Detecting malaria’s bad air: a breath test with a twist

Try looking at this image and not feeling an itch.

Try looking at this image and not feeling an itch.

By Pamela Tyers 

What’s the most deadly creature in the world? The lion? The shark? In fact, it’s a bit of a trick question (do humans count?)… but there is a fair argument that the humble mozzie is the world’s top killer.

Many species of mosquito carry deadly diseases such as malaria, yellow fever and west nile virus. Malaria in particular places a huge health and economic burden on developing countries. According to the World Health Organisation, almost 200 million people caught malaria and more than half a million of them died from it in 2013 alone.

Thankfully, Australian scientists have made a significant discovery that could lead to the development of new tests for diagnosing malaria – potentially saving millions of lives. By identifying distinctive chemicals in our breath, researchers have been able to detect whether someone is infected with the disease.

A team of our scientists joined with QIMR Berghofer Medical Research Institute and the Australian National University to look at the breath of volunteers who had been given a controlled malaria infection, as part of existing studies to develop new malaria treatments.

The research found that the levels of some normally almost undetectable chemicals increased markedly in their breath during the infection.

Stephen Trowell leads our research on the work. He is particularly excited because the new testing method allows us to diagnose malaria much earlier than with other tests.

“The increase in these chemicals were present at very early stages of infection, when many other methods would have been unable to detect the parasite in the body of people infected with malaria.”

“Overall, our breath could prove to be a much better alternative to blood tests for diagnosing the disease.”

The research, published today in the Journal of Infectious Diseases, was undertaken in two independent studies where experimental drug treatments were being tested in volunteers who had been given a very small dose of infection. Using a sophisticated analytical instrument, Stephen and the researchers identified four sulphur-containing compounds whose levels varied during the course of the malaria infection.

These sulphur-containing chemicals have not previously been associated with any disease and their concentrations changed in a consistent pattern over the course of the malaria infection, correlating with the severity of the infection. They effectively disappeared after the patients were cured.

By identifying distinctive chemicals in our breath, researchers have been able to detect whether someone is infected with malaria

By identifying distinctive chemicals in our breath, researchers have been able to detect whether someone is infected with malaria

Currently, diagnosing malaria involves using powerful microscopes to look for parasites in blood using a method discovered in 1880. As the world starts to work towards the elimination of malaria, there is an urgent need for more sensitive and convenient tests to detect early and hidden cases.

The team are now collaborating in regions where malaria is endemic to test for the chemicals in the breath of patients with the disease. They are also developing very specific, sensitive and cheap “biosensors” that could be used in the clinic and the field to breath test for malaria.

We’ve worked on developing a range of similar bioproducts – you can read more about them here.

For media enquiries, contact Andreas Kahl on andreas.kahl(at)csiro.au or +61 407 751 330.


Science with heart: 5 ways we’re helping medical research in Australia (and the world)

The CardioCel patch.

The CardioCel patch.

Australian company Admedus has been making headlines recently for its innovative medical material, CardioCel. The tiny, flexible patch, made using part of a cow’s heart, is being used to treat potentially devastating birth defects like congenital heart disease – and it’s taking the international medical community by storm.

What’s more, we’re proud as punch to say that we were integrally involved in its success.

Our researchers worked with Admedus to assess the suitability of CardioCel for use in stem cell therapy in heart failure patients by comparing it with another commonly-used product. We found that CardioCel was well suited to cardiovascular cell therapy, and that it could have potentially groundbreaking applications in other areas of stem cell delivery too.

It’s since been implanted in more than 1200 patients across Australia, Europe, North America and Asia.

This is just one of many medical success stories we’ve been a part of. So, just because we like the number five, here’s five more:

3D printed titanium heel bones? Why not

When a Victorian man was facing amputation of his leg due to bone cancer in his heel bone, his doctor turned to us for help. Professor Peter Choong, from Melbourne’s St Vincent Hospital, knew about our work in titanium 3D printing and wondered if we could print a workable heel bone transplant, thus removing the need for amputation. We helped turn his vision – a metallic implant which could support a human body’s weight – into a world first-reality.

