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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.

The fossilised teeth of ancient rodents suggest that their ancestors found a way to cross the South Atlantic Ocean to colonise South America.

Hesham Sallam, of Oxford University's Department of Earth Sciences, and colleagues report in this week's PNAS new evidence that shows that the ancestors of new world rodents, such as the Capybara, came over from Africa or Arabia in the late Eocene 40-34 millions years ago.

This means that the ancestors of the world's largest living rodent must have found a way to cross the South Atlantic which divided South America from Africa/Arabia at this time.

Rival theories had given Asia, via North America, as a possible origin for the rodent populations [Caviomorpha] that emerged in South America. But this new research shows that evidence from both the fossil and molecular data points to an African/Arabian origin. 

Hesham tells us: 'The caviomorph colonisation of South America evidently occurred via a chance dispersal across the vast South Atlantic.'

'Future paleontological research in the late middle Eocene should not only help to further clarify the later stages of evolution of these rodents but also the evolution of other mammalian groups such as primates.'

A team including Joseph Silk of Oxford University's Department of Physics have dreamt up the biggest particle collider ever: a rotating black hole.

In an article to appear in Physical Review Letters, the team imagine how, once Earth-based machines such as the Large Hadron Collider can no longer provide enough energy to probe deeper into fundamental particle physics, certain sorts of black hole might do the job.

They have calculated that, in middle-weight black holes that are rotating fast enough, particles of dark matter entering at the right angle would be accelerated towards each other at extremely high energy - making for an explosive high-speed collision.

It may even be that enough energy could escape these natural collisions for us to be able to detect them on Earth right now, using the latest instruments such as the IceCube observatory.

Such observations could tell us much about dark matter, gravity, and the beginnings of the Universe - as well as revealing more about the structure of black holes themselves.

Read more about this story in New Scientist.