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

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