Dogs as Biomedical Research Models (copy)

Scope of Today’s Lecture

• Why dogs serve as a scientific model of disease

• Historic milestones achieved with the help of dogs

• Contemporary areas in which dogs still contribute to science (toxicology, pharmacology, surgery, gene therapy, devices, vaccines, etc.)

• Federal laws, regulations and oversight bodies that protect research dogs

• Daily husbandry, veterinary and behavioral‐welfare considerations

• Career paths in laboratory-animal medicine

Relative Use of Species in U.S. Research

• Mice + rats ≈ >95\% of all research animals

• Dogs + cats combined <0.5\%

• USDA-reported dog numbers per year

  • 1973 ≈ 200{,}000

  • Present ≈ 65{,}000 (includes both bench-research dogs and veterinary-school clinical-trial patients)

• Public support trends

  • Overall support for animal research remains moderate–high

  • Support for using dogs has declined; lay public more comfortable with rodents or swine than with companion species (dogs, cats)

Why the Dog Is a Valuable Model

• Physiologic & anatomic parallels to humans

  • Cardiovascular: comparable heart size, coronary circulation, naturally occurring dilated cardiomyopathy

  • Gastrointestinal: similar mucosal architecture and stomach layering (more human-like than rodents; images contrasted dog, pig vs. ox/llama/rat)

• Practical advantages

  • Social, docile, easily trained → cooperative for procedures & behavioral conditioning

  • Body size allows human-scale surgical instruments, cardiac implants, vascular access ports, orthopedic hardware

  • Lifespan (10–15 yr) enables chronic studies & device longevity follow-up surpassing rodent life span (1–3 yr)

• Breed availability

  • Beagle: standard purpose-bred dog (few hereditary diseases, small/handy size, calm)

  • Larger hounds: orthopedic or weight-bearing models

  • Disease-specific pure breeds: Golden Retriever, Bedlington Terrier, Irish Setter, Collies, Maltese×Beagle (“Malteagle”) for spontaneous genetic diseases

Spontaneous Canine Diseases Homologous to Human Conditions

• Hemophilia A/B, von Willebrand disease

• Diabetes mellitus (esp. Type 1)

• Hip dysplasia, degenerative joint disease

• Dilated cardiomyopathy, congenital heart defects

• Lupus‐like autoimmune disease

• Vitamin deficiencies

• Infectious disorders (Helicobacter spp.)

Historic Breakthroughs Using Dogs

• 1600s—Organ function mapping & cardiovascular discovery

  • First IV drug delivery feasibility (dog)

  • First blood-transfusion experiments

  • Stephen Hales: first arterial blood-pressure measurement (horse & dog carotid cannulation)

• Ivan Pavlov (late 1800s)

  • Salivary-fistula dogs → classical conditioning paradigm (bell/food → salivation)

  • Foundation of modern behavioral psychology & physiology of digestion

• 1921—Discovery of insulin (Banting, Best, Collip, McLeod)

  • Pancreatectomized dogs developed diabetes → pancreatic extracts reversed hyperglycemia

  • Led to mass production of insulin; Nobel Prize; saved first human patient (14-y-old boy)

• 1940s—Blue-Baby cardiac surgery (Blalock–Thomas–Taussig shunt)

  • Surgical correction of Tetralogy of Fallot perfected in canine model → thousands of children saved; one patient lived into his 70s

Modern Research Domains Employing Dogs

• Toxicology

  • FDA & EPA require one rodent + one non-rodent species → dog is standard non-rodent for acute, sub-chronic, chronic tox screens

• Pharmacology / Pharmacokinetics (PK)

  • Dose proportionality, alternative drug-delivery devices, depot formulations, cardiovascular drugs

• Surgical & Interventional Device R&D

  • Heart valves, stents, angioplasty balloons

  • GI surgery (e.g.
    colostomy techniques)

  • Organ transplantation methods

  • Orthopedic implants (HIP/TPLO, prostheses)

  • Human-sized anesthesia ventilators & monitors

• Infectious-disease & Vaccine models

  • Helicobacter pylori challenge in Beagles → human gastric-ulcer prevention studies

