FP Report -- July 1999
Special Section
Those tricky ethical issues ...
With every genetic advance, there's often ethical and legal quicksand to negotiate. For example, when two researchers recently announced success in culturing human stem cells, debate intensified on issues including the moral status of human embryos -- the source of one researcher's cells.
Placing boundaries on human cloning and other controversial procedures is almost impossible for one country to do, given the transnational nature of many biotech firms.Other researchers labor to repair or replace defective genes in somatic cells. But should genes be altered only to prevent disease? Or should "enhancement" be allowed, such as changing genes for increased intelligence? for someone's definition of physical beauty? Should scientists ever alter a human's reproductive cells to eliminate a genetic defect?
Many private companies compete in the race for genetic discoveries -- raising the concern that the patenting of partial and uncharacterized deoxyribonucleic acid sequences will reward those who make routine discoveries but impede the development of diagnostics and therapeutics.
And when human genes are inserted in a cow embryo, is the result human or bovine?
Progress in genetics is so rapid that breakthroughs often occur before issues are debated publicly, and before government and scientific institutions develop guidelines and regulations for the research. And the transnational nature of many biotech firms makes it impossible for any one country to place boundaries on what will be done in the name of progress in areas including human cloning. In the words of one ethicist, an "intercultural, international, multipronged approach" is needed, like the approach used for other global concerns such as the environment.
On the local level, some of the ethical and legal quicksand extends right into the family doctor's office:
- Say you're treating a man for heritable colon cancer and you want to notify blood relatives -- but the patient is upset about confidentiality and implores you not to disclose. So you don't. The blood relatives then suffer the same disease. They might sue you for withholding critical information.
- A patient requests a genetic test, which you provide. She tests positive. Later, she comes in, hopping mad because she didn't get a job. "I had to give them my medical record, and they claim my genetic condition would make the job environment dangerous for me," she laments. "Why didn't you warn me that an employer could discriminate based on my genetic makeup?"
To test or not to test
More and more, patients will be asking family physicians about testing for genetic conditions. But the issue is fraught with ethical dilemmas, including the discrepancy between the capacity to predict risk and the ability to use the information to improve care. Another problem is that genetic testing provides a probability of future risk, but not the categorical yes-or-no answer that patients often want. It's important to help patients understand the meaning of test results -- positive and negative -- before they decide whether to be tested. Referring undecided patients to genetic counselors can sometimes clarify issues for them. And referring to another physician when a patient asks for testing that makes you ethically uncomfortable is always an option.A consensus panel convened by NIH recently recommended that genetic testing for cystic fibrosis be offered to pregnant couples or those contemplating pregnancy, as well as adults with a familial history of CF and partners of people with CF, with testing phased in to ensure that adequate education and appropriate gene testing and counseling services are available. Critics counter that the recommendations in effect promote terminating CF pregnancies, and they worry that emphasis on testing could slow down research on treatments for the disease.
90% of genome sequence should be drafted by 2001
A "working draft" of 90 percent of the human genome sequence should be completed in about a year instead of by the original date of 2005, the director of NIH's National Human Genome Research Institute announced recently. Francis Collins, M.D., Ph.D., made the announcement at a June 10 media briefing on genetics held in San Francisco by the AMA.
The Human Genome Project is an international effort started in 1990. Originally conceived as a 15-year project, the project's completion date previously had been moved up to 2003 because of rapid progress by HGP researchers and private researchers.
HGP goals are to discover all the estimated 80,000 human genes and to make them accessible for further biological study, and to determine the complete sequence of the 3 billion DNA subunits (bases).
The effort was boosted recently when a consortium of private drug firms decided to contribute to the effort, Collins said.
The Department of Energy Human Genome Program and the National Institutes of Health National Human Genome Research Institute together make up the U.S. Human Genome Project.
Confidentiality
Should blood relatives be notified when a patient tests positive for a genetic mutation? "Professional Disclosure of Familial Genetic Information," a report developed by the American Society of Human Genetics, offers some guidance for health care professionals. The report says that disclosures should be permissible when attempts to encourage disclosure on the part of the patient have failed; harm is highly likely to occur and is serious, imminent and foreseeable; the at-risk relative is identifiable; and the disease is preventable or treatable, or medically accepted standards indicate that early monitoring will reduce the genetic risk.Even if the patient and physician decide to keep the information confidential, there's no guarantee it won't be leaked some other way. According to an article in the March-April 1999 Hastings Center Report, most violations of medical privacy seem due to the legally sanctioned, or at least tolerated, flow of medical information from the orbit of the physician-patient-health insurer and health management corporations to other parties, including employers, marketers and the media. The article's author, Amitai Etzioni, called this kind of use "authorized abuse."
Discrimination
"Leaked" health information could lead to discrimination. To combat this, in 1995 the NIH/Department of Energy Joint Working Group on Ethical, Legal and Social Implications of Human Genome Research recommended that insurance providers be prohibited from using genetic information or a person's request for genetic services to deny or limit coverage, or to establish differential rates or premium payments.In October 1996, the NIH/DOE joint working group and National Action Plan on Breast Cancer recommended that employers be prohibited from using genetic information to affect the hiring or termination of an employee unless the employer could prove the information was job related and consistent with business necessity. The U.S. Equal Employment Opportunity Commission has noted that healthy persons with abnormal genes would be protected by the Americans with Disabilities Act of 1990.
Legislation to prevent discrimination has a chance of moving ahead in Congress this year, Francis Collins, M.D., Ph.D., director of the NIH National Human Genome Research Institute, said recently.
