Programming DNA to reverse antibiotic resistance in bacteria

New research introduces a promising new tool to combat the rapid, extensive spread of antibiotic resistance around the world. It nukes antibiotic resistance in selected bacteria, and renders other bacteria more sensitive to antibiotics. The research, if ultimately applied to pathogens on hospital surfaces or medical personnel's hands, could turn the tide on untreatable, often lethal bacterial infections. 

Growing bacteria in petri dishes. (stock image)

Credit: © kasto / Fotolia

New Tel Aviv University research published in PNAS introduces a promising new tool: a two-pronged system to combat this dangerous situation. It nukes antibiotic resistance in selected bacteria, and renders other bacteria more sensitive to antibiotics. The research, led by Prof. Udi Qimron of the Department of Clinical Microbiology and Immunology at TAU's Sackler Faculty of Medicine, is based on bacterial viruses called phages, which transfer "edited" DNA into resistant bacteria to kill off resistant strains and make others more sensitive to antibiotics.
According to the researchers, the system, if ultimately applied to pathogens on hospital surfaces or medical personnel's hands, could turn the tide on untreatable, often lethal bacterial infections. "Since there are only a few pathogens in hospitals that cause most of the antibiotic-resistance infections, we wish to specifically design appropriate sensitization treatments for each one of them," Prof. Qimron says. "We will have to choose suitable combinations of DNA-delivering phages that would deliver the DNA into pathogens, and the suitable combination of 'killing' phages that could select the re-sensitized pathogens."
Reprogramming the system
"Antibiotic-resistant pathogens constitute an increasing threat because antibiotics are designed to select resistant pathogens over sensitive ones," Prof. Qimron says. "The injected DNA does two things: It eliminates the genes that cause resistance to antibiotics, and it confers protection against lethal phages.
"We managed to devise a way to restore antibiotic sensitivity to drug-resistant bacteria, and also prevent the transfer of genes that create that resistance among bacteria," he continues.
Earlier research by Prof. Qimron revealed that bacteria could be sensitized to certain antibiotics -- and that specific chemical agents could "choose" those bacteria more susceptible to antibiotics. His strategy harnesses the CRISPR-Cas system -- a bacterial DNA-reprogramming system Prof. Qimron pioneered -- as a tool to expand on established principles.
According to the researchers, "selective pressure" exerted by antibiotics renders most bacteria resistant to them -- hence the epidemic of lethal resistant infections in hospitals. No counter-selection pressure for sensitization of antibiotics is currently available. Prof. Qimron's strategy actually combats this pressure -- selecting for the population of pathogens exhibiting antibiotic sensitivity.
"We believe that this strategy, in addition to disinfection, could significantly render infections once again treatable by antibiotics," said Prof. Qimron.
Prof. Qimron and his team are now poised to apply the CRISPR/phage system on pseudomonas aeruginosa -- one of the world's most prevalent antibiotic-resistant pathogens involved in hospital-acquired infections -- and to test whether bacterial sensitization works in a more complex microbial environment: the mouse cage.
 

Journal Reference:

1. Ido Yosef, Miriam Manor, Ruth Kiro, Udi Qimron. Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria. Proceedings of the National Academy of Sciences, 2015; 201500107 DOI: 10.1073/pnas.1500107112 

Courtesy: ScienceDaily
 

Why are 95% of people who live to 110 women? You're as old as your stem cells

Human supercentenarians share at least one thing in common--over 95 percent are women. Scientists have long observed differences between the sexes when it comes to aging, but there is no clear explanation for why females live longer. In a discussion of what we know about stem cell behavior and sex, researchers argue that it's time to look at differences in regenerative decline between men and women. This line of research could open up new explanations for how the sex hormones estrogen and testosterone, or other factors, modify lifespan.

"As the search continues for ways to ameliorate the aging process and maintain the regenerative capacity of stem cells, let us not forget one of the most effective aging modifiers: sex," authors write.

Credit: © ia_64 / Fotolia

It's known that estrogen has direct effects on stem cell populations in female mice, from increasing the number of blood stem cells (which is very helpful during pregnancy) to enhancing the regenerative capacity of brain stem cells at the height of estrus. Whether these changes have a direct impact on lifespan is what's yet to be explored. Recent studies have already found that estrogen supplements increase the lifespan of male mice, and that human eunuchs live about 14 years longer than non-castrated males.

More work is also needed to understand how genetics impacts stem cell aging between the sexes. Scientists have seen that knocking out different genes in mice can add longevity benefits to one sex but not the other, and that males in twin studies have shorter telomeres--a sign of shorter cellular lifespan--compared to females.

