̽��ֱ�� of Cambridge - Ben Simons

Scientists reveal the beautiful simplicity underlying branching patterns in tissue

cjb250 — Thu, 21 Sep 2017 16:00:00 +0000

Branching patterns occur throughout nature – in trees, ferns and coral, for example – but also at a much finer scale, where they are essential to ensuring that organisms can exchange gases and fluids with the environment efficiently by the maximising the surface area available.

For example, in the small intestine, epithelial tissue is arranged in an array of finger-like protrusions. In other organs, such as kidney, lung, mammary glands, pancreas and prostate, exchange surfaces are packed efficiently around intricate branched epithelial structures.

“On the surface, the question of how these structures grow – structures that may contain as many as 30 or 40 generations of branching – seems incredibly complex,” says Professor Ben Simons, who led the study, published today in the journal Cell. Professor Simons holds positions in the ̽��ֱ�� of Cambridge’s Cavendish Laboratory and Wellcome Trust/Cancer Research UK Gurdon Institute.

This classic problem of ‘branching morphogenesis’ has attracted the attention of scientists and mathematicians for centuries. Indeed, the mathematical underpinnings of morphogenesis – the biological process that causes organisms to develop their shape – was the subject of D’Arcy Wentworth Thompson's classic text, published in 1917 by Cambridge ̽��ֱ�� Press. Thompson had been a student at Cambridge, studying zoology at Trinity College, and briefly worked as a Junior Demonstrator in Physiology.

During development, branching structures are orchestrated by stem-like cells that drive a process of ductal growth and division (or ‘bifurcation’). Each subsequent branch will then either stop growing, or continue to branch again. In a study published in Nature earlier this year, Professor Simons working in collaboration with Dr Jacco van Rheenen at the Hubrecht Institute in Utrecht showed that, in the mammary gland, these processes of division and termination occur randomly, but with almost equal probability.

“While there’s a collective decision-making process going on involving multiple different stem cell types, our discovery that growth occurs almost at the flip of a coin suggested that there may be a very simple rule underpinning it,” says Professor Simons.

Professor Simons and his colleague Dr Edouard Hannezo observed that there was very little crossover of the branches – ducts seemed to expand to fill the space, but not overlap. This led them to conjecture that the ducts were growing and dividing, but as soon as a tip touched another branch, it would stop.

“In this way, you generate a perfectly space-filling network, with precisely the observed statistical organisation, via the simplest local instruction: you branch and you stop when you meet a maturing duct,” says Dr Hannezo, a Sir Henry Wellcome Postdoctoral Fellow based at the Gurdon Institute. “This has enormous implications for the basic biology. It tells you that complex branched epithelial structures develop as a self-organised process, reliant upon a strikingly simple, but generic, rule, without recourse to a rigid, pre-determined sequence of genetically programmed events.”

Although these observations were based on the mammary gland epithelium, by using primary data from Dr Rosemary Sampogna at Columbia ̽��ֱ��, Professor Anna Philpott in Cambridge and Dr Rakesh Heer at Newcastle ̽��ֱ��, the researchers were able to show that the same rules governed the embryonic development of the mouse kidney, pancreas and human prostate.

“In the mammary gland, you have a hundred or more fate-restricted stem-like cells participating in this bifurcation-growth-bifurcation process, whereas in the pancreas it’s just a handful; but the basic dynamics are the same,” says Professor Simons. “ ̽��ֱ��model is aesthetically beautiful, because the rules are so simple and yet they are able to predict the complex branching patterns of these structures.”

̽��ֱ��researchers say their discovery may offer insights into the development of breast and pancreatic cancer, where the earliest stages of the disease often show an irregular tangled ductal-like organisation.

“A century after the publication of On Growth and Form, it’s exciting to see how the concepts of self-organisation and emergence continue to offer fresh perspectives on the development of biological systems, framing new questions about the regulatory mechanisms operating at the cellular and molecular scale,” Professor Simons adds.

While it may be too early to tell whether similar rules apply to other branched tissues and organisms, there are interesting parallels: branching in trees appears to follow a similar pattern, for example, with side branches growing and bifurcating until they are shaded or until they are screened by another branch, at which point they stop.

̽��ֱ��research was funded by the Wellcome Trust with additional core support from Cancer Research UK and the Medical Research Council.

References
Scheele, C et al. Identity and dynamics of mammary stem cells during branching morphogenesis. Nature 542, 313-317 (2017); DOI: 10.1038/nature21046

Hannezo, E et al. A unifying theory of branching morphogenesis. Cell; 14 Sept 2017; DOI: TBC

In the centenary year of the publication of a seminal treatise on the physical and mathematical principles underpinning nature – On Growth and Form by D’Arcy Wentworth Thompson – a Cambridge physicist has led a study describing an elegantly simple solution to a puzzle that has taxed biologists for centuries: how complex branching patterns of tissues arise.

