Chapter I 1 2 3 4 5 6

Borderlands of Science

Copyright © 1999

by Charles Sheffield


6.1 The miracle molecule. You will read in many places that if the twentieth century was from the scientific point of view the century of physics, then the one after it will be the century of biology. That should make the frontiers of biology of special interest to a science fiction writer. The question then is, where do we begin?

Fifty years ago, a writer on the limits of biology might have had trouble deciding where to start. The biological world offers such a dazzling diversity of forms and creatures at every scale, everything from bacteria and viruses to mushrooms and elephants. Today, there is no such problem. We have to begin with a single molecule, an organic compound with a long name but a famous abbreviation.


Deoxyribonucleic acid, universally shortened to DNA, was discovered in 1869 by the German chemist Friedrich Miescher. It was (and is) found in the nuclei of the cells of most living things, but no one knew its structure, what it did, or how important it was.

DNA is one of a class of chemicals known as nucleic acids. By the beginning of the twentieth century, the components of the DNA molecule were known to be sugars, phosphates, and two types of two chemical bases known as purines and pyrimidines. The functions of the molecule were still obscure, though in 1884 a zoologist, Hertwig, had written that it was the way that hereditary characteristics were passed on from generation to generation.

He was right, but most people didn't accept what he said. So when, in 1943, Erwin Schrödinger gave lectures in Ireland on the mechanisms of heredity, he did not talk about DNA. He proposed, in his lectures and in a short and very readable book WHAT IS LIFE? (Schrödinger, 1944), that the basis for heredity must be some kind of code, in which specific sequences of chemicals were written and interpreted; however, he assumed that the "code-script," as he called it, was contained in proteins, in the form of an aperiodic crystal.

Schrödinger was right, in that heredity, and all cell reproduction, depends on what we now term the genetic code. But it took another decade before the nature of the code and the structure of the code carrier were determined.

DNA, not proteins, carries the genetic code, for humans and for everything remotely like us. Nature is prodigal with DNA. In most (but not all; mature red blood cells lack a nucleus) of the 1014 cells of our bodies, we have the DNA to provide a complete description of the whole organism. Your DNA is in all important respects the same as the DNA in any other animal or plant, everything from a wisteria to a walrus. The same, that is, in all important respects but one: your DNA defines the unique you, the walrus DNA defines the complete walrus. In principle, given one cell from my body a full copy of me could be grown. This idea of "clones" has been widely used in fiction (Varley, 1977, 1979, 1980), with some of the fiction posing as fact (Rorvik, 1978). Sheep and other mammals have been cloned, but no one has yet cloned a human. We can look for that in less than twenty years, regardless of laws passed by those who disapprove of the concept on religious or ethical grounds.

The structure of the DNA molecule was determined by Crick and Watson in 1953. The story of their discovery is told in frank detail by Watson in his book, THE DOUBLE HELIX (Watson, 1968). The title is appropriate, because the molecule has the form of a double helical spiral. Strung out along the spiral, at regular intervals, are molecule after molecule of the four chemical bases. Their names are adenine, cytosine, thymine, and guanine, and they are exactly paired. Wherever on one strand of the double spiral you find a cytosine nucleotide base, paired with it on the other strand you will find guanine; if there is thymine on one strand, on the corresponding site of the other strand there will be adenine. If we were to read off the sequence of nucleotide bases along a single strand, we would find a long string of letters, A-G-T-G-C-T-A-A-C-C-G-T-A- (we are using the obvious abbreviations). The corresponding sites on the other strand would then, without a choice, read T-C-A-C-G-A-T-T-G-G-C-A-T-

Long strands of DNA nucleotide bases, each base with an accompanying sugar and phosphate molecule, make up the chromosomes found in the nucleus of every cell. Individual genes, with which the science of genetics is mainly concerned, are subunits within the chromosomes. The division of the DNA into many separate chromosomes (humans have forty-six of them) seems to be mainly a matter of packing convenience. Efficient packing is necessary. There are about three billion separate nucleotide bases in human DNA, tucked into a cell nucleus only a few micrometers across. The chromosomes that define you totally are invisible to the naked eye.

