There's something about ivy

‘Tis the season to be jolly. A time when geese are getting fat and red-nosed reindeers are given their first big break. At Christmas, your halls may be decked with holly but it’s ivy that grows over everything else. Have you ever wondered how ivy is able to climb up walls?

English ivy (a species name Hedera Helix) makes its own glue-like substance out of natural nanoparticles. The roots of each plant produce millions of tiny, sticky spheres - each 100,000 times smaller than a holly berry. This remarkable feat helps the ivy to bend and twist around trees, chimneys and probably even parked-up sleighs given the chance.

New research (published in the Journal of Nanobiotechnology) has found a way to turn rows of ivy plants into natural factories for these adhesive particles, which also have another hidden talent: they also absorb ultraviolet light. 

In a few years’ time you might be using an ivy-based glue to stick stamps on your Christmas cards and – if you live in the southern hemisphere – wearing an ivy-based sunscreen whilst you eat your turkey.

Happy Christmas everyone!

This article was also published in The Christmas 2012 issue of The Guru Science/Lifestyle magazine.

Reference:
Burris, J., Lenaghan, S., Zhang, M., & Stewart, C. (2012). Nanoparticle biofabrication using English ivy (Hedera helix) Journal of Nanobiotechnology, 10 (1) DOI: 10.1186/1477-3155-10-41

Buddy-cops! Why evolution favours the odd couple

Inside our cells, the battle with viruses has a lot in common with 1980s action-comedy Lethal Weapon: both feature unlikely pairs of heroes. Each partnership  - virus-battling proteins and LA cops alike - has a reliable, straight-laced, by-the-book one and a loose canon, maverick one. 

Mel Gibson as loose canon Martin Riggs paired with Danny
Glover as straight-laced cop Roger Murtagh.
(Lethal Weapon, 1987)
In the cell, buddy-cop proteins police many of life's
important processes.

New research suggests that whether they're crime fighting or fighting an infection, the odd couple always gets the job done.

Life inside our cells may look very complex, but it's actually all a bit of a cheat. Evolution killed off what didn't work early on and copied what did work in massive amounts. Like 'buddy-cop' movies from the 1980s our cells are full of repeated bits, common sets of rules, re-used ideas. After all, why mess with a winning formula?

Research published recently in Nature Molecular Systems Biology has found a familiar pairing at the heart of several of life's processes: proteins which behave very differently, thrown together to protect and serve the cell.

Dr Alexander Ratushny and colleagues at the Seattle Biomedical Research Institute, USA, examined a duo of proteins called Interferon Regulatory Factors (IRFs), which defend  our cells against viruses. They found one of the proteins, IRF7,  responds to a viral threat in an all-or-nothing way, using positive feedback to boost its activity. Its partner protein, IRF3, is more sensitive, reacting to the developing situation by reigning in its partner when needed.

Tango and Cash (1989), a repeated buddy-cop formula.Turning
both partners into mavericks can have destructive results in
the cell, too.

Dr Ratushny's team identified similar partnerships in control of how our cells grow, balancing our cholesterol levels and at the heart of our early development.

The team used mathematical models (using algebra to simulate genes and proteins) to compare how well different combinations of proteins work together - asking which type of pairing could quickly respond to a threat, how sensitive they were to changes in the threat and, most crucially, how balanced the partnership was.

The model of the chalk-and-cheese, 'asymmetric' pair was the only one "predicted to be reliably controlled, which is critical for balanced yet rapid, antiviral and inflammatory responses".

Although the buddy-cop formula
is often repeated, not all examples
work as well as others.

So why have these buddy-cop proteins evolved? What makes them more favourable than, say, pairs of 'maverick' all-or-nothing proteins?

If you've seen the end of 'Tango and Cash' you'll know the answer already - a pair of loose canons can be very destructive. Similarly, when Dr Ratushny's team forced both members of a 'buddy-cop' protein duo to work under positive feedback (inside yeast cells), the results were overkill - their response was too strong. 

It appears that evolution used trial and error to find that the odd couple is the only way to get results.

Drug developers (not the kind found in Lethal Weapon) may now look for ways to trigger the wiring in our cells with an asymmetric pair at its core, such as the wiring connecting the liquorice root to diabetes.

