December 2009, March 2010

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1 December 2009, March

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8 February 2015 Sysmex Corporation National Institute of Advanced Industrial Science and Technology (AIST) Technology Development Utilizing Sugar Chain Functions The World s First Reagent to Determine the Progression of Hepatic Fibrosis by Measuring Changes in the Sugar Chain Measurement of a Hepatic Fibrosis Glycosylation Marker in Blood Within 17 Minutes Development of Fast and High-Precision Measurement Technology Which Received Approval for Health Insurance Coverage in January 2015 The most common cause of chronic hepatitis in Japan is infection with the hepatitis B virus and hepatitis C virus. The number of infected people is said to be approximately three million nationwide, of which nearly two-thirds are asymptomatic carriers. Chronic hepatitis that develops from infection with the hepatitis virus causes chronic cell destruction in the liver, and can advance to hepatic cirrhosis in 20 to 25 years due to fibrosis of the liver (hepatic fibrosis), and can eventually lead to liver cancer or serious disease. The progression of chronic hepatitis and the likely therapeutic efficacy of treatment can be determined by checking the level of hepatic fibrosis. Today, the mainstay test for hepatic fibrosis is a biopsy in which the state of hepatic fibrosis is ascertained by collecting liver tissue with an inserted needle. However, the test imposes a heavy burden on patients, such as the necessity of hospitalization. Therefore, there is a public need for the development of a simple and high-precision liver fibrosis test such as blood testing. A technology that meets this need is Sysmex Corporation s HISCL M2BPGi reagent which uses a hepatic fibrosis glycosylation marker, a biomarker using sugar chains. NEDO has implemented the world s most advanced research and development projects related to sugar chains since the Technology for the Production and Utilization of Glycoconjugates project started in The National Institute of Advanced Industrial Science and Technology (AIST), which has led these projects, found a new glycosylation marker involved in the progression of hepatic fibrosis. In order to utilize this achievement, AIST started to work with Sysmex Corporation, a manufacturer of clinical examination devices and test reagents, for the practical application of the hepatic fibrosis glycosylation marker, and then developed the HISCL M2BPGi reagent. This reagent received manufacturing and marketing approval in December 2013, was released in March 2014, and received approval for health insurance coverage in January It is expected to be widely used in the future. Automatic immunoassay system used in testing HISCL-5000 (Photo courtesy of Sysmex Corporation) Reagents placed in HISCL-5000 Twenty-four R1 to R3 reagent sample sets can be tested at the same time.

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10 Topics CASE 04 Medical Biotechnology CASE Success Story Medical Biotechnology Enormous effort and costs are required for the development of new medicine There are long and difficult processes involved in the development of new medicine. During the basic research stage, various new substances that are potential candidates for new medicine are sought. The properties and structures of such substances are investigated, the effectiveness and safety of an enormous number of new substances are verified using laboratory animals, and then the candidates are narrowed down. Separating candidates by quantifying their efficacy, or screening, is a process that requires a lot of time and money. Traditionally, most laboratory animals have been mice, but because there are numerous substances that are potential candidates, investigating the efficacy of all candidates Development of a Procedure That Dramatically Streamlines Essential Screening in Medicine Development Mie University / HASHIMOTO ELECTRONIC INDUSTRY CO., LTD. Innovation Commercialization Venture Support Project, etc. under various conditions using mice is time-consuming and expensive. On the other hand, another type of experimental animal is the zebrafish, which is known to have a genetic structure similar to humans, as is the case with mice. Zebrafish have recently become more commonly used in order to make experimentation convenient. Another advantage is that zebrafish are cheaper to raise than mice. However, there has been one problem in using zebrafish for experimentation as it was not possible to easily create a human disease model with them. A human disease model refers to a group of laboratory animals which can be affected by a disease that also affects humans. When investigating the efficacy of medicine that treats or alleviates the symptoms of a human disease, the animals in the experiment must be able to be affected with the same human disease The ZF Plate, which simplified the observation of zebrafish 2. Zebrafish in a conventional plate (left) and Zebrafish arranged in the ZF Plate (right). (Photo provided by HASHIMOTO ELECTRONIC INDUSTRY CO., LTD.) 3. Aquariums used in the laboratory of Professor Toshio Tanaka at Mie University. Zebrafish with various human diseases are raised in numerous tanks. 