Strands of Life.
The race to find and map all human genes will likely end this year. This is years ahead of the original schedule set by the government-funded Human Genome Project, but stiff competition from the private sector, particularly from Celera Genomics, is now setting the pace of scientific discovery. Celera announced in April that it had completed the sequencing phase of an individual human being's genome and had now begun to assemble the genome segments into their proper order. In other words, Celera has completely read all of the 3.2 billion DNA base pairs that make up a person's genome.
The four DNA bases--adenine, thymine, cytosine, and guanine (ATCG)--combine into 64 three-letter genetic "words" called "codons" that specify a set of 20 amino acids and three "stop" signals. These amino acids, when linked together by reading the DNA that form the various genes, create the thousands of different proteins that make up the human body. These billions of DNA bases are located on 23 pairs of chromosomes which are harbored in nearly every human cell. Such genetic information is really packed into us: If all of the DNA in a single human cell were stretched out, it would reach six feet in length.
By the time you read this, both Celera and the Human Genome Project likely will have completed draft versions of the human genome. What's more, Celera is sequencing the genomes of six men and women of differing ethnic backgrounds to find single nucleotide polymorphisms (SNPs). The SNPs are single-letter variations in genes that differ among people and that determine, among other things, susceptibility to disease and the ability to combat illness. The British Wellcome Trust and various pharmaceutical companies are also searching for SNPs by funding an "SNP Consortium" that plans to identify at least 300,000, and perhaps as many as 1,000,000, of the most common SNPs in human populations.
The speed with which all this is happening is fantastic. Just consider what has happened in half a year. In the December issue of Nature, the Human Genome Project published the genetic sequence of the first human chromosome to be fully mapped, chromosome 22. Chromosome 22 contains 545 known genes and perhaps as many as 1,000 in total. Some 27 human maladies, including one involved with schizophrenia, are linked to changes in genes on chromosome 22.
In March, Celera, working with the Berkeley Drosophila Genome Project, published the complete genome of that most important genetic research animal, the fruit fly Drosophila melanogaster. (Because fruit flies have relatively large, easy-to-see chromosomes and multiply so quickly, scientists have long used them to track genetic processes.) Writing in Science, the researchers identified nearly 14,000 genes, making the fruit fly genome the largest so far sequenced. The fruit fly is also the first insect and the first organism with a central nervous system to be sequenced. (The genomes of several bacteria and the nematode worm C. elegans had been sequenced earlier.) In April, the Human Genome Project announced that it had assembled "working drafts" of human chromosomes 5, 16, and 19. Working drafts mean that 90 percent of the DNA in the three chromosomes have been "read" at least five times. Each reading--or, if you will, each spell-checking--increases the accuracy of the sequences; reading a sequence 10 times i s considered necessary for complete accuracy.
In the May Nature, the Human Genome Project published the complete sequence for the smallest human chromosome, chromosome 21. Chromosome 21 contains only 225 genes, but those genes are important: Inheriting three copies of the chromosome causes Down Syndrome, the most common form of mental retardation, affecting one out of every 700 live births.
Based on the gene frequencies found on chromosomes 21 and 22, some researchers now believe that the total number of genes that it takes to make a human being might be as few as 40,000, rather than the 70,000 to 140,000 predicted earlier. In fact, there is now a betting pool among genomic scientists as to exactly how many genes go into human beings. (The bets cost $1 per guess this year, $5 next year, and $20 in 2002.) The result will be officially announced in 2003, on the 50th anniversary of the publication of James Watson and Francis Crick's famous double-helix paper, which first described the structure of DNA.
Because so much exciting progress is being made in genomic research, one wants a sure guide to help one understand where the science is going. Fortunately, that guide is at hand: Matt Ridley's excellent Genome: The Autobiography of a Species in 23 Chapters. Ridley, a zoologist and former American editor for The Economist, is both a knowledgeable scientist and an easy-to-read writer. Each of his chapters tours one of our 23 chromosome pairs, the structures inside our cells' nuclei on which our genes are located. By focusing on a particular gene at a time, Ridley is able to illustrate how genes cause disease, direct the production of proteins, or influence intelligence.
