June 17, 1999 For the first time, scientists have disrupted a gene crucial to the sexual development of Plasmodium falciparum, the parasite that causes malaria in humans. It was only the second time a gene from P. falciparum had been successfully disrupted, and the first time a sex-specific gene had ever been disrupted. By altering the gene, the researchers stopped the parasite from producing a protein crucial to its development, a discovery that may lead to the development of drugs that can block the organism's ability to reproduce and transmit malaria. The study appeared in the June 1999 issue of Molecular Cell. Senior author Nirbhay Kumar, PhD, associate professor, Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, said, "Understanding the sexual differentiation and development of Plasmodium falciparum will give us insights into the malaria parasite's life cycle. If we can understand the molecular mechanisms regulating sexual development of the parasite, we may then be able to fashion drugs that will disrupt the life cycle of P. falciparum." Despite intensive mosquito-control campaigns and a range of drug treatments, malaria continues to devastate the health of 300 to 500 million people each year. Before it can become a functional agent of malaria transmission via the mosquito, P. falciparum must first undergo a multi-step development inside its human host, evolving from an asexual into a sexual form. To investigate the molecular mechanisms behind P. falciparum's sexual development, the researchers focused on one specific protein, Pfg27, which accounts for five to ten percent of a normal parasite's cellular protein and is thought to be crucial in moving the parasite from its immature form to its infectious form. The researchers used a recently developed genetic approach to selectively disrupt or "knock out" the expression of the gene responsible for triggering production of Pfg27. First, the scientists combined bits and pieces of the Pfg27 gene--not the complete gene--with pieces of nonessential DNA to form a small segment of DNA that resembled the normal gene but was, in fact, incomplete. When this faulty version of the targeted gene was then introduced into the parasite, its similar (or homologous) appearance enticed the normal gene to pair up with it, so that an incomplete sequence was introduced into the parasite's DNA, a process called homologous recombination. The scientists discovered that the disrupted Pfg27 gene was unable to trigger production of Pfg27 protein, leaving P. falciparum unable to move on to its infectious sexual stage. Dr. Kumar, who also recently led a team in developing a vaccine that may block P. falciparum's development inside the mosquito, said, "Given the complexity and cleverness of this parasite, we may have to rely upon a multi-pronged approach -- that is, drugs and vaccines -- to stop the transmission of this disease that kills millions of innocent victims annually, worldwide." Support for this study was provided by grants from the National Institutes of Health. Public Affairs Media Contacts for the Johns Hopkins Bloomberg School of Public Health: Tim Parsons or Kenna Brigham @ 410-955-6878 or paffairs@jhsph.edu. |