As an interesting side-bar to the development of life, not all the DNA in a cell of your body will be found in the nucleus. Some is located in other small units, known as mitochondria, that control cell energy production. However, the DNA in mitochondria is not your DNA. It belongs to the mitochondria themselves, and it is used to control their own reproduction. It seems that the mitochondria were originally independent organisms, but long, long ago they abandoned that independence in favor of a symbiotic relationship with other creatures.

The means by which the DNA molecule reproduces itself is simple and elegant: the double helix unwinds. One branch of the spiral goes in one direction, the other in the opposite direction. As each site on the helix is left with an unpaired base, the correct pairing, cytosine/guanine or adenine/thymine, takes place automatically (the pairs of bases have a natural chemical affinity). The correct base is collected from a pool of materials within the cell. At the same time, the necessary sugar and phosphates are added to the spine of the helix. When the double helix has finished unwinding, two new double helices, each identical to the original one, have miraculously appeared. The DNA molecule has reproduced itself.

This copying procedure is incredibly accurate, assisted by a "proof-reading" enzyme called DNA polymerase that can correct mistakes. Very rarely, however, there will be a glitch, perhaps an A where the copy ought to have a C, or a short sequence duplicated or left out completely. If this occurs in the reproductive cells of an organism, the copying error will pass on to the offspring. A change in DNA due to imperfect copying, or accidental damage, gives rise to what we term a mutation. Most mutations are changes for the worse. The offspring, if it survives at all, will be unable to perform as well as the parent. Occasionally, however, there will be a favorable mutation. The new version will be an improvement over the original, and produce its own superior offspring. This is the driving mechanism of evolution.

However, we — you and I and the potted begonia in the corner — are not composed entirely of DNA. We have seen how the DNA molecule takes care of itself, but what makes the rest of us?

That calls for some agent to interpret and use the code contained in the DNA molecule. It is a two-stage process. First, another nucleic acid, RNA (ribonucleic acid), copies the information in the DNA molecule onto itself. It has a slightly different chemical composition (uracil, abbreviated to U, takes the place of thymine), but essentially it mimics the relevant DNA structure with matching bases. Note that, because RNA can match any sequence of sites in a DNA molecule, RNA can carry the same information as DNA.

What RNA cannot do, because it lacks the double helix structure, is make a copy of itself. We will return to that later.

RNA copies information from the DNA molecule. Then it goes off to a place in the living cell where small round objects known as ribosomes are located. There, the RNA dictates the production of substances known as amino acids. The amino acids are the small and simple elements from which large and complex protein molecules are made. Just as DNA and RNA have strings of nucleotide bases, proteins have strings of amino acids. Each triplet of symbols in the RNA bases (A, C, G, and U) leads to the production of a unique amino acid. For example, the sequence U-A-C always, without exception, leads to the production of the amino acid, tyrosine. The order of the sequence is important; C-A-U leads not to tyrosine, but to another amino acid, histidine.

Although each triplet leads to a unique amino acid, the converse is not true. There are 64 possible three-letter combinations, but they lead to only 20 amino acids. For example, both C-A-U and C-A-C produce histidine.

Now we have the final step: amino acids, created in the order dictated by the triplets (known as codons) in the RNA, in turn produce the proteins.

Interestingly, not all the three billion nucleotide bases in human DNA are used to make proteins. Only about ten percent of them do that. The other ninety percent, stretches of DNA that are known as "introns," don't seem to do anything at all. That may reflect current ignorance, and we will later learn what this "junk DNA" actually does. Simple organisms don't have introns — all their DNA is used to define the making of proteins. So why do more complex organisms have them?

Feel free to make up your own reasons. No one is in a position to disagree with you.

We have rendered down a century of work to a few hundred words, but the central message, stated by Francis Crick as the "Central Dogma of molecular biology," is simple: DNA codes for the production of proteins; the process never, ever, goes the other way.

