BIOETHICS COUNCIL EXPLORES ALTERNATIVE SOURCES OF HUMAN PLURIPOTENT STEM CELLS
The President's Council on Bioethics has released its analysis on potential alternative sources of human pluripotent stems cells. The Council was created by President George W. Bush in 2001 to advise his office on bioethical issues related to advances in biomedical science and technology. In January 2004, the Council published Monitoring Stem Cell Research, a report providing an overview of the law, ethics, and science of stem cell research. With this new report, issued as a white paper in May 2005, the Council focused on the ethical and scientific challenges facing this research.
Although, at present, new human embryonic cell lines cannot be obtained without destroying human embryos, the Council explored options that might permit scientists to resolve the conflict between the goals of increasing scientific knowledge and treating human disease and maintaining protection and respect for human life. In his letter to the president, Council Chairman Leon R. Kass, MD, offered the paper as the Council's assistance “to promote a biomedical science that will simultaneously serve human needs and preserve human dignity.”
Human embryonic stem cells are useful for science because of their pluripotency and longevity. However, in 1995, Congress enacted legislation prohibiting the use of federal funds for research in which human embryos are destroyed or harmed. In 2001, President Bush instituted the current policy, which permits federal funding for research on those embryonic stem cell lines already in existence but not for derivation or use of any new lines. Many researchers have called for a further loosening of the restrictions but have met with equally passionate arguments in opposition.
In their white paper, the Council examined four broad approaches for the derivation of stem cells: (1) by extracting cells from embryos that had already died spontaneously, (2) by nonharmful biopsy of living embryos, (3) by extracting cells from artificially created nonembryonic but embryo-like cellular systems, or (4) by dedifferentiation of somatic cells back to pluripotency. For each of these proposals, the Council explored the ethical and scientific questions of whether the proposal is ethically sound, scientifically sound, and realistic from the perspective of public policy and research practice.
The Council found indications that it may be possible to obtain useful material from each of the four approaches. The first proposal, deriving cells from organismically dead embryos, has yet to be tested, but the Council generally considered it to be ethically acceptable within stringent guidelines. The second proposal, blastomere extraction from living embryos, was felt to be technically feasible even now but was considered by the panel to be ethically unacceptable for application to humans. The third proposal, cells derived from specially engineered biologic artifacts, was felt to be the most technically demanding and to present the greatest ethical challenges. The Council recommended that experimentation to explore this avenue be restricted to animals and not applied to human material. The fourth proposal, employing the use of cells obtained by dedifferentiation of somatic cells, was considered to pose the fewest ethical problems and ideal if it becomes scientifically practical. However, the Council noted that it was too early to tell which types of stem cells will be most useful for the treatment of which diseases. Each of the potential methods to resolve the initial ethical concerns themselves also created additional ethical issues.
The paper concluded with a call for “further legal interpretation and sober political deliberation” in addition to the obvious scientific investigation. The Council also urged the scientific community to look beyond the four alternatives considered by the panel and explore novel means to advance pluripotent stem cell research.
Additional information may be found at www.bioethics.gov.
NIH IMPLEMENTS POLICY ON ENHANCING PUBLIC ACCESS TO ARCHIVED PUBLICATIONS RESULTING FROM NIH-FUNDED RESEARCH
Beginning May 2, 2005, the National Institutes of Health (NIH) implemented its policy to improve public access to publications that result from NIH-funded research. As a result of the implementation of this policy, on acceptance for publication, NIH-funded investigators are requested to submit an electronic version of the author's final manuscript to the NIH National Library of Medicine's PubMed Central. The policy applies to virtually all research activities supported by NIH funding mechanisms: all research grant and career development award mechanisms, cooperative agreements, contracts, and Institutional and Individual Ruth L. Kirschstein National Research Service Awards. NIH intramural research studies are also subject to this policy. This final NIH Public Access Policy has undergone several changes since it was first released in September 2004. The most important modifications center on greater opportunity for authors to specify the time frame in which their manuscript will be accessible to the public through PubMed Central. In its present form, the policy “requests and strongly encourages that authors specify posting of their final manuscripts for public accessibility as soon as possible (and within 12 months of the publisher's official date of final publication).” Additional details can be found at http://grants2.nih.gov/grants/guide/notice-files/NOT-OD-05-022.html.
