Nathan W. Herschler, Resolving Upcoming Conflicts in the Laboratory Animal Law System
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January 26, 2018 In the United States, two major federal laws apply to vertebrate animals used in laboratory research. The first of these two statutes, the Animal Welfare Act (AWA, under the US Department of Agriculture), celebrated its fiftieth anniversary in 2016. The second statute, the Health Research Extension Act of 1985 (also referred to as the Public Health Services Act, or PHS Act), which is similar to the AWA, applies specifically to work funded by the US Public Health Service (i.e., agencies under the Department of Health and Human Services). Understanding laboratory animal law is necessary and fundamental for all researchers relying on results from animal research, laboratory animal veterinarians, institutional officials, Institutional Animal Care and Use Committee (IACUC) members and veterinarians in training. They require familiarity with both the scope and particulars of these laws. Different parties interested in or impacted by laboratory animal laws can have significantly different perspectives about the scope or efficiency of the regulations or their implementation. The Roundtable on Science and Welfare in Laboratory Animal Use of the Institute for Laboratory Animal Research, the Petrie-Flom Center for Health Law Policy, Biotechnology and Bioethics, and the Animal Law and Policy Program of Harvard Law School convened this pre-workshop webcast and a workshop to discuss the future of federal laboratory animal law in the United States. For more information, visit our website at: http://petrieflom.law.harvard.edu/events/details/future-directions-for-laboratory-animal-law-in-the-united-states
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Nathan W. Herschler, Resolving Upcoming Conflicts in the Laboratory Animal Law System
- 1. NEAVS New England Anti-Vivisection Society Resolving Upcoming Conflicts in the Laboratory Animal Law System
- 2. Overview I. Introduction to NEAVS II. Resolving Pending Conflicts III. Ethical and Legal Implications of Advancing Technology IV. From Conflict to Collaboration
- 3. I. NEAVS Who we are And… What that means.
- 4. We can be friends, right? “You can’t stay in your corner of the forest waiting for others to come to you. You have to go to them sometimes.” — Winnie The Pooh
- 5. II. Resolving pending conflicts 1. The push for de-regulation 2. USDA blackout 3. Third-party investigations
- 7. Points of contention with the FASEB et al. report Reduction of burdensome bureaucracy is fine, but this cannot come at the expense of animal welfare, lack of transparency, or weakened oversight. ■ Moving to the lowest common denominator of regulation ■ Moving from bi-annual to annual IACUC inspection ■ Removing the requirement for annual USDA inspection ■ Limiting IACUC oversight for “low risk, noninvasive, or minimally invasive” research ■ Limiting reporting to include only incidents that jeopardize the health or wellbeing of animals
- 8. USDA transparency and APHIS third-party investigations
- 9. III. Possible legal implications of novel technology A. Regulation of human-animal chimera B. CRISPR, Ethics, and Law i. Animals in Labs ii. Farmed Animals iii. Wildlife iv. Pain
- 10. Human-animal chimera, the slippery slope, and law
- 11. “Human glial chimeric mice exhibit enhanced performance in four different learning tasks…. Moreover, the analysis of auditory fear conditioning indicates that alloengrafment by mouse GPCs did not affect the learning of the recipient mice, supporting the notion that the improved learning in the humanized chimeras resulted from the presence of human glia, rather than from cell engraftment per se.” Han et al., Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice, Cell Stem Cell, Vol 12, Iss. 3, 342-353 (Mar. 7 2013).
- 12. Within one year, the human glial progenitor cells in newborn mouse pup brains almost entirely displaced the mouse glial cells in the brain, resulting in mice with a totally humanized glial progenitor population. However, the team decided not to try putting human cells into monkeys. “We briefly considered it but decided not to because of all the potential ethical issues,” Goldman says. Enard agrees that it could be difficult to decide which animals to put human brain cells into. “If you make animals more human-like, where do you stop?” he says. (emphasis added)
- 13. “Where do you stop?”