There is another way of looking at this, and one that may sound more familiar. DNA controls reproduction, and also the production of proteins and hence our bodies. Nothing that we do to our bodies can ever go back and affect the DNA. In other words, there can be no inheritance of acquired characteristics.



6.2 The mystery of sex. Before we move on to other mysteries of biology, we need to answer an implied question. We can be regarded, as Richard Dawkins has eloquently pointed out in THE SELFISH GENE (Dawkins, 1976), as nothing more than large-scale mechanisms designed to propagate our own genetic material. To most organisms, DNA is the most precious thing in the world, the only way to assure that their line continues. Few people would argue, seeing the powerful imperative to propagate as we see it displayed throughout the living world, that the preservation and multiplication of genetic material is the Prime Directive of nature.

However, when we examine the subject of sex logically (a mental exercise for which, as any newspaper will show, humans show little apparent aptitude) we find a paradox. Your DNA is high-quality stuff, developed and fine-tuned over four billion years. It is you, the essence of you, the only way for you to continue an existence in the future (let us leave aside for the moment the notion of your and my possibly immortal prose).

So what do you do? You mate, with a genetic stranger. At that point your unique and wonderful DNA becomes mixed, fifty-fifty, with other DNA about which you know very little. Even if you have known your partner all your life, it is still true to say that the two of you are strangers at the DNA level. Indeed, the best bet from the point of view of your genes would be to mate with a close relative, where you share a high proportion of common genetic material.

This is not, of course, what happens. Incest is taboo in human societies and mating outside the family seems generally preferred everywhere.

What is going on? Why, taking a genes-eye view of things, is sexual reproduction such a big hit? Why do all the most complex life forms on Earth employ, all or part of the time, sex as a tool for propagation?

I do not think that biology today offers complete answers to these question. Richard Dawkins at one point seems all ready to tackle it in CLIMBING MOUNT IMPROBABLE (Dawkins, 1996). But then he veers away, or at least postpones: "But the whole question of sex and why it is there ... is another story and a difficult one to tell. Maybe one day I'll summon up the courage to tackle it in full and write a whole book about the evolution of sex."

I wish he would. Meanwhile, here is a brief analysis, some of it based on personal speculation. In summary, the main idea is that the driving force for rapid change, and hence for exploiting a changing environment, is selection, not mutation.

Let me repeat and rephrase an earlier statement which I believe is not controversial: changes that take place in an organism over time, as a result of random mutation, take place slowly. Each mutation may be harmful, beneficial, or neutral in terms of survival of the organism's offspring. Beneficial mutations will prosper (there is something of a tautology here, since the definition of beneficial is that organisms with the mutation do well). However, significant changes as a result of mutation require many thousands of generations.

Also changing over time is the environment in which the organism lives. The environmental changes may be slow (tectonic forces that raise mountain ranges) or fast (earthquake and volcano), but in any case their rates of change are largely independent of the rates of organism mutation. I say largely, because changes in chemistry or radioactivity levels certainly affect mutation rates.

Consider changes in environment which take place over time scales that are, in terms of mutation rates, very fast. A volcanic eruption, like Mount Pinatubo in 1993, fills the upper atmosphere with dust and cools the atmosphere by a few degrees. El Nino, in 1998, causes anomalous heating of the seas. A large calving of the Antarctic ice-shelf reduces salinity over much of the southern oceans.

An organism which reproduces asexually will adapt to such changes to the limits of its variability. We can use the term "natural selection" to describe this process, but it will not normally be mutation. An organism cannot mutate fast enough to be useful, nor can it modify its own genetic material. It passes on to the next generation an identical copy of what it possesses.

Now consider sexual reproduction. The mixing of genetic material permits a great variety in offspring, in both appearance and function. Thus adaptation of organisms, accompanied by rapid morphological changes, can be far faster than mutation would permit. Consider the "unnatural selection" process that has led to forms of a single species as disparate in size and shape as the chihuahua and the Great Dane, during the relatively short period of human domestication of animals. Morphological evolution can be fast, when something (humans or Nature) drives it. It will be slow when there is no driving force for change. However, in either case the available pool of DNA for the whole sexually-compatible group of organisms is unchanged, though grossly variable at the individual level. Thus a species can adapt and thrive, using sexual reproduction, without waiting for the slow process of favorable mutation. This is a huge evolutionary advantage.

