英国巴斯大学（University of Bath）的Momna Hejmadi 2016年6月17日在《谈话》（The Conversation）杂志发表了一篇题为“为什么某些癌症突然会不治自愈（Why do some cancers suddenly disappear without treatment?）”的文章。癌症的突然消失，它究竟到哪里去了呢?前不久，自己也写过“从一个晚期癌症病人奇迹般康复的故事谈起 ”的博文，今天就某些癌症突然不治自愈现象进行相关信息的编译，供大家参考。
某些癌症在尚未得到治疗的情况下，奇迹般地消失了，这种情况很难令人相信,但它确实发生了。上千个有关癌症患者的研究文档，这些患者都经历过肿瘤自然复原的经历。为什么会这样,合理解释其原因会使癌症患者从中得到启示吗?
癌症不治自愈的最早案例是在13世纪末，Peregrine Laziosi的一位骨肉瘤（bone sarcoma）患者，严重的细菌感染之后，骨肉瘤自发地消失了。在19世纪末,威廉·科利（William Coley）发现发烧有可能导致肿瘤消失。他开发了一种细菌疫苗，这种疫苗被称之为“科利疫苗(Coley's vaccine) ”, 成功地使其患者当中的许多肿瘤患者肿瘤缩小。
肿瘤自动消失并非什么新鲜事，一直为人所知。就是在癌症的靶向治疗还不存在时，就已经知道肿瘤会自动消失之事了，而且通常是在感染之后消失的，感染包括细菌感染、病毒感染、真菌感染或甚至原生动物的感染（protozoal infection）。这是否意味着仅仅是简单地刺激免疫系统就会使肿瘤改邪归正吗?
没有那么简单
在过去的70年里,对于各种类型的癌症自发复原的报道频频出现,而且特别是在皮肤癌的黑素瘤(melanomas)、肾细胞癌(renal cell carcinomas)、肾上腺成神经细胞瘤(neuroblastomas)以及某些类型的血癌方面报道更多一些。然而,尽管有这些肿瘤复原的历史观察报道,但我们仍然不知道导致这一现象的机制。由于很难量化,很多案例不可能在研究性期刊上报道。
肿瘤自然复原或者衰退的一种可能的原因，那就是患者身体触发了一种针对在肿瘤细胞表面显示的特定抗原的免疫反应。某些恶性黑色素瘤的观察结果支持了这种观点，是因为在肿瘤内发现人体的免疫细胞数量极高。
另一个有趣的病例报告是一位肾癌患者，对其肿瘤实施过部分手术切除,导致尚未切除的肿瘤其他部分慢慢自然复原。这个现象背后的基本原理是手术后，局部免疫反应就足以阻止尚未切除的其他肿瘤的增长。
但众所周知，肿瘤的变化是赫赫有名的，无论是在其遗传学还是在其习性上，都是变化多端,从而导致使一些人的病情在不断恶化,但也可能使另外一些人的病情自然康复。相同类型的肿瘤(如乳腺癌)可以许多不同的方式发生变异。这可影响肿瘤生长的速度，或者扩散到不同位置的可能性,或他们对于治疗有何反应。就肿瘤复原而言，也很有可能与基因突变有关。
一种罕见的儿童癌症提供了一些线索
神经母细胞瘤（Neuroblastoma）是儿童最常见的颅外肿瘤，是婴幼儿最常见的肿瘤。有将近一半的神经母细胞瘤发生在2岁以内的婴幼儿。神经母细胞瘤约占6%~10%的儿童肿瘤，但是占儿童肿瘤死亡率的15%。对于4岁以下儿童，每100万人口的死亡率为10例；对于4-9岁儿童，每100百万人口的死亡率为4例。神经母细胞瘤属于神经内分泌性肿瘤，可以起源于交感神经系统的任意神经脊部位。其最常见的发生部位是肾上腺，但也可以发生在颈部、胸部、腹部以及盆腔的神经组织。目前已知有少数几种人类肿瘤，可自发性地从未分化的恶性肿瘤退变为完全良性肿瘤。神经母细胞瘤就属于其中之一。对于神经母细胞瘤的转化或者自然消失作何解释，也是一个备受关注的问题。在英国每年有大约100个孩子被诊断为患有神经母细胞瘤,但是不同年龄的孩子，疾病进展大不相同。18个月以内的儿童无论采取或没有采取任何治疗，肿瘤都可以消失，这种类型称其为1型；但孩子年龄超过18个月需要强化治疗,而且存活率只有40%~50%，这种类型称其为2型。
研究表明,1型与2型神经母细胞瘤，它们有截然不同的基因特征。例如,这些肿瘤通常有很高的细胞受体(TrkA)数量，而细胞受体(TrkA)可以触发肿瘤细胞杀死自己。相比之下,2型神经母细胞瘤有更高数量的不同受体(TrKB),这种受体会使肿瘤更加放肆、更为活跃。TrkB为酪氨酸激酶受体B,是目前人们已经克隆出来3种酪氨酸激酶受体(Tyrosine kinase receptors, TRKs),即TrkA、TrkB及TrkC之一,是脑源性神经营养因子(brain-derived neuro-trophic factor, BDNF)的特异性受体。近年研究发现许多肿瘤中可见TrkB的过度表达或过度激活,除了神经母细胞瘤之外、还有多发性骨髓瘤等也有TrkB的过度表达或过度激活特征。
关于1型与2型神经母细胞瘤不同的另一个可能的解释：1型和2型神经母细胞瘤相比较，1型显示出端粒酶（telomerase）的活性水平非常低。端粒酶是在细胞中负责端粒延长的一种酶，是基本的核蛋白逆转录酶，可将端粒DNA加至真核细胞染色体末端。端粒酶可以把DNA复制的缺陷填补起来，藉由把端粒修复延长，可以让端粒不会因细胞分裂而有所损耗，使得细胞分裂的次数增加。端粒在不同物种细胞中对于保持染色体稳定性和细胞活性有重要作用，端粒酶能延长缩短的端粒(缩短的端粒其细胞复制能力受限)，从而增强体外细胞的增殖能力。端粒酶在正常人体组织中的活性被抑制，在肿瘤中被重新激活，端粒酶可能参与恶性转化。端粒酶在保持端粒稳定、基因组完整、细胞长期的活性和潜在的继续增殖能力等方面有重要作用。实际上端粒酶就是控制专业DNA片段的长度，使细胞不断分裂。在1型神经母细胞瘤中,由于端粒酶活性低，难以使端粒延长，使其非常短，而且不稳定，无法使细胞继续分裂，诱发细胞死亡。
表观遗传变异（Epigenetic changes）无论是1型还是2型神经母细胞瘤都不能排除。表观遗传变异不影响细胞的DNA序列,但通过对DNA的不同部分加以标记，来修改各种蛋白质的活性。所以具有相同DNA序列,但具有不同的标签的细胞，可使表现完全不同,导致一些肿瘤自杀。最近研究显示，1型和2型神经母细胞瘤相比，标记基因存在显著差异,尽管这些都是一些初步研究结果。
虽然某些肿瘤自发复原的准确机制仍不确定,但是，在具有某些遗传特征的人群当中，刺激强烈的免疫反应很可能在其中扮演了重要角色。进一步的研究探索遗传学和刺激免疫反应之间的关系，将会对如何认识肿瘤具有自发地复原能力提供答案。下一步将是设计可以人为地刺激免疫系统，根据其基因组成设计专门针对肿瘤药物。开发动物模型,模拟人体自发复原将是一个向此方向靠近的非常宝贵的工具。
更多信息请浏览：The Conversation原文。
相关报道：
免疫疗法：强大自身墙堡 不再谈癌色变
免疫系统(immune system)可以是一个对抗癌症(cancer)的强大武器，但如何控制它仍是研究人员需要努力解决的问题。本篇介绍如何利用人体自身免疫系统(immune system)进行癌症(cancer)治疗。
第一个肿瘤是一个小型黑色素瘤(melanoma)，长在马克戈尔曼（MarkGorman）脖子左侧上。医生将它切除了，并向戈尔曼保证，癌症(cancer)已经治好了。
但八年之后，在一次例行体检中，医生看着戈尔曼的腹部，皱起了眉头，问他是不是一个酒鬼。黑色素瘤(melanoma)已经扩散到戈尔曼的肝脏，缠绕在下腔静脉中，形成一个不能通过手术切除的危险肿瘤。
通常确诊患有晚期黑色素瘤(melanoma)的人只能活六到十个月。已经49岁的戈尔曼，没有听从医生建议去安排他的后事。当他的妹妹告诉他有一种叫白细胞介素-2（IL-2）的药物，被科罗拉多州的医院用在抗黑色素瘤(melanoma)的化疗上时，他离开他的家乡，想碰碰运气。
IL-2，是一种被称为T细胞免疫应答的白细胞产生的蛋白质。服用高剂量的IL-2会使T细胞加速成熟，这让它们更容易识别并攻击癌细胞。戈尔曼的癌症(cancer)被治好了，15年都没有复发的迹象。“医生说我的免疫系统(immune system)非常灵敏，”他说“但我只知道，我很幸运。”
延续戈尔曼生命的药物，是首个通过美国食品和药物管理局(FDA)批准的药物，这种治疗方式被称为免疫治疗技术。1992年批准后，研究人员和制药公司多年以来一直努力开发新免疫疗法，希望戈尔曼式的奇迹能够再次发生，但是数十年来都未能如愿。
现在潮流似乎正在逆转。在过去的五年里，临床试验显示，新一代的方法有望治疗几种不能被常规手法治疗的癌症(cancer)。一些分析人士预测，在接下来的十年里，免疫疗法将用于60%晚期癌症(cancer)的患者，并将形成一个350亿美元的市场。“这很疯狂，”Jounce Therapeutics的首席执行官卡里菲费尔（Cary Pfeffer）说，“这一领域已经很拥挤了。这是太疯狂了。”
但早期的药物使用经验提醒许多研究者和临床医生要小心谨慎。尽管有奇迹的产生，但是使用IL-2后完全缓解的只有大约6%的黑色素瘤(melanoma)患者，多达2%患者死去。研究人员正竞相寻找方法来提高接受免疫治疗的病人的数量和减少危险的副作用。“好消息，同时也是坏消息，人体的免疫系统(immune system)非常强大。”Jounce的首席医疗官罗伯特-珀说。
挫败
癌症(cancer)免疫治疗始于1891年，纽约外科医生名威廉姆科利（William Coley）将细菌注入病人的肿瘤，希望引发也会攻击肿瘤的免疫反应的感染。前人有提到感染后癌症(cancer)缓解的现象，科利渴望知道这种治疗性力量。
这一点也不简单。肿瘤有许多防御抗癌免疫系统(immune system)的武器：T细胞的功能是找出并消灭有问题的细胞，但癌细胞会伪装自己，使T细胞很难找到他们。肿瘤也抵挡表达蛋白质的免疫攻击，抑制周围的环境中的T细胞。
几十年来，研究人员追寻对付癌细胞的疫苗(vaccine)。但是那些努力大多失败了：FDA唯一批准的治疗癌症(cancer)疫苗(vaccine)是一个复杂且昂贵的前列腺癌(Prostate Cancer)疗法。它的好处倍受争议。
2011年，这个领域出现了一个新拐点，FDA批准一种新的免疫治疗（immunotherapeutic）药物。Ipilimumab是一种单克隆抗体，能有效阻滞一种叫做细胞毒性T细胞抗原-4（CTLA-4）的分子。CTLA-4会影响人体的免疫系统(immune system)，削弱其杀死癌细胞的能力。Yervoy（Ipilimumab的商品名）的作用机制可能是帮助人体免疫系统(immune system)识别、瞄准并攻击黑色素瘤(melanoma)癌细胞。
与IL-2一样，Yervoy可以带来持续的免疫反应。詹姆斯·埃里森（James Allison）说，一些参与最初试验的患者已经缓解了13年。但这些奇迹只发生在一小部分（大约8%）的病人身上。虽然Yervoy可以唤醒T细胞来对抗癌症(cancer)，但是有时也会攻击健康组织。在最大的540人的试验中，多达15%的人有严重的副作用，七例致死。苏珊娜托帕利安（Suzanne Topalian）说，一些肿瘤学家倾向于不用药物治疗。
尽管如此，Yervoy方面研制出检查点抑制剂，一种抑制检查点蛋白质的药物。这促使研究人员寻找其他潜在的靶蛋白。批准Yervoy的时候，有些研究人员已经开始关注PD-1，某些癌症(cancer)用这种检查点蛋白来关闭肿瘤的周围的T细胞方阵。
早期的临床试验证实，与CTLA-4不同，PD-1直接与肿瘤细胞相互作，其抑制剂有可能更有力，而且毒性更低。由纽约的Bristol-MyersSquibb公司研发的，PD-1抑制剂nivolumab能使晚期黑色素瘤(melanoma)患者的肿瘤缩小至28%。FDA预计在2015年初决定是否批准它，或者更早。
虽然有一些副作用，但新药物的毒性比Yervoy低。有些人甚至没注意到有任何不妥。“许多病人说：‘医生，你给了我什么吗？’”曾参与PD-1抑制剂试验的黑色素瘤(melanoma)专家，安东尼·里巴斯 （Antoni Ribas）说，“等肿瘤开始消失，他们才知道。”
研究人员想要进一步推动免疫疗法。“我们希望响应率高于我们目前所拥有的，”迈克尔·波斯托（Michael Postow）说。其他检查点蛋白质的抑制剂渐渐进入临床试验，临床医生有一天可以通过患者自身的癌细胞所表达的蛋白质来匹配最佳的抑制剂。
对于其他病人，放在第一位的挑战可能是在吸引T细胞对抗肿瘤。Genentech公司的免疫疗法的发展负责人，丹尼尔·陈（Daniel Chen）说，PD-1抑制剂不做到这一点，他们只是除去了积累在肿瘤边缘的T细胞的束缚。“有些病人似乎没有免疫反应，”他补充道，“那么我们需要添加一些能产生免疫反应的东西。”
更好的结合
波斯托说，吸引T细胞的关键，是用组合疗法创建一个“发炎的”肿瘤。在临床试验中，Yervoy和PD-1抑制剂已与一系列其他的治疗方法组合，旨在激活T细胞对抗癌症(cancer)。例如，辐射破裂癌细胞并释放抗原。另一种方法，研究人员用实验性癌症(cancer)疫苗(vaccine)刺激患者的免疫系统(immune system)，疫苗(vaccine)包含由肿瘤细胞过度表达的蛋白。安东尼·马鲁西（Anthony Marucci）：“将来，癌症(cancer)疗法显然是以联合治疗主。”
检查点抑制剂也可以与一种被称为过继性T细胞转移的免疫治疗相结合。这是一种个性化的治疗，医生分离并选择那些对癌症(cancer)有反应的病人的T细胞。然后繁殖T细胞，用分子刺激它们，比如将IL-2注射到血液中。这种实验方法以肿瘤免疫(tumor immunity)学家史蒂文·罗森博格（Steven Rosenberg）为首展开，超过一半的晚期黑色素瘤(melanoma)患者缩小肿瘤，20%的患者已完全缓解。
一种更加新的T细胞转移新形式将会普及到其他癌症(cancer)。由工程提取的T细胞，表达一种称为嵌合抗原受体的人工肿瘤靶向受体。（见图：免疫增强）
但技术上的挑战限制了T细胞转移疗法的推广。目前为止，只有极少数的学术医疗中心能进行细胞转移疗法。“初步看来，我们被黑色素瘤(melanoma)患者包围，”罗森伯格说。“但我们不可能治愈所有病人。”
根据初期的试验，研究人员简化且标准化了试验方案。再加上治疗白血病的显著成绩，吸引了行业的投资者的目光。位于瑞士巴塞尔Novartis公司买了一个新泽西州的设施，处理从美国各地的患者中提取的T细胞。该设施将是公司计划扩大其临床试验的关键。规模较小的公司也纷纷效仿。2015年初，Kite Pharmaceuticals公司希望推出一种淋巴瘤的过继性T细胞转移多中心试验，该种淋巴瘤在5年内杀死了大约37%的患者。
真正的目标
过继性T细胞转移的另一个重大挑战是扩大其范围，要求发现新的分子靶点，引导T细胞对抗特定的肿瘤类型，同时保留健康细胞。该方法适用于白血病和其他影响B细胞或另一类的白血细胞的癌症(cancer)，因为研究人员可以设计出靶CD19的蛋白质的T细胞，但这仅在B细胞上适用。虽然消除癌变的细胞的同时也消除健康的B细胞，但副作用相对容易忍受。但要在固体瘤上找到类似的靶很难，因为它比液体肿瘤更不均匀的。“这是一个主要的限制条件，”里巴斯说。“我们很高兴发现CD19，但目前还不清楚下一个靶是什么。”
研究人员挖掘基因表达数据库企图找到最佳候选。但激发免疫反应的特异性蛋白可能很危险：几年前，四例患者死于工程T细胞的一系列试验中，这类T细胞会攻击表达MAGE-A3蛋白质的细胞。这种蛋白质只在胚胎和成人的某些癌细胞中表达，这似乎是一个理想的目标。但研究人员后来得知T细胞也攻击存在于心脏和大脑的类似的蛋白质。“这些T细胞是职业杀手，”阿里·贝尔德固伦（Arie Belldegrun）说。“即使目标物微量存在于正常细胞，这些超级杀手会发现这些细胞并摧毁它们。”
ImmunoCore公司，开发新的生物信息(bioinformation)学方法，寻找任何可能的迹象来表明靶细胞可以在正常组织中的表达。ImmunoCore公司也开始用三维细胞培养做最初的安全测试，更好地模拟细胞在体的生长自然环境。这种方法集合了各种癌症(cancer)20多个潜在目标。MichelSadelain希望工程T细胞靶向两种蛋白质，这两种蛋白质都必须在摧毁它T细胞上表达。 他说，一个健康的细胞的表面会有两个靶的机会微乎其微。
找到更多的靶就可以达成更多类型的癌症(cancer)免疫疗法。到目前为止，研究人员专注于黑色素瘤(melanoma)和肾癌的免疫疗法，因为在早期的试验中它们效果最好，最明显。
Rosenberg说,他正从事11起临床试验的研究，测试针对多种癌症(cancer)的过继性T细胞疗法，包括尤其致命的和罕见的间皮瘤。 2012年，当结果表明，检查点抑制剂nivolumab将某些类型的肺癌晚期肿瘤缩小至18%时，癌症(cancer)免疫疗法打开更广泛的应用大门。因为肺癌是世界上最普遍的形式的癌症(cancer)，研究结果带来了希望，免疫疗法可能在癌症(cancer)死亡上做出巨大贡献。
匹兹堡宾夕法尼亚大学的癌症(cancer)研究人员，丽莎·巴特菲尔德（Lisa Butterfield）说，对于包括肝癌在内的某些癌症(cancer)，免疫治疗方法仍是一项挑战。肝脏处理血液中的病原体和抗原，而免疫系统(immune system)小心地控制，以避免靶单个的正常细胞的反应。乳腺癌、结肠癌、胰腺癌和卵巢癌也十分擅长抑制免疫细胞。联合治疗可能会提供一种方式，绕过这些限制。
联合疗法可能癌症(cancer)疫苗(vaccine)概念的救命稻草。 癌症(cancer)研究员Willem Overwijk说，尽管疫苗(vaccine)测试到目前为止表现糟糕，他们可能会与其他免疫疗法协同作用。
经历这么多年的失败，振奋人心的免疫治疗令已经很多癌症(cancer)研究人员和患病家庭惊讶。从自身显著回复以来，戈尔曼一次又一次地挺过了癌症(cancer)的侵袭。几年前，他得到Yervoy，癌症(cancer)终于完全的缓解。
现在，戈尔曼每两年扫描一次，检查是否有新的肿瘤。今年2月可能是下一个安排的扫描时间，他也不确定，因为他已经不再担心癌症(cancer)是否会复发了。“我现在非常冷静，”他说。“我的免疫系统(immune system)已经能够控制它了。”
《纽约客》：T细胞大军
——人体免疫系统是治愈癌症的希望吗？
作者：杰罗姆·格鲁普曼（Jerome Groopman）
译者：沈逸尘
简介：这篇长文的翻译缘起于几年前看到的另一篇译文：雷声大雨点大 的《这不是不治之症－－简介淋巴癌（恶性淋巴瘤）》，也缘起于我外婆所得的肺癌。与雷大的亲人不同的是，虽然我外婆当时被医生宣判了“死刑”（只剩下两个月生命），但两年过去了，如今她已与正常人无异。而杀灭她体内癌细胞的正是本文所要谈及的人体免疫细胞——T细胞。在面对癌症时，有多少人能镇定自若？有多少人明知放化疗即使能治好癌症，也会治掉自己半条命，却别无选择？又有多少人知道除放化疗之外还有一种免疫疗法？在这里，我要说我是幸运的，碰到了正确的医生，选择了正确的疗法，我也希望能将这份幸运传递给更多饱受癌症折磨的患者，以及他们的家人，也希望更多人知道，随着医学的进步，癌症将不再是不治之症。
1890年夏，来自美国新泽西州的17岁小冒险家伊丽莎白·达希尔（Elizabeth Dashiell）乘火车横穿美国。在旅途中，她的手被夹在两个座位中间，受了伤。她的手变得肿胀和疼痛不堪，而且直到她到家后仍未痊愈，达希尔只好向纽约的年轻外科医生威廉姆·科利（William Coley）寻求帮助。由于未能确诊病情，科利在达希尔的小指根部关节的下方——此处与手背相连——切开一个小口，以释放压力，但切口处只流出了几滴脓液。在接下来的几周里，科利定期观察达希尔的病情。在手术中，科利将达希尔手部骨骼上变硬的软组织切除，但这并不能减轻多少压力。最后，科利进行了一次活组织检查，发现达希尔手上长的是一种生长于结缔组织的癌症——肉瘤，其并不是由她最初所受的创伤引起的。在一次试图阻止癌细胞扩散的最后尝试中，科利采用了当时通行的手术方式，对达希尔肘部以下进行截肢。但肉瘤很快再次出现，并大量堆积在她的颈部和腹部。1891年1月，达希尔在家中去世，科利伴其床侧。
达希尔死后，科利为此心烦意乱，并对纽约医院里的类似病例进行了检索。最后，他找到了一名从死神魔爪中捡回性命的病人。弗雷德·施泰因（Fred Stein）是一名德国移民，家装油漆工，11年前，他的颈部在短时间内长满了肉瘤。在四次手术均告失败后，一名资深外科大夫宣布施泰因已“无药可救”。之后，施泰因脖子和脸上的红斑处突然爆发了一场由链球菌引发的感染。当时并没有与之对应的抗生素，施泰因的免疫系统只能独自对抗这场感染。值得注意的是，在他的白细胞与病菌激烈厮杀的同时，肉瘤也随之缩减为一道无关痛痒的疤痕。施泰因出院时既没有发生感染，也没有明显的癌症症状。科利推断施泰因体内有一些东西击败了癌细胞。
