Like ongoing research into Huntington, DMD, and many other genetic afflictions, studies of fragile X have been galvanized by those most directly affected: the families and loved ones of sufferers. FRAXA, the Fragile X Association, has been hugely effective in raising money and in inducing Congress to support fragile X research. Though some scientists may cynically view such groups merely as agencies that offer individuals in dire straits the comforting illusion that they are not entirely powerless, experience shows that dedicated, resourceful, and, above all, motivated organizations like FRAXA sometimes do hold the key to cracking these diseases against the long odds. To those who take the biggest gambles – financial and scientific – sometimes, with luck, go the biggest rewards.
Many women reading this may be asking themselves the question: Why wasn't I tested during my pregnancy for cystic fibrosis, or fragile X, or DMD? Sadly, some of them may even have children with one of these afflictions. In the wake of the genetic revolution that has transformed medical technology, one notes a singularly depressing and senseless fact: the uncoupling of scientific progress and patient care. Actually, it might be more accurate to say that due attention never was paid to coupling them properly in the first instance. In any event, many women are simply not informed of their options, and tests now readily available are hugely underused.
As a head of the Human Genome Project, I made sure to fund efforts to promote understanding of how the knowledge that would soon be pouring out of the sequencing machines would affect, for good or ill, the lives of countless people. Having set aside initially 3 percent of our total budget (and later 5 percent) for this purpose, I appointed Nancy Wexler, the Huntington expert, to run a panel called ELSI charged with exploring the ethical, legal, and social implications of our research. One of ELSI's major initiatives was a series of pilot studies of genetic screening. At a time when every newborn was screened for PKU, it was necessary to ask whether medicine could responsibly fail to offer at least the option of screening for cystic fibrosis, DMD, fragile X, and every other grave human ill that was within the power of science to predict. That was in the early nineties. Today, things have scarcely advanced beyond the pilot stage: small-scale studies are still carried out here or there. The reasons for this paralysis are varied, ranging from dollars-and-cents practicality to profound philosophical disagreements about the essence of human life and dignity. In short, they encompass the gamut of social phenomena, from jockeying for funds to collective soul-searching, that have attended the genetic revolution.
Testing for DMD and Huntington is ordinarily done only in families that already have an affected member. The rationale for the limitation is that these disorders are rare and the tests are costly. This social calculus is debatable, but the same reasoning does not hold in the case of cystic fibrosis, for which testing is nevertheless also limited. Cystic fibrosis, remember, affects about 1 in 2,500 people, making it one of the most prevalent genetic disorders. It is especially common among people of northern European descent. The high incidence seems all the more remarkable when we consider that the underlying defect, which occurs in a gene on chromosome 7, follows a recessive pattern of inheritance, meaning that in order to develop cystic fibrosis one must receive two mutated copies. People with just one are unaffected but being carriers they can pass the mutation on to their children. Epidemiological surveys and calculations tell us that 1 in 25 Americans of European ancestry are carriers.
One difficulty with cystic fibrosis testing is technical, having to do with variability in the underlying defect. One specific form of mutation accounts for about 70 percent of cases: a deletion called ΔF508, which eliminates three bases, CTT.* If just a few other mutations accounted for the remaining 30 percent, then general population screening for CF carriers would not be impractical. But most of the other causative mutations occur in just a single family line and more than a thousand different CF-causing mutations have been discovered to date. What does this mean for population screening? In practice any test could screen for at most twenty-five different mutations, but those twenty-five most common forms would still account for only about 85 percent of all cases. As a result, we'd be missing about one in six mutations – not a very good batting average for a diagnostic. Now, say we have a couple, both of whom have tested negative for CF mutations according to our highly imperfect screen. We could hardly tell them with any confidence that there was no danger of their producing a child with cystic fibrosis. Why bother, the argument goes, with an inconclusive test that typically costs $300?
*The 70 percent figure applies to people of northern European ancestry, the population in which cystic fibrosis is most common. However, AF508 only accounts for around 35 percent of CF mutations in both the African American and Ashkenazi Jewish populations. Ancestral differences like these complicate the design of screening programs.
But, despite the technical difficulties, prenatal screening for cystic fibrosis can still identify a large proportion of all affected fetuses. Why isn't it more widely adopted? Paradoxically, cystic fibrosis advocacy groups have played a major part in limiting CF testing to families already affected. Broader testing, it is feared, would divert limited resources away from the ultimate goal of finding a cure. That concern is understandable, particularly at this moment. An estimated thirty thousand Americans have cystic fibrosis. Treatment advances have already extended life expectancies considerably, and it is conceivable that a cure will be in hand before long. Having said that, it would be irresponsible to suggest that a cure is around the corner: babies born today with cystic fibrosis still face the prospect of a lifelong struggle against a debilitating disease. Though curing cystic fibrosis is definitely a top priority, there should still be room to permit an expectant mother to have access, if she wants, to testing. Then, fully informed about the status of her fetus, she has the freedom to make whatever choices she sees fit.
