Posts Tagged ‘DNA’

Sydney Brenner was one of the first to view James Watson and Francis Crick’s double helix model of DNA in April 1953. The 26-year-old biologist from South Africa was then a graduate student at the University of Oxford, UK. So enthralled was he by the insights from the structure that he determined on the spot to devote his life to understanding genes.

Iconoclastic and provocative, he became one of the leading biologists of the twentieth century. Brenner shared in the 2002 Nobel Prize in Physiology or Medicine for deciphering the genetics of programmed cell death and animal development, including how the nervous system forms. He was at the forefront of the 1975 Asilomar meeting to discuss the appropriate use of emerging abilities to alter DNA, was a key proponent of the Human Genome Project, and much more. He died on 5 April.

Brenner was born in 1927 in Germiston, South Africa to poor immigrant parents. Bored by school, he preferred to read books borrowed (sometimes permanently) from the public library, or to dabble with a self-assembled chemistry set. His extraordinary intellect — he was reading newspapers by the age of four — did not go unnoticed. His teachers secured an award from the town council to send him to medical school.

Brenner entered the University of the Witwatersrand in Johannesburg at the age of 15 (alongside Aaron Klug, another science-giant-in-training). Here, certain faculty members, notably the anatomist Raymond Dart, and fellow research-oriented medical students enriched his interest in science. On finishing his six-year course, his youth legally precluded him from practising medicine, so he devoted two years to learning cell biology at the bench. His passion for research was such that he rarely set foot on the wards — and he initially failed his final examination in internal medicine.


Sydney Brenner (right) with John Sulston, who both shared the Nobel Prize in Physiology or Medicine with Robert Horvitz in 2002.Credit: Steve Russell/Toronto Star/Getty

In 1952 Brenner won a scholarship to the Department of Physical Chemistry at Oxford. His adviser, Cyril Hinshelwood, wanted to pursue the idea that the environment altered observable characteristics of bacteria. Brenner tried to convince him of the role of genetic mutation. Two years later, with doctorate in hand, Brenner spent the summer of 1954 in the United States visiting labs, including Cold Spring Harbor in New York state. Here he caught up with Watson and Crick again.

Impressed, Crick recruited the young South African to the University of Cambridge, UK, in 1956. In the early 1960s, using just bacteria and bacteriophages, Crick and Brenner deciphered many of the essentials of gene function in a breathtaking series of studies.

Brenner had proved theoretically in the mid-1950s that the genetic code is ‘non-overlapping’ — each nucleotide is part of only one triplet (three nucleotides specify each amino acid in a protein) and successive ‘triplet codons’ are read in order. In 1961, Brenner and Crick confirmed this in the lab. The same year, Brenner, with François Jacob and Matthew Meselson, published their demonstration of the existence of messenger RNA. Over the next two years, often with Crick, Brenner showed how the synthesis of proteins encoded by DNA sequences is terminated.

This intellectual partnership dissolved when Brenner began to focus on whole organisms in the mid-1960s. He finally alighted on Caenorhabditis elegans. Studies of this tiny worm in Brenner’s arm of the legendary Laboratory of Molecular Biology (LMB) in Cambridge led to the Nobel for Brenner, Robert Horvitz and John Sulston.


Maxine Singer, Norton Zinder, Sydney Brenner and Paul Berg (left to right) at the 1975 meeting on recombinant DNA technology in Asilomar, California.Credit: NAS

And his contributions went well beyond the lab. In 1975, with Paul Berg and others, he organized a meeting at Asilomar, California, to draft a position paper on the United States’ use of recombinant DNA technology — introducing genes from one species into another, usually bacteria. Brenner was influential in persuading attendees to treat ethical and societal concerns seriously. He stressed the importance of thoughtful guidelines for deploying the technology to avoid overly restrictive regulation.

He served as director of the LMB for about a decade. Despite describing the experience as the biggest mistake in his life, he took the lab (with its stable of Nobel laureates and distinguished staff) to unprecedented prominence. In 1986, he moved to a new Medical Research Council (MRC) unit of molecular genetics at the city’s Addenbrooke’s Hospital, and began work in the emerging discipline of evolutionary genomics. Brenner also orchestrated Britain’s involvement in the Human Genome Project in the early 1990s.

