Category Archives: Cell Biology

Cell Biology

Plumbing 101: Building the body’s tubes and branches – Knowable Magazine

At first glance, our bodies seem impossibly complex, with dozens of organs built to precise specifications in exactly the right places. It seems almost miraculous that all this could develop automatically from a single fertilized egg.

But look a little closer and youll see that evolution, the master architect, has been economical with that complexity, relying on the same components again and again in different contexts. Take tubes, for example. Were basically a bag of tubes, says Celeste Nelson, a developmental bioengineer at Princeton University. We have a tube that goes from our mouth to our rear end. Our heart is a tube. Our kidneys are tubes. So, too, are lungs, pancreas, blood vessels and more most of them intricate systems of tubes with many branches.

Branching tubes appear so often because they are the best solution to a key problem that organisms face as they get bigger: As an animal grows, its volume goes up faster than its surface area. That simple physical relationship means that the logistical challenges of supplying oxygen and nutrients, and removing waste products all of which ultimately depend on diffusion through the surfaces of cells get more daunting with size.

But a dense forest of branching tubes increases the available surface area enormously. They allow us to be big, says Jamie Davies, a developmental biologist at the University of Edinburgh.

In recent years, Davies, Nelson and a few other developmental biologists have made great progress in understanding how the body makes tubes and branches in a variety of organs. Though the details usually vary from one organ to the next, some basic principles are beginning to emerge, as outlined in an article coauthored by Nelson in the Annual Review of Biomedical Engineering. So far, it looks like there are only a few ways to make a tube, only a few ways to control how it branches, and only a few ways to regulate when branching should stop.

At the most general level, its not surprising that development is based on a few simple processes. Every tissue is made of cells, and those cells have only limited options to choose among, such as moving (individually or en masse), changing shape, dividing or undergoing self-destruction. I normally tell my students that about 90 percent of what we make we can account for with only about a dozen actions, Davies says.

And once evolution forged a few ways to create tubes and branches (the two go together, more often than not), it makes parsimonious sense that bodies would fall back on that same handful of methods again and again.

Start with a dimple, then extend: Many tubes start from a flat sheet of tissue that develops dimples, or pits. Its likely that these pits originate when a ring of contractile protein molecules scrunches up on one face of the sheet, causing that face to cup as the opposite face bulges outward.

In organs like lungs, mammary glands and kidneys, this initial pit can then get deeper, like dough as a finger pushes into it, until the pit deepens so much it becomes more like an extending tube. In one well-studied example, the ducts of the mammary glands, each growing duct has an unruly mob of cells at its tip. The cells in this mob respond to the hormones of puberty by dividing rapidly. As they pioneer the advance into new territory, some cells insert themselves into the lining of the tube, pushing the mob forward as the tube lengthens. Continued cell division keeps generating new cells that will in turn go on to line the tube.

The cool thing about this mechanism is that puberty says Go, and as long as hormones are still available, youre going to keep making cells, and theyre going to keep inserting, says Andrew Ewald, a developmental cell biologist at Johns Hopkins University School of Medicine, who led the work. In a mouse, this might be an inch of elongation. In a blue whale, youre talking about yards. You just leave the motor running longer.

Tubes form within the body in a variety of ways: by rolling up a single cell (used in tiny blood vessels called capillaries); by rolling up a sheet of cells (in making the spinal cord); by forming a dimple in a sheet of cells that deepens into a tube; or by cells in the center of a rod dying or migrating to leave a hollow inside the rod. The latter two processes are most common in building bodies.

Hollow out a rod: Cells in the interior of a solid rod die or release their contacts with one another to allow a space to form between them. The mammalian vagina forms by this sort of hollowing, as do the ducts of the pancreas, and probably the salivary glands.

Roll up, roll up: Still other tubes especially the tiniest capillaries of the circulatory system form when a single elongated cell rolls up to enclose a space. And the tube that will go on to form the nervous system arises from a much larger roll-up, in which two ridges of tissue atop the early embryo bend toward each other, like two breaking waves, until they meet in the middle and fuse, leaving a tube the barrel of the waves, in essence enclosed beneath a cover of cells.

Almost all the bodys tubes form in one of these ways. And theres another level where developing organs rely repeatedly on a small set of tricks and techniques: the construction of elaborate networks of branches from all those tubes.

Branches generally form either when a single growing tip encounters two different zones of attraction and sends a tip in each direction, or when something physically restricts the tips progression. In the lung, for example, branching occurs when a band of smooth muscle fibers forms across the tip of the growing tube, creating a barrier and forcing growth to both sides.

The developing embryo must also manage the spatial growth of branching tubes so that, for example, the lung fills with just the right amount of tiny, branched airways or the circulatory system delivers capillaries to every part of the body, all without overcrowding or gaps. Researchers are only beginning to understand this control process, although a few key points are emerging.

One simple management strategy is for tubes to branch if space is available and stop when they get crowded. That straightforward system seems to apply for the mammary glands, which are little more than masses of branching milk ducts embedded in a fatty matrix.

To better understand the process, Ben Simons, a developmental biologist at the University of Cambridge, and his colleagues examined preserved mouse mammaries in meticulous detail and mapped out where, and in what context, each individual branching event must have taken place to give rise to the final structure they saw.

They found that each tube continued to grow and branch only if it was not surrounded by other tubes. Actively growing tips formed a front at the edges of the mammary, advancing into new territory, but any new tips that turned inward, to territory already colonized, would shut down. These rules, played out over time, led the ducts to fill in the available space.

This animation illustrates the random branching that occurs in the developing mammary gland as its ducts are formed. The red dots are the tips of actively growing tubes that shut down their growth when they bump into another tube (or in this case, the boundary of the animation space).

CREDIT: E. HANNEZO & B. SIMONS / CELL 2017

The molecular signals that govern this behavior have not been fully worked out, though presumably some sort of inhibition is involved. Simons suspects that the same signaling system may go awry in breast cancer, since the early stages of that disease are characterized by extra branching. Its interesting to ask how tumors reactivate that branching program, and how come it doesnt terminate, he says and hes actively working to understand this.

