The 9th Technology Presentation
March 16, 2012 Table of Contents
1. Opening Remarks Hisashi Ietsugu, President and CEO 2. Strategy and Progress of R&D Mitsuru Watanabe, Member of Managing Board and Executive Officer, Head of R&D (1) Outline of Technology Strategy Strategy for Realizing Personalized Medicine (Initiatives Involving Companion Diagnostics) (2) Launch Stage New Product Technologies 1) XN Series: Proposing Incomparable Laboratory Workflow 2) Silent Design ® 3) CS-5100: Flagship Model in the Hemostasis Field 4) Lab Assay: C2P 5) Progress of OSNA (3) Practical Stage Status of Progress on Development Themes 1) Cervical Cancer Screening 2) Glucose AUC (Minimally Invasive Body Fluid Extraction Technology) 3) Diabetes Bio-Simulation 4) Methylated DNA
3. Status of Progress at the Research Stage Kaoru Asano, Executive Officer, Executive Vice President (1) New Activity: Metabolome Analysis Technology 1) Early Detection of Diabetic Nephropathy (2) High-Performance Protein Recombination Technology 1) Sugar Chain Modification Technology (3) Approach toward e-Health 1) Genetic Diagnosis Support System Using Secret Sharing Scheme
1 2. Strategy and Progress of R&D Mitsuru Watanabe, Member of Managing Board and Executive Officer, Head of R&D 2. Strategy & Progress of R&D
(1) Outline of Technology Strategy Strategy for Realizing Personalized Medicine (Initiatives Involving Companion Diagnostics)
(2) Launch Stage New Product Technologies 1) XN Series: Proposing Incomparable Laboratory Workflow 2) Silent Design ® 3) CS-5100: Flagship Model in the Hemostasis Field 4) Lab Assay: C2P 5) Progress of OSNA
(3) Practical Stage Status of Progress on Development Themes 1) Cervical Cancer Screening 2) Glucose AUC (Minimally Invasive Body Fluid Extraction Technology) 3) Diabetes Simulation 4) Methylated DNA
3 2. (1) Outline of Technology Strategy Technologies for Realizing Personalized Medicine/ Changes in the Environment 1)
Drug reaction simulation, upgrading through structural analysis 抗原Antigen “Humanization” of disease model using iPS cells Amino アミノ酸 acid Patient skin cell iPS cell
iPS cell Antibody抗体 induction
Cell transplantation Culturing, induction therapy (nerve regeneration treatment)
Understanding the reasons for Myocardial neurological diseases cells Pancreatic Evaluation of drug Nerve cells Liver efficaciousness and side cells effects cells
Identification of new treatments and diagnostic targets Changes in drug manufacturing process How the EML4- Normal gene creation Normal gene element ALK lung cancer with cytoskeleton causing cell Drug efficacy differs, depending on the patient gene evolves protein proliferation
Normal second Responder chromosome Patient 1
Portion cut off and rotated Sudden change halfway Drug A S e con d ch rom o som e Intermediate of cancer patient Patient 2 responder
Cancer gene demonstrating abnormal proliferation Patient 3 No responder
5 Technologies for Realizing Personalized Medicine/ Changes in the Environment 2)
ChangesChanges inin drugdrug developmentdevelopment process:process: OpportunitiesOpportunities forfor participationparticipation inin companioncompanion diagnosticsdiagnostics
(Major) Diagnostic (Major) Drug Target disease Technology Agent Manufacturers Manufacturers (Application)
Cancer PCR (patient selection) IHC, ISH Infectious disease Microarray (monitoring)
Cancer (patient selection) PCR
Cancer (patient selection) PCR
Cancer (patient selection) IHC, ISH
The Japanese pharma industry is moving toward companion diagnostics.
