Why the tiny zebrafish can teach us a lot about the human immune system

A 2011 report from the European Union showed that 80 percent of animals used for experimental or other scientific purposes were rodents such as mice and rats. There are obvious reasons why: mice and rats are cheap, well-studied mammal systems that reproduce quickly and are relatively easy to manipulate. But does all the focus on a few model organisms come at the expense of missing the lessons to be learned from other, more diverse species?

One such example is the zebrafish. The tiny, striped fish, each just a few centimeters long, has been gaining in popularity for research. They reproduce and grow quickly-a female lays hundreds of eggs at a time-and it's easy for scientists to keep huge numbers of them in simple aquariums in the lab. But most importantly for research, the zebrafish shares about 70 percent of its genome with humans , meaning that the more we study these silvery little guys, the more we can discover about ourselves.

The zebrafish is already a well-studied organism, but research by scientists from the University of Chicago shows that we still have a lot to learn about them. Sean McConnell, PhD, a postdoctoral scholar in the lab of Jill de Jong, MD, PhD, in the Department of Pediatrics, Hematology/Oncology, led a recent study analyzing immune system genes of the zebrafish.

Their findings, published this month in the Proceeding of the National Academy of Sciences, identified several new genes in the major histocompatibility complex (MHC), which help the immune system identify foreign antigens. Surprisingly, these genes are not in the existing zebrafish reference genome. McConnell and his colleagues believe the newly discovered genes could be evidence of ancient immune system functionality preserved through evolution. Some of these sequences resembled those of other, distantly-related species more closely than fellow zebrafish, showing the wide range of diversity still present in vertebrate immune systems.

"Many of the sequences we found are not present in the reference genome but they're instead found in some very different form," McConnell said. "It's as if instead of looking at a zebrafish MHC gene, we're looking at something from sharks. So from fish to fish, from individual to individual, the sequences were that different. We're talking about sequences being separated by 500 million years of evolution, and so it wasn't clear why that kind of diversity existed between essentially siblings in our zebrafish facility."

All vertebrates evolved from common ancestors, and as species diverged, their immune system functionality diverged too. Fish got bits and pieces of these genes, sharks got bits and pieces, and mammals got their own portion too. As these pieces get pruned away, each species loses a bit of its genetic diversity, while immune system functions become more specialized to their specific needs.But enough of these similarities are preserved in the zebrafish, ancient, long-lost siblings that they are, that they can still be a useful tool for understanding human genetics.

"I think it's surprising how much ancestral diversity is still found throughout the tree of life," McConnell said. "If we're looking at vertebrates going back hundreds of millions of years, we've actually shared bits of our immune system through such a long span of time with sharks, with frogs, with all the different vertebrate classes. Yet we find that we as mammals may be unique now, in that we've only shared a much narrower subset of that diversity. How does that change our understanding of human immune function?"

For example, McConnell studies hematopoietic stem cells, which develop into different types of blood cells. These cells can be transplanted to treat certain cancers of the blood like multiple myeloma or leukemia, so understanding immune system compatibility determined by the MHC of the donor and recipient is crucial. The entire genetic hierarchy of hematopoietic stem cell function is the same between zebrafish and humans, meaning they have essentially the same T cells, red blood cells and macrophages we do. The idea, said McConnell, is that the immune system of the zebrafish can provide a useful comparison to humans.

"We can start to get some leverage there and understand, say, if the immune response to a tumor or an infection is different or the same, and in what ways we can compare the response between species," he said.

A recent report from the National Institutes of Health shows that research on zebrafish has been gaining steam. From 2008 to 2015, even as the number of overall grants declined, the number of R01 grants for zebrafish studies increased by almost 60 percent. For researchers like McConnell with a vested interested in model organisms beyond the common lab rat, this can only be a good sign.

"It's hard for people to understand that the zebrafish would be a good model for studying something like the immune system, in part because fish look so different from humans or mice," he said. "But zebrafish have already been used to study the regulation of hematopoietic stem cell numbers, and some of those discoveries are now being used in clinical trials for cord blood transplants. Fortunately, we can use models like zebrafish to learn the lessons of how things work, and then we can work on new ways of applying them."