Genetic screening aims to reduce the incidence of inherited diseases, which are responsible for about a third of all admissions of children into hospitals and one half of the deaths of children under fifteen. A committee of the National Academy of Sciences defines genetic screening as “a search in an apparently healthy population for those individuals with genotypes that place them or their offspring at high risk of disease.”
Neil Holtzman, a leading pediatrician and epidemiologist at Johns Hopkins University, has written Proceed with Caution to make people aware of powerful new technologies for genetic screening and to warn of their medical, social, legal, and financial implications. The technologies have sprung from scientific advances that are epitomized by a recent visit of mine to one of the new biotechnology companies. They treated me to seminars on their research and showed me all their expensive equipment until I finally asked: “What do you sell?” “We sell genes.” “How do you isolate them?” “We don’t, we make them ourselves.” Even ten years ago this would have been science fiction.
Holtzman introduces the biochemical basis of genetics and the complex interplay of genetic and other factors in health and disease. He describes the ingenious new methods of locating genetic lesions that are responsible for hereditary diseases, and, once located, of detecting their presence in suspected carriers. He fears that commercial pressures will lead to a premature spread of these new technologies, regardless of the tests’ fallibility, the pitfalls in their interpretation, and the emotional and social problems they may raise. Holtzman’s book is a lucid, richly documented, and forcefully argued plea to resist these pressures; it is addressed to physicians, and to administrators and legislators concerned with public health. I shall try to explain the molecular genetics of inherited diseases in plain words, describe some of the suffering caused by them, and discuss some of the evidence for and against screening.
Animal genes are made of long chains of deoxyribonucleic acid, DNA for short. The chains are twisted into a double helix that looks like a spiral staircase, with banisters made of alternate residues of phosphate and the sugar deoxyribose, and steps made of rings of carbon and nitrogen atoms. The rings are of four different kinds, called adenine, thymine, guanine, and cytosine. They provide the letters of the genetic alphabet, abbreviated as A, T, G, and C; their sequence along the DNA chain is the genetic blueprint that determines an organism’s identity. The sequences of the letters in the two intertwining chains are complementary, such that A is paired with T, and G with C. When a cell divides, the two chains separate and each serves as a template for the synthesis of a daughter chain with a sequence of letters complementary to that of the parent. In the process of replication, each of the parent chains forms a new double helix with its daughter chain; this new double helix contains a copy of the genetic information contained in the parent.
The real length of DNA packed into a single human sperm is about one meter; it fits into this tiny volume because the double helix is only two millionths of a millimeter wide. The DNA is distributed over twenty-three chromosomes, the rod-shaped bodies that carry the genes for hereditary characteristics arranged along them in a linear order. Each chromosome contains one continuous double helix. Together, the chromosomes contain between 50,000 and 100,000 genes, and single genes may contain between 100 and 10,000 pairs of letters. The total number of G–C and A–T pairs in a human germ cell is about one billion, the same as the number of letters contained in a library of about five thousand volumes. Each time a cell divides, this enormous amount of genetic information is copied within a few minutes, with an average of only a single misprint. It is one of the miracles of nature.
Genes are chemically inert, and their sole function is to carry the code that is translated by the cellular mechanism into proteins, the workhorses of the living cell. Most misprints are harmless, but very occasionally a misprint manifests itself as a mutation by preventing the synthesis of an essential protein or impairing its function. Even then, such misprints give rise to genetic diseases only very rarely, because body cells contain two copies of nearly all genes, one inherited from each parent, and a disease generally arises only if both copies are defective.
Cystic fibrosis is one of the most frequent inherited diseases. One out of twenty-two people in the white population carries the defect in one of his or her chromosomes. The probability that two such people join and beget a child is 1 in 22u2, or about one in five hundred, and the probability that the child inherits the defective gene from both its parents is one in four. Hence the average frequency of cystic fibrosis is about one birth in two thousand. Diseases that occur only when the defective gene is inherited from both parents are called recessive. Thalassemia, sickle-cell anemia, and phenylketonuria are other frequent recessive diseases.
