(This article is sponsored by The Boston Group)

Proteins are the workhorses of living cells. They carry out such diverse tasks from tissue formation to enzymatic catalysis, and from regulating metabolic flux to assisting in programmed cell death. Most of these functions are dependent on the precise three dimensional shapes of proteins. Proteins are long chains of amino acid building blocks, produced inside cells in tiny chemical factories called ribosomes. To function properly, these chains must fold into exactly the right three-dimensional structure. Proteins "fold", a process which can be thought of as small pieces of Velcro on a long string collapsing on each other resulting in a compact structure.

There is an enormous diversity of protein structures in the human genome. Biological systems have evolved to ensure that proteins fold properly. While properly folded proteins are correctly recognized to be the functional ones, it is assumed that improperly folded proteins are efficiently degraded and recycled by the cellular machinery. Recently however, there is a growing body of evidence that suggests that several debilitating human diseases arise due to improper folding (or "misfolding") of proteins which escape detection by the degradation machinery. The interest in such diseases has gone up sharply due to an increased life expectancy in developed countries. The list of such ailments, already long and growing, includes Alzheimer's disease, transmissible spongiform encephalopathies, Huntington's disease, cystic fibrosis and Parkinson's disease.

In the most popular version of the sequence of events, misfolded proteins either lose function, gain toxicity, or form large clumps and simply precipitate ("deposit") in some part of the body thus causing problems. Alzheimer described such protein deposits about hundred years ago in the brains of his patients, revealed upon post-mortem analysis. In Alzheimer's disease, these protein deposits are called amyloid plaques and in Parkinson's disease, they are referred to as Lewy bodies. These deposits formed by misfolded protein molecules cause tissue damage and organ dysfunction. There is considerable correlation between protein deposits and diseased tissues, which has proved quite helpful in definitive diagnosis.



If one assumes that the deposits are indeed responsible for the pathology of the above diseases (there is still some skepticism whether the deposits are the symptom or the cause of disease), then this presents a new direction in therapeutic approaches. One approach could be to block the misfolding event itself - that is, to stabilize the normal shape of the protein by addition of exogenous agents so that the process of misfolding is not initiated. Another approach is to design molecules that would selectively "dissolve" the protein deposits, and prime it for degradation and clearance from the body. A third approach is to partially (if the protein is essential for survival) or completely (if non-essential) block protein production itself by using cutting-edge techniques like RNA interference (RNAi). All of these methods will ultimately lead to fewer misfolded proteins.

We are at a juncture in biology and chemistry where increasingly sophisticated control of molecular structure and function is possible. Such molecular intervention in previously untreatable diseases should soon be possible, furthering human health and improving quality of life

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