"It is likely that sex plays a role in defining both lifespan and healthspan, and the effects of sex may not be identical for these two variables," the authors write. "As the search continues for ways to ameliorate the aging process and maintain the regenerative capacity of stem cells, let us not forget one of the most effective aging modifiers: sex."

Journal Reference:

1. Ben Dulken, Anne Brunet. Stem Cell Aging and Sex: Are We Missing Something? Cell Stem Cell, 2015; 16 (6): 588 DOI: 10.1016/j.stem.2015.05.006 

Courtesy: ScienceDaily

Reprogramming of DNA observed in human germ cells for first time

A team of researchers has described for the first time in humans how the epigenome -- the suite of molecules attached to our DNA that switch our genes on and off -- is comprehensively erased in early primordial germ cells prior to the generation of egg and sperm. However, the study shows some regions of our DNA -- including those associated with conditions such as obesity and schizophrenia -- resist complete reprogramming. 

Cells (stock image). When an egg cell is fertilized by a sperm, it begins to divide into a cluster of cells known as a blastocyst, the early stage of the embryo. Within the blastocyst, some cells are reset to their master state, becoming stem cells, which have the potential to develop into any type of cell within the body.

Although our genetic information -- the 'code of life' -- is written in our DNA, our genes are turned on and off by epigenetic 'switches'. For example, small methyl molecules attach to our DNA in a process known as methylation and contribute to the regulation of gene activity, which is important for normal development. Methylation may also occur spontaneously or through our interaction with the environment -- for example, periods of famine can lead to methylation of certain genes -- and some methylation patterns can be potentially damaging to our health. Almost all of this epigenetic information is, however, erased in germ cells prior to transmission to the next generation
Professor Azim Surani from the Wellcome Trust/Cancer Research UK Gurdon Institute at the University of Cambridge, explains: "Epigenetic information is important for regulating our genes, but any abnormal methylation, if passed down from generation to generation, may accumulate and be detrimental to offspring. For this reason, the information needs to be reset in every generation before further information is added to regulate development of a newly fertilised egg. It's like erasing a computer disk before you add new data."
When an egg cell is fertilized by a sperm, it begins to divide into a cluster of cells known as a blastocyst, the early stage of the embryo. Within the blastocyst, some cells are reset to their master state, becoming stem cells, which have the potential to develop into any type of cell within the body. A small number of these cells become primordial germ cells with the potential to become sperm or egg cells.
In a study funded primarily by the Wellcome Trust, Professor Surani and colleagues showed that a process of reprogramming the epigenetic information contained in these primordial germ cells is initiated around two weeks into the embryo's development and continues through to around week nine. During this period, a genetic network acts to inhibit the enzymes that maintain or programme the epigenome until the DNA is almost clear of its methylation patterns.
Crucially, however, the researchers found that this process does not clear the entire epigenome: around 5% of our DNA appears resistant to reprogramming. These 'escapee' regions of the genome contain some genes that are particularly active in neuronal cells, which may serve important functions during development. However, data analysis of human diseases suggests that such genes are associated with conditions such as schizophrenia, metabolic disorders and obesity.
Walfred Tang, a PhD student who is the first author on the study, adds: "Our study has given us a good resource of potential candidates of regions of the genome where epigenetic information is passed down not just to the next generation but potentially to future generations, too. We know that some of these regions are the same in mice, too, which may provide us with the opportunity to study their function in greater detail."
Epigenetic reprogramming also has potential consequences for the so-called 'dark matter' within our genome. As much as half of human DNA is estimated to be comprised of 'retroelements', regions of DNA that have entered our genome from foreign invaders including bacteria and plant DNA. Some of these regions can be beneficial and even drive evolution -- for example, some of the genes important to the development of the human placenta started life as invaders. However, others can have a potentially detrimental effect -- particularly if they jump about within our DNA, potentially interfering with our genes. For this reason, our bodies employ methylation as a defence mechanism to suppress the activity of these retroelements.
"Methlyation is effective at controlling potentially harmful retroelements that might harm us, but if, as we've seen, methylation patterns are erased in our germ cells, we could potentially lose the first line of our defence," says Professor Surani.
In fact, the researchers found that a notable fraction of the retroelements in our genome are 'escapees' and retain their methylation patterns -- particularly those retroelements that have entered our genome in our more recent evolutionary history. This suggests that our body's defence mechanism may be keeping some epigenetic information intact to protect us from potentially detrimental effects.
 

Journal Reference:

1. Walfred W.C. Tang, Sabine Dietmann, Naoko Irie, Harry G. Leitch, Vasileios I. Floros, Charles R. Bradshaw, Jamie A. Hackett, Patrick F. Chinnery, M. Azim Surani. A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development. Cell, 2015; 161 (6): 1453 DOI: 10.1016/j.cell.2015.04.053 

Courtesy: ScienceDaily