GENETICS: Unlocking Humanity's Past and Future

[Stormer0628]

Error-free editing of human embryos achieved by US researchers

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Applying the CRISPR gene editing technique at the same time as fertilization corrects a heart disease gene and avoids past errors.

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Though the jury is out on whether we should try to modify the genes of human embryos, that hasn’t stopped researchers from finessing the widely lauded CRISPR gene-editing technique. So far three attempts by Chinese researchers have made the pitfalls clear: the technique introduces more errors than it fixes. It also produces mosaic embryos where some cells get fixed, others don’t.

Now, as reported in Nature, an international team led by Shoukhrat Mitalipov at Oregon Health and Science University has found a way to move past these pitfalls. “It’s a staggering result,” says geneticist Leanne Dibbens, at the University of South Australia. “This is what we’ve all been looking for.”

Mitalipov and his colleagues have convincingly repaired embryos carrying the faulty gene, cardiac myosin-binding protein C (MYBPC3). The defective gene causes hypertrophic cardiomyopathy, the most common cause of sudden cardiac arrest in young athletes. The condition affects one in 500 people. “By using this technique, it’s possible to reduce the burden of this heritable disease on the family and eventually the human population,” Mitalipov says. “Every generation on would carry this repair because we’ve removed the disease-causing gene variant from that family’s lineage.”

Three previous attempts to edit the genes of human embryos by labs in China all showed problems with mosaicism and mistakes, so-called “off-target effects”. The first two of those studies used defective IVF embryos that could never develop into a baby (they had been inadvertently fertilized with two sperm) as a way to sidestep the ethical minefield.

The first study, published in 2015, attempted to repair a defective gene causing the blood disease beta thalassemia. The second study, published in 2016, edited a gene to confer HIV resistance to the embryo. The third, published in March this year, edited genes associated with the diseases beta thalassemia and favism. This time the researchers used normal embryos, which they found increased the proportion of embryos that were edited from 14% to 50%. Nevertheless the embryos still showed evidence of off-target effects and mosaicism.

The Mitalipov-led team is the first to demonstrate error-free editing of human embryos. They seem to have a knack when it comes to manipulating embryos. Mitalipov also carries the distinction of being the first to crack the long-standing problem of cloning human embryos and deriving embryonic stem cells.

The key to the current success appears to come down to when the CRISPR editor is introduced to the embryo. Past attempts introduced CRISPR once the embryo had already been fertilized; in the current report, CRISPR was added to eggs at an earlier stage, at the same time as the sperm.

The sperm came from a donor with hypertrophic cardiomyopathy. Like all those affected, he carried both a normal and a defective copy of the MYBPC3 gene so his sperm population was a 50:50 mix of normal and defective. That meant half the fertilized embryos would be normal; half defective.

The researchers co-injected the affected donor’s sperm together with the CRISPR editor. They then analyzed the embryos after they had undergone two or three divisions. Out of 58 embryos, 42 showed the normal gene in every cell. This means the technique successfully increased the number of healthy embryos from 50% to 70%.

Researchers at collaborating labs in South Korea and China also carried out thorough checks of the embryos’ DNA to see if there had been mistakes elsewhere. Remarkably, no “off-target” effects were detected.

Mitalipov cites two reasons for achieving the accuracy. One was that the editing was done in one hit by delivering CRISPR as a short-acting protein. Past attempts have delivered a string of DNA code which can continue to order up the production of the editor protein for several days. The other is that co-authors Jin-Soo Kim at Seoul National University in South Korea and Juan Carlos Belmonte at the Salk institute in California - both pioneers of the CRISPR technique - had meticulously optimized the choice of ‘guides’ for the CRISPR editor by testing them in iPS cell lines that carried the same genetic fault. These guides navigate the editor through a maze of look-alike DNA, to ensure it tracks only to the correct faulty bit of code.

Another remarkable finding was the way the repairs to the embryos’ faulty DNA took place. Normally the CRISPR editor is added together with a snippet of DNA carrying the correct DNA code. It uses this as a template to make the corrections – rather like checking a dictionary when you correct the spelling of word. The surprise was that instead of checking the foreign DNA to make the corrections, the embryo checked the mother’s copy of the MYBPC3 gene. The preferential use of the mother’s own template may have something to do with using very early stage embryos. It may also be a third factor in explaining why the editing was so accurate. Says co-author Jun Wu at the Salk Institute: “Our technology successfully repairs the disease-causing gene mutation by taking advantage of a DNA repair response unique to early embryos”.

The authors believe their success at avoiding mosaicism also lies in editing early embryos. By co-delivering the CRISPR editor with sperm, there was time for the embryo to carry out its repairs well before it entered the so-called “S” phase, when it starts synthesizing copies of its DNA.This avoids the possibility of cells splitting before receiving a corrected copy of the DNA.

Not all the embryos were perfectly fixed, though: 16 showed erroneous fixes to their MYBPC3 gene.

However, the authors say that, by increasing the number of healthy embryos from 50% to 70%, their work could provide couples with a larger number of healthy embryos, improving the chance of successful IVF. According to another co-author, Paula Amato, professor of obstetrics and gynecology in OHSU’s School of Medicine: “If proven safe, this technique could potentially decrease the number of cycles needed for people trying to have children free of genetic disease.”

Clearly there is still work to do and debates still to be resolved. As Dibbens puts it: “The study advances our understanding of gene editing technologies and again highlights the need for discussions on what situations gene editing will be used in in the future.”

SOURCE

 

[Stormer0628]

White Supremacists Aren't Thrilled With DNA Testing Results

When white supremacist Craig Cobb took a DNA test on The Trisha Goddard Show in 2013 and found out he was 14% sub-Saharan African, he refused to accept the results, preferring instead to call the facts “statistical noise.” Cobb is not uncommon in his reaction to DNA evidence. Like Cobb, who tried to make one town in North Dakota exclusively white, other white supremacists have tested their DNA in an attempt to prove purely European roots, only to be sorely disappointed.

In light of the dual rise of white supremacy and accessible genetic testing, sociologists Aaron Panofsky and Joan Donovan decided to study the connection between the two. They sifted through millions of forum posts on the neo-Nazi website Stormfront, where users post their genetic profile and discuss the results. Earlier this August, Panofsky and Donovan shared their conclusions with fellow sociologists at a conference in Montreal. To the surprise of many, they found that when challenged with non-white backgrounds, white supremacists “overwhelmingly” challenge the results and manipulate their ancestral stories instead of accepting genetic evidence.

Overall, just a third of the forum participants writing about genetic tests were happy with their results. The rest, however, weren’t too jazzed with what they found. But instead of banning them from the online group, other members encouraged them to challenge their results or dismiss them entirely. While some argued it only matters if you’re committed to their racist cause, others pegged the genetic tests as Jewish conspiracies, STAT News reports. They also discovered the truly warped argument circulating in these forums that you don’t need non-white people to have a diverse society because white people are diverse enough on their own.

While there are some bones to pick with genetic testing services, which can be lightly manipulated based on what information (or lack thereof) you give them, for the most part this study shows how adept white supremacists are at distorting reality. To that end, Ancestry.com has stated: “To be clear, we are against any use of our product in an attempt to promote divisiveness or justify twisted ideologies. People looking to use our services to prove they are ethnically ‘pure’ are going to be deeply disappointed. We encourage them to take their business elsewhere.”

SOURCE

 

[Stormer0628]

Blood DNA sequencing reveals there’s a lot more microbes
living inside us— and we’ve never seen over 99% of them before
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A new paper looking at the DNA fragments floating around in human blood reports that there are way more microbes living inside us than we thought — and we’ve never seen most of them before.

The idea behind this paper started taking shape as a team led by Stephen Quake, a professor of bioengineering and applied physics, a member of Stanford Bio-X and the paper’s senior author, were looking for a new non-invasive method to determine the risk of rejection in transplant patients. This is traditionally done using a biopsy, which involves a very large needle and quite a bit of ‘ow’.

Needless to say, nobody was very big on the procedure. So Quake’s lab wanted to see if they can work around the issue by looking at the bits of DNA floating around in patients’ blood — what’s known as cell-free DNA. The team expected to find the patient’s DNA, the donor’s DNA, and genetic material from all the bacteria, viruses, and all the other critters that make up our personal microbiome. A spike of donor DNA would, in theory, be one of the first signs of organ rejection.

But what the team didn’t expect to find was the sheer quantity and diversity of microbiome-derived DNA in the blood samples they used.

Bugs galore

“We found the gamut,” says professor Quake. “We found things that are related to things people have seen before, we found things that are divergent, and we found things that are completely novel.”
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Throughout their project (which spanned several studies), the team gathered samples from 156 heart, lung, and bone marrow transplant recipients, and 32 from pregnant woman — pregnancy also has a huge effect on the immune system, similar to immunosuppressants, although we don’t really know how.

Of all the non-human DNA bits found in these samples, a whopping 99% couldn’t be matched to anything in existing genetic databases. In other words, they came from strains we didn’t even know existed. So the team went to work on characterizing all that genetic material. According to them, the “vast majority” falls into the phylum proteobacteria. The largest single group of viruses identified in this study belong to the torque teno family (TTVs). In fact, Quake says their work has “doubled the number of known viruses in that family” in one fell swoop.

