2434 lines
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2434 lines
167 KiB
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<head><title>Stem cells, cell culture, and culture: Issues in regeneration</title></head>
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<h1>
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Stem cells, cell culture, and culture: Issues in regeneration
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</h1>
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<p>
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Cell renewal is a factor in all aspects of health and disease, not just in aging and the degenerative
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diseases. Many people are doing valid research relating to cell renewal and regeneration, but its usefulness
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is seriously limited by cultural and commercial constraints. By recovering some of our suppressed
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traditional culture, I think regenerative therapies can be developed quickly, by identifying and eliminating
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as far as possible the main factors that interfere with tissue renewal.
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</p>
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<p>
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Science grew up in the highly authoritarian cultures of western Europe, and even as it contributed to
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cultural change, it kept an authoritarian mystique. Any culture functions as a system of definitions of
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reality and the limits of possibility, and to a great extent the "laws of nature" are decreed so that they
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will harmonize with the recognized laws of society.
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</p>
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<p>
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The practical success of Newton's "laws" of motion when they were applied to ballistics and "rocket science"
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has led many people to value calculation, based on those laws, over evidence. In biology, the idea that an
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organism is "the information it contains in its DNA blueprint" is an extention of this. The organism is
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turned into something like a deductive expression of the law of DNA. This attitude has been disastrous.
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</p>
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<p>
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The old feudal idea of a divine and stable social organization was applied by some people to their idea of
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biological organization, in which each cell (ruled by its nucleus) had its ordained place in the organism,
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with the brain and the "master gland," the pituitary, ruling the subordinate organs, tissues, and cells.
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"Anatomy" was taught from dead specimens, microscope slides, and illustrations in books. Most biologists'
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thoughts about cells in organisms reflect the static imagery of their instruction. (<em>"The histological
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image of these tissues actually reflects an instantaneous picture of cells in a continuous flux."</em>
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Zajicek, 1981.)
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</p>
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<p>
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When a person has playful and observant interactions with natural things, both regularities and
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irregularities will be noticed, and in trying to understand those events, the richness of the experience
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will suggest an expansive range of possibilities. Perception and experimentation lead to understandings that
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are independent of culture and tradition.
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</p>
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<p>
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But the mystique of science easily imposes itself, and distracts our attention from direct interactions with
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things. As we learn to operate lab instruments, we are taught the kinds of results that can be expected, and
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the concepts that will explain and predict the results of our operations. Science, as we learn about it in
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schools and the mass media, is mostly a set of catechisms.
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</p>
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<p>
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Our theories about organisms inform our experiments with cells or tissues that have been isolated from those
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organisms. The conditions for growing cells in dishes are thought of as "physiological," in relation to the
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solution's "physiological osmolarity," "physiological pH," nutrients, oxygenation, temperature, pressure,
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etc. But these concepts of what is physiological derive from the monolithic ideology of the doctrinaire, and
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often fraudulent, mainstream of biological science.
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</p>
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<p>
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The catechismic nature of science has led people to expect some "break-throughs" to occur in certain areas,
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and as authoritarian science has grown into "big science" managed by corporations and governments, those
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break-throughs are generally expected to be produced by the newest and most expensive developments of "high
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technology."
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</p>
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<p>
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But looking closely at the real events and processes in the sciences in the last couple of centuries, it
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turns out that useful advances have been produced mainly by breaking away from authoritarian doctrines, to
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return to common sense and relatively simple direct observations.
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</p>
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<p>
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Although people were cloning animals in the 1960s, it was still widely taught that it was impossible. The
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students of the professors who taught that it was impossible are now saying that it requires high technology
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and new research.
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</p>
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<p>
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For the last 100 years the most authoritative view in biology has been that there are no stem cells in
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adults, that brains, hearts, pancreases and oocytes are absolutely incapable of regeneration. But now,
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people seem to be finding stem cells wherever they look, but there is a mystique of high technology involved
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in finding and using them.
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</p>
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<p>
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Whether it's deliberate or not, the emphasis on stem cell technology has the function of directing attention
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away from traditional knowledge, the way allopathic medicine has de-emphasized the intrinsic ability of
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people to recover from disease.
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</p>
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<p>
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This resembles the way that the Mendel-Morgan gene doctrine was used to suppress the knowledge gained from
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centuries of experience of plant and animal breeders, and to belittle the discoveries of Luther Burbank,
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Paul Kammerer, Trofim Lysenko, and Barbara McClintock. The same type of biochemical process that caused the
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hereditary changes those researchers studied are involved in the differentiation and dedifferentiation of
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stem cells that regulate healing and regeneration.
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</p>
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<p>
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In the 1940s, even children discussed the biological discoveries of the 1920s and 1930s, the work in
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regeneration and adaptation, parthenogenesis, and immortalization. The ideas of J. Loeb, T. Boveri, A.
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Gurwitsch, J. Needham, C.M. Child, A. Carrel, et al., had become part of the general culture.
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</p>
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<p>
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But that real biology was killed by a consortium of industry and government that began a little before the
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second world war. In 1940, the government was supporting research in chemical and biological warfare, and
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with the Manhattan Project the role of government became so large that all of the major research
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universities were affected. Shortly after the war, many researchers from the Manhattan Project were
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redeployed into "molecular genetics," where the engineering attitude was applied to organisms.
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</p>
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<p>
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The simplistic genetic dogmas were compatible with the reductionist engineering approach to the organism.
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The role of the government assured that the universities would subscribe to the basic scientific agenda. The
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atmosphere of that time was described by Carl Lindegren as "The Cold War in Biology" (1966).
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</p>
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<p>
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The disappearance of the field concept in developmental biology was one of the strangest events in the
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history of science. It didn't just fade away, it was "disappeared," in a massive undertaking of social
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engineering. In its absence, stem cells will seem to be a profitable technological marvel, rather than a
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universal life function, with a central role in everything we are and everything we do and can become.
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</p>
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<p>
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Many people have tried to explain aging as a loss of cells, resulting from an intrinsic inability of any
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cell other than a germ cell to multiply more than a certain number of times. More than 40 years ago Leonard
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Hayflick popularized this doctrine in its most extreme form, saying that no cell can divide more than 50
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times unless it is converted into a cancer cell. He and his followers claimed that they had explained why
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organisms must age and die. At the moment the ovum is fertilized, the clock starts ticking for the
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essentially mortal somatic cells.
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</p>
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<p>
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In 1970, it was being seriously proposed that memory was produced by the death of brain cells, in a manner
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analogous to the holes punched in cards to enter data into computers. The cultural dogma made it impossible
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to consider that learning could be associated with the birth of new cells in the adult brain.
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</p>
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<p>
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With the announcement in 1997 of the cloning of the sheep Dolly from a somatic cell taken from a 6 year old
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sheep, there was renewed interest in the idea made famous by Alexis Carrel that all cells are potentially
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immortal, and in the possibility of preserving the vitality of human cells. Within a few months, Hayflick
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began reminding the public that "In the early 1960's we overthrew this dogma after finding that normal cells
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do have a finite replicative capacity." ("During the first half of this century it was believed that because
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cultured normal cells were immortal, aging must be caused by extra-cellular events.") The way Hayflick
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"overthrew" more than 35 years of work at the Rockefeller Institute was by growing one type of cell, a lung
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fibroblast, in culture dishes, and finding that the cultures deteriorated quickly.
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</p>
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<p>
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To draw global conclusions about an organism's development and aging from the degenerative processes seen in
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a single type of cell, grown in isolation from all normal stimuli, would have been treated as nothing but
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wild speculation, except that it occurred within a culture that needed it. No aspect of Hayflick's cell
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culture system could properly be called physiological.
