Friday, November 12, 2010

Getting Over the Code Delusion: Epigenetics Review, The New Atlantis

Tags: Epigenetics Review Genomics Behavior Health Vitamin D Nobel Prize Reagan Corporate Revolution

A great scramble to profit scientifically and commercially after the human genome projects succeeded came and went. They could have anticipated this by earlier reports that the human genome has not changed that much since the migration of our human ancestors out of Africa. Since the number of humans leaving Africa was quite small and estimated in the thousands, any gene that insured survival survived that those without it did not survive. The mutation for White skin allowed us to have modern Europeans because vitamin D produced in our skin and needed for every cell in our body was produced from the sunlight UVB, the Burning Rays.

Since the profit for corporations only mentality accelerated during the Reagan Revolution, important regulations regarding the health of the general public went out the window. Without going into detail some of these were the introduction of very cheap High Fructose Corn Sugar without testing for safety on animals or humans, accelerating the approval of drugs with inadequate test with Big Pharma influencing the FDA by funding it with funds needed to show that new drugs are safe, introducing sunscreens without adequate testing for safety and disregarding known health safety problems by excluding UVB from producing vitamin D for our body. A Nobel Prize in medicine was awarded in about 1902 to the person showing that UVB from the sun makes us healthier.

They also reduced funding for government research funds provided for research so Academics had to get more funding from self-interest parties like Big Pharma who had less interest in fundamental studies to understand cancer, for example, which may have helped scientists to start more widely publish their previous vitamin D studies indicated how important it was for our health and survival.

For example, the doubling of Autism among affluent families who are more likely to follow "experts" advice about health started using sunscreens earlier and probably contributed to lots of neurological diseases to mushroom. Melanoma also mushroomed. Only after the introduction of the more expensive UVA and UVB sunscreens did melanoma increase each year stop. Of course when 75% of Americans are deficient in vitamin D which prevents cancers, prevents osteoporosis, prevents flu, colds, allergies, and autoimmune diseases.

I tried to get my friends and acquaintances to start taking thousands IU of vitamin D largely ignored my advice. Those who did had frequent colds and allergies and to their surprise, they stopped having colds and allergies.

Now the scientists are trying to turn genes on or off to prevent diseases. But they forget the very cheap vitamin D does this function every day to make us healthier. Turning the wrong gene off or on can lead to tragedy. Only a small amount of activated vitamin D can be tolerated in our blood stream so each cell activates what it needs and destroys any excess so it does not get into our bloodstream. Our kidneys make enough of the activated vitamin D to allow it to help drive calcium into our bones because bone loses calcium on a continuous basis normally.

The infancy of the research in the new area of Epigenetics on how our environment influences how we behave, learn, how much we weigh, our health, and even how we think. Some of you might have been offended at my theory that Republicans who are largely of the ethnic Scot-Irish group are that way from a long history of conflict and survival. The activated paranoid genes that insure survival are still activated after more than a thousand years because they tend to live in rural or uniform communities to reinforce their way of thinking. Oregon Democrats live in cities or adjacent suburbs. Republicans largely tend to live in more rural communities. This is true for most of the United States. Its not race, it an ethnic phenomena. The same is true in the city ghettos where even fewer escape due to Republican like policies. Put them in jail forever or kill them whether guilty or not.

Jim Kawakami, Nov 12, 2010,

Getting Over the Code Delusion: Epigenetics Review, The New Atlantis, Steve Talbot, Number 28, Summer 2010, pp. 3-27.

... Certainly the idea of a master program seemed powerful to those who were enamored of it. In their enthusiasm they heralded one revolutionary gene discovery after another — a gene for cystic fibrosis (from which the string of letters above is excerpted), a gene for cancer, a gene for obesity, a gene for depression, a gene for alcoholism, a gene for sexual preference. Building block by building block, genetics was going to show how a living organism could be constructed from mindless, indifferent matter.

And yet the most striking thing about the genomic revolution is that the revolution never happened. Yes, it’s been an era of the most amazing technical achievement, marked by an overwhelming flood of new data. It’s true that we are gaining, even if largely by trial and error, certain manipulative powers. But our understanding of the integrity and unified functioning of the living cell has, if anything, been more obscured than illumined by the torrent of data. “Many of us in the genetics community,” write Linda and Edward McCabe in DNA: Promise and Peril (2008), “sincerely believed that DNA analysis would provide us with a molecular crystal ball that would allow us to know quite accurately the clinical futures of our individual patients.” Unfortunately, as they and many others now acknowledge, the reality did not prove so straightforward.

