The Wandering Gene and the Indian Princess Page 15

  Masterminding life from deep within the cell, deoxyribonucleic acid (DNA) performed two tasks, one having to do with form and the other with function. The first task of DNA was to replicate itself and control heredity, thereby preserving the form that enabled the genetic content. The second task was to commission the manufacture of proteins by means of the genetic code. Proteins were the workhorses of the body and were engaged at every level of activity, both physical and mental. Genes and proteins could help explain the problem of the soul. In DNA’s model of human nature, a restless soul was but an agitation of the neurotransmitters, which were a class of proteins ordered up by the genes in response to unsettling cues from the environment.

  Or maybe a restless soul did not operate just that way genetically; it might be a mendelian trait instead. As Mendel sensed, traits like this are produced by powerful, single genes. Tay-Sachs disease and heritable breast and ovarian cancer (HBOC) are familiar mendelian traits, as are benign attributes such as cleft chins. Genes of this sort put their stamp on people at birth with no prompting from the external environment—they pay no heed to the landscape. The original term in medical genetics for such traits was inborn errors of metabolism. Now, if a restless soul were a mendelian trait, it would probably be a recessive one. The condition would be inherited from two ostensibly imperturbable parents, each of whom carried the tendency without knowing it. In the DNA age, you could imagine a genetic test for trouble of the soul, which might be offered to sufferers or potential carriers or both. However, most people would probably not want such a test unless a treatment for the soul were available also.

  Early in the DNA age (to return to actual history), the technology was not good enough to detect genes directly, so medical geneticists worked backward from proteins. Proteins that had gone awry in certain families were indicators that genes must have gone awry. The mendelian genes in question were altered by mutations, and usually the mutations cohabited with copies of genes that worked normally. Remember that genes come in pairs. For carriers of recessive conditions like Tay-Sachs, the healthy copy of the gene prevails, and the carrier is normal, but the disease will strike in the next generation if two carriers mate and their disabled genes come together. In a dominant condition, the malfunctioning gene overrides the healthy copy, in some cases crippling the protein, in other cases leaving the healthy gene open to attack, which is what happens to carriers of BRCA mutations.

  Heritable breast and ovarian cancer and its lead agent, BRCA1.185delAG, came to light relatively late in the DNA age because, as with the Hispano cases, the inherited cancers were masked by the more numerous, sporadic types of the same conditions. BRCA and HBOC have since become special concerns for Ashkenazi Jews, but before they knew about BRCA, they had to deal with Tay-Sachs disease, prefiguring the group’s response to BRCA disease. Tay-Sachs has been mentioned several times. Although the condition was rare, affecting fewer than one in two thousand Jewish babies, the suffering of the children as their muscles failed was unbearable to families, and the predictability of the inheritance pattern was maddening to the community’s doctors. If the carriers could only recognize the Tay-Sachs genotype, the phenotype would have no place to hide. Like a dybbuk wrongfully possessing a soul, the disease could be exposed and perhaps eliminated.

  Tay-Sachs disease is caused by the failure of a gene to make a critical enzyme (an enzyme is a type of protein). In the 1960s, long before the mutation’s location on the DNA was pinpointed, researchers were able to measure the enzyme, or lack of it, in blood. A Tay-Sachs carrier expressed about half the normal amount of enzyme, making enough protein to preclude the disease, but an affected child showed no enzyme at all.

  Population screening for the enzyme began in the early 1970s. First in Baltimore and Washington, DC, and then in other cities, Jewish men and women found out whether or not they were Tay-Sachs carriers. The turnout was extraordinary. Fired by pride and educated to the need by their rabbis, doctors, and local health departments, thousands gathered at synagogues to be tested. Eighteen hundred men and women braved the rain in Bethesda, Maryland, one Sunday in May 1971. On a single day in Riverdale, New York, in 1975, Harry Ostrer and a medical-school classmate drew blood from five hundred people. The experience, which reminded young Dr. Ostrer of the outpouring of Jewish pride during the 1967 Yom Kippur War, inspired his decision to specialize in medical genetics.

