一、精准医学时代已经到来 去年伊始，美国总统奥巴马启动“精准医疗计划”，推动个体化基因组学研究，掀起了全球精准医学的热潮。随后，国家卫计委和科技部先后召开精准医学战略研讨会，对精准医学列为“十三五”健康保障发展问题研究的重大专项进行论证。这标志着精准医学时代已经到来！ 精准医学时代真的来了吗？奥巴马说，来了！科学大咖们说，确实来了！风险投资家说，真的来了，我们也来了！ 我想说的是，在基因组的临床应用方面，“精准医学时代”似乎是来了，但是严格意义上的“精准医学时代”远远没有到来，例如，普通感冒是最常见的疾病了，我们现在能够精准预测它的发生发展了吗？ 二、普通感冒引发的思考 普通感冒的医学名称是上呼吸道感染，包括鼻腔、咽或喉部急性炎症的总称。 70% ～ 80% 的上呼吸道感染是由病毒引起的，包括鼻病毒、冠状病毒、腺病毒、流感和副流感病毒、呼吸道合胞病毒、埃可病毒、柯萨奇病毒等。感冒诱发的过程是，受凉、淋雨、气候突变、过度疲劳等导致全身或呼吸道局部防御功能降低，使得原已存在于上呼吸道的或从外界侵入的病毒或细菌迅速繁殖。 简单的说，感冒是由病毒或细菌引起的，但是我们不可忽视的细节是：在正常情况下，病毒与机体是处于一种平衡的共存状态。 这是一种怎样的共存状态呢？这不禁让我想起了一部 BBC 纪录片： The Hidden Life of theCell 。智人的历史大概十几万年，而病毒在地球上已存活了三十亿年。每时每刻，你的身体中正进行着一场大战，这是起源于几十亿年前的战斗—— 病毒入侵细胞的生死之战 。 三、病毒入侵细胞的“精准”研究 严格来讲，病毒入侵细胞的过程是一个动力学过程。如果要 精准预测 病毒与细胞生死之战的胜负，就得把这个动力学过程搞清楚。下面粗略介绍下病毒入侵细胞的动力学研究进展（摘自 博士学位论文，王开发，病毒感染动力学模型分析，2007年，西南大学 ）。 第一阶段，病毒在宿主内增殖。增殖过程通常会受到宿主理化屏障或捕食者和竞争者的限制和约束，比如皮肤粘膜机械屏障、补体、粘膜表面分泌型抗体（ slgA ）、吞噬细胞、 T 细胞、其他微生物的存在等。 第二阶段，病毒和宿主免疫系统均发生进化：一方面，病毒介导的自然选择使宿主特异性捕食者（如 B 细胞， T 细胞）增殖；另一方面，在宿主免疫压力下，病毒种群也发生选择，导致变异株的不断涌现。病毒与宿主各种因素之间相互作用的力量偏向，决定病毒种群是受到控制还是被清除；是停留于一定水平（宿主发病），还是大量繁殖导致免疫防御失败（宿主死亡）。 在 病毒感染的基础数学模型 中，设 x 代表未感染目标细胞数量， y 代表被感染细胞数量， v 代表游离病毒数量， N 代表一个被感染细胞在它的生命周期内产生的游离病毒平均数，参数 d ， a ， u 分别为未感染细胞、感染细胞和游离病毒颗粒的死亡率：β是未感染细胞和游离病毒颗粒的接触率。它们之间的关系为： 在 免疫调节的数学模型 中，增加以下几个变量： z 代表细胞毒性 T 淋巴细胞反应的强度，参数 p 则代表细胞毒性 T 淋巴细胞杀伤感染细胞的速率，数学模型调整为： 在 免疫调节滞后的数学模型 下，在 药物治疗的数学模型 下，需要不断增加变量。而人体本身是个非常复杂的系统，如果把机体内各种因素综合考虑在一起，病毒感染细胞的动力学模型将会 无限复杂 。 这样类型的“精准”研究什么时候才能计算出普通感冒的发生发展呢？ 10 年后？ 20 年后？不知道，笔者只能长叹一声：吾生也有涯，而知也无涯（当然还有 keng die 的后半句）， 精准无止境也 。 后话：为什么要讲这个故事呢？在上述博士论文的结论中提到：病毒感染后，病毒和细胞数量的平衡点和周期波动都可能出现。同时随着时间滞后效应的增加，稳定点被突破，并最终导致 混沌模式 的出现。（ 是否也存在蝴蝶效应呢？ ） 敬请持续关注我的博客和微信公众号：“非线性科学与医学沙龙”。
寻正 现代社会中食疗这个古老的观念被持续地滥用，使用食疗进行商业欺诈是如此普遍，以致于中国不少缺乏相关专业系统训练的科普作者有全盘否认食疗，倒洗澡水把婴儿一并扔掉的趋势。 食疗是现代医学不可或缺的一部分。如果现代医学用食疗治病，相应的食疗方案就是治愈、减缓、以及控制疾病的灵 丹妙药，其地位与效果没有其它方式可以取代。这里我报告一个分子水平的食疗案例，它可以清晰地表明现代医学能够，也会在将来为中国的普通民众提供的救命良方。限于目前中国的医疗水平，此类良方对绝大多数中国人可望而不可及。 这一案例发表在《新英格兰医学杂志》上，作者为灰尔润医生（ Dr. Marsha K. Fearing ）等人 ( N Engl J Med 2011; 364:1545-1556). 一个顺产婴儿在 9 个月时发病前都健康地成长，发育正常，按照美国推荐接种方案接种了各种疫苗。在入院一个月前他有过一次呼吸道感染，然后就是两天前开始发病，有“乏力、烦燥、鼻涕、间断呕吐、以及无血性腹泻”等症状，都是婴幼儿普通 的病毒感染（比如感冒）中常见的症状。因此，在当地一家诊所他得到对乙酰胺基酚（婴儿泰诺）的治疗。 一天后，其症状加重，父母把他带到了麻省总医院的急诊科。其体检显示体温稍高，而其它则无异常。医院里详细的实验室、 CT 、与超声检查都没有发现太多异常，唯一的异常发现是“显著增大的肝脏伴有弥漫性的低衰减，表明肝脂浸润与胆囊周围积液。”译成常人能懂的语言，即肝脏怀疑有脂相关性病变。 接着医生试图检查是否有病毒的肝感染，未能发现任何东西。他的情况进一步恶化，而进一步的化验与 CT 检查总是显示正常结果。他的肝衰很明显，但医生找不到原因。泰诺中毒导致肝衰在小儿很常见，但是在这一案例中被实验室检查基本上排除了。 如果他在世界上其它大多数国家，他会被诊断为不明原因的肝衰而不得不接受很快死亡的命运。在医院的重症监护室里，他很快就陷入了肝昏迷，对疼痛都没有反应。 即使在美国，可能有半数的幼儿肝衰没有清楚的诊断。另外，肝衰的已知的常见原因包括药物中毒，占 16% 左右，代谢性疾病占 10% ，病毒感染占 6% ，以及缺血缺氧占 4% 。在未明确诊断的病人中，多估计为代谢性疾病，自身免疫性疾病也是一个重要的原因。 医生进一步排除了这个小患者的其它病因可能，而关注于代谢性疾病。代谢性疾病中常见的有胆汁淤积、脂氧化障碍、胆固醇酯储存障碍、糖原储存障碍、以及囊性纤维化。如果他年龄再大一些，超过 3 岁，那么威尔逊病（一种铜沉着病）就是首要考虑对象，这种遗传性疾病是在青年与少儿中最常见的引起肝衰的代谢性疾病。 通过排除法，医生把肝衰的原因归结到两种情况之一，要么是脂肪酸氧化障碍，要么是胆固醇酯储存障碍。这时，他们不得不进行了肝活检。由于肝生产凝血因子，肝衰时就处于低凝状态，若有出血，则不易止血，因此肝活检有不少风险。 肝活检的病理检查包括电镜检查显示其肝脏有弥漫性大泡及小泡脂肪沉积，脂肪在他的肝细胞内积累，太多的脂肪会把其它的细胞结构挤走，最终细胞会功能失常及死亡。 