Abstract
To preserve scientific integrity and maintain public trust in science, researchers must follow responsible conduct of research (RCR) guidelines. However, contemporary research integrity dilemmas may not fit neatly into discrete “checkboxes.” Furthermore, existing guidelines are largely based on conventional ways of conducting research, and may not meet the needs of contemporary interdisciplinary cell and molecular-based science and engineering. The chapter reviews existing and proposed new guidelines for general research integrity, with particular deference to the needs of regenerative medicine researchers. We also flag areas which need further attention. Just as scientists must know RCR principles, ethicists, policy makers, funders, and government officials must stay abreast of contemporary issues in scientific research, particularly in light of international collaborations and increasingly interdisciplinary and translational science.
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Notes
- 1.
The ORI, created in 1992, is under the auspices of the Office of Public Health and Science (a part of the Department of Health and Human Services) and has jurisdiction over ten offices and agencies, including the NIH, CDC, and FDA.
- 2.
Notice number NOT-OD-10-019 (November 24, 2009) applied the policy to the following NIH programs: D43, D71, F05, F31, F32, F33, F34, F37, F38, K01, K02, K05, K07, K08, D12, K18, K22, K23, K24, K25, K26, K30, K99/R00, KL1, KL2, R25, R36, T15, T32, T34, T35, T36, T37, T90/R90, TL1, TU2, and U2R.DY. The NSF requirement of RCR training was formalized in the America Creating Opportunities to Meaningfully Promote Excellence in Technology, Education, and Science America Act, or the so-called America COMPETES Act (42 U.S.C. 18600–1, Sec 7009). It applies to all full research proposals submitted after January 4, 2010.
- 3.
The NIH criteria include the following: (a) the training must not be solely through online instruction; there is value in discussions and instruction with research faculty and other grantees. (b) The training should cover nine areas of responsible conduct, including conflict of interest, human and animal subject practices, mentorship responsibilities and relationships, collaborative research, peer review, data acquisition and laboratory tools, research misconduct, authorship and publication, and the scientist’s role in society (see Table 6.2). (c) The institution’s research facility should take a mentoring role in providing both formal and informal instruction. (d) An effective program should contain at least 8 h of instruction, although a complete semester of programming will result in more significant learning. (e) Researchers are responsible for ongoing training throughout their careers: during graduate school (generally through a seminar-type course), at the early investigator level (through discussions with mentors and possible formal programming), and as senior fellows as career award recipients (as mentors, lecturers, and discussion leaders). The NSF has funded several projects to provide resources for institutions and relevant personnel including the Ethics Collaborative Online Resource Environment (CORE) digital library, at http://nationalethicscenter.org/ and the Online Ethics Center for Engineering and Research. Six broad categories are covered, including emerging technologies, environment, safety and sustainability, employment and legal issues, professional practice, responsible research, and diversity issues (found at http://www.onlineethics.org).
- 4.
The European Science Foundation reports on research integrity can be found here: ESF.org/activities/mo-for a/research-integrity.html.
- 5.
The document is so named because the meeting was held in Singapore in July of 2010. The statement can be found at: Retrieved September 16, 2013.
- 6.
The Canadian Tri-agency framework for Responsible Conduct of Research covers the three major funding agencies (Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council (NSERC), and the Social Sciences and Humanities Research Council (SSHRC)) and can be found here: http://www.rcr.ethics.gc.ca/eng/policy-politique/framework-cadre/.
- 7.
The 2013 list can be accessed at http://www.hhs.gov/ohrp/international/intlcompilation/intlcomp2013.pdf.pdf.
- 8.
- 9.
There is often some confusion about types of policies, and there may be inconsistencies among them: guidelines are not considered binding by the authorities issuing them, whereas regulations issued by governmental agencies such as the NIH and the CIRM (California Institute for Regenerative Medicine) are binding, and may make funding conditional on compliance.
- 10.
The original 2005 Guidelines can be found at: http://www.nap.edu/catalog/11278.html and the 2010 Guidelines at http://www.nap.edu/catalog.php?record_id=12923.
- 11.
