Features

Bioengineering is an exciting and diverse field covering everything from carbon nanotubes to microrobotics and from gene therapy to virtual drug testing.

Oxford’s IBME recently hosted Bioengineering '09, a conference bringing together the latest research in this area.

I caught up with conference organiser Yiannis Ventikos of Oxford University’s Department of Engineering Science to ask him about his group’s research into modelling stents – just one example of what can happen when engineering science meets clinical practice:

OxSciBlog: How does modelling help inform surgical interventions?
Yiannis Ventikos: Uniquely, computational modelling, or ‘simulation’, has the capability to predict the outcome of interventions, in a personalised and patient-specific fashion. Appropriate computer models can answer questions like: ‘how will this disease progress?’, ‘should we intervene aggressively, say surgery, or should we follow a more conservative approach, for example pharmaceutical?’ or ‘if we have decided on intervention, which of the available scenarios is the preferred one?’

The unique power of simulation is that it answers these questions in a personalised fashion. Statistics, demographics and epidemiology of the type commonly used in clinical decision-making are used to validate the models, but once the models are validated, they answer these questions, sometimes from first principles, for the specific genetics, family history and morphology/physiology of each individual patient.

So, the answers obtained are not based on some vague average but on the particular characteristics of the person in need of treatment for the specific disease.

OSB: Why is understanding how different stents work so important?
YV: Stents are used to treat many types of vascular pathologies. A relatively new approach used in interventional neuroradiology is to implant open stents at the neck of cerebral aneurysms in order to reduce blood flow into them. This procedure is a minimally invasive one, since the stents can be delivered using a catheter, through the artery, entering the body via a tiny incision, usually at the thigh.

Oxford and the Department of Neuroradiology are amongst the world’s leading centres where such aneurysms in the brain are treated and therefore making sure that this procedure is done optimally is really important. The open stents used in this procedure are effectively cylindrical-shaped wire meshes that allow blood to pass towards side vessels, but reduce flow adequately towards the aneurysm sack so as to promote stagnation and the formation of a stable clot in the aneurysm.

OSB: How can modelling help to evaluate stents?
YV: Open stents for cerebral aneurysms sound like an interventionist’s dream treatment, a minimally invasive approach that actually addresses the problem for a very wide range of aneurysm morphologies. There is a problem however: not all stents successfully occlude (close) all aneurysms.

The problem here is one of fluid dynamics: putting what is effectively a grid in front of the aneurysm opening must lead to a reduction of inflow that is adequate to induce stagnation and clotting. There is no intuitive way to estimate that however. The reduction of inflow depends on the stent weaving, but also on the local haemodynamics: the speed and direction of blood flow, the morphology and orientation of the opening, and above all, on the interplay of all of the above. Second-guessing whether a stent will work or not is no good – if a wrong decision is made, further interventions are then needed that burden the patient.

Simulation answers this question brilliantly: stents from different manufacturers (or new designs) are virtually placed into position, in a similarly virtual anatomically accurate representation of the vasculature, and their performance is evaluated preoperatively.

Not only can we choose the best device for a particular aneurysm, we can also decide on the best orientation and positioning of the implant. It’s all virtual, done on the computer a day or two before the intervention and it is 100 per cent safe and repeatable. It gives us confidence that when the time for the actual intervention comes, the clinician’s skills will be supplemented with robust knowledge of which device will do the best job for a particular patient, for a particular aneurysm actually, and how this device should be used for best results.

OSB: What are the next steps in your research?
YV: The conceptual framework described above (predictive, simulation-based interventional planning) can be applied to a whole host of conditions. Similarly, the techniques and tools we develop for one disease are often applicable, with little modification, to other diseases too.

We are expanding this technique now to account for a different type of implant, a stentgraft, as used for the treatment of acute aortic disease (like for example, aortic dissections). There, closed conduits (made of reinforced synthetic material) are used to line and so strengthen weak, diseased aortas. Again, models that are as representative of the real situation as possible are being devised; models that incorporate the blood flow dynamics, the vascular wall adaptation and its interaction with the implant, biochemical processes like thrombosis etc.

Over 20 Oxford volunteers recently pitched a tent at this year's Royal Berkshire Show, Newbury, to tempt visitors into exploring scientific experiments and ideas.

The entertainment on offer included mathematical games - such as building a giant fractal - demonstrated by Marcus's Marvellous Mathemagicians, slime-making and burning magic paper performed by chemist Roger Nixon, and a range of smaller experiments out of which the soap and bath bomb-making proved particularly popular.

