Stem cells, cell culture, and culture: Issues in regeneration

干细胞、细胞培养和培养:再生中的问题

by Raymond Peat

Cell renewal is a factor in all aspects of health and disease, not just in aging and the degenerative diseases. Many people are doing valid research relating to cell renewal and regeneration, but its usefulness is seriously limited by cultural and commercial constraints. By recovering some of our suppressed traditional culture, I think regenerative therapies can be developed quickly, by identifying and eliminating as far as possible the main factors that interfere with tissue renewal.

细胞更新在健康和疾病的各个方面都是一个因素，而不仅仅是衰老和退化性疾病。许多人正在进行有关细胞更新和再生的有效研究，但它的用途受到文化和商业限制。通过恢复一些被压抑的传统文化，我认为通过识别和尽可能消除干扰组织更新的主要因素，再生疗法可以迅速发展。

Science grew up in the highly authoritarian cultures of western Europe, and even as it contributed to cultural change, it kept an authoritarian mystique. Any culture functions as a system of definitions of reality and the limits of possibility, and to a great extent the “laws of nature” are decreed so that they will harmonize with the recognized laws of society.

科学在西欧高度专制的文化中成长起来，即使它促成了文化变革，它也保持着一种专制的神秘性。任何文化的功能都是对现实和可能性界限的定义体系，在很大程度上，“自然法则”是为了与公认的社会法则相协调而制定的。

The practical success of Newton's “laws” of motion when they were applied to ballistics and “rocket science” has led many people to value calculation, based on those laws, over evidence. In biology, the idea that an organism is “the information it contains in its DNA blueprint” is an extention of this. The organism is turned into something like a deductive expression of the law of DNA. This attitude has been disastrous.

当牛顿的运动“定律”被应用于弹道学和“火箭科学”时，它的实际成功使许多人重视基于这些定律的计算，而不是证据。在生物学中，有机体是“其DNA蓝图中所包含的信息”的观点是这一观点的延伸。有机体变成了某种类似于DNA法则的演绎表达。这种态度是灾难性的。

The old feudal idea of a divine and stable social organization was applied by some people to their idea of biological organization, in which each cell (ruled by its nucleus) had its ordained place in the organism, with the brain and the “master gland,” the pituitary, ruling the subordinate organs, tissues, and cells. “Anatomy” was taught from dead specimens, microscope slides, and illustrations in books. Most biologists' thoughts about cells in organisms reflect the static imagery of their instruction. (“The histological image of these tissues actually reflects an instantaneous picture of cells in a continuous flux.” Zajicek, 1981.)

旧的封建思想的神圣和稳定的社会组织被一些人他们的想法应用的生物组织,每一个细胞(由其核)的任命在生物体,大脑和“主腺”,垂体,执政的附属器官,组织,细胞。“解剖学”是通过死去的标本、显微镜载玻片和书中的插图来讲授的。大多数生物学家对生物体中细胞的想法反映了它们指令的静态图像。(“这些组织的组织学图像实际上反映了细胞在连续流动中的瞬时图像。”Zajicek, 1981)。

When a person has playful and observant interactions with natural things, both regularities and irregularities will be noticed, and in trying to understand those events, the richness of the experience will suggest an expansive range of possibilities. Perception and experimentation lead to understandings that are independent of culture and tradition.

当一个人与自然事物进行有趣和观察性的互动时，无论是规律还是不规则都会被注意到，而在试图理解这些事件时，丰富的经验将暗示一个广阔的可能性范围。感知和实验导致独立于文化和传统的理解。

But the mystique of science easily imposes itself, and distracts our attention from direct interactions with things. As we learn to operate lab instruments, we are taught the kinds of results that can be expected, and the concepts that will explain and predict the results of our operations. Science, as we learn about it in schools and the mass media, is mostly a set of catechisms.

但科学的神秘性很容易强加于人，分散了我们与事物直接互动的注意力。当我们学习操作实验室仪器时，我们会学到各种可以预期的结果，以及解释和预测我们操作结果的概念。我们在学校和大众媒体上学到的科学，基本上就是一套教义问答。

Our theories about organisms inform our experiments with cells or tissues that have been isolated from those organisms. The conditions for growing cells in dishes are thought of as “physiological,” in relation to the solution's “physiological osmolarity,” “physiological pH,” nutrients, oxygenation, temperature, pressure, etc. But these concepts of what is physiological derive from the monolithic ideology of the doctrinaire, and often fraudulent, mainstream of biological science.

我们关于生物体的理论为我们从这些生物体中分离出来的细胞或组织的实验提供了依据。细胞在培养皿中生长的条件被认为是“生理的”，与溶液的“生理渗透压”、“生理pH值”、营养、氧合、温度、压力等有关。但是，这些关于什么是生理学的概念，来自于教条主义的、经常是虚假的、生物科学主流的整体意识形态。

The catechismic nature of science has led people to expect some “break-throughs” to occur in certain areas, and as authoritarian science has grown into “big science” managed by corporations and governments, those break-throughs are generally expected to be produced by the newest and most expensive developments of “high technology.”

自然科学让人期待一些“突破”发生在某些领域,以及威权科学已经发展成为“大科学”由企业和政府管理,这些突破通常会产生的最新和最昂贵的发展的“高技术”。

But looking closely at the real events and processes in the sciences in the last couple of centuries, it turns out that useful advances have been produced mainly by breaking away from authoritarian doctrines, to return to common sense and relatively simple direct observations.

但仔细观察过去几个世纪里科学领域的真实事件和过程，就会发现，有用的进步主要是通过脱离专制主义教条，回归常识和相对简单的直接观察而产生的。

Although people were cloning animals in the 1960s, it was still widely taught that it was impossible. The students of the professors who taught that it was impossible are now saying that it requires high technology and new research.

For the last 100 years the most authoritative view in biology has been that there are no stem cells in adults, that brains, hearts, pancreases and oocytes are absolutely incapable of regeneration. But now, people seem to be finding stem cells wherever they look, but there is a mystique of high technology involved in finding and using them.

尽管人们在20世纪60年代就克隆动物了，但人们仍然普遍认为这是不可能的。曾经说过这是不可能的那些教授的学生们现在说，这需要高科技和新的研究。

在过去的100年里，生物学中最权威的观点是成人没有干细胞，大脑、心脏、胰腺和卵母细胞绝对不能再生。但现在，人们似乎在任何地方都能找到干细胞，但在寻找和使用它们的过程中，有一种高科技的神秘感。

Whether it's deliberate or not, the emphasis on stem cell technology has the function of directing attention away from traditional knowledge, the way allopathic medicine has de-emphasized the intrinsic ability of people to recover from disease.

This resembles the way that the Mendel-Morgan gene doctrine was used to suppress the knowledge gained from centuries of experience of plant and animal breeders, and to belittle the discoveries of Luther Burbank, Paul Kammerer, Trofim Lysenko, and Barbara McClintock. The same type of biochemical process that caused the hereditary changes those researchers studied are involved in the differentiation and dedifferentiation of stem cells that regulate healing and regeneration.

In the 1940s, even children discussed the biological discoveries of the 1920s and 1930s, the work in regeneration and adaptation, parthenogenesis, and immortalization. The ideas of J. Loeb, T. Boveri, A. Gurwitsch, J. Needham, C.M. Child, A. Carrel, et al., had become part of the general culture.