This system of branching to fill space has the virtue of simplicity, Simons adds. Everything is local. The cells only have to sense whats happening in their neighborhood, and it doesnt require any memory. Cells dont have to remember what decision they made way back when.

But the downside is that the gland doesnt always fill the space perfectly. Occasionally, it leaves gaps in the interior ones that can no longer be filled because the growing tips are now all out at the periphery.

The pancreas also uses local rules to build a branched structure, but by a totally different route. The organ starts its life as a mass of cells that buds from the tube that forms the gut. Gradually, holes begin to appear in the mass, and these holes eventually fuse to create an interconnected meshwork of passages. It doesnt look like branches initially it looks like a net, or a road network in a city, says Anne Grapin-Botton, a developmental biologist at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany. But the process isnt done yet.

CREDIT: PROF. R. BELLAIRS

One of the most crucial tube-forming moments in embryo development is the rolling up, then fusion, of the long neural tube that will go on to form our brains and spinal cords. Yet as a mechanism, its also notoriously sloppy. Why execute a process that's so important in such a loosey-goosey manner?

No one knows why the neural tube forms in this unusual way, but it is known that the method is shared by at least one other tube in the body the urethra in the penis of male mammals. Both those tubes sometimes fail to close properly, leading to conditions known as spina bifida for the neural tube and hypospadias when the urethra opens on the underside of the penis instead of at the tip.

The error-prone nature of both may hold a clue, says developmental biologist Jamie Davies of the University of Edinburgh. Davies speculates that those two tubes would grow too slowly if they formed in other ways, and might not navigate through the body accurately enough. The risk of poor closure, he suggests, is preferable to the risk of a tube routing itself to the wrong spot.

Bob Holmes

The passages initially are tiny. As the cells that line them begin to secrete their fluids into the open spaces, though, Grapin-Botton hypothesizes that the channels with higher flow rates begin to widen, and those with low flow rates narrow. When she simulates this process using the same mathematical equations that describe how rivers shift from braided rivulets to channels with branching tributaries, she gets a pattern matching that of a real pancreas. But she has not yet observed this flow-related adjustment in a living pancreas.

Such a process has an element of randomness, and that is exactly what anatomists see: Every pancreas has its own branching pattern even to the extent that some people have two ducts draining the pancreas, while others have just one. There is no primary design in the pancreas, as far as we know, says Grapin-Botton. What guarantees the reproducibility is the feedback from the flow. The salivary glands and perhaps the tear glands of the eyes may develop their branching networks in the same way, she says.

But not every organ can tolerate the little imperfections that come with this sort of random space-filling. Its easy to imagine, for example, that an animal might need every bit of its potential lung capacity when fleeing a predator, so unfilled spaces could prove lethal. Not surprisingly, then, evolution has shaped a more precise developmental program for the lungs.

Like the pancreas, the mammalian lung begins as a tube-shaped outpocketing again, off the embryonic gut. It then branches into two tubes, and each of those goes on to branch again and again, many times, until the lung is filled with millions of tiny airways. Detailed analyses of mouse lungs suggest that the first 15 of these cycles of branching occur in the same location in every lung, so these branchings must be following a preset plan, Nelson says. After that, the lung switches to a space-filling strategy, so that the final lung conforms to the space available in the chest cavity even if other organs take more or less space than usual.

Even more strikingly, researchers can put embryonic lungs into artificial chambers, and the lungs grow to conform to the space of those, too. You can make cubic lungs or cylindrical lungs, Nelson says.

This two-stage branching strategy might deliver the best of both worlds, Nelson adds. The early hardwired branches ensure a basic structure that fills the whole chest cavity, and the later space-filling branches finish the detailing. From a design perspective, it makes a lot of sense, she says. As an engineer, I love that. But we dont really know how that happens.

Our bodies are full of tubes, most of them branched. Here are some of the main ones.

Some hints are starting to emerge, however. Those early, pre-programmed branches depend on a molecule called FGF10, a growth factor that helps orchestrate development by carrying signals from one cell to another. In mouse embryos genetically engineered to lack FGF10, lung passages lengthen but dont branch. No one knows exactly how FGF10 determines the location of branch points, but many researchers lean toward an explanation first proposed by the mathematician Alan Turing more than half a century ago. Turing showed that under certain conditions, signaling molecules that diffuse freely among cells can spontaneously form regular spatial patterns, even in the absence of any external cue.

Mathematical simulations by Dagmar Iber, a computational biologist at ETH Zurich, and her colleagues have shown that such Turing patterns could indeed cause the regular branching patterns seen in the lung. Ibers team has also shown that the signaling pathways used by real lung cells meet the conditions necessary for Turing patterns to form, though they have not yet demonstrated that this mechanism does indeed direct the branching of a living embryonic lung.

A similar Turing-like organizing principle seems to be at work in another branched organ, the urine-collecting ducts of the kidney. There, too, researchers have found a highly predictable pattern governing early branches, also directed by a key signaling molecule but the kidneys use a different one, called GDNF.

Much remains unknown about branching in these organs. In the case of the lungs, for example, researchers have known since the 1990s that the size of each successive branch within the organ fits a fractal pattern in which the volume of each length of tube is equal to the volume of the two daughter tubes that it gives rise to. This allows air pressure to remain constant as air is drawn in and out of the airways but air pressure itself cannot help shape this pattern, which arises long before the lung is actually used. When the baby takes its first breath, it needs to have a perfect lung, Iber says. How does nature manage to arrive at that architecture?

This video shows the growing tip of a tube (milk duct) in the mammary gland of a mouse, growing toward the upper left. One single cell of the tip is labeled green. Initially, the green cell is migrating forward. It uses dynamic protrusions to push past neighboring cells and move in the direction the tube is growing. Then, at the 6-second point in the movie, the green cell stops migrating and inserts itself stably into the wall of the growing tube.

