The Genetic Disease, Hypoascorbemia
一种古老疾病的全新的处理方法和它的一些医学暗示
A Fresh Approach
to an Ancient Disease and Some
of its Medical Implications
作者: Irwin Stone
来源:WWW.VITAMINCFOUNDATION.ORG.
翻译:蓝 山
现在，L古洛糖酸内酯氧化酶（GLO，一种肝酶），并不是人人知道的。但，这种酶实际上，可能涉及在人类进化过程中，发生在人类身上的最大的单一的生理和生物化学灾难。这种酶是哺乳动物利用葡萄糖合成抗坏血酸的一系列酶的最后一种。这种抗坏血酸的生物合成是发生在几乎所有生物，包植物和动物的一个基本和最重要的代谢过程。
在进化的过程中，人类的灵长类祖先，在控制这种酶蛋白，L-古洛糖酸内酯氧化酶的制造的基因的位置，发生了一次条件性的致死性的突变(Gluecksohn-Waelsch, 1963)，摧毁了制造这种活性酶的能力。这种发生突变的动物，以及他们的后代，都携带这种基因，不能再制造抗坏血酸，他们必须依赖外部的抗坏血酸来源，以维持他们的生存。
数百万年之后，人类最终从这种有生物化学性残缺的动物进化过来。现代的人仍然受这种遗传缺陷的折磨(Stone, 1965)。目前所知，人类的所有种族都携带这种缺陷的基因，同时，正是这种遗传性的缺陷，从生物化学和生理学上，把人类和所有其他哺乳动物区分。
过去50年，人类对抗坏血酸的需要一直看成是为获得“维生素C”的一种营养性或膳食性需要。这种致死的疾病，坏血病，起病于完全失去了外部的维生素C来源，一直认为是一种膳食性缺乏病或维生素缺乏症。最近有指出，这种人类对抗坏血酸的需求，是因肝脏遗传性缺乏一种活性酶—L古洛糖酸内酯氧化酶而引起的一种典型的遗传性疾病综合征的结果(Stone, 1966)。然后，坏血病，是产生于这种遗传性代谢异常的终极后遗症。这种遗传性疾病已经被命名为“抗坏血酸缺乏症”（HYPOASCORBEMIA）。坏血病的遗传病原学的概念，为建立一个完全没有旧的“维生素C”假说的，量化的人类生物化学和人类生理学，提供了一个重要和崭新的前景和更宽的远景。这种新方法的某些医学暗示是本篇的主题。
人类，某些猴子，天竺鼠和一种印度食果蝙蝠(Pteropus medius)，是唯一所知的，不能在其肝脏制造抗坏血酸的哺乳动物。这几种哺乳动物是，失去外源性维生素C来源后，唯一受限甚至死于坏血病的哺乳动物。所有其他哺乳动物制造相当数量的抗坏血酸。人类肝脏提供这种重要的，生物化学活跃的分泌物的无能，令人类的生物化学，对比其他哺乳动物，处于一个明显的低级水平。其他哺乳动物应对生物化学压力，是增加抗坏血酸的制造，以维持其增加的需要。而人类的反应则是进一步耗竭这种存量本已很低的代谢物。在这些哺乳动物中，维持生化自稳态的一个重要因素是他们在受到压力的情况下，增加制造抗坏血酸的本能。
无数的多个世纪以来，人类的生理，已经变得适应很少的抗坏血酸摄入，因为其食物，即使是在最充足的时候，都从不能提供其肝脏本来制造和分泌到血流的抗坏血酸的数量。人每天可以获得以毫克算的抗坏血酸是幸运的。相同体重的哺乳动物每天合成的抗坏血酸是以克计算的。一只野外栖晰的黑猩猩（没有任何场合去适应古怪的人类饮食），消耗巨大体积的新鲜植物，已被估计是为获得每天4.5克的抗坏血酸(Bourne, 1949)。黑猩猩，可能和人一样，患有同样的遗传性缺陷。
随着火的发现和煮食的发展，曾是人类早期的相当丰富的抗坏血酸来源的新鲜肉和鱼，损失了这种重要的物质的多数，因为它对热加速的氧化非常敏感。反对食用其他昆虫和非脊椎动物剥夺了人类的另一丰富的抗坏血酸来源。重点是容易贮存的谷类作物的原始农业，提供的食物基本上是缺乏任何的抗坏血酸。对比其他哺乳动物，人类可以生存在如此低水平的抗坏血酸水平，是其粗壮和适应力的无言证据。人类的确生存进化了，但死于疾病、痛苦和死亡的数量一定是巨大的。
人类现在的生理，像这样，完成了一项很好的工作，能适应很低水平的抗坏血酸摄入，而不表现出显性的坏血病。然而，这不表示，所有许多依赖于抗坏血酸的生化活动维持在颠峰、最优化或甚至仅处于有效活动的边缘。人类可以患有生化坏血病而没有临床坏血病的征象。有证据表明，最少日摄入量“对长时间维持最佳健康或当机体受到常见的压力时，是满足不了身体所需的” (National Research Council, 1964a)。而人类什么时候不受到遇到压力呢？