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</p>
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<p>
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Other researchers, simply by changing a single factor, caused great increases in the longevity of the
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cultured cells. Simply using a lower, more natural oxygen concentration, the cells were able to undergo 20
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more divisions. Just by adding niacin, 30 more divisions; vitamin E, 70 more divisions. Excess oxygen is a
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poison requiring constant adaptation.
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</p>
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<p>
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Hayflick also published the observation that, while the cells kept in dishes at approximately body
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temperature deteriorated, cells kept frozen in liquid nitrogen didn't deteriorate, and he concluded that
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"time" wasn't the cause of aging. When I read his comments about the frozen cells, I wondered how anyone of
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normal intelligence could make such stupid statements. Since then, facts that came out because of the
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Freedom of Information Act, cause me to believe that a financial motive guided his thoughts about his
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cultured fibroblasts.
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</p>
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<p>
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Hayflick and his followers have been attacking the idea of anti-aging medicine as quackery. But he is
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closely involved with the Geron corporation, which proposes that genetic alterations relating to telomeres
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may be able to cure cancer and prevent aging. Their claims were reported by CNN as "Scientists discover
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cellular 'fountain of youth'."
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</p>
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<p>
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The "wear and tear" doctrine of aging that derived from the ideology of the gene was reinforced and renewed
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by Hayflick's cell culture observations, and it continued to rule the universities and popular culture.
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</p>
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<p>
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But detailed investigation of skin cell growth showed that cells in the lower layer of the skin divide at
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least 10,000 times in a normal lifetime, and similar processes occur in the lining of the intestine. The
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endometrium and other highly renewable tissues just as obviously violated Hayflick's limit. Transplantation
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experiments showed that pieces of mammary tissue or skin tissue could survive through ten normal lifetimes
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of experimental animals without suffering the effects of aging.
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</p>
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<p>
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Even the liver and adrenal gland are now known to be continuously renewed by "cell streaming," though at a
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slower rate than the skin, conjunctiva, and intestine. Neurogenesis in the brain is now not only widely
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accepted, it is even proposed as a mechanism to explain the therapeutic effects of antidepressants
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(Santarelli, et al., 2003).
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</p>
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<p>
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August Weismann's most influential doctrine said that "somatic cells are mortal, only the germline cells are
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immortal," but he based the doctrine on his mistaken belief that only the "germline" cells contained all the
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genes of the organism. In 1885, to "refute" Darwin's belief that acquired traits could be inherited, he
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promulgated an absolute "barrier" between "germline" and "soma," and invented facts to show that hereditary
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information can flow only from the germline to the somatic cells, and not the other direction. Shortly after
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DNA became popular in the 1950s as "the genetic material," Weismann's barrier was restated as the Central
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Dogma of molecular genetics, that information flows only from DNA to RNA to protein, and never the other
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direction.
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</p>
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<p>
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It was only in 2003, after the reality of cloning was widely recognized, that a few experimenters began to
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investigate the origin of "germline" cells in the ovary, and to discover that they derive from somatic cells
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(Johnson, et al., 2004). With this discovery, the ancient knowledge that a twig (<em>klon</em>, in Greek)
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cut from a tree could grow into a whole tree, bearing fruit and viable seeds, was readmitted to general
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biology, and the Weismann barrier was seen to be an illusion.
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</p>
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<p>
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Millions of people have "explained" female reproductive aging as the consequence of the ovary "running out
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of eggs." Innumerable publications purported to show the exact ways in which that process occurs, following
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the Weismann doctrine. But now that it is clear that adult ovaries can give birth to new oocytes, a new
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explanation for female reproductive aging is needed. It is likely that the same factors that cause female
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reproductive aging also cause aging of other systems and organs and tissues, and that those factors are
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extrinsic to the cells themselves, as Alexis Carrel and others demonstrated long ago. This is a way of
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saying that all cells are potential stem cells. The "niche" in which new cells are born in the streaming
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organism, and the processes by which damaged cells are removed, are physiological issues that can be
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illuminated by the idea of a morphogenetic field.
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</p>
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<p>
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When the post-war genetic engineers took over biological research, the idea of a biophysical field was
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totally abandoned, but after about 15 years, it became necessary to think of problems beyond those existing
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within a single bacterium, namely, the problem of how an ovum becomes and embryo. Francis Crick, of DNA
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fame, who was educated as a physicist, revived (without a meaningful historical context) the idea of a
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diffusion gradient as a simple integrating factor that wouldn't be too offensive to the reductionists. But
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for events far beyond the scale of the egg's internal structure, for example to explain how a nerve axon can
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travel a very long distance to innervate exactly the right kind of cell, the diffusion of molecules loses
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its simplicity and plausibility. (Early in the history of experimental embryology, it was observed that
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electrical fields affect the direction of growth of nerve fibers.)
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</p>
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<p>
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C. M. Child saw a gradient of metabolic activity as an essential component of the morphogenetic field. This
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kind of gradient doesn't deny the existence of diffusion gradients, or other physical components of a field.
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Electrical and osmotic (and electro-osmotic) events are generated by metabolism, and affect other factors,
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including pH, oxidation and reduction, cell motility and cell shape, ionic selectivity and other types of
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cellular selectivity and specificity. Gradients of DNA methylation exist, and affect the expression of
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inherited information.
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</p>
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<p>
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Methylation decreases the expression of particular genes, and during the differention of cells in the
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development of an embryo, genes are methylated and demethylated as the cell adapts to produce the proteins
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that are involved in the structure and function of a particular tissue. Methylation (which increases a
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molecule's affinity for fats) is a widespread process in cells, and for example regulates cellular
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excitability. It is affected by diet and a variety of stresses.
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</p>
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<p>
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DNA methylation patterns are normally fairly stable, and can help to account for the transgenerational
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transmission of acquired adaptations, and for neonatal imprinting that can last a lifetime. But with injury,
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stress, and aging, the methylation patterns of differentiated tissues can be changed, contributing to the
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development of tumors, or to the loss of cellular functions. Even learning can change the methylation of
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specific genes. During <em>in vitro</em> culture, the enzymes of gene methylation are known to be increased,
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relative to their normal activity (Wang, et al., 2005).
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</p>
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<p>
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The phenomenon of "gene" methylation in response to environmental and metabolic conditions may eventually
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lead to the extinction of the doctrine that "cells are controlled by their genes."
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</p>
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<p>
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During successful adaptation to stress, cells make adjustments to their metabolic systems (for example with
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a holistic change of the degree of phosphorylation, which increases molecules' affinity for water), and
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their metabolic processes can contribute to changes in their state of differentiation. Some changes may lead
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to successful adaptation (for example by producing biogenic stimulators that stimulate cell functioning and
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regeneration), others to failed adaptation. Even the decomposition of cells can release substances that
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contribute to the adaptation of surrounding cells, for example when sphingosines stimulate the production of
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stem cells.
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</p>
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<p>
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DNA methylation is just one relatively stable event that occurs in relation to a metabolic field.
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Modifications of histones (regulatory proteins in chromosomes, which are acetylated as well as methylated)
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and structural-contractile filaments also contribute to the differentiation of cells, but the pattern of DNA
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methylation seems to guide the methylation of histones and the structure of the chromosomes (Nan, et al.,
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1998).
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</p>
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<p>
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Steroids and phospholipids, neurotransmitters and endorphins, ATP, GTP, other phosphates, retinoids, NO and
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CO2--many materials and processes participate in the coherence of the living state, the living substance.
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Carbon dioxide, for example, by binding to lysine amino groups in the histones, will influence their
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methylation. Carbon dioxide is likely to affect other amino groups in the chromosomes.