There are also fresh ideas here for synthetic biologists looking to artificially coax a maverick protein into working with straight-laced partners inside our cells.

When they do, you may see a post here comparing their efforts to 1984 fish-out-of-water comedy "Beverly Hills Cop".

Reference:

Ratushny AV, Saleem RA, Sitko K, Ramsey SA, & Aitchison JD (2012). Asymmetric positive feedback loops reliably control biological responses. Molecular systems biology, 8 PMID: 22531117

Under your skin: taking skin cancer out by its roots

Tumours can spring up amongst
'fields' of healthy skin cells.

The summer sun may finally be on its way. This is great news for barbecue kings and beach bums but also for the weeds lurking below the surface of the soil popping up intermittently to strangle my carrots.

New research published in Cell describes another reason to cake ourselves in sun cream, cover up bare flesh and wear ridiculously wide-brimmed hats in the coming months: weed-like skin cancers which start below the surface of the skin and grow upwards.

"Too much sun" is well known to carry a risk of skin cancer. Prolonged exposure to the sun's Ultraviolet (UV) rays can wither the DNA in cells on the skin's surface sometimes causing multiple tumours to spring up at once.

Dr Bing Hu and colleagues found alarming evidence that some cancers may start much deeper in the tissue. This may explain why skin cancers frequently reappear: surgery may remove a tumour, but its roots may remain.

The new research suggests that skin cancer can be kick-started by changes in the dermis – deeper skin tissue where healthy cells reproduce to replenish the cells on the surface.

The root cause of certain skin
cancers may be much deeper in the
tissue than previously thought.

The team, from the University of Lausanne in Switzerland, discovered that UV light can cause mutations in the wiring of dermal cells, specifically to a protein called 'Notch' which is necessary for individual skin cells to communicate.

They found that mice born with malfunctioning Notch develop severely distorted skin full of lesions and tears. The dermal skin cells of these mice displayed accelerated cell division, a common prelude to tumour formation.

The mouse studies gave the team a vital clue of what to look for in human cells. They have since discovered Notch is disrupted in some human skin cancers too.

Dr Hu says that designing drugs to protect or repair Notch in human cells might be used in “preventing or reversing” the unseen effects of the sun on cells under our skin.

Until then, whether you're weeding, barbe-ing or bathing this summer the advice remains the same: enjoy responsibly. 

And remember to buy ice. And fire-lighters.

Reference:

Hu B, Castillo E, Harewood L, Ostano P, Reymond A, Dummer R, Raffoul W, Hoetzenecker W, Hofbauer GF, & Dotto GP (2012). Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling. Cell, 149 (6), 1207-20 PMID: 22682244

Who needs NASA? Launching genes with lasers in space-travelled fish

Inside the cell genes are launched from promoters on our DNA.
(photo of space shuttle Atlantis)

NASA has its sights on launching rockets into space using lasers. "What if..." they're wondering, "shuttles could be sent up using laser beams to heat their fuel from the ground?"

Biophysicists in Japan have had a similar idea. They've successfully used lasers to 'launch' genes inside living creatures, with a little help from nanotechnology. If this process works in humans, future battles with cancer may be fought by remote control.

Deep within our cells, genes are launched into action from promoters, sequences of DNA where movable machinery assembles to fire copies of a gene, called messenger RNAs (mRNAs), from the nucleus to the cytoplasm.

Promoter ’launch pads’ are triggered by different things – stresses or chemicals or signals from outside the cell. Some promoters are heat sensitive, firing off mRNAs in response to fever or infection. Arriving in the cytoplasm, their mission is to build proteins to defend the cell from invaders such as viruses.

New research published recently in PNAS, describes a way of using laser light to trigger these 'heat shock' promoters from above the skin of living organisms. It's a first step towards launching our own genetic defences to disease from outside the human body.

Could lasers be used to fire mRNAs out from
the nucleus to fight diseases?
(photo: Space shuttle Atlantis from plane, Ryan Graff)

To develop these new pyrotechnics, Eiliro Miyako and colleagues injected carbon nanoparticles called nanohorns into medaka fish, Oryzias latipes. These fish are no strangers to laboratories. They've even been to space (and were the first Earthly vertebrates to reproduce in orbit).

