Drug discovery in ophthalmology: past success, present challenges, and future opportunities

BACKGROUND: Drug discovery has undergone major transformations in the last century, progressing from the recognition and refinement of natural products with therapeutic benefit, to the systematic screening of molecular libraries on whole organisms or cell lines and more recently to a more target-based approach driven by greater knowledge of the physiological and pathological pathways involved. Despite this evolution increasing challenges within the drug discovery industry are causing escalating rates of failure of development pipelines. DISCUSSION: We review the challenges facing the drug discovery industry, and discuss what attempts are being made to increase the productivity of drug development, including a refocusing on the study of the basic biology of the disease, and an embracing of the concept of ‘translational research’. We consider what ophthalmic drug discovery can learn from the sector in general and discuss strategies to overcome the present limitations. This includes advances in the understanding of the pathogenesis of disease; improvements in animal models of human disease; improvements in ophthalmic drug delivery and attempts at patient stratification within clinical trials. SUMMARY: As we look to the future, we argue that investment in ophthalmic drug development must continue to cover the whole translational spectrum (from ‘bench to bedside and back again’) with recognition that both biological discovery and clinical understanding will drive drug discovery, providing safe and effective therapies for ocular disease

An accurate approximation to the distribution of the length of the longest matching word between two random DNA sequences.

An accurate approximation is derived to the distribution of the length of the longest matching word present between two random DNA sequences of finite length, using only elementary probability arguments. The distribution is shown to be consistent with previous asymptotic results for the mean and variance of longest common words. The application of the distribution to assessing the statistical significance of sequence similarities is considered. It is shown how the distribution can be modified to take account of non-independence of neighbouring bases in real sequences

Tests for the statistical significance of protein sequence similarities in data-bank searches.

A suite of tests to evaluate the statistical significance of protein sequence similarities is developed for use in data bank searches. The tests are based on the Wilbur-Lipman word-search algorithm, and take into account the sequence lengths and compositions, and optionally the weighting of amino acid matches. The method is extended to allow for the existence of a sequence insertion/deletion within the region of similarity. The accuracy of statistical distributions underlying the tests is validated using randomly generated sequences and real sequences selected at random from the data banks. A computer program to perform the tests is briefly described

A test for the statistical significance of DNA sequence similarities for application in databank searches.

A method is developed, based on word-searching, which provides a rapid test for the statistical significance of DNA sequence similarities for use in databank searching. The method makes allowance for the lengths and dinucleotide compositions of the sequences being compared. A way is also described to calculate the power of the test, i.e. the probability of detecting a given similarity as being statistically significant. The effects on the power of the test of the scoring method, word length, sequence length, and sequence composition are examined. A novel scoring method is shown to be superior to the method currently used in most word-searching algorithms

Political science and public administration: The saga of a difficult relationship

This paper is based on 'The perennial ugly duckling-public sector education in tertiary institutions before and after Coombs, an invited contribution on management education delivered at the Sydney Academics Symposium on the Coombs Commission in Retrospect, IPAA National Conference, 28 November 2001