| THE BOOK OF MAN The Human Genome Project and the Quest to Discover Our Genetic Heritage Walter Bodmer Robin McKie New York: Oxford University Press, 1994 |
Rating: 5.0 High |
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| ISBN 0-19-511487-6 | 259pp. | SC/BWI | $13.95 | |
This book opens on a sinister scene.1 The left-handed warriors of the Kerr clan have just recaptured their ancestral home, Ferniehirst Castle, from a garrison of English troops. The dreaded southpaw swordsmen slaughtered their foes to a man. The authors use this famous incident2 to illustrate the complexity of the interaction between genetics and environment — nature and nurture.
Chapter 2 describes the first flowering of the science of genetics. At the beginning of the 20th Century, the work of Gregor Mendel on peas3 and Karl Landsteiner on human blood groups laid the foundation for understanding the rules according to which characteristics were inherited. Study of the processes of chromosome separation during cell division (first observed in the large cells of the horse threadworm during the 1880s) led to a concrete mechanism for those rules.
The late 19th Century also saw the first attempts to elucidate the chemistry of life. Indeed, it was a Swiss chemist, Johann Miescher, who in 1868 first isolated and analyzed the nuclei of cells, finding them to contain a substance rich in phosphorus, which he named nuclein. The story of this fascinating investigation, with its many contributors, is told in Chapter 3. The tale involves diseases like sickle-cell anemia, and culminates with Watson and Crick describing the structure of the DNA molecule.
We learn in Chapter 3 of Fred Sanger, who painstakingly disassembled the protein insulin and revealed its structure. But Sanger comes into his own in Chapter 4, Lords of the Genome, where he goes beyond this Nobel-prize-winning achievement to a relatively quick method for sequencing (discovering the exact sequence of bases on) the DNA molecule. In essence, what he did was to combine single-strand DNA with four mixtures of the A, C, G and T bases. Normally, this would produce complete DNA molecules. Sanger's insight was that if each of the mixtures were deficient in one base, the replication would stop when it ran out of that base, leading to fragments of varying lengths. Determining these lengths would pinpoint the locations where the missing base belonged.
This idea, so elegant in principle, proved ineffective in practice. But Sanger scored with his next attempt, which along with full supplies of the four bases used variants of them called dideoxy terminators. The variant molecules would be inserted into the developing strand like normal A, C, G, or T — but once in place they would stop the replication. Samples from the four flasks were placed in parallel electrophoresis tracks, which separated the fragments by length. In this way, Sanger was able to sequence 300 bases at one go. (Previously, the best rate possible was a few dozen per day.) Then, using the technique from his insulin reconstruction, he overlapped the sequences at matching points to get the complete picture. The genome for the first organism sequenced, bacteriophage phi-X-174, was published on 24 February 1977. In 1980, it earned Sanger his second Nobel Prize in science. Only Marie Curie and John Bardeen have done likewise.4
Sanger shared his 1980 Nobel Prize with Walter Gilbert of Harvard University. The two men are very different in character: Sanger is the quintessential dedicated researcher; Gilbert, equally competent as a scientist, is a power broker, ever ambitious for commercial success. Gilbert, working independently, came up with a sequencing technique that is in some sense a mirror image of Sanger's. But his renown comes from financial rather than scientific instruments; he is one of the biotechnology entrepreneurs whose activities inspired the title of this chapter. The chapter goes on to describe the birth of the modern biotechnology industry with a company called Boyer & Swan... a company called Swanson & Boy... a company called Genentech.5 It closes by describing the other key breakthroughs that form the foundation of that industry: gene-splicing (formally known as recombinant DNA techniques), restriction enzymes, and PCR, the polymerase chain reaction invented by Kary Mullis in 1983.