Nanohorns, molecule-thin sheets of carbon folded into cone shapes, have huge potential for scooping up and delivering drugs inside cells and tissues. But it was something else about these tiny metal structures (which measure around 1/100000 cm across) that excited Dr Miyako and his team: nanohorns convert laser light energy into heat.

With a microscopic fuel source in hand the team from collaborating research institutes in Japan, set about building a DNA launch pad.

They pieced together DNA in the lab, placing the gene for a green fluorescent protein (GFP) next to a man-made heat shock promoter. After transferring the whole thing into the cells of the medaka fish, it was time for launch!

A low-powered laser beam was focused beneath the fish's skin. The carbon nanohorns absorbed the laser's energy, emitting it as heat. The surrounding tissue began to warm up. At a temperature of 42°C the heat shock promoters fired into life, launching the GFP gene. Minutes later the cells in the fish were glowing green. Genes had been successfully launched from outside a living body.

Medaka, the first vertebrate to reproduce in space.
In this study its genes were launched by remote control.

Dr Miyako writes "This work is a proof-of-principle study demonstrating that... gene expression can be mediated by the photothermal properties of nanocarbons."

 He believes that they could be used "in various biological fields, including analysis of cell signaling within organisms, investigation of genetic mechanisms, and development of unique cell therapies and tissue engineering techniques."



Makes you wonder which will come first - the fire laser-propelled rocket to the moon, or the first cancerous cell killed by remote control?

What does this mean for me?

This study was not simply about making glowing fish. As Dr Miyato says, this is a proof of principle. In the future, lasers might be used to trigger specific genes inside the human body, boosting the body's response to infection, or triggering cell death in cancer cells. This could compliment drug-based approaches aiming to manipulate genes and proteins in a similar way. The team have also used nanohorns to trigger genes inside living mice and found no signs of toxicity or adverse reaction to the particles, which is encouraging for future trials.

What does this mean for science?

Remote control of gene expression has been achieved before, but this study is the first to use near infrared light (NIR, with wavelengths between 0.7- 2.5um). NIR light lies inside the "optical window" of biological tissue (0.6- 1.1um) and is able to penetrate over 10cm deep. This study adds to the - already impressive - list of potential uses for metal nanoparticles in biology including drug delivery, tissue scaffolding,  the detection of harmful pathogens and improved MRI images.

Reference (free to download via Open Access!):

Miyako, E., Deguchi, T., Nakajima, Y., Yudasaka, M., Hagihara, Y., Horie, M., Shichiri, M., Higuchi, Y., Yamashita, F., Hashida, M., Shigeri, Y., Yoshida, Y., & Iijima, S. (2012). Photothermic regulation of gene expression triggered by laser-induced carbon nanohorns Proceedings of the National Academy of Sciences, 109 (19), 7523-7528 DOI: 10.1073/pnas.1204391109

Death by metal: a hidden detonator inside cancer cells?

Our cells are wired to explode. Given the right signals they can burst open, scattering bits of crunched up DNA, shrivelled membrane and chemicals in all directions. Sometimes this is all part of the plan: controlled cell death it vital to defining the outline of our toes and fingers in the womb, and to the daily act of replacing old cells with new ones. Cell death is a part of life.

Could pools of iron inside cancer cells be exploited
to trigger their demise?
Iron in Lake Khövsgöl, Mongolia
(picture credit Josefontheroad) 

New research has uncovered a hidden route to cell death. Death by iron, or 'ferroptosis' may be a secret weapon against some forms of cancer.

In work published recently in Cell, Scott Dixon and colleagues triggered the death  of cells in a dish using chemicals which causes a build-up of Reactive Oxygen Species (ROS). ROS are volatile and highly damaging to cells, so death within a few hours came as no surprise. What did was another observation: erastin was only effective in cells with a healthy supply of iron.

Iron absorbed from the blood stream (but not other heavy metals such as copper, nickel or cobalt) appeared to sensitise certain cells to erastin and a quick death. 

Exactly what the link is between ROS-inducing chemicals such as erastin and iron has yet to be uncovered. But the team from Columbia University, New York, found evidence that ferroptosis has a "unique genetic network" that is entirely separate from other forms of cell death such as apoptosis (the 'culling' of cells, apoptosis helped to create the gaps between our toes) and necrosis (triggered when a cell is too injured to repair).


