Twenty-three Short Chapters About Human Beings

December 21, 2000

Book review
James Case

Genome: The Autobiography of a Species in 23 Chapters. By Matt Ridley, HarperCollins, New York, 1999, 344 pages, $26.

Matt Ridley is a former science editor, Washington correspondent, and U.S. editor for The Economist. In this his third book, he aims to compress the entire natural history of the human race---along with those of its more significant ancestors---into a single volume. To that end, he builds each chapter around a single newly discovered gene located on one of the 23 human chromosomes. Numbering the latter in order of decreasing size, he associates a particular gene from each with a familiar aspect of the human condition. The resulting chapters bear titles like "Chromosome 6: Intelligence" and "Chromosome 10: Stress."

The association of chromosome 10 with stress seems natural: Chromosome 10 is the site of a gene called CYP_{17}, which enables the body to convert cholesterol into (among other things) a steroid called cortisol, which according to Ridley is "virtually synonymous" with stress. The other association is more of a stretch, reflecting nothing more than the fact that chromosome 6 is the site of a gene called IGF_2R, a rare form of which was found in 1997 to correlate with exceptional IQ scores. Other such genes have since been found on other chromosomes.

The book describes genes that we "hairless primates" share with bacteria, genes that distinguish us from chimpanzees, genes that parasitize us for their own selfish purposes, genes that allow us to remember, and genes that record the history of human migrations. With two separate "first drafts" of the human genome due to be published within the year, and with so much other progress being made in the field, the time seemed right for such a book.

Ridley begins at the beginning, with the fact that the human body contains about a hundred trillion cells, each containing a nucleus, in which (with certain exceptions) reside two complete copies of the human genome. He likens the latter to a book of about a billion (three-letter) words. Rendered in type of approximately the present size, the book would be half again as long as the Danube. The book contains 23 chapters, called chromosomes. Each includes several thousand stories, called genes. Each story is made up of paragraphs, called exons, which are interrupted by apparently meaningless digressions called introns. Each paragraph (exon) is made up of words, called codons. Each word is written in letters called bases, or nucleotides.

Whereas books written in English contain words of variable length, composed from a 26-letter alphabet, all genomes (be they animal or vegetable) are written entirely in three-letter words made up only of the letters A, C, G, and T, which stand for the bases adenine, cytosine, guanine, and thymine. Instead of being written on flat pages, genomes are written on long chains of sugars and phosphates called DNA molecules. Each chromosome consists of a pair of (very long and roughly parallel) "strands" of DNA, held apart by "rungs" corresponding to "base pairs" (either AT or CG) and twisted into the form of a "double helix."

A always pairs with T, and C with G; no other pairs can occur. This pairing property permits a single strand of DNA to assemble, under appropriate conditions, the complementary strand needed to make a complete chromosome, in an act known as replication. In practice, the pro-cess is somewhat more complicated. The DNA is first transcribed into RNA, which differs from DNA only in that thymine is replaced by uracil (U); the RNA then undergoes an
editing process in which all introns are removed. The resulting "messenger RNA" is next translated, one three-letter word at a time, by a microscopic machine in the nucleus known as a ribosome, into a string of amino acids, which then folds itself into a shape determined by its constituents, to become a protein. Almost everything in the human body is either made of or made by proteins. Every protein is a translated gene. The human genome contains an as yet undetermined number of genes, presumably 60,000-80,000, though some estimates run as high as 100,000 genes in all.

*****

The chapter titled "Chromosome 1: Life" begins not in 1953, with the discovery by James Watson and Francis Crick of the structure of the DNA molecule, but in 1943, with a rundown on the whereabouts of those destined to play important roles in the drama beginning to unfold. Many of the names are well known, if not always for their contributions to biology. Crick was working on the design of naval mines near Portsmouth, UK, while Watson was a 15-year-old freshman at the University of Chicago. Maurice Wilkins was helping to design atom bombs in the U.S. Rosalind Franklin was studying the structure of coal for the British government. Josef Mengele was torturing twins at Auschwitz, ostensibly in the name of science. Erwin Schroedinger was delivering a series of lectures titled "What is Life?" at Trinity College, Dublin.