4. A semiautomatic workstation for observation of zebrafish developed by HASHIMOTO ELECTRONIC INDUSTRY CO., LTD. 5. An obese zebrafish developed by Professor Toshio Tanaka. (Photo provided by Professor Toshio Tanaka of Mie University) 6. MieKomachi, a zebrafish with a transparent body that is used for observation. (Photo provided by Professor Toshio Tanaka of Mie University) 7 7. Toshio Tanaka, professor at Mie University Graduate School of Medicine. Professor Toshio Tanaka of the Mie University Graduate School of Medicine speculated that if it is possible to use a large amount of zebrafish in drug development screening, then drug development should be able to be performed more conveniently and broadly. At the time, he was participating in NEDO s Grant for Practical Application of University R&D Results program, and he started working to develop of a zebrafish human disease model from NEDO had actually been focusing on the possibility of drug development screening employing zebrafish long before the start of the project. Investigating drug efficacy with large volume observations of zebrafish human disease models Around that time, a technology called genome editing was being established by American researchers. Using new technology that pinpoints and deletes DNA in a genome, it became possible to develop a model organism more simply than in the past. Using this idea, Professor Tanaka succeeded in creating various NEDO s Role zebrafish human disease models. However, he was not satisfied with the results that he obtained. He believed that in order to realize the type of large-scale drug development screening he had envisioned, it would be necessary to have research tools that can evaluate the results of a large number of potential candidates for new medicine by observing a large number of zebrafish. This process would also need to be automated in the future. Therefore, as a first step, Professor Tanaka developed the Zebrafish (ZF) Plate which is capable of observing many zebrafish at the same time. He also selected HASHIMOTO ELECTRONIC INDUSTRY CO., LTD. from Matsusaka City in Mie Prefecture to be a collaborator in his development work. He selected the company because he had heard about their technology to manipulate fine particles and their advanced knowledge of zebrafish. Next, NEDO adopted the development of the ZF Plate under its Innovation Commercialization Venture Support Project which was continued from Through repeated trial and error by developers at Hashimoto, a general purpose ZF Plate was completed. This then led to the development of a procedure for a commonly used centrifugal separator which could be used without expensive accessories. This made it possible to easily perform experiments anywhere using a large number of zebrafish. For The Future Using the new technology to develop functional foods and personalized cancer treatment For research and development venture companies, development for practical application is an extremely risky phase before reaching commercialization. Therefore, support for superior advanced technology seeds that make use of promising original technology is provided to projects with a specific plan to achieve practical application within three to five years. When adopting a project, NEDO considers the novelty of the technology, the level of goal setting, the superiority of patents and know-how, as well as the possibility for practical application. Goals, problems, and steps needed to solve problems are also clarified, and the suitability of research planning, including cost-effectiveness, is evaluated. Furthermore, in addition to the potential for a new market creation effect, the understanding of market needs, and the A well incorporated into a microplate. A circular well is incorporated into a square-shaped space. (Provided by HASHIMOTO ELECTRONIC INDUSTRY CO., LTD.) 9. Mr. Masatoshi Hashimoto, president and representative director of HASHIMOTO ELECTRONIC INDUSTRY CO., LTD. Drug development research employing zebrafish has only just begun, but there are great expectations for the technology to become a driving force in the development of new medicine and an essential research method. Furthermore, there is a wide variety of applications for drug development screening technology in which zebrafish are used. For example, testing active ingredients contained in food products and the effectiveness of anticancer drugs have been investigated. So, use of the technology has also started in the development of functional foods and for personalized cancer treatment. priority of developed products and services, the reliability of the system for commercialization and business planning are also reviewed as part of NEDO s evaluation process. Evaluations are carried out from various points of view, such as the contribution to revitalization of regional economies, in order to strengthen the foundation of creative innovation. 15