IHC: Immunohistochemistry ISH: In situ hybridization
6 Outline of Technology Strategy
Vision of R&D Activity Providing highly valuable diagnostics Overall医療全体 medical testing to optimize and standardize market medical treatment In vivo Medical治療薬 diagnosis生体計測 treatment
Companionコンパニオン診断 diagnostics ICT ﾌﾟﾗｲﾏﾘｰｹｱPrimary care 個別化医療Personalized medicine Emerging新興国 markets IVD
7 Creating Diagnostic Value by Strengthening the Technology Platform Personalized Medicine Theranostics Companion diagnostics
Cancer, hematology, central nervous system, Primary Care cardiovascular disease Emerging markets Advanced markets Infectious diseases Chronic disease IVD
Cell Gene Protein Biochemical compound Thrombosis, hemostasis Thrombosis, Immunochromatography Thrombosis, hemostasis Thrombosis, Immunochromatography Chemiluminescence Chemiluminescence Non- or minimally or Non- Non- or minimally or Non- Bio-simulator Bio-simulator DNA chip DNA chip OSNA invasive OSNA FCM invasive FCM
TechnologyTechnology PlatformPlatform 8 Companion Diagnostics
◇◇CompanionCompanion diagnosticsdiagnostics (CDx)…(CDx)… 99IsIs an an effective effective approachapproach for for realizing realizing personalized personalized medicine medicine 99InvolvesInvolves development development of of therapeutic therapeutic and and diagnostic diagnostic agents agents inin parallelparallel developmentdevelopment
Co-Co- Co-Co- Co-Co- DevelopmentDevelopment RegistrationRegistration ApprovalApproval Benefits and drawbacks of CDx Personalized medicine Reduces development risk, shortens development time V Realizes patient coverage CDx
Patient benefit: Early realization of personalized medicine
9 Strategy for CDx
Main Focuses in Working toward CDx
Biomarker Assay Design Diagnostic Kit Discovery Development •Joint research with •Prototype development •Automation ✓ outside medical institutes •Evaluation of sensitivity/ •Reagent optimization ✓ •Joint business with other specificity for quality- •Proof of clinical benefits companies guaranteed samples with medium- to large- •License-in developed through joint scale clinical study✓ •Use of established research •Approvals ✓ markers
✓Proactively use external ✓Apply Sysmex technology ✓Use Sysmex expertise R&D resources (HISCL, FCM) for (Global sales channels) personalized medicine ✓Introduce PCR technology
10 Strengthening the Technology Platform
Sample Initiative: Measurement of HISCL Hepatic Fibrosis Markers
11 Sugar Chain
Cell type identification Protecting protein quality Gateway to infection
Protein quality control Application in drugs Transport of drug within body
Maturity Glycoproteome Sugar chain functions Glycoprotein Majority of proteins Extracellular Glycosylation
Glycosyltransferase
Protein Proteome Gene expression Proteins 100,000 types Intracellular Various types of stimulation or changes in the Genome environment alter the structure of the sugar chain such Genes that it expresses the “mode of dress” of the protein. 22,000 Nuclear
12 Hepatic Fibrosis and Liver Disease
Acute Chronic Cirrhosis of Liver Infection感染 急性肝炎hepatitis 慢性肝炎hepatitis the 肝硬変 liver cancer 肝 癌
Pathology発症 5–155～15年 years Approx.約20年 20 years Approx.約25～30年 25–30 years HCC 年7～8%7–8% Interferonインターフェロン virus Fibrosis線維化進展スピード progression per year Cirrhosis肝硬変（F4） (F4) eradicationウイルス駆除 +0.10／年+0.10/year 3–4%年3～4% ↓ F1～3 per year 慢性肝炎重度（F3）Severe chronic 線維化寛解スピードFibrosis reduction 1–2%年1～2% hepatitis (F3) –0.28/year－0.28／年 per year 慢性肝炎中度（F2）Moderate chronic hepatitis (F2) 0.5%年0.5% per year 慢性肝炎軽度（F1）Slight chronic hepatitis (F1) Existing method(C.O.I.)
Shiratori Y, et al: Annals Int Med 32: 517-524, 2000
13 Lectin–Sugar Chain Reaction and Combination with the HISCL Method
Antigen / Antibody Reaction Lectin–Sugar Chain Reaction (Conventional Technology) (New Technology)
ALP ALP ALP Object of ALP detection: protein Antigen Antigen Antigen (antigen) Antigen Sugar chain
Magnetic Lectin particle MagneticMP Antibody particle
Maintains identification through sugar chain detection, and enables use of the highly sensitive HISCL method a short period of time.