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</p>
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<p>
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The number and arrangement of mitochondria is an important factor in producing and maintaining the metabolic
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gradients. Things that decrease mitochondrial energy production--nitric oxide, histamine, cytokines,
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cortisol--increase DNA methylation. Decreased gene expression is associated with reduced respiratory energy.
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It seems reasonable to guess that increased gene expression would demand increased availability of energy.
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</p>
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<p>
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As an ovum differentiates into an organism, cells become progressively more specialized, inhibiting the
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expression of many genes. Less energy is needed by stably functioning cells, than by actively adapting
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cells. A.I. Zotin described the process of maturing and differentiating as a decrease of entropy, an
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increase of order accompanying a decreased energy expenditure. The entropic egg develops into a less
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entropic embryo with a great expenditure of energy.
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</p>
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<p>
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The partially differentiated stem cell doesn't go through all the stages of development, but it does expend
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energy intensely as it matures.
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</p>
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<p>
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The restoration of energy is one requirement for the activation of regeneration. When a hormone such as
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noradrenaline or insulin causes a stem cell to differentiate in vitro, it causes new mitochondria to form.
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This is somewhat analogous to the insertion of mitochondria into the ripening oocyte, by the nurse cells
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that surround it. The conditionally decreased entropy of maturation is reversed, and when sufficient
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respiratory energy is available, the renewed and refreshed cell will be able to renew an appropriate degree
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of differentiation.
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</p>
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<p>
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When simple organisms, such as bacteria, fungi, or protozoa are stressed, for example by the absence of
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nutrients or the presence of toxins, they slow their metabolism, and suppress the expression of genes,
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increasing the methylation of DNA, to form resistant and quiescent spores. Our differentiated state doesn't
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go to the metabolic extreme seen in sporulation, but it's useful to look at maturity and aging in this
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context, because it suggests that the wrong kind of stress decreases the ability of the organism to adapt,
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by processes resembling those in the spore-forming organisms.
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</p>
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<p>
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Charles Vacanti, who has grown cartilage from cells taken from 100 year old human cartilage, believes our
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tissues contain "spore cells," very small cells with slow metabolism and extreme resistance to heat, cold,
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and starvation.
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</p>
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<p>
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If the slowed metabolism of aging, like that of sporulating cells, is produced by a certain kind of stress
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that lowers cellular energy and functions, it might be useful to think of the other stages of the stress
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reaction in relation to the production of stem cells. Selye divided stress into a first stage of shock,
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followed by a prolonged adaptation, which could sometimes end in exhaustion. If the maturity of
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differentiated functioning is equivalent to the adaptation phase, and cellular decline and disintegration is
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the exhaustion phase, then the shock-like reaction would correspond to the birth of new stem cells.
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</p>
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<p>
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Selye described estrogen's effects as equivalent to the shock-phase of stress. Estrogen's basic action is to
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make oxygen unavailable, lowering the oxygen tension of the tissues, locally and temporarily. Like nitric
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oxide, which is produced by estrogenic stimulation, estrogen interferes with energy production, so if its
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stimulation is prolonged, cells are damaged or killed, rather than being stimulated to regenerate.
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</p>
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<p>
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Extrinsic factors elicit renewal, the way stress can elicit adaptation. While aging cells can't use the
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oxygen that is present, a scarcity of oxygen can serve as a stimulus to maximize the respiratory systems.
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Brief oxygen deprivation excites a cell, causes it to swell, and to begin to divide.
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</p>
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<p>
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Oxygen deprivation, as in the normally hypoxic bone marrow, stimulates the formation of stem cells, as well
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as the biogenesis of mitochondria. As the newly formed cells, with abundant mitochondria, get adequate
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oxygen, they begin differentiation.
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</p>
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<p>
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Form, based on cellular differentiation, follows function--a vein transplanted into an artery develops
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anatomically into an artery, a colon attached directly to the anus becomes a new rectum with its appropriate
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innervation, a broken bone restructures to form a normal bone. If the bladder is forced to function more
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than normal, by artificially keeping it filled, its thin wall of smooth muscle develops into a thick wall of
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striated muscle that rhythmically contracts, like the heart. If a tadpole is given a vegetarian diet, the
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absorptive surface of its digestive system will develop to be twice the size of those that are fed meat.
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Pressure, stretching, and pulsation are among the signals that guide cells' differentiation.
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</p>
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<p>
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Very early in the study of embryology it was noticed that the presence of one tissue sometimes induced the
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differentiation of another kind, and also that there were factors in embryonic tissues that would stimulate
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cell division generally, and others that could inhibit the growth of a particular tissue type. Diffusable
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substances and light were among the factors identified as growth regulators.
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</p>
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<p>
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Extracts of particular tissues were found to suppress the multiplication of cells in that type of tissue, in
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adult animals as well as in embryos. In the 1960s, the tissue-specific inhibitors were called chalones.
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</p>
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<p>
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The brain's development is governed by the presence in the organism of the body part to which it
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corresponds, such as the eyes or legs. The number of cells in a particular part of the nervous system is
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governed by the quantity of nervous input, sensory or motor, that it receives. An enriched environment
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causes a bigger brain to grow. Sensory nerve stimulation of a particular region of the brain causes nerve
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cells to migrate to that area (a process called neurobiotaxis; deBeers, 1927), but nerve stimulation also
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causes mitochondria to accumulate in stimulated areas. Nerve activity has a trophic, sustaining influence on
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other organs, as well as on the brain. Nerve stimulation, like mechanical pressure or stretching, is an
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important signal for cellular differentiation.
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</p>
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<p>
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When stem cells or progenitor cells are called on to replace cells in an organ, they are said to be
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"recruited" by that organ, or to "home" to that organ, if they are coming from elsewhere. Traditionally, the
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bone marrow has been considered to be the source of circulating stem cells, but it now appears that a
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variety of other less differentiated cells can be recruited when needed. Cells from the blood can repair the
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endothelium of blood vessels, and endothelial cells can become mesenchymal cells, in the heart, for example.
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</p>
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<p>
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The standard doctrine about cancer is that a tumor derives from a single mutant cell, but it has been known
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for a long time that different types of cell, such as phagocytes and mast cells, usually reside in tumors,
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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.
|
|
</p>
|
|
<p>
|
|
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)
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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 <em>determination</em> 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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
Many factors regulate the process of phagocytosis. Stress and lipid peroxidation decrease phagocytosis
|
|
(Izg"t-Uysal, et al., 2004), and also damage mitochondria and inhibit cell renewal.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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..
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p><h3>REFERENCES</h3></p>
|
|
<p>
|
|
Growth 43, 58-61, 1979. <strong>The effect of progesterone on brain and body growth of chick
|
|
embryos.</strong> G. Ahmad and S. Zamenhof. [This showed that progesterone, added during the time of
|
|
active neuronal proliferation, increased the chicks' brain weight, while the stress hormone, corticosterone,
|
|
reduced the weight.]
|
|
</p>
|
|
|
|
<p>
|
|
J Invest Dermatol. 1990 Sep;95(3):271-4. <strong>Suppressive effects of linoleic acid on neutrophil oxygen
|
|
metabolism and phagocytosis.</strong> Akamatsu H, Komura J, Miyachi Y, Asada Y, Niwa Y.
|
|
</p>
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|
<p>
|
|
Curr Alzheimer Res. 2006 Feb;3(1):11-7. <strong>Preclinical analyses of the therapeutic potential of
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|
allopregnanolone to promote neurogenesis in vitro and in vivo in transgenic mouse model of Alzheimer's
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|
disease.</strong> Brinton RD, Wang JM. "Herein, we present data to support a preclinical proof of
|
|
concept for the therapeutic potential of allopregnanolone to promote neurogenesis. Our recent work has
|
|
demonstrated that the neuroactive progesterone metabolite, allopregnanolone
|
|
(3alpha-hydroxy-5alpha-pregnan-20-one), (APalpha) induced, in a dose dependent manner, a significant
|
|
increase in proliferation of neuroprogenitor cells (NPCs) derived from the rat hippocampus and human neural
|
|
stem cells (hNSM) derived from the cerebral cortex [1]." "The in vitro and in vivo neurogenic properties of
|
|
APalpha coupled with a low molecular weight, easy penetration of the blood brain barrier and lack of
|
|
toxicity, are key elements required for developing APalpha as a neurogenic / regenerative therapeutic for
|
|
restoration of neurons in victims of Alzheimer's disease."