11 Topics CASE 05 Medical Biotechnology CASE 05 Success Story Development of Japan s First PET Device Dedicated for Breast Cancer and Able to Perform High-Precision Examinations Without Inflicting Pain Medical Biotechnology SHIMADZU CORPORATION R&D Project on Molecular Imaging Equipment for Treatment of Malignant Tumors A four-layer DOI detector enables high-precision and high-sensitivity examinations. It incorporates technology that is the core of the Elmammo breast cancer- dedicated PET device. (Photo provided by SHIMADZU CORPORATION) 2. During an examination, the patient lies face-down and positions a single breast in the opening at the top in order to have images taken. (Photo provided by SHIMADZU CORPORA- TION) 3. The female-friendly, fresh and clean examination area. (Photo provided by SHIMADZU CORPORA- TION) 8 8. Cancer incident data based on estimates of regional cancer registration nationwide ( ). Created based on Cancer Registration and Statistics from the National Cancer Center s Cancer Information Service. Enabling high-precision examinations without inflicting pain At first glance, Elmammo appears to have the shape of a bed. On the top, there is a single opening with a diameter of approximately 18.5 cm where the examination takes place. A female patient receiving the examination lies face-down. The examination is performed with the patient positioning one breast in the opening at a time and then having a PET image of each breast taken. Currently, with mammography used for breast cancer examinations, a patient s breasts are pressed tightly together before images are taken, resulting in a heavy burden for the patient as she may experience pain and other discomfort. In comparison, using Elmammo does not require a patient to press her breasts together, so she will not experience any pain. Also, the device is capable of taking 3D tomographic PET images of the breasts when they are not pressed together. Furthermore, the device is extremely effective, offering about twice the resolution and ten times the sensitivity of current whole-body positron emission tomography / computed tomography (PET/CT) devices. The biggest contributing factor to realization of such high resolution and sensitivity is that the detectors are arranged in a ring structure. On a side note, Elmammo was originally developed in cooperation with the National Institute of Radiological Sciences for brain examinations. A NEDO project led to it also being used for breast cancer examinations. Among cancer incidence rates for Japanese women, breast cancer is the highest (see accompanying graph), so early detection can mean the difference between life and death. Shimadzu Corporation determined that its device could be used for breast cancer examinations, and therefore applied to participate in NEDO s project. For The Future Listening to user opinions and taking the technology overseas During the early stage of development of the device, it was difficult to simultaneously achieve high resolution and high sensitivity. However, after improvements in technology, hardware, and software, it became possible to achieve both high resolution and high sensitivity. Furthermore, through medical-engineering cooperation with Kyoto University Hospital, the opinions of doctors using the device and patients undergoing examinations were reflected in the development process, making the device more userfriendly. There are future plans to develop domestic and overseas markets for early-stage detection and treatment of breast cancer, which is increasing every year The completed Elmammo together with its three developers. From the right, Keishi Kitamura, who was in charge of the prototype development and is one of the inventors of the four-layer DOI detector (Senior R&D Manager, Radiation Imaging Device Unit, Technology Research Laboratory); Kazumi Tanaka, who was in charge of circuit design and hardware (R&D Manager, Research and Development Department, Medical Systems Division); and Tetsuro Mizuta, who was in charge of software, such as image processing software (Assistant Manager, Research and Development Department, Medical Systems Division). Detecting cancer in its early stage is the difference between life and death It is extremely important to be able to detect and treat cancer in its early stage. This is because the survival rate for the majority of cancers begins to rapidly decline as the disease progresses. Therefore, detection of cancer in its early stage is necessary. At the same time, there is a need to take measures to reduce medical costs associated with the diagnosis and treatment of the disease. Much attention has been given to imaging technology that is capable of detecting functional changes in living cells at the molecular level, so there are great expectations regarding positron emission tomography (PET) devices in fields related to early-stage diagnosis of cancer. 4. When comparing the four-layer DOI detector with conventional detectors, Elmammo has made it possible to distinguish the depth of interactions of gamma rays. (Image provided by SHIMADZU CORPORATION) 5. Traditionally, the shape at the edges of the field of view has been either unclear or distorted. The four-layer DOI detector can clearly and completely capture the shape from the center to the edges of the field of view. (Image provided by SHIMADZU CORPORATION) However, there is still room for growth in the PET device market of the health care industry. Because of this potential, Shimadzu Corporation developed a PET device dedicated for breast cancer called Elmammo in NEDO s R&D of Molecule Imaging Equipment for Malignant Tumor Therapy Support project carried out from FY2006 to FY Phantom image taken by a whole body PET device with a spatial resolution of 3.5 mm. (Image provided by SHIMADZU CORPORATION) 7. Phantom image taken by the Elmammo breast cancer-dedicated PET device with a spatial resolution of less than 1.5 mm. From this, it