Genetically engineered test mice provide the ray of light in thalassaemia research
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.
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