New hope for malaria drugs as sickle cell protection unravelled
03 May 2011
Sickle cell anaemia, the first disease to be characterised in complete molecular detail, has been in the biochemistry textbooks
for decades. Epidemiologists have linked its astonishing spread across Africa to the fact that carriers of the mutant gene, who
don't get sickle cell anaemia, seem to be protected from malaria. But now researchers have come up with a molecular
mechanism that explains how it protects people from this deadly disease. This discovery could, in the near future, give doctors
a range of new drugs that could save many lives.
Circumstantial evidence, dating back to the 1950s, suggests that the presence of low levels of sickle cell haemoglobin reduces
the number of malaria parasites in the blood, while also making red blood cells less vulnerable to them and speeding up the
clean-up of infected cells. However, evidence as clear-cut as that linking sickle cell anaemia to the mutant gene remained
elusive.
Now, Miguel Soares from the Gulbenkian Institute in Oeiras, Portugal, together with colleagues in France and Germany, have
discovered how the human sickle cell gene protects against malaria. Using a mouse model of cerebral malaria, the most lethal
form of the disease, they uncovered a detailed protective mechanism. In contrast to the current paradigm, the protection is
independent of the number of parasites in the blood. The presence of human sickle cell haemoglobin appears to enable the
mice to tolerate much higher levels of the parasite.
In an earlier study, published in 2007, the researchers observed that mice with cerebral malaria accumulate the haemoglobin
cofactor, haem, in its unbound form, in the blood. This appears to contribute to the pathology of cerebral malaria. The
presence of sickle cell haemoglobin, however, increases production of the enzyme haem oxygenase-1 (HO-1), which was
already known to combat malaria. This enzyme is known to produce carbon monoxide (CO) and Soares and colleagues have
shown that CO is crucial when it comes to protecting the mice against cerebral malaria.
The researchers hope that this insight will lead to new treatment options. 'Having established that the salutary effect of the
sickle cell trait, which confers natural protection against malaria in millions of individuals, acts by avoiding the toxic effect of
free haem, the next step becomes to understand how best to target free haem for therapeutic purposes,' Soares told Chemistry
World. 'While there are probably many ways to do so, we favour the use of a natural haem chelator/scavenger called
haemopexin and are conducting studies to assess whether administration of haemopexin can achieve this goal.'
Nuno Arantes-Oliveira, chief executive of the company Alfama, which develops carbon monoxide therapeutics, praised the
work: 'The results are very exciting and consistent with what others had shown before. They confirm the broad therapeutic
potential of carbon monoxide, and further support the relevance and need for drugs that use this gaseous mediator as their
active principle.'
Rui Wang from Lakehead University, Canada, also welcomed the results as a game-changing achievement. Looking forward, he
speculated that 'other gasotransmitters, NO and H2S, may have the same or even better therapeutical value in this regard. NO
can form nitroxyhaemoglobin and H2S can form sulfhaemoglobin. Both of them would limit the release of free haem. I would
not be surprised to see the NO- or H2S-based intervention with malaria soon.'
Haem's secret life as a hormone exposed
07 December 2007
Researchers in the US have found that haem, the iron-containing molecule best known for its role as the oxygencarrier in haemoglobin, may act as a hormone.1
The groups of Fraydoon Rastinejad at the University of Virginia at Charlottesville and Thomas Burris at the
Pennington Biomedical Research Center at Baton Rouge, Louisiana, have found that haem 'switches on' two proteins
that are part of a family of receptors normally activated by hormones.
REV-ERBalpha and REV-ERBbeta are known to regulate the body's circadian clock 2 but before the discovery no-one
had pinned down a chemical trigger for either receptor. According to the researchers, the two proteins are purely
sensing haem - and not oxygen or other gases bound to its iron atom.
The work also links the biological clock to metabolism, as more haem is produced when the body burns fat.
The authors are optimistic that their discovery will help pave the way to new drugs. '[This finding] allows us to
envision a tremendous range of potential medical applications,' Burris said. Modified versions of haem, he suggests,
could one day be used to treat sleep problems or metabolic disorders.
Ueli Schibler of the University of Geneva, who first linked the REV-ERB receptors to the circadian clock, welcomed
the findings. 'The binding of haem to REV-ERBs is very interesting, but not completely unexpected,' he added. 'The
Drosophila homolog E75 has been shown to bind haem two years ago.3Nevertheless, there is definitely some
romance in this discovery, as it will incite many researchers to uncover the function of haem binding.'
However, scientists contacted by Chemistry World dispute the idea that haem is acting as a hormone. 'In this context
I would regard haem an intracellular ligand, rather than a hormone,' Schibler said.
Burris admits that there is no evidence so far that haem conveys information from one type of cells to another, as
most hormones do. 'Although the classical definition of being secreted by one cell type, travelling to another cell type
by blood is the most common definition... hormones have also been described where the hormone is produced within
the same cell it acts,' he told Chemistry World.