Sometimes a defective gene causes disease even if its partner gene is healthy; there is a chance of one in two that a child inherits such a disease from one affected parent. Such diseases are called dominant. Many of them manifest themselves only after the onset of reproductive age; otherwise they would have died out. Or else they appear as new mutations. Huntington’s disease is an example of a dominant inherited disorder.
Finally, there are the diseases that can be traced to defective genes on one of the two sex chromosomes, called X and Y, of which males carry only single copies, while females have two X chromosomes and no Y. The genes that are defective in hemophilia, Duchenne muscular dystrophy, and color blindness lie on the X chromosome. Women are unaffected by these disorders since their other, healthy X chromosome compensates for the defective gene, but their sons have a fifty-fifty chance of inheriting it. Such diseases are called sex-linked, as opposed to those due to defects on other chromosomes, which are called autosomal.
Victor McKusick’s Mendelian Inheritance in Man catalogs the location of as many as 2,208 defective genes on human chromosomes that have been identified and another 2,136 that have not been fully identified or validated. J.B. Stanbury, J.B. Wyngaarden, and D.S. Frederickson’s The Metabolic Basis of Inherited Diseases is a work of 1,800 closely printed pages. New single gene defects are reported in the medical literature every two or three days. Each of us is believed to be a carrier of at least thirty recessive diseases.
Sir Thomas Browne in his Religio Medici wrote in 1643,
Men that look no further than their outsides, think health an appurtenance unto life, and quarrel with their constitutions for being ill; but I, that have examined the parts of man, and know upon what tender filaments that Fabric hangs, do wonder that we are not always ill; and considering the 1,000 doors that lead to death do thank my God that we can die but once.
Yet Browne’s “tender filaments” were at least a million times thicker than the double helixes of DNA.
Holtzman introduces the molecular genetics of inherited diseases, but he does not describe the ways in which they manifest themselves in illness; without knowing the suffering they cause, the lay reader may not be able to judge the merits of genetic screening aimed at reducing their incidence. I tried to fill that gap by reading the case histories of several children with cystic fibrosis, written in 1977 by Cecilia Falkman, a Swedish psychologist whose son has the disease.1 The parents of these children realized soon after they were born that something was wrong, because they vomited during meals, passed foul-smelling stools fifteen to twenty times a day, lay awake at night crying with stomach pains, and suffered frequent respiratory infections. It took some of the parents years of pilgrimage from doctor to doctor, from hospital to hospital, until the correct diagnosis was made. After that, they were given pills with enzymes that stopped the indigestion, and were told to pummel their babies backs for hours each day to help them cough up the phlegm that obstructed their lungs, and to make them sleep in a mist tent to ease their breathing.
Raising a cystic fibrosis child put these Swedish families under great stress by its exhausting labor, by the feelings of anxiety and helplessness and sometimes of shame and guilt that it raised, and by the mothers’ tendency to concentrate on their sick children to the neglect of their husbands and the healthy brothers and sisters. However, Falkman writes that the families responded very differently to that stress: “What destroys one family, may strengthen another.” Today, most cystic fibrosis patients still die in childhood or adolescence, but about one in ten survives into early adult life and some survive longer. There are about 1,500 adult cystic fibrosis patients in Britain today.
The cause of cystic fibrosis is still unknown, and the affected gene has not yet been identified. Only its approximate position on chromosome 7 has been located, but its pattern of inheritance can be traced by its proximity to other genetic markers. Scientists do this tracing by collecting blood samples from several members of the family. They separate the white blood cells, isolate the DNA, and digest it with enzymes that cut it at the center of a specific sequence of letters, say
. . . . . .
. . . . . .
. . . . . .
Suppose all the DNA of a cystic fibrosis child is cut there, but none of his healthy brother’s, and only half of each of his parents’. Then a geneticist concludes that this locus is linked to cystic fibrosis and is therefore inherited with it. The parents can then use prenatal diagnosis to find out if their next child is affected by the disease. The necessary DNA can be obtained by several different methods: either by teasing a single cell from the fertilized ovum after the first few cell divisions; or by snipping off a tiny fiber from the membrane surrounding the eight- to nine-week-old embryo (chorionic villi sampling); or by inserting a needle into the womb and removing a little of the amniotic fluid surrounding the eighteen-week-old fetus (amniocentesis); or finally by taking a blood sample from the newborn baby. Alternatively, cystic fibrosis can be diagnosed, with lesser certainty, by a deficiency of certain enzymes in the womb.
