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Journal of Heredity 2011:102(5):640–641
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Book Review
Thalassaemia: The Biography
David Weatherall
New York: Oxford University Press, 2010. 247 pp.
Hardback, $24.95. ISBN: 9780199565603
As book review editor for the Journal of Heredity, a number of
books cross my desk. My concern regarding any particular
book is whether our readership would find it relevant to
their interests and research programs. My first inclination on
seeing the main title of this work, Thalassaemia, was not to
review it since we publish very few articles on human
genetics. But then I saw the subtitle. What an interesting
idea—writing a biography of a disease.
Sir David Weatherall, founder of the Institute of
Molecular Medicine at Oxford, has been associated with
research on the group of genetic blood disorders labeled
thalassemia for over half a century. He begins this book
describing his own first thalassemia patient, a Nepalese girl
named Jaspir Thapa, whom he encountered when a young
doctor in Singapore in the 1950s. He follows his personal
story with a history of the discovery of the disease, first
called Cooley’s anemia, and includes a charming description
of how the disease got its name. He explains the various
mutant phenotypes associated with the disorder, which
result in symptoms ranging in severity from mild anemia to
bone deformities, enlarged spleens, and the need for lifelong
blood transfusions. Chapters 2–4 proceed through the
chronology of beginning to understand the disease’s genetic
basis, narrowing its cause to problems in hemoglobin
production, and elucidating the biochemical pathways of
defective hemoglobin synthesis.
Thalassemia was first described as common in people
from the countries surrounding the Mediterranean Sea. It
would later be recognized in sub-Saharan Africa and
Southeast Asia—Jaspir was possibly the first patient
identified from the latter region. The prevalence of
Mediterranean thalassemia patients prompted J. B. S.
Haldane in 1948 to propose that malaria was the selective
agent responsible for high frequencies of thalassemic
mutant alleles, through a heterozygote advantage in resistance to infection. A. C. Allison later showed that for the
related blood disorder, sickle cell anemia, heterozygotes
have lower levels of parasites in their blood and, when
inoculated with the parasites, are less frequently infected
than normal individuals. The malarial hypothesis became
part of the ‘‘dogma’’ of evolutionary biologists in the 1950s.
T. G. Dobzhansky’s vision of populations was that genetic
variation was extensive in natural populations and part of
‘‘coadapted gene complexes’’ maintained by balancing
selection. The overdominance associated with globin mutant
alleles, however, may be the only example in animal
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populations where heterozygotes are the fittest genotype.
More recent studies indicate that populations are highly
variable due to directional selection for the increase and
eventual fixation of advantageous alleles. In addition, neutral
alleles and variants can be fixed by genetic drift or by
hitchhiking when linked to a selectively advantageous allele.
Genetic studies of thalassemia in the 1950s–1960s, in
conjunction with the development of gel electrophoresis,
revealed that the condition is caused by defects in the
structure or production of either a- or b-globin chains. The
best-known hemoglobin disease, sickle cell anemia, is due to
an amino acid substitution in the adult b chain. Several
notable geneticists and biochemists contributed to the early
understanding of the association between thalassemia and
abnormal hemoglobins, notably Linus Pauling, Max Perutz,
and Vernon Ingram. Ingram was the first to propose the
alpha and beta classes of thalassemias.
Chapter 5, The molecular era and the birth of molecular medicine,
is to me the best part of this book. Here, Sir David
documents a lockstep between sequential advances in
molecular genetics and our understanding of the molecular
basis of the mutations causing thalassemia. For example,
incorporation of radiolabeled amino acids in reticulocytes
allowed Weatherall and his colleague, J. B. Clegg, to measure
a- and b-chain synthesis in normal and thalassemic patients.
Later, cDNAs were used to measure levels of globin
mRNAs in various patients. With the arrival of restriction
enzymes, Southern blotting, and cloning, the various a- and
b-chain genes could be mapped with increasing accuracy.
Haplotype analyses could determine the frequency of
specific mutant alleles. Finally, DNA sequencing allowed
molecular lesions to be definitively characterized.
Despite successes in defining the molecular basis for the
thalassemias, Sir David leaves us with 2 important caveats.
First, no disease, even one caused by single mutant alleles, is
simple. Pleiotropy and genetic modifiers will confuse the
situation to various extents in different pedigrees. Examples
abound in this book of these culprits causing clinical
diversity in allelically identical patients, often involving
changes in the levels of other globin chains.
The second caveat is more serious. Sir David describes
quite eloquently the evolution of therapeutic methods
concurrent with development of the molecular techniques
that led to precise identification of the mutant alleles. In
doing so, however, he finds a dichotomy between the ability
to provide precise molecular information and the provision
of truly effective methods of treatment. Blood transfusion,
for decades, was the only treatment available, followed by
the administration of iron-chelating agents and spleen
removal. Early applications of prenatal diagnostic methods
led to population-based attempts at eugenics to reduce the
frequency of thalassemia. Interestingly, one such attempt on
Book Review
Sardinia produced promising results. In recent years, less
intrusive methods of prenatal diagnosis have used more
precise DNA-based technologies. Bone marrow transplantation can be a cure but can only be considered in the most
severe cases; it requires donor cells from a perfect match
and is a risky and costly procedure. Ultimately, gene therapy
may prove the best hope for a permanent solution to the
problem of thalassemia, but vectors and effective delivery
methods have yet to be developed.
The disconnect between precise molecular characterization of cause and imprecise methods of treatment is,
according to Sir David, really due to unrealistic expectations
about the promise of molecular medicine. He asks, ‘‘has
molecular medicine improved the lot of patients?’’ With
regard to thalassemia, I think the answer is yes, certainly
with prenatal diagnosis and possibly in the future with gene
therapy. But Sir David cites other disorders, including
cystic fibrosis, heart disease, and diabetes, where knowledge
of mutations has had no effect on clinical treatment. He
concludes:
‘‘Historians of the future will also want to understand
why the time scale for the medical applications for the
human genome project was so wildly underestimated and,
incidentally, the effect that this may have had on the
direction of medical science in subsequent years. There is no
doubt that the successful completion of the human genome
project was one of the most remarkable achievements in the
biological sciences. But the degree of hyperbole about its
potential for altering the whole pattern of medical practice
was out of all proportion.’’
Given his memories of Jaspir Thapa and his obvious
concern for all patients suffering from thalassemia, one can
hardly blame Sir David for his impatience with the progress
of molecular medicine.
ROSS MACINTYRE
Molecular Ecology & Genetics,
Cornell University Ithaca, NY 14853
doi:10.1093/jhered/esr032
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