Lost in Translation (LiT): IUPHAR Review 6

Abstract

Translational medicine is a roller coaster with occasional brilliant successes and a large majority of failures. Lost in Translation 1 (‘LiT1’), beginning in the 1950s, was a golden era built upon earlier advances in experimental physiology, biochemistry and pharmacology, with a dash of serendipity, that led to the discovery of many new drugs for serious illnesses. LiT2 saw the large‐scale industrialization of drug discovery using high‐throughput screens and assays based on affinity for the target molecule. The links between drug development and university sciences and medicine weakened, but there were still some brilliant successes. In LiT3, the coverage of translational medicine expanded from molecular biology to drug budgets, with much greater emphasis on safety and official regulation. Compared with R&D expenditure, the number of breakthrough discoveries in LiT3 was disappointing, but monoclonal antibodies for immunity and inflammation brought in a new golden era and kinase inhibitors such as imatinib were breakthroughs in cancer. The pharmaceutical industry is trying to revive the LiT1 approach by using phenotypic assays and closer links with academia. LiT4 faces a data explosion generated by the genome project, GWAS, ENCODE and the ‘omics’ that is in danger of leaving LiT4 in a computerized cloud. Industrial laboratories are filled with masses of automated machinery while the scientists sit in a separate room viewing the results on their computers. Big Data will need Big Thinking in LiT4 but with so many unmet medical needs and so many new opportunities being revealed there are high hopes that the roller coaster will ride high again.

Human induced pluripotent stem cells and CRISPR/Cas-mediated targeted genome editing: Platforms to tackle sensorineural hearing loss

“…While animal models have proven indispensable in furthering our understanding of cochlear physiology, the astounding 90% of drugs found to be successful in animals fail in humans. 168,169 Taken together, improvements in hiPSCs are bringing a plethora of opportunities to develop new strategies to understand HL and treat the growing population of patients with SNHL.…”

“…Acquiring and analyzing such specimens is challenging because (a) availability of the samples is limited since people do not commonly donate to research, (b) sample quality is affected by post‐mortem time which is typically several hours long, and (c) histologic processing is laborious and lengthy, typically taking many months. While animal models have proven indispensable in furthering our understanding of cochlear physiology, the astounding 90% of drugs found to be successful in animals fail in humans 168,169 . Taken together, improvements in hiPSCs are bringing a plethora of opportunities to develop new strategies to understand HL and treat the growing population of patients with SNHL.…”

Progressive MS Alliance Industry Forum: Maximizing Collective Impact To Enable Drug Development

“…Despite these positive developments, people with progressive MS still lack disease-modifying treatments [2][3][4]. The pharmaceutical sector has concentrated its efforts and investments on the development of anti-inflammatory and immunomodulatory drugs, and on less-risky relapsing-remitting MS studies where the development and regulatory paths are better defined [5,6]. One key reason for the lack of advancement is the absence of a fundamental understanding of the pathophysiology of disease progression, and this has prevented significant progress that could lead to treatment [7].…”

Nonprofit foundations spur translational research

“…Now, due to diminished earlystage venture capital for Biotechs and reduced public funding to academia, these two actors do not often have the required resources to sustain innovation. Moreover, due to growing early-stage research costs, Pharma and venture capitalists have started focusing on the late, Phase II/III stages of clinical research [3]. As a consequence, a translational gap, often referred to as the 'Valley of Death' [5], appears between Pharma on the one hand, waiting for de-risked programs, and Biotechs/academia on the other hand, doing all they can to move their programs across the Valley.…”