For example, while it is generally agreed that embryo donors should not be paid for their donations due to moral concerns about the nature of embryos, Guideline #16 also bans payment for gamete donors. Many institutions did not adopt the regulation, since such donors are regularly remunerated for other purposes, and often at market rates, rather than merely covering the donor’s basic expenses.
- 12.
Some institutions have decided to expand their purview beyond embryonic stem cell research, anticipating the need to review iPS cells and possibly more, and thus have dropped the “E” from the acronym.
- 13.
There is no complete consensus on the moral status of embryos or what should be morally permissible, but the NAS reached its conclusions based on consultation with legal and ethical authorities and went forward with the best understanding of what could be agreed upon at that time.
- 14.
Fourteen days of development is the point at which the primitive streak forms in humans. Beyond this point, the neural system begins to appear, and eventually, sensation or awareness might be possible. For this reason, 14 days is chosen as the point beyond which research should not continue (Downs 2008).
- 15.
The ISSCR initially published its guidelines for stem cell research in 2006, available at http://www.isscr.org/docs/default-source/hesc-guidelines/isscrhescguidelines2006.pdf. Additionally, the organization published its Guidelines for Clinical Translation of Stem Cells in 2008, which deals with non-regulated clinical trials. See http://www.isscr.org/docs/default-source/clin-trans-guidelines/isscrglclinicaltrans.pdf.
- 16.
- 17.
The ASRM Ethics Committee document on embryo donation can be found at http://www.asrm.org/publications/detail.aspx?id=285; the ISCT regulatory documents can be found at: http://www.celltherapysociety.org/index.php?page=regulatory; and the AABB regulation statement is located at: http://www.aabb.org/resources/bct/Documents/coi_ct1109.pdf. Organizations formed around engineering and informatics research have not yet addressed interdisciplinary, cell-based research, as they traditionally had completely different areas of focus for ethical practice, and have only recently become closely intertwined with biological research.
- 18.
Minimal manipulation is defined as processing that does not alter the relevant biological characteristics of cells or tissues (21 CFR 1271.3 (f) (2)). Homologous use is defined by the FDA as the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function in the recipient as in the donor (21 CFR 1271.3.(c)).
- 19.
The state of Texas, however, approved rules allowing allogeneic and autologous adult-derived stem cells to be used experimentally in clinics after Governor Rick Perry received a stem cell treatment for back pain and became an advocate for adult-derived stem cell research (Cyranoski 2012).
- 20.
The Interstate Alliance on Stem Cell Research (IASCR) is a voluntary body whose stated mission is to advance stem cell research (human embryonic, adult, and other) by fostering effective interstate collaboration, by assisting states in developing research programs, and by promoting efficient and responsible use of public funds (Lomax and Stayn 2008).
- 21.
Numerous country-specific agencies deal with embryonic stem cell research, and in some countries more than one agency is involved. A few include the Canadian Institutes of Health Research, Danish Council of Ethics, Geschäftsstelle des Nationalen Ethikrat (German National Ethics Council), and Zentrale Ethik-Kommission für Stammzellenforschung (Office of Central Ethics Committee for Stem Cell Research in Germany, the Ministries of Science & Technology and Health in China, and the Ministry of Education, Culture, Sports, Science and Technology (MEXT)) in Japan, among others.
- 22.
The principles are beneficence (commonly parsed as “do no harm”), respect for persons (individuals should have a right to autonomy), and justice (subjects should not be exploited and procedures in research should be fair and reasonable). These remain the cornerstone of human subjects protection regulations. The Belmont Report can be found at http://science.education.nih.gov/supplements/nih9/bioethics/guide/teacher/Mod5_Belmont.pdf). Further reading on these principles, including critiques, can be found in Jonsen (1998) and Levine (1988), among others.
- 23.
The National Research Act of 1974 required all institutions involved in federally funded research to create Institutional Review Boards (IRBs), committees at each institution which review, approve, and monitor research involving human subjects. The following agencies and departments have signed onto the Common Rule: Agency for International Development, Consumer Product Safety Commission, Department of Agriculture, Department of Commerce, Department of Defense, Department of Education, Department of Energy, Department of Housing and Urban Development, Department of Justice, Department of Veterans Affairs, Department of Transportation, Environmental Protection Agency, National Aeronautics and Space Administration, and the National Science Foundation.
