Meeting: Wyatt Yue: The genetics of metabolic diseases

University of Oxford: Wyatt Yue: The genetics of metabolic diseases
Nuffield Department of Medicine – Medical Sciences Division

Q: What is a metabolic disease?

Wyatt Yue: In the human body there are many chemical reactions taking place in order to degrade the unwanted toxic materials in the cell, and also to generate the essential compounds and materials necessary for normal function. A metabolic disorder is one in which a particular chemical reaction step is defective. It is a little bit like a factory production assembling line, where a particular assembling step is missing its worker. This leads to the build-up of the unwanted toxic material before the assembling step, and also the lack of the product materials after that assembling step. In the human body these workers are known as enzymes.

Q: What causes this kind of metabolic disease?

WY:The majority of these metabolic disorders are genetic conditions. This means that the molecular cause of the disease is a mutation in the gene responsible for the enzyme or responsible for the chemical reaction. The mutations are usually inherited in autosomal recessive manner, meaning that the patient will inherit a defective copy of the gene from the mother and a defective copy of the gene from the father.

Q: How can we treat this type of genetic metabolic disorder?

WY:There are currently very few therapeutic options available for these disorders. Current mainstay of treatment is the management of symptoms in the patient, the restriction of dietary intake of certain food ingredients, and also the supplementation of nutrients and certain detoxifying agents in the diet. In some diseases organ transplantation is possible. Clearly there is a lack of small molecule drugs available for these metabolic disorders which are an area of my interest.

Q: What are the most important lines of research which have emerged in this area in the past 5-10 years?

WY:The past decade has seen some technological advances in three aspects which have implications in the diagnosis and treatment of the metabolic disorders. The first is the use of next generation sequencing technology to specifically identify and pin point the mutation on the gene. The second is the use of mass spectrometry methods for detection in new-born screening programmes; these are nationwide programmes to identify infants that have the metabolic disorders. The third are some novel discovery in new approaches to treat disorders, for example by replacing the gene that is defective and also replacing the defective enzyme.

Q: Why does your line of research matter & why should we fund it?

WY: My research focuses on the root cause of these disorders, which are the defective enzymes. Enzymes are proteins and we believe that understanding the 3D shapes and the properties of these proteins is the essential first step in understanding the molecular reasons of the defect, and also to design new small molecule drugs for the treatment of these disorders. My line of research is important because of two reasons. The first is that there are unanswered questions. While there are hundreds of known metabolic disorders, new ones are continually identified, many of which are poorly understood at the moment. The second reason is that there is a substantial need. While metabolic disorders are rare individually, collectively they affect 1-3% of the world population; 1 in 1000 infants are known to inherit a metabolic disorder, which therefore creates a health burden in society.

Q: How does your research fit within translational medicine in the department?

WY: My research adopts a transitional approach: I collaborate substantially with clinicians and geneticists who are at the forefront of identifying the mutations and the diseases. I collaborate with the drug developers and the pharmaceutical industry to find new ways of designing small molecule drugs. I also collaborate with patient groups to disseminate our experimental data and to answer any questions they may have on the scientific aspects of the diseases. The objective is to create a platform, where our basic scientific understanding in the bench can be brought closer to the clinic and onwards to the patients.