ALP: Alkaline phosphatase
14 Clinical Research Results (Interim Report)
Strong correlation with diagnostic requests, such as measurement of malignant alteration
HISCLHISCL Method法 Correlation相関 120 100 100.0 25
20 80.0
15
C.O.I.） 60.0 10 （
発光カウント比（ ％ ） 5 40.0
HISCL法 y = 1.73 x + 0.47 0 12345678 R = 0.93 20.0
F1 F2 F3 F4 (C.O.I) Method HISCL
Luminescence Count Comparison (%) Comparison Count Luminescence 0.0 0.0 20.0 40.0 60.0 80.0 100.0
Hepatic肝線維化ステージ fibrosis stage Referenceリファレンス法（C.O.I.） Method (C.O.I.) Source: 2011BioJapan
Future developments: Seek approval during FY2012, and after approval has been granted, look into simultaneous development of therapeutic and diagnostic agents
15 Reporting Subjects and Technology Presentation Policies
1. Reporting Subjects ・Technical features of Sysmex technologies and products ・Technical themes on which Sysmex conducts R&D and their clinical benefits ・Outline of Sysmex technology strategy
2. Policy regarding reporting of technological themes Explain R&D themes at the three stages below:
16 Definition of R&D Stage
ResearchResearch stagestage PracticalPractical stagestage LaunchLaunch stagestage
Start of research or preliminary evaluation Objective means Start of full-scale R&D Completion of product establishment of 10–50% activity towards 50–80% commercialization and measurement commercialization determination of launch principle and verification of clinical value. value.
WNRチャンネル WDFチャンネル
FSC FSC FSC B ASO SFSFSF L L L
NR BC ・フローサイトメトリー MONO IG LYMP H ・電気抵抗式 NEUT Debris Debris EO SFLSFLSFL Abnormal lymph BA SO SFL WPCチャンネル SSC PLT-Fチャンネル FSFSFS C C C Blast RETチャンネル RBC WBC Blast FSFSFS C C C FSC FSC FSC FSC Fragments SS C RET-He IPF
IRF RBC RE T PLT-F SSC
SFL SFL
17 2. (2) Launch Stage: New Product Technologies 2. (2) Launch Stage: New Product Technologies
1) XN Series: Proposing Incomparable Laboratory Workflow
19 2.-(2)-1) XN Series: Proposing Incomparable Laboratory Workflow
Improving Laboratory Value Example: Period elapsed until testing results reported Avg. for all samples Avg. for urgent samples
Previous 24 min., 59 sec. 16 min., 25 sec.
23% reduction 26% reduction
XN-9000 19 min., 09 sec. 12 min., 04 sec.
*Previous: Sysmex’s former system (University)
Reliability Efficiency
Usability Silent Design, Proactive Service automatic reflex test, Flexibility Preventive maintenance Quality Assurance improved throughput, Modular concept, service, online QC Global lotting of calibrators, cartridge-form reagent clinical value issuance of calibration certificates
20 2.-(2)-1) XN Series: Proposing Incomparable Laboratory Workflow
Improving operational efficiency and proposing high added value
Provision of メンテナンスProvision of maintenance e-e-learningラーニング guidesガイド提供 coursesコース提供 Web WEBcameraカメラ supportサポート Bidirectional双方向 screen画面共有 sharing
オンラインOnline Increased precision supportサポート NEW!! 精度向上 Expanded prognosis Failure prognosis 予知項目拡大 リアルタイム解析Failure prognosis 故障予知 categories Basic基本サービス service throughによる real-time故障予知 resolution
NEW!! オンラインOnline QC Preventive動作回数による QC maintenance using Since 2011 Web 予防保守 WEB情報 number of operations information Proactiveプロアクティブ SNCS: serviceサービス Develop into Sysmex products Sysmex Network serviceサービス Communication Systems
21 2. (2) Launch Stage: New Product Technologies
1) Silent Design®
22 2.-(2)-2) 2) Silent Design®
Designed for the people who use it. Creates an environment stressing ease of use.
The five elements of Silent Design
Offers value that is unaffected by the Considers the skin, rather than the clothing. Maintains consistency. changing times.
23 2.-(2)-2) Silent Design® Wins Good Design Gold Award 2011
Developing the concept of product consistency: “Rather than designing individual pieces of equipment, design the laboratory space”
November 2011
24 2. (2) Launch Stage: New Product Technologies
3) CS-5100: Flagship Model in the Hemostasis Field - High processing capacity - Connects to transport lines - Improved sample aspiration mechanism - Stabilized reagent cooling system
25 2.-(2)-3) CS-5100: High Processing Capacity
HighHigh processing processing capacity capacity through through optimizedoptimized design design for for sample sample processing processing Maintains processing capacity* during simultaneous testing of multiple parameters
* Compared with previous models, tripled processing capacity (300 tests per hour) for tests that included such parameters as D-Dimer, which had tended to reduce capacity.
