河北医科大学药学院 "Me,and then Lauterbur" The Shameful Wrong That Must Be Righted Dama dian deserved the Nabe 鱼些叶标)和《年品领中家)善夏璃士导复帆上科香整◆ 里育 t is just sour grap It is just sourgrape visual proof that this sha must he righted 天然药物化学教研室史清文教授
河北医科大学药学院 天然药物化学教研室 史清文教授 1 271 "Me, and then Lauterbur" Dr. Raymond Damadian at his induction into the National Inventors Hall of Fame, February 12, 1989, for the invention of magnetic resonance scanning. Damadian deserved the Nobel？ "The Shameful Wrong That Must Be Righted" 272 "The Shameful Wrong That Must Be Righted" "How I Did It: Raymond Damadian" 1972年3月17日提出了专利申请 《纽约时报》和《华盛顿邮报》甚至瑞士等报纸上刊登整版广告 273 It is just sour grapes? 274 It is just sour grapes? 275 276
河北医科大学药学院 Dr Raymond Damadian,Pioneer of MRI Medicine eer on July 3.19 Assistant Larry Minkoff in Indomitable Building the First MR Dr.Ray Gifted Mind:The Dr.Raymond Damadian Story,Inventor of the MRI MIND AXS bodyMRh calld the 天然药物化学教研室史清文教授
河北医科大学药学院 天然药物化学教研室 史清文教授 2 Raymond Vahan Damadian(1936-)是美国医生，医疗从业人员，也是第一台 MR扫描仪的发明者。 Damadian对活细胞中钠和钾的研究使他首次进行了核磁共 振实验，使他首次在1969年提出了MR人体扫描仪 Raymond V. Damadian: Magnetic Resonance Imaging and the controversy of the 2003 Nobel Prize in Physiology or Medicine Dr Raymond Damadian, Pioneer of MRI Dr Damadian with the history-making prototype of his MRI scanner. The first MR image of a human skull was made with this scanner on July 3, 1977. The prototype is now on permanent display at the Smithsonian Institution‘s Hall of Medical Sciences. Assistant Larry Minkoff in Indomitable ‘super-scientist’ Dr Raymond V. Damadian Damadian's cancer detector. Artist's rendering published in the New York Times on 9 February 1974. FONAR introduced the world's first commercial MRI in 1980, and went public in 1981 Building the First MRI Dr. Damadian with the history-making prototype of Dr. Damadian's MRI scanner. The first MR image of a human chest was made with this scanner on July 3, 1977 which he called the 'Indomitable'. American doctor and scientist Raymond Damadian built a partial body MRI scanner in 1977, which he called the ‘Indomitable’. Dr. Raymond Damadian had plagiarized earlier work of Dr. Erik Odeblad Gifted Mind: The Dr. Raymond Damadian Story, Inventor of the MRI Damadian, R. Tumor Detection by Nuclear Magnetic Resonance. Science, 1971, 171:1151-1153. 天才思维 Creation scientist创世论科学家
河北医科大学药学院 Nobel Prize Controversies Nobel Prize Controversies R5a“Gd”teen间e 2014 or c s and nurtures it to bring to everybody's benefir Nobel Prize Controversies Erik Odeblad-The Forgotten Pioneer in MR dical NyR MRI Pioneer-Herman Y.Carr Erwin Louis Hahn (1921-2016) in 1950,which are essential to modern day MRI 天然药物化学教研室史清文教授 3
河北医科大学药学院 天然药物化学教研室 史清文教授 3 Nobel Prize Controversies According to Dr. Morton Meyers, a radiologist and historian from East Setauket, New York, U.S., there should have been a third recipient of the award: Dr. Raymond Damadian, founder of Fonar. Dr. Morton Meyers from East Setauket, New York, U.S. The long-running and hostile dispute over who should receive credit for the invention of clinical MRI resurfaced during Sunday's Honorary Lecture at ECR 2014 Nobel Prize Controversies Who develops and nurtures it to bring to everybody's benefit? MRI