BOTANICAL RESEARCH CENTERS FUNDED BY NCCAM AND ODS
The National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (ODS), both components of the National Institutes of Health, have jointly funded five dietary supplement research centers that will focus on studies of botanical products. The 2002 National Health Interview Survey conducted by the Centers for Disease Control and Prevention showed that 38.2 million American adults use nonvitamin, nonmineral natural products. Five recipients of 5-year botanical research grants will study a variety of issues dealing with dietary supplements and botanical products. The Botanical Center for Age-Related Diseases, led by Connie Weaver, PhD, will research the effects of polyphenols (a group of chemical components widely found in plants) from different sources, such as soy and kudzu, and will investigate the ability of these components to prevent and treat conditions such as osteoporosis, cognitive decline, and cataracts. The Botanical Dietary Supplements for Women's Health, with Norman Farnsworth, PhD, as the principal investigator, will study the effects of herbal supplements on women's health issues, including menopausal symptoms. Botanicals and Metabolic Syndrome, with William Cefalu, MD, as the principal investigator, will investigate whether extracts of Russian tarragon, Shilianhua (a Chinese herbal product), and grape seed affect molecular and cellular processes associated with obesity, insulin resistance, development of type 2 diabetes, and accelerated cardiovascular disease. Barrie Cassileth, PhD, and Philip Livingston, MD, are the co-principal investigators for the Memorial Sloan-Kettering Cancer Center Research Center for Botanical Immunomodulators, which will study botanicals with the reported ability to modulate immune function and how they may assist in the treatment of cancer and infectious disease. Echinacea, astralgus, and turmeric are some of the botanicals that will be investigated. The Wake Forest and Harvard Center for Botanical Lipids, led by Floyd Chilton, PhD, as the principal investigator, will study polyunsaturated fatty acids derived from botanicals such as flaxseed, echium, and borage to see if their anti-inflammatory actions might prove helpful in the treatment of atherosclerosis, asthma, and other inflammatory diseases.
DEBATE CONTINUES ON STATUS OF IRB SYSTEM
The nature of problems in the nation's system of institutional review boards (IRBs) was debated during the public comment period of a recent meeting of the Secretary's Advisory Committee on Human Research Protections (SACHRP).
Although the current system was described by Alliance for Human Research Protections (AHRP) President Vera Sharav as being “broken,” this description was met with disagreement by others at the meeting. Citing a “steady stream of scandals” in clinical research, Sharav and other members of AHRP faulted SACHRP for failing to take action. Sharav advocates penalties for investigators as a way to improve protection of subjects. Although Ernest Prentice, chair of the Department of Health and Human Services (HHS) Secretary's Advisory Committee on Human Research Protections, conceded that the system had room for improvement and might have been considered “broken” prior to 1998, it has shown great improvement. Prentice also agreed that penalizing noncompliant investigators should be part of further improvement.
Bernard Schwetz, director of the HHS Office for Human Research Protections, drew attention to successful mechanisms for reporting near misses. Such procedures are now being used in the private sector and by the Department of Veterans Affairs. Lessons drawn from these examples could augment the current system instead of needing to replace it.
SACHRP has charged a subcommittee with identifying possible protections for human subjects in research while lifting regulatory burdens on IRBs and investigators.
NIH COMMITTEE INVESTIGATES THE ISSUE OF WOMEN IN THE MEDICAL FIELD
On April 4, the NIH Advisory Committee on Research on Women's Health met, and committee members, including Sally Shumaker, PhD, dean at Wake Forest University School of Medicine, and Joanna Cain, MD, of Oregon Health Sciences University, discussed why few women become medical researchers despite the fact that women account for more than 50% of medical students in the United States. In fact, the number of women who become researchers is actually decreasing, and the percentage of female professors increased only from 10 to 12% from 1995 to 2001. Some areas of medicine have actually experienced a decline in the number of female practitioners; the percentage of female orthopedic specialists has dropped from 2 to 1%. Many characteristics of academic medicine may encourage women to seek employment elsewhere, such as medical practice. Timothy Johnson, MD, of the University of Michigan Medical Center, stated that “there's something profoundly wrong with academic medicine” owing to the fact that women are succeeding in business and law schools in spite of the fact that they are not successful in academic medicine. He theorized that short tenure clocks in academic medicine do not allow women to take time off to raise a family. Cain stated that “what is needed is a cultural change in the institution.” Now, if a woman fails in academic medicine, the fault is her own and not that of the institution. Shumaker believes that men in leadership positions need to be given instruction in mentoring women; Wake Forest appoints chairs based on their leadership ability as well as their scientific knowledge and experience. Vivian Pinn, MD, director of the Office of Research on Women's Health (ORWH), related the methods that the ORWH is using to attract and retain women. They hold job fairs, give workshops empowering women with skills for surviving in science, maintain the WISH-net Web site, and operate the Achieving Xxcelence in Science program.
