Wellcome Sanger Institute

Rayner Group

Human-parasite interactions in malaria

We use large-scale experimental approaches to identify and prioritise drug and vaccine targets in malaria. Focusing on the blood stages of human malaria parasite species, we combine systematic genetic modification, proteomics, cellular phenotyping, biochemistry and sequencing to understand basic biology and to advance new therapeutic targets.

We work in three main areas:

  • Large-scale experimental genetic screens. Working closely with Oliver Billker and Marcus Lee, we develop scalable genetic technologies and apply them to human, simian and rodent Plasmodium parasites to explore the unannotated half of the Plasmodium genome and prioritise drug targets.
  • Host-parasite interactions. Focusing on the invasion of red blood cells by P. falciparum parasites, an essential step for parasite survival and malaria pathogenesis, we work with Gavin Wright to identify new receptor-ligand interactions, and study them in the lab to prioritise new vaccine targets. We also seek to understand the role these interactions play in host specificity, including in the relatives of human Plasmodium parasites in African apes.
  • Partnership and capacity building. Plasmodium parasites are not model organisms, and all malaria research is rooted in the challenges facing endemic countries. We work closely with partners in Kenya, Ghana, India and Colombia to ensure the tools we develop are accessible to all malaria researchers.

Background

Effective malaria control is limited by the evolution and spread of drug resistant parasites and the lack of a highly effective vaccine. To develop new drugs and vaccines we need to understand the true breadth of targets within the Plasmodium genome. The genome of the most important human malaria pathogen, Plasmodium falciparum, was sequenced nearly 20 years ago, but we still only understand the function of a small fraction of it. Our fundamental goal is to use the technologies and resources that are only available at the Sanger Institute to identify and prioritise new drug and vaccine targets.

Large-scale experimental genetic screens

One method of understanding gene function is to delete or modify specific genes, and then measure the effect on cell growth or behaviour. Gene knockout approaches were developed for Plasmodium parasites more than 20 years ago, but the work is often still technically challenging and slow. Only 400 P. falciparum genes have been modified in the last 20 years, less than 10% of the total genes in the genome – at that rate, it would take two centuries to study every single gene. With Oliver Billker we have developed methods to radically change the scale of Plasmodium experimental genetics, and have recently carried out a screen of >2,500 genes in the rodent malaria model, P. berghei. We are now transferring that technology to the human malaria parasites P. falciparum and P. knowlesi, and combining genetic screens with small molecules to identify new malaria drug targets. The unique Sanger Institute facilities allow us to tackle Plasmodium experimental genetics on a scale that is not possible in many other institutes.

Host-parasite interactions

Plasmodium parasites must invade human cells in order to survive, and all of the symptoms of malaria occur when they invade and develop inside red blood cells, where they feed on haemoglobin. After 48 hours a single parasite will have multiplied into 12-30 new parasites, which then burst open their host cell and seek new red blood cells to invade to begin the cycle again. The process of red blood cell invasion is essential for parasite survival, and depends on multiple protein-protein interactions between the parasite and red blood cell. Working with Gavin Wright we seek to understand which interactions are important to allow invasion to continue and how those interactions are influenced by variation in either the human or parasite genome. These interactions are also potential vaccine targets, and we carry out systematic screening of Plasmodium proteins to identify those that should be prioritised for testing in future vaccine trials.

Partnership and capacity building

While our work is primarily lab-based and uses parasite strains that can grow easily in cell culture conditions, not all questions can be addressed using this approach. We therefore work closely with friends and colleagues in Africa, Asia and South America to study parasites in their real world setting. We also participate actively in technology transfer and capacity building, frequently hosting students and fellows from malaria endemic countries in our lab at Sanger, and contributing to training courses in endemic countries in partnership with Wellcome Genome Campus Advanced Courses.

Connecting Science

Genomics is revolutionising health research, but is also a deeply personal science, relevant to us all. As well as my research work, I am Director of Wellcome Genome Campus Connecting Science, which delivers learning and engagement events to more than 30,000 scientists, healthcare professionals and members of the public every year. We connect researchers, health professionals and the wider public, creating opportunities and spaces for everyone to explore genomic science and its impact on research, health and society. Connecting Science inspires new thinking, sparks conversation and supports learning by drawing on the ground-breaking research taking place on the Wellcome Genome Campus.

Core team

Photo of Rachael Coyle

Rachael Coyle

Advanced Research Assistant

Photo of Nadia Cross

Nadia Cross

Advanced Research Assistant

Photo of Dr Alejandro Marin-Menendez

Dr Alejandro Marin-Menendez

Postdoctoral Fellow

Photo of Dr Alena Pance, PhD; MSc;

Dr Alena Pance, PhD; MSc;

Senior Staff Scientist

Photo of Liam Prestwood

Liam Prestwood

Laboratory Manager

Photo of Alison Kemp

Alison Kemp

Postdoctoral Fellow

Photo of Dr Sasha V Siegel

Dr Sasha V Siegel

Postdoctoral Fellow

Previous team members

Photo of Sumana Sharma

Sumana Sharma

PhD Student

Photo of Sarah Marsden, MSc

Sarah Marsden, MSc

Research Assistant

Photo of Dr Duncan Ndegwa Ndungu

Dr Duncan Ndegwa Ndungu

Postdoctoral Fellow

Photo of Dr Theo Sanderson

Dr Theo Sanderson

Postdoctoral Fellow

Photo of Dr Mehdi Ghorbal

Dr Mehdi Ghorbal

Staff Scientist

Partners

We work with the following groups

External

Dr. Beatrice Hahn

We work with the Hahn lab to understand the primate origins of human malaria parasites.

External

Dr. Manoj Duraisingh

Dr. Duraisingh and I share a deep interest in the molecular basis of red blood cells invasion, and collaborate on multiple projects

External

Dr. John Adams

We collaborate with Dr. Adams on developing and applying nextgen sequencing tools in transposon-based genetic screens.

External

Dr. David Conway

We collaborate with Prof. Conway on understanding erythrocyte invasion in field samples.

External

KEMRI- Wellcome Trust Research Programme

We work in partnership with Philip Bejon, Faith Osier and Kevin Marsh from the KEMRI- Wellcome Trust research institute in Kilifi, Kenya to help identify and prioritise new vaccine targets.

External

Dr. Vladimir Corredor

Dr. Corredor and I collaborate on a project to understand the genomic epidemiology of Plasmodium parasites on the Pacific Coast of Colombia.

External

Medical Research Council (MRC)

The MRC has funded part of our protein-protein collaborative work with Gavin Wright.

External

National Institute of Health (NIH)

We are collaborators on an NIH award to Dr. Beatrice Hahn to understand the origins of human malaria parasites.

External

Cambridge-Africa Partnership for Research Excellence (CAPREx)

CAPREx supports deeper collaboration between Cambridge and African scientists, and has supported several fellowships and collaborative workshops between us and partners in Africa.

 

Publications

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