The Zebrafish as a Mainstream Laboratory Animal

1
The Zebrafish as a Mainstream Laboratory Animal

• Christian Lawrence
• Aquatic Resources Program

2
The Rise of Zebrafish

• Zebrafish have exploded in popularity as an
  experimental model over the past fifteen years
• This growth is expected to continue completion
  of genome sequence, amenability to genetic drug
  screening, in-vivo analysis, etc.
• Viable complement and alternative to rodents

ZEBRAFISH INTEGRATON
3
Annual Number of Publications (Zebrafish)
ZEBRAFISH INTEGRATON
4
Annual Number of Publications (Mouse)
ZEBRAFISH INTEGRATON
5
Percent Change in Number of Publications
(Selected Major Model Organisms)
ZEBRAFISH INTEGRATON
6
Zebrafish Here to Stay

• Zebrafish are now a part of the animal program at
  most research institutions.
• Large core facilities are increasingly common in
  expansion plans.
• Zebrafish can be considered a mainstream
  laboratory animal.

www.zebrafishmed.utah.edu
ZEBRAFISH INTEGRATON
7
Mainstream in Use Only

• The rigorous standards in place in the U.S. to
  regulate the care and use of mainstream
  laboratory animals do not adequately address the
  use of zebrafish.
• The result?
• Zebrafish are not being maintained at the same
  level and to the same standard as their mammalian
  counterparts.

ZEBRAFISH INTEGRATON
8
Why are Zebrafish On the Outside Looking In?

• Four primary factors underlying the current
  situation of zebrafish care and use in the U.S.
• History (with respect to who developed field)
• Focus of laboratory animal science on mammalian
  species
• Regulations and the Guide dont adequately
  address fish
• Innate qualities of zebrafish themselves

ZEBRAFISH INTEGRATON
9
Historical Aspects

• Mainstream use of zebrafish as an experimental
  model was pioneered by developmental
  neurobiologists at the University of Oregon in
  the 1980s.
• Genetic Screens
• Brilliant scientists? Unequivocally, yes. But
  fish biologists? No.
• Past, present, and future users of zebrafish are
  not necessarily
• (and in most cases are not) experts in their
  biology and care.

ZEBRAFISH INTEGRATON
10
Historical Aspects

• Science of zebrafish husbandry very poorly
  developed
• Voodoo instead of biologically based protocols

ZEBRAFISH INTEGRATON
11
Laboratory Animal Science Mammalian-Centric

• Expertise of lab animal professionals is
  primarily in mammalian biology, medicine, and
  husbandry
• Responsible for administering animal resource
  programs
• Orchestrating, overseeing, and participating in
  regulatory functions (animal use guidelines,
  facility inspections, animal use protocol review,
  etc.)
• Training laboratory animal care and research
  personnel
• Caring for animals

ZEBRAFISH INTEGRATON
12
Laboratory Animal Science Mammalian-centric
AALAS National Meeting Platform Sessions and
Posters
ZEBRAFISH INTEGRATON
13
Existing Regulatory Guidelines

• Two primary regulations governing use of
  laboratory animals
• Animal Welfare Act (AWA) Fishes are not covered
• U.S. Public Health Service (PHS) Policy on Humane
  Care and Use of Laboratory Animals Fishes are
  covered
• the PHS Policy is intentionally broad in scope
  and does not prescribe specifics about the care
  and use of any species, assigning the task to
  IACUCs and allowing for professional judgment"
  (Potkay et al. 1997)

ZEBRAFISH INTEGRATON
14
Existing Regulatory Guidelines

• The Guide to the Care and Use of Laboratory
  Animals is the primary reference for animal
  research adopted by PHS policy
• Contains minimal information relative to fishes

ZEBRAFISH INTEGRATON
15
Zebrafish are Tough

• Zebrafish are easy to culture
• Situation capitalized on by fish hobbyists and
  scientists
• Makes it difficult to identify problems

Photo courtesy of R. Spence
ZEBRAFISH INTEGRATON
16
Where is the Oversight?

• The four aforementioned factors tend to promote
  substandard care and management.
• Various levels of control and oversight built
  into the system should prevent this from
  happening.
• Soif there are problems in a zebrafish program,
  who detects - and corrects - them?

ZEBRAFISH INTEGRATON
17
IACUCs?

• In many cases (especially biomedical research
  institutions), IACUC committees do not have
  requisite expertise in fishes.
• Must rely on regulatory guidelines to inform
  decisions
• Ad-hoc consultants can be utilized
• The ability of IACUC to positively influence a
  zebrafish program may be limited

ZEBRAFISH INTEGRATON
18
Animal Resources Departments?

• Institutional animal resources departments are
  formally responsible for management and care of
  zebrafish.
• Typical situation in such departments is that
  no one has necessary expertise (via formal
  training and/or hands on experience).
• Animal resources departments include zebrafish,
  but often do not directly manage them as they do
  other lab animal species.
• In such situations, operational responsibility
  for zebrafish management is shunted to
  investigators.
• Technically responsible party is disconnected
  from management of the animals

ZEBRAFISH INTEGRATON
19
Accrediting Bodies?

• AAALAC International
• Do council members and ad-hoc consultants really
  know fish?
• Some do, some dont.
• When then answer is no, utility of such
  oversight for zebrafish programs is limited
• Focus on non-relevant issues, opportunities to
  correct real problems missed

ZEBRAFISH INTEGRATON
20
Investigators Using Zebrafish?

• In most cases, investigators do not possess
  adequate formal training in disciplines of fish
  biology/husbandry.
• Experts in using fish to study particular system,
  but not in zebrafish themselves
• Keeping zebrafish alive (or breeding) is not
  necessarily indicative of expertise
• Intrinsic conflict of interest can be problematic
• Complete reliance on investigators to run
  zebrafish facilities is a flawed strategy

ZEBRAFISH INTEGRATON
21
The Reality Oversight is Typically Inadequate

• In many cases, investigators using zebrafish are
  the primary arbiters of care and use of the fish.
  
• Who oversees investigators?
• IACUC?
• Animal Resources?
• AAALAC?

ZEBRAFISH INTEGRATON
22
The Way Forward

• How can this problem be solved?
• The following presentations will illustrate how 5
  different institutions are meeting these
  challenges

ZEBRAFISH INTEGRATON