27 January 2012

Malaria: one of life's big puzzles

Sammy Assefa hopes to contribute to solving the malaria puzzle

Malaria is a major global public health challenge with nearly half a billion cases each year. It's responsible for almost one million deaths annually, mostly children under the age of five in sub-Saharan Africa. Sammy Assefa joined the Wellcome Trust Sanger Institute's Malaria Team to pursue his PhD, studying the malaria genome. He's piecing together a full sequence of a family of 60 genes that allow the parasite spread in the human body.

Sammy's Research

Malaria is a debilitating and sometimes fatal illness that is caused by infection passed between people and mosquitoes. Sammy Assefa is one of the researchers from the Sanger Institute's Malaria Programme hoping to make a contribution to the global control and elimination of malaria. The central aim of Malaria Programme is to tackle fundamental questions in malaria biology and to discover host-parasite interactions that are critical for drug and vaccine development.

" Malaria is a tough opponent. In the bloodstream, the parasite invades our blood cells; it makes them sticky, clogging the vessels and in the worst scenario, leads to severe cases of cerebral and placental malaria. "

Sammy Assefa

Sammy is in the final phase of his PhD, working in Dr Matt Berriman's team to piece together the genetic mechanisms that allow the malaria parasite to evade the immune system.

"Malaria is a tough opponent," explains Sammy. "In the bloodstream, the parasite invades our blood cells; it makes them sticky, clogging the vessels and in the worst scenario, leads to severe cases of cerebral and placental malaria. The parasite has an extraordinary array of 60 genes [known as var genes] dedicated to evading the host immune response."

How malaria evades our immune system

"The difficulty with my research is that the family of genes I am studying, var genes, are evolving rapidly," continues Sammy.

This family of 60 var genes code for a particular protein that controls the interaction of the malaria parasite with the human host. To stop our immune system from recognising the active protein, members of the var gene family work in a mutually exclusive manner. A gene recognised by the immune system is switched off and another gene in the family is activated, cloaking the parasite once more.

"These genes are highly mosaic in nature which enables parasites to rapidly generate new gene types by a random shuffling of smaller blocks. By assembling sequences and looking at the stable and variable regions, we can begin to ask questions such as, 'what is the global diversity of these genes?' and, 'which features afford the parasite to cause severe illness?'" says Sammy.

"Imagine that the sequencing machine returns each gene in the malaria parasite's armoury in a puzzle of DNA fragments," explains Sammy. "My goal is to piece together these individual puzzles out of these fragments. The real difficulty is that all of these puzzles share pieces that are mixed together in one big pot!"

Sammy Assefa, PhD student at the Wellcome Trust Sanger Institute.

Sammy Assefa, PhD student at the Wellcome Trust Sanger Institute. [Genome Research Limited]

To work out the full sequences of the var genes, Sammy has developed a new method. He first identifies short sequences (motifs) that are shared between a known set of var genes. He then uses these as 'bait' to select relevant sequence reads from the millions that are derived from sequencing a new parasite. These reads can then be assembled into larger fragments and used to identify new shared motifs. Iterating over this process many times leads to reconstruction of many novel full length var genes.

Once the family of genes is constructed, researchers will see the first complete view of var gene diversity in clinical samples. To understand more about how these genes relate to the severity of the symptoms of malaria, scientists need to understand the repertoire of the gene family within an individual patient and how they evolve in hope to get a clearer picture of how the parasite evolves.

Sammy's work is the result of a longstanding collaboration with the the KEMRI-Wellcome Trust Research Programme in Kenya and other research groups in the MalariaGEN network. This remarkable international network comprises of a community of researchers in over 20 countries that allow large-scale collaborative projects to be conducted across multiple populations.

In the future, Sammy would like to extend his research to try to correlate gene activity with the severity of the symptoms. His overall ambition is to see his insights translate as strategies that could help treat patients.

"We know that the battle against malaria is an evolutionary arms race - and genomic research will be at the heart of resolving this battle," says Professor Dominic Kwiatkowski, who leads the Sanger Institute's Malaria Programme. "We are now at a threshold in genomic research where we can begin to look in detail at many individual genomes to try to pinpoint those genetic factors that allow the parasite to thrive and cause the specific outcomes we see as a result of this devastating disease."

Var Genes

var genes code for a particular protein that controls the interaction of the malaria parasite with the human host.

var genes code for a particular protein that controls the interaction of the malaria parasite with the human host. [doi:10.1038/nature01097]

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The malaria parasite, P. falciparum, has evolved to evade the immune system. It does this by continuously changing the version of a protein, known as PfEMP1, which it deposits on the surface of infected cells. var genes are a family of genes that code for this protein and control interaction with the human host.

The malaria genome contains a family of approximately 60 var genes which are highly unstable and variable and encode a single set of proteins that allow the parasite to mount this attack. By expressing different molecules on the surface of the cells, the parasite can evade the immune system, causing prolonged and chronic infections in patients.

The parasite uses only one of the 60 genes at a time. As the host immune system can see these surface proteins, it launches a protective antibody response. The parasite is able to avoid this response by regularly switching between different versions of the proteins. This is called antigenic variation.

Because of the importance for parasite survival, there is extremely high diversity in the var gene family which makes reconstructing these genes from short sequences (typically ~70 base pairs) very challenging.

Sammy's Story

Sammy Assefa with Dame Claire Bertschinger. Sammy is a Trustee for A-CET and has an active role in providing IT support, fundraising and student counselling.

Sammy Assefa with Dame Claire Bertschinger. Sammy is a Trustee for A-CET and has an active role in providing IT support, fundraising and student counselling. [Genome Research Limited]

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Sammy's insights into malaria are different from those of many of his colleagues at the Institute. He suffered malaria many times while growing up in North Western Ethiopia. From the ages of 11-18 he was struck by the disease once or twice a year. It inflicted people he knew, causing the deaths of young children in his community.

Throughout his early years, Sammy had ambitions to enter the medical profession. However, with limited educational choices, at the age of 18, he embarked on a degree in Industrial Engineering at Mekelle University, in Ethiopia.

One day Sammy had a chance encounter in an internet cafe with David Stables, chairman of a small charity called the African Children's Educational Trust (A-CET). David suggested that A-CET sponsor Sammy's continued education in the UK, their first student to benefit from an international scholarship, and in 2005, Sammy began his Master's degree in Information Systems Management at DeMontford University, Leicester.

After completing his Masters, an advertisement for an MPhil in Computational Biology at the University of Cambridge sparked Sammy's interest. Supported by A-CET again, Sammy studied in Cambridge for a year. During this time, he collaborated with researchers in the Sanger Institute's Malaria Programme. Dr Matt Berriman, a Faculty leader at the Sanger Institute, suggested Sammy join his team at the Institute to work on malaria.

After one year working for the Institute, Sammy applied for the Institute's four-year PhD programme, where he is now in his final year supervised by Dr Matt Berriman and Professor Chris Newbold.

The value of Sammy's research is recognized by his scientific leader who suggested Sammy should join his team.

"Sammy's dedication to his research is borne out of a real desire to enact positive change in the lives of people living in malaria-endemic countries," says Dr Matt Berriman, who heads the Parasite Genomics group at the Sanger Institute and Sammy's PhD superviser. "It is great that Sammy can connect with a cause that he saw first-hand in his youth in Ethiopia."

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