Health, wealth and longevity

The phrase ‘the Japan syndrome’ has often been used to describe socioeconomic upheavals unique to the island state, such as nuclear disasters, financial crises and reliance on grain imports. Recently, it has come to refer to the dramatic demographic changes Japan is facing and which also threaten nations globally.

Japan tops the list of the most aged countries in the world, with more than 30 per cent of its population over the age of 60 and an average life expectancy of almost 84. Combined with a low birth rate, this high life expectancy has seen the workforce shrink, slashing tax revenues needed to pay for ballooning social security expenses. In Japan, there are now only two working-age adults per elderly person, down from nearly six in 1990. And spending on medical care rose by almost USD 171 billion between 1995 and 2013, reaching 10.3 per cent of the gross domestic product (GDP).

Improved medical care offers many opportunities for alleviating the burden of this vicious demographic cycle by extending the number of active and healthy years available to an exploding elderly population. In this way, societies can benefit from increased productivity and economic growth. The RIKEN Preventive Medicine & Diagnosis Innovation Program (PMI) is driving advances in treatment and diagnosis by bringing the results of research at RIKEN in biology, physics, chemistry and engineering to the clinic.

Elias Zerhouni, former director of the US National Institutes of Health, first emphasized the necessity of shifting from curative to preventive medicine to maximize wellness at a national level. He argued for the need to manage the entire life cycle of a disease, from susceptibility and risk, to prevention, diagnosis, treatment and cure. Zerhouni identified four long-term goals, branded “the 4 ‘P’s of medicine”, of making medical care more ‘predictive’, ‘personalized’, ‘preventive’ and ‘participatory’.

Recent large-scale studies of the genome and its many ‘ome’ derivatives, such as proteomics and metabolomics, together with other breakthrough technologies, have opened the possibility of adding three more ‘P’s—we can now strive to deliver ‘precise’ and ‘preemptive’ medicine at the ‘point of care’. When executed together, these seven ambitious goals will lead to diagnoses and treatments that account for the unique biological characteristics of individual patients as well as those of different types of diseases. It will, for example, catch emerging malignancies earlier than before and consider inherited variations when prescribing drugs.

Precision medicine will intervene at the right time and place, taking snapshots of a patient’s health that reflect their present state. Take influenza, for example, a common viral infection typically left to run its course of sniffles, fever and misery, which can rapidly deteriorate into more serious lung and brain infections. Dangerous complications can be prevented by precisely identifying the causative virus at the point of care.

In 2009, a virulent strain of the influenza virus A (H1N1), or swine flu, spread across Japan and the world, causing about 18,000 deaths. While diagnostic tests were used to detect the virus, they proved unreliable during the early stages of infection. In 2012, researchers at the RIKEN Omics Science Center, the PMI’s predecessor organization, developed the RT-SmartAmp assay, a simple, quick and sensitive method for clinically detecting swine flu within 24 hours of fever onset¹. The technique involves reverse transcribing a specific sequence of viral RNA into DNA and isothermally amplifying the complementary DNA strands—all in one reaction tube, in contrast to the two-step process of conventional polymerase chain reaction amplification. The technique could be applied to various other infectious diseases.

PMI researchers are leading these efforts through their contributions to the research consortium established in 2000, named Functional Annotation of the Mammalian Genome (FANTOM).

FANTOM takes a multi-omics approach, integrating large-scale analyses of the genome with maps of transcripts, transcription factor proteins, promoters² and enhancers³ to develop new biomarkers of disease. The fifth edition, FANTOM5, now provides proteome, transcriptome, promotome and enhancerome analyses for 180 mammalian cell type.

In one of many potential applications of these cell-specific expression profiles, a team of researchers, including Masayoshi Itoh and Hideya Kawaji affiliated with the PMI, are developing biomarkers to specifically tag corneal endothelial cells derived from induced pluripotent stem cells⁴. Corneal endothelium is crucial for maintaining transparency in the eye’s outer layer. The technique could be used in the regeneration and surgical transplantation of corneal endothelium into patients with damaged corneal tissue due to injury or inherited degenerative diseases such as Fuchs’ Dystrophy.

Recently, the FANTOM5 consortium and an international team of researchers, including Itoh, Kawaji and Jun Kawai at the PMI, identified associations between common diseases and single-nucleotide errors in non-protein-coding enhancer regions—mutations previously overlooked by researchers focusing primarily on the protein-coding segments of DNA. They also found a disproportionately high number of mutations in enhancers predominantly expressed in pathologically relevant cell types. The researchers were then able to link abnormal enhancer activity to disorders primarily found in that type of cell, such as Grave’s disease and thyroid tissue, or chronic lymphocytic leukemia and lymphocytes.

In a separate study on transcribed enhancer sequences known as enhancer RNA, FANTOM5 researchers concluded that enhancer RNA molecules are the first to become active in a wave of transcriptional activity that occurs when cells differentiate into more specialized states⁵.

A crucial factor of FANTOM’s success has been its interdisciplinary approach. The consortium brings together more than 500 researchers from 20 countries with expertise in areas as far-reaching as molecular biology, bioinformatics and engineering. The PMI is replicating this strategy to introduce precision technologies enhanced by omics to research laboratories and hospitals.