Known torque teno viruses infect either animals or humans, but many of the TTVs the team identified don’t fit in either group.

“We’ve now found a whole new class of human-infecting ones that are closer to the animal class than to the previously known human ones, so quite divergent on the evolutionary scale,” Quake adds.
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The team believes that we’ve missed all these microbes up to now because narrow studies, by their very nature, miss the bigger picture. Researchers often focus their attention on a few interesting microbes and glance over everything else. Blood samples, by contrast, allowed them to look at everything swimming around inside of us, instead of looking at a few individual pieces. It was this net-cast-wide approach — which the team humorously refer to as a “massive shotgun sequencing” of cell-free DNA — that allowed the team to discover how hugely diverse human microbiomes are.

In the future, the team plans to take a similar look at other animals to see what species their microbiomes harbor.

“There’s all kinds of viruses that jump from other species into humans, a sort of spillover effect, and one of the dreams here is to discover new viruses that might ultimately become human pandemics,” Quake says.

“What this does is it arms infectious disease doctors with a whole set of new bugs to track and see if they’re associated with diseases. That’s going to be a whole other chapter of work for people to do.”
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The paper “Numerous uncharacterized and highly divergent microbes which colonize humans are revealed by circulating cell-free DNA” has been published in the journal Proceedings of the National Academy of Sciences.

SOURCE

 

[Stormer0628]

Evidence Shows Natural Selection
Is Working Right Now to Cull Bad Genes in Humans

Yep, we're definitely still evolving.

Genes associated with Alzheimer's disease and heavy smoking are broadly less prevalent in people with longer lifespans, suggesting that in spite of our mix of smarts and self-awareness, natural selection is still shaping our species.

In a massive genomic study covering over 170,000 people from across Britain and the United States, researchers identified a variety of individual genes and gene sets that painted a picture of how our genome is slowly evolving from one generation to the next.

Researchers from Columbia University, New York Genome Center and University of Cambridge set out to make a critical step to achieving a rather ambitious goal – to directly measure human evolutionary fitness.

Hindsight is 20-20, and over an incredibly long timescale it's easy to see how anatomically modern humans slowly changed in size and shape.

On shorter timescales, we've been able to compare how genes have come and gone to allow us to adapt to our environment.

Changes in diet have seen many populations adapt to tolerate the sugar lactose within the past 20,000 years, for example.

About 10,000 years ago, a change in the HERC2 gene gave us the first instance of blue eyes, for example – a trait that is now widespread in some parts of the world.

Even more recently our move to live in cities has selected for genes that reduce the risk of contracting debilitating diseases such as tuberculosis and leprosy.

There's no reason to think humans are no longer under the influence of natural selection, even if that selection often feels less 'natural' and more 'urban'.

In fact, past research suggests over the past 40,000 years evolution of Homo sapiens hasn't merely continued, it has accelerated.

To see just how our current genes are contributing to our fitness as a species, and potentially get a better grasp on how we will continue to evolve into the future, scientists have cast a wide net over a large section of our global population to see exactly what kinds of genes are linked with our longevity.

The team combined data on 57,696 individuals from the Genetic Epidemiology Research on Adult Health and Aging study with details on 117,648 participants' parents from the UK Biobank.

"It's a subtle signal, but we find genetic evidence that natural selection is happening in modern human populations," says researcher Joseph Pickrell from Columbia University.

One example is in the frequency of a mutation in a gene labelled CHRNA3, which encodes for a subunit of the nicotinic acetylcholine receptor.

The research showed a marked drop in the prevalence of this variation among men starting in middle age, indicating a stronger addiction to nicotine is slowly being selected out of our global population.

Another gene variation that appears to be on the way out is ApoE ε4, which encodes for a type of protein that carries cholesterol and supports injury repair in the brain.

Carrying this variation of the protein increases the likelihood of developing Alzheimer's disease. The study found a significant decrease in the gene's presence in women over 70.

While neither discovery is itself surprising, the researchers did expect to find more hazardous variants of each of these genes.

The fact they didn't spot any suggests it's possible that those genes have already been purged from our populations as individuals without the genes outcompeted those who had them.

"It may be that men who don't carry these harmful mutations can have more children, or that men and women who live longer can help with their grandchildren, improving their chance of survival," says researcher Molly Przeworski from Columbia University.

In addition to those two common mutations, the researchers identified a bunch of other traits predicted by genes associated with shorter life spans, including higher levels of LDL (the so-called bad kind) cholesterol, higher body mass indexes, heart disease, and to a lesser extent, asthma.

Genes that delayed puberty and child-bearing also seemed to being selected for by contributing to longer lives, in line with previous research that showed earlier onsets of puberty was linked with higher risks for type 2 diabetes and angina.

As tempting as it is to extrapolate these findings into predictions on how our species might look in the far future, it's important to note that our surroundings – including medicine and technology – can always throw in a wild card or two.

"The environment is constantly changing," says lead researcher Hakhamanesh Mostafavi from Columbia University.

"A trait associated with a longer lifespan in one population today may no longer be helpful several generations from now or even in other modern day populations."

More data, as usual, will help refine the changes our genomes are undergoing from generation to generation, and better pinpoint exactly how these genes might be helping or hindering our population's fitness.

When it comes to natural selection, humans are still far from being in control of their own genetic destiny.

This research was published in PLOS Biology.


SOURCE

 

[Stormer0628]

Bacteria Use Brainlike Bursts of Electricity to Communicate

Bacteria Use Brainlike Bursts of Electricity to Communicate
With electrical signals, cells can organize themselves
into complex societies and negotiate with other colonies

Bacteria have an unfortunate—and inaccurate—public image as isolated cells twiddling about on microscope slides. The more that scientists learn about bacteria, however, the more they see that this hermitlike reputation is deeply misleading, like trying to understand human behavior without referring to cities, laws or speech. “People were treating bacteria as … solitary organisms that live by themselves,” said Gürol Süel, a biophysicist at the University of California, San Diego. “In fact, most bacteria in nature appear to reside in very dense communities.”

The preferred form of community for bacteria seems to be the biofilm. On teeth, on pipes, on rocks and in the ocean, microbes glom together by the billions and build sticky organic superstructures around themselves. In these films, bacteria can divide labor: Exterior cells may fend off threats, while interior cells produce food. And like humans, who have succeeded in large part by cooperating with each other, bacteria thrive in communities. Antibiotics that easily dispatch free-swimming cells often prove useless against the same types of cells when they’ve hunkered down in a film.

As in all communities, cohabiting bacteria need ways to exchange messages. Biologists have known for decades that bacteria can use chemical cues to coordinate their behavior. The best-known example, elucidated by Bonnie Bassler of Princeton University and others, is quorum sensing, a process by which bacteria extrude signaling molecules until a high enough concentration triggers cells to form a biofilm or initiate some other collective behavior.

But Süel and other scientists are now finding that bacteria in biofilms can also talk to one another electrically. Biofilms appear to use electrically charged particles to organize and synchronize activities across large expanses. This electrical exchange has proved so powerful that biofilms even use it to recruit new bacteria from their surroundings, and to negotiate with neighboring biofilms for their mutual well-being.

“I think these are arguably the most important developments in microbiology in the last couple years,” said Ned Wingreen, a biophysicist who researches quorum sensing at Princeton. “We’re learning about an entirely new mode of communication.”

Biofilms were already a hot topic when Süel started focusing on them as a young professor recruited to San Diego in 2012. But much about them was still mysterious, including how individual bacteria give up their freedom and settle into large, stationary societies. To gain insight, Süel and his colleagues grew biofilms of Bacillus subtilis, a commonly studied rod-shaped bacterium, and observed them for hours with sophisticated microscopes. In time-lapse movies, they saw biofilms expand outward until cells in the interior consumed the available reserves of the amino acid glutamate, which the bacteria use as a nitrogen source. Then the biofilms would stop expanding until the glutamate was replenished. Süel and his colleagues became curious about how the inner bacteria were telling the outer cells when to divide and when to chill.

Quorum sensing was the obvious suspect. But Süel, who was trained in physics, suspected that something more than the diffusion of chemical messengers was at work in his Bacillus colonies. He focused on ion channels—specialized molecules that nestle into cells’ outer membranes and ferry electrically charged particles in and out. Ion channels are probably most famous for their role in nerve cells, or neurons. Most of the time, neurons pump out sodium ions, which carry a single positive charge, and let in a different number of potassium ions, also with single positive charges. The resulting charge imbalance acts like water piling up behind a dam. When an electrical impulse jolts a neuron’s membrane, specialized channels open to allow the concentrated ions to flood in and out, essentially opening the dam’s floodgates. This exchange propagates along the neuron, creating the electrical “action potentials” that carry information in the brain.

Süel knew that bacteria also pump ions across their membranes, and several recent papers had reported spikes of electrical activity in bacteria that at least loosely resembled those found in the brain. Could bacteria also be using the action-potential mechanism to transmit electrical signals? he wondered.

He and his colleagues treated biofilms in their lab with fluorescent markers that are activated by potassium and sodium ions, and the potassium marker lit up as ions flowed out of starved cells. When the ions reached nearby cells, those cells also released potassium, refreshing the signal. The signal flowed outward in this way until it reached the biofilm’s edge. And in response to the signal, edge cells stopped dividing until the interior cells could get a meal, after which they stopped releasing potassium.