- Optimized for high-dimensionality unit placement and software controls - Realizes compact size and high speed through structural simulation
26 2.-(2)-3) CS-5100: Connects to Transport Lines
ConnectsConnects with with SIEMENS’ SIEMENS’ and and major major Japanese Japanese manufacturers’ manufacturers’ sample sample transport transport systems systems
Urgent sample measurement SIEMENS transport line (example)
Provides a workflow that balances high-volume throughput with urgent sample measurement
27 2.-(2)-3) CS-5100: Improved Sample Aspiration Mechanism
HandlesHandles mixed mixed testing testing of of capped capped blood-collection blood-collection tubes tubes and and small-volumesmall-volume samples samples
Piercer: Sample aspiration compartment Sampler can sort samples correctly handles biohazard-capped blood-collection according to test tube type and sample size. tubes Pipette: Sample aspiration compartment handles small-volume samples
ImprovedImproved operatoroperator workflow,workflow, suchsuch asas inin preparationpreparation ofof complicatedcomplicated samplessamples
28 2.-(2)-3) CS-5100: Stabilized Reagent Cooling Function
RealizesRealizes stabilizedstabilized reagent reagent cooling cooling function function through through quality quality engineering engineering
CS-5100 ・Reagent cool storage unit construction allows a broad range of changes in device placement and environments ・Effective cooling through coolant and air channel controls (See diagram at left)*
*About twice the stability of previous models, even in severe environments Diagram of interior of reagent cool storage unit (arrows show direction of airflow) Reagent stand A Reagent stand B
ProvidesProvides improvedimproved reagentreagent coolingcooling andand moremore accurateaccurate testingtesting datadata
29 2. (2) Launch Stage: New Product Technologies
4) Lab Assay: C2P
C2P: Cell Cycle Profiling
30 2.-(2)-4) Lab Assay: C2P
Cell Cycle Profiling (Breast Cancer)
Providing appropriate treatment for each patient
z From surgically dissected tumor tissue, measure the specific activity Cell Cycle (activity/expression) of proteins CDK1 and CDK2 related to the cell cycle z Classify low/medium/high risk of recurrence z Target patient is lymph note metastasis negative, hormone receptor positive
Dynamic state of cell proliferation⇒ CDK2 SA / CDK1 SA
Specific Activity (SA) = activity / expression
31 2.-(2)-4) Lab Assay: “C2P Breast”
In January 2012, began a testing service (for research) in Japan involving the risk of recurrence of early-stage breast cancer Target region: Japan Cost: ¥200,000/test Test order flow:
Customer (hospital) Sysmex (BMA(BMA lab)ラボ) 1. Customer (hospital) application
2. Send test transport kit and transport box to customer
3. Customer provides sample (frozen at – 80°C) 4. Measure sample
5. Report results to customer
32 2.-(2)-4) Lab Assay: “C2P Breast”
Awareness Activities BMA Lab: Kobe Medical Japanese Breast Cancer Society Industry Development Project (Association Booth)
SeeksSeeks toto makemake anan earlyearly contributioncontribution toto customerscustomers andand accelerateaccelerate commercializationcommercialization
33 2. (2) Launch Stage: New Product Technologies
4) Progress of OSNA
34 2.-(2)-5) Progress of OSNA
Expansion of regions where introduced
Breast China: Applying cancer AP: Preparing for sales United States: Reconsidering market launch
Expansion of application Colon Japan: NHI points assigned, considering business prospects, clinical significance and other factors cancer Europe: Acquired CE mark, conducting clinical evaluations at multiple centers
Stomach Japan: Applying to have NHI cancer points assigned
35 2.-(2)-5) Progress of OSNA: Status of Introduction for Breast Cancer
85 Status of Introduction 60 in Japan, 142
As of February 29, 2012 overseas (195 facilities)
17 6 13 16 3 2
Others 60 50
60
As of January 31, 2011
12 11 9 4 2 Planning to expand Others into the AP market
36 2.-(2)-5) Initiatives to Encourage OSNA Prevalence (Centered on Europe)
・Amass data using the OSNA web database (Lynolog)
Amass clinical information using examples of OSNA introduction on common database Each country group amasses data, structures evidence and consolidates data across countries France Group Note: Planned for use in Japan フランスグループ Spain Group スペイングループ
UKグループUK Group
1. ①各施設よりIndividual institutions input viaweb入力 web イタリアグループItaly Group Lynolog 2. Accumulated②蓄積データ data Lynolog data データサーバserver