Putting blood tests on the spot

We’re working with Universal Biosensors to trial on-the-spot testing and results for a range of crucial blood tests. The immediacy of results means that patients avoid the dreadful stress that comes with waiting, as well as receiving treatment faster.  By broadening the application of point-of-care testing, we will see time and cost savings for already-stretched healthcare providers. Not bad for a little prick.

Supercomputers for (sort of) super hearts

Using the same technology that drives state-of-the-art video games, we created a ‘virtual heart’ simulation that the Victor Chang Cardiac Research Institute are using to better diagnose and treat heart rhythm disease. Who said nothing good ever came from gaming?

Winning the waiting game in our hospitals
Our Demand Prediction Analysis Tool can predict bed demand in hospital emergency rooms by the hour, day and week, greatly easing the pressure on their emergency wards. A similar technology has already been rolled out in more than 30 hospitals in Queensland (hello, Schoolies!) and is currently being trialled in Victoria.

Know your enemy
Collectively, Alzheimer’s and Type 2 diabetes impact the lives of millions of Australians. Their symptoms on the surface are known only too well – but how they affect us on the cellular level is a mystery to many. We brought the science behind the illnesses to life, using animations that explain very complex biological processes related to each disease with scientific accuracy. This is a truly unique way of zooming in on what happens inside our body, but can’t be seen with the naked eye.

For more information on our medical research, check out the health hub on our new website.


Healing is a numbers game, make no bones about it

Quicker healing bones - something everybody could benefit from.

A clever statistical analysis could lead to quicker healing bones. Image credit: Flickr.com/taedc

By Andrea Wild 

Statistics help us with many things. Using stats we can count how many whales there are in the sea, protect the Great Barrier Reef from agricultural run-off, and even decide whether playing lotto is a good investment or not. In fact, stats could even help us better grow our own bones back.

Thanks to a mishap on the soccer field, a car accident or a disease like osteoporosis, many of us will need to grow new bone at some stage of our lives. Luckily, our stem cells are pretty good at patrolling our bodies and fixing any damage. But when bones need help to heal, surgical grafts  (of either bone itself or a biomaterial) can encourage new bone to grow in the right place. These biomaterials are used in medicine to repair or replace diseased or damaged parts of the body.

The UK’s Imperial College London (ICL) has been developing a biomaterial known as strontium-modified bioactive glass for use as a bone graft. The bioactive glass dissolves slowly and releases the strontium, which coaxes mesenchymal stem cells to turn into bone cells, healing the damaged bone.

But how does it work? What’s happening inside the cell? Many researchers have wondered.

Thanks to what are known as gene expression microarrays, it’s possible to screen the body cells’ response to a treatment at the genetic level. But this process creates masses of data, which can be a mystery in themselves. The answers are in there, but where?

Enter our computational modellers, led by Dave Winkler, and their new statistical technique for analysing gene data: sparse feature selection. They collaborated with the ICL’s Helene Autefage and Molly Stevens, who head up one of the world’s leading biomaterials groups, to solve the strontium bioactive glass mystery.

A close up of strontium treated cells. Understanding why strontium helps bones grow could aid new drug development.

A close up of strontium-treated cells. Understanding why strontium helps bones grow could aid new drug development.

Here’s how it works, in four easy steps (not that we suggest trying this at home):

  1. Take human mesenchymal stem cells from three patients and treat them with strontium bioactive glass extracts.
  2. Run a microarray experiment to find out which genes have been effected by strontium in these cells.
  3. Put the data into a hat.
  4. Wave your sparse feature selection wand, and pull out eleven genes that matter most in stimulating bone growth from the 1000 or so genes that were influenced by strontium.

Sounds simple, right? We should note that we glossed over some very important researchers and their work, which you can learn more about here.

But the next step is the really exciting bit: drug discovery. Understanding why strontium helps new bones grow opens the way for drug development.

Statistical analysis has taught us that the biological pathways involved are those that make fatty acids and sterols inside our cells. If we can use this knowledge now to develop more targeted drugs, it’s possible that some surgical bone grafts won’t be necessary in the future. There may be a less invasive way of encouraging bone to regenerate and that would be fantastic news for an ageing population facing degenerative diseases like osteoporosis.

