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Regulating genes to treat illness, grow food, and understand the brain

Genes are not enough to explain the difference between a skin cell and a stem cell, a leaf cell and a root cell, or the complexity of the human brain. Genes don’t explain the subtle ways in which your parents’ environment before you were conceived might affect your offspring.

Another layer of complexity—the epigenome—is at work determining when and where genes are turned on and off.

Ryan Lister is unravelling this complexity. He’s created ways of mapping the millions of molecular markers of where genes have been switched on or off, has made the first maps of these markers in plants and humans, and revealed key differences between the markers in cells with different fates.

He’s created maps of the epigenome in plants, which could enable plant breeders to modify crops to increase yields without changing the underlying DNA.

He’s explained a challenge for stem cell medicine—showing how, when we persuade, for example, skin cells to turn into stem cells, these cells retain a memory of their past. Their epigenome is different to that of natural embryonic stem cells. He believes this molecular memory could be reversed.

He has also recently explored the most complex system we know—the human brain—discovering that its epigenome is extensively reconfigured in childhood during critical stages when the neural circuits are forming and maturing. These epigenome patterns may even underpin learning and memory. All of this in just 15 years since the beginning of his PhD.

For his contribution to the understanding of gene regulation and its potential ability to change agriculture and the treatment of disease and mental health, Professor Ryan Lister of the Australian Research Council Centre of Excellence in Plant Energy Biology at the University of Western Australia has been awarded the 2014 Frank Fenner Prize for Life Scientist of the Year.

The human body is composed of hundreds of different types of cells. Yet all are formed from the same set of instructions, the human genome. How does this happen?

“On top of the genetic code sits another code, the epigenome. It can direct which genes are switched on and which are switched off,” Ryan Lister says. “The genome contains a huge volume of information, a parts list to build an entire organism. But controlling when and where the different components are used is crucial. The epigenetic code regulates the release of the genome’s potential. Cells end up with different forms and functions through using different parts of the genome.”

Because such gene regulation is so fundamental, malfunctions in the epigenetic code can lead to disease and disability. For instance, cancer and neurological disorders can involve changes in gene regulation that are connected to changes in the epigenome. The epigenetic code also enables rapid cellular responses to environmental change that may be important, for instance, in adapting food crops to challenging conditions.

We have only just begun to learn about this regulatory system in the past couple of decades. And Ryan has been at the forefront.

When he was a boy living in the Perth suburb of Cottesloe, Ryan Lister learned about the natural world of plants and animals on trips to the south-west corner of Western Australia with his parents and his primary school, Moerlina. He was fascinated. Later, he started to wonder about how such intricate organisms could form from such a simple set of plans, the genes.

So at university, while he initially enrolled a joint science–engineering degree, he soon switched to straight science, majoring in genetics, molecular biology and biochemistry. For his PhD at the University of Western Australia, Ryan studied how plant cells control the growth and activity of their mitochondria—the internal bodies where sugars are broken down to release energy. It turns out that regulating mitochondria involves extensive switching on and off of genes, changing the patterns of the production and movement of the proteins they encode.

This research sparked his interest in how the activity of the genes is controlled genome-wide. “I developed a taste for large-scale genome biology.” And he began to follow the work of Professor Joseph Ecker at the Salk Institute for Biological Studies in La Jolla, California, who had developed techniques to track gene activity comprehensively in cells. It soon became clear that this was where Ryan wanted to continue his research.

A couple of months after Ryan started his postdoctoral fellowship at the Salk Institute, Ecker’s laboratory gained access to one of the first next-generation rapid DNA sequencers. This was a game changer.

Although gene activity can be regulated in many ways, a highly flexible and reversible means is to add a small ‘methyl’ chemical group—a carbon and three hydrogen atoms—to cytosine, one of the four nucleic acids the sequence of which forms the genetic code. If cytosines in or near a gene are modified with a methyl group, it can cause the gene to be switched off. The methyl groups effectively act as molecular signposts of genome regulation.

Ryan knew that Dr Marianne Frommer from CSIRO and Professor Susan Clark of Sydney’s Garvan Institute of Medical Research had developed a chemical treatment to allow these methyl–cytosines to be identified in the DNA sequence. It had previously only been possible to do this in tiny parts of the genome at any one time. But, by combining this chemical treatment with the new DNA sequencer, Ryan developed a technique to determine the exact position of every methyl–cytosine in an entire genome, and hence their potential influence on controlling the activity of genes in a cell. Ryan tried out his new method first on the model plant Arabidopsis.

The resulting map of the epigenome, published in 2008 in the journal Cell, was the first comprehensive guide to DNA methylation and gene activity in a complex organism. It provided new insights into epigenetic control of the genome. This knowledge is important for efforts to develop crops better equipped to survive in changing and challenging environments.

In 2009, Ryan turned his attention to humans, and successfully constructed the first complete maps of the human epigenome. These pioneering maps identified unexpected complexity in the epigenome of embryonic stem cells, and are already serving as an important reference for medical researchers.

Next, continuing to study stem cells, Ryan showed that the epigenome of the stem cell–like induced pluripotent (iPS) cells—generated from adult cells using the process that won Japanese researcher Shinya Yamanaka the Nobel Prize in 2012—is not the same as natural embryonic stem cells. It turns out that some of the epigenetic signposts present in the adult cells remain when they are reprogrammed into iPS cells. So the new iPS cells retain characteristics of the adult cells from which they came—skin or liver or lung or wherever—which may have consequences for their use in regenerative medicine. Ryan believes he can reverse or utilise this ‘molecular memory’.

Most recently, Ryan has studied how the epigenetic code regulates gene activity in the mammalian brain, revealing that the human epigenome undergoes widespread reconfiguration in childhood development during the critical stages when the neural circuits are forming and maturing. Ryan’s work has unearthed a new form of DNA methylation that appears in brain cells during development, and may be critical for controlling gene activity. He suspects that some neurological disorders may stem from disruption of these epigenome patterns.

Ryan’s discoveries have been acknowledged as highly influential by TIME magazine and the US National Institute of Mental Health. Dr Francis Collins, the man who led the Human Genome Project and is the current head of the US National Institutes of Health, recently commented that Ryan’s brain epigenome research “reveals an entirely new perspective on a fundamental issue in biology or medicine”.

Although offered positions around the world, Ryan opted to return to the University of Western Australia, which he regards as a great research environment with high quality and stimulating colleagues. One of the attractions of his position there is that it allows him to explore both sides of his work—plants and mammals.

At the molecular and cellular level, plants and mammals have a lot more in common than they appear to have as whole organisms, and similar techniques can be used to study them. Even where they differ has its advantages, Ryan says. “Mammalian cells are much easier to culture, control and differentiate in a dish. Plant cells do not form stable cultures, but they have a remarkable ability to survive despite major perturbation of their genome and epigenome.”

Ryan is working with both plant and animal cells to develop tools to edit methylation patterns. “In the past, we have only been able to do this in a crude and untargeted fashion using chemicals,” he says. “By developing new molecular editing tools, we aim to be able to engineer the epigenome to trigger stem cells to differentiate into the specific types of cells we want, or to develop regenerative and remodelling processes and therapies.”

Meanwhile, every so often, he and his wife get away to ramble in the south-west, where they are growing olive and citrus trees, and introducing their children to the natural world.

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