This is true about certain recent attacks against animal research at UW-Madison.  Our Institutional Animal Care and Use Committees recently approved a proposal to subject 20 rhesus monkeys to “peer-rearing”, a form of early life stress.  Here’s what the Animal Legal Defense Fund (ALDF) has to say about this experiment’s design and consequences.

“Infant monkeys are immediately removed from their mothers after birth and kept in total isolation.  They will be given ‘surrogate’ materials known to provoke heightened anxieties.  For 42 days, the confused monkeys will be subjected to relentless fear and panic-inducing tests while totally isolated.  These tests include being intentionally terrified by human researchers, being left alone with a live King snake, and being left alone in a strange room with a strange monkey.”  Later, they add: “These tests will cause serious psychological torment to baby monkeys.”

They did get one half of one sentence right.  Infant monkeys will be removed from their mothers.  After that, it’s all wrong.  The monkeys are not kept in total isolation.  They are reared in a human-style baby incubator by people who feed and otherwise care for these infants until they have grown enough to regulate their own body temperature.  Once that happens (at 3 to 6 weeks of age), they are permanently paired with another young rhesus.  During their stay in the isolator, the “surrogate” materials they receive are known to actually REDUCE anxiety.  I’ll also note that this same approach is taken to rearing baby rhesus monkeys whose mothers reject them at birth and who are not adopted by a foster mother.  In other words, sometimes peer-rearing is used to save a baby monkey’s life.

The monkeys are not subjected to “relentless fear”.  Instead, approximately once a month for up to 18 months their reaction to a novel situation is observed.  What are these novel situations?  An unfamiliar human stands in front of their cage.  An unfamiliar monkey is housed in an adjoining cage, or the two are housed together in a play cage.  And one time, the monkey can see a snake, closed within a solid glass aquarium that sits outside the monkey’s cage.  That does not constitute relentless fear.

What about the “serious psychological torment” claimed by ALDF?  UW-Madison colony records of peer-reared monkeys spontaneously rejected by their mothers indicate that, typically, they respond to novel situations by increased thumb sucking, not by increased self-injury, compared to monkeys raised by their mothers. From 2002 to present, only one peer-reared monkey injured herself within the first 18 months of life.  She now no longer exhibits this behavior, and currently is raising an offspring of her own.

In previous studies, these UW-Madison researchers mapped out pathways in the brain that are overactive in anxious monkeys (it turns out the same pathways are overactive in anxious humans too).  They identified which parts of the brain are altered when predisposition to anxiety is inherited, which are altered when anxiety is caused by adversity in early life, and how genetic vulnerability and environment interact.  These discoveries demonstrate the benefit of the past use of monkeys in this laboratory.

So what, then, is the reason for the current studies?  The point of these studies is to identify changes in brain chemistry and gene expression in those overactive areas of the brain that accompany anxiety caused by early adversity. This knowledge can provide new specific candidate chemical and genetic targets for potential therapies. It builds on the earlier findings, and could not be obtained by a different experimental approach.

Anxiety disorders affect millions of people in the United States, and the mechanisms of this disease are similar between humans and rhesus monkeys.  Early adversity is the most important determinant of later development of anxiety and depression.  Current treatments are only marginally effective.  As for any study involving animals, we each need to decide for ourselves if using 20 monkeys in the experimental approach described above is balanced by the potential benefits of this research.

I want to thank Professor Gruen for her attention to this issue. Regardless of whether one supports or opposes the research, we can agree that it raises important ethical issues that deserve an open and informed discussion. Here, I wish to further that discussion by responding to Gruen’s concerns.

But first, I need to point out that Gruen’s writing implies that the effect of peer-rearing on the well-being of these monkeys is more severe than it really is.  In her second post, Gruen states:

“There was no oversight system in place back in the days when Harry Harlow’s experiments psychologically tormenting baby monkeys were making news.  Surely that sort of horrible work in which infant primates are taken from their mothers to make them crazy wouldn’t be approved of today.  On my recent visit to the University of Wisconsin I was shocked to learn otherwise.”

In fact, the proposed studies produce at most a moderate early life stress. I have described the peer-rearing experiment design elsewhere, but will restate two pertinent observations.  First, peer-rearing actually is used to save a monkey’s life when a mother rhesus rejects its infant and a foster mother cannot be found.  Second, clinical records show that, in the UW-Madison colony, peer-rearing typically only is associated with thumb sucking behavior (just one young monkey in 10 years injured herself, and she recovered).  Peer-rearing will measurably increase anxiety, as required by the experimental design, but does not make a monkey “crazy”.