Taking similar steps to provide in-depth knowledge of the effects of specific biomaterials on cell behaviour could lead to new treatments for many different diseases that are more effective, easier to administer, less toxic, and cause fewer side effects.

And it’s all thanks to a little statistics.

This research was published today in the journal PNAS. Read about other new health technologies we’re developing.

For media inquiries, contact Andrea.Wild@csiro.au or +61 415 199 434


Life animated in 3D: Alzheimer’s disease and type 2 diabetes

Using 3-D modelling tools,  wee can look deeper into the causes of diseases like Alzheimer's and diabetes.

Using 3D modelling tools, we can look deeper into the causes of diseases like Alzheimer’s and type 2 diabetes. Here we have neurons with amyloid plaque attached.

By Emily Lehmann

Oscar hype is in full-swing, and we all have our favourites for Hollywood’s night of nights (we must admit we are partial to Birdman taking home the ‘best picture’ gong). But the big-screen isn’t the only place to find world-class movies.

At our Discovery Centre in Canberra yesterday, we unveiled two world-class movies of our own. The animations, created by up-and-coming Australian biomedical animators, uses the latest data visualisation techniques to bring science to life in incredible 3D detail.

An animated cross-section of the insulin receptor inside the cell membrane.

An animated cross-section of the insulin receptor inside the cell membrane.

Created by Australian up-and-coming biomedical animators using the latest data visualisation techniques, they feature key research into Alzheimer’s disease and type 2 diabetes from CSIRO and the Walter and Eliza Hall Institute of Medical Research (WEHI).

Through narrated picture, the animations explain very complex biological processes related to each disease with scientific accuracy: zooming in on what happens inside our body but can’t be seen with the naked eye.

The animations illustrate key research techniques into Alzheimer’s disease and type 2 diabetes, based on work we have done with the Walter and Eliza Hall Institute of Medical Research (WEHI).

Alzheimer’s Enigma

The first video looks at Alzheimer’s disease – the most common form of dementia – which affects one in four people over the age of 85, a number that will increase significantly as our population ages.

This animation takes you on a journey to the neurons of the human brain, revealing how normal protein breakdown processes become dysfunctional, and cause plaque to form during Alzheimer’s disease.

This build up of plaque in the brain can take decades and is one of the main indicators of the disease.

The Insulin Receptor and Type 2 Diabetes

About one million Australians currently live with diabetes and about 100,000 new diagnoses are made each year.

These staggering statistics are fuelling research efforts aimed at finding a cure or ways to prevent or better manage the disease.

Highlighting a recent discovery by WEHI, this animation focuses on the role that the insulin receptors play in the disease and what might cause resistance to the hormone insulin.

It’s part two in a series of animations on type 2 diabetes, you can check out part one here.

These are the second round of animations created through VizbiPlus – a joint project between CSIRO, WEHI and the Garvan Institute of Medical Research.

Under the guidance of internationally-acclaimed biomedical animator Drew Berry from WEHI, VizbiPlus is training-up the next generation of biomedical animators, to raise the bar in science communication and bring critical research to the world.

You can read more about our data visualisation work here.


How our supercomputers are helping fight heart rhythm disease

Dr Adam Hill and Professor Jamie Vendenberg are driving this groundbreaking research.

Dr Adam Hill and Professor Jamie Vendenberg working on the groundbreaking technology.

Heart rhythm disease is a life-threatening, electrical disorder that stops the heart from pumping blood effectively. It is a lethal condition that is responsible for around 12 per cent of Australian deaths each year.

In order to open the door to better diagnosis and treatment for heart rhythm disease, we’ve been working with the Victor Chang Cardiac Research Institute to develop our very own ‘virtual heart’. What’s more, we’ve done this using the same technology that drives your favourite computer games.

