̽��ֱ�� of Cambridge - physics of medicine

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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Finding malaria's weak spot

admin — Wed, 06 Feb 2013 09:06:33 +0000

After over a decade of research into malaria, biologists Dr Teresa Tiffert and Dr Virgilio Lew at the Department of Physiology, Development and Neuroscience found their efforts to observe a key stage of the infection cycle severely hindered by the limits of available technology. An innovative collaboration with physicist Dr Pietro Cicuta at the Cavendish Laboratory and bio-imaging specialist Professor Clemens Kaminski in the Department of Chemical Engineering and Biotechnology is now yielding new insights into this devastating disease.

Under attack

Malaria is caused by parasites transmitted to humans through the bites of infected mosquitoes. According to the World Malaria Report 2011, there were about 216 million cases of malaria causing an estimated 655,000 deaths in 2010. Tiffert and Lew established their malaria laboratory in Cambridge in 1999 to investigate the most deadly form of the parasite, Plasmodium falciparum. Becoming increasingly resistant to available drugs, this species in particular is a growing public health concern.

Their current focus is a mysterious step in the life cycle of P. falciparum occurring inside the infected human’s bloodstream. ̽��ֱ��parasites, at this stage called merozoites, attach to and enter red blood cells (RBCs) to develop and multiply. After two days, the new merozoites are released and infect neighbouring RBCs. Over several days, this process amplifies the number of parasitised RBCs and causes severe and potentially lethal symptoms in humans.

“A huge amount of research has been devoted to understanding the RBC penetration process,” said Tiffert. “ ̽��ֱ��focus of many vaccine efforts is the molecules on the surfaces of both parasite and red cell that are instrumental in recognition and penetration. Our collaboration with Clemens developed new imaging approaches to investigate what happens in the cells after invasion. But the pre-invasion stage, when a merozoite first contacts a cell targeted for invasion, remained a profound mystery. Our research indicates that this stage is absolutely critical in determining the proportion of cells that will be infected in an individual.”

For invasion to occur, the tip of the merozoite has to be aligned perpendicularly to the RBC membrane. Tiffert and Lew are focusing on how this alignment comes about, which has proved a formidable technical challenge. “ ̽��ֱ��merozoites are only in the bloodstream for less than two minutes, where they are vulnerable to attack by the host’s immune system, before entering a RBC. To investigate what is going on we need to record lots of pre-invasion and penetration sequences at high speed, using high magnification and variable focusing in three dimensions. And the real challenge is to have the microscope on the right settings and to be recording at exactly the time when an infected cell has burst and released merozoites – something that is impossible to predict,” said Tiffert.

Techniques used by previous investigators have produced few useful recordings of this process occurring in culture, but from these an astonishing picture is emerging. “ ̽��ֱ��contact of the merozoite with the RBC elicits vigorous shape changes in the cell, not seen in any other context,” said Lew. “It seems clear that this helps the merozoite orientate itself correctly for penetration, because all movement stops as soon as this happens. ̽��ֱ��parasite is somehow getting the RBC to help it invade.”

A collaborative approach

Cicuta, a ̽��ֱ�� Lecturer involved in the ̽��ֱ��’s Physics of Medicine Initiative – which is bringing together researchers working at the interface of physical sciences, life sciences and clinical sciences – met the trio by chance three years ago. He realised he could use his background in fundamental physics to pioneer a new approach to understanding malaria. “It’s been a gradual move for me to apply what I’ve learnt in physics to biology,” he said. “From the physics point of view, RBC membranes are a material. This material is very soft and undergoes deformations and fluctuations, and I was interested in understanding the mechanics involved during infection with malaria.”

Drawing on his expertise in the development of experimental techniques, Cicuta collaborated with Tiffert, Lew and Kaminski to pioneer a completely automated imaging system that pushes the boundaries of live cell imaging, enabling individual RBCs and merozoites to be observed throughout the process of infection. ̽��ֱ��research was funded by the Biotechnology and Biological Sciences Research Council and the Engineering and Physical Sciences Research Council.

“This microscope can not only run by itself for days, it can perform all the tasks that a human would otherwise be doing. It can refocus, it can find infected cells and zoom in, and when it detects a release of parasites it can change its imaging modality by going into a high frame-rate acquisition. And when the release has finished it can search around in the culture to find another cell to monitor automatically,” said Cicuta. “We also want to integrate a technique called an optical trap, which uses a laser beam to grab cells and move them around, so we can deliver the parasites to the cells ourselves and see how they invade.”