The authors describe many excruciating diseases. But nothing better illustrates the heartbreak such relatively obscure maladies can cause than Huntington's chorea, described in Chapter 5 (see pages 70-78.) Folksinger Woody Guthrie is perhaps the best-known sufferer of Huntington's. His wife Marjorie, along with California psychiatrist Milton Wexler and his daughter Nancy, in 1976 persuaded Congress to create a Huntington's Disease Commission. On page 73, Nancy recalled for this book some of the testimony the Commission heard:
We heard of people who had spent their life savings trying to get proper diagnosis of the disease; of a seventy-six-year-old woman, with no social security, who had to look after middle-aged sons who were so badly affected they had to wear nappies all the time; of people visiting relatives in psychiatric hospitals, hearing them screaming and seeing them tied up; of one woman who spent $26,000 on medical bills for thirty-one different doctors before anyone recognized her condition; of families that had been decimated by Huntington's; and of men and women who lost jobs because they were thought to be drunk. It certainly put Huntington's in context. |
![[Rant Warning]](../../../../RantWarn.gif)
Yes, it does. And part of that context, it must be said, is the abysmal quality of diagnosis provided. No one should have to visit thirty-one doctors to get their disease properly identified, no matter how rare that disease is (provided that it is not totally unknown). And Huntington's chorea is not that rare; it affects five out of every 100,000 births. It was described in 1872, and Woody Guthrie began to show its effects in 1951. Such defective diagnosis is not a problem specific to Huntington's chorea; it is a systemic and persistent shortcoming of the American medical establishment. But that is a topic for another day. Regarding Huntington's, this chapter shows that while even palliative measures remain elusive, those who are susceptible to its ravages can at least be identified and forewarned.
One paragraph on page 83 struck me as misleading. I quote it here in its entirety so the sense of it will come across.
(It is worth emphasizing at this point the exact difference between a recessive and a dominant disease. In the latter case, a mutant gene is doing something that actively harms the body, as we saw with Huntington's chorea. One gene, on its own, is therefore sufficient to do serious damage, even when its partner gene is normal. That is how the gene 'dominates'. But in the case of a recessive disease, the responsible gene is failing to make a crucial protein. In carriers, one gene makes enough of this protein for normal function, and the other makes none. Such is the plasticity of the human frame that these carriers usually get by on a half dose of protein. Only when a person gets two faulty genes are they in a position in which no functional protein is being made. Then they suffer from symptoms due to the lack of that protein.) |
My concern is that this ignores the body's feedback mechanisms. Look at it this way: With two functional genes making a certain protein, the expression of that protein will continue until a related feedback mechanism shuts it down because enough of that protein has been produced. With one gene unable to express that protein, the same thing should happen; it just might take longer. Thus there is no reason that half the genes would make half the protein. I'm not calling the above paragraph mistaken, but it may be an oversimplification of the true situation, judged appropriate for the book's lay audience.6 A passage on pages 201-202 seems to imply that one copy of a gene is sufficient:
In particular, from victims of ADA deficiency — one of the main types of "Scid" — it was found that the cause of the condition lay on chromosome 20 on which rests the gene responsible for manufacturing adenosine deaminase. This gene occasionally undergoes mutations; sometimes a tiny sliver of DNA is excised, now and then a fairly hefty section is missed out. For carriers with a normal gene on their other chromosome this is no problem. |
And then, on page 207, the original point is reinforced:
Familial hypercholesterolaemia comes in two forms. In the first, a patient lacks a single functioning gene that codes for the LDL receptor protein. It is the job of this receptor to mop up excess of cholesterol in the blood. Without such a gene operating on one chromosome, a person's power to eradicate cholesterol is halved. He or she has to work on genetic "half-power" with only one normal gene coding for a protein that eliminates excess cholesterol. |
All this suggests that there's something I'm missing. The key difference between these three cases may be the amount of a specific protein required by the body. ADA is one that is needed in relatively minute quantities.
New Scientist says this book is "Highly readable, clear, and accurate". I'll concur with that, and add that it conveys Walter Bodmer's lifelong passionate involvement in medicine. (Indeed, as Chapter 12 reveals, a fair case could be made that he is one of the "Lords of the Genome" — though not in the same sense as Walter Gilbert.) It covers a lot of ground. The 13 chapters could be divided into three parts: The first four chapters cover the basics; the next four describe the discovery and application of medical techniques for various diseases; and the final five deal with other applications of gene-mapping, and with their ethical implications. I found the wide-ranging discussion fascinating. The illustrations complement the text well and (with the exception of the one on page 93) are illuminating.
There are more errors that I could wish. (These are listed on the Errata page, linked below.) However, I was not distracted by them, and I conclude that my concern about "genetic half-power" is due to my own misunderstanding. If the book has a defect, it is that Bodmer is over-optimistic about the near-term prospects for the Human Genome Project, which was about halfway complete as this book went to press. The book is thoroughly indexed. I recommend it; I doubt there is a better introduction to the overall impact of genetic mapping.
To contact Chris Winter, send email to this address.