The Best Australian Science Writing 2015 (31 page)

To do this we must collect data through observations and experiments of natural phenomena, and then compare them to the mathematical predictions and laws. The word central to this endeavour is ‘evidence'.

The scientific detective

The mathematical side is pure and clean, whereas the observations and experiments are limited by technologies and uncertainties. Comparing the two is wrapped up in the mathematical fields of statistics and inference.

Many, but not all, rely on a particular approach to this known as ‘Bayesian reasoning' to incorporate observational and experimental evidence into what we know and to update our belief in a particular description of the universe.

Here, belief means how confident you are in a particular model being an accurate description of nature, based upon what you know. Think of it as being like the betting odds on a particular outcome.

Our description of gravity appears to be pretty good, so it might be an odds-on favourite that an apple will fall from a branch to the ground.

But I have less confidence in super-string theory, which proposes that electrons are tiny loops of rotating and gyrating string, and the odds that this theory will provide accurate descriptions of future phenomena might be thousand-to-one.

So, perhaps science is like an ongoing courtroom drama, with a continual stream of evidence being presented to the jury. But there is no single suspect and new suspects are regularly wheeled
in. In light of the growing evidence, the jury is constantly updating its view of who is responsible for the data.

But while evidence is continually gathered and more suspects are paraded in front of the court, no verdict of absolute guilt or innocence is ever returned. All the jury can do is decide that one suspect is more guilty than another.

What has science proved?

In the mathematical sense, despite all the years of researching the way the universe works, science has proved nothing.

Many theoretical models have given us a good description of the universe around us. But at the same time exploring new territories reveals further gaps in our knowledge, lowering our belief in the accuracy of our existing experiments.

Will we ultimately know the truth and hold the laws that truly govern the workings of the cosmos within our hands?

We can believe that our mathematical models are providing ever more accurate descriptions of nature, but we'll never know if we've found reality. In the words of one of the greatest physicists, Richard Feynman, on what being a scientist is all about:

‘I have approximate answers and possible beliefs in different degrees of certainty about different things, but I'm not absolutely sure of anything.'

What shall we teach the children

Imagine there's new metrics (it's easy if you try)

Germ war breakthrough

John Ross

It was the first full week of the year, when sport and holiday weather dominate the headlines. For medical researchers, it held the promise of lab time uninterrupted by the usual meetings and grant applications.

Then something happened to marshal researchers around water coolers in excited conversation. A Boston-led team reported the discovery of a completely new class of antibiotics – the first in a quarter of a century.

The breakthrough, reported in the journal
Nature
, was one of the best pieces of news since the 1960s emergence of antibiotic resistance sparked alarm across the medical world. Health authorities feared the antibiotic era spawned by the 1928 discovery of penicillin could be a fleeting thing, with the world once more at the mercy of microbes that kill millions in infancy and make simple surgery a hazardous undertaking.

In July 2014, British Prime Minister David Cameron warned that the world could be ‘cast back into the dark ages of medicine', with people dying from routine infections. In 2012, World Health Organisation chief Margaret Chan said rampant antimicrobial resistance was propelling the world into a ‘post-antibiotic' era. ‘In terms of new replacement antibiotics, the pipeline
is virtually dry,' she warned. ‘The cupboard is nearly bare.'

Chan said ‘first-line' antibiotics were already increasingly ineffective, forcing doctors to resort to more expensive drugs which required longer courses, caused nasty side effects and carried 50 per cent higher mortality rates.

A major concern is the ancient scourge of tuberculosis (TB), with resistance threatening to reverse a long-term decline in deaths from the disease. About 5 per cent of an estimated 12 million TB cases a year involve strains that are resistant to the two major first-line drugs – isoniazid and rifampicin – and sometimes others. Treatment can take years and only about half of affected people are cured.

Chan also highlighted the highly resistant pathogens turning hospitals into killing grounds. They include drug-resistant golden staph, also known as MRSA, and bacteria resistant to carbapenems, the antibiotics of last resort for infections such as
E. coli.

The new class of antibiotics, dubbed teixobactin, has only been tested on mice. But it appears to work against both MRSA and TB. And it will take at least two decades for bacteria to evolve defences against it, according to Grant Hill-Cawthorne of Sydney University.

Hill-Cawthorne, of the Marie Bashir Institute for Infectious Diseases and Biosecurity, says bacteria typically have two ways of protecting themselves from antibiotics that attacked their surfaces. They either mutate the ‘target' that the antibiotic attaches itself to on the bacteria cell wall, or they produce enzymes that disable the antibiotics.

‘In this case, the part of the cell wall that it's acting upon is so vital to the bacteria that they can't afford to mutate it. That means it's harder for the bacteria to become resistant. The only way is to generate enzymes to attack the antibiotic. That's a slower process in their evolution, and it typically takes about 20 to 30 years.'

Monash University microbiologist Julian Rood says the buzz around teixobactin is justified, not only because of the drug's potential but also because of the ‘elegant' way it was discovered.

He says the team at Boston's Northeastern University developed a variation on the technique which yielded the first two antibiotics – penicillin and streptomycin, the first effective TB treatment – when researchers harnessed the organisms that yeast and bacteria produce naturally to protect themselves against other microbes.

‘You go into a natural environmental sample, like soil, and try and grow organisms on artificial media (such as) an agar plate,' Rood says. ‘(But) only a very small percentage of the organisms are capable of being grown under those conditions. They just don't make it.'