Süel’s team then created mutant bacteria without potassium channels, and they found that the cells did not grow in the same stop-start manner. (The researchers also saw no movement of labeled sodium ions in their experiments.) Like neurons, bacteria apparently use potassium ions to propagate electrical signals, Süel and his colleagues reported in Nature in 2015.

Despite the parallels to neural activity, Süel emphasizes that biofilms are not just like brains. Neural signals, which rely on fast-acting sodium channels in addition to the potassium channels, can zip along at more than 100 meters per second—a speed that is critical for enabling animals to engage in sophisticated, rapid-motion behaviors such as hunting. The potassium waves in Bacillus spread at the comparatively tortoise-like rate of a few millimeters per hour. “Basically, we’re observing a primitive form of action potential in these biofilms,” Süel said. “From a mathematical perspective they’re both exactly the same. It’s just that one is much faster.”

BACTERIAL BROADCASTING
Süel and his colleagues had more questions about that electric signal, however. When the wave of potassium-driven electrical activity reaches the edge of a biofilm, the electrical activity might stop, but the cloud of potassium ions released into the environment keeps going. The researchers therefore decided to look at what happens once the potassium wave leaves a biofilm.

The first answer came earlier this year in a Cell paper, in which they showed that Bacillus bacteria seem to use potassium ions to recruit free-swimming cells to the community. Amazingly, the bacteria attracted not only other Bacillus, but also unrelated species. Bacteria, it seems, may have evolved to live not just in monocultures but in diverse communities.

A few months later, in Science, Süel’s team showed that by exchanging potassium signals, two Bacillus biofilms can “time-share” nutrients. In these experiments, two bacterial communities took turns eating glutamate, enabling the biofilms to consume the limited nutrients more efficiently. As a result of this sharing, the biofilms grew more quickly than they could have if the bacteria had eaten as much as they could without interruption. When the researchers used bacteria with ion channels that had been modified to give weaker signals, the biofilms, no longer able to coordinate their feeding, grew more slowly.

Süel’s discoveries about how bacteria communicate electrically have exhilarated bacteria researchers.

“I think it’s some of the most interesting work going on in all of biology right now,” said Moh El-Naggar, a biophysicist at the University of Southern California. El-Naggar studies how bacteria transfer electrons using specialized thin tubes, which he calls nanowires. Even though this transfer could also be considered a form of electrical communication, El-Naggar says that in the past, he would “put the brakes on” if someone suggested that bacteria behave similarly to neurons. Since reading Süel’s 2015 paper, he’s changed his thinking. “A lot of us can’t wait to see what comes out of this,” he said.

For Gemma Reguera, a microbiologist at Michigan State University, the recent revelations bolster an argument she has long been making to her biologist peers: that physical signals such as light, sound and electricity are as important to bacteria as chemical signals. “Perhaps [Süel’s finding] will help the scientific community and [people] outside the scientific community feel more open about other forms of physical communication” among bacteria, Reguera said.

Part of what excites researchers is that electrical signaling among bacteria shows signs of being more powerful than chemically mediated quorum sensing. Chemical signals have proved critical for coordinating certain collective behaviors, but they quickly get diluted and fade out once they’re beyond the immediate vicinity of the bacteria emitting the signal. In contrast, as Süel’s team has found, the potassium signals released from biofilms can travel with constant strength for more than 1,000 times the width of a typical bacterial cell—and even that limit is an artificial upper bound imposed by the microfluidic devices used in the experiments. The difference between quorum sensing and potassium signaling is like the difference between shouting from a mountaintop and making an international phone call.

Moreover, chemicals enable communication only with cells that have specific receptors attuned to them, Wingreen noted. Potassium, however, seems to be part of a universal language shared by animal neurons, plant cells and—scientists are increasingly finding—bacteria.

A UNIVERSAL CHEMICAL LANGUAGE
“I personally have found [positively charged ion channels] in every single-celled organism I’ve ever looked at,” said Steve Lockless, a biologist at Texas A&M University who was Süel’s lab mate in graduate school. Bacteria could thus use potassium to speak not just with one another but with other life-forms, including perhaps humans, as Lockless speculated in a commentary to Süel’s 2015 paper. Research has suggested that bacteria can affect their hosts’ appetite or mood; perhaps potassium channels help provide that inter-kingdom communication channel.

The fact that microbes use potassium suggests that this is an ancient adaptation that developed before the eukaryotic cells that make up plants, animals and other life-forms diverged from bacteria, according to Jordi Garcia-Ojalvo, a professor of systems biology at Pompeu Fabra University in Barcelona who provided theoretical modeling to support Süel’s experiments. For the phenomenon of intercellular communications, he said, the bacterial channel “might be a good candidate for the evolutionary ancestor of the whole behavior.”

The findings form “a very interesting piece of work,” said James Shapiro, a bacterial geneticist at the University of Chicago. Shapiro is not afraid of bold hypotheses: He has argued that bacterial colonies might be capable of a form of cognition. But he approaches analogies between neurons and bacteria with caution. The potassium-mediated behaviors Süel has demonstrated so far are simple enough that they don’t require the type of sophisticated circuitry brains have evolved, Shapiro said. “It’s not clear exactly how much information processing is going on.”

Süel agrees. But he’s currently less interested in quantifying the information content of biofilms than in revealing what other feats bacteria are capable of. He’s now trying to see if biofilms of diverse bacterial species time-share the way biofilms of pure Bacillus do.

He also wants to develop what he calls “bacterial biofilm electrophysiology”: techniques for studying electrical activity in bacteria directly, the way neuroscientists have probed the brain for decades. Tools designed for bacteria would be a major boon, said Elisa Masi, a researcher at the University of Florence in Italy who has used electrodes designed for neurons to detect electrical activity in bacteria. “We are talking about cells that are really, really small,” she said. “It’s difficult to observe their metabolic activity, and there is no specific method” for measuring their electrical signals.

Süel and his colleagues are now developing such tools as part of a $1.5 million grant from the Howard Hughes Medical Institute, the Bill and Melinda Gates Foundation, and the Simons Foundation (which publishes Quanta).

The findings could also lead to new kinds of antibiotics or bacteria-inspired technologies, Süel said, but such applications are years away. The more immediate payoff is the excitement of once again revolutionizing our conceptions about bacteria. “It’s amazing how our understanding of bacteria has evolved over the last couple decades,” El-Naggar said. He is curious about how well potassium signaling works in complex, ion-filled natural settings such as the ocean. “Now we’re thinking of [bacteria] as masters of manipulating electrons and ions in their environment. It’s a very, very far cry from the way we thought of them as very simplistic organisms.”

“Step by step we find that all the things we think bacteria don’t do, they actually do,” Wingreen said. “It’s displacing us from our pedestal.”

SOURCE: QUANTA

 

[Stormer0628]

Re: Bacteria Use Brainlike Bursts of Electricity to Communicate

DNA sequencing technology is revealing mysterious gaps in the genomes of many animals.​

DNA sequencing technology is helping scientists unravel questions that humans have been asking about animals for centuries. By mapping out animal genomes, we now have a better idea of how the giraffe got its huge neck and why snakes are so long. Genome sequencing allows us to compare and contrast the DNA of different animals and work out how they evolved in their own unique ways.

But in some cases we’re faced with a mystery. Some animal genomes seem to be missing certain genes, ones that appear in other similar species and must be present to keep the animals alive. These apparently missing genes have been dubbed “dark DNA”. And its existence could change the way we think about evolution.

My colleagues and I first encountered this phenomenon when sequencing the genome of the sand rat (Psammomys obesus), a species of gerbil that lives in deserts. In particular we wanted to study the gerbil’s genes related to the production of insulin, to understand why this animal is particularly susceptible to type 2 diabetes.

But when we looked for a gene called Pdx1 that controls the secretion of insulin, we found it was missing, as were 87 other genes surrounding it. Some of these missing genes, including Pdx1, are essential and without them an animal cannot survive. So where are they?

The first clue was that, in several of the sand rat’s body tissues, we found the chemical products that the instructions from the “missing” genes would create. This would only be possible if the genes were present somewhere in the genome, indicating that they weren’t really missing but just hidden.

The DNA sequences of these genes are very rich in G and C molecules, two of the four “base” molecules that make up DNA. We know GC-rich sequences cause problems for certain DNA-sequencing technologies. This makes it more likely that the genes we were looking for were hard to detect rather than missing. For this reason, we call the hidden sequence “dark DNA” as a reference to dark matter, the stuff that we think makes up about 25% of the universe but that we can’t actually detect.

By studying the sand rat genome further, we found that one part of it in particular had many more mutations than are found in other rodent genomes. All the genes within this mutation hotspot now have very GC-rich DNA, and have mutated to such a degree that they are hard to detect using standard methods. Excessive mutation will often stop a gene from working, yet somehow the sand rat’s genes manage to still fulfil their roles despite radical change to the DNA sequence. This is a very difficult task for genes. It’s like winning Countdown using only vowels.

This kind of dark DNA has previously been found in birds. Scientists have found that 274 genes are “missing” from currently sequenced bird genomes. These include the gene for leptin (a hormone that regulates energy balance), which scientists have been unable to find for many years. Once again, these genes have a very high GC content and their products are found in the birds’ body tissues, even though the genes appear to be missing from the genome sequences.

