Graduate School Life

Variety in Model Organisms Shows Range of Training in Genetics & Development

By Virginia E. Papaioannou, Ph.D., Professor of Genetics & Development

Mice and worms and flies, OH MY!
    This year marks the 40th anniversary of the founding of the Department of Human Genetics & Development at P&S and the 35th year of the NIH Predoctoral Training Grant in Genetics & Development. Human in the department name was dropped in 1985 to reflect the increased emphasis on fundamental genetics research, but the connection to human biomedical genetics and development continues to thrive.
    Many model organisms are represented in the department, and every research program has a strong component of relevance to human biomedical issues. Here is a look at a few of our graduate students and the model organisms they chose.

worm Alyssa Bost, Ripla Arora, and Sumeet Sarin
Alyssa Bost, Ripla Arora, and Sumeet Sarin, graduate students in the Genetics & Development program, with their favorite model organisms

Ripla Arora is a fourth-year student in my lab. Born in Nigeria but raised and schooled in India, Ripla has undergraduate and master’s degrees in biochemistry from the University of Delhi. For her Ph.D. she wanted less of the “chem” and more of the “bio.” With interests shaped by a desire to understand how chemical reactions make biological functions, she found what she was looking for in developmental biology. Bored with working in a test tube, Ripla chose a model organism at the opposite extreme — the mouse. With its complexity and diversity of organ systems, the mouse is the closest thing to humans but still offers scope for genetic and developmental manipulations. Ripla had never worked with the mouse, but after several years of dissecting mouse embryos of all developmental stages, she has found her intellectual interest in mammalian development matched by the excitement of watching embryonic development unfold before her eyes.
    Ripla studies the development of that most mammalian of structures, the umbilical cord. The cord, the vascular link between mother and fetus, is essential during the period of gestation. The Papaioannou lab produces targeted mutations in transcription factor genes to study the role of these genes in development. In one of the mutants, the umbilical cord does not develop and the embryos die at midgestation. In investigating this defect, Ripla is uncovering a web of downstream target genes that affect different aspects of cord development, including blood vessel formation or angiogenesis. Ripla’s project is important not only for the understanding of umbilical cord defects, which can lead to fetal abnormalities in humans, but also to the field of cancer genetics, where angiogenesis is an important topic in tumor biology.

Sumeet Sarin is nearing completion of his Ph.D. in the lab of Oliver Hobert, Ph.D., associate professor of biochemistry & molecular biophysics. He comes from Blacksburg, Va., and did his undergraduate work at Cornell. He did not foresee working on worms; his interests were in memory and cognitive function. (Besides, he had heard that people begin to resemble the organisms they work on.) However, a rotation in Dr. Hobert’s lab convinced him of the worm’s potential to address neurological issues with genetics, and he soon became enamored with C. elegans as a powerful tool for genetic screens. Sumeet’s project centers on asymmetry in the nervous system. In worms, as in humans, certain functions are localized on one side; for example, the language center in humans is localized to the left side of the brain. Although the neuronal system of the worm is complex, it is simpler than the human brain and offers a tractable system to approach the question of asymmetry.
    Sumeet concentrated on taste or gustatory neurons, which demonstrate asymmetric functions: The left is the primary sensor of sodium and potassium; the right senses chloride. By genetically marking the left neuron with green fluorescent protein (GFP), indicating its terminal differentiated cell fate, then mutagenizing the worms and using the GFP to screen for mutants that showed a disruption in left/right asymmetry, Sumeet was able to isolate genes that affect the specification of left versus right cell fate.
    Why is this important? Broadly speaking, we do not know much about the early steps that lead to laterality differences in the left and right sides of the nervous system, yet children with reading disabilities and patients with depression or schizophrenia demonstrate impaired lateralization of the brain. Sumeet’s mutant worms provide the material to investigate the early stages of laterality differences in a (relatively) simple and easily manipulated laboratory model.

Alyssa Bost recently joined the laboratory of our newest faculty member, Ben Ohlstein, M.D., Ph.D., assistant professor of genetics & development. She hails from Shavertown, Pa., and attended Cornell University and San Francisco State. Alyssa’s main interest is in stem cells and homeostasis, which gave her a broad choice of model organisms. Although the smell of fly broth almost put her off, she chose the fruit fly, Drosophila melanogaster, for its versatility and the power of fly genetics to tackle basic problems. Besides, she liked the amusing names given to genes (e.g., the grunge gene regulates the teeshirt gene). Gut stem cell research in the Ohlstein laboratory was also intriguing, as the simplicity of the fly gut, not to mention the genome — only four chromosomes and not a lot of duplication and redundancy — makes it an ideal organism to establish basic principles. Alyssa enjoys the rapid pace of research made possible by the availability of thousands of mutants; the time between thinking up an experiment and carrying it out can be a matter of only a few weeks.
    Alyssa’s project is to characterize the intestinal stem cell “niche,” the physical location in which a stem cell resides to remain a stem cell. Presumably factors promote “stem-ness” within the niche and Alyssa is using a candidate gene approach to identify these factors in the gut. Alyssa has developed a method of live imaging of the entire gut in culture that will allow her to follow fluorescently marked cell clones in real time in the living organ. This combined with mutagenesis of specific candidate genes will aid in analyzing the effect of specific factors on stem cell behavior. Her work will eventually impact the basic machinery of stem cell systems and could have broad applicability in stem cell biology.

Three students, three organisms, but only a sample of the range in the graduate program in Genetics & Development.