For millions of people who live along its shores, theMediterranean Sea is literally "a sea of blood." That'swhat the word "thalassemia" means in Greek, and Greeceis one of the earliest areas known to have a highpopulation of thalassemia sufferers.
Actually, this hereditary disorder of red blood cellsaffects two levels of sufferers: Those who have inheriteda faulty hemoglobin gene from only one parent areheterozygotic carriers, afflicted with almost symptom-freethalassemia minor.
When two such carriers marry, one in four of theiroffspring stands a genetic chance of acquiring bothmutant genes. Such luckless homozygotes have the severeform of the disease, thalassemia major, a.k.a. Cooley'sanemia.
Besides ravaged blood cells, they go through life withenlarged spleens and dysfunctional heart, livers andkidneys, as well as gross bone deformities. Only frequentblood transfusions, typically every other month, keepthem alive, and even that therapy exacts its own price.
"The red cells they receive," said molecular biologistBaoli Yang, of the University of North Carolina inChapel Hill, "contain globin and heme, which deliveroxygen to tissues and organs. But they also deliver iron,the element that carries the oxygen."
Yang explained that "because the body does not have amechanism for excreting iron, the metal gets deposited inother organs, the heart, kidneys, liver and spleen, where itis toxic to cells." So in the long run, he told BioWorldToday, "it leads to organ failure, most dominant amonghuman patients being heart failure."
Like so many serious diseases currently under intensestudy, thalassemia major lacks a faithful animal model.Yang is first author of a paper in the latest Proceedings ofthe National Academy of Sciences, (PNAS) dated Dec. 5,1995, titled: "A mouse model for b0 thalassemia."
Despite being heterozygotes, these mutant mice mimicthe human disease by actually contracting the symptomsof thalassemia major in their own murine chromosomesand cells. "Even though our mouse models haven't hadany blood transfusions" Yang observed, "they do get ironoverload.
"Because they are so anemic," he explained, "they givetheir cells a signal to absorb all the iron available in thediet. So they take in more iron than normal, whichdeposits in spleen, kidney and liver, and I think willeventually lead to organ failure in those mice too."
Yang, a post-doc in the laboratory of the paper's principalauthor, molecular geneticist Oliver Smithies, engineeredhis model mice by deleting both their beta genes, whichencode the adult form of globin, the hemoglobin protein.This left intact only the two alpha genes, responsibleprenatally for making the embryonic stages of the protein.He and his co-authors carried out this knockout blow by ahigh-tech variant of gene targeting they call "plug-and-socket."
Soon, Yang said, the Smithies lab intends to deposit acolony of its b0 thalassemic mice with the JacksonLaboratory in Bar Harbor, Maine, one of the world'sleading suppliers of research animals. Meanwhile, italready has sent breeding stocks of the model toinvestigators at Columbia University, the University ofCalifornia, San Francisco, and the University ofRotterdam, the Netherlands.
"Those three groups," Yang explained, "have sickle-cellanemia transgenic mouse models, containing the humansickle globin gene. They will breed our mice to theirs toreduce the endogenous murine beta-globin in their mice,which inhibits sickle formation."
The North Carolina researchers also plan their ownsickle-cell model mouse, but by a different route, whichthey consider more precise
"What we'll do," Yang said, "is replace the mouse'salpha or beta globin genes with the human forms of both,at the original endogenous chromosomal loci. Then if webreed those mice with human sickle beta and alphatogether, their offspring will have only the humanhemoglobin, not the murine."
Human neonates continue using their fetal globin for adiminishing proportion of oxygen delivery all throughlife. This margin sustains patients with sickle cell anemia,whose own adult globin fails them. Homozygous mouseembryos, which receive a double dose of mutantthalassemia genes, die in utero, or during the first hoursafter birth. Their embryonic hemoglobin switches to theadult form before gestation ends.
Besides modeling sickle cell anemia, Smithies pointedout in the PNAS paper, "The mice homozygous for the b1and b2 deletions should be of great value in developingtherapies for the treatment of thalassemia in utero."
To which Yang added: "If we can deliver functional adultgenes before the switch, after birth they should be able tolive a normal life." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.