- 24.
Personally identified information is that which can be directly tied to an individual, including name, geographic information smaller than a state, social security number, birth and death dates, phone and fax numbers, email and IP addresses, medical record and health plan numbers, vehicle license numbers, device serial numbers, and biometric identifiers (including voice print and photos) (45 C.F.R. § 160.103). A summary of the rule can be found at http://www.hhs.gov/ocr/privacy/hipaa/understanding/summary/index.html.
- 25.
Significantly, considerable data had already been published from several lines, a few of which have become the “gold standard” for research. If those lines had been disallowed due to inability to trace the donor consent process, the result could be catastrophic, raising questions about how far a rule intended to protect donor privacy should go without damaging the research enterprise.
- 26.
21 CFR 10.115(g)(4)(i) Part 1271 subpart D, effective May 25, 2005 now applies to donors of cells and tissues including hematopoietic stem cells derived from peripheral and umbilical cord blood, reproductive cells and tissues, in addition to tissues previously covered by statutes (part 1270), such as human dura mater, human heart valves, and other tissue for transplantation. Part 1271 is far broader than the prior 1270 which was primarily for biological entities, because it applies to HCT/Ps regulated in any category of regulatory entity (e.g., drug, device, or biological). Exempted are the Wisconsin lines, which were created before 2005.
- 27.
Coercion exists if individuals are offered incentives that may induce them to participate when it may or may not be in their best interest, or when they feel the implications of not participating.
- 28.
The case is well known and will not be repeated in detail here, but see, for example, Gottweis and Triendl (2006), Beasley et al. (2002), and Lee and Park (2006). The Hwang Woo-Suk case further illustrates the international variation in definitions of misconduct, investigatory procedures, and penalties. Hwang was convicted of bioethics violations and embezzlement in his native South Korea, sentenced to 2 years in prison (suspended) and his funding was withdrawn, but he was not convicted of fraud. A senior coauthor, Gerald Schatten (University of Pittsburgh), was found to have committed “research misbehavior” (an ill-defined, less severe version of research misconduct) for accepting senior author status while not verifying the accuracy of the data and participating significantly in any of the experiments (Marris and Check 2006). He was not suspended from continuing research.
- 29.
The question came up again when the Human Fertility and Embryology Authority in 2007 authorized the payment of women for oocyte donation to support stem cell research. Two long-standing questions were raised: whether offering money in exchange for bodily materials unduly places women at risk for harm (whether or not they willingly donate) and whether payment for human reproductive materials which may be used to create an embryo is ethical in any case (Baylis and McLeod 2007). While it is beyond the scope of this chapter, information about payment for gamete and embryo donors can be found in the NAS guidelines at 82–89.
- 30.
The nine principles can be accessed here: http://grants.nih.gov/grants/olaw/references/phspol.htm#USGovPrinciples.
- 31.
The PHS document can be found here: http://grants.nih.gov/grants/olaw/references/phspol.htm.
- 32.
- 33.
These can be mutated cells of the host organism or cells from a different organism or species (Human Genome Initiative glossary, found at http://www.ornl.gov/sci/techresources/Human_Genome/glossary).
- 34.
Arguments center around the ambiguous moral status of creatures that are neither fully human nor animal (Robert and Baylis 2003). Critics of this concept argue that the focus on species identity is based upon an incorrect view of human personhood (Haber and Benham 2012; Siegel 2003). Some ethicists conclude that “status-enhancing” research (such as integrating human stem cells into animal brains) should not be conducted unless it has minimal risk and probable therapeutic benefits to the subject (Streiffer 2005). However, it is not clear that chimera creation is, in fact, status-enhancing (id.).
- 35.
At the University of Wisconsin-Madison, any experiment involving the introduction of hESCs into embryonic animals past Carnegie Stage 23 (which is E16 in mice) is prohibited. The UW policy on chimera use in stem cells can be found at: http://www.grad.wisc.edu/admin/committees/scro/documents/ChimeraGuidanceDocument090527.doc.