无论是有意还是无意，对干细胞技术的重视具有将人们的注意力从传统知识上转移开的功能，就像对抗疗法弱化了人们从疾病中恢复的内在能力一样。

这类似于孟德尔-摩根基因学说被用来压制从植物和动物育种家几个世纪的经验中获得的知识，并贬低路德·伯班克、保罗·凯默勒、特罗菲姆·李森科和芭芭拉·麦克林托克的发现。这些研究人员所研究的引起遗传变化的生物化学过程，也涉及调节愈合和再生的干细胞的分化和去分化。

在20世纪40年代，甚至连孩子都在讨论20世纪20年代和30年代的生物学发现、再生和适应、孤雌生殖和不朽等方面的工作。J. Loeb、T. Boveri、A. Gurwitsch、J. Needham、C.M. Child、A. Carrel等人的思想已经成为一般文化的一部分。

But that real biology was killed by a consortium of industry and government that began a little before the second world war. In 1940, the government was supporting research in chemical and biological warfare, and with the Manhattan Project the role of government became so large that all of the major research universities were affected. Shortly after the war, many researchers from the Manhattan Project were redeployed into “molecular genetics,” where the engineering attitude was applied to organisms.

但真正的生物学在二战前就被一个由工业界和政府组成的联盟扼杀了。1940年，政府支持化学和生物战争的研究，随着曼哈顿计划，政府的作用变得如此之大，以至于所有主要的研究型大学都受到了影响。战争结束后不久，曼哈顿计划的许多研究人员被重新部署到“分子遗传学”，在那里，工程学的态度被应用到生物体上。

The simplistic genetic dogmas were compatible with the reductionist engineering approach to the organism. The role of the government assured that the universities would subscribe to the basic scientific agenda. The atmosphere of that time was described by Carl Lindegren as “The Cold War in Biology” (1966).

The disappearance of the field concept in developmental biology was one of the strangest events in the history of science. It didn't just fade away, it was “disappeared,” in a massive undertaking of social engineering. In its absence, stem cells will seem to be a profitable technological marvel, rather than a universal life function, with a central role in everything we are and everything we do and can become.

简单的遗传教条与生物的简化工程方法是一致的。政府的作用保证了各大学将支持基本的科学议程。当时的气氛被卡尔·林德格伦描述为“生物学中的冷战”(1966)。

发育生物学领域概念的消失是科学史上最奇怪的事件之一。它不仅消失了，而且在一项大规模的社会工程中“消失了”。如果没有它，干细胞似乎将是一个有利可图的技术奇迹，而不是一个普遍的生命功能，在我们是什么、我们做什么和我们能成为什么方面发挥核心作用。

Many people have tried to explain aging as a loss of cells, resulting from an intrinsic inability of any cell other than a germ cell to multiply more than a certain number of times. More than 40 years ago Leonard Hayflick popularized this doctrine in its most extreme form, saying that no cell can divide more than 50 times unless it is converted into a cancer cell. He and his followers claimed that they had explained why organisms must age and die. At the moment the ovum is fertilized, the clock starts ticking for the essentially mortal somatic cells.

许多人试图将衰老解释为细胞的损失，这是由生殖细胞以外的任何细胞内在无法繁殖超过一定数量的结果。40多年前，伦纳德·海弗利克(Leonard Hayflick)以其最极端的形式推广了这一学说，他说，除非转化为癌细胞，否则任何细胞都不能分裂超过50次。他和他的追随者声称他们已经解释了为什么生物体必须老化和死亡。在卵子受精的那一刻，生物钟就开始为基本上会死亡的体细胞计时。

In 1970, it was being seriously proposed that memory was produced by the death of brain cells, in a manner analogous to the holes punched in cards to enter data into computers. The cultural dogma made it impossible to consider that learning could be associated with the birth of new cells in the adult brain.

With the announcement in 1997 of the cloning of the sheep Dolly from a somatic cell taken from a 6 year old sheep, there was renewed interest in the idea made famous by Alexis Carrel that all cells are potentially immortal, and in the possibility of preserving the vitality of human cells. Within a few months, Hayflick began reminding the public that “In the early 1960's we overthrew this dogma after finding that normal cells do have a finite replicative capacity.” (“During the first half of this century it was believed that because cultured normal cells were immortal, aging must be caused by extra-cellular events.”) The way Hayflick “overthrew” more than 35 years of work at the Rockefeller Institute was by growing one type of cell, a lung fibroblast, in culture dishes, and finding that the cultures deteriorated quickly.

1970年，有人严肃地提出，记忆是由脑细胞死亡产生的，其方式类似于在卡片上打孔以将数据输入计算机。文化教条使人不可能把学习与成人大脑中新细胞的诞生联系起来。

宣布1997年从体细胞克隆绵羊多莉取自一个6岁的羊,有兴趣重燃的想法因想到出名,所有细胞可能是不朽的,并且在保持人体细胞活力的可能性。几个月后，海弗利克开始提醒公众:“在20世纪60年代早期，我们发现正常细胞确实有有限的复制能力，从而推翻了这一教条。”(“上半年这个世纪人们相信,因为正常细胞培养是不朽的,老化必须由细胞外的事件引起的。”)的海弗利克“推翻”洛克菲勒研究所超过35年的工作是种植一种类型的细胞,肺成纤维细胞,在培养皿中,并发现文化迅速恶化。

To draw global conclusions about an organism's development and aging from the degenerative processes seen in a single type of cell, grown in isolation from all normal stimuli, would have been treated as nothing but wild speculation, except that it occurred within a culture that needed it. No aspect of Hayflick's cell culture system could properly be called physiological.

Other researchers, simply by changing a single factor, caused great increases in the longevity of the cultured cells. Simply using a lower, more natural oxygen concentration, the cells were able to undergo 20 more divisions. Just by adding niacin, 30 more divisions; vitamin E, 70 more divisions. Excess oxygen is a poison requiring constant adaptation.

Hayflick also published the observation that, while the cells kept in dishes at approximately body temperature deteriorated, cells kept frozen in liquid nitrogen didn't deteriorate, and he concluded that “time” wasn't the cause of aging. When I read his comments about the frozen cells, I wondered how anyone of normal intelligence could make such stupid statements. Since then, facts that came out because of the Freedom of Information Act, cause me to believe that a financial motive guided his thoughts about his cultured fibroblasts.

从一种脱离所有正常刺激而单独生长的细胞中观察到的退化过程中得出关于有机体的发展和衰老的整体结论，只能被视为一种疯狂的猜测，除非它发生在一个需要它的培养中。海弗利克细胞培养系统的任何方面都不能恰当地称为生理学。

其他研究人员，仅仅通过改变一个因素，就大大延长了培养细胞的寿命。简单地使用更低、更自然的氧气浓度，细胞就能进行20次分裂。只要加入烟酸，就能再分30次;维生素E, 70多个部门。过量的氧气是一种需要不断适应的毒物。

海弗利克还发表了一项观察结果，即当细胞被保存在接近体温的培养皿中时，细胞会恶化，而被冷冻在液氮中的细胞不会恶化，他得出结论，“时间”不是衰老的原因。当我读到他关于冷冻细胞的评论时，我想知道一个正常智力的人怎么能做出如此愚蠢的声明。从那时起，因为《信息自由法》而出现的事实，让我相信是经济动机引导了他对培养成纤维细胞的想法。

Hayflick and his followers have been attacking the idea of anti-aging medicine as quackery. But he is closely involved with the Geron corporation, which proposes that genetic alterations relating to telomeres may be able to cure cancer and prevent aging. Their claims were reported by CNN as “Scientists discover cellular 'fountain of youth'.”