̽��ֱ��model is aesthetically beautiful, because the rules are so simple and yet they are able to predict the complex branching patterns of these structures

Ben Simons

Olivia Harris, Felicity Davis, Bethan Lloyd-Lewis and Christine Watson, ̽��ֱ�� of Cambridge, Wellcome Images

Mammary gland, 4 day-old mouse

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Where did it all go wrong? Scientists identify ‘cell of origin’ in skin cancers

cjb250 — Fri, 08 Jul 2016 14:24:38 +0000

Our skin is kept healthy by a constant turnover, with dying skin cells being shed and replaced by new cells. ̽��ֱ��process is maintained by ‘progenitor’ cells – the progeny of stem cells – that divide and ‘differentiate’ into fully-functional skin cells to replenish dying skin. These cells are in turn supported by a smaller population of ‘stem cells’, which remain silent, ready to become active and repair skin when it becomes damaged.

However, when this process goes awry, cancers can arise: damaged DNA or the activation of particular genes known as ‘oncogenes’ can trigger a cascade of activity that can lead ultimately to unchecked proliferation, the hallmark of a cancer. In some cases, these tumours may be benign, but in others, they can spread throughout the body – or ‘metastasise’ – where they can cause organ failure.

Until now, there has been intense interest in the scientific field about which types of cell – stem cell, progenitor cell or both – can give rise to tumours, and how those cells become transformed in the process of tumour initiation and growth. Now, in a study published in Nature, researchers led by Professor Cédric Blanpain at the Université Libre de Bruxelles, Belgium, and Professor Ben Simons at the ̽��ֱ�� of Cambridge, have demonstrated in mice how skin stem and progenitor cells respond to the activation of an oncogene. Their studies have shown that, while progenitor cells can give rise to benign lesions, only stem cells have the capacity to develop into deadly invasive tumours.

̽��ֱ��researchers used a transgenic mouse model – a mouse whose genes had been altered to allow the activation of an oncogene in individual stem and progenitor cells. ̽��ֱ��oncogene was coupled with a fluorescent marker so that cells in which the oncogene was active could be easily identified, and as these cells proliferate, their ‘daughter’ cells could also be tracked. These related, fluorescent cells are known as ‘clones’.

By analysing the number of fluorescently-labelled cells per clone using mathematical modelling, the team was able to show that only clones derived from mutant stem cells were able to overcome a mechanism known as ‘apoptosis’, or programmed cell death, and continue to divide and proliferate unchecked, developing into a form of skin cancer known as basal cell carcinoma. In contrast, the growth of clones derived from progenitor cells becomes checked by increasing levels of apoptosis, leading to the formation of benign lesions.

“It’s incredibly rare to identify a cancer cell of origin and until now no one has been able to track what happens on an individual level to these cells as they mutate and proliferate,” says Professor Blanpain. “We now know that stem cells are the culprits: when an oncogene in a stem cell becomes active, it triggers a chain reaction of cell division and proliferation that overcomes the cell’s safety mechanisms.”

“While this has solved a long-standing scientific argument about which cell types can lead to invasive skin tumours, it is far more than just a piece of esoteric knowledge,” adds Professor Simons from the Cavendish Laboratory at the ̽��ֱ�� of Cambridge. “It suggests to us that targeting the pathways used in regulating cell fate decisions – how stem cells choose between cell proliferation and differentiation – could be a more effective way of halting tumours in their tracks and lead to potential new therapies.”

̽��ֱ��work was supported by the FNRS, TELEVIE, the Fondation Contre le Cancer, the ULB fondation, the foundation Bettencourt Schueller, the foundation Baillet Latour, the European Research Council, Wellcome Trust and Trinity College Cambridge.

Reference
Sánchez-Danés, A et al. Defining the clonal dynamics leading to mouse skin tumour initiation. Nature; 8 July 2016; DOI: 10.1038/nature19069

Image
̽��ֱ��green-labelled cells show a basal cell carcinoma in mouse tail epidermis derived from a single mutant stem cell and expanding out of the normal epidermis stained in red. Credit: Adriana Sánchez-Danés.

Scientists have identified for the first time the ‘cell of origin’ – in other words, the first cell from which the cancer grows – in basal cell carcinoma, the most common form of skin cancer, and followed the chain of events that lead to the growth of these invasive tumours.

