Here, then, is an interesting possibility. Since some organisms have no DNA, but do have RNA, suppose that RNA came first, and DNA was a later development? We know that RNA can produce proteins, and it doesn't need DNA for that. This central early role for RNA has strong advocates, particularly since RNA has been found to contain ribozymes. Not to be confused with ribosomes, ribozymes are enzymes able to snip and reorganize the sequence of nucleotide bases in the RNA itself.
The argument for RNA is interesting, but not yet persuasive. We can make proteins, yes, but without the DNA double helix for exact copying, RNA, with or without the protein factory, cannot produce the next generation.
Where might we find a method of reproduction that does not need DNA, but might lead to DNA and RNA's eventual development?
The answer, even twenty years ago, would have belonged to Chapter 13. Today, thanks in large part to Stanley Prusiner's receipt of the 1997 Nobel Prize for Medicine, the idea is in the scientific mainstream. However, it was pure scientific heresy when Prusiner, in the late 1970s, decided that what we "know" in molecular biology is possibly not so.
What we know is the Central Dogma, according to which DNA, working via RNA, produces proteins. Proteins do not reproduce, nor can their actions affect the DNA. As an organism succeeds or fails in the world, so will its DNA be more or less present in the world.
Prusiner had been studying certain peculiar diseases with a long incubation time. They include scrapie, mostly affecting sheep and goats; kuru, the "laughing death" disease of the natives of New Guinea, that became famous because cannibalism was involved in its spread; Creutzfeldt-Jakob disease, a rare and fatal form of dementia and loss of coordination in humans; and, most recently, the "mad cow disease" (bovine spongiform encephalopathy) that required the killing by farmers of millions of cattle in Great Britain. These diseases have a long latency period before the infected animal or human shows symptoms, and the standard theory was that a "slow virus" was responsible for them.
If that were the case, the infecting agent for the diseases would have to contain DNA, or, if this happened to be a retrovirus, RNA. However, the analysis of infecting material showed no evidence of either nucleic acid. Finally, in 1982, Prusiner proposed that the infectious agent for scrapie and related diseases consists exclusively of protein. The term prion (pronounced pree-on), for "proteinaceous infectious particles," was introduced. Soon afterwards, Prusiner and his co-workers discovered a protein that seemed to be present always in the infectious agent for scrapie. They termed it PrP, for "prion protein." Moreover, the same protein occurs naturally, in animals that are not sick. There is a tiny chemical difference between the two forms of PrP, amounting to a single amino acid. The bigger difference, however, is not chemical but conformational. In other words, PrP can exist in two different molecular shapes.
This suggests a mechanism by which infection can take place. Call one form of the protein PrPi, i for infectious. Call the other PrPn, n for normal, since it is normally present in the body. When PrPi invades the body, it induces the PrPn molecules that it encounters to change their shape to its shape. It may also force the substitution of a single amino acid. The changed forms become PrPi molecules, which can then go on and modify more PrPn. Eventually, there are so many PrPi molecules that the body begins to display symptoms of the disease.
We have found, with prions, a way of reproducing PrPi without the use of DNA. All we needed was a supply of PrPn.
We seem to have run far afield from our original question, of how the process of reproduction started, but we may in fact be close to answering one of the most basic questions of all: What was the origin of life?
Given a supply of energy and basic inorganic components, it is not difficult to produce amino acids. That was shown experimentally by Stanley Miller, back in the early 1950s. Further, if we had a plentiful supply of various kinds of amino acids, floating free in the early seas of Earth, they would naturally combine to produce a variety of different proteins. And if one of those, an ur-protein that was some ancient relative of PrPi, could induce a conformational change and a minor chemical change in other proteins, so that they became exact copies of itself, we would have reproduction. The spread of our ur-protein would be limited by the extent of its "food supply"; i.e., the other proteins in the ancient ocean. However, evolution would be at work, creating modified, and sometimes improved, ur-protein.