CREDIT:A.J. EWALDET AL / JOURNAL OF CELL SCIENCE2012, REPRODUCED WITH PERMISSION. DOI: 10.1242/JCS.096875

Yet another variation on the programmed-then-local-control theme plays out in the blood vessels of the body. Here, too, the developing embryo needs to ensure that a basic framework of major blood vessels is reliably in place. The first and most important thing is to get a vessel to every important part of the body. There, you have to hardwire it, says Markus Affolter, a developmental biologist at the Biozentrum of the University of Basel, Switzerland.

But once that basic scaffold is in place, the embryo switches to a supply-and-demand system. Tissues that find themselves short of oxygen send out a signal, a molecule known as VEGF, which prompts existing blood vessels to sprout new branches that grow toward the oxygen-starved area. Once the new blood vessels begin delivering oxygen, VEGF secretion drops off, and no further vessels sprout. Eventually, the newly created vessels with high blood flow stabilize, while those with minimal blood flow are pruned away, and the network of blood vessels settles into a stable, efficient configuration.

Developmental biologists are encouraged by these common themes in the genesis of tubes and branches. We wouldnt want to claim that all branching processes are the same that would be much too strong, Simons says. But we think there is a conservation of principles. That doesnt mean that the molecular underpinnings are the same, but the rules are.

Where possible, it seems, evolution has usually chosen relatively local controls to determine where and when branches are made as when mammary ducts keep branching until they bump into a boundary, or when blood vessels grow toward cells starved of oxygen. Its neater in terms of evolvability to have these simple programs that you run over and over, Davies says.

But when the system needs to meet more stringent specifications as when the early embryo needs to guarantee that blood vessels serve every organ it looks as though evolution opted to pay the higher costs for a more precise, preordained script.

And even when different organs implement the same strategy, the particular molecular tools they use in each case can differ. The devil is in the details, and the details are different from organ to organ, says Nelson. I think thats beautiful.

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Plumbing 101: Building the body's tubes and branches - Knowable Magazine

Cell Biology

The second most popular oil in the world is a health disaster, study suggests – The New Daily

Soybean oil, the second most important oil in the world and by far the most widely produced and consumed edible oil in the US is probably not healthy for human consumption.

A 2015 study found a diet high in soybean oil causes more obesity and diabetes than a diet high in fructose, a sugar commonly found in soft drinks and processed foods.

New research shows soybean oil causes genetic changes in the brain, leading scientists to suspect it may be associated with neurological conditions like autism, Alzheimers disease, anxiety and depression.

Both studies came from the University of California, Riverside (UCR) and involved experiments on mice, and the results cant be meaningfully asserted as evidence of human vulnerability.

The authors acknowledge this limitation, but theyre urging consumers to limit their amount of soy oil intake anyway.

Male mice were fed a series of four diets that contained 40 per cent fat, similar to what Americans consume.

Diet one: Coconut oil, which consists primarily of saturated fat.

Diet two: About half of the coconut oil was replaced with soybean oil, which contains primarily polyunsaturated fats and is a main ingredient in vegetable oil.

The researchers note that the second diet corresponded with roughly the amount of soybean oil Americans currently consume.

Diet three: Coconut oil with added fructose.

Diet four: Coconut and soybean oils, with added fructose.

All four diets contained the same number of calories and there was no significant difference in the amount of food eaten by the mice on the diets.

This allowed the researchers to study the effects of the different oils and fructose in the context of a constant caloric intake.

According to a prepared statement from the university, compared to mice on the high coconut oil diet, mice on the high soybean oil diet showed increased weight gain, larger fat deposits, a fatty liver with signs of injury, diabetes and insulin resistance, all of which are part of the Metabolic Syndrome.

Fructose in the diet had less severe metabolic effects than soybean oil although it did cause more negative effects in the kidney and a marked increase in prolapsed rectums, a symptom of inflammatory bowel disease that like obesity is on the rise.

The mice on the soybean oil-enriched diet gained almost 25 per cent more weight than the mice on the coconut oil diet and 9 per cent more weight than those on the fructose-enriched diet.

Male mice were fed three diets: Coconut oil, soybean oil and genetically modified soybean oil, engineered to be low in linoleic acid (a 2017 study found it induced less obesity and insulin resistance, but was harmful to liver function).

The scientists found that the soybeans, modified and naturally grown, had pronounced effects on the hypothalamus, which regulates body weight via your metabolism, maintains body temperature, is critical for reproduction and physical growth as well as a bodys response to stress.

The researchers determined a number of genes in mice fed soybean oil were not functioning correctly.

One such gene produces the love hormone, oxytocin. In soybean oil-fed mice, levels of oxytocin in the hypothalamus went down.

(Coconut oil, which contains saturated fats, produced very few changes in the hypothalamic genes.)

The research team discovered roughly 100 other genes also affected by the soybean oil diet.

They believe this discovery could have ramifications not just for energy metabolism, but also for proper brain function and diseases such as autism or Parkinsons disease.

They were careful to make the point that there is no proof the oil causes these diseases.

They also advised that their findings only apply to soybean oil and not to other soy products or to other vegetable oils.

Do not throw out your tofu, soy milk, edamame or soy sauce, said Dr Frances Sladek, a UCR toxicologist, professor of cell biology and corresponding author.

Many soy products only contain small amounts of the oil, and large amounts of healthful compounds such as essential fatty acids and proteins.

The research team has not yet isolated which chemicals in the oil are responsible for the changes they found in the hypothalamus a problem they intend to address in future research.

This could help design healthier dietary oils in the future, said Dr Poonam Jot Deol, an assistant project scientist in Sladeks laboratory and first author on the study.

The take away: If theres one message I want people to take away, its this: Reduce consumption of soybean oil In all likelihood its not healthy for humans.

But according to a market report, the low cost, easy availability and eco-friendly nature of soybean oil has further facilitated its use in various sectors such as food, industrial and feed.

Demand is expected to continue to grow.