Gruen suggests this study “violates the spirit, if not the promulgated regulations, of the Animal welfare Act (AWA) which specifically requires that the psychological well-being of primates be protected (not intentionally destroyed).”  Later, however, Gruen concedes that “the AWA allows exceptions for scientific reasons if they are approved by an Institutional Animal Care and Use Committee (IACUC).”  The purpose of peer-rearing in this study is to create monkeys that are environmentally predisposed to anxiety, so that we can compare their brain chemistry and pattern of gene expression to monkeys raised with their mothers.  Thus, peer-rearing in this study both has a clear scientific rationale, and it was IACUC approved.  Its use therefore violates neither spirit nor letter of the law.

Next, Gruen states, “it isn’t clear that the monkey model is adequate.” In support of this claim, she suggests, with unclear relevance, that differences in the developmental onset of nerve myelination between humans and chimpanzees makes the rhesus monkey a bad model for humans.  To the contrary, at the level of behavior and brain neural pathways, monkeys and humans manifest anxiety very similarly.  Monkeys are considered to be a scientifically appropriate species for these studies.

To further support her contention, Gruen then quotes a pediatric psychologist who says that she
“sees many patients in our offices who have grown up under ‘adverse’ conditions, and they are hardly a uniform set.  There are a wide variety of stressors that traumatized human children have to deal with, including various types of abuse and neglect, and these can never be replicated with any kind of accuracy using animal models.”

I accept this statement, but rather than indicating that the monkey is a bad model, it points out why humans would be a terrible model even if they could be ethically used.  There is extreme variability in both the causes of anxiety in humans and the quality of the person’s subsequent environment.  Peer-rearing, in contrast, produces a moderate adversity that reliably and more uniformly produces brain changes associated with anxiety, and thus permits comparison between groups of individuals who differ principally in this one variable of early experience—peer-rearing versus maternal rearing. This ability to carefully match control and experimental animals is critical to this experimental design, and makes it likely that any differences found between groups will be highly relevant to the root causes of anxiety in monkeys.  The similarities of anxiety between monkeys and humans suggest this study also will be highly relevant to the causes of anxiety in humans.  In short, the monkey IS a good model.

So far, I’ve argued that the peer-rearing study is legal and likely to provide valuable information.  Now let’s look at whether there are better ways to accomplish the same objectives.  The goal of the current study is to identify changes in brain pathway chemistry and gene expression in anxious monkeys.  What does Gruen suggest as an alternative?

She proposes that the research funds be redirected to social programs that “can prevent the psychological harms that arise from childhood trauma.”  But when dealing with complex problems, multiple approaches are almost always more effective than putting all of our eggs in one basket.  By all means, let’s spend money supporting parenting skills classes, affordable childcare, and so forth.  But that approach will never eliminate the problem or reach everyone in need.  Given the cost of social programs, redirecting all the research funding from these studies would barely make a dent.

A more significant difficulty with Gruen’s argument is the fact that the purpose of these experiments is not to eliminate anxiety, but rather to identify molecular changes in the brain.  This more modest and specific goal can lead to targets for medical treatments.  And it can’t be achieved with social programs.  Remove the funding, and it would have to be dropped.

So to achieve the benefit of reducing anxiety disorders, let’s tackle the problem from several directions.  Fund social programs.  But when that approach fails to prevent disease, let’s supplement it with effective treatments that only the research can give us.

I have explained why I believe the research is legal, uses an appropriate model, and proposes methods that are necessary to achieving its stated aim.  Equally important is the question of whether the IACUC followed required procedures to reach a similar conclusion.

IACUCs are mandated by law, and, among other responsibilities, must review any proposed use of animals in research, teaching, or outreach before it can begin.  Each IACUC must have at least a veterinarian with expertise in the species used, a scientist knowledgeable about experimental design, a non-scientist, and a community member not affiliated with the institution.  A typical proposal (the “protocol”) undergoing full IACUC review will be assigned to a single committee, read beforehand, discussed, and voted up or down.  I calculate that review of a relatively uncomplicated protocol not associated with significant animal pain or distress takes around 4 person-hours (number of reviewers multiplied by time of review).

What about the quality of IACUC review?  Gruen gives two reasons for thinking it must have been poor.  First, she states, “the oversight committee chairs [at UW-Madison] told me they have never rejected a proposal.  Not one.”  I expect she considers failure to reject a protocol to imply that the review process is a rubber stamp.  Let’s dig deeper into the facts.

When our IAUCUC chairs say “failure to reject”, they mean that almost all protocols eventually reach a state that the IACUC can accept.  There are two principle reasons for this.  First, protocol preparation is an intensive process, involving careful description by investigators of what they want to do and how they want to do it.  They typically receive extensive veterinary input.  In other words, the protocols are good to begin with.  Second, even after careful preparation, very few protocols are approved the first time around.  Data from IACUC protocol review during January 2013 (a typical month) indicates that, of 51 new or renewal protocols submitted, only 4 (8 percent) were approved as written.  The rest were rejected, deferred, or “required modifications to secure approval”.  Perhaps a more accurate statement would be that our IACUCs reject 92 percent of the proposals they receive.  I do not believe it is a criticism of our system that ICUCs are willing to work with investigators until a protocol finally receives approval.