From the late 1980s, Brenner steered the development of biomedical research in Singapore. Here he masterminded Biopolis, a spectacular conglomerate of chrome and glass buildings dedicated to biomedical research. He also helped to guide the Janelia Farm campus of the Howard Hughes Medical Institute in Ashburn, Virginia, and to restructure molecular biology in Japan.

Brenner dazzled, amused and sometimes offended audiences with his humour, irony and disdain of authority and dogma — prompting someone to describe him as “one of biology’s mischievous children; the witty trickster who delights in stirring things up.” His popular columns in Current Biology (titled ‘Loose Ends’ and, later, ‘False Starts’) in the mid-1990s led some seminar hosts to introduce him as Uncle Syd, a pen name he ultimately adopted.

Sydney was aware of the debt he owed to being in the right place at the right time. He attributed his successes to having to learn scientific independence in a remote part of the world, with few role models and even fewer mentors. He recounted the importance of arriving in Oxford with few scientific biases, and leaving with the conviction that seeing the double helix model one chilly April morning would be a defining moment in his life.

The Brenner laboratories (he often operated more than one) spawned a generation of outstanding protégés, including five Nobel laureates. Those who dedicated their careers to understanding the workings of C. elegans now number in the thousands. Science will be considerably poorer without Sydney. But his name will live forever in the annals of biology.

https://www.nature.com/articles/d41586-019-01192-9

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Birds do it, bees do it, even educated fleas do it: No, they don’t fall in love, they sleep. However, exactly why all animals with a nervous system evolved to sleep has been a longstanding scientific mystery. Slumber certainly feels great, but it doesn’t exactly make sense — why should we spend a third of our lives passed out?

In a study published Tuesday in Nature Communications, scientists say they’ve figured out why on the cellular level. The core cellular function of sleep, they explain, is to combat the neuronal DNA damage that accumulates during waking hours. Sleep allows neurons to perform the efficient DNA maintenance that’s essential to a healthy life: Scientists already know that less sleep means greater vulnerability to anxiety, frustration, and ill health, but now they’re closer to understanding exactly why that’s the case.

“We’ve found a causal link between sleep, chromosome dynamics, neuronal activity, and DNA damage and repair with direct physiological relevance to the entire organism,” study lead Lior Appelbaum, Ph.D., said Tuesday. “Sleep gives an opportunity to reduce DNA damage accumulated in the brain during wakefulness.”

Applebaum and his team examined how sleep is linked to nuclear maintenance by examining one of the most frequently used model organisms for genetic and developmental studies: the zebrafish. These transparent zebrafish were genetically engineered so that the chromosomes in their neurons carried colorful chemical tags. While the fish were awake and asleep, the scientists observed the movement of DNA and nuclear proteins inside the fish with a high-resolution microscope, which can be seen in the video above.

They witnessed that when the fish were awake, the chromosomes were relatively inactive, and broken strands of DNA accumulated in the neurons. However, when the fish were asleep the chromosomes became more active, and the DNA damage that had accumulated began to be repaired. Subsequent analysis confirmed that in order to perform nuclear maintenance, single neurons need an animal to go to sleep.

The accumulation of DNA damage, says Appelbaum, is the “price of wakefulness.” During wakefulness, chromosomes are less active, leaving them vulnerable to DNA damage caused by radiation, oxidative stress, and neuronal activity. Sleep kickstarts chromosomal activity and synchronizes nuclear maintenance within individual neurons, allowing the brain to be repaired while it’s not being used to the extent that it is during the day.

“It’s like potholes in the road,” Applebaum says. “Roads accumulate wear and tear, especially during daytime rush hours, and it is most convenient and efficient to fix them at night, when there is light traffic.”

Anecdotally, we know that a good night’s sleep can be restorative. Now it appears that it’s quantifiably restorative for the brain as well, allowing it to naturally mend the damage of the day.

Abstract:

Sleep is essential to all animals with a nervous system. Nevertheless, the core cellular function of sleep is unknown, and there is no conserved molecular marker to define sleep across phylogeny. Time-lapse imaging of chromosomal markers in single cells of live zebrafish revealed that sleep increases chromosome dynamics in individual neurons but not in two other cell types. Manipulation of sleep, chromosome dynamics, neuronal activity, and DNA double-strand breaks (DSBs) showed that chromosome dynamics are low and the number of DSBs accumulates during wakefulness. In turn, sleep increases chromosome dynamics, which are necessary to reduce the amount of DSBs. These results establish chromosome dynamics as a potential marker to define single sleeping cells, and propose that the restorative function of sleep is nuclear maintenance.

by Mike McRae

Earth might have a dizzying array of life forms, but our biology ultimately remains a solitary data point – we simply don’t have a reference for life based on DNA different from our own. Now, scientists have taken matters into their hands to push the boundaries on what life could be like.

