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Big Data and Drug Discovery

  • Big Data and Drug Discovery

  • Source: www.ox.ac.uk

    At Friday’s launch of the Li Ka Shing Centre for Health Information and Discovery at Oxford University, researchers spoke about the potential to revolutionise health research and offer patients better, safer and more personalised treatments through ‘big data’ and improved approaches to drug discovery.

    The new centre is being supported by a £20m gift from the Li Ka Shing Foundation and £10m from the Higher Education Funding Council for England.

    Professor Peter Donnelly, who will be involved in the analysis of large health-related data sets in the new centre, said Oxford is achieving something by bringing all these elements together that has not been done anywhere in the academic world before, ‘moving forward understanding of human biology and turning this into new treatments’.

    The Li Ka Shing Centre is being developed in two phases on the University’s Old Road Campus. The first phase, the Target Discovery Institute under Professor Peter Ratcliffe, is now complete (above) and researchers will shortly start moving in. The Institute will use high-throughput biology to define better drug targets in collaboration with industry, addressing a critical ‘blockage’ in the existing drug development process.

     

    The Target Discovery Institute will generate comprehensive data about disease using genomic and chemical screens – important data for the early stages of drug discovery.

     

    The second phase will focus on the analysis of large data sets in a Big Data Institute, bringing together leading researchers from across genetics, epidemiology and public health, clinical medicine, computer science and IT, statistics and bioinformatics.

     

    Very large sets of medical data are now routinely collected – through electronic patient records, DNA sequencing (the image shows genome sequencers at Oxford University), comprehensive biological data on disease mechanisms, treatment monitoring, clinical trials, pharmacy records, medical imaging, and national registries of hospitalisations, cancers and other outcomes.

    Bringing health-related datasets together for researchers to use in an anonymised way, and making use of new tools to scrutinise that data to gain insights, will provide powerful new insights into who develops illnesses and why.

    Oxford University already has world-leading expertise in these areas: pioneering the introduction of genomics into medical care, leading giant cohort studies like the Million Women Study and UK Biobank, running some of the largest clinical trials of treatment worldwide, and establishing methods for global disease surveillance in malaria and other major infectious diseases.

    (Full story)

  • Quantum cellmates with noisy networks

    Pete Wilton | 24 Apr 13 | 0 comments

     

    Being locked in a cell with three companions can be a good thing if you are a component of a quantum computer.

    These components, called quantum bits, are fragile and susceptible to outside interference, making them easier to control when isolated in cells of four.

    Now scientists from Oxford and Singapore report in Nature Communications a way these cells could be networked up with light even if these links are ‘noisy’ and unreliable.

    I asked Simon Benjamin of Oxford University’s Department of Materials and National University of Singapore, an author of the report, about quantum cells, noisy networks, and computing with pink diamonds…

    OxSciBlog: What are the problems with conventional designs for a quantum computer?
    Simon Benjamin: One way to build a quantum computer is similar to how today’s microchips work: thousands or millions of basic components, all laid out in a dense pattern like buildings in a city. There are two problems with doing this:

    First, the basic components of a quantum computer, called qubits, are hard to control and need to be kept as isolated as possible. Ideally you’d like to have each qubit in its own space with its own dedicated control systems around it.

    The second problem is that some of the best candidate systems for qubits cannot be formed into ordered patterns, even if we want to. An example is something called an ‘NV centre‘ which can occur naturally in diamond (technically it’s a ‘defect’, but a very useful one!) Experimentalists can locate the NV centres in a piece of diamond and control them, but we can’t force them to appear in specific places. Not yet anyway.

    OSB: How might cells and a ‘noisy network’ overcome these problems?
    SB: The approach we advocate is to replace that pattern of millions of qubits with many little chunks, or ‘cells’. Each cell would only have a few qubits in it, for example four. It is a manageable task to control four qubits with a single set of control equipment, and most physical systems (like the NV centres mentioned above) can manage to store four qubits.

    But of course this leaves us with a problem: how to link up the little cells? We know that linking quantum systems is possible using photons but sadly those links tend to be quite prone to errors. Fortunately we’ve found that it’s ok to use those ‘noisy’ links: we can put up with them going wrong 10% of the time, or even more. And the qubits inside each cell can go wrong too, although they need to be better behaved, let’s say they should go wrong less than 1% of the time.

    The upshot of all this is that replacing the big, complex system with lots of little cells linked by noisy connections is fine – you don’t really lose any performance, and the targets for how well behaved the qubits should be don’t change much either.

    OSB: What sort of systems might a noisy network work best with?
    SB: Well I’ve already mentioned NV centres in diamond. The NV stands for Nitrogen-Vacancy, and this means that inside the diamond there is a place where a Nitrogen atom has replaced the normal Carbon, and beside this intruder atom there is a ‘hole’ where another Carbon is missing.