The “wear and tear” doctrine of aging that derived from the ideology of the gene was reinforced and renewed by Hayflick's cell culture observations, and it continued to rule the universities and popular culture.

But detailed investigation of skin cell growth showed that cells in the lower layer of the skin divide at least 10,000 times in a normal lifetime, and similar processes occur in the lining of the intestine. The endometrium and other highly renewable tissues just as obviously violated Hayflick's limit. Transplantation experiments showed that pieces of mammary tissue or skin tissue could survive through ten normal lifetimes of experimental animals without suffering the effects of aging.

Even the liver and adrenal gland are now known to be continuously renewed by “cell streaming,” though at a slower rate than the skin, conjunctiva, and intestine. Neurogenesis in the brain is now not only widely accepted, it is even proposed as a mechanism to explain the therapeutic effects of antidepressants (Santarelli, et al., 2003).

海弗利克和他的追随者一直在攻击抗衰老药物的想法，认为这是庸医把戏。但他与Geron公司密切合作，该公司提出，与端粒有关的基因改变可能能够治愈癌症和防止衰老。他们的声明被CNN报道为“科学家发现了细胞的‘不老泉’”。

源于基因意识形态的衰老的“磨损”学说被海弗利克的细胞培养观察所强化和更新，并继续统治着大学和流行文化。

但对皮肤细胞生长的详细研究表明，皮肤底层的细胞在正常寿命中至少分裂一万次，类似的过程也发生在肠内壁。子宫内膜和其他高度可再生的组织显然也违反了海弗利克的限制。移植实验表明，乳腺组织或皮肤组织的碎片可以在实验动物的正常寿命中存活10年而不受衰老的影响。

即使是肝脏和肾上腺现在也知道通过“细胞流动”不断更新，尽管速度比皮肤、结膜和肠慢。大脑中的神经发生现在不仅被广泛接受，甚至被提议作为一种机制来解释抗抑郁药物的治疗效果(Santarelli, et al.， 2003)。

August Weismann's most influential doctrine said that “somatic cells are mortal, only the germline cells are immortal,” but he based the doctrine on his mistaken belief that only the “germline” cells contained all the genes of the organism. In 1885, to “refute” Darwin's belief that acquired traits could be inherited, he promulgated an absolute “barrier” between “germline” and “soma,” and invented facts to show that hereditary information can flow only from the germline to the somatic cells, and not the other direction. Shortly after DNA became popular in the 1950s as “the genetic material,” Weismann's barrier was restated as the Central Dogma of molecular genetics, that information flows only from DNA to RNA to protein, and never the other direction.

It was only in 2003, after the reality of cloning was widely recognized, that a few experimenters began to investigate the origin of “germline” cells in the ovary, and to discover that they derive from somatic cells (Johnson, et al., 2004). With this discovery, the ancient knowledge that a twig (klon, in Greek) cut from a tree could grow into a whole tree, bearing fruit and viable seeds, was readmitted to general biology, and the Weismann barrier was seen to be an illusion.

韦斯曼(August Weismann)最有影响力的学说是“体细胞是会死的，只有生殖细胞才是不朽的”，但他的学说建立在自己的错误信念之上，即只有“生殖细胞”包含生物体的所有基因。1885年，为了“反驳”达尔文的“后天特征可以遗传”的观点，他在“生殖细胞”和“体细胞”之间设立了一道绝对的“屏障”，并捏造事实证明遗传信息只能从生殖细胞流向体细胞，而不能从体细胞流向生殖细胞。20世纪50年代，DNA作为“遗传物质”开始流行后不久，魏斯曼的障碍被重申为分子遗传学的中心信条，即信息只从DNA流向RNA，再流向蛋白质，而非其他方向。

直到2003年，在克隆的现实被广泛承认之后，一些实验者才开始研究卵巢中“生殖系”细胞的起源，并发现它们来源于体细胞(Johnson, et al.， 2004)。有了这一发现，从树上砍下的树枝(希腊语为klon)可以长成整棵树、结出果实和有活力的种子的古老知识重新被纳入了一般生物学，而魏斯曼障碍被视为一种错觉。

Millions of people have “explained” female reproductive aging as the consequence of the ovary “running out of eggs.” Innumerable publications purported to show the exact ways in which that process occurs, following the Weismann doctrine. But now that it is clear that adult ovaries can give birth to new oocytes, a new explanation for female reproductive aging is needed. It is likely that the same factors that cause female reproductive aging also cause aging of other systems and organs and tissues, and that those factors are extrinsic to the cells themselves, as Alexis Carrel and others demonstrated long ago. This is a way of saying that all cells are potential stem cells. The “niche” in which new cells are born in the streaming organism, and the processes by which damaged cells are removed, are physiological issues that can be illuminated by the idea of a morphogenetic field.

数百万人将女性生殖能力的老化解释为卵巢“卵子耗尽”的结果。数不清的出版物声称，按照韦斯曼的理论，展示了这一过程发生的确切方式。但是，既然成年卵巢可以产生新的卵母细胞，就需要对女性生殖衰老作出新的解释。很可能导致女性生殖衰老的因素也会导致其他系统、器官和组织的衰老，而这些因素是细胞本身的外在因素，正如亚历克西斯·卡雷尔(Alexis Carrel)和其他人很久以前证明的那样。这是一种说法，所有的细胞都是潜在的干细胞。新细胞在流动的生物体中诞生的“生态位”，以及受损细胞被移除的过程，都是可以用形态发生场的概念来阐明的生理学问题。

When the post-war genetic engineers took over biological research, the idea of a biophysical field was totally abandoned, but after about 15 years, it became necessary to think of problems beyond those existing within a single bacterium, namely, the problem of how an ovum becomes and embryo. Francis Crick, of DNA fame, who was educated as a physicist, revived (without a meaningful historical context) the idea of a diffusion gradient as a simple integrating factor that wouldn't be too offensive to the reductionists. But for events far beyond the scale of the egg's internal structure, for example to explain how a nerve axon can travel a very long distance to innervate exactly the right kind of cell, the diffusion of molecules loses its simplicity and plausibility. (Early in the history of experimental embryology, it was observed that electrical fields affect the direction of growth of nerve fibers.)

