Major Research Papers

A major paper that dissects how an inherited abnormality in a protein in the nucleus of heart muscle cells causes dilatation of the heart leading to heart failure.

Demonstrates for the first time that a human disease can be caused not by a structural defect in one of our genes but a defect in its functioning.

A major review of a large family of enzymes that have multiple biological effects as a result of their ability to crosslink proteins thereby forming protein polymers, and which when defective cause serious inherited disease resulting, for example, in excessive bleeding or a severe dermatitis with marked scaling of the skin.

How enzymes and other proteins have evolved is critical to understanding how they function and how they may be altered to advantage, to produce "designer" enzymes with new functions. In this paper, a Jurassic enzyme (over 170 million years old) is recreated and studied, revealing a major new understanding of how it evolved and functions.

A detailed review of inherited causes of heart muscle disease that result in excessive thickening or dilatation of the heart disorders that often lead to severe heart failure requiring a heart transplant.

This paper reports for the first time on a new drug treatment for patients with a serious and progressive disease characterized by marked constriction of their pulmonary (lung) arteries.

Identifies a gene defect that may predispose to the development of schizophrenia.

The ability of adrenaline and the great majority of other hormones and neurotransmitters to regulate the body’s response to stress and other stimuli results from their activation of unique receptor proteins on the surface of cells. This paper reports on a single amino acid change in one of these receptors that locks it in a state that is not only unresponsive to adrenaline, but also blocks the responses of many other hormones that utilise a common pathway inside the cell for regulating the cells’ function. This receptor variant should be uniquely useful for understanding how hormones activate receptors and influence the cell’s responsiveness.

The regulated expression of genes during development and differentiation is influenced by the availability of regulatory proteins and accessibility of the DNA to the transcriptional apparatus. There paper considers how changes in nuclear organization help to establish specific patterns of gene expression.

The mechanisms that determine which set of approximately 10,000 of the entire 100,000 genes in a cell are active, and which are silent or inactive, are poorly understood. Nevertheless, it is precisely such regulation of gene activity that determines whether a cell develops into a heart muscle or other type of cell, and as importantly, once it has developed into a heart muscle cell, whether or not it can respond appropriately to the variety of changing conditions to which we are all constantly subjected. This paper and Francastel et al. 1999 (above) represent a very major step in our understanding of gene activity, and demonstrates that this is regulated by the localisation of active genes at distinct sites in the complex structure of our chromosomes within the nucleus of our cells. Moreover, the papers show, for the first time, that critical control elements surrounding genes can actually relocate the genes within the nucleus.

See Rubin et al. 2002.

See Francastel et al. 2000.

Considers new findings related to gene abnormalities causing inherited forms of heart disease that result in severe heart failure, and that usually necessitate heart transplantation.

An entirely unexplained but important phenomenon is the fact that even in identical twins disease severity can vary markedly. Thus, one twin may have very severe disease whereas the other is only mildly affected or normal. Given that such twins have identical genes, the difference cannot be in the genes themselves, but rather, as discovered in this paper, to differences in the functioning of their genes. Furthermore, these differences can be inherited.

Reports the discovery of the pathway leading to enlargement and strengthening of muscle.

Although our body seems to be symmetrical, our internal organs, including our heart, lungs, kidneys, liver and spleen, are asymmetric. The mechanisms leading to this asymmetry remain poorly understood but defects in them can cause severe disease. This paper reviews progress in the identification of the molecular mechanisms involved in left-right asymmetry.

Provides major new understandings of the structure and function of a growth factor that is critically involved in the development of the embryonic heart as well as in the well being of the adult heart.

Reports a landmark study demonstrating the far-reaching benefits of lowering cholesterol regardless of how high it is before treatment.

Demonstrates how clumping of red blood cells results in changes that can be observed non-invasively with an echcardiogram and used to diagnose patients with an increased risk for blood clots and stokes.

Major review of the family of proteins on the surface of cells that allow adrenaline, released at times of stress, to regulate heart function.

A major finding demonstrating how the metabolism of an expensive immunosuppressant drug widely used in transplant patients can be slowed (and therefore costs saved) by the use of another must cheaper drug used to prevent infections in these patients.

Reports for the first time that an enzyme involved in forming protein polymers is also able to function as a critical molecule linking the activation of cells, such as those in the heart, with enhanced functioning of these cells in response to stress.