- 14. ALDF petition to regulate chimeras under Public Health Services Act (PHSA) The HHS Policy for Protection of Human Research Subjects (“the Common Rule”) requires: ■ IRB initial approval of research proposals and continued monitoring. 45 C.F.R. § 46.109 ■ Approval only if, among other requirements: informed consent is given, confidentiality is protected, risks to research subjects are minimized, and selection of subjects is equitable. 45 C.F.R. §§ 46.109(b); 46.116; 46.102(f)(2); 46.111(a)(1)-(2); 46.111(a)(3) ■ There are limited exceptions to informed consent requirement where there is no more than minimal risk to the subjects and research could not be carried out without the waiver. See 45 C.F.R. §§ 46.116(c), (d)
- 15. Petition to regulate chimeras under Public Health Services Act (PHSA) 2009 NIH Guidelines for Human Stem Cell Research: ■ Deny federal funding to research involving the transplant of human embryonic or induced pluripotent stem cells in nonhuman primate blastocysts. ■ Deny federal support for research involving the breeding of human- animal chimeras where human embryonic or induced pluripotent stem cells may contribute to the germ line.
- 16. Key criteria of the petition’s proposal ■ Humanized chimera should have the same protection as other human research subjects; ■ If during review IRB finds there is a substantial risk that the subject will become or has obtained humanized chimera status, it shall require researchers to reduce risks, it shall require researchers to reduce risks to a non-substantial level or to protect the individual as a research subject under existing rules; ■ IRB shall monitor human-animal chimera testing even if it initially determines there is no substantial risk of the chimera becoming humanized.
- 17. What regulation might look like At 42 C.F.R. Pt. 45 Sub. E-F. Research Not Eligible for NIH Funding: E. Research in any way involving animals where human stem cells or other human genetic material has contributed or might contribute to substantively enhanced cognitive capacity, where “substantively enhanced” is defined as mental ability substantively increased from animal baselines and attributable to human genetic material. F. Research involving the introduction of human stem cells or other human genetic material that does not provide for regular oversight from an IRB to ensure that human genetic material are not contributing to substantively enhanced cognitive capacity in an animal.
- 18. CRISPR “Next year we will have it; will we allow it?”
- 19. Ethical considerations ■ We can use CRISPR to make animals sick; ■ We can use cloning to make more sick animals.
- 20. Ethical considerations—farmed animals Risks include (but are not limited to): ■ Off-target edits ■ Reduced genetic diversity ■ Potential for environmental damage if gene-edited material is spread to closely related populations.
- 21. Ethical considerations—wildlife ■ De-extinction ■ Competition with native species
- 22. Eliminating an animal’s ability to feel pain
- 23. IV. From conflict to collaboration 1. Reducing regulatory burden 2. Co-development of alternatives (Reuters/Pool photo) (National Center for Advancing Translational Sciences photo)
- 24. Nathan Herschler, Esq. Executive Director nherschler@neavs.org | 617 523 6020 | neavs.org Contact
Editor's Notes
- Thank you Rick and Jerry, and thanks to the organizers of this fantastic workshop, and to everyone who has stayed all day today – either here in person or online via the webinar. I also want to give a special thank you to the NEAVS team, our President Emeritus Dr. Capaldo, Delci, Sue Leary at AAVS and ARDF, and Chris Berry at ALDF for their support and review.
- The New England Anti Vivisection Society (I’m going to refer to us as NEAVS from here on out), as you can all tell from our name, exists to move society as quickly as possible toward ending the use of animals in research. As you can see from this image from NEAVS’ first ever newsletter, published in 1915 for distribution to our membership, that NEAVS “opposes the contention of vivisectors, ‘implied or expressed,’… that it is no one’s business what happens to an animal, so long as the individual who is handling it can plead that to increase science is his aim.” Since that time, science and law have caught up with this contention. And passage of law such as the AWA and the PHS policy demonstrate – as my copanelist noted in his article “ethics and pain research in animals” that our society has agreed that ethical treatment of animals is not just morally obligatory, it is required by law. Outside the law, society is also increasingly recognizing that animals possess remarkable cognitive and emotional capacities. Decades of research have shown that many animals have the capacity for conscious experience, emotion, sensitivity to reward and punishment, and self recognition. Those ways that we have traditionally defined humans as distinct from other animals are slowly falling away as science documents these capacities, and our norms shift to embrace the complexity and dare I say rights of non-human animals. We – all of us - have accomplished much since 1915, and also very little. Another section of this first issue of “living tissue” voiced fear from our opposition that women’s suffrage would bring the end of both war and vivisection. I’m pleased to report that we have achieved women’s suffrage, although as we saw through coverage of last week’s Women’s march, we still have a ways to go to achieve equality. But suffrage did not result in the end of war or vivisection. We have argued about vivisection across World Wars, the Great Depression, the New Deal, the Civil Rights Movement, the drafting and passing of the Animal Welfare Act (a reflection itself on the public discourse over vivisection), the rise of the Animal Rights movements, and all the way to today.
