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Guidelines to Prevent Malevolent Use of Biomedical Research

Published online by Cambridge University Press:  09 August 2006

SHANE K. GREEN ,
SARA TAUB ,
KARINE MORIN  and
DANIEL HIGGINSON
SHANE K. GREEN
Affiliation:
American Medical Association's Institute for Ethics and the Council on Ethical and Judicial Affairs of the American Medical Association American Medical Association's Institute for Ethics, the Council on Ethical and Judicial Affairs
SARA TAUB
Affiliation:
American Medical Association's Institute for Ethics and the Council on Ethical and Judicial Affairs of the American Medical Association American Medical Association's Council on Ethical and Judicial Affairs
KARINE MORIN
Affiliation:
American Medical Association's Institute for Ethics and the Council on Ethical and Judicial Affairs of the American Medical Association Ethics Standards Group of the American Medical Association, and the Council on Ethical and Judicial Affairs
DANIEL HIGGINSON
Affiliation:
American Medical Association's Institute for Ethics and the Council on Ethical and Judicial Affairs of the American Medical Association Ethics Standards Group of the American Medical Association, and the Council on Ethical and Judicial Affairs
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Extract

In February 1975, a group of leading scientists, physicians, and policymakers convened at Asilomar, California, to consider the safety of proceeding with recombinant DNA research. The excitement generated by the promise of this new technology was counterbalanced by concerns regarding dangers that might arise from it, including the potential for accidental release of genetically modified organisms into the environment. Guidelines developed at the conference to direct future research endeavors had several consequences. They permitted research to resume, bringing to an end the voluntary moratorium that the National Academy of Sciences (NAS) had instituted several months earlier. They also served to illustrate that the scientific community was capable of self-governance, thereby securing public trust and persuading Congress not to institute legislative restrictions. Finally, they underscored the importance of weighing unforeseen risks inherent in some research against potential benefits that may arise from these same endeavors.The Council on Ethical and Judicial Affairs of the American Medical Association (AMA) formulates ethical policies for the medical profession through its interpretations of the AMA's Principles of Medical Ethics. The Council at the time this report was adopted consisted of Michael S. Goldrich, M.D. (Chair); Priscilla Ray, M.D. (Vice-Chair); Regina M. Benjamin, M.D., M.B.A.; Daniel Higginson (student member); Mark A. Levine, M.D.; John M. O'Bannon III, M.D.; Robert M. Sade, M.D.; Monique A. Spillman, M.D., Ph.D. (resident member); and Dudley M. Stewart, Jr., M.D. Staff to the Council at the time the report was adopted were Audiey Kao, M.D., Ph.D. (Vice President, Ethics Standards Group); Karine Morin, L.L.M. (Secretary); and Sara Taub, M.Be. Shane K. Green, Ph.D., was a Fellow in the AMA's Institute for Ethics.

Type
SPECIAL SECTION: BIOETHICS AND WAR
Information
Cambridge Quarterly of Healthcare Ethics , Volume 15 , Issue 4 , October 2006 , pp. 432 - 439
Copyright
© 2006 Cambridge University Press

In February 1975, a group of leading scientists, physicians, and policymakers convened at Asilomar, California, to consider the safety of proceeding with recombinant DNA research. The excitement generated by the promise of this new technology was counterbalanced by concerns regarding dangers that might arise from it, including the potential for accidental release of genetically modified organisms into the environment. Guidelines developed at the conference to direct future research endeavors had several consequences. They permitted research to resume, bringing to an end the voluntary moratorium that the National Academy of Sciences (NAS) had instituted several months earlier. They also served to illustrate that the scientific community was capable of self-governance, thereby securing public trust and persuading Congress not to institute legislative restrictions.1

Barinaga M. Asilomar revisited: lessons for today. Science 2000;287:1584–5.

Finally, they underscored the importance of weighing unforeseen risks inherent in some research against potential benefits that may arise from these same endeavors.

