In most living organisms, the ubiquitin-proteasome system is responsible for the degradation of proteins, either because they’re damaged or they reach the end of their life span. Ubiquitin marks a protein for elimination. Alterations in this process are responsible for many human diseases. Professor Benedikt Kessler studies the role of deubiquitylating enzymes that remove ubiquitin from substrate proteins.
Biomarkers are molecular features that give us clues about underlying biological processes. They are typically used to monitoring a disease or predicting the outcome of a treatment. Modern analytical equipment allows us to measure thousands of molecules at the same time. This technology will accelerate the discovery of more accurate biomarkers, with the aim to improve medical diagnosis and treatment.
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.
Q: What is a biomarker?
BK: A biomarker is a molecular feature, or an indicator that gives us clues about the biological process typically for monitoring a disease or disease progression. That can consist of proteins, peptides, lipids, metabolites we can measure. A biomarker could also be, to give you an example, things like your hair starting to become thin and to fall out as you age, or blood pressure. But I think in the more biomedical terms these are molecules that we can precisely measure and that can give us clues about the underlying biological process.
Q: What are the most important lines of research that have developed in the past five or ten years?
BK: In the area of biomedical research and biomarkers I would say that the technical advances in analytical equipment may have provoked a huge boost. In other words, technical equipment that allows us to measure molecule features, biomarkers, much more precisely, in a much more sensitive way and also quantitative.
Q: How can proteomics help us find new biomarkers?
BK: Like in the genomics area where the analytical equipment was able to allow us to sequence the human genome, in proteomics we use a different kind of analytical equipment to look at the products of what the genome encodes, which are basically the building blocks that living organisms are made of. These are mostly proteins and peptides, and one of these techniques to measure these is based on mass spectrometry, so we measure the masses of these proteins and peptides and the information about the mass can give us clues about the identity of these proteins, and what happens to them, and also how much is actually there. This technique has turned out to be very powerful in the many areas of biomedical sciences because we can measure not just one molecule, we can measure hundreds and thousands at the same time so we get a much broader picture of what is actually happening in the sample that we analyze. So we can then do comparisons, for example we can take blood from a normal individual or from a diseased individual, a person with cancer or a person with a neurodegenerative disease. We can provide molecular profiles and any differences that we observe we can then zoom in and identify what these molecular features, or potential biomarkers are, and they can give us clues what is actually wrong with the person.
Q: Which diseases would be the best targets?
BK: The application of proteomics to find new biomarkers is now widely used in practically all diseases that are known because it is a very powerful entry point to really find out where the differences could lie on a molecular level. In particular it has been successful in areas of infectious diseases: HIV, herpes simplex virus infection, and also the hepatitis virus. To give you an example in our case we were able to use that technology to measure and identify the very earliest response that people develop when they become HIV infected. This happens within the first few days of infection where so far we thought we couldn't detect anything. Some of these molecular components that we have identified may become useful biomarkers for infectious diseases in general. However the area that could benefit most from this biomarker research is probably cancer because cancer takes a long time to develop, and it would be very useful to obtain biomarkers at a very early stage, so to detect people who develop cancer in a very early stage, because the earlier you can detect a person with a cancer the higher the likelihood that you can then treat the person and the person will then be cured.
Q: Why does your line of research matter? Why should we put money into it?
BK: Proteomics, as I said before, has turned out to be extremely powerful and informative in areas of basic biomedical research because we have learned a lot about molecular details of biological processes, particularly in diseases. If you know exactly what goes wrong you may be able to define or develop a drug that can stop that process. Biomarkers could be very useful for doctors to make decisions on how to treat patients. If a biomarker can be developed that can tell you 'yes this patient will respond to this kind of therapy', you can reduce the costs because you don't have to try it out , you don't waste time or energy on treating someone who will not respond at all, and you also reduce side effects.
Q: How does your research fit into translational medicine within the department?
BK: I think to illustrate that I would like to give you an example. One of our interests is to study how proteins are turned over. It's a little bit like in your house when your garbage builds up; if you don't put it out and you just keep it inside your house, at some point it is going to be unbearable to live in there. Like in this situation, the cells have to get rid of their molecular garbage, the proteins that are accumulating. There is a particular system which is present in each cell, in most living organisms, in humans in particular, which is called ubiquitin proteasome system that does this in a normal case. There are situations where that system doesn't work well, and proteins accumulate and form aggregates. That is very often the underlying cause for neurodegenerative diseases like Alzheimer's and Parkinson's, where these protein aggregates can lead to cell death of neurons, and then problems with the brain. What we have done in the lab is develop small molecular inhibitors to block this system, to be able to study what happens when you interfere with this molecular disposal system in each cell. It turns out that the inhibitors that we worked with were precursors for a drug that was developed called Velcade™ that turned out to be very effective in treating patients with multiple myeloma, which is a blood cancer. It turns out that cancer cells in general are more susceptible to these types of inhibitors because they grow faster, they proliferate faster, and they also produce more garbage. If you stop the garbage disposal system or interfere with it, these cells are then more susceptible to die. So that turned out to be a real therapy that was evolved for these types of cancer patients.