接下来的十年里，科利一直期望重现施泰因的神奇康复。在1997年出版的《血液骚动》一书中，斯蒂芬·S·霍尔（Stephen S. Hall）描述了科利给癌症患者接种疫苗的过程，首先提取链球菌脓肿，即“良性脓”，然后将其与从微生物上提取的更纯净的细菌进行培养。科利称有几例取得了成功，但医学界权威并没有认可他的方法，因其成果并不能十拿九稳地进行复制。科利的主要批评者，病理学家詹姆斯·尤因（James Ewing）认为新型放射治疗技术是在科学上唯一行之有效的癌症疗法。
科利的研究得到了小约翰·戴维森·洛克菲勒（John D. Rockefeller,Jr. 美孚石油创始人约翰·洛克菲勒之子）的资金支持，洛克菲勒是达希尔的哥哥的同学，并将达希尔视为自己的“干妹妹”。洛克菲勒同时还资助了尤因的研究项目。科利向洛克菲勒讲述了施泰因奇迹般的康复，尤因则展示了治愈病例的数字——其足以让人感受到放疗的威力。最终洛克菲勒选择了尤因担任他的科学顾问。洛克菲勒的支持也促成了今天的纪念斯隆——凯特琳癌症治疗中心（Memorial Sloan-Kettering Cancer Center）的诞生，该中心是美国最著名的研究和治疗恶性肿瘤的研究机构之一。人体免疫系统能够担当根除癌症的关键角色——这一概念被遗忘在了角落。当时的一名医生称科利的假说是“自然之轻语”。
历史没有如果，洛克菲勒选择资助的是放疗
在过去百年里，癌症治疗的进步大多来自于放疗和化疗。以前被视为绝症的血细胞癌，如儿童白血病和何杰金氏病现在都已能治愈。而生长于肺部、结肠和的实体瘤，一旦从初始病灶开始扩散，现有的癌症疗法往往就对其莫之奈何了。
干扰素疗法阶段
1971年，尼克松政府发起了一场“抗癌战争”，其向美国民众承诺用10年时间攻克癌症。当时，很多研究人员认为癌症是由一种病毒引发的，这种病毒能加快细胞的新陈代谢速度，从而导致细胞出现非正常增殖。而且，他们也已在两栖类、鸟类和哺乳类动物中发现了数百种能引发癌症的病毒。20世纪70年代早期，医学界普遍认为干扰素是治疗癌症的一种可能途径（注：干扰素是一种病毒侵入时动物白细胞释放的抑制病毒繁殖的蛋白质），1980年，干扰素疗法登上了《时代》杂志的封面。使用干扰素后，实验鼠体内的肿瘤显著缩减，但应用于人体时，干扰素并不能治愈实体瘤，而且黑素瘤只在极少数情况下对其产生应答。
接下来的十年里，其他一些由人体免疫系统应答产生的蛋白质被制成抗癌药物，其中最著名的是白细胞介素-2（interleukin-2）。1988年，罗纳德·里根的癌症专家组主席，已90岁高龄的石油大亨阿尔曼德·哈默（Armand Hammer）寻求发起10亿美元的抗癌基金，以期在其百岁生日时实现攻克癌症的目标。白细胞介素-2被他吹捧为一种能够治愈癌症的免疫系统增幅剂。然而就像干扰素一样，大多数实体瘤也并不对白细胞介素-2产生应答。
在过去的50年里，随着研究人员发现肿瘤中存在能引发细胞异常增殖的基因突变，研究的焦点也转向了肿瘤的基因组。用于阻断这些基因突变的癌症标靶疗法目前已成为癌症治疗的前沿技术。诺华“格列卫”（Gleevec）是首例获得成功的标靶疗法药物，其在治疗慢性髓细胞性白血病时起效迅速，且副作用较少，程度温和。赫赛汀（Herceptin），即人类的抗HER2单克隆抗体，其对HER2过度表达的乳腺癌患者有效——该人群约占所有乳腺癌患者的20～30％。
诺华“格列卫”（Gleevec）是首例获得成功的标靶疗法药物
所有这些进步让科利的生物疗法变得湮没无闻。诺贝尔奖得主，美国国家癌症研究所（National Cancer Institute）所长哈罗德·瓦姆斯（Harold Varmus）告诉我，直到最近，“除了单克隆抗体类（药物），所有利用人体免疫系统的癌症疗法几无所取之处。医学界也搞不清为什么免疫疗法会没有效果。”然而目前这些对现有免疫疗法不产生应答的癌症患者，却对一种释放人体免疫系统的新型系列疗法产生了显著和出乎意料的应答。科利的疗法突然间成了癌症研究中最有前途的研究方向。2011年3月，美国国家癌症研究所宣布，其将出资组建一个贯穿北美，联合了27家大学和癌症中心的癌症研究网络，以引领免疫疗法的研究。该项目的主管，西雅图弗莱德·哈金森癌症研究中心的麦克·奇弗（Mac Cheever），将其称作加速癌症治疗取得实际成效的一种方式，“所有用于有效免疫疗法的元件都已准备就绪。”
T细胞试验初显成效
吉姆·阿利森（Jim Allison）是纪念斯隆——凯特琳癌症治疗中心的肿瘤免疫疗法研究项目主管，他从1978年开始在德州癌症中心（Texas Cancer Center）担任研究员，并从此开始了自己的职业生涯。在那段时间里，他持有一种观点——T细胞能直接对抗癌症。T细胞是一种强力白细胞，其可以杀灭受到细菌感染的细胞，这种细胞被人体免疫系统视作外来入侵者。人体免疫系统会调用不同种类的白细胞来对抗疾病，中性白细胞和巨噬细胞这类白细胞可以吞噬和嚼碎细菌，T细胞则与之相反，其以酶为武器从外部对细菌发动连续攻击。癌症会瓦解免疫系统，产生能引发T细胞迅速变得饥渴、死亡或主动忽视癌细胞的蛋白质。阿利森的研究专注于T细胞为何既无法识别已产生畸变的癌细胞，也不像攻击细菌一样去攻击这些癌细胞。
阿利森的导师并不鼓励他从事T细胞的研究。去年12月，当我们在斯隆——凯特琳癌症治疗中心他的实验室里会面时，他告诉我，“肿瘤免疫学真是不受待见。”阿利森今年63岁，体格粗壮，蓄着络腮胡，说话声音沙哑。“很多人认为人体免疫系统在癌症治疗中不起任何作用。”干扰素和白细胞介素-2这类雷声大雨点小的疗法已伤透了科学家的心。而免疫疗法也被流行的说法所误导——通过特定的饮食或改善情绪，就能自然而然地提高免疫力，从而杀灭肿瘤，且不存在放疗和化疗的痛苦副作用。
阿利森的研究始于免疫系统是如何对抗疾病的，他使用实验鼠作为研究模型，并充分利用了一个决定性发现：T细胞需要接收两种信号才能有效攻击目标。阿利森说，第一种信号好比“点火开关”，第二种则类似“油门”。当攻击细菌时，T细胞能有效接收两种信号。然而面对癌细胞时，“T细胞无法收到信号发动攻击。”阿利森解释道。之后，他开始思考如何有效的激活免疫系统来对抗癌细胞。
阻碍免疫应答的关键——CTLA-4
1987年，法国研究人员发现了一种名为细胞毒性T淋巴细胞抗原（cytotoxic T-lymphocyte antigen-4）的蛋白质，即CTLA-4，其突起于T细胞表面。“全球各大实验室为此展开了一场识别其功能的激烈竞赛。”阿利森回忆道。美国百时美施贵公司的一名科学家引用其实验室的研究结果，声称CTLA-4能增强T细胞和免疫系统的活性。而阿利森和一名免疫学家杰弗里·布鲁斯通（Jeffery Bluestone）通过独立实验所取得的研究结果否定了这一论断。阿利森和布鲁斯通认为CTLA-4实际上扮演着T细胞的刹车装置，阿利森还认为可能正是CTLA-4阻止了免疫系统攻击肿瘤。“杰夫和我没有按常理出牌。”阿利森说，“在这一发现之前，人们认为T细胞只是自生自灭。”阿利森推测，那些设计用于激活免疫系统的疗法之所以失效，正是因为这些疗法实际上是激活了CTLA-4。他说：“我们必须释放免疫系统，以使其能攻击肿瘤细胞。”
A. 正常应答； B．CTLA-4 1g融合蛋白阻断共刺激信号
阿利森的博士后研究员将癌细胞注入实验鼠的皮下，然后又对其中一些实验鼠注入能封锁CTLA-4的抗体。数周后，带有抗体的实验鼠体内的癌细胞消失。1995年12月初，其中一名研究员将实验数据交给阿利森。实验室当时正准备开始圣诞节休假，但阿利森想要立刻重复实验。“我告诉这名研究员，他需要将癌细胞注入一组新的实验鼠体内，并有一组不注入抗体的实验鼠作为控制组。而我将亲自检测癌细胞数量。”阿利森回忆道，“这真是一次盲目的实验，因为我对此毫无头绪。”一周后，阿利森检测了癌细胞数量。“癌细胞仍在增长，我开始感到失望。之后，在（注入抗体的）半数实验鼠体内，癌细胞仅仅只是看起来停止增长，而在该组另一半实验鼠体内，癌细胞仍持续增长。再然后，前者体内的癌细胞开始减少，并最终消失。”阿利森补充道，“这直接证明了我们最初的假设，该疗法对各种癌症都行之有效。”
接下来的两年里，在继续进行小鼠实验的同时，阿利森也接触了一些制药和生物科技公司，以寻求帮助研发用于患者的治疗方案，但他每次都失望而归。“人们对免疫学和免疫疗法的成见很深。他们会说，‘得了吧，在实验鼠身上治癌症谁不会啊’。有时他们会说，‘只是移除T细胞里的负面信号就可以治疗癌症，你真是这么想的？’”
阿利森还了解到，百时美施贵公司已提交了一份认定CTLA-4可激发T细胞增长的专利申请。“如果该专利获批，你就再也别想将能封锁CTLA-4的抗体注入癌症患者体内了，因为这会让事情变得更糟。”阿利森说，“医生会害怕将抗体注入患者体内。”但阿利森仍固执的告诉业界大佬们百时美施贵是错的。最后，他说服了一家名为美达莱（Medarex）的小公司为其研究提供资金支持。
百时美施贵——美达莱人体试验
在2001年首次开展的人体试验中，美达莱引入了恶性黑素瘤患者，这是因为在使用干扰素和白细胞介素-2等基于人体免疫系统的疗法中，恶性黑素瘤是廖廖几种偶尔产生应答的肿瘤之一。在初步研究中，患者接受了CTLA-4抗体注射，与之前的小鼠实验一样，患者体内的癌细胞在几周内持续增长，之后有少数肿瘤出现缩减。2004年，百时美施贵与美达莱建立合作伙伴关系，共同研发免疫治疗药物。而在随后的试验中，抗体注射12周后出现了负面影响——很多肿瘤变得更大，而且在一些患者体内还出现了新的病变。辉瑞制药也测试了一种CTLA-4抗体，得出结论是该抗体无效。人体试验被迫提前中断。
然而在百时美施贵试验停止的数月后，参与试验的一些临床医生（包括斯隆——凯特琳中心的杰达·沃尔克霍克（Jedd Wolchok）和波士顿达纳法伯癌症研究所的斯蒂芬·霍迪（Stephen Hodi））发现，患者体内的肿瘤不是停止增长，就是出现缩减。沃尔克霍克和他的同事说服百时美施贵记录数年后的患者总存活率。（由于判断化疗药物有效率的已有指标是基于用药的第一个月，所以百时美施贵的试验被认为是失败了。）“这是一次大胆的尝试，”阿利森说，“因为这变成了一项长期研究。”2010年6月，研究结果被呈送给美国肿瘤临床学会（American Society of Clinical Oncology）的年度会议。尽管试验用药只让患者寿命中位数延长了4个月，但有近四分之一参与试验的患者多活了两年时间，而这些患者之前被认为只能活7个月。“这是一种不同于任何你所知道的药，”阿利森说，“你不是在对付癌细胞，而是在治疗免疫系统。而且这是在恶性黑素瘤晚期患者的随机试验中，绝无仅有的首例显现出生存益处的药物。”
阿利森的研究成果让癌症专家为之震惊。2011年12月，《自然》杂志发表了一篇评论文章指出，CTLA-4抗体“为黑素瘤患者——尤其是对那些只有极少存活机会的晚期患者——带来了真正的希望。更广泛的用途是，其通常能为癌症免疫疗法提供明晰的临床确诊。”我问哈罗德·瓦姆斯为何其他免疫疗法的研究人员失败，而唯独阿利森取得成功。“我们需要知道自己在做什么，”他说，“而吉姆知其所以然。”
“需谨慎使用‘治愈’一词，因为一些患者的体内仍有残余肿瘤，”阿利森说，“但这没有关系，因为他们体内的癌细胞没有继续增长。而在其他患者体内，肿瘤只是突然出现，然后消失。所以（这种药）令肿瘤变成了一种慢性病，而非死亡判决书。”阿利森加入了斯隆——凯特琳中心，以期更紧密的跟进由沃尔克霍克和其他研究员开展的临床试验。“我只是想让大家都感受到我的热忱。”
黑素瘤治愈实例
2003年秋天，22岁的莎伦·贝尔文（Sharon Belvin）是一名实习教师，她计划第二年6月份结婚。每天她都要跑上4到5英里，有一天她在晨跑后感到胸痛。学校的学生保健处认为她可能是因为被她班上的学生传染了病毒性支气管炎。但她的症状并没有缓解，然后医生又给出了其他诊断，包括哮喘和肺炎。不久后，贝尔文发现自己连走路都会感到不舒服。在一次探访母亲时，家庭医生在贝尔文的锁骨上发现了一个肿块。活体检查显示她得的是转移性黑素瘤。“我懵了，”贝尔文告诉我，“我并不喜欢晒日光浴，而且我的皮肤也没有任何损伤。”
在婚礼的前一周，她做了一次全身检查。“X光片上的图像看起来就像圣诞树一样（表明有很多肿块），”她回忆道，“而我得到的结果是，周一、周二和周三放疗，周六结婚。”经过四个月的治疗，肿瘤稍有缩小，然后又开始增长。核磁共振成像显示，黑素瘤已扩散至贝尔文的脑部。贝尔文来到斯隆——凯特琳癌症治疗中心，这儿采用放疗治疗脑瘤。从放疗中恢复后，医生给贝尔文注射了白细胞介素-2，以激活她体内的T细胞。“（白细胞介素-2）引起了极坏的反应，我的表皮严重脱落。”贝尔文说，“我病得很厉害，我已不太记得清当时的情况。”更糟的是，（注射白细胞介素-2后）癌细胞的增长也无法控制。“医生告诉我，如果还想去度假，最好趁早。”贝尔文和她的丈夫随后去加勒比海来了次游轮游。
度假归来后，贝尔文回到医院，并从胸腔抽出12升积液。之后，沃尔克霍克向贝尔文推荐了仍处于实验阶段的CTLA-4抗体疗法。“由于这是实验疗法，谁也没有把握，我不得不告诉我丈夫，‘如果这个疗法还不起效，那我真的是去日无多了’。”贝尔文回忆道。沃尔克霍克给了她一份知情同意书，上面列出了该疗法所有可能存在的副作用。“（知情同意书上面）一页接一页地写着你可能会面对什么。我连一页都没看，就在末尾签字并对他说，‘开始吧’。”
战胜癌症，恢复正常生活的莎伦·贝尔文一家
在通过静脉注入CTLA-4抗体后，贝尔文出现了剧烈反应：免疫系统在攻击她的甲状腺的同时，她浑身颤抖，汗出如浆。“我想我是快死了，身体在不停地打冷颤。”她回忆道。经过每三周四个疗程的治疗后，贝尔文去做了一次扫描。“我仍记得当沃尔克霍克医生走进病房时，他脸上简直乐开了花，嘴里喊着‘太棒了！’”她肺部的大部分肿瘤都明显缩减。
沃尔克霍克并不想让贝尔文高兴得太早。“然而自从那次后，我每次去做扫描，结果都显示肿瘤在缩小。”她说。在她被诊断为肺癌8年后，她至今仍没有出现患癌迹象。
虽然贝尔文的病例非比寻常，但其反驳了流行的概念——激发免疫系统是治疗癌症，并免遭放化疗副作用之苦的“天然”途径。免疫疗法的治疗范围包括皮肤癌、肠癌、肺癌、肝癌、甲状腺癌、脑下垂体癌、肾癌和胰腺癌。当T细胞被激发至能杀灭癌细胞的水平时，它们同时也会对人体正常组织带来附加伤害。“这是一把双刃剑，要想激发免疫系统有效的对抗癌细胞，就得付出一定的代价。”由于贝尔文的甲状腺在治疗过程中被破坏，目前她需要注射替代激素。
美国国家肿瘤研究所外科手术主任史蒂文·罗森伯格（Steven Rosenberg）曾在白细胞介素-2的研发中担当了重要角色，他也推动了CTLA-4抗体的一些早期研究。罗森伯格指出，在（使用CTLA-4抗体）治疗过程中，患者的肠道通常会出现严重炎症。“你一天会拉十几次肚子。结肠炎可不是闹着玩的，而且几乎所有患者都会得上。如果不迅速对这些患者使用皮质醇，他们将会死亡。”
“肿瘤学领域的大门几乎对所有人敞开。” 罗森伯格告诉我。他很高兴看到贝尔文这样的患者能够痊愈，但他对类似疗法的长期效果持谨慎态度。“虽然患者随访的时间不长，但我相信CTLA-4抗体将治愈一些黑素瘤患者。不过除非所有可检测到的癌细胞都消失了，否则肿瘤最终仍会长回来。”他说。
免疫疗法的进化——继承性免疫细胞疗法
罗森伯格在免疫疗法的另一项技术——“继承性细胞转化”的研究上走在了前列。该技术的原理是：从患者肿瘤细胞中取出T细胞，然后给予类似白细胞介素-2这样的免疫刺激，激发其自我繁殖，再将这些T细胞回注患者体内。在国家肿瘤研究所使用继承性细胞转化疗法治疗黑素瘤的最近三次试验中，25名患者中有9人完全康复，且康复时间超过五年。在整个试验中，有5名较早接受CTLA-4抗体治疗失败的患者正处于康复阶段。
萨姆·布雷登巴赫（Sam Breidenbach）在威斯康星州运营一家建筑公司，他也是试验中接受CTLA-4抗体治疗失败的五人之一。1999年9月，布雷登巴赫的妻子注意到他背上长了一小颗瘤。他来到麦迪逊威斯康星大学附属医院做检查，结果查出是黑素瘤。此时还是早期，在手术移除了肿瘤后，医生告诉他癌细胞似乎没有扩散。然而三年后，当他有一次在打排球，深吸一口气准备扣球时，他感到左肋腹处有拉伤的痛感。“我左臀的骨头顶部有一小块圆鼓鼓的肿瘤，这是从之前的黑素瘤转移过来的。当地的肿瘤科医生只是告诉我，‘你最多还能活五年。’” 布雷登巴赫回忆道。他又住进了威斯康星大学附属医院，医生给他注射了大量干扰素。“治疗的头一个月，我真感到生不如死，连动都动不了。”治疗方案并未起效。数月后，他左侧腹股沟的淋巴结上出现了黑素瘤。
布雷登巴赫是通过他女儿找到罗森伯格的，他女儿当时在一个小提琴班里上课，班上有一个女孩的父亲曾在国家肿瘤研究所治疗过黑素瘤。布雷登巴赫与罗森伯格取得了联系，罗森伯格为其接种了一种实验性黑素瘤疫苗。布雷登巴赫并没有对疫苗产生应答，黑素瘤又蔓延至他的肝脏和肺部。2003年夏天，在接受了CTLA-4抗体注射后，他感到腹部出现剧烈绞痛——经检查，这是因免疫应答引发的胰腺炎。“我当时实在疼得不行了，医生只好停止治疗。” 布雷登巴赫说，“他们已无计可施。”布雷登巴赫的主治医生告诉他顶多还能活四到六个月。有一个肿瘤科医生建议我做化疗，“我心里有数，我妻子和我都认为，如果我真的只能活这么几个月，为什么还要去白白遭罪呢？”
感恩节前一周，罗森伯格打电话给布雷登巴赫，告诉他研究团队在实验室里研究了他的T细胞。“你的T细胞跳出了培养皿。”罗森伯格说。他解释说，这意味着布雷登巴赫的T细胞能接受免疫刺激，以识别和攻击黑素瘤。“罗森伯格医生让我周一上飞机，然后在他的实验室待三周。”布雷登巴赫的T细胞已从肿瘤中分离，并在实验室里致敏。当他抵达国家肿瘤研究所后，医生将致敏后的T细胞通过一根连接心脏的静脉回输进他体内。“手术里所有的医生都对我咧着嘴笑，我恍惚有种‘奇爱博士’（Dr. Strangelovc）的感觉。”布雷登巴赫告诉我。他发高烧40度，皮肤上也突然出现皮疹。布雷登巴赫于圣诞节前夜回到家中，虽然此时他连走路都走不稳，但在一个月时间里，他体内四处转移的肿瘤开始缩减。现在，他身上连一个黑素瘤细胞都没有了。“我的T细胞就像火焰一样烧尽了肿瘤。”布雷登巴赫说。不过这次治疗也给他带来了一个永久性副作用——致敏的T细胞不仅杀灭了癌细胞，还将带有黑色素的正常细胞也一并杀死，从而引发了白癜风，布雷登巴赫的皮肤出现掉色，头发也变白了。
罗森伯格认为黑素瘤与免疫系统有着独特的联系：黑素瘤细胞发生的突变越多，T细胞越容易将其识别为外来入侵者。这种特性更有利于免疫疗法的发展。“这种能够自我增强的免疫应答并没有出现在其他类型的癌症中。”他说。
治愈癌症——成就与挑战并存
不过罗森伯格认为他已经掌握了治疗更多癌症的钥匙。“每年有60万美国人死于癌症，我们需要能治疗常见癌症的疗法。”他说。他承认格列卫之类的标靶药物有一定疗效，但他同时指出大部分标靶疗法的疗效会迅速消退。一项最近开发的治疗黑素瘤的标靶疗法能杀灭超过半数的肿瘤，但几乎所有患者体内的肿瘤都会在一年内复发。今年3月发表的一项研究指出，随着癌细胞在体内扩散——从肾脏到肝脏和肺——癌细胞在其间的变化并不依常理，所以肝脏细胞内的DNA可能与肺部癌细胞里的DNA不同。这种变化过程意味着，只针对一种细胞变异的药物在面对遍及全身的癌细胞时可能收效甚微。
按照罗森伯格的观点，随着继承性细胞的转化，免疫系统会将这些恶性肿瘤一律视作外来入侵者。他正着手于完善针对其他癌症的疗法：首先提纯患者的血液，然后在其T细胞中注入一种基因，其指向一种名为NY-ESO的异常蛋白质。这种蛋白质是由斯隆——凯特琳中心识别出的，在胎儿发育后，其通常在人体组织中缺失（除睾丸外），但在三分之一的常见肿瘤中都会出现它的身影。“我认为继承性细胞转化将成为治疗常见癌症的免疫疗法的关键环节。”罗森伯格说，“当T细胞能在遗传层面靶向攻击NY-ESO，那么黑素瘤、乳腺癌、前列腺癌、肠癌、卵巢癌、肉瘤等等癌症（在治疗方式上）就都没有区别了。”
瓦姆斯认同这种方法有可能让更多肿瘤对免疫疗法敏感，这也在罗森伯格的疗法的早期试验中得到了印证。安妮塔·罗伯逊（Anita Robertson）是加利福尼亚州长滩市的一名会计师，2008年，时年63岁的罗伯逊的臀部长了一颗大肉瘤，其与杀死伊丽莎白·达希尔的肿瘤类型相似。2010年7月，在使用了继承性T细胞疗法后，罗伯逊离开了美国国家卫生研究院（N.I.H.）。同年9月的一张计算机化X射线轴向分成造影（CAT）扫描图显示，肉瘤开始缩减；如今这块肉瘤已缩小了50％。此前饱受肿瘤折磨、行动不便的罗伯逊，现在已可以开车、购物和去教堂祷告了。
宾夕法尼亚大学的研究人员使用类似疗法根治了三名患有慢性淋巴细胞白血病的患者，此前，其他疗法对这三名患者已不再产生任何效果。今年4月，罗森伯格报告称，采用该疗法治疗的9名淋巴癌晚期患者中有8人康复，其中三名患者的癌细胞已完全消失。
