Features

Fruit flies may have more individuality and personality than we imagine.

And it might all be down to a bit of genetic shuffling in nerve cells that makes every fly brain unique, suggest Oxford University scientists.

Their new study has found that small genetic elements called 'transposons' are active in neurons in the fly brain. Transposons are also known as 'jumping genes', as these short scraps of DNA have the ability to move, cutting themselves out from one position in the genome and inserting themselves somewhere else.

The inherent randomness of the process is likely to make every fly brain unique, potentially providing behavioural individuality – or 'fly personality'. So says Professor Scott Waddell, who led the work at the University of Oxford Centre for Neural Circuits and Behaviour: 'We have known for some time that individual animals that are supposed to be genetically identical behave differently.

'The extensive variation between fly brains that this mechanism could generate might demystify why some behave while others misbehave,' he suggests.

The Oxford researchers, along with US colleagues at the University of Massachusetts Medical School and Howard Hughes Medical Institute, were able to deep-sequence the DNA from small numbers of nerve cells in the brains of Drosophila fruit flies.

They identified many transposons that were inserted in a number of important memory-related genes. Whether this is detrimental or advantageous to the fly remains an open question, the researchers say.

Scott Waddell notes that neural transposition has been described in rodent and human brains, and transposons have historically been considered to be problematic parasites. New insertions of transposons can on occasion disrupt genes (as was found in this study), and transposons have been associated to some human disorders such as schizophrenia.

However, it is also possible that organisms have harnessed transposition to generate variation within cells, and by extension create variation between individual animals that may turn out to be favourable.

Scott Waddell wants next to determine whether neural transposition provides an explanation for variation in fruit fly behaviour by finding ways of halting the process in flies in his lab.

The peat swamps of Sabangau are home to vast array of wildlife including the world's largest orangutan population.

For the last three years OxSciBlog has been following work by Dr Susan Cheyne of Oxford University's WildCRU, one of the leaders of the OuTrop Project, to study and protect the creatures and habitat found in this corner of Borneo.

Now you can take part in a free public vote to help save the home of all Sabangau's special primates, rare clouded leopards, bears, and other wildlife. Simply go to the National Geographic Germany website where you can vote for OuTrop (see 'Protect and Restore Orangutan Habitat, Southern Borneo') to receive funding from the European Outdoor Conservation Agency (EOCA).

If successful EOCA funding will go towards restoring orangutan populations in the peat swamp, analysing the needs of the forest apes, and making sure any solution is sustainable and also benefits local people working there.

How would you look for something that can be in two 'places' at once?

The answer, according to Oxford University research into a quantum phenomenon called superposition, seems to be to ask where it isn't rather than where it is.

'Superposition allows an atom to be simultaneously 'here' and 'there'. Electrons behave like tiny magnets which can point both North and South at the same time,' explains Professor Andrew Briggs of Oxford University's Department of Materials. 'This is a distinctive quantum effect; it is quite different from anything in our intuitive every day experience of the world.'

Professor Briggs tells me that you can imagine an electron as being rather like a spinning top, as it spins it generates a magnetic effect.

'Just as a magnetic compass aligns itself with the Earth's magnetic field, because its energy is lower when it points that way, so a single electron in a magnetic field has a different energy depending on which way its spin points,' he says. 

But in the quantum world nothing is easy: try to look directly at which way this 'quantum compass' is pointing and the very superposition you wanted to catch in the act - of it pointing north and south at the same time - is destroyed. Instead the superposition state will be replaced with one where the magnet is pointing either north or south at random.

To get around this problem Dr Richard George and others from Oxford worked with colleagues at TU Delft in the Netherlands to prepare a series of experiments.

The researchers used the magnetism of a single atom of nitrogen trapped in a high-purity diamond as their 'quantum mechanical compass'. Under laser light, the nitrogen atom fluoresced according to how it was magnetised.

Rather than asking, 'Is the magnet pointing north or south?' the team asked, 'Is it pointing not east?' Measurements that confirm 'not east' were still compatible with the quantum superposition of pointing both north and south at the same time. The researchers studied three successive rounds of measurement on the nitrogen quantum compass, and used correlations between different rounds to prove the presence of quantum superposition in their system. 

The team recently reported the results in the journal PNAS.

'We had previously performed experiments in which the nuclei of our atoms had two states available to them. Now we have extended this to a superposition of three states, if you like North, South, and East,' Professor Briggs explains.

