Malaria, which has been observed and recorded in some form for no less than 4,000 years all over the world, is a disease caused by the parasite, Plasmodium. It is transmitted in the bites of Anopheles mosquitoes that harbor the parasite from other recently infected animals they have fed on. Once introduced in the human body, the parasites multiply in the liver and then disperse to infect red blood cells. The symptoms of malaria, therefore, usually emerge within 10 to 15 days of after the mosquito bite and include periodic fever (either every other day or every third day depending on the form), headache, shaking-chills, and vomiting. When left untreated, the symptoms of malaria can turn fatal, disrupting proper blood flow which in turn impedes the functions of vital organs in the body.
Several governmental and international non-profit organizations such as the Centers for Disease Control and Prevention (CDC); World Health Organization (WHO); U.S. Agency for International Development (USAID); Bill & Melinda Gates Foundation; The Global Health Fund to Fight AIDS, Tuberculosis, and Malaria; PATH; and many more have been devoted to take heed and control the disease. With the implementation of certain environmental control methods such as eliminating standing water near homes, DDT and other insecticide use, drug treatment, insecticide-treated bed net installation and indoor residual spraying, malaria has been effectively eradicated or depleted almost entirely in some areas of the world. Despite these control methods, however, malaria persists and continues to threaten and define the lives of millions on a global scale.
According to the World Health Organization, an estimated 300-500 million cases of malaria occur each year, and more than 1 million people die of malaria annually—most of whom are young children and other residents in developing countries in regions like Sub-Saharan Africa.
a brief history of malaria drug development
As early as the 17th century, Cincona bark, now commonly known as Quinine, was used by Peruvian Indians to treat fever and continued to be used through the 19th century as the primary treatment for malaria-like symptoms. During the early 1900s, various synthetic drugs were developed and used to combat malaria such as plasmoquine and mepacrine until 1946 when the drug chloroquine became the standard malaria treatment around the world. Due to the adaptive nature of the malaria parasite, chloroquine resistance was seen in the early 1960s. Following chloroquine, a series of drugs were developed and used including primaquine (for vivax malaria), tafenoquine, proguanil, pyrimethamine, Fansidar, mefloquine (or Lariam), and finally atavaquone combined with proguanil sold as Malarone. Unfortunately, most of these drugs have all faced growing resistance and decreased efficacy as well.
The most recent major breakthrough for malaria drug development was the discovery of the strong anti-malarial qualities of a Chinese herbal medicine derived from the Chinese Sweet Wormwood plant called Artemisia annua. Used in China as a traditional herbal medicine for at least 2000 years, artemisinin was discovered by the Chinese government during a national program to uncover new potential drugs around 1967. It took several years until the World Health Organization recognized artemisinin as a first-line malaria treatment. In 2001, the WHO officially recommended the use of artemisinin-based combination therapies (ACTs) as the first line drug choice against malaria. In order to prevent further development of drug resistance, artemisinin is combined with other anti-malarial drugs. The WHO has repeatedly urged countries to rid their pharmaceutical markets of artemisinin monotherapies, which have the potential to encourage artemisinin resistance and threaten the effectiveness of ACTs. Below is a list of the current WHO recommended ACTs for the treatment of uncomplicated falciparum malaria (via Roll Back Malaria):
- Artesunate + amaodiaquine,
- Artesunate + mefloquine,
- Artesunate + sulfadoxine-pyrimethamine,
- Dihydroartemisinin + piperaquine,
- Artesunate + pyronaridine tetraphosphate.
Despite these warning and efforts, artemisinin resistance has been found in South East Asia and is suspected in some parts of South America. If this resistance spreads to India or Sub-Saharan Africa, where the largest numbers of malaria infections occur, the results would be catastrophic with no other treatments as effective as ACTs in existence.
synthetic biology and malaria
According to the UK Royal Society, “Synthetic biology is an emerging area of research that can broadly be described as the design and construction of novel artificial biological pathways, organisms or devices, or the redesign of existing natural biological systems.” In sum, synthetic biology combines biology and engineering to design, modify and construct biological parts, devices or systems. As a field, synthetic biology strives to find novel solutions for society’s unmet needs and may have applications in diverse fields including pharmaceuticals, food products, chemicals, energy, diagnostics, the environment and more.
In the context of malaria, synthetic biology has been used to create a secure and reliable source of artemisinin, the key component in artemisinin combination therapies (ACTs), which are the top-tier treatment available today. As mentioned above, artemisinin is extracted naturally from the Sweet Wormwood plant; however, the process to procure the compound is expensive and time-consuming, and access to ACTs remains low in many malaria endemic areas. In 2005, Amyris was awarded a five-year grant from the Bill & Melinda Gates Foundation to create artemisinic-acid (a precursor to artemisinin) in yeast using the synthetic biology platform in partnership with OneWorld Health (now PATH) and UC Berkeley. The grant was awarded as part of the Artemisinin Enterprise, a funding approach from the Gates Foundation that aimed to improve artemisinin production and reduce ACTs prices. In 2008, Amyris licensed the yeast strains to pharmaceutical company Sanofi-Aventis; and in 2013, Sanofi started using large-scale production to produce the semi-synthetic artemisinin for ACT treatments. You can learn more about this project on the Amyris website.Sources:
Dalrymple, Dana G. Artemisia annua, Artemisinin, ACTs & Malaria Control in Africa: Tradition, Science and Public Policy. www.mmv.org/artemisinin. 2012.
Rosenthal, P.J. Antimalarial Chemotherapy. Mechanisms of Action, Resistance and New Directions in Drug Discovery. Ed. Humana Press, Totowa, NJ, USA. 2001.