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|
</p>
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|
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|
<p>
|
|
Arch Biochem Biophys. 1996 Jan 1;325(1):107-12.<strong>
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|
Thyromimetic action of the peroxisome proliferators clofibrate, perfluorooctanoic acid, and
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|
acetylsalicylic acid includes changes in mRNA levels for certain genes</strong>
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|
<strong>
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|
involved in mitochondrial biogenesis.</strong> Cai Y, Nelson BD, Li R, Luciakova K, dePierre JW.
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</p>
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<p>
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Biochem Mol Biol Int. 1996 Nov;40(4):833-42. <strong>The effect of N-3 PUFA rich diet upon macrophage and
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|
lymphocyte metabolism and function.</strong> Costa Rosa LF, Safi DA, Guimar"es AR.
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</p>
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<p>
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|
G. R. de Beer, <strong><em>An Introducton to Experimental Embryology,</em></strong>
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|
Oxford, 1926.
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</p>
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<p>
|
|
Biol. Rev. 1927;2:137-197, <strong>The mechanics of verterate development. </strong>
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de Beer GR.
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|
</p>
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<p>
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|
Vrach delp. 1937, 20: 803-820. <strong>Summary of 20 years' achievements in ophthalmology.</strong>
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Filatov VP.
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</p>
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|
<p>
|
|
Vestnik oftal. 1938, 12: 107-159.<strong>
|
|
Tissue transplantation in intra-ocular diseases.</strong> Filatov VP.
|
|
</p>
|
|
|
|
<p>
|
|
Med zhur 1937, 9: 847-853.<strong>
|
|
Intramuscular injections of cod liver oil in therapy of pigmented retinitis.</strong> Filatov VP,
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|
Verbitska E A.
|
|
</p>
|
|
<p>
|
|
Am Rev Soviet Med. 1946, 3: 388-395.<strong>
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|
The treatment of retinitis pigmentosa with intramuscular injection of cod liver oil.</strong>
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|
Filatov VP, Verbitska EA.
|
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</p>
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|
<p>
|
|
Am Rev Soviet Med 1946, 3: 395-397. <strong>Retinitis pigmentosa.</strong> Filatov VP.
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|
</p>
|
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|
<p>
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|
Am Rev Soviet Med 1946, 3: 397-398.<strong>
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The implantation of preserved placenta in retinitis pigmentosa.</strong> Filatov VP Verbitska EA.
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</p>
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<p>
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|
Hippocampus. 2006;16(3):225-32.<strong>
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Gonadal hormone modulation of hippocampal neurogenesis in the adult.
|
|
</strong>Galea LA, Spritzer MD, Barker JM, Pawluski JL. <strong>
|
|
Estradiol, the most potent estrogen, initially enhances and subsequently suppresses cell proliferation
|
|
in the dentate gryus of adult female rodents.</strong>
|
|
</p>
|
|
<p>
|
|
Glia. 1999 Feb 1;25(3):247-55. <strong>Cerebellar astrocytes treated by thyroid hormone modulate neuronal
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|
proliferation.</strong> Gomes FC, Maia CG, de Menezes JR, Neto VM. "Thyroid hormones are important for
|
|
neurogenesis and gliogenesis during brain development. We have previously demonstrated that triiodothyronine
|
|
(T3) treatment induced proliferation in primary culture astrocytes derived from the cerebellum of neonatal
|
|
rats." "Interestingly, the cerebellar neuronal population increased by 60-80% in T3CM."
|
|
</p>
|
|
<p>
|
|
Biochem Int. 1992 Jun;27(1):9-16. <strong>Metabolic and functional changes in macrophages of rats fed
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polyunsaturated or saturated fatty acid rich-diets during ageing.
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</strong>Guimar"es AR, Costa Rosa LF, Safi DA, Curi R.
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</p>
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<p>
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|
Biochem Int. 1991 Feb;23(3):533-43. <strong>Effect of polyunsaturated (PUFA n-6) and saturated fatty
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|
acids-rich diets on macrophage metabolism and function.</strong>
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Guimar"es AR, Costa Rosa LF, Sitnik RH, Curi R.
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</p>
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<p>
|
|
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2007 Apr;15(2):433-6. <strong>[Effect of hypoxia on mesenchymal stem
|
|
cells - review.]</strong> [Article in Chinese] He MC, Li J, Zhao CH.
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</p>
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|
<p>
|
|
Nat Rev Cancer. 2007 Apr;7(4):246-55. <strong>Reprogramming metastatic tumour cells with embryonic
|
|
microenvironments.</strong> Hendrix MJ, Seftor EA, Seftor RE, Kasemeier-Kulesa J, Kulesa PM, Postovit
|
|
LM. "Aggressive tumour cells share many characteristics with embryonic progenitors, contributing to the
|
|
conundrum of tumour cell plasticity." "This Review will summarize the embryonic models used to reverse the
|
|
metastatic melanoma phenotype, and highlight the prominent signalling pathways that have emerged as
|
|
noteworthy targets for future consideration."
|
|
</p>
|
|
<p>
|
|
FEBS Lett. 1973 May 15;32(1):1-8.<strong>
|
|
Chalones. Specific endogenous mitotic inhibitors.</strong> Houck JC, Hennings H.
|
|
</p>
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|
<p>
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|
Med Hypotheses. 2005;64(6):1138-43. <strong>Melatonin seems to be a mediator that transfers the
|
|
environmental stimuli to oocytes for inheritance of adaptive changes through epigenetic inheritance
|
|
system.</strong> Irmak MK, Topal T, Oter S.
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|
</p>
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|
|
|
<p>
|
|
Nature. 2007 May 17;447(7142):316-20. <strong>Wnt-dependent de novo hair follicle regeneration in adult
|
|
mouse skin after wounding.
|
|
</strong>
|
|
Ito M, Yang Z, Andl T, Cui C, Kim N, Millar SE, Cotsarelis G.
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</p>
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|
<p>
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|
Cell Biol Int. 2004;28(7):517-21. <strong>Effect of stress-induced lipid peroxidation on functions of rat
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|
peritoneal macrophages.</strong> Izg"t-Uysal VN, Tan R, B"lb"l M, Derin N.
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|
</p>
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|
<p>
|
|
J Cereb Blood Flow Metab. 2007 Mar 28;<strong>
|
|
Regeneration and plasticity in the brain and spinal cord.</strong> Johansson BB.
|
|
</p>
|
|
|
|
<p>
|
|
Nature, 428, 145 - 150, (2004). Johnson, J., Canning, J., Kaneko, T., Pru, J.K. & Tilly, J.L.
|
|
</p>
|
|
<p>
|
|
Annals of Ophthalmology No. 1, 2005, p. 54, <strong>Life devoted to fight against blindness</strong> (on the
|
|
130th birthday anniversary of V. P. Filatov) Knopov M. Sh., Klyasov A. V.
|
|
</p>
|
|
<p>
|
|
R. Levi-Montalcini, <strong>"Neuronal regeneration in vitro," </strong>
|
|
pages 54-65 in Windle,<em> Regeneration in the Central Nervous System,</em>
|
|
|
|
C. C. Thomas, 1955.
|
|
</p>
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|
<p>
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|
Neurobiol Aging. 2006 Nov;27(11):1705-14. Epub 2005 Nov 4.<strong>
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Salivary cortisol and memory function in human aging.</strong> Li G, Cherrier MM, Tsuang DW, Petrie EC,
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|
Colasurdo EA, Craft S, Schellenberg GD, Peskind ER, Raskind MA, Wilkinson CW.
