Recombinant rodents, human hemoglobin.

Recombinant rodents, human hemoglobin 

Borrowing genes from human red blood cells, researchers have created a strain of genetically altered mice whose red cells contain large amounts of functioning human hemoglobin. The work represents the first successful manipulation of an animal's genetic code to produce human hemoglobin, the crimson protein responsible for transporting oxygen throughout the body.

Scientists say the accomplishment will provide the first animal models to test experimental treatments for human hemoglobin disorders such as sickle cell anemia. It may also lead to the use of farm animals as "biofactories" capable of producing large quantities of human hemoglobin that could serve as a cell-free blood substitute compatible with recipients of any blood type. Blood types, such as A, B and O, are a characteristic of red blood cells, not of hemoglobin itself.

Mice, like humans, use hemoglobin to distribute oxygen from their lungs to body tissues. But mouse hemoglobin is very different from human hemoglobin, says Toshio Asakura of the University of Pennsylvania in Philadelphia, who helped create the transgenic rodents. In mice, where the distance from lungs to oxygen-dependent tissues is relatively small, hemoglobin releases its oxygen readily. In larger animals, hemoglobin binds oxygen more tenaciously.

Scientists remain uncertain about what differences account for these varying oxygen-binding properties in different species. Moreover, while researchers have identified several inherited, disease-causing defects in human hemoglobin chains, they remain stymied in their efforts to find laboratory animals that mimic those errors. The new mice, created under the direction of University of Pennsylvania physiologist Richard R. Behringer and described in the Sept. 1 SCIENCE, have already begun to solve these and other problems.

"This is really exciting," says Leland C. Clark Jr., a blood-substitute researcher at the University of Cincinnati. "It opens up some very interesting possibilities."

Among them, say Clark and others, is the possibility of similarly engineering horses or other large animals and periodically drawing their blood to obtain human hemoglobin. Several researchers, including Enrico Bucci of the University of Maryland School of Medicine in Baltimore, have developed ways of cross-linking human hemoglobin molecules into cell-free blood substitutes (SN: 9/26/87, p.200). But their research and its applications have been hindered by a lack of sufficient hemoglobin to work with. "If this technique breaks loose in large animals, the possibilities become really limitless," Bucci says.

More immediately, the work should prove useful to researchers studying hemoglobin-related diseases. Asakura and his colleagues have already come close to creating mice whose blood contains human "hemoglobin S" -- the defective hemoglobin that causes sickle cell anemia. At present, researchers have no animal model for testing potential therapies for the disorder or for studying the feasibility of inserting genes for normal hemoglobin production into sickle cell patients.

The gene-altered mice, which produce human hemoglobin, mouse hemoglobin and two kinds of "hybrid" hemoglobins, also offer a living laboratory for studying the basic chemistry of oxygen transport in blood -- research that scientists say could someday introduce a new age of "blood doping" that could improve the speed and endurance of racehorses and human athletes. Early findings lead Asakura to predict that researchers may create novel hemoglobins capable of super-efficient oxygen delivery. If so, he says, "we may be able to create a horse that runs 20 percent faster."