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. . . .the invention of a useful product can only follow the understanding of the relevant underlying science. -——G. Ling
2020年3月时事通讯
Two studies have estimated that the annual number of deaths in the US caused by medical errors ranks third, behind heart disease and cancer, with estimates ranging from 250,000 to 440,000 deaths per year (Makary and Daniel, 2016; James, 2013, 2017). Many doctors acknowledge that a failure to report “adverse events” resulting in death is common. Behind these estimates is the fact that those are errors recognized by doctors; their validity depends on the quality of medical education, and medical science. The presence of mistaken beliefs in the medical culture could mean that medicine’s real effect on life, health, and death is radically underestimated. This is something Gilbert Ling has often spoken about.
两项研究估算,美国每年因医疗失误造成的死亡人数排名第三,仅次于心脏病和癌症,每年大约有 250,000 至 440,000 人死亡(Makary 和 Daniel,2016 年;James,2013 年,2017 年)。 许多医生承认,未能报告哪些因为“不良事件”而导致死亡的事件很常见的。 这些估算背后的事实是,这些“不良事件”为医生所承认; 它们的有效性取决于医学教育和医学科学的质量。 医学文化中错误信念的存在可能意味着医学对生命、健康和死亡的真正影响被彻底低估了。 这是Gilbert Ling经常谈到的事情。
I don't think it's possible to think about Gilbert Ling's work (which began in the 1940s) without evaluating the way that the science industry has been working during this period, at least in the US and England. “Science” has its rules, but they don't apply when the ruling ideology or paradigm is challenged. In biology, this paradigm insists that all cells are enclosed in a “semipermeable” membrane that actively maintains concentrations of dissolved substances inside the cell, that are different from the concentrations in the water surrounding the cell. This image of the cell implies many other things, for example that the water inside cells has the same solvent properties as water outside cells, and that something that’s true of an enzyme outside a cell must be true of enzymes inside cells.
我认为,如果不评估科学产业在这一时期的运作方式,至少在美国和英国,就不可能思考Gilbert Ling的工作(始于20世纪40年代)。“科学”有它的规则,但当统治意识形态或范式受到挑战时,规则却并不适用。在生物学中,这一范式坚持认为所有细胞都被封闭在一个“半透膜”中,该膜能有效地维持细胞内溶解物质的浓度,与细胞周围水中的浓度不同。 这个细胞的图像暗示了许多其他的东西,例如,细胞内的水和细胞外的水具有相同的溶剂性质,细胞外的酶的真实性必须是细胞内的酶的真实性。
These assumptions are built into the educational system, and govern the way medicine is practiced, and the way research is done. Soon after beginning graduate study in the US, Ling developed a new electrode capable of making measurements inside a single cell (the Ling-Gerard glass microelectrode), and his observations using that instrument led him to question the ruling doctrine that bioelectricity was produced by an active membrane on the surface of cells.
这些假设被构建在教育系统中,并支配着医学实践和研究的方式。在美国开始研究生学习后不久,Ling开发了一种能够在单个细胞内进行测量的新电极(Ling-Gerard玻璃微电极),他使用该仪器进行的观察使他质疑了生物电是由细胞表面的活性膜产生的主导学说。
.… I have learnt from Professor Gerard's example the critical importance to seek a broader perspective than the experimental subject being pursued at any one time ——Gilbert Ling
In the early 70s, I saw that Ling's view was misstated in an article by a well known physiologist, citing an article by Ling as his source. Using the Science Citations Index, I found that the misstatement had been quoted verbatim by a series of other biologists, as the reason Ling's theory was to be dismissed, and in each case they cited Ling's original article, rather than where they had actually found the misstatement. Not many biologists even mentioned Ling's work, but most of those that I found who did, were lying about having read it.
70年代初,我看到一位著名生理学家在一篇文章中错误地陈述了Ling的观点,引用Ling的一篇文章作为他的来源。通过使用科学引文索引,我发现其他一系列生物学家都一字不差地引用了这一错误陈述,以此作为驳回Ling的理论的理由。在每一个案例中,他们都引用了Ling的原始文章,而不是引用那个错误的陈述。甚至没有多少生物学家提到Ling的工作,但我发现大多数提到的人都在谎称读过。
In 1975, two Cambridge professors wrote a review of the “sodium pump,” in which they discussed 245 studies supporting the existence of the pump, and not a single study questioning its existence. Hundreds of studies, by numerous researchers besides Ling, had been published giving evidence against such a pumping membrane. On many scientific issues it's considered scandalous when only the evidence supporting one side is presented, but in this case the professors could count on the fact that most of their readers didn't know anything that wasn't in their textbooks. The situation in our science culture resembles the Jim Carrey movie, “The Truman Show,” except that very few of the participants understand that it's a constructed illusion.