is an “old” technique "You should get your facts and then talk," he said. Rinck added that Damadian had plagiarized earlier work by Dr. Erik Odeblad from Stockholm who should have received a Nobel Prize for MRI, because in 1955 he published the first medical NMR s tu d i es , i n cl u d i n g re l a xa t i o n ti m e measurements, of living cells and excised tissue. Dr. Peter Rinck, PhD, chairman of the European Magnetic Resonance Forum and president of the Council of the Round Table Foundation Nobel Prize Controversies Dr. Erik Odeblad 2012年，Erik Odeblad荣获欧洲磁 共振奖时，展示了他 的第一台NMR谱仪 1954 年 12 月 由 Erik Odeblad 和 Gunnar Lindström提交到Stockholm的Acta Radiologica杂 志并于1955年获得发表“生物样品质子磁共振的 初步观察结果” Erik Odeblad-The Forgotten Pioneer in MRI Erik Odeblad 1922- MRI Pioneer- Herman Y. Carr Herman Y. Carr (1924 –2008) was an American physicist and pioneer of magnetic resonance imaging. He received his Master’s degree in 1949 and his Ph.D. in 1953 from Harvard University. His doctoral thesis, published in 1952, described techniques for using gradients in magnetic fields and was the first example of magnetic resonance imaging or MRI. Erwin Louis Hahn (1921-2016) “The person who really missed out the Nobel Prize for his contribution to the principles of Spin Echoes” in 1950, which are essential to modern day MRI. Spin echo and FID signal -Hahn Echo“自旋回波
河北医科大学药学院 NMR Vs NMRI Vs MRI single pervon or team i ated the NRI in iselation tthe culmination of decades of sie progressd uderstanding MRI tecmoly beginsith the discoveryof a quantum-physics phem resomance (NMR)in 1937 by Isidor I.Rabi,a Polish-born K Im American physicist. as to MR Vs NMR Vs MRI MRI按主磁场的场强分类 Nuclear magnetic rese0 nance(MR)核量共a兼 Magnefic resonance(MR)imaging (MRI减共暴减绿 Nuclear Magnetic resonance im国gi面gMR)被雅共绿表像 gnetie resomance ang0 grapby (MRA黑共添点浅减绿 (1.T、L5T、2T ：大于10T(3.T、4T,7T) 高斯(Gauss,G) 特斯拉(Tesl品，T)“电气时代之父 高新为距离5安培电流的直 5尖墙 kola To 9四数开的*教 应用的免之 天然药物化学教研室史清文教授 4
河北医科大学药学院 天然药物化学教研室 史清文教授 4 What are the developments which lead to the MRI? No single person or team invented the MRI in isolation; it is the culmination of decades of scientific progress and understanding. MRI technology begins with the discovery of a quantum-physics phenomenon called nuclear magnetic resonance (NMR) in 1937 by Isidor I. Rabi, a Polish-born American physicist. NMR Vs NMRI Vs MRI MR Image Making an Image Functional Imaging Because of patients' worrying dangers of nuclearradioactivity, the word "nuclear" had been largely dropped in the mid 1980s when referring to Magnetic resonance (MR) imaging. "Nuclear"=原子核 MR Vs NMR Vs MRI Nuclear induction 核感应 Nuclear paramagnetic resonance 核顺磁共振 Nuclear magnetic resonance (NMR) 核磁共振 Magnetic resonance (MR) imaging (MRI) 磁共振成像 Nuclear Magnetic resonance imaging (MRI) 核磁共振成像 Magnetic resonance angiography (MRA 磁共振血流成像) functional Magnetic resonance imaging (fMRI) 功能磁共振成像 –MRI图像信噪比与主磁场场强成正比 –低场: 小于0.5 T –中场：0.5T－1.0 T –高场: 1.0T－2.0 T（1.0T、1.5T、2.0T） –超高场强：大于2.0 T（3.0T、4.7T、7T） MRI按主磁场的场强分类 MRI 3T 4.7 T=200 MHz 7 T=400 MHz 质子共振频率 1 T = 10000 G Carolus Fridericus Gauss (1777-1855) 1高斯为距离5安培电流的直导线1厘米处检测到的磁场强度 德国著名数学家、物理学家，于1832年首次测量了地球的磁场 5安培 1厘米 1高斯 高斯（Gauss, G） 地球磁场（the earth magnetic field）多强？ 特斯拉（Tesla, T）“电气时代之父” Nikola Tesla (1857-1943) 奥地利电器工程师，物理 学家，旋转磁场原理及其 应用的先驱者之一。 磁密度单位（1Tesla=10000Gause） 地球的磁场强度分布图 1960年在巴黎召开的国际计量大会上， 磁感应强度的单位被命名为特斯拉
