How Cambridge scientists are exploring the incredible transport system inside our cells
Tiny machines are at work inside us, carrying important cargo, as Simon Bullock of the MRC Laboratory of Molecular Biology explains
Our cells may be tiny but they are a hive of activity.
Simon Bullock, at the MRC Laboratory of Molecular Biology in Cambridge, is studying what is going on within them.
“The department I work in, the cell biology division, is trying to understand how cells and tissues are organised, and there is also a strong interest in how those processes go wrong in human disease,” he says.
“My research team works on how components are transported within cells by tiny machines called motor proteins. These proteins can walk along tracks within the cell, dragging associated cargo as they go,” Simon explains.
“It’s the cellular equivalent of a railway system, sorting different components to the right places at the right times. This transport process operates in all cells but is particularly important in our nerve cells. That’s because these cells, called neurons, stretch over long distances and consequently rely on a very efficient haulage system within them.”
The components being transported are many and various but Simon’s team have dedicated most of their time to exploring the sorting of ribonucleic acid molecules. These ‘RNAs’ convey the genetic code in our DNA to another type of machine that reads the code and produces specific proteins from it.
“We’ve really focused on understanding how these RNAs are targeted to different regions of the cell by motor proteins because that dictates where a protein is made and functions,” says Simon.
“But the transport system we are studying is important for many other processes in cells. For example, different compartments of the cell need to exchange materials, and this is often done by small membrane-bound structures called vesicles. These vesicles are also moved through the cell by motor proteins.”
Moving components around cells by motor proteins, which can take up to 100 steps per second along the track, is much more efficient than having them float around the inside of our cells until they reach their destination.
“Each cell has a structure which we call the cytoskeleton,” says Simon. “It’s made up of different types of filaments. As well as providing structural support for the cell, the filaments are used as tracks for the motors.”
There are different types of tracks in our cellular railway system – some are the equivalent of an inter-city route while others are more akin to a local branch line.
“Microtubules are one of the types of tracks. They are used for most long-distance transport in animal cells.
“The other kind of track is actin, which is very important in cells for a number of processes. In terms of transport, actin is mostly used for short-distance delivery after cargo has left the microtubules,” explains Simon.
The microtubules are hollow tubes, and the motor proteins move along the outside of them.
“Some of the motors step in a hand-over-hand fashion, moving in a straight path along one part of the tube. Others appear to have a more chaotic walk, which might allow them to move around obstacles in their path,” Simon adds.
While this transport system is essential for normal cell functioning, unfortunately for us it can also be used by some very unpleasant hitchhikers.
“We know that the motor proteins in our cells are not just important for trafficking our own cellular components, they are also hijacked by viruses like HIV, rabies and herpes. The viruses have evolved a way to stick to the motors, because this helps them get to where they need to be in the cell, for instance to replicate,” says Simon.
“One potential long-term benefit of research on motor proteins is that we might have a better understanding of how to block the viral proteins binding to them and thus combat infection.
“Viruses can evolve very quickly to prevent a drug binding but this is less of an issue when the virus must preserve the target site in order to interact with a motor in the cell.”
Work on motors might also shed light on what goes wrong in neurodegenerative diseases.
“One of the earliest things that appears to go wrong in neurodegenerative diseases is transport of cargo along microtubules. It has been speculated that stimulating the transport process could alleviate some of the problems associated with neurodegeneration,” says Simon.
“However, we are really at the early stages of trying to understand the basic biology of how transport processes work, and translating the results into medicines will be challenging and take a long time.”
Simon’s team use a range of techniques to study the basic biology of transport processes. One line of research involves fruit flies, which can have their genes changed very quickly and easily.
“We have been doing a lot of imaging of the cells of fruit flies,” says Simon. “Part of that has involved labelling cargoes to make them fluorescent, which includes using a protein initially identified in jellyfish by other researchers. We fuse the fluorescent protein to the cargo and then we can use our microscopes to watch it being moved by motors with the cell.”
Simon’s colleagues at the MRC Laboratory of Molecular Biology have also made use of the institute’s £5million cryo-electron microscopes to help them put together the first complete 3D model of one of these tiny motors, known as dynein.
This family of motor proteins move along microtubules to transport cargoes, including proteins and RNAs, to different parts of our cells.
Dynein is also known to be involved with many diseases, including viral infections.
Andrew Carter’s group in the LMB’s structural studies division collaborated with Alexander Bird’s group at the Max Planck Institute in Dortmund on the work.
On its own, dynein does not move for long distances – it acts like a train with its brakes on. But once bound to a protein complex called dynactin and proteins on the cargo, it forms a formidable transport machine capable of taking thousands of steps without stopping. Disrupting this process can cause defects in the formation of the brain, leading to learning disabilities or certain forms of epilepsy. The work by Andrew and his colleagues shows how dynein is held in an inactive state and how it is triggered to move only after the cargo is loaded.
Research at the taxpayer-funded Medical Research Council facility is driven by a remit to improve our understanding of human biology – and the lab, which last month attracted 2,000 people to an open day at its Cambridge Biomedical Campus home, has an incredible 10 Nobel Prizes to its name.
“A lot of major scientific discoveries have been driven by curiosity,” observes Simon. “People often didn’t set out to make a specific discovery but they followed their interests. They saw something unexpected and that led to a completely new line of research. Curiosity-driven research continues to be really important.”
Nonetheless, the benefits of translating this research into treatments through collaborating with pharmaceutical companies are clear. With AstraZeneca building its global HQ and R&D facility over the road from the LMB, the opportunities for collaboration will only increase. LMB and AstraZeneca have already been collaborating closely on some projects, as the Cambridge Independent has reported.
“I think having AstraZeneca as our neighbours will be fantastic,” says Simon. “The expertise at AstraZeneca and LMB are highly complementary and there is lots of room for synergy.”
Bringing microscopic life into our schools to inspire pupils
Simon Bullock was drawn into biology as a teenager by what he observed when he peered down a microscope.
“Rather than learning details of how biochemical reactions work, it was seeing a water flea’s heartbeat that really got me hooked. And I still love looking down a microscope in my work,” he says.
Simon and colleagues at the MRC Laboratory of Molecular Biology have developed a project that aims to offer younger children the opportunity to be amazed by life at a microscopic level.
Microscopes4Schools is a hands-on science outreach activity for primary school children, now led by Mathias Pasche and delivered by volunteer scientists from the LMB.
They visit local schools to provide a short interactive talk about cells and microscopy, which is followed by a practical hands-on session where pupils can use high-quality educational microscopes to look at different biological samples such as banana cells, water fleas and even their own cheek cells.
“It’s about giving children an experience that could spark an interest in science,” said Simon.
A basic microscope can cost £40, while a higher-quality one will set you back about £300. Budgetary pressures mean that many pupils don’t otherwise get to use a microscope until they are in secondary school or sixth-form – although parents can inspire their children if they have a microscope at home.
“Things that are moving are great for children,” said Simon. “In summer you can get some pond water and see a lot of life. You can also look at bacteria in yoghurt, or pond weed from an aquarium.”
You can find out more about Microscopes4Schools and find valuable resources on experiments on the Microscopes4Schools website.