UNSW researchers are pioneering the development of a new generation of microscopes with the power to unravel the molecular chaos of life. By Amy Coopes.

More than 50 years ago, Nobel Prize–winning physicist Erwin Schrödinger famously asked the question: What is life? By way of answer, he postulated that biology somehow emerges from molecular chaos.

Half a century later, Professor Katharina Gaus believes Schrödinger’s question is on the brink of being answered by the nascent field of molecular imaging.

A new generation of “super” microscopes is allowing scientists to peer into the molecular “chaos” of living cells. By doing so, they are slowly deciphering the rules behind this chaos.

“We are right now at the beginning of a molecular revolution,” says Gaus, an NHMRC Senior Research Fellow and deputy director of the recently funded ARC Centre of Excellence in Advanced Molecular Imaging.

One of these super-resolution fluorescent microscopes sits below Gaus’ lab within the University’s BioMedical Imaging Facility. Through its lens, the interior of a single cell gleams like a constellation, each twinkle a single molecule with the potential to affect life or death.

UNSW was the first institution in Australia to secure the hyper-powered microscope, which can capture images of objects 10 nanometers (or 10 billionths of a metre) in size. A decade ago these images would have been the realm of science fiction.

“To understand how molecules behave and how cells use those behaviours to make life and death decisions … this is not just a road less travelled, it’s a road not travelled at all in terms of scientific discovery,” says Gaus. “It is a game-changing technology and in terms of how far we can take it, the limitation is really our imagination.”

Focusing on T-cells, Gaus is leading her field in establishing what causes these front line soldiers of our immune system to switch on and fight disease, or remain dormant and ‘overlook’ a proliferating tumour.

The powerful microscope allows her to pinpoint and view the workings of individual components within the fully functioning T-cell, without having to take the cell apart.

“Every second of every minute T-cells are making ‘fate decisions’ to activate or not, triggered by traces of pathogens or the altered proteins of a cancer,” Gaus explains. They are so sensitive that a single peptide from a virus is enough to swing the immune system into action, and the activation of a single T-cell can trigger a full-blown response. An overactive T-cell response can cause crippling autoimmune disease while underactive T-cells can leave the immune system vulnerable to illness.

The work has won Gaus the prestigious Elizabeth Blackburn Fellowship, given by the NHMRC to the top-ranked female research fellowship applicant in biomedical science in 2013.

Gaus says rather than a simple on and off switch or a “CEO molecule” that orchestrates the action, T-cells appear to respond to the frequency of certain activity.

In a pair of papers published in Nature Communications in 2012 and Nature Immunology in 2013, Gaus and her team demonstrated a kinase protein called Lck ‘yo-yos’ in and out of clusters providing a central role in the cell’s signalling and activation machinery.

The team has also found that lipids – or fats – in the membrane of cells contribute to communication within the T-cell structure. T-cells removed from mice that had been fed a high-fat diet showed impaired signalling function, which may help explain why immune function can be compromised in obese people.

Progress is painstaking – it takes 20,000 individual frames to examine a single cell, using fluorescent protein markers to track individual molecules. But the rewards, when they come, will be immense.

“One of the things that could come from understanding how cells make decisions is the ability to give our own immune cells a man-made tool to fight cancer,” Gaus says.

Harnessing the body’s defences in this way is an attractive prospect but not just for its immediate potential in combating diseases like cancer. Because the immune system is self-regulating, its defensive action will shut down once the cancer is gone, but it will store memory cells allowing it to swing back into action if a recurrence is detected, even in minuscule amounts.

“This is the ultimate cancer-fighting tool,” says Gaus.

Drug companies, including the  California-based biotech giant Genentech, are following her work with interest. A pharmaceutical inhibitor already exists for the Lck protein shown by Gaus to be so vital in cell signalling but at present “you can’t give it to patients because then you don’t have any T-cellmediated immunity anymore”. Essentially the immune system’s decision-making machinery is knocked out.

But if new knowledge about the cell’s function could be used to develop a drug that alters the molecule’s behaviour rather than switching it off completely, science would have a powerful new anticancer therapy.

And in the case of autoimmune disease, an overactive T-cell attacking the body’s tissues could similarly be reset so its activation threshold was less sensitive.

German-born Gaus has blazed a trail since landing at UNSW in 2002. In 2005 she was awarded an NHMRC grant to establish her own laboratory.

That same year she also won a NSW Young Tall Poppy Award, an ARC Research Fellowship and was awarded the Alexander von Humboldt Fellowship, which allowed her to spend six months at Germany’s Max Planck Institute of Molecular Cell Biology and Genetics.

Back then the University had no advanced microscopes and Gaus was largely on her own. Today her lab boasts 18 staff and she was recently awarded seven years’ funding to establish the ARC Centre for Excellence in Advanced Molecular Imaging.

Gaus originally trained in physics and mathematics in Heidelberg but reinvented herself as a cell biologist as a PhD student at Cambridge. It was during this time she met her husband Professor Justin Gooding – a surface chemist who went on to found the Australian Centre for NanoMedicine at UNSW – and decided to give his country a go.

They work together on a range of projects and co-supervise a number of students, even applying for joint grants. In 2013 they became the first husband and wife team to win NSW Science and Engineering Awards.

“Australia has been good to me – I managed to get funding early on and then build up my own group,” says Gaus. “I guess I always knew I wanted to do my own thing.”

Though she is no longer in physics her earlier training continues to exert an influence. Half her laboratory consists of cellular biologists and immunologists while the other half are physicists who build the microscopes and write analysis tools.

“There are very few labs right now that can do both as well as we can,” she says. “It’s important that we have both these sides together.”

The first “universal rules” governing cell function are beginning to take shape. Each discovery brings new knowledge on experimental methods and reveals the next molecule to be explored.

Though the focus is on T-cells, Gaus says the molecular rules she is beginning to uncover will apply to any number of processes from DNA repair and cancerous growth through to neuroscience.

“In life nothing stands still, so molecular rules are the basis for everything. And what’s most exciting is that we are now beginning to discover these fundamental aspects of life.”

This story first appeared in UNSW Uniken Winter 2014 (Issue 73).