Pharmacogenetics may help FPs tailor prevention and therapy
In the future, genetic information might help family physicians custom-design preventive care to a patient's genetic risks and strengths, or tailor drug therapy to the patient's genotype. Pharmacogenetics is a relatively new component of pharmaceutical science that studies how an individual's genotype can influence drug response and metabolism.
"I expect family medicine to see the impact in these areas, whether or not gene therapy is widely available," said Louise Acheson, M.D., M.S., associate professor of family medicine and assistant professor of reproductive biology at Case Western Reserve University School of Medicine in Cleveland. Acheson holds a translational oncology fellowship sponsored by NIH that allows her to focus on the application of new genetic knowledge to clinical practice, and she's a co-author of Clinical Genetics, the most recent AAFP Home Study Self-Assessment monograph.
There eventually may be "gene chips" that could test small amounts of DNA from blood to determine whether a patient has genes that either increase risk or reduce susceptibility to some common conditions. "Of course, there are societal issues that wll have to be resolved," Acheson said. "We'll be more comfortable doing the tests if we know that people are protected against insurance and employment discrimination."
In addition, FPs in the future should have access to genetic testing that identifies how a patient likely would respond to certain drugs, says Acheson. "If there are dozens of genes involved in high blood pressure, or clots in arteries, and also quite a few that determine how a person metabolizes medications, then someday we may be able to understand how genetic differences would play out so we could tailor our therapies to the person."
Pharmacogenetics received a major boost in April when 10 drug companies joined with the Wellcome Trust of London, the world's largest medical research charity, in the nonprofit SNP Consortium, pooling efforts to create a fine-scale map of the human genome. SNPs -- single nucleotide polymorphisms -- are one-letter differences in the genetic map. Working together, consortium members hope to speed discovery of disease-related genetic variations. The knowledge would help them fine-tune current drugs and develop new ones, as well as devise genetic tests to better match drugs to individuals.
Research results will be available to the public at the same time they're available to consortium members -- a move hailed by officials at the NIH National Human Genome Research Institute. The consortium's work will be carried out by the centers doing the publicly financed work on the Human Genome Project; each center will be given six powerful new DNA sequencing machines. The resulting publicly available genome map should reduce the chances that biotech companies will be able to get patents on large areas of the genome.
Here's the bad news: Diagnostic tests now are available for many genetic conditions, with more on the way. But for some conditions, once a patient tests positive, there's little you can do to help.
The good news is that some researchers think the gap between tests and treatments will begin to close fairly soon. The question is, how soon? It depends on who's predicting.
Gene therapy -- replacing a DNA sequence that causes or places a patient at risk for a disease -- could have some "limited success in clinical use within the next five years," predicted Savio Woo, Ph.D., incoming president of the American Society of Gene Therapy. He is director of the Institute for Gene Therapy and Molecular Medicine at the Mount Sinai School of Medicine in New York City.
Nelson Wivel, M.D., deputy director of the Institute for Human Gene Therapy at the University of Pennsylvania in Philadelphia, offered a more conservative estimate. "Gene therapy will turn medicine upside down within 20 years," Wivel said.
It's a therapeutic extension of organ transplantation, he said. It took about 25 years to sort out organ transplantation's developmental problems, and "I see no reason why gene therapy should have any easier time of it," he said.
But there's definitely progress. Presentations of about 1,000 studies, mostly animal research, were made at ASGT's June 9-13 annual meeting in Philadelphia. Some highlights:
- In one study, researchers with the U.S. Department of Veterans Affairs used an adenovirus vector to insert a gene into the liver cells of diabetic rats, which caused the cells to produce insulin. The gene also shut down insulin production before blood glucose fell dangerously low. More than two months after receiving the new gene, the rats were still alive and healthy.
- Two other studies found ways to administer gene therapy for high cholesterol in mice. Researchers at Baylor College of Medicine in Houston used an adenovirus vector, while those at the University of Pennsylvania Medical Center in Philadelphia used an adeno-associated virus. If the approaches work in humans, then patients with familial hypercholesterolemia could benefit.
- Some studies are moving to safety trials in humans. In one phase II trial, researchers at the City of Hope Beckman Research Institute in Duarte, Calif., succeeded in inserting a therapeutic gene against AIDS into pluripotent stem cells, using a retrovirus vector. Because these stem cells can survive for long periods in the body and produce daughter cells that comprise the human immune system, this approach could eventually lead to long-term immunity against AIDS.
Another phase II trial reportedearlier, at the American Association for Cancer Research annual meeting, showed dramatic results: A locally injected, genetically engineered adenovirus, used with two chemotherapy drugs, eliminated head and neck cancers in six patients and reduced tumors by more than half in another 10 of the 26 participating patients. Some of the patients have had no cancer recurrence during more than a year of followup. The two chemotherapy drugs alone have historically produced about a 35 percent partial response rate and almost never completely eliminate tumors, the researchers said. The study was conducted at the University of California- San Francisco Cancer Center.
A locally injected, genetically engineered adenovirus, used with two chemotherapy drugs, eliminated head and neck cancers in six patients and reduced tumors by more than half in another 10 of 26 participating patients.
Currently, about 313 protocols for gene therapy clinical trials have been approved by NIH. Wivel said gene therapy was initially seen as an ideal therapy for heritable, single-gene deficiency diseases such as sickle cell anemia. Now, almost 10 years later, only about 20 percent of protocols are studying those kinds of diseases. The rest are studying cancer, AIDS, cardiovascular disease and other conditions that have multiple genetic components, so "genetics will more and more influence the entire practice of medicine," he said.
"The sea change will occur when such products become readily available," he said. "Then, gene therapy will be available to every licensed physician in the United States."
FP Report is published by the AAFP News Department. Copyright © 1999 by American Academy of Family Physicians.
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