Research funded by NASA and led by the Foundation for Applied Molecular Evolution in the US has led to the creation of an entirely new flavour of the DNA double helix, one that has an additional four nucleotide bases.

It’s being called hachimoji DNA (from the Japanese words for ‘eight letters’) and it includes two new pairs to add to the existing partnerships of adenine (A) paired with thymine (T), and guanine (G) with cytosine (C).

This work to expand on nature’s own genetic recipe might sound a little familiar. The same scientists already successfully squeezed in two new letters in 2011. Only last year yet another version of an extended alphabet, also with six letters, was made to function inside a living organism.

Now, in what might seem like a case of overachievement, researchers have gone back to the drawing board to develop even more non-standard nucleotides.

They have a purpose for doubling the number of codes in the recipe book, though.

“By carefully analysing the roles of shape, size and structure in hachimoji DNA, this work expands our understanding of the types of molecules that might store information in extraterrestrial life on alien worlds,” says chemist Steven Benner.

We already know a lot about the stability and functionality of ‘natural’ DNA under a range of environmental conditions, and are slowly teasing apart possible scenarios describing its evolution from simpler organic materials to living chemistry.

But to really get a good sense of how a genetic system could evolve, we need to test the limits of its underlying chemistry.

Hachimoji DNA certainly allows for that. The new codes, labelled P, B, Z and S, are based on the same kind of nitrogenous molecules as existing ones, categorised as purines and pyrimidines.

Similarly, they link up with hydrogen bonds to form their own base pairs – S bonding with B, and P with Z.

That’s where the similarities fade out. These new ‘letters’ introduce dozens of new chemical parameters to the double helix structure that potentially affect how it zips and twists.

By devising models that predict the molecule’s stability and then observing actual structures made of this ‘alien’ DNA, researchers are better equipped what’s truly important when it comes to the fundamentals of a genetic template.

The researchers constructed hundreds of hachimoji helices made up of different configurations of natural and synthetic bases and then subjected them to a range of conditions to see how well they held up.

While there were a few minor differences in how the new letters behaved, there was no reason to believe hachimoji DNA wouldn’t work well as an information-carrying template that could mutate and evolve.

The team not only showed their synthetic letters could contribute to new codes without swiftly disintegrating, the sequences were also translated into synthetic RNA versions.

Their work falls well short of a second genesis. But a novel DNA format such as this is a step towards determining what living chemistry might – and might not – look like elsewhere in the Universe.

“Life detection is an increasingly important goal of NASA’s planetary science missions, and this new work will help us to develop effective instruments and experiments that will expand the scope of what we look for,” says NASA’s Planetary Science Division’s acting director, Lori Glaze.

Devising new bases that can operate alongside our own DNA also has applications closer to home, not only as a way to reprogram life with a different code base, but in our effort to build new kinds of nanostructures.

The sky really isn’t the limit with synthetic DNA. This is going to take us to the stars and back again.

This research was published in Science.

https://www.sciencealert.com/scientists-made-synthetic-dna-using-8-letters-and-it-could-help-us-find-aliens

By Rafi Letzter

A kid in France transcribed parts of the Hebrew book of Genesis and the Arabic-language Quran, into DNA and injected them into his body — one text into each thigh.

Adrien Locatelli, a 16-year-old high school student, posted a paper Dec. 3 on the preprint server OS, in which he claimed, “It is the first time that someone injects himself macromolecules developed from a text.”

Locatelli, a student at the boarding school Lycée les Eaux Claires in Grenoble, France, told Live Science that he didn’t need any special equipment for his project.

“I just needed to buy saline solution and a syringe because VectorBuilder sent me liquid and ProteoGenix sent me powder,” he told Live Science.

VectorBuilder is a company that creates viruses that can sneak DNA strands into cells for gene-editing purposes. ProteoGenix synthesizes, among other things, custom strands of DNA. Both companies primarily serve scientists, but their products are available to anyone who purchases them.