In February 2000, a second meeting was held at Asilomar, bringing together members from the same groups, including some of the original attendees.2

Russo E. Reconsidering Asilomar: Scientists see a much more complex modern-day environment. The Scientist 2000;14:15.

This meeting was held in honor of the historic event's 25th anniversary and in recognition of the scientific community's increasing attention to the potentially harmful applications of biotechnology in general—for example, to facilitate the use of pathogens as deadly weapons.3

Tucker JB. Viewpoint: In the shadow of anthrax: Strengthening the biological disarmament regime. The Nonproliferation Review 2002;IX:112–21.

Risk of this latter sort that arises not from research per se but from its intentional misapplication for nefarious purposes constitutes the focus of this report.

The possibility that scientific research may generate knowledge with the potential for harmful as well as beneficial applications is not new. In recent years, however, it has become imperative to develop parameters within which to address such research, as heightened concerns have arisen from the threat of biochemical terrorism and warfare.

Background

Physicians' involvement in biomedical research, whether clinical or preclinical, traditionally has been guided by a desire to help alleviate patient morbidity and mortality. In the AMA's Principles of Medical Ethics, research activities are grounded in obligations to advance scientific knowledge and to contribute to the betterment of public health (Principles V and VII).4

Principles of Medical Ethics, Principle V. In: Council on Ethical and Judicial Affairs. Code of Medical Ethics: Current Opinions with Annotations, 2004–2005 Edition. Chicago: AMA Press; 2004:xiv. Also available at: http://www.ama-assn.org/go/policyfinder.

The Association's more recent Declaration of Professional Responsibility, which has been supported by numerous state and specialty medical societies, further encourages physicians to “work freely with colleagues to discover, develop, and promote advances in medicine.”5

Council on Ethical and Judicial Affairs. Declaration of Professional Responsibility. In: Council on Ethical and Judicial Affairs. Code of Medical Ethics: Current Opinions with Annotations, 2002–2003 Edition. Chicago: AMA Press; 2002:291–2. Also available at: http://www.ama-assn.org/go/declaration.

Although the fundamental goals of biomedical research may be morally sound, it remains that researchers sometimes make discoveries that can be put to harmful, as well as beneficial, use. Despite providing considerable guidance to ensure the ethical conduct of physicians engaged in human subjects research,6

Council on Ethical and Judicial Affairs. Opinion 2.07, Clinical Investigations. In: Council on Ethical and Judicial Affairs. Code of Medical Ethics: Current Opinions with Annotations, 2004–2005 Edition. Chicago: AMA Press; 2004:25–7. Also available at: http://www.ama-assn.org/go/policyfinder.

the Code of Medical Ethics does not currently address the importance of physicians playing a proactive role in trying to assess foreseeable consequences of their biomedical research endeavors, nor does it offer a framework to assist them in doing so.

In this, the Code's research guidelines may reflect the uneven impact of the Nuremberg Code, which was drafted in response to wartime atrocities that Nazi physicians committed against captive human subjects under the guise of biomedical research. To prevent the recurrence of such blatantly unethical “research,” the Nuremberg Code set out ethical principles intended to guide all future medical research involving human subjects. It focused largely on the requirement for informed consent from all research subjects, rather than on possible ramifications of the research; these were addressed only briefly in a statement that “experiment[s] should be such as to yield fruitful results for the good of society.”7

Permissible medical experiments. In: Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10. Nuremberg, October 1946–April 1949. Washington, D.C: U.S. Government Printing Office, 1949–1953:181–2.

The requirement for consent has remained integral to modern clinical research in the United States. With regard to the latter provision, however, research has been vetted only to ensure that it produces beneficial results, while neglecting to consider the harmful ways in which the results could be misapplied. Arguably, this constituted a missed opportunity to develop normative guidance for the assessment of the goals and potential impact(s) of biomedical research in general.

