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Learning from a Fish Out of Water (and Air)
Learning from a Fish Out of Water (and Air)

 

Few animals have a lifecycle as unique as the annual killifish (Austrofundulus limnaeus). They live their entire lives in temporary bodies of water, ponds that form in the South American rainy season and then become completely desiccated in the warm, dry months, and at times remain so for much of the year. Despite the long terms of inhospitable conditions for an aquatic animal, this species not only survives, but thrives regardless the stresses from their habitat thanks to some curious adaptions.

So how do the annual killifish survive in the parched ghosts of seasonal ponds? They rely on some very uncommon traits they’ve evolved and pass along to the next generation. When the fish spawn, their eggs settle into the substrate. Under the tropical sun, the water evaporates. The earth dries, and the developing embryos become encased in mudcrack, robbed of nutrients and oxygen. Then they do something most would find strange and unexpected, something few organisms do. They enter a state of diapause—suspended development, meaning no metabolic or cellular activity, as if they’ve become frozen in time. Later, when the environment is right and water returns to the pond, the embryos reanimate and continue on with life.

According to Dr. Jason Podrabsky, this is what initially interested him about the annual killifish. This species can shut off their metabolism, stop their cells from dividing, stop growing, and survive without oxygen for a very long time—things that are really difficult to do, biologically speaking. If we could discover the processes that allow the embryos of the annual killifish to perform these astonishing tasks, we might be able to extrapolate testable theories about our own cellular mechanics, and knowledge like that could be put to use in the medical sciences where there might be applications in the treatment of cancer, stroke, heart attack, and other diseases. Dr. Podrabsky, Professor, Dept. of Biology, and researcher in the Center for Life in Extreme Environments, arrived at PSU after a post doc at Stanford University where he conducted research at the Hopkins Marine Station. This past fall, he was awarded a grant of $810,000 from the National Science Foundation for his proposal “Regulation of Extreme Anoxia Tolerance via MicroRNAs in the Embryos of the Annual Killifish (Austrofundulus limnaeus).” Podrabsky’s study will lay the groundwork for future studies of the species by sequencing a reference genome of the fish for scientists to work from, and will explore the possibility that the annual killifish’s extraordinary ability to survive without oxygen is the result of some biologically counter-intuitive activity involving microRNAs (miRNAs) at the molecular level.

“The embryos of these animals are fascinating,” said Dr. Podrabsky. “We struggle with managing the growth of cancer cells, and yet, here’s a species that can stop their cells from growing entirely. They’re tolerant of a really wide range of what we consider extreme environments. You can take all the oxygen out of their environment and their embryonic brains and hearts can survive hundreds of days. When you think about a heart attack or stroke, you’ve got about three minutes until your brain is irreparably damaged and five until your heart is beyond repair. These creatures sit dormant without oxygen for months. We give them oxygen and their hearts start right back up and they take off from where they left off.”

In the lab, Dr. Podrabsky and his team of graduate students apply genomic-scale approaches to the questions they’re investigating. They examine the ways the genes of the annual killifish are expressed and how that expression may or may not support the metabolic dormancy and massive tolerance to environmental stress the species possesses with the hope of uncovering data that may inform similar processes in human cellular biology. At the center of Dr. Podrabsky’s most recently funded project is the supposition that some anoxia exposed miRNAs are causing the expression of genes inside the nuclear genome, which leads to mutations in the genetic makeup of the fish. According to Dr. Podrabsky, if this is so, and molecules coded for the mitochondrial genome are causing the expression of genes in the nuclear genome, then it would stand against the “central dogma” of molecular biology that posits genetic information does not flow from RNA molecules to DNA molecules.

“We’ve found miRNAs in these anoxia exposed embryos are coded for the mitochondrial genome, but they look like they have targets encoded in the nuclear genome. In this instance the mitochondrion might be able to control nuclear gene expressions, which nobody has ever found before,” said Podrabsky.

In order to test his hypothesis, Dr. Podrabsky and two of his graduate students will spend the next several years using state of the art technology and deep sequencing techniques to develop a functional reference genome that he and future researchers will be able to use when studying changes in the species’ genome that may be associated with miRNA expressed nuclear genes. 

 

“This study will establish a model for future biomedical research around the annual killifish,” Podrabsky said. “And if we’re right about our hypothesis and the mitochondrial genome is controlling the nuclear genome in this circumstance, this could fundamentally change the way we look at how cells operate. If there’s a return feedback loop where the mitochondria can alter the nuclear genome and its expression, that’s something people haven’t explored yet.”

While the prospect of discoveries in cellular mechanics is exciting and possibly paradigm shifting, just adding a model genome of a species where one has not previously existed will be a major research accomplishment with lasting effects. With a precise picture of the genetic makeup of the annual killifish, scientists like Dr. Podrabsky will have a new tool to help them better examine the possible answers to other important questions concerning this species’ unique biology that may then be applied to other questions, such as what role does epigenetics play the development of an organism?

“Epigenetics is the focus of a related project we’re currently working on in the lab. “We’ve been looking at the role the maternal genome plays in determining the outcomes of development for an embryo,” said Podrabsky. “The basic question is, what is the interaction between the genome and the developmental environment and how does that contribute to the diversity of phenotypes we see around us—the outcomes in development?”

Gaining an understanding of the complex processes involved in the expression of genes and the ways history and the environment can effect development as Dr. Podrabsky and his graduate students are endeavoring to do in the lab with the annual killifish as a model will provide insights not only into the lifecycle of this strange animal, but will also help scientists better understand the lifecycles of other organisms, including ourselves. Such knowledge may one day lead to treatments for a variety of ailments such as heart disease, stroke, cancer, and diseases that are the results of mutations in our DNA.