The astonishing new technical achievement lies in the ability to tag any desired stretch of DNA in a single cell, to isolate it from the hundreds of other, similar stretches of DNA that digestion with enzymes produces, and to copy and recopy the vital stretch until enough copies have been made for chemical analysis. With cystic fibrosis the diagnostic answer has a certainty of a hundred to one; with other diseases it may be hedged with ifs and buts and provide mere probabilities.
Altogether about twenty-five inherited diseases that are caused by defects in single genes can now be diagnosed from DNA probes. For them, genetic analysis provides a simple yes or no; in the case of others, several different genes may be at play and the probabilities may be complex. In other instances a disease may arise from an interplay between genetic factors that predispose the body to incur it and life habits that bring it to the surface. There the outcome may be even harder to predict.
If the births of the majority of children with the most frequent inherited diseases were to be prevented, then all the carriers of the diseases would have to be identified, so that prenatal diagnosis could then be used to detect affected babies and terminate those pregnancies or continue healthy ones. If all American women in their first pregnancy were to be screened for being carriers of cystic fibrosis, sickle-cell anemia, hemophilia, and Duchenne muscular dystrophy, their detection would require about 2.8 million tests per year. Screening of the male partners of those found to be carriers would require another 50,000 tests. This program would lead to the identification of about 50,000 carriers and allow nearly all new cases of sickle-cell anemia and cystic fibrosis resulting from the union of known carriers to be detected by prenatal diagnosis. On the other hand, no more than two thirds of the cases of hemophilia and muscular dystrophy are detectable in this way; the remainder are caused by new mutations that could not have been predicted and would show up only after birth.
We now know of genetic factors that predispose people to insulin-dependent diabetes and arteriosclerosis. Although we are not yet sure how to prevent their development, those at risk would benefit from regular checks and early diagnosis. If it were decided to screen all newborn infants for these predispositions, another seven million tests a year would be needed. Predisposition to certain cancers, manic depression, and Alzheimer’s disease might also eventually become detectable. Holtzman estimates that this would require the screening of nine million teenagers each year. These numbers look frighteningly large, but not if we compare them to the total number of five billion medical laboratory tests done in the US each year; genetic screening would increase that load by only 4 percent. In any case, Holtzman is not concerned about the cost to the state of genetic screening:
So long as military expenditures consume an inordinate percentage of the federal budget (in relation to the threat of war or negotiations to reduce the threat) I will not say that we have reached the limit of public spending to improve health care.
Holtzman is worried that genetic screening will spread widely before it can be done reliably, and before its meaning is properly understood by the medical profession and the public. He complains that human genetics is rarely taught in high school, partly because publishers of textbooks are frightened of reprisals from creationists and other zealots. Few physicians have learned it because it was not part of their medical curriculum, and many do not know how to apply it. Until they have acquired a better understanding of genetics, of the high fallibility of tests applied to a healthy population, and of the need to double-check positive test results, Holtzman fears that much harm might result from widespread screening. Couples who are told that their children are liable to suffer from a genetic disease, or that their unborn baby has the disease, will be faced with hard decisions and will need advice from counselors who understand human nature and can explain both medical genetics and statistical probabilities that many people find hard to grasp. According to Holtzman, there are few such counselors now, and not nearly enough are being trained to satisfy the demand that would be created by widespread screening.
Holtzman fears that under mainly commercial pressures caution will be cast to the wind. Biotechnology companies will be eager to sell their instruments and reagents, insurance companies will be anxious to exclude people at risk from cover, industrial companies will not want to employ them, and law courts will award damages to parents of an affected child whose physician has failed to screen them.
He fears that couples may be put under financial and social pressures to be tested, and that the results would be stored in computer files to which companies and police could gain access, leading to unfair discrimination. Apparently something like this is happening already. Normal males carry two sex chromosomes, one X and one Y. A small minority of males carries two Y chromosomes. Some years ago it was discovered that the frequency of XYY males is greater among violent criminals than among other males. This finding has led to XYY males being stigmatized as prone to crime even though 96 percent of such males never commit one.