- But today I wanted to speak as NEAVS’ new Executive Director and state that we – all of us in this room - have a lot in common. We can stand together on the platform of science. We all want to witness the end of cancer, inherited diseases and more. I’m confident that everyone here will happily replace their animal tests with alternatives when they believe those alternatives have been adequately validated. I truly believe that most labs in the US think and care about the welfare of the animals in their care. I believe that many researchers have a personal ethical framework that includes a respect for animals, and that many of you in the room have companion animals that you love as family. There is room for us to sit and dialogue about what is working and what isn’t with current law. There is room for us to sit and think through ethical and legal frameworks that may help guide decision-making around the use of some of the innovative tools we’ve heard about today and will learn more about in the future. I’m so thankful for the opportunity to sit here with you today. We are here to problem solve. We are here to agree where there is room for agreement, and to disagree with each other respectfully. My substantive presentation today will start with a number of areas where we are likely to disagree with one another, and then conclude with the ways in which we’d like to work together moving forward.
- We do have a lot to disagree over. I’m going to cover this section on the push for de-regulation, the USDA blackout, and the discussions over third-party investigations very quickly as Delci covered this all earlier.
- I also want to quickly highlight the FASEB Reforming Animal Research Regulations report released late last year, and also to reiterate some of the concerns that Delci highlighted. We understand that there’s tremendous regulatory burden associated with regulatory compliance. I have had the joy of drafting proposals, developing compliance systems, and filling out monitoring and evaluation reports for USAID, the State Department and other agency funding in my career, and I’m hopeful that I don’t have to do any of that again in the future. And I, like you, wished the burden imposed on those who receive those funds was lower, but understood why those compliance systems are in place. Unfortunately, we are very concerned that the report’s recommendations put far too much focus on recommendations reducing administration at the expense of animal welfare. Here are some of our key areas of concern:
- Won’t belabor these points since Delci has covered them nicely earlier today. The conclusion of the FASEB report highlights that, quote, providing exceptional welfare is paramount when conducting animal research, and regulatory requirements are vital to ensuring that research is executed safely, ethically, and humanely. End quote. The push to amend regulations, policies, and even legislation as recommended in this report takes that commitment to welfare and oversight far too lightly. If relevant agencies and legislators decide to move on some of these recommendations, it’s likely that they will see strong and unified opposition from the animal protection community and the hundreds of millions of supporters across the United States we represent.
- Again, we won’t spend time on these with Delci having covered them earlier today, but we want to reiterate our concerns over the push toward de-regulation and lack of transparency, and what that might mean for animals. NOTE: In August, the USDA unveiled a new limited database to search for inspection reports and research facility annual reports. However, the documents posted have significant information redacted, including the name of some of the permitted facilities, and does not provide previously included information such as animal inventories. To date, the USDA also continues to withhold important enforcement action records such as administrative complaints and official warning letters. – ALDF http://aldf.org/press-room/press-releases/animal-legal-defense-fund-appeals-dismissal-lawsuit-usda-blackout-animal-welfare-records/
- The word chimera dates back to the 14th century, where it was used to refer to a fire-breathing monster from Greek mythology. In modern times, it refers to an organism with at least two populations of genetically distinct cells originating from different individual zygotes. The creation of human-animal chimeras, created by transplanting human cells into animal recipients, is morally and politically controversial. Researchers, believe that these types of chimeras are a valuable research tool due to the possible application of the technology for human benefit including: 1) evaluating the potential for chimera to grow cells, tissues, and organs suitable for transplanting into humans; 2) studying in vivo biological development; and 3) testing therapies or cures for human disease. Chimeric animals with implanted human brain cells have shown evidence of improved cognitive ability. This was shown most clearly in the now famous study reflected on my next slide (CLICK)
- Han et al.’s release and findings indicating that mice grafted with human glial progenitor cells had increased mental capacity led to the publication of many bioethical articles regarding the ethical implications of conferring improved cognition to a nonhuman animal through chimerization with human cells. Two of the formative articles discussing this advancement came from Greene and Greely, and both agreed that such experiments should be subject to careful oversite because those procedures could possibly increase cognitive capacity that would be morally significant. However, neither article participated in line-drawing to indicate precisely what increased capacity may signify, or more importantly, at what level it becomes morally significant. And this is important, ethically, because the common justification for human interests trumping animal interests is that humans have more or more complex interests than animals. They are either not as smart, not as rational, or not as sentient. Since, this study a number of other articles have been published showing the risk in having little or no regulation over modified human-animal beings.