“So far, we’ve been able to gather over 50 videos of infections, which my PhD student Alex Crick has processed to show very clearly that the RBCs undergo large changes in shape when the merozoites touch them. We’ve also seen very strange shape changes just before the parasites come out of the cells, and we want to see whether this has a bearing on the parasites’ ability to infect subsequent cells.”

During the development of the microscope, the team discovered variability in the way the infected RBCs behave before they burst. “It’s important to know that there isn’t just one story. ̽��ֱ��only way to find this out is to look at many cells, which this system allows,” said Lew. “It’s a new level of data that allows us to get experimentally significant results, and better understand the diversity of the merozoites,” Cicuta added.

Used in conjunction with other tools such as fluorescent indicators and molecular biological tools, the new technology will allow Tiffert and Lew to test their hypotheses about the pre-invasion stage of the disease. They hope to determine the critical steps, which could provide clues as to how to stop an infection. “This microscope is an extraordinary new tool that has potential for use across a huge field of biological problems involving cellular interactions,” explained Lew.

“It may provide a route to designing effective antimalarial drugs, reducing invasive efficiency and decreasing mortality,” said Tiffert. “ ̽��ֱ��automation we have achieved with this microscope will also be very important for future testing of malaria drugs and vaccines,” added Cicuta.

A visionary initiative

“ ̽��ֱ��Physics of Medicine Initiative has been essential to our work,” said Cicuta. ̽��ֱ�� ̽��ֱ�� formally established the Initiative in December 2008 through the opening of a new purpose-built research facility adjacent to the Cavendish Laboratory, funded by the ̽��ֱ�� and ̽��ֱ��Wolfson Foundation. ̽��ֱ��goal is to break down traditional barriers that have tended to limit interactions between researchers in the physical and biomedical sciences.

“I met my collaborators through a Physics of Medicine symposium, and the new building is the only place in the ̽��ֱ�� where this type of research can be done,” added Cicuta. “It’s set up for safe handling of hazardous biological organisms like P. falciparum, and also has the facilities to design hardware for our advanced microscopes. This work is exciting because it’s interdisciplinary. By applying physics to the knowledge biologists have been developing for many years, we can make very fast progress.”

For more information, please contact Jacqueline Garget at the ̽��ֱ�� of Cambridge Office of External Affairs and Communications

A ground-breaking imaging system to track malarial infection of blood cells in real time has been created by a collaboration catalysed by the ̽��ֱ��’s Physics of Medicine Initiative.

Finding Malaria's Weak Spot

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Science award boosts physics research at Cambridge

tdk25 — Thu, 21 Dec 2006 00:00:00 +0000

̽��ֱ�� ̽��ֱ�� of Cambridge is to form one third of a new £6 million research collaboration looking at quantum physics.

̽��ֱ��sum, one of several new science and innovation awards, has been given to three UK universities by the Engineering and Physical Sciences Research Council.

Cambridge, Oxford and Imperial College London will share expertise from their respective Physics departments to examine quantum coherence. This promises to improve our understanding not just of the quantum world, but to develop fundamental new technologies in nanoscience.

̽��ֱ��money will enable the ̽��ֱ�� to appoint two new specialists in ultracold atoms and another in semiconductor optics. It is also investing an additional £3million of its own money in new equipment and the refurbishment of existing facilities within its Cavendish Laboratory to help further improve its capacity for experimental research in coherent quantum systems.

̽��ֱ��new funding adds to a much wider-reaching hiring programme currently underway at the Cavendish Laboratory. During the next two years, six lecturers, two readers and three professors will be added to the Department of Physics' staff. ̽��ֱ��construction of a £12.5million Centre for the Physics of Medicine to house interdisciplinary research in medicine and biology is beginning. A new Kavli Institute of Cosmology - a joint venture with the Institute of Astronomy and the Department of Applied Mathematics and Theoretical Physics - is also planned.

Professor Peter Littlewood, Cambridge's Principal Investigator in the collaboration, said: "We see tremendous opportunities in the science and technology of manipulating the quantum states of light and matter, a discipline that now spans atomic physics, optics and condensed matter, and that is moving forward at a great rate.

"Because of the breadth of this subject, it is important to have a collective national effort. Oxford, Imperial and Cambridge have complementary skills and research programmes so we can help each other to move forward. We already have many collaborative activities, and I am looking forward to making these even stronger."

̽��ֱ��science and innovation award is one of seven announced today by the Engineering and Physical Sciences Research Council (ESPRC). ̽��ֱ��awards were introduced in 2005 to stimulate research and nurture future scholars in important areas where such support is deemed to be lacking.

̽��ֱ�� ̽��ֱ�� of Cambridge is to form one third of a new £6 million research collaboration looking at quantum physics.

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Yes