Alan Turing was at Bletchley Park, a short distance north of London, helping to build a (modifiable stored-program) computer called Colossus for breaking military codes. Claude Shannon was at home in New Jersey, ruminating on the notion that information and entropy are opposite sides of a single coin, both intimately connected with energy. Like Turing, Shannon was not then concerned with biology. But both were learning to process, transmit, and interpret digital information---the kind of information contained in every genome---automatically.

Finally, in New York, a 60-year-old Canadian scientist named Oswald Avery was discovering that he could transform pneumonia bacteria from a harmless to a virulent strain merely by placing the bacteria in a certain chemical solution. Moreover, the virulence of the saturated bacteria was seen to be inherited by their offspring. When isolated, the active ingredient of the chemical solution turned out to be DNA. Avery couched his findings in such cautious terms that years were to pass before anyone began to suspect their significance.

It now appears that RNA first appeared on Earth about 4 billion years ago, shortly after the formation of the planet itself and long before the
appearance of DNA. Unlike both DNA and protein, RNA can reproduce all by itself. It needs only the right conditions and ingredients, both of which appear to have been abundant in the primeval soup.

RNA can act as a catalyst: It can cut long molecular chains, join the severed ends together, and even fabricate a few of its own building blocks. It can also operate on itself, cutting out a chunk of text and splicing the free ends together again. These remarkable properties---discovered during the early 1980s---suggest that the very first gene may well have been a combined replicator/catalyst, able to duplicate itself by combining then common reagents. Indeed, by repeatedly selecting randomly generated RNA molecules in a test tube for their ability to catalyze reactions, it is possible to "evolve" catalytic RNA from scratch. These synthetic RNAs often contain passages that read a lot like parts of the text of a ribosomal RNA gene, such as the 5S gene on chromosome 1 of the human genome.

There probably was, at one time, an entire RNA world. Yet because RNAs are chemically unstable, it is hard to imagine that such a world harbored extensive complexity or diversity. Those properties probably didn't emerge until certain varieties of RNA "learned" to store durable templates of chemically inactive materials like DNA nearby, from which they could clone themselves repeatedly. And if the environment in which all this was taking place had been rich in amino acids, the results might have included an RNA molecule capable of storing its genetic recipe on DNA, combining amino acids into useful proteins, and serving the two as a go-between. There may have been many such molecules, or only one, but evidence suggests that all surviving life on the planet is based on a single one of them.

The organism that presumably grew up around this widely postulated molecule is called Luca, for Last Universal Common Ancestor. New evidence suggests that she did not live in a warm slimy pond on the Earth's surface, as once supposed, but deep underground, among hot igneous rocks, dining on iron, hydrogen, carbon, and raw sulphur.

*****

One of Ridley's least amusing tales concerns the number 23. It seems that, in 1921, one Theophilius Painter sliced thin sections from the testicles of two black men and one white man who had been castrated by the state of Texas for insanity and "self-abuse." After fixing the samples chemically, Painter placed them under a microscope and tried to count the tangled mass of unpaired chromosomes in their thwarted spermatocytes. He found 24, and later expressed considerable confidence in his conclusion. Other observers employing other techniques soon concurred. Only in 1955 did an Indonesian named Joe-Hin Tjio, working in Sweden with superior techniques, observe that humans have only 23 chromosomes. He and his host Alfred Levan then confirmed the revised count from textbook photographs published over captions asserting the presence of 24!

Another of Ridley's cautionary tales involves Francis Crick's "comma-free code" for the 20 amino acids. In an effort to discover which of the 64 three-letter words that can be made from the alphabet {A,C,G,T} correspond to a given amino acid, Crick reasoned that AAA, CCC, GGG, and TTT should not occur, because long repetitions of a single letter are uncommon along strands of DNA. Moreover, the words ACT, CTA, and TAC should all correspond to the same amino acid, since repeated sequences of just two or three letters are not uncommon, and the ribosome assigned to perform the task might easily start reading such a sequence at the wrong place. The result was a code consisting of exactly 20 "equivalence classes" of three-letter words, one for each amino acid.

Unable to offer even a shred of empirical support for his suggestion, Crick tried to dissuade others from taking it too seriously. Indeed, the code's chief merit was that it gave 20, the magic number. But his efforts were in vain: For about five years, others in the field were inclined to believe the code correct. Only later was it found that a piece of RNA composed of pure U, corresponding to an uninterrupted sequence of Ts on a strand of DNA, placed in a solution rich in ribosomes and amino acids, will breed a protein consisting entirely of the amino acid phenylalanine. The first word of the code had thus been broken: UUU means phenylalanine. The most elegant solution to a problem need not always be nature's solution.