Japan日本グループ Group
Japan (OSNA method study group)
FutureFuture developments: developments: IncreaseIncrease clinical clinical value value of of OSNA OSNA method, method, accelerate accelerate awareness awareness activities activities to to expandexpand market market
37 2. (3) Practical Stage: Status of Progress on Development Themes 2. (3) Practical Stage: Status of Progress on Development Themes
1) Cervical Cancer Screening
39 2.-(3)-1) Cervical Cancer Screening: New Diagnostic Flow
Proposed new diagnostic flow Definitive test (tissue diagnosis)精密検査 擬陽性 False positive Cross section of cervix (Primary ((Secondary１次検診 ) Clinical value: test) 細胞診test) Improved overall FCM cytodiagnosis accuracy Positive Economic value: Labor savings, サンプル Sample increased efficiency, allows acceptance of higher percentage of tests Negative陰性
Negative Sort out 次回定期検診Next regular examination
40 2.-(3)-1) Cervical Cancer Screening: Improvement with New Algorithm for Classification by Target Character
・Extract resolution target cell nuclei using index of cell and nuclei sizes (N/C ratio) ・Analyze ploidy and proliferation using quantitative analysis of DNA
Sample FCM Measurement Results Reference Method New Algorithm 100 Cell with high N/C ratio
80
60
40 Cell sizeCell index value Example of analysis target cell nucleus 20 Cell with low N/C ratio Cell sizeCell 0 0.0 0.2 0.4 0.6 0.8 1.0 N/C ratio Index value corresponding to NC ratio Superficial (n = 170) Parabasal cell (n = 198) Intermediate (n = 218) Metaplasia (n = 39) Example of cell nucleus outside analysis target
41 2.-(3)-1) Cervical Cancer Screening: Confirmation of Clinical Performance
Target performance For a practical system, sensitivity of 90%, specificity of 80%, and a sort-out rate of ≧ 70 % (Note: The cutoff is tissue diagnosis CIN2+ or higher) Based on internal evaluations, nearly on target ⇒ External market evaluation of clinical value is underway
Sensitivity Specificity N=633 100% 87% (21/21) (529/612)
Future developments: In fiscal 2012, verify clinical value in Japan, Europe and China (the United States is under consideration), and in fiscal 2013, launch into the market a system for research use
42 2. (3) Practical Stage: Status of Progress on Development Themes 2) Glucose AUC (Minimally Invasive Body Fluid Extraction Technology
43 2.-(3)-2) Glucose AUC (Minimally Invasive Body Fluid Extraction Technology): Proposal of New Diabetes Screening
Taking blood samples to measure post-prandial hyperglycemia Medical significantly reduces QOL test at General Concept place of checkup business
School Regional medical medical test test Glucose AUC
1 3 A method is needed for measuring post- prandial hyperglycemia that is simple and inconspicuous 2 Measure, analyze (Biochemical(Biochemical field,field, Note: Post-prandial hyperglycemia: Stamp other)other) A risk factor for large vessel disease (cerebral apoplexy, Affix gel patch myocardial infarction) Affix gel patch
44 2.-(3)-2) Glucose AUC (Minimally Invasive Body Fluid Extraction Technology): Verification Results through Clinical Research
Diabetes Screening Comparison with Conventional Screening Indicators
600 8 HHｂｂA1cA1c (Glycemic(Glycemic 180 Blood Glucose 0 BloodBlood GlucoseGlucose AUCAUC TwoTwo Blood Glucose 0 h/dl) Loading Unnecessary) 160 ･ Loading Unnecessary) when Fasting HoursHours AfterAfter GlycemicGlycemicLoading Loading 7.5 when Fasting 500 140 7 120 400 6.5 6.5 126 mg/dl % 100 300 6 80
300mg・h/dl FPG(mg/dl) 60 HbA1c(NGSP)(%) 5.5 200 40 5 100 20 4.5 0 NGT IFG IGT DM NGT IFG IGT DM predicted blood glucose AUC(mg 0
NGT IFG IGT DM Patients with normal Patients with abnormal Patients with normal Patients with abnormal Patients with normal Patients with abnormal glucose tolerance glucose tolerance glucose tolerance glucose tolerance glucose tolerance glucose tolerance
Measured by administering OGTTs to Note: Published in article in Diabetes Technology and Therapeutics, June 2012 50 outpatients undergoing diabetes tests
ContinueContinue efforts efforts at at academic academic conferences conferences to to heighten heighten recognition recognition of of AUC AUC as as novel novel diagnosticdiagnostic parameter parameter for for early-stage early-stage diabetes diabetes
OGTT: Oral glucose tolerance test
45 2.-(3)-2) Glucose AUC (Minimally Invasive Body Fluid Extraction Technology): Structural Unit
Body組織液採取キット Fluid Sampling Kit アッセイキットAssay Kit
