The Painful Experience
This case highlights potential dilemmas encountered by postdoctoral fellows in a research setting. What are the moral issues and questionable practices in biomedical research with animals? It also explores the potential problems of pain research and the advisor/advisee relationship.
Dr. Eric Brown is a research scientist investigating the treatment of chronic pain. Utilizing a rodent model of inflammatory bowel disease, he is currently elucidating the mechanisms underlying chronic visceral pain associated with inflammation.
The animals used in this model experience varying levels of pain and anxiety throughout the experiment. First, the animals are deeply anesthetized, and surgery is performed under sterile conditions. A catheter is inserted near the spinal cord to administer drugs, and an electrode is sutured into the abdominal muscles to measure the animal's visceromotor response.
After the animals recover from surgery, a compound is administered intracolonically to induce an inflammatory response in the colon. Three to five days later, the ability of various compounds to reduce visceral pain with inflammation is tested using colorectal distention, a model of visceral pain transmission. Colorectal distention involves inserting a balloon securely attached to flexible plastic tubing into the colon and inflating the balloon with a pressure control device. As the balloon is inflated in the colon, the animal experiences a considerable amount of pain and anxiety. The animal responds by contracting its abdominal muscles, and this reflex is recorded using the electrode implanted in the abdominal musculature. In this model, the animals are tested repeatedly to establish their baseline response and their response after various drug treatments.
1. As a knowledgeable member of the community, do you think the use of animals can be justified in these circumstances?
2. How do you think a research scientist would justify use of animals in these circumstances?
3. The protocol specifies an intra-animal study, where the same animals are used repeatedly to test the effects of specific drug treatments. Would it be better to change the studyÀs design from intra-animal to between-animal, thereby minimizing the pain each animal experienced but using more animals?
While investigating the mechanisms underlying chronic visceral pain, Eric discovered a report in the literature of a drug used in animal research. Since he believed the drug might have potential therapeutic efficacy, he asked Michael, one of his graduate students, to test it using the rodent model of inflammatory bowel disease. Before performing the experiment, Michael researched the drug Eric wanted to test. He found data suggesting it would not be an effective therapeutic agent against visceral pain and inflammation using the rodent model. He presented these data to Eric; however, Eric decided that there was still a possibility that the experiment would produce successful results.
Michael was very apprehensive about the situation. He felt the procedure was extremely painful to the animals, and he continued to believe that the drug would not be useful in inhibiting pain transmission. However, he carefully carried out the experimental protocol and obtained inconclusive results. Assuming that a procedural error had occurred, Eric asked Michael to repeat the experiment. Upon meticulously repeating the study, Michael obtained inconclusive results once again.
In the literature, Michael found an alternative model of visceral nociception that is much less painful for the animal. He presented the idea to his adviser, explaining both the advantages and disadvantages of the new animal model. Eric contemplated using the new technique, but in the end he decided to continue using the original animal model since the alternative approach is not widely accepted in the field of pain research. At this point, Eric is still quite confident that the drug will be effective in the treatment of pain. Therefore, he tells Michael to repeat the study once again.
4. Should Michael repeat the experiment?
5. What resources are at Michael's disposal to help him?
6. Are Eric's directions to repeat the experiment unethical?
Brian Schrag, ed., Research Ethics: Cases and Commentaries, Volume 5, Bloomington, Indiana: Association for Practical and Professional Ethics, 2001.
The debate over the use of animals in scientific research, particularly when pain is inflicted, proceeds at both a general level and at the level of particular cases. (For discussions of some of the broader moral considerations in the use of animals in research see "The Gladiator Sparrow: Ethical Issues in Behavioral Research on Captive Populations of Wild Animals," pp 32-44; "Counting Sheep: Ethical Problems in Animal Research" pp. 82-96, and "Changing the Subject," pp. 97-106, in Research Ethics: Cases and Commentaries, Volume 2 ).
Even if all were to agree that research on animals is sometimes justified, that would not settle the question of whether it would be justified in this case. We all recognize that there is no moral ground for gratuitously inflicting pain on animals. Thus in research experiments that involve inflicting pain on animals, the burden of proof must be on those proposing the experiment to show that the animals' suffering is somehow outweighed by the benefits of the experiment. A written scientific justification for any painful or distressing procedure to animals that cannot be relieved or minimized must be included in the Animal Study Protocol submitted to the Institutional Animal Care and Use Committee (IACUC).
In these comments, I will focus on this particular case, which raises a number of ethical issues. 1) Should the experiments have been done at all? What are the relative merits of the researcher's viewpoint and that of someone from the nonscientific community? 2) Even if the experiment is initially justified, is there a point at which it ought to be terminated, and if so, at what point? Related to this question is the issue of whether standards of certainty should be lowered when the cost of achieving involves infliction of pain on animals. 3) Should the protocol approved by the IACUC include points that trigger an evaluation of the decision to continue the experiment?