INSTITUTE OF MEDICINE OUTLINES CREATION OF NATIONAL CORD BLOOD STEM CELL BANK PROGRAM
A new report from the Institute of Medicine was released April 14 as required by Congress in HR 2673, the Consolidated Appropriations Act for 2004, which allocated $1 million for the Health Resources and Services Administration to conduct the Institute of Medicine study. The national cord blood stem cell bank program was to be put into effect after the study was conducted. Kristine Gebbie, RN, an associate professor of nursing at Columbia University, chaired the Institute of Medicine Committee on Establishing a National Cord Blood Stem Cell Bank Program, which produced the report. The committee reported that hematopoietic progenitor stem cells (HPSCs), which are found in abundance in umbilical cord blood, have saved at least 20,000 lives in the United States. By transplanting the HPSCs, leukemia, metabolic disorders, immunodeficiencies, and sickle cell anemia have been treated effectively. The goals of a national banking program are to enhance access to beneficial HPSCs, make oversight a priority, and create standards for the collection of cord blood to ensure its safe collection and storage. The committee made several recommendations, including that the Food and Drug Administration act quickly to establish a system for licensing clinical cord blood units; that cord blood banks exist under an investigational new drug application; that consent to collect, store, and use cord blood be obtained before delivery; and that donors be given easily understandable information about donation options and not be misinformed about the availability of cord blood following donation. The committee also noted that the current system used for cord blood donation is uncoordinated and insufficient for present and future needs.
JAMES BATTEY RESIGNS OWING TO CONFLICT OF INTEREST
James Battey, MD, PhD, director of the National Institute on Deafness and Other Communication Disorders (NIDCD) and head of the National Institutes of Health (NIH) Task Force on Stem Cell Research, announced on April 4 that he will resign his position. As a senior staff fellow, Battey joined the NIH in 1983. He later became director of intramural research at NIDCD in 1995. He was chosen as director of NIDCD in 1998. Allen Spiegel, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases, and Story Landis, MD, director of the National Institute of Neurological Disorders and Stroke, will jointly lead the NIH Task Force on Stem Cell Research, until Battey's replacement is found. Battey's resignation is due to new rules regarding conflict of interest rules that apply to NIH employees. Under the new regulations, which took effect February 3, employees are limited in the amount of holdings they can possess in biotechnology or pharmaceutical companies. Some employees are required to file financial disclosure forms and are not allowed to hold stock in such firms. Other employees are restricted to a $15,000 limit on investments in biomedical companies. Owing to the fact that Battey held a position as an institute director, he was subject to the strictest conflict of interest regulations and said that because of the regulations, he would not be able to continue to manage his family's trust fund. However, because Battey is a member of the US Commissioned Corps, his resignation will have to be approved. Although several top-level scientists, including Emmanuel Petricoin, PhD, and Lance Liotta, MD, PhD, have left the NIH owing to the new conflict of interest rules, Battey is the first director to announce his resignation. Battey predicts that the new regulations will prove difficult, especially for intramural scientists.
NIH FAILING TO RECRUIT RESEARCHERS
At the second meeting of the National Institutes of Health (NIH) Advisory Board for Clinical Research (ABCR) on March 28, Thomas Insel, MD, director of the National Institute of Mental Health, expressed concern that the NIH needs to restructure its recruitment efforts to raise the number of in-house researchers at the NIH. The NIH is currently underperforming in recruiting researchers into its intramural program, perhaps owing to budget issues and violations regarding conflict of interest. NIH is having difficulty competing with the private sector and other research entities owing to the way in which the NIH is currently viewed by prospective recruits. Barry Coller, MD, of Rockefeller University is chair of the ABCR Working Group on Research Opportunities. His suggestions for increasing the recruitment of the best and brightest research scientists to the NIH include enhancing the relationship between the Food and Drug Administration (FDA) and the intramural research program at the NIH, creating training fellowships similar to the National Cancer Institute/FDA training fellowships, and using exit interviews to determine the impact of the conflict of interest regulations on resigning employees. Insel's suggestions for bolstering recruitment efforts include advertisements on the Web and specifically focused marketing programs.
PHARMACEUTICAL INDUSTRY INVESTIGATIONS
James Sheehan, Philadelphia associate US attorney, spoke about the upcoming clinical trial and research conduct investigations at the International Pharmaceutical Compliance Summit in Philadelphia on March 31. Sheehan is currently leading investigations into the promotion practices of a group of pharmaceutical manufacturers. He stated that there are often problems with institutional review boards related to subject disclosure and issues with protection. However, there are few problems with fraud associated with clinical trials or research. He also stated that most of the cases are National Institutes of Health cases or Department of Health and Human Services grant cases. The problem seems to be a direct result of fierce competition in the market, with companies realizing that their competitors were not following the rules and regulations. He also noted that once a problem is noted, it is often exaggerated long after the problem has begun to be resolved. As a result, he predicts a continued focus on the pharmaceutical and research industries and says that a more intense focus on clinical research trials could occur in 3 to 4 years.
