Personalising treatments for genetic diseases

Project Details

Inherited genetic diseases, while rare on their own, have significant health consequences, affecting 1 in 100 births. While the same genetic disease can result from many different mutations on the same gene, the nature of these mutations can dramatically affect patient symptoms and the efficacy of available treatment options. High-throughput sequencing and proteomics approaches now mean that tens of thousands of positional variations within genes or proteins can be identified in a single experiment. The vast majority of such variations are patient specific and require advanced methods to identify those that are important for disease or biological mechanism. Our aim is to be able to, for each mutation/modification and for each gene/protein, scalably and effectively assess the overall consequences of the molecular effects and their potential phenotypic outcomes.

We have developed a range of computational tools to deconvolute the molecular mechanisms of a mutation giving rise to different phenotypes. In collaboration with clinical partners we have shown that even though patients may present the same disease, they may arise from many different mutations that alter a patient’s outcome or how they may respond to a particular treatment. By analysing these mutations and predicting their effects on protein structure and function we are trying to revolutionise treatment strategies, an important step towards personalised medicine.

We are now integrating these predictions into a single computational pipeline to allow the rapid investigation of consequences of genetic mutations on protein structure and function at the molecular level, developing a framework for understanding the mechanism of diseases. In collaboration with clinicians, this is already being used to classify patients, and help guide their treatment. We are also using this information to guide the identification of mutation specific therapies- potential therapies that can reverse these molecular effects. This will ultimately lead to the development of improved and novel personalised treatments for both hereditary genetic diseases and cancer.


Dr Douglas Pires (Fiocruz-Minas)

Carlos Henrique Miranda Rodrigues, Masters Student (UFMG / CPqRR, Brazil), CNPq, co-supervised with Douglas Pires


Professor Eamonn Maher, University of Cambridge

Dr Andrea Zatkova, Slovak Academy of Sciences

Professor Lakshminarayan Ranganath, University of Liverpool

Professor Sergio Penna, UFMG, Brazil

Dr Lisa Kaminskas, University of Queensland

Dr Ottavia Spiga, Università degli Studi Siena


Jack Brockhoff Foundation Grant: “Understanding the Molecular Mechanisms of Complex Mutations”.

Research Opportunities

This research project is available to PhD students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.

Research Publications

  1. Pires DEV, Chen J, Blundell TL, Ascher DB.  In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity. Scientific Reports 2016; 6: 19848.
  2. Jubb HC, Pandurangan A, Turner MA, Ochoa-Montaño B, Blundell TL, Ascher DB. Mutations at protein-protein interfaces: Small changes over big surfaces have large impacts on human health. Progress in Biophysics and Molecular Biology 2016; In Press.
  3. Nemethova M, Radvanszky J, Kadasi L, Ascher DB, Pires DEV, Blundell TL, Porfirio B, Manoni A, Santucci A, Milucci L, Sestini S, Biolcati G, Sorge F, Aurizi C, Aquaron R, Alsbou M, Lourenço CM, Ramadevi K, Ranganath LR, Gallagher JA, Kan V, Hall AK, Junestrand C, Sireau N, Ayoob H, Timmis OG, Quan Sang K, Genovese F, Imrich R, Rovensky J, Zatkova A.  Twelve novel HGD gene variants identified in 99 alkaptonuria patients: focus on 'black bone disease' in Italy. European Journal of Human Genetics 2016; 24(1): 66-72.
  4. Jafri M, Wake NC, Ascher DB, Pires DEV, Gentle D, Morris MR, Rattenberry E, Simpson MA, Trembath RC, Weber A, Woodward ER, Donaldson A, Blundell TL, Latif F, Maher ER.  Germline Mutations in the CDKN2B tumor suppressor gene predispose to renal cell carcinoma. Cancer Discovery 2015); 5(7): 723-729.
  5. Usher JL, Ascher DB, Pires DEV, Milan AM, Blundell TL, Ranganath LR. Analysis of HGD gene mutations in patients with Alkaptonuria from the United Kingdom: Identification of novel mutations. Journal of Inherited Metabolic Disease 2015; 24: 3-11.

Research Group

Ascher laboratory: Structural biology and bioinformatics

Faculty Research Themes


School Research Themes

Cancer, Molecular Mechanisms of Disease, Therapeutics & Translation

Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Biochemistry and Molecular Biology