Centre for Developmental and Biomedical Genetics
Centre profile from the MRC Network publication issued March/April 2008
Many labs are aspiring to convert the discoveries of research into medical benefits. The Centre for Developmental and Biomedical Genetics in Sheffield has been doing it for some time. Network visited the centre to uncover the recipe for ‘translational’ success.
Dr Tim Chico spends three days in his lab and two days in the clinic. In his lab, he studies the blood vessels of zebrafish and watches blood cells underneath transparent skin, trying to understand what affects their flow and testing drugs that change this. In the clinic he treats patients with atherosclerosis – a condition arising from blocked blood vessels and altered blood flow. Blocked vessels are the cause of most heart attacks and strokes.
Tim is not the only scientist at the Centre for Developmental and Biomedical Genetics (CDBG) in Sheffield who swings between the lab and the clinic. The centre houses a mixture of clinicians and basic scientists, all keen to collaborate and learn from each other. Turning discoveries about how the body works into new ways to treat and prevent disease is viewed as an essential part of the process. This is a fertile environment – as Professor Philip Ingham, Director of the centre, explained: “The exciting thing is the opportunity for clinician scientists to work side by side with developmental geneticists – these close interactions are helping us establish novel disease models which, in turn, have great potential for the discovery of new therapeutic agents.”
Early insights
The centre has been dynamic from its inception. Six years ago, the MRC received an application for a centre development grant from a small group of basic research scientists at the University of Sheffield, led by Philip. But this was a group with a difference. Fuelled by Philip’s vision and leadership, the researchers were hosting clinical researchers in their labs and had set up joint PhD studentships and collaborations between scientists working on all stages of the translational research spectrum.
Now, the centre boasts an annual income of more than £2 million and has grown its number of principal investigators to 24. Constant communication between its staff is key. “We enjoy having the clinicians around. And they like being able to understand model systems and how organ systems and organisms function normally,” said Professor Marysia Placzek, a basic scientist and Deputy Director of the centre.
Model centre
Scientists at the CDBG use animal models, such as zebrafish – a tropical fish from the minnow family – the fruit fly Drosophila and chicks to study normal and aberrant cellular mechanisms. These help to identify genes that underlie human disease – neurodegenerative, cardiovascular and musculoskeletal disease, as well as cancer – and can be used in drug discovery.
“Developmental genetic analysis of model organisms has revealed much about the genes that underlie our own development as well as the diseases that afflict us,” said Philip Ingham. His own landmark discoveries include the characterisation of a biological signal that acts as a key regulator of animal development and also underlies a number of human cancers. A major focus of Philip’s current research is understanding how this signal controls growth in the developing embryo, which may yield new leads for tumour therapies.
The scientists at the CBDG appreciate the importance of basic research, but are also very aware of what their work might lead to. Marysia Placzek’s lab, for example, uses chick embryos to study a part of the brain called the hypothalamus, which is thought in humans to be involved in regulating and maintaining normal functions, including behaviour.
Dr Vincent Cunliffe, one of the founding members of the centre, recruited from the biotechnology sector by Philip Ingham, researches genes associated with neurological disorders, such as Hereditary Spastic Paraplegia – an inherited disorder characterised by progressive weakness and stiffness of the legs – and Huntington’s disease. He looks at the zebrafish’s equivalent of the human genes that are thought to cause these conditions in order to unravel the underlying biology. He also examines the regulation of genes associated with cancer in the fish, and works with neurologists who have found the equivalent genes in humans that are responsible for prostate cancer.
In the bones
Another basic scientist, Dr Henry Roehl, investigates bone and cartilage conditions. This includes a cellular mechanism in zebrafish that is similar to a mechanism responsible for skeletal defects in humans. For example, he examines bone cells that cannot stack properly, which causes a human condition called Hereditary Multiple Exostoses, which affects one in 50,000 of the population and results in a short stature and tumours in cartilage. Henry hosts a clinician in his lab who is working on tooth development and runs a repository of bone samples in Leiden, the Netherlands.
Zebrafish are also the model for work in Dr Freek van Eeden’s lab, who is interested in Von Hippel-Lindau, a disease that involves the abnormal growth of blood vessels in some parts of the body, and affects one in 36,000 people. There is a mutation of a gene in zebrafish that is equivalent to the human version.
Immunolabelling of the zebrafish head 120 hours after fertilisation showing the skeleton in blue and muscle in red.
From pisces to person
Work on fish is directly relevant to consultant clinicians who see patients in the hospital. Professor Moira Whyte, the clinical co-Director of the centre, and Dr Steve Renshaw study inflammatory diseases, which are widespread and life-threatening with few available treatments. Steve explained: “The zebrafish has the same building blocks of the immune system as humans.”
These mechanisms can be manipulated genetically or with drugs in the fish, with the aim of eventually designing therapeutic drugs to treat the human conditions. In the clinic, Steve and Moira see patients with chronic obstructive pulmonary disease, asthma and other lung diseases, and their observations feed back into ideas for research that they carry out in the lab.
Similarly, Tim Chico’s observations in people give him ideas for his zebrafish work. Studies from his patients have highlighted the important role of inflammation in atherosclerosis and heart attacks. This has led the team to start looking at the interplay between inflammatory cells and the blood vessels in zebrafish to try to understand why inflammatory cells may be the basis for arterial disease.
A flying success
The fruit fly, also known as Drosophila, is another model used at the centre. Dr David Strutt focuses on fly eyes and their structure: “We are trying to understand what the genes do in Drosophila.”
Dr Alex Whitworth looks at the molecular mechanisms of Parkinson’s Disease and other neurological disorders.
There are genes that are directly linked to the health of nerve cells in the brain because they affect their acidity and ability to generate energy. These findings have been applied to models in other animals and screening for drugs is in progress.
Translation of research at the centre works because of the proximity between scientists and clinicians – the university medical school at the Royal Hallamshire Hospital is not far from the centre – as well as the vibrant attitude and support of everyone involved, including the Dean of the Medical School and the Vice-Chancellor of the University of Sheffield.
The centre plans to increase in size and have even more impact, an ambition reflected by the number of zebrafish it accommodates. There are tanks upon tanks of fish of varying genetic strains, all potential models to study or test drugs on. Currently, there are 55,000 fish in the aquarium, but with the addition of a further state-of-the-art aquarium, capacity will increase to 90,000. “We don’t intend to rest on our laurels,” said Marysia Placzek. “In the future we hope to target even more disease areas in our research. This will include training more PhD students whose work crosses the boundary of basic and clinical science.”