当战后基因工程师接管生物学研究时，生物物理领域的想法被完全抛弃了，但大约15年后，有必要考虑存在于单个细菌之外的问题，即卵子如何形成和胚胎的问题。弗朗西斯克里克(Francis Crick)，因DNA而闻名，他曾是一名物理学家，他复活了(没有一个有意义的历史背景)扩散梯度作为一个简单的整合因素的想法，这对还原论者来说不会太冒犯。但是，对于远远超出卵子内部结构范围的事件，例如，解释神经轴突如何能移动很长一段距离来精确地支配某种细胞，分子扩散就失去了它的简单性和合理性。(早在实验胚胎学的历史上，就已经观察到电场会影响神经纤维的生长方向。)

C. M. Child saw a gradient of metabolic activity as an essential component of the morphogenetic field. This kind of gradient doesn't deny the existence of diffusion gradients, or other physical components of a field. Electrical and osmotic (and electro-osmotic) events are generated by metabolism, and affect other factors, including pH, oxidation and reduction, cell motility and cell shape, ionic selectivity and other types of cellular selectivity and specificity. Gradients of DNA methylation exist, and affect the expression of inherited information.

Methylation decreases the expression of particular genes, and during the differention of cells in the development of an embryo, genes are methylated and demethylated as the cell adapts to produce the proteins that are involved in the structure and function of a particular tissue. Methylation (which increases a molecule's affinity for fats) is a widespread process in cells, and for example regulates cellular excitability. It is affected by diet and a variety of stresses.

Child认为代谢活动的梯度是形态发生领域的一个重要组成部分。这种梯度并不否认扩散梯度或场的其他物理分量的存在。电和渗透(和电渗透)事件是由代谢产生的，并影响其他因素，包括pH、氧化和还原、细胞运动性和细胞形状、离子选择性和其他类型的细胞选择性和特异性。DNA甲基化存在梯度，影响遗传信息的表达。

甲基化降低了特定基因的表达，在胚胎发育过程中细胞的分化过程中，随着细胞适应产生与特定组织的结构和功能有关的蛋白质，基因被甲基化和去甲基化。甲基化(增加分子对脂肪的亲和力)是细胞中广泛存在的过程，例如调节细胞的兴奋性。它受到饮食和各种压力的影响。

DNA methylation patterns are normally fairly stable, and can help to account for the transgenerational transmission of acquired adaptations, and for neonatal imprinting that can last a lifetime. But with injury, stress, and aging, the methylation patterns of differentiated tissues can be changed, contributing to the development of tumors, or to the loss of cellular functions. Even learning can change the methylation of specific genes. During in vitro culture, the enzymes of gene methylation are known to be increased, relative to their normal activity (Wang, et al., 2005).

DNA甲基化模式通常是相当稳定的，可以帮助解释后天适应的代际传递，以及可以持续终生的新生儿印记。但随着损伤、压力和衰老，分化组织的甲基化模式会发生改变，从而导致肿瘤的发展，或细胞功能的丧失。甚至学习也能改变特定基因的甲基化。在体外培养中，已知基因甲基化酶相对于其正常活性有所增加(Wang, et al.， 2005)。

The phenomenon of “gene” methylation in response to environmental and metabolic conditions may eventually lead to the extinction of the doctrine that “cells are controlled by their genes.”

During successful adaptation to stress, cells make adjustments to their metabolic systems (for example with a holistic change of the degree of phosphorylation, which increases molecules' affinity for water), and their metabolic processes can contribute to changes in their state of differentiation. Some changes may lead to successful adaptation (for example by producing biogenic stimulators that stimulate cell functioning and regeneration), others to failed adaptation. Even the decomposition of cells can release substances that contribute to the adaptation of surrounding cells, for example when sphingosines stimulate the production of stem cells.

环境和代谢条件引起的“基因”甲基化现象可能最终导致“细胞由基因控制”学说的消亡。

在成功适应压力的过程中，细胞对其代谢系统进行调整(例如磷酸化程度的整体改变，这增加了分子对水的亲和性)，它们的代谢过程有助于改变它们的分化状态。一些变化可能导致成功的适应(例如产生生物刺激因子刺激细胞功能和再生)，另一些则导致失败的适应。即使是细胞的分解也能释放出有助于周围细胞适应的物质，例如当鞘氨醇刺激干细胞的产生时。

DNA methylation is just one relatively stable event that occurs in relation to a metabolic field. Modifications of histones (regulatory proteins in chromosomes, which are acetylated as well as methylated) and structural-contractile filaments also contribute to the differentiation of cells, but the pattern of DNA methylation seems to guide the methylation of histones and the structure of the chromosomes (Nan, et al., 1998).

Steroids and phospholipids, neurotransmitters and endorphins, ATP, GTP, other phosphates, retinoids, NO and CO2–many materials and processes participate in the coherence of the living state, the living substance. Carbon dioxide, for example, by binding to lysine amino groups in the histones, will influence their methylation. Carbon dioxide is likely to affect other amino groups in the chromosomes.

The number and arrangement of mitochondria is an important factor in producing and maintaining the metabolic gradients. Things that decrease mitochondrial energy production–nitric oxide, histamine, cytokines, cortisol–increase DNA methylation. Decreased gene expression is associated with reduced respiratory energy. It seems reasonable to guess that increased gene expression would demand increased availability of energy.

DNA甲基化只是与代谢场相关的一个相对稳定的事件。组蛋白的修饰(调节蛋白在染色体,乙酰化和甲基化)和structural-contractile丝也有助于细胞的分化,但DNA甲基化的模式似乎引导组蛋白的甲基化和染色体的结构(Nan, et al ., 1998)。

类固醇和磷脂，神经递质和内啡肽，ATP, GTP，其他磷酸盐，类维生素a, NO和CO2——许多物质和过程参与了生物状态的连贯性，生物物质。例如，二氧化碳通过与组蛋白中的赖氨酸氨基结合，会影响组蛋白的甲基化。二氧化碳可能会影响染色体上的其他氨基。

线粒体的数量和排列是产生和维持代谢梯度的重要因素。一氧化氮、组胺、细胞因子、皮质醇等降低线粒体能量产生的物质会增加DNA甲基化。基因表达减少与呼吸能量减少有关。推测增加的基因表达需要增加能量的可用性似乎是合理的。

As an ovum differentiates into an organism, cells become progressively more specialized, inhibiting the expression of many genes. Less energy is needed by stably functioning cells, than by actively adapting cells. A.I. Zotin described the process of maturing and differentiating as a decrease of entropy, an increase of order accompanying a decreased energy expenditure. The entropic egg develops into a less entropic embryo with a great expenditure of energy.

The partially differentiated stem cell doesn't go through all the stages of development, but it does expend energy intensely as it matures.

The restoration of energy is one requirement for the activation of regeneration. When a hormone such as noradrenaline or insulin causes a stem cell to differentiate in vitro, it causes new mitochondria to form. This is somewhat analogous to the insertion of mitochondria into the ripening oocyte, by the nurse cells that surround it. The conditionally decreased entropy of maturation is reversed, and when sufficient respiratory energy is available, the renewed and refreshed cell will be able to renew an appropriate degree of differentiation.