This distinct wiring presents an intriguing opportunity: to selectively activate ferroptosis to kill certain cancer cells.

Can death by iron, or 'ferroptosis' be aimed at cancer?
Or blocked in nerve cells to protect the nervous system?
(Iron Maiden. ' The Trooper' (1983))

"The RAS family [of genes] is mutated in 30% of cancers," Dr Dixon writes. These mutations lead to uncontrolled cell division, but also "for better or worse... elevated levels of iron... are observed in some cancer cells".

His team believes it is possible to activate ferroptosis in RAS-mutated cancers inside the human body, using the abnormal iron levels to sensitise the cells to chemicals like erastin.

But activating ferroptosis in cancer may not be its only health benefit. There may be a use for blocking the process too.

The team successfully rescued neurons in rodent brains from cell death by blocking ferroptosis with a chemical inhibitor called ferrostatin-1. They propose that blocking ferroptosis in human brain cells following a stroke or epileptic fit (when ROS and iron levels are high) might protect the central nervous system from long-term damage.

Although the wiring inside our cells is complex (and multitasking is common), ferroptosis is a rare example of independence. Its distinct wiring may allow selective activation or inhibition of cell death, and maybe even the treatment of cancer with fewer side effects. That this metal-based killer might be used to protect life is, in more ways than one, quite ironic.

What does this mean for me?

This study might lead to a whole new line of approach for the treatment of some cancers and diseases which damage the central nervous system. High levels of iron have been reported in cases of Alzheimer's and Parkinson's disease. Understanding exactly how our cells are wired to use ferroptosis will make it easier for scientists to manipulate its effects with drugs similar to erastin or ferrostatin-1.

What does this mean for science?

The discovery of a previously unknown route to cell death shows just how much about our cells we have yet to understand. Indeed, the authors of this work suggest there may be much more "hidden" wiring  used by the cell, waiting to be discovered.

Reference:

Dixon, S., Lemberg, K., Lamprecht, M., Skouta, R., Zaitsev, E., Gleason, C., Patel, D., Bauer, A., Cantley, A., Yang, W., Morrison, B., & Stockwell, B. (2012). Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death Cell, 149 (5), 1060-1072 DOI: 10.1016/j.cell.2012.03.042

Want to build the perfect smartphone? Take a lesson from your cells

The multitasking smartphone has
only been evolving for 20 years.

Today's smartphones could do better. Yes, they send texts, make video calls, talk to satellites, take, edit (and share) your pictures, play games and music... one even makes a whipping noise if you waggle it a bit. Some of them can make phone calls too. But surely there's so much more that could be crammed in?

The human cell has functionality that would put any smartphone to shame. The secret, as new research investigates, was learning how to multitask.

Smartphones are still evolving. They're getting smaller, lighter and more streamlined. At the same time consumers are demanding 'more connectivity!', 'more integration!'. They want Apps that talk to other Apps; Facebook statuses that automatically log GPS positions, whips that crack by themselves. Maybe they're spoilt, or perhaps this is all part of the evolution: people expect more because the technology promises so much. Increasing the  "smartness" of your next phone will probably require a balance between efficiency and functionality. Apps must share software and hardware; in order for you to multitask so must your phone. Perhaps there is a lesson for smartphone developers inside mammalian cells.

The wiring inside our cells has evolved over millions of years to overcome problems with multi-tasking. In a recent paper published in PLoS Computational Biology, Jeffrey Wong and colleagues found that, surprisingly, being flexible isn't always the best option.

The cell has evolved over millions of years.
Inside, thousands of proteins multitask to
co-oridinate and control its 'Apps'. And it's only
~1/100 of a centimetre across. Beat that, smartphone!

The team from Duke University, North Carolina, investigated the wiring of the E2-Factor (E2F) network, a system of proteins inside the cell which changes its structure to control both the cell cycle (enabling the cell to grow and proliferate) and apoptosis (programmed cell death), making E2F one of life's most important multitaskers.

They asked a simple question: what happens when you increase the demand on the wiring? How does the cell cope?

The team built a mathematical model of E2F's wiring, using algebra in place of genes and proteins. They then ran simulations to see if it was possible for E2F to multi-task by compromising its structure to cope with several tasks at once.

