Background on Malaria Malaria is a life-threatening parasitic disease transmitted by the female Anopheles mosquito, which requires blood to nurture her eggs. Malaria causes or contributes to 3 million deaths and up to 500 million acute clinical cases each year. At least 40% of the world population, or an estimated 2.5 billion people in over 90 countries are at risk of becoming infected each year. The main risk areas are Africa, South East Asia, India and South America. Risk groups include pregnant women, refugees, migrant workers, travelers to high risk areas and children. The majority of deaths are in children with a mortality rate of 4 children a minute or 35,000 children a week. Malaria was once widespread, but it was successfully eliminated or drastically reduced in 37 countries with temperate climates in the 1950's (in large part due to the WHO insecticide spraying program 1956-69). This situation has been rapidly reversing, especially over the last decade. This reversing trend can be attributed to the cost of sustaining programs, loss of motivation in the face of a seemingly declining threat, the development of insecticide resistance and resistance against existing treatments. Malaria parasites are developing unacceptable levels of resistance to one therapeutic after another and many insecticides are no longer useful against mosquitoes transmitting the disease. Years of vaccine research have produced few hopeful candidates and although scientists are redoubling the search, an effective vaccine may be years away.

Background on TSC Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the presence of benign tumors, known as hamartomas, which occur in many tissues and organs including the brain, eyes, kidney, heart, lungs and skin. Hamartomas are lumps of disorganized, but differentiated, cells, which in the case of TSC rarely progress to malignancy. During the first few years, the severity of TSC can range from mild skin abnormalities to severe epilepsy, mental retardation, autism, or attention deficit-hyperactivity disorder. Three common and life threatening manifestations of the disease are renal Angiomyolypomas (AMLs), Lymphangioleiomyomatosis (LAM), and Subependymal Giant Cell Astrocytomas (SEGAs). We are therefore focusing our drug discovery efforts towards identifying compounds to treat these specific lesions. In recent years significant advances in the understanding of the underlying cause of TSC has been made. In particular the mutable genes (TSC1 and TSC2) responsible for the condition were identified and the role of their respective gene products (harmatin and tuberin) explored. The CommunityTSC (also utilizing the D2OL Software) project uses TSC-relevant proteins identified by sponsored collaborators at Harvard, Yale, and Fox Chase Cancer Center as therapeutic targets for computational screening. The targets are screened against all commercially available drug-like chemical entities (an estimated 2.5 million potential therapeutics) to prioritize the compounds to be tested in the laboratory both at TRI and collaborating academic institutions worldwide. To date, five targets have been identified and are currently screened by a user-community in excess of 18,000 members.

About D2OL D2OL is based on Sengent's CommunityOS(TM), a grid computing program that harnesses idle time on volunteer computers from the online community to create a "supercomputer." This system is capable of using chemical docking algorithms and statistical models to rapidly test potential medicines against any potential target with a known crystal structure. The Drug Design and Optimization Laboratory was established in November of 2001 to expedite and lower the cost of identifying therapeutics capable of addressing general health issues. The software was first applied to targets of potential bio-warfare/terrorism agents such as Anthrax and Smallpox. With the potential threat posed by emerging Pathogens such as SARS, the use of D2OL was expanded specifically to protein targets of the SARS Virus in May of 2003. TRI first applied D2OL to find a cure for TSC in April of 2002.

About the Rothberg Institute for Childhood Diseases The Rothberg Institute for Childhood Diseases is a private, non-profit research institution dedicated to discovering and developing therapeutics capable of treating the clinical manifestations of Tuberous Sclerosis complex (TSC) and other orphan childhood diseases. TSC is a genetic disorder that causes benign tumors to form in many different organs, primarily in the brain, eyes, heart, kidney, skin and lungs. The Rothberg Institute operates at the intersection of modern biology, chemistry and computer science by leveraging technologies including chemical genomics and grid computing to accelerate its medicine discovery efforts. Furthermore, the Rothberg Institute collaborates with academic laboratories at Yale, Harvard and the Fox Chase Cancer Institute through the Rothberg Award for Courage in Research administered by the TS-Alliance. The Rothberg Institute is located in Guilford; CT. Additional information is available at http://www.childhooddiseases.org. The latest Version of D2OL used in the fight against TSC is available at: http://www.childhooddiseases.org The latest Version of D2OL used in the fight against emerging pathogens such as Malaria and SARS and potential bio-weapons such as anthrax and smallpox is available at: http://www.d2ol.com .