It is easy to suggest a direction of improvement. The ur-protein would be more successful if the range of other proteins that it could adapt to its own form could be increased. One way to do this would be through the assembly of the necessary protein from simpler, smaller units—ideally, from the basic amino acids themselves.
This is very close to the processes of eating, digestion, and reproduction so familiar to us today. RNA and DNA could evolve from ur-proteins, as more efficient methods of reproduction. The best process of reproduction would naturally employ the simplest, and therefore the most widely available, components.
Is this what actually happened, in life's earliest history?
No one knows. In fact, no one has any mechanism to offer more plausible than the one offered here. As fiction writers, we can go with a prion approach; or we can assume any other that leads in a rational way to today's world of living creatures.
6.4 Local, or universal? Life elsewhere. It is possible that life did not begin on Earth, but was brought here. That does not avoid the question of an origin—we are then forced to ask how that life came into being—but it does remove a constraint on the speed with which life had to develop. We know that life was present relatively early in Earth's history. The planet is about four and a half billion years old, and there were living organisms here close to four billion years ago. Did they develop here, or were they imported from outside?
That suggests another question: Did primitive Earth possess the warm, placid oceans often pictured in considering the origin of life (we have hinted at it already as the womb for our ur-protein); or was the early world all storm and violence?
Modern ideas of solar system formation and evolution favor the latter notion. The early system was dominated by celestial collisions on the largest scale. Great chunks of matter, some as big as the Moon, hit Earth and the other planets of the inner system. The impact effects must have been prodigious. For example, a small asteroid one kilometer in radius would release into the Earth's biosphere four hundred times as much energy as the biggest volcanic eruption of modern times (the 1815 explosion of Tambora in Indonesia; the following year, 1816, was known as "the year without a summer" because crops failed to ripen). The asteroid whose arrival is believed to have led to the extinction of the dinosaurs (see Chapter 13) was a good deal bigger, perhaps ten kilometers across, and it delivered a blow with 50,000 times the energy of Tambora's eruption. Even so, it is minute in size compared with many of the bodies roaming the solar system four billion years ago. Our Moon, for example, has a diameter of about 3,500 kilometers.
Earth in its early days was subject to a deadly rain from heaven, each impact delivering the energy equivalent to hundreds of thousands of full-scale nuclear wars. As long as this was going on, it would surely be impossible for life to develop.
Or would it? Not if the idea proposed by A.G. Cairns-Smith in several books, (Cairns-Smith, 1971, 1982, 1985) turns out to be true. He suggests that the site of life's origin was not some warm, amniotic ocean, but that the first living organisms formed in clays. This life was not based on DNA and RNA. Those were later developments, taking over because they were more efficient or more stable. The original self-replicating entities were inorganic crystals. Clays are a perfect site for such crystals to form, because clay is "sticky," not only in the usual sense of the word, but as a place where chemical ions readily attach and remain. Life could begin and thrive in clays at a time when Earth was still too chaotic and inhospitable for anything like today's organisms to survive.
The Cairns-Smith idea does two things. It offers another possib
ility for the beginnings of life on Earth; and it makes us wonder, under what strange conditions might life arise and thrive? We know of organisms three miles down in the ocean, living at pressures of two hundred atmospheres near vents of superheated water, and dying if the temperature drops too far below boiling point. Many of these creatures depend not on photosynthesis for their basic energy supply, but on sulfur-based chemosynthesis.
Could anything sound more alien?
It could. For one thing, all these organisms are just like us, in that they employ DNA or RNA in their genetic codes. Recently, a full genome (the complete code sequence) was developed for a deep ocean bacterium known as Methanococcus jannaschii. Its 1.66-million base bacterial genome was built up from the A, C, G, and T nucleotides. Currently, a huge effort goes on to provide the complete mapping of the human genome, with its three billion nucleotide base pairs.