“目前，我们在继承性细胞转化上已取得了显著进步。”罗森伯格告诉我，“但还没到大范围推广的地步。”该疗法只能为每个病人单独设计治疗方案，这使其价格非常昂贵，对制药公司来说也价值不大。“制药公司需要的是通用药物，他们不在乎你研发时花了好几百万美元，因为到大规模生产时他们能把一瓶药的成本降到一美元。”罗森伯格说。由于罗森伯格的研究仍处于实验阶段，其研究工作得到了数家基金的联合资金支持。当然，这些疗法的定价最终会依照其能弥补传统疗法多少损失而定。对于目前很多无法痊愈的癌症患者来说，虽然新疗法会花上数十万美元，但可能仍比他们花在化疗、住院和临终护理上的钱要少。
但杰达·沃尔克霍克主张常见肿瘤可能无需采用继承性细胞疗法治疗。他提到了免疫疗法中的三个“E”：根除（elimination）、平衡（equilibrium）和逃脱（escape）。所有疗法的目标都应是彻底根除癌细胞，“但我们需要考虑免疫系统的平衡，在这种平衡状态中，虽然仍存在癌细胞，但它们并不生长或扩散。” 沃尔克霍克说。在经历了几十年临床上的挫折和失败后，大部分科学家都不敢妄断免疫疗法将能够完全治愈多数癌症患者。肿瘤细胞已通过自身变异逃脱了放疗、化疗和标靶药剂的攻击，免疫疗法可能也不能免俗。
虽然CTLA-4仍是大部分研究的焦点，但科学家目前已识别出至少五种其他类型的T细胞抑制物。初始研究表明，对这些抑制物的定向疗法能杀灭一些最致命的肿瘤细胞——包括肺癌和肠癌。耶鲁大学的肿瘤学家马里奥·斯诺尔（Mario Sznol）领导开展了一项临床试验，使用抗体定向作用于其中一种抑制物——PD-1蛋白质。“我相信未来我们能够为患者单独定制免疫治疗方案。”斯诺尔说。医生将检查患者体内肿瘤的特性，然后施以合适的抗体。
阿利森的实验室是一个开放实验室，其占据了斯隆——凯特琳中心扎克曼研究大厦15层的大部分空间。我到访的那天，博士后研究员和毕业生正在电脑上分析最近的实验数据。实验室的一角摆着活体显微镜，通过它可以观察活体动物身上的细胞和组织。阿利森向我演示了将CTLA-4抗体注入麻醉后实验鼠体内的过程。注射前，实验鼠已标有萤光染剂，并对从肿瘤中提取的一种蛋白质致敏。“通过活体显微镜，你可以清楚地看到T细胞进入淋巴结，”阿利森说，“一个个翠绿的圆环（T细胞）驶向的灰色血管。然后它们离开淋巴结，开始攻击癌细胞。”
在实验室的另一边，一名博士后研究员准备了一系列已接种黑素瘤的实验鼠。一些实验鼠作为控制组，肿瘤有一英寸厚，或有更多的肿瘤长在它们的肋腹处；其他实验鼠则被注射了CTLA-4抗体，或PD-1抗体，或两者皆有。“（肿瘤）最明显的缩减出现在同时注射了两种抗体的实验鼠身上。”阿利森指着实验鼠的肋腹说，这里的肿瘤已缩小成黑色小点。在人体临床试验中，已开始使用同时具备抗CTLA-4和PD-1功效的抗体，以移除T细胞里两种独特的阻碍物。
2011年3月25日，由CTLA-4抗体制成的药品Yervoy经美国食品药品监督局（FDA）批准上市，用于治疗黑素瘤。这是免疫疗法的一次胜利，也是迈向治愈癌症的一大步。而对免疫疗法的研究也揭示了我们在理解癌细胞变异上能走多远，这种变异使得癌症成为最复杂多变的疾病。“癌症治疗的未来将取决于细致的抗体组合、不同的抗体选择，可能还有标靶疗法。”沃尔克霍克告诉我，“没人能做到一药治百癌。”
“Coley 毒素”癌疗法重燃希望
2006年10月5日生物制药公司 MBVax Bioscience 宣布，该公司推出了用于官方批准的临床试验的 Coley 毒素 （Coley Fluid）和用于免疫研究的MB毒素（MB Fluid）。
William Coley 于1893年开发的 Coley Fluid 作为癌症的主要疗法持续了长达60年。自20世纪50年代出现了化学疗法以来，癌症患者可延长5年的寿命，但死亡率仍几乎保持不变。癌症高致死率激发人们了对 Coley Fluid新的兴趣，因为这种药物能有效对抗晚期癌症。100多种科技出版物描述了曾利用 Coley Fluid成功治疗晚期癌症的案例，这些癌症包括乳癌、结肠癌、肾癌、肝癌、肉瘤、淋巴癌、骨髓瘤和白血病。MBVax Coley Fluid 被认为是有史以来拥有最多成功治疗案例的药物。该公司将为权威认可的临床试验免费提供Coley Fluid和一整套临床试验资料。
MB Fluid 可以称得上是有史以来用于动物类癌症和体外试验研究的最好的制剂。但是，MB Fluid不适用于人类。研究先天性免疫系统的研究人员将对MB Fluid特别感兴趣。
2016年6月21日星期二
2016年6月18日星期六
The Lovely Hill: Where People Live Longer and Happier
When Ellsworth Wareham was in his nineties, he decided that his house in Loma Linda, California -- a beautiful city 60 miles east of Los Angeles, Spanish for "lovely hill" -- needed a new fence. But rather than hire a contractor to install the wood fence, as most nonagenarians would no doubt do, Wareham went to the hardware store, bought the supplies he needed, and returned to dig some post holes. As Dan Buettner recounts in his book Blue Zones: Lessons for Living Longer From the People Who've Lived the Longest, Wareham proceeded to put the wood fence up himself.
A few days later, Wareham was in the hospital -- performing open-heart surgery on a patient.
Some Adventists get personally offended if they get colon cancer or some other disease.
Wareham has had some extraordinary experiences. During World War II, he was a doctor in the Navy; once, when he was on board a destroyer near the coast of Okinawa, he removed the appendix of an officer as the ship was being tossed about in the middle of a typhoon. In the 1950s, he did pioneering work on open-heart surgery when it was still a new technique. On a U.S. State Department sponsored trip in 1963, some surgeons from Loma Linda -- including Wareham -- were with a team of doctors that brought open-heart surgery to Pakistan for the first time. And during the Vietnam War, the work that he and other heart surgeons did in Saigon was featured on the Walter Cronkite show.
By many accounts, Wareham, now 98, has led a good, full, and meaningful life. What does he know that we don't?
As a middle-aged man, Wareham spent a lot of time in the operating room cutting into one patient after another who had heart problems. There, he noticed something: patients who were vegetarian mostly had much cleaner and smoother arteries than those who ate meat. The arteries of meat-eaters tended to be full of calcium and plaque.
So he made a choice. He decided to become a vegan. That decision was not too hard to make given the fact that many of the inhabitants of his southern Californian community were already very health conscious. Consider: there is no meat sold at one of the largest grocery stores in town. In fact, as recently as a generation ago, meat was difficult to find in the grocery stores of Loma Linda, as the New York Times reports. On top of that, smoking is banned in the town; alcohol is scarcely available; and fast food restaurants are hard to come by.
But make no mistake: Loma Linda is not some bohemian enclave of free-spirited vegans. Rather, what makes the community remarkable -- and remarkably health conscious -- is that it is home to one of the largest concentrations of Seventh-Day Adventists in the world. A conservative denomination of Christianity founded during this country's Second Great Awakening in the mid-1800s, the religion advocates a healthy lifestyle as a main tenet of the faith. This is a major reason why Wareham, a Seventh-Day Adventist, takes his health so seriously.
"Adventists believe in the body and soul as one," according to Dr. Daniel Giang of Loma Linda University's Medical Center. Pastor Randy Roberts of the same university references scripture to drive the point home: "In Corinthians, Paul speaking of the human body says specifically, 'you are the temple of the Holy spirit.' Therefore, he says, whatever you do in your body, you do it to the honor, the glory and the praise of God." The Seventh-Day Adventists, like Jews and Muslims, stay away from foods that the Bible deems impure, like pork.
Many Seventh-Day Adventists are vegetarians, physically active, and involved in their community. In other words, their lifestyles are quite unique in an America where community has become less and less important and over one third of the population is obese. Smoking and drinking are discouraged by the faith, as is the consumption of caffeine, rich foods, and certain spices. By most of our hyper-connected standards, the Seventh-Day Adventists are also an isolated community. Unlike other Christian sects that take their Sabbath on Sunday, they take theirs on Saturday. The more conservative members of the religion cut themselves off from popular culture altogether.
Because of their unique lifestyle, scientists from a variety of organizations like the National Health Institute and the American Cancer Society have since 1958 been studying how the community's dietary habits, lifestyle, disease rates, and mortality interact in a series of studies known as the Adventist Health Studies. What they have found in the decades since is remarkable.
Loma Linda leads the country in longevity. While the average American woman will live to be 81, vegetarian Adventist women in Loma Linda will on average live to be 86. While the average American man will live until 76, the average vegetarian Adventist man will live until 83.
The Adventists are also notably resilient. "Some Adventists get personally offended if they get colon cancer or some other disease," says a doctor from the town.
The death rate from cancer for Adventist men is 60 percent lower than that of the average California male; for Adventist women, it is 75 percent lower. According to Loma Linda University, ground zero in the Adventist Health Studies, "Death from coronary heart disease among Adventist men was 66 percent [lower compared to their California peers]; for Adventist women, it was 98 percent [lower]. Stroke death rates for Adventist men were 72 percent [lower], compared to their non-Adventist counterparts. For Adventist women, death from stroke was 82 percent [lower]."
These facts have led Buettner, a National Geographic Explorer, to label Loma Linda America's hot spot (or "blue zone") of health and longevity. Their physical health is not the only thing outpacing that of regular Americans. On measures of mental health and well-being, the Adventists also score much higher than the average American.
What are the Adventists doing differently from the rest of us? Beyond their conservative lifestyle and commitment to faith -- research shows that attending religious services regularly is associated with greater longevity and happiness -- there is also the matter of what they eat, which is a mostly Mediterranean diet. Eating like Greeks not only can account for their excellent health, but it may also explain why they score higher on measures of well-being.
According to research in psychology, happiness is determined by three variables. Your genetic makeup accounts for 50 percent, and your circumstances account for 10 percent. The remainder of your enduring happiness is determined by the choices we voluntarily make -- how we think and act and what we do on a day-to-day basis. That 40 percent, as social psychologist Sonja Lyubomirsky points out in her book The How of Happiness, can go a long way.