Paracentesis穿刺具 tool
ゲルパッチGel patch
Tubesゲル内組織液回収用チューブ for collecting tissue fluid within gel
High-sensitive高感度 reagent for 微細針アレイMicro needle array glucoseグルコース測定試薬 measurement
FutureFuture developments: developments: WithWith the the aim aim of of receiving receiving approval approval within within one one year,year, establish establish studystudy group, group, while while atat the the samesame time time conducting conducting body body fluid fluid samplingsampling andand developing developing assay assay kits kits
46 2. (3) Practical Stage: Status of Progress on Development Themes
3) Diabetes Bio-Simulation
47 2.-(3)-3) Diabetes Bio-Simulation
Input入力 Analysis解析 Output出力 Treatment治療 Model parameters Index 1 Index 2 Index 7 Liver Periphery
Index 6 Index 3
Pancreas Kinetics Index 5 Index 4
Support information Input of test values Analysis of clinical 糖尿病患者の検査 製品Aがインスリン分泌 Output定量化された of disease解析結 患者for personalizedに適した薬物治 for diabetes conditions from the 値を入力します 不全、インスリン抵抗性 profiles果を病態プロファイル as analysis 療の判断材料としてtherapeutic patients viewpoint of insulin の観点から病態を解析 results ご活用strategiesいただけます secretion and action として表示します します
Quantification of individual’s disease state by simulation of pancreas function, insulin function and sugar metabolism
48 2.-(3)-3) Diabetes Simulation: Clinical Research Result Showing Predicted Response to Oral Preparation Shanghai Jiao Tong University School of Drug A (n=49) Medicine Renji Hospital 60% 54% 50% Response prediction based on the Ave. 39% 40% disease status inferred from OGTT data 33% at the start of treatment 30% 20%
10% or more reduction in HbA1c after (%) rate Response six months of treatment with oral 10% preparation = response 0% Positive Area Negative Area 12 Ave: Average response rate Drug C (n=35) 60% Drug B (n=42) 100% 52% 80% 50% 80% Ave. 66% Ave. 38% 40% 60% 30% 21% 40% 30% 20% Response rate (%) rate Response
Response rate (%) 20% 10% 0% 0% Positive Area Negative Area Positive Area Negative Area 12 12( IDF @ Dubai, 2011/12, Seike et al ) 49 2.-(3)-3) Status of Clinical Research at Multiple Centers
• Objective Using the diabetes simulator, confirm predictive capabilities of response to oral preparation at multiple institutions • Target cases 200
• Participating institutions Total of five institutions, including level 3 hospitals, centered on Shanghai Jiao Tong University
FutureFuture developments: developments: DuringDuring fiscal fiscal 2012,2012, conduct conduct clinical clinical evaluations evaluations inin target target marketsmarkets inin ChinaChina and and other other emerging emerging markets. markets. Aim Aim to to move move to to practical practical stagestage fromfrom fiscal fiscal 2013, 2013, and and consider consider expanding expanding business business intointo ICT-basedICT-based personalizedpersonalized medicine medicine andand the the drug drug development development process process
50 2. (3) Practical Stage: Status of Progress on Development Themes
4) Methylated DNA
51 2.-(3)-4) Methylated DNA
Initiatives Volume Epigenetic Regulation switch Main switch •Establishment of methylation
Cytosine 5-methylcytosine measurement system Methylated DNA Unmethylated DNA Develop OS-MSP method Construct automated pre-treatment Methylation of cytosine via DNA methyl conversion system enzymes
Active state Dormant state •Collaborative research with Shift to inactivity (dormant state) Epigenomics Colon cancer marker (SEPT9)
Chromatin structure changes due to DNA methylation and histone modifiers •Epigenomics submits PMA application in December 2011
Contributes to onset of cancer
52 2.-(3)-4) Methylated DNA: Evaluation of the Clinical Value of Colon Cancer Diagnostics
Target Nearly the same function as Epigenomics’ results for a large-scale clinical study of Europeans and Americans (sensitivity of 67%, specificity of 88%)
Sensitivity Specificity Positives / Total Patients with (%) (%) colon cancer 24 / 37 65 - Sensitivity Specificity Negatives / Total Healthy (%) (%) patients 6 / 42 - 86
FutureFuture developments: developments: FromFrom fiscal fiscal 2012, 2012, verifyverify clinical clinical value,value, suchsuch as as early early detection detection of of colon colon cancer.cancer. Based Based on on these these results, results, conduct conduct clinical clinical research research (expected(expected to to taketake 3–7 3–7 years)years) inin advance advance of of application/approval. application/approval.