In some instances, genetic tests may arouse anxieties that outweigh their likely benefits. A deficiency of αu1-antitrypsin is a disorder that predisposes people to pulmonary emphysema, a dangerous and agonizing disease. Those who are deficient are certain to contract it if they smoke. Some years ago the Swedish government decided to screen all infants for this condition. If the test result was positive, counselors told parents that they had nothing to worry about because their child would develop normally, but they advised them to warn the child later not to smoke. This seemed a harmless enough message, well worth conveying to save the future adult from a terrible disease. In fact it created so much anxiety, overprotection of children, and recrimination between in-laws or between father and mother that the resulting bad effects exceeded those likely to arise from the genetic abnormality, and the government abandoned the screening. At a medical school in New Zealand, a visiting professor argued that fetuses with αu1-antitrypsin deficiency should be aborted, whereupon a student got up and said that she had the deficiency. She came from a working-class family and was the first of its members that had made it to a university. She and her family were pleased that she had not been aborted.
Finally Holtzman fears that genetic tests might set off a new drive for eugenics, which he defines as “any effort to interfere with individuals’ procreative choices to attain a societal goal.” He reminds us of Nazi Germany, where geneticists, anthropologists, and psychiatrists conspired to cleanse the German race of “inferior” types whose condition they regarded, often incorrectly, as hereditary. These included people with subnormal intelligence, schizophrenics, manic depressives (like Virginia Woolf), epileptics (like Fyodor Dostoevsky), and severe alcoholics (like Ernest Hemingway). At first such people were sterilized, but later they were killed. In the early Twenties, the Englishwoman Marie Stopes founded the Society for Constructive Birth Control and Racial Progress in order to stem the breeding of the lower classes, for fear that they might overwhelm their betters.2
Holtzman conjures up the nightmare of the state imposing eugenic birth control on its citizens. I am haunted by the opposite nightmare, a democracy so scared of science that it may accede to the shrill demands and intimidation by those who want termination of pregnancies to be banned together with genetics and all its works. Just as Lysenko gained the ear of Stalin and had Mendelian genetics proscribed in the Soviet Union, so American creationists and others may inveigle the President to appoint Supreme Court judges who will let them have their way, or else they may intimidate businesses, schools, hospitals, and physicians, without the courts, Congress, and state legislatures daring to take firm action against them.
Holtzman’s concerns about the possible abuses of genetic screening and prenatal diagnosis have led him to underemphasize their great potential for the prevention of severe suffering. He reports that siblings of children with autosomal recessive diseases who have one chance in two of being carriers themselves are eager to use prenatal diagnosis when they begin families of their own. Clearly, their eagerness springs from their firsthand experience of the kind of suffering that Falkman described so vividly in her case histories of cystic fibrosis children. A social worker among families with children who suffer from sickle-cell anemia has told me similar tales. Children with cystic fibrosis or sickle-cell anemia are at least mentally normal, but children with other inherited diseases can be crippled both mentally and physically.
In thalessemic children, the blood does not carry enough oxygen from their lungs to the brain, muscles, and other organs. This disease is common in Mediterranean countries and in the Far East, especially Thailand.
