Tuesday, 24 July 2012

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. 

buddy cop proteins police our cells
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.

too many loose canons
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".

cop and a half
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".


ResearchBlogging.org 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

Wednesday, 4 July 2012

Under your skin: taking skin cancer out by its roots

the sun can cause field cancerization
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 roots of skin cancers can begin deep in the tissue
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.


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