As minor tokens of the changing consciousness among biologists, one could cite recent articles in the world’s two premier scientific journals, each reflecting upon the 1989 discovery of the “gene for cystic fibrosis.” “The Promise of a Cure: 20 Years and Counting” — so ran the headline in Science, followed by this slightly sarcastic gloss: “The discovery of the cystic fibrosis gene brought big hopes for gene-based medicine; although a lot has been achieved over two decades, the payoff remains just around the corner.” An echo quickly came from Nature, without the sarcasm: “One Gene, Twenty Years: When the cystic fibrosis gene was found in 1989, therapy seemed around the corner. Two decades on, biologists still have a long way to go.”

The story has been repeated for one gene after another, which may be why molecular biologist Tom Misteli offered such a startling postscript to the unbounded optimism of the Human Genome Project. “Comparative genome analysis and large-scale mapping of genome features,” he wrote in the journal Cell, “shed little light onto the Holy Grail of genome bio­logy, namely the question of how genomes actually work in vivo” (that is, in living organisms).

But is this surprising? The human body is not a mere implication of clean logical code in abstract conceptual space, but rather a play of complexly shaped and intricately interacting physical substances and forces. Yet the four genetic letters, in the researcher’s mind, became curiously detached from their material matrix. In many scientific discussions it hardly would have mattered whether the letters of the “Book of Life” represented nucleotide bases or completely different molecular combinations. All that counted were certain logical correspondences between code and protein together with a few bits of regulatory logic, all buttressed by the massive weight of an unsupported assumption: somehow, by neatly executing an immaculate, computer-like DNA logic, the organism would fulfill its destiny as a living creature. The details could be worked out later.

The misdirection in all this badly needs elaborating — a task I hope to advance here. As for the differences between humans and chimpanzees, the only wonder is that so many were so exercised by it. If we had wanted to compare ourselves to chimps, we could have done the obvious and direct and scientifically respectable thing: we could have observed ourselves and chimps, noting the similarities and differences. Not such a strange notion, really — unless one is so transfixed by a code abstracted from human and chimp that one comes to prefer it to the organisms themselves.

I’m not aware of any pundit who, brought back to reality from the realm of code-fixated cerebration, would have been so confused about the genetic comparison as to invite a chimp home for dinner to discuss world politics. If we had been looking to ground our levitated theory in scientific observation, we would have known that the proper response to the code similarity in humans and chimps was: “Well, so much for the central, determining role we’ve been assigning to our genes.”

The central truth arising from genetic research today is that the hope of finding an adequate explanation of life in terms of inanimate, ­molecular-level machinery was misconceived. Just as we witness the distinctive character of life when we observe the organism as a whole, so, too, we encounter that same living character when we analyze the organism down to the level of molecules and genes. One by one every seemingly reliable and predictable “molecular mechanism” has been caught deviating from its “program” and submitting instead to the fluid life of its larger context. And chief among the deviants is that supposed First Cause, the gene itself. We are progressing into a post-genomic era — the new era of epigenetics.

Genomic Perplexities

The term “epigenetics” most commonly refers to heritable changes in gene activity not accounted for by alterations or mutations in the DNA sequence. But in order to understand the important developments now underway in biology, it’s more useful to take “epigenetics” in its broadest sense as “putting the gene in its living context.”

The genetic code was supposed to reassure us that something like a computational machine lay beneath the life of the organism. The fixity, precision, and unambiguous logical relations of the code seemed to guarantee its strictly mechanistic performance in the cell. Yet it is this fixity, this notion of a precisely characterizable march from cause to effect — and, more broadly, from gene to trait — that has lately been dissolving more and more into the fluid, dynamic exchange of living processes. Organisms, it appears, must be understood and explained at least in part from above downward, from context to subcontext, from the general laws or character of their being to the never-fully-independent details. To realize the full significance of the truth so often remarked in the technical literature today — namely, that context matters — is indeed to embark upon a revolutionary adventure. It means reversing one of the most deeply engrained habits within science — the habit of explaining the whole as the result of its parts. If an organic context really does rule its parts in the way molecular biologists are beginning to recognize, then we have to learn to speak about that peculiar form of governance, turning our usual causal explanations upside down.

A number of conundrums have helped to nudge molecular biology toward a more contextualized understanding of the gene. To begin with, the Human Genome Project revised the human gene count downward from 100,000 to 20,000–25,000. What made the figure startling was the fact that much simpler creatures — for example, a tiny, transparent ­roundworm — were found to have roughly the same number of genes. More recently, researchers have turned up a pea aphid with 34,600 genes and a water flea with 39,000 genes. Not even the “chimps are human” boosters were ready to set themselves on the same scale with a water flea. The difference in gene counts required some sort of shift in ­understanding.

