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Category: genetics

Genetic perturbations that affect bacterial resistance to antibiotics have been characterized genome-wide, but how do such perturbations interact with subsequent evolutionary adaptation to the drug? Here, we show that strong epistasis between resistance mutations and systematically identified genes can be exploited to control spontaneous resistance evolution. We evolved hundreds of Escherichia coli K-12 mutant populations in parallel, using a robotic platform that tightly controls population size and selection pressure. We find a global diminishing-returns epistasis pattern: strains that are initially more sensitive generally undergo larger resistance gains. However, some gene deletion strains deviate from this general trend and curtail the evolvability of resistance, including deletions of genes for membrane transport, LPS biosynthesis, and chaperones. Deletions of efflux pump genes force evolution on inferior mutational paths, not explored in the wild type, and some of these essentially block resistance evolution. This effect is due to strong negative epistasis with resistance mutations. The identified genes and cellular functions provide potential targets for development of adjuvants that may block spontaneous resistance evolution when combined with antibiotics.

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“Despite their abundance, astrocytes have been relatively overlooked by neuroscientists,” says Mirko Santello, last author of the study. Yet these cells are extremely important to clear transmitters released by neurons. In their study the researchers were able to show that in familial migraine the astrocytes cannot remove excessive transmitters released by neurons. “The impairment in astrocytic glutamate uptake in the cingulate cortex strongly enhances cortical dendritic excitability and thus enhances firing of the neurons,” Santello says…

Migraine is a complicated disorder that affects part of the nervous system. “Our results provide a clear example of how astrocyte dysfunction produced by a genetic defect affects neuronal activity and sensitivity to head pain triggers,” explains Mirko Santello. The findings help to better understand migraine pathophysiology and suggest that the cingulate cortex may represent a critical hub in the disease. The demonstration of the link between dysfunction of astrocytes in the cingulate cortex and familial migraine could help in devising new migraine treatment strategies.

Neuroscientists of the University of Zurich shed a new light on the mechanisms responsible for familial migraine: They show that a genetic dysfunction in specific brain cells of the cingulate cortex area strongly influences head pain occurrence.

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Automated tabletop machine could accelerate the development of novel drugs to treat cancer and other diseases.

Many proteins are useful as drugs for disorders such as diabetes, cancer, and arthritis. Synthesizing artificial versions of these proteins is a time-consuming process that requires genetically engineering microbes or other cells to produce the desired protein.

MIT chemists have devised a protocol to dramatically reduce the amount of time required to generate synthetic proteins. Their tabletop automated flow synthesis machine can string together hundreds of amino acids, the building blocks of proteins, within hours. The researchers believe their new technology could speed up the manufacturing of on-demand therapies and the development of new drugs, and allow scientists to design artificial proteins by incorporating amino acids that don’t exist in cells.

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Former astronaut Jeffrey Hoffman: For the long-term survival of our species, we have to become a multi-planet being.

With our rising planet’s population competing for space and resources, some people are convinced we need to look beyond Earth to help ensure humanity’s survival. As Elon Musk, the entrepreneur behind space tourism company SpaceX told Aeon’s Ross Andersen: “I think there is a strong argument for making life multi-planetary in order to safeguard the existence of humanity in the event that something catastrophic were to happen.”

Last month’s NASA and SpaceX successful launch of astronauts from US soil for the first time in almost a decade, has reignited discussion about space travel to Mars and beyond. Musk has been pushing Mars colonisation as extinction insurance for more than a decade now and he told Andersen that he would need a million people to form a sustainable, genetically diverse civilisation. Andersen reports:

‘Even at a million, you’re really assuming an incredible amount of productivity per person, because you would need to recreate the entire industrial base on Mars,’ he said. ‘You would need to mine and refine all of these different materials, in a much more difficult environment than Earth. There would be no trees growing. There would be no oxygen or nitrogen that are just there. No oil.’

I asked Musk how quickly a Mars colony could grow to a million people. ‘Excluding organic growth, if you could take 100 people at a time, you would need 10,000 trips to get to a million people,’ he said. ‘But you would also need a lot of cargo to support those people. In fact, your cargo to person ratio is going to be quite high. It would probably be 10 cargo trips for every human trip, so more like 100,000 trips. And we’re talking 100,000 trips of a giant spaceship.’