因此，去推测（推测是我们唯一能做的，因为没有可得的医学文献的直接资料）人类生理的各个方面会对“完全纠正”这种存在已久的遗传缺陷做出怎样反应是很有趣的。“纠正”这个字用得不精确，通过“纠正”，意思是长时间给机体提供其肝脏本来将会制造的抗坏血酸的数量，如果这种突变没有发生的话(cf. Note in bibliography)。
遗传缺陷的这种全面纠正只有在过去30年，自从可得到大量纯正的抗坏血酸后，才变得可能。通过依靠食物作为外源性抗坏血酸来源，是不可能实现全面纠正的。因为，食物抗坏血酸的极少含量以及人类消化食物体积的生理极限。没有任何人作过全面的研究，以测定人类长时间服用接近哺乳动物在正常和应激情况下合成抗坏血酸的数量的结果。自从发现抗坏血酸，30年来，有关抗坏血酸的数千份报告，其中只有极零散的资料提到哺乳动物合成抗坏血酸的数量。确定人类的大约的最优化水平的摄入量的分岐依然很大(National Research Council, 1964a)。在其他方面，无数的报告建立于发现预防显性坏血病的症状的最少摄入量的研究结果。像抗坏血酸这样一种有广泛和关键作用的物质，看来，有比仅预防坏血病更多的用途。而所有花费大剂量的研究时间所取得的，只是测定人类在长间内其生理机能如何适应这种强迫性的抗坏血酸最少摄入量。
作为坏血病综合征的膳食性原因的这种虚伪的观点和狭窄的概念的“维生素假说”，长期以来主宰医学思维，成为阻碍对抗坏血酸作有力和深入研究的很大的阻力。通过定义维生素为食物中的一种微量物质，过去30年的大部分研究者，在研究抗坏血酸对坏血病以外的其他疾病的治疗作用的时候，把它作为一种“微量”物质，使用如治疗坏血病的极小剂量水平。他们从没试图使用接近哺乳动物在对等的病理应急情况下合成抗坏血酸的大剂量。经过对这类医学文献的广泛评估，结合正准备出版一本有关此主题的书，作者的观点是，我们几乎没有触及抗坏血酸治疗潜能的表面。由于研究者集中于缓解一种微量的“维生素缺乏症”，以及忽视给予病人维持持续性的可能有治疗效果的最低基础量的血液肾上腺素浓度，导致在这项研究中，连续性和思维清晰的临床结果的缺乏。他们，当然没有在这个遗传性疾病概念中固有的，使用大剂量抗坏血酸的逻辑性和理论依据的优势。很清楚地，这个领域需要很多新的临床研究，但这种研究应规划在一个更宽的基础，也就是说，人只是另一种哺乳动物，他原始的对抗坏血酸的生理和生化需求和其他的哺乳动物是类似的。
现在所有有关人类的统计数据，如人均寿命，某种疾病的发病率和死亡率，都是从所谓“正常”的人口获得的数据所得出的结果。然而，这些正常的“人口”，就整体而言，在其一生以及他们的父母、祖父母，以及所有祖先的一生中，都患人这种“未纠正”的遗传疾病。这种“正常”人口所摄入的抗坏血酸量，从遗传疾病的概念来判断，大概仅达到所需要的最少摄入量的边缘之下，而大部人口，某些时候甚至在其一生中，即使以“维生素”标准来衡量，都属于低水平。现已清楚，在坏血病状态，对感染的抵抗力更低下。如果从婴儿期开始，这种遗传性疾病就被连续完全“纠正“，对这些人口的患病率、死亡率和人均寿命的统计数据将会出现什么变化？我们称为“正常”的人口，当对比那些被完全持续“纠正”的个体，可能最终被发现“非常不正常”。
我们刚提到从婴儿开始“纠正”这种遗传疾病，但，对这些出生前的遗传疾病如何“纠正”，现已认识到，妊娠是一个生化性应急反应，需要更多的抗坏血酸，而在现在的维生素理论计算下，增加的摄入推荐量为：每日70~100毫克(National Research Council, 1964b)。通过全面“纠正”这种遗传疾病，给予准妈妈在同样条件下哺乳动物合成抗坏血酸的数量，会孕育出更好、更健康的婴儿同时使孕妇有更少的分娩困难及更少机会流产吗？很久以来，就已知道坏血病在天竺鼠的母体和胚胎会产生有害的改变，导致高比率的流产(Harman and Gillum, 1937; Harmon and Warren, 1951; Ingier, 1915; Kramer et al., 1933)。这里也有更大的想象空间，并值得进行更多的试验。