We still have to address an important question: Is it possible for changes to take place in a organism, sufficient that we can say we now have a new species, other than by the slow processes of mutation? If not, then although in the short run sexual reproduction has an advantage over asexual reproduction, in the long term that advantage diminishes.

I argue that there is also the following long-term gain in sexual reproduction. When a male and female produce offspring, they mix their DNA fifty-fifty. However, this is not a random mixing. Certain very specific segments of DNA, which we call genes, come from one parent, and this is an all-or-nothing process. Thus, an offspring gets that whole segment from one parent, or from the other. It does not get half and half, or if it does get a fractional gene, the result cannot survive. Since there are thousands of segments (genes) we have a gigantic number of possible offspring, with all sorts of gene mixes.

Now take one group of offspring away to a different environment. Natural selection takes place, and some gene segments, rather than existing in the population equally in their two possible forms, are preferred because of environmental pressures in just one form. Offspring with that form thrive, others fail. The organisms begin to look and act differently from the original form, because their gene choices are selected to suit the new environment. Finally, one form of a gene may exist in the new environment, while the complementary form of the gene, selected against, does not. It has been removed completely from the organisms in that environment.

In the same way, in some other environment, other genes have a preferred form for organism survival. Their complementary form does not exist in that environment.

If mutations did not occur and we put specimens of organisms from the two environments back into their original settings, they would mate and their offspring would have all the original forms of genes.

However, we cannot ignore mutation completely. It is a random process, but it happens. A beneficial mutation will spread rapidly through a population. We might say that we had a new species every time such a mutation occurred and spread, except that we will normally have no way of observing such a change. Over time, however, there will be recognizable changes, and we then say that the organism has evolved. We would see the evolution of a single species, whether or not the organism propagates sexually.

Now here is the key, if obvious, piece of the argument: mutations cannot occur in genes that are not present in an organism. Different environments, for sexually reproducing organisms, will have different mutations. At some point, the original organisms that were placed into two different environments will be different not only morphologically in appearance and behavior (accomplished via sexual selection of genes), but through the accumulation of different changes in their actual genetic make-up. The new versions of genes will not be compatible with the old complementary set of genes. We see speciation. One species has become two. And that process, the creation of new permanent forms, is easier and faster with the aid of sexual reproduction. Sex is, in fact, a good thing.

At this point, I ought to say that not everyone agrees as to why sex is a good thing. Steven Pinker, in HOW THE MIND WORKS (1996) supports a different theory as to why sex was a valuable invention for living creatures. First, he points out that an organism cannot practice any policy that implies present sacrifice for future benefit. "Playing on the come" will not work, since everything from squash to squids must maximize the number of its immediate descendants. (Not only that, an organism does not sacrifice itself, even for the good of the species, unless there are sound reasons, based on the selfishness of genes, for doing so. This has caused workers, including Dawkins, considerable trouble, explaining how altruism can also be a form of self-interest.)

Pinker favors a theory proposed by John Tooby, which claims that sex was developed as a way of protecting organisms against disease. The argument goes as follows: We are invaded all the time by a variety of tiny critters, who see us as a plentiful food supply. We have built up protections against them, but they in turn have become very cunning at penetrating our defenses. When an organism employs asexual reproduction, and some parasite organism finds a way around the defense, the game is over, because the same trick will penetrate the defenses of future generations with identical genetic make-up. Sexual reproduction, however, scrambles the genes, and makes the offspring less susceptible to parasitic invasion. Thus, sex provides a partial fresh start with each generation.

I am less persuaded than Pinker by this argument (although I strongly recommend HOW THE MIND WORKS for a hundred other good reasons). It seems to me that there is no inconsistency between optimizing for the present generation, and sexual reproduction. In fact, the mixing of genes that sex offers increases the total variation in the next generation, without the dangers presented by mutation (which is normally unfavorable to an organism), and therefore improves the short-term odds.

