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

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