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</p>
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<p>
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|
Med Hypotheses. 2007 Mar 27; [Epub ahead of print] <strong>Effects of hypoxia on proliferation and
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|
differentiation of myoblasts.</strong> Li X, Zhu L, Chen X, Fan M.
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</p>
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<p>
|
|
Exp Neurol. 2003 Nov;184(1):196-213. <strong>Suppression of hippocampal neurogenesis is associated with
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|
developmental stage, number of perinatal seizure episodes, and glucocorticosteroid level.</strong> Liu
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|
H, Kaur J, Dashtipour K, Kinyamu R, Ribak CE, Friedman LK.
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|
</p>
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|
|
|
<p>
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|
J Nutr Sci Vitaminol (Tokyo). 1989 Feb;35(1):49-59.<strong>
|
|
Effects of dietary restriction on cellular immunity in rats.</strong> Moriguchi S, Toba M, Kishino Y.
|
|
</p>
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|
<p>
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|
Nature. 1998 May 28;393(6683):386-9. <strong>Transcriptional repression by the methyl-CpG-binding protein
|
|
MeCP2 involves a histone deacetylase complex.</strong> Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM,
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|
Eisenman RN, Bird A.
|
|
</p>
|
|
<p>
|
|
L. V. Polezhaev and E. N. Karnaukhova, <strong>"Stimulation of physiologic regeneration of nervous tissue of
|
|
the cerebral cortex and its significance for biogenic therapy of neuro-mental diseases," pages 86-116 in
|
|
</strong>
|
|
|
|
<em>Sbornik: Klinicheskie eksperimentalnye osnovy biogennoi terapii psikhozov</em>,<strong> </strong>
|
|
1962.
|
|
</p>
|
|
<p>
|
|
Doklady AN SSSR 150, 430-433, 1963., <strong>"Stimulation of nerve cell reproduction of cerebral cortex in
|
|
mammals,"</strong> L. V. Polezhaev and E. N. Karnaukhove
|
|
</p>
|
|
<p>
|
|
L. V. Polezhaev, <strong><em>Loss and Restoration of Regenerative Capacity in Tissues and Organs of
|
|
Animals,</em></strong> page 219, 1972.
|
|
</p>
|
|
|
|
<p>
|
|
J Hirnforsch 1991;32(5):659-664. <strong>Normalization of protein synthesis and the structure of brain
|
|
dystrophic neurons after the action of hypoxia, 10% NaCl and organ-specific RNA.</strong> Polezhaev LV,
|
|
Cherkasova LV, Vitvitsky VN, Timonin AV <strong>"Transplantation of embryonic nervous tissue (ENT) in one of
|
|
the hemispheres normalizes all the above abnormalities observed in some neurologic and mental diseases
|
|
in humans."</strong>
|
|
<strong>
|
|
"At the beginning 10% NaCl increased the destruction of brain cortical neurons and then stimulated
|
|
protein synthesis in them.</strong> RNA injections stimulated the synthesis in cortical neurons and
|
|
normalized their structure. Thus, we propose a safe and simple method for normalization of dystrophic
|
|
neurons which can be used after certain improvement for curing neurodegenerative and neuropsychic diseases
|
|
in humans."
|
|
</p>
|
|
<p>
|
|
Science. 2003 Aug 8;301(5634):757. <strong>Requirement of hippocampal neurogenesis for the behavioral
|
|
effects of antidepressants.</strong> Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S,
|
|
Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R.
|
|
</p>
|
|
|
|
<p>
|
|
Chin J Traumatol. 2002 Aug;5(4):246-9. <strong>Experimental study on He-Ne laser irradiation to inhibit scar
|
|
fibroblast growth in culture.</strong>
|
|
Shu B, Wu Z, Hao L, Zeng D, Feng G, Lin Y.
|
|
</p>
|
|
<p>
|
|
J Cell Biochem 2001; 80:455-60.<strong>
|
|
Identification and initial characterization of spore-like cells in adult mammals.</strong> Vacanti, M.
|
|
P., A. Roy, J. Cortiella, L. Bonassar, and C. A. Vacanti.
|
|
</p>
|
|
<p>
|
|
Am J Ophthalmol 1947, 30: 635-636. <strong>Biogenic Stimulators.</strong> (Editorial) Vail D.
|
|
</p>
|
|
|
|
<p>
|
|
Clin Immunol Immunopathol. 1989 Aug;52(2):257-70.<strong>
|
|
Depression of humoral responses and phagocytic functions in vivo and in vitro by fish oil and
|
|
eicosapentanoic acid.</strong> Virella G, Kilpatrick JM, Rugeles MT, Hyman B, Russell R.
|
|
</p>
|
|
<p>
|
|
Reprod Biomed Online. 2005 May;10(5):607-16.<strong>
|
|
Gene expression in the preimplantation embryo: in-vitro developmental changes.
|
|
</strong>
|
|
Wang S, Cowan CA, Chipperfield H, Powers RD.
|
|
</p>
|
|
<p>
|
|
Tissue Eng. 2006 Oct 1; [Epub ahead of print]<strong>
|
|
Effects of Glutamine, Glucose, and Oxygen Concentration on the Metabolism and Proliferation of Rabbit
|
|
Adipose-Derived Stem Cells.</strong> Follmar KE, Decroos FC, Prichard HL, Wang HT, Erdmann D, Olbrich
|
|
KC.
|
|
</p>
|
|
|
|
<p>
|
|
J Urol. 2007 Apr;177(4):1568-72. <strong>Over expression of stem cell homing cytokines in urogenital organs
|
|
following vaginal distention.</strong> Woo LL, Hijaz A, Kuang M, Penn MS, Damaser MS, Rackley RR.
|
|
</p>
|
|
<p>
|
|
Med Hypotheses. 1981 Oct;7(10):1241-51. <strong>The histogenesis of glandular neoplasia.</strong> Zajicek G.
|
|
</p>
|
|
<h1>
|
|
<strong>Stem cells, cell culture, and culture: Issues in regeneration
|
|
</strong>
|
|
</h1>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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. (<em>"The histological
|
|
image of these tissues actually reflects an instantaneous picture of cells in a continuous flux."</em>
|
|
Zajicek, 1981.)
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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."
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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).
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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'."
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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).
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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 (<em>klon</em>, 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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.)
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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 <em>in vitro</em> culture, the enzymes of gene methylation are known to be increased,
|
|
relative to their normal activity (Wang, et al., 2005).
|
|
</p>
|
|
|
|
<p>
|
|
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."
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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).
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
The partially differentiated stem cell doesn't go through all the stages of development, but it does expend
|
|
energy intensely as it matures.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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)
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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 <em>determination</em> 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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
Many factors regulate the process of phagocytosis. Stress and lipid peroxidation decrease phagocytosis
|
|
(Izg"t-Uysal, et al., 2004), and also damage mitochondria and inhibit cell renewal.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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..