According to a new large study, which will be published in a forthcoming issue of the Journal of Psychosomatic Research, eating Mediterranean foods is linked to feeling happy. People who eat foods associated with a Mediterranean diet -- non-starchy fresh vegetables, fresh fruits, olive oil, legumes, and nuts -- experience more of those emotions associated with being happy than people who eat a typically American diet, which consists of high-fat dairy products, eggs, refined grains, and processed food.
The health benefits of eating Mediterranean foods have been well documented. People whose diets incorporate a healthy serving of fresh vegetables, olive oil, fish, whole grains, and fruit are at lower risk for heart disease and cancer, the two leading causes of death in the United States. They are also at lower risk for diabetes and Alzheimer's. They are better able to control their weight and cholesterol levels; they tend to be more alert; they exhibit less depressive symptoms; and they may live longer.
To see what a difference eating Greek makes, consider the effects that just three simple patterns of the Mediterranean diet have had on the Adventists.
The first is the role of nuts, which forms a large part of the Adventist diet in Loma Linda. According to Gary Fraser, a doctor and professor at the Loma Linda University School of Medicine, "Adventists who consumed nuts at least five times a week had about half the risk of heart disease of those who didn't. This was true of men, women, vegetarian, non-vegetarian--we split the population up about 16 or 17 different ways and each time asked the question, 'Does nut consumption matter?' And every time we saw that it did." The nut eaters also lived two years longer than those who did not regularly consume nuts.
Then there are tomatoes, a staple of the Mediterranean diet. If you are an Adventist woman who eats tomatoes three or four times a week, you are 70 percent less likely to get ovarian cancer than your friends who eat tomatoes more sparingly. For men, eating tomatoes decreases the chances of getting prostate cancer.
Finally, eating meat makes a big difference. Adventist men who do not eat meat outlive American men by seven years. Adventist women who do not eat meat outlive American women by five years. Many Adventists do not eat meat, but even those that do outlive their peers thanks to the amount of vegetables, fruits, and other healthy foods they eat. Meat-eating Adventist men live 7.3 years longer while the women live 4.4 years longer than other Californians.
On the other side of the spectrum, we know that certain dietary patterns, like eating lots of fatty foods, are associated with depression and mental illness.
Drew Ramsay, MD, of Columbia University elaborates:
Emerging research in the fields of neuroscience and nutrition show that people who eat a diet of modern processed foods have increased levels of depression, anxiety, mood swings, hyperactivity, and a wide variety of other mental and emotional problems. One study found that adolescents with low-quality junk food diets are 79 percent more likely to suffer from depression. Another found that diets high in trans fats found in processed foods raised the risk of depression by 42 percent among adults over the course of approximately six years. And a huge study of women's diets by the Harvard School of Public Health concluded that those whose diets contained the greatest number of healthy omega-3 fats (and the lowest levels of unhealthy omega-6s) were significantly less likely to suffer from depression.
While scientists know a lot about the health benefits of a Mediterranean diet and eating patterns associated with mental illness, they know far less about the eating habits that are related to a thriving and good life. This new study steps in to fill that void.
"Much of the published research has focused upon food's association with depression and foods association with disease," Patricia Ford, the lead author of the study, tells me. "This study is focusing upon positive health and positive well-being."
Ford and her team at Loma Linda University examined the eating patterns of over 9,000 healthy Seventh-Day Adventists in North America over a four-year period. How often did they eat fast food? Did they eat meat? What kinds of dairy products were they consuming? What about nuts? Desserts? Fish? They then examined their self-reported feelings of positive and negative emotions--how often did they feel inspired? Excited? Enthusiastic? Upset? Scared? Distressed?
The researchers found that those who eat like Greeks feel more inspired, alert, excited, active, inspired, determined, attentive, proud, and enthusiastic than those who consume a more typically American diet consisting of highly processed foods, soda, and sweets like cookies and doughnuts. People who eat foods associated with a Mediterranean diet also experienced less negative emotions like being afraid, nervous, upset, irritable, scared, hostile, and distressed. The more people ate those foods that are more typically American -- specifically, red meat, sweets, and fast food -- the less of these positive emotions they felt.
For women, the findings of Ford's study were particularly dramatic. Though men ate more red meat, processed foods, desserts, sodas, and fast foods than women, when women ate unhealthily, they experienced more emotional distress. Not only did those who ate red meat and fast food frequently experience less positive moods, but they also experienced more negative feelings, a pattern not seen in men who ate less healthy foods.
Those women might look to the life of Marge Jetton for inspiration. Like Wareham, Jetton is a model of the Adventist lifestyle. At 100 years old, Jetton, a former nurse, would wake up at 4.30 am each morning. After getting dressed and reading from the Bible, she would work out. When she completed her mile-long walk and 6-8 miles on the stationary bike, she had oatmeal for breakfast. For lunch, she would mix up some raw vegetables and fruit. Occasionally, she would splurge on a treat like waffles made from soy and garbanzo beans. That wasn't all. The centenarian volunteered regularly, barreled around town in her Cadillac Seville, and pumped iron. She also tended to a garden that grew tomatoes, corn, and hydrangeas.
Though she was sad and lonely after her husband died in 2003, she found happiness in serving other people. "I found that when you are depressed, that's when you do something for somebody else ... My motto is: A stranger is a friend we haven't met yet." Another motto: "Try to be happy in spite of your trials."
She died in February 2011 at the age of 106. Her friends and community remembered her as being quick-witted and funny. "She represented the promise of good living," Buettner said when she died.
A few days later, Wareham was in the hospital -- performing open-heart surgery on a patient.
Some Adventists get personally offended if they get colon cancer or some other disease.
Wareham has had some extraordinary experiences. During World War II, he was a doctor in the Navy; once, when he was on board a destroyer near the coast of Okinawa, he removed the appendix of an officer as the ship was being tossed about in the middle of a typhoon. In the 1950s, he did pioneering work on open-heart surgery when it was still a new technique. On a U.S. State Department sponsored trip in 1963, some surgeons from Loma Linda -- including Wareham -- were with a team of doctors that brought open-heart surgery to Pakistan for the first time. And during the Vietnam War, the work that he and other heart surgeons did in Saigon was featured on the Walter Cronkite show.
By many accounts, Wareham, now 98, has led a good, full, and meaningful life. What does he know that we don't?
As a middle-aged man, Wareham spent a lot of time in the operating room cutting into one patient after another who had heart problems. There, he noticed something: patients who were vegetarian mostly had much cleaner and smoother arteries than those who ate meat. The arteries of meat-eaters tended to be full of calcium and plaque.
So he made a choice. He decided to become a vegan. That decision was not too hard to make given the fact that many of the inhabitants of his southern Californian community were already very health conscious. Consider: there is no meat sold at one of the largest grocery stores in town. In fact, as recently as a generation ago, meat was difficult to find in the grocery stores of Loma Linda, as the New York Times reports. On top of that, smoking is banned in the town; alcohol is scarcely available; and fast food restaurants are hard to come by.
But make no mistake: Loma Linda is not some bohemian enclave of free-spirited vegans. Rather, what makes the community remarkable -- and remarkably health conscious -- is that it is home to one of the largest concentrations of Seventh-Day Adventists in the world. A conservative denomination of Christianity founded during this country's Second Great Awakening in the mid-1800s, the religion advocates a healthy lifestyle as a main tenet of the faith. This is a major reason why Wareham, a Seventh-Day Adventist, takes his health so seriously.
"Adventists believe in the body and soul as one," according to Dr. Daniel Giang of Loma Linda University's Medical Center. Pastor Randy Roberts of the same university references scripture to drive the point home: "In Corinthians, Paul speaking of the human body says specifically, 'you are the temple of the Holy spirit.' Therefore, he says, whatever you do in your body, you do it to the honor, the glory and the praise of God." The Seventh-Day Adventists, like Jews and Muslims, stay away from foods that the Bible deems impure, like pork.
Many Seventh-Day Adventists are vegetarians, physically active, and involved in their community. In other words, their lifestyles are quite unique in an America where community has become less and less important and over one third of the population is obese. Smoking and drinking are discouraged by the faith, as is the consumption of caffeine, rich foods, and certain spices. By most of our hyper-connected standards, the Seventh-Day Adventists are also an isolated community. Unlike other Christian sects that take their Sabbath on Sunday, they take theirs on Saturday. The more conservative members of the religion cut themselves off from popular culture altogether.
Because of their unique lifestyle, scientists from a variety of organizations like the National Health Institute and the American Cancer Society have since 1958 been studying how the community's dietary habits, lifestyle, disease rates, and mortality interact in a series of studies known as the Adventist Health Studies. What they have found in the decades since is remarkable.
Loma Linda leads the country in longevity. While the average American woman will live to be 81, vegetarian Adventist women in Loma Linda will on average live to be 86. While the average American man will live until 76, the average vegetarian Adventist man will live until 83.
The Adventists are also notably resilient. "Some Adventists get personally offended if they get colon cancer or some other disease," says a doctor from the town.
The death rate from cancer for Adventist men is 60 percent lower than that of the average California male; for Adventist women, it is 75 percent lower. According to Loma Linda University, ground zero in the Adventist Health Studies, "Death from coronary heart disease among Adventist men was 66 percent [lower compared to their California peers]; for Adventist women, it was 98 percent [lower]. Stroke death rates for Adventist men were 72 percent [lower], compared to their non-Adventist counterparts. For Adventist women, death from stroke was 82 percent [lower]."
These facts have led Buettner, a National Geographic Explorer, to label Loma Linda America's hot spot (or "blue zone") of health and longevity. Their physical health is not the only thing outpacing that of regular Americans. On measures of mental health and well-being, the Adventists also score much higher than the average American.
What are the Adventists doing differently from the rest of us? Beyond their conservative lifestyle and commitment to faith -- research shows that attending religious services regularly is associated with greater longevity and happiness -- there is also the matter of what they eat, which is a mostly Mediterranean diet. Eating like Greeks not only can account for their excellent health, but it may also explain why they score higher on measures of well-being.
According to research in psychology, happiness is determined by three variables. Your genetic makeup accounts for 50 percent, and your circumstances account for 10 percent. The remainder of your enduring happiness is determined by the choices we voluntarily make -- how we think and act and what we do on a day-to-day basis. That 40 percent, as social psychologist Sonja Lyubomirsky points out in her book The How of Happiness, can go a long way.
According to a new large study, which will be published in a forthcoming issue of the Journal of Psychosomatic Research, eating Mediterranean foods is linked to feeling happy. People who eat foods associated with a Mediterranean diet -- non-starchy fresh vegetables, fresh fruits, olive oil, legumes, and nuts -- experience more of those emotions associated with being happy than people who eat a typically American diet, which consists of high-fat dairy products, eggs, refined grains, and processed food.
The health benefits of eating Mediterranean foods have been well documented. People whose diets incorporate a healthy serving of fresh vegetables, olive oil, fish, whole grains, and fruit are at lower risk for heart disease and cancer, the two leading causes of death in the United States. They are also at lower risk for diabetes and Alzheimer's. They are better able to control their weight and cholesterol levels; they tend to be more alert; they exhibit less depressive symptoms; and they may live longer.
To see what a difference eating Greek makes, consider the effects that just three simple patterns of the Mediterranean diet have had on the Adventists.
The first is the role of nuts, which forms a large part of the Adventist diet in Loma Linda. According to Gary Fraser, a doctor and professor at the Loma Linda University School of Medicine, "Adventists who consumed nuts at least five times a week had about half the risk of heart disease of those who didn't. This was true of men, women, vegetarian, non-vegetarian--we split the population up about 16 or 17 different ways and each time asked the question, 'Does nut consumption matter?' And every time we saw that it did." The nut eaters also lived two years longer than those who did not regularly consume nuts.
Then there are tomatoes, a staple of the Mediterranean diet. If you are an Adventist woman who eats tomatoes three or four times a week, you are 70 percent less likely to get ovarian cancer than your friends who eat tomatoes more sparingly. For men, eating tomatoes decreases the chances of getting prostate cancer.
Finally, eating meat makes a big difference. Adventist men who do not eat meat outlive American men by seven years. Adventist women who do not eat meat outlive American women by five years. Many Adventists do not eat meat, but even those that do outlive their peers thanks to the amount of vegetables, fruits, and other healthy foods they eat. Meat-eating Adventist men live 7.3 years longer while the women live 4.4 years longer than other Californians.
On the other side of the spectrum, we know that certain dietary patterns, like eating lots of fatty foods, are associated with depression and mental illness.
Drew Ramsay, MD, of Columbia University elaborates:
Emerging research in the fields of neuroscience and nutrition show that people who eat a diet of modern processed foods have increased levels of depression, anxiety, mood swings, hyperactivity, and a wide variety of other mental and emotional problems. One study found that adolescents with low-quality junk food diets are 79 percent more likely to suffer from depression. Another found that diets high in trans fats found in processed foods raised the risk of depression by 42 percent among adults over the course of approximately six years. And a huge study of women's diets by the Harvard School of Public Health concluded that those whose diets contained the greatest number of healthy omega-3 fats (and the lowest levels of unhealthy omega-6s) were significantly less likely to suffer from depression.
While scientists know a lot about the health benefits of a Mediterranean diet and eating patterns associated with mental illness, they know far less about the eating habits that are related to a thriving and good life. This new study steps in to fill that void.
"Much of the published research has focused upon food's association with depression and foods association with disease," Patricia Ford, the lead author of the study, tells me. "This study is focusing upon positive health and positive well-being."
Ford and her team at Loma Linda University examined the eating patterns of over 9,000 healthy Seventh-Day Adventists in North America over a four-year period. How often did they eat fast food? Did they eat meat? What kinds of dairy products were they consuming? What about nuts? Desserts? Fish? They then examined their self-reported feelings of positive and negative emotions--how often did they feel inspired? Excited? Enthusiastic? Upset? Scared? Distressed?
The researchers found that those who eat like Greeks feel more inspired, alert, excited, active, inspired, determined, attentive, proud, and enthusiastic than those who consume a more typically American diet consisting of highly processed foods, soda, and sweets like cookies and doughnuts. People who eat foods associated with a Mediterranean diet also experienced less negative emotions like being afraid, nervous, upset, irritable, scared, hostile, and distressed. The more people ate those foods that are more typically American -- specifically, red meat, sweets, and fast food -- the less of these positive emotions they felt.
For women, the findings of Ford's study were particularly dramatic. Though men ate more red meat, processed foods, desserts, sodas, and fast foods than women, when women ate unhealthily, they experienced more emotional distress. Not only did those who ate red meat and fast food frequently experience less positive moods, but they also experienced more negative feelings, a pattern not seen in men who ate less healthy foods.
Those women might look to the life of Marge Jetton for inspiration. Like Wareham, Jetton is a model of the Adventist lifestyle. At 100 years old, Jetton, a former nurse, would wake up at 4.30 am each morning. After getting dressed and reading from the Bible, she would work out. When she completed her mile-long walk and 6-8 miles on the stationary bike, she had oatmeal for breakfast. For lunch, she would mix up some raw vegetables and fruit. Occasionally, she would splurge on a treat like waffles made from soy and garbanzo beans. That wasn't all. The centenarian volunteered regularly, barreled around town in her Cadillac Seville, and pumped iron. She also tended to a garden that grew tomatoes, corn, and hydrangeas.
Though she was sad and lonely after her husband died in 2003, she found happiness in serving other people. "I found that when you are depressed, that's when you do something for somebody else ... My motto is: A stranger is a friend we haven't met yet." Another motto: "Try to be happy in spite of your trials."
She died in February 2011 at the age of 106. Her friends and community remembered her as being quick-witted and funny. "She represented the promise of good living," Buettner said when she died.
