Fish Tools for the Future of Comparative Medicine
Dr. Postlethwait and many other investigators subsequently turn to zebrafish as an in-lab model for examining the functions of potential disease-related genes.
One burgeoning domain for this popular aquarium fish is as an in vivo model for aneuploidy in cancer. Aneuploidy—or an abnormal number of chromosomes—is universally observed in all types of human cancer, yet genetic mouse models of these diseases rarely feature aneuploidy.
This chromosomal phenomenon is relatively easy to replicate in zebrafish, according to Guang Jun Zhang, Ph.D., assistant professor of genetic epidemiology and comparative medicine at Purdue University, whose lab mutates either ribosomal proteins or p53 to develop tumors in zebrafish.
Dr. Zhang has pioneered zebrafish-human oncogenomics, a comparative approach that can reveal novel cancer driver genes. The zebrafish genome shares about 70% identity with the human genome, but through evolutionary synteny, many of the genetic loci have moved to different chromosomal locations.
Oncogenomics allows Dr. Zhang to illuminate patterns in the aneuploidy of human cancers and contrast those with genetic arrangements in zebrafish tumors. Cancer is an automatic evolution process, so the technique reflexively selects for chromosome-related growth advantages.
This investigation has yielded a plethora of gene candidates that may function as oncogenes or tumor suppressors, which Dr. Zhang’s team is now using to build new zebrafish lines that model cancer.
“You cannot explore 100 new genes in mice; it would cost a fortune. But in zebrafish, it is very possible,” said Dr. Zhang, who cites their rapid breeding, cost effectiveness, and broad availability as benefits of the model.
He added that the Sanger Institute’s comprehensive Zebrafish Mutation Project, which aims to create a knockout allele in every protein-coding gene in the animal’s genome, should be completed in the next two years, providing an exceptional resource for comparative medicine studies within the model.
Moreover, recently developed technologies for gene editing—zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), CRISP/CAS-9—are rapidly moving into fish models.
“These innovative tools are opening two types of doors,” said molecular physiologist Aron Geurts, Ph.D., of the Medical College of Wisconsin, who specializes in gene targeting with rat models of cardiovascular disease but was invited to attend the conference as a guest lecturer.
“First, gene-editing technology is enabling very elegant experiments that were previously restricted only to the mouse,” remarked Dr. Geurts. “In addition, these tools are empowering precision editing of genomes for the assessment of specific disease-linked alleles.”
This will move animal models away from the realm of simple knockouts and knock-in breeding and will allow future investigators to ask very specific questions about the role of particular single-nucleotide polymorphisms (SNPs) in pathogenic phenotypes.
GWAS and large-scale genetic investigations, like the Encyclopedia of DNA Elements (ENCODE) Consortium and the 1000 Genomes Project, are really driving this research, according to Dr. Geurts, who is a big proponent of using aquatic models in scenarios where biological questions are not easily answered by mammalian systems.
“We’re going to see more people working with genetic engineering in these models, which may be better than mice in some areas of translational medicine,” concluded Dr. Geurts. “That’s where the field is going.”