By Payal Ray, PhD
Biomedical research has come a long way in the last 50 years, and we owe much of this advancement to the use of animal models. The recent NICHD Exchange meeting highlighted several NICHD laboratories, including those using fruit flies, zebrafish, and non-human primates, and facilitated a discussion on the use and benefits of animal models.
Dr. Lorette Javois, co-chair of the Trans-NIH Zebrafish Coordinating Committee, began the event with an introduction to the main benefits of animal models. First, evolutionary processes have led to similarities within genomes of various animals. Humans show 90 percent sequence conservation with mice, 60 percent with fruit flies, 70 percent with zebrafish and 96 to 98 percent with non-human primates. Therefore, it is reasonable to extend the knowledge gained from animal studies to humans. Second, even the most sophisticated in-vitro system cannot replicate the interactions within a biological system. Third, model systems like fruit flies, worms, and zebrafish can be grown in the lab with relatively low cost of maintenance. These organisms have short generation time, a large progeny size, simple chromosomal structure, and researchers can use them to generate inbred strains.
The bulk of the meeting included several talks about animal model use at the NICHD. Dr. Stuart Moss, program director of Male Reproductive Health in the Fertility and Infertility Branch, reported on the latest studies on human fertility and contraception using the fruit fly as a model system. In the United States population, about 10 to15 percent of couples are infertile, and about one-third of the cases are due to problems arising in males. A detailed understanding of the mechanisms of spermatogenesis will accelerate the development of therapeutics needed to address infertility. Much of the current understanding of spermatogenesis comes from studies using Drosophila gonads, given their conservation of developmental and metabolic pathways with mammals.
A lot of the research on spermatogenesis focuses on spermatogenic stem cells (SSCs), the progenitor cells that differentiate and mature into functional sperm. SSCs maintain fertility by critically balancing self-renewal and differentiation. A wide range of intrinsic and extrinsic factors tightly regulate this program. Dr. Moss reported that non-primate stem cells can be transplanted into mice to study the early development of sperm. An extension of this technique could potentially be used for preservation of fertility in infertile patients (e.g., pediatric patients undergoing chemotherapy).
Animal studies on spermatogenesis have also uncovered transgenerational epigenetic effects—changes that are passed on from a parent to child without any physical modification to the DNA (epi=outside, genetic = DNA). Research has shown that offspring of male mice fed a high fat diet had an adverse health outcome later in life. There are several conditions that have been ascribed to transgenerational epigenetic inheritance, such as obesity, diabetes, stress, and fertility; however, the exact mechanisms are unknown. According to Dr. Moss, future studies on spermatogenesis using animal models are critical to uncovering these mechanisms.
The next speaker was Branch Chief Dr. Brant Weinstein from the Program in Genomics of Differentiation. His group uses zebrafish to study blood vessel development, with clinical implications such as:
- Therapy for Ischemia (to grow blood vessels)
- Anti-angiogenic therapy (for targeting vascularization of tumor)
- Treatment for vascular malformations, which can be debilitating or life threatening
Unlike humans, the zebrafish embryo develops outside the body and is optically clear. Researchers can follow developmental processes and examine mutant phenotypes using a standard light microscope. Most importantly for Dr. Weinstein’s work, zebrafish embryos can survive without any circulation for three to four days. During that time, they can live without a heart or blood vessels—a great asset for identifying and studying mutant animals.
Dr. Weinstein described the results from a study in which they coupled genetic screens with next generation sequencing techniques to identify genes important for vessel development, heart development, and anatomical patterning of vessels. Using such screening methods, researchers have identified a key player in the pathogenesis of hereditary hemorrhagic telangiectasia (a multi-systemic vascular disorder).
Studies from zebrafish have also helped to uncover mechanisms that lead to hemorrhagic stroke (or intercerebellar hemorrhage, ICH). This condition, which accounts for 13 percent of stroke cases, occurs when a weakened vessel ruptures and bleeds into the surrounding brain. The resulting blood accumulation compresses brain tissue and can be life threatening. Zebrafish carrying genetic mutations in the vessel development pathway can be easily screened for due to embryo transparency. Analyses of such mutants are yielding new insights into the etiology of ICH and vascular function and maintenance.
The final speaker of the event, Dr. Stephen Suomi, presented a talk titled “Modeling Human Developmental Processes in Monkeys.” His group uses the Rhesus monkey to correlate behavioral outcomes with underlying genetic differences within a species. He took the audience on an interesting journey, starting with the discovery of a single nucleotide polymorphism (SNP) in the serotonin transporter (a target of anti-depressants). A SNP is a single nucleotide variation in DNA that is common in a population and does not necessarily cause an overt change or problem. The discovery of a serotonin transporter SNP led to a culmination of studies that eventually proved that behavioral issues in humans can have a genetic cause.
During one such study in the early 1990’s, researchers observed that peer-reared monkeys (i.e., those that were not reared by their moms as infants) were not able to adjust to stress as well as the mother-reared controls. Amongst the peer-reared group, individuals who expressed a particular isoform (called the short isoform) of the serotonin receptor showed higher levels of aggression when stressed. The monkeys carrying this short isoform of the serotonin receptor also ingested more alcohol as compared to the control group. Parallel studies in human subjects showed that mothers who came from an underprivileged background and had low levels of education were at a higher risk of post-partum depression if they carried the short allele.
Ongoing animal studies are examining how an individual’s genetic architecture can influence behavior and sensitivity to social environment. Dr. Soumi’s presentation was a great example of how animal and human studies can go hand-in-hand to propel the field of behavioral genetics forward.
More and more similarities between model systems are coming to the forefront due to genomic sequencing efforts. As a result, model organisms are being characterized at increasing resolution, giving researchers the opportunity to harness the full potential of these systems to make inroads into complex biological problems.