Which theory is right? I don't know. Nor, I argue, does anyone else. However, this is not an either/or situation, where one theory must be right at the expense of another. Perhaps sexual reproduction allows organisms to adapt more rapidly to new environmental niches, and also serves as a defense against disease.

Is there a third reason why sexual reproduction has been such an overwhelming success? Feel free to conjecture. Alternate scientific theories are exactly the place where science fiction stories flourish. And if you would like to read a radically different suggestion as to why evolution seems to proceed far more rapidly than simple mutation would suggest, try PATHS TO OTHERWHERE (Hogan, 1996), where the subject is dealt with, amazingly, in terms of the many-worlds theory of Everett and Wheeler (see Chapter 2).



6.3 Viruses, RNA, prions, and the origin of life. The story of DNA seems astonishingly simple and complete. Let us ask the usual questions: What don't we know, and what do we know what ain't so?

For one thing, we don't know how this whole process started.

The inter-dependence of the proteins and the DNA is a highly improbable connection. To make a new cell, both are needed. If you lack either one, the process cannot work. It seems ridiculous to suggest that both DNA and the necessary protein production factory could have developed, independently of each other, and work together without a hitch. It is as though you developed a car body while I without consulting you developed an engine, neither of us having done anything like it before. We put them together, and the whole automobile runs like a dream.

It would be a dream. That independent development of DNA and proteins is obviously not what happened. But what did?

To provide a possible explanation, we go to the world of viruses. At first that may seem to make the problem worse. A virus is a mystery organism (but a godsend, I sometimes feel, for the medical profession. The doctor's pronouncement, "You have a virus," is often the equivalent of, "I don't know what is wrong with you, but I know I can't give you anything to cure it.")

Viruses are minute, much smaller even than cells. Their small size is possible because they lack a cell structure or a protective cell wall, and they don't have their own ribosome protein factories. All they are is a tiny chunk of DNA, wrapped in a coat of protein. Some of them also have little tails.

It is possible that viruses are degenerate forms, organisms that once possessed the full machinery for self-reproduction but at some point abandoned it. Be that as it may, we must still explain how something so small, on the very borderline between living and non-living, go about reproducing itself when it has none of the equipment we have described as necessary? If we find the answer to that, maybe we will solve the problem of the separate development of proteins and DNA.

A memorable report in a British newspaper of a Divorce Court proceedings a few years ago ended as follows (with minor changes as to names): "Living at the time as a paying house-guest of Mr. and Mrs. Smith was Mr. Jones, a man with an artificial leg. One day Mrs. Smith asked her husband, if a woman had a baby by Mr. Jones, would the baby have an artificial leg? Mr. Smith then began to be suspicious."

If, metaphorically speaking, the paying guest in your house happened to be a virus, then the chance of your cells having an artificial leg would be very good indeed.

What happens is this. The virus penetrates the wall of a normal, healthy cell, often with the aid of its little tail of protein. Once inside, the virus takes over the cell's own copying equipment, using it to produce hundreds or thousands of new viruses until the chemical supplies of the cell are used up. Then the cell wall bursts, releasing the viruses, which go on to repeat the process. The virus doesn't carry its own protein factory, because it doesn't need it. Viruses are, and must be, parasitic on cells.

Again, the story seems neat and complete, but not useful to resolve our mystery of how the whole process began. Then, to add confusion, certain viruses were discovered that have no DNA at all.

What they have is RNA. Such viruses are known as retroviruses, and they are famous, or infamous, because their number includes the Human Immunodeficiency Virus, HIV, associated with the disease AIDS. (The naming of the HIV virus, and the battle over priority of discovery, is an astonishing story that I won't go into here. Science is the search for absolute truth, and scientists are objective, dispassionate people. Right? Look out of the window, and you will see the Easter Bunny.)