1975年,两位剑桥教授撰写了一篇关于“钠泵”的评论,他们在评论中讨论了245项支持钠泵存在的研究,没有一项研究质疑它的存在。除了Ling之外,还有许多研究人员已经发表了数百项研究,证明这种泵膜是不可行的。在许多科学问题上,只陈述支持一方的证据被认为是可耻的,但在这种情况下,教授们可以相信的事实是,他们的大多数读者都不知道教科书中没有的东西。我们科学文化中的情况类似于 Jim Carrey的电影《楚门的世界》,只是很少有参与者理解这是一个虚构的幻觉。
In the 1960s, Gilbert Ling's idea of a “living state” had overtones of holism and self-regulation, but to disciples of the ruling paradigm, one of the most offensive things about it was that it proposed to explain all biological processes in terms of known laws of physics and principles of physical chemistry. 20世纪60年代,Gilbert Ling的“生存状态(living state)”理念带有整体主义和自我调节的色彩,但对于统治范式的信徒来说,最令人反感的事情之一是它提出用已知的物理定律和物理化学原理来解释所有生物过程。
For many years, the science culture of the US has at times denounced holism, intentionality, consciousness, epigenetics, self-organization and self-regulation, along with vitalism, as unscientific and superstitious. In the 1960s, Gilbert Ling's idea of a “living state” had overtones of holism and self-regulation, but one of the most offensive things about it was that it proposed to explain all biological processes in terms of known laws of physics and principles of physical chemistry. While biologists claimed to be defending mechanistic materialist science against vitalism, in fact they were rarely able to think in the physical chemical ways that were the essence of Ling's work. His criticism of the membrane sodium pump made it clear that the pump was just the ghost in the machine that was needed to animate the conventional theory of the living cell.
多年来,美国的科学文化时不时地谴责整体论、意向性、意识、表观遗传学、自组织和自我调节以及活力论是不科学和迷信的。20世纪60年代,Gilbert Ling的“生存状态(living state)”理念带有整体主义和自我调节的色彩,但其中最具攻击性的是,它提出用已知的物理定律和物理化学原理解释所有生物过程。虽然生物学家声称为机械唯物主义科学辩护,反对活力主义,但事实上,他们很少能够以物理化学的方式思考,而这正是Ling的工作的精髓所在。他对膜钠泵的批评清楚地表明,该泵只是机器中的幽灵,而这个幽灵正是使活细胞的传统理论生动化所需要的。
While US and British biologists were occupied with either ignoring or slandering Ling, Karol Mysels, a leading physical chemist, found that when he was writing about our contemporary understanding of ion exchange resins, such as those used in water softeners, the best physical theory existing to describe their function was the theory that Ling had developed to explain the behavior of ions in living cells. In trying to understand cell function he had used existing laws in ways that hadn't yet occurred to people like Mysels, and that turned out to be useful in their work and to have great generality for explaining the interactions of water, ions, and proteins and other polymers.
当美国和英国生物学家忙于忽视或诽谤Ling时,物理化学家中的领军人物Karol Mysels发现,当他在写对离子交换树脂(例如用于软水器的树脂)的当代理解时,现有能描述其功能的最佳物理理论是Ling为解释活细胞中离子的行为而发展的理论。在试图理解细胞功能的过程中,他运用了现有的规律,而这些规律在Mysels这样的人身上还没有出现过,这在他们的工作中被证明是有用的,并且在解释水、离子、蛋白质和其他聚合物的相互作用时具有很大的通用性。
The principle of ion exchange has been widely recognized for a long time; in Aristotle's time it was known that the salt in sea water could be reduced by passing it through a certain mineral. For hundreds of years it has been known that soils generally retain potassium while allowing sodium to leach away, where it eventually concentrates in the oceans. The water in soil can be absorbed by plants during their growth along with the needed potassium, because most of the potassium in the soil isn't dissolved in the water. If all the potassium needed were in solution the concentration would be osmotically too high, and would dehydrate the roots. As the plant removes potassium from the ground water, solids in the soil release more potassium into solution. Water held in clay and similar materials in the soil is in an unusual state, with physical properties different from those of bulk liquid water; there is no dispute about that, and there is general agreement that these unusual properties of water in clay are involved in its ion exchange functions.
长期以来,离子交换原理已被广泛认可;在亚里士多德时代,人们知道海水中的盐可以通过某种矿物被还原。数百年来,人们已经知道,土壤通常保留钾,同时允许钠流失,最终在海洋中富集。土壤中的水分可以在植物生长过程中与所需的钾一起被吸收,因为土壤中的大部分钾不溶于水。 如果所有需要的钾都在溶液中,那么浓度会过高,并会使根系脱水。当植物从地下水中去除钾时,土壤中的固体会向溶液中释放更多的钾。土壤中粘土和类似材料中的水处于异常状态,其物理性质不同于游离液态水;关于这一点没有争议,人们普遍认为粘土中水的这些不同寻常的性质与它的离子交换功能有关。
Although the special properties of water in clay are calmly acknowledged, it was Ling's suggestion that water in the living state is not the same as bulk liquid water that caused the most offense, because it directly challenges the assumptions that underly standard physiology and biochemistry, which assume that water is water, inside or outside of cells. Those assumptions (the Gibbs-Donnan equilibrium, the Nernst equation, and the Michaelis-Menten equation) were put into mathematical form more than 100 years ago, long before there were methods such as nuclear magnetic resonance to study the properties of water in different situations.