  • Canine oral papilloma virus → paved way for human HPV vaccine (e.g.
    Duke the Beagle)

• Dentistry & Periodontal research—natural dental calculus resembles human pattern

• Vascular-Access Port validation—indwelling central & enteral lines

Genetic / Molecular Disease Models

(Genome fully sequenced 2005; outbred genetics parallel human heterogeneity)

Neurologic

• Narcolepsy

  • Breeds: Doberman, Weimaraner, Chihuahua, Labrador

  • Canine mutation alters hypocretin; human patients have low hypocretin without that mutation → therapeutic cross-talk

Hematologic & Immunologic

• Cyclic Hematopoiesis ("Gray Collie Syndrome")

  • Neutrophil oscillation every 10!\text{–}!12 days (dog) vs. \approx21 days (human)

  • Gene-therapy trials underway

• Leukocyte Adhesion Deficiency (LAD)

  • Irish/Red-&-White Setter; prevalence 1/100{,}000 humans; impaired neutrophil migration → infection risk

• Hemophilia & von Willebrand disease

  • Irish Setter (Hem A), Cairn Terrier (Hem B), Doberman, Scottie (vWD)

  • Dogs remain gold standard for evaluating gene-editing and clotting-factor replacement, esp.
    for orthopedic-surgery bleeding

Metabolic & Hepatic

• Copper Storage Disease

  • Human “Wilson’s disease” vs.
    canine Copper Toxicosis

  • 1/30{,}000 human incidence; Bedlington Terrier & Labrador models; allows serial liver biopsies not feasible in mice

• Glycogen Storage Disease 1A (GSD 1A; von Gierke)

  • Found spontaneously in Maltese → crossed with Beagle for “Malteagle” colony

  • Mouse lacks lactic acidosis component; dog replicates full human phenotype (hypoglycemia, growth failure, hepatomegaly)

Musculoskeletal

• Duchenne Muscular Dystrophy (DMD)

  • Golden Retriever, Cavalier King Charles, Corgi, etc.

  • Absence of dystrophin → progressive skeletal & cardiac muscle wasting; lifespan ≈15 yr (human) or early—dogs similar

  • Brazilian outlier dogs (Ringo & son Sulflare) had Jagged-1 up-regulation → potential therapeutic modifier gene

Reciprocal Benefits to Companion-Animal Health

• 70 million U.S.
  pet dogs benefit from research advances originally aimed at people

• Improved canine vaccines, flea/tick/heartworm preventives

• Joint-disease therapies, hip-replacement hardware

• Oncology: canine osteosarcoma protocols borrowed from human chemo/radiotherapy; comparative-oncology trials inform both fields

• 2016—FDA cleared first closed-loop artificial pancreas (Medtronic MiniMed 670G); conceptual roots in 1920s canine insulin work

Ethical Framework: When to Use Dogs

• Employ only when they provide the most scientifically accurate, interpretable, and translational data

• Continuity: sometimes selected because historical data sets are dog-based (to maintain comparability)

• Replacement, Reduction, Refinement (3Rs) philosophy still applies; dogs sit high on ethical hierarchy due to companion status

Legal & Regulatory Oversight

Animal Welfare Act (AWA)

• Enacted 1966, amended 1970, 1976, etc.

• Governs sale, transport, handling, and research use of covered species

• Definition of “animal” excludes purpose-bred rats (Rattus), mice (Mus) and birds; includes dogs, cats, primates, guinea pigs, hamsters, etc.