Shedding light on dark DNA
Most textbook definitions of evolution state that it occurs in two stages: mutation followed by natural selection. DNA mutation is a common and continuous process, and occurs completely at random. Natural selection then acts to determine whether mutations are kept and passed on or not, usually depending on whether they result in higher reproductive success. In short, mutation creates the variation in an organism’s DNA, natural selection decides whether it stays or if it goes, and so biases the direction of evolution.

But hotspots of high mutation within a genome mean genes in certain locations have a higher chance of mutating than others. This means that such hotspots could be an underappreciated mechanism that could also bias the direction of evolution, meaning natural selection may not be the sole driving force.

So far, dark DNA seems to be present in two very diverse and distinct types of animal. But it’s still not clear how widespread it could be. Could all animal genomes contain dark DNA and, if not, what makes gerbils and birds so unique? The most exciting puzzle to solve will be working out what effect dark DNA has had on animal evolution.

In the example of the sand rat, the mutation hotspot may have made the animal’s adaptation to desert life possible. But on the other hand, the mutation may have occurred so quickly that natural selection hasn’t been able to act fast enough to remove anything detrimental in the DNA. If true, this would mean that the detrimental mutations could prevent the sand rat from surviving outside its current desert environment.

The Conversation
The discovery of such a weird phenomenon certainly raises questions about how genomes evolve, and what could have been missed from existing genome sequencing projects. Perhaps we need to go back and take a closer look.

This article was originally published on The Conversation and is republished here with permission. Read the original article.

SOURCE

 

[brunomarso]

Re: Bacteria Use Brainlike Bursts of Electricity to Communicate

napaka-informative naman ito
read ode muna TS salamat sa thread na ito

 

[Stormer0628]

Re: Bacteria Use Brainlike Bursts of Electricity to Communicate

napaka-informative naman ito
read ode muna TS salamat sa thread na ito

Welcome.

Ito kaseng ginagawa ko is trying to inform discussions or arguments with facts and evidence, hindi lang basta haka-haka o mga claims na walang laman, na walang matibay na suporta.

 

[Stormer0628]

Re: Bacteria Use Brainlike Bursts of Electricity to Communicate

Childhood is a defining period in anybody's life. For many of us, those early life experiences could change the body right down to a genetic level.

Researchers can now accurately predict whether a handful of genes responsible for regulating inflammation are altered by identifying key childhood events, suggesting the illnesses we get later in life could be the result of events in our formative years.

A team of scientists from Northwestern University in the US analysed over a hundred genes associated with inflammation, looking for hints of epigenetic changes.

They were led by suspicions that links between childhood environments and differences in inflammation processes could come down to the genes themselves.

While our genome's DNA sequence is more or less locked in at conception, we've understood for some time that individual genes can continue to be modified through processes we refer to as epigenetic.

One of the more prominent forms of these epigenetic processes is methylation, which involves a methyl (CH3) group being added to the DNA's structure in such a way that it interferes with its function.

Methylation, along with other epigenetic changes, has revolutionised how we interpret our genetic blueprints.

Where once our biology was considered a genetic destiny, we've come to understand that even subtle environmental phenomena can have a knock-on effect that results in the silencing of key genes.

Epigenetics appears to have evolved to tweak our genomes in rapid response to changes in our surroundings.

"We could have genes in our bodies that might lead to some bad outcomes or adverse health outcomes, but if those genes are silent, if they're turned off due to epigenetic processes, that can be a good thing," the study's lead author Thom McDade explains to Lorena Infante Lara at Univision.com.

It's still relatively early days in terms of understanding the full range of epigenetic changes that can be wrought by everything from how we sleep to how wealthy we are.

Childhood is clearly an important part of life that can establish biological processes that can affect our health and wellbeing for years to come.

This latest study involved a sample of just under 500 participants from the Philippines, and included a trail of data that dated back to the early 1980s.

Blood collected in 2005 was used to analyse 114 genes associated with immune processes that regulate inflammation.

The methylation of nine of those genes was found to have a close relationship with a number of childhood variables including household socioeconomic status in childhood, extended absence of a parent in childhood, and even whether the person was born in the dry season.

This isn't the first indication of our birth season being stamped into our DNA and affecting our immune system, either.

In other words, by identifying certain childhood experiences, it was possible for the researchers to predict whether one or more of those nine inflammation genes would be on or off.

Inflammation can be something of a two-edged sword as far as immunity goes – while the opening of blood vessels and swelling that goes with it can help fight infections and promote healing, it can cause discomfort and damage if it persists.

Regulation of inflammation genes might help balance that cost under certain circumstances, but since the genes are then silenced – and rarely switched back on again – it could also open the way for sickness later in life.

The research could help explain the prevalence of cardiovascular and certain inflammatory diseases in specific communities.

It also adds to the ever growing body of evidence that highlights the diverse ways changes to our immune system can affect how our adult bodies cope with disease.

More research on the genes emphasised by the study could reveal additional clues on how the environment influences the functioning of our genes.

Meanwhile, we now have even more evidence that what happens to us early in our lives can stick with us for a long time to come.

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

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Have it ever occurred to you to ask why, if evolution is so good, then why hasn't it bestowed humans the capability to live forever but instead chose the way of the rabbit—that is, allowing humans to breed wildly to such large numbers but to the extent that we are now filling the earth over its capacity to support us all?

Darwin and other scientists after him did ask the question, but no one could come up with any good answer. Until now.

Now, researchers at the Institute of Molecular Biology (IMB) in Mainz, Germany, have made a breakthrough in understanding the origin of the ageing process. They found that genes belonging to a process called autophagy—one of the cell's most critical survival processes—promote health and fitness in young worms but drive the process of ageing later in life. This research published in the journal Genes & Development gives some of the first clear evidence for how the ageing process arises as a quirk of evolution. These findings may also have broader implications for the treatment of neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's disease where autophagy is implicated. The researchers show that by promoting longevity through shutting down autophagy in old worms, there is a strong improvement in neuronal and subsequent whole body health.

Getting old is something that happens to everyone and nearly every species on this planet, but the question is, should it? In a recent publication in the journal Genes & Development titled "Neuronal inhibition of the autophagy nucleation complex extends lifespan in post-reproductive C. elegans," the laboratory of Dr Holger Richly at IMB has found some of the first genetic evidence that may put this question to rest.

As Charles Darwin explained, natural selection results in the fittest individuals for a given environment surviving to breed and pass on their genes to the next generation. The more fruitful a trait is at promoting reproductive success, the stronger the selection for that trait will be. In theory, this should give rise to individuals with traits which prevent ageing as their genes could be passed on nearly continuously. Thus, despite the obvious facts to the contrary, from the point of evolution ageing should never have happened. This evolutionary contradiction has been debated and theorized on since the 1800s. It was only in 1953 with his hypothesis of antagonistic pleiotropy (AP) that George C. Williams gave us a rational explanation for how ageing can arise in a population through evolution. Williams proposed that natural selection enriches genes promoting reproductive success but consequently ignores their negative effects on longevity. Importantly, this is only true when those negative effects occur after the onset of reproduction. Essentially, if a gene mutation results in more offspring but shortens life that's fine. This is because there can be more descendants carrying on the parent's genes in a shorter time to compensate. Accordingly, over time, these pro-fitness, pro-ageing mutations are actively selected for and the ageing process becomes hard-wired into our DNA. While this theory has been proven mathematically and its implications demonstrated in the real world, actual evidence for genes behaving in such as fashion has been lacking.

This evidence has now arrived according to the co-lead author of the paper, Jonathan Byrne, "The evolutionary theory of ageing just explains everything so nicely but it lacked real evidence that it was happening in nature. Evolution becomes blind to the effects of mutations that promote ageing as long as those effects only kick in after reproduction has started. Really, ageing is an evolutionary oversight." Jonathan continues, "These AP genes haven't been found before because it's incredibly difficult to work with already old animals. We were the first to figure out how to do this on a large scale." He explains further, "From a relatively small screen, we found a surprisingly large number of genes [30] that seem to operate in an antagonistic fashion."

Previous studies had found genes that encourage ageing while still being essential for development, but these 30 genes represent some of the first found promoting ageing specifically only in old worms. "Considering we tested only 0.05% of all the genes in a worm, this suggests there could be many more of these genes out there to find," says Jonathan.

The evidence for ageing driven by evolution was not the only surprise the paper had in store, according to Thomas Wilhelm, the other co-lead author on the paper. "What was most surprising was what processes those genes were involved in." Not content to provide just the missing evidence for a 60-year-old puzzle, Wilhelm and his colleagues went on to describe what a subset of these genes do in C. elegans and how they might be driving the ageing process. "This is where the results really get fascinating," says Dr Holger Richly, the principal investigator of the study. "We found a series of genes involved in regulating autophagy, which accelerate the ageing process."