尽管人们冷静地承认粘土中水的特殊性质,但Ling的想法是,生存状态(living state)下的水与大量游离水(bulk liquid water)不同,这是最具攻击性的,因为它直接挑战了标准生理学和生物化学的假设,即水就是水,无论细胞内或细胞外。这些假设(吉布斯-多南平衡、能斯特方程和米切里斯-门汀方程)在100多年前就已经形成了数学形式,远远早于核磁共振等研究不同情况下水的性质的方法。
The property of cells that was most responsible for the invention of the active cell membrane theory was their ability to concentrate potassium and to exclude sodium; blood and other fluids in the body contain much more sodium than 2 potassium, but the water inside cells contains much more potassium than sodium.
最有助于发明活性细胞膜理论的细胞的特性是它们浓缩钾和排除钠的能力;血液和其他体液中的钠含量远远高于钾含量,但细胞内的水中钾含量远远高于钠。
Hair is made up of dead cells, but in an experiment hair was washed thoroughly with dilute acid until it was completely free of ions. The hair was dipped into serum containing the normal high concentration of sodium and low concentration of potassium. When the hair was then analyzed, it contained more potassium than sodium (though the gradient was lower than in living cells, which also regulate water content). The membrane theory says that the process of concentrating a substance against its gradient is “active transport,” and requires the use of ATP. Experiments by Ling and others showed that the energy metabolism of cells could be poisoned so that no ATP was being produced, but that cells were able to maintain their ionic gradient, although sodium was free to diffuse into the cell, “through the membrane.” All the ATP has to do is to be present, passively occupying its place in the cell.
头发是由死细胞组成的,但在一项实验中,头发用稀酸彻底清洗,直到完全没有离子为止。将头发浸入含有正常高浓度钠和低浓度钾的血清中。当分析头发时,它所含的钾比钠多(尽管梯度比活细胞低,活细胞也调节水分含量)。膜理论认为,物质在梯度上浓缩的过程是“主动运输”,需要使用ATP。Ling等人的实验表明,细胞的能量代谢可能被毒害,因此不会产生ATP,但细胞能够保持其离子梯度,尽管钠可以“通过膜”自由扩散到细胞中。ATP所要做的就是存在,被动地占据其在细胞中的位置。
Around 1970, a famous muscle physiologist was visiting the university to give a talk on his famous new theory of how muscles work, using the energy from the “high energy phosphate bond” of ATP, which he said was 14 kcal/mol, a quantity still commonly cited. He showed how that chemical energy might be used to operate the mechanism of muscle contraction, like little oars rowing a boat. Other people referred to that same bond energy when they wanted to explain the electrical, ion-moving work involved in nerve conduction, imagining little arms plucking and flinging the atoms. During the muscle physiologist's visit, I mentioned to my professor, Sidney Bernhard, that I had read his paper clearly showing that the ATP phosphate bond energy isn't especially high, and asked him why “everyone,” such as the guest speaker and his audience, kept talking about it as if it were a reality. All he said was “not everyone does.” One thing encouraging people to preserve the myth of the high bond energy is its convenience for running their imaginary machines.
1970年左右,一位著名的肌肉生理学家访问大学,利用ATP的“高能磷酸盐键”提供的能量,就其著名的肌肉如何工作的新理论发表演讲。他说,ATP的能量为14 kcal/mol,这是一个仍被普遍引用的量。他展示了化学能是如何被用来操作肌肉收缩机制的,就像小桨划船一样。 其他人在想解释神经传导所涉及的电、离子运动功时,也提到了同样的键能,他们想象着小手臂拉扯和投掷原子。在肌肉生理学家的访问期间,我向我的教授Sidney Bernhard提到,我读了他的论文,清楚地表明ATP-磷酸键能量不是特别高,并问他为什么“所有人”,比如嘉宾演讲者和他的听众,都一直在谈论它,好像这是一个现实。他所回答的只有短短几个字:“不是每个人都这么做”。有一件事鼓励人们保留高键能的神话,那就是它便于运行他们想象中的机器。
In one of Ling's papers, he noted the amount of ATP energy that was, according to various authors, needed to operate the membrane sodium pumps. He used the commonly accepted figure for ATP's energy, and found that a typical cell would need at least 15 times as much energy as could be produced by the cell, just to perform this single essential minimal chore, and much more would be needed to account for all the other substances that are concentrated by cells against their gradient. Since Ling didn't imagine that ATP bond energy was being consumed constantly to run membrane sodium pumps, he wasn't concerned with any energy that might be released by hydrolyzing that bond. He, like Albert Szent-Gyorgyi, was aware that the ATP molecule adsorbs with considerable energy to protein molecules, and that its presence governs the shape of the protein molecule. In a muscle cell, the presence of ATP stabilizes the muscle in its relaxed state, and in any cell, similar associations between ATP and proteins stabilize the cell in a basic resting condition in which it favors the presence of potassium over sodium.