当卵子分化成一个有机体时，细胞变得越来越专门化，抑制了许多基因的表达。稳定运转的细胞比积极适应的细胞需要更少的能量。A.I. Zotin将成熟和分化的过程描述为熵的减少，伴随着能量消耗的减少而增加的顺序。熵卵发育成熵较小的胚胎，消耗大量的能量。

部分分化的干细胞不会经历所有的发育阶段，但它在成熟过程中会消耗大量的能量。

能量的恢复是激活再生的一个必要条件。当去甲肾上腺素或胰岛素等激素导致干细胞在体外分化时，就会形成新的线粒体。这有点类似于在成熟的卵母细胞周围的看护细胞将线粒体插入卵母细胞。成熟熵的有条件下降被逆转，当有足够的呼吸能量时，更新和更新的细胞将能够更新适当程度的分化。

When simple organisms, such as bacteria, fungi, or protozoa are stressed, for example by the absence of nutrients or the presence of toxins, they slow their metabolism, and suppress the expression of genes, increasing the methylation of DNA, to form resistant and quiescent spores. Our differentiated state doesn't go to the metabolic extreme seen in sporulation, but it's useful to look at maturity and aging in this context, because it suggests that the wrong kind of stress decreases the ability of the organism to adapt, by processes resembling those in the spore-forming organisms.

Charles Vacanti, who has grown cartilage from cells taken from 100 year old human cartilage, believes our tissues contain “spore cells,” very small cells with slow metabolism and extreme resistance to heat, cold, and starvation.

If the slowed metabolism of aging, like that of sporulating cells, is produced by a certain kind of stress that lowers cellular energy and functions, it might be useful to think of the other stages of the stress reaction in relation to the production of stem cells. Selye divided stress into a first stage of shock, followed by a prolonged adaptation, which could sometimes end in exhaustion. If the maturity of differentiated functioning is equivalent to the adaptation phase, and cellular decline and disintegration is the exhaustion phase, then the shock-like reaction would correspond to the birth of new stem cells.

当简单的有机体，如细菌、真菌或原生动物受到压力时，例如由于营养物质的缺乏或毒素的存在，它们会减慢新陈代谢，抑制基因的表达，增加DNA的甲基化，从而形成具有抗性和静止的孢子。我们的分化状态并没有达到产孢过程中所见的代谢极端，但在此背景下观察成熟和衰老是有用的，因为它表明，错误的压力通过类似于产孢生物体的过程，降低了生物体的适应能力。

Charles Vacanti从100岁的人类软骨细胞中培养出软骨，他认为我们的组织含有“孢子细胞”，这是一种非常小的细胞，新陈代谢缓慢，对热、冷和饥饿有很强的抵抗力。

如果衰老的代谢减缓，就像产孢细胞的代谢一样，是由某种降低细胞能量和功能的压力产生的，那么考虑一下与干细胞产生相关的压力反应的其他阶段可能是有用的。Selye将压力分为第一阶段的震惊，随后是长期的适应，这有时会以疲惫告终。如果分化功能的成熟相当于适应期，细胞衰退和解体相当于衰竭期，那么休克样反应就相当于新的干细胞的诞生。

Selye described estrogen's effects as equivalent to the shock-phase of stress. Estrogen's basic action is to make oxygen unavailable, lowering the oxygen tension of the tissues, locally and temporarily. Like nitric oxide, which is produced by estrogenic stimulation, estrogen interferes with energy production, so if its stimulation is prolonged, cells are damaged or killed, rather than being stimulated to regenerate.

Extrinsic factors elicit renewal, the way stress can elicit adaptation. While aging cells can't use the oxygen that is present, a scarcity of oxygen can serve as a stimulus to maximize the respiratory systems. Brief oxygen deprivation excites a cell, causes it to swell, and to begin to divide.

Oxygen deprivation, as in the normally hypoxic bone marrow, stimulates the formation of stem cells, as well as the biogenesis of mitochondria. As the newly formed cells, with abundant mitochondria, get adequate oxygen, they begin differentiation.

Selye认为雌激素的作用相当于应激的冲击阶段。雌激素的基本作用是使氧气不可用，降低组织的氧张力，局部的和暂时的。就像一氧化氮一样，它是由雌激素刺激产生的，雌激素会干扰能量的产生，所以如果它的刺激延长，细胞就会被损坏或杀死，而不是被刺激再生。

外在因素诱发更新，就像压力诱发适应一样。虽然衰老的细胞不能利用现有的氧气，但氧气的缺乏可以作为一种刺激，使呼吸系统最大化。短暂的缺氧会刺激细胞，使其膨胀并开始分裂。

在正常情况下缺氧的骨髓中，缺氧会刺激干细胞的形成，以及线粒体的形成。当新形成的细胞，有丰富的线粒体，获得足够的氧气，他们开始分化。

Form, based on cellular differentiation, follows function–a vein transplanted into an artery develops anatomically into an artery, a colon attached directly to the anus becomes a new rectum with its appropriate innervation, a broken bone restructures to form a normal bone. If the bladder is forced to function more than normal, by artificially keeping it filled, its thin wall of smooth muscle develops into a thick wall of striated muscle that rhythmically contracts, like the heart. If a tadpole is given a vegetarian diet, the absorptive surface of its digestive system will develop to be twice the size of those that are fed meat. Pressure, stretching, and pulsation are among the signals that guide cells' differentiation.

Very early in the study of embryology it was noticed that the presence of one tissue sometimes induced the differentiation of another kind, and also that there were factors in embryonic tissues that would stimulate cell division generally, and others that could inhibit the growth of a particular tissue type. Diffusable substances and light were among the factors identified as growth regulators.

Extracts of particular tissues were found to suppress the multiplication of cells in that type of tissue, in adult animals as well as in embryos. In the 1960s, the tissue-specific inhibitors were called chalones.

形式，以细胞分化为基础，遵循功能——移植到动脉的静脉在解剖学上发展成动脉，直接连接到肛门的结肠成为一个新的直肠，具有适当的神经支配，骨折重建成正常的骨。如果膀胱被迫超出正常功能，通过人工保持膀胱充满，它的薄壁平滑肌会发展成厚壁的横纹肌，有节奏地收缩，就像心脏一样。如果蝌蚪吃素食，它消化系统的吸收表面将发育成食肉蝌蚪的两倍大。压力、拉伸和脉动是引导细胞分化的信号。

很早就在胚胎学的研究发现,一个组织的存在有时诱导分化的另一种,也有因素胚胎组织通常会刺激细胞分裂,和其他人可以抑制特定组织的生长类型。可扩散物质和光是被鉴定为生长调节剂的因素。

研究发现，在成年动物和胚胎中，特定组织的提取物可以抑制该类型组织中细胞的增殖。在20世纪60年代，这种组织特异性抑制剂被称为查隆。

The brain's development is governed by the presence in the organism of the body part to which it corresponds, such as the eyes or legs. The number of cells in a particular part of the nervous system is governed by the quantity of nervous input, sensory or motor, that it receives. An enriched environment causes a bigger brain to grow. Sensory nerve stimulation of a particular region of the brain causes nerve cells to migrate to that area (a process called neurobiotaxis; deBeers, 1927), but nerve stimulation also causes mitochondria to accumulate in stimulated areas. Nerve activity has a trophic, sustaining influence on other organs, as well as on the brain. Nerve stimulation, like mechanical pressure or stretching, is an important signal for cellular differentiation.