Classes of Research with Potential for Malignant Application

The development, production, stockpiling, or use of biological weapons (BW) by any nation is banned under the 1972 Biological and Toxin Weapons Convention (BTWC),8

Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction. The Biological and Toxin Weapons Convention Website. Bradford, West Yorkshire, UK: University of Bradford; 1972. Available at: http://www.opbw.org/convention/documents/btwctext.pdf (accessed Jan 15 2004).

which has been signed by 167 nations and ratified by 151.9

List of States Parties to the Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological (Biological) and Toxin Weapons and on Their Destruction as at November 2003. The Biological and Toxin Weapons Convention Website. Bradford, West Yorkshire, UK: University of Bradford; 1972. Available at: http://www.opbw.org/MSPs/BWC_MSP2003_INF.2.pdf (accessed Jan 22, 2004).

Still, the World Medical Association (WMA) contends that there remains “a need for the creation of and adherence to a globally accepted ethos that rejects the development and use of biological weapons.”10

World Medical Association. The WMA Declaration of Washington on Biological Weapons. Ferney-Voltaire, France: World Medical Association; c2003. Available at: http://www.wma.net/e/policy/b1.htm (accessed Sep 18, 2003).

Moreover, according to the WMA, physicians are morally obligated to play prominent roles in establishing such an ethos because biological and toxin weapons (BTW) are intended to incapacitate or kill individuals, outcomes that are antithetical to the professed duties of physicians. Moreover, as professionals entrusted by society to advance human welfare, physician–researchers should actively speak out in condemnation of the creation and use of BTW. As to participation in defensive weapons development, physicians should consider the potential for offensive application of their research and carefully weigh the risk of misapplication against the risks associated with forgoing all weapons research.

Additionally, researchers have begun to contend with the possibility that countless areas of biomedical research can lead to nefarious applications and inadvertently may aid in the creation of BW. A recent report from the U.S. National Research Council (NRC), Biotechnology Research in an Age of Terrorism: Confronting the Dual Use Dilemma,11

National Research Council. Biotechnology Research in an Age of Terrorism: Confronting the Dual Use Dilemma. Washington, D.C.: The National Academies Press; 2003.

listed seven classes of “experiments of concern” considered to be especially problematic due to their potential implications for the creation and use of BW. Specifically, the NRC called attention to experiments that
  1. Would demonstrate how to render a vaccine ineffective
  2. Would confer resistance to therapeutically useful antibiotics or antiviral agents
  3. Would enhance the virulence of a pathogen or render a nonpathogen virulent
  4. Would increase transmissibility of a pathogen
  5. Would alter the host range of a pathogen
  6. Would enable the evasion of diagnostic/detection modalities
  7. Would enable the weaponization of a biological agent or toxin.

This list excludes many other areas of research that are less easily distinguished but equally dangerous if misapplied. For example, researchers have been able to construct functional polio virus particles de novo using relatively standard laboratory techniques and equipment and freely available genetic information.12

Molla A, Paul AV, Wimmer E. Cell-free, de novo synthesis of poliovirus. Science 1991;254:1647–51.

Although the potential danger of such an experiment has not been overlooked,13

See note 11, National Research Council 2003.

many of the prerequisite experiments that allowed for it, such as the sequencing of the polio virus genome, certainly could be considered innocuous. Similarly, genome sequencing of many other pathogens, including those responsible for anthrax, Ebola hemorrhagic fever, and bubonic plague, would not fall within the NRC's categorization; however, the publication of these sequences in the open scientific literature,14

Fraser CM. A genomics-based approach to biodefense preparedness. Nature Reviews Genetics 20045:23–33.

although undeniably important to further understanding of pathogenicity, could unintentionally facilitate the illegitimate creation and subsequent misuse of these pathogens.

Categorical classifications run the risk of being either over- or underinclusive, as a broad range of important and seemingly innocuous biomedical research could be used malevolently. This inherent ambiguity necessitates that all biomedical research be ethically assessed.