Yes - the model predicted - but only for tasks that were similar. Different tasks would pull E2F in opposite directions, making a compromise not only hard to find, but damaging. As the strain or "tension" in the network increased, it would become less "robust" and liable to break or crash (which may sound familiar to smartphone users who have ever tried to run multiple Apps at once).

But what if - suggested the model - what if E2F could change its structure dynamically between competing tasks; or even duplicate part of its wiring to cope with the tug-o-war?

This all makes a lot of sense if we look at what we know about human evolution. Previous studies have shown that the E2F network does dynamically change in structure during the cell cycle. Also, mammals have evolved a set of similar E2F proteins, some of which share tasks.

Dr Wong believes E2F (and other systems in our cells) evolved to mimise the tension in our cells' wiring. He suggests that multitasking in this way is an "evolutionary feasible" way of "reusing a common set of components... to accomplish multiple biological goals."

Maybe smartphone developers could take some useful multitasking tips from inside their cells? They might just save themselves millions of years' worth of trial and error.


What does this mean for me?

This study improves our understanding of the design of the cell - how has it evolved? and why? Answering such questions is essential not just for our knowledge but also for scientists attempting to understand how the cell changes in diseases such as cancer.

What does this mean for science?

Models built from algebra are used to simulate everything ftrom air traffic to climate change to volcanic ash clouds. They've been used in biology for almost a 100 years. Here a model is put to good use as part of a Systems biology approach. Their model was built based on prior knowledge (of E2F), and then made experimentally-testable predictions: in this case for the behaviour of E2F when different demands are placed on its wiring. The authors suggest that synthetic biologists might find "vast potential" in the different ways a single system can reorganise themselves to multitask.

Reference (open-access article, freely-available as PDF here):

Wong JV, Li B, & You L (2012). Tension and robustness in multitasking cellular networks. PLoS computational biology, 8 (4) PMID: 22577355 

Getting to the root of Type II diabetes... with liquorice?

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Metabolism is a balancing act that gets harder with age
(Picture of Philippe Petit on high wire, Notre-Dame
Cathedral, Paris, 1971. picture: Cordisere)

The liquorice root is full of surprises. Chewed as a breath freshener in Italy and a sweet in Sweden (and the north of England), this little brown stick has also been used as a remedy for mouth ulcers for thousands of years.

New research has identified a natural chemical extracted from the liquorice root that could be used to treat Type II diabetes.

Our metabolism is a delicate balance. Insulin, a hormone secreted by the pancreas, regulates levels of glucose and fatty acids in the blood by storing them out of the way in fat and muscle tissue. Some stored compounds can be converted back into glucose when the body needs energy.

Wear and tear on this balance,  as our cells age or through diet or stress, can overload our tissues with fatty acids. Fat and muscle cells become unable to soak up excess glucose and in some cases build a resistance to insulin, a hallmark of Type II diabetes.

Recent drug-based therapies aimed to restore the metabolic balance by targeting the wiring of PPAR-gamma, a receptor protein in the nuclei of many fat cells.  PPAR-gamma responds to fatty acids in digested food by activating genes to boost metabolism. The hope was to manipulate PPAR-gamma to lower the level of fatty acids and improve the cells' sensitivity to insulin.

But there was a problem. The synthetic drug rosiglitazone triggers PPAR-gamma very strongly, successfully lowering blood glucose levels but also firing many other genes at the same time. Out of context, some of these genes were linked to unforeseen side-effects such as weight gain, fluid retention and heart disease.

The liquorice root.
Amorfruitins found at low levels inside
might be extracted to treat Type II diabetes.
(Picture: Ryan Opaz)

In a recent study in PNAS, Christopher Weidner and colleagues investigated a natural alternative. Amorfruitins, extracted from the edible roots of Amorpha fruticosa (the indigo bush) and  Glycyrrhiza foetida (a species of liquorice) are natural activators of PPAR-gamma. Amorfruitins were shown to influence glucose and fatty acid metabolism similarly to rosiglitazone but with more selective targeting of PPAR-gamma,  respectful of its powerful role in controlling different sets of genes.

The team, led by Sascha Sauer from Max Planck Institute for Molecular Genetics in Berlin  showed that amorfruitins decreased insulin resistance in the fat cells of diabetic mice without any observed weight gain. Amorfruitins also reversed some of the genetic changes brought about by a high-fat diet.