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The second most popular oil in the world is a health disaster, study suggests - The New Daily

Cell Biology

Six is better than two: assay assesses multiple cellular pathways at once – Baylor College of Medicine News

Scientists strive to have a better understanding of the complex biological processes involved in health and disease, and what they can learn usually goes hand-in-hand with the number, quality and type of measurements techniques provide.

Cancer, for instance, usually originates through changes on many different genes and pathways, not just one, but currently most cell-based screening assays conduct single measurements, said Dr. Koen Venken, assistant professor of biochemistry and molecular biology, and pharmacology and chemical biology at Baylor. We thought that if we could see what happens to more than one cellular pathway at once, we could have a more complete picture of what goes on inside a cancer cell.

To get a more detailed picture of the cellular processes that differentiate normal versus cancer cells, researchers resort to conduct several independent screening assays at the expense of time and additional cost.

In his lab at Baylor College of Medicine, Venken and his colleagues apply state-of-the-art synthetic biology, cell biology, genetics, genome engineering and transgenic technologies to have a better understanding of the processes involved in cancer.

Our goal in this study was to measure multiple cellular pathways at once in a single biological sample, which would also minimize experimental errors resulting from conducting multiple separate assays using different samples, said Venken, a McNair Scholar and member of the Dan L Duncan Comprehensive Cancer Center at Baylor.

Dr. Alejandro Sarrion-Perdigones, first author of the paper, wanted to develop an experimental assay that would expand the number of molecular pathways that can be studied simultaneously in a cell sample.

He focused on developing a multiplexed method a method for simultaneously detecting many signals from complex systems, such as living cells. He developed a sensitive assay using luciferases, enzymes that produce bioluminescence. The assay includes six luciferases, each one emitting bioluminescence that can be distinguished from the others. Each luciferase was engineered to reveal the activity of a particular pathway by emitting bioluminescence.

To engineer and deliver the luciferase system to cells, we used a molecular Lego approach, said co-author Dr. Lyra Chang, post-doctoral researchers at the Center for Drug Discovery at Baylor. This consists of connecting the DNA fragments encoding all the biological and technological information necessary to express each luciferase gene together sequentially forming a single DNA chain called vector. This single vector enters the cells where each luciferase enzyme is produced separately.

Treating the cells with a single multi-luciferase gene vector instead of using six individual vectors, decreased variability between biological replicates and provided an additional level of experimental control, Chang explained. This approach allowed for simultaneous readout of the activity of five different pathways (a control makes number six), compared to just one using traditional approaches, providing a much deeper understanding of cellular pathways of interest.

The new assay is sensitive, saves time and expense when compared to traditional approaches, reduces experimental error and can be adapted to any research field where the dual luciferase assay is already implemented, and beyond.

In addition to applications in cancer research, as we have shown in this work, our multiplex luciferase assay can be used to study other cellular pathways or complex diseases across different research fields, Venken said. For instance, the assay can be adapted to study the effect of drugs on insulin sensitivity in different cell types, the immune response to viral infections or any other combinations of pathways.

Interested in this new technology? Find all the details in the journal Nature Communications.

Other contributors to this work include Yezabel Gonzalez, Tatiana Gallego-Flores and Damian W. Young, all at Baylor.

This work was supported by start-up funds provided by Baylor College of Medicine, the Albert and Margaret Alkek Foundation and the McNair Medical Institute at The Robert and Janice McNair Foundation. Additional support was provided by March of Dimes Foundation grant #1-FY14-315, the Foundation For Angelman Syndrome Therapeutics grant FT2016-002, the Cancer Prevention and Research Institute of Texas grants R1313 and R1314 and the National Institutes of Health grants 1R21GM110190, 1R21OD022981 and R01GM109938.

The authors dedicate this work to the memory of Dr. Alejandro Sarrion-Perdigones, who passed away before the paper was published.

By Ana Mara Rodrguez, Ph.D.

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Six is better than two: assay assesses multiple cellular pathways at once - Baylor College of Medicine News

Cell Biology

Scientists Have Grown Snake Venom Glands in The Lab. Here’s Why That’s Awesome – ScienceAlert

For the first time, scientists have produced snake venom toxins in the lab, opening up a much-needed path for developing drugs and venom antidotes that doesn't involve having to breed and milk real-life snakes.

The toxins have been produced through mini glands called organoids, following a process adapted from growing simplified human organs something that is already helping in a wide range of scientific and medical research projects.

In the case of the snakes, researchers were able to blow organoids matching the Cape coral snake (Aspidelaps lubricus cowlesi) and seven other snake species, and they say this new approach is a welcome upgrade on current methods of farming snakes to extract their venom.

"More than 100,000 people die from snake bites every year, mostly in developing countries," says molecular biologist Hans Clevers, from Utrecht University in the Netherlands. "Yet the methods for manufacturing antivenom haven't changed since the 19th century."

By tweaking the recently developed process for growing human organoids including reducing the temperature to match reptiles rather than mammals the researchers were able to find a recipe that supports the indefinite growth of tiny snake venom glands.

Tissue was removed from snake embryos and put into a gel mixed with growth factors, but access to stem cells which is how human and mouse organoids are usually developed wasn't required.

The cells quickly began dividing and forming structures, giving the team hundreds of growing samples in the space of a couple of months, and producing small white blobs from which venom toxins could be harvested.

Al least four distinct types of cell were identified by the researchers within the artificially grown venom glands, and they were also able to confirm that the venom peptides produced were biologically active, closely resembling those in live snake venom.

Snake venom gland organoids. (Ravian van Ineveld/Princess Mxima Center)

"We know from other secretory systems such as the pancreas and intestine that specialised cell types make subsets of hormones," says developmental biologist Joep Beumerfrom Utrecht University.

"Now we saw for the first time that this is also the case for the toxins produced by snake venom gland cells."

The use of snake venom toxins to develop medicines and treatments has been going on since the time of ancient Greece. In the modern age, drugs fighting everything from cancer to haemorrhages have been developed with the help of toxins we find in snake venom.

Having faster and more controlled access to these toxins could mean these treatments can be developed more easily and on a shorter time scale, say the researchers.

