Thursday, 31 May 2012

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

cells and smartphones multitask
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.
apps in the cell
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):

plos computational biologyWong JV, Li B, & You L (2012). Tension and robustness in multitasking cellular networks. PLoS computational biology, 8 (4) PMID: 22577355 This post was chosen as an Editor's Selection for

Thursday, 24 May 2012

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

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 contains amorfruitins
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?


ResearchBlogging.orgPNAS 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

Thursday, 17 May 2012

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

neural stem cells in a niche
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.
stem cell migration
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.

nature cell biologyReference:

ResearchBlogging.orgNiola, 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

Friday, 11 May 2012

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

keratin repairs skin lesions
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 migrate into a wound
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.

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

Wednesday, 2 May 2012

New research: Morphine gets our wires crossed

Morphine and inflammation
Morpheus, the Greek god of dreams
 (pictured, fairly content, bottom left).
Guérin painted this picture in 1811,
six years before morphine was first sold
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 home cure
morphine cure advertisement circa 1900.
"The most remarkable remedy ever discovered"


ResearchBlogging.orgWang, 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