肝细胞脂肪沉着仍然是一个粗糙的诊断，因为同样地有许多原因可以造成脂肪沉积。脂肪在线粒体（相当于细胞中的电厂，为其它活动提供能量）中代谢，其分解过程包括氧化磷酸化、脂肪酸氧化、与尿素生成。任何一个过程出了问题，都会导致脂肪不能完全分解，从而积累在肝细胞中。药物与毒素会造成脂肪沉积，比如，阿斯匹林、丙戊酸（一种抗癫痫药）、四环素、铁中毒或过量。在成年人如果过分爱好杯中物，酒精很容易通过细胞膜，能干挠许多正常的生理功能，包括脂代谢，酒精刺激脂细胞内的脂质溶解，脂质被搬运到肝脏后同时又抑制它们在肝中的分解，从而导致了脂质沉着。如果你难舍弃杯内物，就当牢记每天一两白酒已经是你能承受的上限，超过则会产生脂肪肝。在这个小孩，这些药物与毒素因素都被排除了。 在排除外在的因素后，医生剩下的是内在的总是由基因缺陷引起的代谢障碍。其中值得一提的是 LCHAD 缺陷，它是常染色体隐性遗传。 LCHAD 学名叫长链 3- 羟基 / 辅酶 A 脱氢酶。此酶的缺乏导致中长链脂肪酸的沉积。它发生在胎儿（孕中后期），当胎儿不能分解那些脂肪酸时，就会将它们释放出来，通过胎盘流到母亲的肝脏。即使母亲的肝脏功能正常，也可能不能负担这么多的额外脂肪分解，从而产生所谓的妊娠急性脂肪肝。在以前，爆发的妊娠急性脂肪肝中者无救，随着现代医学的认知能力与技术水平的提高，现在 80% 的母亲都能得保全。 在婴儿，目前所知有六种代谢疾病涉及各种脂肪代谢过程中的酶。根据临床表现，医生把诊断限定在两种： CACT 与 CPT2 的缺陷。这两种缺陷导致极长链的脂肪酸在肝内沉积。美国著名的贝勒医学院的科学家对该小儿的基因进行了测序，发现其编码 CACT 的基因（ SLC25A20 ）中有三个突变而 CPT2 的基因没有问题。这种疾病目前在世界上准确诊断出来的，不到 30 例。 CACT 是肉碱 / 酰基肉碱移位酶的简称。它是协助长链脂肪酸通过线粒体膜的三个酶（ CPT1/CACT/CPT2 ）之一，前面已交待，线粒体是燃烧脂肪产生能量的细胞器。肉碱在其中也起决定性作用，人类大约 75% 的肉碱来源于肉类、奶制品、以及豆类产品，只有 25% 为自体产生。 当分子水平的诊断明确以后，对这位小病人的治疗就出乎意料地简单。显然，他不能摄入长链脂肪，他的食谱中就只含有极少量的长链脂肪。医生还给他开了熊去氧胆酸，抑制脂肪的吸收，进一步减低长链脂肪酸的摄入。如果我们禁食，我们的身体就会尝试燃烧脂肪，这种现象必须预防，因此，小病人就需要多次进食，不制造饥饿动员身体脂肪的机会。他的人食谱中还额外加入肉碱，以增强他仅剩下的代谢长链脂肪的能力。 在该案例发表时，这个小孩已经 3 岁了，健康成长没有后遗症。如果他没有获得准确诊断，他就可能死于他吃的食物，分子水平的诊断与食疗拯救了他的生命。这就是国人在未来可能获得的医疗。 The Age of Molecular Level Nutritional Therapy Nutritional therapy is an old idea that has been constantly abused in modern society. There is a general trend among Chinese science writers to reject the idea of nutritional or food therapy altogether because of the rampant abuse by scammers of nutritional therapy. Nutrition is an integral part of modern medicine. When nutritional therapy is indicated, the specific nutritional approach is indeed the silver bullet that cures, alleviates, and contains diseases. Their roles in medicine are non-substitutable. I report here of a case of molecular level nutritional therapy, which clearly illustrate what modern medicine can and will offer. This case is published in New England Journal of Medicine by Dr. Marsha K. Fearing and colleagues ( N Engl J Med 2011; 364:1545-1556). A healthy baby was delivered full term and lived a perfect healthy life until he was 9 month old. He was following regular vaccination schedules and developed normally. He had a respiratory infection one month before this admission. Then two days before admission, he developed symptoms including “lethargy, irritability, rhinorrhea, intermittent vomiting, and nonbloody diarrhea”, nothing you would not expect out of a usual virus infection (common cold) of babies and small children. Therefore, he was treated as such with acetaminophen (infant Tylenol). After one day, the symptoms progressed and he was brought to emergency department of Massachusetts General Hospital. His physical examination revealed slightly increased temperature and everything else was about normal. He underwent many lab screening tests, CT, and ultrasonography extensively