HARVARD GAZETTE ARCHIVES
A new look at anemia
A cure in fish could work in humans
By William J. Cromie
Harvard News Office
Scientists have discovered a new pathway by which animals make hemoglobin, the red molecule vital for delivery of oxygen throughout the body. That knowledge has led to curing anemia in fish. Humans could be next.
Leonard Zon and his colleagues at the Harvard Medical School were trying to find out how this amazing molecule forms by studying zebrafish, small piscians whose transparent bodies allow their inner workings to be easily seen while they are alive. The effort centered on a mutated strain of fish known as "shiraz." The researchers name their mutants after red or white wines, depending on whether red or white blood cells are involved. The shiraz fish lacks hemoglobin, the molecule that binds with oxygen in the cells of all red-blooded animals. Other mutants have names such as "Chianti" and "chardonnay."
The zebrafish is so important to researchers that its genome has been sequenced along with that of humans. Zon and his team used this information to find and clone the gene that makes shiraz so pale. The gene has a less fun name, glutaredoxin 5, or grx5 for short.
More scientific detective work revealed that yeast has its own version of the same gene. That's strange because yeast doesn't have blood, so it doesn't need hemoglobin. But yeast does need iron and its grx5 gene is involved in manipulating iron in this fungus, best known for making beer and wine.
Zon and his team then made a mutant zebrafish with a doctored rendering of the yeast gene. "That rescued the fish," Zon declares. "It could now make hemoglobin. Without hemoglobin, zerbrafish embryos lacking grx5 can absorb oxygen from water through their skin. But eventually they die, most likely from their anemia."
Yeast, fish, and us
The big discovery here is that two biological functions, once thought to be entirely separate, act together to produce hemoglobin, a substance without which creatures like humans become anemic. "It's nice to know about this pathway," Zon comments. "It raises the possibility of developing a drug that might mimic the function of the grx5 gene. In yeast, there may be other genes that suppress this defect and can be turned off. We have evidence that such suppressors exist in mice and humans. We are working on these things now."
Several different types of anemia plague humans, but the most common form stems from a reduced level of hemoglobin. This shortage, in turn, comes from a deficiency of iron, an essential ingredient of the red molecule. Similarities in the way yeast, fish, and humans handle iron tie the whole thing together.
About five years ago, Zon and some colleagues discovered a gene, called ferroportin or iron transporter, which is responsible for carrying iron from other parts of a cell to where hemoglobin is made. When you eat beef or spinach, this gene sees to it that iron is moved from your intestines to the rest of your body. It also, Zon found, moves iron through the placenta from a mother to her fetus. Zebrafish embryos get their iron in the same way. Thus, he says, "300 million years of evolution have preserved the biochemical process by which moms deliver iron to their babies."
Zon's research also revealed that humans with mutated transporters have iron metabolism problems. "This was the first time that a fish mutant was found to be associated with a human disease," he notes.
The newest discovery of how zebrafish combine iron transport with hemoglobin production is reported in the August 18 issue of Nature. Lead author of the report is Rebecca Wingert, who was a graduate student when she, Zon, and their co-workers did the research at Children's Hospital Boston and Dana-Farber Cancer Institute, teaching hospitals associated with Harvard Medical School.
"We see patients that look like zebrafish mutants in that they both have trouble making hemoglobin in the same way," Zon points out. "What we want to do next is to see if they have the mutated shiraz gene, grx5. After that, our hope is to find ways to provide the missing parts that will keep this type of anemia from happening."
His laboratory also works on other diseases that can be traced to faulty iron transport. One such problem produces iron overload rather than iron deficiency. Then there is anemia paired with ataxia, which causes certain brain cells to die, resulting in impaired balance and walking, as well as problems with limb and eye movements and with speech.
Zon will do such studies in zebrafish. then apply what he learns to humans. "This small, transparent fish," he says, "turns out to be a powerful tool for learning about many things that affect you and me."