大脑的发育受与之相对应的身体部位的存在所控制，如眼睛或腿。神经系统某一特定部位的细胞数量由它接收到的感觉或运动神经输入的数量决定。丰富的环境会导致更大的大脑生长。对大脑某个特定区域的感觉神经刺激会导致神经细胞迁移到该区域(这个过程被称为神经生物趋向性;deBeers, 1927)，但神经刺激也会导致线粒体在受刺激区域积聚。神经活动不仅对大脑，对其他器官也有营养的、持续的影响。神经刺激，如机械压力或拉伸，是细胞分化的重要信号。

When stem cells or progenitor cells are called on to replace cells in an organ, they are said to be “recruited” by that organ, or to “home” to that organ, if they are coming from elsewhere. Traditionally, the bone marrow has been considered to be the source of circulating stem cells, but it now appears that a variety of other less differentiated cells can be recruited when needed. Cells from the blood can repair the endothelium of blood vessels, and endothelial cells can become mesenchymal cells, in the heart, for example.

The standard doctrine about cancer is that a tumor derives from a single mutant cell, but it has been known for a long time that different types of cell, such as phagocytes and mast cells, usually reside in tumors, and it is now becoming clear that tumors recruit cells, including apparently normal cells, from other parts of the same organ. For example, a brain tumor of glial cells, a glioma, recruits glial cells from surrounding areas of the brain, in a process that's analogous to the embryological movement of nerve cells to a center of excitation. Each tumor, in a sense, seems to be a center of excitation, and its fate seems to depend on the nature of the cells that respond to its signals.

当干细胞或祖细胞被召唤来替代某个器官中的细胞时，它们被该器官“招募”，如果它们来自其他地方，则被称为该器官的“家”。传统上，骨髓一直被认为是循环干细胞的来源，但现在看来，在需要的时候，各种其他分化程度较低的细胞也可以被招募。来自血液的细胞可以修复血管的内皮细胞，内皮细胞可以变成间充质细胞，例如在心脏。

标准的学说是癌症肿瘤来源于一个突变的细胞,但它已经知道了很长一段时间,不同类型的细胞,如吞噬细胞和肥大细胞,通常驻留在肿瘤,和招聘现在越来越清楚的是,肿瘤细胞,显然包括正常细胞,其他地区的相同的器官。例如，一个神经胶质细胞的脑瘤，一个神经胶质瘤，从大脑周围区域招募神经胶质细胞，这一过程类似于胚胎学中神经细胞向兴奋中心的运动。从某种意义上说，每个肿瘤似乎都是一个兴奋的中心，它的命运似乎取决于对其信号作出反应的细胞的性质。

To accommodate some of the newer facts about tumors, the cancer establishment has begun speaking of “the cancer stem cell” as the real villain, the origin of the tumor, while the bulk of the tumor is seen to be made up of defective cells that have a short life-span. But if we recognize that tumors are recruiting cells from beyond their boundaries, this process would account for the growth and survival of a tumor even while most of its cells are inert and dying, without invoking the invisible cancer stem cell. And this view, that it is the field which is defective rather than the cell, is consistent with the evidence which has been accumulating for 35 years that tumor cells, given the right environment, can differentiate into healthy cells. (Hendrix, et al., 2007)

为了适应一些关于肿瘤的新事实，癌症研究机构已经开始将“癌症干细胞”称为真正的恶棍，即肿瘤的起源，而肿瘤的大部分被认为是由有缺陷的细胞组成的，这些细胞的寿命很短。但如果我们认识到肿瘤正在从它们的边界之外招募细胞，这个过程就可以解释肿瘤的生长和存活，即使它的大多数细胞是惰性的和死亡的，而不需要调用看不见的癌症干细胞。这种观点，即缺陷的是细胞而不是细胞，这与已经积累了35年的证据是一致的肿瘤细胞，在适当的环境下，可以分化成健康的细胞。(Hendrix等，2007)

Simply stretching an organ (Woo, et al., 2007) is stimulus enough to cause it to recruit cells from the bloodstream, and will probably stimulate multiplication in its local resident cells, too. Every “cancer field” probably begins as a healing process, and generally the healing and regeneration are at least partially successful.

When an organ–the brain, heart, liver, or a blood vessel–is inflamed or suffering from an insufficient blood supply, stem cells introduced into the blood will migrate specifically to that organ.

Organ specific materials (chalones) are known to circulate in the blood, inhibiting cell division in cells typical to that organ, but it also seems that organ specific materials are secreted by a damaged organ, that help to prepare stem cells for their migration into that organ. When undifferentiated cells are cultured with serum from a person with liver failure, they begin to differentiate into liver cells.

简单地拉伸一个器官(Woo, et al.， 2007)就足以刺激它从血液中吸收细胞，也可能刺激其本地细胞的增殖。每一个“癌症场”可能开始于一个愈合过程，通常愈合和再生至少是部分成功的。

当一个器官——大脑、心脏、肝脏或血管——发生炎症或血液供应不足时，注入血液的干细胞会专门迁移到那个器官。

器官特异性物质(chalones)已知在血液中循环，抑制该器官典型细胞的细胞分裂，但似乎器官特异性物质是由受损的器官分泌的，帮助干细胞准备迁移到该器官。当未分化细胞与肝衰竭患者的血清一起培养时，它们开始分化为肝细胞。

It is still common to speak of each organ as having a “clonal origin” in the differentiating embryo, as a simple expansion of a certain embryonic anlage. The implication of this way of thinking is that differentiation is determination in an irreversible sense. This is another case of medical ideas being based on images of fixed histological material. Normal cells, including nerve and muscle cells, can change type, with connective tissue cells becoming nerve cells, nerve cells becoming muscle and fiber cells, fat, fiber, and muscle cells redifferentiating, for example.

Cell movements in solid tissues aren't limited to the short distances between capillaries and the tissues nourished by those capillaries, rather, cells can migrate much greater distances, without entering the bloodstream. The speed of a single cell moving by ameboid motion can be measured by watching cells on a glass slide as they move toward food, or by watching cells of the slime mold Dictyostelium when they are aggregating, or by watching the pigment cells in and around moles or melanomas, under the influence of hormones. At body temperature, a single cell can crawl about an inch per day. Waves or spots of brown pigment can be seen migrating through the skin away from a mole, preceding the disintegration of the mole under the influence of progesterone or DHEA. Under ordinary conditions, pigment cells can sometimes be seen migrating into depigmented areas of skin, during the recovery of an area affected by vitiligo. These organized movements of masses of cells happen to be easy to see, but there is evidence that other types of cell can reconstruct tissues by their ameboid movements, when circumstances are right. Tumors or tissue abnormalities can appear or disappear with a suddenness that seems impossible to people who have studied only fixed tissue preparations.