By 1965, the entire "genetic code"---which translates codons into amino acids--- was known, and the age of modern genetics had begun. Later, during the 1960s, the field took another giant leap forward with the discovery of restriction enzymes, which cut strands of DNA in very predictable places, making it possible to produce identical fragments of DNA for detailed study.

It appears, from the patterns of black bands on each, when viewed through a microscope, that chromosome 2---the second largest human chromosome---was formed long ago by the fusion of two medium-sized ape chromosomes. Chimps, gorillas, and orangutans---unlike humans---all have 24 chromosomes. This curious fact has been reconciled with the teachings of the Catholic Church by Pope John-Paul II. In his message to the Pontifical Academy of Sciences on October 22, 1996, he argued that there is an "ontological discontinuity" between ancestral apes and modern human beings---a point at which, as Ridley puts it, God injected an immortal soul into the animal lineage. Then if, as Ridley suggests, the fusion of the two ape chromosomes constituted the critical event, the genes for the soul should lie near the middle of chromosome number 2.

There certainly aren't a lot of other places to look for such genes. In 13 chromosomes, there is no visible difference between chimps and humans. In the other ten, the differences are minimal. There is no single bone in the chimp body that humans do not share. There is no known chemical in the chimpanzee brain that does not occur in the human brain as well. There are no known components of the human immune system, digestive system, vascular system, lymph system, or nervous system that chimps lack. Humans and chimpanzees have in common 98% of their DNA; humans and gorillas, and chimps and gorillas, are 97% identical DNAwise. If species were vertices in a graph, the edge separating chimps from humans would be the short leg in the (almost equilateral) triangle representing chimps, humans, and gorillas. Indeed, according to Ridley, no one even knows for sure whether chimps and humans can interbreed.

One of the themes that Ridley harps on is that, although genes may be associated with specific "genetic" diseases, the genes are not there to cause disease. A much-studied gene is located on chromosome 4. It consists of the single word CAG, repeated an indeterminate number of times. Little is known of the gene's ordinary function, except that it must be a vital one: A complete absence of it---zero repetitions---causes a condition known as Wolf-Hirschhorn syndrome, which is so serious that its victims invariably die in childhood.

In most people who do have the gene, the CAG is repeated about 15 times. While those in whom the word is repeated up to about 35 times suffer no ill effects, those in whom it is repeated 39 times or more eventually fall prey to a wasting disease known as Huntington's chorea. They start in midlife to lose their balance and to deteriorate intellectually. In time, they experience jerking limbs, occasional hallucinations, and delusions. The disease is incurable but takes 15-25 years to run its course. The more numerous the repetitions, the earlier the disease will set in; victims cursed with 50 or more repetitions succumb in their late twenties. Their fate lies sealed in their genes. There seems to be no escape.

Ridley dwells at some length on the issues raised by foreknowledge. Should a doctor inform the parents of a child doomed to develop Huntington's chorea? At what age should they inform the child? Should the doomed be discouraged from becoming parents? He points with some admiration to the efforts of Jewish Americans to protect their progeny from cystic fibrosis and Tay-Sachs disease, both of which are consequences of specific mutations of the BRCA2 gene, located on chromosome 13.

In the United States, the Committee for the Prevention of Jewish Diseases organizes the testing of schoolchildren's blood. When matchmakers later consider potential marriages, they can call a hotline and quote the anonymous number assigned to each child at the time of testing. If both potential partners are carriers of the same mutation, be it for cystic fibrosis or Tay-Sachs disease, the committee advises against the marriage. Compliance is purely voluntary. Tay-Sachs disease is becoming increasingly rare in the U.S., and cystic fibrosis has been all but eliminated from the American Jewish population.

Genes, according to Ridley, determine aspects of behavior as well as health. Mating behavior is perhaps the most obvious example. Chimps in the wild are promiscuous; gorillas are harem-polygamous, and humans tend to form lasting pair bonds. How, he wonders, can a collection of genes-strings of quaternary code-make an animal polygamous or monogamous? Although no one yet claims to know how such messages are transmitted, Ridley expresses confidence that a definitive answer will one day be found. Right or wrong on this point, his book is an artful blend of vital information and informed speculation.

James Case writes from Baltimore, Maryland.


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