Access Coordinator and organiser Naomi Capell tells us: 'The main part of the tent was a variety of little science busking experiments, things like creating homemade lava lamps, making coloured non-Newtonian fluid with cornflour, water and food colouring, and exploding cola bottles with mints.'

'It was a very busy day but the feedback we got from parents and teachers was great!'

If you fancy a taste of what was on offer at Newbury then you can join Marcus's Marvellous Mathemagicians tomorrow [1 October] where they'll be running a show called Playing with Numbers at London's Barbican.

Whilst you're at the Barbican why not also go to see their mathematical leader, Marcus du Sautoy, give a talk tomorrow evening on Symmetry: A Journey into the Patterns of Nature [tickets for these events sold separately].

How did a flatfish's eyes end up on one side of its head?

It's a question that puzzled Darwin when developing his theory of evolution but in a talk this week to the Society of Vertebrate Palaeontologists Matt Friedman, of Oxford's Department of Earth Sciences, presented fossil evidence showing how such a strange bodyplan gradually evolved.

Still at the conference, Matt gave some quickfire responses to OxSciBlog's questions:

OxSciBlog: What was it about flatfish evolution that so puzzled Darwin?
Matt Friedman: Flatfishes - like the gastronomically familiar halibut and plaice - are unusual in having both eyes on one side of the head. The tricky bit for Darwin was making sense of intermediates between normal symmetrical fishes and asymmetrical flatfishes. What good is it having an eye moved slightly over?

In fact, the origin of flatfishes was used as an early attack on natural selection, and actually led some scientists to propose that sometimes evolution operates in leaps and bounds rather in a more gradual fashion.

OSB: What evidence did you study to understand how flatfish evolved?
MF: I examined fossil fishes from the Eocene (about 50 million years ago) of Italy and France, combined with study of skeletal materials of living fishes.

OSB: What does this fossil evidence show?
MF:The fossil evidence clearly shows fishes with an arrangement of eyes intermediate between that of normal fishes and flatfishes. One eye is shifted toward the opposite side of the skull, but does not quite make it there. This is precisely the arrangement dismissed out of hand as 'unlikely' or 'not functional', which is what led to all the problems for Darwin.

OSB: How does this add to our knowledge of how evolution works?
MF:Well, each individual evolutionary story is unique, so care must be taken in not pushing this too far. However, in this particular instance, I am able to reject the scenario that the unusual bodyplan of flatfishes evolved suddenly (ie, went from symmetrical to the modern condition in a single step), but rather occurred in a more gradual, conventionally Darwinian, fashion.

Dr Matt Friedman recently moved to join Oxford University's Department of Earth Sciences from the University of Chicago.

Developing new drugs against diseases like Alzheimer's can be a long and tortuous process. It can take even longer, if initial tests to find new candidate drugs aren’t quite testing for the right activity.

David Vaux and colleagues at the Dunn School of Pathology believe that may be happening with some of the test-tube assays used to identify potential drugs for diseases like Alzheimer’s and type II diabetes, in which deposits of broken and misfolded proteins build up.

Their results that highlight the problem – and a new assay they have developed to overcome it – have just been published online in FASEB journal.

Alzheimer’s disease has been known since the beginning of the 20th century to be associated with a build up of deposits in the brain called amyloid plaques. More and more has been learnt about the formation of these plaques since. Small fragments get broken off from an innocuous protein normally present in the brain. One of these fragments – beta amyloid – becomes distorted and misfolded, and begins to stick together into fibres that eventually aggregate to form the amyloid plaques.

But sorting out the connection of this many-staged build up of protein with disease progression in Alzheimer’s has been difficult. A consensus is now building, says David Vaux, that it is the very early stages when the beta amyloid fragments first start accumulating into clusters a few strong that is toxic to nerve cells. Big pharma is now targeting these early protein assemblies in the hope of finding new drugs.

The standard way new drugs are found is first to take a protein that’s implicated in the cause or progression of a disease, and throw thousands of compounds at it. The hope is that a few compounds will be found that stop the protein in its tracks. The few ‘hits’ that are generated in this way are used as the starting point for drug development.

But there may be a problem in this case, suggests David Vaux. ‘Attempts by multinational pharmaceutical companies to identify potential drugs that might inhibit the assembly of amyloid precursors into neurotoxic intermediates have relied on assays in multi-well plates. Although they have generated hits, these have not yet translated into in vivo active drug candidates.’