将每个器官称为在分化胚胎中具有“克隆起源”，即某一胚胎器官的简单扩展，仍然是很常见的。这种思维方式的含义是，分化是一种不可逆转的决定。这是另一个基于固定组织材料图像的医学想法的案例。正常细胞，包括神经和肌肉细胞，可以改变类型，例如，结缔组织细胞变成神经细胞，神经细胞变成肌肉和纤维细胞，脂肪，纤维，肌肉细胞再分化。

固体组织中的细胞运动并不局限于毛细血管和由这些毛细血管滋养的组织之间的短距离，而是细胞可以移动更远的距离，而不需要进入血液。单个细胞的速度移动,变形运动可以测量通过观察细胞在载玻片朝着食物,或通过观察细胞黏菌的盘基网柄菌聚集时,或通过观察周围色素细胞痣或黑色素瘤,在激素的影响下。在体温下，单个细胞每天可以爬行大约一英寸。痣在孕酮或脱氢表雄酮的作用下解体之前，可以看到棕色色素波或斑点从痣的皮肤移开。在正常情况下，在白癜风影响区域的恢复过程中，有时可以看到色素细胞迁移到皮肤脱色区域。这些细胞群的有组织的运动恰好很容易看到，但有证据表明，在条件合适的情况下，其他类型的细胞可以通过它们的变形虫运动重建组织。肿瘤或组织异常可能突然出现或消失，这对只研究固定组织准备的人来说似乎是不可能的。

Stimulation is anabolic, building tissue, when the organism is adapting to the stimulation. Unused structures in cells and tissues are always being recycled by metabolic processes. When tissues are injured and become unable to function, some of their substances stimulate the growth of replacement cells.

Some types of injury or irritation can activate regenerative processes. A dermatology journal described the case of an old man who had been bald for many years who fell head-first into his fireplace. As his burned scalp healed, new hair grew. In the U.S., experimenters (Ito, et al., 2007) have found that injuring the skin of mice stimulates the formation of stem cells that are able to become hair follicle cells, supporting the regeneration of cells that had been absent. A brief exposure to estrogen, and other stress related signals (nitric oxide, endorphin, prostaglandins) can initiate stem cell proliferation.

In the years after the first world war, Vladimir Filatov, who developed techniques of reconstructive surgery, including corneal transplants, found that cold storage of tissues (for example, corneas from cadavers) caused them to function better than fresh tissues, and he found that these stressed tissues would often spread a healing influence out into the surrounding tissues. Extracts of stressed tissues produced similar effects.

当机体适应刺激时，刺激就是合成代谢，构建组织。细胞和组织中未使用的结构总是被代谢过程循环利用。当组织受伤并失去功能时，其中的一些物质会刺激替代细胞的生长。

某些类型的损伤或刺激可以激活再生过程。一本皮肤病杂志描述了这样一个例子:一位秃顶多年的老人头朝下掉进了壁炉里。他烧伤的头皮愈合后，长出了新的头发。在美国，实验者(Ito, et al.， 2007)发现，损伤小鼠的皮肤会刺激干细胞的形成，这些干细胞能够成为毛囊细胞，支持原本缺失的细胞的再生。短暂接触雌激素和其他压力相关信号(一氧化氮、内啡肽、前列腺素)可以启动干细胞增殖。

在第一次世界大战后的几年里，开发了包括角膜移植在内的重建手术技术的弗拉基米尔·菲拉托夫(Vladimir Filatov)发现，组织(例如，来自尸体的角膜)的冷藏使它们比新鲜组织的功能更好，他发现这些受到压力的组织通常会向周围的组织扩散愈合的影响。应激组织的提取物也产生了类似的效果。

L.V. Polezhaev began studying the regenerative capacities of mammals in the late 1940s, and his work showed that processes similar to embryonic induction are involved in the organism's responses to damaged tissues. For example, when a piece of killed muscle tissue is enclosed in a capsule (“diffusion chamber”) that permits molecules, but no cells, to diffuse through it, and implanted subcutaneously, it had no inductive effect on surrounding cells. But when the pores of the capsule allowed cells to enter, skeletal muscle formed where the dead tissue had been, and tissue resembling heart muscle formed outside the capsule. Phagocytosis had been essential for the induction to occur.

Macrophages are ordinarily thought of as “antigen-presenting cells” that help to activate the specific immune responses. But apparently phagocytosis is involved in the replacement of damaged tissues, by recruiting or inducing the differentiation of replacement cells. The phagocytosis function isn't limited to the blood cells commonly called phagocytes; even nerve cells can ingest particles and fragments of damaged tissues.

Many factors regulate the process of phagocytosis. Stress and lipid peroxidation decrease phagocytosis (Izgüt-Uysal, et al., 2004), and also damage mitochondria and inhibit cell renewal.

波列扎耶夫(L.V. Polezhaev)在20世纪40年代末开始研究哺乳动物的再生能力，他的工作表明，类似胚胎诱导的过程参与了有机体对受损组织的反应。例如，当一块被杀死的肌肉组织被包裹在胶囊(“扩散室”)中，允许分子而不是细胞扩散穿过它，并被植入皮下，它对周围的细胞没有诱导作用。但当囊孔允许细胞进入时，骨骼肌在坏死组织所在的地方形成，类似心肌的组织在囊外形成。吞噬作用是诱导发生的必要条件。

巨噬细胞通常被认为是“抗原提呈细胞”，帮助激活特定的免疫反应。但显然吞噬作用通过招募或诱导替代细胞的分化参与了受损组织的替代。吞噬功能并不局限于通常被称为吞噬细胞的血细胞;甚至神经细胞也能吸收受损组织的颗粒和碎片。

许多因素调节吞噬过程。应激和脂质过氧化降低了吞噬能力(Izgüt-Uysal, et al.， 2004)，也损害线粒体并抑制细胞更新。

Unsaturated fatty acids inhibit phagocytosis (Guimaraes, et al., 1991, 1992; Costa Rosa, et al., 1996; Virella, et al., 1989; Akamatsu, et al., 1990), and suppress mitochondrial function (Gomes, et al., 2006). Dietary restriction activates phagocytosis (Moriguchi, et al., 1989), suggesting that normal diets contain suppressive materials.

Subnormal temperatures cause a shift from phagocytosis to inflammation. Light, especially the red light which penetrates easily into tissues, activates the formation of new cells as well as their differentiation. It affects energy production, increasing the formation of mitochondria, and the activity of the DNA methyltransferase enzymes. Red light accelerates wound healing, and improves the quality of the scar, reducing the amount of fibrosis. The daily cycling between darkness and light is probably an important factor in regulating the birth and differentiation of cells.

Darkness suppresses mitochondrial function, and light activates it. Prolonged darkness increases cortisol, and cortisol (which makes cells more susceptible to excitotoxic death) inhibits stem cell proliferation (Li, et al., 2006; Liu, et al., 2003). Neurogenesis is suppressed by stress, and increased by spontaneous activity, and has a circadian rhythm. Aging and depression both involve a diminished ability to rhythmically lower the production of cortisol. Cell renewal requires a rhythmic decrease in the exposure to cortisol..

不饱和脂肪酸抑制吞噬作用(Guimaraes等，1991,1992;科斯塔·罗莎等，1996;Virella等，1989;Akamatsu等，1990)，并抑制线粒体功能(Gomes等，2006)。饮食限制会激活吞噬作用(Moriguchi等，1989)，表明正常饮食中含有抑制物质。

低于正常温度会导致吞噬转变为炎症。光，特别是容易穿透组织的红光，会激活新细胞的形成和分化。它影响能量生产，增加线粒体的形成和DNA甲基转移酶的活性。红光可以加速伤口愈合，改善疤痕的质量，减少纤维化。每天在黑暗和光明之间的循环可能是调节细胞的诞生和分化的重要因素。

黑暗抑制了线粒体功能，而光激活了它。长时间的黑暗会增加皮质醇，而皮质醇(使细胞更容易受到兴奋毒性死亡的影响)会抑制干细胞增殖(Li等人，2006;Liu等，2003)。神经发生受压力抑制，自发活动增加，并有昼夜节律。衰老和抑郁都与节律性地降低皮质醇分泌的能力有关。细胞更新需要有节奏地减少皮质醇的暴露。

In the spring, with increased day length, the brains of song-birds grow, with an increased proliferation of cells in the part of the brain involved in singing. The production of progesterone increases in most animals in the spring, and it is the main hormone responsible for the birds' brain growth.

