Some of us use Windex to give our windows that streak-free shine that lets us look out at a pristine world. What if we could use that clarity to see how our organs develop? Steven Farber of the Department of Embryology at the Carnegie Institution for Science has discovered just that clarity in a very specific animal model, the zebrafish. Its advantage: it is clear during its development, so one can see precisely how its organs form. Using fluorescently-tagged lipids, Farber and his lab explored the organization of the digestive system in six-day-old transparent zebrafish larvae.
"One of the great things about zebrafish is that the larvae are optically clear and they have basically all the same genes as mammals have," Farber said. "This is one of the great discoveries we have in the era of modern genomics — sequencing all of these critters."
It has long been known that vertebrates, which include a tiny creature like the zebrafish and an intellectual human being like us, share an essentially similar genetic code. It is because of this similarity that Farber and his lab have decided to watch the glow-in-the-dark lipids go through the zebrafish during its development under a confocal microscope.
"We have seen things that no one has ever seen before in a mammal," Farber said. "Historically, if you had a mammal, you'd have to fix the sample, put it on a slide, stain it and then visualize it. This is our claim to fame. We see beautiful live animal pictures."
The pictures have allowed Farber to explore not only the structural development of digestive organs, but also the biochemical processes that underlie this development. This study centered on fatty acid metabolism, so Farber's lab observed the outcomes of using fatty acids of various lengths. The longer the carbon chain becomes, the more hydrophobic (water-resistant) it is. While a carbon chain of only two carbon molecules essentially disappeared in water, longer fatty acids were found to metabolize into different cellular structures of the developing zebrafish. The team examined a fluorescently-tagged five-carbon fatty acid incorporated into the phospholipid bilayer of cell membranes.
"What was interesting was that we were relating what we saw in the animal's organ to what we were seeing biochemically," Farber said. "We aren't just looking at the structure of the organ, but the fluorescent metabolism."
Farber and his lab have worked with fatty acids as well as cholesterol, and in an upcoming paper Farber will discuss how cholesterol is taken up in the gut and what factors influence that process.
Lipid metabolism is a process that extends far beyond the digestive system of larval zebrafish. In fact, disorders in lipid metabolism are often one of many causes of human diseases that Farber had in mind when he began his research.
"If you think of obesity and cardiovascular disease, they are all under the realm of how lipids in the body are perturbed," Farber said. "It is these diseases that are primarily responsible for the decrease in life span in this generation — there are kids who will not live as long as their parents because of obesity and lipid-related disorders."
However, Farber recognizes that such cardiovascular and metabolic diseases stem from a variety of causes, one of them being socioeconomic status and the marketing of food products. Still, he is hopeful that understanding the science of these disorders in zebrafish models will aid in controlling the obesity epidemic in humans.
It may seem unlikely that a tiny fish could provide a solution to gigantic problems such as cardiovascular disease and obesity, but Farber stressed the genetic similarities between humans and zebrafish.
"It's like the periodic table of elements," explained Farber. "Just imagine this table of genes that makes the vertebrates. It changes subtly in how much we use, and since we know it's about the same set of genes, we can work with fish in ways we can't with mice or humans."
Farber and his lab are continuing to explore mysteries of organ development, on both a structural and biochemical level, which may help us better understand the science underlying some of the most widespread human diseases.