Besides drug development, these organoid venom glands should make it easier and faster to develop antivenoms and with so many people suffering deaths, injuries or disabilities because of snake bites, that will make a considerable difference.

"It's a breakthrough," snake venom toxicologist Jos Mara Gutirrez from the University of Costa Rica, told Science.

"This work opens the possibilities for studying the cellular biology of venom-secreting cells at a very fine level, which has not been possible in the past."

The research has been published in Cell.

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Scientists Have Grown Snake Venom Glands in The Lab. Here's Why That's Awesome - ScienceAlert

Cell Biology

A new study reveals a link between sleep and glowing skin – Times of India

If your skin has been looking dull and lifeless, then you need to look at your sleep pattern. A good night's sleep can actually be good for your skin, which is now backed by scientists. A new study by Nature Cell Biology shed light on how a good night rest can be good for your skin.The study was conducted on mice and their collagen. It was found out that the sleep phase can regulate the extracellular matrix, which provides structural support to cells in the form of connective tissue like bone, skin, cartilage, etc. Half of our body is made of matrix and half of it is collagen.The study discovered that collagen is made of two types of structure. One is a thicker form, which is fully formed by the age of 17. It remains the same for the rest of our lives and is permanent. The second type is the thinner structure, which breaks down under stress. The study found out that these structures can actually repair itself while we rest at night.The thinner fibres protect the permanent structures from the daily wear and tear on the skin cells."If you imagine the bricks in the walls of a room as the permanent part," says lead author Karl Kadler, B.Sc., Ph.D., "the paint on the walls could be seen as the sacrificial part which needs to be replenished every so often."Collagen is the most abundant protein in the body. It provides the glow and improves skin's elasticity and strength. Beauty sleep is pretty much real, as good rest can now actually help to boost collagen naturally.

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A new study reveals a link between sleep and glowing skin - Times of India

Cell Biology

Quench Bio emerges with $50M to treat severe inflammatory disease – FierceBiotech

Most treatments for inflammatory disease have single targets, such as an inflammation-promoting cytokine or a protein complex called an inflammasome. Quench Bio is taking aim at a family of proteins involved in inflammatory cell deathand its picked up $50 million to do so.

Incubated at Atlas Venture since its inception in 2018, Quench's first target is gasdermin D, the best understood member of the gasdermin family of proteins. With its $50 million in series A cash, the company expects to fund three years worth of research, as well as come up with its first clinical candidate, CEO Samantha Truex told FierceBiotech. It also hopes to screen for drug candidates that inhibit other members of the gasdermin family.

Gasdermin D plays a role in multiple inflammatory cell death pathways; when those pathways are activated, the protein forms pores in the cell membrane.

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By forming pores, it does two things: one is it allows for the release of inflammatory signals. Those can be inflammatory cytokines, alarmins, or what we call DAMPs: danger-associated molecular patterns, Quench CEO Samantha Truex told FierceBiotech.

In addition, once enough of those pores form, the cell membrane loses its integrity and the cell literally explodes in an inflammatory way, she added.

One of those types of cell death is called pyroptosis, derived from pyroliterally firewhile another is NETosis, a type of cell death linked to white blood cells called neutrophils. The hope is that inhibiting gasdermin D will delay cell death, or lead cells to die by apoptosis, a quieter, calmer, noninflammatory form of cell death, Truex said.

Gasdermin could be a more complete way to treat inflammatory disease as it is downstream of inflammasome targets like NLRP3 and upstream of pro-inflammatory cytokines, like IL-1 beta, Truex said. For example, targeting NLRP3 could stop cells on their way to pyroptosis if NLRP3 is indeed the inflammasome that is triggered, she said. But the drug would be ineffective if the cell has another inflammasome triggered, such as NLRC4 or pyrin, she said.

And Quench believes that going upstream of the release of cytokines and heading off explosive cell death could be a better approach than aiming to block a cytokine that is already being released. Truex said.

Its almost like an hourglass, with inflammatory targets at the top, and at the bottom there are things leaking out of the cell. If we hit at the middle, we can have an impact on all of it, she said.

Quench spent most of 2019 coming up with its clinical game plan. As it looks to 2020, the company still has much to learn about its targets.

We assessed over 25 diseases in the autoimmune, autoinflammatory and severe inflammatory category and we have come to the conclusion that pyroptosis and NETosis are known to be associated with numerous inflammatory diseases, Truex said. Those include rheumatoid arthritis, lupus, nonalcoholic steatohepatitis (NASH) and multiple sclerosis. The company isnt sharing yet which ones its going after first, but Truex noted that the company plans to work on treatments for diseases that have no treatments, or those that have many treatments, but still have unmet need.

We could start with rare diseases and subsets of patients with lupus and rheumatoid arthritis who appear specifically to have disease driven by gasdermin D. Our center of excellence in gasdermin biology will do more research in gasdermins role in those diseases in parallel with our efforts to discover inhibitors of gasdermin, she said.

Quench draws its series A funding from RA Capital Management and AbbVie Ventures, as well as Atlas Venture and Arix Bioscience.

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Quench Bio emerges with $50M to treat severe inflammatory disease - FierceBiotech

Cell Biology

Books in Brief: Lucky Caller by Emma Mills, From the Desk of Zoe Washington by Janae Marks; Wild Honey From the Moon by Kenneth Kraegel – Buffalo News

YOUNG ADULT

Lucky Caller by Emma Mills; Henry Holt, 323 pages ($17.99) Ages 14 and up.

...

Emma Mills has a gift for creating appealing characters, believable family situations and funny dialogue, and "Lucky Caller" is a well-crafted gem of a teen romance.

Hoping for an easy and fun elective her senior year, 17-year-old Nina signs up for a radio broadcasting class where she is teamed up with a volleyball player, a wooden-voiced guy named Joydeep and Jamie, a childhood friend she has been trying to avoid since an awkward incident in 8th grade. Her parents are divorced, and her absentee father is actually a popular deejay in California, but Nina struggles to master the technical side of broadcasting, accidentally broadcasting remarks that weren't meant to be public. Her team's grade will depend on how many listeners they can get for their "Sounds of the '90s" music show.