Bernadette Modell is a London pediatrician who observed the distress thalassemic children caused to Cypriot families. With the help of expert colleagues she organized prenatal diagnosis at University College Hospital, London. Her clinic was soon beleaguered by pregnant Cypriot women, and her work proved so successful that Mediterranean doctors came to be trained so that they could introduce prenatal diagnosis in their own countries. By 1983 such diagnosis has reduced the number of thalassemic children born annually in Cyprus from 70 to 2, in Greece from 300 to 150, in Sardinia from 70 to 30, and in the Italian city of Ferrara from 25 to 0. In Italy as a whole the number has dropped by 60 percent.3 It is interesting that the Pope has had little influence on the procreative choices of these predominantly Catholic women. Statistics of the World Health Organization confirm this by showing that two Catholic countries, Italy and France, are also the ones where the greatest proportion of women exercise birth control.4
Holtzman argues that the churches, the political parties, the state, and the law courts should let parents decide whether they want prenatal diagnosis and allow them to take the responsibility for termination of pregnancy after making an informed choice. The strongest argument in favor of such a policy comes from the observation that couples who have had one thalassemic child and then do not resort to prenatal diagnosis do not risk having more children, while couples who do make use of it tend to have more and healthy ones. Statistics show that Cypriot couples who have had one thalassemic child and do not resort to prenatal diagnosis have had only one healthy child per forty-seven years of marriage (averaged over many couples over, say, ten years), while those who do have had one healthy child per 4.6 years of marriage.5 Prenatal diagnosis is a recipe for life, not death.
In the United States between seventy and eighty babies with thalassemia major and about one thousand with sickle-cell anemia are born each year. The Mediterranean experience shows that an educational campaign linked to prenatal services could drastically reduce the large number of babies born with sickle-cell anemia and increase the number of healthy babies born to sickle-cell carriers.
All the same, genetic screening can present people with agonizing choices. Huntington’s disease is a serious disorder that destroys people’s mental powers when they reach middle age. It is a dominant autosomal trait liable to be passed on to children before parents become aware of being afflicted with it. Holtzman writes that of eighty-seven people at risk who wanted to be tested, thirteen said they might commit suicide if the result were positive. I have heard of someone who did actually kill himself, but also of someone else to whom the possibility of prenatal diagnosis has given new hope and zest for life. He is an able young Italian whose mother died of Huntington’s disease. He became engaged, but before marrying he wanted to know if he carried the gene for the terrible disease. A psychiatrist warned him not to submit himself to the test since he might take his life if the answer was yes, but the young man insisted and the answer was yes. The couple got married all the same and decided to have children. Prenatal diagnosis of the wife’s first pregnancy showed that the child was affected. She had that pregnancy terminated and tried again. The second child is free from the gene, and now the third one, healthy again, is on the way. The young man’s state of mind is transformed by the certainty that he can have normal healthy children, that science has helped him to eliminate the disease that had hung over his forebears for generations, and that he may have twenty to twenty-five years of active life in front of him before he is stricken; he hopes that by then a cure might have been discovered.
I was disappointed that Holtzman’s book is parched of stories from real life. Medical opinion rejects these as anecdotal and has replaced them with computer analyses of anonymous answers to soulless questionnaires. Yet our hearts are not moved by statistics but by tales of pain and sorrow, of love and joy; there are none in this book. Holtzman pleads that society must allow parents to decide whether to submit themselves and their unborn child to genetic screening and whether or not to terminate the pregnancy of an afflicted child; but his pleas would carry greater force if he had made his readers aware of some of the terrible suffering of children and adults with genetic diseases and of the deep relief experienced by carriers of such diseases to know that they can have healthy children. I am proud that advances in my own subject, molecular biology, have made this possible.
If I have voiced misgivings about such omissions from this book, I do not mean these to detract from its merits. I admire the author’s scholarly expertise in subjects ranging from biochemical genetics to law, the breadth and cogency of his arguments, and the important material he has mustered in their support. I also respect his tolerant and compassionate outlook, his skepticism of technical and human perfection, and his passion for social justice. I hope that health policy makers will heed his message.
May 18, 1989
Cecilia Falkman, “Cystic fibrosis—A psychological study of fifty-two children and their families,” Acta Pediatrica Scandinavia Supplement 269 (1977). ↩
R. Hall, Marie Stopes: A Biography (Deutsch 1978, Virago 1978). ↩
B. Modell, R.H.T. Ward, and D.V.L. Fairweather, “Effect of introducing antenatal diagnosis on reproductive behaviour of families at risk for thalassaemia major,” British Medical Journal, Part 1 (1980), p. 1,387. ↩
World Development Report, 1986 (Oxford University Press for the World Bank, 1986). ↩
Report of the World Health Organisation/Mediterranean Working Group on Haemoglobinopathies (Brussels, March 14, 1986; Paris, March 20–21, 1987). ↩