    It turns out that this tiny structure has amazing properties: it can store several quantum bits, and they can be read out using a pulse of laser light. In fact, if you look at a diamond with a pink hue in a jewellery shop then the pink colour is typically coming from NV centres!

    As well as NV centres, another good quantum system is the ion trap, where a few atoms are held frozen in a vacuum by an electromagnetic trap. It’s hard to make a trap that can hold hundreds of atoms in an ordered way (let alone the millions that might be needed for computing). But it’s not so hard to build many traps, each holding a few atoms, and link them with light. 

    OSB: What other types of ‘noise’ or ‘error’ does your approach not account for?
    SB: In our study we’ve tried to be pretty general and put in all kinds of noise. Also, there are kinds of noise that we don’t need to worry about because of the network architecture: something called ‘correlated noise’ can cause a lot of trouble, it means errors clumping together instead of appearing randomly. But in our system this shouldn’t happen between different cells of the network, because they are far apart and disconnected except when we want them to communicate.

    OSB: What does your work tell us about how hard it will be to build useful quantum computers?
    SB: I would say that this work helps to show that the network approach (connecting lots of little computers) is very practical. Since some of the most promising candidate systems work well in the network picture, this is very encouraging.

    One exciting recent result is that researchers in the Netherlands have just successfully shown a quantum link between two pieces of diamond, each inside its own fridge! So the idea of linking quantum systems definitely works… now we’ll have to see how rapidly we can progress to a real network with lots of cells in it. A few years perhaps!

    (Full story)

  • Being there: turning research into action in Gabon

    Shelly Lachish | 08 Apr 13 | 0 comments

    Michelle Lee first set foot in Gabon in 2001: ‘I went with just a backpack expecting to stay three weeks, but ended up being the project manager there for six years,’ she tells me.

    Now a DPhil student at Oxford University’s WildCRU, working on land-use and conservation planning, back then Michelle gave up her desk job at the Smithsonian Institute in Washington to fly out and take over after the manager of the Institute’s Gabon biodiversity project quit.

    Gabon is a haven for wildlife and a hotspot of global biodiversity. Its small and highly urbanised population, along with its substantial petroleum and mineral deposits, have reduced typical pressures on land conversion. Consequently, Gabon boasts some of the largest remaining tracts of pristine tropical forest in the world.

    During her time spearheading the Smithsonian project, Michelle became acutely aware not only of Gabon’s significance for conservation but also of the sparse ecology and land-use data that was crippling conservation efforts. ‘When I started my doctoral studies there wasn’t even a national bird or mammal list compiled, let alone any species-distribution maps,’ she recalls. ‘There were also no maps of existing land uses, and the latest habitat maps were from the 1970s.’

    Over the past four years, Michelle has worked with local experts to gather this vital data. In a process similar to that used by the IUCN’s for their Red List threat assessments, she has completed a prioritization analysis of Gabon’s terrestrial vertebrates and produced distribution maps for the top priority species. She has also updated the nationwide habitat maps for the country and assessed how different habitat types are allocated across different land uses throughout Gabon.

    Her research is providing a foundation for science-based land use planning and policy development in Gabon, whose government is unusual amongst its neighbours in its strong commitment to fostering biodiversity preservation and ecotourism, alongside economic expansion.

    ‘The slow and painstaking task of prioritisation and mapping allowed me to identify key habitats that were poorly represented in Gabon’s national reserve system and to propose improvements to the current protected area network,’ she tells me.

    Michelle has presented her scientific findings directly to the head of National Parks, and is working with the government to identify areas that require more field verification. ‘As a signatory to the International Convention on Biological Diversity, Gabon is legally required to meet certain targets for habitat and wildlife protection,’ she explains. ‘My research enabled the government to see where they fell short of these targets, and together we are planning scenarios to address these shortfalls and improve the efficacy of the reserve design.’

    A large part of Michelle’s success at conveying her research findings and expert opinion to Gabon’s policy-makers comes from the fact that she drew together the many disparate sources of data needed for the planning process.

    ‘I think that being in-country helped me figure out what would be helpful for us to know, and then I tried to address this.’ However, as she is quick to point out, the process of being heard required more than just researching the right questions and a government willing to listen. ‘My involvement would probably have been impossible without my history of working in the country and my understanding of the context on the ground,’ she says. ‘This has helped me gain the confidence of the people involved. So I am able to present conservation options that I think might be both internationally appreciated and politically palatable.’

    What she only casually alludes to though, is the importance of persistence, perseverance, and passion. ‘For a long time I carried around these big maps of mineral depositions and habitat and wildlife distributions wherever I went,’she remembers, smiling. ‘I would unroll them at any opportunity and encourage people to see how conservation and development could be accommodated and planned for together in a spatially-structured scientific process. I guess I eventually got my message through. Or perhaps they just got sick of seeing me carrying them around!’