Aside from the experiment itself, the case raises issues about the researcher's interaction with his graduate student. 5) Is there adequate dialogue about experimentation on the animals and an atmosphere that encourages open dialogue? Should a lab that routinely experiments on animals have substantive introductory discussions with all entering graduate students on the ethical issues of research on animals in order to create an environment of ongoing dialogue in which students are free to raise issues?
Should the IACUC have approved this experiment? Eric wants to test a drug that might have potential therapeutic efficacy for humans, for example, to relieve pain in inflammatory bowel disease. Thus, the research appears to be on a topic of significance to human welfare. What is at issue is whether that significance outweighs the suffering of the animals in the experiment.
However significant the problem being investigated, one issue that is always relevant in research that inflicts pain on animals is whether or not a particular experiment is likely to yield useful information. It is troubling in this case that, after the experiment is approved, Eric's graduate student Michael does further research and finds data (of which Eric is apparently unaware) that suggest this drug "would not be an effective therapeutic agent against visceral pain and inflammation using the rodent model." Did Eric do an adequate literature search before proposing this experiment? Would the IACUC have approved this proposal had they been aware of Michael's findings? It is possible that the data Michael found were inconclusive and that in Eric's considered opinion, the data were not sufficient to discount the value of the investigation. Nevertheless, it appears that Eric was unaware of the data going into the experiment, and he ought to have a reason for discounting the data. Absent that, it does seem to weaken the case for doing the experiment.
It is also troubling that Michael finds an "alternate model of visceral no inception that is much less painful to the animal" (which again is something of which Eric is unaware or at least did not consider in developing his original protocol). Eric contemplates using the new model, but he decides to use the original model since the alternate is not widely accepted. Eric's judgment may be right, but it does raise questions about how thoroughly he researched the issue before designing the experiment and presenting his protocol to the IACUC.
Finally, the protocol specifies an intra-animal study where the same animals are used repeatedly as opposed to a between-animal study, which uses each animal only once, hence minimizing pain to any one animal but using more animals. One advantage of the former design is a reduction in the amount of variability in results since fewer animals are used. It may be that Eric is justified in using a model that gives results less subject to variability. This model may increase the certainty of the results, but at the cost of more pain to individual animals.
Suppose one grants that Eric's original design was justified. As the testing progresses, Michael gets inconclusive results. Eric assumes there is a procedural error in the experiment and asks for a repeat of the experiment. Michael again finds inconclusive results. Eric asks for the experiment to be repeated again.
Eric seems to be in denial about the findings of the experiment. One wonders how long he will continue to repeat the experiment if the results continue to be inconclusive. All science must deal with levels of certainty of results. In principle, the more one repeats an experiment, the more confidence one can have in the results. But at what cost should that certainty be purchased? There is a difference between the cost of increasing levels of certainty gained by repeating an experiment in inorganic chemistry, for example, and the cost of increasing levels of certainty when the experiment involves causing considerable pain to animals. The burden of proof is higher for justifying the value of incremental increases in levels of certainty of results when pain to animals is involved.
It is important to realize that the justification for a protocol of an experiment involving pain to animals at the beginning of an experiment may weaken as the results of the experiment come in. When one combines the literature results, which suggest this drug may not be efficacious, with the results of the first two trials, the justification for continuing the experiment may be weaker than the initial justification for the experiment. In an experiment involving infliction of pain on animals, it would be preferable to have some guidelines to indicate when it is no longer appropriate to continue the experiment.
Researcher-graduate student interaction
Michael's obvious discomfort with the experiment and Eric's interaction with him suggests other concerns. If Eric is requesting a repeat of the experiment because he suspects Michael is not correctly performing the experiment, then, in light of the animal suffering involved, he has a responsibility to review procedures with Michael and to monitor Michael's work to ensure yet a third trial is not required because of errors on Michael's part. If there is nothing wrong with Michael's execution, then Eric's request for repeated work appears to be inappropriate pressure on Michael to get positive results. Michael may need some vehicle to raise the issue with Eric, and, if that fails, access to someone else to discuss the issue.
If this is a lab that routinely engages in experimentation with animals, it may be desirable to have initial faculty-graduate student discussions as graduate students join the laboratory, regarding the moral issues involved in research on animals as well as reporting new research on models for animal research and guidelines for research on animals. This setting would be appropriate for informing students of the proper procedures to follow if they have questions about the justification of particular experiments or experimental procedures involving animals. This forum would allow issues to be raised in a setting conducive to open discussion and not in the more threatening context of a professor's particular experiment. In this case, Michael would have had an opportunity to understand and evaluate the justification of various animal models before engaging in this specific research. Such a practice may also open lines of communication when students have a particular concern with a professor's experiment; in this case, that may have made it more comfortable for Michael to raise the issues with Eric. It may also open lines of communication when students have a particular concern with a professor's experiment.
Author: Brian Schrag, Indiana University.