For example, the gene for the devastating disease Huntington's chorea is found on chromosome 4. It is not known what a "healthy" version of the gene does, but it contains a single codon, CAG (cytosine, adenine, and guanine), which is repeated as few as six times or as many as 100. "Your destiny, your sanity and your life hang by the thread of this repetition," explains Ridley. When the CAG codon is repeated 35 times or fewer, there is no disease, but if the repetition is higher, inevitable madness looms. "The age at which madness will appear depends strictly and implacably on the number of repetitions of the word CAG in one place in one gene. If you have thirty-nine, you will have a ninety per cent probability of dementia by age 75 and will on average get the first symptoms at sixty-six; if forty, on average you will succumb at fifty-nine; if forty-one, at fifty-four; if forty-two, at thirty-seven; and so on until those who have fifty repetitions of the word will lose their minds at roughly twenty-seven year s of age," writes Ridley. "The scale is this: if your chromosomes were long enough to stretch around the equator, the difference between health and insanity would be less than one extra inch." Ridley points out that since 1986 there has been a test for Huntington's, but only 20 percent of people at risk have chosen to take it.
The news, of course, is not always bad. Looking at chromosome 6, researcher Robert Plomin has found that children with high IQs--around 160--are twice as likely as the general population to have a slightly different version of the IGF2R gene. IGF2R is associated with insulin-like proteins and may have an effect on how a person burns glucose to produce energy in the body. It is not obviously a gene for intelligence, but according to Ridley, "it is perhaps relevant that another study has found that people with high IQs are more efficient at using glucose in their brains." The IGF2R variant apparently can add four points to your IQ. Plomin believes that he has identified perhaps 10 other "intelligence genes." While Ridley points out that "no study of the causes of intelligence has failed to find a substantial heritability," he also notes that untangling environmental from genetic influences on intelligence is impossible. "You inherit not your IQ but your ability to develop a high IQ under certain environmental c ircumstances," he concludes.
One of the more fascinating discoveries made by genomic researchers is that "ninety-seven percent of our genome does not consist of true genes at all. It consists of a menagerie of strange entities called pseudogenes, retropseudogenes, satellites, minisatellites, microsatellites, transposons, and retrotransposons: all collectively known as 'junk DNA.'"
For example, our genome contains the nearly complete genomes of several thousand viruses that infected our ancestors and then hitched a permanent ride in our bodies. Unlike viruses for the common cold or those associated with AIDS, human endogenous retroviruses no longer bother with the tedious effort involved in infecting and taking over cells. They've instead taken up cozy residence inside our cells and they "infect" other human beings simply by being passed along from parents to children the same way hair and eye color are.
Another parasitic form of DNA is retrotransposons. One version, known as LINE-1, is essentially a gene that instructs your genome to make and insert more of itself in your genome. LINE-1 comprises 14.6 percent of the entire human genome--making it five times more common than actual genes. "Approximately thirty-five per cent of human DNA consists of various forms of selfish DNA, which means that replicating our genes takes thirty-five per cent more energy than it need," writes Ridley. "Our genomes badly need worming."
Genomic research is also illuminating such questions as, How does a fertilized egg organize itself into something as complex as a human being? A good part of the answer lies on chromosome 12. A crucial breakthrough in developmental genetics occurred in the 1970s, when two German scientists working with fruit flies found a series of eight genes lying together on the same chromosome; these were later called "Hox genes."
"What is truly strange," writes Ridley, "was that each of the eight genes affected a different part of the fly and they were lined up in the same order as the part of the fly they affected. The first gene affected the mouth, the second the face, the third the top of the head, the fourth the neck, the fifth the thorax, the sixth the front half of the abdomen, the seventh the rear half of the abdomen, and the eighth various other parts of the abdomen." To appreciate how odd this was, explains Ridley, one must appreciate how random the locations of genes usually are: "[T]here is very little rhyme or reason for where a gene lies. Sometimes it needs to be close to certain other genes. But it is surely rather literal of Mother Nature to lay these homeotic genes out in the order of their use."
