Rhesus Monkey Anxiety Study – Comprehensive Notes

Participants & Background

• Dr. Eric Sandrin

  • Born in $Wisconsin$; BA from $UW$ in zoology, biochemistry & molecular biology
  • VMD + PhD (genetics) from $University\ of\ Pennsylvania$
  • Arrived at $UW$ $1993$–$1994$; Associate Professor, Dept. of Pathobiological Sciences
  • Research: genetic mechanisms of breast, pancreas & liver cancer via genetically-modified mice
  • Compliance roles: member → vice-chair → chair of Graduate School IACUC; later chaired all-campus IACUC
  • Acting Director ( $9$ yrs) of Research Animal Resources Center (RARC)

• Dr. Jeffrey Khan

  • BA $UCLA$; PhD $Georgetown$; MPH $Johns\ Hopkins$ Bloomberg School
  • Inaugural Robert H. Levy & Rita R. Levy Professor of Bioethics & Public Policy; Deputy Director, Johns Hopkins Berman Institute of Bioethics
  • Expertise: human & animal research ethics, public health ethics, emerging biotechnologies
  • Chairs Institute of Medicine (IOM) Board on Health Sciences Policy; chaired $2011$ IOM Committee on Use of Chimpanzees
  • Publications: $3$ books, >115 articles; recent papers on chimpanzee research constraints

• Moderator & Format

  • Opening talk by Sandrin (experiment description + justification)
  • Response by Khan (ethical critique)
  • $5$-min rebuttals
  • Moderator questions
  • Audience Q&A after short break

Experiment Under Discussion

• Subjects: $40$ infant rhesus macaques divided into two cohorts
  • Control group: $20$ mother-reared for $6$ months
  • Experimental group: $20$ nursery-reared (peer-reared) from birth; human care $\approx$ $3$–$6$ weeks; paired with age-matched peer
• Timeline: lifespan $\approx$ $12$–$18$ months (dashed variability)
• Objective: compare high-anxiety vs low-anxiety phenotypes; identify brain regions & molecular pathways driving anxiety / depression
• End-point: euthanasia + harvest of targeted brain tissue for biochemical & gene-expression profiling

Testing & Data Collection Schedule

• Repeated every $\approx$ $2$ months:
  • Human Intruder Paradigm (HBPM)
  • Blood draw for cortisol (stress hormone)
  • PET scan (functional activity mapping)
  • Follow-up MRI (structural imaging)
• Every $6$ months: lumbar puncture for cerebro-spinal fluid + blood (with anesthesia & analgesia)
• Behavioral assays:
  • Test-cage adaptation
  • Conspecific social interaction
  • Play-cage exploration
  • Snake-visibility test (snake in separate enclosure)
• Once/yr: skin biopsy

Rationale & Scientific Context

• Childhood-origin anxiety & depression are common, disabling psychiatric disorders
• Prior work (Dr. Kalin & others) mapped hyper-active circuits shared by monkeys & humans
• Goal: isolate biological targets (neurotransmitters, receptors, gene networks) → enable rational drug design
  • Analogy: discovery of selective serotonin re-uptake inhibitors (SSRIs) after link between low $\text{5-HT}$ & depression
• Epidemiology: psychiatric conditions = #1 global cause of disability
  • U.S. Anxiety disorders: $\approx55\,\text{million}$ adults annually; severe cases $\approx12\,\text{million}$
  • Current therapies: $\sim$ one-third effective, $\tfrac{1}{3}$ partially effective, $\tfrac{1}{3}$ ineffective
  • Major depression $12$-mo prevalence $\approx7\%$; elevated in women & youth; serious sequelae (suicidal ideation, psychomotor retardation, dysfunction)

Ethical Review Framework (Utilitarian Balancing)

