MRC National Institute for Medical Research, London
Science for Health
2010 meeting - Understanding the heart in health and disease
Research on heart disease is a vast worldwide enterprise that aims to identify the origins of disease and to find better methods for diagnosis and treatment. This requires enormous resources focussed on genetics, potential targets for drugs, and imaging techniques. However, heart disease is a complex phenomenon that requires a profound understanding of the developmental origins of the heart to fully appreciate the significance of disease states. Heart disease is caused by a combination of mysterious genetic deficits, cumulative damage to the heart sustained during life activities and possibly the malign effects of the ageing process.
At NIMR our strategy has been to explore the development of the heart using novel technology and to use this to improve our understanding of diseased hearts. Our clinician-scientist colleague Ross Breckinridge bridges the gap between the fundamentals of developmental biology and the reality of the clinic.
Identifying the cause of heart malfunctions - Dr Tim Mohun
By the time a child is born the heart is already fully formed. Thereafter, cell renewal by division is very rare and many cells present at birth will not divide again, although they continue to expand after birth. Heart cells connect with their neighbours through very strong junctions that are also conductors of the electrical impulses that make muscle cells contract in unison. The vertebrate heart forms early in the life of an embryo from a simple tube that is transformed into a multi-chambered organ, with valves, blood vessels and a conduction system to drive the heart beat.
As developmental biologists, our strategy is to find out which genes are important in embryonic heart formation and to determine their precise function. This has been a productive line of enquiry as genes that direct heart formation are also important to the normal and diseased adult hearts. New sophisticated high resolution imaging methods have enabled us to take this analysis further. We also use it to study the cardiac defects associated with Down syndrome, a disorder that occurs in humans born with an extra copy of chromosome 21. Almost 50% of children with Down syndrome have a congenital heart defect in which the atria and ventricles are joined so that venous blood mixes with re-oxygenated blood from the lungs, almost certainly because of an imbalance in the contribution of a critical gene. A way to investigate this phenomenon further became available when colleagues at the Institute of Neurology constructed a transgenic mouse containing the human chromosome 21 in which most of the characteristic features of Down syndrome were present.
Why should a cardiologist care about developmental biology? - Dr Ross Breckenridge
Malfunctions of the heart and the vascular system are the most common cause of death and ill health amongst the elderly and a major cause of premature death and disability. Most forms of heart disease remain incurable. Efforts to manage heart disease range from heroic surgery (such as transplants and coronary bypass operations) and the use of drugs that treat symptoms without resolving the fundamental problem.
Progress in understanding the development of the heart is helping clinicians to interpret more complicated forms of heart disease and to contemplate novel regenerative therapies. Genes that co-ordinate development of the fetal heart are being identified and mutations in some of them clearly underlie certain kinds of inherited heart disease. This information can be used to identify family members at risk of developing heart disease before symptoms commence so that appropriate advice can be given. The profession hopes this information can be used in conjunction with stem cell therapies to develop definitive treatments of some types of heart disease in the future.
A particularly interesting collaboration is emerging between clinicians and developmental biologists in understanding the dramatic events affecting heart development during the birth of a baby. The baby emerges from a relatively oxygen-poor regime to an oxygen-abundant environment that precipitates an abrupt reorganisation of heart blood vessels that allows the neonate to use its lungs for the first time. This coincides with interesting changes in energy metabolism and the conduction system of the heart.
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