河北医科大学药学院 The Genius Who Lit the World The MRI Environment-A Dangerous Place 轮椅「亲南」上核磁共振收 【时代》周刊评速世界最伟大人物第2名 of New York MRI Is A Unique Biomedical The MRI“Experience' Imaging Technique MRI forms images from an in insic tissue sigmal that does not result from radioactive decay -The gradient hardware makes a very large amount of cedure The First"Brain Imaging Experiment" The Machine That Tried To Scan The Brain-In 1882 补经个国 天然药物化学教研室史清文教授
河北医科大学药学院 天然药物化学教研室 史清文教授 5 The Genius Who Lit the World Nikola Tesla (1857-1943) 《时代》周刊评选世界最伟大人物第2名 轮椅「亲吻」上核磁共振仪 核磁共振检查前，身体上的金属物全部拿掉,如手表、金属项链、假牙、 金属纽扣、金属避孕环等磁性物品。此外，戴心脏起搏器，体内有顺磁性金 属植入物，如金属夹、支架、钢板和螺钉等，都不能进行磁共振成像检查。 The MRI Environment-A Dangerous Place MRI Is A Unique Biomedical Imaging Technique • MRI forms images from an intrinsic tissue signal that does not result from radioactive decay • Computed Tomography (CT) and conventional radiography form images by measuring the attenuation of external Xrays The MRI “Experience” • – Imaging is a slow process during which the subject must not move • – The magnet space is small and many subjects are claustrophobic • – The gradient hardware makes a very large amount of audio noise • MRI is widely regarded as a safe biomedical imaging procedure • – No (ionizing) radiation is used • – No radioactive materials are used The Machine That Tried To Scan The Brain — In 1882 Angelo Mosso's "human circulation balance" machine worked like a seesaw to measure blood flow changes to the brain Angelo Mosso (1846-1910) Italian physiologist 自从1890年代开始，人们就知道血流与血氧的改变（两者合称为血液动力 学）与神经元的活化有着密不可分的关系
河北医科大学药学院 History of fMRI 功能性磁共振成像(MR) (functional Magnetic Resonance Imaging) BOLD eftect with T2" rain imagi Jack Belliveau:The New Mind Reader Jack belliveau was a scientist who shed new ligh on the thought processes of the human brain The Pioneer in Functional MRI edit K 天然药物化学教研室史清文教授
河北医科大学药学院 天然药物化学教研室 史清文教授 6 功能性磁共振成像（fMRI) (functional Magnetic Resonance Imaging） Seiji Ogawa (小川 誠二) the father of modern functional brain imaging Cover of November 1991 Science with an artist's rendition of the landmark paper by J. Belliveau The primary form of fMRI uses the bloodoxygen-level dependent (BOLD) contrast, discovered by Seiji Ogawa in 1990. PNAS. 1992, 89 (13): 5675–79 小川 誠二 Jack Belliveau: The New Mind Reader John (Jack) Belliveau 1959-2014 Dr. Belliveau had recently developed a technique to track blood flow in the brain, which he called dynamic susceptibility contrast, using an MRI machine. John (Jack) Belliveau 1959-2014 Belliveau also pioneered multimodal imaging, exploring the workings of the brain with combinations of fMRI and other imaging techniques Jack Belliveau was a scientist who shed new light on the thought processes of the human brain 邝健民 Kenneth Kin Man Kwong Harvard Medical School Most researchers credit Kwong and Ogawa independently with the discovery of what is now called Functional MRI (fMRI). The Pioneer in Functional MRI PNAS. 19992, 89 (12): 5951–5955 fMRI 读心技术-未来是否可以 成为法庭上的证据？ fMRI: Still Not a Mind Reader fMRI “Mind Reader”? Are you lying?
