Wellcome Research Round-up: 26.01.15

Our fortnightly round-up of research news from the Wellcome Trust community…

New insight into genetics of antimalarial drug resistance

A global research collaboration has identified 20 mutations in the kelch13 gene – a known marker for artemisinin resistance – that appear to work with a set of background mutations in four other genes to support artemisinin resistance.

Carrying out the largest genome-wide association study of the malaria parasite Plasmodium falciparum to date, the researchers uncovered complex genetic interactions that enable the parasite to develop resistance.

“Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance — until mutations occurred in the kelch13 gene,” explains Dr Roberto Amato, a first author and Research Associate in Statistical Genomics at the Wellcome Trust Sanger Institute and Oxford University’s Wellcome Trust Centre for Human Genetics. He compares it to the accumulation of genetic changes in pre-cancerous cells that only become malignant when critical mutations kick-off growth.

Malaria parasite, Plasmodium falciparum
Credit: Wellcome Photo Library. Wellcome Images

Since there is a large variety of continually emerging kelch13 mutations, it is difficult to use this gene alone as a surveillance marker, but monitoring parasite populations for a specific genetic background – in this case, a fixed set of four well-defined mutations in the fd, arps10, mdr2, and crt genes – could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions even before resistant parasites take hold.

“We are at a pivotal point for malaria control. While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective,” says Nick Day, Director of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand. “We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”

The paper, Genetic architecture of artemisinin resistant Plasmodium falciparum, is published in Nature Genetics.

Researchers identify possible new target for epilepsy treatment

A single gene that coordinates a network of around 400 genes involved in epilepsy, could be a target for new treatments according to research published recently in Nature Communications.

The Wellcome Trust-supported study, carried out by researchers from Imperial College London, used novel computational and genetics techniques to systematically analyse the activity of genes in epilepsy, rather than taking the traditional approach of studying individual genes.

It is known that epilepsy has a strong genetic component but the risk is related to multiple factors that are ‘spread’ over hundreds of genes. Identifying how these genes are coordinated in the brain is important in the search for new anti-epilepsy medications. This requires a “systems genetics” approach that analyses how multiple genes work together to cause disease.

Researchers studied samples of brain tissue removed from patients during neurosurgery for their epilepsy. Starting with these samples, they identified a gene network that was highly active in the brain of these patients, and then discovered that an unconnected gene, Sestrin 3 (SESN3), acts as a major regulator of this epileptic gene network. This is the first time SESN3 has been implicated in epilepsy and its coordinating role was confirmed in studies with mice and zebra fish.

Dr Enrico Petretto, co-senior author of the study, said “systems genetics allows us to understand how multiple genes work together, which is far more effective than looking at the effect of a gene in isolation.”

Trust-funded researcher and co-senior author of the paper, Dr Michael Johnson, explained “we have taken a new approach, and identified a network of genes underlying the epilepsy itself in these patients and mapped its control to a single gene, SESN3. This offers hope that new disease-modifying therapies can be developed for the treatment of epilepsy itself”.

Study identifies key control mechanism for blood glucose levels

A team of researchers from the UK and the USA have found a novel pathway and hormone key to sensing and responding to low blood glucose levels. The research, carried out in mice, is published in Nature Neuroscience and could eventually help clinicians to devise new strategies to help control diabetes more safely.

Biosensor for blood glucose level testing.
Credit: Wellcome Library, London. Wellcome Images

The work identified the previously unknown pathway, buried deep within a region of the brain called the parabrachial nucleus. Here they found that a brain hormone, cholecystokinin (CCK), is a crucial sensor of blood glucose levels and orchestrates responses around the body when levels drop too low. Professor Lora Heisler, a Wellcome Trust funded researcher from the University of Aberdeen, said: “It is remarkable to find that such an incredibly small set of cells in the brain play such an important role in maintaining normal glucose levels.”

Dr Martin Myers, co-author from the University of Michigan, added, “We knew that CCK cells in the brain modify things like appetite and anxiety but they had previously been overlooked in terms of any link to blood sugar levels.

“The discovery of the important function of this brain hormone raises the possibility of using drugs targeting the CCK system to boost defences against hypoglycaemia, the clinical syndrome that results from low blood sugar. This can be extremely serious and in the most severe cases can lead to seizures, unconsciousness, brain damage and even death.”

In other news…

Researchers on the Wellcome Trust funded Avon Longitudinal Study of Parents and Children (ALSPAC) – also known as ‘Children of the 90s’ – have published an open access article on the influence of childhood growth on asthma and lung function in adolescence.

Researchers from the Wellcome Trust Centre for Neuroimaging at University College London are part of a team who have published a paper entitled “Ventral aspect of the visual form pathway is not critical for the perception of biological motion” in the journal PNAS.

Congratulations to Kevin Fong for the AAAS award for his book Extreme Medicine: How Exploration Transformed Medicine in the Twentieth Century – written during his time as a Wellcome Trust Engagement Fellow.

Congratulations are also in order for former Wellcome Trust Clinical Fellow in Malawi, Steven Gordon, who has won the ATS World Lung Health Award.

Syncona Partners  have launched an immunotherapy company, Autolus. Read about it here.