Growth hormones and cytokines regulate the key physiological processes of growth and differentiation as well as responses to injury and infection. However, inappropriate growth signals can drive human cancer, while excessive cytokine responses underlie autoimmune and inflammatory diseases such as rheumatoid arthritis, diabetes and asthma. Dr Alex Bullock is interested in how these signals are regulated inside the cells.
Growth factors and signals are fundamental to many diseases. A single point mutation in the DNA coding for a bone morphogenetic protein is responsible for the development of FOP, a very debilitating disease where muscles are progressively turned into bones. Understanding these mechanisms allowed the selection of a drug, currently used to treat cancer, that may possibly be repurposed to treat FOP.
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: Why is it important to understand growth signals in cells?
Alex Bullock: Growth signals are fundamental to many disease processes like cancer. Growth factors have to be carefully controlled so that our body develops in a unique pattern. Too much growth factor signalling can cause developmental tumours or developmental disease. Perhaps the best known growth hormone is Human Growth Hormone which is used by athletes to gain competitive advantage. But too much hormones and too much growth factors are not always a good thing.
We are particularly interested in bone morphogenetic protein hormones that control bone development and stem cell differentiation. Now we are very interested in one particular disease called FOP or Fibrodysplasia ossificans progressiva which results from too much signalling in that pathway.
This causes the breakdown of muscle and infiltration of stem cells, and then the differentiation of these stem cells into bone. What happens is that from early childhood, patients get slowly paralysed by bone formation in their muscles and they lose most of their movement. It is very debilitating and a paralysis-causing disease, and we are trying to understand the causes of the disease and to develop new treatments to counter that disease.
Q: How does your group look at this kind of problem?
AB: We take a multi-disciplinary approach. One of the major focuses is to learn more about the 3D structures of the proteins, the molecular machines in our body that are doing the work for us. We use these structures to identify various properties about the protein. We would like to learn, for example, how a disease modifies these proteins, how mutations in the proteins change their structure and activity.
We also like to use whatever activity assays we can, so we can build a correlation between the structure of the protein and its function, and so we can look at binding assays for various partners that cooperate and work with the protein and signalling, and also the interaction with drug molecules that might be useful in fighting disease.
Q: What kind of techniques do you use?
AB: 3D structures of proteins are not visible to the naked eye so we have to use another technique. The technique we use is called X-Ray crystallography. Basically this involves shining really powerful X-rays at protein crystals: just from the way X-rays scatter off the protein, we can back-calculate the original structure of the protein that scattered the X-rays, with clever mathematical modelling.
On top of that we use a barrage of techniques to delve into the protein activity in more detail: the structure just gives us a more static picture and what we want to do is know a bit more about its function and activity. For that we can use a range of binding assays like fluorescence, binding assays where the signal changes upon binding, or we can use luminescence. We can also use those techniques for our drug screening assays as well.
Q: What are the most important lines of research that have emerged in the last 5-10 years?
AB: Most fundamental to us has been the human genome project and the long awaited era of genomic medicine. The human genome is the code book for life and our tool for understanding all the disease processes and normal development. What we do on a daily basis is read parts of that code and try to interpret them in terms of understanding what that code is doing and how it has gone wrong.
For example, in the FOP disease that we study, we know that there is a single point mutation (just one letter in the DNA code is changed) and that is sufficient to cause unwanted bone formation in muscle. Now that we know that we have that point mutation we can say: what is that doing to the protein involved in FOP, how has it changed its activity, and can we find drug molecules that can block that change in activity.
Q: Why does your line of research matter and why should we fund it?
AB: FOP is just one of 7,000 rare diseases, and these affect almost 10% of the population in total, even though individually they are rare diseases. There is a great unmet medical need: possibly only a handful of these diseases have at the moment any form of medicine that can help mitigate the symptoms. So there is a huge medical need to counter that.
We would like to translate into other diseases what we have done for FOP. We have a five year programme funded by the Wellcome Trust to support early investigations that could feed into drug discovery programmes, particularly in cancers, metabolic diseases and neuro psychiatric diseases.
Q: How does your line of work fit into translational medicine within the department?
AB: Our most advanced study has been on FOP. For that, we have identified an investigational drug that is currently being used to treat several thousand humans. We would like to take that drug which has mainly been trialled for cancer and repurpose it into a clinical trial study for FOP. Ultimately, we would like to take that approach, what we have learned about developing small molecules for FOP, and try to expand that to other conditions related to FOP. What we would like to do is take basic research, understand the mechanisms and the drug binding characteristics of proteins in disease, and then translate that into drug discovery programmes across the country and into clinical trials.