, and sugars, and we look in the cell nucleus, the membrane, and the cytoplasm. A microarray can tell you if a gene is expressed, but — even if a protein is present in the cells — you need to know where it is active and what it is doing. Microarrays are keys that opens some — but not all — doors.”
Caring for a patient, circa 2020.
Here’s one vision of how a routine visit to the doctor’s office could change over the next 15 years.
ILLUSTRATION BY TOM WHITE
The year is 2020. It’s time for your routine genetic screening test. A nurse swabs the inside of your cheek, puts a few cells on a glass slide, and places the slide in a small computer that analyzes the cells for DNA-to-RNA misspelling due to random mutations or environmental stressors. The machine compares your genetic information with that of millions of other patients with certain diseases. The database is updated every 20 minutes with information from a worldwide data pool administered by the Centers for Disease Control and Prevention and the World Health Organization.
The computer notes a mutation in the P53 gene and androgen receptor gene, as well as inactivation of the ribonuclease L (RNASEL) gene. The genetic marker for benign prostatic hypertrophy is absent. The nurse obtains a blood sample via a painless pore-opening device. Just as she suspects, based on the computer algorithm, the blood sample is positive for a “red-flag” protein — PCa-24 (present only in people with prostate cancer). The nurse then scans your information into the database, thereby adding another case to the millions of patient cases already registered there.
The nurse then requests that you obtain a drop of prostate aspirate using a painless aspiration device. She places the slide into a computerized microscope that reads and records protein markers and sugar markers for subtypes of prostate disease. Taking into account your genetic information, your prostate-specific antigen [PSA] score, your Gleason score, and other information, the machine delivers a likely diagnosis and prognosis to your personal Web site.
After reviewing a Web site with your family history, medical records, prognosis report, and blood test results, the physician examines you. She suspects the onset of an invasive type of cancer within a few years and has requested instructions on interpreting the computer results and suggested experts to contact. The medical technologist convenes a virtual team on a secure office au-dioconferencing tool, provides access to your medical history and data from patients with similar genetic profiles by computers of proposed experts. The conferencing tool locates available experts, and an on-the-spot team is formed.
In this case, the virtual clinical team comprises a geneticist in Boston, a California oncologist with expertise in this cancer type, and a stem-cell replacement specialist in Philadelphia. You and your doctor are present. The computer technician loads your data for all to view.
The oncologist in California states, “I wish the prostate cancer vaccine had already been approved, but it’s still a couple of years away. It looks as if you’d be a perfect candidate for it.” The geneticist then explains, “You won’t have to undergo any hormone therapy, because your mutated androgen receptor gene would make that ineffective. Instead, I would suggest you choose gene therapy, which can repair the DNA damage.”
The family physician finishes by explaining the proposed treatment. “First, we’ll have to replace some of your prostate cells with recombinant mouse stem cells containing a normal copy of the P53 gene and also the PCa-24 gene. We can do that in the outpatient clinic. You’ll need to take a mild immunosuppressant, which you can access from an online medical cabinet paid for by your health plan. A medical technologist adds “I would recommend installing a smart-toilet in the home so we can continue to check for these protein markers. The information will be automatically transmitted from your home to the lab for review and analysis. Also, we’ll send you a special electronic toothbrush. It will record an accurate daily reading of your blood chemistry using a minute sample of blood.”
Acknowledgment: Thanks to Dadong Wan, senior researcher with Accenture Technology Labs in Chicago, for help with this scenario.
Clarient’s technology utilizes immunohistochemistry to apply an antibody to the protein under study. Image analysis software tracks tumor development and tests the progress of therapy. Using similar technology, physicians will be able to detect, with certainty, whether any circulating tumor cells remain after treatment.
Genetic testing allows a clinician to determine not only if a patient has cancer but with a greater degree of precision than was possible in the past, what kind, and whether it is treatable. There is an increasing ability to probe tumor tissue optically at a very early stage, before it’s too late to intervene. This increases the ability to treat the underlying cause and view the results, compressing the cycle of prognosis, treatment, and follow up. With as many as 300 new biologic treatments under study, the expanded number of treatment options could make treatment decisions impossibly complex. Genetics and pharmacogenomics should limit the range of options for each individual.
Genetic screening also will help clinicians see, or more accurately foresee, which patients are the best candidates for specific biologics and chemical drugs. Reactions to biologic treatments are immunological, not metabolic. The body considers the biologic a potentially infectious invader and mounts an immune response as if an invader were present. Diagnostic tests are on the horizon that will predict these immunologic responses for safer use of biologics. The liver enzyme known as cytochrome P450 (CYP) is actually a family of enzymes, a key component of the body’s detoxification system. As many as 40 percent of individuals have subfunctional genes for these enzymes, says Gualberto Ruano, president and CEO of Hartford, Conn.-based Genomas, which develops diagnostic products for personalized medicine.
