Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Misfolded proteins can either create the loss of a cellular function, or escape degradation, causing aggregation diseases. Better knowledge of these mechanisms helps us understand the root cause of different kind of diseases, and also develop targets for therapeutic intervention.

Q: Why is it important for the body to clean up proteins?

John Christianson: Proteins are the machinery of the body, and like any machine, it is important that it functions correctly. This usually happens in the cells, and the cells are pretty good at making the proper architecture and structure. But occasionally, under certain conditions and if you have any changes in the genome, those proteins are not made correctly. When they are not made correctly, the cell has a problem and has to get rid of them.

Q: What part of this process does your research focus on?

JC: My lab works on the degradation mechanisms: how those misfolded proteins are recognised as misfolded and differentiated from those that are correctly folded, and then how that misfolded protein is targeted for degradation and proteolysis within the cell.

Q: What kind of things can happen when this process goes wrong?

JC: Misfolded proteins are bad for the cells. Misfolding can cause one of two things: if the misfolded protein is made incorrectly and destroyed, then we end up with a loss of function. An important gene that the cell needs to survive is then lost, and the cell dies or malfunctions.

A common example is the gene responsible for the disease cystic fibrosis. This is a protein that has a single point mutation that causes that protein to not be made at the level it should be made. When this protein is not made, we end up with a physiological manifestation that is the cause of the disease.

The other issue that may happen when a protein misfolds is that it is not recognised for degradation when it should be and these are commonly called protein aggregation diseases. These are at the heart of neurodegenerative diseases such as Alzheimer's and Huntington's disease.

Q: What are the most important lines of research that have emerged in the last 5-10 years?

JC: One of the things that we are starting to appreciate is the diversity of regulations that goes on in overseeing protein misfolding - what we like to call quality control. There are large gene families within the cell that generate proteins that are responsible for overseeing the integrity or the fidelity of the proteome. A real advance over the last 5-10 years is an appreciation for the diversity of how this system works.

The other very interesting aspect is the idea that you can use degradation as a potential target for therapeutics. One of the best examples is the drug Bortezomib or Velcade® which has been used to target multiple myeloma and certain other haematological malignancies. These small molecules work by inhibiting the degradation process, which leads to an increase in the level of cellular stress to the point where the cells are no longer able to function. In a normal cell that would be bad but in a cancer cell this is what we want to do: we want to kill that cancer cell, and this is a specific way to target those particular cancer cells.

Q: Why does this line of research matter and why should we put money in to it?

JC: From my perspective, we work on basic molecular mechanisms trying to understand the root cause of cellular functions which underlie many different kinds of disease. We are working to try to delineate the components that are responsible for maintaining, in our case, quality control or fidelity of the proteome. We look at these processes in normal cells and also when this process malfunctions, as a way to identify components that may be suitable for therapeutic interventions.

Q: How does your research fit in to translational medicine within the department?
JC: The department has a broad range of interests and my lab works particularly at the basic level. We are interested in trying to understand molecular components and identifying those that are important in this process. The long term goal with collaborators and colleagues within the department is to develop targets and assays that may be suitable for development of therapeutic interventions in the form of small molecules.

John Christianson

Dr John Christianson's research focusses on ER-associated degradation, which is responsible for clearing non-functional and orphan translation products. These processes play a central role in inherited diseases such a cystic fibrosis and various forms of cancer. Dr Christianson's long term goal is to identify novel points of interventions for cancer therapies.

More podcasts related to Cancer

Raghib Ali: INDOX Cancer Research Network

INDOX is a collaboration between Oxford and twelve leading cancer centres in India. It aims to develop effective and affordable cancer treatments in low and middle income countries, to improve the early detection of cancer, and to reduce the incidence of cancer by establishing the population specific risk factors.

Vincenzo Cerundolo: Cancer immunology

The development of therapeutic vaccines is more challenging. Current lines of research include the development of antibodies blocking inhibitory T cell signals, and the characterisation of adjuvants.

David Jackson: The Lymphatic System in Immunity and Cancer

Our lymphatic system protects us against pathogens: it collects micro-organisms and carries them to the lymph nodes where they will meet and activate T cells and B cells. Cancer cells also migrate to the lymph nodes, but instead of activating the immune system they actually suppress it. A better understanding of these mechanisms might help us better control the spread of tumours, and also block unwanted immune responses in autoimmune diseases, block tissue rejection and make vaccines more effective.

Tim Key: Role of Lifestyle and Diet in Cancer

We know that although smoking is still the most important cause of cancer, obesity and high intakes of alcohol increase the risk for several types of cancer. The role of diet in the development of cancer is much less clear, but there is a lot of evidence suggesting that diet does matter.

Patrick Pollard: Cancer Metabolism

Dr Pollard’s work is focused on a form of kidney cancer for which no effective therapy exists once it metastasizes. By integrating analyses of these cancer cells and novel models he hopes to provide insights into altered cancer metabolism and a real, innovative route into the design of therapies for various cancers.

Catherine Green: DNA replication and Cancer

The process of DNA replication is complex, and mistakes can lead to genome instability. Surveillance systems are not always successful which results in mutations that have the potential to inactivate genes or change their activity. This can lead to cancer, and many chemotherapeutic drugs are designed to disrupt DNA replication. A better understanding of these mechanisms can help us develop new drugs with reduced side effects.

Skirmantas Kriaucionis: Epigenetic modifications and cancer

Although all cells in our body have the same genome, they look different and perform different functions. Epigenetic modifications such as methylations ensure which sets of genes are expressed in specific cells and how this specificity is inherited. Cancer cells show particular epigenetic abnormalities which can be targeted for cancer therapies.

Ross Chapman: Repairing DNA damage

Whilst controlled DNA breaks allow for our vast repertoire of antibodies, DNA damage happening out of context can lead to cancer or predisposition to cancer. Recent developments in personalised medicine exploit the DNA repair weaknesses of cancer cells to selectively kill them. A better understanding of the underlying mechanisms can help develop innovative and targeted therapies.

Robert Gilbert: Targeting cancer mechanisms

Switching mechanisms within our cells are in part responsible for their development. MicroRNAs control a whole set of proteins associated with stem cell biology, particularly cancer stem cells. Targeting these components raises the potential for new anti-cancer therapeutics, which work by switching off protein production rather than inhibiting them later.

Colin Goding: Melanoma

Melanoma or skin cancer is one of the fastest rising cancer types. When identified early, melanoma is relatively easy to cure, but once it starts to metastasise, it becomes very difficult to treat. Treatments rapidely induce drug resistance. However, recent research has shown that within a tumour, it is possible to change drug resistant cells to drug sensitive cells, opening possibilities for new therapies.

Translational Medicine

From Bench to Bedside

Ultimately, medical research must translate into improved treatments for patients. At the Nuffield Department of Medicine, our researchers collaborate to develop better health care, improved quality of life, and enhanced preventative measures for all patients. Our findings in the laboratory are translated into changes in clinical practice, from bench to bedside.