Features

In the second of a series of articles marking the 10th anniversary of the Human Genome Project [HPG], OxSciBlog talks to Professor Chris Ponting of the MRC Functional Genomics Unit at Oxford University.

Chris explains what we can learn about ourselves by comparing our DNA with the genomes of other animal species.

OxSciBlog: What genome efforts have you been involved with?
Chris Ponting: It all started when I was phoned up and asked whether I’d like to help coordinate a set of analyses for the Human Genome Project. Of course, I jumped at the chance but still feel it ironic that, as someone who gave up biology at school at 16 to focus on a training in physics, I was offered this chance. Since then I’ve worked with many people and groups from around the world on the genomes of the mouse, rat, dog, marsupial, duck-billed platypus, chicken, zebra finch, fruit fly and lizard.

OSB: What can all this genetic information from different species tell us?
CP: Having DNA from different species is crucial to understanding the human genome. Each additional genome is an evolutionary yardstick against which human DNA can be compared.

For example, when you ‘walk’ down each chromosome you see DNA letters that are the same in us and in mice – they have stayed unaltered over tens of millions of years because of their biological importance. This is because spontaneous changes (mutations) in important, conserved DNA tend not to be carried over into subsequent generations as they cause illness or even death.

By separating DNA that has remained relatively unaltered across animal evolution from DNA that has changed rapidly, we efficiently separate ‘functional’ DNA from ‘junk’ DNA. One of the biggest surprises has been the amount of ‘junk’ DNA. Only about 10% of the human genome appears to ‘do’ something, the rest appears not to be important at all.

OSB: What does your own research focus on?
CP: Genomics is rapidly permeating into many areas of biology and medicine, and we have tried our hand at many things over the past few years. My group is trying to understand which genetic changes cause disorders such as autism, intellectual disability or Parkinson’s disease, whilst thinking about how zebra finches learn how to sing or how the platypus senses its prey under water.

It has been particularly enjoyable discovering that there are no more genes making protein in the human genome than they are in a microscopic nematode worm. Science is good like that: its perspective is often humbling.

We can learn a lot just from the gene sequences, seeing how they’ve been conserved or have changed across the millennia and across the tree of life. But most of what we do is to solve puzzles: putting together pieces of information drawn from diverse areas such as evolution, genetics, natural history and clinical medicine. Synthesising this information is often very rewarding and tells us something new.

OSB: What can we look forward to in the future?
CP: As sequencing becomes cheaper, some are advocating sequencing the DNA from all animals. Certainly, most of the species that are important to biology and medicine are being, or have been, sequenced. I look forward to seeing soon the DNA sequence of many animals, from ants to zebras.

Nowadays, we’re looking past the DNA that encodes protein to the hundreds of millions of DNA letters that appear to be doing something, but certainly don’t make protein. It is this ‘genomic dark matter’ that we need to illuminate if we are to better understand the differences between ourselves, or even between us and other animals.

OSB: Might this research hold benefits for human health?
CP: Sequencing DNA is becoming cheaper and cheaper. The first human genome, sequenced ten years ago, cost a staggering $3 billion. Soon one genome will cost $1000. With these plummeting costs come the realisation that individuals’ genomes can be sequenced to try and understand the DNA changes that cause rare or common diseases.

Some might be fearful of what their own genomes could tell them: might they, and perhaps their children, carry some genetic change that predisposes them to disease? In the vast majority of cases, the outcomes aren’t likely to be as simple or as clear cut as that.

I think there are two things to be said here. First, everyone’s genomes carry many changes (‘genetic blemishes’) that give marginal changes to disease susceptibility. In this sense, everyone’s genomes are far from ‘perfect’. Second, despite being able to read someone’s genomes, we are a long way from understanding them so, as scientists and clinicians, we are usually far from assigning single DNA changes to diseases.