2016年6月8日星期三
申请医学院必读 - 评审安省医学院特征
1.安省各大医学院的特征
- 多伦多大学：最大 （2009班申请2734人， 收224人，不包括上届申请推迟入学人数），有MD/PhD (即毕业后可从事临床科学研究)，四年课程，需要MCAT
- 强：学校有强大资金后盾，注重科研，收学生讲究学历高，成绩高，有科研经验，论文发表。入学后科研机会多，有较高比例进专科; 华裔学生比例最高，略有20%
- 弱：教学系统死板，学习压力最大，校内竞争强。学费最高
- 皇后大学：第2小班 （2009班申请1851人，收100人, 不包括上届申请推迟入学人数），四年课程，需要MCAT, 而且底分要求高，verbal 分在10以上 ，每年根据申请人统计更改
- 强：班小，教育质量高，有意入热门专科的成功率高；学校资金多，给与学生补贴多。实践机会高。
- 弱：城市就一间医院，病例见的少，知识相对狭隘。
- 西安大学：中等大小（2009班申请1803人，收149人, 不包括上届申请推迟入学人数），四年课程，需要MCAT, 而且底分要求高，verbal 分在10以上，writing 至少要P （最高T）以上, 数文科较重的学校；只收四年本科毕业生。
- 强：气氛团结，很多social，学生文笔普遍较好，有边区实习机会（有补贴），实践率较好, 政治意识强; 外科数各大学院中最强
- 弱：城市有两间医院，分别在城内两端，实习间奔波不易；太多派对
- 麦克大学：中等大小（2009班申请4733人，收176人, 不包括上届申请推迟入学人数, 但Hamilton 中心校园只收150人，其余分配在waterloo 和 st.catherines 校园）；有MD/PhD (即毕业后可从事临床科学研究); 三年课程，不需要MCAT； 没有指定必读科目
- 强：采取自学式教育，课堂时间少，有利于学生自由发展，从兴趣出发，教学使用临床案例 （此教学方案已被哈佛采用）。一入学便可进入医院见习，实践率最好。离多伦多近；城市有5所大医院，案例广泛，仅次于多伦多
- 弱： 城市污染严重 (但不涉及在城西的校园)，城市普遍是蓝领阶层，文化程度低；中国人少；由于本校不按考试成绩评分，自我纪律不强的学生很容易混水摸鱼过关，所以产生良差不齐 - 强者一般比其他学校要强，但弱者也相对更弱; 个人建议:需要依靠外在动力督促的学生还是去多大比较好。
- 渥太华大学：中等大小（2009班申请3268人，收143人, 不包括上届申请推迟入学人数）, 四年课程，不需要MCAT，含有法语教学；注重课外活动，尤其是领导才能，偏好学历高人士。
- 强：先进，每人必备手提电脑；城市乃国家首都，美，从事政治机会多；城市先进，设备及科研方面仅次于多大
- 弱：入取附外条件扑朔迷离，不知道想要什么。城市相对小，病例次于麦大，数各大医院第三。
- 西北安大学：最小（2009班申请1892人收56人, 不包括上届申请推迟入学人数）. 四年课程，不需要MCAT
- 要求有过边远地区的生活或实践经验才可申请，不适合华人学生，无谓多讲
简介
我是2006年进入医学院，那年的申请可说是历年来最激烈的一年。由于安省在2003年取消了Grade 13 (OAC), 03年入大学本科的人数比往年多出150%, 相对报考医学院的学生们也多出许多。由于加国医生出现严重短缺，所有的医学院已逐渐增加录取量，所以竞争似乎比以往小了一些。
申请医学院这个话题很多家长们都有兴趣。无奈的是，我当年写出的过程无优编辑不感兴趣，直到我看到新出的博客评论才感觉到这是一个值得写的话题。这个过程中有很多误区，不了解的人在里面转会浪费时间和金钱，而一知半解也会导致失去很多机会。 现讲一下安省各大医学院的特征：
好学生们对McMasterHS趋之若鹜，不单单是为了进医学院，而是为了McMaster医学院。HS的学生可能不是所有人都能进McMaster医学院，但是能被某个加拿大医学院录取基本是十拿九稳的（比如麦子说所认识的十个华人孩子中九个进医学院，另一个读研究生）。但是为什么HS只有50%进医学院呢？这并不是因为剩下的50%不够格。麦子已经说得很清楚了，另外的50% McMaster HS学生去了其他地方如牙医，商学，工程，法学，或读研究生将来当faculty等等。Google一下英文主流媒体，发现说的更清楚，那是因为这些孩子发现学医并非是自己的志向而转行。 由于HS的课程广泛，加上学生本身出类拔萃，转行的学生基本上都如鱼得水。
Western Ontario有一个Medical Sciences与McMaster HS竞争。录取分数要低好几分。UWO MS目的是专攻医学院，三四年级由医学院来教课，这对将来能进医学院的学生很有帮助。虽然医学院升学率不如McMaster HS，但比其他一般专业还是高很多。然而UWO MS的主要问题是其课程只针对医学院，一旦进不了医学院，专行是一个巨大问题。即使能继续读医学院，除了特别拔尖的，很多只能进本校。UWO的医学院在安省五所医学院中排第四，与McMaster不可同日而语。 所以读UWO MS要有破釜沉舟的决心。
好学生们对McMasterHS趋之若鹜，不单单是为了进医学院，而是为了McMaster医学院。HS的学生可能不是所有人都能进McMaster医学院，但是能被某个加拿大医学院录取基本是十拿九稳的（比如麦子说所认识的十个华人孩子中九个进医学院，另一个读研究生）。但是为什么HS只有50%进医学院呢？这并不是因为剩下的50%不够格。麦子已经说得很清楚了，另外的50% McMaster HS学生去了其他地方如牙医，商学，工程，法学，或读研究生将来当faculty等等。Google一下英文主流媒体，发现说的更清楚，那是因为这些孩子发现学医并非是自己的志向而转行。 由于HS的课程广泛，加上学生本身出类拔萃，转行的学生基本上都如鱼得水。
Western Ontario有一个Medical Sciences与McMaster HS竞争。录取分数要低好几分。UWO MS目的是专攻医学院，三四年级由医学院来教课，这对将来能进医学院的学生很有帮助。虽然医学院升学率不如McMaster HS，但比其他一般专业还是高很多。然而UWO MS的主要问题是其课程只针对医学院，一旦进不了医学院，专行是一个巨大问题。即使能继续读医学院，除了特别拔尖的，很多只能进本校。UWO的医学院在安省五所医学院中排第四，与McMaster不可同日而语。 所以读UWO MS要有破釜沉舟的决心。
2016年5月30日星期一
腰椎間盤突出微創手術
椎間盤突出即脊椎之間的軟骨向後突出，繼而壓着神經線。隨着年紀大，腰椎老化，脊椎的神經管道變小，壓迫神經線，會引致椎管狹窄。患者會有背部或下肢疼痛、麻痹無力，甚至不良於行，影響大小便功能。
症狀輕微的患者可經非手術方法如藥物及復健改善，但若病情嚴重就可能要進行手術。傳統開放性手術須全身麻醉，於背部開刀，切開約4厘米造口，移開肌肉，箝走部份椎板骨，再切除突出的椎間盤。傳統開放性手術缺點是對腰背軟組織，特別是背部肌肉傷害較大，手術後疼痛較大，須住院幾日。
醫院管理局近年引入微創脊椎手術，包括顯微內窺鏡切除術和全內窺鏡切除術。當中全內窺鏡切除術以微創方式，只須在背部開一粒豆大小，約一厘米造口，再將導管伸入，穿梭於脊椎部位肌肉之間，並避開脊椎神經，抵達目標位置切除突出的椎間盤。
症狀輕微的患者可經非手術方法如藥物及復健改善，但若病情嚴重就可能要進行手術。傳統開放性手術須全身麻醉，於背部開刀，切開約4厘米造口，移開肌肉，箝走部份椎板骨，再切除突出的椎間盤。傳統開放性手術缺點是對腰背軟組織，特別是背部肌肉傷害較大，手術後疼痛較大，須住院幾日。
醫院管理局近年引入微創脊椎手術，包括顯微內窺鏡切除術和全內窺鏡切除術。當中全內窺鏡切除術以微創方式，只須在背部開一粒豆大小，約一厘米造口，再將導管伸入，穿梭於脊椎部位肌肉之間，並避開脊椎神經，抵達目標位置切除突出的椎間盤。
適合長者 即日可出院
手術以局部麻醉進行，因手術期間病人要告訴醫生有否感到痛楚麻痹，讓醫生知道導管穿梭體內時有否觸及神經線。德國研究顯示，接受全內窺鏡切除術治療病人，經過約兩年觀察及跟進，發現術後背痛減少，出現手術造成創傷減少，並較快復原。
這種微創脊椎手術適合部份不耐受傳統開刀手術的年長患者，因為手術創傷性較少，可以使用局部麻醉，伸入的導管只撥開周圍肌肉，毋須把肌肉切開，以盡量保留肌肉的功能。
術後疼痛較開放性手術少，所以醫生只須處方較少、較輕的止痛藥便可，病人更可即日下床行走及出院。
微創脊椎手術技術亦能應用於治療脊椎退化、創傷及變形等，亦可紓緩脊椎腫瘤造成痛楚。但是部份病情複雜、脊椎嚴重變形等患者並不適合用微創方法治療。
這種微創脊椎手術適合部份不耐受傳統開刀手術的年長患者，因為手術創傷性較少，可以使用局部麻醉，伸入的導管只撥開周圍肌肉，毋須把肌肉切開，以盡量保留肌肉的功能。
術後疼痛較開放性手術少，所以醫生只須處方較少、較輕的止痛藥便可，病人更可即日下床行走及出院。
微創脊椎手術技術亦能應用於治療脊椎退化、創傷及變形等，亦可紓緩脊椎腫瘤造成痛楚。但是部份病情複雜、脊椎嚴重變形等患者並不適合用微創方法治療。
2016年5月12日星期四
AN OLD IDEA, REVIVED: STARVE CANCER TO DEATH
In the early 20th century, the German biochemist Otto Warburg believed that tumors could be treated by disrupting their source of energy. Hisidea was dismissed for decades — until now.
The story of modern cancer research begins, somewhat improbably, with the sea urchin. In the first decade of the 20th century, the German biologist Theodor Boveri discovered that if he fertilized sea-urchin eggs with two sperm rather than one, some of the cells would end up with the wrong number of chromosomes and fail to develop properly. It was the era before modern genetics, but Boveri was aware that cancer cells, like the deformed sea urchin cells, had abnormal chromosomes; whatever caused cancer, he surmised, had something to do with chromosomes.
Today Boveri is celebrated for discovering the origins of cancer, but another German scientist, Otto Warburg, was studying sea-urchin eggs around the same time as Boveri. His research, too, was hailed as a major breakthrough in our understanding of cancer. But in the following decades, Warburg’s discovery would largely disappear from the cancer narrative, his contributions considered so negligible that they were left out of textbooks altogether.
Unlike Boveri, Warburg wasn’t interested in the chromosomes of sea-urchin eggs. Rather, Warburg was focused on energy, specifically on how the eggs fueled their growth. By the time Warburg turned his attention from sea-urchin cells to the cells of a rat tumor, in 1923, he knew that sea-urchin eggs increased their oxygen consumption significantly as they grew, so he expected to see a similar need for extra oxygen in the rat tumor. Instead, the cancer cells fueled their growth by swallowing up enormous amounts of glucose (blood sugar) and breaking it down without oxygen. The result made no sense. Oxygen-fueled reactions are a much more efficient way of turning food into energy, and there was plenty of oxygen available for the cancer cells to use. But when Warburg tested additional tumors, including ones from humans, he saw the same effect every time. The cancer cells were ravenous for glucose.
Warburg’s discovery, later named the Warburg effect, is estimated to occur in up to 80 percent of cancers. It is so fundamental to most cancers that a positron emission tomography (PET) scan, which has emerged as an important tool in the staging and diagnosis of cancer, works simply by revealing the places in the body where cells are consuming extra glucose. In many cases, the more glucose a tumor consumes, the worse a patient’s prognosis.
In the years following his breakthrough, Warburg became convinced that the Warburg effect occurs because cells are unable to use oxygen properly and that this damaged respiration is, in effect, the starting point of cancer. Well into the 1950s, this theory — which Warburg believed in until his death in 1970 but never proved — remained an important subject of debate within the field. And then, more quickly than anyone could have anticipated, the debate ended. In 1953, James Watson and Francis Crick pieced together the structure of the DNA molecule and set the stage for the triumph of molecular biology’s gene-centered approach to cancer. In the following decades, scientists came to regard cancer as a disease governed by mutated genes, which drive cells into a state of relentless division and proliferation. The metabolic catalysts that Warburg spent his career analyzing began to be referred to as “housekeeping enzymes” — necessary to keep a cell going but largely irrelevant to the deeper story of cancer.
“It was a stampede,” says Thomas Seyfried, a biologist at Boston College, of the move to molecular biology. “Warburg was dropped like a hot potato.” There was every reason to think that Warburg would remain at best a footnote in the history of cancer research. (As Dominic D’Agostino, an associate professor at the University of South Florida Morsani College of Medicine, told me, “The book that my students have to use for their cancer biology course has no mention of cancer metabolism.”) But over the past decade, and the past five years in particular, something unexpected happened: Those housekeeping enzymes have again become one of the most promising areas of cancer research. Scientists now wonder if metabolism could prove to be the long-sought “Achilles’ heel” of cancer, a common weak point in a disease that manifests itself in so many different forms.
There are typically many mutations in a single cancer. But there are a limited number of ways that the body can produce energy and support rapid growth. Cancer cells rely on these fuels in a way that healthy cells don’t. The hope of scientists at the forefront of the Warburg revival is that they will be able to slow — or even stop — tumors by disrupting one or more of the many chemical reactions a cell uses to proliferate, and, in the process, starve cancer cells of the nutrients they desperately need to grow.
Even James Watson, one of the fathers of molecular biology, is convinced that targeting metabolism is a more promising avenue in current cancer research than gene-centered approaches. At his office at the Cold Spring Harbor Laboratory in Long Island, Watson, 88, sat beneath one of the original sketches of the DNA molecule and told me that locating the genes that cause cancer has been “remarkably unhelpful” — the belief that sequencing your DNA is going to extend your life “a cruel illusion.” If he were going into cancer research today, Watson said, he would study biochemistry rather than molecular biology.
“I never thought, until about two months ago, I’d ever have to learn the Krebs cycle,” he said, referring to the reactions, familiar to most high-school biology students, by which a cell powers itself. “Now I realize I have to.”
Born in 1883 into the illustrious Warburg family, Otto Warburg was raised to be a science prodigy. His father, Emil, was one of Germany’s leading physicists, and many of the world’s greatest physicists and chemists, including Albert Einstein and Max Planck, were friends of the family. (When Warburg enlisted in the military during World War I, Einstein sent him a letter urging him to come home for the sake of science.) Those men had explained the mysteries of the universe with a handful of fundamental laws, and the young Warburg came to believe he could bring that same elegant simplicity and clarity to the workings of life. Long before his death, Warburg was considered perhaps the greatest biochemist of the 20th century, a man whose research was vital to our understanding not only of cancer but also of respiration and photosynthesis. In 1931 he won the Nobel Prize for his work on respiration, and he was considered for the award on two other occasions — each time for a different discovery. Records indicate that he would have won in 1944, had the Nazis not forbidden the acceptance of the Nobel by German citizens.
That Warburg was able to live in Germany and continue his research throughout World War II, despite having Jewish ancestry and most likely being gay, speaks to the German obsession with cancer in the first half of the 20th century. At the time, cancer was more prevalent in Germany than in almost any other nation. According to the Stanford historian Robert Proctor, by the 1920s Germany’s escalating cancer rates had become a “major scandal.” A number of top Nazis, including Hitler, are believed to have harbored a particular dread of the disease; Hitler and Joseph Goebbels took the time to discuss new advances in cancer research in the hours leading up to the Nazi invasion of the Soviet Union. Whether Hitler was personally aware of Warburg’s research is unknown, but one of Warburg’s former colleagues wrote that several sources told him that “Hitler’s entourage” became convinced that “Warburg was the only scientist who offered a serious hope of producing a cure for cancer one day.”
Although many Jewish scientists fled Germany during the 1930s, Warburg chose to remain. According to his biographer, the Nobel Prize-winning biochemist Hans Krebs, who worked in Warburg’s lab, “science was the dominant emotion” of Warburg’s adult life, “virtually subjugating all other emotions.” In Krebs’s telling, Warburg spent years building a small team of specially trained technicians who knew how to run his experiments, and he feared that his mission to defeat cancer would be set back significantly if he had to start over. But after the war, Warburg fired all the technicians, suspecting that they had reported his criticisms of the Third Reich to the Gestapo. Warburg’s reckless decision to stay in Nazi Germany most likely came down to his astonishing ego. (Upon learning he had won the Nobel Prize, Warburg’s response was, “It’s high time.”)
“Modesty was not a virtue of Otto Warburg,” says George Klein, a 90-year-old cancer researcher at the Karolinska Institute in Sweden. As a young man, Klein was asked to send cancer cells to Warburg’s lab. A number of years later, Klein’s boss approached Warburg for a recommendation on Klein’s behalf. “George Klein has made a very important contribution to cancer research,” Warburg wrote. “He has sent me the cells with which I have solved the cancer problem.” Klein also recalls the lecture Warburg gave in Stockholm in 1950 at the 50th anniversary of the Nobel Prize. Warburg drew four diagrams on a blackboard explaining the Warburg effect, and then told the members of the audience that they represented all that they needed to know about the biochemistry of cancer.
Warburg was so monumentally stubborn that he refused to use the word “mitochondria,” even after it had been widely accepted as the name for the tiny structures that power cells. Instead Warburg persisted in calling them “grana,” the term he came up with when he identified those structures as the site of cellular respiration. Few things would have been more upsetting to him than the thought of Nazi thugs chasing him out of the beautiful Berlin institute, modeled after a country manor and built specifically for him. After the war, the Russians approached Warburg and offered to erect a new institute in Moscow. Klein recalls that Warburg told them with great pride that both Hitler and Stalin had failed to move him. As Warburg explained to his sister: “Ich war vor Hitler da” — “I was here before Hitler.”
Imagine two engines, the one being driven by complete and the other by incomplete combustion of coal,” Warburg wrote in 1956, responding to a criticism of his hypothesis that cancer is a problem of energy. “A man who knows nothing at all about engines, their structure and their purpose may discover the difference. He may, for example, smell it.”
The “complete combustion,” in Warburg’s analogy, is respiration. The “incomplete combustion,” turning nutrients into energy without oxygen, is known as fermentation. Fermentation provides a useful backup when oxygen can’t reach cells quickly enough to keep up with demand. (Our muscle cells turn to fermentation during intense exercise.) Warburg thought that defects prevent cancer cells from being able to use respiration, but scientists now widely agree that this is wrong. A growing tumor can be thought of as a construction site, and as today’s researchers explain it, the Warburg effect opens the gates for more and more trucks to deliver building materials (in the form of glucose molecules) to make “daughter” cells.
If this theory can explain the “why” of the Warburg effect, it still leaves the more pressing question of what, exactly, sets a cell on the path to the Warburg effect and cancer. Scientists at several of the nation’s top cancer hospitals have spearheaded the Warburg revival, in hopes of finding the answer. These researchers, typically molecular biologists by training, have turned to metabolism and the Warburg effect because their own research led each of them to the same conclusion: A number of the cancer-causing genes that have long been known for their role in cell division also regulate cells’ consumption of nutrients.
Craig Thompson, the president and chief executive of the Memorial Sloan Kettering Cancer Center, has been among the most outspoken proponents of this renewed focus on metabolism. In Thompson’s analogy, the Warburg effect can be thought of as a social failure: a breakdown of the nutrient-sharing agreement that single-celled organisms signed when they joined forces to become multicellular organisms. His research showed that cells need to receive instructions from other cells to eat, just as they require instructions from other cells to divide. Thompson hypothesized that if he could identify the mutations that lead a cell to eat more glucose than it should, it would go a long way toward explaining how the Warburg effect and cancer begin. But Thompson’s search for those mutations didn’t lead to an entirely new discovery. Instead, it led him to AKT, a gene already well known to molecular biologists for its role in promoting cell division. Thompson now believes AKT plays an even more fundamental role in metabolism.
The protein created by AKT is part of a chain of signaling proteins that is mutated in up to 80 percent of all cancers. Thompson says that once these proteins go into overdrive, a cell no longer worries about signals from other cells to eat; it instead stuffs itself with glucose. Thompson discovered he could induce the “full Warburg effect” simply by placing an activated AKT protein into a normal cell. When that happens, Thompson says, the cells begin to do what every single-celled organism will do in the presence of food: eat as much as it can and make as many copies of itself as possible. When Thompson presents his research to high-school students, he shows them a slide of mold spreading across a piece of bread. The slide’s heading — “Everyone’s first cancer experiment” — recalls Warburg’s observation that cancer cells will carry out fermentation at almost the same rate of wildly growing yeasts.
Just as Thompson has redefined the role of AKT, Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania, has helped lead the cancer world to an appreciation of how one widely studied gene can profoundly influence a tumor’s metabolism. In 1997, Dang became one of the first scientists to connect molecular biology to the science of cellular metabolism when he demonstrated that MYC — a so-called regulator gene well known for its role in cell proliferation — directly targets an enzyme that can turn on the Warburg effect. Dang recalls that other researchers were skeptical of his interest in a housekeeping enzyme, but he stuck with it because he came to appreciate something critical: Cancer cells can’t stop eating.
Unlike healthy cells, growing cancer cells are missing the internal feedback loops that are designed to conserve resources when food isn’t available. They’re “addicted to nutrients,” Dang says; when they can’t consume enough, they begin to die. The addiction to nutrients explains why changes to metabolic pathways are so common and tend to arise first as a cell progresses toward cancer: It’s not that other types of alterations can’t arise first, but rather that, when they do, the incipient tumors lack the access to the nutrients they need to grow. Dang uses the analogy of a work crew trying to put up a building. “If you don’t have enough cement, and you try to put a lot of bricks together, you’re going to collapse,” he says.
Metabolism-centered therapies have produced some tantalizing successes. Agios Pharmaceuticals, a company co-founded by Thompson, is now testing a drug that treats cases of acute myelogenous leukemia that have been resistant to other therapies by inhibiting the mutated versions of the metabolic enzyme IDH 2. In clinical trials of the Agios drug, nearly 40 percent of patients who carry these mutations are experiencing at least partial remissions.
Researchers working in a lab run by Peter Pedersen, a professor of biochemistry at Johns Hopkins, discovered that a compound known as 3-bromopyruvate can block energy production in cancer cells and, at least in rats and rabbits, wipe out advanced liver cancer. (Trials of the drug have yet to begin.) At Penn, Dang and his colleagues are now trying to block multiple metabolic pathways at the same time. In mice, this two-pronged approach has been able to shrink some tumors without debilitating side effects. Dang says the hope is not necessarily to find a cure but rather to keep cancer at bay in a “smoldering quiet state,” much as patients treat their hypertension.