Professional Obligations of Physician–Researchers

It has been argued that pure scientific research is morally neutral and thus only its subsequent application should be subject to ethical scrutiny.15

Virginia Center for Digital History. Protesting Napalm. Charlottesville, Va.: University of Virginia; c2002. Available at: http://moderntimes.vcdh.virginia.edu/PVCC/mbase/docs/napalm.html (accessed Jan 9, 2004).

Many of the scientists whose discoveries in atomic energy gave birth to nuclear weapons initially held this position. However, in the wake of the bombings of Hiroshima and Nagasaki at the end of World War II, some of these same scientists openly grappled with the possibility that they were ethically responsible in part for the destructive applications of their findings. As their experience suggests, researchers may be morally accountable for harms that do not result from their research per se, but are born of its applications.

Indeed, there is growing acceptance in the scientific community that scientists are obligated to pursue knowledge both as an end in itself and as a means of improving the world for humankind. For instance, the preface of the American Society for Biochemistry and Molecular Biology's (ASBMB's) Code of Ethics states:

Members of the ASBMB are engaged in the quest for knowledge in biochemical and molecular biological sciences with the ultimate goal of advancing human welfare. Underlying this quest is the fundamental principle of trust. The ASBMB encourages its members to engage in the responsible practice of research required for such trust by fulfilling the following obligations: … [including that] investigators [should] promote and follow practices that enhance public interest or well-being.16

American Society for Biochemistry and Molecular Biology. Code of Ethics. Bethesda, Md.: American Society for Biochemistry and Molecular Biology; c1998. Available at: http://www.asbmb.org/ASBMB/site.nsf/Sub/CodeofEthics?opendocument (accessed Jan 9, 2004).

Similarly, in its Code of Ethics, the American Society for Microbiology (ASM) states that its members should “aspire to use their knowledge and skills for the advancement of human welfare.”17

American Society for Microbiology. Code of Ethics. Washington, D.C.: American Society for Microbiology; c2005. Available at: http://www.asm.org/ASM/files/ccLibraryFiles/FILENAME/000000001596/ASMCodeofEthics05.pdf (accessed Jun 30, 2005).

With respect to the potential for malign use of research findings, the Society's Code recently was revised to include the following language:

ASM members are obligated to discourage any use of microbiology contrary to the welfare of humankind, including the use of microbes as biological weapons. Bioterrorism violates the fundamental principles upon which the Society was founded and is abhorrent to the ASM and its members. ASM members will call to the attention of the public or the appropriate authorities misuses of microbiology or of information derived from microbiology.18

See note 17, American Society for Microbiology 2005.

Unlike the ASBMB and the ASM, however, most scientific societies have not codified this notion of social responsibility. Nonetheless, the obligation to preserve public trust extends to all scientists, as a critical element of their collective professional responsibility.

Physician–researchers share in this obligation not only by virtue of their membership in the scientific community, but also because the preservation of public trust is a fundamental aspect of medical professionalism, the moral duties of which bear upon the whole of their professional conduct. The WMA has articulated this requirement in its Declaration of Washington on Biological Weapons, which states that “physicians who participate in biomedical research have a moral and ethical obligation to consider the implications of possible malicious use of their findings.“19

See note 10, World Medical Association 2003.

Although this is an undeniably complicated undertaking, physician–researchers, who possess profound knowledge of their research and of human health and disease, are arguably in the best position to assess the potential for and the ramifications of misapplications of their research.

Self-regulation

The Code states that “[t]he ultimate responsibility for the ethical conduct of science resides within the institution (academic, industrial, public, or private) which conducts scientific research and with the individual scientist [emphasis added].”20

See note 6, Council on Ethical and Judicial Affairs 2004.

