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How worms are helping scientists understand the function of genes in the human brain

Hunched over a high-powered microscope in a laboratory at Monash University in Melbourne, Roger Pocock observes hundreds of 1mm-long roundworms grazing on a lawn of E coli bacteria while squirming around a palm-sized circular glass dish. The neurogeneticist from England has been mesmerised by these tiny creatures ever since he first saw them in a TV documentary in 1992, which, coincidentally, also sparked his dramatic career change from high street banker to research scientist.

Omnipresent in soil and rotting vegetation, these Caenorhabditis elegans worms, or C elegans for short, are helping Pocock and his team uncover secrets of the development of the human nervous system and how genes function in the human brain.

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Pocock’s enthusiasm for the worms was evident when we met one morning in Melbourne recently. “If you think about model organisms and the major breakthroughs that have occurred over the past 20 years, worms kick butt,” says Pocock. “There are so many major groundbreaking fundamental research breakthroughs that have occurred in C elegans over the past 20 to 30 years.”

Since the emergence of worms in the mid-1970s as an important experimental model, the creatures have continued to reveal new information in such diverse areas of biology as the nervous system, behaviour, metabolism and ageing.

In Hong Kong, at the lab of associate professor Mak Ho-yi of the Division of Life Science at the Hong Kong University of Science and Technology, researchers use C elegans and mammalian cells to uncover the genetic pathways and molecular mechanisms that regulate food intake, fat storage and mobilisation. Their findings could help in the battle against obesity.

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Researchers at the University of Delaware in the US have been using C elegans to study the effects of being in outer space for extended periods of time, in particular, the effect of gravity on epigenetics and other long-term health consequences. The team have conducted many simulated microgravity experiments at considerably reduced time, effort and cost compared to experiments in space.

“We’re prescreening the worms in simulated microgravity to select about 100 or so genes to closely monitor on the International Space Station,” says Chandran Sabanayagam, an associate scientist at the university’s Delaware Biotechnology Institute.

Already on the International Space Station, the Japanese Aerospace Exploration Agency have been using C elegans to seek clues to physiological problems found in astronauts – which could lead not only to new treatments for bone and muscle loss in humans living in space, but may also be beneficial to people on Earth suffering from muscle and bone diseases.

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In September, researchers from Florida Atlantic University reported the development of an electroconvulsive seizure model using C elegans that could lead to an efficient rapid screening tool for drugs that treat seizures in humans, such as those with epilepsy. “The cost of high throughput testing for antiepileptic drug candidates would decrease in time and money compared to the experiments available today,” says Ken Dawson-Scully, the study’s corresponding author and associate director of the university’s Brain Institute.

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The worm and us are genetically speaking, similar in size. C elegans contains 20,000 genes compared to up to 25,000 in humans, about 70 per cent of the worm’s genes are present within our own DNA and approximately 40 per cent of genes implicated in human disease have equivalents in the worm. In 1998, the worm became the first multicellular organism to have its entire genome sequenced. This makes it possible to learn more about the underlying mechanisms of many human diseases by examining the function of the related gene in the worm.

A small, well-defined nervous system makes the worm the perfect model to study neurodegenerative diseases. The worm has only 302 neurons compared to the billions in humans, but these neurons represent most types of neurons in the human brain. The entire “neuron connection” map for the worm was worked out more than 30 years ago. When injected with a fluorescent jellyfish protein, the transparent worm’s nervous system glows, allowing researchers to observe its workings.

In total, including neurons, C elegans has 959 cells – far less than the trillions of cells in a human, yet the worm has a variety of similar tissue types such as muscles, nerves and intestinal cells.

Reaching adulthood in just three days and living just two to three weeks, the worm is an excellent model for studying ageing because of its short lifespan and easily manipulated genetics. Like humans, the worm’s muscle degenerates during ageing.

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It is also straightforward to introduce new genes into C elegans, including those from humans. This approach has, for example, been used to create worm models for studying Alzheimer’s disease.

As a hermaphrodite – a female that produces and stores sperm at one stage in its life cycle before beginning to produce eggs – the worm is self-fertile and produces more than 300 offspring at a time. This allows for the large-scale production of animals within a short time – a huge advantage for genetic research, Pocock says. It is easy and inexpensive to maintain in a lab. With scientific research constantly facing the challenge of funding, C elegans research makes economic sense.

These days, there are thousands of labs worldwide using C elegans as their model organism, including about 50 in China, Pocock says. It’s a stark increase from the early ’90s, when there were fewer than 100 labs around the world.

“When Robert Horvitz identified the apoptotic pathway,[the key genes controlling programmed cell death], and found the components were all conserved in humans and highly implicated in cancer – boom! All the labs started opening up,” says Pocock.

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Horvitz, an American researcher from Massachusetts, was a joint winner of the Nobel Prize in Physiology or Medicine for 2002, along with two other C elegans researchers Sydney Brenner and John Sulston. C. elegans researchers also won Nobel Prizes in 2006 and 2008, indicating how groundbreaking these worm studies have been.

While C elegans research will probably never directly result in a cure for diseases such as cancer, Pocock says a lot of therapies being developed now are based on fundamental research questions answered years ago through worm research. “My work is not directly translatable within the next five years, but we’ll contribute to the knowledge over a period of time,” he says.

In one of his studies published in the journal Nature Neuroscience in 2010, Pocock identified a hidden neuronal circuit that modulates sensory perception under stress. It suggests that such circuits form part of an escape response that enables animals to sense their environment and adapt their behaviour under unfavourable conditions – like how we are able to perform complex tasks when under stress.

Another Pocock study that appeared in 2013 in the journal Science revealed how a tiny molecule called mir-79, which has an equivalent called mir-9 in humans, regulates neural development in the worms, shedding light on how our nervous system develops during fetal growth. The findings also added to the understanding of how nerve cells may be stimulated to repair damage in the brain or spinal cord.

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Now Pocock is working on a gene called a transcription factor that controls fat levels in the intestine.

“Worms that don’t have this gene or have a mutated gene store much more fat and they actually feel sated. So instead of moving around their environment, they just sleep and wait and they’re very content,” he explains.

“We’re now working on finding out how these neurons communicate with the intestine to regulate fat levels and then how the intestine regulates sleep behaviour and locomotion. We’re trying to identify novel pathways and genes that control metabolism and fat in humans.”

So the next time you’re out in the countryside, you may have more empathy for the creatures underfoot.