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p><h3>REFERENCES</h3></p>
|
|
<p>
|
|
Growth 43, 58-61, 1979. <strong>The effect of progesterone on brain and body growth of chick
|
|
embryos.</strong> G. Ahmad and S. Zamenhof. [This showed that progesterone, added during the time of
|
|
active neuronal proliferation, increased the chicks' brain weight, while the stress hormone, corticosterone,
|
|
reduced the weight.]
|
|
</p>
|
|
|
|
<p>
|
|
J Invest Dermatol. 1990 Sep;95(3):271-4. <strong>Suppressive effects of linoleic acid on neutrophil oxygen
|
|
metabolism and phagocytosis.</strong> Akamatsu H, Komura J, Miyachi Y, Asada Y, Niwa Y.
|
|
</p>
|
|
<p>
|
|
Curr Alzheimer Res. 2006 Feb;3(1):11-7. <strong>Preclinical analyses of the therapeutic potential of
|
|
allopregnanolone to promote neurogenesis in vitro and in vivo in transgenic mouse model of Alzheimer's
|
|
disease.</strong> Brinton RD, Wang JM. "Herein, we present data to support a preclinical proof of
|
|
concept for the therapeutic potential of allopregnanolone to promote neurogenesis. Our recent work has
|
|
demonstrated that the neuroactive progesterone metabolite, allopregnanolone
|
|
(3alpha-hydroxy-5alpha-pregnan-20-one), (APalpha) induced, in a dose dependent manner, a significant
|
|
increase in proliferation of neuroprogenitor cells (NPCs) derived from the rat hippocampus and human neural
|
|
stem cells (hNSM) derived from the cerebral cortex [1]." "The in vitro and in vivo neurogenic properties of
|
|
APalpha coupled with a low molecular weight, easy penetration of the blood brain barrier and lack of
|
|
toxicity, are key elements required for developing APalpha as a neurogenic / regenerative therapeutic for
|
|
restoration of neurons in victims of Alzheimer's disease."
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|
</p>
|
|
|
|
<p>
|
|
Arch Biochem Biophys. 1996 Jan 1;325(1):107-12.<strong>
|
|
Thyromimetic action of the peroxisome proliferators clofibrate, perfluorooctanoic acid, and
|
|
acetylsalicylic acid includes changes in mRNA levels for certain genes</strong>
|
|
<strong>
|
|
involved in mitochondrial biogenesis.</strong> Cai Y, Nelson BD, Li R, Luciakova K, dePierre JW.
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</p>
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<p>
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|
Biochem Mol Biol Int. 1996 Nov;40(4):833-42. <strong>The effect of N-3 PUFA rich diet upon macrophage and
|
|
lymphocyte metabolism and function.</strong> Costa Rosa LF, Safi DA, Guimar"es AR.
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|
</p>
|
|
<p>
|
|
G. R. de Beer, <strong><em>An Introducton to Experimental Embryology,</em></strong>
|
|
|
|
Oxford, 1926.
|
|
</p>
|
|
<p>
|
|
Biol. Rev. 1927;2:137-197, <strong>The mechanics of verterate development. </strong>
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|
de Beer GR.
|
|
</p>
|
|
<p>
|
|
Vrach delp. 1937, 20: 803-820. <strong>Summary of 20 years' achievements in ophthalmology.</strong>
|
|
Filatov VP.
|
|
</p>
|
|
<p>
|
|
Vestnik oftal. 1938, 12: 107-159.<strong>
|
|
Tissue transplantation in intra-ocular diseases.</strong> Filatov VP.
|
|
</p>
|
|
|
|
<p>
|
|
Med zhur 1937, 9: 847-853.<strong>
|
|
Intramuscular injections of cod liver oil in therapy of pigmented retinitis.</strong> Filatov VP,
|
|
Verbitska E A.
|
|
</p>
|
|
<p>
|
|
Am Rev Soviet Med. 1946, 3: 388-395.<strong>
|
|
The treatment of retinitis pigmentosa with intramuscular injection of cod liver oil.</strong> Filatov
|
|
VP, Verbitska EA.
|
|
</p>
|
|
<p>
|
|
Am Rev Soviet Med 1946, 3: 395-397. <strong>Retinitis pigmentosa.</strong> Filatov VP.
|
|
</p>
|
|
|
|
<p>
|
|
Am Rev Soviet Med 1946, 3: 397-398.<strong>
|
|
The implantation of preserved placenta in retinitis pigmentosa.</strong> Filatov VP Verbitska EA.
|
|
</p>
|
|
<p>
|
|
Hippocampus. 2006;16(3):225-32.<strong>
|
|
Gonadal hormone modulation of hippocampal neurogenesis in the adult.
|
|
</strong>Galea LA, Spritzer MD, Barker JM, Pawluski JL. <strong>
|
|
Estradiol, the most potent estrogen, initially enhances and subsequently suppresses cell proliferation
|
|
in the dentate gryus of adult female rodents.</strong>
|
|
</p>
|
|
<p>
|
|
Glia. 1999 Feb 1;25(3):247-55. <strong>Cerebellar astrocytes treated by thyroid hormone modulate neuronal
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|
proliferation.</strong> Gomes FC, Maia CG, de Menezes JR, Neto VM. "Thyroid hormones are important for
|
|
neurogenesis and gliogenesis during brain development. We have previously demonstrated that triiodothyronine
|
|
(T3) treatment induced proliferation in primary culture astrocytes derived from the cerebellum of neonatal
|
|
rats." "Interestingly, the cerebellar neuronal population increased by 60-80% in T3CM."
|
|
</p>
|
|
<p>
|
|
Biochem Int. 1992 Jun;27(1):9-16. <strong>Metabolic and functional changes in macrophages of rats fed
|
|
polyunsaturated or saturated fatty acid rich-diets during ageing.
|
|
</strong>Guimar"es AR, Costa Rosa LF, Safi DA, Curi R.
|
|
</p>
|
|
<p>
|
|
Biochem Int. 1991 Feb;23(3):533-43. <strong>Effect of polyunsaturated (PUFA n-6) and saturated fatty
|
|
acids-rich diets on macrophage metabolism and function.</strong>
|
|
Guimar"es AR, Costa Rosa LF, Sitnik RH, Curi R.
|
|
</p>
|
|
<p>
|
|
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2007 Apr;15(2):433-6. <strong>[Effect of hypoxia on mesenchymal stem
|
|
cells - review.]</strong>
|
|
|
|
[Article in Chinese] He MC, Li J, Zhao CH.
|
|
</p>
|
|
<p>
|
|
Nat Rev Cancer. 2007 Apr;7(4):246-55. <strong>Reprogramming metastatic tumour cells with embryonic
|
|
microenvironments.</strong> Hendrix MJ, Seftor EA, Seftor RE, Kasemeier-Kulesa J, Kulesa PM, Postovit
|
|
LM. "Aggressive tumour cells share many characteristics with embryonic progenitors, contributing to the
|
|
conundrum of tumour cell plasticity." "This Review will summarize the embryonic models used to reverse the
|
|
metastatic melanoma phenotype, and highlight the prominent signalling pathways that have emerged as
|
|
noteworthy targets for future consideration."
|
|
</p>
|
|
<p>
|
|
FEBS Lett. 1973 May 15;32(1):1-8.<strong>
|
|
Chalones. Specific endogenous mitotic inhibitors.</strong> Houck JC, Hennings H.
|
|
</p>
|
|
|
|
<p>
|
|
Med Hypotheses. 2005;64(6):1138-43. <strong>Melatonin seems to be a mediator that transfers the
|
|
environmental stimuli to oocytes for inheritance of adaptive changes through epigenetic inheritance
|
|
system.</strong> Irmak MK, Topal T, Oter S.
|
|
</p>
|
|
<p>
|
|
Nature. 2007 May 17;447(7142):316-20. <strong>Wnt-dependent de novo hair follicle regeneration in adult
|
|
mouse skin after wounding.
|
|
</strong>
|
|
Ito M, Yang Z, Andl T, Cui C, Kim N, Millar SE, Cotsarelis G.