  Local hospitals responded quickly to the screening programs. The pregnancies of carrier couples could be monitored by amniocentesis and terminated if the fetus was affected. Soon the statistics registered a drop in Tay-Sachs from about sixty cases a year among Ashkenazim to fewer than ten. And by the turn of the twenty-first century, a million and a half American Jews had undergone carrier testing. Hundreds of fetuses were aborted, it is true, but during the same period some twenty-five hundred children were born to couples in which both husband and wife were carriers. Group screening having accomplished all it could, the testing for Tay-Sachs takes place today in outpatient clinics, on college campuses, and via online services. The handful of cases that still occur are most likely to affect non-Jews—that is, families carrying mutations other than the distinctly Ashkenazi variants of the Tay-Sachs gene.

  Fundamentalist Jews were the last branch of Ashkenazim to take advantage of Tay-Sachs screening. The Orthodox and especially the ultraobservant Hasidic Jews considered childbearing an essential duty not to be interfered with. Carrier testing not only opened the door to contraception and abortion but also could destroy a person’s prospects of marrying. In the close-knit urban wards of the Hasidim, where men dressed in black suits, women covered their hair, and young people were funneled into marriage via the shidduch, the rabbi wielded more authority than the doctor. Medical information was not private. When two families were sizing up a match, just the whiff of a genetic problem could taint everyone on one side. The concern with stigmatization cannot be underestimated, said Harry Ostrer. Once the neighbors hear that Shmuel has been to the geneticist, Harry explained, they assume the worst about his having a genetic condition and might conduct a whisper campaign.

  Orthodox rabbis therefore refused to cooperate with Tay-Sachs screening. In the early 1980s, Josef Ekstein, a Hasidic rabbi in Brooklyn, New York, devised a testing method that brought the Orthodox into the DNA age, although it was not the way Ostrer and his colleagues would have wished. Reclusive and snappish, Ekstein had firsthand knowledge of Tay-Sachs disease. He and his wife were carriers. Their first two children died of the disease before the age of four. Exceeding the odds, the couple produced a total of four sick children within a brood of ten. In shame, Ekstein had hidden his fourth doomed child from view; after the boy died, the rabbi was all the more ashamed for having done so.

  An expert on the intricate dos and don’ts of kashrut, the Jewish dietary laws, Josef Ekstein took it upon himself to study Mendel’s laws. Genetics, after all, was about applying the letter of the law of nature. The rabbi believed that God had created an order, a natural course of events, which scientists and doctors ought to investigate. Everything is managed from upstairs, Ekstein explained in his gravelly voice, but nature also has its rules. As before the great Flood, when the subdivisions of nature, clean and unclean, two by two, marched up the ramp beneath Noah’s discriminating gaze, this one goes with that but never with this, the wonderful hairsplitting order of life, of which there was no more wonderful example than the biochemical rule pairing A with T but never with C or G, and the complementary rule matching G with C but never with T or A.

  Ekstein’s idea was to dissuade the Tay-Sachs carriers in his community from getting together in the first place. Under his program, high school boys and girls submitted their blood for testing, but the results were withheld from them. Later, when a pair started to date in earnest or their families were exploring a match, they contacted the database to learn whether they were genetically compatible. Most of the time they were. If incompatible, they were strongly u
rged to part and find someone else. Everything was handled confidentially—no names were recorded, only an identifying number and birth date for each youth. Ekstein called the program Dor Yeshorim, meaning Generation of the Righteous. By the late 1980s, the decline in Tay-Sachs births was more dramatic within Orthodox neighborhoods than outside of them.

  Dor Yeshorim occupies a small, graffiti-splashed brownstone just south of the rumbling Williamsburg Bridge, near Brooklyn’s East River waterfront. On the first floor of the office, half a dozen young women, all wearing head scarves, fielded phone calls at computer terminals. It looked like a telemarketing operation that had taken a deadly serious turn. We took the medical science and we applied it to the needs of the community, Ekstein said, gesturing proudly.

  He believed he had been born a Tay-Sachs carrier for a reason. I have a mission to prevent misery, the rabbi explained. I had to find out the hard way, but we think everything happens for a divine purpose. We can override, with good deeds, the bad things in the universe. If you’re a carrier of a disease, he said, it’s predestined, but it’s also for a purpose. You were also given the means to protect yourself. It is like clothing against the weather. You have to protect yourself with whatever tool you’re given by the Almighty.