If you saw the texts that Locatelli injected into his body, they wouldn’t look like much. DNA is just a long molecule that can store information. Mostly, it stores the information living things use to go about their business. But it can be used to store just about any kind of information that can be written down.

Locatelli’s method for translating the texts into DNA was straightforward, if a bit crude. DNA encodes its information using repeating strings of four nucleotides, which scientists have abbreviated as A, G, T and C. Locatelli lined up each letter of the Hebrew and Arabic alphabets (which correspond closely to each other) with a nucleotide, so each nucleotide represented more than one letter. So if you were to write a Hebrew sentence using his scheme, every aleph, vav, yud, nun, tsade, and tav would become a G. Every dalet, khet, ayin, and resh would become a T. And so on.

So, is this a good idea? Locatelli thinks so.

“I did this experiment for the symbol of peace between religions and science,” he said, adding, “I think that for a religious person it can be good to inject himself his religious text.”

Locatelli said he didn’t experience any significant health problems following the procedure, though he reported some “minor inflammation” around the injection site on his left thigh for a few days.

This account of only minimal complications fits with what Sriram Kosuri, a professor of biochemistry at UCLA, told Live Science.

“[The injected texts] are unlikely to do anything except possibly cause an allergic reaction. I also don’t know how likely the rAAV vector would be to make actual virus, given the way he injected. I honestly don’t know enough about the vector he used and how he did it (details are scarce),” he wrote in a message.

https://www.livescience.com/64388-boy-encoded-and-injected-dna-bible-quran.html#?utm_source=ls-newsletter&utm_medium=email&utm_campaign=12252018-ls

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The NIHR and King’s College London are calling for 40,000 people diagnosed with depression or anxiety to enrol online for the Genetic Links to Anxiety and Depression (GLAD) Study and join the NIHR Mental Health Bioresource.

Researchers hope to establish the largest ever database of volunteers who can be called up to take part in research exploring the genetic factors behind the two most common mental health conditions – anxiety and depression.

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The GLAD study will make important strides towards better understanding of these disorders and provide a pool of potential participants for future studies, reducing the time-consuming process of recruiting patients for research.

Research has shown 30-40% of the risk for both depression and anxiety is genetic and 60-70% due to environmental factors. Only by having a large, diverse group of people available for studies will researchers be able to determine how genetic and environmental triggers interact to cause anxiety and depression.

Leader of the GLAD study and the NIHR Mental Health BioResource, Dr Gerome Breen of King’s College London, said: “It’s a really exciting time to become involved in mental health research, particularly genetic research which has made incredible strides in recent years – we have so far identified 46 genetic links for depression and anxiety.

“By recruiting 40,000 volunteers willing to be re-contacted for research, the GLAD Study will take us further than ever before. It will allow researchers to solve the big unanswered questions, address how genes and environment act together and help develop new treatment options.”

The GLAD Study, a collaboration between the NIHR BioResource and King’s College London, has been designed to be particularly accessible, with a view to motivating more people to take part in mental health research.

Research psychologist and study lead Professor Thalia Eley, King’s College London, said: “We want to hear from all different backgrounds, cultures, ethnic groups and genders, and we are especially keen to hear from young adults. By including people from all parts of the population, what we learn will be relevant to everyone. This is a unique opportunity to participate in pioneering medical science.”

https://www.nihr.ac.uk/news/nihr-launches-largest-ever-study-of-genetic-links-to-depression-and-anxiety/9201

Human sperm, artwork

Half-siblings conceived with donated sperm and eggs are connecting online using DNA testing and online registries, forming extraordinarily large genetic families with dozens to hundreds of children linked to one parent, The Washington Post reports.

The modern family ties and genetic sleuthing are making it easier for donor-conceived children to learn about their backgrounds—and harder for anonymous donors to maintain anonymity. That has clearly been proven in tragic cases in which fertility doctors misled patients about their donor’s identity, even using their own sperm to sire dozens of children. But in legal, less-scandalous cases, the online connections are also highlighting the complex consequences of America’s lax regulations of the fertility industry, particularly on sperm and egg donations.

Many other countries have set legal limits on the number of children, families, or pregnancies to which one donor can contribute. Sperm donors in Taiwan can only sire one child, for instance. In Britain, they can donate to 10 families, and in China they can provide starter material for five pregnancies. But in the US, no such limits exist.