These results are surprising, indeed: the process of autophagy is a critical recycling process in the cell, and is usually required to live a normal full lifetime. Autophagy is known to become slower with age and the authors of this paper show that it appears to completely deteriorate in older worms. They demonstrate that shutting down key genes in the initiation of the process allows the worms to live longer compared with leaving it running crippled. "This could force us to rethink our ideas about one of the most fundamental processes that exist in a cell," Holger explains. "Autophagy is nearly always thought of as beneficial even if it's barely working. We instead show that there are severe negative consequences when it breaks down and then you are better off bypassing it all together." "It's classic AP," he continues, "In young worms, autophagy is working properly and is essential to reach maturity but after reproduction, it starts to malfunction causing the worms to age."

In a final revelation, Richly and his team were able to track the source of the pro-longevity signals to a specific tissue, namely the neurons. By inactivating autophagy in the neurons of old worms they were not only able to prolong the worms life but they increased the total health of the worms dramatically. "Imagine reaching the halfway point in your life and getting a drug that leaves you as fit and mobile as someone half your age who you then live longer than—that's what it's like for the worms," says Thomas Wilhelm. "We turn autophagy off only in one tissue and the whole animal gets a boost. The neurons are much healthier in the treated worms and we think this is what keeps the muscles and the rest of the body in good shape. The net result is a 50% extension of life."

While the authors do not yet know the exact mechanism causing the neurons to stay healthier for longer, this finding could have real-world implications. "There are many neuronal diseases associated with dysfunctional autophagy such as Alzheimer's, Parkinson's, and Huntington's disease. It is possible that these autophagy genes could represent a good way to help preserve neuronal integrity in these cases," elaborates Thomas Wilhelm. While any such a treatment would be a long way off, assuming such findings could be recapitulated in humans, it does offer a tantalizing hope—prevent disease and get younger and healthier while doing it.

SOURCE

 

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New Research Explains the Origin of Complex Life on Earth

Researchers from the Wits University in South Africa have discovered an important step in the evolution of complex life on Earth. Their study shows how small non-living RNA molecules combined to form larger, self-replicating molecules.


SIMPLY COMPLEX
Life remains one of the greatest and most beautiful mysteries of the universe. For one, it continues to baffle scientists that we only seem to have found life here on Earth and nowhere else in the vast expanse of space. For the time being, at least. The origins of life itself, from the simple to the complex, is a story of scientific wonder — one that is still being written today.

In a recent study published in the journal Royal Society Open Science, researchers from the Evolutionary Studies Institute at the University of the Witwaterstrand (Wits University), Johannesburg in South Africa discussed a discovery regarding how complex life evolved on Earth. “Life was a chance event, there is no doubt about that,” researcher Pierre Durand from the Evolution of Complexity Laboratory said in a press release.

This chance event Durand was referring to was that small strands of molecules linked up to form larger molecules capable of self-replication. Through a chemical reaction called ligation, simple RNA molecules join with other RNA molecules thanks to an enzyme they possessed. Supposedly, RNAs randomly connected with each other and replicated, thereby jump starting the process of life. “Molecular trade-offs in RNA ligases affected the modular emergence of complex ribozymes at the origin of life,” Durrand explained.


LIFE’S SIMPLE BEGINNINGS
In their research, Durrand and his colleagues successfully demonstrated how it’s possible for small, non-living molecules to become larger molecules capable of reproducing themselves. This is a crucial step in a series of many that made it possible for life to evolve over a long period of time. “Something needed to happen for these small molecules to interact and form longer, more complex molecules and that happened completely by chance,” Durand added.

Even more surprising was how the smallest of these simple molecules (a 40-nucleotide RNA) was smaller than what the researchers expected. Nucleotides are the building blocks of nucleic acids, which in turn make up RNA and DNA. “The small molecules are very promiscuous and can join other pieces to themselves,” Durrand explained. “What was interesting was that these smaller molecules were smaller than we had originally thought.”

As our understanding of how complex life came to be continues to evolve, we learn more about what makes life possible. Furthermore, now that we know how complex life came to be on Earth, perhaps we’ll be better equipped to find life elsewhere. Whether complex life started on the oceans — as is widely accepted — or on land, what’s clear is that it started at a particular moment in Earth’s history.



SOURCE

 

[Stormer0628]

How Mighty Dinos Became Chickens and Birds

From Apex Predator Straight into the Frying Pan:
How Mighty Dinos Became Chickens and Birds

ONCE YOU KNOW that many dinosaurs had feathers, it seems much more obvious that they probably evolved into birds. But there’s still a big question. How did a set of dinosaurian jaws with abundant teeth (think T. rex) turn into the toothless jaws of modern birds, covered by a beak? Two things had to happen in this transition, suppression of the teeth and growth of the beak. Now new fossil evidence has shown how it happened.

In a new study, Shuo Wang from the Capital Normal University of Beijing and colleagues studied a series of dinosaur and early bird fossils to see the transition. They found that some dinosaurs evolved to lose their teeth as they got older and sprouted a small beak. Over time, this process happened earlier and earlier until eventually the animals emerged from their eggs with a fully formed beak.

The oldest birds actually had reptilian-like teeth – for example Archaeopteryx from the late Jurassic period (150m years ago) and Sapeornisfrom the early Cretaceous (125m years ago). But other early birds had lost their teeth, such as Confuciusornis, also from the early Cretaceous.

Modern birds all lack teeth, except for the South American hoatzin, Opisthocomus, whose hatchlings have a small tooth that they use to help them escape from their egg and then shed. Developmental experiments in the 1980s showed that modern birds could probably generate teeth if their jaw tissue was artificially stimulated with the right molecules. This suggests their ancestors at some point grew teeth naturally.

A Hoatzin​

Meanwhile, many dinosaurs actually did have beaks of some kind. Beaks are composed of keratin, the tough, flexible protein that also makes fingernails and cow horns, as well as feathers and hairs. We typically think of beaks as all-encompassing structures, extending from the pointed tip at the front back to the eyes, and including the nostrils in modern birds. But fossil examples show that many toothed dinosaurs actually possessed a minimal beak at the front of the snout.

To find out exactly how beaks came to replace dinosaur teeth, the researchers had to look inside the animals’ jaw bones. Dinosaur bone fossils are not simply rocky casts of the original bone, but they nearly always show all the internal structure. A microscopic thin section from any dinosaur bone shows all the detail of internal canals for blood vessels and nerves, as well as pits where the bone-generating cells sat. Thin sections of fossil jaw bones show the teeth in as much detail as in any modern jaw bone.

Nowadays, bones are rarely cut up, and it is much more common to use computed tomography (CT) scanning to look inside the bones without damaging them. The CT scans are a closely spaced series of X-rays that allow researchers to construct detailed 3D models showing every fine detail within the bone.

Wang and colleagues observed that the theropod dinosaur Limusaurus, which was closely related to birds’ ancestors, and the early bird Sapeornishad teeth right to the front of the jaws when they were young but lost them as they grew up. The detailed internal scans of the fossils showed adult Limusaurus had no teeth but still had tooth sockets in their lower jaws, closed off and forming a single canal. In adult Sapeornis, there were teeth at the back of the jaw but not at the front of the jaw.

As modern birds develop inside their eggs, the beak keratin begins to form at the tip of the snout and then grows back to cover both upper and lower jaws. Wang and colleagues argue that the mechanisms that regulate beak growth also suppress tooth formation. This is supported by studies of the gene BMP4 that show it controls both functions in modern birds.

Using the fossils to show how the animals evolved over time suggests beaks in some dinosaurs and bird relatives originally expanded backwards as the animals grew up and tooth sockets closed off. Eventually, this process happened earlier and earlier in the developmental cycle until hatchlings emerged with beaks and no teeth. Today, the bone gene BMP4 controls aspects of beak growth and tooth suppression, and these might have been acting early in bird evolution.

For more evidence, Wang and colleagues looked more widely across vertebrates that have lost or reduced their teeth as they evolved, including some fishes, frogs, pangolins, whales and the entirely toothless turtles. In all cases, animals that had lost their teeth were associated with replacement of the teeth by a keratin beak.

These kind of developmental observations help confirm the theory that the exquisite dinosaur fossils point to. In becoming birds, dinosaurs had to change in many ways, including shrinking in size, sprouting wings, adapting feathers that were used for display and flight , improving their senses, shortening their tails, losing teeth, and many other characters. It is important to be able to identify plausible evidence for how each of these amazing changes happened.

Michael J. Benton is a Professor of Vertebrate Palaeontology at the University of Bristol



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New Editing Technique Removes Disease in Human Embryo for First Time

Precise "chemical surgery" has been performed on human embryos to remove disease in a world first, Chinese researchers have confirmed.

The team at Sun Yat-sen University used a technique called base editing to correct a single error out of the three billion "letters" of our genetic code.

They altered lab-made embryos to remove the disease beta-thalassemia. The embryos were not implanted.

The team says the approach may one day treat a range of inherited diseases.

Base editing alters the fundamental building blocks of DNA: the four bases adenine, cytosine, guanine and thymine.

They are commonly known by their respective letters, A, C, G and T.

All the instructions for building and running the human body are encoded in combinations of those four bases.

The potentially life-threatening blood disorder beta-thalassemia is caused by a change to a single base in the genetic code—known as a point mutation.
The team in China edited it back.

They scanned DNA for the error then converted a G to an A, correcting the fault.

Junjiu Huang, one of the researchers, told the BBC News website: "We are the first to demonstrate the feasibility of curing genetic disease in human embryos by base editor system."

