Exploiting the parasites to our advantage

In a recent paper (Oct 20, 2006) in the journal Science, scientists have reported the use of a parasite-specific machinery in to correct certain deficiencies in human cells, which can be then used to tackle critical genetic disorders in humans.

This is cool for several reasons: taking lessons from a one-celled parasite to apply and solve complex genetic disorders in humans is cool by itself. What made me more happy is that the paper is from a group of scientists at the Indian Institute of Chemical Biology, Calcutta, India. One of the few (AFAIK, one of the first this year) all-indian authored papers from an Indian lab in the very prestigious journal Science. (Atleast in the field of molecular biology/diseases).

Eukaryotic cells are divided into compartments: the nucleus of the cell contains the genetic blueprint of the organism (instructions coded in DNA) and is responsible for it's maintenance, expression and regulation amongst other functions. The mitochondrion, known as the "power-house" of the cell, is where energy is produced from macromolecules through a series of biochemical reactions. The mitochondria possess their own set of genetic instructions (mtDNA) which store some mitochondria-specific instructions. Mutations in the mtDNA lead to some serious disorders given that the mitochondria are the energy-centres of the cell. One such syndrome is the Kearns-Sayre syndrome (KSS) : a nervous system disorder characterized in humans by hearing loss, difficulty in swallowing, loss of muscle co-ordination and cardiac function. KSS is caused by a large deletion in the mitochondrial DNA which disrupts mitochondrial function due to loss of the information encoded in that portion.

Fixing defects in mtDNA is challenging. The mitochondria are a double-membrane enclosed compartment; delivery of material to reach the mitochondrion and get incorporated is not trivial.

This is where scientists decided to take a leaf out of the book of the protist parasite Leishmania. Leishmania is a Trypanosomatid protist parasite that is transmitted by some species of the sandfly and causes leishmaniasis ( kala azar) that is endemic to several tropical and sub-tropical countries. This group of critters are characterized by some very divergent pathways in terms of their genetic organisation. One of these includes the fact that their mitochondrial genomes do not encode any tRNA genes. (tRNA refers to a set of genes involved in the making of proteins). As a result, the entire set of tRNA genes needs to be imported from the cytosol, for which these parasites have evolved a highly specialized machinery. The transport of tRNAs from the nucleus to the mitochondria is brought about by the RIC complex (RNA Import Complex) : a mulit-subunit complex found in the inner membrane of the leishmania mitochondria. The first significant accomplishment by Adhya and colleagues was to isolate this complex and purify it. Next. they show that Leishmania RIC is capable of transporting human tRNA molecules. Then, in a series of elegant experiments described in the science paper, they went on to test if human cells are capable of taking up leishmania RIC and using it to transport tRNA molecules to the mitochondria. They incubated a variety of human cell-cultures (including cells from patients of mitochondrial disorders) with Leishmania RIC and showed that RIC was successfully localized to the mitochondria of humans. Furthermore, they showed that the defective human cells were capable of transporting a specific tRNA molecule after incorporating the RIC, which they were unable to do earlier. Thus, RIC was capable of restoring defective human cells with the required mitochondrial function, showing great promise to reverse the effects of the inherited disorder. This has great therapeutic value in correcting several defects caused by various mitochondrial mutations which are hard to reach and correct otherwise.

Think about the myriad of distances travelled here: they have crossed millions of years on an evolutionary time scale to bring a mechanism from a one-celled critter to a multicellular human system. Then, at the cellular level, crossing multiple membranes and barriers to transport molecules to the right destination. Simply fascinating!

Ref: Mahata et al, Science 20 Oct 2006 vol. 314, pp 471-474.