Genomics in Action: Shelley Hoogstraten-Miller, D.V.M.

The Three R's of Laboratory Animal Care

Posters in the halls of the National Institutes of Health (NIH) depict laboratory rats with this simple statement, "They save more lives than 911." It is the unofficial motto of laboratory animal research at NIH, and Shelley Hoogstraten-Miller, D.V.M., the Director of the National Human Genome Research Institute (NHGRI) Office of Laboratory Animal Medicine believes it completely.

"As a veterinarian, people wonder how I can do this job, but there is no way to bring research from the laboratory to a patient's bedside unless you study animals," Dr. Hoogstraten-Miller said. "After a new treatment is tried on cells in a culture dish, it has to be tested in a living organism to see how it fares when many different biochemical events are taking place at once. You need an animal to accomplish that. My job is to see that studies involving animals are carried out as humanely and responsibly as possible."

Research in the NHGRI intramural program requires about 50,000 mice and 5,000 zebrafish per year. For all such research, Dr. Hoogstraten-Miller says NHGRI practices "the three R's" of laboratory animal care: Reduce the numbers of animals. Refine the research so it is conducted as humanely as possible. Replace higher animals with lower animals.

"We replace mice with fish, fruit flies or cultured cells whenever possible," she said. "We care about all life and want to do as little harm as possible."

The NHGRI animal program has been under Dr. Hoogstraten-Miller's stewardship since 1997, and is now considered one of the best in the world. Rooms that house animals use filtered air and are kept spotlessly clean, and staff members wear protective gear at all times, mostly for the animals' safety. Since Dr. Hoogstraten-Miller thinks that working with animals is a privilege, not a right, she makes sure that all NHGRI researchers meet very high standards before they are allowed to work on their own with animals.

"You cannot spontaneously decide you want to try something on an animal and pick up some mice," she said. "Your research protocol must show us that there is no other way to obtain the desired information, and you have to successfully complete our animal training program, no matter how much experience you have had in the past."

"A mouse is a sentient creature that deserves our compassion and respect," Dr. Hoogstraten-Miller continued. "We do not just toss them in a cage. The number of animals allowed in one space is strictly limited. We give them shelters they can hide in and nesting material they can shred, and we try to make their environment as much like the wild as we can. They may get food treats as well, so their diet is not boring. We make sure they get what they need, but we also make sure that the enrichment plan does not interfere with the research."

When an NHGRI scientist wants to conduct research that involves animals, the first step is to meet with Dr. Hoogstraten-Miller, who offers guidance on what kind of animals to use and what procedures to perform to best answer the questions posed by the research project. Dr. Hoogstraten-Miller and her staff then work with the investigator to develop a written animal care protocol, which is reviewed by the NHGRI Animal Care and Use Committee (ACUC). The ACUC consists of Dr. Hoogstraten-Miller; several NIH scientists; a non-scientist, who makes sure that research plans are written in plain language; and a member of the lay public, who is not affiliated with NIH and whom Dr. Hoogstraten-Miller describes as "the conscience of the community."

After researchers meet with Dr. Hoogstraten-Miller, their protocols are usually so clear and well-documented that the ACUC rapidly approves them. "The hard work that Shelley puts into these protocols really makes the ACUC's job and the researcher's work much easier," said David Bodine, Ph.D., Chairman of the NHGRI ACUC and Chief of NHGRI Genetics and Molecular Biology Branch. "After scientists work with Shelley, their protocols describe the way they will use the animals and their provisions for animal safety so well that we don't need to ask many questions during the review. It makes the whole process go better for everyone."

Animal research protocols are approved for three years, but are reviewed annually. If the reviews uncover a way to make an experiment easier on an animal, the researcher and Dr. Hoogstraten-Miller write an amendment to the protocol describing the needed changes and submit it to the ACUC for approval.