We have no idea if life must be this way, right across the universe. Is an intelligent mud possible, a crystalline matrix layered like the silicon chips of our computers? Or on the massive planet of an unnamed star in the Andromeda Galaxy, do the creatures wriggling across the seabed inevitably possess a molecular pattern, G-C-T-A-A-G-, that we would recognize at once?
Are there a million different ways of writing the book of life, only one volume of which we have seen? Or do they all have a double helix? Why not a triple helix? That would permit better mixing of genetic material during sexual reproduction, with one-third provided by each of the three parents.
A few years ago, these questions seemed unanswerable. The recent discovery of possible archaic life in a meteorite that originated on Mars has changed everything. The Mars Sampler spacecraft, visiting the planet and examining the surface, is currently scheduled for 2005, but may be advanced to 2003. In six or seven years, we may know: are DNA and RNA local to Earth, or do they represent a more universal solution?
6.5 Aging and immortality. Juan Ponce de Leon searched for years, but he did not find the elixir of life and the secret of perpetual youth.
Perhaps he was looking in the wrong place. Just as the study of the faint astronomical objects known as galaxies led us in Chapter 4 to the age of the universe, the study of the curious double helix within our own cells may lead to the understanding of aging, and its ultimate reversal.
I believe that this understanding will come in a decade or less. Would-be storytellers should start now, or be too late.
Chromosomes are made of long strands of DNA. At its very end, each chromosome has something called a telomere. This is just a repeated sequence of a particular set of nucleotide bases. The sequence is not used for RNA or protein production, and for most organisms the repeated set is mainly thymine and guanine. Human telomeres, and those of all vertebrates, are T-T-A-G-G-G, repeated a couple of thousand times; roundworms have T-T-A-G-G-C. At the most basic level, we are not much different from worms.
The telomeres serve a well-defined and useful purpose. They prevent chromosomes sticking to each other or mixing with each other, and hence they aid in stable and accurate DNA replication. However, the telomeres themselves are not stable bodies. They repeatedly shorten and (in certain cases) lengthen.
For example, when a cell divides and DNA is copied, the copying does not extend right to the end of the chromosome. A small piece of the telomere is lost. Over time, if no compensating mechanism were at work, the telomere would disappear. The chromosomes would then develop the equivalent of split ends, and vital genetic information would be lost.
This does not happen, because an enzyme called telomerase generates new copies of the telomere base sequence and adds them to the ends of the chromosomes. The telomeres will then be always of approximately the same length.
The presence of telomerase in single-cell organisms allows them to be effectively immortal. (Some bacteria have no need of telomores and telomerase. Their DNA is arranged in the form of a continuous ring, and it can therefore be completely copied.) They can divide an indefinitely large number of times, with the vital DNA of their genetic code protected by the telomeres. However, many human cells are devoid of telomerase. As has been known since the work of Leonard Hayflick in the 1960s, human body cells are able to reproduce only a certain number of times; after that they become, in Hayflick's term, "senescent" and eventually die. Moreover, cells from a human newborn can divide 80 to 90 times when they are grown in a suitable cell culture; but cells from a 70-year-old will divide successfully only 20 to 30 times.
In the 1970s, an explanation was proposed. Without telomerase, the chromosomes lose part of the telomere at each cell division. Eventually, there are no protective telomeres left. Cell division ceases, and the cell dies. This also provides at least a partial explanation of human aging. If cells are not able to keep dividing, body functions will be impaired.
There is still a mystery to be explained. Although normal human cells die after a limited number of divisions, the same is not true of cancer cells. They will go on growing and dividing in culture, apparently indefinitely. Not surprisingly, in view of what we have learned so far, cancer cells produce telomerase. They do so, even when they derive from body cell types in which telomerase is absent.