As important, it turns out that each of the genes contains the same bit of a "text" that is always 180 "letters" long. Now known as the "homeobox," this information "is the bit by which the protein made by the gene attaches to a strand of DNA to switch on or off another gene. All homeotic genes are genes for switching other genes on or off," explains Ridley. Such genes essentially tell other genes to get to work on making heads, abdomens, and tails. If the head homeotic gene fails to switch on the cascade of genes that construct the head, then the animal won't develop a head.
Having identified the homeobox segment, researchers searched for it in other organisms. Mice, it turns out, have 4 clusters of Hox genes, which are laid out in the same head-to-tail way as they are in the fruit fly. Humans have the same Hox clusters as mice, one of which is located on chromosome 12. Interestingly, the first gene in line is the first one to be expressed followed in temporal order by the others. "All animals develop from the bow to stern ...At the level of embryology we are glorified flies," jokes Ridley. "The evolutionary implication is that we are descended from a common ancestor with flies which used the same way of defining the pattern of the embryo more than 530 million years ago, and that the mechanism is so good that all this dead creature's descendants have hung onto it."
Ridley explores how genomic research will eventually help doctors treat heart disease, cancer, dementia, arthritis, diabetes, and other diseases. For example, a defect in the ADA gene on chromosome 20 causes severe combined immune deficiency (SCID), which renders the sufferer incapable of fighting off infections. Originally, researchers thought that SCID could be cured if the normal gene could somehow be inserted into a patient's genome. In a pioneering experiment in 1990, French Anderson and Michael Blaese used genetically engineered retroviruses to deliver normal ADA genes to a 3-year-old girl. Her immune response improved somewhat, though not completely. In late April, French scientists reported that two infants suffering from another type of SCID were developing normal immune systems after normal genes were introduced into their bone marrow using genetically modified viruses. Gene therapy may have its first unqualified success.
Ridley is not only good at explaining the science, but is also sound on policy. Unlike so many other authors of books on genetic science, he doesn't waste a lot of time decrying the supposed ethical conundrums posed by scientific progress. He crisply dismisses ethical concerns about the type of gene therapy that cures diseases like SCID. "It is just another form of therapy and nobody who has watched a friend or relative go through chemotherapy or radiotherapy for cancer would begrudge them, on far-fetched safety grounds, the comparatively painless possibility of gene therapy instead," he asserts.
Ridley also investigates the long, sorry history of eugenics. He documents not only well-known Nazi attitudes on the subject but also those of the Fabian socialists, including H.G. Wells, John Maynard Keynes, and George Bernard Shaw. They all believed, notes Ridley, in "the urgent need to stop stupid or disabled people from breeding." H.G. Wells was particularly creepy, writing, "It has become apparent that whole masses of human population are, as a whole, inferior in their claim upon the future. To give them equality is to sink to their level, to protect and cherish them is to be swamped by their fecundity." Wells did have a touch of compassion in him, however. "All such killing," he insisted, "will be done with an opiate." Ridley concludes his discussion of eugenics by insisting on a distinction ignored by many who indiscriminately inveigh against all forms of genetic manipulation. "Many modern accounts of the history of eugenics present it as an example of the dangers of letting science, genetics especial ly, out of control," he writes. "It is much more an example of the danger of letting government out of control."
Such clear thinking is particularly valuable on a topic that often gives rise to muddy arguments. Indeed, Genome disappoints on only one count: It was written at the dawn of an enormously important era. As exciting as the news about genetic research has already been and will certainly be later this year, it will be even more breathtaking over the next few decades. According to Steve Fodor, president of the biotechnology company Affymetrix, "Ninety-nine percent of people don't have an inkling about how fast this revolution is coming." To Matt Ridley's credit, readers of Genome will have far more than an inkling.
Ronald Bailey REASON's science correspondent and the editor of Earth Report 2000: Revisiting the True State of the Planet (McGraw-Hill).
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|Article Type:||Book Review|
|Date:||Aug 1, 2000|
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