Introduction


introduction T


his edition of Drug Discovery World includes a number of articles describing advances and improvements in established technologies already in common use in drug discovery laboratories with the objective of providing more useful and meaningful data and, if possible, increasing throughput. For many years now high throughput screening (HTS) has played a critical role in the drug discovery process. The authors of one of our articles report that a majority of laboratories using HTS have now incorporated high content screening (HCS) into their operations. The use of the latter is primarily in secondary screening although there is a continuing trend towards use in primary screening. There are still barriers to adoption including costs, the current state of analytical software and data management, throughputs and the quality of antibodies and labels. Suppliers are working to reduce these barriers and our authors predict that the use of HCS will continue to increase.


The value of HTS as a generator of good leads to drug candidates is debated in another article. Opinions vary but what is clear is that enormous amounts of effort and money have been devoted to synthesising very large chemical libraries in the search for the elusive hit. A case is made in this article to ‘listen to the call of nature’ and to revive natural product research to utilise the very diverse libraries that have evolved over millions of years. Flow cytometry is another established technology, previously employed mainly by immunologists and haematologists for cell sorting and analysis. As the technology has evolved it is now being used increasingly in drug screening laboratories especially following the introduction of plate-based sampling. However, as is pointed out in one of our articles, better computational analysis tools are still needed to handle the complexity and quantity of the data generated. Only then will the full potential of the technology in the drug discovery process be realised.


DNA sequencing provides a means of deciphering the genetic code. There have been rapid developments in the methodology and we include an article which discusses the progression towards the third generation of sequencing and beyond. The technology increasingly has the potential to improve diagnosis and treatment of diseases, notably cancer. However, as with technologies discussed above, challenges remain and again these include cost and analytical capability. Our author notes that sequencing vendors are constantly improving the performance of their systems and he suggests that carrying out a human scale genome sequence for $1,000 in a single day could well become a reality. On the same theme of genetic sequence information, another author points out that the completion of the Human Genome Project about 10 years ago was heralded as a new dawn in that it would, by increasing understanding of physiological processes and biochemical pathways, provide immediate leads to novel and useful therapeutic agents. However, it soon became apparent that the systems involved were much more complex than had been envisaged and our author considers that to realise the potential of the genome it has to be considered in the context of the living


Drug Discovery World Spring 2013


human cell and he points out that there are nearly 3,000 cell therapies in development worldwide. Exam- ples are given of how the develop- ment of high- speed, high-resolu- tion imaging tech- nologies have fac- ilitated the under- standing of cellular mechanisms.


As always in the pages of DDW we return to the high attrition rate in the drug development process. Safety


concerns commonly dictate that development should not continue and in another article it is stated that cardiovascular toxicity accounts for about a quarter of drug failures in the preclinical phase. Among these failures a common finding is adverse effects on cardiac ion channels such as hERG. The standard method of measuring hERG inhibition is a manual patch clamp technique but now automated processes are becoming available. Some are compared in our article.


There are about 7,000 rare diseases, defined somewhat differently from the regulatory point of view in the US, EU and Japan, and an estimate, quoted by our author, is that in the US plus the EU more than 55 million people suffer from a rare disease. Orphan drug legislation in all three main jurisdictions with periods of exclusivity, tax credits for clinical research, conditional marketing authorisatins, etc, has resulted in an increase in efforts to develop therapies for such diseases. In the US, for example, in the period 2006 to 2010 28% of all new drug applications were for rare diseases. It is suggested in the article that even more opportunities should arise as the field of genomics continues to advance. Finally, we return to the point made several times above that, in the current economic climate, cost of new technologies represents a significant barrier to their introduction. A recent survey, results of which are reported in these pages, indicates that there is an increasing appetite for the rental or leasing of laboratory equipment and, although vendors would prefer to sell instruments, they should be encouraged to offer rental or lease options to prospective customers.


Dr Roger Brimblecombe PhD, DSc, FRCPath, FIBiol 7


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