胶原蛋白，这种重要的组织蛋白的合成，是一个依赖抗坏血酸的过程。胶原蛋白是一种支撑性和结构性组织成分，构成约三分之一的身体蛋白质。由缺乏抗坏血酸造成的，这种至重要的生化合成的紊乱，引起坏血病的某些最痛苦的症状。边缘水平以下的抗坏血酸摄入，足以预防有害的坏血病急性反应。但远少于长时间维持胶原蛋白合成于最优化水平所需，可能是机体走向形成胶原蛋白疾病，关节病，风湿性疾病，甚至衰老过程的道路的引发机制。在所有这些生物化学应激反应的条件下，身体对抗坏血酸的需求都是增加的，而体内存在的抗坏血酸水平是很低的。最近有证据显示(Steven, 1965)，风湿性病变的组织的胶原蛋白的结构和正常的胶原蛋白的结构是有区别的。通过长期（一生当中）保持胶原蛋白合成和修复在最优化水平，而完全“纠正”这种遗传性疾病，可能会令机体对风湿性疾病有高度的抵抗力。这种新概念为在这些疾病的治疗中使用每天25~50克或更多的抗坏血酸提供了理论依据的基础。过去30年，许多以“维生素”水平的抗坏血酸治疗风湿性疾病的研究的报告指出，没有取得预期的效果。但，没有任何连续使用接近完全“纠正”量的抗坏血酸的研究报告。只有在病毒性疾病领域的治疗，抗坏血酸被以这样的幅度的量用于治疗。而得知抗坏血酸是强力、无毒的杀病毒剂已很久(Amato, 1937; Holden and Molloy, 1937; Holden and Resnick, 1936; Jungeblut, 1935; Kligler and Bernkopf, 1937; Langenbeck and Dnderling, 1937; Lojkin, 1936; Lominski, 1936; Martin, 1940)。只有使用在接近或超过这些“纠正”的水平，才有临床成功的连续性报告(Greer, 1955; Klenner, 1949, 1951, 1952, 1953)。
在衰老过程中，胶原蛋白是头等重要的。作为皮肤、血管和骨骼肌系统的主要支撑组织蛋白，因衰老而引起的这种蛋白质的任何改变都将有广泛的身体效应。在影响身体衰老的生物化学方面，胶原蛋白发生不间断和重要的反应，这种影响在其他身体组织是未发现的。在衰老过程，胶原蛋白将失去渗透膨胀能力。并将因此导致一种弹性的改变。这种胶原蛋白的酸溶解性减少，以及，随着老化的进行，变得更加抵抗胶原酶的消化(Kohn, 1963)。人类肌腱胶原蛋白的膨胀能力的最大退化，出现在30~50岁之间，在达到成熟期之后出现。由衰老而发生在胶原蛋白的改变，已被认为归功于分子间的交联，并因组织分子间的紧密联系，增加组织的缰硬。胶原蛋白的交联，以及加速这种交联过程的因子，尚未不清楚。辅酶Q， 被认为参与这个过程(Bjorksten, 1962)。这是一个自然发生的长链，是O-儿茶酚的替代衍生物，这个衍生物如氧化，可形成交联因子。这个蛋白的另一交联反应是由于包含在这些链中的硫氢基团的氧化结合，在这条肽链的一个稳定的双硫键交联的形成。所有这两个氧化反应都可以被完全“纠正”的个体的组织里的持续的高浓度高度还原的抗坏血酸抑制。而且，可能，伴随的衰老过程亦可能会被抑制。在一份讨论妊娠纹可被抗坏血酸抑制的临床试验的报告里，因为改善了的胶原蛋白合成和维护，McCormick (1948)作了下述有关抗坏血酸的倡导声明：“今天的年青女士，将可借助一种真正的内源性化妆品，通过一种膳食方法，同时是可行和友善的，避免她们年青的组织的弹性的过早失去”。关于衰老现象的一种全新的观点已被这种遗传概念提供，对其进行一些研究是可行的。数百万年来，第一次有可能去完全“纠正”这种遗传缺陷。
出血很久以来一直被认为是坏血病的特异性病征。这是依赖抗坏血酸的胶原蛋白在血管系统产生有缺陷的结构性组织蛋白的另一紊乱的结果。在血管系统，完全的“纠正”应该可以产生这样一个人，他的动脉、静脉和毛细血管，在机械强度和对抗血流的生理压力方面，是最佳的。因而，更少可能出现物理和化学性损伤和出血。通过终生服用足够大量的抗坏血酸，这种遗传缺陷的长期的“纠正”，将对心脏病、心血管病和中风的发病率有惊人的效果。
在癌症中，在最优化水平的胶原蛋白合成的维持，可以提供这样坚韧的组织基质，围绕在任何正在生长的癌细胞周围，这样，这些癌细胞就会被牢牢“锁死”，不能向外突破，以进一转移(McCormick, 1954, 1959)。而且，抗坏血酸有强力的解毒作用，以“纠正”这种遗传缺陷的高水平的抗坏血酸摄入，对致癌物对组织的作用将有肯定的抑制(Warren, 1943)。哺乳动物接触致癌物的反应是增加抗坏血酸的合成(Boyland and Grover, 1961)。而在人类，癌症的剌激引发抗坏血酸水平的巨大赤字(Antes and Molo, 1939; Gaehtgens, 1938; Griebel, 1939; Kudlac and Storck, 1938; Schneider, 1938; Spellberg and Keeton, 1939; Vogt, 1939)。在癌症治疗的临床试验中，已有煽动性的结果，但，研究者从未给予每日多于1克或2克的抗坏血酸，虽然这个数量可以缓解“维生素”不足，但远低于可“纠正“这种遗传缺陷所需。这些研究者没有给予接近哺乳动物在同等应急条件下将会合成的抗坏血酸的量。因而，在他们的病人中，从未能再现典型的哺乳动物的生化反应。癌症治疗是另一领域，在这里，这种新的遗传概念的应用，为各种临床试验，使用巨大的每日剂量，提供了更清晰的见识和新的理论依据。