UNIVERSITY OF ALABAMA SETTLEMENT AGREEMENT
The University of Alabama at Birmingham (UAB) has agreed to a settlement with the United States involving investigations of research grants and Medicare billing at UAB, the UAB Health System, and the Health Services Foundation (HSF) between 1996 and 2004. As a result of the settlement, the United States will receive a $3,390,000 reimbursement. The amount is less than one-tenth of 1% of the $3.5 billion that the US government paid UAB during that time period for funding research and health care services. UAB has also reached a settlement involving lawsuits filed against UAB by two former employees. The plaintiffs will receive a combination of $500,000. The investigations of UAB focused on the methods of research compliance and billing, the way in which UAB research investigators accounted for their overall effort and research support, methods of charging for grant-related services, the billing practices for services provided to patients participating in clinical studies, and the funding relationships between UAB Hospital, the School of Medicine, and the HSF, which is UAB's faculty practice plan. The government did not find any wrongdoing by UAB or any university personnel, nor did it find fault with the quality of research or health care services provided by UAB or the HSF. As part of the settlement, UAB is committed to continuing its hospital compliance program at, or even exceeding, the current funding and staffing levels.
LATIN AMERICAN, CANADIAN RESEARCHERS SOUGHT BY HHMI
The Howard Hughes Medical Institute (HHMI) invites scientists who have full-time appointments at nonprofit scientific research institutions in Canada, Mexico, Argentina, Brazil, Chile, Peru, Uruguay, and Venezuela to apply to become HHMI international research scholars. The deadline for applications is September 14, 2005, and grants will be awarded in October 2006. Each 5-year grant provides a total of $250,000 to $500,000. Peter Bruns, HHMI vice president of grants and special programs, stated that the quality of their research is the main criterion when grants are awarded and that the grants are to be used to support the research of dedicated scientists in their own home countries. The awards are for fundamental biomedical research on basic biologic processes and disease mechanisms; clinical trials, health education, and health care services are ineligible. The awards support not only the individual scientists but also shared resources at the researcher's institution, with the goal of enhancing the scientific environment in which the researcher works. HHMI first established its international grants program in 1991, and since then, scientists in 32 countries around the world have received awards in excess of $100 million, with many of those scientists making distinguished and renowned achievements. Former award recipients include Marcelo Rubinstein of Argentina, who founded one of the principal mouse transgenics facilities in South America and is currently working with Pedro Labarca to create a similar facility in Chile; Peter St. George-Hyslop of the University of Toronto, who discovered genes associated with Alzheimer's disease; and Mariano Levin of Argentina, who assisted in sequencing the genome for Trypanosoma cruzi, the parasite that spreads Chagas' disease, which handicaps or kills tens of thousands of people annually in Central America, South America, and Mexico.
NEW METHOD OF GENE THERAPY
Dr. Matthew Porteus, MD, PhD, assistant professor of pediatrics and biochemistry at University of Texas (UT) Southwestern Medical Center, and scientists from Sangamo Biosciences in Richmond, California, discovered a way to use a method of gene therapy to replace a mutated version of the gene that encodes a portion of the interleukin-2 receptor (IL-2R) in human cells. By artificially initiating homologous recombination, a deoxyribonucleic acid (DNA) repair process, the method restores gene function and IL-2R production. Severe combined immunodeficiency disease (SCID) is a rare immune disease associated with mutations in the IL-2R gene. Children with SCID usually have shortened life spans because they are unable to resist infections. According to Dr. Porteus, SCID is ideal for this kind of gene therapy because, owing to selective advantage, when the defect is corrected in a small number of immune cells, the healthy cells grow and divide selectively over the mutant cells. Different from previous gene therapies, Dr. Porteus's method affects only the mutant gene. After being treated, the cells seem to be permanently changed, and the correct gene does not mutate even after many cell divisions. Dr. Porteus, who recently received a 2004 Distinguished Young Researcher Award from the President's Research Council at UT Southwestern, believes that this method of gene therapy might prove beneficial in the treatment of other diseases, such as sickle cell disease.
ADRIANE FUGH-BERMAN WRITES COMMENTARY ON GHOSTWRITING
Adriane Fugh-Berman, MD, published a commentary in the April 14 ediiton of the Journal of General Internal Medicine entitled “The Corporate Coauthor.” In this article, Fugh-Berman comments on the practice of drug marketers to employ articles authored by academic physicians or researchers. The articles are submitted to peer-reviewed medical journals, with some of the articles being written by ghostwriters hired by the pharmaceutical companies or medical education companies (MECs). The potential conflicts of interest are obvious, and some articles may serve to bolster the perceived need for a marketed drug. Often the arrangements, financial and otherwise, between the physician and the pharmaceutical company or MEC are vague or undisclosed. In her commentary, she relates her personal anecdote regarding being approached by an MEC and asked to be a ghostwriter for an article detailing a new oral anticoagulant, an offer that she declined. She advocates a national public database to make available information regarding conflicts of interest and ethical infractions.