Broader testing is also resisted for less material reasons. There are those who view screening as an admission of defeat, the wrong manner of solution. Advocacy groups are in the business of ensuring that people with the disease feel that they belong to a community and are valued by society – how does one reconcile that mission with testing, which, to put it in bluntest possible terms, is promoting the abortion of affected fetuses?
Cystic fibrosis advocates are anxious that people with CF do not become stigmatized, and they worry that indirectly testing does just that. In fact, there is an unfortunate precedent in the history of genetic testing that haunts all patient advocacy groups. Long before the advent of DNA screening, one of the earliest diagnostics for a genetic disease was developed to detect sickle-cell anemia, which in the United States affects primarily African Americans. As we saw in chapter 3, those with two copies of the mutated "sickle" hemoglobin gene will suffer painful, debilitating symptoms, while those with only a single copy – carriers – will notice little effect.
Following the development of simple blood tests in the 1960s, screening programs were hastily established across the country. Despite the best of intentions they did more harm than good. Screeners generally failed to counsel test subjects properly as to the significance of the test or its results. Many diagnosed as carriers mistakenly assumed that they themselves had the disease; some were even denied jobs or health insurance on the basis of the test; and couples who were at risk of producing sickle-cell children were advised rather heavy-handedly to think twice. The tests – some programs were mandatory – were coercive in effect, suggesting to some that the United States was entering a renaissance of racist eugenics, stigmatizing all who tested positive. The sad irony is that, from a purely medical point of view, the campaign was in fact sensibly conceived: despite advances in treatment, sickle-cell anemia remains a chronic, painful condition. Screening is the best remedy for a disease that is far more easily avoided than confronted, but the first mechanisms designed to eradicate it were so badly managed as to have rightly angered many intended beneficiaries.
Fortunately in 1972 ne
w federal guidelines redesigned the sickle-cell screening program, allowing it to be effective without the widespread concern raised by the initial effort. Harder to repair has been the trust of advocacy groups for genetic diseases in general; the experience of the community of those affected by sickle-cell disease has left them ever leery of screening programs, and the fear of stigma persists, sometimes, alas, at the expense of better public health.
In so many ways, genetic testing, despite its incontrovertible usefulness, proves to be flypaper for controversy. Randi Hagerman, then at Denver Children's Hospital, decided to apply a DNA test for fragile X to children in special education classes in Denver. The reasoning was simple: children whose learning was impaired by that disorder would be better served if they were identified, whereupon their schooling could be tailored to their particular needs. Of 439 students tested, 5 with fragile X mutations were discovered. (A more extensive survey of schools in Holland had found 11 previously undiagnosed cases of fragile X in a group of 1,531 students.)
Perhaps the most interesting part of the Denver study was the response of the parents and guardians to Hagerman's offer. Most recognized the benefit of a diagnosis, both for the potential to improve their child's education and for the identification of the presence of the disorder in the family line. But fully a third refused the test, citing either a certainty that their children did not have fragile X or a concern that their children might find the test too stressful. Hagerman has been criticized for her efforts; it was a field day for those who insist upon seeing the menace of a totalitarian genetic future in every attempt at harnessing DNA to address a social problem.
The issue is indeed social as well as personal. The high incidence of the fragile X premutation – it is on perhaps as many as 1 in 200 X chromosomes – may warrant population screening. In the United States, it is estimated that just one reasonably severe case will cost, over a lifetime of nonwork and institutionalization, some $2 million in current dollar value. The ever-increasing challenge of providing affordable health care should itself suggest a potent argument for giving every mother the opportunity to be tested. The logic of hard realities is not lost on smaller countries, where the margins for policy error are not as great. A pilot study in Israel screened 14,334 women; 207 were found to have a premutation. Prenatal diagnosis was made available upon request, identifying five fetuses with extended CGG repeats. The fate of those pregnancies was rightly the choice of the expectant mother: a free society should no more require a woman to abort a fetus with a genetic disorder than it should require her to carry it to term. But not every woman is prepared to raise a disabled child, nor is every woman prepared to terminate a pregnancy on account of the child's foreseeable quality of life. Whatever the individual choice, however, the fact remains that screening can only reduce the incidence of affliction, and that is an unambiguous social good.
Despite the frustrating reluctance to take advantage of genetic screening on a broad scale, the short history of the practice hasn't been entirely one of small-scale pilot studies and damning controversy. There are some happy and illuminating stories to tell about the triumphs of screening programs for genetic disorders in high-risk populations.
Hemoglobinopathies are diseases caused by some malfunction in the hemoglobin molecule. Including the various thalassemias and sickle-cell disease, they are thought to make up the most common class of genetic disorders, with about 4.5 percent of the world's population carrying a mutation for one of them. As we have seen, the sickle-cell gene carried with it antimalarial properties, and so was promoted by natural selection in areas where malaria was prevalent. As a result, the mutation was originally at high frequency only in such parts of the world. The same adaptive advantage accounts for the similar distribution pattern of other hemoglobinopathies as well. Medicine has for some time understood that certain mutations therefore tend to be much more common in some ethnic groups than others, wherever the individuals may now find themselves.