of multiple organs. The only significant findings are “a markedly enlarged liver with diffuse hypoattenuation consistent with fatty infiltration and pericholecystic fluid.” In common language, the liver is suspected to have problems related to fat. The child was then screened for multiple viruses that could potentially cause liver infection and none was identified. His condition continued to worsen while expanded lab and CT tests always come back as normal. He was experiencing liver failure but the doctors had been struggling to identify the cause. Tylenol toxicity was a common cause for liver failure in children, however, this possibility was ruled out with lab test early on. Had this baby been in most of the other countries in the world, he would be diagnosed as liver failure with unknown cause and quickly accepted his fate. He had quickly become stuporous upon admitting to intensive care unit and unresponsive to pain stimulation. Even in U.S., about half of liver failures in children were without a clear diagnosis. Otherwise the common cause of liver failure includes drug toxicity (mainly acetaminophen) for 16%, metabolic disorders for 10%, viruses for 6%, and ischemia for 4%. The most common cause for those with indeterminate diagnosis is suspected as metabolic diseases. Autoimmune diseases also contribute significantly to liver failure with unknown diagnosis. The doctors did extensive studies of this young patient that excluded diagnoses other than metabolic disorders. The common causes of metabolic disorders include cholestasis, fatty-oxidation defects, cholesteryl ester storage disease, glycogen storage diseases, and cystic fibrosis. If this child was older—close or up to 3 years of age, Wilson’s disease where copper accumulation in tissues would be considered. This genetic disease is the most common cause of liver failure among metabolic conditions for older children and young adults. By exclusion, the doctors narrowed the cause of liver failure in this child down to two conditions, either fatty acid-oxidation defects or cholesteryl ester storage disorders. Then they performed a liver biopsy, which is risky under this critical condition. Many of the coagulation factors are produced by liver. When the liver fails, the blood is anti-coagulated, i.e., it takes longer time for blood to form blood clots to stop bleeding. With electron microscopy and other pathological examination, the child was diagnosed as diffuse microvesicular and macrovesicular steatosis (small bubble and big bubble fat accumulation). Fat had been accumulating in his liver cells. Too much fat in cells will drive out everything else. The cells will malfunction and ultimately die. A diagnosis of fat accumulation in liver cells is still a crude diagnosis because there are numerous factors could contribute to the diagnosis. Fat metabolism involves the mitochondrial