Warburg, too, appreciated that a tumor’s dependence upon a steady flow of nutrients might eventually prove to be its fatal weakness. Long after his initial discovery of the Warburg effect, he continued to research the enzymes involved in fermentation and to explore the possibility of blocking the process in cancer cells. The challenge Warburg faced then is the same one that metabolism researchers face today: Cancer is an incredibly persistent foe. Blocking one metabolic pathway has been shown to slow down and even stop tumor growth in some cases, but tumors tend to find another way. “You block glucose, they use glutamine,” Dang says, in reference to another primary fuel used by cancers. “You block glucose and glutamine, they might be able to use fatty acids. We don’t know yet.”
Given Warburg’s own story of historical neglect, it’s fitting that what may turn out to be one of the most promising cancer metabolism drugs has been sitting in plain sight for decades. That drug, metformin, is already widely prescribed to decrease the glucose in the blood of diabetics (76.9 million metformin prescriptions were filled in the United States in 2014). In the years ahead, it’s likely to be used to treat — or at least to prevent — some cancers. Because metformin can influence a number of metabolic pathways, the precise mechanism by which it achieves its anticancer effects remains a source of debate. But the results of numerous epidemiological studies have been striking. Diabetics taking metformin seem to be significantly less likely to develop cancer than diabetics who don’t — and significantly less likely to die from the disease when they do.
Near the end of his life, Warburg grew obsessed with his diet. He believed that most cancer was preventable and thought that chemicals added to food and used in agriculture could cause tumors by interfering with respiration. He stopped eating bread unless it was baked in his own home. He would drink milk only if it came from a special herd of cows, and used a centrifuge at his lab to make his cream and butter.
Warburg’s personal diet is unlikely to become a path to prevention. But the Warburg revival has allowed researchers to develop a hypothesis for how the diets that are linked to our obesity and diabetes epidemics — specifically, sugar-heavy diets that can result in permanently elevated levels of the hormone insulin — may also be driving cells to the Warburg effect and cancer.
The insulin hypothesis can be traced to the research of Lewis Cantley, the director of the Meyer Cancer Center at Weill Cornell Medical College. In the 1980s, Cantley discovered how insulin, which is released by the pancreas and tells cells to take up glucose, influences what happens inside a cell. Cantley now refers to insulin and a closely related hormone, IGF-1 (insulinlike growth factor 1), as “the champion” activators of metabolic proteins linked to cancer. He’s beginning to see evidence, he says, that in some cases, “it really is insulin itself that’s getting the tumor started.” One way to think about the Warburg effect, says Cantley, is as the insulin, or IGF-1, signaling pathway “gone awry — it’s cells behaving as though insulin were telling it to take up glucose all the time and to grow.” Cantley, who avoids eating sugar as much as he can, is currently studying the effects of diet on mice that have the mutations that are commonly found in colorectal and other cancers. He says that the effects of a sugary diet on colorectal, breast and other cancer models “looks very impressive” and “rather scary.”
Elevated insulin is also strongly associated with obesity, which is expected soon to overtake smoking as the leading cause of preventable cancer. Cancers linked to obesity and diabetes have more receptors for insulin and IGF-1, and people with defective IGF-1 receptors appear to be nearly immune to cancer. Retrospective studies, which look back at patient histories, suggest that many people who develop colorectal, pancreatic or breast cancer have elevated insulin levels before diagnosis. It’s perhaps not entirely surprising, then, that when researchers want to grow breast-cancer cells in the lab, they add insulin to the tissue culture. When they remove the insulin, the cancer cells die.
“I think there’s no doubt that insulin is pro-cancer,” Watson says, with respect to the link between obesity, diabetes and cancer. “It’s as good a hypothesis as we have now.” Watson takes metformin for cancer prevention; among its many effects, metformin works to lower insulin levels. Not every cancer researcher, however, is convinced of the role of insulin and IGF-1 in cancer. Robert Weinberg, a researcher at M.I.T.’s Whitehead Institute who pioneered the discovery of cancer-causing genes in the ’80s, has remained somewhat cool to certain aspects of the cancer-metabolism revival. Weinberg says that there isn’t yet enough evidence to know whether the levels of insulin and IGF-1 present in obese people are sufficient to trigger the Warburg effect. “It’s a hypothesis,” Weinberg says. “I don’t know if it’s right or wrong.”
During Warburg’s lifetime, insulin’s effects on metabolic pathways were even less well understood. But given his ego, it’s highly unlikely that he would have considered the possibility that anything other than damaged respiration could cause cancer. He died sure that he was right about the disease. Warburg framed a quote from Max Planck and hung it above his desk: “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die.”
The story of modern cancer research begins, somewhat improbably, with the sea urchin. In the first decade of the 20th century, the German biologist Theodor Boveri discovered that if he fertilized sea-urchin eggs with two sperm rather than one, some of the cells would end up with the wrong number of chromosomes and fail to develop properly. It was the era before modern genetics, but Boveri was aware that cancer cells, like the deformed sea urchin cells, had abnormal chromosomes; whatever caused cancer, he surmised, had something to do with chromosomes.
Today Boveri is celebrated for discovering the origins of cancer, but another German scientist, Otto Warburg, was studying sea-urchin eggs around the same time as Boveri. His research, too, was hailed as a major breakthrough in our understanding of cancer. But in the following decades, Warburg’s discovery would largely disappear from the cancer narrative, his contributions considered so negligible that they were left out of textbooks altogether.
Unlike Boveri, Warburg wasn’t interested in the chromosomes of sea-urchin eggs. Rather, Warburg was focused on energy, specifically on how the eggs fueled their growth. By the time Warburg turned his attention from sea-urchin cells to the cells of a rat tumor, in 1923, he knew that sea-urchin eggs increased their oxygen consumption significantly as they grew, so he expected to see a similar need for extra oxygen in the rat tumor. Instead, the cancer cells fueled their growth by swallowing up enormous amounts of glucose (blood sugar) and breaking it down without oxygen. The result made no sense. Oxygen-fueled reactions are a much more efficient way of turning food into energy, and there was plenty of oxygen available for the cancer cells to use. But when Warburg tested additional tumors, including ones from humans, he saw the same effect every time. The cancer cells were ravenous for glucose.
Warburg’s discovery, later named the Warburg effect, is estimated to occur in up to 80 percent of cancers. It is so fundamental to most cancers that a positron emission tomography (PET) scan, which has emerged as an important tool in the staging and diagnosis of cancer, works simply by revealing the places in the body where cells are consuming extra glucose. In many cases, the more glucose a tumor consumes, the worse a patient’s prognosis.
In the years following his breakthrough, Warburg became convinced that the Warburg effect occurs because cells are unable to use oxygen properly and that this damaged respiration is, in effect, the starting point of cancer. Well into the 1950s, this theory — which Warburg believed in until his death in 1970 but never proved — remained an important subject of debate within the field. And then, more quickly than anyone could have anticipated, the debate ended. In 1953, James Watson and Francis Crick pieced together the structure of the DNA molecule and set the stage for the triumph of molecular biology’s gene-centered approach to cancer. In the following decades, scientists came to regard cancer as a disease governed by mutated genes, which drive cells into a state of relentless division and proliferation. The metabolic catalysts that Warburg spent his career analyzing began to be referred to as “housekeeping enzymes” — necessary to keep a cell going but largely irrelevant to the deeper story of cancer.
“It was a stampede,” says Thomas Seyfried, a biologist at Boston College, of the move to molecular biology. “Warburg was dropped like a hot potato.” There was every reason to think that Warburg would remain at best a footnote in the history of cancer research. (As Dominic D’Agostino, an associate professor at the University of South Florida Morsani College of Medicine, told me, “The book that my students have to use for their cancer biology course has no mention of cancer metabolism.”) But over the past decade, and the past five years in particular, something unexpected happened: Those housekeeping enzymes have again become one of the most promising areas of cancer research. Scientists now wonder if metabolism could prove to be the long-sought “Achilles’ heel” of cancer, a common weak point in a disease that manifests itself in so many different forms.
There are typically many mutations in a single cancer. But there are a limited number of ways that the body can produce energy and support rapid growth. Cancer cells rely on these fuels in a way that healthy cells don’t. The hope of scientists at the forefront of the Warburg revival is that they will be able to slow — or even stop — tumors by disrupting one or more of the many chemical reactions a cell uses to proliferate, and, in the process, starve cancer cells of the nutrients they desperately need to grow.
Even James Watson, one of the fathers of molecular biology, is convinced that targeting metabolism is a more promising avenue in current cancer research than gene-centered approaches. At his office at the Cold Spring Harbor Laboratory in Long Island, Watson, 88, sat beneath one of the original sketches of the DNA molecule and told me that locating the genes that cause cancer has been “remarkably unhelpful” — the belief that sequencing your DNA is going to extend your life “a cruel illusion.” If he were going into cancer research today, Watson said, he would study biochemistry rather than molecular biology.
“I never thought, until about two months ago, I’d ever have to learn the Krebs cycle,” he said, referring to the reactions, familiar to most high-school biology students, by which a cell powers itself. “Now I realize I have to.”
Born in 1883 into the illustrious Warburg family, Otto Warburg was raised to be a science prodigy. His father, Emil, was one of Germany’s leading physicists, and many of the world’s greatest physicists and chemists, including Albert Einstein and Max Planck, were friends of the family. (When Warburg enlisted in the military during World War I, Einstein sent him a letter urging him to come home for the sake of science.) Those men had explained the mysteries of the universe with a handful of fundamental laws, and the young Warburg came to believe he could bring that same elegant simplicity and clarity to the workings of life. Long before his death, Warburg was considered perhaps the greatest biochemist of the 20th century, a man whose research was vital to our understanding not only of cancer but also of respiration and photosynthesis. In 1931 he won the Nobel Prize for his work on respiration, and he was considered for the award on two other occasions — each time for a different discovery. Records indicate that he would have won in 1944, had the Nazis not forbidden the acceptance of the Nobel by German citizens.
That Warburg was able to live in Germany and continue his research throughout World War II, despite having Jewish ancestry and most likely being gay, speaks to the German obsession with cancer in the first half of the 20th century. At the time, cancer was more prevalent in Germany than in almost any other nation. According to the Stanford historian Robert Proctor, by the 1920s Germany’s escalating cancer rates had become a “major scandal.” A number of top Nazis, including Hitler, are believed to have harbored a particular dread of the disease; Hitler and Joseph Goebbels took the time to discuss new advances in cancer research in the hours leading up to the Nazi invasion of the Soviet Union. Whether Hitler was personally aware of Warburg’s research is unknown, but one of Warburg’s former colleagues wrote that several sources told him that “Hitler’s entourage” became convinced that “Warburg was the only scientist who offered a serious hope of producing a cure for cancer one day.”
Although many Jewish scientists fled Germany during the 1930s, Warburg chose to remain. According to his biographer, the Nobel Prize-winning biochemist Hans Krebs, who worked in Warburg’s lab, “science was the dominant emotion” of Warburg’s adult life, “virtually subjugating all other emotions.” In Krebs’s telling, Warburg spent years building a small team of specially trained technicians who knew how to run his experiments, and he feared that his mission to defeat cancer would be set back significantly if he had to start over. But after the war, Warburg fired all the technicians, suspecting that they had reported his criticisms of the Third Reich to the Gestapo. Warburg’s reckless decision to stay in Nazi Germany most likely came down to his astonishing ego. (Upon learning he had won the Nobel Prize, Warburg’s response was, “It’s high time.”)
“Modesty was not a virtue of Otto Warburg,” says George Klein, a 90-year-old cancer researcher at the Karolinska Institute in Sweden. As a young man, Klein was asked to send cancer cells to Warburg’s lab. A number of years later, Klein’s boss approached Warburg for a recommendation on Klein’s behalf. “George Klein has made a very important contribution to cancer research,” Warburg wrote. “He has sent me the cells with which I have solved the cancer problem.” Klein also recalls the lecture Warburg gave in Stockholm in 1950 at the 50th anniversary of the Nobel Prize. Warburg drew four diagrams on a blackboard explaining the Warburg effect, and then told the members of the audience that they represented all that they needed to know about the biochemistry of cancer.
Warburg was so monumentally stubborn that he refused to use the word “mitochondria,” even after it had been widely accepted as the name for the tiny structures that power cells. Instead Warburg persisted in calling them “grana,” the term he came up with when he identified those structures as the site of cellular respiration. Few things would have been more upsetting to him than the thought of Nazi thugs chasing him out of the beautiful Berlin institute, modeled after a country manor and built specifically for him. After the war, the Russians approached Warburg and offered to erect a new institute in Moscow. Klein recalls that Warburg told them with great pride that both Hitler and Stalin had failed to move him. As Warburg explained to his sister: “Ich war vor Hitler da” — “I was here before Hitler.”
Imagine two engines, the one being driven by complete and the other by incomplete combustion of coal,” Warburg wrote in 1956, responding to a criticism of his hypothesis that cancer is a problem of energy. “A man who knows nothing at all about engines, their structure and their purpose may discover the difference. He may, for example, smell it.”
The “complete combustion,” in Warburg’s analogy, is respiration. The “incomplete combustion,” turning nutrients into energy without oxygen, is known as fermentation. Fermentation provides a useful backup when oxygen can’t reach cells quickly enough to keep up with demand. (Our muscle cells turn to fermentation during intense exercise.) Warburg thought that defects prevent cancer cells from being able to use respiration, but scientists now widely agree that this is wrong. A growing tumor can be thought of as a construction site, and as today’s researchers explain it, the Warburg effect opens the gates for more and more trucks to deliver building materials (in the form of glucose molecules) to make “daughter” cells.
If this theory can explain the “why” of the Warburg effect, it still leaves the more pressing question of what, exactly, sets a cell on the path to the Warburg effect and cancer. Scientists at several of the nation’s top cancer hospitals have spearheaded the Warburg revival, in hopes of finding the answer. These researchers, typically molecular biologists by training, have turned to metabolism and the Warburg effect because their own research led each of them to the same conclusion: A number of the cancer-causing genes that have long been known for their role in cell division also regulate cells’ consumption of nutrients.
Craig Thompson, the president and chief executive of the Memorial Sloan Kettering Cancer Center, has been among the most outspoken proponents of this renewed focus on metabolism. In Thompson’s analogy, the Warburg effect can be thought of as a social failure: a breakdown of the nutrient-sharing agreement that single-celled organisms signed when they joined forces to become multicellular organisms. His research showed that cells need to receive instructions from other cells to eat, just as they require instructions from other cells to divide. Thompson hypothesized that if he could identify the mutations that lead a cell to eat more glucose than it should, it would go a long way toward explaining how the Warburg effect and cancer begin. But Thompson’s search for those mutations didn’t lead to an entirely new discovery. Instead, it led him to AKT, a gene already well known to molecular biologists for its role in promoting cell division. Thompson now believes AKT plays an even more fundamental role in metabolism.
The protein created by AKT is part of a chain of signaling proteins that is mutated in up to 80 percent of all cancers. Thompson says that once these proteins go into overdrive, a cell no longer worries about signals from other cells to eat; it instead stuffs itself with glucose. Thompson discovered he could induce the “full Warburg effect” simply by placing an activated AKT protein into a normal cell. When that happens, Thompson says, the cells begin to do what every single-celled organism will do in the presence of food: eat as much as it can and make as many copies of itself as possible. When Thompson presents his research to high-school students, he shows them a slide of mold spreading across a piece of bread. The slide’s heading — “Everyone’s first cancer experiment” — recalls Warburg’s observation that cancer cells will carry out fermentation at almost the same rate of wildly growing yeasts.
Just as Thompson has redefined the role of AKT, Chi Van Dang, director of the Abramson Cancer Center at the University of Pennsylvania, has helped lead the cancer world to an appreciation of how one widely studied gene can profoundly influence a tumor’s metabolism. In 1997, Dang became one of the first scientists to connect molecular biology to the science of cellular metabolism when he demonstrated that MYC — a so-called regulator gene well known for its role in cell proliferation — directly targets an enzyme that can turn on the Warburg effect. Dang recalls that other researchers were skeptical of his interest in a housekeeping enzyme, but he stuck with it because he came to appreciate something critical: Cancer cells can’t stop eating.
Unlike healthy cells, growing cancer cells are missing the internal feedback loops that are designed to conserve resources when food isn’t available. They’re “addicted to nutrients,” Dang says; when they can’t consume enough, they begin to die. The addiction to nutrients explains why changes to metabolic pathways are so common and tend to arise first as a cell progresses toward cancer: It’s not that other types of alterations can’t arise first, but rather that, when they do, the incipient tumors lack the access to the nutrients they need to grow. Dang uses the analogy of a work crew trying to put up a building. “If you don’t have enough cement, and you try to put a lot of bricks together, you’re going to collapse,” he says.
Metabolism-centered therapies have produced some tantalizing successes. Agios Pharmaceuticals, a company co-founded by Thompson, is now testing a drug that treats cases of acute myelogenous leukemia that have been resistant to other therapies by inhibiting the mutated versions of the metabolic enzyme IDH 2. In clinical trials of the Agios drug, nearly 40 percent of patients who carry these mutations are experiencing at least partial remissions.
Researchers working in a lab run by Peter Pedersen, a professor of biochemistry at Johns Hopkins, discovered that a compound known as 3-bromopyruvate can block energy production in cancer cells and, at least in rats and rabbits, wipe out advanced liver cancer. (Trials of the drug have yet to begin.) At Penn, Dang and his colleagues are now trying to block multiple metabolic pathways at the same time. In mice, this two-pronged approach has been able to shrink some tumors without debilitating side effects. Dang says the hope is not necessarily to find a cure but rather to keep cancer at bay in a “smoldering quiet state,” much as patients treat their hypertension.
Warburg, too, appreciated that a tumor’s dependence upon a steady flow of nutrients might eventually prove to be its fatal weakness. Long after his initial discovery of the Warburg effect, he continued to research the enzymes involved in fermentation and to explore the possibility of blocking the process in cancer cells. The challenge Warburg faced then is the same one that metabolism researchers face today: Cancer is an incredibly persistent foe. Blocking one metabolic pathway has been shown to slow down and even stop tumor growth in some cases, but tumors tend to find another way. “You block glucose, they use glutamine,” Dang says, in reference to another primary fuel used by cancers. “You block glucose and glutamine, they might be able to use fatty acids. We don’t know yet.”
Given Warburg’s own story of historical neglect, it’s fitting that what may turn out to be one of the most promising cancer metabolism drugs has been sitting in plain sight for decades. That drug, metformin, is already widely prescribed to decrease the glucose in the blood of diabetics (76.9 million metformin prescriptions were filled in the United States in 2014). In the years ahead, it’s likely to be used to treat — or at least to prevent — some cancers. Because metformin can influence a number of metabolic pathways, the precise mechanism by which it achieves its anticancer effects remains a source of debate. But the results of numerous epidemiological studies have been striking. Diabetics taking metformin seem to be significantly less likely to develop cancer than diabetics who don’t — and significantly less likely to die from the disease when they do.
Near the end of his life, Warburg grew obsessed with his diet. He believed that most cancer was preventable and thought that chemicals added to food and used in agriculture could cause tumors by interfering with respiration. He stopped eating bread unless it was baked in his own home. He would drink milk only if it came from a special herd of cows, and used a centrifuge at his lab to make his cream and butter.
Warburg’s personal diet is unlikely to become a path to prevention. But the Warburg revival has allowed researchers to develop a hypothesis for how the diets that are linked to our obesity and diabetes epidemics — specifically, sugar-heavy diets that can result in permanently elevated levels of the hormone insulin — may also be driving cells to the Warburg effect and cancer.