河北医科大学药学院 Mind-reading brain-decoding tech 历史上中毒事件 he Death of ra苏格拉席之死 "Devi's Bread魔鬼的面包” "Angel of Death"-Digoxin "Devil's Porridge鬼的 马钱子碱Strychninet中毒 塑造历史的谋杀案 一葡·斯坦福的死亡奇案 活 天然药物化学教研室史清文教授
河北医科大学药学院 天然药物化学教研室 史清文教授 7 Mind-reading brain-decoding tech Scientists Can Now Read Your Thoughts With a Brain Scan 大脑活动的可视化 历史上中毒事件 The Death of Socrates 苏格拉底之死 "Devil's Bread 魔鬼的面包" The Death of Socrates苏格拉底 coniine毒芹碱 "Devil's Porridge 魔鬼的粥" 公元前469-399年 "Angel of Death"- Digoxin Charles Edmund Cullen (1960-) is an American serial killer. Cullen confessed to authorities that he killed up to forty patients during the course of his sixteen-year career as a nurse in New Jersey. Experts have estimated that Cullen may ultimately be responsible for 400 deaths, which would make him the most prolific serial killer in recorded history. He is currently serving a sentence of life in prison without parole for over 100 years, to be served consecutively with his other sentences in Pennsylvania. 马钱子碱Strychnine中毒 Agatha Christie (1890～1976） 英国女侦探小说家、剧作家，三 大推理文学宗师之一：《东方快 车谋杀案》和《尼罗河谋杀案》 Halil Turgut Özal (Turkish，1927-1993) was the 8th President of Turkey from 1989-1993 N N H H H O H H O 马钱子碱（strychnine） David Starr Jordan (1851-1931) The founding president of Stanford University Jane Elizabeth Lathrop Stanford (1828 –1905) She funded and operated the university almost single-handedly until her mysterious death in 1905 塑造历史的谋杀案 —简•斯坦福的死亡奇案 N N O O H H H H H Strychnine
河北医科大学药学院 西加鱼中毒事件 Ciguatera Fish Poisoning Saxitoxin (STX PSP). 我们能称一个分子吗？ Mass Spectrometry 质谱是什么？ What is a Mass Spectrum? n. aDHPERfSOFM5 合的—是什么？ ，茶、、 七上 天然药物化学教研室史清文教授 8
河北医科大学药学院 天然药物化学教研室 史清文教授 8 西加鱼中毒事件 石房蛤毒素因中毒后产生麻痹性中毒效应，又称麻痹性贝毒 (Paralytic shellfish poison，PSP)。它是海洋生物中毒性最强烈的麻痹性毒 素之一， 0.5 mg即可使人毙命，其毒力与神经毒气沙林相同，STX在国际 条约中已被列为化学武器。作为潜在的化学生物战剂。It was used by the Central Intelligence Agency, CIA) from the 1950’s to 1975 in “suicide pills” Saxitoxin (STX) N N H N N H NH2 H2N O H OH OH H H + + 1 6 8 H H2N O 11 President Kennedy's Death A poison arrow-assisted homicide? 血红蛋白Hemoglobin是个大分子，但它的质量也只是10-19g，我们如 何去称它的质量？如何能用显微镜去看它的结构？ 我们能称一个分子吗？ 316 Mass Spectrometry • Analytical method to measure the molecular or atomic weight of samples 质谱是什么？ 质谱的基本概念 1、质谱是什么？ Mass Spectromety 特殊的天平：称量离子的质量。 质谱学：研究气相离子结构、性质及反应行为的科学。 2、质谱能做什么？ 定性：化合物的结构——是什么？ 定量：混合物的组成——是多少？ 领域： 化学、生物学、医学、药学、环境、物理、材料等 3、质谱的独到之处是什么？ 4S特性： Sensitivity 灵敏 Speed 快速 Specificity 特异 Stoichiometry 化学计量 318 What is a Mass Spectrum?