is possible to distinguish smaller diameters than what is possible with the whole body PET image on the left (from the top left, the diameters are 4.8 mm, 4.0 mm, 3.2 mm, 2.4 mm, 1.6 mm, and mm). (Image provided by SHIMADZU CORPORATION) NEDO s Role In this project, NEDO promoted medical-engineering cooperation by functioning as an intermediary between industry and academia. From medical and industrial perspectives, NEDO promoted the development of molecular imaging technology capable of performing high-precision, early-stage diagnosis of malignant tumors. In particular, a molecular imaging research center was established at Kyoto University Hospital. Information sharing was encouraged between Kyoto University, which was the joint research platform for the project, and participating companies by performing comprehensive progress management and periodically hosting research promotion planning meetings, resulting in the construction of a system that supported the project leaders. The advanced equipment conformed to clinical needs, and was improved based on appropriate evaluation and clinical research (clinical data). The development and evaluation of molecular probes for such advanced equipment were also promoted. In addition, the project was successfully carried out due to management that responded to a changing situation. When an midterm evaluation was conducted in FY2008, the challenges of research and development and final targets were revised based on the results of the evaluation. A supplementary budget was then provided for molecular probe pharmaceutical formulation technology for molecular imaging in order to accelerate development

12 Medical Biotechnology Culture bag attached to cell culture apparatus Adding Momentum to Clinical Applied Research on ES and ips Cells Through Enhanced Qualitative and Quantitative Stabilization Kyoto University Nissan Chemical Industries, Ltd. Nipro Corporation Development to Accelerate the Practical Application of Human Stem Cells / Development of Basic Evaluation Technologies for the Practical Application of Human Stem Cells Development of Innovative Culture Media for Human Pluripotent Stem Cells (ES and ips Cells) and an Automated Cell Culture System To promote regenerative medicine, research is under way using two types of human pluripotent stem cells: embryonic stem (ES) cells and induced pluripotent stem (ips) cells. Clinical application of the research requires development of mass culture and quality control technologies for ES and ips cells. These technologies were successfully established during the course of this project, in which government, industry, and academia collaborated to commercialize world-class products. Working to establish a new method for managing the culture of ES and ips cells and an automated cell culture system ES and ips cells play important roles in regenerative medicine. In a typical laboratory setting, culture dishes and other devices are usually employed to grow these cells, but even with a large dish, only several million to ten million cells can be grown at a time. In regenerative medicine, however, about one billion stem cells per patient are needed. It is also vital that cultured stem cells be free of contaminants such as impurities, toxic substances, and pathogens. In a NEDO project, a collaborative team from industry and academia led by Kyoto University s Institute for Integrated Cell-Material Sciences (icems) worked to address these challenges. It was able to achieve technological breakthroughs that enabled the automated mass culture of stem cells. Realizing 3D stem cell culture using food additives and achieving mass culture using applied culture bag systems Nissan Chemical Industries, Ltd., a team member from industry, developed a three-dimensional (3D) culture system required for large-scale stem cell production. This system promotes growth of stem cells while suspended in a liquid medium, allowing the cells to be cultured with minimum damage. This enables both mass culture and quality control of cells. The food additive gellan gum is used for the stem cell suspension culture. The development of a system to uniformly mix gellan gum with the liquid media led to the commercial application of a 3D culture system. Nipro Corporation, another team member from industry, worked to develop an automated cell culture system. By establishing a closed culture system using culture bags, the company significantly reduced the risk of contamination, including that caused by mixing with other cell lines, relative to the risk of an open system using culture dishes. The company also developed a method to detach and dissociate cell colonies using a small amount of reagent (enzyme) to transfer them between culture bags. This made culture work much less labor-intensive and enabled efficient and large-scale stem cell production. Clinical application of the developed technologies is expected to bring regenerative stem cell-based medicine to many people. Left: Stem cells in 3D culture Top right: FCeM Preparation Kit for Stem Cells developed jointly by Kyoto University and Nissan Chemical Industries, Ltd. Bottom right: An experimental model of an automated stem cell culture system was jointly developed by Kyoto University and Nipro Corporation. The latest model, CELLAFORTE, was launched in April NEDO PROJECT SUCCESS STORIES 2017 SUCCESS STORIES 11