system, including oxidative phosphorylation, fatty acid oxidation, and ureagenesis. Any of the processes go wrong, fat cannot be breakdown in the liver cells, it will accumulate. Drugs and toxins can cause steatosis. For example, aspirin, valproic acid, tetracycline, and iron overload and poisoning can cause steatosis. For common knowledge, if a fatty liver happens in adults, alcoholism is one of the most common causes. In this child all the drug and toxin causes had been ruled out. After drugs and toxins excluded, doctors were left with intrinsic metabolic defects that are always caused by genetic factors. One of such conditions is worth mentioning is LCHAD deficiency. It’s an autosomal recessive disease. LCHAD stands for long-chain 3-hydroxyacyl-coenzyme A dehydrogenase. Lack of this enzyme causes accumulation of medium and long chain fatty acids. It happens in fetus. When fetus cannot breakdown those fatty acids, they are kicked back to the mother through the placenta. When mother’s liver is overwhelmed, it fails, causing what is called acute fatty liver of pregnancy. Traditionally, the mother always dies. With modern technology, four out of five can survive. Currently there are six known disorders involving various enzymes for fatty metabolism in infants. Based on clinical presentation, doctors narrowed down their diagnoses to two, CACT and CPT2 deficiency. Either condition will cause accumulation of very-long-chain fatty acids in the liver. Scientists at Baylor College of Medicine sequenced genes of the child. It was found that the gene coding CACT (SLC25A20) contains three mutations while CPT2 gene was intact. This condition was identified less than 30 cases worldwide. CACT stands for carnitine acylcarnitine translocase. It is one of three enzymes (CPT1/CACT/CPT2) that facilitate transportation of long-chain fatty acids into mitochondria to be breakdown for energy. Carnitine is critical for the process. Humans acquire 75% of their carnitine from meat, dairy, and soybean products. Once the diagnosis is elucidated on molecular level, the treatment is unbelievably simple. One thing he cannot have is long-chain fatty acids. His dietary consists of very low content of long-chain fatty acids. The doctors also put him on ursodeoxycholic acid, a medication that reduces fat absorption. When we fast, the body tends to burn fat for energy, which was to be avoided in this child. He was suggested to take frequent meals. His dietary is also supplemented with carnitine, which enhances his limited capability to metabolize long-chain fatty acids. At the time of publication of this case, this child was 3 years of age and developed very well. Had the doctors not been able to make an accurate diagnosis, the boy may have died from the food he ate. Molecular level diagnosis and dietary therapy saved his life. This is one of our futures in medicine.
标签: 病毒感染