这些只是许多来自坏血病的遗传病源学的概念的合理推测的少数。而人类为维持生化内环境的稳定而对抗坏血酸的需求是其中之一。讨论主要限于其中一个抗坏血酸密切关联的生化系统。因为这篇文章的实质是想促进沿着这个方向的思考。作者将对这个问题和其他疾病在另一本正在准备的书作更深的论述。
在任何建议的临床试验的“纠正“剂量，还有一个”股息分红“应该提及，就是，这些剂量的服用不会对参与者带来危害。抗坏血酸可能是已知的有同等生理活性的物质当中的最小毒性的一种。应分隔在一天的不同时间服用，以模似哺乳动物在其肝脏的连续合成。可以口服或静脉给药（缓冲至合适的PH值）。这里有足够的进化原因以支持其完全缺乏毒性。生物体在无限漫长的时历史上，一直接触相当高水平的抗坏血酸。这个可从现在的所有的生物形式，从最简单的到最复杂的得到判断；如果,抗坏血酸曾有任何毒性，对生物的生存造成损害，它早应被进化过程所淘汰。
希望这篇文章的出版，在上述的和其它医学领域，引发更广和更深入的思考。尤其是，认识到这种事实，在生化应急的情况下，普通哺乳动物为维持内环境稳定而增加抗坏血酸的合成的生化反应，也适用于人类。外源性抗坏血酸不应该被假定为只是专用于坏血病的有限的微量物质。人类生理的许多长期的生化反应的最优化的维持，可能需要其他哺乳动物合成抗坏血酸的同等数量。
说明
作者已连续服用，每天3~5克的抗坏血酸，超过10年（他估计的成人的肝脏在应急情况下，合成抗坏血酸的数量）。在应急情情况下（接近致命的外伤），这个数量增加到每日20~40克，连续几个月。在这十年，他没有患过任何其他疾病（连一次普通的感冒也没有）以及享受充满活力的健康。
小结
最近已知道，人类对抗坏血酸的需要以及，坏血病这种病，是由于一个控制一种肝酶—L-古洛糖酸内酯氧化酶的基因的缺陷，而引起的一种典型的遗传疾病综合症的结果。这种活性酶在肝脏的缺乏，阻碍了人类合成自己的抗坏血酸，而这种合成几乎在所有哺乳动物进行。这种遗传性疾病已被命名为抗坏血酸缺乏症(HYPOASCORBEMIA)。这种坏血病的遗传病原学的新概念给出了一个更广宽的前景，同时开创了过去50年或微量“维生素”假说所没有的远景。自从可获得大批量的抗坏血酸之后，人类的这种遗传疾病的“纠正”已变得可能。“纠正” ，意思是长期服用人类肝脏本来合成的抗坏血酸的数量，如这种遗传缺陷没有发生的话。在应激情况下，哺乳动物很久以来就利用增加肝脏生物合成抗坏血酸，以维持生化内环境稳定。这种遗传疾病阻碍了人类利用这种哺乳动物的生化保护机制。为完全“纠正”这种疾病，提供足够、合适的外源性抗坏血酸，只是复制一种正常的哺乳动物生化反应。讨论了这种遗传疾病的完全“纠正”的医学暗示以及，从可得的贫乏的医学文献，推测这种完全“纠正”，对风湿性疾病，心血管疾病，中风，癌症和衰老过程的影响。这篇文章只是一个恳求，希望获得更多的这个新概念开启的医学潜能的思想以及，以这个遗传疾病观点为理论基础的更多的临床试验。
At the present time, the liver enzyme, L-gulonolactone oxidase, is not too widely known and yet this enzyme was involved in what may be eventually regarded as the greatest single physiological and biochemical catastrophe to have happened to Man in the course of Evolution. This enzyme is the final one of a series of enzymes utilized by the mammalian liver to synthesize ascorbic acid from glucose. This biosynthesis of ascorbic acid is a basic and vital process occurring in nearly all living organisms both plant and animal.