• Institutional Animal Care & Use Committees (IACUCs) must weigh:
  1. Potential Benefits
  2. Potential Harms / Costs
  3. Alternatives (3Rs: Replace, Reduce, Refine)
• Regulatory composition: $\ge1$ veterinarian, $\ge1$ scientist, $\ge1$ non-scientist, $\ge1$ unaffiliated community member
  • UW-Madison: $5$ IACUCs, $\approx60$ total members
• Decision outcomes in this case:
  • Committee A – unanimous approval
  • Committee B – $5$ to $2$ approval
  • Months-long review with protocol modifications

Detailed Harm Assessment

• Induced Stress via Peer Rearing
  • Considered mild → moderate anxiety
  • Naturalistic precedent: orphaned or rejected infants are peer-reared to avoid death
  • Historical data: $158$ peer-reared macaques over $12$ yrs → $1$ case of self-injury pre-$18$ mo
• Procedural Stress
  • Frequency quantified above; all procedures mirrored in some human clinical contexts
  • Analgesia/anesthesia for invasive acts
• Ultimate Harm: euthanasia of $40$ juveniles + separation stress on dams
• Not part of study: total isolation, “pit of despair,” physical torture, snake thrown directly into cage, etc. → Sandrin labels such claims inaccurate

Misconceptions Addressed

• Terms such as “relentless fear,” “panic-inducing tests,” “archaic,” “redundant,” “no payoff” flagged as misleading
• Snake test involves visual exposure; no direct contact
• Nursery enrichment objects reduce, not amplify, anxiety
• Study distinct from historic Harlow deprivation studies

Alternatives Considered & Rejected

• In vitro / in silico: cannot recapitulate developmental neuro-circuitry
• Human imaging or post-mortem: lacks molecular resolution; ethical barrier to early-life manipulation; tissue degrades rapidly
• Rodent models: divergent prefrontal anatomy & anxiety phenotypes; less translational validity
• Conclusion: rhesus macaque best available model for the specific mechanistic question

Sandrin’s Utilitarian Equation (Summarized)

$\text{Net\ Welfare} = \text{Expected\ Human\ Benefit} - (\text{Housing\ cost} + \text{Induced\ anxiety} + \text{Procedural\ stress} + \text{Euthanasia})$

• Deems benefits “potentially very large” vs “moderate” animal costs
• Argues unethical not to proceed given global psychiatric burden & lack of alternatives

Khan’s Ethical Critique & Broader Themes

• Distributive Justice Concern: harms to one species, benefits to another ≠ symmetric utilitarianism
• Compliance ≠ moral sufficiency: meeting regulations may still leave research ethically unacceptable
• Necessity Test (IOM Chimpanzee Criteria generalized)
  1. No other suitable model
  2. Cannot be done ethically in humans
  3. Use accelerates prevention/treatment of life-threatening or debilitating disease
  • Adds captive-colony welfare & acquiescence (animal assent) as further constraints in higher-order species
• Skeptical of face-value benefit claims; IACUCs often lack expertise to critique scientific necessity
• Raises issue of quantity of procedures: when does repetition become unnecessary burden?
• Warns of linear-progress fallacy: molecular targets → drug → cure is multi-step, high-attrition path
• Calls for restrictive standards to spur innovation in non-animal alternatives
• Ultimately “deeply skeptical” about necessity; if not necessary, then not ethical

Audience Q&A Highlights

• Total vs mild anxiety: committees sought objective vet data; Sandrin asserts balance point narrowly met
• Human genetic/skin-cell alternatives: induced pluripotent neurons promising but not yet replacement; skin gene expression ≠ brain
• Depression vs anxiety conflation: study targets anxious temperament as developmental risk factor; pathways may generalize
• Search for multiple pathways: expectation of $6$–$10$ distinct circuits; SSRIs only modulate one
• Necessity frontier: if future step required harsher deprivation, Sandrin doubts approval
• Funding for alternatives: only $20\%$ UW research involves animals; NIH encouraged to invest in replacement technologies
• Threats & safety: investigators & staff received harassment; reason for limited public presence

Closing Statements

• Sandrin: universities must defend decisions transparently; condemns agenda-driven misinformation; praises civil dialogue
• Khan: applauds open forum; urges continued public scrutiny of animal research necessity & ethics