Teaching stem cells to forget the past

Embargoed, National Stem Cell Foundation of Australia

Ryan Lister has discovered how adult stem cells retain a memory of what they once were.

He believes he can make them forget their past lives, as for example skin cells, so their history doesn’t limit their new potential to become brain, heart, liver, blood and other cells.

In recognition of his leadership in stem cell research, Professor Ryan Lister of the University of Western Australia has received one of two $50,000 Metcalf Prizes from the National Stem Cell Foundation of Australia.

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Ryan Lister (Photo credit: Harry Perkins Institute of Medical Research)

In 2009, Ryan constructed the first complete maps of the complex human epigenome—millions of small chemical signposts added to our DNA that can turn genes ‘on’ and ‘off’. TIME magazine named this the second most important discovery that year. Over the life of a cell this packaging accumulates chemical changes or ‘memories’ of the cell’s role.

Ryan then turned his attention to studying adult stem cells or ‘induced pluripotent stem (iPS) cells’ made from, for example, adult skin cells. While iPS cells appear to have reverted back to embryonic childhood, Ryan found they carry some adult baggage with them, retaining chemical memories. These memories may result in unpredictable and undesirable cell growth, limiting medical potential of iPS cells.

“We want to create a tool that will allow us to understand, edit and correct any ‘memories’ that might result in cell behaviour that we want to avoid. Ultimately, this could lead to new stem cells derived from adult cells that can be safely used to treat patients, for example, new cardiac cells to heal damaged heart tissues.”

Stem cell research is a long way from Ryan’s roots in plant research, but he successfully applied his ideas to animals, then humans. By making cell reprogramming more reliable and predictable, his research has the potential to transform stem cell medicine.

Ryan is a Professor and Sylvia and Charles Viertel Senior Medical Research Fellow / ARC Future Fellow at the University of Western Australia, where he leads research groups at the Harry Perkins Institute of Medical Research and the ARC Centre of Excellence in Plant Energy Biology.

The award is named for Australia’s pioneering stem cell researcher, the late Professor Donald Metcalf, AC, an internationally renowned expert on haematopoiesis or blood cell formation, who died late last year.

“We’ve created the Metcalf Prizes to support the rising stars of Australian stem cell science,” says Dr Graeme Blackman, OAM, the Chairman of the Foundation.

“We’re excited by the thought that Ryan Lister’s research will help towards a goal of providing safe and reliable stem cell therapies.”

Profile

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’s research is unravelling this complexity.

From plant genome research…

Ryan’s research career builds on his life-long fascination with the natural world. He wondered how intricate and complex organisms could form from such a simple set of plans, the genes.

Following doctoral studies at the University of Western Australia, Ryan commenced a postdoctoral fellowship at the Salk Institute for Biological Studies in La Jolla, California, working with Professor Joseph Ecker who had developed techniques to track gene activity comprehensively in cells.

Not long after Ryan started at the Salk Institute, Ecker’s laboratory gained access to one of the first next-generation rapid DNA sequencers. Ryan was in the right place at the right time.

“When this technology first emerged, we developed a technique to use the new DNA sequencing instruments to identify and map the exact sites on the genome that possess the small chemical tags that control the cell’s use of the underlying DNA sequence,” says Ryan.

“We can tell exactly where these chemical signposts are located and how they change between different types of cells.”

In the past, this kind of analysis had only been possible to perform for a very small snippet of the genome in a localised region, for example, through a thousand letters (or ‘bases’) of the genome.

The availability of cheap and rapid sequencing meant that Ryan and his colleagues could scale up this process and find the locations of these signposts throughout an entire genome.

Ryan applied these techniques to plants, particularly the model plant Arabidopsis (thale cress). This small flowering plant has a small compact genome, which is useful for conducting genome-wide studies.

The resulting map of the Arabidopsis 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.

…to human genome research

“Once we demonstrated our techniques worked well, we could set our sights on more complex organisms with larger genomes as, month by month, the cost of sequencing DNA progressively decreased. We could go from sequencing the Arabidopsis cell genome, which is around 120 million letters long, to the 3 billion letter long human genome.”

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.

Managing the memories of stem cells

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 blood or hair follicle or wherever—which may have consequences for their use in regenerative medicine. Ryan believes he can reverse or utilise this ‘molecular memory’.