Once the protocol or amendment is approved, Dr. Hoogstraten-Miller's real work begins. All the investigators listed on an approved protocol must complete a rigorous training program in animal research. First, they watch an award-winning video called Training in Basic Biomethodology for Laboratory Mice. Distributed on CD, this video was developed by Dr. Hoogstraten-Miller and her staff for NHGRI scientists, but has been so well-received that thousands of CDs have been distributed in all 50 states and 52 foreign countries. The mouse biomethodology video is the second instructional CD produced by Dr. Hoogstraten-Miller and her staff, with the first focusing on rodent surgery. The success of the NHGRI-produced training series prompted officials from the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC) to ask Dr. Hoogstraten-Miller to produce a third video on the biomethodology of laboratory rats, which is one of her current projects. It is also noteworthy that under Dr. Hoogstraten-Miller's leadership, the NHGRI animal program has consistently received the AAALC's highest possible rating of "outstanding."

After viewing the instructional video, researchers suit up in protective booties, coveralls, caps, and masks, and are then taken into the animal facility to practice the techniques they will use in their studies. They work side-by-side with Dr. Hoogstraten-Miller until she and her staff feel they have mastered what they need to know.

"Some people are naturals and some are afraid of the mice," said Dr. Hoogstraten-Miller. "Some need me to hold their hand for many months, and there's no shame in that. After a couple of lessons, we can usually tell if they will be okay, and if we feel they will not, we do the animal work for them. We turn no one loose unless we are confident they can perform their tasks humanely and without causing an injury to themselves or to an animal. If problems arise, we stop the work and re-train the scientist until our standards are met."

Dr. Hoogstraten-Miller thinks the success of any animal program depends on the alliance the veterinarian builds with the researchers. "You have to get to know each other and work together as friends," she said. "The animals deserve that partnership."

At NHGRI, the Embryonic Stem Cell and Transgenic Mouse Core often produces genetically altered, or transgenic, mice to serve as models of human disease. Dr. Hoogstraten-Miller and her staff must give these transgenic animals special care to make sure they survive, but even caring for normal lab mice is a major undertaking given the complexities of the mouse life cycle. Young mice are weaned at three weeks. Males can mate at around seven weeks, but females are ready at six weeks and can produce litters every 21 days if they are housed with a male. If the staff fails to wean young animals on time, they soon have older mice trampling newborns.

Normal mice can breed for about eight months, but transgenic mice may have shorter fertility spans or have trouble reproducing at all. Since they are often a researcher's most valuable animals, the Core trains technicians in assisted fertility techniques to ensure that transgenic mouse lines stay alive.

In addition to her degree in veterinary medicine, Dr. Hoogstraten-Miller is a Captain in the Public Health Service (PHS). Over the years, she has earned a PHS Unit Commendation, a PHS Citation Medal, a PHS Achievement Medal, and a PHS Commendation Medal, as well as Plain Language Awards from the NIH for her two instructional videos.

Recently, the PHS awarded Dr. Hoogstraten-Miller one of its highest honors, the Outstanding Service Medal for Sustained Excellence. She received the medal for orchestrating the instructional videos, improving animal health and welfare, upgrading the animal program's internal administration and management, working on numerous NIH committees, and speaking at international meetings.

"The development of animal models for human diseases is one of the critical missions of the NHGRI Division of Intramural Research," the award citation reads. "In the past few years, NHGRI investigators have published high profile papers describing the use of animal models to develop treatments for inherited immune disorders, deafness, Parkinson's disease, leukemia, breast cancer, and myocardial infarctions. The enormous impact of Dr. Hoogstraten-Miller on the NHGRI animal research program is demonstrated by the fact that she has been a co-author on six of these important papers in the peer-reviewed literature."

NHGRI Scientific Director Eric Green, M.D., Ph.D., agrees that Dr. Hoogstraten-Miller and her animal care team have played a vital role in helping genomic researchers in their quest to expand understanding of biology and improve human health. "NHGRI is incredibly proud that one of our senior staff members received such a prestigious award," Dr. Green said. "It is gratifying to see the PHS recognize the talent and dedication of Dr. Hoogstraten-Miller - something that NHGRI has known about for years."

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Last Reviewed: March 13, 2012