Enforcement & Inspection

• USDA Animal & Plant Health Inspection Service (APHIS) – Animal Care division

  • Unannounced inspections at least once/yr; extra visits for repeat issues

  • Publicly accessible inspection reports; penalties include fines, license suspension, criminal prosecution

Procurement

• Class A licensed dealers (purpose-bred on single site) are mandatory source for research dogs

• Shelter sourcing no longer permitted (historically prompted by “Pepper the Dalmatian” case, Sports Illustrated 1965)

Institutional Oversight

• Institutional Animal Care & Use Committee (IACUC)

  • Mandated by AWA & PHS Policy

  • Minimum membership: veterinarian, unaffiliated community member; PHS adds at least one scientist + one nonscientist

  • Reviews all animal protocols, inspects facilities, investigates concerns

Other Key Guidances

• Guide for the Care & Use of Laboratory Animals (National Research Council)

• PHS Policy on Humane Care & Use of Laboratory Animals (NIH-OLAW)

• Air-Transport Guidelines for Animals (domestic & international)

Housing, Space & Environmental Enrichment

• Caging must be non-injurious, sanitizable, temperature/humidity-controlled, with species-appropriate light cycles

• Group housing whenever compatible (visual/olfactory contact minimum)

• Minimum floor-space formula (AWA):
  \text{Floor area (ft}^2)=\frac{(\text{Length of dog (in) }+6)^2}{144}

• If less than double minimum space (e.g.
  metabolic cages), must provide supplementary daily exercise plan

• Enrichment modalities

  • Toys, chew items, raised resting boards/cots

  • Human interaction: play, grooming, clicker training, leash walks

• Positive-reinforcement training reduces procedure stress; facilitates voluntary blood/saliva collection

Identification

• Acceptable: collar + tag, tattoo, or subcutaneous microchip

• Institution must own a working chip reader on site (USDA citation if absent)

Veterinary Preventive & Clinical Care

• Daily health observations by trained staff (365 days/yr)

• 24/7 emergency veterinary availability

• Maintenance of comprehensive medical records

• Specific-pathogen-free (SPF) colony standards; pathogen list covers distemper, parvovirus, internal/external parasites, etc.

• Vaccination policy may be altered if it interferes with study vectors (e.g.
  adenoviral gene-therapy work)

• Routine services: annual physicals, CBC/chemistry panels, dental prophylaxis, heartworm & ectoparasite prevention, grooming

• Breeding colonies → responsibilities in reproductive & neonatal medicine; body-condition scoring; prenatal imaging; elective C-section when required

Occupational Health & Safety

• Monitor zoonotic risks (Salmonella, dermatophytosis, etc.)

• Provide personnel training, PPE, and medical surveillance

Career Pathways in Laboratory-Animal Science

• Laboratory Animal Technician (husbandry) — daily care, early health detection

• Veterinary Technician — anesthesia, dosing, sample collection, dentistry, radiology

• Facility Supervisor/Manager — operations, compliance, staff oversight

• Laboratory Animal Veterinarian (research support & clinical medicine) — protocol consultation, surgical support, colony health, regulatory compliance, training programs

Ethical Closing Statement

• Use of companion species in research is a privilege, not a right.

• Carries moral, ethical, and legal obligations to safeguard welfare and justify necessity.

• Commitment: refine procedures, reduce numbers, replace when possible, while honoring the historic and ongoing contributions of dogs to both human and canine health.

Select Resources & Further Reading (mentioned)

• Animal Welfare Act & Regulations (USDA online)

• Guide for the Care and Use of Laboratory Animals (NRC)

• Public Health Service Policy on Humane Care and Use of Laboratory Animals (NIH-OLAW)

• Online Mendelian Inheritance in Animals (OMIA) database

• Sports Illustrated (1965) “The Dog That Started It All” (Pepper case)

Why We Study Dogs

• Why dogs are used for studying diseases

• Old discoveries made with dogs

• What dogs help with now (like drug tests, surgery, gene treatments, vaccines)

• Rules and laws that keep research dogs safe

• How to care for and look after research dogs every day

• Jobs you can get working with lab animals

How Many Animals Are Used in U.S. Research

• Mice and rats are used far more: >95\% of all research animals

• Dogs and cats are used very little: <0.5\% combined

• Number of dogs used has dropped: was about 200{,}000 in 1973, now about 65{,}000

• People are less supportive of using dogs, preferring rodents or pigs.

