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 Gâ€“C and Aâ€“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.
Cecilia Falkman, "Cystic fibrosis—A psychological study of fifty-two children and their families," Acta Pediatrica Scandinavia Supplement 269 (1977).↩
Cecilia Falkman, “Cystic fibrosis—A psychological study of fifty-two children and their families,” Acta Pediatrica Scandinavia Supplement 269 (1977).↩