Dangerous Misprints

M.F. Perutz

We are now within reach of being able to map all the genes on the human chromosomes, some hundred thousand of them maybe, and to decipher all the genetic information that defines a human being. This will include its sex, the chemistry of its body and its predisposition to a variety of diseases, but not, at least not yet, its personality. All this information is laid down in the human germ cells. Each of them contains 46 chromosomes, worm-like objects only just visible under a good light microscope. Each chromosome is made up of two chains of deoxyribonucleic acid, DNA for short, combined with protein. Along these chains, the genes are spread out in a linear order. A complete genetic map might tell us, for example, that the gene for little Johnny’s brown eyes is number 1349 on chromosome 23, but it would not explain why Johnny tells so many lies. So what use would that map be to you and me? Not much, as long as we keep in good health, but many serious scientists believe that such a map would be of signal benefit to medicine. On the other hand, it would also face us with formidable new moral, social, financial and legal problems. This book recounts some of the scientific adventures that brought the Genome Project into being and presents the cases for and against it, but without attempting any judgment about their relative merits.

The remarkable new scientific developments which it describes originate from a discovery by Oswald Avery, an American bacteriologist of English parents who devoted his life to finding out why some of his pneumonia patients recovered, while others died. In 1943, very near the end of his career, he solved the problem. His patients were liable to be infected by two different strains of pneumococci, distinguished by the presence and absence of only a single gene. To his own and the entire scientific world’s surprise, Avery and his collaborators found that the lethal gene was made of DNA. At first few scientists believed that so simple a molecule could specify genetic information, but its role became clear when Francis Crick and Jim Watson in Cambridge determined its three-dimensional structure. Their famous double helix showed how the genetic information is written on DNA and how it is copied every time a cell divides. Some years after this, scientists also deciphered the genetic code.

Occasionally, very rarely in fact, an error occurs in the copying of the message that makes up a gene. Even more rarely, such an error manifests itself in a malfunction or absence of the protein specified by that gene, and gives rise to a congenital disease. Queen Victoria, for instance, carried the gene for haemophilia which surfaced in some of her male descendants as a malfunctioning of a protein needed for the clotting of blood: consequently several of them bled to death.

Thanks to discoveries made over a span of many years, the genes responsible for haemophilia and several other congenital diseases have recently been mapped. The scene was set by an apparently irrelevant observation made in 1952 by Jean Weigle, a Swiss biologist in California. Weigle was puzzled by a virus that thrived in one strain of coli bacteria, languished at first in another closely-related strain, and then mysteriously regained its former vigour. Years later, another Swiss biologist, Werner Arber, decided to follow up Weigle’s seemingly trivial observation. Arber found that Weigle’s second strain restricted the virus’s growth, because it contained a scissor-like enzyme that cut its DNA. After a while the virus mobilised its defences against the bacterial scissors and thrived as before. The enzyme did not cut the DNA randomly, but at a specific word which, like ‘madam’, read the same either way and which the enzyme evidently recognised.

Until 1973 Arber’s discovery did not look like one that could be put to practical use. In that year Daniel Nathans, a biologist in Baltimore, wanted to find out which of the genes carried by a tumour virus actually made tumours grow. He happened to work in the same laboratory as Hamilton Smith, who had succeeded in isolating and purifying an enzyme similar to Arber’s. Nathans therefore borrowed some of it to cut his long viral DNA chain into shorter pieces. After that he put the fragments on a strip of wet blotting-paper and passed an electric current through it. Being negatively charged, the DNA fragments migrated to the positive pole; the smallest fragments went fastest and the largest lagged behind. When the current was switched off, the fragments formed a set of bands according to their size. Each band contained one or several genes; one of these contained the tumour gene that Nathans had been looking for. In deference to Weigle’s original observation, Smith called his enzyme a restriction enzyme and Nathans called the pattern of bands a restriction map. Nathans’s new method offered a simple way of isolating genes, and a useful way of characterising DNA.