Why Dogs Are Good for Research

• Dogs are like humans in many ways:

  • Heart: similar size, blood flow, and common heart issues

  • Stomach: similar insides, more like humans than rats

• Dogs are easy to work with:

  • Friendly, calm, and can be trained, making tests easier

  • Big enough for human-sized tools, implants, and surgery

  • Live 10–15 years, good for long studies (rodents live 1–3 years)

• Different types of dogs are available:

  • Beagles: common lab dog (healthy, small, calm)

  • Big dogs: for bone or weight studies

  • Certain breeds: for specific natural diseases (like Golden Retrievers for muscle disease)

Dog Diseases Like Human Ones

• Blood clotting problems (Hemophilia, von Willebrand disease)

• Diabetes (especially Type 1)

• Joint issues (hip dysplasia, arthritis)

• Heart defects and enlarged heart

• Autoimmune diseases (like Lupus)

• Vitamin problems

• Infections (like Helicobacter)

Big Discoveries from Dogs

• 1600s—Discoveries about body parts and blood:

  • First time drugs given into a vein

  • First blood transfusions

  • First time blood pressure was measured in arteries (by Stephen Hales)

• Ivan Pavlov (late 1800s):

  • Dogs with special tubes showed how they learned to drool at a bell (classical conditioning)

  • Started modern psychology and studies of digestion

• 1921—Insulin found (by Banting, Best, Collip, McLeod):

  • Dogs without a pancreas got diabetes; extracts from a pancreas helped them

  • Led to making insulin for people; saved the first human patient

• 1940s—Heart surgery for “Blue Babies” (Blalock–Thomas–Taussig shunt):

  • Surgery for a heart problem (Tetralogy of Fallot) was perfected in dogs

  • Saved thousands of children

What Dogs Help With in Modern Science

• Safety Testing (Toxicology): Drug tests often need one rodent and one non-rodent animal; dogs are usually the non-rodent.

• Drug Studies (Pharmacology / PK): How much drug to give, new ways to give drugs, heart medicines.

• Surgery & Device Testing: Heart valves, stents, stomach surgery, organ transplants, artificial joints, human-sized anesthesia machines.

• Infection & Vaccine Research: Studies on stomach ulcers (using Beagles with H. pylori) and HPV vaccine (using dogs with papilloma virus).

• Dental Research: Dog teeth naturally get plaque like human teeth.

• Medical Port Testing: Checking how well central lines work.

Dog Genetic Disease Models

(Dog DNA was mapped in 2005; their genes are varied like humans)

Brain Problems

• Narcolepsy:

  • Seen in Dobermans, Labradors, etc.

  • A specific gene change in dogs helps understand why humans have low hypocretin, even without that exact change.

Blood & Immune System Problems

• Cyclic Hematopoiesis ("Gray Collie Syndrome"):

  • White blood cells go up and down every 10!\text{–}!12 days in dogs (about 21 days in humans).

  • New gene treatments are being tested.

• Leukocyte Adhesion Deficiency (LAD):

  • Found in Irish Setters; makes it hard for infection-fighting cells to move, causing infection risk.

• Hemophilia & von Willebrand disease:

  • Found in Irish Setters (Hemophilia A), Cairn Terriers (Hemophilia B), Dobermans (vWD).

  • Dogs are key for testing gene editing and blood-clotting treatments, especially for surgery bleeding.

Metabolism & Liver Problems

• Copper Storage Disease:

  • Like human Wilson’s disease; found in Bedlington Terriers and Labradors.

  • Allows many liver samples to be taken, which is hard in mice.

• Glycogen Storage Disease 1A (GSD 1A; von Gierke):

  • Found in Maltese dogs, then bred with Beagles ("Malteagle" colony).

  • Unlike mice, dogs show all parts of the human disease, like low blood sugar and liver swelling.

Muscle & Bone Problems

• Duchenne Muscular Dystrophy (DMD):

  • Found in Golden Retrievers, etc.

  • Muscles waste away; dog lifespan is similar to early human disease progression.

  • Some Brazilian dogs had a gene called Jagged-1 that seemed to help; this might lead to new treatments.

How Research Helps Pet Dogs Too

• 70 million pet dogs in the U.S. benefit from research first done for people.

• Better dog vaccines, flea/tick/heartworm medicines.

