Chicken embryos and zebrafish help biologists understand oxygen deprivation, blood clotting
University-based biologists can be hard pressed to describe their basic research to nonscientists. They might find it difficult, for instance, to drum up excitement for zebrafish genetics or avian respiratory system development for people interested in how science can help humans today.
Two researchers with the University of North Texas Developmental Physiology and Genetics Research Group, based in the Department of Biological Sciences, have the answer. Their work involves basic study of species chosen specifically for their ability to model human development at the embryonic and genetic stages.
Through their work, Edward Dzialowksi and Pudur Jagadeeswaran can already explain worlds more than scientists knew even a few years ago about how humans develop and about diseases and conditions that humans might avoid developing in the future.
Even in this age of big science, superconductors and high-tech research labs, some of the most exciting work is being done small. Very small - like in a refrigerator, in the egg carton and inside the eggs.
Dzialowski, UNT assistant professor of biological sciences, is interested in what goes on inside that chicken embryo because it yields big clues about the development of human respiratory and cardiovascular systems. Dzialowski's lab is halfway through a National Science Foundation grant to research the ductus arteriosus - two blood vessels that allow blood returning to the heart to bypass the developing chick's not-yet-functioning lungs.
You might have noticed the air cell that develops in eggs that have been left in the fridge a little past their prime. That cell is filled with a hypoxic gas used by the developing embryo until it breaks forth from its shell. The developing respiratory and cardiovascular systems of certain avian species in the embryonic stage - such as chickens - are roughly comparable to those of humans; both have ductus arteriosi.
But the human process of taking that first breath comes pretty much all at once. A baby is born and instinctively fills its lungs with that first gasp of air; its blood-oxygen levels rise. Developing chickens give scientists a nicer window of time in which to study the process
"In mammals, the ductus closes over the first few hours after birth because the neonate no longer has access to the fetal gas exchanger but receives all of its necessary oxygen via the lungs," Dzialowski explains. "Hatching in the chicken is a much slower process. The embryo goes through a stage known as internal pipping when it gets oxygen from both the embryonic gas exchanger and the lungs. This period can last from 8 to 24 hours, depending on the species. Over this period, the ductus closes much more slowly in the bird than the mammal, allowing us to tease apart the physiological, cellular and genetic processes governing closure."
What does all the opening and closing say about developing human organisms? Dzialowski says he hopes the work will allow his lab team to piece together the effect of any number of environmental factors surrounding hypoxia, which is characterized by a lack of oxygen on the developing human fetus.
Smoking and indomethacin use are two examples. Smoking is thought to cause congenital heart defects in infants by interfering with the development of the ductus. Indomethacin, sometimes prescribed to pregnant mothers prone to pre-term labor, has been shown to affect closure of the ductus in the developing infant.
"I am interested in how environmental factors influence an animal during development and how its physiology and morphology might change to allow it to deal with these challenges," Dzialowski says. "At the end of this three-year study, I hope to be able to fully describe the ductus and make some prediction of how it will respond to certain environmental factors."
When humans cut themselves, they count on hemostasis - successful blood clotting - to stop the bleeding. Unfortunately, the same process inside a vessel is not so positive.
"We call that thrombosis, and of course it can be devastating," says Jagadeeswaran, UNT professor of biological sciences. "If the clot occurs in the blood vessels leading to the heart, we call it a myocardial infarction. If it occurs near the brain, we call it a stroke."
Jagadeeswaran has conducted a longtime study of hemostasis and thrombosis at several posts, including the University of Texas Health Science Center in San Antonio and the University of Illinois College of Medicine in Chicago, since his first research appointment at Yale in 1979.
Along the way, Jagadeeswaran - students call him Dr. Jag - has become a renowned expert in the use of the zebrafish. The clear, inch-long, striped fish, which originated in the River Ganges in India, has become a model for study of human disease and is now used in labs worldwide.
With Jagadeeswaran's recent appointment at UNT comes a new, state-of-the-art zebrafish facility, an upgrade from a few aquariums to upwards of 50,000 fish in specialized breeding tanks.
Jagadeeswaran's team was the first to use aspirin with zebrafish to model human blood thinning. But what interests him most about the fish today is how they can be used to model human genetics and then to predict how best to counteract thrombosis in humans by refining the blood thinning process.
Male zebrafish can be mutated by being soaked in water containing a chemical called a mutagen before breeding. The resulting offspring carry mutated genes. Those fish are bred to produce homozygous random mutations. The end result is a library of gene mutations in something like 30 to 40 zebrafish, which provides plenty of subjects on which to test how random genetic mutations might affect the hemostatic system in zebrafish and gives researchers a tool to identify human genes by using fish mutations as bait.
For the past seven years, Jagadeeswaran's team has worked on a genetic test for use on his inch-long subjects that allows the researchers to detect developing hemostatic and thrombotic problems.
Before coming to UNT, he identified several major genetic mutations in hemophilia patients, as well as the problems in platelet thinning that lead to hemophiliac conditions. Jagadeeswaran's latest big question surrounds the unusual development in hemophiliac patients who make it to adulthood - they're usually not hemophiliac anymore.
"Something is broken that corrects as they age. We have to identify that part in order to solve the puzzle," Jagadeeswaran says.
UNT's new zebrafish facility offers the Jag team's best shot yet, and he's hopeful they can get their questions answered.