OSB: You suggest that these approaches could lead to fewer animals being used in research. How?
CP: All our work is done in the computer and, as time has gone on, we’ve become more sophisticated at spotting genes that do equivalent things in different species. As a result, we have separated genes which are less informative from others which, if studied in model organisms such as fruit flies and mice, immediately provide insights into human biology. Also, evolutionary approaches can now make good guesses of what a gene’s functions are, all of which reduces the number of uninformative experiments. Computational studies are certainly doing their bit to reduce the use of animals in science.

What do shells, solar panels and DVDs have in common?

At the atomic scale they are ‘amorphous’, that is – unlike crystals – they are built from irregular arrangements of atoms.

As Andrew Goodwin of Oxford University’s Department of Chemistry explains this irregularity is important: it’s what allows shells to grow their curved edges and gives silicon its incredibly useful electronic properties.

But for scientists this irregularity also makes such materials tricky.

‘Our main technique for establishing what materials look like on the atomic scale is crystallography,’ Andrew tells me, ‘and this relies explicitly on the existence of a repeating arrangement of atoms in order to work. So the problem of studying amorphous materials with their seemingly-random arrangements of atoms has remained just that: a problem.’

Now, Andrew, and colleagues from Cambridge and Ohio, report in this week’s Physical Review Letters how tantalising crystallographic clues could offer a new approach to understanding amorphous materials.

‘For decades we’ve known that the ring-like patterns amorphous materials produce in crystallographic experiments contain limited information about the surrounding environment of each atom,’ Andrew comments, ‘but the big question has always been how to use this to create a coherent picture of the structure of a material.’

He explains that the new approach comes from the ‘neighbourly behaviour’ of atoms which means that similar atoms should experience a similar environment.

‘The spacing of the rings in the 'ring-like pattern' is related to the distances between atoms in the material, and the intensity of the rings is essentially related to how many neighbours each atom has,’ Andrew tells me.

‘So, using silicon as an example, a typical analysis of its corresponding crystallographic pattern would have told us that the distance between silicon atoms is about 235 trillionths of a metre [picometres], and that on average each silicon atom has four neighbours.’

Yet this information alone isn’t enough to build reliable models of what the atomic structure of a material such as silicon actually looks like.

Such models fail because they rely on the average ‘neighbourly behaviour’ of the atoms which means in these models some silicon atoms can have three neighbours if others have five – something other techniques such as spectroscopy show is incorrect.

The new insight relates to the fact that such experiments are sensitive to the number of neighbours each atom has, so an atom with three neighbours would appear as a different ‘type’ of atom to one with five neighbours.

‘Because there is only one ‘type’ of atom observed for silicon we know that not only is the average number of neighbours equal to four, but that each silicon atom must have exactly four neighbours,’ Andrew adds.

‘If we incorporate this extra information when building a model, the answer seems to fall out almost straight away. We simply tell our program how many different types of atom there are, and in what proportions, and this is enough to produce a realistic model from the ring-like patterns.’

The findings suggest that crystallography might, after all, be able to unlock the structural secrets of some of Nature’s most irregular materials: opening the way for new kinds of science and powerful new technologies.

Dr Andrew Goodwin is based at Oxford University's Department of Chemistry.

Image: Ring-like pattern observed using crystallographic techniques, in this example silicon has been used.

The first UK trial of a promising new retinal implant technique is to be led by Oxford University researchers.

The technology, developed by the firm Retinal Implant, AG, involves implanting a device underneath a patient's retina.

The device itself is light sensitive, with a 1,500 pixel array, and is stimulated by the natural image focused by the eye - eliminating the need for an external camera (typically mounted on spectacles).

Retinal implants hold particular promise for the treatment of retinitis pigmentosa (RP) a form of inherited retinal degeneration affecting approximately 200,000 people worldwide that typically causes severe vision problems in adulthood.

The trial will be led by Professor Robert MacLaren of Oxford University's Nuffield Laboratory of Ophthalmology. 'I have been working in developing new treatments for patients with retinal diseases for many years and I was initially sceptical about the role of electronic devices,' he said.

'However, this recent work by the Retina Implant team is very impressive indeed and I would now certainly consider this technology as a viable treatment option for patients blind from RP.'

