There’s strength in flexibility

Faculty Scientists have made an important discovery about how cells change the strength of the connection between one another to match the various needs of the body.

The team, led by Dr Lydia Tabernero and Prof David Garrod, looked at desmosomes – structures that help to bind two cells together. Specifically, they looked at the desmosomes that are present between two cells in the heart and two cells in the skin.

Desmosomes are known to be specialised for their strong adhesion and this is what allows tissue cells to stick together despite the rigours of everyday life.  However, under different situations, like embryonic development and wound healing, these connections would need to become ‘weaker’ in order to allow cells to move and grow. Until this point, scientists have been unable to determine how the desmosomes were able to change their adhesiveness.

Cell AdhesionsThe team found that the ‘adaptive strength’ of desmosomes is achieved by special proteins which protrude from the cell. These proteins are the ‘sticky’ points which connect two cells together. They found that the proteins were much more flexible than was previously thought, allowing cells to change the strength of the bond between one another.

To study the role of desmosomes, the team extracted these special proteins to see what they consisted of. They used a combination of different techniques which allowed them to build a computer model of the molecules that make the connections between the cells. They found that the molecules were much more ordered in stronger adhesions than in weaker ones. The molecules were able to change their level of organisation because of their flexibility.

Dr Tabernero comments:

“What is really fascinating about desmosomes is that they become weaker during wound healing and embryonic development, and this weakening is necessary to allow cells to move. In contrast, desmosomes are very strong in adult tissues, particularly in skin and heart. It has been incredibly difficult to work out how they do that but our findings shed new light on this.”

Professor David Garrod has studied desmosomes for decades. He says there are exciting implications for these findings:

“This is the first time that any structural information has been reported for desmosome adhesion. Understanding these cell junctions will be important for future biotechnology applications. We also hope our research will contribute to studies into wound healing, cancer and embryonic development.”

The paper “Cadherin flexibility provides a key difference between desmosomes and adherens junctions” was published in PNAS on April 28th 2015.

Structure may hold clues to help detect and combat kidney disease

Faculty scientists have made a key finding that could help develop an early test for kidney disease.

Dr Rachel Lennon from the Wellcome Trust Centre for Cell-Matrix Research, led the investigation that looked at why some people are more susceptible to kidney disease than others. In particular, the study looked at why impaired kidney function is more common in Afro-Caribbean individuals and in males.

Dr Lennon and her team focused on the structure around the cells in the kidney, as this is where they believed crucial differences may lie. Kidneys contain numerous small filter cells which help to maintain the blood in a healthy, steady state. The filters are surrounded by a mesh of two different types of proteins which act like scaffolding, giving structure and protection. It is these two proteins that the team wanted to investigate.

To do this, they used mass spectrometry to analyse the kidney tissue from mice who had a variety of genetic backgrounds – some of which they knew were more susceptible to kidney disease.

The team found that there were significant differences in the compositions of the two kidney proteins between the mice. This difference was found to be greater between mice of different genetic backgrounds as opposed to gender.

After the analysis, the team then used an electron microscope to get a closer look at the two types of cells. The team found that the cells from the various mice had structural differences – showing that both the composition and the structure of the scaffolding around the kidney filters changed between mice.

Dr Lennon comments: “The most surprising thing about our findings were that the mice weren’t actually exhibiting any symptoms of kidney disease and were all still in full health despite having this different structure in their filters. Their kidneys appeared to be functioning normally.”

The team are now looking to use human tissue to investigate the reasons behind these differences and are hoping that they will be able to find a mechanism that could be switched off before symptoms of kidney disease become more apparent and damage occurs:

“What we’re hoping is that this research will help develop a test that picks up kidney disease or even just a susceptibility to kidney disease before any damage has been done. We’re also keen to look at whether we could manipulate the process which leads to the structural change to develop new, more effective treatments.”

View Rachel Lennon’s Minute Lecture on kidneys:

Tuesday Feature episode 8: Benjamin Stutchbury

Benjamin Stutchbury is a PhD student in the Faculty. As you’ll see below, it took him a while to find the topic he wanted to study,Ben Stutchbury but now that he has he seems to excelling.

With ambitions of being involved in science communication, Ben has already been involved in some exciting events. In fact, the day after this article goes live he will be performing in the national final of the FameLab competition. You can see his North West Final performance in one of the videos below.

We’re confident that you’ll be hearing Ben’s name in the future, so we thought we’d get in on the ground floor and interview him for this week’s Tuesday Feature.

Could you please explain your research, for the layman, in ten sentences or less?

I research how a cell in your body is able to understand the environment that it’s in.

Particularly how it’s able to understand the mechanical properties of the environment; so how soft it is, or how rigid it is. For example, brain is very soft and bone is very rigid. Cells in these areas of your body need to respond to, and change how they react to, changes in these different environments.

How can your research benefit the people reading this blog?

It’s difficult to say, really. It’s a very, very young area of research. It was only in the last ten years that this idea of cells responding to forces rather than chemicals has really emerged as a field. So at the moment it’s more that we’re trying to understand how they’re actually doing it and what’s actually going on.