'The investigation involved an intermediate measurement, which was equivalent to opening one of three boxes and seeing if a ball was not in it. We showed that not only could you not tell which box had been opened; you could not even tell whether a box had been opened. This in turn, thorough some rather detailed reasoning, allowed us to prove experimentally some fundamental conjectures about the nature of reality.'

According to Professor Briggs this work is pushing the boundaries of 'quantumness' and developing techniques that will help to investigate whether quantum superposition applies to larger and more complex objects.

Dr George adds: 'Our confirmation of these subtle quantum predictions is an important step on the road to transplanting quantum mechanics from a theoretical and laboratory curiosity and into the devices which we use in commerce and everyday life. Our vision is to scale up and build computers in which every 'bit' is replaced with a 'quantum bit' that uses superposition as an integral part of their operation.'

All human clinical trials of new treatments begin with phase I, where drugs are tested in isolation to confirm their safety. Yet most effective cancer treatments use a combination of drugs, so-called 'multi-agent' treatments. After phase I trials are completed, it can sometimes take up to two years before multi-agent trials are approved, never mind conducting the lengthy phase II and III trials necessary before a new drug finally reaches the market.  

Professor Adrian Harris at the University of Oxford is currently leading a new type of trial which aims to significantly accelerate multi-agent drug development. Working with the Cancer Research UK Drug Development Office (DDO) and AstraZeneca, Professor Harris' team are now running phase I trials of a new cancer drug, AZD0424.

The big difference with this trial is that researchers and patients will not need to spend years waiting for approval after phase I is complete. Since the trial was awarded flexible approval right from the start, researchers will be able to move straight to multi-agent trials to begin testing the new drug in three different 'arms'. Each treatment arm will pair AZD0424 with a pre-approved cancer drug from a shortlist of 5.

All drugs on the shortlist have been approved for use in the trial, and the final three partner drugs will be chosen based on experiments in mice currently being undertaken at the Edinburgh and Belfast Cancer Research UK Centres. Refining the choice of partner drugs while phase I trials are underway in Oxford adds a further time saving to the development process, and is possible thanks to the advanced approval process.

'Although the drug may be effective on its own, we expect substantial synergy in combinations,' says Professor Harris. 'So the strength of this trial is that we are able to pair it with other drugs without having to wait for further approval between stages.'

AZD0424 works by partially blocking two proteins, Src and ABL1, which are abundant in cancerous tissue. These proteins are important for cell growth, metastasis (the spread of cancer) and blood vessel development, so blocking them helps to halt the growth of cancer cells and shuts off their blood supply. Researchers have selected a list of drugs whose effects are expected to complement AZD0424, and the results from Edinburgh and Belfast will help decide which ones to use.

'By pairing this drug with others, we can block multiple signalling pathways to improve the overall treatment,' explains Professor Harris. 'We hope that they will have additive or synergistic effects which could reduce or inhibit tumour growth.'

When the overall effect of multiple drugs is equal to adding up their individual effects, this is known as additive. Synergistic effects are when drugs interact such that the result isgreater than the sum of their individual effects. The partner drugs have already been shown to work individually, but this trial is about finding their combined effects in humans.      

'With conventional trial structures, it's unlikely that we would be investigating this drug in a multi-agent trial,' says Professor Harris. 'The flexibility to adapt the treatments used in the multi-agent stage will allow us to match specific patient groups and cancer types to the most promising drug pairs for their circumstances. By removing the considerable cost and delay of waiting for approval between stages, we can widen the pool of viable treatments and accelerate drug development.'

Yet doesn't removing this stage compromise the safety of the trials? Not according to Professor Harris. 'The approval granted before phase I was no less rigorous than it would have been if it was given between phases,' he explains. 'All of the drugs used in the trial have been tested for safety. One of the reasons for choosing AZD0424is that similar drugs have minimal side effects, so it's a relatively low-risk compound to begin with. We will also reduce the dosage when we begin the multi-agent phase.'

Of course, this multi-arm trial design isn't suitable for all drugs. It does take a little longer to get advanced approval in the first place, delaying the start of phase I. The design is well suited to a drug like AZD0424, which is expected to be most effective when used with other drugs. It is also important that patients in the trial receive good clinical care at all times.

'Professor Mark Middleton leads the clinical side,' says Professor Harris. 'He's currently running the phase I clinic, and every day he provides the highest quality of care to all patients in the trial. It's important that patients are treated holistically in the clinic.'