Adriana Sánchez-Danés

Basal cell carcinoma in mouse tail epidermis derived from a single mutant stem cell

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Cambridge scientists receive Royal Society awards

Anonymous — Mon, 20 Jul 2015 13:44:01 +0000

̽��ֱ��Royal Society, the UK’s independent academy for science, has announced the recipients of its 2015 Awards, Medals and Prize Lectures. ̽��ֱ��scientists receive the awards in recognition of their achievements in a wide variety of fields of research. ̽��ֱ��recipients from the ̽��ֱ�� of Cambridge are:

Professor George Efstathiou FRS (Institute of Astronomy) receives the Hughes Medal for many outstanding contributions to our understanding of the early Universe, in particular his pioneering computer simulations, observations of galaxy clustering and studies of the fluctuations in the cosmic microwave background.

Professor Benjamin Simons (Wellcome Trust/Cancer Research UK Gurdon Institute, Cavendish Laboratory) receives the Gabor Medal for his work analysing stem cell lineages in development, tissue homeostasis and cancer, revolutionising our understanding of stem cell behaviour in vivo.

Professor Russell Cowburn FRS (Department of Physics) receives the Clifford Paterson Medal and Lecture for his remarkable academic, technical and commercial achievements in nano-magnetics.

Dr Madan Babu Mohan (MRC Laboratory of Molecular Biology) receives the Francis Crick Medal and Lecture for his major and widespread contributions to computational biology.

View the full list of recipients.

Four Cambridge scientists have been recognised by the Royal Society for their achievements in research.

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Stem cell physical

lw355 — Fri, 10 Oct 2014 13:55:38 +0000

One of the many mysteries surrounding stem cells is how the constantly regenerating cells in adults, such as those in skin, are able to achieve the delicate balance between self-renewal and differentiation – in other words, both maintaining their numbers and producing cells that are more specialised to replace those that are used up or damaged.

“What all of us want to understand is how stem cells decide to make and maintain a body plan,” said Dr Kevin Chalut, a Cambridge physicist who moved his lab to the ̽��ֱ��’s Wellcome Trust-MRC Cambridge Stem Cell Institute two years ago. “How do they decide whether they’re going to differentiate or stay a stem cell in order to replenish tissue? We have discovered a lot about stem cells, but at this point nobody can tell you exactly how they maintain that balance.”

To unravel this mystery, both Chalut and another physicist, Professor Ben Simons, are bringing a fresh perspective to the biologists’ work. Looking at problems through the lens of a physicist helps them untangle many of the complex datasets associated with stem cell research. It also, they say, makes them unafraid to ask questions that some biologists might consider ‘heretical’, such as whether a few simple rules describe stem cells. “As physicists, we’re very used to the idea that complex systems have emergent behaviour that may be described by simple rules,” explained Simons.

What they have discovered is challenging some of the basic assumptions we have about stem cells.

One of those assumptions is that once a stem cell has been ‘fated’ for differentiation, there’s no going back. “In fact, it appears that stem cells are much more adaptable than previously thought,” said Simons.
By using fluorescent markers and live imaging to track a stem cell’s progression, Simons’ group has found that they can move backwards and forwards between states biased towards renewal and differentiation, depending on their physical position in the their host environment, known as the stem cell niche.

For example, some have argued that mammals, from elephants to mice, require just a few hundred blood stem cells to maintain sufficient levels of blood in the body. “Which sounds crazy,” said Simons. “But if the self-renewal potential of cells may vary reversibly, the number of cells that retain stem cell potential may be much higher. Just because a certain cell may have a low chance of self-renewal today doesn’t mean that it will still be low tomorrow or next week!”

Chalut’s group is also looking at the way in which stem cells interact with their environment, specifically at the role that their physical and mechanical properties might play in how they make their fate decisions. It’s a little-studied area, but one that could play a key role in understanding how stem cells work.
“If you go to the grocery store to buy an avocado, you’re not going to perform lots of chemistry on it in order to decide which is the best one: you’re going to pick it up and squeeze it,” said Chalut. “In essence, this is what we’re trying to do with stem cells.”

Chalut’s team is looking at the exact point where pluripotency – the ability to generate any other cell type in the body – arises in the embryo, and determining what role physical or mechanical signals play in generating this ‘ultimate’ stem cell state.

Using fluid pressure to squeeze the stem cells through a channel, as well as miniature cantilevers to push down on the cells, the researchers were able to observe and measure the mechanical properties of these master cells.

What they found is that the nuclei of embryonic stem cells display a bizarre and highly unusual property known as auxeticity. Most materials will contract when stretched. If you pull on an elastic band, the elastic will get thinner. If you squeeze a tennis ball, its circumference will get larger. However, auxetic materials react differently – squeeze them and they contract, stretch them and they expand.