Dr Sauer said. “In view of the rapid spread of metabolic diseases like diabetes, it is intended to develop these substances further so that they can be used on humans in the future.”

Sauer's team have begun to investigate how amorfruitins steer the wiring of PPAR-gamma so effectively. They found differences between the genes expressed by PPAR-gamma in response to rosiglitazone or amorfruitins. This is something of a smoking gun: a first step towards understanding what it is about liquorice, a legume, that gives amorfruitins their remarkable ability to correct wiring inside mammalian cells.

What does this mean for me?

It’s estimated that 190 million people are affected by Type II diabetes worldwide and that this figure will double over the next 20 years. This study shows not only a direct health benefit of a natural plant extract on metabolic diseases, but also suggests the mechanisms for how it might work inside mammalian cells. Sauer's team hope the edible nature of the liquorice root, will make it easier to obtain approval for the use of amorfruitins in humans.

What does this mean for science?

This study highlights the importance of "basic" cell biology research to support medicine: only after investigating how a drug works can we confidently predict what (side) effects it may have on the wiring inside our cells. The differences in gene expression patterns between natural and synthtic PPAR-gamma activators suggest clear differences in how they act inside the cell. This raises questions for future drug design approaches - what makes amorfruitins so subtle and selective? Can their mechanism be copied synthetically, maybe to target other important transcription factors?


Reference:

Weidner, C., de Groot, J., Prasad, A., Freiwald, A., Quedenau, C., Kliem, M., Witzke, A., Kodelja, V., Han, C., Giegold, S., Baumann, M., Klebl, B., Siems, K., Muller-Kuhrt, L., Schurmann, A., Schuler, R., Pfeiffer, A., Schroeder, F., Bussow, K., & Sauer, S. (2012). From the Cover: Amorfrutins are potent antidiabetic dietary natural products Proceedings of the National Academy of Sciences, 109 (19), 7257-7262 DOI: 10.1073/pnas.1116971109

Anchors away! When neural stem cells decide a change is as good as a rest

Neural stem cells are anchored to their niche until they
decide to migrate.
Painting: 'Canada Timber Docks, Liverpool.
Towards close of day' by Robert Dudley (active 1865-1891)

Between 1830 and 1930, over nine million people left England from Liverpool  on ships bound for Australia, Canada and America. The Merseyside port swelled with would-be emigrants, all holding tightly to the decision to leave their homes for the promise of a new life.

Stem cells in the brain are similarly destined for change. A recent study suggests their transformation into specialised cells, a process known as differentiation, is combined with the decision to migrate to where they are needed, bringing new understanding of the development and repair of brain tissue.

In the brain, neural stem cells (NSCs) can be found anchored in  'niches': port-like microenvironments which shelter the cells in a dormant, undifferentiated state. NSCs might eventually migrate all over the brain, some becoming neurons along the way, but this can only happen correctly if differentiation is timed precisely with release from the niche.

In a paper published recently in Nature Cell BIology, Francesco Niola and colleagues found the same set of proteins inside a neural stem controls both anchorage to the niche and the onset of differentiation, synchronising the two processes. This control may prevent differentiation from misfiring, leading to problems in development or even cancer.

Neural stem cells migrate to different parts of the brain, becoming different
types of brain cell such as neurons.
Painting: 'Ship off Liverpool', Robert Salmon (1811)

The team from Colombia University, New York looked inside mouse NSCs. They found that Inhibitor of DNA-binding (Id) proteins prevent an NSC from differentiating too soon by repressing the transcription of certain genes. Id proteins were also found to control RAP1, a protein involved in adhesion between the stem cell and its niche.

Dr Anna Lasorella, a senior author of this paper said a key question for the future was to, "determine whether Id proteins also maintain stem cell properties in cancer stem cells in the brain." "In fact," she said, "normal stem cells and cancer stem cells share properties and functions." She added that targeting Id proteins in cancer stem cells might, "lead to more effective therapies for malignant brain tumours".

What does this mean for me?

Better understanding of how neural (and other) stem cells differentiate may influence when and where injected stem cell therapies are used. Also, as Dr Lasorella said (above), studying processes involved in stem cell regulation may give insight into similar processes in cancerous stem cells leading to malignant brain tumours.