He said their study opens new avenues for treating patients and preventing babies being born with beta-thalassemia, "and even other inherited diseases".

The experiments were performed in tissues taken from a patient with the blood disorder and in human embryos made through cloning.

Genetics revolution
Base editing is an advance on a form of gene-editing known as Crispr, that is already revolutionising science.

Crispr breaks DNA. When the body tries to repair the break, it deactivates a set of instructions called a gene. It is also an opportunity to insert new genetic information.

Base editing works on the DNA bases themselves to convert one into another.

Prof David Liu, who pioneered base editing at Harvard University, describes the approach as "chemical surgery".

He says the technique is more efficient and has fewer unwanted side-effects than Crispr.

He told the BBC: "About two-thirds of known human genetic variants associated with disease are point mutations.

"So base editing has the potential to directly correct, or reproduce for research purposes, many pathogenic [mutations]."

The research group at Sun Yat-sen University in Guangzhou hit the headlines before when they were the first to use Crispr on human embryos.

Prof Robin Lovell-Badge, from the Francis Crick Institute in London, described parts of their latest study as "ingenious".

But he also questioned why they did not do more animal research before jumping to human embryos and said the rules on embryo research in other countries would have been "more exacting".

The study, published in Protein and Cell, is the latest example of the rapidly growing ability of scientists to manipulate human DNA.

It is provoking deep ethical and societal debate about what is and is not acceptable in efforts to prevent disease.

Prof Lovell-Badge said these approaches are unlikely to be used clinically anytime soon.

"There would need to be far more debate, covering the ethics, and how these approaches should be regulated.

"And in many countries, including China, there needs to be more robust mechanisms established for regulation, oversight, and long-term follow-up."


SOURCE

 

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Genes that control complexity found

Genes that determine animal complexity—or what makes humans so much more complex than a fruit fly or a sea urchin—have been identified for the first time. The finding also places a limit on the usability of biomedical research on lower animal form in laboratory experiments, since what works for mice or other lower life forms may not necessarily transfer to the more complex genetic structures of humans.

The secret mechanism for how a cell in one animal can be significantly more complex than a similar cell in another animal appears to be due to proteins and their ability to control 'events' in a cell's nucleus.

The research, by biochemist Dr Colin Sharpe and colleagues in the University of Portsmouth, is published in PLoS One.

Dr Sharpe said: "Most people agree that mammals, and humans in particular, are more complex than a worm or a fruit fly, without really knowing why. The question has been nagging at me and others for a long time.

"One common measure of complexity is the number of different cell types in an animal, but little is known about how complexity is achieved at the genetic level. The total number of genes in a genome is not a driver, this value varies only slightly in multicellular animals, so we looked for other factors."

Dr Sharpe and MRes student, Daniela Lopes Cardoso interrogated large amounts of data from the genomes of nine animals—from humans and macaque monkeys to nematode worms and the fruit fly, and calculated how diverse each was at the genetic level.

They found a small number of proteins which were better at interacting with other proteins and with chromatin, the packaged form of DNA in the cell nucleus.

"These proteins appear to be excellent candidates for what lies behind enormously varied degrees of complexity in animals," Dr Sharpe said.

"We expected to identify genes that interacted directly with DNA to regulate other genes, but this was not the case. Instead we identified genes that interacted with 'chromatin'.

"Our results suggest that the increased ability of certain proteins to interact with each other to regulate the dynamic organisation of chromatin in the nucleus as a component of animal complexity."

The results matter, he said, because biomedical scientists depend on better understanding human disease by studying it in animals. While this has value, there is an underlying concern that an animal model may be too simple to be useful, that results seen in a simpler animal may not correlate with what happens in a more complex animal.

Understanding the inherent differences in how animals are organised at genetic level and the limitations to interpretations that this imposes, will provide a more rational selection of appropriate animal models in biomedicine.

Dr Sharpe and team's previous research found that three factors lay behind the proteins made by one gene—NCoR—being more diverse in complex animals such as humans compared to, for example, sea urchins:

• Gene duplication, although the total number of genes in the genome doesn't vary significantly, some specific genes duplicate one or more times, for example there is one NCoR gene in sea urchin and two in humans.
• Single genes often make more than one protein. The messenger RNA (mRNA) that links gene to protein can be processed by 'splicing' to generate a range of different mRNAs, each of which encodes a related, but different protein. For example, the sea urchin gene produces just one type of RNA while in humans the NCoR2 gene produces well over 30 and each is likely to have a different function.
• Most proteins consist of domains that have a specific function. Dr Sharpe and team found that the number of domains increases, again with NCoR, from one in sea urchins to three in humans.

SOURCE

 

[Stormer0628]

Re: Genes that control complexity found

What If We Could Literally Rewrite the Human Genome?​

Some years ago, basic science research led to CRISPR, a remarkable new tool that gives us the power to edit DNA—the source code of life itself. Now, a fourth-generation DNA base editor is already here, packed with more power than the original and promising more capabilities to manipulate the human genome.

In this video, Berkeley biochemist and CRISPR expert Sam Sternberg shares the thrilling story that led to this development and what it means for the future of humanity.

 

[Stormer0628]

Re: Genes that control complexity found

Loved and loathed in equal measure, the durian’s genes reveal why the fruit smells so pungent​

There are only two types of people in the world: those who absolutely love durian, and those who absolutely hate it. There is no middle ground.

There's a good reason why durian – a large, spiky fruit common in Southeast Asia (Thailand, Indonesia, Malaysia, Philippines) – evokes such a mixed reaction.

It is a major cash crop, and while its millions of devotees call it the king of fruit, it’s critics are not so kind. Typical is US chef and food writer Anthony Bourdain, who wrote that “it smelled like you'd buried somebody holding a big wheel of Stilton in his arms, then dug him up a few weeks later.”

Indeed, the smell of durian is so strong, a rich blend of sulfur, onion and (some add) old sock, that it is banned on many forms of public transport and in most major hotel chains.

Despite the fact that more than 250,000 hectares are given over to durian cultivation, until recently very little was known about the genetic basis for its shape, texture, taste and smell.

Now, however, a team, led by Bin Tean Teh from Thorn Biosystems in Singapore has succeeded in sequencing the durian genome for the first time, down to single-molecule resolution.

The scientists used a popular cultivar of the plant (Durio zibethinus) in an attempt to unlock the genetic mechanisms that cause the ripened fruit to give off – as they diplomatically describe it – “a complex suite of odour-active compounds including sulfur volatiles, esters, alcohols, and acids”.

The team found the plant had undergone a whole genome replication event, which probably occurred before it split with its distant relatives, cotton and cacao.

Such duplication events, the scientists note, are often strong drivers of evolution, in part because they create a lot of newly redundant alleles that can then develop novel functions. This appears to have happened with durian, where there has been a boost to genes linked to the presence of sulfur compounds, particularly in the fruit of the plant.

The research also found a genetic link for increased production of ethylene – a sweet-smelling compound that lends durian’s odor its “oniony” dimension and is a key olfactory indicator of ripeness.

“It is possible that linking odour and ripening may provide an evolutionary advantage for durian in facilitating fruit dispersal,” the researchers write, suggesting that sweet smells are prime tools used by some other plant species that depend on large animals, such as primates, to distribute their seeds.

Bin Tean Teh and colleagues conclude that the fully sequenced genome will be useful in research to better manage the hundreds of D. zibethinus cultivars that are grown through southeast Asia.

The data will also be useful in studying the 30 species that share the durian’s genus, many of which don’t produce fruit, and some of which are endangered.

The research was published in the journal Nature Genetics.


SOURCE

 

[Stormer0628]

Frustrating Race Supremacists, Again

Racism is a grotesque inheritance passed down from light-skinned people living in Europe in the Middle Ages, whose newfound ability to travel long distances led to their first encounters with darker-skinned people. So alarmed by the differences in skin color, they failed to comprehend that the people they encountered were, in fact, human — and treated them as such.

Those long-held racist assumptions based on skin color have been scientifically proven wrong, according to a groundbreaking new study in the journal Science published on Thursday.

With their observations, the team of geneticists led by the University of Pennsylvania’s Sarah Tishkoff, Ph.D., tear down that notion by discrediting the idea that race has any biological roots. (The paper is titled “Loci associated with skin pigmentation identified in African populations.”)

The researchers identified the genes linked to the diversity of human skin color and when and where those genes emerged.

“The fact is that many of these variants that we found to be associated with light skin — that are really common now in Eurasians — originated in Africa,” she tells Inverse. “Here are these genes that impact skin color, and they have an African origin. Even the ones associated with light skin.”

Tishkoff and her team had been studying genetic diversity among different African populations when they realized the strikingly vast range of skin colors present in African people, from the darker tones that are commonly associated with people in Africa to the very pale skin commonly linked with Europeans.

“In Ethiopia, you’ll find people with very dark skin tones who have this Nilo-Saharan ancestry, who originated in southern Sudan, and then you’ll see people not that far away who have pretty light skin tones,” says Tishkoff. Her team wanted to know what genes were linked to those different skin tones, and whether they were the same genes linked to light or dark skin elsewhere in the world.