But classmates find ingenious ways to sabotage each other's radio shows, and Nina finds herself in a pickle when she invites her dad to guest-host a broadcast and a rumor spreads that the frontman of an obscure '90s band is going to appear on the show. The drama at school unfolds while Nina's home life is undergoing a major change: her mother is getting remarried, to a dentist who has a popular YouTube show offering paint-by-numbers tutorials. An unlikely hero emerges to save the day, offering a perfect ending to this sweet story.

Even the setting for much of the action an old apartment building called the Eastman in Indianapolis where Nina and Jamie both live is charming. There's also an incidental STEM aspect to the book. Nina's mother works in science; the author finished her PhD in cell biology while writing "Lucky Caller."

CHILDREN'S

From the Desk of Zoe Washington by Janae Marks; Katherine Tegen Books/HarperCollins, 286 pages ($16.99) Ages 8 to 12.

...

A 12-year-old girl works through conflicts with her mother and her best friend and turns her passion for baking into more than a hobby, all while fighting for justice for her imprisoned dad in this marvelous debut novel by Janae Marks for middle-grade readers.

Zoe lives with her mom and stepfather in the Boston area and knows very little about her biological dad, Marcus, who has been in prison since he was convicted of murder at the age of 19 before she was born. Then Zoe gets a birthday letter from Marcus, mailed from prison (he calls her "My Little Tomato"), and without telling her mother, she writes him back.

With each letter and song recommendation, she feels as though she's getting to know her real dad. He says he is innocent of the crime he was convicted of, but Zoe isn't sure whether to believe him. Why would an innocent person be in prison? Marks offers a compelling mystery as Zoe and her friend Trevor research the crime and then search for the alibi witness who was never called to testify at Marcus' trial.

Marks has managed to write a middle-grade novel that explores racial justice issues and addresses the routine bias Zoe faces (funny looks when she's out with her white stepfather, being tailed by clerks at stores while shopping with her mom) while also dealing with such coming-of-age issues as changing friendships with boys. She also offers a compelling portrait of a girl with a serious interest in pursuing her passion for baking, interning at a bakery where she experiments at inventing a new cupcake flavor that will wow the owner. The book also serves as a valuable introduction to The Innocence Project for its target audience.

PICTURE BOOK

Wild Honey From the Moon by Kenneth Kraegel; Candlewick Press ($17.99)

...

A mother shrew is willing to go to the moon and back to cure her sick young son in this whimsical, sweet story with delicate and distinctive illustrations by a self-taught artist. Young Hugo's "feet were hot, his head was cold, and he just slept and slept." According to "Dr. Ponteluma's Book of Medical Inquiry and Physiological Know-How," the only cure is "a teaspoon of wild honey from the moon." In lyrical and humorous style, Kraegel spins storyteller magic his appealing tale is divided into short chapters as mama shrew outwits a Great Horned Owl, falls into a raging stampede of "night mares," hitches a ride with a butterfly and braves swarms of angry bees to get what she came for.

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Books in Brief: Lucky Caller by Emma Mills, From the Desk of Zoe Washington by Janae Marks; Wild Honey From the Moon by Kenneth Kraegel - Buffalo News

Cell Biology

Ervaxx and Cardiff University Enter Collaboration to Develop Novel T-cell and T-cell Receptor-based Immunotherapeutics Targeting Dark Antigens | DNA…

DetailsCategory: DNA RNA and CellsPublished on Saturday, 25 January 2020 09:59Hits: 391

Collaboration also focuses on exciting research published earlier this week in Nature Immunology identifying MR1 as a target for novel anti-cancer immunotherapies

LONDON, UK I January 24, 2020 I Ervaxx, a biotechnology company pioneering the use of Dark Antigens to developT-cell receptor (TCR)-based immunotherapies and off-the-shelf cancer vaccines, has entered a licensing and research collaboration with a leading T-cell immunology group at Cardiff University (Cardiff, UK).

The new collaboration will support a multi-year research program with Prof. Andrew Sewell's T-cell modulation group at Cardiff University focusing on the discovery and characterization of T-cells and TCRs reactive to cancer-specific antigens and ligands, including Ervaxx' proprietary Dark Antigens. Ervaxx will fund the program.

The collaboration will also advance exciting new research published earlier this week by the Cardiff University team in Nature Immunology1, where they identified a T cell clone that recognized and killed multiple different types of human cancer, while remaining inert to non-cancerous cells. The T cell clone targets MR1, an MHC class 1-related protein, via an unidentified cancer-specific ligand. These exciting findings, validated in a preclinical model, open the prospect of immunotherapies with broad utility across patients with diverse cancers. This approach into previously unexplored cell surface epitopes complements and extends Ervaxx's exploration of novel cancer-specific antigens.

Under the agreement, Ervaxx gains an exclusive license to relevant Cardiff University patents claiming T cells and TCRs reactive to cancer-specific antigens. The Company has the right to advance resulting candidate T-cell/TCR-based immunotherapeutics and cancer vaccines through development and commercialization. Cardiff University is eligible to receive milestone payments on any candidates that advance from the discovery collaboration into clinical development and royalty payments on sales of any products that reach the market.

Prof. Andrew Sewell, Head of the T-cell modulation group, Cardiff University, commented:

"Ervaxx's Dark Antigens, which are derived from the 98% of the genome that does not encode known proteins, constitute a promising and yet untapped source of targets for immunotherapies. This collaboration will use our world-class expertise in T-cell biology to identify T cells and TCRs reactive to those targets and pave the way for a new wave of treatments in cancer, and potentially other areas. This includes our most recent discovery, published in Nature Immunology, of a T-cell clone that targets MR1 to recognize and kill cancer cells, irrespective of cancer or human leukocyte antigen (HLA) type, offering opportunities for pan-cancer, pan-population cancer immunotherapies."