In the course of Evolution a Primate ancestor of Man suffered a conditional lethal mutation (Gluecksohn-Waelsch, 1963) on the site of the gene controlling the production of the enzyme protein, L-gulonolactone oxidase, destroying its ability to produce an active enzyme. This mutated animal, and all its progeny carrying this defective gene, were no longer able to synthesize ascorbic acid and made them wholly dependent upon exogenous sources of ascorbic acid for their survival.
After many millions of years Man eventually evolved from this biochemically handicapped animal and present day Man is still afflicted with this genetic defect (Stone, 1965). As far as is known, the whole human race carries this defective gene and it is this inherited defect that sets Man apart, biochemically and physiologically, from nearly all the other mammals.
For the past fifty years, the human need for ascorbic acid has been regarded as a nutritional or dietary requirement for “vitamin C”. The fatal disease, scurvy, resulting from complete deprivation of exogenous ascorbic acid, has been considered as a Dietary Deficiency Disease or an Avitaminosis. It has recently been pointed out that this human need for ascorbic acid is the result of a typical genetic disease syndrome due to the inherited lack of the active enzyme, L-gulonolactone oxidase in the human liver (Stone, 1966). Scurvy, then is the extreme sequela resulting from this hereditary metabolic anomaly. The genetic disease has been named, Hypoascorbemia. The concept of the genetic etiology of scurvy provides an important new outlook and broader perspectives regarding ascorbic acid in quantitative human biochemistry and in human physiology which were completely lacking in the old “vitamin C” hypothesis. Some of the medical implications of this new approach is the subject of this paper.
Man, some monkeys, guinea pigs and an Indian fruit eating bat (Pteropus medius) are the only mammals known to be unable to produce ascorbic acid in their livers. These few species are the only mammals that can contract and die of scurvy if deprived of exogenous ascorbic acid. The other mammals all synthesize ascorbic acid in fairly substantial amounts. The inability of the human liver to supply this important, biochemically active secretion places Man’s physiological chemistry on a distinctly inferior level to that of the other mammals. The response of these other mammals to biochemical stress is to increase their production of ascorbic acid to take care of the increased needs, while the response in Man is to further deplete his already low stores of this metabolite. An important factor in maintaining biochemical homeostasis in these mammals is their inborn ability to increasingly produce ascorbic acid under stress.
Over the countless centuries Man’s physiology has become adapted to very low intakes of ascorbic acid because his foodstuffs, even in the best of times, could never supply the amounts of ascorbic acid that his liver should be synthesizing and pouring into his bloodstream. Man was fortunate to be able to obtain milligram amounts of ascorbic acid per day while the synthesis in an equivalent sized mammal would be measured in many grams a day (Stone, 1966). An adult gorilla in the wild state (who had no occasion to adapt to the peculiar human diet) consuming enormous volumes of fresh vegetation has been estimated to get about 4.5 gm of ascorbic acid per day (Bourne, 1949). The gorilla presumably suffers from the same genetic defect as Man.
With the discovery of fire and the development of cooking, the fresh raw meat and fish of Man’s early dietary which were fairly rich sources of exogenous ascorbic acid lost much of this vital substance because of its sensitivity to heat-enhanced oxidation. Dietary inhibitions against eating raw insects and other invertebrates deprived Man of another rich source. Primitive agriculture with its emphasis on the easily storable cereal crops provided foodstuffs essentially devoid of any ascorbic acid. It is mute testimony to the ruggedness and adaptability of the human organism that Man was able to survive on such low levels of ascorbic acid compared with the amounts produced by other mammals. Survive he did but the toll in disease, misery and death must have been great.
Man’s present physiology thus has accomplished a pretty good job of adapting to conditions of very low intake levels of ascorbic acid without showing symptoms of frank scurvy. This does not mean, however, that all of the many ascorbic acid-dependent biochemical processes are operating at peak, optimal or even marginal levels of efficiency. The human organism can be suffering from biochemical scurvy without showing the signs of clinical scurvy. There is evidence that minimal levels of intake “are not satisfactory for the preservation of optimum health through long periods of time or when the body is subjected to common forms of stress” (National Research Council, 1964a). And when aren’t humans subjected to stress?
