Interview: Heartfelt genetics

Melissa Trudinger meets Richard Harvey, the recipient of the 2005 Julian Wells Medal.

Each year at Lorne Genome, the Julian Wells Medal is given every year to an Australian scientist who has made an outstanding contribution to the understanding of gene action, genome organisation or genomic evolution, has a special link to the scientist commemorated by the medal.

This year's recipient, Prof Richard Harvey, deputy director and head of the developmental biology program at the Victor Chang Cardiac Research Institute, completed both his honours and PhD with Wells at the University of Adelaide during the period when genetic engineering and the issues surrounding it were being hotly debated by scientists in Australia and abroad. "My training in molecular biology was a very formative period in my life," Harvey says.

These days Harvey is still using molecular biology, applying it to gain a better understanding of how the mammalian heart develops in an embryo and foetus. The research got a kick-start 10 years ago with the discovery of a mammalian homologue -- Nkx2-5 -- of the Drosophila tinman gene, a member of the homeobox family of genes that, in Drosophila, was involved in the development of the insect's heart-like structure.

The discovery surprised embryologists, who had believed that there was no evolutionary comparison between invertebrate and vertebrate heart development. "The discovery of very close homologues of tinman in the mouse told us there was a cardiac program that was conserved in evolution," Harvey says. "It's probably likely that it's a very ancient program that specifies cardiac muscle type, not morphology."

Harvey's lab has built on that initial finding using genetic manipulation techniques such as transgenic gene expression and gene knockouts to precisely study gene function. The research is aimed at identifying the origins of the mammalian heart and understanding the processes used in its development. Eventually, Harvey hopes that insights into congenital heart disease -- which affects around one in 100 live human births -- will result from the research.

A key aspect in Harvey's research is its role in redefining our understanding of the heart's development. Traditional dogma says the heart is initially formed as segments that then develop into the four chambers, but a shift in thinking has led to the view that the chambers, rather than forming as discrete entities, form through regional specialisation of a cardiac muscle type by a separate patterning process.

Using genetic markers, the expression of genes can be followed in the developing heart and researchers can use the patterns of gene expression to intuit what processes are going on, Harvey says. "The gene expression is regional not segmental -- the regions are specified by specific processes. The developmental processes are laying down a pattern that is then embellished by differentiation and growth," he says.

One of the early decisions made during the patterning process is which regions will go on to form chambers such as the left and right ventricles, and which will form the non-chamber tissue, such as the valves and the electrical systems that keep the heart beating. "It's a binary decision that needs to be made early on -- the early embryo has a very simple tube, but by birth it's a very complicated organ," Harvey says. "And unlike many other organs, morphological development has to occur side by side with function. The function actually participates intimately in the generation of form."

Harvey says that while cardiac embryologists have come a long way in understanding the morphology and the genes involved in cardiac development, there are many challenges ahead. "Our understanding of congenital heart disease is only just beginning," he says. "We're trying to establish the importance of particular genes involved in congenital heart disease."

Most of the genes identified as playing a role in congenital heart disease to date have been mutations of transcription factors such as Nkx2-5, underpinning the central role these genes have in the developing heart. But it will be harder to identify genes that play a role in heart defects with polygenic causes, or combinations of genes that may interact with the environment during development to cause problems. "To get a molecular or genetic understanding of those processes will be very difficult," Harvey says. "Any minor genetic or epigenetic difference can have a significant effect on the outcome."

Adding a layer of complication is the fact that babies born with congenital heart disease are survivors -- more severe defects don't survive to birth, and probably don't survive in utero for very long at all. And minor abnormalities in form can end up being major problems due to the function-form relationship, which can compound the error into a serious abnormality by the time the heart is fully developed.

It's all leading to the development of techniques for early identification of problems in utero, and eventually even to interventions in the foetus to fix problems before they get worse. It's a big issue for cardiac scientists, Harvey says, and fraught with controversy and taboos. "There is a tenuous relationship between the basic biology in the lab and congenital heart disease in the clinic," he says. But on the bright side, many of the clinical techniques used to study heart function in patients are being miniaturised and adapted to use in the laboratory to study heart development and function in embryonic and adult mice.

"We're now developing tools to study cardiac function in mice, even though they are a fraction of the size of human hearts and beat 600 times a minute instead of 60 times," Harvey says. "The tools are becoming very useful from a developmental perspective as well -- we can use them to study our animal models."