在Ling的一篇论文中,他指出了根据不同作者的说法,操作膜钠泵所需的ATP能量。他使用了公认的ATP能量数据,并发现一个典型的细胞需要至少15倍于细胞所能产生的能量来完成这一简单的基本任务,并且需要更多的能量来解释细胞根据其梯度聚集的所有其他物质。 由于Ling没有想到ATP键能量会被不断消耗以运行膜钠泵,因此他不关心通过水解该键可能释放出的任何能量。他和Albert Szent Gyorgyi一样,知道ATP分子以相当大的能量吸附到蛋白质分子上,并且ATP的存在决定了蛋白质分子的形状。在肌肉细胞中,ATP的存在使肌肉在松弛状态下保持稳定,而在任何细胞中,ATP和蛋白质之间的类似联系使细胞在基本静止状态下保持稳定,在这种状态下,ATP有利于钾的存在,而不是钠的存在。
Ling's suggestion that water in the living state is not the same as bulk liquid water directly challenged the assumptions that underly standard physiology and biochemistry, which assume that water is water, inside or outside of cells.
Ling wasn't alone in publishing disproofs of the membrane pump theory, but he persisted for many years, repeating important experiments scores of times, and answering even criticisms that hadn't been made. During these decades, condensed matter physics and physical chemistry were continuing to advance their understanding of the nature of matter. The image of the living state of matter that Ling had sketched out was now being surrounded by a rich landscape of information about colloids, gels, coacervates, liquid crystals, nanoscale surface effects, selforganization, and membraneless organelles.
Ling并不是唯一一个发表膜泵理论反证的人,但他坚持了多年,多次重复重要的实验,甚至回答了尚未提出的批评。在这几十年中,凝聚态物理和物理化学继续推进他们对物质本质的理解。Ling勾勒出的物质生存状态的图像现在被丰富的信息包围,这些信息包括胶体、凝胶、凝聚物、液晶、纳米级表面效应、自组织和无膜细胞器。
Biological and medical education has assumed a reductionism based ultimately on physics, but it has been a rudimentary physics in which there are three phases of matter, solid, liquid, and gas, and organisms have been seen exclusively in terms of those states of matter; if water isn't in the gaseous or solid state, then it has to be in the liquid state.
生物学和医学教育假定还原论最终建立在物理学的基础上,但它是一种初级物理学,其中有物质的三个阶段,即固体、液体和气体,生物仅从这些物质的状态来看待;如果水不是气态或固态,那么它必须是液态。
By 1970, anyone who was interested in the subject could see, using a nuclear magnetic resonance (NMR) apparatus, that cell water isn't the same as bulk water. In connection with my dissertation work, I found that the water in uterine tissue was affected both by estrogen and by aging. Raymond Damadian, recognizing from Ling's work that the water in cancer tissue is different from the water in the related healthy tissue, and that the difference can be shown by NMR, built a magnetic resonance scanning apparatus that produced an image of a tumor in a mouse in 1976. Normally, a person would assume that such an accomplishment would merit a Nobel Prize at least for Damadian, for designing the first MRI instrument, and also for Ling, whose theory led to the production of the instrument, but it didn't.
到了1970年,任何对这一课题感兴趣的人都可以通过核磁共振(NMR)仪器看到,细胞水和游离水是不同的。结合我的论文工作,我发现子宫组织中的水分同时受到雌激素和衰老的影响。 Raymond Damadian从Ling的工作中认识到癌症组织中的水与相关健康组织中的水是不同的,并且这种差异可以通过核磁共振来显示。1976年,他建立了一个磁共振扫描装置,从老鼠身上拍出了一个肿瘤的图像。 正常情况下,人们会认为这样的成就应该获得诺贝尔奖,至少是因为Damadian设计了第一台核磁共振仪器,还有Ling,他的理论导致了仪器的生产,但事实并非如此。
With the appearance of a powerful medical organization in the US early in the 20th century, empirical medicine and traditional remedies were stigmatized, to be replaced by “scientific medicine.” In the official new view, urea was a metabolic waste said to cause “uremia,” and carbon dioxide was a toxic gas.
When something is about to change its physical state, as when water boils or freezes, it will sometimes persist in its present state long past the time that conditions had become right for the new state to come into being, like supercooled or superheated water. Reductionist biology has long outlived any conditions that justified its existence. Everything around it in the world of knowledge is now showing the impossibility of its mechanistic models of cell structure.
当某物即将改变其物理状态时,例如当水沸腾或结冰时,它有时会保持目前的状态,直到新的状态形成,比如过冷水或过热水。还原论生物学比任何证明其存在的条件活的都长。在知识世界中,它周围的一切都显示出它的细胞结构的机械模型是不可能的。
In 1960, the painter David Alfaro Siqueiros said that the Rockefellers and the US Government had created “ghost art,” abstract expressionism, to destroy society's consciousness. Much of contemporary science has been a ghost science, a mental impediment imposed on society, limiting our ability to perceive the nature of our problems and possibilities.
1960年,画家大卫·阿尔法罗·西奎罗斯(David Alfaro Siqueiros)说,洛克菲勒夫妇和美国政府创造了“幽灵艺术”,即抽象表现主义,以摧毁社会意识。许多当代科学都是幽灵科学,是强加在社会上的一种精神障碍,限制了我们感知问题和可能性本质的能力。
When the more objective holistic understanding of the organism becomes acceptable, nearly every part of physiology and biochemistry will be reinterpreted.