What does this mean for science?

This study presents a new idea - it was previously thought that the niche itself controls the release of NSCs with chemical signals. Here we see the decision is influenced, at least in part, by the NSC's internal wiring. More generally, the central role of Id proteins is another good example of multi-tasking, involving co-ordination between internal wiring of differentiation and the cell's external environment.

Reference:

Niola, F., Zhao, X., Singh, D., Castano, A., Sullivan, R., Lauria, M., Nam, H., Zhuang, Y., Benezra, R., Di Bernardo, D., Iavarone, A., & Lasorella, A. (2012). Id proteins synchronize stemness and anchorage to the niche of neural stem cells Nature Cell Biology, 14 (5), 477-487 DOI: 10.1038/ncb2490

Faultless: Your skin's battle with open wounds and cancer

The San Andreas fault.
In our skin, fringes of cells meet to close a wound.
(picture credit: David Parker)

New research has revealed a connection between how our skin heals and the prevention of skin cancers.

In a paper published  two weeks ago in JCB, Jeremy Rotty and colleagues showed that keratin 6 (K6), a fibrous protein used to repair skin lesions, can also put the brakes on skin cells growing too quickly.

When the surface of your skin is scratched, the wound is quickly bridged by keratinocytes, cells full of K6 which migrate through the tissue and mesh together. Researchers found that K6, as well as providing scaffolding inside these cells, also attaches to and controls Src, a protein at the heart of the wiring for cell migration and growth.

It is here that a careful balance is struck. If there isn't enough Src activity inside a keratinocyte, it may not migrate at all, leaving wounds exposed. Too much Src, however, and the cells could migrate too far, growing into tumours. Skin cells lacking K6 to control Src activity have been shown to  produce aggressive cancers.

Keratinocytes actually roll into a wound
in the skin, like stones into a valley.
(picture credit: moonjazz)

The researchers from John Hopkins University, Baltimore, USA suggested that inside skin cancer cells K6 might be a “protective mechanism that maintains epithelial (skin surface) tumours in a ... less aggressive state".

What does this mean for me?

Future treatments for skin cancer might target the relationship between K6 and Src. A lack of K6 might also be looked for as a marker for predisposition to certain types of skin cancer.

What does this mean for science?

This is a great example of multi-tasking inside our cells. Keratin K6 can regulate both the structure and movement of keratinocytes. The relationship between K6 and Src  shows how important the inner-wiring of each individual cell can be to the overall tissue, where lesions need to be repaired despite the risk of cancer.

Reference:

Rotty, J., & Coulombe, P. (2012). A wound-induced keratin inhibits Src activity during keratinocyte migration and tissue repair The Journal of Cell Biology, 197 (3), 381-389 DOI: 10.1083/jcb.201107078

New research: Morphine gets our wires crossed

Morpheus, the Greek god of dreams
 (pictured, fairly content, bottom left).
Guérin painted this picture in 1811,
six years before morphine was first sold
commerically.

Researchers may have found the cause of a mysterious side-effect of morphine.

Morphine, a drug used to treat chronic pain, is also known to cause inflammation of the central nervous system (CNS), reducing its pain-killing effects. The question is ‘how?’

In a study published in April in PNAS, Xiaohui Wang and colleagues demonstrated that morphine can directly trigger inflammatory signals in endothelial cells, which line the blood vessels carrying the drug to the CNS and the brain.

The team from  The University of California, San Francisco showed that morphine chemically attaches to a protein complex  made up of myeloid differentiation protein 2 (MD-2) and Toll-like receptor 4 (TLR4) on the surface of the cell. A chemical chain reaction carries a signal from the TLR4 receptor through the cytoplasm to the nucleus where pro-inflammatory genes are found in our DNA.

Inflammation is important for our cells in times of stress or injury. Tissues must change shape and structure, swelling with blood to enable the healing process to begin. But inflammation is an entirely unwanted side-effect after morphine treatment and ultimately demonstrates the body protecting itself against the pain-killer, rather than the cause of the pain.

The authors believe that by stopping morphine from attaching to MD-2 it's possible to increase the efficiency of morphine treatments and pain relief.