It is interesting, therefore, to speculate (speculate is all we can do because there is no direct information available in the medical literature) as to how the various aspects of Man’s physiology would respond to full “correction” of this long-standing genetic defect. The word correction is used loosely and by “correction” we mean supplying ascorbic acid to humans for long periods of time in the amounts that the human liver normally would be producing had this mutation not occurred (cf. Note in bibliography).
The full “correction” of this genetic defect has only been possible in the last thirty years since the availability of pure ascorbic acid in large quantities. It is impossible to establish full “correction” by dependence on foodstuffs as the source of the exogenous ascorbic acid because of the meager amounts present and the physical limitations upon the volumes of food that can be consumed. No one in these thirty years has undertaken a comprehensive program to determine the effects on humans of the long time administration of ascorbic acid in amounts approaching those synthesized by the mammals under normal and stressed conditions. In the thousands of papers that have appeared in the three decades since the discovery of ascorbic acid, there is only scant information on the amount produced in mammalian metabolism. Opinions still differ widely as to the approximately optimal levels of intake for Man (National Research Council, 1964a). On the other hand, a vast literature has developed on finding the minimal intakes of ascorbic acid to prevent the appearance of frank scorbutic symptoms. A substance with such wide and vital functions, in so many biochemical processes of life as ascorbic acid, would appear to be much more useful to Man than just preventing scurvy. About all that this tremendous expenditure of research time in finding minimal levels has accomplished, has been to determine how well human physiology has adapted to its enforced low levels of intake for so long a time.
The false notions and narrow concepts of the “vitamin C” hypothesis, as the dietary cause of the scorbutic syndrome, has dominated medical thinking for so long that it has been a big factor in restricting the pursuit of clinical research with the vigor and depth required. By definition a vitamin is a trace substance in foodstuffs. Most workers in the past thirty years, investigating the therapeutic applications of ascorbic acid to diseases other than scurvy, have regarded it as a trace “vitamin” substance and used it at the trace levels found curative for scurvy. They never attempted administration at the large dosage levels approaching that which the mammals would be synthesizing under comparable conditions of the stresses of pathology. After an extensive review of this medical literature in connection with the preparation of a book on the subject, it is the author’s belief that we have hardly scratched the surface of the potential uses of ascorbic acid in therapy. The lack of consistent and clear cut clinical results in this prior work being due to the investigators concentrating on relieving a trace “vitamin deficiency” and neglecting to give the high dosages of ascorbic acid necessary to maintain continuous supra renal-threshold blood levels that might be therapeutically effective. They, of course, did not have the advantage of the logic and rationale for these large doses which are inherent in this new genetic disease concept. Clearly much new clinical work is required in this area but it should now be planned on the broader base that Man is just another mammal and his original optimal biochemical and physiological requirements for ascorbic acid were similar to other mammals.
All our present statistics relating to Man, such as Life Expectancy, the Incidence and Morbidity of Disease is based on data obtained from studies on the so-called “normal” population. However, this “normal” population, in its entirety, has been suffering from this uncorrected genetic disease throughout their lives, the lives of their parents and grandparents and so on. The intake of ascorbic acid by this “normal” population would be grossly submarginal from the standpoint of the genetic disease concept and for a large proportion of the population at some time or other during their lives it would have been considered low even by “vitamin” standards. It has long been known that there is less resistance to infection in the scorbutic state. What, therefore, would happen to the statistics on Disease Incidence and Morbidity and to Life Expectancy in a population where this genetic defect was fully “corrected” continuously from infancy on? Our so-called “normals” may eventually be found to be quite abnormal when compared to a population of fully “corrected” individuals.
We have just mentioned “correcting” the genetic defect from infancy on, but how about “correcting” the defect prenatally? It is now recognized that pregnancy is a biochemical stress requiring more ascorbic acid and under the quantitation of current “vitamin” theory an increase in intake is conservatively recommended of from 70 mg to 100 mg per day (National Research Council, 1964b). Would full “correction” of this genetic disease by administering ascorbic acid to potential human mothers, in the large amounts the mammals synthesize under similar stresses of pregnancy, produce better and healthier babies with less trouble in labor and less chance of miscarriage? It has long been known that scurvy in pregnant guinea pigs produces pronounced deleterious changes in the maternal tissues and in the embryo and causes a high rate of abortions (Harman and Gillum, 1937; Harmon and Warren, 1951; Ingier, 1915; Kramer et al., 1933). Here too, there is much room for more thought and many more tests.