Since that pioneering work scientists have isolated hundreds of different restriction enzymes from micro-organisms, each cutting DNA at different words and into fragments of different lengths which line up in an electric current to give a different restriction map. The maps are characteristic for each species – maps from dog DNA differ from those of human DNA. In addition, not all human maps turn out to be exactly the same. Scientists found slight differences in the positions of single bands on the maps derived from different individuals, which implies that at some time in the past a misprint in the genetic message has shifted the position of the word at which a restriction enzyme cuts the DNA. These harmless misprints are inherited. Since a child inherits half of its DNA from each parent, half of the bands on any one restriction map are inherited from the father and half from the mother.

Very occasionally, a harmless misprint that causes the DNA to be cut in a position different from that found in the bulk of the population occurs in an individual who also suffers from a genetic disease, due to an unknown misprint that you are trying to detect. If the disease and the harmless misprint are inherited together, there is a likelihood that the latter occurs on the same chromosome as the misprint responsible for the disease. This can be a clue to guide the investigator to the position of the diseased gene, but only if he can prove that the harmless misprint and the disease have been inherited together in many affected families over several generations.

Genome begins with the tragic story of Leonore Weber, a healthy, active, middle-aged woman who suddenly went down with a terrible disease that rots and finally kills the brain – Huntington’s Chorea. Unlike cystic fibrosis, Huntington’s Chorea kills even if it is inherited from only one parent. Carriers do not realise that they harbour it until it suddenly erupts in middle age, perhaps only after they have passed the fatal gene on to some of their own children. Mrs Weber’s daughter Nancy was nagged by the fear that she, too, harboured the deadly gene, but she soon learned that there was no way of finding out. Her father then set up a foundation for the study of inherited diseases, and she mobilised scientists to search for the responsible gene.

She heard of a community in a remote Venezuelan fishing village where Huntington’s Chorea was common and dreaded as ‘El Mal’. Nancy Weber went there, befriended the affected families and then organised expeditions to establish its incidence among them. She took blood samples from all of them back to America for analysis of their DNA and found a young scientist, James Gusella, who was eager to search for the gene, even though the chances of finding it seemed remote.

Against all odds, however, he and his collaborators succeeded in locating it on one specific human chromosome, although no one has yet been able to pinpoint its position there. Nancy Weber was thrilled all the same. Scientists, overjoyed that restriction mapping had, for the first time, homed in on a gene for a congenital disease whose cause was unknown, hoped that it would soon become possible to diagnose the gene’s presence in symptom-free carriers or in unborn babies. Their hopes have been realised, but the gene itself and the deleterious protein specified by it remain to be identified, and consequently there is as yet no cure in sight.

This situation has given rise to heart-rending dilemmas. Nancy Weber told the authors of Genome: ‘Knowledge alone does not provide the support you need for your life; you must know there is hope.’ And as yet there is none. As far as I could tell, she had not yet brought herself to face the diagnostic test. Another woman with a family history of the disease finally did decide to take the test, because she found that ‘it’s the waiting and wondering that kills. It kills from within.’ When the result was negative, a crushing weight was lifted from her mind, but later, when her brother came down with it, she felt guilty at having escaped it herself. Some people have committed suicide after being told that they harbour the gene. On the other hand, the authors describe the immeasurable joy of affected couples whom pre-natal diagnosis has assured that their child will be free from it.

Genome relates a succession of exciting scientific adventures that led to the discovery of the genes of other congenital diseases: muscular dystrophy, cystic fibrosis, retinoblastoma (an inherited cancer of the eye) and Tay-Sachs Disease, an inherited degeneration of the brain in small infants, frequent among Sephardic Jews. Scientists have also located genes that can predispose people to colorectal, lung or breast cancer, and to cardiovascular disease, manic depression, schizophrenia or alcoholism. Some of these diseases manifest themselves if inherited from only one parent; others only if inherited from both. Some are caused by defects in single genes, while others surface only when two or more genes are affected, or if habits like smoking or unhealthy diets collude with the predisposition.

Techniques are now available for detecting the presence of any of these genes in a single human cell. It might be a cell that has been detached from a fertilised egg after it has divided a few times, or from the membrane surrounding an eight-week-old embryo, or it might be an adult white blood cell. The information derived from such a genetic screen may bear on a person’s future health, life-expectancy and mental stability. Science has presented us with these far-reaching new possibilities before their implications have been thought through.