当对有机体的更客观的整体理解被接受时,几乎生理学和生物化学的每一部分都将被重新解释。
The first chemicals produced by animals to be chemically identified, in the late 18th century, were urea and carbon dioxide. For thousands of years before their chemical natures were known, both of them were used therapeutically, in the form of urine therapy and bathing in carbonated mineral springs, then in the 19th century the pure substances began to be used by doctors.
18世纪末,动物生产的第一批被化学鉴定的化学物质是尿素和二氧化碳。在它们的化学性质被发现之前的几千年里,它们都被用于治疗,如尿疗和在碳酸矿泉中洗澡,然后在19世纪,纯物质开始被医生使用。
With the appearance of a powerful medical organization in the US early in the 20th century, empirical medicine and traditional remedies were stigmatized, to be replaced by “scientific medicine.” In the official new view, urea was a metabolic waste said to cause “uremia,” and carbon dioxide was a toxic gas.
20世纪初,随着美国强大医疗机构的出现,经验主义医学和传统疗法被污名化,取而代之的是“科学医学”。在官方的新观点中,尿素是一种代谢废物,据说会导致“尿毒症”,二氧化碳是一种有毒气体。
Carbon dioxide had once been seen as a hormone, and it had been used medically for ulcers, arthritis, cancer, and mental problems, and Yandell Henderson's work had led to its use as “carbogen” (5% CO2, 95% O2) for resuscitation, but by the middle of the century most therapeutic uses had been stopped, and hospitals had been taught to use pure oxygen instead of carbogen, and patients with brain swelling were being hyperventilated with oxygen to lower their blood carbon dioxide.
二氧化碳曾被视为一种激素,在医学上被用于治疗溃疡、关节炎、癌症和精神问题,Yandell Henderson的工作使其被用作“碳素”(5%CO2,95%O2)用于复苏,但到本世纪中叶,大多数治疗用途已经停止,医院被教导使用纯氧而不是碳素,脑肿胀的患者正在用氧气进行过度通气以降低血液中的二氧化碳。
Oral urea had been used to treat ulcers, heart failure, sickle cell anemia, glaucoma and Meniere’s disease, etc., intravenous urea had been used to treat brain swelling, and topical urea had been used to treat wounds. As recently as the 1950s urea was recognized as the most effective treatment for brain swelling, but the “science based” membrane theory reasoned that the removal of water from cells was always governed by osmosis, and since urea could remove water from cells, it must be osmotically active. As an osmolyte, it was added to distilled water for intravenous use, and the red blood cells behaved as they would in distilled water, dissolving. The report that urea causes hemolysis led to general discontinuation of its use for treating brain injury. It is still common to refer to its “osmotic” effects on water. As urea is ubiquitous, the dangerous confusion caused by the membrane theory is ubiquitous. People who die because they don’t receive urea therapy are among the casualties of the membrane theory. In the 1950s, Gilbert Ling noticed that in the presence of increased carbon dioxide, a given stimulus produces less contraction of a muscle than with a lower concentration of carbon dioxide. Around the same time, Russian physiologists found that the CO2 produced by active brain cells relaxes brain blood vessels, including capillaries, increasing the flow of blood in proportion to the increasing metabolic needs.
口服尿素用于治疗溃疡、心力衰竭、镰状细胞贫血、青光眼和梅尼埃病等,静脉注射尿素用于治疗脑肿胀,局部尿素用于治疗伤口。就在20世纪50年代,尿素被认为是治疗脑肿胀最有效的药物,但“基于科学的”膜理论认为,细胞中水分的去除始终受渗透作用的控制,而且由于尿素可以去除细胞中的水分,因此它必须具有渗透活性。作为渗透压,它被添加到蒸馏水中供静脉注射使用,红细胞的行为和它们在蒸馏水中一样,溶解。尿素引起溶血的报道导致其治疗脑损伤的应用普遍中断。 人们仍然经常提到它对水的“渗透”效应。由于尿素无处不在,膜理论引起的危险混乱无处不在。因为没有接受尿素治疗而死亡的人是膜理论的受害者之一。 20世纪50年代,Gilbert Ling注意到,在二氧化碳浓度增加的情况下,特定刺激产生的肌肉收缩比二氧化碳浓度降低时要少。大约在同一时间,俄罗斯生理学家发现,活跃的脑细胞产生的二氧化碳放松了包括毛细血管在内的脑血管,增加了血液流量,与不断增加的代谢需求成比例。
Hemoglobin's ability to transport carbon dioxide and oxygen has been studied as an example of how changes in a protein's structure affects its functions. When CO2 associates with an amino (-NH2) group on the protein (forming a carbamino compound), hemoglobin's properties are altered, causing it to release the oxygen that had been bound.