The nonprofit organization the American Society of Reproductive Medicine recommends limiting each sperm donor’s contributions to 25 births within a population of 800,000, which is about the size of San Francisco. As the Post points out, that could allow for one donor to sire more than 10,000 children across the entire country.

Though that number may seem absurdly large, the real numbers are also eye-popping. In one instance, half-siblings used online registries and DNA testing to discover that their biological father, sperm donor #2757, sired at least 29 girls and 16 boys. The half-siblings range in ages from 1 to 21 and live in eight states and four countries. Other sibling networks linked online ranged in size from dozens to nearly 200.

Such large genetic families raise concerns about half-siblings meeting unknowingly, falling in love, and having children of their own, risking genetic disorders. The vast family connections also exacerbate concerns that donors are often not required to provide medical histories and updates. There are already cases in the medical literature of half-siblings discovering each other while seeking treatments for rare genetic conditions, the Post points out.

Last month, the US Food and Drug Administration rejected a petition put forth by donor-offspring that sought to limit the number of births to which a donor could contribute. The petition also urged the FDA to track the number of each donor’s offspring and make collecting donor medical histories and updates mandatory. The FDA responded by saying that such oversight extended beyond its authority, which for now is limited to making sure that donors are screened for certain infectious diseases.

The response has infuriated families with donor-conceived children who want more regulations and transparency for donors. Meanwhile, donor-offspring continue to link up online. One daughter of donor #2757 told the Post:

“Every time I find a new sibling, I get anxiety and think to myself: when is it going to end?”

https://arstechnica.com/science/2018/09/sperm-donor-2757-sired-at-least-45-kids-now-theyre-connecting-online/

Methyl chemical groups dot lengths of DNA, helping to control when certain genes are accessible by a cell. In new research, UCLA scientists have shown that at the connections between brain cells—which often are located far from the central control centers of the cells—methyl groups also dot chains of RNA. This methyl markup of RNA molecules is likely key to brain cells’ ability to quickly send signals to other cells and react to changing stimuli in a fraction of a second.

To dictate the biology of any cell, DNA in the cell’s nucleus must be translated into corresponding strands of RNA. Next, the messenger RNA, or mRNA—an intermediate genetic molecule between DNA and proteins—is transcribed into proteins. If a cell suddenly needs more of a protein—to adapt to an incoming signal, for instance—it must translate more DNA into mRNA. Then it must make more proteins and shuttle them through the cell to where they are needed. This process means that getting new proteins to a distant part of a cell, like the synapses of neurons where signals are passed, can take time.

Research has recently suggested that methyl chemical groups, which can control when DNA is transcribed into mRNA, are also found on strands of mRNA. The methylation of mRNA, researchers hypothesize, adds a level of control to when the mRNA can be translated into proteins, and their occurrence has been documented in a handful of organs throughout the bodies of mammals. The pattern of methyls on mRNA in any given cell is dubbed the “epitranscriptome.”

UCLA and Kyoto University researchers mapped out the location of methyls on mRNA found at the synapses, or junctions, of mouse brain cells. They isolated brain cells from adult mice and compared the epitranscriptome found at the synapses to the epitranscriptomes of mRNA elsewhere in the cells. At more than 4,000 spots on the genome, the mRNA at the synapse was methylated more often. More than half of these spots, the researchers went on to show, are in genes that encode proteins found mostly at the synapse. The researchers found that when they disrupted the methylation of mRNA at the synapse, the brain cells didn’t function normally.

The methylation of mRNA at the synapse is likely one of many ways that neurons speed up their ability to send messages, by allowing the mRNA to be poised and ready to translate into proteins when needed.

The levels of key proteins at synapses have been linked to a number of psychiatric disorders, including autism. Understanding how the epitranscriptome is regulated, and what role it plays in brain biology, may eventually provide researchers with a new way to control the proteins found at synapses and, in turn, treat disorders characterized by synaptic dysfunction.

More information: Daria Merkurjev et al. Synaptic N6-methyladenosine (m6A) epitranscriptome reveals functional partitioning of localized transcripts, Nature Neuroscience (2018). DOI: 10.1038/s41593-018-0173-6

Read more at: https://phys.org/news/2018-08-methyl-rna-key-brain-cell.html#jCp