河北医科大学药学院 Application of Mass Spectrometry 质谱发展史 1898 W.Wien 发见带正电着的高于来在碱场中发生偏持 191 Forensi:Toxicology,identifio fdrugs The man behind the mass spectrograph 质谱发展史 1918人L.Dempster秉用电于衰击楼术使分子高于化。 195车Arn山r.山Dempster设计的质潘分新仪 质谱发展史 质谱发展史 1981年关因受物斯补大学1934-199开度了快原子麦击 (Fast-atom-bombardment Mass Spectrometry,FAB-MS 应厕，装好地解决了易分解的化合斯的质谱测定。 chael Barber 天然药物化学教研室史清文教授 9
河北医科大学药学院 天然药物化学教研室 史清文教授 9 • Biotechnology: the analysis of proteins, peptides, oligonucleotides • Pharmaceutical: drug discovery, combinatorial chemistry, pharmacokinetics, drug metabolism, drug degradation product analysis • Clinical: Therapeutic drug monitoring, neonatal screening, haemoglobin analysis, drug testing • Environmental: Pesticides on foods, water quality, food contamination • Forensic: Toxicology, identification of drugs Application of Mass Spectrometry 320 1898 W. Wien 发现带正电荷的离子束在磁场中发生偏转。 1911 J. J. Thomson 使用简单的电场-磁场组合装置, 获得了抛物线族的 质谱, 证明了20Ne, 22Ne两种同位素的存在。1906年诺贝尔物理学奖。 1918 Francis William Aston制得了第一台速度聚焦质谱仪。他获得了 1922年诺贝尔化学奖。提出每种同位素的质子和中子在结合成原子核时, 具有特定的质量亏损(并非整数值)。1922年诺贝尔化学奖。 质 谱 发 展 史 Joseph John Thomson (1856-1940) 1906 NP F. W. Aston （1887-1945）1922 NP The man behind the mass spectrograph Francis William Aston热爱运动，定期到瑞士、挪威等地参加越野滑 雪、滑雪等冬季项目; 花了相当多业余时间投入到自行车运动中。他还参 与游泳、高尔夫(尤其是在剑桥与卢瑟福等同事一起)、网球等运动，并且 在英格兰、威尔士和爱尔兰举行的一些公开赛中获奖。1909年，他到檀香 山学习冲浪。出身于音乐世家的他，能够弹奏钢琴、小提琴和大提琴，时 常在剑桥演出。另外，他还热衷于在世界各地旅行。 322 1918 A. J. Dempster 采用电子轰击技术使分子离子化。 质 谱 发 展 史 1945年Arthur J. Dempster 设计的质谱分析仪 323 质 谱 发 展 史 1981年英国曼彻斯特大学(1934-1991)开发了快原子轰击 电离(Fast-atom-bombardment Mass Spectrometry, FAB-MS) 应用，较好地解决了易分解的化合物的质谱测定。 Michael Barber Wolfgang Paul (1913-1993) 1989 NP Hans Georg Dehmelt (1922-2017) 1989 NP 质 谱 发 展 史 They co-developed the non-magnetic quadrupole mass filter which laid the foundation for what is now called an ion trap. 100多年的质谱史，已有11个诺贝尔奖授予了与质谱技术的诞生和发展以 及有关应用方面的研究
河北医科大学药学院 质谱发展史 质谱发展史 a咳 新复福大季的C 孕药之父 洋枝水基定天格产物结构的开起者。 在天 How are mass spectra produced? How does a mass spectrometer work? Mass Spectrometer Principles Create ions Separate ions Deteet ion Sample Datab MALDI ata system 质谱仪框图Components of MS 质谱 进样系Sample Inlet Mass Spectroscopy ◆确定分子量V (Low Resolution) ◆骑定分子式MF(High Resolution) 加速区 ◆了解分子内原子连接的详铜情况 Output 质量分析on separatio丽 Unsaturation Number (UN) 酸制Detector Hydrogen Deficieney Index(HDI) 天然药物化学教研室史清文教授 10
河北医科大学药学院 天然药物化学教研室 史清文教授 10 325 1960s 麻省理工学院 Klaus Biemann（1926-2016）用质谱技术鉴定了 两个具有完全相同碎片的吲哚生物碱Ajmaline 和Sarpagine,并产生了质 谱变换技术(mass spectrometric shift technique)。K. Biemann成为用质 谱技术鉴定天然产物结构的开拓者。 质 谱 发 展 史 “质谱学之父” Klaus Biemann 326 1960s 质谱在天然产物的结构鉴定中得到推广 质 谱 发 展 史 斯坦福大学的Carl Djerassi—避孕药之父 翟若适，杰拉西 327 Mass Spectrometer Principles Ionizer Sample + _ Mass Analyzer Detector Data system How are mass spectra produced ? 328 How does a mass spectrometer work? • Ionization method – MALDI – Electrospray (Proteins must be charged and dry) • Mass analyzer – MALDI-TOF • MW – Triple Quadrapole • AA seq – MALDI-QqTOF • AA seq and MW – QqTOF • AA seq and protein modif. Create ions Separate ions Detect ions • Mass spectrum • Database analysis 329 计算机数据 处理系统 真空系统 加速区 进样系统 离子源 质量分析器 检测器 质谱仪框图Components of MS Ionisation source Ion separation Detector Output Sample Inlet 330 质 谱 Mass Spectroscopy 确定分子量 MW (Low Resolution) 确定分子式 MF (High Resolution) 了解分子内原子连接的详细情况 Unsaturation Number (UN) Hydrogen Deficiency Index (HDI)