We now see two exciting possibilities. On the one hand, if we could prevent the production of telomerase we would inhibit the spread of cancer cells, while not affecting normal cells which already lack telomerase. On the other hand, if we could stimulate the production of telomerase in all the cells of our bodies, cell division would not result in the gradual destruction of the telomeres. Tissue repair would take place in the 70-year-old at the same rate as in the newborn. The aging process would be halted, and perhaps even reversed.
There is a fine balance here, one which we do not yet know how to maintain. Too much telomerase, and the cells run wild and become cancerous (though there is evidence, based on the short telomeres of cancerous cells, that telomerase is produced only after a cell begins to multiply uncontrollably). Too little telomerase, and the aging process sets in at the cellular level. After a while the effects are felt through the whole organism.
There is one other factor to note, and it suggests that we do not have the full story. During the duplication of DNA associated with the reproduction of a multi-celled organism, as opposed to cell division within the organism, the telomeres are somehow kept intact. This is absolutely essential, otherwise a baby would be born senescent. But how is the body able to preserve the telomeres in one type of copying, while they are degraded in another?
There is one simple explanation, though it may be a personally unpalatable one. Aging and death are desirable from an evolutionary point of view. Only by reproducing do we open the door for the biological improvements that keep us competitive with the rest of Nature. Only by mortality do we provide the best assurance for the long-term survival of our DNA.
This runs counter to our desire for personal survival, but in the words of Richard Dawkins, "DNA neither knows nor cares. DNA just is. And we dance to its music" (River Out of Eden, Dawkins, 1995). That has apparently been true for all of life's long history. But when we fully and finally understand telomeres and cell division, perhaps we will have a chance to dance to music of our own choosing.
Telomeres, and their role in aging and the prevention of aging, have already been used in science fiction. See, for example, Bruce Sterling's Holy Fire (1996) and my own Aftermath (1998).
6.6 Aging: a second look. We have proposed the erosion of the telomeres as a mechanism for aging, but it is unlikely to be the only factor. For one thing, people usually die long before they reach the "telomere limit" at which chromosome copying is impaired. This implies reasons for aging that go beyond what is happening at the level of the single cell. If we again invoke Philip Anderson's "More is different" argument, the large, complex assembly of the human body has properties that cannot be deduced by analysis of its separate components. Consciousness, to take one example, does not seem to exist at the cellular level. It emerges only when a sufficiently lar
ge aggregate of cells has been created.
Humans have uniquely large brains as a fraction of total body mass. We do not know if we are the only creatures on Earth with consciousness of self, but we do know other, well-measured ways in which we are unique. For instance, we have a peculiarly long life span for animals. The sturgeon (150 years) and the tortoise (140 years) definitely live longer, but among mammals only those land and sea giants, the elephant (70) and the whale (80), come close to human maximum life expectancy. The difference between humans and other animals is more striking if we work in terms of number of heartbeats. With that measure, we live longer than anything. Big brains seem to help, though we don't know how.
I am taking it for granted that we would all like to live longer, provided that we can do so in good health. Aging and death may be necessary from an evolutionary point of view, but from a personal point of view both are most undesirable. If we cannot escape death, can we at least postpone aging?
At the cellular level, one class of frequently-named suspects as causes of both aging and cancer is free radicals. Vitamin C (discussed further in Chapter 13) and Vitamin E neutralize free radicals.
Whether or not the secret of human longevity involves the whole organism rather than being defined at the single cell level, we can certainly identify particular organic changes associated with aging. Two that continue to arouse a great deal of attention involve the thymus organ and the pineal gland.
The thymus is small. Less than half an ounce at birth, it sits above the heart and is about an ounce at maximum size, close to puberty. After puberty the thymus begins to shrink, and becomes inactive by age forty. It is an important part of T-cell production and hence of the body's immune response system.
The pineal gland is small also, about a centimeter across, and it sits at the base of the brain. Its main known function is the production of melatonin. The pineal gland begins to diminish in activity very early in life, with changes already occurring by the time we are seven or eight years old. Like the thymus, the pineal seems to close down its activity completely by the fortieth year.
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