    When I ask Michelle for her advice to other conservation scientists, she replies that patience, flexibility and the ability to compromise are critical for negotiating the path from science to policy.

    ‘Trying to do conservation science in a developing nation, even one as environmentally aware as Gabon is a balancing act. I realised early on that I could not adopt a ‘conservation agenda’ if I wanted to achieve the greatest outcomes for environmental sustainability,’ Michelle says. ‘Gabon is trying hard to balance job creation, food security, and economic development alongside biodiversity retention and carbon sequestration. At some point, detrimental impacts are unavoidable and you have to make difficult decisions. Conserving 50% of elephant habitat is great, but it also means that you are prepared to lose 50% of their habitat.’

    This means that transcending the divide between research and policy requires a slightly different breed of scientist. One who is willing to adapt their focus and adjust their expectations of outcomes, one who can balance the analytically correct answer with what makes real-life sense, and one who views science as a means of solving a problem rather than an end in itself.

    As Michelle notes: ‘Applied science is an entirely different process to research science, as it should be. Because of my background, I am able to wear both hats, and operate as research scientist in my doctoral studies and as applied scientist when I interact with the Gabonese government. Ultimately, though, we need both.’ 

    (Full story)

  • Flies with personality

    Jonathan Wood and Karen David | 05 Apr 13 | 0 comments

     

    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.

    (Full story)

  • Vote to save orangutan homeland

    Pete Wilton | 26 Mar 13 | 0 comments

    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.  

    (Full story)

  • Hide & seek with a quantum compass

    Pete Wilton | 08 Mar 13 | 0 comments

     

    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.’

    (Full story)

  • Accelerating drug development

    Harry Dayantis | 07 Mar 13 | 0 comments

     

    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 is greater 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.’

    (Full story)

  • Flying moths inspire robotics

    Shelly Lachish | 28 Feb 13 | 0 comments

    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.

    (Full story)

  • Capturing cancer cells

    Harry Dayantis | 25 Feb 13 | 0 comments

     

    When dealing with cancer, time is critical. Identifying cancer before it spreads can often be the difference between life and death, so early diagnosis is key.

    Cancers begin in one part of the body and often spread through the bloodstream into other organs. This process is known as ‘metastasis’, and causes secondary tumours, ‘metastases’, to grow at other locations in the body. These cells which are released from the primary tumour into the bloodstream are called ‘circulating tumour cells’ (CTCs).

    CTCs can be circulating through the bloodstream for years before any metastases form. If small numbers of CTCs can be detected in blood samples, cancers can be diagnosed before they spread. This is no easy task; blood samples might only contain a single CTC among millions of blood cells, and it can be difficult to distinguish between CTCs and normal cells.

    ‘A common signature that a cell in the blood is cancerous is that the CTC has a protein called EpCAM on its surface,’ says Dr Mark Howarth, a biochemist at the University of Oxford. Dr Howarth develops innovative biological and chemical techniques to image and diagnose cancer, and his group has recently been investigating the use of magnetic beads in cancer diagnosis.

    ‘To catch CTCs, the most common way is to use magnetic attraction,’ explains Dr Howarth. ‘We use small magnetic beads coated with antibodies. Antibodies are proteins, normally produced by the immune system, which bind to specific targets. By using antibodies which bind only to EpCAM, we ensure that the beads only stick to CTCs. When a magnet is applied, the CTCs move to the magnet and the normal blood cells are washed away.

    ‘We can then study the captured cells in the microscope to understand if the cell really is cancerous. By sequencing the cell’s DNA we can discover other features, such as whether the cancer might be vulnerable to particular drugs. For this reason, even if a person has already been diagnosed with cancer, studying their CTCs could be an important way to make sure that they get the best treatment.’

    This technique has great diagnostic potential, as it only requires a standard blood sample from the patient. Yet current methods fail to catch CTCs whose surface contains low levels of markers such as EpCAM. Jayati Jain and Gianluca Veggiani in Dr Howarth’s group investigated ways of ensuring that CTCs with fewer surface markers were still picked up by the magnetic beads. This was recently published in the journal Cancer Research.

    ‘We showed that it makes a huge difference to use antibodies with the best binding affinity for their target,’ says Dr Howarth. ‘For imaging cancer cells, moderate binding affinity is okay, but for isolating cancer cells, there is a force from the magnet pulling the antibody off its target and so only the best antibodies survive.’

    The ‘binding affinity’ between an antibody and its target determines how strongly they are held together. Antibodies with higher binding affinities provide stronger links between CTCs and magnetic beads, so fewer beads will be torn from CTCs when magnetic fields are applied. As a result, more CTCs end up in the final isolated sample.

    Another problem with isolating CTCs is that the surface markers which the antibodies must bind to are not simply static.