53 3. Status of Progress at the Research Stage Kaoru Asano, Executive Officer, Executive Vice President 3. Status of Progress at the Research Stage (1) New Activity: Metabolome Analysis Technology 1) Early Detection of Diabetic Nephropathy
(2) High-Performance Protein Recombination Technology 1) Sugar Chain Modification Technology
(３) Approach toward e-Health 1) Genetic Diagnosis Support System Using Secret Sharing Scheme
55 3. Status of Progress at the Research Stage
(1) New Activity: Metabolome Analysis Technology 1) Early Detection of Diabetic Nephropathy
56 About Metabolome
• Metabolism: Gene Homeostatic regulation of biochemical reactions that sustain life
mRNA
Protein Metabolic map = Route map of chemical reactions
• Metabolites: The intermediates and products of metabolism Cell • Metabolome: Randomized approach of metabolism
57 Metabolic Disorders a Source of Homeostatic Breakdown ← Fluctuation → Homeostasis is: The behavior of a system that tends to transcriptometranscriptome maintain a stable, constant condition of properties (100,000) II Very complex For example, maintaining a balance between blood’s many components
Homeostatic breakdown results in diseases, proteomeproteome such as diabetes, hyperlipidemia and gout
Homeostasis (20,000) These diseases can be distinguished by Very complex changes in the level of metabolites in the blood Transcriptome: Comprehensive analysis and research procedure involving the total set of transcripts, including mRNA, of an metabolome organism Proteome: Comprehensive analysis and research procedure (3,000) involving the proteins expressed by an organism Metabolome: Comprehensive analysis and research procedure Relatively simple involving the metabolic products (low-molecular compounds) present in an organism MetabolomicsMetabolomics is is anan effectiveeffective meansmeans ofof pursingpursing changeschanges inin conditioncondition owingowing toto lifestylelifestyle diseases,diseases, agingaging andand otherother acquiredacquired factorsfactors
58 1) Early Detection of Diabetic Nephropathy: The Background of Diabetic Nephropathy Number of patients: Worldwide, 28 million (3 million in Japan), occurring in approximately 30% of diabetes patients Of patients with chronic kidney disease, there is a marked increase in the percentage of people undergoing dialysis ManagementManagement ofof diabeticdiabetic nephropathynephropathy enablesenables thethe controlcontrol ofof patientspatients onon dialysisdialysis Number of Patients Undergoing Dialysis Each Year (Japan) 16,000 (People) Total number of dialysis patients: 290,000 Diabetic nephropathy 12,000 Medical cost: ¥1.4 trillion
Chronic glomerulonephritis 8,000
Nephrosclerosis 4,000
0 1985 1990 1995 2000 2005 (Year) From the CKD Medical Care Guide 59 1) Early Detection of Diabetic Nephropathy: Marker Discovery Concept
EarlyEarly stage stage ofof ManifestationManifestation stage stage kidneykidney pathologypathology ofof kidney kidney pathologypathology Ongoing Kidney tissue disease Breakdown of the hyperglycemia resulting from metabolic filtration function = disorders in kidney cells albumin leakage
MetabolitesMetabolites inin thethe urineurine detecteddetected duringduring thethe earlyearly stagestage ofof kidneykidney diseasedisease ⇒⇒MetabolomeMetabolome marker marker
Perform marker discovery using metabolome analysis
Metabolite Database extraction search SelectionSelection of of diagnosticdiagnostic marker marker Early-stage urine candidatescandidates CE-MS measurement Collaborative research: Human Metabolome Technologies
60 1) Early Detection of Diabetic Nephropathy: Clinical Value of Marker Candidates
10
● FS Feasibility study (FS) ● VS Sensitivity 100% / Specificity 100%
Validity study (VS) Nephro- Sensitivity 88% / Specificity 85% pathy 1 Marker X Marker
0.77 PerformPerform additional additional validation validation through through retrospectiveretrospective and and prospective prospective studies,studies, including including for for other other marker marker 0.1 candidates, to ascertain practical Pre- candidates, to ascertain practical Early-stage Manifestation nephropathy applications Healthy nephropathy stage applications stage (Stage 2) (Stage 3) (Stage 1)
61 3. Status of Progress at the Research Stage