How can something without DNA reproduce? We have emphasized the importance of the DNA double spiral, which RNA lacks. A retrovirus has to work hard indeed to produce the next generation. First, it invades a cell. Next, it uses the one-to-one correspondence between its own RNA bases (A, C, G, U) to make matching DNA (T, G, C, A). Then it employs the cell's own DNA-reproducing mechanism to make DNA copies. Finally, the virus employs the rest of the cell machinery to make matching RNA (its own genetic material) and hence more copies of itself.

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 re-organize 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 consist 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 thirty-five hundred 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 possibility 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 story-tellers 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. 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 large 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.

The medical profession insists that the use of drugs to substitute for the output of the thymus organ and the pineal gland, or to stimulate their renewed activity, or even to reduce the number of free radicals in the body, is a total waste of time and money. The general public, on the other hand, often seems to agree with the student who answered the question on an English test, "What is a word for an ignorant pretender to medical knowledge?", with "A doctor."

At any rate, there is current widespread interest in such non-prescription drugs as melatonin, Co-enzyme Q, Vitamin C, Vitamin E, Vitamin B-6, Vitamin B-12, DHEA (de-hydro-epi-androsterone), and SAM (S-adenosyl-methionine). In less than ten years we will have evidence as to whether these diet additives have any beneficial effect on the aging process. Meanwhile, many people are not waiting. The drugs may be no more than stop-gap measures, retarding aging but certainly not halting or reversing it; but, the logic goes, that's a good deal better than nothing.

One other whole-body function seems to correlate with aging. The first signs that we are beginning to age appear when our bodies stop growing. Moreover, animals such as carp, which grow continuously, also seem to live indefinitely long. They die only when some disease or predator disposes of them.

Continuous growth hardly appears an answer for humans. I doubt if anyone wants to be twelve feet tall and fifteen hundred pounds, unable to move or even to stand up. But might there be some "growth extract" that we could take from animals, to increase our own life expectancy?

I'm not optimistic. In any case, the science fiction story using that idea was written long ago. In Aldous Huxley's book AFTER MANY A SUMMER DIES THE SWAN (Huxley, 1939), an eccentric old oil magnate adopts the unpleasant diet of "triturated carp viscera" — chopped-up carp guts. He lives to be over two hundred years old, but at a price. Like Tithonus who asked the gods only for immortality, he does not die but continues to age. As he does so he goes through a process of devolution, by the end of the story becoming an ape.

I'm not sure any of us want that. On the other hand, for another century or more of life... maybe just a trial taste?



6.7 Tissue engineering. It is a great annoyance when the "dumb beasts" of the animal world do things that we supposedly super-smart humans cannot; not just things based on specialization of body structure, such as flying like an eagle, swimming like a dolphin, or jumping like a flea, but things which by all logic our bodies should be able to manage without modification.

Why can't we hibernate or estivate, slowing our metabolism in times when food or water is short? Surely that was once a valuable survival mechanism, even if food for many of us is now almost too easily available. Still of importance today, why can't we grow a new finger or foot if we lose one, or connect a spinal cord severed by injury? We grow new skin without any problem, so some regeneration capability is clearly built in to us. But amphibians can grow whole new limbs, which means they also have the capacity to regenerate nerve cells.

If we cannot re-grow a limb or an organ, you might think that we ought at least to be able to accept one from some other human donor. The heart is nothing more than a pump, and one person's pancreas is in all important details exactly like another's. Livers, spleens, testicles or ovaries, hearts, wombs, lungs and kidneys are functionally identical in you and in me. It seems reasonable that you should be able to take one of my kidneys if yours are failing.

As the first surgeons to attempt organ transplants quickly learned, it's not so easy. The operation is relatively straightforward, but unless the donor happens to be your identical twin there is a big danger of organ rejection. The body treats the new part not as an essential and helpful component of itself, but as an intruder.