He described it as 'much more logical' to implant a device underneath the retina, as this is 'where the residual neurons are orientated towards the implant electrodes, because this should equate to a much higher pixel resolution.'

Making the implant itself light sensitive is, he believes, a major advance 'because the whole device can be contained within the eye. A power supply is fed through a battery behind the ear similar to a hearing aid.'

'This represents a true fusion of an electronic interface with the human central nervous system and we are likely now to learn a lot more about this technology as the trial progresses.' 

The Oxford-led clinical trial using the technology, which will take place at the John Radcliffe Hospital, is due to start later this year.

Images: courtesy of Retinal Implant, AG.

A hydrogel material promises better treatment for cleft palates - a birth defect that affects 1 in 700 babies in the UK.

As today's Daily Mail reports the breakthrough comes from work by researchers at Oxford University, the John Radcliffe Hospital, and the Georgia Institute of Technology using STFC's ISIS neutron source.

The team, including Jinhyun Hannah Lee and Zamri Radzi from Oxford University's Department of Materials, used ISIS to look at the hydrogel polymer's molecular structure in order to see how the material might be used as part of a simplified surgical treatment.

The treatment involves inserting an anisotropic hydrogel material - similar to that used in contact lenses - under the mucosa of the roof of the mouth.

Once inserted, the hydrogel gradually expands as fluid is absorbed, encouraging skin growth over and around the plate. After sufficient skin has been generated to repair the palatal cleft, the plate is removed and the cleft is repaired using this additional tissue.

The success of the preliminary results of self-inflating anisotropic hydrogel tissue expanders means clinical trials are expected to take place early in 2011.

The study is the first to be carried out using the Offspec instrument at the recently opened second target station at ISIS.

Offspec is the world’s most advanced neutron instrument for studying new surface structures and can be used for a number of applications including biological membranes and patterned materials for data storage media.

Read more about the research in this ISIS release

Oxford University's technology transfer company Oxford University Innovation is looking for commercial partners to help develop the technology, for more details, contact Renate Krelle: [email protected]

The reddest part of Jupiter’s Great Red Spot corresponds to a warm core within this otherwise cold storm system.

The discovery comes from new thermal images taken by ground-based telescopes that have enabled scientists to make the first detailed interior weather map of the Solar System’s biggest storm.

The international team, including scientists from Oxford University and NASA JPL, used thermal images from the Very Large Telescope (Chile), Gemini Observatory telescope (Chile) and Japan’s Subaru telescope (Hawaii). They report their findings in the journal Icarus.

‘This is the first time we can say that there’s an intimate link between environmental conditions - temperature, winds, pressure and composition - and the actual colour of the Great Red Spot,’ lead author Leigh Fletcher, from Oxford University’s Department of Physics, told me.

‘Although we can speculate, we still don’t know for sure which chemicals or processes are causing that deep red colour, but we do know now that it is related to changes in the environmental conditions right in the heart of the storm.’

As well as this warm ‘heart’ the images show dark lanes at the edge of the storm where gases are descending into the deeper regions of the planet.

One of the most intriguing findings is that the most intense orange-red central part of the spot is about 3 to 4 Kelvin warmer than the environment around it.

Leigh explains that while this temperature differential might not seem like a lot it is enough to allow the storm circulation, usually counter-clockwise, to shift to a weak clockwise circulation in the very middle of the storm. Not only that, but on other parts of Jupiter the temperature change is enough to alter wind velocities and affect cloud patterns in the belts and zones.

‘This is our first detailed look inside the biggest storm of the solar system,’ said Glenn Orton, a senior research scientist at NASA’s Jet Propulsion Laboratory, one of the authors. ‘We once thought the Great Red Spot was a plain old oval without much structure, but these new results show that it is, in fact, extremely complicated.’

Unlocking the secrets of Jupiter’s giant storm systems will be one of the targets for infrared spacecraft observations from future missions including NASA’s Juno and the NASA/ESA Europa-Jupiter System Mission concept.

Dr Leigh Fletcher is based at Oxford University’s Department of Physics