血红蛋白输送二氧化碳和氧气的能力已被研究作为蛋白质结构变化如何影响其功能的一个例子。 当二氧化碳与蛋白质上的氨基(-NH2)基团结合(形成氨基氨基化合物)时,血红蛋白的性质发生改变,导致血红蛋白释放已结合的氧气。
Although this form-changing property of proteins (“allostery”) is well recognized (Monod, et al., 1963; Abdel-Magid, 2015), nearly all biologists that I have known have been unaware of the fact that CO2's ability to form carbamino compounds with hemoglobin extends to other proteins, including those that are called “specific receptors.” For several decades high altitude physiologists have been perplexed by what they call the “lactate paradox,” the fact that exercise at high altitude, with less oxygen, produces less increase in lactic acid in the blood than it does at sea level, allowing quicker recovery, since it is understood that it is oxidative metabolism that prevents the formation of lactic acid—the lower oxygen availability should lead to a higher lactate content at high altitude, and slower recovery.
尽管蛋白质的这种形态变化特性(“变构”)已得到广泛认可(Monod等人,1963年;Abdel Magid,2015),我所认识的几乎所有生物学家都不知道二氧化碳与血红蛋白形成氨基化合物的能力延伸到其他蛋白质,包括那些被称为“特定受体”的蛋白质。几十年来,高海拔生理学家一直被他们称之为“乳酸悖论”的说法所困扰,事实上,与海平面相比,在氧气较少的高海拔地区进行运动,血液中乳酸的增加较少,因此可以更快地恢复,众所周知,正是氧化代谢阻止了乳酸的形成,因此较低的氧气利用率应导致高海拔地区乳酸含量较高,恢复较慢。
They consistently neglect to think of CO2's influence on everything in every cell, not just on hemoglobin. The organism is reorganized when there is less oxygen to displace CO2 from the proteins to which it is adsorbed. The principle of induction, central to Ling's view of cell structure and function, is something every student hears about early in the study of chemistry, the transmission of the electron withdrawing properties of various atoms and groups through connected atoms. Carbon dioxide, a Lewis acid, strongly withdraws electrons from the proteins on which it is adsorbed, increasing their acidity. This affects properties such as contraction and nerve activation, as well as oxygen binding and enzyme action.
他们总是忽略了二氧化碳对每个细胞中所有物质的影响,而不仅仅是对血红蛋白的影响。当从蛋白质中吸收二氧化碳的氧气减少时,生物体就会重组。诱导原理是Ling对细胞结构和功能的看法的核心,是每个学生在化学研究的早期都听说过的,即通过连接的原子传递的各种原子和基团的吸电子性质。二氧化碳,一种刘易斯酸,强烈地从吸附它的蛋白质中提取电子,增加了它们的酸度。这会影响诸如收缩、神经激活以及氧结合和酶作用等特性。
Everything that associates with a protein, such as potassium or ammonium, has an inductive effect on the protein's structure and interactions with its surroundings, and substances that adsorb powerfully, especially ATP and steroids, have powerful influences on the properties of the system. Molecules that bind powerfully to proteins change the ways the proteins influence the properties of water, and the properties of water govern cell's metabolism and their interactions with each other and with the environment. Ling called these influential binding molecules “cardinal adsorbents.”
任何与蛋白质有关的物质,如钾或铵,都会对蛋白质的结构及其与周围环境的相互作用产生诱导作用,而吸附力强的物质,尤其是ATP和类固醇,会对系统的性质产生强大的影响。与蛋白质强力结合的分子改变了蛋白质影响水的性质的方式,而水的性质控制着细胞的新陈代谢及其与彼此和环境的相互作用。Ling称这些有影响力的结合分子为“基数吸附剂”。
Molecules that bind powerfully to proteins change the ways the proteins influence the properties of water, and the properties of water govern cell's metabolism and their interactions with each other and with the environment.
Besides this fundamental stabilizing, regulatory function of carbon dioxide, it combines with ammonia to form urea. Urea, like carbon dioxide, powerfully contributes to the regulation of water, modifying its properties. The elimination of ammonia protects against its toxic effects, which include creating pseudohypoxia, increasing the hypoxia inducible factor, HIF, and aerobic glycolysis, the characteristic cancer metabolism and the associated proliferation of cells, while blocking renewal of nerve cells. Reduced availability of CO2 leads to the failure to detoxify ammonia.
除了基础的稳定、调节功能外,二氧化碳还与氨结合形成尿素。尿素和二氧化碳一样,对水的调节起着重要作用,改变了水的性质。消除氨可防止其毒性作用,包括产生假性缺氧,增加缺氧诱导因子、HIF和有氧糖酵解,这是肿瘤的特征代谢和相关的细胞增殖,同时阻止神经细胞的更新。二氧化碳的可用性降低导致无法对氨进行解毒。
Stresses activate the enzyme carbonic anhydrase, which converts the gaseous CO2 (the form that binds to protein and favors “structured” surface or vicinal water) into the ionizable carbonic acid/bicarbonate, which leaves cells. Activating this enzyme raises the intracellular pH, tending to excite cells, and inhibiting it lowers the intracellular pH, quieting cells, saving energy. The activity of carbonic anhydrase, needed for short term survival, exemplified by wound healing (Barker, et al., 2017), disrupts the fundamental organizing processes of carbon dioxide if it is chronically activated.