Impressively, when we ran a simulation through the virtual heart, it was able to model hundreds of thousands of different heart beats. This then allowed scientists to screen all of those heart beats, and search for abnormalities.

hearts

According to the Victor Chang Institute’s Dr Adam Hill who led the research, this has taken us a step closer to understanding rhythm disturbances in our most vital muscle.

“This research is hugely exciting! We were able to identify why some patients have abnormal ECG signals, and how a person’s genetic background can affect the severity of their disease,” he says.

Analysis on this scale has simply never been possible before. The simulation took just ten days, thanks to the computational grunt of CSIRO’s Bragg supercomputer cluster, which combines traditional CPUs with more powerful graphics processing units or GPUs.

GPUs have typically been used to render complex graphics in computer games. However they can also be used to accelerate scientific computing by multi-tasking on hundreds of computing cores.

By comparison, if you were to try to do the same simulation using a standard desktop PC, it would take 21 years to get the job done.

Powerful and eco-friendly? This is one super computer worth Bragging about.

Powerful and eco-friendly? This is one super computer worth Bragging about.

Adam hopes the new technology will help doctors read ECGs more accurately, which will mean faster, more accurate diagnosis of heart rhythm disease. By understanding why the same disorder affects people differently, the right treatment can be given to the right patients.

Scientists at the Victor Chang Institute are now using these discoveries to develop automatic computerised tools for diagnosing heart rhythm disorders.

Read more about how we’re using data and digital technologies to tackle health challenges on our website.


Powerful new tool produces proteins in 3D

Cover_proposal (1)

The amazing depth of atomic-scale 3D structural information now available via Aquaria.

By Andrew Warren

If you’re a regular at the gym or an early morning boot-camp fanatic, it’s possible that the first thing you picture when you think of protein is the powder you use to make your post-workout recovery shake.

But when our scientists discuss protein, they’re talking about the many thousands of molecules that act as the essential building blocks of life as we know it. Because proteins are so important to constructing life, researchers need a way to visualise the exact ways in which they fit together so that they can better understand the functions they play in our bodies.

With this in mind, a team of international programmers and bioinformaticians (think biology, computer science and maths mixed together) led by our very own Dr Seán O’Donoghue have created a new web-based tool named Aquaria that can create unprecedented 3D representations of protein structures.

Aquaria is based on the Protein Data Bank, an online resource which houses more than 100,000 structures of proteins that contains a wealth of detail about the molecular processes of life. But Sean and his teams were conscious that few biologists were taking full advantage of the site. The Protein Data Bank is designed for and by biologists who are expert in structures; however for most biologists, its organisation can be confusing.

So, they created Aquaria to make this valuable information more accessible and easier to use for discovery purposes.

Freely and publicly accessible, Aquaria can help scientists like ecologists, nutritionists and agriculture, biosecurity and medical researchers to streamline their discovery process and gain new insight into protein structures.

Sean’s team added additional layers of information (like genetic differences) to the basic protein structure and made it accessible in a fast, easy-to-use interface that’s visualised in a fully 3D environment.

“We’ve added protein sequences that don’t yet have a structure, but are similar to something in the Protein Data Bank,” says Sean.

“That meant we first had to find all these similarities. We took over 500,000 protein sequences and compared every one of them with the 100,000 known protein structures, and that has given us around 46 million computer models.

ICAM-1 a

This image shows an example of one of the many spectacular molecular structures that science has determined at atomic resolution. This is the Aquaria view of Intercellular Adhesion Molecule 1, a protein that occurs on the surface of endothelial and immune system cells.

“For example, you can add Single Nucleotide Polymorphisms (SNPs) that cause protein changes, then visualise exactly where those changes occur in the protein structure. This provides valuable insight into why proteins sometimes completely change their function as a result of one small change in the DNA code.

“You can then ask interesting questions like ‘Does this set of SNPs cluster in 3D?’ and the answers to such questions can set new research directions.”

Aquaria was developed in collaboration with Dr Andrea Schafferhans from the Technical University of Munich, and is hosted with support of a grant from Amazon Web Services.

To learn more about Aquaria, you can take part in a special webinar scheduled for 9am Tuesday, 3 February (AEDST).