• Treatments for joint disease, new hip implants.

• Cancer: Dog bone cancer treatments use ideas from human cancer therapy; studies on dogs help both human and dog cancer care.

• 2016—First artificial pancreas cleared by FDA (Medtronic MiniMed 670G); its idea came from dog insulin work in the 1920s.

When is it OK to Use Dogs for Research?

• Use dogs only when they give the best and clearest scientific information.

• Sometimes dogs are used to keep data consistent with older studies.

• We still follow the 3Rs (Replace, Reduce, Refine); dogs are given high ethical priority because they are pets.

Laws & Rules for Research Dogs

Animal Welfare Act (AWA)

• Passed in 1966, changed later.

• Sets rules for selling, moving, handling, and studying certain animals.

• Doesn't cover specially bred rats, mice, or birds; does cover dogs, cats, monkeys, guinea pigs, hamsters.

Checks & Enforcement

• USDA (Department of Agriculture) inspects labs at least once a year without warning.

• Inspection reports are public; labs can be fined, lose their license, or face criminal charges.

Getting Dogs for Research

• Labs must get research dogs from Class A licensed dealers (who breed them on one site).

• Cannot get dogs from shelters anymore (this rule came from the "Pepper the Dalmatian" case in 1965).

Lab Oversight

• Institutional Animal Care & Use Committee (IACUC):

  • Required by law.

  • Must include a vet and a community member not tied to the lab.

  • Checks all animal study plans, inspects labs, and looks into problems.

Other Important Guides

• "Guide for the Care & Use of Laboratory Animals" (from National Research Council)

• "PHS Policy on Humane Care & Use of Laboratory Animals" (from NIH)

• Rules for transporting animals by air.

Housing, Space & Fun for Dogs

• Cages must be safe, cleanable, have the right temperature/humidity, and light cycles.

• Dogs should be housed together if possible.

• Minimum floor space rule (AWA): \text{Floor area (ft}^2)=\frac{(\text{Length of dog (in) }+6)^2}{144}

• If space is less than double the minimum, dogs must get extra daily exercise.

• Ways to keep dogs happy:

  • Toys, chew items, raised beds

  • Playing with people, grooming, training, walks

• Positive training makes tests less stressful and helps with getting samples like blood.

How Dogs Are Identified

• Collar with tag, tattoo, or microchip are all OK.

• Labs must have a working microchip reader on site.

Vet Care for Lab Dogs

• Trained staff check dogs daily for health (every day of the year).

• Emergency vet care is available 24/7.

• Detailed medical records are kept.

• Labs try to keep dogs free of specific diseases.

• Vaccinations might be changed if they interfere with a study.

• Regular checks: yearly exams, blood tests, dental cleanings, heartworm and flea/tick medicine, grooming.

• For breeding dogs: special care for mothers and puppies, including checks during pregnancy and c-sections if needed.

Worker Safety & Health

• Check for diseases that can spread from animals to people (like Salmonella).

• Provide staff training, safety gear, and health check-ups.

Jobs in Lab Animal Science

• Laboratory Animal Technician: Does daily care, first to spot health issues.

• Veterinary Technician: Helps with anesthesia, giving drugs, taking samples, dental work, X-rays.

• Facility Supervisor/Manager: Runs the daily operations, makes sure rules are followed, manages staff.

• Laboratory Animal Veterinarian: Helps plan studies, assists in surgery, watches over animal health, ensures rules are followed, runs training programs.

Final Ethical Point

• Using companion animals like dogs in research is a special privilege, not a given right.

• This comes with moral, ethical, and legal duties to keep them safe and show why their use is necessary.

• We promise to make methods better, use fewer animals, and replace them if possible, while still honoring how much dogs have helped human and dog health through history.

Places to Learn More

• Animal Welfare Act & Regulations (USDA website)

• Guide for the Care and Use of Laboratory Animals (NRC)

• Public Health Service Policy (NIH-OLAW)

• Online Mendelian Inheritance in Animals (OMIA) database

• Sports Illustrated (1965) "The Dog That Started It All" (Pepper case)