In science as in medicine, individual responsibility is a fundamental aspect of professionalism. To that end, physician–researchers need to understand research ethics norms, such as scientific responsibility and integrity. Research ethics education, beginning at the trainee level and extending throughout a career, can sensitize physician–researchers to the possibility for misapplications of scientific knowledge and empower them to make responsible assessments of the research used to generate it. Still, differences in opinion will continue to arise. It is precisely because no one physician's ethical judgment is infallible that human subjects research protocols are vetted by Institutional Review Boards. Similarly, physician–researchers engaged in preclinical biomedical research should peer-review each other's work.

Some experiments present such a degree of potential risk of harmful application that more rigorous oversight may be warranted. The aforementioned NRC report firmly echoes this notion in its proposal for a regulatory system that relies on both voluntary self-governance and scientific review committees to provide oversight for “experiments of concern.”21

See note 11, National Research Council 2003.

Other proposals have included establishing registries, perhaps within the Centers for Disease Control and Prevention (CDC), of researchers who are working with certain pathogens and toxins and requiring that potentially dangerous results, including inadvertent discoveries, be reported.22

See note 3, Tucker 2002.

To date, the U.S. Department of Health and Human Services has created the National Science Advisory Board for Biosecurity (NSABB) that, as part of its mandate, will develop guidelines regarding appropriate oversight by local Institutional Biosafety Committees or federal officials of potentially harmful research.23

National Science Advisory Board for Biosecurity. Home page. Bethesda, Md.: Office of Biotechnology Activities, National Institutes of Health. Available at: http://biosecurityboard.gov/ (accessed Mar 10, 2004).

Final authority over whether to accept these guidelines, however, will reside with the federal departments and agencies that support the research. Already, classified research, presumably for biodefense purposes, has been exempted from any guidelines developed by the NSABB.

With the exception of research involving select agents or toxins identified by the CDC as posing a severe health threat,24

Centers for Disease Control. Select Agent Program. Atlanta, Ga.: Centers for Disease Control; 2005. Available at: http://www.cdc.gov/od/sap/ (accessed Feb 10, 2004).

formal oversight currently is mandatory only for studies and/or institutions that receive NIH funding for recombinant DNA research.25

Steinbruner JD, Harris ED. Controlling dangerous pathogens. Issues in Science and Technology 2003;19:47–54.

Although some privately funded research organizations voluntarily comply with current NIH research guidelines, and may elect to comply with NSABB guidelines, they are not required to do so. The NSABB can seek to close the significant gap in the current regulatory framework by extending the scope of federally regulated research and encouraging the private sector to adopt the Board's system of oversight. Cooperation between different countries' research bodies also should be promoted, because research increasingly is becoming a global enterprise. Physician–researchers will be able to play a leading role in calling for the creation of and adherence to such global standards for research governance.

Transparency

In some cases, the dangers presented by research either cannot be fully appreciated before it is conducted or are the inevitable consequence of research of such importance that it must be allowed to proceed nevertheless. Such dangers could be addressed by restricting the dissemination of especially hazardous information. However, such restrictions may be undesirable for a number of reasons. The Code, for example, emphasizes that timely publication of research is an essential element in the foundation of good medical care.26

Council on Ethical and Judicial Affairs. Opinion 9.08, New Medical Procedures. In: Council on Ethical and Judicial Affairs. Code of Medical Ethics: Current Opinions with Annotations, 2004–2005 Edition. Chicago: AMA Press; 2004:274–275. Also available at: http://www.ama-assn.org/go/policyfinder.

The elimination of openness in biomedical research would not only create an aura of secrecy likely to compromise public trust in science, but also would impede progress and innovation—notably within biodefense research,27

National Institute of Allergy and Infectious Diseases Biodefense Research. Home page. Bethesda, Md.: National Institute of Allergy and Infectious Diseases. Available at: http://www.niaid.nih.gov/biodefense/ (accessed Jan 23, 2004).

the development of vaccines and therapeutics necessary to effectively counter any use of BW.

