Lost in translation:
What stops basic science from being translated into new drugs?
Els Torreele, DNDi Project Manager
In a perfect world, the pharmaceutical industry complements its own discovery programmes by scanning the progress and outcome of basic science through publications and conferences, and picks the most promising new targets and leads to feed its drug development pipeline with commercially attractive, potential new products. Neglected diseases lie outside this perfect world. For these diseases the industry is generally absent, and at best, enters the equation only at a much later and less risky stage. Public research institutions, on the other hand, have traditionally been averse to applied pharmaceutical research, focusing instead on basic and early discovery research, or on clinical research at the other end of the pipeline.
The big challenge for DNDi and other product development partnerships lies in bridging this gap, in translating new knowledge of how to kill disease-bearing parasites, into drugs that can be tested in patients. While increased involvement of the pharmaceutical industry is to be encouraged, a more active role in the process that develops compounds into true drug candidates is expected from the publicly-funded scientific community.
Basic science versus translational research
When basic scientists undertake to study the molecular basis of Leishmania transmission from sandfly to man, or the sophisticated ways in which trypanosomes have evolved to evade immune surveillance, or the 3D structure of a unique parasite enzyme, they do so out of sheer scientific curiosity. Using increasingly sophisticated research tools (e.g., bio-engineering, bio-informatics, structural biology) they relentlessly pursue new knowledge and insights from their academic ivory towers. They believe it is up to others to translate this knowledge into applications.
The goals and rewards of basic scientists are publications in high-ranking scientific journals, and concomitant career and research funding prospects. Indeed, the public scientific community is governed by the publish-or-perish principle, and research progress is more readily published when it is the result of innovative approaches and technologies, tackles a new research question, or provides new or unexpected insights etc.
In drug discovery, this means that most of the innovation is in the identification of possible new drug targets (preferably with a beautiful 3D structure to present at conferences), or the discovery that selective inhibitors of such a target can be generated. But that is still a far cry from finding a new drug candidate. Indeed, once a selective inhibitor of a parasite is identified (a “hit”), it takes 2-4 years of continuous research by a multidisciplinary team to transform it into a drug lead, and then into a drug candidate that can be tested for use against the disease in humans.
In essence, this hit-to-lead-to-candidate optimisation activity involves the synthesis of many compounds that closely resemble the identified inhibitor, and an iterative assessment of these compounds in a series of predefined, routine tests to identify the best ones in terms of drug candidate. And there lies the problem.
Rescuing drug candidates lost in translation
In recent years, however, things have started to change. Several public research groups around the world have started to expand their expertise and focus beyond early drug discovery to also encompass the next steps of lead optimisation following drug development criteria, particularly in disease areas where the pharmaceutical industry has been largely absent, such as tropical and parasitic diseases or tuberculosis.In fact, one initiative has chosen to focus mainly on human African trypanosomiasis, Chagas disease and leishmaniasis: the Drug Discovery for Tropical Diseases initiative (DDTD) at the University of Dundee (see interview with Alan Fairlamb, page 3). This initiative and other recent efforts to revive neglected disease drug development efforts in public research (University of California, San Francisco; Broad Institute at Harvard; National Institutes of Health; Walter and Eliza Hall Institute etc.) as well as industry (GSK’s facility at Tres Cantos Spain, the Novartis Institute for Tropical Diseases Singapore, and some biotech companies) will be crucial to feeding the R&D pipelines of DNDi and other initiatives.
Published by Drugs for Neglected Diseases Initiative - 1 Place St Gervais 1201 Geneva Switzerland
Editor: Jaya Banerji - Tel: +41 22 906 9230 - Fax: +41 22 906 9231 - www.dndi.org