The insulin hypothesis can be traced to the research of Lewis Cantley, the director of the Meyer Cancer Center at Weill Cornell Medical College. In the 1980s, Cantley discovered how insulin, which is released by the pancreas and tells cells to take up glucose, influences what happens inside a cell. Cantley now refers to insulin and a closely related hormone, IGF-1 (insulinlike growth factor 1), as “the champion” activators of metabolic proteins linked to cancer. He’s beginning to see evidence, he says, that in some cases, “it really is insulin itself that’s getting the tumor started.” One way to think about the Warburg effect, says Cantley, is as the insulin, or IGF-1, signaling pathway “gone awry — it’s cells behaving as though insulin were telling it to take up glucose all the time and to grow.” Cantley, who avoids eating sugar as much as he can, is currently studying the effects of diet on mice that have the mutations that are commonly found in colorectal and other cancers. He says that the effects of a sugary diet on colorectal, breast and other cancer models “looks very impressive” and “rather scary.”
Elevated insulin is also strongly associated with obesity, which is expected soon to overtake smoking as the leading cause of preventable cancer. Cancers linked to obesity and diabetes have more receptors for insulin and IGF-1, and people with defective IGF-1 receptors appear to be nearly immune to cancer. Retrospective studies, which look back at patient histories, suggest that many people who develop colorectal, pancreatic or breast cancer have elevated insulin levels before diagnosis. It’s perhaps not entirely surprising, then, that when researchers want to grow breast-cancer cells in the lab, they add insulin to the tissue culture. When they remove the insulin, the cancer cells die.
“I think there’s no doubt that insulin is pro-cancer,” Watson says, with respect to the link between obesity, diabetes and cancer. “It’s as good a hypothesis as we have now.” Watson takes metformin for cancer prevention; among its many effects, metformin works to lower insulin levels. Not every cancer researcher, however, is convinced of the role of insulin and IGF-1 in cancer. Robert Weinberg, a researcher at M.I.T.’s Whitehead Institute who pioneered the discovery of cancer-causing genes in the ’80s, has remained somewhat cool to certain aspects of the cancer-metabolism revival. Weinberg says that there isn’t yet enough evidence to know whether the levels of insulin and IGF-1 present in obese people are sufficient to trigger the Warburg effect. “It’s a hypothesis,” Weinberg says. “I don’t know if it’s right or wrong.”
During Warburg’s lifetime, insulin’s effects on metabolic pathways were even less well understood. But given his ego, it’s highly unlikely that he would have considered the possibility that anything other than damaged respiration could cause cancer. He died sure that he was right about the disease. Warburg framed a quote from Max Planck and hung it above his desk: “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die.”
2016年5月5日星期四
After ‘The Biggest Loser,’ Their Bodies Fought to Regain Weight
Danny Cahill stood, slightly dazed, in a blizzard of confetti as the audience screamed and his family ran on stage. He had won Season 8 of NBC’s reality television show “The Biggest Loser,” shedding more weight than anyone ever had on the program — an astonishing 239 pounds in seven months.
When he got on the scale for all to see that evening, Dec. 8, 2009, he weighed just 191 pounds, down from 430. Dressed in a T-shirt and knee-length shorts, he was lean, athletic and as handsome as a model.
“I’ve got my life back,” he declared. “I mean, I feel like a million bucks.”
Mr. Cahill left the show’s stage in Hollywood and flew directly to New York to start a triumphal tour of the talk shows, chatting with Jay Leno, Regis Philbin and Joy Behar. As he heard from fans all over the world, his elation knew no bounds.
But in the years since, more than 100 pounds have crept back onto his 5-foot-11 frame despite his best efforts. In fact, most of that season’s 16 contestants have regained much if not all the weight they lost so arduously. Some are even heavier now.
Yet their experiences, while a bitter personal disappointment, have been a gift to science. A study of Season 8’s contestants has yielded surprising new discoveries about the physiology of obesity that help explain why so many people struggle unsuccessfully to keep off the weight they lose.
Kevin Hall, a scientist at a federal research center who admits to a weakness for reality TV, had the idea to follow the “Biggest Loser” contestants for six years after that victorious night. The project was the first to measure what happened to people over as long as six years after they had lost large amounts of weight with intensive dieting and exercise.
The results, the researchers said, were stunning. They showed just how hard the body fights back against weight loss.
“It is frightening and amazing,” said Dr. Hall, an expert on metabolism at the National Institute of Diabetes and Digestive and Kidney Diseases, which is part of the National Institutes of Health.
“I am just blown away.”
It has to do with resting metabolism, which determines how many calories a person burns when at rest. When the show began, the contestants, though hugely overweight, had normal metabolisms for their size, meaning they were burning a normal number of calories for people of their weight. When it ended, their metabolisms had slowed radically and their bodies were not burning enough calories to maintain their thinner sizes.
Researchers knew that just about anyone who deliberately loses weight — even if they start at a normal weight or even underweight — will have a slower metabolism when the diet ends. So they were not surprised to see that “The Biggest Loser” contestants had slow metabolisms when the show ended.
What shocked the researchers was what happened next: As the years went by and the numbers on the scale climbed, the contestants’ metabolisms did not recover. They became even slower, and the pounds kept piling on. It was as if their bodies were intensifying their effort to pull the contestants back to their original weight.
Mr. Cahill was one of the worst off. As he regained more than 100 pounds, his metabolism slowed so much that, just to maintain his current weight of 295 pounds, he now has to eat 800 calories a day less than a typical man his size. Anything more turns to fat.
‘A Basic Biological Reality’
The struggles the contestants went through help explain why it has been so hard to make headway against the nation’s obesity problem, which afflicts more than a third of American adults. Despite spending billions of dollars on weight-loss drugs and dieting programs, even the most motivated are working against their own biology.
Their experience shows that the body will fight back for years. And that, said Dr. Michael Schwartz, an obesity and diabetes researcher who is a professor of medicine at the University of Washington, is “new and important.”
“The key point is that you can be on TV, you can lose enormous amounts of weight, you can go on for six years, but you can’t get away from a basic biological reality,” said Dr. Schwartz, who was not involved in the study. “As long as you are below your initial weight, your body is going to try to get you back.”
The show’s doctor, Robert Huizenga, says he expected the contestants’ metabolic rates to fall just after the show, but was hoping for a smaller drop. He questioned, though, whether the measurements six years later were accurate. But maintaining weight loss is difficult, he said, which is why he tells contestants that they should exercise at least nine hours a week and monitor their diets to keep the weight off.
“Unfortunately, many contestants are unable to find or afford adequate ongoing support with exercise doctors, psychologists, sleep specialists, and trainers — and that’s something we all need to work hard to change,” he said in an email.
The study’s findings, to be published on Monday in the journal Obesity, are part of a scientific push to answer some of the most fundamental questions about obesity. Researchers are figuring out why being fat makes so many people develop diabetes and other medical conditions, and they are searching for new ways to block the poison in fat. They are starting to unravel the reasons bariatric surgery allows most people to lose significant amounts of weight when dieting so often fails. And they are looking afresh at medical care for obese people.
The hope is that this work will eventually lead to new therapies that treat obesity as a chronic disease and can help keep weight under control for life.
Most people who have tried to lose weight know how hard it is to keep the weight off, but many blame themselves when the pounds come back. But what obesity research has consistently shown is that dieters are at the mercy of their own bodies, which muster hormones and an altered metabolic rate to pull them back to their old weights, whether that is hundreds of pounds more or that extra 10 or 15 that many people are trying to keep off.
There is always a weight a person’s body maintains without any effort. And while it is not known why that weight can change over the years — it may be an effect of aging — at any point, there is a weight that is easy to maintain, and that is the weight the body fights to defend. Finding a way to thwart these mechanisms is the goal scientists are striving for. First, though, they are trying to understand them in greater detail.
Dr. David Ludwig, the director of the New Balance Foundation Obesity Prevention Center at Boston Children’s Hospital, who was not involved in the research, said the findings showed the need for new approaches to weight control. He cautioned that the study was limited by its small size and the lack of a control group of obese people who did not lose weight. But, he added, the findings made sense.
“This is a subset of the most successful” dieters, he said. “If they don’t show a return to normal in metabolism, what hope is there for the rest of us?”
Still, he added, “that shouldn’t be interpreted to mean we are doomed to battle our biology or remain fat. It means we need to explore other approaches.”
Slimmer and Hungrier
Some scientists say weight maintenance has to be treated as an issue separate from weight loss. Only when that challenge is solved, they say, can progress truly be made against obesity.
“There is a lot of basic research we still need to do,” said Dr. Margaret Jackson, who is directing a project at Pfizer. Her group is testing a drug that, in animals at least, acts like leptin, a hormone that controls hunger. With weight loss, leptin levels fall and people become hungry. The idea is to trick the brains of people who have lost weight so they do not become ravenous for lack of leptin.
While many of the contestants kept enough weight off to improve their health and became more physically active, the low weights they strived to keep eluded all but one of them: Erinn Egbert, a full-time caregiver for her mother in Versailles, Ky. And she struggles mightily to keep the pounds off because her metabolism burns 552 fewer calories a day than would be expected for someone her size.
“What people don’t understand is that a treat is like a drug,” said Ms. Egbert, who went from 263 pounds to just under 176 on the show, and now weighs between 152 and 157. “Two treats can turn into a binge over a three-day period. That is what I struggle with.”
Six years after Season 8 ended, 14 of the 16 contestants went to the N.I.H. last fall for three days of testing. The researchers were concerned that the contestants might try to frantically lose weight before coming in, so they shipped equipment to them that would measure their physical activity and weight before their visit, and had the information sent remotely to the N.I.H.
The contestants received their metabolic results last week. They were shocked, but on further reflection, decided the numbers explained a lot.
“All my friends were drinking beer and not gaining massive amounts of weight,” Mr. Cahill said. “The moment I started drinking beer, there goes another 20 pounds. I said, ‘This is not right. Something is wrong with my body.’”
Sean Algaier, 36, a pastor from Charlotte, N.C., feels cheated. He went from 444 pounds to 289 as a contestant on the show. Now his weight is up to 450 again, and he is burning 458 fewer calories a day than would be expected for a man his size.
“It’s kind of like hearing you have a life sentence,” he said.
Losing a Key Hormone
Slower metabolisms were not the only reason the contestants regained weight, though. They constantly battled hunger, cravings and binges. The investigators found at least one reason: plummeting levels of leptin. The contestants started out with normal levels of leptin. By the season’s finale, they had almost no leptin at all, which would have made them ravenous all the time. As their weight returned, their leptin levels drifted up again, but only to about half of what they had been when the season began, the researchers found, thus helping to explain their urges to eat.
Leptin is just one of a cluster of hormones that control hunger, and although Dr. Hall and his colleagues did not measure the rest of them, another group of researchers, in a different project, did. In a one-year study funded by Australia’s National Health and Medical Research Council, Dr. Joseph Proietto of the University of Melbourne and his colleagues recruited 50 overweight people who agreed to consume just 550 calories a day for eight or nine weeks. They lost an average of nearly 30 pounds, but over the next year, the pounds started coming back.
Dr. Proietto and his colleagues looked at leptin and four other hormones that satiate people. Levels of most of them fell in their study subjects. They also looked at a hormone that makes people want to eat. Its level rose.
“What was surprising was what a coordinated effect it is,” Dr. Proietto said. “The body puts multiple mechanisms in place to get you back to your weight. The only way to maintain weight loss is to be hungry all the time. We desperately need agents that will suppress hunger and that are safe with long-term use.”
370, 400, 460, 485
Mr. Cahill, 46, said his weight problem began when he was in the third grade. He got fat, then fatter. He would starve himself, and then eat a whole can of cake frosting with a spoon. Afterward, he would cower in the pantry off the kitchen, feeling overwhelmed with shame.
Over the years, his insatiable urge to eat kept overcoming him, and his weight climbed: 370 pounds, 400, 460, 485.
“I used to look at myself and think, ‘I am horrible, I am a monster, subhuman,’” he said. He began sleeping in a recliner because he was too heavy to sleep lying down. Walking hurt; stairs were agony. Buying clothes with a 68 waist was humiliating.
“I remember sitting in a dressing room one day, and nothing would fit. I looked at the traffic outside on the street and thought, ‘I should just run out in front of a car.’”
He eventually seized on “The Biggest Loser” as his best chance to lose enough weight to live a normal life. He tried three times and was finally selected.
Before the show began, the contestants underwent medical tests to be sure they could endure the rigorous schedule that lay ahead. And rigorous it was. Sequestered on the “Biggest Loser” ranch with the other contestants, Mr. Cahill exercised seven hours a day, burning 8,000 to 9,000 calories according to a calorie tracker the show gave him. He took electrolyte tablets to help replace the salts he lost through sweating, consuming many fewer calories than before.
Eventually, he and the others were sent home for four months to try to keep losing weight on their own.
Mr. Cahill set a goal of a 3,500-caloric deficit per day. The idea was to lose a pound a day. He quit his job as a land surveyor to do it.
His routine went like this: Wake up at 5 a.m. and run on a treadmill for 45 minutes. Have breakfast — typically one egg and two egg whites, half a grapefruit and a piece of sprouted grain toast. Run on the treadmill for another 45 minutes. Rest for 40 minutes; bike ride nine miles to a gym. Work out for two and a half hours. Shower, ride home, eat lunch — typically a grilled skinless chicken breast, a cup of broccoli and 10 spears of asparagus. Rest for an hour. Drive to the gym for another round of exercise.
If he had not burned enough calories to hit his goal, he went back to the gym after dinner to work out some more. At times, he found himself running around his neighborhood in the dark until his calorie-burn indicator reset to zero at midnight.
On the day of the weigh-in on the show’s finale, Mr. Cahill and the others dressed carefully to hide the rolls of loose skin that remained, to their surprise and horror, after they had lost weight. They wore compression undergarments to hold it in.
Mr. Cahill knew he could not maintain his finale weight of 191 pounds. He was so mentally and physically exhausted he barely moved for two weeks after his publicity tour ended. But he had started a new career giving motivational speeches as the biggest loser ever, and for the next four years, he managed to keep his weight below 255 pounds by exercising two to three hours a day. But two years ago, he went back to his job as a surveyor, and the pounds started coming back.
Soon the scale hit 265. Mr. Cahill started weighing and measuring his food again and stepped up his exercise. He got back down to 235 to 240 pounds. But his weight edged up again, to 275, then 295.
His slow metabolism is part of the problem, and so are his food cravings. He opens a bag of chips, thinking he will have just a few. “I’d eat five bites. Then I’d black out and eat the whole bag of chips and say, ‘What did I do?’”
Brain Sets the Calories
Dr. Lee Kaplan, an obesity researcher at Harvard, says the brain sets the number of calories we consume, and it can be easy for people to miss that how much they eat matters less than the fact that their bodies want to hold on to more of those calories.
Dr. Michael Rosenbaum, an obesity researcher at Columbia University who has collaborated with Dr. Hall in previous studies, said the body’s systems for regulating how many calories are consumed and how many are burned are tightly coupled when people are not strenuously trying to lose weight or to maintain a significant weight loss. Still, pounds can insidiously creep on.
“We eat about 900,000 to a million calories a year, and burn them all except those annoying 3,000 to 5,000 calories that result in an average annual weight gain of about one to two pounds,” he said. “These very small differences between intake and output average out to only about 10 to 20 calories per day — less than one Starburst candy — but the cumulative consequences over time can be devastating.”
“It is not clear whether this small imbalance and the resultant weight gain that most of us experience as we age are the consequences of changes in lifestyle, the environment or just the biology of aging,” Dr. Rosenbaum added.
The effects of small imbalances between calories eaten and calories burned are more pronounced when people deliberately lose weight, Dr. Hall said. Yes, there are signals to regain weight, but he wondered how many extra calories people were driven to eat. He found a way to figure that out.
He analyzed data from a clinical trial in which people took a diabetes drug, canagliflozin, that makes them spill 360 calories a day into their urine, or took a placebo. The drug has no known effect on the brain, and the person does not realize those calories are being spilled. Those taking the drug gradually lost weight. But for every five pounds they lost, they were, without realizing it, eating an additional 200 calories a day.
Those extra calories, Dr. Hall said, were a bigger driver of weight regained than the slowing of the metabolism. And, he added, if people fought the urge to eat those calories, they would be hungry. “Unless they continue to fight it constantly, they will regain the weight,” he said.
All this does not mean that modest weight loss is hopeless, experts say. Individuals respond differently to diet manipulations — low-carbohydrate or low-calorie diets, for example — and to exercise and weight-loss drugs, among other interventions.
But Dr. Ludwig said that simply cutting calories was not the answer. “There are no doubt exceptional individuals who can ignore primal biological signals and maintain weight loss for the long term by restricting calories,” he said, but he added that “for most people, the combination of incessant hunger and slowing metabolism is a recipe for weight regain — explaining why so few individuals can maintain weight loss for more than a few months.”
Dr. Rosenbaum agreed. “The difficulty in keeping weight off reflects biology, not a pathological lack of willpower affecting two-thirds of the U.S.A.,” he said.
Mr. Cahill knows that now. And with his report from Dr. Hall’s group showing just how much his metabolism had slowed, he stopped blaming himself for his weight gain.
“That shame that was on my shoulders went off,” he said.
Short Answers to Hard Questions About Weight Loss
Almost everyone who has ever dieted knows how hard it is to keep the weight off. And almost everyone, including many scientists, has wondered what works. An article on Monday about what happened to contestants from “The Biggest Loser” television show is a vivid illustration of the problem. Although there is no magic formula for weight maintenance, here are answers to some questions that arise over and over.
Are you more likely to maintain weight loss if you lose weight slowly?
That is the advice dieters often get, but studies have not found that to be the case. For example, a recent Australian study, funded by the Australian National Health and Medical Research Council and the Sir Edward Dunlop Medical Research Foundation, randomly assigned 204 obese people to subsist on just 450 to 800 calories a day for 12 weeks, or to cut a more modest 400 to 500 calories a day from their diets over 36 weeks. The goal for both groups was a 15 percent weight loss. Three years after the study began, almost everyone had regained the weight they lost, despite counseling on diet and exercise. There was also no difference in the levels of two hormones, leptin and ghrelin, that drive hunger. The main difference between the groups was that more people in the rapid weight loss group lost at least 12.5 percent of their weight (80 percent, compared with 50 percent in the slow loss group) and fewer dropped out (3 percent, compared with 18 percent).
To maintain weight loss, should you avoid snacks?
Although it seems to make sense that snacks can pack on the pounds, studies that randomly assigned people to snack or not have failed to confirm this, and even observational studies have not found evidence that snacks undermine weight loss.
If you build muscle with exercise, including weight lifting, will you be able to maintain a higher metabolism?
Muscle burns more calories than fat, so it might stand to reason that the more muscle you have the faster you will burn calories. But it turns out that building muscles has almost no effect on resting metabolism, which determines how many calories a person burns when at rest. The reason is that any muscle you add is small compared with the total amount of skeletal muscle on your body. And most of the time that muscle is at rest. (You can’t go around flexing your biceps nonstop.) Muscles have a very low metabolic rate at rest. One researcher calculated that if a man weighing about 175 pounds lifts weights and puts on about 4½ pounds of muscle — a typical amount for men who lift weights for 12 weeks — he will burn an extra 24 calories a day, the amount in a couple of Life Saver candies.
Can you defeat your body’s slowed metabolism after weight loss by doing vigorous cardiovascular exercises?