The problem lies not at the organ level, but at the cell level. Our bodies, as part of their defense mechanisms against invading organisms, seek out and destroy anything that does not carry the correct chemical markers that denote "self." The body functions that perform such recognition, and label something as "friend" (ignore) or "foe" (destroy) are known collectively as the immune system. Identical twins have the same immune system, and transplants between such twins are not rejected. Lacking an identical twin, your chances of a successful transplant are best if your organ donor is a close relative.

Today, organ transplants are usually accompanied by drugs that inhibit the action of the immune system. That, of course, carries its own risk. What happens when the bacteria of disease enter your body after a transplant operation? Without your immune system to recognize and devour the intruders, bacteria will multiply freely. You will die — not from organ rejection, but from some conventional infection.

Transplant patients live on the fine edge between two dangers. Too many immune system inhibitors, and infection gets you; too few, and the new organ is rejected by the body. When the immune system is weakened, it is vital to recognize the signs of disease and use antibiotics and other drugs to fight it in its earliest stages.

Is there a way out?

There is, but it is not yet a standard part of the medical community's arsenal. It is known as tissue engineering.

The basic idea is simple. Suppose that one of your body organs is failing. To be specific, let us suppose that it is your kidney. Even a diseased kidney has healthy cells. If we could just take a few of those cells, and encourage them to divide and multiply in the right way (including making structural components of the kidney, such as veins and arteries), then we could grow a whole kidney outside your body. When we performed the transplant, the new kidney would be in no danger of rejection. The immune system would identify the replacement organ as "self."

Unfortunately we cannot grow a kidney in vitro, using some nutrient bath; and if we try to grow a copy of one of your kidneys in some other person or animal, the host's immune system will send up the red flag that denotes "enemy," and proceed to destroy the intruder cells before they can begin the task of kidney construction. Again, we seem to be stymied.

However, occasionally an item appears in the news about a "bubble child." This is a person who has been born without a working immune system. The only way this unfortunate can survive is by complete isolation from all people and diseases. It is a precarious existence, and the fact that such a person could in principle accept any organ transplant without rejection is little consolation.

What nature occasionally does to humans, scientists have been able to do with animals. Lines of mice and rats have been bred that lack immune systems. They will not reject foreign tissue introduced into their bodies. Suppose that we introduce under the skin of such an animal a mold of porous, biodegradable polymer, configured to match the shape and structure of a kidney. We "seed" this mold with cells from your own kidney. These cells will be nourished by the blood of the host mouse or rat. They will multiply, to produce a whole kidney as the biodegradable "scaffolding" dissolves away. There will finally be a whole kidney, ready for removal and use as a replacement for your own failing kidney.

That is the idea. The execution, to make any organ we choose, is years in the future. At the moment there has been success only with the growth of cartilage. The other organs mentioned represent a far tougher problem.

There is also the problem that a mouse or rat is much too small to support the growth of a human liver weighing three pounds or more. In addition, some people would certainly find such a use of animals inhumane and unacceptable.

My own preferred solution to both problems is simple. The one living organism in the world whose immune system is guaranteed not to reject my tissue is me. When tissue engineering is perfected, I will grow copies of my own heart, lungs, and other necessary organs, on or in my own body, in advance of need. When full-grown they will be removed from me and placed in cold storage until the time comes to use them.

As a final note, let us recognize that for some diseases organ replacement will never be an option. This is the case with anything affecting the brain. Alone of all our organs, the brain contains our sense of identity. Another approach can then sometimes be used. Fetal tissue has not yet developed its own characteristic signature for immune system recognition. Thus, implanted fetal tissue is less likely to suffer rejection by the host body. Parkinson's disease is characterized by a loss of dopamine production. The implanting of fetal dopamine-producing tissue in a patient's brain alleviates the worst symptoms of the disease.

The most effective such tissue is human fetal tissue. The treatment does not, of course, produce a cure. It also leads, in an aggravated form, to ethical questions similar to those arising whenever animals or humans become a part of human medical procedures.

A discussion of other ethical questions and possible societal response to tissue engineering can be found in a novel by Nancy Kress, MAXIMUM LIGHT (Kress, 1997).

Copyright © 1999 by Charles Sheffield
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Baen Books 02/02/03