Second, Gruen quotes from an IACUC meeting minutes, in which members seemed concerned about the research and confused about their roles.  The meeting she cites was the first time this committee had seen the protocol, and the fact that they were willing to openly express their concerns about this unfamiliar and ethically charged proposal is the sign of a robust review process. The quote from a veterinarian (who, by the way, was not the IACUC chair) implying uncertainty about IACUC authority was taken out of context.  His intent was to indicate that IACUCs should not reject NIH-approved studies only because they have the potential to cause animal distress.  All IACUC members understand that the committee can vote down any proposal.

For this peer-rearing study, the protocol was assigned to two IACUCs, since it requested use of animals from two facilities overseen by different committees.  It was reviewed at five individual IACUC meetings and 3 meetings involving both committees.  A conservative estimate of the total person-hours of review: 170.  Over the course of review, the investigators were required to address adequately a total of 187 IACUC questions before they finally secured protocol approval.  I have not seen a more intensive protocol review in 18 years as an IACUC member.  Even those who disagree with the IACUC’s decision should acknowledge that, in this case, the data demonstrate that approval was nothing like a rubber stamp.

Gruen concludes her second blog, which primarily criticizes IACUCs, with the following question:  “What does this say about the ethicists who serve on these oversight committees?”  I’ll answer that.  A faculty ethicist chaired one of the two IACUCs evaluating this research, and he also chaired the three combined IACUC meetings.  As chair, he ensured that all components of ethical protocol review—identifying costs and benefits, considering alternatives and consequences—were fully and explicitly addressed.

When the final vote was taken, the protocol was approved by a majority vote of each IACUC.  He may or may not have voted to approve (the final ballot was confidential), but he made certain that the process honored the spirit and the letter of the law.  This kind of direct experience with the subject of one’s ethical enquiries is less common than it should be.  I commend him and all the members of our IACUCs for their lengthy and thoughtful participation in the review of this and other important research.

Stories about animal research are a good source of facts.  Under the heading “Animal Research in the News”, we link to press releases and published articles that connect animal experiments with outcomes, and give the sources of the story should you wish to find more information.  In “Animal Research Background” we provide you with links to additional information on the topic.

Animal research is practiced with multiple levels of oversight.  You can get an idea of just what this means for UW–Madison by looking at “UW Animal Research Links”  and “Federal Laws/Guidelines”.  We also provide you with names of press contacts for issues related to animal research at UW–Madison.

Finally, we acknowledge that ethical considerations must guide animal research. This is and will remain an important topic for this site.

For human subjects, how do we identify those studies that are ethical?  At UW–Madison, and nationally, this is accomplished by requiring that any proposed study be evaluated and approved by a review board before it can be started.  In other words, the decision is made on a case-by-case basis.

For animal subjects, we and other institutions do the same thing.  As a guiding tool, we employ the ethical philosophy of utilitarianism, in which actions are justified only after benefits are balanced against harm: any ethical analysis must consider both.  Nationally, the elements of this analysis are described by the “U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training”.

Consider Principle Ⅱ in this document: “Procedures involving animals should be designed and performed with due consideration of their relevance to human or animal health, the advancement of knowledge, or the good of society”. Here is an explicit requirement to evaluate whether a given study has the potential to produce benefits.  Compare this with a question on the UW–Madison application for animal use:  “Outline the specific scientific goal(s) and significance of this research. Be convincing as to why this work is important for advancement of knowledge, improving human or animal health, or for the good of society.”  Other principles outlined in the document identify the need for pain relief, veterinary care, and appropriate animal housing and husbandry, explicitly addressing potential for harm.  Each is matched with a corresponding request for information on our animal use application.

Thus, ethical considerations are built in to every single review of proposed animal use.  In this way, UW–Madison Animal Care and Use Committees answer the question of whether experimenting on primates, or any animal, is ethical.  Just as for experiments involving humans, only if the answer is yes will an animal study be allowed to proceed.

Ethical consideration of animal use is not limited to application review.  Review committees on this campus have discussed ethics explicitly.  Graduate students and other research trainees take a class on research ethics that includes a unit devoted to animals, and this provides them with the framework to develop their own ethical stand on the issue.  Campus-sponsored seminars have included animal ethicists, and faculty and staff participate in public programs and debates about animal use and ethics.  Nationally, scientific societies, funding agencies, and the federal government review, refine, and set standards for animal use based on both ethical and scientific considerations.  Policy-guiding ethical decisions are made at the national level, balancing the public’s interests in animals and its desire to find treatments for disease.

The people who work with animals are themselves members of the “general public”, and have ethical standards of their own.  They have pets, have families, contribute to social causes, and donate time and money to charities.  Most feel passionately about both the importance of their work and the wellbeing of their animal subjects.  These are not contradictory feelings; rather, they exemplify essential elements of the balancing test that informs both personal and institutional use of any animal in research, education, and outreach.