The synthesis of the important tissue protein, collagen, is an ascorbic acid-dependent process. Collagen is a main supportive and structural tissue component and comprises about one-third of the body protein. The derangement of this vital biochemical synthesis by deprivation of ascorbic acid causes some of the most distressing symptoms of scurvy. Submarginal levels of ascorbic acid intake, too high to produce the noxious acute reactions of scurvy but too low for too long to maintain collagen synthesis at optimal levels, may be the trigger that sets off the organism down the path of the collagen diseases — the arthropathies, the rheumatoid diseases and even the aging process; all conditions of biochemical stress in which the bodily requirements for ascorbic acid are increased and the levels usually present are very low. It has recently been shown (Steven, 1965) that the structure of collagen derived from rheumatoid tissue is different from normal collagen. Full “correction” of this genetic defect, by keeping collagen synthesis and repair at optimal levels throughout lifetime, may produce an organism highly resistant to the rheumatoid disease process. This new concept also provides a basis for a rationale for the therapeutic use of ascorbic acid in these diseases at possibly 25 to 50 gm per day or even higher. While much work has been reported in the last three decades on the therapeutic use of ascorbic acid in rheumatoid conditions at “vitamin” levels without conspicuous success, there has been no clinical work reported where ascorbic acid was consistently used at dosages approaching the levels of full “correction”. Only in the area of the viral diseases have doses of ascorbic acid of this magnitude been employed in therapy. While ascorbic acid has long been known as a potent, non-toxic virucidal agent (Amato, 1937; Holden and Molloy, 1937; Holden and Resnick, 1936; Jungeblut, 1935; Kligler and Bernkopf, 1937; Langenbeck and Dnderling, 1937; Lojkin, 1936; Lominski, 1936; Martin, 1940), it was only when tested at doses approaching or exceeding these “corrective” levels, has clinical success been consistently reported (Greer, 1955; Klenner, 1949, 1951, 1952, 1953).
In the aging process, collagen is of prime importance. Being the main supporting tissue protein of the skin, vascular and musculo-skeletal systems, any molecular changes induced in this protein with age would have widespread bodily effects. In work on the physical biochemistry of aging, collagen has responded with a regularity and magnitude not found in other human tissues. On aging, collagen will lose osmotic swelling ability and there will be a resulting alteration of elasticity. The acid solubility of collagen decreases and it becomes more resistant to digestion with collagenase with age (Kohn, 1963). The highest rate of loss of swelling ability of human tendon collagen appears to be at the ages of thirty to fifty years, after maturity is attained. The changes occurring in collagen due to aging have been ascribed to intermolecular cross linking resulting in increased rigidity of the tissues due to the firm association of the constituent molecules. The nature of the cross links in collagen and the agents accelerating the cross linking process are not known. Coenzyme Q or ubiquinone is suspected as being involved in this process (Bjorksten, 1962). This is a naturally occurring long chain, substituted derivative of O-catechol which on oxidation could form cross linking agents. Another cross linking reaction in the proteins is the formation of stable disulfide cross links on the peptide chains due to oxidative combinations of the sulfhydryl groups contained in these chains. Both these oxidative reactions should be inhibited by the continued presence in the tissues of high levels of the strongly reducing ascorbic acid in a fully “corrected” individual, and possibly the concomitant aging effects. In a paper, discussing clinical tests on the inhibition by ascorbic acid of the abdominal striae of pregnancy, because of improved collagen production and maintenance, McCormick (1948) makes the following prophetic statement regarding ascorbic acid, “the young women of today, will be able to have recourse to a veritable internal cosmetic, a dietetic measure, at the same time practical and pleasant, to avoid premature loss of elasticity of their still youthful tissue”. A fresh outlook on aging phenomena is now provided by this genetic concept and the possibility of doing something about it is feasible. For the first time in millions of years, it is possible to fully “correct” this genetic defect.
Hemorrhage has long been considered a pathognomonic sign of scurvy. This is another result of disturbance in the ascorbic acid-dependent collagen synthetic system producing defective structural tissue protein in the vascular system. Full “correction” should produce a human whose arterial, venous and capillary systems are second to none in mechanical strength and resistance to the physical stresses of blood flow and thus be less prone to mechanical and chemical damage and hemorrhaging. Long term “correction” of this genetic disease by administration of necessary large levels of ascorbic acid throughout life, may have some startling effects on the incidence of heart disease, cardiovascular conditions and strokes.