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The role genetics and gut bacteria play in human health has long been a fruitful source of scientific enquiry, but new research marks a significant step forward in unraveling this complex relationship. Its findings could transform our understanding and treatment of all manner of common diseases, including obesity, irritable bowel syndrome, and Alzheimer’s disease.

The international study, led by the University of Bristol and published today in Nature Microbiology, found specific changes in DNA — the chains of molecules comprising our genetic make-up — affected both the existence and amount of particular bacteria in the gut.

Lead author Dr David Hughes, Senior Research Associate in Applied Genetic Epidemiology, said: “Our findings represent a significant breakthrough in understanding how genetic variation affects gut bacteria. Moreover, it marks major progress in our ability to know whether changes in our gut bacteria actually cause, or are a consequence of, human disease.”

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A newly discovered Alzheimer’s gene may drive the first appearance of amyloid plaques in the brain, according to a study led by researchers at Columbia University Irving Medical Center.

Some variants of the gene, RBFOX1, appear to increase the concentration of protein fragments that make up these plaques and may contribute to the breakdown of critical connections between neurons, another early sign of the disease.

The finding could lead to new therapies that prevent Alzheimer’s and better ways of identifying people with the greatest risk of developing the disease.

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One of the world’s greatest anti-aging scientists continues his groundbreaking efforts. In the photo next to Dr David Sinclair, there is a fella who kind of looks like my friend, Dr Yuancheng Ryan Lu. Is that you? (Dr Lu has confirmed that he is indeed the scientist on the right. Dr Sinclair is on the left.)

I can’t wait to see what they develop next!

Harvard scientist David Sinclair is one of Longevity’s big hitters. Just a year after raising $50M in Series B financing, his company Life Biosciences LLC is looking for $100M to progress its anti-aging research [1].

Longevity. Technology: Life Biosciences had an original Series B goal of $25M; it doubled it. As NAD continues to embed in the anti-aging supplement marketplace, the company is looking to expand, with a range of subsidiaries under its Longevity umbrella. Although the company isn’t spilling any secrets on its proposed clinical trials, we will be sure to keep a close eye on progress.

Life Biosciences, valued last year at approximately $500M, is built on Sinclair’s experience as co-Director of the Paul F Glenn Center for the Biology of Aging at Harvard Medical School, as a genetics professor at Harvard University and on previously-founded companies Arc Bio, Genocea and Ovascience.

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By Valentina Lagomarsino figures by Sean Wilson

Nearly four months ago, Chinese researcher He Jiankui announced that he had edited the genes of twin babies with CRISPR. CRISPR, also known as CRISPR/Cas9, can be thought of as “genetic scissors” that can be programmed to edit DNA in any cell. Last year, scientists used CRISPR to cure dogs of Duchenne muscular dystrophy. This was a huge step forward for gene therapies, as the potential of CRISPR to treat otherwise incurable diseases seemed possible. However, a global community of scientists believe it is premature to use CRISPR in human babies because of inadequate scientific review and a lack of international consensus regarding the ethics of when and how this technology should be used.

Early regulation of gene-editing technology.

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:oooooo.

CRISPR-Cas9 is a revolutionary gene-editing technology that offers the potential to treat diseases such as cancer, but the effects of CRISPR in patients are currently unknown. Stadtmauer et al. report a phase 1 clinical trial to assess the safety and feasibility of CRISPR-Cas9 gene editing in three patients with advanced cancer (see the Perspective by Hamilton and Doudna). They removed immune cells called T lymphocytes from patients and used CRISPR-Cas9 to disrupt three genes (TRAC, TRBC, and PDCD1) with the goal of improving antitumor immunity. A cancer-targeting transgene, NY-ESO-1, was also introduced to recognize tumors. The engineered cells were administered to patients and were well tolerated, with durable engraftment observed for the study duration. These encouraging observations pave the way for future trials to study CRISPR-engineered cancer immunotherapies.

Science, this issue p. eaba7365; see also p. 976.

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