Progesterone and its metabolites protect brain cells against injury, and improve the brain's ability to recover after traumatic injury (Brinton and Wang, 2006). In the 1960s, Marion Diamond's group showed that environmental enrichment, or progesterone, caused brains to grow larger, and that these changes were passed on to descendants in a cumulative, increasing way. This suggests that the factors that promote neurogenesis also cause changes in the apparatus of reproduction and inheritance, that support the development of the brain–probably including the methylation system, which is involved in regulating genes, and also mood and behavior.

在春天，随着白昼长度的增加，鸣禽的大脑也在生长，大脑中与鸣叫有关的部分的细胞增多。在春天，大多数动物体内的孕酮分泌都会增加，而孕酮是鸟类大脑发育的主要激素。

孕酮及其代谢物可以保护脑细胞免受损伤，提高创伤后大脑的恢复能力(Brinton和Wang, 2006)。20世纪60年代，马里恩·戴蒙德(Marion Diamond)的研究小组表明，环境富集或黄体酮会导致大脑变大，而且这些变化会以累积的、递增的方式传递给后代。这表明，促进神经发生的因素也会导致支持大脑发育的生殖和遗传器官的变化——可能包括甲基化系统，该系统涉及调节基因，也涉及情绪和行为。

Women's monthly cycles, in which a brief estrogen dominance is followed by sustained exposure to progesterone, are probably an important factor in the renewal of the cells of the brain and other organs, as well as those of the reproductive organs. The daily rhythms of hormones and metabolism are known to be involved in the regulation of cell renewal.

Environmental enrichment, learning, high altitude, and thyroid hormone promote the formation of new mitochondria, and stimulate stem cell proliferation. At least in some laboratories, 20% oxygen, approximately the amount as in the atmosphere, suppresses the proliferation of stem cells (He, et al., 2007). This was the unphysiologically high concentration of oxygen used in Hayflick's cell cultures. At high altitudes, where tissues are exposed to less oxygen, and more carbon dioxide, there is a lower incidence of all the degenerative diseases, including cancer, heart disease, and dementia. Improved cellular energy production and more active renewal of cells would probably account for those differences.

女性的月经周期可能是大脑和其他器官细胞以及生殖器官细胞更新的重要因素。在月经周期中，短暂的雌性激素占优势之后，持续接触孕酮。众所周知，激素和新陈代谢的日常节律与细胞更新的调节有关。

环境富集、学习、高海拔和甲状腺激素促进新的线粒体的形成，并刺激干细胞增殖。至少在一些实验室中，20%的氧气，大约相当于大气中的氧气量，抑制了干细胞的增殖(He, et al.， 2007)。这是海弗利克细胞培养中使用的非生理高浓度氧气。在高海拔地区，组织暴露在更少的氧气和更多的二氧化碳中，包括癌症、心脏病和痴呆症在内的所有退行性疾病的发病率都较低。改进的细胞能量生产和更积极的细胞更新可能是这些差异的原因。

For Crick, the idea of a diffusion gradient to explain embryonic development was simply an extension of his reductionist orientation, in which diffusing molecules induced or inhibited bacterial genes, and in which genes controlled cells. For people with that orientation, the adaptive mutations described by Carl Lindegren, and later by John Cairns, or even the stress-induced variability described by Lysenko, Strong, and McClintock, were heretical. Polezhaev's demonstration that cells could do something that molecular diffusion didn't do, threatened to take biology away from the reductionists. If the organism's adaptation to the environment involves changing its own genes, Crick's paradigm fails.

Crick's Central Dogma, derived from the ideology that produced Weismann's Barrier, has been invoked by generations of professors who wanted to deny the possibility of adaptive tissue renewal and regeneration. Without the dogma, new ideas about aging and disease will be needed. If somatic cells can adjust their genes, and if they can also differentiate into new eggs and sperms, new ideas about inheritance of acquired traits will be needed.

对于克里克来说，用扩散梯度来解释胚胎发育的想法仅仅是他还原主义倾向的延伸，在还原主义倾向中，扩散分子诱导或抑制细菌基因，基因控制细胞。对于具有这种取向的人来说，卡尔·林德格(Carl Lindegren)以及后来约翰·凯恩斯(John Cairns)所描述的适应性突变，甚至是李森科(Lysenko)、斯特朗(Strong)和麦克林托克(McClintock)所描述的压力诱导变异，都是异端邪说。波列扎耶夫证明了细胞可以做一些分子扩散做不到的事情，这威胁到了还原论者的生物学观点。如果生物体对环境的适应涉及到改变自己的基因，克里克的范例就失败了。

克里克的中心信条(Central教条)源自产生了韦斯曼的“屏障”(Barrier)理论的意识形态，被几代想要否认适应性组织更新和再生可能性的教授所援引。没有这些教条，我们就需要关于衰老和疾病的新观点。如果体细胞能调整它们的基因，如果它们也能分化成新的卵子和精子，那么关于后天性状遗传的新想法将是必要的。

The replacement of injured cells means that mutations need not accumulate. Cell renewal with elimination of mutant cells has been observed in sun-damaged skin simply by stopping the damage, and mitochondria with damaged DNA can be replaced by healthy mitochondria simply by doing the right kind of exercise.

The regulation of cell renewal probably involves all of the processes of life, but there are a few simple, interacting factors that suppress renewal. The accumulation of polyunsaturated fats, interacting with a high concentration of oxygen, damages mitochondria, and causes a chronic excessive exposure to cortisol. With mitochondrial damage, cells are unable to produce the progesterone needed to oppose cortisol and to protect cells.

Choosing the right foods, the right atmosphere, the right mental and physical activities, and finding the optimal rhythms of light, darkness, and activity, can begin to alter the streaming renewal of cells in all the organs. Designing a more perfect environment is going to be much simpler than the schemes of the genetic engineers.

受损细胞的替换意味着突变不需要累积。在被太阳晒伤的皮肤中，可以观察到通过消除突变细胞而实现的细胞更新，而带有受损DNA的线粒体可以通过适当的运动被健康的线粒体所替代。

细胞更新的调节可能涉及到生命的所有过程，但有一些简单的、相互作用的因素抑制了更新。多不饱和脂肪的积累，与高浓度的氧气相互作用，损害线粒体，并导致长期过度暴露于皮质醇。线粒体受损后，细胞无法产生对抗皮质醇和保护细胞所需的孕酮。

选择合适的食物，适当的氛围，适当的精神和身体活动，找到最佳的光、暗和活动节奏，可以开始改变所有器官细胞的流动更新。设计一个更完美的环境将比基因工程师的计划简单得多。

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