压力会激活碳酸酐酶,该酶将气态CO2(与蛋白质结合并有利于“结构化”表面或附近水的形式)转化为可电离的碳酸/碳酸氢盐,从而离开细胞。 激活这种酶可以提高细胞内的pH值,有利于刺激细胞,而抑制它可以降低细胞内的pH值,使细胞安静,节省能源。碳酸酐酶的的激活以应对短期生存所需,参考伤口愈合的例子(Barker等人,2017年),如果被长期激活,会破坏二氧化碳的基本组织过程。
Seeing hormones and drugs in terms of the carbon dioxide system, rather than the reductionist system of cascades of receptors and messengers, makes the organism intelligible as a single system. The oxidative processes that support purposive, creative functioning of the organism, optimize CO2 by inhibiting carbonic anhydrase; this enzyme is inhibited by thyroid hormone T3, progesterone, urea, caffeine, antipsychotic drugs, and aspirin. Agents that tend to cause reversion to the primitive anaerobic energy production activate the enzyme—serotonin, tryptophan, cysteine, histamine, estrogen, aldosterone, HIF, SSRIs, angiotensin, and parathyroid hormone, for example.
从二氧化碳系统的角度来看激素和药物,而不是受体和信使级联的还原论系统,使有机体作为一个单一系统可以理解。支持生物体有目的、创造性功能的氧化过程,通过抑制碳酸酐酶优化CO2;这种酶被甲状腺激素T3、孕酮、尿素、咖啡因、抗精神病药物和阿司匹林抑制。趋向于原始无氧能量供能的药剂会激活碳酸酐酶,例如5-羟色胺、色氨酸、半胱氨酸、组胺、雌激素、醛固酮、HIF、SSRIs、血管紧张素和甲状旁腺激素。
If life is spontaneously ordered even on the molecular level, the ordering process has to be taken into account when trying to correct health problems. . . . . The purpose should be to support the patient’s recovery, not to “eliminate a disease.”
When the opposing aerobic energy processes are debilitated, more and more tissues fail to resolve the short term restorative, “wound healing,” processes. These barely surviving cells spread the stress signals to adjoining tissues, modifying their metabolism and creating inflammation, fibrosis, atrophy, and tumefaction. In the 1960s, at the peak of the membrane craze, when Otto Warburg, Albert Szent-Gyorgyi, and Gilbert Ling talked about the difference between health and cancer in terms of holistic metabolic energy-structure interactions, their ideas were ridiculed. Many of their basic discoveries are now individually accepted, but seen in terms of the mechanical membrane/pump/receptor doctrine, their meaning isn't accessible.
当相反的有氧能量过程被削弱时,越来越多的组织无法解决短期的恢复性“伤口愈合”过程。 这些勉强存活的细胞将压力信号传播到邻近组织,改变其代谢,造成炎症、纤维化、萎缩和肿胀。 20世纪60年代,在膜热的鼎盛时期,Otto Warburg、Albert Szent-Gyorgyi和Gilbert Ling从整体代谢能量结构相互作用的角度讨论了健康和癌症之间的区别,他们的想法遭到了嘲笑。他们的许多基本发现现在都被单独接受,但从机械膜/泵/受体学说的角度来看,他们的意义是不可理解的。
The implication of Gilbert Ling's revolution in cell physiology is that a new way of thinking is needed. If life is spontaneously ordered even on the molecular level, the ordering process has to be taken into account when trying to correct health problems. A medical approach that thinks in terms of cardinal adsorbents, induction, association and cooperative phase transitions, is using mental processes analogous to Norbert Wiener's conception of cybernetics, thinking in terms of observably responding wholes, rather than the Shannon-Weaver model of information and control systems—sender, encoder, channel, noise, decoder, and receiver—which is implicit in the drug-receptor-gene-enzyme paradigm, and suitable only for an authoritarian system.
Gilbert Ling细胞生理学革命的含义是需要一种新的思维方式。如果生命是自发有序的,即使是在分子水平上,那么在试图纠正健康问题时,也必须考虑有序过程。 一种从基本吸附剂、诱导、联想和合作相变的角度思考的医学方法,是使用类似于诺伯特·维纳控制论概念的心理过程,从可观察响应整体的角度思考,而不是信息和控制系统的香农·韦弗模型(发送者、编码者、控制者、通道、噪声、解码器、接收器——它们隐含在药物受体基因酶范式中,仅适用于专制系统)。
The diseases that are becoming epidemic—hypertension, diabetes, autoimmune inflammatory diseases, mental and neurological diseases—are seen by the drug industry as an exciting new market. An alternative future would involve a rethinking of biomedical doctrines and education, focusing on the environmental changes needed to support the body’s restorative processes. Like intracellular ATP, an appropriate amount of progesterone, T3, urea and carbon dioxide each has an infinity of beneficial effects, individually and in combination, and with their synergizing nutritional, botanical and pharmaceutical substances their use could transform the nature of health care.