In cancer, the maintenance of collagen synthesis at optimal levels, may provide such tough and strong tissue ground substance around any growing cancer cells so that they would be firmly anchored and could not break away and metastasize (McCormick, 1954, 1959). In addition, ascorbic acid has potent detoxicating effects and at the high levels of intakes for “correcting” the genetic defect there could be definite inhibition of the action of carcinogens on tissues (Warren, 1943). The mammalian reaction to exposure to carcinogens is to increase the synthesis of ascorbic acid (Boyland and Grover, 1961), while in Man the stresses of cancer induces large deficits in ascorbic acid levels (Antes and Molo, 1939; Gaehtgens, 1938; Griebel, 1939; Kudlac and Storck, 1938; Schneider, 1938; Spellberg and Keeton, 1939; Vogt, 1939). Provocative results have been reported in clinical tests on the use of ascorbic acid in cancer but the investigators never administered more than a gram or two a day. While this amount would relieve a “vitamin” deficit, it would be much below the level required to “correct” the genetic defect. These workers did not give ascorbic acid in amounts approaching that which the mammals would be synthesizing under equivalent stresses and thus never reproduced the typical mammalian biochemical response in their patients. Cancer therapy is still another area where the application of these new genetic concepts of ascorbic acid provides clearer insights and new rationales for programs of clinical testing, using massive daily doses.
These are but a few of the many possibilities derived from the logic of the concept of the genetic etiology of scurvy and the human need for ascorbic acid for the maintenance of biochemical homeostasis. The discussion has been limited mainly to only one of the biochemical systems in which ascorbic acid is intimately involved. The treatment has been necessarily brief because of the survey nature of this article which has been written mainly to stimulate thinking along these lines. The author will treat these and other diseases in greater depth in a book now in preparation.
In any proposed clinical testing of these “corrective” doses, there is an additional “dividend” that should be mentioned and that is, that these doses can be administered without danger to the participants. Ascorbic acid is probably the least toxic of any known substance of comparable physiologic activity (Abt and Farmer, 1938; Cass et al., 1954; Demole, 1934; Kieckebusch, 1963; Lamden and Schweiker, 1955; Lowry et al., 1952). The administration should be in spaced doses throughout the day to duplicate as far as possible its continuing synthesis in the mammalian liver. It can be given both orally and intravenously (neutralized to the proper pH). There is a good evolutionary reason for this complete lack of toxicity. Living organisms have been exposed to fairly high levels of ascorbic acid throughout eons of Time, if this can be judged from its widespread occurrence in all forms of present day life from the simplest to the most complex. If ascorbic acid had any toxicity that would have been detrimental to survival, it would have been eliminated long ago by the evolutionary process.
It is hoped that the publication of this paper will trigger much wider and deeper thought in the above and other areas of Medicine. Especially, the recognition of the fact that the general mammalian reaction for maintaining homeostasis under biochemical stress, by increasing available ascorbic acid, is also applicable to Man. Exogenous ascorbic acid should not be merely presumed a limited trace-level nutritional specific for scurvy. The maintenance at optimal efficiency of many long-term biochemical reactions in human physiology may require ascorbic acid in the large amounts produced in the other mammals.
The author has been consistently ingesting, at least, 3 to 5 gm of ascorbic acid daily for the past 10 years (his estimate of the amount the adult human liver should be synthesizing under unstressed conditions). Under conditions of stress (severe injuries from a near fatal auto accident) this was increased to 20 to 40 gm a day for several months. During this decade he has suffered no other illness (not even a common cold) and has otherwise enjoyed vibrant health.
It has been recently shown that the human requirement for exogenous ascorbic acid and the disease, scurvy, are the result of a typical genetic disease syndrome caused by a defect on the gene controlling the synthesis of the enzyme protein, L-gulonolactone oxidase. The lack of this active enzyme in the human liver prevents Man from producing his own ascorbic acid; a synthesis which is regularly carried out by nearly all other mammals. This genetic disease has been named, Hypoascorbemia. This new concept of the genetic etiology of scurvy gives a much broader outlook and opens perspectives which were lacking in the previous fifty year old nutritional or trace “vitamin C” hypothesis. “Correction” of this genetic defect in Man is now possible since the availability of ascorbic acid in large quantities. By “correction” is meant the long-term administration of ascorbic acid in the large amounts the human liver would be synthesizing had this genetic defect not occurred. The mammals have long used the increased liver biosynthesis of ascorbic acid, under stress, to maintain homeostasis. The genetic defect prevents Humans from utilizing this important mammalian biochemical protective mechanism. Supplying exogenous ascorbic acid at the proper high dosage for full “correction” is merely duplicating a normal mammalian reaction. The medical implications of the full “correction” of this genetic disease are discussed and speculations on the effects of “correction” in the rheumatoid diseases, cardiovascular conditions, strokes, cancer and the aging process are extrapolated from the meager data already in the medical literature. This paper is mainly a plea for more thought along the medical possibilities opened by this new concept and for more clinical tests based on the rationales derived from the genetic
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From Acta Geneticae Medicae et Gemellologiae, Volume 16, Number 1, 1967, pp. 52-60
http://seanet.com/~alexs/ascorbate/196x/stone-i-acta_genet_med_et_gemell-1967-v16-n1-p52.htm