“Advances in DNA sequencing technology have given us fantastic abilities to read the epigenome and locate exactly where all these tags are on the genome, but what we’ve lacked is the ability to change these tags,” says Ryan.

The Metcalf Prize will help Ryan in the next stage of his research, rising to this challenge.

Ryan and his colleagues will make very small and precise molecular tools that can be put into a cell to target a region of the genome and add or remove specific chemical tags to see how this influences the behaviour of the cell. He is particularly interested in finding and targeting those involved in certain disease states and, in stem cells, those that determine the type of cells they specialise into.

“We want to be able to go into these cells and to edit the patterns of these chemical tags, to see whether this affects the characteristics and functions of the cells,” says Ryan.

“In the case of iPS cells, we might want to remove the epigenetic memories that result in undesirable cell behaviour, or even put in different memories so that they’re predisposed to become a particular cell type.”

Ryan will also use his Metcalf Prize funds to conduct the first analysis of the reprogrammed epigenome of in vivo iPS cells.

“That’s the precursor to understanding what it is about the living in vivo environment, in the body of a mouse model, that is different to the environment of the petri dish, and how this influences the reprogramming of adult cells to stem cells.”

Qualifications

2005     Doctor of Philosophy, The University of Western Australia, Molecular Biology

2000     Honours, The University of Western Australia, Molecular Biology

1999     Bachelor of Science, The University of Western Australia, Biochemistry and Genetics

Career Highlights, Awards, Fellowships, Grants

2015     Senior Medical Research Fellowship, 2015 – 2020, Sylvia and Charles Viertel Foundation

2014     Frank Fenner Prize for Life Scientist of the Year (Prime Minister’s Prizes for Science)

2014     Ruth Stephens Gani Medal for Distinguished Research in Human Genetics (Australian Academy of Science)

2013     Young Tall Poppy of the Year, Western Australia

2012     Australian Research Council Future Fellowship, 2012-2016

2010     Genome Technology Young Investigators Award

2009     Postdoctoral Training Fellowship, 2009-2011, California Institute for Regenerative Medicine

2006     Long Term postdoctoral Fellowship, 2006 – 2009, USD $157,000, Human Frontier Science Program

Recent Key Publications

Lister R*^, Mukamel EA*, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y, Dwork A, Schultz MD, Tonti-Filippini J, Yu M, Heyn H, Hu S, Wu JC, Rao A, Esteller M, He C, Haghighi FG, Sejnowski TJ, Behrens MM^, Ecker JR^ (2013) Global epigenomic reconfiguration during mammalian brain development. Science 341(6146):1237905. (Impact factor = 31, Citations = 211, ^ = Corresponding author, * = Equal contribution)

Lister R*, Pelizzola M*, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR^ (2011) Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471(7336):68-73. (Impact factor = 42, Citations = 788)

Lister R*, Pelizzola M*, Dowen RH, Hawkins RD, Hon G, Tonti-Filippini J, Nery JR, Lee L, Ye Z, Ngo QM, Edsall L, Antosiewicz-Bourget J, Stewart R, Ruotti V, Millar AH, Thomson JA, Ren B, Ecker JR^ (2009) Human DNA methylomes at base resolution show widespread epigenomic differences. Nature 462(7271):315-22. (Impact factor = 42, Citations = 1,883)

Lister R*, O’Malley RC*, Tonti-Filippini J*, Gregory BD, Berry CC, Millar AH, Ecker JR^ (2008) Highly integrated single-base resolution maps of the epigenome in Arabidopsis. Cell 133(3):523-36. (Impact factor = 33, Citations = 1,168)

Xie W, Schultz M*, Lister R*, Hou Z*, Rajagopal N*, Ray P*, Whitaker JW*, Tian S*, Hawkins RD*, Leung D*, Yang H, Wang T, Lee AY, Swanson SA, Zhang J, Zhu Y, Kim A, Nery J, Urich MA, Kuan S, Yen C, Klugman S, Yu P, Suknuntha K, Propson NE, Chen H, Edsall LE, Wagner U, Li Y, Ye Z, Kulkarni A, Xuan Z, Chung W, Chi NC, Antosiewicz-Bourget J, Slukvin I, Stewart R, Zhang MQ, Wang W, Thomson JA^, Ecker JR^, Ren B^ (2013) Epigenomic Analysis of Multi-lineage Differentiation of Human Embryonic Stem Cells. Cell 153(5):1134-48. (Impact factor = 33, Citations = 130)