A second oddity centered on the fact that, upon “deciphering” the genetic Book of Life, we found that our coding scheme made the vast bulk of it read like nonsense. That is, some 95 or 98 percent of human DNA was useless for making proteins. Most of this “noncoding DNA” was at first dismissed as “junk” — meaningless evolutionary detritus accumulated over the ages. At best, it was viewed as a kind of bag of spare parts, borne by cells from one generation to another for possible employment in future genomic innovations. But that’s an awful lot of junk for a cell to have to lug around, duplicate at every cell division, and otherwise manage on a continuing basis.

Another conundrum — perhaps the most decisive one — has been recognized and wrestled with (or more often just ignored) since the early twentieth century. With few exceptions, every different type of cell in the human body contains the same chromosomes and the same DNA sequence as the original, single-celled zygote. Yet somehow this zygote manages to differentiate into every manner of tissue — liver, skin, muscle, brain, blood, bone, retina, and so on. If genes determine the form and substance of the organism, how is it that such radically different cellular architectures result from the same genes? What directs genes to produce the intricately sculpted and differentiated form of a complex organism, and how can this directing agency be governed by the very genes that it directs?

The developmental biologist F.R. Lillie, remarking in 1927 on the contrast between “genes which remain the same throughout the life history” and a developmental process that “never stands still from germ to old age,” asserted that “Those who desire to make genetics the basis of physiology of development will have to explain how an unchanging complex can direct the course of an ordered developmental stream.”

Think for a moment about this ordered developmental stream. When a cell of the body divides, the daughter cells can be thought of as ­“inheriting” traits from the parent cell. The puzzle about this cellular-level inheritance is that, especially during the main period of an organism’s development, it leads to a dramatic, highly directed differentiation of tissues. For example, embryonic cells on a path leading to heart muscle tissue become progressively more specialized. The changes each step of the way are “remembered” (that is, inherited) — but what is remembered is caught up within a process of continuous change. During development you cannot say that every cell reproduces “after its own likeness.”

Over successive generations, cells destined to become a particular type lose their ability to be transformed into any other tissue type. And so the path of differentiation leads from totipotency (the single-celled zygote is capable of developing into every cell of the body), to pluripotency (embryonic stem cells can transform themselves into many, but not all, tissue types during fetal development), to multipotency (blood stem cells can yield red cells, white cells, and platelets), to the final, fully differentiated cell of a particular tissue. In tissues where cell division continues further, the inheritance thereafter may take on a much greater constancy, with like giving rise (at least approximately) to like.

Cells of the mature heart and brain, then, have inherited entirely different destinies, but the difference in those destinies was not written in their DNA sequences, which remain identical in both organs. If we were stuck in the “chimp equals human” mindset, we would have to say that the brain is the same as the heart.

From Junk to Living Organism

So what’s going on? These puzzles turn out to be intimately related. As organisms rise on the evolutionary scale, they tend to have more “junk DNA.” Noncoding DNA accounts for some 10 percent of the genome in many one-celled organisms, 75 percent in roundworms, and 98 percent in humans. The ironic suspicion became too obvious to ignore: maybe it’s precisely our “junk” that differentiates us from water fleas. Maybe what counts most is not so much the genes themselves as the way they are regulated and expressed. Noncoding DNA could provide the complex regulatory functions that direct genes toward service of the organism’s needs, including its developmental needs.

That suspicion has now become standard doctrine — though a still much-too-simplistic doctrine if one stops there. For noncoding as well as coding DNA sequences continue unchanged throughout the organism’s entire trajectory of differentiation, from single cell to maturity. Lillie’s point therefore remains: it is hardly possible for an unchanging complex to explain an ordered developmental stream. Constant things cannot by themselves explain dynamic processes.

We need a more living understanding. It is not only that noncoding DNA is by itself inadequate to regulate genes. What we are finding is that at the molecular level the organism is so dynamic, so densely woven and multidirectional in its causes and effects, that it cannot be explicated as living process through strictly local investigations. When it begins to appear that, as one European research team puts it, “everything does everything to everything,”[1] the search for “regulatory control” necessarily leads to the unified and irreducible functioning of the cell and organism as a whole — a living, metamorphosing form within which each more or less distinct partial activity finds its proper place.

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