  Ekstein went after the other recessive diseases affecting his community. Although it was not his intention, he was one of the instigators of the DNA era because he started looking for disease genes just as biotechnology became capable of discovering them. There are some forty Ashkenazi genetic disorders, each very rare, but up to half of Ashkenazim harbor at least one adverse mutation. The mutations act like the submerged mass of an iceberg. Absent prevention, about one in three hundred Ashkenazi matings will produce a child with a genetic defect. Ten recessive conditions, less rare and more serious than the others, deserve mention. Tay-Sachs, Niemann-Pick, Canavan, and mucolipidosis type IV top the list because they are essentially untreatable and usually lethal in early childhood. Bloom syndrome, familial dysautonomia, Fanconi anemia, glycogen storage disease, maple syrup urine disease, and cystic fibrosis leave the young patients gravely impaired. A battery of drugs can prolong their lives but do little to alleviate their suffering. Cystic fibrosis, to be sure, affects all Caucasians; it is the one disease in the group for which Ashkenazim aren’t at higher risk. The core list of conditions rounds out with Gaucher disease, which has the most carriers but also is the easiest to treat. Again, it should be stressed that all these illnesses crop up in other populations, but at lower rates.

  Focusing on the top ten, Josef Ekstein added carrier tests to his program as the underlying genes became accessible. In effect, he expanded the grounds for incompatibility among Orthodox young people. Still, ninety-nine of one hundred pairs received Dor Yeshorim’s blessing to proceed with courtship or dating, their carrier profiles unrevealed to them. Meanwhile, the hundreds of thousands of blood samples that Dor Yeshorim gathered have been a great resource for DNA research. Dor Yeshorim contributed to the discovery or the confirmation of the genes for Gaucher disease, Canavan disease, and Fanconi anemia. In the late 1990s, during a race to discover the gene for familial dysautonomia, Ekstein and his scientific collaborators competed with a rival group that included Harry Ostrer. That didn’t help the relationship between the two men, which was already strained by their opposing views about genetic information.

  The rabbi would spare Jews the psychological burden of their DNA so that they would focus on making a good marriage and a healthy family. They would be fruitful and multiply as the Almighty had commanded, while he, Ekstein, worked to rid the community of genetic disease. But for Harry, a Reform Jew, a scientist, a liberal, the primary commandment was informed consent. He wanted to eradicate the Ashkenazi disorders as much as the other man did, but not through an authoritarian and secretive program. Rabbi Ekstein wants to control who does and doesn’t get information, Harry said. As you know, that is contrary to the egalitarian and participatory style of genetic counseling.

  Genetic counseling of that sort, said Ekstein, is not there to take away the worry but to increase the worry. The rabbi nursed a broad critique of modern medicine. Having worked with a good many doctors and scientists over the years, he had decided that the professionals made it more difficult for a man and a woman having a baby, not easier. There was too much unnecessary testing, too much technical information being generated that was not supportive of the persons who had generated it. Through the tests and scans the doctor offered parents a sense of control over the birth and health of their child, but he caused tremendous anxiety in the interim and in the end it wasn’t his problem. The doctor stood there with a printout from the lab. What did the couple want to do, considering the odds? The science of genetics is a tremendous tool, it can be very good, Ekstein stated, but most doctors are not using it the right way. They lack compassion for their patients.

  This was a stiff charge if he had Harry Ostrer in mind. Harry hated to hear of congenitally damaged children. After a residency in pediatrics he had gravitated toward the academic aspects of medical genetics in part because the clinic was painful for him. In medical school I wanted to be a pediatric oncologist for a while, he said. Then I found out: They all die. (Prognoses are much better today.) Harry’s global interest in the DNA of Jewish populations sprang from a sad desire never again to hold the hand of a distraught Jewish parent. At New York University Medical Center, a sprawling complex in Manhattan across the East River from Ekstein’s redoubt, Harry offered genetic testing to Jews and non-Jews alike, about five thousand patients per year. Many of the patients were pregnant, educated white women who were concerned about something going wrong and who wanted answers fast. The lab’s eight genetic counselors provided information and referrals before and after the testing.

