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Wellcome Trust Research Round-up 29.06.15

29 Jun, 2015

Our fortnightly round-up of news from the Wellcome Trust Community

Expanding our DNA’s alphabet

B0009740 DNA double helix, illustration Credit: Maurizio De Angelis. Wellcome Images images@wellcome.ac.uk http://wellcomeimages.org Illustration of the DNA double helix structure first discovered by Watson and Crick in 1953. Three DNA fragments are depicted here. The sugar-phosphate backbone is visible on complementary nucleotide strands with paired bases represented as rungs on a ladder. Digital artwork/Computer graphic 2014 Published:  -  Copyrighted work available under Creative Commons by-nc-nd 4.0, see http://wellcomeimages.org/indexplus/page/Prices.html

Our DNA’s alphabet may be more extensive than previously thought according to Wellcome Trust-funded research published in Nature Chemical Biology.

Researchers have found that a rare DNA base, that was previously thought to be just a temporary modification, is stable in living mouse tissue. This rare base, called 5-formyclcytosine (5fC), has currently unknown function. However, scientists believe that due to its position in the genome, it is likely to play a role in regulating the activity of our genes.

The order of the four known DNA bases (A, T, C and G) determines our genetic makeup, but scientists have also identified small modifications to these chemical structures. These epigenetic changes can alter how the DNA is ‘read’ and therefore whether certain genes are switched ‘on’ or ‘off’.

5fC is a modified version of the cytosine (C) base.. The addition of oxygen to methylated DNA by TET enzymes was thought to be a transitional state; however, researchers found very small amounts of it in all tissues, showing that it can exist in a stable form.

“If 5fC is present in the DNA of all tissues, it is probably there for a reason,” said Professor Shankar Balasubramanian from the University of Cambridge, who led the research. “It had been thought this modification was solely a short-lived intermediate, but the fact that we’ve demonstrated it can be stable in living tissue shows that it could regulate gene expression and potentially signal other events in cells.”

Rapid diagnostic hopes for drug-resistant Tuberculosis  

B0006594 Scientist loading enzyme beads into DNA sequencing plateA new diagnostic test will enable doctors to rapidly identify which drugs can and cannot be used to effectively treat patients with drug-resistance tuberculosis (TB), according to research published in the Lancet Infectious Diseases.

Multi-drug-resistant strains of TB (MDR-TB) affect nearly half a million people globally and treatment is currently a long-term regime of second-line drugs. One of the biggest problems associated with MDR-TB is the lack of rapid diagnostic tools which would allow faster treatment with the right drugs?, decreasing infectiousness.

Although doctors have been carrying out genetic tests on small sections of TB DNA for the last 20 years, they still have to confirm their results using time-consuming laboratory tests. The new technique sequences the entire TB genome allowing doctors to identify any mutations that may cause drug resistance.

The most effective drugs can then be selected, and any drugs that the strain is resistant to will be ruled out.

The new results from the largest study of its kind involving over 3,600 samples from the UK, Germany and further afield from Sierra Leone, South Africa and Uzbekistan. Researchers now hope to develop the test into an affordable, handheld device which would be especially useful in developing countries where TB rates are highest.

Lead investigator Professor Tim Peto, a consultant in infectious diseases at the Churchill and John Radcliffe Hospital said:  “This is the beginning of the end for routine laboratory culture for TB drug resistance. We are moving from 130 years of culturing TB to a new digital era in microbiology. It is particularly exciting for low-income settings where the lack of laboratories currently leads to under diagnosis of drug resistance.”

Can cancer drug slow down time?

B0007386 Fruit flyWellcome Trust-funded researchers have found a way to potentially slow the ageing process in fruit flies using a cancer treatment drug.

Trametinib, originally developed for the treatment of skin cancer in humans, was shown to increase the lifespan of adult fruit flies to 12% longer than average. Adding the equivalent of a daily adult dose for a human to the food of female fruit flies increased their life span by 8%, with the 12% increase recorded in flies given a much higher dose of the drug.

Researchers also tested the effects of giving the drug to flies much later in their life, to examine how the drug could work if given to the elderly. Older flies given the higher dose still exhibited an increased lifespan of 4%, suggesting that the earlier the drug is given, the greater effect it has on slowing the ageing process.

Trametinib works by targeting the Ras-Erk-ETS signalling pathway in cells, which is already identified as a key target for cancer therapies. Defects within this pathway can lead to the uncontrollable cell growth exhibited in cancer patients, but it has also been shown to be involved in the ageing process.

First author, Dr Nazif Alic from the UCL Institute of Healthy Ageing, said: “Our aim is to understand the mechanisms of ageing and alter the processes that lead to loss of function and to disease. We studied this molecular pathway in flies because they are reasonably complex and yet age more quickly than mammals. We were able to extend their lifespan both genetically and by using a cancer drug to target the Ras pathway, which provides us with the first evidence for the anti-ageing potential of drugs developed to dampen this pathway.”

This study is published in Cell. A video explaining the research can be viewed here.

Understanding Klebsiella pnuemoniae

KlebsiellaResearchers at the Wellcome Trust Sanger Institute have sequenced the genomes of the largest collection of Klebsiella pnuemoniae bacteria, with samples taken from around the world.

The data set has also given scientists an insight into the impact of antibiotics on the bacterial population and it’s rapidly emerging resistance to certain antibiotics. K. pneumonia can cause serious health complications, such as meningitis and pneumonia. The bacterium is also one of the leading causes of bloodstream infections in children in lower income countries.

The 300 samples were taken from plants, cattle and humans from across the globe with the aim of increasing researchers’ understanding of how the bacterium may evolve and how resistance could spread between lineages.

Most samples that contained drug resistant genes were taken from people who were already being treated for a hospital-acquired infection and from people who showed no symptoms of being ill. These strains are less likely to infect a healthy person, but researchers are still concerned that drug-resistant genes may appear in more virulent strains of the bacterium.

“For too long with Klebsiella, we have focussed on single lineages,” says Professor Nick Thomson from the Wellcome Trust Sanger Institute. “We will now be able to recognise emerging lineages from a huge cloud of Klebsiella diversity, helping us to follow and tackle drug resistance in this increasingly dangerous pathogen.”

This research is published in Proceedings of the National Academy of Sciences.

Other Wellcome Trust research news

A new study using data from the Wellcome Trust-funded UK Biobank has found that the timing of puberty in both men and women is associated with 48 health conditions later in life. Of the half a million samples tested, those in the earliest or latest 20% to go through puberty were at a higher risk of diseases including psoriasis, irritable bowel syndrome, arthritis and depression. The study is published in Scientific Reports.

Newborn babies’ visual attention to objects and later behavioural patterns, including hyperactivity, could be linked according to a new study published in Scientific Reports. Through observations of babies’ looking patterns in their first days of life, scientists found that spending longer looking at an individual object or stimulus was associated with less behavioural problems in middle childhood.

Rat (2)Researchers from UCL have discovered that a sleeping rat’s brain will simulate a journey to a point in the future – perhaps a place where food can be found. By monitoring brain activity, researchers could see that the rats replayed a journey in their sleep using specialised brain cells in the hippocampus that are involved in navigation. Published in eLife, the study may help to explain why people who have damaged their hippocampus are unable to imagine the future.

Image credits: (from top to bottom) Maurizio De Angelis, Wellcome Images; Wellcome Library, London;  Anne Weston, LRI, CRUK, Wellcome Images; Klebsiella pneumonia Bacterium by NIAID via Flickr CC-BY; Rat graphic © Deepmind Ltd

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