Facilitating collaboration on a global scale
Some projects are so ambitious in scope that they require teams of scientists from many different countries to collaborate. AMED is helping Japanese researchers to participate in these studies.
Most medical research projects are done by teams of a dozen or so scientists headed by a principal investigator. But increasingly, highly ambitious projects are being undertaken whose scales require the collaboration of tens or even hundreds of researchers around the world. The Japan Agency for Medical Research and Development (AMED) contributes to some of these huge multinational projects and in so doing supports projects that are too big for one country to do alone. AMED has helped Japanese researchers to participate in more than a dozen major international research consortia, through funding the acquisition of essential equipment, expertise and other research essentials.
Entering the era of epigenetics
In March 2009, Kyushu University researcher Hiroyuki Sasaki attended a meeting in Bethesda, USA, alongside numerous fellow experts in epigenetics from around the world. This field is focused on understanding how chemical modifications to the genome alter patterns of gene expression. The Bethesda meeting laid the foundation for a global effort to map out such epigenetic ‘marks’ and their role in health and disease. With support from AMED, Sasaki was able to participate and ultimately assume a leadership role in the International Human Epigenome Consortium (IHEC).
Sasaki’s lab is focused on epigenetic factors that regulate expression of genes involved in reproductive health. “Perturbations can cause infertility, moles, abortion, intrauterine growth retardation, congenital malformation syndromes, eclampsia, endometriosis and tumors,” he says. His group has performed much of its foundational work in mice, but had been struggling with a lack of equivalent epigenetic data from human tissues that might help them to home in on medically relevant patterns.
Funding from AMED allowed Sasaki to assemble a diverse team of gynecologists, molecular biologists and bioinformatics experts for the IHEC effort. “We gained access to new technologies, resources and datasets that assisted us to produce high-quality human epigenomic maps of the human placenta and endometrium,” he says. Sasaki’s group devised a strategy for generating human trophoblast stem cells—direct precursors of the placenta. This was something that scientists had struggled to achieve for more than two decades. Sasaki now hopes to use this method to generate a biologically relevant laboratory model for studying this tissue in culture conditions.
Brain imaging sheds light on disorders
Yoshiyuki Hirano at Chiba University likewise saw an opportunity to advance his research into neuropsychiatric disorders by joining a multinational effort. His team uses brain imaging to understand the anatomical and functional features associated with conditions such as obsessive−compulsive disorder. In 2017, he came across a paper from the obsessive−compulsive disorder working group of the Enhancing Neuro Imaging Genetics through Meta Analysis (ENIGMA) consortium and recognized a number of his colleagues on the author list. After getting in contact with the group’s leaders, he began to share some of his own lab’s research data on obsessive−compulsive disorder with the ENIGMA team. “We were able to reconfirm the importance of our data using several new data-processing methods that we hadn’t tried previously,” he says.
A five-year grant from AMED to support his participation in ENIGMA and two other research groups headed by Japanese neuroscientists has allowed Hirano to hire additional researchers and obtain essential equipment. “We got support to buy a new head coil, which will facilitate the building of a new magnetic resonance imaging database,” says Hirano. This coil is an essential element for the standardized brain-imaging protocol Hirano’s group is using. The team plans to use the resulting data to identify biomarkers that might guide the diagnosis and treatment of patients with obsessive−compulsive disorder and other disorders.
Monitoring the gene expression of single cells
AMED funding has also created opportunities for Japanese researchers to improve the quality of data being generated by international consortia. For example, Itoshi Nikaido’s group at the RIKEN Center for Biosystems Dynamics Research developed an experimental protocol and algorithmic tool that is now being used to generate high-quality data for the Human Cell Atlas (HCA) initiative. HCA scientists are using a technique called single-cell RNA-seq to profile the gene expression behavior of every cell type in the human body. However, there are many ways to conduct such experiments, and different techniques can yield variable results. “This required a study in which each organization performed experiments on the same cell samples, using exactly the same data analysis pipeline and comparing them fairly,” says Nikaido.
Nikaido used support from AMED to develop and optimize a single-cell RNA-seq method known as Quartz-Seq2, and this approach outperformed many of the other protocols tested by HCA scientists. “Quartz-Seq2 performed well on many metrics,” says Nikaido, “detecting 1.5 to 5 times more genes than other methods.” Indeed, this method performed so well that he has begun to develop it commercially for use by the pharmaceutical industry, through a startup called Knowledge Palette, Inc.
His group has continued to develop and refine their protocol, which can analyze large numbers of cells in a single sample, but still requires considerable effort to profile many samples in parallel. With further improvements, Quartz-Seq2 could become a potent tool for rapidly determining how the biological activity of cells shifts in different disease states and identifying drugs that normalize that behavior. Nikaido strongly credits AMED for creating this opportunity. “AMED supported setting up our laboratory to develop single-cell RNA-seq techniques,” he says. “Without this grant, we never would have succeeded in developing this technique.”
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