  The information of course could be upsetting. But Harry believed that if a person wanted a test, a glimpse of the future for herself or her fetus, it should be provided, just as long as the patient understood the implications. Consumers don’t want to be told what to do, he said. Moreover, since other medical centers in New York promoted the same genetic services, Ostrer, to stay in the forefront, pushed to expand the number of tests that NYU offered. We are adding value to patient care—it is a growth business, he said. Let the marketplace decide.

  But Ostrer wholeheartedly agreed with Ekstein that a couple shouldn’t be exploring their genetics during pregnancy, which was already a stressful time. Carrier status should be factored in much sooner. So periodically Harry went to college campuses to screen Jewish students, intending to intervene before they married, as Ekstein did. On religious campuses such as New York’s Yeshiva University, Ostrer and his helpers competed directly with Dor Yeshorim to raise student awareness of the recessive disorders. Personally drawing the boys’ and girls’ blood kept him connected to his original mission as a doctor. I am trying to prevent Tay-Sachs disease, Harry said stoutly. People are still falling through the cracks. The modern Orthodox kids, he added tartly, want to know their results. Like Dor Yeshorim, he saved the blood samples for his own research, although for that part of the work the subjects signed consent forms stipulating that their names would be stripped from the samples.

  There was a political element to the information. Outside of their own forums, websites, and newspapers, Jewish health professionals have not courted publicity for genetic screening. On the one hand, they didn’t want to reawaken early twentieth-century stereotypes about sickly Jews. On the other hand, they were sensitive to the charge that mass screening was akin to eugenics, a subject with Nazi overtones. Ekstein in particular was accused of practicing eugenics. Several years ago Ostrer and a colleague, Susan Gross, lobbied Jewish foundations and philanthropists to underwrite a national program of carrier testing and genetic education about the recessive conditions. Would organized Judaism, in Harry’s words, rise to the occasion? It didn’t back the campaign, and Ekstein for one was just as glad. All this attention on Jews! he exclai
med. More recently, a group called the Jewish Genetic Disease Consortium—Harry was one of its medical advisers—has taken a higher profile. The organization has enlisted rabbis in its educational effort.

  In the DNA age, no group of human beings has undergone a greater genetic scrutiny than Ashkenazi Jews. A 2003 study found that in relation to the size of their population, Jews were overrepresented in the human genetic literature. A preponderance of Jewish geneticists is one reason—the positive-feedback loop. Another reason is that Ashkenazi DNA is relatively easy to study, because there’s less clutter in the genetic structure, owing to the group’s history of inwardness. A third reason is that Jews readily volunteer for research; many regard it as a divine command, a mitzvah, to participate. While other minorities, such as blacks and Native Americans, backed away from genetic probes, fearing that the results could be used to discriminate against them, Jews took custody of their DNA, both the raw material and the interpretations.

  In short, the community was well prepared—in its fractious fashion, ranging from Ostrer’s camp to Ekstein’s—for the revelation of BRCA1.185delAG in the mid-1990s.

  Whenever a field of natural science produces a swarm of noteworthy results, as genetics did during that period, you can expect to find great gains in the technical apparatus running ahead of the field and laying the groundwork. Because the text of the human genome was both very long and very small, a complex set of editing and magnifying tools was needed to make sense of it. Hence the development of restriction enzymes, which cut DNA molecules into fragments; ligases, which glued DNA back together; cloning, which inserted pieces of DNA into colonies of bacteria or yeast and vastly ramped up the volumes; PCR, an ingenious system for fishing out and copying pieces of DNA; then the sequencers and microarrays to read the letters of the DNA fragments; and finally, down the hall from the wet lab, bioinformatics, the software to wrangle the herds of data through computers. Its four-letter alphabet easily digitized, DNA was a natural for computer programming. When computer science was applied to molecular biology, a new specialty was created, called genomics, standing for the lightning-fast appraisal of multiple genes. Gene, genome, genomics: that was the cutting-edge progression.