The Northeastern team took a one-gram soil sample from a grassy field in Maine, removed the solid material, diluted the solution and placed it in a tiny multi-channel gadget known as an iChip. The device was shielded with two semipermeable membranes and reburied in the soil.

‘The idea was to say to the organisms that this is not artificial growth media at all,' Rood says. ‘You're in the soil; do your normal thing. They left it there for a month, and looked at what had grown. When you consider the method you think gee, that's nice, I should have thought of that. Elegant experiments are always conceptually simple.'

Teixobactin was merely the most promising of 25 new organisms discovered in the study, with the others also showing potential as drugs. But Rood says they could be the tip of the iceberg. ‘We all know from our gardening experience that every soil is different – it's different in its biological and chemical make-up, its nutrient content, its water content.

‘My assumption would be, if you took their apparatus and did the same experiment in different soils, you'd come up with very
different organisms. A lot would be the same, but a lot would be different. People are probably out there right now replicating this approach.'

The Northeastern team says just 1 per cent of cells from soil can be grown on agar plates. But close to 50 per cent can survive the team's quasi-natural technique. ‘Once a colony is produced, a substantial number of uncultured isolates are able to grow in (the laboratory),' the paper says.

It says synthetic approaches to producing new antibiotics have been unable to replace the techniques that delivered the original examples. ‘Most antibiotics introduced into the clinic were discovered by screening cultivable soil microorganisms,' it says. ‘Overmining of this limited resource by the 1960s brought an end to the initial era of antibiotic discovery.'

Flinders University research associate Ramiz Boulos says the Northeastern approach shows there are still ‘mines' to be discovered. ‘The discovery of teixobactin is very exciting,' he says.

Boulos heads a South Australian biotech company which is developing its own new antibiotics, with clinical trials planned next year. ‘We are in urgent need of a constant supply of new and effective antibiotics that work in new ways to slow down antibiotic resistance.'

But enthusiasts stress it will be years before teixobactin appears in hospitals or pharmacies, if ever. ‘They've shown that it's not toxic and works in mice,' Hill-Cawthorne says. ‘Normally the (US) Food and Drug Administration and other regulatory authorities require that to be shown in two animal models.'

He says the drug needs to be tested on another animal before human trials can begin. The aim then would be to demonstrate its safety in healthy people before trying it out on the sick, in small and then larger groups. ‘You're looking at about five years at least to go through all those processes. The key is attracting funding – it's very expensive.'

This may not prove easy, with pharmaceutical companies reluctant to invest in drugs that require only short courses – unlike profitable medications such as cholesterol-lowering statins, which people end up using all their lives. ‘Major pharma has withdrawn to a large extent from the antibiotic discovery process,' Rood says.

Global charities like the Wellcome Trust and the Bill and Melinda Gates Foundation have stepped into the breach. And Hill-Cawthorne says that as an anti-TB drug, teixobactin could qualify for one of the FDA's accelerated approval programs.

This happened recently with bedaquiline, another TB drug. ‘But it would still be a few years before it becomes available.'

And while successful negotiation of these regulatory hurdles would give the world a new drug against TB and MRSA – not to mention scarlet fever, perhaps the most feared of the old illnesses threatening a comeback – it won't work against the ‘Gram-negative' bacteria responsible for diseases such as dysentery, typhoid, severe gastroenteritis and many surgical infections.

Gram-negative bacteria, so called because of the way they react to the ‘Gram stain' dye test used to identify microbes, are structurally different from Gram-positive bugs like staphylococcus, bacillus and listeria. Gram-negative bacteria have thinner walls with two rather than one set of membranes. Antibiotics that attack them are often ineffective against Gram-positive bacteria, and vice versa.

And while Gram-positive bacteria would initially be defenceless against this new class of antibiotics, resistance would only be a matter of time. Boulos says bacteria reproduce asexually, with some species spawning new generations in as little as a few minutes.

Bacteria have ‘highly sophisticated' means of exchanging genetic material, he says, and mutations are frequent. ‘The genetic material passed from one generation to another is constantly changing, exacerbated by selective pressures in their
environment (such as) antibiotics and other hostile (microbes). Bacteria have the upper hand in this race.'

Eman Aleksic, a TB specialist with the Burnet Institute in Melbourne, says the size of bacteria cells is part of the problem. ‘Their DNA's bigger (than viruses), so there's more chance across the lifespan to evolve and change. It's just so big, it spontaneously mutates.'

But the size of the cells means they harbour more potential drug targets than viruses, and advances in genomics are helping to find them. Aleksic co-authored a recent study which identified 15 such genes in drug-resistant ‘Beijing' strains of TB.

But the same study, published in the journal
Nature Genetics
, underlines just how resilient these strains are – with the advent of antibiotics proving just a blip in their evolution. A declining population coinciding with rising antibiotic use in the 1960s was reversed in the early '90s, when the Soviet Union's public health system collapsed.

Aleksic says such events squeeze the availability of antibiotics, allowing resistance to develop when people fail to take full courses. The same thing still happens in countries such as TB-ravaged Kiribati, where authorities personally monitor sufferers taking their drugs under a scheme called ‘directly observed short course therapy'.

‘There aren't that many drugs available for TB, (so) we can't jeopardise those antibiotics for the rest of the population,' Aleksic says. ‘We want to make sure people take their drugs on time, daily, the way they're supposed to for the duration of their treatment.'