- Where do you stop indeed? That comment from Dr. Enard really highlights the slippery slope arguments we’re dealing with here. And here’s one more thought experiment to think through. Endangered Species Act aside, imagine a chimpanzee intentionally created with largely humanized brain cells. This is literally what happened in the movie Planet of the Apes. We could end up with a human-animal chimera that seems an awful lot like a human-being in a chimpanzee body. Chimpanzees really already demonstrate all of these attributes, but how do we ethically or legally distinguish a this new chimerized being that has all those attributes that we say hold moral value - linguistic ability, a degree of self awareness, a sense of past and future self, moral and rational agency, and human genetics. If a researcher was able to secure private funding for this initiative, what laws related to research would stop her from doing that research? I’m sure we here today and in the animal protection community could brainstorm some interesting ideas to legally argue against this type of experimentation from occurring, but we can certainly imagine a research team doing a cursory look through the law and determining that this would be legal. This is the potential reality of what we are dealing with right now. In the next slides I will review a really interesting petition submitted a few years ago by Chris Berry at ALDF that seeks regulation protecting humanized chimeras and proposes one place to draw the line. I’ll also discuss where NEAVS would likely fall on this issue, and discuss why that tactical decisions is appropriate despite its inherent anthropocentrism.
- The question at the heart of ALDF’s petition is: why do we not owe human-animal chimeras with the cognitive capacity of a normal adult human – the planet of the apes example - the same level of protection owed to human beings? ALDFs citizen petition for rulemaking to protect humanized chimeras under the public health services act relies on the context discussed in previous slides, the HHS policy for Protection of Human Research Subjects, sometimes referred to as “the Common Rule,” which lays out rules designed to protect human subjects through IRB oversight, and proposes new regulations to protect human-animal chimeras with the cognitive capacity of a normal adult human. On this slide you can see the legal protections that would apply to human-animal chimera if regulated under this petition. This, as you can see, would be a tremendous advancement when compared to existing regulation for those animals.
- ALDF notes in their petition that HHS has done little to ensure that humanized chimeras receive protection to date, and certainly do not ensure that such individuals receive appropriate treatment as human research subjects. They also say that the narrow prohibitions on research involving nonhuman primate blastocysts and breeding chimeras will not necessarily prevent the creation of humanized individuals, does not afford protection to humanized chimeras, and do not prohibit research with a relatively high risk of creating a humanized chimera. Finally, they acknowledge that while some chimeras are protected as animals under the AWA, the AWA does not protect rats, mice, birds that are bred for use in research, amphibians or fish, all of which are frequently used in research, and certainly does not protect most of those animals against invasive research involving intentional harm or more than minimal risk in the same way that human research subjects would be protected.
- While ALDF’s petition essentially seeks a line drawn at “high-level cognitive capacity” standard for humanized animals and argue that this is an ethical minimum standard, NEAVS advocates for NIH to adopt even broader standards to define human research subjects. Read slide In contrast to ALDF, NEAVS believe that NIH should adopt a precautionary approach and qualify human-animal chimeras that have “substantively enhanced” cognition as human research subjects. Only this standard will adequately protect potential or actual human-animal chimeras from the risks associated with testing. Now, either approach opens up ALDF and NEAVS to claims that the approach is inherently anthropocentric because it relies on the moral value of humans as the organizing principle, rather than equivalent moral, normative rights between humans and animals. However, the progress this regulatory change would represent in terms of coverage and respect to human-animal chimera is so substantial that it is clearly progress toward our goals.
- Within the framework of the Guidelines, NIH could include a prohibition on research involving human-animal chimeras demonstrating substantively enhanced cognition, and effective monitoring of chimera research to ensure protection of these cognitively enhanced chimera as follows in this slide. At this stage, HHS has not responded to the ALDF rulemaking petition. Eventually, a lack of response to the petition will open the agency to APA unreasonable delay litigation, which has not yet been instigated, but that I will be looking for from our friends over at ALDF in the future. And if and when the agency does proceed to rulemaking, NEAVS will be advocating for a precautionary approach as laid out here.