|
|
</p>
|
|
<p>
|
|
Cell Biol Int. 2004;28(7):517-21. <strong>Effect of stress-induced lipid peroxidation on functions of rat
|
|
peritoneal macrophages.</strong> Izg"t-Uysal VN, Tan R, B"lb"l M, Derin N.
|
|
</p>
|
|
|
|
<p>
|
|
J Cereb Blood Flow Metab. 2007 Mar 28;<strong>
|
|
Regeneration and plasticity in the brain and spinal cord.</strong> Johansson BB.
|
|
</p>
|
|
<p>
|
|
Nature, 428, 145 - 150, (2004). Johnson, J., Canning, J., Kaneko, T., Pru, J.K. & Tilly, J.L.
|
|
</p>
|
|
<p>
|
|
Annals of Ophthalmology No. 1, 2005, p. 54, <strong>Life devoted to fight against blindness</strong> (on the
|
|
130th birthday anniversary of V. P. Filatov) Knopov M. Sh., Klyasov A. V.
|
|
</p>
|
|
|
|
<p>
|
|
R. Levi-Montalcini, <strong>"Neuronal regeneration in vitro," </strong>
|
|
pages 54-65 in Windle,<em> Regeneration in the Central Nervous System,</em>
|
|
C. C. Thomas, 1955.
|
|
</p>
|
|
<p>
|
|
Neurobiol Aging. 2006 Nov;27(11):1705-14. Epub 2005 Nov 4.<strong>
|
|
Salivary cortisol and memory function in human aging.</strong> Li G, Cherrier MM, Tsuang DW, Petrie EC,
|
|
Colasurdo EA, Craft S, Schellenberg GD, Peskind ER, Raskind MA, Wilkinson CW.
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</p>
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<p>
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Med Hypotheses. 2007 Mar 27; [Epub ahead of print] <strong>Effects of hypoxia on proliferation and
|
|
differentiation of myoblasts.</strong> Li X, Zhu L, Chen X, Fan M.
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</p>
|
|
<p>
|
|
Exp Neurol. 2003 Nov;184(1):196-213. <strong>Suppression of hippocampal neurogenesis is associated with
|
|
developmental stage, number of perinatal seizure episodes, and glucocorticosteroid level.</strong> Liu
|
|
H, Kaur J, Dashtipour K, Kinyamu R, Ribak CE, Friedman LK.
|
|
</p>
|
|
<p>
|
|
J Nutr Sci Vitaminol (Tokyo). 1989 Feb;35(1):49-59.<strong>
|
|
Effects of dietary restriction on cellular immunity in rats.</strong> Moriguchi S, Toba M, Kishino Y.
|
|
</p>
|
|
|
|
<p>
|
|
Nature. 1998 May 28;393(6683):386-9. <strong>Transcriptional repression by the methyl-CpG-binding protein
|
|
MeCP2 involves a histone deacetylase complex.</strong> Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM,
|
|
Eisenman RN, Bird A.
|
|
</p>
|
|
<p>
|
|
L. V. Polezhaev and E. N. Karnaukhova, <strong>"Stimulation of physiologic regeneration of nervous tissue of
|
|
the cerebral cortex and its significance for biogenic therapy of neuro-mental diseases," pages 86-116 in
|
|
</strong>
|
|
<em>Sbornik: Klinicheskie eksperimentalnye osnovy biogennoi terapii psikhozov</em>,<strong> </strong>
|
|
1962.
|
|
</p>
|
|
|
|
<p>
|
|
Doklady AN SSSR 150, 430-433, 1963., <strong>"Stimulation of nerve cell reproduction of cerebral cortex in
|
|
mammals,"</strong> L. V. Polezhaev and E. N. Karnaukhove
|
|
</p>
|
|
<p>
|
|
L. V. Polezhaev, <strong><em>Loss and Restoration of Regenerative Capacity in Tissues and Organs of
|
|
Animals,</em></strong> page 219, 1972.
|
|
</p>
|
|
<p>
|
|
J Hirnforsch 1991;32(5):659-664. <strong>Normalization of protein synthesis and the structure of brain
|
|
dystrophic neurons after the action of hypoxia, 10% NaCl and organ-specific RNA.</strong> Polezhaev LV,
|
|
Cherkasova LV, Vitvitsky VN, Timonin AV <strong>"Transplantation of embryonic nervous tissue (ENT) in one of
|
|
the hemispheres normalizes all the above abnormalities observed in some neurologic and mental diseases
|
|
in humans."</strong>
|
|
<strong>
|
|
"At the beginning 10% NaCl increased the destruction of brain cortical neurons and then stimulated
|
|
protein synthesis in them.</strong> RNA injections stimulated the synthesis in cortical neurons and
|
|
normalized their structure. Thus, we propose a safe and simple method for normalization of dystrophic
|
|
neurons which can be used after certain improvement for curing neurodegenerative and neuropsychic diseases
|
|
in humans."
|
|
</p>
|
|
<p>
|
|
Science. 2003 Aug 8;301(5634):757. <strong>Requirement of hippocampal neurogenesis for the behavioral
|
|
effects of antidepressants.</strong> Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S,
|
|
Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R.
|
|
</p>
|
|
<p>
|
|
Chin J Traumatol. 2002 Aug;5(4):246-9. <strong>Experimental study on He-Ne laser irradiation to inhibit scar
|
|
fibroblast growth in culture.</strong>
|
|
Shu B, Wu Z, Hao L, Zeng D, Feng G, Lin Y.
|
|
</p>
|
|
|
|
<p>
|
|
J Cell Biochem 2001; 80:455-60.<strong>
|
|
Identification and initial characterization of spore-like cells in adult mammals.</strong> Vacanti, M.
|
|
P., A. Roy, J. Cortiella, L. Bonassar, and C. A. Vacanti.
|
|
</p>
|
|
<p>
|
|
Am J Ophthalmol 1947, 30: 635-636. <strong>Biogenic Stimulators.</strong> (Editorial) Vail D.
|
|
</p>
|
|
<p>
|
|
Clin Immunol Immunopathol. 1989 Aug;52(2):257-70.<strong>
|
|
Depression of humoral responses and phagocytic functions in vivo and in vitro by fish oil and
|
|
eicosapentanoic acid.</strong> Virella G, Kilpatrick JM, Rugeles MT, Hyman B, Russell R.
|
|
</p>
|
|
|
|
<p>
|
|
Reprod Biomed Online. 2005 May;10(5):607-16.<strong>
|
|
Gene expression in the preimplantation embryo: in-vitro developmental changes.
|
|
</strong>
|
|
Wang S, Cowan CA, Chipperfield H, Powers RD.
|
|
</p>
|
|
<p>
|
|
Tissue Eng. 2006 Oct 1; [Epub ahead of print]<strong>
|
|
Effects of Glutamine, Glucose, and Oxygen Concentration on the Metabolism and Proliferation of Rabbit
|
|
Adipose-Derived Stem Cells.</strong> Follmar KE, Decroos FC, Prichard HL, Wang HT, Erdmann D, Olbrich
|
|
KC.
|
|
</p>
|
|
<p>
|
|
J Urol. 2007 Apr;177(4):1568-72. <strong>Over expression of stem cell homing cytokines in urogenital organs
|
|
following vaginal distention.</strong> Woo LL, Hijaz A, Kuang M, Penn MS, Damaser MS, Rackley RR.
|
|
</p>
|
|
|
|
<p>
|
|
Med Hypotheses. 1981 Oct;7(10):1241-51. <strong>The histogenesis of glandular neoplasia.</strong> Zajicek G.
|
|
</p>
|
|
<h1>
|
|
<strong>Stem cells, cell culture, and culture: Issues in regeneration
|
|
</strong>
|
|
</h1>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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. (<em>"The histological
|
|
image of these tissues actually reflects an instantaneous picture of cells in a continuous flux."</em>
|
|
Zajicek, 1981.)