If the trial proves successful, Professor Harris hopes that the drug could be licensed for use with partner drugs within 4-5 years. 'It's worth remembering that by using combined approaches, including radiotherapy and surgery, half of common cancers are now curable,' he adds. 'A lot of people don't realise how far we've come in recent years. While there is still much work to be done, existing treatments for many cancers are highly effective. People often forget that, and it's important to focus on the positive sometimes.'

The AZD0424 trial is supported by the Cancer Research UK Drug Development Office and AstraZeneca

The hawk moth's wings are a blur of mottled grey motion as it hovers tethered to a steel rod in large white plastic orb. Outside the orb in the darkened room where I stand, a projector casts moving patterns of dimmed light onto the sphere's surface, illuminating the moth's field of vision with oscillating stripes.

Tonya Muller, a DPhil student in Oxford University's Department of Zoology, sits at the computer controlling the experiment. At regular intervals, she directs the computer to alter the direction, amplitude and frequency of the light stripes.

These changing light patterns create altered visual environments for the moth inside, which aim to simulate real-world visual disruptions the moth might experience when exposed to wind gusts. As the patterns change, the moth makes rapid adjustments to its flight behaviour to maintain constant stability.

Though imperceptible to the human eye, the moth's responses to the visual stimuli are detected by a force sensor attached to the end of the steel rod and relayed to Tonya's computer. These recordings are helping Tonya to understand the moth's remarkable visual-motor system, and identify the mechanisms of visual feedback in insect flight control.

'Understanding vision-based flight control in insects has far reaching uses in the fields of sensor development, signal processing, and robotics,' says Tonya, whose background is in mechanical engineering. Vision is important for information gathering in insects and up to 50% of an insect's brain can be composed of visual neurons. In fact, despite their small brain size, insects can solve extremely sophisticated orientation problems both rapidly and reliably. Yet their eyes are far less sophisticated than our own.

'Insects receive visual information through a relatively noisy, low-resolution sensor. But with this sensor they are able to processes information at sufficient speeds to react and respond to unexpected disturbances,' Tonya tells me. 'This is extremely interesting from an engineering perspective because developing technologies that use simpler and fewer electrical sensors and perform equally well can reduce manufacturing costs and computational power.'

Insects also assess changes in their environment using information they receive from other sensory organs on their bodies (including antennae, airflow sensors, and wing-load sensors). Studies have shown that insects pre-process and combine the information from these multiple sensory inputs, prior to reaching the controller. Current robotic technologies, on the other hand, use serial processing systems in which multiple sensors deliver separate and distinct input to the controller. Robot sensors are also currently designed for a very narrow and pre-defined range of conditions.

These limitations impede the response time of today's robots and restrict their ability to maintain or regain stability after unforeseen disturbances. For these reasons, discovering how the efficient parallel processing system seen in insects operates is an area of great interest for engineers developing sensory control systems in robotics.

'Insects might just be the perfect neural information processing model for improving sensory technologies and control systems in electronic applications such as robotics. Yet we are only just beginning to understand the basics of the mechanisms and pathways involved,' Tonya explains. 'We still don’t know how insects extract visual cues from their environment, which cues are the most important, and how those cues are processed to achieve the fast and efficient flight stabilisation that we see,' she says.

By measuring the hawk moth's flight behaviour in response to the visual stimuli presented on the white sphere, Tonya's novel experiments are beginning to shed light on these questions. 'This experimental set-up is really exciting. We can now simulate a 360 degree visual environment for the first time and measure all the forces and moments associated with the moth’s response to a particular stimulus,' she says. 'This is a huge advancement over previous studies that projected visual stimuli in just two dimensions and recorded only a subset of the insects' motion.'

Preliminary results from Tonya's experiments suggest that hawk moths use the angular position and velocity of the projected stripes as a primary cue to stabilise their flight. While describing flight dynamics accurately is an important advancement in the field, it is only the first step towards identifying the mechanisms of the active control of visual feedback in insect flight.

'The next stage of this work will involve measuring the activity of the moths' neurons in response to the visual stimuli presented,' says Tonya. 'These measurements will describe the electrophysiological pathways from the visual sensor to the flight dynamics in this species.'

In the future, Tonya hopes to be able to use implanted electrodes to measure neural activity in the moths. 'The ability to obtain this kind of data remotely from free-flying moths is the cutting-edge of science in this field and a truly exciting prospect,' she says enthusiastically.

Shelly Lachish is a Research Fellow in Oxford's Department of Zoology and a freelance writer.