And so, they compared the skin tone and the DNA of 1,600 people from ethnically and genetically diverse populations all across Africa to find those genes. To capture skin tone accurately, they used a color meter to measure the light reflectance on each individual’s inner arm, where the sun is least likely to alter the natural skin color. Then, by comparing these observations with their analysis of each person’s genome sequence, they pinpointed four genes whose genetic code showed significant variation between people with different skin colors.

The vast diversity of human skin color, they found, is largely due to a few tiny tweaks to the gene sequences in these regions.

Of the four genes they identified, the one most strongly associated with skin tone was SLC24A5, which has been shown to influence light skin tones in European and some southern Asian populations. The others include the MFSD12 gene, which is associated with a skin condition called vitiligo that makes skin lighter in some areas, and OCA2 and HERC2, which are also associated with light skin. These genes, Tishkoff says, aren’t just widespread both inside and outside of Africa but are also very old, suggesting that the idea that some humans have them and others do not is completely bunk.

“These mutations are old. Most of them predate the origin of modern humans. They’ve been variable for tens of thousands, if not hundreds of thousands of years in Africa,” she says. “Everyone had the alleles for light skin.”

Many scientists previously believed that the mutations responsible for light skin arose very recently, but “that’s not entirely the case,” says Tishkoff. She explains that research in the genetics of skin color has been complicated because previous studies had all been conducted on Europeans, and the genes that emerged from those efforts all seemed to have a distinctly European origin. As the new study shows, however, many of the alleles associated with light skin tones, in fact, have an African origin.

How those alleles became so common in certain parts of the world and less common in others is the story of early human migration and their interaction with the environment. Modern humans are thought to have emerged in Africa between 200,000 and 300,000 years ago and spread out somewhere between 50,000 and 80,000 years ago, but where they went (and whether they returned to Africa) is up for debate.

There are two leading hypotheses describing how they traveled. The first is that there was single African source population that traveled out of Africa and spread all over the globe. The second, which she says her data is more consistent with, suggests humans first moved toward south Asia and Australo-Melanesia about 80,000 years ago, and then moved again, this time northward, around 60,000 years ago, giving rise to all other populations.

“We don’t know for sure which is correct,” she says.

What we do know is that during these migrations, alleles for certain skin tones were naturally selected for or against depending on the amount of sun in that region. Skin tone is thought to be an adaptation for dealing with varying levels of sunlight; dark skin, which is better able to deal with harmful UV rays, is better suited for people in high-sun environments, while light skin is better suited for creating vitamin D in minimal sunlight.

After generations of natural selection, the light skin alleles became uniform among European populations, and dark skin alleles were maintained in sunnier, hotter regions. But in the original modern human source population, everyone had those genes — in fact, we probably inherited them from our hominin ancestors.

“Any population that left [Africa] almost certainly had the light and the dark alleles because they’re so old,” says Tishkoff, who explains that with the genes her team identified, many of the ancestral variants were, in fact, the light-skinned variant. “One of the reasons for thinking that is that our closest ancestors are chimps,” she says.

Dark skin isn’t necessary when you have body hair, she explains, but around the time of Homo habilis, who left the forest and went into the savannah, there would have been natural selection to lose the body hair and increase the number of sweat glands, and if they lost the body hair there would be a selection to have darker pigmented skin because of more skin exposure.

There’s a lot we still don’t know about the biology of skin color, but the more we learn about it, the less important skin color seems to be. If you think of every human’s genome as a novel written in just four nucleotide letters — G, A, T, and C — the genetic differences between people with different skin tones don’t amount to much more than alternate spellings of certain words.


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[Stormer0628]

The Invisible Universe of Human Microbiome

...

MORE:

Meet Your Microbiota and the Universe Inside Your Body

 

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Re: The Invisible Universe of Human Microbiome

Curing any disease is difficult, from sickle cell to HIV. Cancer, being an umbrella term for 200 or so different biological afflictions, is notorious in this sense – but thanks to the advancement of science over the years, survival rates are going up, and innovative cures are increasing in number.

A trio of new studies, published in the journals eLife, Cell Cycle and Oncotarget, hint at a method that may one day be used to cure any type of cancer.

This technique has been rather dramatically described by Northwestern University scientist and the study’s lead author, Marcus Peter. In a statement he explained that, for the cancer, “it’s like committing suicide by stabbing yourself, shooting yourself and jumping off a building all at the same time.”

“You cannot survive,” he adds, somewhat superfluously. So what exactly is this game-changing discovery?

First, it’s worth remembering that cancer is unchecked cell division and growth, triggered by genetic damage. It’s a malfunctioning biological program that appears to be extremely primitive, one that may have long-ago been a self-preservation response to an ancient disease.

What something like this needs is a “kill switch,” some sort of command that will stop these cells from dividing ad infinitum. This kill switch is precisely what Peter and his colleagues appear to have identified.

After perusing through the human genome, they found a handful of sequences that acted rather strangely when converted from DNA into RNA – a simpler form of biological “data storage” that is thought to have emerged before DNA.

These RNA strands, known as small interfering RNAs, have been identified by researchers before. They’re notable because instead of helping genes influence the organism, they seem to actively suppress the gene they were transformed from.

The RNA strands isolated by Peter’s team don’t just suppress their original genes, however: they also switch off cancerous cells when reinserted back into them, thanks to a similar genetic suppression mechanism.

The team found no exceptions to this rule, and any cancer cell they tested self-destructed. Importantly, cancer doesn’t seem to be able to build up a resistance to the RNA over time either, something the team describes as a world first.

The team posited that this kill switch has been present in life ever since the first multicellular organism appeared more than 2 billion years ago. If it didn’t, then cancer would have wiped out complex creatures long ago. Sadly, along the way – perhaps as immune systems became more adaptive to infections – plenty of animals appear to have lost the ability to use these RNA strands.

This revelatory research suggests that, finally, this kill switch could be reactivated in humans, potentially ushering in a new age of chemotherapy. Human trials are a fair way off for now, but one of the team’s papers reveals that in cancer-riddled mice, use of these RNA strands killed off much of the cancer with no harm to the mice themselves.

Yes, cancer is a many-headed beast, one that robs the world of millions of lives every single year. Treatments can vary wildly from patient to patient, from disease to disease. You can cure some quite easily with early detection, whereas others have a very low survival rate even today.

Chemotherapy has some dreadful side-effects, and even the nascent fields of gene-editing immunotherapy – which provokes the body’s own defense mechanisms into fighting the cancer – isn’t side-effect free.

Now imagine if this RNA technique works on human cancers of any type, to no major detriment. It would be a cure for all cancers; a genuine revolution in biomedical sciences.

“Our findings could be disruptive,” Peter concludes.



SOURCE


Scientists Discovered a “Kill Switch” That Destroys Any Cancer Cell

 

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Gene editing breakthrough could destroy thousands of deadly diseases

A new gene editing breakthrough allows scientists to easily snip out problems in genetic code, potentially removing thousands of deadly inherited diseases.

The new technique could allow doctors to make changes to people's DNA and alter the molecular machines that help create us – along with problems in the form of genetic diseases.

It would allow them to remove the mutations blamed for inherited conditions ranging from genetic blindness to sickle-cell anaemia, metabolic disorders and cystic fibrosis. And it could also be used to "write in" useful mutations, according to the scientists who made the discovery.

The "base editor" is a molecular machine that directly converts one building block of DNA into another. DNA sequences contain four "base" chemicals that pair up on the molecule's twin-stranded double helix in specific ways.

As such, edits made to the DNA using the new tools are far more precise than the leading and most famous technology, CRISPR. "CRISPR is like scissors, and base editors are like pencils," said David Liu, the chemical and molecular biologist who led the study.

Together, guanine (G), adenine (A), thymine (T) and cytosine (C) make up the letters of the genetic code. The new system converts the DNA base-pair A-T to G-C, a microscopically small effect that has massive implications for science and medicine.

Roughly half the 32,000 single-letter changes in the genetic code known to be associated with human disease involve change the other way, from G-C to A-T.

The technique employs a modified form of the "molecular scissors" gene-editing tool CRISPR-Cas9, which has transformed genetics research since its power was first demonstrated in 2012.

But unlike standard CRISPR-Cas9, it does not make changes by slicing through the double helix.

Professor Liu, from Harvard University said: "We developed a new base editor, a molecular machine, that in a programmable, irreversible, efficient and clean manner can correct these mutations in the genome of living cells.

"When targeted to certain sites in human genomic DNA, this conversion reverses the mutation that is associated with a particular disease."

The "machine," called an Adenine Base Editor (ABE), was tested in the laboratory by correcting the mutation responsible for hereditary haemochromatosis (HHC), a disease that causes iron overload in the body.

ABE was also used to install a beneficial mutation that protects against blood diseases including sickle cell anaemia.

The results are reported in the journal Nature.

Dr Liu said a lot more work needed to be done before the technique could be used to help human patients.

"We still have to deliver that machine, we have to test its safety, we have to assess its beneficial effects in animals and patients and weigh them against any side effects, we need to do many more things," he added.

British scientists called the research "exciting" and "incredibly powerful."

Professor Robin Lovell-Badge, group leader at The Francis Crick Institute, London, said: "This is both clever and important science...

"Many genetic diseases are due to alterations (mutations) where a single base pair has been substituted for another.

"This makes these new base editing methods of great value in both basic research to make disease models and, in theory, to correct genetic disease.