(2) High-Performance Protein Recombination Technology 1) Sugar Chain Modification Technology
62 Application of Recombinant Silkworms
DevelopmentDevelopment ofof rawraw materialsmaterials forfor diagnosticdiagnostic reagentsreagents • Immunochemistry reagents • Coagulation reagents
ContractContract manufacturingmanufacturing forfor proteinprotein
Recombinant silkworms HighlyHighly functionalfunctional proteinprotein creationcreation technologytechnology
• Sugar chain modification
63 Protein Expression Using Recombinant Silkworms
Chrysalis Larva Target gene
or
Introduce gene into larval virus Recombinant virus produces protein in silkworm
Chrysalides
Silkworm Purification
Preparation of Larvae chrysalides and larvae Infect with recombinant virus Protein raw material
64 Production Characteristics of Various Recombinant Proteins
Produc- Production Nearness Sugar Chain Structure Cost to Human tivity Period Type (N Type)
E. Coli ○◎ ○ × (None)
Yeast ○○ ○ △
Silkworm ○ ○ ○ ○
Animal ×× × ◎
Acetyleglucosamine Mannose Galactose Sialic acid
65 Expectations for Controlling the Sugar Chain Structure
＊ The sugar chain structure substantially impacts protein function (activity, stability, solubility) ・High activity ・High stability Improved product function ・Increased solubility
＊ Recognizing the sugar chain structure contributes to higher diagnostic agent functionality (qualitative alteration)
・Development of Improved sensitivity/specificity antibodies that can recognize the sugar chain structure
Normal cell Cancer cell
66 Status of Sugar Chain Structure Control
Silkworm-type sugar chain Protein ASN
N- acetyleglucosamine transferase Protein ASN
Galactosyl transferase
Protein Current status ASN Acetyleglucosamin e Sialyl transferase Mannose Galactose Protein Sialic acid Human-type ASN ASN: Asparagine sugar chain
67 3. Status of Progress at the Research Stage
(3) Approach toward e-Health 1) Genetic Diagnosis Support System Using Secret Sharing Scheme
68 The Era of Personal Genomes
Cost of Genome Analysis Cost of Genome Analysis Supercomputer “K” •• 2003 2003 InternationalInternational HumanHuman GenomeGenome ProjectProject upup toto ¥100¥100 billionbillion •The use of a supercomputer for •• Currently Currently analysis leads to the generation of 1010 days,days, ¥500,000¥500,000 new knowledge related to cancer •• In In twotwo yearsyears 55 days,days, ¥100,000¥100,000 CancerCancer GenomeGenome •2020•2020 Within 1 hour, ¥10,0000 Within 1 hour, ¥10,0000 •• International International CancerCancer GenomeGenome ConsortiumConsortium -- Creating Creating catalogcatalog ofof majormajor cancercancer genomegenome abnormalitiesabnormalities -- Includes Includes informationinformation onon allall genomesgenomes forfor 50,00050,000 people,people, includingincluding 25,00025,000 cancercancer samplessamples
PersonalizedPersonalized medicine medicine based based on on DNA DNA information:information: TheThe time time isis nearingnearing when when anyone anyone will will be be able able to to present present their their DNA DNA whenwhen obtaining obtaining medical medical care, care, as as with with medical medical insuranceinsurance cards cards today today
69 Using ICT to Realize Personalized Medicine
Hospital B Hospital A Medical treatment details
Test Drugs Database
Medical office
Provide as application Health check institution New information and knowledge Simulation z Securely store individual test data Home z Easily confirm past test data at any hospital zProvide medical treatment support information based on scientific evidence
70 Secret Sharing Scheme (Data Separation*)
Electronic separation Restoration (data separation*)
* Global Friendship, Inc.
Key point: Even if personal data is included in the original data, data that is separated at the bit level does not constitute personal information.
71 Demonstration Experiments of Gene Diagnosis Support System Using Secret Sharing Scheme Now Genetic testing laboratory Medical department
Print Scan Test report
Verification testing Genetic testing laboratory Medical department
LAN
Transmitting Segment 1 Browsing application application
Segment 2
Segment 3
72 Chapter 3
Sysmex Corporation
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