What does this mean for me?

The possibility of more effective pain killers in the future. The link between morphine treatment and inflammation in the CNS is also proposed to affect drug dependence leading to abuse.

What does this mean for science?

This is a great example of crossed wires inside the cell: on the way to the brain to trigger opiod receptors and numb pain, morphine sets off our inflammation receptors (in this case a combination of MD-2 and TLR-4 proteins*) which are sensitive to all sorts of "alien" chemcials. Similar crossed wires can cause some drugs to fail completely.

* Don't be put off by the names. Some are easier on the ear, there's even a protein called 'Sonic hedgehog'.

morphine cure advertisement circa 1900.
"The most remarkable remedy ever discovered"

Reference:

Wang, X., Loram, L., Ramos, K., de Jesus, A., Thomas, J., Cheng, K., Reddy, A., Somogyi, A., Hutchinson, M., Watkins, L., & Yin, H. (2012). Morphine activates neuroinflammation in a manner parallel to endotoxin Proceedings of the National Academy of Sciences, 109 (16), 6325-6330 DOI: 10.1073/pnas.1200130109

Feedback

Jimi Hendrix.
Master of feedback, burner of guitars.

At six in the morning, on 18th August 1969, Jimi Hendrix took to the stage at the Woodstrock festival. In amongst his two and half hour set were many of his hallmarks - smashed guitars, fires, unpredictable guitar solos, playing behind the head and with teeth, and a new technique which Hendrix himself had invented.

Newspapers described his new effect as a protest against the Vietnam war because it sounded like "falling rockets". It was, simply, feedback.

Biologists (and Physicists) might qualify that a little - it was "positive" feedback. The vibrations from Jimi's guitar strings fed down into his guitar's pickups and across the stage in a wire. The sound was amplified and pumped back at the crowd. But it didn't end there.

Jimi turned to point his Fender at a wall of amplifiers so the sound caused new vibrations aross the strings. These fed back down through the guitar's pickups again, were amplified again, and spat back at his guitar again... The loop repeated, building and boosting until it reached a scream. Then, well... it was anyone's guess what Jimi would do next!

Positive feedback.
It happens in our cells as well.

In nature feedback is everywhere. 

Positive feedback loops happen in all of the cells in our body, and have done since the day we were born.

 

A protein called Cyclin B, for example, is boosted by positive feedback. As Cyclin B levels rise, they have a knock-on effect on another protein, Cdc25 which boosts Cyclin B even further. Just like Jimi with his Strat, biologists call this "amplification". Without amplification of Cyclin B our cells couldn't divide.

The natural world has also evolved forms of negative feedback, which has the opposite effect: instead of amplifying higher and higher it pushes back, reducing noise to silence or, in some cases, producing ellaborate cycles and patterns.

To see how, let's forget guitar heroes and cells for a moment and think about foxes and rabbits.

Rabbit and fox, prey and predator

In the wild, a thriving rabbit population naturally leads to a healthy surge in the population of foxes looking for an easy meal. The rabbit population inevitably falls, which leaves the fox population hungry so, after a delay, it too begins to fall. With fewer foxes around, the rabbits begin to multiply again...The two populations - predators and prey - are locked together, they rise and fall repeatedly. They oscillate.

Negative feedback.
Guess what? It happens in  our cells too.

Negative feedback loops are the driving force behind all sorts of biological oscillations - everything from seasonal changes to our heart beats to the hundreds of proteins wired together in our cells to control the response to diseases. (more about those in another post!)

On stage, Jimi Hendrix played around with negative feedback too. His wah-wah pedal used negative feedback to cancel-out some frequencies of sound whilst boosting others. Combining negative and positive feedbacks helped Jimi to define a new era of guitar playing.

It's no suprise that inside the cell, to achieve its incredible range of different functions, many sets of proteins are wired into positive and negative feedback loops which are also wired to each other! 

Jimi using feedback during "Star-spangled banner"

Woodstock festival, 1969

For more on biological cycles, have a look at this. I'll be writing on what oscillations actually do inside cells in a later post!

Reference (one of the earliest):

VOLTERRA, V. (1926). Fluctuations in the Abundance of a Species considered Mathematically Nature, 118 (2972), 558-560 DOI: 10.1038/118558a0