You can as long as you do not eat more calories to make up for the ones you burned. It sounds simple enough, but “this is not as easy a proposition as it sounds,” says Dr. Michael Rosenbaum, a doctor and obesity researcher at Columbia University. The brain controls your hunger and your cravings for food, and it is all too easy to accidentally consume more calories than you burned exercising. That is a major reason studies that use exercise alone to help people lose weight have generally failed to find an effect.
Exercise also has an unexpected effect, documented by Dr. Rosenbaum and Dr. Rudolph Leibel at Columbia University. They found that after you lose 10 percent or more of your weight by diet alone, your muscles start using genes that make them more efficient. They burn 20 to 30 percent fewer calories for the same exercise.
Is there a type of diet that helps keep weight off?
Many people swear by diets that are low in carbohydrates or gluten free, or revolve around fasting two days out of seven. Dr. Lee Kaplan, an obesity researcher at Harvard, says there is no diet or weight-loss regimen that is guaranteed to work but that people can often maintain a loss of 5 percent of their weight, which is enough for health benefits to kick in. He tells his patients to try one weight-loss program after another in hopes of finding something that works for them.
So what hope is there for weight maintenance?
Anecdotal reports by people who have succeeded in keeping weight off tend to have a common theme: constant vigilance, keeping close track of weight, controlling what food is eaten and how much (often by weighing and measuring food), exercising often, putting up with hunger and resisting cravings to the best of their ability. Those who maintain a modest weight loss often report less of a struggle than those trying to keep off large amounts of weight.
When he got on the scale for all to see that evening, Dec. 8, 2009, he weighed just 191 pounds, down from 430. Dressed in a T-shirt and knee-length shorts, he was lean, athletic and as handsome as a model.
“I’ve got my life back,” he declared. “I mean, I feel like a million bucks.”
Mr. Cahill left the show’s stage in Hollywood and flew directly to New York to start a triumphal tour of the talk shows, chatting with Jay Leno, Regis Philbin and Joy Behar. As he heard from fans all over the world, his elation knew no bounds.
But in the years since, more than 100 pounds have crept back onto his 5-foot-11 frame despite his best efforts. In fact, most of that season’s 16 contestants have regained much if not all the weight they lost so arduously. Some are even heavier now.
Yet their experiences, while a bitter personal disappointment, have been a gift to science. A study of Season 8’s contestants has yielded surprising new discoveries about the physiology of obesity that help explain why so many people struggle unsuccessfully to keep off the weight they lose.
Kevin Hall, a scientist at a federal research center who admits to a weakness for reality TV, had the idea to follow the “Biggest Loser” contestants for six years after that victorious night. The project was the first to measure what happened to people over as long as six years after they had lost large amounts of weight with intensive dieting and exercise.
The results, the researchers said, were stunning. They showed just how hard the body fights back against weight loss.
“It is frightening and amazing,” said Dr. Hall, an expert on metabolism at the National Institute of Diabetes and Digestive and Kidney Diseases, which is part of the National Institutes of Health.
“I am just blown away.”
It has to do with resting metabolism, which determines how many calories a person burns when at rest. When the show began, the contestants, though hugely overweight, had normal metabolisms for their size, meaning they were burning a normal number of calories for people of their weight. When it ended, their metabolisms had slowed radically and their bodies were not burning enough calories to maintain their thinner sizes.
Researchers knew that just about anyone who deliberately loses weight — even if they start at a normal weight or even underweight — will have a slower metabolism when the diet ends. So they were not surprised to see that “The Biggest Loser” contestants had slow metabolisms when the show ended.
What shocked the researchers was what happened next: As the years went by and the numbers on the scale climbed, the contestants’ metabolisms did not recover. They became even slower, and the pounds kept piling on. It was as if their bodies were intensifying their effort to pull the contestants back to their original weight.
Mr. Cahill was one of the worst off. As he regained more than 100 pounds, his metabolism slowed so much that, just to maintain his current weight of 295 pounds, he now has to eat 800 calories a day less than a typical man his size. Anything more turns to fat.
‘A Basic Biological Reality’
The struggles the contestants went through help explain why it has been so hard to make headway against the nation’s obesity problem, which afflicts more than a third of American adults. Despite spending billions of dollars on weight-loss drugs and dieting programs, even the most motivated are working against their own biology.
Their experience shows that the body will fight back for years. And that, said Dr. Michael Schwartz, an obesity and diabetes researcher who is a professor of medicine at the University of Washington, is “new and important.”
“The key point is that you can be on TV, you can lose enormous amounts of weight, you can go on for six years, but you can’t get away from a basic biological reality,” said Dr. Schwartz, who was not involved in the study. “As long as you are below your initial weight, your body is going to try to get you back.”
The show’s doctor, Robert Huizenga, says he expected the contestants’ metabolic rates to fall just after the show, but was hoping for a smaller drop. He questioned, though, whether the measurements six years later were accurate. But maintaining weight loss is difficult, he said, which is why he tells contestants that they should exercise at least nine hours a week and monitor their diets to keep the weight off.
“Unfortunately, many contestants are unable to find or afford adequate ongoing support with exercise doctors, psychologists, sleep specialists, and trainers — and that’s something we all need to work hard to change,” he said in an email.
The study’s findings, to be published on Monday in the journal Obesity, are part of a scientific push to answer some of the most fundamental questions about obesity. Researchers are figuring out why being fat makes so many people develop diabetes and other medical conditions, and they are searching for new ways to block the poison in fat. They are starting to unravel the reasons bariatric surgery allows most people to lose significant amounts of weight when dieting so often fails. And they are looking afresh at medical care for obese people.
The hope is that this work will eventually lead to new therapies that treat obesity as a chronic disease and can help keep weight under control for life.
Most people who have tried to lose weight know how hard it is to keep the weight off, but many blame themselves when the pounds come back. But what obesity research has consistently shown is that dieters are at the mercy of their own bodies, which muster hormones and an altered metabolic rate to pull them back to their old weights, whether that is hundreds of pounds more or that extra 10 or 15 that many people are trying to keep off.
There is always a weight a person’s body maintains without any effort. And while it is not known why that weight can change over the years — it may be an effect of aging — at any point, there is a weight that is easy to maintain, and that is the weight the body fights to defend. Finding a way to thwart these mechanisms is the goal scientists are striving for. First, though, they are trying to understand them in greater detail.
Dr. David Ludwig, the director of the New Balance Foundation Obesity Prevention Center at Boston Children’s Hospital, who was not involved in the research, said the findings showed the need for new approaches to weight control. He cautioned that the study was limited by its small size and the lack of a control group of obese people who did not lose weight. But, he added, the findings made sense.
“This is a subset of the most successful” dieters, he said. “If they don’t show a return to normal in metabolism, what hope is there for the rest of us?”
Still, he added, “that shouldn’t be interpreted to mean we are doomed to battle our biology or remain fat. It means we need to explore other approaches.”
Slimmer and Hungrier
Some scientists say weight maintenance has to be treated as an issue separate from weight loss. Only when that challenge is solved, they say, can progress truly be made against obesity.
“There is a lot of basic research we still need to do,” said Dr. Margaret Jackson, who is directing a project at Pfizer. Her group is testing a drug that, in animals at least, acts like leptin, a hormone that controls hunger. With weight loss, leptin levels fall and people become hungry. The idea is to trick the brains of people who have lost weight so they do not become ravenous for lack of leptin.
While many of the contestants kept enough weight off to improve their health and became more physically active, the low weights they strived to keep eluded all but one of them: Erinn Egbert, a full-time caregiver for her mother in Versailles, Ky. And she struggles mightily to keep the pounds off because her metabolism burns 552 fewer calories a day than would be expected for someone her size.
“What people don’t understand is that a treat is like a drug,” said Ms. Egbert, who went from 263 pounds to just under 176 on the show, and now weighs between 152 and 157. “Two treats can turn into a binge over a three-day period. That is what I struggle with.”
Six years after Season 8 ended, 14 of the 16 contestants went to the N.I.H. last fall for three days of testing. The researchers were concerned that the contestants might try to frantically lose weight before coming in, so they shipped equipment to them that would measure their physical activity and weight before their visit, and had the information sent remotely to the N.I.H.
The contestants received their metabolic results last week. They were shocked, but on further reflection, decided the numbers explained a lot.
“All my friends were drinking beer and not gaining massive amounts of weight,” Mr. Cahill said. “The moment I started drinking beer, there goes another 20 pounds. I said, ‘This is not right. Something is wrong with my body.’”
Sean Algaier, 36, a pastor from Charlotte, N.C., feels cheated. He went from 444 pounds to 289 as a contestant on the show. Now his weight is up to 450 again, and he is burning 458 fewer calories a day than would be expected for a man his size.
“It’s kind of like hearing you have a life sentence,” he said.
Losing a Key Hormone
Slower metabolisms were not the only reason the contestants regained weight, though. They constantly battled hunger, cravings and binges. The investigators found at least one reason: plummeting levels of leptin. The contestants started out with normal levels of leptin. By the season’s finale, they had almost no leptin at all, which would have made them ravenous all the time. As their weight returned, their leptin levels drifted up again, but only to about half of what they had been when the season began, the researchers found, thus helping to explain their urges to eat.
Leptin is just one of a cluster of hormones that control hunger, and although Dr. Hall and his colleagues did not measure the rest of them, another group of researchers, in a different project, did. In a one-year study funded by Australia’s National Health and Medical Research Council, Dr. Joseph Proietto of the University of Melbourne and his colleagues recruited 50 overweight people who agreed to consume just 550 calories a day for eight or nine weeks. They lost an average of nearly 30 pounds, but over the next year, the pounds started coming back.
Dr. Proietto and his colleagues looked at leptin and four other hormones that satiate people. Levels of most of them fell in their study subjects. They also looked at a hormone that makes people want to eat. Its level rose.
“What was surprising was what a coordinated effect it is,” Dr. Proietto said. “The body puts multiple mechanisms in place to get you back to your weight. The only way to maintain weight loss is to be hungry all the time. We desperately need agents that will suppress hunger and that are safe with long-term use.”
370, 400, 460, 485
Mr. Cahill, 46, said his weight problem began when he was in the third grade. He got fat, then fatter. He would starve himself, and then eat a whole can of cake frosting with a spoon. Afterward, he would cower in the pantry off the kitchen, feeling overwhelmed with shame.
Over the years, his insatiable urge to eat kept overcoming him, and his weight climbed: 370 pounds, 400, 460, 485.
“I used to look at myself and think, ‘I am horrible, I am a monster, subhuman,’” he said. He began sleeping in a recliner because he was too heavy to sleep lying down. Walking hurt; stairs were agony. Buying clothes with a 68 waist was humiliating.
“I remember sitting in a dressing room one day, and nothing would fit. I looked at the traffic outside on the street and thought, ‘I should just run out in front of a car.’”
He eventually seized on “The Biggest Loser” as his best chance to lose enough weight to live a normal life. He tried three times and was finally selected.
Before the show began, the contestants underwent medical tests to be sure they could endure the rigorous schedule that lay ahead. And rigorous it was. Sequestered on the “Biggest Loser” ranch with the other contestants, Mr. Cahill exercised seven hours a day, burning 8,000 to 9,000 calories according to a calorie tracker the show gave him. He took electrolyte tablets to help replace the salts he lost through sweating, consuming many fewer calories than before.
Eventually, he and the others were sent home for four months to try to keep losing weight on their own.
Mr. Cahill set a goal of a 3,500-caloric deficit per day. The idea was to lose a pound a day. He quit his job as a land surveyor to do it.
His routine went like this: Wake up at 5 a.m. and run on a treadmill for 45 minutes. Have breakfast — typically one egg and two egg whites, half a grapefruit and a piece of sprouted grain toast. Run on the treadmill for another 45 minutes. Rest for 40 minutes; bike ride nine miles to a gym. Work out for two and a half hours. Shower, ride home, eat lunch — typically a grilled skinless chicken breast, a cup of broccoli and 10 spears of asparagus. Rest for an hour. Drive to the gym for another round of exercise.
If he had not burned enough calories to hit his goal, he went back to the gym after dinner to work out some more. At times, he found himself running around his neighborhood in the dark until his calorie-burn indicator reset to zero at midnight.
On the day of the weigh-in on the show’s finale, Mr. Cahill and the others dressed carefully to hide the rolls of loose skin that remained, to their surprise and horror, after they had lost weight. They wore compression undergarments to hold it in.
Mr. Cahill knew he could not maintain his finale weight of 191 pounds. He was so mentally and physically exhausted he barely moved for two weeks after his publicity tour ended. But he had started a new career giving motivational speeches as the biggest loser ever, and for the next four years, he managed to keep his weight below 255 pounds by exercising two to three hours a day. But two years ago, he went back to his job as a surveyor, and the pounds started coming back.
Soon the scale hit 265. Mr. Cahill started weighing and measuring his food again and stepped up his exercise. He got back down to 235 to 240 pounds. But his weight edged up again, to 275, then 295.
His slow metabolism is part of the problem, and so are his food cravings. He opens a bag of chips, thinking he will have just a few. “I’d eat five bites. Then I’d black out and eat the whole bag of chips and say, ‘What did I do?’”
Brain Sets the Calories
Dr. Lee Kaplan, an obesity researcher at Harvard, says the brain sets the number of calories we consume, and it can be easy for people to miss that how much they eat matters less than the fact that their bodies want to hold on to more of those calories.
Dr. Michael Rosenbaum, an obesity researcher at Columbia University who has collaborated with Dr. Hall in previous studies, said the body’s systems for regulating how many calories are consumed and how many are burned are tightly coupled when people are not strenuously trying to lose weight or to maintain a significant weight loss. Still, pounds can insidiously creep on.
“We eat about 900,000 to a million calories a year, and burn them all except those annoying 3,000 to 5,000 calories that result in an average annual weight gain of about one to two pounds,” he said. “These very small differences between intake and output average out to only about 10 to 20 calories per day — less than one Starburst candy — but the cumulative consequences over time can be devastating.”
“It is not clear whether this small imbalance and the resultant weight gain that most of us experience as we age are the consequences of changes in lifestyle, the environment or just the biology of aging,” Dr. Rosenbaum added.
The effects of small imbalances between calories eaten and calories burned are more pronounced when people deliberately lose weight, Dr. Hall said. Yes, there are signals to regain weight, but he wondered how many extra calories people were driven to eat. He found a way to figure that out.
He analyzed data from a clinical trial in which people took a diabetes drug, canagliflozin, that makes them spill 360 calories a day into their urine, or took a placebo. The drug has no known effect on the brain, and the person does not realize those calories are being spilled. Those taking the drug gradually lost weight. But for every five pounds they lost, they were, without realizing it, eating an additional 200 calories a day.
Those extra calories, Dr. Hall said, were a bigger driver of weight regained than the slowing of the metabolism. And, he added, if people fought the urge to eat those calories, they would be hungry. “Unless they continue to fight it constantly, they will regain the weight,” he said.
All this does not mean that modest weight loss is hopeless, experts say. Individuals respond differently to diet manipulations — low-carbohydrate or low-calorie diets, for example — and to exercise and weight-loss drugs, among other interventions.
But Dr. Ludwig said that simply cutting calories was not the answer. “There are no doubt exceptional individuals who can ignore primal biological signals and maintain weight loss for the long term by restricting calories,” he said, but he added that “for most people, the combination of incessant hunger and slowing metabolism is a recipe for weight regain — explaining why so few individuals can maintain weight loss for more than a few months.”
Dr. Rosenbaum agreed. “The difficulty in keeping weight off reflects biology, not a pathological lack of willpower affecting two-thirds of the U.S.A.,” he said.
Mr. Cahill knows that now. And with his report from Dr. Hall’s group showing just how much his metabolism had slowed, he stopped blaming himself for his weight gain.
“That shame that was on my shoulders went off,” he said.
Short Answers to Hard Questions About Weight Loss
Almost everyone who has ever dieted knows how hard it is to keep the weight off. And almost everyone, including many scientists, has wondered what works. An article on Monday about what happened to contestants from “The Biggest Loser” television show is a vivid illustration of the problem. Although there is no magic formula for weight maintenance, here are answers to some questions that arise over and over.
Are you more likely to maintain weight loss if you lose weight slowly?
That is the advice dieters often get, but studies have not found that to be the case. For example, a recent Australian study, funded by the Australian National Health and Medical Research Council and the Sir Edward Dunlop Medical Research Foundation, randomly assigned 204 obese people to subsist on just 450 to 800 calories a day for 12 weeks, or to cut a more modest 400 to 500 calories a day from their diets over 36 weeks. The goal for both groups was a 15 percent weight loss. Three years after the study began, almost everyone had regained the weight they lost, despite counseling on diet and exercise. There was also no difference in the levels of two hormones, leptin and ghrelin, that drive hunger. The main difference between the groups was that more people in the rapid weight loss group lost at least 12.5 percent of their weight (80 percent, compared with 50 percent in the slow loss group) and fewer dropped out (3 percent, compared with 18 percent).
To maintain weight loss, should you avoid snacks?
Although it seems to make sense that snacks can pack on the pounds, studies that randomly assigned people to snack or not have failed to confirm this, and even observational studies have not found evidence that snacks undermine weight loss.
If you build muscle with exercise, including weight lifting, will you be able to maintain a higher metabolism?
Muscle burns more calories than fat, so it might stand to reason that the more muscle you have the faster you will burn calories. But it turns out that building muscles has almost no effect on resting metabolism, which determines how many calories a person burns when at rest. The reason is that any muscle you add is small compared with the total amount of skeletal muscle on your body. And most of the time that muscle is at rest. (You can’t go around flexing your biceps nonstop.) Muscles have a very low metabolic rate at rest. One researcher calculated that if a man weighing about 175 pounds lifts weights and puts on about 4½ pounds of muscle — a typical amount for men who lift weights for 12 weeks — he will burn an extra 24 calories a day, the amount in a couple of Life Saver candies.
Can you defeat your body’s slowed metabolism after weight loss by doing vigorous cardiovascular exercises?
You can as long as you do not eat more calories to make up for the ones you burned. It sounds simple enough, but “this is not as easy a proposition as it sounds,” says Dr. Michael Rosenbaum, a doctor and obesity researcher at Columbia University. The brain controls your hunger and your cravings for food, and it is all too easy to accidentally consume more calories than you burned exercising. That is a major reason studies that use exercise alone to help people lose weight have generally failed to find an effect.
Exercise also has an unexpected effect, documented by Dr. Rosenbaum and Dr. Rudolph Leibel at Columbia University. They found that after you lose 10 percent or more of your weight by diet alone, your muscles start using genes that make them more efficient. They burn 20 to 30 percent fewer calories for the same exercise.
Is there a type of diet that helps keep weight off?
Many people swear by diets that are low in carbohydrates or gluten free, or revolve around fasting two days out of seven. Dr. Lee Kaplan, an obesity researcher at Harvard, says there is no diet or weight-loss regimen that is guaranteed to work but that people can often maintain a loss of 5 percent of their weight, which is enough for health benefits to kick in. He tells his patients to try one weight-loss program after another in hopes of finding something that works for them.
So what hope is there for weight maintenance?
Anecdotal reports by people who have succeeded in keeping weight off tend to have a common theme: constant vigilance, keeping close track of weight, controlling what food is eaten and how much (often by weighing and measuring food), exercising often, putting up with hunger and resisting cravings to the best of their ability. Those who maintain a modest weight loss often report less of a struggle than those trying to keep off large amounts of weight.
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