“ ̽��ֱ��nucleus of an embryonic stem cell is an auxetic sponge – it can open up and soak up material when it’s pulled on and expel all that material when it’s compressed,” said Chalut. “But once the cells have differentiated, this property goes away.”

Auxeticity arises precisely at the point in a stem cell’s development that it needs to start differentiating, so it’s possible that the property exists so that the nucleus is able to allow entrance and space to the molecules required for differentiation.

“There’s a lot of discussion about what exactly it means to be pluripotent, and how pluripotency is regulated,” said Chalut. “Many different factors play a role, but we believe one of those factors may be a mechanical signal. This may also be the case in the developing embryo.”

By bringing together physics and biology, Simons and Chalut believe not only that some of the defining questions in embryonic and adult stem cell biology can be addressed, but also that new insights can be found into mechanisms of dysregulation in disease, cancer and ageing.

“One of the reasons that this bringing together of disciplines sometimes doesn’t work so well is that physicists don’t want to understand the biology and biologists don’t want to understand the physics,” said Chalut. “In a sense, biologists don’t know the physical questions to ask, and physicists don’t know the biological questions to ask. As a physicist, the main reason I wanted to move my lab to the Stem Cell Institute is I thought there was no point working in biology if I didn’t understand which questions to ask.”

“There’s a real effort being made to combine biology and physics much more than they have been in the past,” added Simons. “It takes a bit of a leap of faith to believe physics will enrich the field of biology, but I think it’s a very reasonable leap of faith. Scientific history is full of fields that have been enriched by people coming in and looking at an issue from different directions.”

Inset image: Kevin Chalut (left) and Ben Simons.

Looking at stem cells through physicists’ eyes is challenging some of our basic assumptions about the body’s master cells.

What all of us want to understand is how stem cells decide to make and maintain a body plan

Kevin Chalut

Effigos AG

Stem cells show auxeticity; the nucleus expands, rather than thins, when it's stretched

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Unraveling tumour growth one stem cell at a time

gm349 — Tue, 04 Jun 2013 16:06:35 +0000

Researchers at the ̽��ֱ�� of Cambridge have discovered that a single mutation in a leukaemia-associated gene reduces the ability of blood stem cells to make more blood stem cells, but leaves their progeny daughter cells unaffected. Their findings have relevance to all cancers that are suspected to have a stem cell origin as they advance our understanding of how single stem cells are subverted to cause tumours.

Published this week in PLOS Biology, the study by Professor Tony Green and his team at the Cambridge Institute for Medical Research (CIMR) is the first to isolate highly purified single stem cells and study their individual responses to a mutation that can predispose individuals to a human malignancy. This mutation is in a gene called JAK2, which is present in most patients with myeloproliferative neoplasms (MPNs)—a group of bone marrow diseases that are characterized by the over-production of mature blood cells and by an increased risk of developing leukaemia.

Using a unique mathematical modelling approach, carried out in collaboration with Professor Ben Simons at the Cavendish Laboratory in Cambridge, in combination with experiments on single mouse stem cells, the researchers identified a distinct cellular mechanism that operates in stem cells but not in their daughter cells.

“This study is an excellent example of an inter-disciplinary collaboration pushing the field forward,” says lead author Dr David Kent. “Combining mathematical modelling with a large number of single stem cell assays allowed us to predict which cells lose their ability to expand. We were able to reinforce this prediction by testing the daughter cells of single stem cell divisions separately and showing that mutant stem cells more often undergo symmetric division to give rise to two non-stem cells.”

Characterizing the mechanisms that link JAK2 mutations with this pattern of stem cell division—a pattern that eventually leads to the development of MPNs—will inform our understanding of the earliest stages of tumour establishment and of the competition between tumour stem cells, say the authors. ̽��ֱ��next step, currently underway at the Cambridge Institute for Medical Research, is to understand the effect that acquiring additional mutations has on blood stem cells, as these are thought to drive the expansion of blood progenitor cells, leading to the eventual transformation to leukaemia that occurs in patients with MPNs.

Citation: Kent DG, Li J, Tanna H, Fink J, Kirschner K, et al. (2013) Self-Renewal of Single Mouse Hematopoietic Stem Cells Is Reduced by JAK2V617F Without
Compromising Progenitor Cell Expansion. PLoS Biol 11(6): e1001576. doi:10.1371/journal.pbio.1001576

Press release provided by PLOS Biology.

Study has relevance to all cancers that are suspected to have a stem cell origin

David Kent, Tony Green Lab

A small colony of cells derived from a single blood stem cell. Hundreds of such colonies were assessed for their proliferation kinetics and blood cell types produced.

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