Genomics research has yielded hundreds of catalogued DNA variations of enzymes that cause disparate reactions to the same drug. Pharmaceutical companies routinely assess the major cytochrome P450 pathways for drug metabolism to help predict both patient response and potential adverse effects. These DNA diagnostics can help doctors prescribe drugs for their patients, and keep useful medicines on the market by averting administration to patients who cannot metabolize them. The U.S. Food and Drug Administration is working on updating labeling to include availability of genetic drug safety tests offered in clinical labs.
Traditional fields of medicine are overlapping in response to new disease knowledge. Because diseases cross specialty lines, a more integrated team model of medicine will likely replace the relay model of handing off patients from family practitioner to specialist. Until genetic training is more common in undergraduate programs and medical schools, reps selling diagnostic and treatment tools may be, by default, the prime educators about new products and tests based on fields like pharmacogenomics.
17 things healthcare professionals should know about genetics.
The National Coalition for Health Professional Education in Genetics endorsed these core competencies in 2000. NCHPEG is an interdisciplinary group comprising leaders from approximately 120 diverse health professional organizations, consumer and voluntary groups, government agencies, private industries, managed care organizations, and genetics professional societies.
All health professionals should understand:
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SOURCE: NCHPEG, LUTHERVILLE, MD
“Everyone knows genetics is in medicine to stay,” says McInerney. Medical schools “are trying to figure out the best way to integrate it into the curriculum. Under the traditional model, medical students study genetics in their basic science classes early in medical school. When they begin clinical rotations, they may not see the relevance of those principles unless someone on the faculty makes the connection explicit. Unfortunately, the faculty may not be sufficiently conversant with genetics to make those points.”
He points to forward-looking medical schools — such as Duke University and the University of Vermont — that integrate genetics into their curricula. Duke’s Genetics Interdisciplinary Faculty Training (GIFT) program in its nursing school has trained nursing, physician assistant, and nurse-midwifery faculty from universities around the country to augment genetics training.
8 skills healthcare professionals should master.
The National Coalition for Health Professional Education in Genetics lists eight skills that all health-care professionals should possess. The group recommends competency in an additional nine skills for clinicians who provide genetic counseling. These, and a set of attitudes that NCHPEG recommends that healthcare professionals keep in mind, are available at: «www.nchpeg.org».
All healthcare professionals should be able to:
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SOURCE: NCHPEG, LUTHERVILLE, MD.
The University of Vermont College of Medicine is integrating genetics into each year of undergraduate medical education. A Vermont Integrated Curriculum (VIC), now in its second year, weaves a theme of genetics, ethics, and epidemiology into the curriculum. These disciplines are introduced in the first course in VIC and reinforced in subsequent courses devoted to gene-environment interaction in disease and health. VIC students periodically regroup during their clinical years in weeklong sessions that address complex issues that transcend individual clerkship training.
ETHICAL CONCERNS
Predictive medicine will be possible only when the thousands of remaining mysteries between genotype and phenotype are solved by amassing and analyzing genetic databases. But solving clinical mysteries is just part of the challenge. Medical ethicists will have their hands full in coming years as they sort through the implications of genetic medicine. Among the controversial ethical issues emerging: predicting a nontreatable disease, genetic privacy, and genetic nondiscrimination.
Whole-genome analysis will influence reproductive decision making and create difficult issues. Further, payment for medical care and the possibility of rationing are issues as yet unsolved. People who use more medical services, or who can be expected to in the future due to a genetic predisposition to a disease, might face higher health insurance premiums.
Other ethical issues relate to exclusion from clinical studies on the basis of genetics. Currently, it is unknown whether patients will tend to resist genetic screening or, conversely, clamor for testing and hold physicians and payers who have not done a specific test responsible for adverse outcomes.
Finally, there is a potential for abuses of the new knowledge, including genetic discrimination in health insurance and employment, bioterrorism, and eugenics. Federal legislation already governs the use of genetic information for employment and insurance decisions; a genetic nondiscrimination act, endorsed by President Bush, is making its way through Congress.
Genetics will drive radical change in healthcare. For clinicians, rapid advances in knowledge will make it a challenge just to know what to stay current on. In time, though, payers and patients alike may well come to expect providers to keep up.
Footnotes
For basic genetics, McInerney suggests starting with the Web site for the Department of Energy’s Office of Science «www.doegenomes.org», a link to the Human Genome Project «www.ornl.gov/sci/techresources/Human_Genome/home.shtml», and the National Human Genome Research Institute Web site «www.genome.gov».