Modelled on mice

THALASSAEMIA patients have reason to rejoice. Dominic Ciavatta and his colleagues at the University of Alabama, us, have managed to generate thalassaernic mice which can help in finding genetic methods for treatment of the disease in humans (Proceedings of the us National Academy ofSciences, Vol 92, 1995).

Haemoglobin, responsible for transporting oxygen from the lungs to tissues, is a protein made up of two pairs of sub-units, referred to as alpha and beta. Each is encoded by a gene, and because every gene exists in two copies (one inherited from each parent), we have two copies of alpha and beta genes. A defect in any one of the haernoglobin genes can lead to poor oxygen delivery and an anaernic condition; beta thalassaemia results when the beta globin gene malfunctions.

Thalassaernics suffer from excessive cellularisation of the bone marrow, enlargement of the spleen and aberrantly shaped red blood cells. India alone is home to an estimated 20 million carriers of the trait. There is a one-in-four chance that a thalassaernic child may be born from a marraige between two carriers. Yet, treatments for the genetic disorder, such as bone marrow transplants, remain inordinately expensive and risk- prone.

Ciavatta's achievement bears particular significance for this reason. The research team created the test mice first using standard methods of genetic engineering to delete parts of both the beta globin genes in a special kind of embryonic cell (mice have two pairs of beta globin genes as opposed to the single pair in humans). Following this, engineered cells lacking beta globin genes were injected into very early mouse embryos that had been removed from the uterus, after which the embryos were re-implanted.

There were 12 cases in which the operation was followed by birth and the development of an adult animal carrying the mutated beta globin genes. From these adults, the researchers managed to breed five mice in which the mutation was passed on to the offspring. These offspring, with one defective beta globin gene each, suffered from fairly severe anaernia and were similar to humans lacking both the beta globin genes. This is in contrast to the human situation: in our case, carriers of the thalassaemia trait are only poorly affected; on the other hand, mice lacking both sets of their beta globin genes die during early gestation.

Even though they are severely anaernic, these carrier mice can mate and reproduce and thus transmit the mutant beta globin gene. When mated to other mice that have been engineered to overproduce human haemoglobin, the resulting progeny, which have a mutant native beta globin and an excess of human haemaglobin, appear normal. More interestingly, by using this form of mating, Ciavatta and his colleagues have also succeeded in 'rescuing' mice with no beta globin genes of their own. This work opens up the possibility of systematic therapeutic investigations that might one day lead to a cure for thalassaernia.