- Whitelaw, B. Open Season is Seen in Gene Editing of Animals. NYT. (Last visited: https://www.nytimes.com/2015/11/27/us/2015-11-27-us-animal-gene-editing.html) We’ve heard a fair amount about CRISPR here today, and I only want to spend a bit of time highlighting some interesting ethical and legal considerations that we are looking out for as this technology and regulation advances. One of the challenges with CRISPR gene editing technology is that there are many interdependencies for its potential regulation across many different areas of law.
- At the end of last year, a Chinese firm cloned a puppy named Longlong from another dog named Apple whose genome had been edited to develop the disease atherosclerosis. Longlong is the world’s first dog cloned from a gene-edited donor who was designed to have a serious disease. This example highlights how CRISPR can be used to both make animal sick and make more sick animals. And all of this is covered only by our existing laws and regulations that haven’t caught up to the new risks posed by these technologies. In the US context, it’s likely that most animals being experimented on using CRISPR technology will be mice and rats, animals exempt from the AWA. But to what extent should we be adopting laws and regulation that anticipates CRISPR being used for ethically questionable means such as designed companion animals or de-extinction?
- NOTE: Just a quick additional note that last year, FDA proposed draft guidelines that define every specific DNA alteration as a new animal drug at each site in the genome where the alteration occurs because the specific alteration sequence and the site at which the alteration is located can affect both the health of the animals in the lineage and the level and control of expression of the altered sequence, which influences its effectiveness in that lineage. Approval is based on showing that the product is safe for animals, humans, and the environment, and effective for the intended use. Can we rely on tort liability for environmental damage? Do we build legislation like CERCLA that adopts joint and several liability?
- Does the Endangered Species Act kick in for animal species once listed as extinct, but now back and probably in private possession of a research facility or zoo? Would they once again be listed as endangered? Would people be subject to CITES and ESA import and export permitting if we produce enough of these animals to reintroduce them to the wild?
- Finally, there has been some discussion about the welfare benefits of creating animals that cannot feel pain. The argument is essentially: if we’re going to have these use-based industries like factory farming or animal research, the least we can do is eliminate the unpleasantness of pain in the animals that must live and die on those farms and in those labs. In this study, mice with their global Nav1.7 function knocked out are subject to complete loss of acute pain perception. The mice here were completely insensitive to painful tactile, thermal, and chemical stimuli and had no sense of smell. But while acute pain perception is a key factor in animal welfare, these considerations take no account of emotional and holistic well-being of the animals. Suffering and Pain are not equivalent moral constructs, and emotional or psychological wellbeing should be a key consideration of our treatment of animals. We see animals rescued and placed into sanctuary following time in research facilities exhibit all sorts of psychological trauma, much of which looks like PTSD. We shouldn’t be focusing on knocking out pain while we keep these animals in conditions that are incredibly damaging from a psychological wellbeing perspective. It was a good thought, but misguided, and I truly hope we can stop discussing it as a reasonable way forward for animal welfare.
- So there’s a lot that we are looking out for, and much that will likely be subject to robust ethical and legal discussion over the next years as this technology continues to develop. I do want to highlight a number of areas where I do think we see much overlap and opportunity for collaboration moving forward. We do think there is opportunity to join together to adjust the existing regulatory system to reduce the compliance burden on researchers and increase the protection of animals through, for example, maintaining the coverage of mice, rats, birds, and fish through the PHS. Aligning agency reporting and inspection requirements is a reasonable suggestion, and one we would support so long as animals do not receive lower levels of protection, private and public oversight, or public transparency. We are incredibly excited about the development of alternatives to animal testing – from high throughput computational models to organs on chips – we think there is an incredibly valuable market for alternative products that will ultimately be cheaper and more effective than animal models. Over the next years, NEAVS will be working toward building investment in the field of alternatives and ultimately bring more resources to this field in an attempt to speed the transition away from animal models to a 21st century approach to research and science. And sure, there may even be a “clean meat” for the world of alternatives that replicates human and animal biology but is grown in-vitro without the capacity to suffer. We need to agree not to see each other as “the enemy.” We can disagree and collaborate all at the same time as we work toward our respective visions of the future, a world where humans and animals suffer less. Thank you for your time, and I look forward to collaborating with you in the future. to eliminate the need for sentient animals