高血压、糖尿病、自身免疫性炎症疾病、精神和神经疾病正在变得流行,这被制药行业视为一个令人兴奋的新市场。另一种未来将包括重新思考生物医学理论和教育,重点关注支持身体恢复过程所需的环境变化。与细胞内ATP一样,适量的孕酮、T3、尿素和二氧化碳,无论是单独还是联合使用,都具有无限的有益效果,它们的使用可以通过协同营养、植物和药物物质改变医疗保健的性质。
Combinations of substances such as CO2, progesterone, angiotensin receptor blockers, acetazolamide and aspirin that affect fundamental properties of the organism are appropriate for use in a great range of problems now treated with drugs considered to be “specific” for particular ailments. The purpose should be to support the patient's recovery, not to “eliminate a disease.”
二氧化碳、孕酮、血管紧张素受体阻滞剂、乙酰唑胺和阿司匹林等影响机体基本性质的物质的组合适用于目前被认为对特定疾病具有“特异性”的药物治疗的大量问题。目的应该是支持患者的康复,而不是“消灭疾病”
In the past, when doctors in a region have gone on strike, the death rate fell sharply for the duration of the strike. If it becomes possible to stop all medical practices based on the irrational membrane theory, a similar or greater decrease of mortality is likely to become permanent.
过去,当一个地区的医生罢工时,死亡率在罢工期间急剧下降。如果有可能停止基于非理性膜理论的所有医疗实践,那么死亡率的类似或更大幅度下降很可能成为永久性的。
ACS Med Chem Lett. 2015 Feb 12; 6(2): 104–107. **Allosteric Modulators: An Emerging Concept in Drug Discovery.** Abdel-Magid AF.
J Enzyme Inhib Med Chem. 2015 Jun;30(3):420-9. **Chromatographic evaluation and QSAR optimization for benzoic acid analogues against carbonic anhydrase III**.Alzweiri M, Al-Balas Q, Al-Hiari Y.
Exp Mol Med. 2017 May 19;49(5):e334.** Role of carbonic anhydrases in skin wound healing**.Barker H, Aaltonen M, Pan P, Vähätupa M, Kaipiainen P, May U, Prince S, Uusitalo-Järvinen H, Waheed A, Pastoreková S, Sly WS, Parkkila S, Järvinen TA.
Bioorg Med Chem. 2008 Oct 15;16(20):9101-5.**In vitro inhibition of salicylic acid derivatives on human cytosolic carbonic anhydrase isozymes I and II**. Bayram E, Senturk M, Kufrevioglu OI, Supuran CT.
Drug Chem Toxicol. 2005;28(4):409-21.**Combined treatment potentiates the developmental toxicity of ibuprofen and acetazolamide in rats.** Cappon GD, Fleeman TL, Cook JC, Hurtt ME.
Proc Natl Acad Sci U S A. 1980 Sep;77(9):5562-6. **Mitochondrial carbonic anhydrase.** Dodgson SJ, Forster RE 2nd, Storey BT, Mela L.
J Am Soc Nephrol. 2016 Jul;27(7):2082-91.**Acetazolamide Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus.** de Groot T, Sinke AP, Kortenoeven ML, Alsady M, Baumgarten R, Devuyst O, Loffing J, Wetzels JF, Deen PM.
J Appl Physiol (1985). 2004 Aug;97(2):515-21.**Acetazolamide prevents hypoxic pulmonary vasoconstriction in conscious dogs. **Höhne C(1), Krebs MO, Seiferheld M, Boemke W, Kaczmarczyk G, Swenson ER.
Journal of Patient Safety 2013 Sept; 9(3) 2013 122-128. **A New, Evidence-based Estimate of Patient Harms Associated with Hospital Care. **James JT.
Afr Health Sci. 2018 Dec;18(4):1303-1310.**Inhibition of cell proliferation, migration and colony formation of LS174T Cells by carbonic anhydrase inhibitor.** Karakuþ F, Eyol E, Yýlmaz K, Ünüvar S.
Am J Surg. 1982 Nov;144(5):554-7. **Inhibition of gastric mucosal carbonic anhydrase by taurocholic acid and other ulcerogenic agents.**Kivilaakso E.
Physiol Chem Phys Med NMR. 1983;15(2):137-54. **Studies on the physical state of water in living cells and model systems.II. NMR relaxation times of water protons in aqueous solutions of gelatin and oxygencontaining polymers which reduce the solvency of water for NA+, sugars, and free amino acids.** Ling GN, Murphy RC.
BMJ. 2016 May 3;353:i2139. **Medical error—the third leading cause of death in the US. **Makary MA, Daniel M.
J Mol Biol. 1963 Apr;6:306-29. **Allosteric proteins and cellular control systems.** Monod J, Changeux JP, Jacob F.
Biochem Int. 1991 Mar;23(4):779-89.**Changes in carbonic anhydrase may be the initial step of altered metabolism in hypertension.** Parui R, Gambhir KK, Mehrotra PP.
Int J Clin Lab Res. 2000;30(3):119-25. **The mechanism of action of angiotensin II is dependent on direct activation of vascular smooth muscle carbonic anhydrase I.** Puscas I, Coltau M, Gilau L, Baican M, Pasca R, Domuta G, Hecht A.