Eventually, where it will benefit people is cancer. Which is kind of what every researcher says.

It’s about how cells sense and respond to changes in the mechanical properties of their environment and cancer is a stiffer environment than normal tissue. That’s why you can feel a cancer lump underneath your skin.

Cancer cells are stiffer than normal tissue. They respond differently to this stiffer environment, and that’s one of the reasons they divide faster and move faster. Which is why cancer is so good at killing.

Can we ask you how you first got interested in your research area?

Yeah, it kind of happened by accident to be honest.

I always thought I was interested in immunology, the study of the immune system. Then I went and did an immunology placement in a lab for three months and absolutely hated it.

I went into my final year of undergrad knowing that I wanted to carry on doing science, but with no idea of what I wanted to do. And then I kind of stumbled upon this area of, I guess they call it, mechanobiology; the cells and mechanical forces.

It was quite interesting and different to anything I’d seen before because it’s such a young area. I did a placement in a lab as a kind of try out before doing a PhD and really enjoyed it so decided to stick with it as a PhD topic.

Do you have any science heroes? Who inspired you?

Not really, to be honest.

This might be a new one, but I was actually more inspired by a disease than anything else. I have type 1 diabetes and I was diagnosed when I was eleven. When I was twelve I decided that my life dream was going to be to cure diabetes.

I kind of went down the path of doing science, and was interested in it enough to want to carry on looking into curing diabetes. Then I did a module in second year about metabolism and metabolic diseases and found them really dull. So then I decided that diabetes was really boring.

But actually, my desire to sort of carry on researching other things kind of stuck.

And then I chose immunology, and hated immunology. Everyone was getting a bit worried that I hated all biology but still wanted to do it. And then I found my area to focus on.

But I don’t think I have an individual who kind of fuelled my desire to do science, it was more my own personal circumstances.

Could you tell us a bit about your interests outside of science?

I do a lot of sport. If I hadn’t done science, if I hadn’t got a PhD offer, my fall back was to train as an outdoor instructor. Mountaineering, mountain biking, kayaking, and that kind of thing. I do a lot of rock climbing and mountaineering.

Oh, and squash. I play a lot of squash, kind of three or four times a week. If it involves an activity, I’ll generally be happy to do it.

How has working at the Faculty benefited your research?

Stutchbury, BenMassively, I think.

The main reason for that is the size of the Faculty and the huge variety of different areas of science that are being carried out within this one Faculty.

As I said I kind of came into this not knowing what area I wanted to go into. The PhD I’m doing allowed the opportunity to go into and try out a couple of different labs before choosing one to settle in.

There aren’t many universities in the UK that offer that kind of PhD. It’s becoming more popular now, but it’s still not that common. So the fact that Manchester allowed you to do a PhD where you could sample labs before choosing one means you can find out if you enjoy the topic, if you  like doing the techniques that you have to do, if you like the people you’re working with, and if you get on with the supervisor.

That’s quite a unique thing for Manchester, I think. It was a big influence on me choosing here for my PhD placement.

And so we come to the end of another Tuesday Feature. Our thank yous go to Ben and we wish him a great deal of luck in the FameLab final. 

Ben’s is a great story, and it’s fascinating to see how a love for science drove him on even when he struggled to find the exact topic that suited him. That’s pretty inspirational! If you want to hear more from him, please head over to his blog.

Anyway, enough mushiness for now. Thank you, Ben – and thank you all for reading. Please come back next week!

Interview by Fran Slater, Videos by Theo Jolliffe and Ben Stutchbury, Images courtesy of Nick Ogden and Ben Stutchbury

Mind the gap – new insight could lead to more effective drug treatments

Faculty researcher Professor Dan Davis has made a discovery that could improve drug treatments. Alongside his team at the Manchester Collaborative Centre for Inflammation Research (MCCIR), Professor Davis was investigating how different types of immune cells communicate with each other and how they kill cancerous or infected cells. Professor Davis says:

“We studied the immune system and stumbled across something that may explain why some drugs don’t work as well as hoped. We found that immune cells secrete molecules to other cells across a very small gap. This happens when immune cells talk to each other, and also when they kill diseased cells. But crucially, some types of drugs aren’t able to penetrate the gap between the cells. So they can’t easily reach targets within the gap and work effectively.”

Comparing molecules of different sizes, the team used microscopic imaging to see which ones could fit into the gap between an immune cell and another cell. Only the smaller molecules could penetrate the gap. They even found that when an immune cell attaches itself to another cell, it clears out all but the smallest molecules between them. Professor Davis explains:

“Our research demonstrates that any drugs targeting immune cells need to be very small. Antibody proteins, for example, are too big. They aren’t able to get into the gap between the cells – they’re even cleared away when cells meet. To make them more effective they must be smaller – which is something that GSK (GlaxoSmithKline) are working on.”

PhD student Adam Cartwright played a key role in the research, splitting his time between Professor’s Davis’s lab and GSK. He says:

“Being able to test out our theory with medicines that GSK has designed was fantastic.  The idea that something I found out can be used to develop treatments to help patients is incredibly exciting.”