Among the population of Greek Cypriot immigrants in London, thalassemia carriers represent a remarkable 17 percent. In its severe form the condition is the most pernicious of the hemoglobinopathies, resulting in misshapen and sometimes nucleated red blood cells that cause enlargement of the liver and spleen, often leading to death before adulthood. A systematic screening program begun in 1974 by Bernadette Modell of the Royal Free Medical School was welcomed enthusiastically by London's Cypriots, who were only too well aware of the seriousness of the disorder that had long blighted their community. A similar program in Sardinia, also begun in 1974, has dramatically reduced the incidence of thalassemia from 1 in 250 to 1 in 4,000.
Ashkenazi Jews are another group with a bitter awareness of what a deadly mutation can do to a genetically isolated population. Tay-Sachs (TS) is a ghastly disease 100 times more common in this group than in most non-Jewish ones. TS babies are born apparently healthy, but gradually their development slows and they begin to go blind. By about two, they are stricken with seizures. Deterioration continues until they die usually by the age of four, blind and paralyzed. Unlike hemoglobinopathies, whose relative commonness in certain populations can usually be explained by the concomitant adaptive protection against malaria, the high frequency of TS among the Ashkenazim remains a mystery. Perhaps a genetic bottleneck is to blame: the mutation may have been present among the relatively small segment who branched off to become the Ashkenazim during the second Diaspora. A similar phenomenon might also account for why the mutation is also anomalously common among the French Canadians of southwest Quebec as well as the Cajuns in Louisiana: the chance presence of an unfortunate mutation in the small founding populations. An alternative explanation holds that being a carrier of this recessive gene (having one copy of the TS mutation) may confer some resistance to tuberculosis, an advantage perhaps for European Jews who historically tended to live in densely populated urban centers.
The cause of Tay-Sachs was discovered in 1968 when it was recognized that the red blood cells of patients were overloaded with ganglioside GM2. This chemical is an essential component of the cell membrane, and in normal individuals any excess is broken down into related compounds by a key enzyme, which is lacking in TS sufferers. In 1985, Rachel Myerowitz and her colleagues at NIH isolated the gene coding for that enzyme and showed that it was indeed mutated in Tay-Sachs patients.
Thereafter we had the basis for a foolproof prenatal test and a well-defined target population – conditions tailor-made for the implementation of a successful screening program. But prenatal screening effectively offers only one remedy in the event of a positive diagnosis: abortion, which, at least among the observant Orthodox segment of the Ashkenazim, is forbidden. Fortunately, it is also possible to screen prospective parents and so the solution morally acceptable to the devout was a program aimed at couples. Rabbi Yosef Eckstein of New York saw four of his ten children die from Tay-Sachs. In 1985, he established Dor Yeshorim, the "generation of the righteous," a program to carry out TS testing in the local Orthodox Jewish community. Young people are encouraged to take advantage of free-testing days at high schools and colleges. An unusual aspect of this program is its extreme confidentiality: not even those tested are informed whether they are carriers; instead, each is given a code number. Later, when two people are contemplating marriage, they each phone Dor Yeshorim and give their numbers. Only in the event of both being carriers is the status of either partner revealed, together with an offer of counseling. This disclosure on a need-to-know basis is intended to avoid stigmatization of carriers, while still countering the threat of Tay-Sachs.
To date, the Dor Yeshorim program has tested more than seventy thousand individuals and detected more than a hundred couples at risk. Steadily reducing the incidence of Tay-Sachs, it would appear an unqualified success, yet there are those within the Jewish community who find fault with it. Some see coercion in the program's call for all young people to be tested, and intimidation in its strong recommendation that some individuals reconsider their d
ecision to marry. Opponents have labeled Rabbi Eckstein's crusade "eugenics" (a word whose resonance is nowhere more painful than in the Jewish community), but such demagoguery hardly alters the central fact of the matter: the program clearly enjoys strong support within the community it serves, a community that understands the horrors of Tay-Sachs. Indeed, Dor Yeshorim has demonstrated that a screening program can be both effective and culturally responsive, working even in a situation where social mores and religious precepts seem to be at odds with genetic testing in principle.
Prenatal screening offers a stark choice for any woman carrying a fetus that has tested positive for a genetic disorder: to terminate or not to terminate the pregnancy. The fact that amniocentesis cannot be performed until a fetus is at least fifteen weeks old makes the option of termination only more traumatic. At this stage an abortion does not eliminate a featureless ball of cells, but a tiny being – real enough that a parental bond may have already formed with the developing fetus, thanks to the power of ultrasound imaging. Most parents – at least those who do not oppose all abortion on principle – would infinitely prefer to make hard choices presented by genetic testing at an earlier stage of development. Such was the inspiration for the invention of preimplantation diagnosis.
Dna: The Secret of Life Page 38