Multi-well plates are plastic trays with many lines of little cylindrical wells in which separate reactions can be carried out. It’s like hundreds or even thousands of tiny test tubes lined up in rows. Using multi-well plates allows tens of thousands of potential drug compounds to be tested swiftly and easily. But each well is open to the air, and this ‘air-water interface’ is key: beta amyloid tends to gather at the surfaces of solutions, where the protein fragments begin to organise and come together.

‘All the protein fragments need to come together in a particular orientation. It’s like trying to build a tower of lego bricks,’ explains David Vaux. ‘If you took a sack of bricks and shook it around, it’s very unlikely indeed that they’d come together to form that tower. But if you float the bricks on the surface of water, they are far more likely to join up.’

Of course, such surfaces, or air-water interfaces, aren’t present in the nerve cells of the brain. So the multi-well assays don’t capture the situation in the body. Potential drug compounds that appear to block the assembly of amyloid protein fragments in a multi-well plate may not go on to work in tissue cultures. Or worse, potential compounds that could lead to valuable new drugs could be lost and never tried because they don’t show an effect in this initial screen.

In cells, the proteins are known to orient and assemble mostly at the cell membranes. So David Vaux and his team set out to come up with a new assay that replicated this situation much better.

They introduced a simple Perspex cover to fit over the reaction wells in the multi-well plate, getting rid of the air-water interface at a step. They also introduce liposomes – lipid capsules that mimic cell membranes – into the mix to provide a template on which the Alzheimer’s protein fragments could assemble. The researchers have shown that beta amyloid assembles as expected in this new assay, but not because of any surface effects at the top of the well.

The team, with funding from Synaptica, is now using this new assay to screen for potential new drug compounds. They are just beginning to get tantalising hints that some compounds do act differently in their assay, which mimics the situation in cells much better.

This allows David Vaux to conclude: ‘I am sure that the new assay can identify potentially valuable hits that would be missed by conventional assays.’

A new way of measuring biodiversity, developed at Oxford University, has shown how genetic diversity, as well as population numbers, can plummet due to human activity.

The lost biodiversity is epitomised by a study of the plight of rockfish: ancient species once well-known to California's coast-dwellers.

Mike Bonsall of Oxford's Department of Zoology, along with colleague Sandrine Pavoine, was part of the team reporting their research in a recent issue of Ecology Letters. I asked Mike about rockfish, their decline, and how the new approach might help conservationists:

OxSciBlog: What's been the impact of fishing on rockfish populations?
Mike Bonsall: Awful. First it has to be realised that rockfish are extremely long-lived vertebrates. Some species live for up to 50 years and others have been recorded to live for over 200 years. As the technological ability to harvest fish from the ocean has increased we have overexploited (and collapsed) many stocks.

Rockfish are no exception: by 2003, some species were down to less than 5 per cent of their 1970 levels - so, over 40 years, (and given these harvested species live for more than this time period) we have selectively removed the reproductive cohort and the stocks have no opportunity to recover.

OSB: How has fishing affected the genetic diversity of rockfish?
MB: Sustained fishing affects not only biomass (population size) but also genetic diversity. We have shown that the declining numbers with a rockfish hotspot (off the west coast of California) is accompanied by changes in the phylogenetic (evolutionary) structure of the species assemblage.

For instance, evolutionary-old (basal) species had higher contributions to the diversity and large-bodied species were shown to decline (affecting genetic diversity).

OSB: What advantages does you approach have over other ways of measuring biodiversity?
MB: Our approach allows us to see if changes between communities (either in time or across space) correspond to changes in the different evolutionary lineages (and species that evolve from each lineage). We can weight species differently (depending on their rarity) and allow different classical indices for biodiversity to be used in our ecological-evolutionary analyses. In sum,  our methodology has broad applications that can be used to integrate geographical space, current history (ecological time) and evolutionary history in measuring biodiversity.

OSB: How might your approach be applied to the study of other at-risk species/ecosystems?
MB: It could be applied widely, to many species: We are currently using it to explore how butterfly diversity alters on chalk grasslands and how plant communities are structured in Algerian marshes. However, there is a debate in ecology about whether communities are structured randomly (neutral) or by the evolution of niches. Our approach will allow us to explore a range of different communities where evolutionary histories are well-known to understand the relative contribution of neutral versus niche mechanisms.