"Much more research will be needed to show the methods are entirely safe and, perhaps, to find ways to increase their efficiency, which is already at an impressive 50 per cent, but this is an exciting development."

Dr Helen O'Neill, reproductive science programme director at University College London, said: "The ability to now directly alter all four base-pairs with such specificity adds more ammunition to the genome editing artillery and will be incredibly powerful in the research of diseases and future restoration of disease-causing mutations."

Darren Griffin, professor of genetics at the University of Kent, said: "The work represents another step change in the Crispr story."

Another ground-breaking study reported in the journal Science showed how a new version of Crispr could be used to target and edit RNA, the molecule that carries genetic instructions to protein-making machinery in cells.

The system, called Repair, has the potential to render single-letter disease-causing mutations in DNA harmless.

David Cox, a member of the US team at the Massachusetts Institute of Technology's Broad Institute, said: "Repair can fix mutations without tampering with the genome, and because RNA naturally degrades, it's a potentially reversible fix."



SOURCE



MORE:


Groundbreaking DNA and RNA editing could cure up to 15,000 diseases: Scientists can swap out genetic mutations including cystic fibrosis


Gene Editing Just Became More Precise And Powerful Than Ever Before

 

[Stormer0628]

Re: Gene editing breakthrough could destroy thousands of deadly diseases

The so-called “year without a summer,” 1816, was bleak, if not strangely gothic. Mount Tambora in Indonesia had erupted the year before, pitching volcanic ash into the atmosphere and obscuring the sun. Torrential rains pressed deep into the year, resulting in global crop failures. The birds quieted down by midday, as darkness descended, and for days at a time, a group of writers huddled by candlelight in a rented mansion on Lake Geneva. The dashing 23-year-old poet Percy Shelley and his 18-year-old companion, Mary, who had already taken to calling herself “Mrs. Shelley,” traveled to the lake to spend the summer with the poet Lord Byron. On the night of June 15, 1816, they read ghost stories aloud. And then, Byron suggested they each try their hand to write one.

Mary Shelley would write her stunning exegesis Frankenstein, or The Modern Prometheus in just under 11 months. She set forth to write a penny dreadful but instead wrote a stinging commentary on the times that came to her in a flash, a waking dream. A collision of forces discharged in her writing, and she produced something more than a ghost story—a “book of ideas.”

Many in Shelley’s generation, including her companion Percy, sought to break with traditional values such as the monarchy, military, marriage, and social class, opting instead for reason of scientific inquiry, free love, and atheism; but this shift to impersonal rationalism also triggered recoil. Mary’s father, William Goodwin, author of Enquiry into the Principals of Political Justice “believed, like Voltaire, in the power of pure reason to solve all social, political, and personal problems. And like Rousseau, Godwin felt that humans are by nature benevolent and become evil only when abused by society. Government, he preached, and other institutions like marriage and the family, impose evil restraints on citizens and “must be abolished” urging “well-educated citizens working toward a better world by repressing emotions and reasoning person-to-person.”

Shelley was struggling to bring competing ideas into a “symbolic synthesis,” which, as literary critic Walter James Miller notes, included “her anguish as the neglected child of a genius” and “her dread of her father’s impersonal rationalism and her husband’s unconditional love of science.” The trick she pulls on the men in her life is to let them win to the full extent—the name of the main character in Frankenstein, “Victor,” is ironic. “I have described myself as always having been imbued with a fervent longing to penetrate the secrets of nature,” the scientist tells us. Frankenstein sets out to create a perfect human. So shall it be. The figure that he creates, which never gets a name, has a penetrating intelligence, and a ferocious love of life. He is 8 feet tall and bolts through the Swiss Alps with stag-like swiftness, has translucent, yellowish skin. He is, in a sense, engineered as the perfect machine. But no one cares a damn for him. He is alone, and his loneliness and existential grief drive him to exhaustion and the brink of insanity. As scholar Harold Boom has noted, Frankenstein and the figure he creates are “antithetical halves of a single being.” The monster signifies the rise of the Industrial Revolution and its machines, and shows how the things we create come to subordinate us to its apparatus, schedules, and order. . It needs us. It demands our time.

Frankenstein’s monster started out good. He saves a young girl who falls into a slipstream, but a mountaineer calls it out for malicious intent, shooting him through the shoulder with a shotgun. The fiend stares through windows. He has incredible intelligence and ability, but he cannot connect. This perfect figure is everything science could hope to dream about, but he is a neglected orphan. He soon demands friendship. Victor learns he is bound to the figure he creates, which results in a haunting effect.

What we seek from technology is based on our
existential fear of being in control over our own lives.​

Deeply distraught by his loneliness, the fiend ends up stalking members of Frankenstein’s family, killing them. When the fiend plants evidence that leads to the wrongful conviction of a servant, the scientist willfully buys into the gambit. The repression of the scientist relates to his obsession with mastering a technology—so much so that he is no longer conscious of his own role and motivations, which are concealed in his transhumanist project.

Shelley drew on a mythology of technology that goes back to the 6th century B.C. when the figure Prometheus stole fire from the gods and bestowed it to mankind. The “fire bringer,” is often associated with Lucifer, (literally meaning “light bearer”), who pilfered light from the heavens and brought it down to Earth. The “fall of man” implies an age when mortals are illuminated with knowledge. Immanuel Kant was the first to modernize the term, when he nicknamed his pal, Benjamin Franklin, “the Prometheus of modern times” for his nifty work with kites. In the early 19th century, Shelley’s Frankenstein, or The Modern Prometheus put the concept into terms of controlling biological forces. She not only arguably invented science fiction, but her novel offered a plot device for modern tales, including Flowers for Algernon, The Stand, The Andromeda Strain, Jurassic Park, 2001: A Space Odyssey, and Yann Martel’s short story “We Ate the Children Last.” We all understand the illusions. A scientist sets out to create a more perfect entity, only to have it backfire as the thing he creates gets out of control.

By the early 1980s, Richard Mulligan at the Massachusetts Institute of Technology isolated genetic code and wrapped it up in a virus, returning it to humankind as a tool. In the same decade, companies such as Biogen and Genentech claimed the patents to control the first applications of genetic engineering. Scientists today are using the gene editing tool CRISPR to do things such as tinker with the color of butterfly wings, genetically alter pigs, and engineer microbes with potentially pathogenic or bioterror purposes. Last year, a group of 150 scientists held a closed-door meeting at Harvard Medical School to discuss a project to synthesize the code of a human genome from scratch using chemical techniques. As Andrew Pollack wrote in The New York Times, “the prospect is spurring both intrigue and concern in the life sciences community because it might be possible, such as through cloning, to use a synthetic genome to create human beings without biological parents.” In August, Shoukhrat Mitalipov at the Oregon Health and Science University in Portland reported using CRISPR to alter a human embryo.

We are at the very start of the “industrial revolution of the human genome,” just as Shelley was writing at the start of the Industrial Revolution. Her essential insight is that science and technology can progress but will never achieve social control without a willful and ongoing abdication, or repression, of our agency. Shelley wants to tell us that what we seek from technology is based on our existential fear of being in control over our own lives, which have no ultimate solution, and which compels us to so eagerly pursue what psychologists call an external locus of control. But mythology is often first presented as a utopia, only to result in a dystopian reality: disenchantment, even nihilism, new inequalities due to the commodification of life, a dystopian capitalism where wealthy parents can use in vitro fertilization to improve the fate of their children.

Shelley’s novel is visionary. The equation of STEM fields with what is moral, good, and responsible is the hinge of the mythology as it continues to this day, both in overt projects of science, and in the subtle psychology. Clones would be parentless children, a “product of science,” while germline engineering would engender a quality of “otherness.” The murder that is pervasive in her novel is reflective of a solipsistic logic that achieves its authority in science and eliminates alternative perspectives and absorbs motives into the very practice of science. The orphans that are left in it—and Shelley is obsessed with the orphan—exemplify an existential grief that continues to permeate life even in the case of scientific mastery. Shelley is not so much concerned that technology—and this extends to AI or CRISPR organisms—will take over the planet, as she is incredulous that we hope it would; we hope something would be in control.

The insistence on genetic science and neuroscience as a wellspring of meaning and an illuminated reality is at odds with the existentialists’ observation that personality often finds itself foreign—this foreignness is problematic for science. We think if only we had better data, we’d have complete control. Data has illuminated everything, so much so that we can no longer imagine a deeper reality, or counter-reality, as expressed in a “year without a summer.”

Shelley wants to tell us that despite the awesome progress of science, we will never be free from the circular discussions of who we are, or why we are doing anything at all, or whether life is even worth it. In the darkness and depths, and in the night, is where we struggle to grasp at these answers. She shows that devotion to science and its patriarchal work culture can be a form of repression, or a denial of agency. Any genetically engineered organisms or CRISPR babies will struggle for survival and a meaning of existence too, and may return to haunt us through their impact on their ecosystem, which would include us. In Frankenstein, Victor tells the fiend he must go. But the fiend asserts his own sanctity in defiance. “Life, although it may only be an accumulation of anguish, is dear to me, and I will defend it.”



Jim Kozubek is the author of Modern Prometheus: Editing the Human Genome with Crispr-Cas9 published by the Cambridge University Press.



SOURCE