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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."
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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).
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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'."
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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).
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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 (<em>klon</em>, 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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.)
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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 <em>in vitro</em> culture, the enzymes of gene methylation are known to be increased,
|
|
relative to their normal activity (Wang, et al., 2005).
|
|
</p>
|
|
|
|
<p>
|
|
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."
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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).
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
The partially differentiated stem cell doesn't go through all the stages of development, but it does expend
|
|
energy intensely as it matures.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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)
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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 <em>determination</em> 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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
Many factors regulate the process of phagocytosis. Stress and lipid peroxidation decrease phagocytosis
|
|
(Izg"t-Uysal, et al., 2004), and also damage mitochondria and inhibit cell renewal.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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..
|
|
</p>
|
|
<p>
|
|
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..
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p>
|
|
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.
|
|
</p>
|
|
|
|
<p>
|
|
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.
|
|
</p>
|
|
<p><h3>REFERENCES</h3></p>
|
|
<p>
|
|
Growth 43, 58-61, 1979. <strong>The effect of progesterone on brain and body growth of chick
|
|
embryos.</strong> G. Ahmad and S. Zamenhof. [This showed that progesterone, added during the time of
|
|
active neuronal proliferation, increased the chicks' brain weight, while the stress hormone, corticosterone,
|
|
reduced the weight.]
|
|
</p>
|
|
|
|
<p>
|
|
J Invest Dermatol. 1990 Sep;95(3):271-4. <strong>Suppressive effects of linoleic acid on neutrophil oxygen
|
|
metabolism and phagocytosis.</strong> Akamatsu H, Komura J, Miyachi Y, Asada Y, Niwa Y.
|
|
</p>
|
|
<p>
|
|
Curr Alzheimer Res. 2006 Feb;3(1):11-7. <strong>Preclinical analyses of the therapeutic potential of
|
|
allopregnanolone to promote neurogenesis in vitro and in vivo in transgenic mouse model of Alzheimer's
|
|
disease.</strong> Brinton RD, Wang JM. "Herein, we present data to support a preclinical proof of
|
|
concept for the therapeutic potential of allopregnanolone to promote neurogenesis. Our recent work has
|
|
demonstrated that the neuroactive progesterone metabolite, allopregnanolone
|
|
(3alpha-hydroxy-5alpha-pregnan-20-one), (APalpha) induced, in a dose dependent manner, a significant
|
|
increase in proliferation of neuroprogenitor cells (NPCs) derived from the rat hippocampus and human neural
|
|
stem cells (hNSM) derived from the cerebral cortex [1]." "The in vitro and in vivo neurogenic properties of
|
|
APalpha coupled with a low molecular weight, easy penetration of the blood brain barrier and lack of
|
|
toxicity, are key elements required for developing APalpha as a neurogenic / regenerative therapeutic for
|
|
restoration of neurons in victims of Alzheimer's disease."
|
|
</p>
|
|
|
|
<p>
|
|
Arch Biochem Biophys. 1996 Jan 1;325(1):107-12.<strong>
|
|
Thyromimetic action of the peroxisome proliferators clofibrate, perfluorooctanoic acid, and
|
|
acetylsalicylic acid includes changes in mRNA levels for certain genes</strong>
|
|
<strong>
|
|
involved in mitochondrial biogenesis.</strong> Cai Y, Nelson BD, Li R, Luciakova K, dePierre JW.
|
|
</p>
|
|
<p>
|
|
Biochem Mol Biol Int. 1996 Nov;40(4):833-42. <strong>The effect of N-3 PUFA rich diet upon macrophage and
|
|
lymphocyte metabolism and function.</strong> Costa Rosa LF, Safi DA, Guimar"es AR.
|
|
</p>
|
|
<p>
|
|
G. R. de Beer, <strong><em>An Introducton to Experimental Embryology,</em></strong>
|
|
|
|
Oxford, 1926.
|
|
</p>
|
|
<p>
|
|
Biol. Rev. 1927;2:137-197, <strong>The mechanics of verterate development. </strong>
|
|
de Beer GR.
|
|
</p>
|
|
<p>
|
|
Vrach delp. 1937, 20: 803-820. <strong>Summary of 20 years' achievements in ophthalmology.</strong>
|
|
Filatov VP.
|
|
</p>
|
|
<p>
|
|
Vestnik oftal. 1938, 12: 107-159.<strong>
|
|
Tissue transplantation in intra-ocular diseases.</strong> Filatov VP.
|
|
</p>
|
|
|
|
<p>
|
|
Med zhur 1937, 9: 847-853.<strong>
|
|
Intramuscular injections of cod liver oil in therapy of pigmented retinitis.</strong> Filatov VP,
|
|
Verbitska E A.
|
|
</p>
|
|
<p>
|
|
Am Rev Soviet Med. 1946, 3: 388-395.<strong>
|
|
The treatment of retinitis pigmentosa with intramuscular injection of cod liver oil.</strong> Filatov
|
|
VP, Verbitska EA.
|
|
</p>
|
|
<p>
|
|
Am Rev Soviet Med 1946, 3: 395-397. <strong>Retinitis pigmentosa.</strong> Filatov VP.
|
|
</p>
|
|
|
|
<p>
|
|
Am Rev Soviet Med 1946, 3: 397-398.<strong>
|
|
The implantation of preserved placenta in retinitis pigmentosa.</strong> Filatov VP Verbitska EA.
|
|
</p>
|
|
<p>
|
|
Hippocampus. 2006;16(3):225-32.<strong>
|
|
Gonadal hormone modulation of hippocampal neurogenesis in the adult.
|
|
</strong>Galea LA, Spritzer MD, Barker JM, Pawluski JL. <strong>
|
|
Estradiol, the most potent estrogen, initially enhances and subsequently suppresses cell proliferation
|
|
in the dentate gryus of adult female rodents.</strong>
|
|
</p>
|
|
<p>
|
|
Glia. 1999 Feb 1;25(3):247-55. <strong>Cerebellar astrocytes treated by thyroid hormone modulate neuronal
|
|
proliferation.</strong> Gomes FC, Maia CG, de Menezes JR, Neto VM. "Thyroid hormones are important for
|
|
neurogenesis and gliogenesis during brain development. We have previously demonstrated that triiodothyronine
|
|
(T3) treatment induced proliferation in primary culture astrocytes derived from the cerebellum of neonatal
|
|
rats." "Interestingly, the cerebellar neuronal population increased by 60-80% in T3CM."
|
|
</p>
|
|
<p>
|
|
Biochem Int. 1992 Jun;27(1):9-16. <strong>Metabolic and functional changes in macrophages of rats fed
|
|
polyunsaturated or saturated fatty acid rich-diets during ageing.
|
|
</strong>Guimar"es AR, Costa Rosa LF, Safi DA, Curi R.
|
|
</p>
|
|
<p>
|
|
Biochem Int. 1991 Feb;23(3):533-43. <strong>Effect of polyunsaturated (PUFA n-6) and saturated fatty
|
|
acids-rich diets on macrophage metabolism and function.</strong>
|
|
Guimar"es AR, Costa Rosa LF, Sitnik RH, Curi R.
|
|
</p>
|
|
<p>
|
|
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2007 Apr;15(2):433-6. <strong>[Effect of hypoxia on mesenchymal stem
|
|
cells - review.]</strong> [Article in Chinese] He MC, Li J, Zhao CH.
|
|
</p>
|
|
|
|
<p>
|
|
Nat Rev Cancer. 2007 Apr;7(4):246-55. <strong>Reprogramming metastatic tumour cells with embryonic
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