Kevin Pojasek, CEO of Ervaxx, said:

"We are excited to announce this collaboration with Prof. Sewell's world-class research group. We have great hope that through the combination of this expertise with our Dark Antigens and application of our EDAPT platform, we will be able to identify further targets to expand our portfolio of TCR-based therapies and cancer vaccines. We are also thrilled to contribute to the development of the group's exciting new MR1 research, which shows early but enormous potential for the treatment of cancers. This partnership, which follows those with the University of Oxford, University of Cambridge and Johns Hopkins University School of Medicine, reinforces our ambition to collaborate with leading academic institutions and be at the cutting edge of the T-cell immunology field to drive the development of novel off-the-shelf cancer therapies."

Prof. Andrew Sewell is a member of Ervaxx' Scientific Advisory Board.

About Ervaxx

Ervaxx is pioneering the use of Dark Antigens to deliver targeted immunotherapies for treating and preventing cancer. Ervaxx Dark Antigens derive from vast untapped expanses of genetic 'dark matter' beyond the normal coding regions of the genome, which are generally silenced in normal tissue but can become selectively activated in cancer.

Ervaxx' powerful, proprietary EDAPT platform has been developed to discover and validate Dark Antigens providing an in-depth assessment of candidate antigens on primary tumor cells along with their immunogenic potential. The EDAPT platform has identified proprietary antigens that map to multiple solid tumor types and generate robust, antigen-specific T-cell responses. Ervaxx is advancing a pipeline of T cell receptor (TCR)-based therapies, off-the-shelf cancer vaccines and other immunotherapies leveraging these insights into the role of Dark Antigens in cancer.

Ervaxx was co-founded by SV Health Investors and is based on pioneering research at the Francis Crick Institute (London, UK). The company has offices in London, UK and a laboratory in the Bioescalator Building at Oxford University, UK. Ervaxx also has a strategic partnership with a global pharmaceutical company.

For more information visit: http://www.ervaxx.com

Ervaxx, Dark Antigen and EDAPT are trademarks of Ervaxx Limited

About the T-cell Modulation Group, Cardiff University

Cardiff University T-cell modulation group, within the Division of Infection and Immunity, consists of 16 researchers with a diverse skill and knowledge base that covers all areas of T-cell biology including T-cell genetics, molecular biology, protein chemistry, crystallography, and cell biology. The overall goal of the T-cell modulation group is to understand the genetic, biochemical and cellular mechanisms that govern T-cell responses to human disease. Our research outputs are extremely wide ranging and include basic studies which are aimed at understanding how the T-cell immune response is regulated, through to translational studies which are aimed at developing tools, diagnostics and treatments for human diseases such as cancer, HIV, EBV, tuberculosis and many more.

1Crowther, M.D., Dolton, G., Legut, M. et al. Genome-wide CRISPRCas9 screening reveals ubiquitous T cell cancer targeting via the monomorphic MHC class I-related protein MR1. Nat Immunol (2020) doi:10.1038/s41590-019-0578-8

SOURCE: Ervaxx

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Ervaxx and Cardiff University Enter Collaboration to Develop Novel T-cell and T-cell Receptor-based Immunotherapeutics Targeting Dark Antigens | DNA...

Cell Biology

Tiny organs grown from snake glands produce real venom – Science Magazine

Researchers grew tiny venom glands from nine different snake species, including the cape coral cobra.

By Erin MalsburyJan. 23, 2020 , 11:00 AM

Venomous snakes kill or permanently injure more than a half-million people every year. Yet researchers still know surprisingly little about the biology behind venom, complicating efforts to develop treatments. A new advance could help: Researchers have successfully grown miniature organs from snake stem cells in the lab that function just like snake venom glands; they even produce real venom.

Its a breakthrough, says Jos Mara Gutirrez, a snake venom toxicologist at the University of Costa Rica, San Jos, who was not involved in the study. This work opens the possibilities for studying the cellular biology of venom-secreting cells at a very fine level, which has not been possible in the past. The advance could also help researchers study the venom of rare snakes that are difficult to keep in captivity, he says, paving the way for new treatments for a variety of venoms.

Researchers have been creating miniorgansor organoidsfrom adult human and mouse stem cells for years. These so-called pluripotent cells are able to divide and grow into new types of tissues throughout the body; scientists have coaxed them into tiny livers, guts, and even rudimentary brains. But scientists hadnt tried the technique with reptile cells before.

Nobody knew anything about stem cells in snakes, says Hans Clevers, a molecular biologist at the Hubrecht Institute and one of the worlds leading organoid scientists. We didnt know if it was possible at all. To find out, Clevers and colleagues removed stem cells from the venom glands of nine snake speciesincluding the cape coral cobra and the western diamondback rattlesnakeand placed them in a cocktail of hormones and proteins called growth factors.

To the teams surprise, the snake stem cells responded to the same growth factors that work on human and mouse cells. This suggests certain aspects of these stem cells originated hundreds of millions of years ago in a shared ancestor of mammals and reptiles.

Miniature, lab-grown snakevenom glands

By the end of 1 week submerged in the cocktail, the snake cells had grown into little clumps of tissue, a half-millimeter across and visible to the human eye. When the scientists removed the growth factors, the cells began to morph into the epithelial cells that produce venom in the glands of snakes.The miniorgans expressed similar genes as those in real venom glands, the team reports today inCell.

The snake organoids even produced venom; a chemical and genetic analysis of the secretions revealed that they match the venom made by the real snakes. The labmade venom is dangerous as well: It disrupted the function of mouse muscle cells and rat neurons in a similar way to real venom.

Scientists didnt know whether the many toxins found in snake venom are made by one general type of cell or specialized, toxin-specific cells. By sequencing RNA in individual cells and examining gene expression, Cleverss team determined that both real venom glands and organoids contain different cell types that specialize in producing certain toxins. Organoids grown using stem cells from separate regions of the venom gland also produce toxins in different proportions, indicating that location within the organ matters.