Under exceptional circumstances, it may be appropriate to limit accessibility to the results of particular experiments. For example, the unexpected discovery of a means by which to engineer a virus capable of infecting even immunized animals recently prompted a reexamination of openness in biomedical research,28

Jackson RJ, Ramsay AJ, Christensen CD, Beaton S, Hall DF, Ramshaw IA. Expression of mouse interleukin-4 by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox. Journal of Virology 2001;75:1205–10.

on account of the potential to misuse the research's findings toward the design of uniquely effective bioweapons. A group including scientist–authors, government officials, and editors of major scientific journals was convened by the NAS to discuss these concerns and issued a statement conceding that “there is information that, although we cannot now capture it with lists or definitions, presents enough risk of use by terrorists that it should not be published.”29

Journal Editors and Authors Group. Uncensored exchange of scientific results. Proceedings of the National Academy of Sciences, USA. 2003;100:1464.

The screening mechanism employed by the NAS was again tested by a May 2005 paper posted on the Proceedings of the National Academy of Sciences Web site that described in detail how a terrorist might contaminate a milk truck with botulinum toxin. The Department of Health and Human Services promptly requested that the paper be withdrawn from the Web site and future print versions.30

Feds: Science paper a terrorist's road map. Atlanta, Ga.: Cable News Network; 2005 Jun 7. Available at: http://www.cnn.com/2005/US/06/06/milk.terror/index.html.

Publication restrictions alone would likely prove ineffective, because scientific information is disseminated not only through mainstream scientific literature, but also through presentations at scientific meetings and increasingly on the Internet. Hence, it will be essential for members of the scientific community, including physician–researchers, to consider the implications of presenting their data in any form. As an additional part of its mandate, the NSABB will be working with stakeholders, including researchers and editors, to develop guidelines for the communication, in any form, of potentially harmful research. In the absence of such guidelines, if there is any doubt as to the propriety of open presentation, researchers would be wise to consult with colleagues in deciding how to proceed.

Conclusion

Biomedical research is essential for providing means by which medicine can continue to advance human welfare. For it to proceed responsibly, an overall ethical framework must be established that seeks to balance the ability of biomedical research to generate medical innovations against harms that may be incurred through its corruption, notably including its application to the development of biological weapons. As scientists and medical professionals, physician–researchers should seek to play a major role in the creation of such a framework and in the execution of any steps that must be taken to fulfill the obligations it imposes. Chief among these steps is for physician–researchers to appreciate and advocate the need for diligence and moral fortitude in assessing the ethical implications and foreseeable consequences of their research and the dissemination of its findings.

Recommendations

Physicians who engage in biomedical research are bound by the ethical obligations of the medical profession and also are required to meet responsibilities of the scientific community. Beyond their commitment to the advancement of scientific knowledge and the betterment of public health, physician–researchers must strive to maintain public trust in the profession through their commitment to public welfare and safety, as demonstrated through individual responsibility, commitment to peer review, and transparency in the design, execution, and reporting of research.

Biomedical research may generate knowledge with potential for both beneficial and harmful application. Before participating in research, physician–researchers should assess foreseeable ramifications of their research in an effort to balance the promise of benefit from biomedical innovation against potential harms from corrupt application of the findings.

In exceptional cases, assessment of the balance of future harms and benefits of research may preclude participation in the research, for instance, when the goals of research are antithetical to the foundations of the medical profession, as with the development of biological or chemical weapons. Properly designed biomedical research to develop defenses against such weapons is ethical.

The potential harms associated with some research may warrant regulatory oversight. Physician–researchers have a responsibility not only to adhere to standards for research, but also to lend their expertise to the development of safeguards and oversight mechanisms, both nationally and internationally. Oversight mechanisms should balance the need to advance science with the risk of malevolent application.

After research has been conducted, consideration should be given to the risk of unrestricted dissemination of the results. Only under rare circumstances should findings be withheld, and then only to the extent required to reasonably protect against dangerous misuse.

These ethical principles should be part of the education and training of all physicians involved in biomedical research.