The Use of Animals in Research
The Student-Adviser Relationship
This case study is designed to raise ethical issues encountered in biomedical research. The goal is to have the participants identify moral issues and questionable practices in order to learn how to deal with future ethical concerns more appropriately. The first part of the case addresses the use of animals in pain research, while the second half focuses on concerns in the student-adviser relationship.
The Use of Animals in Research
Animals have been utilized in the advancement of medicine for decades. However, it was not until 1966 that their use was protected and controlled under the Animal Welfare Act (AWA). Since then, additional regulations have been passed, and the AWA has been revised multiple times. As a result, the number of animals used in laboratories has been reduced, and their treatment has improved. Despite these changes over the years, the use of animals in scientific research is still a controversial issue.
Are animal models appropriate for studying human disease? Can the use of animals in the laboratory be justified? Perhaps these questions could be better answered if considered from two contrasting points of view: first from the standpoint of a knowledgeable member of the community and second from that of a research scientist. Knowledgeable members of the community are required on every university's Institutional Animal Care and Use Committee to represent the community's concerns and interests. Their point of view on this subject is very important to the advancement of scientific research. They may allow the use of animals as long as unnecessary pain or anxiety is avoided. They could say that the knowledge gained from these experiments could benefit human lives. A member of the community should only justify animal use when the guidelines outlined in the AWA are strictly followed, including all measures to avoid or minimize the animals' suffering and distress.
In contrast, the use of animals can be considered from a research scientist's point of view. It is important to consider the individual animal model and its similarity to human pathology and physiology. The animal model discussed in this case study is used to investigate the transmission of acute visceral pain. According to Ness and Gebhart,(1) this procedure is a valid model of visceral nociception, as the animals react appropriately to colorectal distention with significant changes in the cardiovascular and visceromotor response.
This type of visceral pain is associated with a variety of clinical pathologies, including a condition known as inflammatory bowel disease. According to de Dombal et al.,(2) 50 to 100 people out of 100,000 suffer from this disease. Furthermore, it has been a challenge to develop better therapeutic agents that will alleviate the pain associated with this condition but will not cause adverse side effects. To develop new therapeutic agents, scientists are using this animal model to further elucidate the mechanisms of visceral pain transmission. When one considers the cost-benefit equation, the cost is the suffering and distress that the animals must experience, and the benefit is that human suffering will be eased through this research with the development of better antinociceptive medications. Ultimately, if animals are going to be used in the laboratory, then the research scientist has an obligation to provide the utmost care and to avoid animal suffering and distress.
Using a within-animal design, each subject is tested repeatedly to obtain its baseline response and its response after multiple drug treatments. This protocol can be changed to a between-animal design where the animal will only be tested once; however, more animals will be needed to complete the study. Which design is better? Again, this question can be considered from opposing points of view. A knowledgeable member of the community may prefer a between-animal design, as the amount of suffering that each animal experiences will be significantly reduced. However, a research scientist may wish to keep the study a within-animal experiment, thus saving costs, as fewer animals are needed. Further, a considerable amount of variability in the results would be avoided if the within-animal design were retained. Finally, increasing the number of animals would take much more time, as surgery is necessary for every animal used in the experiment.
Overall, the use of animals in the laboratory will always remain a controversial issue between research scientists, members of the community and animal welfare activists. Although some animal models of human disease may be ethically questionable, there will always be a need to study animals to further scientific research and relieve human suffering.
The Student-Adviser Relationship
Relationships within the scientific community are susceptible to all types of conflicts and miscommunications, especially the student-adviser relationship. One of the problems that arise in the second part of this case study is that the student-adviser relationship is suffering from a lack of communication. It initially appears as though Michael is not comfortable working with this particular animal model. Furthermore, he questions his adviser's theory that the specific drug has therapeutic efficacy. Before performing any more experiments, Michael should speak with his adviser about both of these concerns. If Eric is unresponsive to Michael's problems, then Michael should seek other resources. He could speak with his mentor, a member of his thesis committee or perhaps a member of an arbitrary advisory committee. In order to resolve these issues, Michael and Eric must open lines of communication and work toward a compromise.
Another ethical issue in this situation concerns Eric's behavior toward his graduate student. Eric is asking Michael to repeat an experiment after it has already been performed multiple times. Despite obtaining inconclusive results, Eric still believes that the experiment should work. In his advisory role, Eric is placing inappropriate pressure upon Michael to produce positive results. In resolving this situation, Michael could discuss his results with a member of his thesis committee who is familiar with Michael's work. Another option is for Eric to be present in the laboratory while Michael repeats the experiment, ensuring that he does not make any mistakes. On the other hand, perhaps Michael is performing the experiment correctly but the animal model he is using is not appropriate. Therefore, Eric should seriously consider optimizing the alternative model that Michael found in the literature. Fine-tuning another animal model of visceral nociception may be time consuming, but it may lead to a significant scientific discovery.