- 36.
In an often-cited case, William Summerlin claimed to have transplanted donor tissue into a genetically unrelated recipient while avoiding graft versus host rejection. As proof, he presented white mice with spots of black fur he claimed came from donor mice. In reality, he had colored spots on the white mice using felt-tipped pens, which was discovered by one of his technicians (LaFollette 2000). In another case in the early 1980s, John Darsee, a promising young researcher of Brigham and Women’s Hospital, was found to have fabricated data throughout his career, leading to the retraction of eight papers and 45 abstracts. Congress became involved when delays in the investigation and proceedings led to allegations of press cover up (id).
- 37.
Available at: http://ori.hhs.gov/federal-research-misconduct-policy.
- 38.
The Department of Health and Human Services, Department of Defense, Department of Labor, Department of Transportation, Department of Veteran Affairs, the Environmental Protection Agency, National Aeronautics and Space Administration, National Endowment for the Humanities, the National Science Foundation, and the Smithsonian Institution have done so, and have published their policies online. The Department of Energy has published a Notice of Proposed Rulemaking. At the time of this writing, the Departments of Agriculture, Commerce, Education, Interior, and Justice are still in the process of drafting and reviewing policies.
- 39.
Federal Register, Vol. 70, p. 28370, May 17, 2005. Codified at 42 CFR Part 93.
- 40.
Interestingly, those surveyed claimed that 14.2 % of their colleagues had engaged in serious misconduct and an overwhelming 72 % in questionable practices, either indicating a lack of trust in colleagues, or, possibly, observation of underreported incidences of misconduct practices.
- 41.
Some journals have specific standards regarding image submission. For example, Nature acknowledges that “a certain degree of image processing is acceptable for publication (and for some experiments, fields and techniques is unavoidable), but the final image must correctly represent the original data and conform to community standards,” but has guidelines for submission, including retention of the original, untouched image. The Journal of Cell Biology screens all figures for any evidence of manipulation, and sets forth examples of such manipulation; for example, “no specific feature within an image maybe enhanced, obscured, moved, removed, or introduced.”
- 42.
“Forensic droplets” detect image alteration by searching for similarities and differences between images. The program color-codes each pixel in the images and superimposes them onto a single image for comparison. Common features appear in red, while unique features remain black or white, helping editors pinpoint potential erasures. Editors also use contrast enhancement and histogram equalization which reveal weak borders around objects (due to a cut-and-paste manipulation), or areas where an object has been removed from an image.
- 43.
The ORI reviewed the case and found that Dr. Shane Mayack engaged in research misconduct regarding the two papers. The flow cytometry contour plots were found to be falsely represented; additionally, the identical plots contained different labels and numerical percentages (Federal Register, 77(167), 52034–52035; Aug 28, 2012).
- 44.
Referees often require authors perform further experiments prior to publication, signaling mistrust in the peer review process today. Lack of trust increases costs and causes publication delay (Ploegh 2011).
- 45.
For example, what if a junior author or a graduate student realizes that coauthors have omitted data that might tell a different story? There are protections for whistleblowing, however, in the reality of day-to-day laboratory environments, relationships with mentors and senior personnel could be compromised, creating considerable risk for the junior researcher.
- 46.
Thanks to Tom Keenan, Ph.D., for elaborating the following examples.
- 47.
Loewenstein argues that disclosures of COI may be harmful, for example, if the discloser attempts to overstate a position in order to overcome a predicted discount of his or her advice, or when disclosers feel they can provide biased information because they disclosed the conflict. Another type of harm exists when patients decide not to enroll in certain beneficial studies because of their doctor’s disclosed affiliations (Loewenstein et al. 2012).
- 48.
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Von Reyn, J., Das, A., Hogle, L.F. (2014). Beyond the Checkboxes: Research Integrity for Regenerative Medicine Researchers. In: Hogle, L. (eds) Regenerative Medicine Ethics. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9062-3_6
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