    ‘Surface markers like EpCAM in the membrane of the cell are moving in a sea of lipids and cholesterol,’ explains Dr Howarth. ‘Cholesterol plays an important role in the physical properties of the cell membrane, affecting its fluidity, elasticity and integrity. We found that the cell’s cholesterol level was crucial to how sensitively the cell could be isolated by the magnetic beads.

    ‘Feeding cells extra cholesterol for an hour meant that even cells with low EpCAM levels were caught. It’s worth bearing in mind that all of this is done to blood samples after they have been taken from the patient – we’re not talking about pumping people full of cholesterol!’

    If enhanced CTC isolation techniques could be rolled out nationwide, cancers could potentially be identified years earlier than they are currently. A recent survey found that around a quarter of cancers in the UK are only diagnosed when the symptoms are so severe that patients are admitted to A&E.

    ‘Using the information we gained about cell isolation, we could capture cancer cells expressing lower levels of distinguishing marker than before,’ according to Dr Howarth. ‘As the next step we are going on to explore, through collaboration with the Oxford Cancer Research Centre, how our enhanced technique will affect the ability to find CTCs in breast cancer patients and understand the changes happening during the course of the disease. In the long term, we hope that this approach will help searching for CTCs to become a standard tool in looking for early signs of cancer in the most susceptible populations.

    ‘It’s worth emphasizing that our modification of this technology has a long way to go before we see it in clinical diagnosis. Clinics in the US already use magnetic isolation techniques, but only to detect cancer recurrence rather than for the initial diagnosis. We need to test our enhanced techniques on the blood samples of real cancer patients to assess their clinical value.

    ‘We must also improve our understanding of CTCs, so that clinicians can reliably identify them under a microscope. With typical current approaches, a few percent of samples give a ‘false positive’, because some normal cells look like CTCs. In several years, if we could address these issues, CTC isolation could be a powerful and cost-effective tool for primary diagnosis of cancer.’  

    (Full story)

  • Models move from brain to rain

    Pete Wilton | 06 Feb 13 | 0 comments

     

    One of climate scientists’ key ambitions is to predict future climate change more accurately. They create incredibly detailed computer models, but even these cannot calculate all the infinite detail of the real climate.

    The inevitable approximations they have to make mean that when it comes to rainfall – one of the most important, yet tricky, aspects of climate – different models seem to say very different things.

    But what if, fundamentally, they’re not so different? 

    What if they all agree that a monsoon will become wetter in future years; it’s just that they disagree on the time of year that the monsoon will appear and where exactly it tends to pass over?

    ‘Each model is a bit like a photograph of the same object taken from a slightly different angle,’ Adam Levy from Oxford University’s Department of Physics tells me. ‘If you simply overlaid them they wouldn’t match up in many places, but if you can adjust for the different perspectives – of monsoons coming a month or two earlier or later or shifting a bit further south or north – many of the differences between models might just melt away.’

    Adam is part of an Oxford University team that recently reported in Geophysical Research Letters a new way of applying techniques used to analyse human brains to climate models. 

    In medical imaging, researchers use mathematical techniques to work out the relationships between anatomical regions of the brain that can look different in different patients – something that needs to be adjusted for so that the images ‘fit’ and they can spot common symptoms or patterns.

    In their new approach the Oxford team applied these techniques to 14 of the latest global climate models, first transforming the historical simulations generated by these models so that they lined up better with observations, and then applying these transforms to the models’ predictions to see how this affected their agreement on future rainfall. 

    To do this, the team have worked in collaboration with medical image analysis researchers in the Oxford Centre for Functional MRI of the Brain (FMRIB).

    ‘Climate models seem to disagree about rainfall quite a lot, which is a huge problem, as changes in rainfall will have bigger human impact than many other aspects of climate change. What we found, though, was that when we transformed the models using our technique we had managed to iron out a substantial part of the disagreement,’ Adam explains.

    The transformation increased agreement between the models by an average of 15%, although some areas saw more benefits than others. Overall there was increased agreement across 66% of the globe about rainfall patterns. This first test run used an extreme climate scenario in which unabated carbon dioxide emissions have quadrupled atmospheric levels. However, the plan is to apply the technique to more realistic and subtle simulated scenarios.

    The team are currently working on dedicated software which takes into account the many ways that climate models differ from brains – for instance in being wrapped around a sphere as opposed to a 3D ‘image’ of a subject’s brain – to create tools tailored to this new application.

    ‘The long-term goal is to be able to make accurate predictions of how climate change will affect average rainfall at a given time, at a given location on the globe,’ says Adam.

    Such techniques could give us a much clearer picture of what climate models are really saying about how rainfall patterns are likely to change – and this could help to ease the strain on the brains of policy makers trying to plan for our planet’s future.