The proportions and types of toxins in venom differ amongand even withinspecies. That can be problematic for antivenom production, says study author Yorick Post, a molecular biologist at the Hubrecht Institute. Most antivenoms are developed using one type of venom, so they only work against one type of snakebite.

Now that Clevers and his colleagues created a way to study the complexity of venom and venom glands without handling live, dangerous snakes, they plan to compile a biobank of frozen organoids from venomous reptiles around the world that could help researchers find broader treatments. This would make it much easier to create antibodies, Clevers says. The biobank could also be a rich resource for identifying new drugs, he adds. (Scientists think snake venom may hold the keyfor treatments against pain, high blood pressure, and cancer, for instance.)

Another new study, published earlier this month inNature, could also help. Researchers have assembled anear-complete genome for the Indian cobrathat could aid drug development. The organoids created by Cleverss team will provide an unprecedented and incredibly important new avenue to complement genomic information for venomous snakes, says the senior author of the cobra study, molecular biologist Somasekar Seshagiri of the SciGenom Research Foundation. Theyve done an amazing job making this work.

*Correction, 23 January, 1:35 p.m.: An earlier version of this story misspelledSomasekar Seshagiri's name.

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Tiny organs grown from snake glands produce real venom - Science Magazine

Cell Biology

The biology of coffee, one of the world’s most popular drinks – Salon

You're reading this with a cup of coffee in your hand, aren't you? Coffee is the most popular drink in many parts of the world. Americans drink more coffee than soda, juice and tea combined.

How popular is coffee? When news first broke that Prince Harry and Meghan were considering Canada as their new home, Canadian coffee giant Tim Hortons offered free coffee for life as an extra enticement.

Given coffee's popularity, it's surprising how much confusion surrounds how this hot, dark, nectar of the gods affects our biology.

Coffee's ingredients

The main biologically active ingredients in coffee are caffeine (a stimulant) and a suite of antioxidants. What do we know about how caffeine and antioxidants affect our bodies? The fundamentals are pretty simple, but the devil is in the details and the speculation around how coffee could either help or harm us runs a bit wild.

The stimulant properties of caffeine mean that you can count on a cup of coffee to wake you up. In fact, coffee, or at least the caffeine it contains, is the most commonly used psychoactive drug in the world. It seems to work as a stimulant, at least in part, by blocking adenosine, which promotes sleep, from binding to its receptor.

Caffeine and adenosine have similar ring structures. Caffeine acts as a molecular mimic, filling and blocking the adenosine receptor, preventing the body's natural ability to be able a rest when it's tired.

This blocking is also the reason why too much coffee can leave you feeling jittery or sleepless. You can only postpone fatigue for so long before the body's regulatory systems begin to fail, leading to simple things like the jitters, but also more serious effects like anxiety or insomnia. Complications may be common; a possible link between coffee drinking and insomnia was identified more than 100 years ago.

Unique responses

Different people respond to caffeine differently. At least some of this variation is from having different forms of that adenosine receptor, the molecule that caffeine binds to and blocks. There are likely other sites of genetic variation as well.

There are individuals who don't process caffeine and to whom drinks like coffee could pose medical danger. Even away from those extremes, however, there is variation in how we respond to that cup of coffee. And, like much of biology, that variation is a function of environment, our past coffee consumption, genetics and, honestly, just random chance.

We may be interested in coffee because of the oh-so-joyous caffeine buzz, but that doesn't mean that caffeine is the most biologically interesting aspect of a good cup of coffee.

In one study using rats, caffeine triggered smooth muscle contraction, so it is possible that caffeine directly promotes bowel activity. Other studies, though, have shown that decaffeinated coffee can have as strong an effect on bowel activity as regular coffee, suggesting a more complex mechanism involving some of the other molecules in coffee.

Antioxidant benefits

What about the antioxidants in coffee and the buzz that surrounds them? Things actually start out pretty straightforward. Metabolic processes produce the energy necessary for life, but they also create waste, often in the form of oxidized molecules that can be harmful in themselves or in damaging other molecules.

Antioxidants are a broad group of molecules that can scrub up dangerous waste; all organisms produce antioxidants as part of their metabolic balance. It is unclear if supplementing our diet with additional antioxidants can augment these natural defences, but that hasn't stopped speculation.

Antioxidants have been linked to almost everything, including premature ejaculation.

Are any of the claims of positive effects substantiated? Surprisingly, the answer is again a resounding maybe.

Coffee and cancer

Coffee won't cure cancer, but it may help to prevent it and possibly other diseases as well. Part of answering the question of coffee's connection to cancer lies in asking another: what is cancer? At its simplest, cancer is uncontrolled cell growth, which is fundamentally about regulating when genes are, or are not, actively expressed.

My research group studies gene regulation and I can tell you that even a good cup of coffee, or boost of caffeine, won't cause genes that are turned off or on at the wrong time to suddenly start playing by the rules.

The antioxidants in coffee may actually have a cancer-fighting effect. Remember that antioxidants fight cellular damage. One type of damage that they may help reduce is mutations to DNA, and cancer is caused by mutations that lead to the misregulation of genes.

Studies have shown that consuming coffee fights cancer in rats. Other studies in humans have shown that coffee consumption is associated with lower rates of some cancers.

Interestingly, coffee consumption has also been linked to reduced rates of other diseases as well. Higher coffee consumption is linked to lower rates of Parkinson's disease and some other forms of dementia. Strikingly, at least one experimental study in mice and cell culture shows that protection is a function of a combination of caffeine and antioxidants in coffee.

Higher coffee consumption has also been linked to lower rates of Type 2 diabetes. Complexity, combined effects and variation between individuals seems to be the theme across all the diseases.

At the end of the day, where does all this leave us on the biology of coffee? Well, as I tell my students, it's complicated. But as most reading this already know, coffee will definitely wake you up in the morning.

Thomas Merritt, Professor and Canada Research Chair, Chemistry and Biochemistry, Laurentian University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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The biology of coffee, one of the world's most popular drinks - Salon