In the United States, doctors and scientists are worried that commercial pressures and fear of damage suits may precipitate routine genetic screening before it has been made sufficiently reliable, before counsellors have been trained to explain the often complicated meaning of the results and before the public has been taught the elements of human genetics and statistical probability. Insurance companies fear that confidentiality of test results would allow people with a short life-expectancy to cover their families by large life policies. On the other hand, if companies were to make life policies conditional on genetic screening, and if they were to refuse policies to people at high risk, then an underclass would be created to whom death of the breadwinner spells ruin. Screening could also lead to much unjust discrimination. Employers may turn down men with a predisposition to alcoholism because they fail to understand that four-fifths of the people with such a genetic predisposition never become alcoholics and that only a quarter of the men who do become alcoholics are genetically predisposed to the habit. Parents may be persuaded to abort foetuses with a genetic predisposition to alcoholism or manic depression, forgetting that Ernest Hemingway was an alcoholic, Virginia Woolf a manic depressive, Dostoevsky an epileptic. Lincoln is suspected to have suffered from a hereditary connective tissue disorder. Achievement does not necessarily go with good health.

Genetic screening could be beneficial if it were to be restricted to the most common life-threatening diseases, or to cases where there is a family history of congenital disease. Otherwise, we might finish with a society of genetic hypochondriacs. For example, ∝1-antitrypsin deficiency is an inherited defect that predisposes people to emphysema, particularly if they become smokers. Some years ago, the Swedish Government decided that much ill health could be avoided if new-born babies were screened for the deficiency, and parents of affected babies were told to warn them later on to avoid smoking. In fact, this screening led to so much morbidity as a result of guilt, recrimination between married couples, and quarrels with in-laws for having brought a deleterious gene into the family, that the Swedish Government had to abandon it.

Supposing a woman is told she is predisposed to breast cancer. There is nothing she can do about it short of always watching for its first signs. This may help her to have the tumour removed in time, but would that advantage outweigh the effects of life-long anxiety on her own health and on the health of those around her? Anxiety is known to depress the immune response, which could contribute to the development of the very tumour that genetic screening was meant to forestall. These potentially counterproductive aspects of genetic screening for diseases that you might – or might not – get are not mentioned in Bishop and Waldholz’s book and, so far as I know, have not been publicly aired.

Their book gives an accurate and readable account of the scientific advances that have placed a complete map of the human genome within our grasp, and it warns of many of the difficult issues that its possession would raise. In places it is marred by unnecessary hype and irrelevant gossip. Each study is made into a race and each result hailed as a breakthrough. Scientists’ motivation is painted as purely opportunistic and competitive. ‘A budding star scientist’ takes up restriction mapping of human diseases ‘because it would assure him of an ample and steady stream of research funds and a large laboratory at some prestigious university’. Oswald Avery, Jean Weigle and Werner Arber and the other pioneers harboured no such ambitions when they sowed the seeds of the genome project, nor would they have looked upon themselves as ‘budding star scientists’. They were not engaged in any race, because no one else had thought of pursuing the same fundamental problems. Races are run mostly when the path is already obvious.

We read of scientists who said that it would take them no more than five million dollars and five years to locate the gene for muscular dystrophy. Their boast reminded me of a man who claimed that given a million dollars he would solve the structure of proteins in five years. He got the dollars, but to no avail, because he went about the solution in the wrong way. In science dollars are helpful but ideas are decisive. Many more of these will be needed to bring the Human Genome Project to fruition in a reasonable time.

Will its benefits outweigh its drawbacks? I believe that detailed knowledge of the human genome will reduce the sum total of human suffering, partly by its potential for diagnosis, and partly because it will deepen our understanding of cancer and other non-infectious diseases. In time this will also lead to better treatments. The dangers to society are very real, but they could be mitigated by enlightened legislation. It worries me, though, that the billions of dollars to be spent on the Genome Project are likely to benefit only the people in the rich world who are already very healthy, but will do nothing to rid the vast majority of people in the poor world of the host of crippling and deadly parasitic diseases that are the real scourge of mankind. On these very little money is being spent, and there has been no clarion call to stir scientists to action.