BERKELEY, CA -- Genetically engineered mice that fully mimic all thesymptoms of human sickle cell disease have been developed by scientists at theLawrence Berkeley National Laboratory. With this new mouse model, medicalresearchers finally have a means of effectively testing experimental treatmentsfor the disease.
A team led by Dr.Chris Paszty of Berkeley Lab's Life Sciences Division hasreported the creation of a new strain of mice that carries human hemoglobingenes with no counteracting mouse genes. This enables the mice to develop allclinical manifestations of the sickle cell disease.
The research has been reported in this week's issue (October 31) of themagazine Science. In addition to, P‡szty, other members of the team includedCatherine Brion, Mary Stevens, Mohandas Narla, and Edward Rubin of Berkeley Lab,plus Ewa Witkowska of the Children's Hospital Oakland Research Institute andElizabeth Manci of the University of South Alabama Doctors Hospital.
Each year approximately 100,000 babies in the world, mostly of Africandescent, are born with sickle cell disease, a painful and debilitating conditioncaused by a mutant hemoglobin gene. Although sickle cell disease has beenextensively studied, there is still no effective treatment -- a failureattributed in part to the lack of an animal model that accurately reproduces thedisease's symptoms.
"This work marks the end of an almost decade long effort to create mice thatfaithfully model human sickle cell disease." says Paszty.
Transgenic mice containing the human sickle genes have been engineeredbefore, but these mice developed only mild symptoms of the disease. The problemwas that in addition to carrying the mutant human genes responsible for sicklecell disease, these strains also carried normal mouse genes which counteractedthe defective human genes.
"Through a series of complex transgenic and gene knock-out manipulations wewere able to add the appropriate human genes as well as delete the(corresponding) mouse genes," says Paszty. "The end products are mice withirreversibly sickled red blood cells, anemia, and multi-organ pathology. Incontrast to the limited studies that can be performed in humans, these animalsprovide an opportunity for rapidly performing a wide range of experiments. Theyshould play an important role in furthering our understanding of sickle celldisease and in developing improved therapies for treating sickle cell patients."
Sickle cell disease was once referred to as sickle cell anemia but the term"anemia" was dropped because it emphasized only one manifestation of thecondition. Victims inherit from both their parents a gene that makes a mutantform of hemoglobin, the iron-containing protein in red blood cells which carriesoxygen from the lungs to the rest of the body.
This mutant form of hemoglobin is called "hemoglobin S." Under certain physiological stresses, such as a decrease in oxygen, thehemoglobin S protein will polymerize, forming a rigid chain that may distort ablood cell into the shape of a "sickle." Lacking the flexibility of normaldisc-shaped cells, these sickled cells are unable to squeeze throughcapillaries. This impairs the flow of blood, reducing the body's supply ofoxygen. Damage from the reduction in oxygen accumulates, causing cell death invarious tissues, most notably in the kidneys, liver, lungs, and spleen. Thisultimately results in organ dysfunction and death of the individual.
All hemoglobin is made up of two polypeptide chains -- an alpha globin and abeta globin chain. Sickling occurs when a hemoglobin protein with a normalalpha globin chain and a mutant beta S globin chain precipitates out of solutionduring a state of deoxygenation.
Creation of the new sickle cell mouse model began about five years ago whenBerkeley Lab researchers set out to engineer two new strains of knock-out mice,one which would no longer produce mouse alpha globin and one which would nolonger produce mouse beta globin. At about the same time they succeeded increating knock-out mice which did not produce any mouse alpha globin chains, aresearch group led by Dr.Tim Townes of the University of Alabama at Birminghamsuceeded in creating knock-out mice which did not produce any mouse beta globinchains.
"Rather than duplicating each others' work we exchanged knock-out mice andthen went our seperate ways in terms of creating the human sickle hemoglobintransgenics," says Paszty. "It worked out well for both of our groups becauseafter the long process of breeding these three strains of mice together we bothmanaged to create mice with sickle cell disease."
Townes and his collaborators also have a paper describing their sickle celldisease mice in the October 31 issue of Science magazine.
With experts predicting a worldwide surge in the incidents of sickle celldisease, the perfection of this mouse model is extremely timely. Mice are highlyvalued for medical research because their physiology is quite similar to that ofhumans, they are fast-breeding, and their small size makes them easy to maintainand handle in large numbers.
Development of the sickle cell mouse was funded by grants from the NationalHeart, Lung, and Blood Institute, and the National Institute for Diabetes,Digestive, and Kidney Diseases.
The Berkeley Lab is a U.S. Department of Energy national laboratory locatedin Berkeley, California. It conducts unclassified scientific research and ismanaged by the University of California.
The above story is based on materials provided by Lawrence Berkeley National Laboratory. Note: Materials may be edited for content and length.
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