Making molecules crystal clear

A crystal image of a breakdown pathway of atrazine

A crystal image of a breakdown pathway of atrazine

The International Year of Crystallography is drawing to a close, and we’re not going to let it finish without showing you something about what crystallographers do. Which is not what most people would assume when they hear the word: there are crystals involved, but it’s not exactly the study of crystals as we generally think of them. It’s the study of how matter is organised, using crystals as a tool.

Now, naturally we want to know how matter is arranged. Apart from being very, very interesting to find out about, it also helps in many different fields, from drug delivery to materials science. In fact, it was crystallography that provided – controversially – the key to understanding the structure of DNA.

So assume you want to look at something in the greatest possible detail, seeing its smallest possible components. Obviously, you’d use a microscope. But there’s a limit to the smallness of things you can see that way: the wavelength of the light human eyes see. Visible light has a frequency of between roughly 400 and 700 nanometres, and can’t detect atoms, which are separated by 0.1 nanometres. This is the perfect frequency for X-rays.

We can’t make appropriate X-ray lenses to make x-ray microscopes to study molecules: we have to do it in a roundabout way. We beam X-rays onto crystals, scattering the rays, in just the same way that light reflects when it hits an object. Then we use a computer to reassemble the rays —the diffraction pattern —into an image. The diffraction of a single molecule would be so weak that we couldn’t get any meaningful information from it, so we use crystals, which have many molecules in an ordered array, to amplify the signal so we can see it. Crystals are highly ordered structures, made up of 1012 or more molecules, makes the x-ray diffraction patterns — the main tool of crystallography —possible to analyse.

Crystallographers were among the first scientists to use computers, and used them to do the advanced calculations needed to reassemble diffraction patterns into coherent images. That’s why it seemed fitting to name our supercomputer after the founders of crystallography – Lawrence and Henry Bragg. Lawrence was the first person to solve a molecular structure using x-ray diffraction.

Today we can not only view molecules in 3D, but also study the way they operate. Improvements in x-ray machines have also led to synchrotron facilities, which can produce far more efficient and precise beams.

And speaking of synchrotrons …

One of our crystallographers, Tom Peat, has deposited more than 120 structures in the Protein Data Bank using data collected at the Australian Synchrotron. They were all derived from crystals developed in CSIRO’s Collaborative Crystallisation Centre.

This is one of our favourite structures.

AtzF structure (the Australia crystal)

AtzF structure (the Australia crystal)

It’s the structure of AtzF. This enzyme forms part of the breakdown pathway for atrazine, a commonly used herbicide. We’re trying to understand enzymes better and use them for bioremediation – cleaning up environmental detritus such as pesticides and herbicides – and we’ve now solved the structures of four of the six enzymes involved in the atrazine breakdown pathway. We also look at protein engineering, to see if we can make these enzymes even more effective at cleaning up the environment.

Before we get to the crystal image, there are other steps on the way. First, someone has to grow the crystals (clone the protein, express it, purify it and crystallise it). Then it’s off to the Synchrotron to get a data set (many diffraction images in sequence). Here you can see an actual protein crystal.

An actual protein crystal

An actual protein crystal

The picture on the right is the diffraction image.

Diffraction image

Diffraction image

The crystallographers measure the intensity of the reflections (the dark dots). They combine that with the geometry and use some complicated maths (a Fourier Transform) to produce an electron density map. They then use that map to build a model.

Not all our crystallography work is in the same area. We also work on some pharmaceutical applications. One of our projects, with hugely important implications for human health, is on the design of desperately needed new antibiotics.  We’ve been collaborating with Monash University, looking at the pathway that sulpha drugs (such as sulfamethoxazole)– the ones we used to treat bacterial infections prior to the discovery of penicillin – take to treat Golden Staph infections in humans. The aim is to design new antibiotics that target the same pathway. You can read a paper that describes our recent findings in the Journal of Medicinal Chemistry, and here’s a picture of what we’ve been doing.

Golden Staph treatment pathway

Golden Staph treatment pathway

We think this deserves its own Year. And we hope it’s clear just how important it is. Crystal clear.


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